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"abstract": "We report a case of a male patient of 52 years old with a 3 months history of pushing, tenesmus, hematochezia, pain while defecating, lost of 18 kg of weight, fever, fecaloid and purulent discharge through an perianal hole. During the colonoscopy procedure, we found many ulcers in the ascending, transverse and descending colon.We also found an elevated lesion of about 5 cm in the rectum. We used hematoxylin - eosin and Gomori-Grocott stain in the biopsies and identified many microorganisms inside macrophages which were compatible with histoplasmosis. ELISA tests for HIV, HTLV I- II were negative. Colon and rectal histoplasmosis in an immunocompetent patient is extremely rare. There are few cases of colonic histoplasmosis reported.",
"affiliations": "Departamento de Gastroenterología, Hospital Nacional Arzobispo Loayza. Lima, Perú.;Departamento de Gastroenterología, Hospital Nacional Arzobispo Loayza. Lima, Perú.",
"authors": "Alcántara Figueroa|Christian|C|;Sánchez Cerna|Víctor|V|",
"chemical_list": null,
"country": "Peru",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1022-5129",
"issue": "36(4)",
"journal": "Revista de gastroenterologia del Peru : organo oficial de la Sociedad de Gastroenterologia del Peru",
"keywords": null,
"medline_ta": "Rev Gastroenterol Peru",
"mesh_terms": "D003108:Colonic Diseases; D006660:Histoplasmosis; D006801:Humans; D008297:Male; D008875:Middle Aged; D010568:Peru; D012002:Rectal Diseases",
"nlm_unique_id": "9108294",
"other_id": null,
"pages": "365-368",
"pmc": null,
"pmid": "28062876",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Colon and rectum histoplasmosis in a patient from Peru.",
"title_normalized": "colon and rectum histoplasmosis in a patient from peru"
} | [
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"companynumb": "PHHY2017PE028387",
"fulfillexpeditecriteria": "1",
"occurcountry": "PE",
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"abstract": "BACKGROUND\nThere is insufficient information in the literature on the comparative efficacy and tolerability of methotrexate (MTX) and methylprednisolone (MP) in patients with pulmonary sarcoidosis in assessing primary outcomes and the relapse rate.\n\n\nOBJECTIVE\nThe aim of our study was to evaluate primary and long-term outcomes of using MTX and MP in patients with pulmonary sarcoidosis.\n\n\nMETHODS\nA total of 143 patients with newly diagnosed pulmonary sarcoidosis, verified by high-resolution computed tomography (CT) data, were examined. Corticosteroid (CS) therapy was used in 97 patients using MP at a dose of 0.4 mg/kg body weight for 4 weeks, followed by a dose reduction to 0.1 mg/kg by the end of the sixth month. The total duration of CS therapy was 12 months on average. Forty-six patients were treated with MTX at a dose of 10 mg/week (28) and 15 mg/week (18) per os for 6 to 12 months. The study of the relapse rate was conducted within 12 months after the CT data normalization in 60 patients after CS therapy and in 24 after MTX treatment.\n\n\nRESULTS\nMP treatment was successfully completed in 68 (70.1%), and MTX in 29 (60.4%) patients. In five MP patients (5.2%) and in five (10.9%) MTX, treatment was discontinued due to serious side effects. In seven (7.2%) MP patients and ten (21.7%) MTX patients, treatment required additional therapy due to the lack of efficacy. Progression with MP treatment (17-17.5%) was more common than with MTX (2-4.3%; Chi square = 4.703, p = 0.031). Relapses after MP therapy were observed in 26 (43.3%) patients, and after MTX therapy in 2 (8.3%; Chi square = 9.450, p = 0.003).\n\n\nCONCLUSIONS\nIn patients with pulmonary sarcoidosis, MTX monotherapy does not differ significantly from MP monotherapy in terms of the level of efficacy and the rate of serious side effects. Increasing the MTX dose from 10 to 15 mg/week accelerates the rate of regression of sarcoidosis, improves treatment efficacy, and does not affect the rate of serious side effects. When using MTX, there is a significant decrease in the incidence of treatment resistance and the relapse rate.",
"affiliations": "Department of Interstitial Lung Diseases, National Institute of Phthisiology and Pulmonology Named after F. G. Yanovsky, 10, M. Amosova str., 03038 Kyiv, Ukraine.;Department of Interstitial Lung Diseases, National Institute of Phthisiology and Pulmonology Named after F. G. Yanovsky, 10, M. Amosova str., 03038 Kyiv, Ukraine.;Department of Interstitial Lung Diseases, National Institute of Phthisiology and Pulmonology Named after F. G. Yanovsky, 10, M. Amosova str., 03038 Kyiv, Ukraine.;Department of Interstitial Lung Diseases, National Institute of Phthisiology and Pulmonology Named after F. G. Yanovsky, 10, M. Amosova str., 03038 Kyiv, Ukraine.;Department of Interstitial Lung Diseases, National Institute of Phthisiology and Pulmonology Named after F. G. Yanovsky, 10, M. Amosova str., 03038 Kyiv, Ukraine.;Department of Interstitial Lung Diseases, National Institute of Phthisiology and Pulmonology Named after F. G. Yanovsky, 10, M. Amosova str., 03038 Kyiv, Ukraine.;Department of Differential Diagnosis of Tuberculosis and Nonspecific Lung Deseases, National Institute of Phthisiology and Pulmonology Named after F. G. Yanovsky, 10, M. Amosova str., 03038 Kyiv, Ukraine.",
"authors": "Gavrysyuk|Volodymyr|V|0000-0001-6942-4504;Merenkova|Ievgenia|I|0000-0003-1299-7058;Dziublyk|Yaroslav|Y|0000-0002-6497-5267;Morska|Nataliia|N|0000-0001-5255-8290;Pendalchuk|Nataliia|N|0000-0001-7875-3561;Bychenko|Olesia|O|;Vlasova|Nataliia|N|0000-0002-7590-4704",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/diagnostics11071289",
"fulltext": "\n==== Front\nDiagnostics (Basel)\nDiagnostics (Basel)\ndiagnostics\nDiagnostics\n2075-4418\nMDPI\n\n10.3390/diagnostics11071289\ndiagnostics-11-01289\nArticle\nEfficacy and Tolerability of Methotrexate and Methylprednisolone in a Comparative Assessment of the Primary and Long-Term Outcomes in Patients with Pulmonary Sarcoidosis\nhttps://orcid.org/0000-0001-6942-4504\nGavrysyuk Volodymyr 1\nhttps://orcid.org/0000-0003-1299-7058\nMerenkova Ievgenia 1*\nhttps://orcid.org/0000-0002-6497-5267\nDziublyk Yaroslav 1\nMorska Nataliia 1\nhttps://orcid.org/0000-0001-7875-3561\nPendalchuk Nataliia 1\nBychenko Olesia 1\nVlasova Nataliia 2*\nTana Claudio Academic Editor\nPasipanodya Jotam G. Academic Editor\n1 Department of Interstitial Lung Diseases, National Institute of Phthisiology and Pulmonology Named after F. G. Yanovsky, 10, M. Amosova str., 03038 Kyiv, Ukraine; gavrysyuk@ukr.net (V.G.); dziublyk@gmail.com (Y.D.); nmorska@gmail.com (N.M.); pendalchuk@gmail.com (N.P.); olesia_bychenko@ukr.net (O.B.)\n2 Department of Differential Diagnosis of Tuberculosis and Nonspecific Lung Deseases, National Institute of Phthisiology and Pulmonology Named after F. G. Yanovsky, 10, M. Amosova str., 03038 Kyiv, Ukraine\n* Correspondence: merenkova1@gmail.com (I.M.); vlasovanataliia2016@gmail.com (N.V.)\n19 7 2021\n7 2021\n11 7 128931 5 2021\n16 7 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nBackground: There is insufficient information in the literature on the comparative efficacy and tolerability of methotrexate (MTX) and methylprednisolone (MP) in patients with pulmonary sarcoidosis in assessing primary outcomes and the relapse rate. Purpose: The aim of our study was to evaluate primary and long-term outcomes of using MTX and MP in patients with pulmonary sarcoidosis. Methods: A total of 143 patients with newly diagnosed pulmonary sarcoidosis, verified by high-resolution computed tomography (CT) data, were examined. Corticosteroid (CS) therapy was used in 97 patients using MP at a dose of 0.4 mg/kg body weight for 4 weeks, followed by a dose reduction to 0.1 mg/kg by the end of the sixth month. The total duration of CS therapy was 12 months on average. Forty-six patients were treated with MTX at a dose of 10 mg/week (28) and 15 mg/week (18) per os for 6 to 12 months. The study of the relapse rate was conducted within 12 months after the CT data normalization in 60 patients after CS therapy and in 24 after MTX treatment. Results: MP treatment was successfully completed in 68 (70.1%), and MTX in 29 (60.4%) patients. In five MP patients (5.2%) and in five (10.9%) MTX, treatment was discontinued due to serious side effects. In seven (7.2%) MP patients and ten (21.7%) MTX patients, treatment required additional therapy due to the lack of efficacy. Progression with MP treatment (17–17.5%) was more common than with MTX (2–4.3%; Chi square = 4.703, p = 0.031). Relapses after MP therapy were observed in 26 (43.3%) patients, and after MTX therapy in 2 (8.3%; Chi square = 9.450, p = 0.003). Conclusion: In patients with pulmonary sarcoidosis, MTX monotherapy does not differ significantly from MP monotherapy in terms of the level of efficacy and the rate of serious side effects. Increasing the MTX dose from 10 to 15 mg/week accelerates the rate of regression of sarcoidosis, improves treatment efficacy, and does not affect the rate of serious side effects. When using MTX, there is a significant decrease in the incidence of treatment resistance and the relapse rate.\n\npulmonary sarcoidosis\nmethotrexate\nmethylprednisolone\noutcomes\n==== Body\n1. Introduction\n\nSarcoidosis is a multisystemic disease of unknown nature, characterized by the formation of noncaseating epithelioid cell granulomas in the affected organs [1,2,3].\n\nUsually, sarcoidosis affects young and middle-aged people. In more than 90% of patients, it is manifested as intrathoracic lymphadenopathy and lung parenchymal lesions [4]. The eyes, skin, liver, spleen, other groups of lymph nodes, salivary glands, heart, nervous system, muscles, bones, and other organs may also be involved [5,6]. The lungs and intrathoracic lymph nodes are affected in more than 90% of patients [4,7].\n\nIf there are indications for systemic pharmacotherapy (dyspnea, cough, pulmonary function impairment, involvement of the heart, nervous system, eyes, hypercalcemia, as well as all cases of disease progression [1,8,9]), first-line agent corticosteroids (CS) are prescribed [1,8,10,11]. Their efficacy in assessing the immediate results has been proven in randomized trials [12,13]. At the same time, the study of the long-term outcomes of CS therapy showed a high relapse rate, which is currently one of the most acute problems in the management of patients with pulmonary sarcoidosis [14]. The relapse rate of sarcoidosis ranges from 13% to 75% depending on the study population [15,16].\n\nIn three categories of patients, effective and safe CS therapy is not possible. The first of them includes patients with contraindications to CS treatment, the second one includes patients with serious side effects of CS requiring discontinuation of the drug, and the third one includes patients with resistance to CS therapy [17].\n\nIn cases of contraindications, serious side effects, and resistance to CS therapy, second-line agents are prescribed—such immunosuppressants as methotrexate, azathioprine and leflunomide [18,19,20,21]. Currently, methotrexate (MTX) is most widely used in clinical practice as a drug with an acceptable safety profile and efficacy level in assessing primary outcomes [18]. However, encouraging data on the low relapse rate of pulmonary sarcoidosis after MTX therapy have only been published in recent years [22,23].\n\nThe aim of this work was to study the efficacy and tolerability of methotrexate and methylprednisolone as monotherapy in a comparative assessment of short-term and long-term outcomes in patients with newly diagnosed pulmonary sarcoidosis.\n\n2. Materials and Methods\n\n2.1. Study Groups\n\nThe study included 143 patients with pulmonary sarcoidosis with clinical symptoms and/or impaired ventilation function and lung diffusion capacity—60 males (41.9%) and 83 females (58.1%), with a mean age of 42 (range, 22–57) years. The diagnosis of pulmonary sarcoidosis was verified by high resolution computed tomography (CT) using the criteria described by Veltkamp M., Grutters J. C. [4]; a surgical lung biopsy was performed in 7 cases due to the presence of atypical CT signs. All patients had bilateral hilar lymphadenopathy and/or mediastinal lymphadenopathy in combination with lung parenchymal lesions (X-ray stage II) [1].\n\nWhen selecting patients, two principles were strictly adhered to: firstly, the study included patients with only newly diagnosed sarcoidosis without any prior specific therapy; secondly, an important selection criterion which allowed with the maximum possibility to exclude patients with a long-term ongoing disease was the absence of CT signs of interstitial pulmonary fibrosis.\n\nThe ventilation function of the lungs was assessed by spirometry and bodyplethysmography, and the diffusing capacity of the lung for carbon monoxide (DLCO) by the single-breath method.\n\nGeneral weakness and increased fatigue were the most frequent subjective manifestations of sarcoidosis at the onset of the disease.\n\nThe second most frequent were respiratory symptoms—coughs, mostly dry, and dyspnea. Chest pains were relatively rare (4.2% of cases). A temperature rise predominantly to subfebrile values was observed in almost every sixth patient (16.1%). During auscultation, pathological findings in the lungs were not detected, as a rule.\n\nExtrapulmonary manifestations of sarcoidosis were observed in 31.5% of patients. In this case, arthralgia, hepatomegaly, lesions of the skin and peripheral lymph nodes were most often noted.\n\nModerate impairments of the pulmonary ventilation function were observed in 29 patients (20.3%). Among them, 16 patients (11.2%) had a predominantly obstructive type of ventilation disorder, and 13 patients (9.1%) had a predominantly restrictive type. As a rule, there was a slight decrease in DLCO in patients with impaired pulmonary ventilation.\n\n2.2. Study Design\n\nCS therapy was carried out in 97 patients. MP was used at a dose of 0.4 mg/kg of body weight, which corresponds to the maximum dose in the category of medium doses (30 mg of prednisolone in equivalent for a patient weighing 60 kg) [24] within 4 weeks. The dose was then tapered within 8 weeks so that by the end of the third month, it was 0.2 mg/kg. After 3 months from the start of treatment, its efficacy was assessed. With positive dynamics of clinical and CT data, the dose was gradually tapered to 0.1 mg/kg by the end of the 6th month. During the subsequent period of treatment, the dose remained unchanged. The total duration of CS therapy was at least one year.\n\nMTX was used as an initial treatment in 46 patients. A total of 28 patients had relative contraindications to long-term CS therapy: diabetes mellitus—5 patients, arterial hypertension—9 patients, osteochondrosis—4 patients, obesity (body mass index > 30 kg/m2)—6 patients, peptic ulcer—2 patients, and mental disorders—2 patients. Eighteen patients were included in the MTX arm due to a lack of compliance with long-term CS therapy, that is, alternative treatment was the patient’s personal preference.\n\nIn accordance with the recommendations of the experts of the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) [18], MTX for sarcoidosis is prescribed at doses of 5 to 15 mg per week. We used the drug at two doses—10 mg/week (28 patients) and 15 mg/week (18 patients) per os—to study the possible dependence of the drug efficacy and tolerability on the dose. The treatment duration was at least 6 months.\n\nThe outcomes of using MP and MTX were assessed as:successful completion of treatment—the disappearance of clinical symptoms with the normalization of PFTs and CT data;\n\nlack of efficacy—the absence of positive dynamics of CT symptoms (stabilization) during the last 3 months of treatment, despite the fact that there may be a good clinical, functional, and radiographic response to the initial therapy;\n\nprogression during treatment (resistance to therapy)—worsening of symptoms at any stage of treatment;\n\nserious side effects—side effects which require the drug discontinuation.\n\nPossible side effects of MP were monitored taking into account clinical symptoms, blood pressure dynamics and blood glucose levels. In the group of patients taking MTX, a blood test was performed to determine the content of leukocytes, platelets, alanine aminotransferase (ALT), and creatinine in the blood 2 weeks after the start of therapy, and then once a month during the treatment period.\n\nThe relapse rate was studied 6 and 12 months after the successful completion of treatment assessing possible clinical symptoms and CT data.\n\n2.3. Statistics\n\nAll results for the categorical variables are presented as a number and a percentage. A Chi-squared test was used to compare data of categorical variables and Fisher’s exact test was used as appropriate. The null hypothesis for the Chi-squared test is that no relationship exists on the categorical variables; they are independent. The hypothesis about the correspondence of the studied numerical samples to the normal distribution law was tested using the D’Agostino’s D criterion. Normally distributed continuous variables are expressed as a mean with standard deviation. Comparisons were made between groups using the Student’s t-test. All tests were two-sided with the significance level set to p < 0.05.\n\n3. Results\n\n3.1. Baseline Characteristics\n\nAssessment primary outcomes, used for evaluation of the efficacy and safety of MP and MTX, were based on the change of clinical, functional, and CT symptoms. During the initial stage of the study, we conducted a comparative analysis of the baseline clinical symptoms of the patients (Table 1).\n\nIn the group of patients who received corticosteroid therapy (n = 97), there were 54 (55.7%) females and 43 (43.3%) males; the mean age was 40 years (range, 22–50 years). In the MTX treatment group (n = 46), women were also more prevalent (29–63.0%); the mean age was 46 years (range, 28–57 years).\n\nComparative analysis of baseline demographical data, clinical, functional and radiological symptoms demonstrated no significant differences between study groups.\n\n3.2. Efficacy and Tolerability of MP and MTX in a Comparative Assessment of Primary Outcomes\n\nComparative efficacy analysis showed that immunosuppressive therapy with MTX does not significantly differ from CS therapy with MP in terms of the rate of successful completion of treatment (Table 2).\n\nAn overall Chi-squared test was also performed using 4 by 2 tables: the results indicate a relationship between primary outcomes and drug choice: the chi-square statistic is 11.3005, the p value is 0.010, and the result is significant at p ˂ 0.05; statistical power is 86.7%.\n\nAt the same time, the average duration of CS therapy until clinical remission with normalization of CT data (12.7 ± 3.0 months) was higher than that in patients taking MTX (10.8 ± 2.7); p ˂ 0.05; statistical power—96.6%.\n\nResistance to CS therapy (progression during treatment) was observed in 17 (17.5%) patients, which was significantly more frequent than in patients taking MTX (2–4.3%; Chi-square = 4.703, p = 0.031). At the same time, in two patients, progression began already at the initial stage of treatment with the use of MP at a dose of 0.4 mg/kg of body weight. Two cases of progression were observed during treatment with MTX at a dose of 10 mg/week.\n\nLack of efficacy was observed more often in patients after MTX therapy in almost all cases when using the drug at a dose of 10 mg/week.\n\nSerious side effects of MP requiring drug discontinuation occurred in five patients—osteoporosis with clinical manifestations in three patients and steroid diabetes in two patients—all cases after 6 months of therapy. At the first stage of CS therapy, when relatively high doses of MP were used, side effects such as weight gain, a tendency to peripheral oedema, mild hyperglycemia, hyperexcitability, and sleep disturbances were often observed, which disappeared or decreased with subsequent therapy in an MP dose reduction mode.\n\nIn the group of patients taking MTX, serious side effects with subsequent drug discontinuation were reported in five patients: methotrexate-induced pneumonitis at the 11th month of MTX therapy at a dose of 10 mg/week in one case; in two patients—an increase in ALT more than three times compared to the normal level; and in two patients—leukocytopenia with a leukocyte level below 3.5 × 109/L after long-term treatment (more than 6 months). It should be noted that gastrointestinal disorders in the treatment of MTX per os were successfully stopped by dividing the therapeutic dose into two doses within a 12 h period [18], by adding folic acid (5 mg/week), or by changing the route of administration to parenteral.\n\nThus, in patients with newly diagnosed pulmonary sarcoidosis, MTX monotherapy does not significantly differ from MP monotherapy in terms of successful completion of treatment with normalization of CT data and the frequency of side effects. However, cases of insufficient efficacy (stabilization) after MTX therapy are observed more often.\n\nAt the same time, when using MTX, a significant decrease in the frequency of treatment resistance is observed.\n\n3.3. Efficacy and Tolerability of MTX on Depending on the Dose\n\nTable 3 shows the results of a comparative assessment of primary outcomes in 28 patients with pulmonary sarcoidosis after MTX therapy at a dose of 10 mg/week, and in 18 patients receiving MTX at a dose of 15 mg/week.\n\nAn improvement in the indicators of the treatment efficacy was noted with the use of MTX at a dose of 15 mg/week. At the same time, no significant dependence of the rate of treatment resistance and the number of serious side effects on the MTX dose has been established.\n\nWe did not perform the overall Chi-squared test using 4 by 2 tables to investigate the relationship between outcomes and different MTX dosages due to the inherent limitations of this method associated with an insufficient number of observations.\n\nIn patients treated with MTX at a dose of 15 mg/week, the average duration of therapy until clinical remission with normalization of CT data (10.1 ± 2.1 months) was less than in patients receiving MTX at a dose of 10 mg/week (12.8 ± 4.2; p ˂ 0.05); statistical power—82.3%. That is, increasing the MTX dose to 15 mg/week accelerates the rate of regression of sarcoidosis.\n\nAs an illustration, below you can find a brief description of the successful treatment with MTX 15 mg/week in a 27-year-old patient with severe sarcoidosis—massive consolidations in lungs, respiratory failure (MRC 3), and moderate impairment of pulmonary ventilation and diffusion capacity of the lungs. At the same time, the patient had subcompensated diabetes mellitus, which excluded the possibility of CS therapy.\n\nThe patient underwent monotherapy with MTX at a dose of 15 mg/week. As a result, by the second visit (after 3 months of treatment), a pronounced positive dynamic of subjective symptoms was noted—dyspnea occurred only when performing the usual load (when climbing the stairs to the third or fourth floor), the cough disappeared, and the body temperature returned to normal. Figure 1 shows a thoracic CT scan (axial section at the level of the tracheal bifurcation): the almost complete resolution of consolidations in S3,6 of both lungs is clearly visible.\n\nThe tolerability of MTX was satisfactory: there were no gastrointestinal disturbances; at the seventh month of the treatment period, when conducting a clinical blood analysis, moderate leukocytopenia and mild thrombocytopenia were found, while the value of these parameters did not require dose adjustment and the regimen of MTX use.\n\nFigure 2 shows CT axial sections, on the left—on the day of diagnosis, on the right—after the end of methotrexate therapy.\n\nThus, increasing the MTX dose from 10 to 15 mg/week accelerates the rate of regression of sarcoidosis, improves treatment efficacy, and does not affect the rate of serious side effects.\n\n3.4. Relapse Rate after Successful Management\n\nA relapse is considered as a recurrence of clinical and/or radiological symptoms after successful management with the normalization of CT findings.\n\nThe patients were invited to visit the clinic for assessments using CT 6 and 12 months after the end of treatment. Findings on the relapse rate from 60 post-CS patients and 24 post-MTX patients were collected.\n\nPost-MP relapses were reported in 26 (43.3%) patients, and for post-MTX, in 3 (8.3%; Chi-square = 9.450, p = 0.003).\n\n4. Discussion\n\nHistorically, CS are the first-line drugs in sarcoidosis management due to their sufficiently high efficacy [8,11,12,13,25,26]. Overall, a response to CS is obtained in 80% to 90% of patients, from a few weeks (3 to 4 weeks in case of lung involvement [27]) to 3 months, with a complete response often obtained at 6 weeks [28].\n\nSecond-line drugs, with MTX being the most common, are considered if CS treatment is contraindicated, and in the case of steroid-resistance and steroid-induced serious adverse effects.\n\nIn 2013, WASOG experts published multinational evidence-based World Association of Sarcoidosis and Other Granulomatous Disorders recommendations for the use of methotrexate in sarcoidosis: integrating systematic literature research and expert opinions of sarcoidologists worldwide [18]; however, only one randomized controlled MTX efficacy study in pulmonary sarcoidosis was conducted at this point [29].\n\nThe limitation for a wider MTX prescription in pulmonary sarcoidosis patients is due to a common perception among practicing pulmonologists that MTX, as opposed to CS, results in a less pronounced clinical effect and is associated with serious hepatotoxicity and haematotoxicity. In recent years, rebuttal clinical studies were conducted [22,23,30].\n\nA retrospective methotrexate efficacy and tolerability study in pulmonary sarcoidosis patients conducted by Fang, C. et al. [22] has shown a good clinical response to MTX in 80% of patients. Good drug tolerability and low drug withdrawal rates were observed in these patients even without folic acid supplements in clinical practice.\n\nA large retrospective study by Baughman, R.P. et al. [23] assessed haematotoxicity and hepatotoxicity of methotrexate at a dose of 10 mg weekly in 607 sarcoidosis patients over a 6-year period. Leukopenia and elevated hepatic transaminases were reported in about 10% of cases. Only one patient had severe leukopenia. Only nine patients presented with transaminases elevated > 3 × ULN. Methotrexate was effective in the majority of these patients. The authors did not reveal other adverse effects resulting in methotrexate withdrawal at that time.\n\nThe results of a retrospective observational study in 1276 sarcoidosis patients conducted by Vizel’, A.A. et al. [30] allowed them to conclude that 15 mg MTX weekly per os in patients with advanced sarcoidosis who were previously on systemic CS is an effective second-line drug. The sufficient safety level of MTX allows its long-term prescription from 3 months to ≥ 1 year.\n\nOur findings are in line with the above data on methotrexate efficacy and tolerability in the management of patients with pulmonary sarcoidosis. Meanwhile, we have shown that MTX did not significantly differ from treatment using an MP first-line drug in terms of clinical response and the rate of severe adverse effects requiring drug discontinuation. At the same time, cases of resistance to MTX were reported as substantively rare versus CS therapy at the stage of MP dose reduction.\n\nA high relapse rate after CS therapy is one of the main challenges in the management of sarcoidosis patients [14].\n\nIn 1997, J.E. Gottlieb et al. published a paper [15] which provides observations from 337 patients with different stages of sarcoidosis over 4 years. The authors have established a significantly higher relapse rate in patients treated with CS (74%) versus those who were not prescribed these drugs (8%). They came to a conclusion that long-term CS treatment may promote increased relapse risk.\n\nIt was also found that relapses were more common over the 12 months after the end of treatment [14], as well as in patients on higher CS doses [16,31].\n\nIn our study, the relapse rate over the 12 months after a successful MTX treatment was significantly lower versus post-MP patients, which is in line with literature findings on a low relapse rate after MTX treatment [22,23] and confirms a hypothesis, at least partially, that long-term CS therapy is a risk factor for sarcoidosis relapse. In our opinion, this is the most significant result of our study.\n\nLimitations of the Study\n\nThis is a real-life observational study, that is, non-randomized and uncontrolled. Only two main inclusion criteria were used: newly diagnosed pulmonary sarcoidosis without prior specific therapy, and the absence of fibrosis on CT. In addition, in contrast to the CS group, 50% of patients in the MTX group had concomitant diseases or contraindications to CS, which could affect the effectiveness and tolerability of MTX. Furthermore, the limited number of observations in the study of the dependence of outcomes on the dose of MTX did not provide statistically flawless evidence.\n\n5. Conclusions\n\nWe believe that the literature data provided [22,23,30] and the results of our own MTX and MP efficacy and tolerability studies in patients with pulmonary sarcoidosis may be helpful for practicing pulmonologists in the objective assessment of the risk–benefit ratio in the case of relative contraindications or limitations to the use of CS therapy and they may choose the appropriate treatment agent.\n\nAuthor Contributions\n\nConceptualization, V.G.; methodology, V.G. and I.M.; software, Y.D.; validation, V.G., I.M. and N.M.; formal analysis, N.P. and O.B.; investigation, N.M., O.B. and N.V.; resources, Y.D.; data curation, N.P. and N.V.; writing—original manuscript, V.G.; writing—review and editing, I.M.; visualization, V.G. and I.M.; supervision, V.G. and I.M.; project administration, N.P.; and funding acquisition, V.G. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research received no external funding.\n\nInstitutional Review Board Statement\n\nThe study was performed in accordance with the ethical standards laid down in the Declaration of Helsinki and approved by the Ethics Committee of National Institute of Phthisiology and Pulmonology named after F.G. Yanovsky NAMS of Ukraine (protocol: A.19.01, approval date: 17 December 2018).\n\nInformed Consent Statement\n\nInformed consent was obtained from all subjects involved in the study.\n\nData Availability Statement\n\nFor data availability, contact the corresponding author.\n\nConflicts of Interest\n\nThe authors declare no conflict of interest.\n\nAbbreviations\n\nMTX\tmethotrexate\t\nMP\tmethylprednisolone\t\nCT\tcomputed tomography\t\nCS\tcorticosteroids\t\nDLCO\tdiffusing capacity of the lung for carbon monoxide\t\nWASOG\tWorld Association of Sarcoidosis and Other Granulomatous Disorders\t\nALT\talanine aminotransferase\t\nPFTs\tpulmonary functional tests\t\n\nFigure 1 Pulmonary sarcoidosis, stage II, atypical form—multiple massive consolidations in both lungs; a thoracic CT scan (axial section at the level of the tracheal bifurcation): (a) on the left—before treatment, (b) on the right—regression after 3 months of MTX therapy (15 mg/week).\n\nFigure 2 Pulmonary sarcoidosis, stage II, atypical form—multiple massive consolidations in both lungs; a thoracic CT scan (axial section at the level of division of the main bronchi): (a) on the left—before treatment, (b) on the right—after 12 months of MTX therapy, 15 mg/week (complete resolution with residual changes in the form of limited interstitial fibrosis).\n\ndiagnostics-11-01289-t001_Table 1 Table 1 Baseline clinical, functional, and CT symptoms.\n\nSymptoms\tMP (n = 97)\tMTX (n = 46)\tChi-Squared Test\t\nClinical symptoms:\t73 (75.3%)\t39 (84.9%)\t1.667\np = 0.197\t\nGeneralized weakness\t58 (59.8%)\t30 (65.2%)\t0.388\np = 0.534\t\nDyspnea on moderate exertion\t24 (24.7%)\t12 (26.1%)\t0.030\np = 0.863\t\nDyspnea on mild exertion\t8 (8.25)\t5 (10.8%)\t0.260\np = 0.611\t\nCough\t39 (40.2%)\t21 (45.7%)\t0.380\np = 0.538\t\nSub-febrile body temperature\t17 (17.5%)\t6 (13.0%)\t0.464\np = 0.494\t\nPulmonary ventilation disturbances\t17 (17.5%)\t12 (26.1%)\t1.415\np = 0.235\t\nDecreased DLCO (range, 61–79% predicted)\t13 (13.4%)\t9 (19.6%)\t0.910\np = 0.340\t\nCT symptoms:\t\t\t\t\nClassical findings—bilateral hilar lymphadenopathy and micronodular pattern with perilymphatic distribution\t90 (92.8%)\t41 (89.1%)\t0.542\np = 0.462\t\nUncommon findings—macronodules, consolilations\t7 (7.2%)\t5 (10.9%)\t0.542\np = 0.462\t\n\ndiagnostics-11-01289-t002_Table 2 Table 2 Primary outcomes in patients with pulmonary sarcoidosis after MP and MTX therapy.\n\nPrimary Outcomes\tMP (n = 97)\tMTX (n = 46)\tChi-Squared Test\t\nSuccessful completion\nof treatment\t68 (70.1%)\t29 (63.0%)\t0.703\np = 0.399\t\nLack of efficacy\t7 (7.2%)\t10 (21.7%)\t6.283\np = 0.013 *\t\nProgression during treatment\t17 (17.5%)\t2 (4.3%)\t4.703\np = 0.031 *\nFisher’s exact test:\np = 0.035 *\t\nSerious side effects\t5 (5.2%)\t5 (10.9%)\t1/567\np = 0.211\t\nNote: *—the difference in the value of the indicator in the groups is statistically significant with a critical level of significance = 0.05.\n\ndiagnostics-11-01289-t003_Table 3 Table 3 Primary outcomes of patients with pulmonary sarcoidosis depending on the dose of MTX.\n\nPrimary Outcomes\t(MTX—10 mg/Week),\nn = 28\t(MTX—15 mg/Week),\nn = 18\tChi-Squared Test\t\nSuccessful completion\nof treatment\t14 (50.0%)\t15 (83.3%)\t5.225 *\np = 0.023\t\nLack of efficacy\t9 (32.1%)\t1 (5.6%)\t4.552 *\np = 0.033\t\nProgression during treatment\t1 (3.6%)\t1 (5.6%)\t0.104\np = 0.748\t\nSerious side effects\t4 (14.3%)\t1 (5.6%)\t2.090\np = 0.149\t\nNote: *—the difference in the value of the indicator in the groups is statistically significant with a critical level of significance = 0.05.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Hunninghake G.W. Costabel U. Ando M. Baughman R. Cordier J.F. du Bois R. Eklund A. Kitaichi M. Lynch J. Rizzato G. ATS/ERS/WASOG statement on sarcoidosis. American Thoracic Society/European Respiratory Society/ World Association of Sarcoidosis and other Granulomatous Disorders Sarcoidosis Vasc. Diffus. Lung Dis. 1999 16 149 173 10560120\n2. Judson M.A. The Diagnosis of Sarcoidosis Pulmonary Sarcoidosis: A Guide for the Practicing Clinician, Respiratory Medicine, 17 Judson M.A. Springer Science + Business Media New York, NY, USA 2014 1 18\n3. Baughman R.P. Teirstein A.S. Judson M.A. Rossman M.D. Yeager H. Bresnitz E.A. DePalo L. Hunninghake G. Iannuzzi M.C. Johns C.J. Clinical characteristics of patients in a case control study of Sarcoidosis Am. J. Respir. Crit. Care Med. 2001 164 1885 1889 10.1164/ajrccm.164.10.2104046 11734441\n4. Veltkamp M. Grutters J.C. The Pulmonary Manifestations of Sarcoidosis Pulmonary Sarcoidosis: A Guide for the Practicing Clinician, Respiratory Medicine, 17 Judson M.A. Springer Science + Business Media New York, NY, USA 2014 19 39\n5. Sharma O.P. Mihailovich-Vucinic V. Lesions of Sarcoidosis. A Problem Solving Approach Jaypee Brothers Medical Publishers (P) Ltd. New Delhi, India 2014 187p\n6. Tana C. Tana M. Mezzetti A. Schiavone C. Sarcoidosis: Old certainties and new perspectives Ital. J. Med. 2012 6 186 194 10.1016/j.itjm.2012.05.002\n7. Baughman R.P. Pulmonary Sarcoidosis Clin. Chest Med. 2004 25 521 530 10.1016/j.ccm.2004.04.006 15331189\n8. Baughman R.P. Drent M. The Treatment of Pulmonary Sarcoidosis Pulmonary Sarcoidosis: A Guide for the Practicing Clinician, Respiratory Medicine, 17 Judson M.A. Springer Science + Business Media New York, NY, USA 2014 41 64\n9. El Jammal T. Jammiloux Y. Gerfaud-Valentin M. Valeyre D. Seve P. Refractory Sarcoidosis: A Review Ther. Clin. Risk Management. 2020 16 323 345 10.2147/TCRM.S192922 32368072\n10. Judson M.A. The treatment of pulmonary sarcoidosis Respir. Med. 2012 106 1351 1361 10.1016/j.rmed.2012.01.013 22495110\n11. Schutt A.C. Bullington A.C. Judson M.A. Pharmacotherapy for pulmonary sarcoidosis: A Delphi consensus study Respir. Med. 2010 104 717 723 10.1016/j.rmed.2009.12.009 20089389\n12. Gibson G.J. Prescott R.J. Muers M.F. Middleton W.G. Mitchel D.N. Connolly C.K. Harrison B.D. British Thoracic Society Sarcoidosis study: Effects of long term corticosteroid treatment Thorax 1996 51 238 247 10.1136/thx.51.3.238 8779124\n13. Pietinalho A. Tukianen P. Haahtela T. Persson T. Selroos O. Finish Pulmonary Sarcoidosis Study Group Early treatment of study II sarcoidosis improves 5-year pulmonary function Chest 2002 121 24 31 10.1378/chest.121.1.24 11796428\n14. Baughman R.P. Judson M.A. Relapses of sarcoidosis: What are they and can we predict who will get them? Eur. Respir. J. 2014 43 337 339 10.1183/09031936.00138913 24488991\n15. Gottlieb J.E. Israel H.L. Steiner R.M. Triolo J. Patrick H. Outcome in sarcoidosis. The relationship of relapse to corticosteroid therapy Chest 1997 111 623 631 10.1378/chest.111.3.623 9118698\n16. Rizzato G. Montemurro L. Colombo P. The late follow-up of chronic sarcoid patients previously treated with corticosteroids Sarcoidosis Vasc. Diffus. Lung Dis. 1998 15 52 58 9572002\n17. Korsten P. Strohmayer K. Baughman R.P. Sweiss N. Refractory pulmonary sarcoidosis—Proposal of definition and recommendation for the diagnostic and therapeutic approach Clin. Pulm. Med. 2016 23 67 75 10.1097/CPM.0000000000000136 26973429\n18. Cremers J.P. Drent M. Bast A. Shigemitsu H. Baughman R.P. Valeure D. Sweiss N.J. Jansen T.L. Multinational evidence-based World Association of Sarcoidosis and Other Granulomatous Disorders recommendations for the use of methotrexate in sarcoidosis: Integrating systematic literature research and expert opinion of sarcoidologists worldwide Curr. Opin. Pulm. Med. 2013 19 545 561 10.1097/MCP.0b013e3283642a7a 23880702\n19. Lewis S.J. Ainslie G.M. Bateman E.D. Efficacy of azathioprine as second-line treatment of pulmonary sarcoidosis Sarcoidosis Vasc. Diffus. Lung Dis. 1999 16 87 92 10207946\n20. Baughman R.P. Lower E.E. Lefludomide for chronic sarcoidosis Sarcoidosis Vasc. Diffus. Lung Dis. 2004 21 43 48 15127974\n21. Sahoo D.H. Bandyopadhyay D. Xu M. Pearson K. Parambil J.G. Lazar C.A. Chapman J.T. Culver D.A. Effectiveness and safety of leflunomide for pulmonary and extrapulmonary sarcoidosis Eur. Respir. J. 2011 38 1145 1150 10.1183/09031936.00195010 21565914\n22. Fang C. Zhang Q. Wang N. Jing X. Xu Z. Effectiveness and tolerability of methotrexate in pulmonary sarcoidosis: A single center real-world study Sarcoidosis Vasc. Diffus. Lung Dis. 2019 36 217 227\n23. Baughman R.P. Cremers J.P. Harmon M. Lower E.E. Drent M. Methotrexate in sarcoidosis: Hematologic toxicity ehcountered in a large cohort over a six year period Sarcoidosis Vasc. Diffus. Lung Dis. 2020 37 1 10\n24. Buttgereit F. da Silva J.A. Boers M. Burmester G.R. Cutolo M. Jacobs J. Kirwan J. Köhler L. Van Riel P. Vischer T. Standardised nomenclature for glucocorticoid dosages and glucocorticoid treatment regimens: Current questions and tentative answers in rheumatology Ann. Rheum. Dis. 2002 61 718 722 10.1136/ard.61.8.718 12117678\n25. Grutters J.C. Van den Bosch J.M.M. Corticosteroid treatment in sarcoidosis Eur. Respir. J. 2006 28 627 636 10.1183/09031936.06.00105805 16946094\n26. Paramothayan N.S. Lasserson T.J. Jones P. Corticosteroids for pulmonary sarcoidosis Cochrane Database Syst. Rev. 2005 2005 CD001114 10.1002/14651858.CD001114.pub2\n27. Broos C.E. Wapenaar M. Looman C.W.N. in ’t Veen J.C.C.M. van den Toorn L.M. Overbeek M.J. Grootenboers M.J.J.H. Heller R. Mostard R.L. Poell L.H.C. Daily home spirometry to detect early steroid treatment effects in newly treated pulmonary sarcoidosis Eur. Respir. J. 2018 51 1702089 10.1183/13993003.02089-2017 29348185\n28. McKinzie B.P. Bullington W.M. Mazur J.E. Judson M.A. Efficacy of Short-Course, Low-Dose Corticosteroid Therapy for Acute Pulmonary Sarcoidosis Exacerbations Am. J. Med. Sci. 2010 339 1 4 10.1097/MAJ.0b013e3181b97635 19996733\n29. Baughman R.P. Methotrexate is steroid sparing in acute sarcoidosis: Results of a double blind, randomized trial Sarcoidosis Vasc. Diffus. Lung Dis. 2000 17 60 66 10746262\n30. Vizel A.A. Vizel I.Y. Shakirova G.R. Evaluation of the efficacy and safety of methotrexate in progressive sarcoidosis: A retrospective observational study Russ. Pulmonol. 2020 30 213 218 10.18093/0869-0189-2020-30-2-213-218\n31. Panselinas E. Judson M.A. Acute Pulmonary Exacerbation of Sarcoidosis Pulmonary Sarcoidosis: A Guide for the Practicing Clinician, Respiratory Medicine, 17 Judson M.A. Springer Science + Business Media New York, NY, USA 2014 65 78\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2075-4418",
"issue": "11(7)",
"journal": "Diagnostics (Basel, Switzerland)",
"keywords": "methotrexate; methylprednisolone; outcomes; pulmonary sarcoidosis",
"medline_ta": "Diagnostics (Basel)",
"mesh_terms": null,
"nlm_unique_id": "101658402",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34359372",
"pubdate": "2021-07-19",
"publication_types": "D016428:Journal Article",
"references": "22495110;9118698;15127974;32368072;33264378;10207946;12117678;16946094;24488991;32476957;21565914;8779124;26973429;9572002;11796428;15846612;20089389;23880702;19996733;10560120;29348185;10746262;11734441;15331189",
"title": "Efficacy and Tolerability of Methotrexate and Methylprednisolone in a Comparative Assessment of the Primary and Long-Term Outcomes in Patients with Pulmonary Sarcoidosis.",
"title_normalized": "efficacy and tolerability of methotrexate and methylprednisolone in a comparative assessment of the primary and long term outcomes in patients with pulmonary sarcoidosis"
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"companynumb": "UA-PFIZER INC-202101016202",
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"activesubstancename": "METHYLPREDNISOLONE"
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"abstract": "Leflunomide is an immunosuppressive agent commercialized for treatment of rheumatoid arthritis. Because of its immunosuppressive and possible antiviral properties, leflunomide has been evaluated in some case series of BKVAN with favorable results, mostly in adult patients. Leflunomide targeted levels are usually between 50 and 100 mg/L in kidney transplant adult patients. Data in pediatric population are scarce.\nTo assess the effect of leflunomide on BKvirus in kidney-transplanted children.\nTherapeutic drug monitoring of leflunomide is routinely performed by measuring its active metabolite, teriflunomide, using a simple HPLC-UV method. Pediatric kidney transplant patients with at least one teriflunomide sample between 2010 and 2017 were retrospectively included in this study. Viremia control was defined as undetectable BK viremia or a decrease of more than 1 log in the viral load from the baseline after two months of treatment. Adverse events were recorded.\nA total of 7 patients from 3 centers was included. 6 were only kidney transplant recipients; 1 was a lung-kidney transplant recipient with cystic fibrosis. All patients reported high load BK viremia but none developed BKVAN. For 67% of the patients, complete BK viral clearance was observed during leflunomide treatment with drastic immunosuppressive therapy reduction. Mycophenolate was indeed discontinued in almost all patients. Of note, leflunomide concentrations were significantly higher when viremia was controlled. Only 33% of the observed concentrations were >40 mg/L. The patient with cystic fibrosis had lower concentrations with higher drug doses. No hepatotoxicity was observed in this study and no patient experienced graft rejection. Leflunomide was suspected to cause hemolytic anemia and one patient experienced biological pancreatitis.\nThis study evidenced the wide interindividual variability of the exposure and supported the routine practice of leflunomide with a suggested target level of 30-40 mg/L in pediatric kidney transplanted patient. However, because of the very limited number of patients in our series, further investigations are needed to validate this suggestion.",
"affiliations": "Laboratory of Pharmacology and Toxicology, European Hospital Georges Pompidou - APHP, France.;Pediatric Nephrology Department, Robert Debré University Hospital - APHP, France.;Thoracic Transplantation, European Hospital Georges Pompidou - APHP, France.;Pediatric Nephrology Department, Robert Debré University Hospital - APHP, France.;Pediatry Department, Hospital of La Reunion, France.;Laboratory of Pharmacology and Toxicology, European Hospital Georges Pompidou - APHP, France.;Laboratory of Pharmacology and Toxicology, European Hospital Georges Pompidou - APHP, France.;Laboratory of Pharmacology and Toxicology, European Hospital Georges Pompidou - APHP, France.;Laboratory of Pharmacology and Toxicology, European Hospital Georges Pompidou - APHP, France.",
"authors": "Launay|M|M|;Baudouin|V|V|;Guillemain|R|R|;Maisin|A|A|;Flodrops|H|H|;Douez|E|E|;Mavoungou|S|S|;Jullien|V|V|;Billaud|E M|EM|",
"chemical_list": null,
"country": "Iran",
"delete": false,
"doi": null,
"fulltext": null,
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"issn_linking": "2008-6482",
"issue": "9(4)",
"journal": "International journal of organ transplantation medicine",
"keywords": "BK virus; Cystic fibrosis; Kidney transplantation; Leflunomide; Mycophenolate; Pediatrics",
"medline_ta": "Int J Organ Transplant Med",
"mesh_terms": null,
"nlm_unique_id": "101535773",
"other_id": null,
"pages": "178-183",
"pmc": null,
"pmid": "30863521",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": "12048288;12074690;16148843;16534472;17666021;18360267;19344337;19715969;19916579;21079551;22461534;23782063;23957710;25445121;26590390;27047808;28210457;28247238;28258601",
"title": "Leflunomide for BKvirus: Report of Seven Kidney-Transplanted Children.",
"title_normalized": "leflunomide for bkvirus report of seven kidney transplanted children"
} | [
{
"companynumb": "FR-PBT-000045",
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"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "1",
... |
{
"abstract": "Childhood primary angiitis of the central nervous system (cPACNS) is a rare inflammatory disease of brain vessels. The small vessel subtype is diagnosed on brain biopsy and often presents with cognitive and behavioral changes, headaches, and seizures. However, there are few reported cases of super-refractory status epilepticus in children. We present a case of small vessel cPACNS complicated by super-refractory status epilepticus requiring burst suppression for 4 weeks in addition to multiple antiseizure medications and the ketogenic diet. Our patient was also treated with intravenous and oral steroids, intravenous immunoglobulin, and cyclophosphamide before starting maintenance therapy with mycophenolate mofetil. After prolonged rehabilitation, he recovered almost completely and has a normal neurologic examination with rare epileptiform activity on electroencephalogram (EEG). This is one of the longest cases of status epilepticus in small vessel cPACNS in the literature. We illustrate that super-refractory status epilepticus can be the first manifestation of small vessel cPACNS in previously healthy children and that symptomatic management of seizures with concurrent immunosuppression to treat the underlying pathology resulted in favorable neurologic outcomes.",
"affiliations": "University of British Columbia and BC Children's Hospital, Division of Neurology, Department of Pediatrics, Vancouver, BC, Canada.;University of British Columbia and BC Children's Hospital, Division of Neurology, Department of Pediatrics, Vancouver, BC, Canada.",
"authors": "Chiu|Michelle|M|0000-0002-7585-2764;Datta|Anita|A|0000-0001-7620-4868",
"chemical_list": "D016756:Immunoglobulins, Intravenous; D007166:Immunosuppressive Agents; D003520:Cyclophosphamide; D008775:Methylprednisolone",
"country": "United States",
"delete": false,
"doi": "10.1177/0883073819872579",
"fulltext": null,
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"issn_linking": "0883-0738",
"issue": "35(1)",
"journal": "Journal of child neurology",
"keywords": "EEG; autoimmune; pediatric; refractory; seizures; status epilepticus",
"medline_ta": "J Child Neurol",
"mesh_terms": "D002648:Child; D003520:Cyclophosphamide; D004569:Electroencephalography; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007166:Immunosuppressive Agents; D008297:Male; D008775:Methylprednisolone; D013226:Status Epilepticus; D016896:Treatment Outcome; D020293:Vasculitis, Central Nervous System",
"nlm_unique_id": "8606714",
"other_id": null,
"pages": "31-36",
"pmc": null,
"pmid": "31530228",
"pubdate": "2020-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Childhood Small Vessel Primary Angiitis of the Central Nervous System: A Treatable Cause of Super-refractory Status Epilepticus.",
"title_normalized": "childhood small vessel primary angiitis of the central nervous system a treatable cause of super refractory status epilepticus"
} | [
{
"companynumb": "CA-PFIZER INC-2020394447",
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"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MIDAZOLAM"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nStatus Epilepticus is the most common non-traumatic neurologic emergency in childhood. Current algorithms prioritize the use of benzodiazepines as first line treatment followed by Levetiracetam or Valproic Acid, possibly Fosphenytoin and eventually high dose Propofol and intubation.\n\n\nMETHODS\nA 9-month old girl was brought to the emergency department with a continuous seizure involving the right upper and lower extremity for 45 min prior to arrival. Patient received a dose of rectal Diazepam, intramuscular Midazolam, 2 doses of Lorazepam, Levetiracetam, Fosphenytoin and 2 additional doses of Lorazepam. The seizure remained refractory and generalized. In anticipation of intubation, and because of its action on the NMDA receptor, Ketamine (1 mg/kg IV) was administered. The clonic movements and eye deviations stopped. Patient was intubated for airway protection, sedated with Propofol, then admitted to the PICU. EEG showed no evidence of a seizure pattern. Labs (CBC, CMP, COVID) were unremarkable except for WBC 24.5, blood glucose of 346 and CO2 of 17 with normal anion gap. Urinalysis showed a urinary tract infection. Patient was at her baseline on 1 week post-discharge re-evaluation. Ketamine theoretically may abort seizures through blockade of NMDA receptors which are unregulated in status epilepticus. To date, no randomized controlled trials have been reported. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Ketamine may have a role in treating status epilepticus. It may be considered for induction for rapid sequence intubation and possibly as a third or fourth line agent in refractory cases.",
"affiliations": "Department of Emergency Medicine, Western Michigan University Homer Stryker M.D. School of Medicine, 1000 Oakland Drive, Kalamazoo, MI 49008, United States of America.;Wayne State University School of Medicine, 540 E. Canfield St., Detroit, MI 48201, United States of America.;Department of Emergency Medicine, Western Michigan University Homer Stryker M.D. School of Medicine, 1000 Oakland Drive, Kalamazoo, MI 49008, United States of America. Electronic address: whakmeh@yahoo.com.",
"authors": "Howing|Colleen Elizabeth|CE|;Razi|Farzad|F|;Hakmeh|Wael|W|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajem.2021.10.052",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-6757",
"issue": null,
"journal": "The American journal of emergency medicine",
"keywords": "Ketamine; NMDA; Pediatric; Seizure; Status epilepticus",
"medline_ta": "Am J Emerg Med",
"mesh_terms": null,
"nlm_unique_id": "8309942",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34763960",
"pubdate": "2021-11-03",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Resolution of status epilepticus after ketamine administration.",
"title_normalized": "resolution of status epilepticus after ketamine administration"
} | [
{
"companynumb": "US-ALVOGEN-2021-ALVOGEN-117844",
"fulfillexpeditecriteria": "1",
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"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LORAZEPAM"
},
"drugadditional": "3",
... |
{
"abstract": "The objective of this study was to determine a safe and effective dose of granulocyte-colony stimulating factor (G-CSF) to mobilize hematopoietic stem cells in patients with advanced heart failure and to determine its effects on the cytokine profile. Patients with advanced heart failure (n = 6) and implantable defibrillators in situ were administered G-CSF after baseline echocardiographic and laboratory evaluation, using an escalating dose schedule designed to ensure safety. The peripheral CD34+ hematopoietic stem cell count increased from 3.6 +/- 0.5/microl to 38.7 +/- 13/microl (p= 0.022) after 5 days of 5 microg/kg/day G-CSF therapy. The baseline or peak white blood cell count did not predict the stem cell response. G-CSF increased plasma levels of interleukin-10. Left ventricular ejection fraction increased significantly in the 4 patients with ischemic cardiomyopathy 9 months after treatment. No major adverse effects attributable to the drug occurred during administration or 9 months of follow-up. Our results have shown that low-dose G-CSF significantly mobilized hematopoietic stem cells in advanced heart failure and improved left ventricular function in the ischemic subset of patients. G-CSF significantly increased plasma levels of the anti-inflammatory cytokine interleukin-10, without changing pro-inflammatory cytokine levels. In conclusion, these results indicate a novel mechanism of action for the potential therapeutic benefit of G-CSF in advanced ischemic cardiomyopathy.",
"affiliations": "Department of Medicine, VA Boston Healthcare System and Boston University School of Medicine, Boston, MA, USA. jacob.joseph@med.va.gov",
"authors": "Joseph|Jacob|J|;Rimawi|Asem|A|;Mehta|Paulette|P|;Cottler-Fox|Michele|M|;Sinha|Anjan|A|;Singh|Balkrishnaman K|BK|;Pacheco|Rebecca|R|;Smith|Eugene S|ES|;Mehta|Jawahar L|JL|",
"chemical_list": "D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D016179:Granulocyte Colony-Stimulating Factor",
"country": "United States",
"delete": false,
"doi": "10.1016/j.amjcard.2005.09.112",
"fulltext": null,
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"issn_linking": "0002-9149",
"issue": "97(5)",
"journal": "The American journal of cardiology",
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"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D002465:Cell Movement; D002470:Cell Survival; D002908:Chronic Disease; D016207:Cytokines; D004305:Dose-Response Relationship, Drug; D005500:Follow-Up Studies; D016179:Granulocyte Colony-Stimulating Factor; D006333:Heart Failure; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells; D006801:Humans; D016753:Interleukin-10; D008875:Middle Aged; D017202:Myocardial Ischemia; D012720:Severity of Illness Index; D013318:Stroke Volume; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha; D018487:Ventricular Dysfunction, Left",
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"title": "Safety and effectiveness of granulocyte-colony stimulating factor in mobilizing stem cells and improving cytokine profile in advanced chronic heart failure.",
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"abstract": "Background and Aim: The vast majority of the 2.7 million individuals in the United States who are currently infected with hepatitis C virus (HCV) were born between 1945 and 1965. The median age of these patients in this particular generation at the time of this writing was 55 years. In the general population, older age is a risk factor for multiple myeloma (MM) and other monogammopathies. As the baby boomer population ages, HCV providers are increasingly likely to encounter HCV-infected patients with a monoclonal gammopathy. Guidelines for managing these patients are needed. Methods: We conducted a detailed case series investigation of 4 HCV-positive patients with MM or a monoclonal gammopathy disorder. Patients were followed at the Mount Sinai Faculty Practice liver clinic. We also performed a detailed review of the literature exploring if there is any known association between HCV, MM, and monoclonal gammopathy. Results and Conclusions: There is no convincing evidence of a causal association between HCV and MM. HCV is linked to type II and type III cryoglobulinemia, specific kinds of monoclonal gammopathies of determinable significance. Whether a link exists between HCV and MM or monoclonal gammopathy of undetermined significance is unclear. Our case series provides the first evidence that modern HCV treatments with direct-acting antivirals can be safely and effectively co-administered with MM chemotherapy.",
"affiliations": "Icahn School of Medicine at Mount Sinai, New York City, NY, USA.;Icahn School of Medicine at Mount Sinai, New York City, NY, USA.;Icahn School of Medicine at Mount Sinai, New York City, NY, USA.;Icahn School of Medicine at Mount Sinai, New York City, NY, USA.;Icahn School of Medicine at Mount Sinai, New York City, NY, USA.;Icahn School of Medicine at Mount Sinai, New York City, NY, USA.;Icahn School of Medicine at Mount Sinai, New York City, NY, USA.",
"authors": "Hannaford|Alisse|A|;Del Bello|David|D|;Leng|Siyang|S|;Chari|Ajai|A|;Perumalswami|Ponni|P|;Dieterich|Douglas|D|;Branch|Andrea|A|",
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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 10.1177/232470961769685410.1177_2324709617696854Case ReportManagement of Patients With Hepatitis C Virus, Monoclonal Gammopathy of Undetermined Significance, and Multiple Myeloma Hannaford Alisse BS1Del Bello David MD1Leng Siyang MD1Chari Ajai MD, PhD1Perumalswami Ponni MD1Dieterich Douglas MD1Branch Andrea PhD11 Icahn School of Medicine at Mount Sinai, New York City, NY, USAAlisse Hannaford, BS, Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, NY 10029-6574, USA. Email: Alisse.hannaford@icahn.mssm.edu26 4 2017 Apr-Jun 2017 5 2 23247096176968548 9 2016 23 1 2017 26 1 2017 © 2017 American Federation for Medical Research2017American Federation for Medical ResearchThis article is distributed under the terms of the Creative Commons Attribution 3.0 License (http://www.creativecommons.org/licenses/by/3.0/) 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).Background and Aim: The vast majority of the 2.7 million individuals in the United States who are currently infected with hepatitis C virus (HCV) were born between 1945 and 1965. The median age of these patients in this particular generation at the time of this writing was 55 years. In the general population, older age is a risk factor for multiple myeloma (MM) and other monogammopathies. As the baby boomer population ages, HCV providers are increasingly likely to encounter HCV-infected patients with a monoclonal gammopathy. Guidelines for managing these patients are needed. Methods: We conducted a detailed case series investigation of 4 HCV-positive patients with MM or a monoclonal gammopathy disorder. Patients were followed at the Mount Sinai Faculty Practice liver clinic. We also performed a detailed review of the literature exploring if there is any known association between HCV, MM, and monoclonal gammopathy. Results and Conclusions: There is no convincing evidence of a causal association between HCV and MM. HCV is linked to type II and type III cryoglobulinemia, specific kinds of monoclonal gammopathies of determinable significance. Whether a link exists between HCV and MM or monoclonal gammopathy of undetermined significance is unclear. Our case series provides the first evidence that modern HCV treatments with direct-acting antivirals can be safely and effectively co-administered with MM chemotherapy.\n\nhepatitis Cmultiple myelomamonoclonal gammopathy of undetermined significancedirect-acting antiviralNational Institutes of Healthhttp://dx.doi.org/10.13039/100000002DA031095National Institutes of Healthhttp://dx.doi.org/10.13039/100000002DK090317cover-dateApril-June 2017\n==== Body\nIntroduction\nApproximately 2.7 million individuals in the United States are currently infected with the hepatitis C virus (HCV). Most were born between 1945 and 1965.1 As the baby boomer cohort ages, diseases typical of older patients are beginning to appear in HCV-positive patients, posing diagnostic and management challenges to hepatologists and other providers. These diseases include multiple myeloma (MM) and other disorders of plasma cells. Herein, we provide background information about MM, present several cases of HCV-positive patients with plasma cell disorders, and describe diagnostic strategies and management options.\n\nMM is defined by the presence of more than 10% monoclonal plasma cells in the bone marrow (BM), as well as one or more of the following symptoms: hypercalcemia, renal insufficiency, anemia, and/or bone lesions (“CRAB” symptoms). MM is thought to often be preceded by monoclonal gammopathy of undetermined significance (MGUS), an asymptomatic condition in which there is production of a small amount of monoclonal protein from a relatively small burden of monoclonal plasma cells.2 No known molecular or phenotypic markers distinguish MGUS and MM, and the genetic mutations in the abnormal antibody producing cells are largely the same.3 Characteristics of MM versus MGUS are delineated in Supplemental Table 1 (available at http://hic.sagepub.com/supplemental). Risk factors for MM include male sex, age over 55 years, African American race, obesity, and a family history of MM.4\n\nMethods\nThis is a case series review from December 2013 to June 2016. All cases were seen in the Mount Sinai Faculty Practice liver clinic. Cases are HCV-infected patients who also have a diagnosis of MGUS and/or MM. For historical comparison, we conducted a systematic literature search on PubMed to find all studies that examined HCV and MM/MGUS.\n\nResults and Discussion\nPathophysiology\nAbnormal responses to antigenic stimulation lead to chromosomal alterations, which in turn lead to the development of one or more premalignant clones derived from postgerminal center plasma cells, resulting in MGUS.5,6 Subsequent accumulation of additional genetic alterations leads to increased proliferation of the altered clone(s).7 The increased proliferation results in end-organ damage as the buildup of plasma cells reduces marrow function, and the excess immunoglobulins can cause complications such as myeloma cast nephropathy and hyperviscosity.8-10\n\nHCV’s main effect is immune-mediated hepatocyte injury; however, chronic infection also increases the risk of hepatocellular carcinoma and certain lymphoproliferative disorders. HCV is most strongly associated with the non-Hodgkin’s B cell lymphomas11,12 and the mixed cryoglobulinemias, specifically type II and type III cryoglobulinemias (for a breakdown of the different cryoglobulinemias, see Supplemental Table 2; available at http://hic.sagepub.com/supplemental). HCV causes chronic antigenic B-cell stimulation and antibody production.3 While limited epidemiological studies have linked monoclonal plasma cell disorders with HCV, no direct pathophysiological proof links HCV and MM.13-15\n\nEpidemiology\nMM is a relatively uncommon cancer, representing only 1% of all cancer diagnoses and 10% of all hematological malignancies. It is estimated that 0.7% of the US population will be diagnosed with MM, with 85% of diagnoses occurring in individuals 55 or older—an age range that a steadily increasing number of HCV patients in the United States and Europe are reaching.4 The well-known associations between HCV and other B-cell abnormalities support the possibility of an epidemiological link between HCV and MM; however, published data do not show a firm epidemiological association. A recent study conducted at Kaiser Permanente Southern California reported MM rates in patients with HCV versus those without HCV and found a relative risk (RR) of 3.41 (P < .0001). However, after adjusting for alcohol abuse, tobacco use, body mass index, and diabetes, the RR was no longer significant.13 An earlier meta-analysis of data from 5 studies did not find a significant association between HCV and MM.14 One case-control study in the meta-analysis reported an odds ratio of 4.2 in HCV-positive patients for developing MM.15 However, the data presented in this small study were not stratified for any established MM or cancer risk factors. Thus, the weight of the epidemiological evidence indicates that HCV infection is not a risk factor for MM. Nevertheless, even if there is no causal relationship between chronic HCV and MM, as the cohort of HCV-infected patients reaches the age of heightened MM risk, hepatologists and other clinicians are sure to see more patients affected by both diseases and will need guidance about how to manage them.\n\nBelow, we present 4 cases from the Mount Sinai Faculty Practice Liver Clinic. Each case involves HCV-positive patients of advancing age with either MGUS or MM. It is our hope that these cases offer guidance for hepatologists and other clinicians seeing similar patients who have concomitant diagnoses of HCV and MM/MGUS.\n\nCase Presentation 1: Diagnostic work-up of monoclonal gammopathy in a human immunodeficiency virus and HCV co-infected patient\nA 68-year-old Caucasian male with a history of well-controlled human immunodeficiency virus (HIV) on abacavir, lamivudine, and raltegravir (CD4 count 234, 19%, and an undetectable HIV viral load), chronic HCV, genotype 1a, HCV treatment naïve with cirrhosis (transient elastography score: 21 kPa) was diagnosed with MGUS in August 2014. The diagnosis was made as a result of tests carried out to investigate an elevated total protein-albumin (TPA) ratio. The patient had no complaints of CRAB symptoms, and a skeletal survey was negative for lytic lesions. The patient was referred to the myeloma clinic where a BM biopsy was discussed, but the patient declined. He was started on a 12-week course of sofosbuvir/ledipasvir (SOF/LDV) to treat his HCV in November 2014. He tolerated the antiviral course well and achieved a sustained virological response of 4 weeks (SVR4) in March before being lost to follow-up.\n\nAsymptomatic monoclonal gammopathy encompasses both MGUS and smoldering multiple myeloma (SMM). SMM is distinguished from MGUS by a higher disease burden; however, both entities are clinically asymptomatic (Supplemental Table 1; available at http://hic.sagepub.com/supplemental). Patients should be referred to a hematologist for risk stratification of their disease, determination of follow-up intervals, and consideration for clinical trial participation. Follow-up should be life-long.16 Patients with MGUS have an estimated transformation rate to MM of 25% to 30% over 25 years.2 Several basic tests are used in the MGUS/MM work-up, including a serum protein electrophoresis, serum immunofixation, serum kappa/lambda chains, urine protein electrophoresis and urine immunofixation (Supplemental Tables 3 and 4; available at http://hic.sagepub.com/supplemental).\n\nCase Presentation 2: Impact of HCV cure on a familiar type of monoclonal gammopathy for hepatologists, type II cryoglobulinemia\nA 59-year-old diabetic male with HCV and biopsy-proven stage 1 fibrosis, a history of end-stage renal disease secondary to combined diabetic nephropathy, atherosclerotic disease, and cryoglobulinemic vasculitis, who had a deceased donor kidney transplant in April 2014 (see Figure 1), presented with symptomatic cryoglobulinemia while still on tacrolimus, mycophenolate mofetil, and prednisone (it was difficult to taper immunosuppressants due to problems of nonadherence and concerns centering on rejection). Symptoms of cryoglobulinemia included joint pain and a relapsing/remitting rash on his torso and arms. The patient had been diagnosed with genotype 2b HCV, received an HCV-positive kidney, switched to genotype 1a HCV after the transplant, and never received interferon treatment for HCV. The patient had an IgM kappa gammopathy (MGUS), first detected in May 2013 during an extensive work-up of a subacute profound worsening of renal function (creatinine increased from 2.5 to 6.8 in less than 9 months). While an IgM kappa gammopathy is not uncommon in cryoglobulinemia, especially type I and II cryoglobulinemia, given the patient’s worsening renal function at the time, it was necessary to rule out MM. BM biopsy performed shortly after the detection of the IgM kappa gammopathy showed a normocellular marrow with no plasma cell infiltrate. Kidney biopsy at the time showed advanced diabetic nephropathy with patchy interstitial fibrosis, tubular atrophy, and diffuse arteriosclerosis. Electron microscopy showed focal rare subepithelial deposits. In short, there was no pathological evidence of myeloma kidney at the time. The patient was followed in the myeloma clinic. The most recent BM biopsy in August 2015 showed plasma cells comprising only 3% to 5% of the overall cellularity with no excess of lambda or kappa chains. In mid-2015, the patient received a 12-week course of SOF/LDV and achieved an SVR12. In March 2016, cryoglobulins were retested and the patient was negative; however, the patient is still experiencing joint pain and neuropathy. This case illustrates the intersection of MGUS with cryoglobulinemia, a well-known extrahepatic manifestation of HCV. This patient received 12 weeks of SOF/LDV, resulting in an SVR12. He had resolution of his cryoglobulinemia and a negative M-spike after treatment, thereby resolving his monoclonal gammopathy of determinable significance.\n\nFigure 1. Timeline for Case 2.\n\nAbbreviations: HCV, hepatitis C virus; CKD, chronic kidney disease; Cr, creatinine; BM, bone marrow; MM, multiple myeloma; DD, deceased donor; SOF/LDV, sofosbuvir/ledipasvir; SVR12, sustained virological response at 12 weeks.\n\nCase Presentation 3: HCV treatment in a patient with active MM\nA 60-year-old Caucasian male with chronic genotype 1a HCV infection, treatment naïve, with F3 fibrosis (transient elastography score: 12 kPa) presented with IgA-kappa MM with extensive lytic lesions in the skull, ribs, spine, sacrum, and left femur diagnosed in the winter of 2014-2015. There was no kidney involvement and no anemia at the time of MM diagnosis. The patient started a 12-week course of SOF/LDV 3 months after the monoclonal protein was initially discovered. Approximately 1 month after starting direct-acting antiviral (DAA) therapy, the patient was started on anti-myeloma chemotherapy with lenalidomide, bortezomib, and dexamethasone. He began monthly intravenous bisphosphonate due to the presence of the lytic lesions. Of note, the patient was on DAA therapy and chemotherapy at the same time for what amounted to a 7- to 8-week overlap (see Table 1). Overall, he tolerated his DAA and chemotherapy agents well, but he did develop mild bilateral upper extremity peripheral neuropathy, which was ascribed to be most likely from bortezomib. The patient completed 12 weeks of SOF/LDV and achieved SVR12. At last report, the patient had a complete response after 3 cycles of chemotherapy with no detectable M-spike in his serum or his urine.\n\nTable 1. Direct-Acting Antiviral and Multiple Myeloma Chemotherapy Drug-Drug Interactionsa.\n\n\tDEX\tMEL\tCYCLO\tDOXO\tTHAL\tLENA\tPOMA\tBORT\tCARF\tPANO\t\nLDV\tCb\tA\tA\tDb\tA\tA\tA\tA\tCb\tA\t\nDAC\tDb\tA\tA\tDb\tA\tA\tA\tA\tCb\tA\t\nEBV\tA\tA\tA\tA\tA\tA\tA\tA\tA\tA\t\nVEL\tCb\tA\tA\tDb\tA\tA\tA\tA\tCb\tA\t\nSOF\tA\tA\tA\tA\tA\tA\tA\tA\tA\tA\t\nSMV\tXc\tA\tA\tDc\tA\tA\tA\tA\tCc\tCc\t\nGZR\tA\tA\tA\tA\tA\tA\tA\tA\tA\tA\t\n3-D\tDc\tA\tA\tDc\tA\tA\tA\tCc\tA\tDc\t\nRBV\tA\tA\tA\tA\tA\tA\tA\tA\tA\tA\t\nAbbreviations: DEX, dexamethasone; MEL, melphalan; CYCLO, cyclophosphamide; DOXO, doxorubicin; THAL, thalidomide; LENA, lenalidomide; POMA, pomalidomide; BORT, bortezomib; CARF, carfilzomib; PANO, panobinostat; LDV, ledipasvir; DAC; daclatasvir; EBV, elbasvir; VEL, velpatasvir; SOF, sofosbuvir; SMV, simeprevir; GZR, grazoprevir; 3-D, ombitasvir, dasabuvir, paritaprevir, and ritonavir; RBV, ribavirin.\n\na All drug-drug interactions run through Lexicomp drug interaction search engine.\n\nA = No interaction.\n\nB = The specified agents may interact, but there is little to no evidence of clinical concern.\n\nC = Agents can be co-administered, but physicians should monitor therapy.\n\nD = Consider therapy modification.\n\nX = Co-administration not recommended.\n\nb The direct-acting antiviral in question can increase serum levels of anti-myeloma agent.\n\nc The chemotherapy agent in question can increase serum levels of the direct-acting antiviral.\n\nWhile there are reports of cotreatment of MM and HCV during the interferon era, we are unaware of any literature looking at patients placed on both therapies in the DAA era. Table 1 reflects theoretical drug-drug interactions given what is known regarding metabolism of anti-HCV and MM drugs in the cytochrome p450 system.\n\nAs of the time of this writing, there are several classes of agents approved by the Food and Drug Administration to treat MM: proteasome inhibitors, traditional chemotherapeutic agents (eg, melphalan, cyclophosphamide, carmustine), histone deacetylase inhibitors (panobinostat), and immunotherapy (elotuzumab, daratumumab). MM remains an incurable malignancy. Patients are expected to relapse after their initial therapy, and subsequent therapy consists of additional lines of therapy utilizing agents from the classes mentioned above in combination. For a detailed description of relapsed and/or refractory MM, the reader is directed to excellent reviews of this topic.17-19 It is preferable to refer patients to centers specializing in the treatment of MM, as these centers have greater access to clinical trials incorporating novel therapies and therapeutic strategies.\n\nReturning to the individual patient in case 3, the patient tolerated DAA treatment and chemotherapy well, with the exception of the development of peripheral neuropathy, most likely due to bortezomib.\n\nCase Presentation 4: Stem cells harvested and stored for possible future use from a patient with MM and HCV, who was later cured of HCV\nA 65-year-old Caucasian male with chronic genotype 1a HCV, stage F1 liver fibrosis (transient elastography score: 6.6 kPa), unsuccessfully treated with pegylated interferon and ribavirin over a decade previously, presented to liver clinic with a complex MM history (see Figure 2).\n\nFigure 2. Timeline for Case 4.\n\nAbbreviations: SMM, smoldering multiple myeloma; MM, multiple myeloma; SOF/LDV, sofosbuvir/ledipasvir; SVR4, sustained virologic response for 4 weeks.\n\nThe patient was diagnosed in 1992 with SMM (BM biopsy was positive for 40% plasma cells, but he was asymptomatic without extra-marrow organ involvement at the time). In October 2013, the patient was found to have an elevation in his total protein to 10.7 and an increase in his M-spike to 4.72 (values had been 8.6 and 1.91, respectively, 1 year prior). The patient was complaining of rib pain at the time. A computed tomography scan of the chest showed lytic lesions and pathologic fractures of the ribs on the left side. Shortly afterward, the patient was started on bortezomib, lenalidomide, and dexamethasone. One month after starting chemotherapy, he developed a rash at the bortezomib injection site, which led to discontinuation of the agent. Patient was continued on lenalidomide and dexamethasone, which he tolerated well for several months. In March 2014, after 5 cycles of a lenaldomide-based regimen, the patient had an 85% reduction in his paraproteinemia, reflecting a successful response to therapy. Stem cells were harvested when the patient was still viremic with HCV in January 2015, his M-spike increased again, this time to 3.36. Carfilzomib was added to the patient’s chemotherapy regimen.\n\nAt this time, the patient was placed on 12 weeks of SOF/LDV concurrently with his carfilzomib, lenaldidomide, and dexamethasone. Patient achieved SVR48 as of April 2016. At last report, the patient had remission of his MM after several cycles of chemotherapy with no M-spike. Again, the case illustrates the fact that MM and HCV can be treated at the same time. Providers should of course be careful of drug-drug interactions (see Table 1) when combining treatments.\n\nThis case has an interesting complexity in that the patient had his stem cells harvested while he was still viremic with HCV, raising the concern that should his MM worsen again, he would need to undergo stem cell transplantation and his HCV may reoccur, prompting retreatment with DAAs. Recurrence of viremia after BM or solid organ transplantation is well described with many viruses, including, but not limited to, cytomegalovirus,22 Epstein-Barr virus,23,24 and hepatitis B.25,26 However, we were unable to find any reports of a patient auto-infecting oneself with HCV from previously harvested stem cells. If the patient were to undergo stem cell transplant in the future, the best course of action, in our expert opinion, would be to monitor HCV viral loads and to treat again with DAAs should viremia reoccur.\n\nConclusion\nAs the HCV population ages, it will be important for hepatologists to be familiar with MGUS and MM. Primary care providers and hepatologists should know the basic warning signs and risk factors for MM, so that they can obtain appropriate initial data, and refer as necessary. Hepatologists should also know that while there is a paucity of data regarding the cotreatment of HCV and MM with modern therapies, simultaneous treatment is possible, as our case series illustrates, and appears to be safe for patients. Current evidence is inconclusive as to whether or not there is a link between HCV and MGUS/MM. More data are needed. However, it is our opinion that patients with HCV and MGUS/MM should be prioritized for DAA therapy.\n\nDeclaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: David Del Bello has received research support from Gilead Sciences. Ponni Perumalswami has received research support from Gilead Sciences. Douglas Dieterich has been a consultant and scientific advisor for Gilead Sciences. Andrea Branch has received research support from Gilead Sciences.\n\nFunding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by research funding from the National Institutes of Health (DA031095, DK090317).\n==== Refs\nReferences\n1 \nCenters for Disease Control and Prevention . Hepatitis C FAQs for the public . http://www.cdc.gov/hepatitis/hcv/cfaq.htm. Accessed February 23, 2017 .\n2 \nBlade J Rosinol L Cibeira MT de Larrea CF \nPathogenesis and progression of monoclonal gammopathy of undetermined significance . Leukemia . 2008 ;22 :1651 -1657 .18668131 \n3 \nKuehl WM Bergsagel PL \nEarly genetic events provide the basis for a clinical classification of multiple myeloma . Hematology Am Soc Hematol Educ Program . 2005 :346 -52 .\n4 \nAmerican Cancer Society . What are the risk factors for multiple myeloma . http://www.cancer.org/cancer/multiplemyeloma/detailedguide/multiple-myeloma-risk-factors. Accessed February 23, 2017 .\n5 \nMatsui W Wang Q Barber JP \nClonogenic multiple myeloma progenitors, stem cell properties, and drug resistance . Cancer Res . 2008 ;68 :190 -197 .18172311 \n6 \nWillis TG Dyer MJ \nThe role of immunoglobulin translocations in the pathogenesis of B-cell malignancies . Blood . 2000 ;96 :808 -822 .10910891 \n7 \nKuehl WM Bergsagel PL \nMultiple myeloma: evolving genetic events and host interactions . 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J Clin Oncol . 2006 ;24 :953 -960 .16418500 \n12 \nVisco C Arcaini L Brusamolino E \nDistinctive natural history in hepatitis C virus positive diffuse large B-cell lymphoma: analysis of 156 patients from northern Italy . Ann Oncol . 2006 ;17 :1434 -1440 .16766591 \n13 \nNyberg AH Chung JW Cheetham TC \nIncreased cancer rates in patients with chronic hepatitis C: an analysis of the cancer registry in a large U.S. health maintenance organization . J Hepatol . 2015 ;62 :S220 .\n14 \nDal Maso L Franceschi S \nHepatitis C virus and risk of lymphoma and other lymphoid neoplasms: a meta-analysis of epidemiologic studies . Cancer Epidemiol Biomarkers Prev . 2006 ;15 :2078 -2085 .17119031 \n15 \nMontella M Crispo A de Bellis G \nHCV and cancer: a case-control study in a high-endemic area . Liver . 2001 ;21 :335 -341 .11589770 \n16 \nvan de Donk NW Palumbo A Johnsen HE \nThe clinical relevance and management of monoclonal gammopathy of undetermined significance and related disorders: recommendations from the European Myeloma Network . Haematologica . 2014 ;99 :984 -996 .24658815 \n17 \nNooka AK Kastritis E Dimopoulos MA Lonial S \nTreatment options for relapsed and refractory multiple myeloma . Blood . 2015 ;125 :3085 -3099 .25838342 \n18 \nCottini F Anderson K \nNovel therapeutic targets in multiple myeloma . Clin Adv Hematol Oncol . 2015 ;13 :236 -248 .26352582 \n19 \nDimopoulos MA San-Miguel JF Anderson KC \nEmerging therapies for the treatment of relapsed or refractory multiple myeloma . Eur J Haematol . 2011 ;86 :1 -15 .20942854 \n20 \nLeng S Moshier E Tremblay D \nA comparison of the outcomes of early versus delayed autologous stem cell transplantation for multiple myeloma in the era of novel therapies . Paper presented at: ASH Annual Meeting ; 2015 ; Orlando, FL .\n21 \nAttal M Harousseau JL Stoppa AM \nA prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma . N Engl J Med . 1996 ;335 :91 -97 .8649495 \n22 \nBhat V Joshi A Sarode R Chavan P \nCytomegalovirus infection in the bone marrow transplant patient . World J Transplant . 2015 ;5 :287 -291 .26722656 \n23 \nRasche L Kapp M Einsele H Mielke S \nEBV-induced posttransplant lymphoproliferative disorders: a persisting challenge in allogeneic hematopoetic SCT . Bone Marrow Transplant . 2014 ;49 :163 -167 .23832092 \n24 \nCohen JM Cooper N Chakrabarti S \nEBV-related disease following haematopoietic stem cell transplantation with reduced intensity conditioning . 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"journal": "Journal of investigative medicine high impact case reports",
"keywords": "direct-acting antiviral; hepatitis C; monoclonal gammopathy of undetermined significance; multiple myeloma",
"medline_ta": "J Investig Med High Impact Case Rep",
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"title": "Management of Patients With Hepatitis C Virus, Monoclonal Gammopathy of Undetermined Significance, and Multiple Myeloma.",
"title_normalized": "management of patients with hepatitis c virus monoclonal gammopathy of undetermined significance and multiple myeloma"
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"abstract": "A 19-year-old man presented with unilateral sudden onset vision loss following an intra-articular triamcinolone injection in the right temporomandibular joint. At fundus examination emboli of triamcinolone were visible in multiple retinal arteries. Choroidal ischaemia and occlusion of the central retinal artery and its branches were documented at fluorescein angiography. Optical coherence tomography revealed significant thickening of the inner retinal layers. Optical coherence tomography angiography clearly demonstrated an abrupt cut-off of flow in a vessel below the optic disc. Lack of perfusion of the superficial and deep retinal plexuses beyond the areas of embolisation and at the posterior pole was also appreciated. The visual outcome was poor despite treatment.",
"affiliations": "Department of Ophthalmology, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, AIIMS, New Delhi, Delhi, India.;Department of Ophthalmology, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, AIIMS, New Delhi, Delhi, India.;Department of Ophthalmology, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, AIIMS, New Delhi, Delhi, India.;Department of Ophthalmology, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, AIIMS, New Delhi, Delhi, India.",
"authors": "Gaur|Nripen|N|;Singh|Pallavi|P|;Chawla|Rohan|R|;Takkar|Brijesh|B|",
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"title": "Triamcinolone emboli leading to central retinal artery occlusion: a multimodal imaging study.",
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"abstract": "The occurrence of seizures during pregnancy is really a challenging situation which risks the health of both mothers and fetuses. However, new onset epilepsy is unpredictable in pregnancy, and its clinic feature is barely known. This study aimed to explore the clinical characteristics and pregnancy outcomes of new onset epilepsy during pregnancy.We screened consecutive women with epilepsy and reproductive history from June 2013 to November 2018 from 3 hospitals in West China. Detailed demographics, clinical features, neurological status, related tests, managements, seizure and pregnancy outcomes were recorded and followed-up. Within them, patients with first seizure during pregnancy and spontaneous recurrent seizures after delivery or abortion were defined as new onset epilepsy during pregnancy.We screened a total of 1041 consecutive women with epilepsy and reproductive history. Twenty-two of them (2.1%) had new onset epilepsy during pregnancy. The average age at seizure onset was 22.7 ± 3.0 years. All their first seizures occurred in pregnancy period, including 4 (18.2%) in the first trimester, ten (45.4%) in the second trimester and eight (36.4%) in the third trimester. Most patients delivered healthy babies, except one patient had to choose induced abortion because of the disappearance of fetal heart rate, one child was diagnosed with mild harelip and one was diagnosed with trisomy 21 syndrome, tetralogy of Fallot and congenital duodenal atresia. All 3 complications happened in patients with their first seizures in first trimester.Although the risk of new onset epilepsy during pregnancy was relatively low, accurate diagnosis and appropriate treatment were required to reduce the damage to both mothers and fetuses. New onset epilepsy during pregnancy mostly began in middle and late pregnancy. However, seizures occurred from early pregnancy had bad effects on the embryo or fetus.",
"affiliations": "Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.",
"authors": "Li|Wei|W|;Hao|Nanya|N|;Xiao|Yingfeng|Y|;Zhou|Dong|D|",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 31277117MD-D-19-0216110.1097/MD.0000000000016156161565300Research ArticleObservational StudyClinical characteristics and pregnancy outcomes of new onset epilepsy during pregnancy Li Wei MDHao Nanya MDXiao Yingfeng MDZhou Dong MD, PhD∗Liu. Feng Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.∗ Correspondence: Dong Zhou, Department of Neurology, West China Hospital, Sichuan University, No. 37 Guo Xue Lane, Chengdu 610041, Sichuan, China (e-mail: zhoudong66@yahoo.de).7 2019 05 7 2019 98 27 e1615616 3 2019 4 5 2019 30 5 2019 Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.2019This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc/4.0Abstract\nThe occurrence of seizures during pregnancy is really a challenging situation which risks the health of both mothers and fetuses. However, new onset epilepsy is unpredictable in pregnancy, and its clinic feature is barely known. This study aimed to explore the clinical characteristics and pregnancy outcomes of new onset epilepsy during pregnancy.\n\nWe screened consecutive women with epilepsy and reproductive history from June 2013 to November 2018 from 3 hospitals in West China. Detailed demographics, clinical features, neurological status, related tests, managements, seizure and pregnancy outcomes were recorded and followed-up. Within them, patients with first seizure during pregnancy and spontaneous recurrent seizures after delivery or abortion were defined as new onset epilepsy during pregnancy.\n\nWe screened a total of 1041 consecutive women with epilepsy and reproductive history. Twenty-two of them (2.1%) had new onset epilepsy during pregnancy. The average age at seizure onset was 22.7 ± 3.0 years. All their first seizures occurred in pregnancy period, including 4 (18.2%) in the first trimester, ten (45.4%) in the second trimester and eight (36.4%) in the third trimester. Most patients delivered healthy babies, except one patient had to choose induced abortion because of the disappearance of fetal heart rate, one child was diagnosed with mild harelip and one was diagnosed with trisomy 21 syndrome, tetralogy of Fallot and congenital duodenal atresia. All 3 complications happened in patients with their first seizures in first trimester.\n\nAlthough the risk of new onset epilepsy during pregnancy was relatively low, accurate diagnosis and appropriate treatment were required to reduce the damage to both mothers and fetuses. New onset epilepsy during pregnancy mostly began in middle and late pregnancy. However, seizures occurred from early pregnancy had bad effects on the embryo or fetus.\n\nKeywords\nepilepsynew onsetoutcomespregnancyseizureOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nEpilepsy is one of the common chronic disorders affecting women of reproductive age.[1] The occurrence of seizures during pregnancy is really a challenging situation which risks the health of both mothers and fetuses.[2] Lots of evidences indicate that seizures in pregnancy are related to miscarriage, stillbirth, preterm delivery, antepartum and post-partum bleeding, caesarean section, developmental delay and congenital malformation.[1–3] Seizures in pregnancy mainly result from 3 conditions: first and most frequent is uncontrolled pre-existing seizures; second is the new onset seizures; and third is some pregnancy-related conditions, especially the eclampsia.[4] Women with pre-existing epilepsy can plan their pregnancies after controlling seizures and consulting doctors. Women with risk of eclampsia may have some evidences of preeclampsia which can be regularly monitored and prevented in advance. However, new onset seizures are unpredictable in pregnancy, which need extremely accurate diagnosis and appropriate treatment.\n\nPrevious studies showed that structural and metabolic changes may precipitate new onset seizures during pregnancy, including intracranial hemorrhage, cerebral venous sinus thrombosis, ischemic stroke, brain tumor, hydrocephalus, infection, hypoglycemia, acute intermittent porphyria, and so on.[5,6] However, most of these seizures were only the acute symptoms of underlying diseases; rare would develop into epilepsy, especially without obvious structural abnormalities. There is a condition that some women may have their first seizures during pregnancy and continue to get spontaneous recurrent seizures after delivery, which is called new onset epilepsy during pregnancy.[7]\n\nUp to now, the characteristics of new onset epilepsy during pregnancy and its effect to both mothers and fetuses are barely known. Here, we investigated the clinical features, managements and pregnancy outcomes of a series of patients with new onset epilepsy during pregnancy from West China. To our knowledge, this is the first comprehensive assessment of new onset epilepsy during pregnancy, with a relatively large cohort of patients.\n\n2 Methods\n2.1 Patients and registrations\nPatients were selected from West China Pregnancy Register for epilepsy patients. Women with epilepsy and reproductive history were consecutively registered and followed up from June 2013 to November 2018. We collected patients from 3 hospitals in West China, including 2 general hospitals (West China Hospital, Sichuan Provincial People's Hospital) and one specialist women and children's hospital (West China Second Hospital). All patients were diagnosed with epilepsy according to the 2010 International League Against Epilepsy (ILAE) Classification Schemes of Epileptic Seizures and Epilepsy Syndromes.[8] Generalized seizures are defined as seizures occurring in and rapidly engaging bilaterally distributed networks. Generalized tonic-clonic seizure (GTCS) is the common type of generalized seizures. Patients with GTCS will quickly lose consciousness and their skeletal muscles will suddenly tense, often causing a fall. A few seconds later, the patient's muscles start to contract and relax rapidly, causing convulsions. And focal seizures (FS) are defined as seizures occurring within networks limited to one hemisphere and either discretely localized or more widely distributed. Symptoms vary according to where the seizures occur, including asymmetrical tonic or excessive exercise from the frontal lobe, the feeling of déjà vu or automatism from the temporal lobe, the numbness or tingling from the parietal lobe, the visual disturbance or hallucination from the occipital lobe, etc. Furthermore, convulsive status epilepticus (CSE) is characterized either by continuous bilateral convulsive activity (lasting more than five minutes) or by generalized convulsive seizures that recur without significant recovery between them. Detailed demographics, clinical features, neurological status, related tests, managements, seizure and pregnancy outcomes were recorded. Women would be followed up at the clinic or by telephone every 3 months before delivery and every year after delivery. Their seizure outcomes and the condition of their babies would be collected and recorded. Seizure frequency in pregnancy was fixed for each trimester and was categorized as no seizures, sporadic seizures (less than one seizure per month), frequent seizures (more than one seizure per month) and very frequent seizures (more than one seizure per week).\n\nWithin them, patients with new onset epilepsy during pregnancy were recruited into our final analysis. The inclusion criteria were as follows:\n\n1. women with first seizure during pregnancy;\n\n2. women with spontaneous recurrent seizures after delivery.[7]\n\nThe exclusion criteria were as follows:\n\n1. women with first seizure before pregnancy;\n\n2. women with first seizure after delivery;\n\n3. women with evidence of eclampsia;\n\n4. women with other severe neurological, psychiatric or systemic diseases.\n\nThe study was approved by the ethics committee of West China Hospital, Sichuan University and we confirmed that all methods were performed in accordance with the relevant guidelines and regulations. Informed consents were obtained from all participants.\n\n2.2 Statistical analysis\nStatistical analysis was performed using SPSS (version 20.0, SPSS Inc., Chicago, IL). Descriptive analysis was applied to deal with the demographics, clinical features and pregnancy outcomes, showing as percentages, means, and standard deviations (SD). Table 1\n\nTable 1 Sociodemographic and clinical characteristics of patients with new onset epilepsy during pregnancy.\n\n3 Results\n3.1 Clinical features\nWe screened a total of 1041 consecutive women with epilepsy and reproductive history from June 2013 to June 2018. Twenty-two of them (2.3%) reached the standard of new onset epilepsy during pregnancy and were finally included into this study. The sociodemographic and clinical characteristics of these 22 patients were showed in Table 2. The average age at seizure onset was 22.7 ± 3.0 years (range: 19–28 years). All their first seizures occurred in the pregnancy period, including 4 (18.2%) in the first trimester, 10 (45.4%) in the second trimester and 8 (36.4%) in the third trimester. Most patients (13/22, 59.1%) suffered primary or secondary GTCS in pregnancy, while 7 (31.8%) suffered FS. Furthermore, 2 patients (9.1%) only suffered CSE in the third trimester. As for the seizure frequencies of other 20 patients without CSE, sporadic seizures were found in most patients (16/22, 71.7%), while frequent seizures and very frequent seizures were only found in 2 patients respectively.\n\nTable 2 Detailed clinical information of each patient with new onset epilepsy during pregnancy.\n\n3.2 Related examinations\nRoutine antenatal examinations were performed in almost all patients, including physical examination, laboratory tests and prenatal ultrasounds. There was no evidence of preeclampsia, including hypertension, proteinuria, thrombocytopenia or dysfunction of liver and kidney. Chromosome test was performed in 18 patients (81.8%) and obvious abnormality (trisomy 21 syndrome) was found in 1 fetus. Besides, congenital heart disease (tetralogy of Fallot) was also detected in the same fetus. The mother suffered her first seizure in first trimester and insisted to deliver the baby because of her religion for not killing.\n\n3.3 Treatment and outcome\nFolate (0.4 mg/day) was supplemented throughout the first trimester in 11 patients (50%). Fourteen patients were diagnosed with epilepsy during pregnancy and were advised to begin antiepileptic drug (AED) therapy, while only 8 of them took the AED (levetiracetam in 4, carbamazepine in 1, phenytoin in 1 and intravenous diazepam in 2 CSE) in pregnancy. The other 6 chose to start the AED after delivery because of worrying about the teratogenic effect of AED. Moreover, the other 8 patients were diagnosed with epilepsy and began AED therapy after delivery or abortion. All patients suffered similar unprovoked seizures after delivery (21/22, 95.5%) or abortion (1/22, 4.5%) because of bad response to initial AED or inappropriate AED withdrawal.\n\nMost patients (16/22, 72.7%) had easy deliveries and gave birth to healthy babies, while 6 of them (27.3%) faced abnormal situations. Three babies suffered fetal distress before delivery and had to get treatment in neonatology department, fortunately, without severe complications. Two of them happened in patients with CSE in third trimester. However, the other 3 were much worse. One patient had to choose induced abortion in first trimester because of the disappearance of fetal heart rate. One baby was diagnosed with mild harelip. And 1 was diagnosed with trisomy-21 syndrome, tetralogy of Fallot and congenital duodenal atresia. All the 3 serious complications happened in patients with first seizure in first trimester. Detailed clinical information of each patient was showed in Table 2.\n\n4 Discussion\nSeizures in pregnancy risk the health of both mothers and fetuses. Previous studies mostly focused on uncontrolled pre-existing epilepsy or provoked seizures during pregnancy, while rare focused on the new onset epilepsy.[4] New onset epilepsy during pregnancy was a challenging and long-term problem affecting patients before and after delivery. Thus, accurate diagnosis and appropriate treatment were of great importance. In this study, we reviewed the features and pregnancy outcomes of patients with new onset epilepsy during pregnancy, which was barely explored before.\n\nUp to now, little had been known about the accurate incidence of new onset epilepsy during pregnancy. This present study showed a relatively low risk of new onset epilepsy during pregnancy in our Pregnancy Register for epilepsy patients (22/1041, 2.1%). It was similar to the proportion of gestational onset focal epilepsy (FE) (4/116, 3.4%) reported by Yakunina et al.[9] However, in another study from Azerbaijan, the proportion was much higher (10.5%).[10] They prospectively recruited 105 pregnant women with epilepsy (WWE) and found 11 women with their first seizures during the current pregnancy. Different populations and inclusion criteria may be the reason. Besides, it was difficult to confirm whether the 11 patients got spontaneous recurrent seizures after delivery or it was just acute symptom of pregnancy-related condition, especially the eclampsia.\n\nIn our 22 patients, mean age at seizure onset was 22.7 ± 3.0 years (range: 19–28 years), which was in the favorable reproductive stage and indicated that age might not be the risk factor for new onset epilepsy during pregnancy. However, the pregnancy period of their first seizures was different, including 4 (18.2%) in the first trimester, 10 (45.4%) in the second trimester and 8 (36.4%) in the third trimester. It seemed that new onset epilepsy during pregnancy preferred to occur in the middle and late pregnancy (18/22, 81.8%), which might reduce the bad effect on fetus. It was proved by our finding that all 3 bad complications (induced abortion because of the disappearance of fetal heart rate; trisomy-21 syndrome, tetralogy of Fallot and congenital duodenal atresia; mild harelip) occurred in patients with their first seizure in first trimester. As the key development period of embryo or fetus, any abnormal conditions in first trimester would become vital risks, especially one or more seizures. By contrast, although 2 patients experienced CSE and 3 fetuses suffered fetal distress in third trimester, no obvious complications occurred in mothers or babies.\n\nAs for the seizure type in pregnancy, other studies about pre-existing epilepsy showed that generalized epilepsy was more common than focal epilepsy.[11,12] It was in keeping with our findings that most patients (59.1%) suffered primary or secondary GTCS in pregnancy. Furthermore, CSE was observed in 2 patients (2/22, 9.1%) in third trimester, which was more common than that of pre-existing epilepsy. It was reported that only 1% to 2% of women with pre-existing epilepsy may experience CSE in pregnancy.[11] Although CSE during pregnancy was associated with high morbidity and mortality, timely and appropriate treatment could lead to a satisfying result. Besides, most patients (16/22, 71.7%) only suffered sporadic seizures (less than 1 seizure per month) during pregnancy. The new onset seizures in pregnancy seemed to be either mild or serious.\n\nIn addition to new onset seizures, AED was another problem that patients with new onset epilepsy during pregnancy had to face. To avoid the maternal and fetal risk associated with seizures, AED therapy was often maintained during pregnancy, despite increasing the risk of congenital malformation and adverse cognitive development in babies.[13] In this study, only 8 patients started their AED therapies during pregnancy (1 from the first trimester, 4 from the second trimester, 3 from the third trimester). Levetiracetam (LEV) was the most favorable drug, prescribed to 4 patients (50%). Only 1 patient with LEV (1 g/d) and sporadic focal seizure from first trimester delivered a baby with major congenital malformation (trisomy-21 syndrome, tetralogy of Fallot and congenital duodenal atresia).\n\nStructural and metabolic changes were regarded to precipitate new onset seizures during pregnancy.[5,6,10] Most provoked seizures, however, could not be diagnosed as epilepsy, except spontaneous recurrent seizures occurred. In this study, 3 positive neuroimaging findings were detected from brain MRI images (3/22, 13.6%), including hippocampus sclerosis (HS) in 1 patient and possible focal cortical dysplasia (FCD) in 2 patients. This was different from usual gestational cerebral complications, such as cerebral venous sinus thrombosis, intracranial hemorrhage and ischemic stroke. Furthermore, eclampsia, the most common disease needed to be distinguished in pregnancy, was defined as the onset of generalized seizures that could not be attributed to other causes in pregnant women with pre-eclampsia.[14] And pre-eclampsia was traditionally diagnosed by the de-novo hypertension combined with proteinuria, while in the new definition, with other maternal organ dysfunctions, such as renal insufficiency, liver involvement, neurological or haematological complications, uteroplacental dysfunction, or fetal growth restriction.[15,16] These signs were regularly examined in pregnancy and were used to exclude patients with eclampsia in our study. Moreover, there was barely evidence that patients with eclampsia could develop into chronic epilepsy after delivery.\n\n5 Limitations\nThe current study had several limitations that needed to be addressed. First, since the incidence of new onset epilepsy during pregnancy was relatively low, the sample size was small, which may limit the power of our findings for clinical applications. Second, some information during pregnancy were retrospectively collected in some cases, which may contain some recall bias. We attempted to minimize the bias by verifying the information through examining corresponding medical records as much as possible. Third, our pregnancy register was conducted in one province, thus some selection bias seemed to be inevitable. However, our patients were selected from 3 general hospitals, which increased the representativeness of our population. More prospective, population-based and nationwide data are needed in the future studies.\n\n6 Conclusion\nAlthough the risk of new onset epilepsy during pregnancy was relatively low, accurate diagnosis and appropriate treatment were required to reduce the damage to both mothers and fetuses. New onset epilepsy during pregnancy mostly began in middle and late pregnancy. However, seizures occurred from early pregnancy had bad effects on the embryo or fetus. Furthermore, the risk of convulsive status epilepticus seemed high in patients with new onset epilepsy during pregnancy.\n\nAcknowledgments\nWe are grateful to all the subjects who participated in this study.\n\nAuthor contributions\nConceptualization: Dong Zhou.\n\nData curation: Wei Li, Nanya Hao, Yingfeng Xiao, Dong Zhou.\n\nFormal analysis: Wei Li, Nanya Hao, Yingfeng Xiao, Dong Zhou.\n\nFunding acquisition: Dong Zhou.\n\nInvestigation: Wei Li, Nanya Hao, Yingfeng Xiao, Dong Zhou.\n\nMethodology: Wei Li, Nanya Hao, Yingfeng Xiao, Dong Zhou.\n\nProject administration: Dong Zhou.\n\nResources: Dong Zhou.\n\nSoftware: Wei Li, Nanya Hao, Dong Zhou.\n\nSupervision: Dong Zhou.\n\nValidation: Wei Li, Nanya Hao, Dong Zhou.\n\nVisualization: Wei Li, Nanya Hao, Yingfeng Xiao, Dong Zhou.\n\nWriting – original draft: Wei Li, Nanya Hao.\n\nWriting – review & editing: Wei Li, Nanya Hao, Dong Zhou.\n\nDong Zhou orcid: 0000-0001-7101-4125.\n\nAbbreviations: ILAE = International League Against Epilepsy; SD = standard deviations; GTCS = generalized tonic-clonic seizures; sGTCS = secondary generalized tonic-clonic seizures; FS = focal seizures; CSE = convulsive status epilepticus; AED = antiepileptic drug; WWE = women with epilepsy; LEV = Levetiracetam; PHT = phenytoin; CBZ = carbamazepine; HS = hippocampus sclerosis; FCD = focal cortical dysplasia.\n\nWL and NH contributed to this work equally.\n\nThis study was supported by National Natural Science Foundation of China (NSFC, Grant No.81401076). The authors have no conflicts of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.\n==== Refs\nReferences\n[1] Viale L Allotey J Cheong-See F \nEpilepsy in pregnancy and reproductive outcomes: a systematic review and meta-analysis . Lancet \n2015 ;386 :1845–52 .26318519 \n[2] Shuster EA \nSeizures in pregnancy . Emerg Med Clin North Am \n1994 ;12 :1013–25 .7956885 \n[3] Yerby MS \nPregnancy, teratogenesis, and epilepsy . Neurol Clin \n1994 ;12 :749–71 .7845341 \n[4] Aya AG Ondze B Ripart J \nSeizures in the peripartum period: Epidemiology, diagnosis and management . Anaesth Crit Care Pain Med \n2016 ;35 :S13–21 .27393078 \n[5] Robert LB Peter WK \nSeizures in pregnancy: diagnosis and management . Int Rev Neurobiol \n2008 ;83 :259–71 .18929087 \n[6] Van Loenena NTVM Hintzenb RQ de Groota CJM \nNew onset seizures in pregnancy caused by an unexpected neurologic disorder . Eur J Obstet Gynecol Reprod Biol \n2004 ;117 :109–11 .15474255 \n[7] Thomas SV \nManagement of epilepsy and pregnancy . J Postgrad Med \n2006 ;52 :57–64 .16534170 \n[8] Berg AT Berkovic SF Brodie MJ \nRevised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009 . Epilepsia \n2010 ;51 :676–85 .20196795 \n[9] Yakunina AV Poverennova IE Veldiaksova ED \nThe peculiarities of the focal epilepsy during pregnancy and after childbirth . Sib Med Rev \n2017 ;1 :63–9 .\n[10] Shahla M Hijran B Sharif M \nThe course of epilepsy and seizure control in pregnant women . Acta Neurol Belg \n2018 ;118 :459–64 .29981006 \n[11] EURAP Study Group . Seizure control and treatment in pregnancy: observations from the EURAP epilepsy pregnancy registry . Neurology \n2006 ;66 :354–60 .16382034 \n[12] Thomas SV Syam U Devy JS \nPredictors of seizures during pregnancy in women with epilepsy . Epilepsia \n2012 ;53 :85–8 .\n[13] Razaz N Tomson T Wikström AK \nAssociation between pregnancy and perinatal outcomes among women with epilepsy . JAMA Neurol \n2017 ;74 :983–891 .28672292 \n[14] ACOG. Diagnosis and management of preeclampsia and eclampsia. ACOG practical bulletin. Clinical management guidelines for obstetrician-gynecologists. 2002. Obstet Gynecol. 2002:99:159-166 .\n[15] Ananth CV Keyes KM Wapner RJ \nPre-eclampsia rates in the United States, 1980-2010: age-period-cohort analysis . BMJ \n2013 ;347 :f6564.24201165 \n[16] Mol BWJ Roberts CT Thangaratinam S \nPre-eclampsia . Lancet \n2016 ;387 :999–1011 .26342729\n\n",
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"abstract": "BACKGROUND\nThe anaplastic lymphoma kinase (ALK) gene fusion rearrangement is a potent oncogene, accounting for 2-7% of lung adenocarcinomas, with higher incidence (17-20%) in non-smokers. ALK-positive tumors are sensitive to ALK tyrosine kinase inhibitors (TKIs), thus ALK-positive non-small-cell lung cancer (NSCLC) is currently spearheading precision medicine in thoracic oncology, with three generations of approved ALK inhibitors in clinical practice. However, these treatments are eventually met with resistance. At the molecular level, ALK-positive NSCLC is of the lowest tumor mutational burden, which possibly accounts for the high initial response to TKIs. Nevertheless, TP53 co-mutations are relatively frequent and are associated with adverse outcome of crizotinib treatment, whereas utility of next-generation ALK inhibitors in TP53-mutant tumors is still unknown.\n\n\nMETHODS\nWe report the case of an ALK-positive, TP53-mutant NSCLC patient with about five years survival on ALK TKIs with continued next-generation regimens upon progression.\n\n\nRESULTS\nThe tumor showed progression on crizotinib, but long tumor control was achieved following the incremental administration of next-generation ALK inhibitors, despite lack of evident resistance mechanisms.\n\n\nCONCLUSIONS\nTP53 status should be taken into consideration when selecting ALK-inhibitor treatment for personalized therapies. In TP53-mutant tumors, switching TKI generations may overcome treatment exhaustion even in the absence of ALK-dependent resistance mechanisms.",
"affiliations": "Department of Pulmonology, Mátraháza University and Teaching Hospital, 3233 Mátraháza, Hungary.;Oncompass Medicine Hungary Ltd., 1024 Budapest, Hungary.;Oncompass Medicine Hungary Ltd., 1024 Budapest, Hungary.;Department of Internal Medicine and Lymphomatherapy V., BAZ County Central and Teaching Hospital, 3526 Miskolc, Hungary.;Department of Pulmonology, Mátraháza University and Teaching Hospital, 3233 Mátraháza, Hungary.;Department of Internal Medicine and Lymphomatherapy V., BAZ County Central and Teaching Hospital, 3526 Miskolc, Hungary.;Oncompass Medicine Hungary Ltd., 1024 Budapest, Hungary.;Oncompass Medicine Hungary Ltd., 1024 Budapest, Hungary.;Oncompass Medicine Hungary Ltd., 1024 Budapest, Hungary.;Oncompass Medicine Hungary Ltd., 1024 Budapest, Hungary.;National Hematology and Infectology Institute, Centrum Hospital of Southern Pest, 1097 Budapest, Hungary.;Oncompass Medicine Hungary Ltd., 1024 Budapest, Hungary.",
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"fulltext": "\n==== Front\nJ Pers Med\nJ Pers Med\njpm\nJournal of Personalized Medicine\n2075-4426 MDPI \n\n32872120\n10.3390/jpm10030107\njpm-10-00107\nCase Report\nEfficacy of Incremental Next-Generation ALK Inhibitor Treatment in Oncogene-Addicted, ALK-Positive, TP53-Mutant NSCLC\nUrbán László 1* Dóczi Róbert 2 Vodicska Barbara 2 Kormos Dóra 3 Tóth László 1 Takács István 34 Várkondi Edit 2 Tihanyi Dóra 2 Lakatos Dóra 2 Dirner Anna 2 Vályi-Nagy István 5 Peták István 267* 1 Department of Pulmonology, Mátraháza University and Teaching Hospital, 3233 Mátraháza, Hungary; tothrad@gmail.com\n2 Oncompass Medicine Hungary Ltd., 1024 Budapest, Hungary; robert.doczi@oncompassmedicine.com (R.D.); barbara.vodicska@oncompassmedicine.com (B.V.); edit.varkondi@oncompassmedicine.com (E.V.); dora.tihanyi@oncompassmedicine.com (D.T.); dora.lakatos@oncompassmedicine.com (D.L.); anna.dirner@oncompassmedicine.com (A.D.)\n3 Department of Internal Medicine and Lymphomatherapy V., BAZ County Central and Teaching Hospital, 3526 Miskolc, Hungary; kormosdora92129@gmail.com (D.K.); stevenweavermd@gmail.com (I.T.)\n4 Faculty of Healthcare, University of Miskolc, 3515 Miskolc, Hungary\n5 National Hematology and Infectology Institute, Centrum Hospital of Southern Pest, 1097 Budapest, Hungary; drvnistvan@gmail.com\n6 Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1089 Budapest, Hungary\n7 Department of Pharmaceutical Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA\n* Correspondence: drurban.laszlo@magy.eu (L.U.); istvan.petak@oncompassmedicine.com (I.P.)\n28 8 2020 \n9 2020 \n10 3 10717 7 2020 22 8 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/).Background: The anaplastic lymphoma kinase (ALK) gene fusion rearrangement is a potent oncogene, accounting for 2–7% of lung adenocarcinomas, with higher incidence (17–20%) in non-smokers. ALK-positive tumors are sensitive to ALK tyrosine kinase inhibitors (TKIs), thus ALK-positive non-small-cell lung cancer (NSCLC) is currently spearheading precision medicine in thoracic oncology, with three generations of approved ALK inhibitors in clinical practice. However, these treatments are eventually met with resistance. At the molecular level, ALK-positive NSCLC is of the lowest tumor mutational burden, which possibly accounts for the high initial response to TKIs. Nevertheless, TP53 co-mutations are relatively frequent and are associated with adverse outcome of crizotinib treatment, whereas utility of next-generation ALK inhibitors in TP53-mutant tumors is still unknown. Methods: We report the case of an ALK-positive, TP53-mutant NSCLC patient with about five years survival on ALK TKIs with continued next-generation regimens upon progression. Results: The tumor showed progression on crizotinib, but long tumor control was achieved following the incremental administration of next-generation ALK inhibitors, despite lack of evident resistance mechanisms. Conclusion: TP53 status should be taken into consideration when selecting ALK-inhibitor treatment for personalized therapies. In TP53-mutant tumors, switching TKI generations may overcome treatment exhaustion even in the absence of ALK-dependent resistance mechanisms.\n\nNSCLCALK rearrangementTP53 mutationTKIpersonalized treatment\n==== Body\n1. Introduction\nFusion rearrangements of the anaplastic lymphoma kinase (ALK) gene lead to dimerization and constitutive activation of the encoded tyrosine kinase and thus the downstream transforming signaling pathways [1]. ALK fusions account for approximately 2–7% of patients with lung adenocarcinoma, with this frequency being higher, 17–20% within non-smoker patients [2]. ALK-positive non-small-cell lung cancer (NSCLC) is currently spearheading the advent of precision medicine in thoracic oncology. At the molecular level, this is attributable to the lowest tumor mutational burden, with few co-occuring mutations, and to the lowest frequency of TP53 (encoding cellular tumor antigen p53) mutations (20–25%) among NSCLCs [3].\n\nALK-positive tumors are sensitive to small-molecule ALK tyrosine kinase inhibitors (TKIs). The FDA approved the first-generation inhibitor crizotinib as a monotherapy for the treatment of ALK-positive metastatic NSCLC patients based on the results of two clinical trials. As first-line therapy, crizotinib was shown to be superior to standard chemotherapy (pemetrexed and platinum) in 343 advanced ALK-positive NSCLC patients, in an open-label, phase 3 trial (NCT01154140). The objective response rate (ORR) was 74% versus 45% in the crizotinib and the chemotherapy-receiving groups, respectively. Statistically significant improvement was obtained in the median progression-free survival (PFS) in response to crizotinib compared with chemotherapy (10.9 versus 7.0 months; hazard ratio (HR): 0.45; 95% confidence interval (CI): 0.35–0.60; p < 0.001) [4]. The median overall survival (OS) was not reached (NR) in the crizotinib arm (95% CI: 45.8 months to NR) and was 47.5 months in the chemotherapy arm (95% CI: 32.2 months to NR) [5].\n\nSecond-generation ALK inhibitors, ceritinib, alectinib, and brigatinib, proved to be active in patients with tumor progression on crizotinib [6]. Ceritinib was also approved by the FDA for the treatment of ALK-positive metastatic NSCLC patients based on the outcomes of two clinical trials. In the ASCEND-4 randomized, open-label, phase 3 study (NCT01828099), the efficacy of ceritinib versus platinum-based chemotherapy (cisplatin or carboplatin and pemetrexed) was evaluated in advanced ALK-positive NSCLC patients (n = 376). The overall response rate was 73% (95% CI: 66–79%) versus 27% (95% CI: 21-34%), the median PFS was 16.6 months (95% CI: 12.6–27.2) versus 8.1 months (95% CI: 5.8-11.1) (HR: 0.55; 95% CI: 0.42–0.73; p < 0.00001) in the ceritinib group compared with the chemotherapy-receiving group, respectively. The median OS was not reached in the ceritinib group (95% CI: 29.3 months to NR) and was 26.2 months (95% CI: 22.8 months to NR) in the chemotherapy group (HR: 0.73; 95% CI: 0.50–1.08; p = 0.056) [7].\n\nIn the ASCEND-1 open-label, phase 1 trial (NCT01283516), the efficacy of ceritinib was tested among ALK-positive NSCLC patients, both in the ALK-inhibitor naive (n = 83) and crizotinib-pretreated (n = 163) setting. The overall response rate was obtained as 72.3% (95% CI: 61.4–81.6%) and 56.4% (95% CI: 48.5–64.2%), median PFS was 18.4 months (95% CI: 11.1 months to NR) and 6.9 months (95% CI: 5.6–8.7 months), and median OS was not reached (95% CI: 19.6 months to NR) and 16.7 months (95% CI: 14.8 months to NR) in the ALK-inhibitor naive and pretreated groups, respectively [8].\n\nLorlatinib is a third-generation, reversible, ATP-competitive inhibitor of ALK and ROS1 (Proto-oncogene tyrosine-protein kinase ROS), which can also penetrate the blood–brain barrier and overcome known ALK resistance mutations [9]. The FDA approved lorlatinib for ALK-positive metastatic NSCLC patients whose disease progressed on at least one previous ALK-inhibitor therapy, based on a non-randomized, dose-ranging phase 2 study (NCT01970865). Of the 276 enrolled patients, 229 were ALK-positive, among them 30 were treatment-naive (EXP1), 59 patients received crizotinib without (n = 27; EXP2) or with chemotherapy (n = 32; EXP3A), 28 received one previous non-crizotinib ALK inhibitor, with or without chemotherapy (EXP3B), 66 received two (EXP4) and 46 received three (EXP5) previous ALK inhibitors with or without chemotherapy. In treatment-naive patients (EXP1) the ORR was 90% (95% CI: 73.5–97.9%), in patients with at least one previous ALK-inhibitor therapy (EXP2-5) the ORR was obtained as 47.0% (95% CI: 39.9–54.2%). In the EXP2-3A, EXP3B, and EXP4-5 subgroups, ORR values were 69.5% (95% CI: 56.1–80.8%), 32.1% (95% CI: 15.9–52.4%) and 38.7% (95% CI: 29.6–48.5%), respectively. In treatment-naive patients (EXP1) and ALK-inhibitor pretreated patients (EXP2-5) the median PFS values were obtained as NR (95% CI: 11.4 months to NR) and 7.3 months (95% CI: 5.6–11.0 months), respectively. In the EXP2-3A, EXP3B, and EXP4-5 subgroups, median PFS was NR (95% CI: 12.5 months-NR), 5.5 months (95% CI: 2.7–9.0 months), and 6.9 months (95% CI: 5.4–9.5 months), respectively. OS results were not published [10].\n\nDespite sensitivity to ALK TKIs, relapse or tumor progression is systematically noted, as tumor evolution invariably leads to acquired resistance to ALK TKIs [1,6,11]. Resistance mechanisms are driven by two distinct underlying processes—ALK-dependent mechanisms, such as secondary resistance mutations or amplification of ALK; and ALK-independent mechanisms, leading to activation of signaling pathways so tumor cells are enabled to escape ALK dependency [1]. It is generally viewed that secondary ALK mutations indicate continued ALK dependency and sensitivity to ALK TKIs with activity against the resistance mutation, whereas in the absence of resistance mutations, ALK-independent mechanisms give rise to resistance and thus combinatorial treatments or standard therapy approaches should be considered.\n\nDespite the relatively low mutational burden of ALK-positive tumors, TP53 co-mutations occur relatively frequently and they have been recently identified as main molecular determinants of adverse outcome, representing a negative prognostic factor for PFS and OS [12,13]. These studies focused on crizotinib and thus the utility of next-generation ALK inhibitors in TP53-mutant ALK-positive tumors is still to be addressed. Moreover, it is long established that TP53 mutations can affect chemotherapy treatments [14,15] and they are negative prognostic factors for chemotherapy in ALK-rearranged NSCLC [16].\n\nHere we present an interesting case of a TP53-mutant, ALK-positive NSCLC patient, who was resistant to crizotinib, but responded to next-generation ALK inhibitors in the absence of ALK-dependent resistance mechanisms (Figure 1a).\n\n2. Case Report\nIn December 2014, a 50-year-old male never-smoker showed up at a medical examination with increasing cough over the last five months. The cough had recently become productive, and the sputum was occasionally red. Chest CT scan, bronchoscopy and positron emission tomography–computed tomography (PET-CT) confirmed stage III lung adenocarcinoma in the left lower lobe with mediastinal and hilar lymph node involvement on both sides (T3N3M0, stage III/B) (Figure 1c). Below the affected region he developed atelectasis. In January 2015, the patient underwent mediastinoscopy. Pathology test results showed that the lymph node metastasis was negative for EGFR (Epidermal growth factor receptor) and KRAS (GTPase KRas (Kirsten rat sarcoma)) mutations and ALK rearrangement.\n\nIn February, treatment with cisplatin and docetaxel (75 mg/m2 each) was commenced, but due to an allergic reaction to taxol, they were switched to cisplatin (75 mg/m2) + gemcitabine (1200 mg/m2)/pemetrexed (500 mg/m2). In March 2015, sampling of the primary tumor was successful with explorative thoracotomy and the tumor turned out to be inoperable. Histopathologic examination of formalin-fixed paraffin-embedded (FFPE) block section of the tissue revealed positivity for ALK in 56% of cells (63/113) using two channels of the ZytoLight SPEC ALK/EML4 TriCheck Probe specific for ALK (Figure 1b). The fusion partner has not been determined. Fluorescence in situ hybridization (FISH) was negative for HER2 (Receptor tyrosine-protein kinase erbB-2 (human epidermal growth factor receptor 2)), MET (Hepatocyte growth factor receptor), FGFR1 (Fibroblast growth factor receptor 1), and PIK3CA (Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform) amplification and ROS1 rearrangement. Next-generation sequencing of 50 genes (50-gene Cancer HotSpot Ampliseq panel, Thermo Fisher) detected two missense mutations: R273H (c.818G > A) in exon #7/10 of TP53, which hits the DNA-binding domain of p53, and Q472H (c.1416A > T) in exon #11/30 of KDR (encoding vascular endothelial growth factor receptor 2 (VEGFR-2)), which hits the immunoglobulin-like C2-type 5 domain within the extracellular region of VEGFR-2.\n\nIn the light of the findings, from May 2015, crizotinib (first generation ALK inhibitor) therapy was started (2 × 250 mg (MD 250 mg)). After five months on crizotinib, PET-CT demonstrated progression on the primary left lower lobe tumor and on the mediastino-hilar lymph nodes (Figure 1c). Novel metastatic mass was not detected. Due to progression, in November 2015, his treatment was changed to the second-generation ALK inhibitor ceritinib (450 mg/day) plus nivolumab (240 mg biweekly). Two months after the second administration of nivolumab, the patient was hospitalized with severe liver failure demonstrated by subicterus and elevated liver enzymes (alkaline phosphatase (AP) values over 3000 U/L) and a C-reactive protein (CRP) value of 175 mg/L. Endoscopic retrograde cholangiopancreatography (ERCP) revealed cholelithiasis and immune-related hepatitis. Nivolumab was held. Ceritinib therapy (450 mg/day) was continued and resulted in stable disease for over 2.5 years without metastatic lesions. In June 2018, PET-CT revealed morphometabolic progression of the mediastino-hilar lymph nodes (Figure 1c).\n\nTherefore, in July 2018, therapy was switched to the third-generation ALK inhibitor, lorlatinib (100 mg/day), which stabilized the disease (Figure 1c). ALK inhibitor resistance mutations (C1156Y, I1171N, L1196M, G1202R, or G1269A) were not detected by droplet digital PCR (ddPCR) on liquid biopsy. After showing no signs of progression or metastatic lesions for 17 months on lorlatinib, the patient arbitrarily discontinued medication without informing his physician. One month later, in January 2020, he was hospitalized with severe liver failure, which turned out to be the consequence of multiple liver metastases. The patient’s health condition and organ function could not be improved due to the advanced tumor stage and he succumbed to the disease one week after admission to the hospital.\n\n3. Discussion\nHere we report the case of an ALK-positive, TP53-mutant NSCLC patient with about five years survival on ALK-inhibitor TKIs with continued next-generation regimens upon progression.\n\nNon-small-cell lung cancer encompasses a wide spectrum of molecular subtypes by driver mutations. The EML4-ALK gene fusion is the consequence of a paracentric inversion of chromosome two, which was first reported in NSCLC in 2007 [17]. The never-smoker history of the patient is in line with ALK fusions being more prevalent in the non-smoker NSCLC subpopulation. Moreover, ALK positivity is a biomarker of poor prognosis in a population of non-smoker patients [18], further highlighting the importance of personalized treatment.\n\nThe development of three generations of ALK TKIs has substantially changed the landscape for the treatment of ALK-positive tumors [1,19], as the OS of patients with ALK-rearranged NSCLC is five years [20]. Yet, despite frequent long-lasting responses to ALK TKIs, resistance to these drugs almost inevitably occurs [1,20]. ALK TKI resistance may emerge either in an ALK-dependent fashion (i.e., secondary resistance mutations or amplification of ALK) or ALK independently (i.e., activating downstream mutations, such as KRAS or BRAF) whereby tumor cells escape ALK dependency [1]. During the course of the disease, progression developed at each line of systemic therapy, yet successive next-generation ALK TKIs demonstrated disease control at each consecutive line.\n\nThe rapid and dramatic progression of the disease immediately after the patient quit TKI treatment clearly indicates oncogene addiction, implying the absence of ALK-independent resistance mechanisms. The notion of oncogene addiction is further underscored by the failure of nivolumab combination therapy. Nevertheless, liquid biopsy tests were negative for the common secondary ALK mutations, suggesting that disease progression was probably not caused by resistance mutations either. Therefore, it is plausible that differential responses to different generations of ALK TKIs may be related to the underlying biology of the tumor.\n\nThe detected KDR-Q472H alteration is usually not considered as a targetable driver, its role in tumorigenesis is possibly through enhanced vascularization [21,22]. The tumor harbored a TP53-R273H mutation, which is a common pathogenic TP53 variant [23,24,25,26]. Based on preclinical experiments, TP53-R273H can cause resistance to cisplatin and doxorubicin [14,15], which prompted the immediate switch to targeted TKI therapy from the started first-line cisplatin+gemcitabine/pemetrexed treatment. It has been well established that the presence of TP53 mutations indicates higher risk in ALK-positive NSCLC [3,13,16]. Rapid progression on first-line crizotinib treatment is in line with published evidence demonstrating poor efficacy of this drug in TP53-mutant ALK-positive tumors [3,13,16], thus our results further confirm that TP53 status should be taken into consideration when selecting ALK-inhibitor treatment for personalized therapies. Moreover, the second-generation ALK inhibitor, ceritinib, achieved tumor response for well over two years, then, following progression, the third-generation ALK inhibitor, lorlatinib also achieved disease control for the duration of the treatment. It has been proposed that future studies are required to determine whether TP53 mutations present a similarly negative prognosis for next-generation ALK inhibitors as for crizotinib [16]. Our results thus also warrant future studies to analyze whether this observation can be conceptualized.\n\nIn conclusion, the presented case strongly underscores the importance of continuous personalized treatment decisions based on molecular diagnostics and monitoring results of ALK-positive NSCLC cases. In a TP53-mutant background, crizotinib has proved to be ineffective, whereas switching TKI generations may overcome treatment exhaustion even in the absence of evident ALK-dependent resistance mechanisms.\n\nAuthor Contributions\nConceptualization, L.U., R.D. and I.P.; Methodology, L.U., E.V. and I.P.; Validation, L.U., L.T. and I.P.; Formal Analysis, L.U., D.K., L.T. and I.T.; Investigation, L.U., D.K., L.T. and I.T.; Resources, L.U., E.V. and I.P.; Data Curation, R.D., B.V., D.T., D.L. and A.D.; Writing—Original Draft Preparation, R.D. and B.V.; Writing—Review and Editing, L.U., D.T., D.L., A.D. and I.P.; Visualization, L.U., L.T. and B.V.; Supervision, L.U., I.T., I.V.-N. and I.P.; Project Administration, L.U., R.D., I.T., I.V.-N. and I.P.; Funding Acquisition, I.V.N. and I.P. All authors have read and agreed to the published version of the manuscript.\n\nFunding\nThis work was supported by the Hungarian Innovation Agency (grant numbers NVKP_16-1-2016-0005 and 2019-1.1.1-PIACI-KFI-2019-00367).\n\nConflicts of Interest\nThe authors declare no conflict of interest.\n\nEthical Statement\nThe study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethics Committee of the National Institute of Pharmacy and Nutrition (approval ID: OGYÉI/50268/2017).\n\nFigure 1 Case representation. (a) Time course of the case presented. First line chemotherapy of cisplatin+docetaxel (CDDP + TXT), then cisplatin + gemcitabine/pemetrexed (CDDP + GEM/PEM) was changed to 1st generation anaplastic lymphoma kinase (ALK) inhibitor after molecular diagnostic results. Following fast progression on crizotinib, a 2nd generation ALK inhibitor, ceritinib was started in combination with nivolumab. Due to liver damage, nivolumab was stopped two months later. Ceritinib resulted in disease control for 2.5 years. Upon progression, with no ALK resistance mutations detected, a 3rd generation ALK inhibitor, lorlatinib, controlled disease progression for 1.5 years until the patient stopped taking medication, that ultimately led to a fast development of fatal liver metastases. L1-4—treatment lines. PD—progressive disease. SD—stable disease. Mets—metastases. (b) Representative image of ALK FISH analysis. Yellow arrows at split signals indicate ALK rearrangement. Nuclei are stained with DAPI (blue). Scale bar: 5 µm. (c) Representative PET-CT slices showing pulmonary tumor mass in different time points. Numbers in brackets indicate months on treatment. Yellow arrow indicates tumor mass.\n==== Refs\nReferences\n1. Carpenter E.L. Mossé Y.P. Targeting ALK in neuroblastoma-preclinical and clinical advancements Nat. Rev. Clin. Oncol. 2012 9 391 399 10.1038/nrclinonc.2012.72 22585002 \n2. 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"fulltext_license": "CC BY",
"issn_linking": "2075-4426",
"issue": "10(3)",
"journal": "Journal of personalized medicine",
"keywords": "ALK rearrangement; NSCLC; TKI; TP53 mutation; personalized treatment",
"medline_ta": "J Pers Med",
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"pmid": "32872120",
"pubdate": "2020-08-28",
"publication_types": "D002363:Case Reports",
"references": "26389762;31139322;25470694;21712447;30165392;30843662;17625570;17417627;30413378;27573756;24990411;19881536;24065105;26973324;24677579;28805682;30599201;30657349;22134072;9927204;22585002;29768118;28126333;29910648;11435891",
"title": "Efficacy of Incremental Next-Generation ALK Inhibitor Treatment in Oncogene-Addicted, ALK-Positive, TP53-Mutant NSCLC.",
"title_normalized": "efficacy of incremental next generation alk inhibitor treatment in oncogene addicted alk positive tp53 mutant nsclc"
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"abstract": "BACKGROUND\nSystemic adverse effects of intravenous antivascular endothelial growth factor (VEGF) therapy include: hypertension, proteinuria, renal failure, and thrombotic microangiopathy. Intravitreal therapy with these agents is generally believed to be safe.\n\n\nMETHODS\nWe report 2 cases of renal transplant recipients who developed significant allograft dysfunction after the initiation of intravitreal anti-VEGF therapy.\n\n\nRESULTS\nThe first case is a 67-year-old man with polycystic kidney disease and recipient of a zero-antigen mismatch kidney allograft which developed worsening proteinuria over the first year after transplantation. At 4 months, a biopsy showed only minimal fibrosis and atrophy. At 1 year, an allograft biopsy showed phospholipase A 2 receptor-negative membranous nephropathy. The second patient was a 52-year-old man with tuberous sclerosis who was a recipient of a living related kidney allograft with diminished but stable graft function 16 years from transplantation. After the initiation of intravitreal anti-VEGF therapy, there was an escalating degree of proteinuria. Renal biopsy revealed acute and chronic antibody-mediated rejection with glomerular thrombi and transplant glomerulopathy.\n\n\nCONCLUSIONS\nThese cases, although do not prove causality, point to the need for careful follow-up of renal transplant recipients undergoing intravitreal therapy with anti-VEGF agents. These locally administered agents may play a role in the development of proteinuria and modulate antibody-mediated phenomena. We recommend that in renal transplant recipients undergoing therapy with intravitreal anti-VEGF agents, proteinuria be checked monthly, and there should be a low threshold for performing a biopsy to evaluate for allograft injury.",
"affiliations": "1 Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN. 2 Department of Laboratory Medicine and Anatomic Pathology, Mayo Clinic, Rochester, MN. 3 The William J von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN.",
"authors": "Cheungpasitporn|Wisit|W|;Chebib|Fouad T|FT|;Cornell|Lynn D|LD|;Brodin|Michelle L|ML|;Nasr|Samih H|SH|;Schinstock|Carrie A|CA|;Stegall|Mark D|MD|;Amer|Hatem|H|",
"chemical_list": "D020533:Angiogenesis Inhibitors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D000069579:Ranibizumab",
"country": "United States",
"delete": false,
"doi": "10.1097/TP.0000000000000750",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1337",
"issue": "99(11)",
"journal": "Transplantation",
"keywords": null,
"medline_ta": "Transplantation",
"mesh_terms": "D000368:Aged; D064591:Allografts; D020533:Angiogenesis Inhibitors; D000068258:Bevacizumab; D001706:Biopsy; D005455:Fluorescent Antibody Technique; D005921:Glomerulonephritis; D006084:Graft Rejection; D006801:Humans; D058449:Intravitreal Injections; D007668:Kidney; D016030:Kidney Transplantation; D008268:Macular Degeneration; D008297:Male; D008854:Microscopy, Electron; D008875:Middle Aged; D011507:Proteinuria; D000069579:Ranibizumab; D012307:Risk Factors; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A",
"nlm_unique_id": "0132144",
"other_id": null,
"pages": "2382-6",
"pmc": null,
"pmid": "25905984",
"pubdate": "2015-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Intravitreal Antivascular Endothelial Growth Factor Therapy May Induce Proteinuria and Antibody Mediated Injury in Renal Allografts.",
"title_normalized": "intravitreal antivascular endothelial growth factor therapy may induce proteinuria and antibody mediated injury in renal allografts"
} | [
{
"companynumb": "US-REGENERON PHARMACEUTICALS, INC.-2014-19746",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RANIBIZUMAB"
},
"drugaddi... |
{
"abstract": "Objectives: To compare the efficacy of cyclosporin A (CsA) alone and CsA combined with recombined human thrombopoietin (rhTPO) in patients with non-severe aplastic anemia (NSAA) . Methods: Data from 83 patients with NSAA between August 2014 and February 2019 were collected retrospectively. The study population included 35 men and 48 women, with a median age of 45 years (14-85 years) . Among them, 57 had been treated with CsA + rhTPO, TPO was administered at 15 000 U QD for 7 days, once a month for 3 months, and the other 26 patients with compatible baseline characters were treated with CsA alone. All the enrolled patients had been treated with CsA for at least 6 months and were followed up for at least 1 year. The efficacy and outcome were compared between the two groups. Results: Total 23 men and 34 women, with a median age of 46 years (14-85 years) were treated with CsA + rhTPO. The median duration of CsA treatment was 17 (8-28) months, and the patients were followed up for a median of 27 (12-45) months. Total 12 men and 14 women, with a median age of 40 years (20-64) were treated with CsA alone. The median duration of CsA treatment was 19 months (9-30 months) , and the median follow-up duration was 29 months (16-66 months) . There was no significant difference in the baseline characteristics of the two groups (P>0.05) . There was no significant difference in the CR and OR rates of the two groups at 1, 3, 6, 12, and 24 months of treatment (P>0.05) . The change in the platelet level for the CsA + rhTPO treated group after 1 month[8 (-12-86) ×10(9)/L vs. 3 (16-57) ×10(9)/L, P=0.029) , 3 months[24 (-6-102) ×10(9)/L vs. 7 (-9-76) ×10(9)/L, P=0.006], and 6 months[33.5 (-4-123) ×10(9)/L vs. 12.5 (-14-109) ×10(9)/L, P=0.048] of treatment was higher than that in the CsA alone group, while no significant difference was found between the two groups at other time points. There was no significant difference in the change in the megakaryocyte level between the two groups[3 (0-4) vs. 2 (0-5) , z=-0.868, P=0.385] after 6 months of treatment. Apart from 10.5% (6/57) of the patients in the CsA + rhTPO treated group who reported soreness at the injection site, there was no other significant difference between the two groups in terms of adverse effects. During the follow-up period, there were two cases of increasing paroxysmal nocturnal hemoglobinuria clone to over 10%, one in the CsA + rhTPO treated group, the other in the CsA alone group; and there was one case of progression to SAA in the CsA + rhTPO treated group; while no case of death or thromboembolic event (TEE) , fibrosis or reticulin proliferation, progression to myelodysplastic syndrome (MDS) , or acute myeloid leukemia was observed in either group. There was one case of progression to SAA in the CsA + rhTPO treated group but none in the CsA alone group. Conclusion: Compared to CsA alone, CsA + rhTPO treatment can accelerate the recovery of the platelet level with acceptable adverse effects.",
"affiliations": "Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medicine Sciences, Beijing 100730, China.;Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medicine Sciences, Beijing 100730, China.;Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medicine Sciences, Beijing 100730, China.",
"authors": "Zhang|M L|ML|;Chen|W S|WS|;Han|B|B|",
"chemical_list": "D011994:Recombinant Proteins; D016572:Cyclosporine; D013926:Thrombopoietin",
"country": "China",
"delete": false,
"doi": "10.3760/cma.j.issn.0253-2727.2020.08.004",
"fulltext": "\n==== Front\nZhonghua Xue Ye Xue Za Zhi\nZhonghua Xue Ye Xue Za Zhi\nCJH\nChinese Journal of Hematology\n0253-2727 2707-9740 Editorial office of Chinese Journal of Hematology No. 288, Nanjing road, Heping district, Tianjin \n\n32942816\ncjh-41-08-637\n10.3760/cma.j.issn.0253-2727.2020.08.004\n论著\n重组人血小板生成素对非重型再生障碍性贫血免疫抑制治疗疗效的影响\nEvaluation of the efficacy of cyclosporin A combined with recombined human thrombopoietin for treating patients with non-severe aplastic anemia 张 梦露 Zhang Menglu 陈 婉淑 Chen Wanshu 韩 冰 Han Bing 中国医学科学院、北京协和医学院北京协和医院血液内科 100730Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medicine Sciences, Beijing 100730, China\n刘 爽 通信作者：韩冰(Han Bing), Email：hanbing_li@sina.com.cn\n8 2020 \n41 8 637 642\n8 3 2020 2020年版权归中华医学会所有Copyright © 2020 by Chinese Medical Association2020This work is licensed under a Creative Commons Attribution 3.0 License (CC-BY-NC). The Copyright own by Publisher. Without authorization, shall not reprint, except this publication article, shall not use this publication format design. Unless otherwise stated, all articles published in this journal do not represent the views of the Chinese Medical Association or the editorial board of this journal.目的\n比较环孢素A（CsA）联合重组人血小板生成素（rhTPO）和单用CsA治疗非重型再生障碍性贫血（NSAA）的疗效。\n\n方法\n回顾2014年8月至2019年2月83例初治NSAA患者临床资料，男35例，女48例，中位年龄45（14~85）岁。其中57例使用CsA+rhTPO治疗（TPO治疗组），TPO 15 000 U，皮下注射，每日1次，共7 d，28 d为1个疗程，最多治疗3个疗程；26例为同期基线相匹配的患者，仅单用CsA治疗（对照组）。入选患者CsA使用至少6个月，并随访至少1年。比较两组的疗效及转归。\n\n结果\nTPO治疗组患者男23例，女34例；中位年龄46（14~85）岁；CsA中位应用时间为17（8~28）个月；中位随访时间为27（12~45）个月。对照组26例，男12例，女14例；中位年龄40（20~64）岁；CsA中位应用时间为19（9~30）个月；中位随访时间为29（16~66）个月。两组基线水平差异均无统计学意义（P值均>0.05）。两组1、3、6、12和24个月的CR率及OR率差异均无统计学意义（P值均>0.05）。TPO治疗组1个月[8（−12~86）×109/L对3（16~57）×109/L，P=0.029]、3个月[24（−6~102）×109/L对7（−9~76）×109/L，P=0.006]和6个月[33.5（−4~123）×109/L对12.5（−14~109）×109/L，P=0.048]血小板升高水平均显著高于对照组，但12个月及24个月与对照组差异无统计学意义（P值均>0.05）。两组6个月时骨髓巨核细胞变化水平差异无统计学意义[3（0~4）个对2（0~5）个，z=−0.868，P=0.385]。TPO治疗组10.5%（6/57）出现注射部位疼痛，除此之外，两组不良反应无明显差异。随访期间，两组患者各有1例阵发性睡眠性血红蛋白尿（PNH）克隆>10%；TPO治疗组1例进展为SAA；均无死亡、无血栓事件发生，未见网状纤维及胶原纤维增生，未见骨髓增生异常综合征和急性髓系白血病转化。\n\n结论\nCsA联合TPO治疗相比CsA单药治疗可较快提升NSAA患者血小板水平，而不增加明显的不良反应。\n\nObjective\nTo compare the efficacy of cyclosporin A (CsA) alone and CsA combined with recombined human thrombopoietin (rhTPO) in patients with non-severe aplastic anemia (NSAA).\n\nMethods\nData from 83 patients with NSAA between August 2014 and February 2019 were collected retrospectively. The study population included 35 men and 48 women, with a median age of 45 years (14–85 years). Among them, 57 had been treated with CsA + rhTPO, TPO was administered at 15 000 U QD for 7 days, once a month for 3 months, and the other 26 patients with compatible baseline characters were treated with CsA alone. All the enrolled patients had been treated with CsA for at least 6 months and were followed up for at least 1 year. The efficacy and outcome were compared between the two groups.\n\nResults\nTotal 23 men and 34 women, with a median age of 46 years (14–85 years) were treated with CsA + rhTPO. The median duration of CsA treatment was 17 (8–28) months, and the patients were followed up for a median of 27 (12–45) months. Total 12 men and 14 women, with a median age of 40 years (20–64) were treated with CsA alone. The median duration of CsA treatment was 19 months (9–30 months), and the median follow-up duration was 29 months (16–66 months). There was no significant difference in the baseline characteristics of the two groups (P>0.05). There was no significant difference in the CR and OR rates of the two groups at 1, 3, 6, 12, and 24 months of treatment (P>0.05). The change in the platelet level for the CsA + rhTPO treated group after 1 month[8 (−12–86) ×109/L vs. 3 (16–57) ×109/L, P=0.029), 3 months[24 (−6–102) ×109/L vs. 7 (−9–76) ×109/L, P=0.006], and 6 months[33.5 (−4–123) ×109/L vs. 12.5 (−14–109) ×109/L, P=0.048] of treatment was higher than that in the CsA alone group, while no significant difference was found between the two groups at other time points. There was no significant difference in the change in the megakaryocyte level between the two groups[3 (0–4) vs. 2 (0–5), z=−0.868, P=0.385] after 6 months of treatment. Apart from 10.5% (6/57) of the patients in the CsA + rhTPO treated group who reported soreness at the injection site, there was no other significant difference between the two groups in terms of adverse effects. During the follow-up period, there were two cases of increasing paroxysmal nocturnal hemoglobinuria clone to over 10%, one in the CsA + rhTPO treated group, the other in the CsA alone group; and there was one case of progression to SAA in the CsA + rhTPO treated group; while no case of death or thromboembolic event (TEE), fibrosis or reticulin proliferation, progression to myelodysplastic syndrome (MDS), or acute myeloid leukemia was observed in either group. There was one case of progression to SAA in the CsA + rhTPO treated group but none in the CsA alone group.\n\nConclusion\nCompared to CsA alone, CsA + rhTPO treatment can accelerate the recovery of the platelet level with acceptable adverse effects.\n\n再生障碍性贫血血小板生成素环孢素A治疗结果不良反应Aplastic anemiaRecombined human thrombopoietinCyclosporin ATreatment outcomeAdverse effects基金项目：北京市自然科学基金（7192168）；中国医学科学院医学创新基金（2016-I2M-3-004）；中国医学科学院中央级公益性科研院所基本科研业务费专项（2019XK320047）Fund program: Natural Science Foundation of Beijing（7192168）; Chinese Academy of Medical Sciences（CAMS）Innovation fund for Medical Sciences（2016-I2M-3-004）; Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences（2019XK320047）\n==== Body\n获得性再生障碍性贫血（AA）是一种骨髓造血衰竭综合征[1]。按照血细胞减少的程度，AA分为重型（SAA）及非重型（NSAA）[2]。重组人血小板生成素（rhTPO）是肝脏分泌的特异性调节血小板生成的造血生长因子，通过与TPO受体（MPL）结合，诱导造血干细胞向巨核细胞分化，刺激巨核细胞增殖分化，促进血小板生成和释放[3]–[4]。文献报道，免疫抑制治疗（IST）联合rhTPO可以提高SAA近期有效率，减少血小板输注量，改善血小板数量，且不增加克隆演变和骨髓纤维化发生率[5]–[6]。但rhTPO在NSAA中的作用国内外尚无相关研究。本研究我们回顾性分析了单中心83例NSAA患者，比较环孢素A（CsA）联合rhTPO和单用CsA的疗效，旨在探索rhTPO对NSAA近期疗效及疾病转归的影响。\n\n病例与方法\n1．病例：回顾性分析2014年8月至2019年2月在北京协和医院就诊的有治疗指征的初治NSAA患者83例，其中57例接受了标准的CsA联合rhTPO治疗，设为TPO治疗组，26例仅接受了标准CsA治疗，为对照组。NSAA诊断参照《再生障碍性贫血诊断与治疗中国专家共识（2017年版）》标准[7]，分型满足Camitta标准[8]。所有患者均行染色体检查，外周血细胞流式细胞术CD55、CD59检查，40岁以下的患者诊断时常规进行彗星试验、丝裂霉素试验和端粒酶基因检测，以排除遗传性骨髓衰竭。纳入标准：①治疗前PLT<30×109/L；②治疗开始时无明确活动性感染和（或）大出血，无重要脏器严重功能异常；③治疗开始时阵发性睡眠性血红蛋白尿（PNH）克隆≤10%；④未进行造血干细胞移植及抗胸腺细胞球蛋白（ATG）治疗；⑤接受标准剂量CsA治疗，至少使用6个月，且治疗后随访时间超过12个月；⑥随访资料较为完整，且能提供至少每6个月1次的骨髓象、骨髓活检、染色体结果。\n\n2．治疗方案：所有患者均接受了标准剂量CsA治疗：3~5 mg·kg−1·d−1分两次口服起始，2周后检测血药浓度，调整剂量维持CsA全血谷浓度100~200 µg/L。当达到最佳血液学反应并血液学参数稳定至少3个月后开始缓慢减量，每3个月约减量1 mg·kg−1·d−1。CsA总疗程为2~3年。TPO治疗组在开始CsA治疗时开始予rhTPO（沈阳三生制药公司产品）15 000 U，皮下注射，每日1次，共7 d，28 d为1个疗程，治疗3个疗程。PLT升高超过50×109/L，停用rhTPO。对照组仅接受CsA治疗。\n\nHGB<60 g/L时予红细胞输注，PLT<10×109/L或者有明显出血倾向时予血小板输注治疗。未再使用其他造血生长因子及艾曲泊帕。\n\n3．疗效观察及随访：通过病历资料与电话进行随访，随访截至2020年2月18日，中位随访时间为27（12~66）个月。治疗后1、3、6、12、24个月复查患者血常规、生化指标及其他相关指标，统计药物治疗不良反应、输血及血小板依赖情况并记录疾病转归。\n\n疗效判定参照Camitta标准[8]略加修改：①完全血液学反应（CR）：脱离血制品输注，HGB正常，ANC>1.5×109/L，PLT>100×109/L，随访12个月以上未复发。②部分血液学反应（PR）：A.脱离既往输血依赖；B.至少一系血细胞恢复至正常或增长到基线的2倍；C.任何一系血细胞基线水平上升并维持3个月：HGB增长30 g/L以上（治疗前<60 g/L）、ANC增长0.5×109/L以上（治疗前<0.5×109/L）、PLT增长20×109/L以上（治疗前<20×109/L）。③无效（NR）：症状、血常规未达PR。总体血液学反应（OR）为CR+PR。\n\n4．统计学处理：使用SPSS 26.0软件进行统计学分析，分类变量的组间比较采用卡方检验或Fisher精确概率法；连续变量以中位数（范围）描述，组间比较采用2个独立样本的非参数秩和检验（Mann-Whitney U检验）。P<0.05为差异有统计学意义。\n\n结果\n1．患者基本特征：83例NSAA患者中，男35例，女48例，中位年龄45（14~85）岁。CsA中位应用时间为18（8~30）个月。其中TPO治疗组57例，男23例，女34例，中位年龄46（14~85）岁。6例患者rhTPO治疗1个疗程停药，原因分别为CR（2例）、PLT>50×109/L（4例）；另10例患者治疗2个疗程停药，原因分别为CR（3例）、PLT>50×109/L（7例）；其余41例患者TPO治疗3个疗程。CsA中位应用时间为17（8~28）个月，中位随访27（12~45）个月。对照组26例，男12例，女14例，中位年龄40（20~64）岁。CsA中位应用时间为19（9~30）个月，中位随访29（16~66）个月。两组患者治疗前各临床特征比较见表1，TPO治疗组PLT略低于对照组，接近有统计学差异[17（5~30）×109/L对22（6~30）×109/L，P=0.056]，其他临床资料差异无均统计学意义。\n\n表1 非重型再生障碍性贫血患者TPO治疗组与对照组临床特征比较\n临床特征\tTPO治疗组（57例）\t对照组（26例）\tP值\t\n中位年龄（岁）\t46（14～85）\t40（20～64）\t0.068\t\n性别（例，男/女）\t23/34\t12/14\t0.620\t\n中位HGB（g/L）\t83（55～101）\t90（60～108）\t0.992\t\n中位PLT（×109/L）\t17（5～30）\t22（6～30）\t0.056\t\n中位ANC（×109/L）\t1.4（0.8～3.0）\t1.6（1.0～3.3）\t0.175\t\n中位WBC（×109/L）\t3.2（1.5～7.4）\t2.9（1.3～8.0）\t0.293\t\n中位Ret（×109/L）\t49.9（17.1～99.5）\t45.9（8.7～98.0）\t0.176\t\n中位CsA剂量（mg/kg）\t3.5（3.1～4.6）\t3.8（3.4～4.5）\t0.583\t\n红细胞输注依赖[例（%）]\t8（14.0）\t2（7.7）\t0.494\t\n血小板输注依赖[例（%）]\t9（15.8）\t4（15.4）\t1.000\t\nPNH克隆>5%[例（%）]\t2（3.5）\t1（3.8）\t1.000\t\n骨髓增生程度[例（%）]\t\t\t\t\n Ⅲ级\t11（19.3）\t4（15.3）\t0.767\t\n Ⅳ级\t32（56.1）\t17（65.4）\t0.427\t\n Ⅴ级\t11（19.3）\t8（30.8）\t0.249\t\nCD4+/CD8+比值[M（范围）]\t1.39（0.94～1.60）\t1.34（0.97～1.54）\t0.682\t\n注：TPO治疗组：环孢素A（CsA）联合重组人血小板生成素；对照组：单用CsA治疗；Ret：网织红细胞绝对计数；PNH：阵发性睡眠性血红蛋白尿\n\n2．血液学疗效比较（表2）：治疗1、3、6、12及24个月，TPO治疗组与对照组CR率、OR率差异均无统计学意义。提示两组各时间点疗效未有明显差异。\n\n表2 非重型再生障碍性贫血患者TPO治疗组与对照组各时间点疗效比较[例（%）]\n组别\t1个月\t3个月\t6个月\t12个月\t24个月\t\nCR\tOR\tCR\tOR\tCR\tOR\tCR\tOR\tCR\tOR\t\nTPO治疗组\t2（3.6）\t11（20.0）\t5（8.9）\t28（50.0）\t9（15.8）\t37（64.9）\t13（28.3）\t31（67.4）\t16（35.6）\t34（75.6）\t\n对照组\t0（0.0）\t3（12.5）\t0（0.0）\t9（34.6）\t3（11.5）\t13（50.0）\t5（20.0）\t16（64.0）\t6（30.0）\t14（70.0）\t\n\t\nP值\t1.000\t0.533\t0.173\t0.193\t0.745\t0.198\t0.445\t0.773\t0.662\t0.638\t\n注：TPO治疗组：环孢素A（CsA）联合重组人血小板生成素；对照组：单用CsA治疗；CR：完全血液学反应；PR：部分血液学反应；OR：总体血液学反应\n\n3．血小板恢复情况及骨髓巨核细胞恢复情况：TPO治疗组患者治疗1、3及6个月PLT较基线升高水平的中位数均高于对照组，差异有统计学意义（表3）。TPO治疗组患者治疗6个月巨核细胞数量较基线升高水平与对照组相比，差异无统计学意义[3（0~4）个对2（0~5）个，z=−0.868，P=0.385]。\n\n表3 非重型再生障碍性贫血患者TPO治疗组与对照组各时间点PLT较基线升高水平比较[×109/L，M（范围）]\n组别\t1个月\t3个月\t6个月\t12个月\t24个月\t\nTPO治疗组\t8（−12～86）\t24（−6～102）\t33.5（−4～123）\t41（−7～212）\t32.5（−29～207）\t\n对照组\t3（16～57）\t7（−9～76）\t12.5（−14～109）\t20（−7～152）\t27（−9～129）\t\n\t\nz值\t−2.180\t−2.722\t−1.978\t−1.475\t−0.828\t\nP值\t0.029\t0.006\t0.048\t0.140\t0.407\t\n注：TPO治疗组：环孢素A（CsA）联合重组人血小板生成素；对照组：单用CsA治疗\n\n4．不良反应与疾病转归：TPO治疗组主要不良反应：胆红素轻度升高7例（12.3%）、肌酐升高6例（10.5%）、胃肠道反应6例（10.5%）、注射部位的疼痛6例（10.5%）、齿龈轻中度增生5例（8.8%）、转氨酶升高5例（8.8%）。对照组主要不良反应：齿龈轻中度增生3例（11.5%）、胆红素轻度升高3例（11.5%）、胃肠道反应3例（11.5%）、转氨酶升高2例（7.7%）、肌酐升高2例（7.7%）。两组不良反应差异均无统计学意义（P值均>0.05）。所有不良反应经减量或对症治疗好转。随访期间，两组患者均无死亡，无血栓事件发生，未见网状纤维及胶原纤维增生，未见骨髓增生异常综合征（MDS）和急性髓系白血病（AML）转化；但各有1例PNH克隆>10%。1例TPO治疗组患者在治疗1个月后进展为SAA，且在随访期末仍为SAA；对照组无一例患者进展为SAA。\n\n讨论\nTPO是调节巨核细胞增殖成熟和血小板生成的内源性因子，通过与造血干细胞、巨核系祖细胞表面的特异性受体c-MPL结合，激活JAK/STAT信号传导途径而发挥生物作用[3]–[4]，被广泛用于各类血小板减少症的治疗[9]–[12]。近年来，国内学者采用rhTPO联合IST一线治疗SAA，亦获得较好疗效[5]–[6]。部分NSAA患者同样存在严重的血小板减少，甚至引起严重的出血而威胁生命。然而，在IST基础上联合rhTPO是否可以增加疗效、加快血小板水平的提升，尚未见相关报道。\n\n在本研究中，从血小板的计数变化可以看出，使用TPO组在治疗1、3、6个月后，较对照组血小板恢复更快。这一结果与既往关于SAA的结果[5]–[6]类似，即TPO联合IST可以在治疗早期快速提升患者PLT水平。由于治疗早期的出血是治疗失败、甚至是威胁患者生命的重要因素，这一研究结果表明，治疗早期在IST基础上联合使用TPO，对于减少出血事件、降低治疗失败的风险、提高患者治疗的信心等，是有积极意义的。由于本研究TPO使用时间小于3个月，且每月仅1周，疗效可能无法持续。随着治疗时间延长，CsA有效率也逐渐上升，到1年及随访期末，两组血小板水平变化无显著差异。\n\nTPO治疗AA的机制尚未得到深入的阐述。研究发现，rhTPO可以促进SAA患者移植后血小板的植入[13]–[14]。Liu等[15]进一步研究发现，TPO可以促进联合免疫缺陷小鼠的骨髓移植后造血干/祖细胞（HSPC）的归巢。在研究其他TPO受体激动剂如艾曲泊帕时发现，其在体外不仅可以扩增巨核细胞和血小板，还有刺激骨髓中造血干细胞和祖细胞的作用；同时，还发现其有免疫调节作用[16]。尽管结合位点不尽相同，TPO也可能有类似的作用机制，有待于进一步的研究。\n\n虽然TPO的使用加快了血小板恢复的速度，但本组研究结果显示，在3、6、12及24个月时，TPO治疗组与对照组相比，无论是CR还是OR率差异均无统计学意义。这与既往的报道并不完全一致。由于MPL存在于各种造血细胞表面，包括造血干细胞和各系造血祖细胞，因此，TPO理论上也可以对ANC、HGB恢复起作用。文献报道，TPO可以促进SAA患者三系血细胞的恢复[6],[17]–[18]。张莉等[5]及Wang等[6]发现rhTPO联合IST组治疗SAA/极重型AA（VSAA），患者疗效明显提高，血小板输注依赖和血小板支持治疗输注比例均明显减少。他们的研究还表明，对于SAA患者，TPO不仅对血小板的上升有帮助，对部分患者红细胞和粒细胞的生成也有一定促进作用。Komatsu等[18]使用rhTPO对AA和MDS患者进行治疗时，发现其不仅增加血小板计数，在部分患者中也有多系血细胞反应的效果。其他TPO受体激动剂如艾曲泊帕、罗米司亭等在多项研究中被证实可以有效治疗难治SAA，提升初治SAA患者IST的疗效[19]–[22]，并可以提升各系血细胞的反应[23]。由于本组入组患者都是NSAA，疾病相对较轻，且我们使用TPO时间较短，我们并未比较其他两系的变化。本组研究在CR和OR率上与上述文献存在一定差异，原因可能为：国际上使用艾曲泊帕或罗米司亭治疗SAA时间都较长，且为持续给药，停药都需逐渐减量，Wang等[6]使用TPO中位时间也达7.8个月。而我们TPO使用时间相对较短，剂量也较小，可能影响了疗效；TPO和其他TPO受体激动剂可能存在一定的疗效差异；NSAA残存造血相对较多，IST基础上短期联合TPO可能难以显示统计学差异；两组在绝对值上有差异，但未达到统计学意义，可能受到例数的影响。未来通过前瞻性设计，扩大样本量，并探索合适的TPO剂量，可进一步明确联合使用TPO是否可以增加CsA治疗NSAA的疗效。\n\n同样的发现也见于骨髓的检查。治疗后6个月骨髓复查也并未发现TPO组和对照组巨核细胞数量变化的明显差别。Wang等[6]报道了在SAA患者中，与单用IST相比，联合使用TPO与IST在治疗3、6、9个月后，骨髓巨核细胞数的提升幅度明显更大。在一项艾曲泊帕治疗SAA的研究中，使用艾曲泊帕后并停用一段时间后，部分患者还可以保持骨髓细胞数的正常，提示骨髓造血的恢复[24]。这些差异同样可能与我们的患者多为NSAA，基础造血残存较多，且使用TPO的疗程较短有关。\n\n本研究中TPO治疗组患者个别出现注射部位疼痛的不良反应，经治疗都可好转。根据Ghanima等[25]的综述，TPO受体激动剂可能增加静脉血栓的风险，但其增加骨髓纤维化风险的观点并未得到证实，只有少部分患者发生网状蛋白纤维化、胶原蛋白纤维化，并且在停药后都能得到缓解。目前报道克隆演化的患者，在治疗初始时就存在高风险转化的可能。有研究者发现TPO可以增加AA向MDS转化，但艾曲泊帕未发现类似现象[6],[21],[25]。本组患者rhTPO治疗时间较短，随访时间相对较长，密切监测尚未发现克隆演变证据。\n\n综上，本研究结果显示对于初治NSAA患者，使用CsA联合rhTPO治疗，可以加速PLT回升，而未明显增加不良反应。\n==== Refs\nReferences\n1 Brodsky RA Jones RJ Aplastic anaemia[J] Lancet 2005 365 9471 1647 1656 10.1016/S0140-6736(05)66515-4 15885298 \n2 Peslak SA Olson T Babushok DV Diagnosis and Treatment of Aplastic Anemia[J] Curr Treat Options Oncol 2017 18 12 70 10.1007/s11864-017-0511-z 29143887 \n3 Kuter DJ The biology of thrombopoietin and thrombopoietin receptor agonists[J] Int J Hematol 2013 98 1 10 23 10.1007/s12185-013-1382-0 23821332 \n4 Jing FM Zhang XL Meng FL Anti-c-Mpl antibodies in immune thrombocytopenia suppress thrombopoiesis and decrease response to rhTPO[J] Thromb Res 2018 170 200 206 10.1016/j.thromres.2018.08.021 30199786 \n5 张 莉 杨 文睿 叶 蕾 重组人血小板生成素对重型再生障碍性贫血免疫抑制治疗近期疗效的影响[J] 中华血液学杂志 2015 36 3 181 185 10.3760/cma.j.issn.0253-2727.2015.03.002 \n6 Wang H Dong Q Fu R Recombinant human thrombopoietin treatment promotes hematopoiesis recovery in patients with severe aplastic anemia receiving immunosuppressive therapy[J] Biomed Res Int 2015 2015 597293 10.1155/2015/597293 25861635 \n7 中华医学会血液学分会红细胞疾病(贫血)学组 再生障碍性贫血诊断与治疗中国专家共识(2017年版)[J] 中华血液学杂志 2017 38 1 1 5 10.3760/cma.j.issn.0253-2727.2017.01.001 \n8 Camitta BM Storb R Thomas ED Aplastic anemia (second of two parts): pathogenesis, diagnosis, treatment, and prognosis[J] N Engl J Med 1982 306 12 712 718 10.1056/NEJM198203253061204 7038485 \n9 Kong Z Qin P Xiao S A novel recombinant human thrombopoietin therapy for the management of immune thrombocytopenia in pregnancy[J] Blood 2017 130 9 1097 1103 10.1182/blood-2017-01-761262 28630121 \n10 卢 园园 管 娜 孟 庆红 rhTPO联合大剂量地塞米松治疗儿童难治性免疫性血小板减少症的临床分析[J] 中国当代儿科杂志 2018 20 7 534 537 10.7499/j.issn.1008-8830.2018.07.004 \n11 Kashiwagi H Tomiyama Y Recent advances in pathophysiology and treatment of immune thrombocytopenia[J] Rinsho Ketsueki 2015 56 2 177 184 10.11406/rinketsu.56.177 25765798 \n12 Kuter DJ Managing thrombocytopenia associated with cancer chemotherapy[J] Oncology (Williston Park) 2015 29 4 282 294 25952492 \n13 Wang H Huang M Zhao Y Recombinant Human Thrombopoietin 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Scheinberg P Activity of eltrombopag in severe aplastic anemia[J] Blood Adv 2018 2 21 3054 3062 10.1182/bloodadvances.2018020248 30425070 \n23 Lengline E Drenou B Peterlin P Nationwide survey on the use of eltrombopag in patients with severe aplastic anemia: a report on behalf of the French Reference Center for Aplastic Anemia[J] Haematologica 2018 103 2 212 220 10.3324/haematol.2017.176339 29170252 \n24 Desmond R Townsley DM Dumitriu B Eltrombopag restores trilineage hematopoiesis in refractory severe aplastic anemia that can be sustained on discontinuation of drug[J] Blood 2014 123 12 1818 1825 10.1182/blood-2013-10-534743 24345753 \n25 Ghanima W Cooper N Rodeghiero F Thrombopoietin receptor agonists: ten years later[J] Haematologica 2019 104 6 1112 1123 10.3324/haematol.2018.212845 31073079\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0253-2727",
"issue": "41(8)",
"journal": "Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi",
"keywords": "Adverse effects; Aplastic anemia; Cyclosporin A; Recombined human thrombopoietin; Treatment outcome",
"medline_ta": "Zhonghua Xue Ye Xue Za Zhi",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000741:Anemia, Aplastic; D016572:Cyclosporine; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010976:Platelet Count; D011994:Recombinant Proteins; D012189:Retrospective Studies; D013926:Thrombopoietin; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "8212398",
"other_id": null,
"pages": "637-642",
"pmc": null,
"pmid": "32942816",
"pubdate": "2020-08-14",
"publication_types": "D016428:Journal Article",
"references": "30199786;28219216;23821332;25952492;30022753;28423296;29562465;31073079;30425070;25861635;29143887;25854458;29170252;28630121;32125099;25765798;22683680;24345753;30915499;28642072;15180875;15885298;7038485;31292909",
"title": "Evaluation of the efficacy of cyclosporin A combined with recombined human thrombopoietin for treating patients with non-severe aplastic anemia.",
"title_normalized": "evaluation of the efficacy of cyclosporin a combined with recombined human thrombopoietin for treating patients with non severe aplastic anemia"
} | [
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"companynumb": "NVSC2020CN264488",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
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"drugadditional": "3",
"dru... |
{
"abstract": "Most pregnancy-related sacral stress fractures occur after delivery. This case aims to emphasise that stress fractures can occur before delivery, and since excessive weight gain is a risk factor, pregnant women should avoid gaining excess weight, especially during quarantine. This patient, who gained 20 kgs during first pregnancy, started complaining of severe pain in the left sacral region in the 40th week of pregnancy, without any trauma. Despite conservative follow-up, her pain increased, and a caesarean section was performed. The patient continued to complain of pain in the left sacral region. Magnetic resonance imaging (MRI) identified a sacral stress fracture which was treated conservatively and resolved after 4 months. Complaints of severe back pain during the last stage of pregnancy require a detailed physical examination. When localised sensitivity is detected in the sacral region during pregnancy, a diagnosis can be made using MRI, thereby avoiding radiation exposure. Key Words: Stress fractures, COVID-19, Sacrum, Pregnancy.",
"affiliations": "Department of Orthopaedia and Traumatology, Recep Tayyip Erdogan University, Rize, Turkey.",
"authors": "Sahin|Rıfat|R|",
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"journal": "Journal of the College of Physicians and Surgeons--Pakistan : JCPSP",
"keywords": null,
"medline_ta": "J Coll Physicians Surg Pak",
"mesh_terms": "D000086382:COVID-19; D002585:Cesarean Section; D005260:Female; D015775:Fractures, Stress; D006801:Humans; D017116:Low Back Pain; D008279:Magnetic Resonance Imaging; D058873:Pandemics; D011247:Pregnancy; D011790:Quarantine; D000086402:SARS-CoV-2; D012445:Sacrococcygeal Region; D012447:Sacrum; D016103:Spinal Fractures; D015430:Weight Gain",
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"pubdate": "2021-07",
"publication_types": "D002363:Case Reports",
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"title": "Sacral Stress Fracture due to Excess Weight Gain during Pregnancy while Self-Quarantining during the COVID-19 Pandemic.",
"title_normalized": "sacral stress fracture due to excess weight gain during pregnancy while self quarantining during the covid 19 pandemic"
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"abstract": "We compared three fludarabine-based regimens for systemic sclerosis patients with a high-risk cardiac phenotype that according to EBMT criteria would be a contraindication for a high-dose cyclophosphamide (200 mg/kg) transplant regimen. All three regimens included fludarabine, ATG, and cyclophosphamide (60 mg/kg), while two regimens also included rituximab with or without IVIG. Treatment related mortality (TRM) was 2.4%. The mean number of days of neutropenia (ANC < 500) was 5.2, the mean number of platelet and red blood cell transfusions was 0.3 and 1.85, respectively. Skin score, forced vital capacity (FVC), and total lung capacity (TLC) improved with all three regimens. For patients whose regimen did not include rituximab versus those that included rituximab, 1-year overall relapse rate was higher 36% (5/14) versus 3.6% (1 of 28) (p = 0.01), secondary autoimmune diseases were higher 21% (3/14) versus 0% (0/28) (p = 0.03), and upper respiratory tract infections were higher 28% (4/14) versus 3.6% (1/28) (p = 0.04). In this safety study, a fludarabine-based regimen was relatively safe with a TRM of 2.4% and a neutropenic interval of only 5.2 days in systemic sclerosis patients with a high-risk cardiac phenotype. The addition of rituximab decreased 1-year relapse rate, risk of late secondary autoimmune diseases, and upper-respiratory tract infections.",
"affiliations": "Division of Immunotherapy, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. rburt@northwestern.edu.;Division of Immunotherapy, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.;Division of Immunotherapy, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.;Division of Immunotherapy, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.;Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.;Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.;Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.;Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.;Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.",
"authors": "Burt|Richard K|RK|http://orcid.org/0000-0002-0922-4145;Han|Xiaoqiang|X|;Quigley|Kathleen|K|;Arnautovic|Indira|I|;Shah|Sanjiv J|SJ|;Lee|Daniel C|DC|;Freed|Benjamin H|BH|;Jovanovic|Borko|B|;Helenowski|Irene B|IB|",
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"mesh_terms": "D003520:Cyclophosphamide; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D009364:Neoplasm Recurrence, Local; D012595:Scleroderma, Systemic; D019172:Transplantation Conditioning; D014740:Vidarabine",
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"title": "Cardiac safe hematopoietic stem cell transplantation for systemic sclerosis with poor cardiac function: a pilot safety study that decreases neutropenic interval to 5 days.",
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"abstract": "Boerhaave's syndrome is an uncommon syndrome characterized by spontaneous rupture of the oesophagus with a high mortality rate. While excessive alcohol intake and binge-eating are the classic precipitants of this syndrome, medication-induced vomiting causing Booerhave's is quite uncommon. Traditionally managed operatively, conservative management is being increasingly reported in selected cases. We report the case of 21-year-old male with who developed sudden onset chest pain and dyspnoea after pentazocine induced vomiting. He was referred after lack of response to initial treatment for acute severe asthma. A chest CT scan showed pneumomediastinum, subcutaneous emphysema and oesophageal tear. He was managed conservatively with oxygen therapy, nil per mouth and antibiotics with improvement of symptoms and discharge after 8 days.",
"affiliations": "Cardiocare Specialty Hospital, Limi Hospital, Abuja, Nigeria.;Cardiocare Specialty Hospital, Limi Hospital, Abuja, Nigeria.;Cardiocare Specialty Hospital, Limi Hospital, Abuja, Nigeria.;Cardiocare Specialty Hospital, Limi Hospital, Abuja, Nigeria.",
"authors": "Awofisoye|Oyindamola Ibukun|OI|;Olalekan|Olaleye Emmanuel|OE|;Anumenechi|Ndubuisi|N|;Onwukpa|Frankilin|F|",
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"doi": "10.11604/pamj.2021.38.74.27031",
"fulltext": "\n==== Front\nPan Afr Med J\nPan Afr Med J\nPAMJ\nThe Pan African Medical Journal\n1937-8688\nThe African Field Epidemiology Network\n\nPAMJ-38-74\n10.11604/pamj.2021.38.74.27031\nCase Report\nBoerhaave’s syndrome after pentazocine-induced vomiting in a 21-year-old male with asthma: a case report\nAwofisoye Oyindamola Ibukun 1&\nOlalekan Olaleye Emmanuel 1\nAnumenechi Ndubuisi 1\nOnwukpa Frankilin 1\n1 Cardiocare Specialty Hospital, Limi Hospital, Abuja, Nigeria\nCorresponding author: Oyindamola Ibukun Awofisoye, Cardiocare Specialty Hospital, Limi Hospital, Abuja, Nigeria. dammiet@yahoo.com\n21 1 2021\n2021\n38 7418 11 2020\n13 1 2021\nCopyright: Oyindamola Ibukun Awofisoye et al.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ The Pan African Medical Journal (ISSN: 1937-8688). This is an Open Access article distributed under the terms of the Creative Commons Attribution International 4.0 License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nBoerhaave's syndrome is an uncommon syndrome characterized by spontaneous rupture of the oesophagus with a high mortality rate. While excessive alcohol intake and binge-eating are the classic precipitants of this syndrome, medication-induced vomiting causing Booerhave's is quite uncommon. Traditionally managed operatively, conservative management is being increasingly reported in selected cases. We report the case of 21-year-old male with who developed sudden onset chest pain and dyspnoea after pentazocine induced vomiting. He was referred after lack of response to initial treatment for acute severe asthma. A chest CT scan showed pneumomediastinum, subcutaneous emphysema and oesophageal tear. He was managed conservatively with oxygen therapy, nil per mouth and antibiotics with improvement of symptoms and discharge after 8 days.\n\nBoerhaave’s\npneumomediastinum\noesophageus\ncase report\n==== Body\nIntroduction\n\nSpontaneous rupture of the oesophagus associated with forceful vomiting (Boerhaave's syndrome) is an uncommon disease of the gastrointestinal tract, but with a very high mortality rate. The rupture is longitudinal and transmural. The syndrome was first described in 1724 by the German doctor, Hermann Boerhaave. It classically followed excessive alcohol intake and vomiting [1]. Other triggers are less common and include binge-eating and caustic ingestion. Boerhaave´s syndrome complicating medication-induced vomiting is rare with only a handful of cases in the literature. The classic symptoms constitutes the Mackler´s triad: vomiting, lower thoracic pain and subcutaneous emphysema [2]. Because of its rarity, the diagnosis can easily be missed or delayed, leading to complications like mediastinitis, sepsis and shock. In such situations, the mortality can be very high [3]. We report the occurrence of Boerhaave´s syndrome in a 21-year-old Nigerian male which developed after pentazocine-induced vomiting.\n\nPatient and observation\n\nThe patient was a 21-year-old male, known to have mild intermittent asthma. He was being treated for malaria at another centre after he presented with headaches and myalgia. He initially had parenteral antimalarials, but after pentazocine was administered, he vomited forcefully three times with retching. Shortly after vomiting, he developed a worsening retrosternal pain, with cough, dyspnoea and dysphagia. He was thought to have acute severe asthma and he was treated by nebulization with salbutamol, steroids and antibiotics but he continued to deteriorate with respiratory distress and oxygen saturation falling to about 80-85%, requiring supplemental oxygen therapy. This necessitated referral to our facility. On evaluation here, further history revealed that he has not had any asthma symptoms in 3 years nor required inhaler use. Additionally, the chest pain was retrosternal and markedly pleuritic.\n\nExamination revealed a young man in respiratory distress on oxygen therapy. He was neither pale nor cyanosed. His respiratory rate was 28 breaths per minute. He was without wheeze or stridor. The percussion notes were hyper-resonant in the in the left hemithorax medially. The breath sounds were normal without rhonchi. He had mild chest wall tenderness. Abdominal examination was unremarkable. The pulse rate on admission was 106/min, regular with normal volume. The blood pressure was 130/88mmHg, while he required oxygen at 4 litres per minute to keep the SpO2 above 94%. His temperature was 37.6 degrees celsius, though was normal after the first day of admission.\n\nA possible spontaneous pneumothorax complicating resolved acute severe asthma was considered. An urgent chest CT scan was requested (Figure 1, Figure 2, Figure 3) which revealed a pneumomediastinum, a patulous oedematous oesophagus with an area of discontinuity about 2cm to the gastroesophageal junction (Figure 3). There was also right cervical subcutaneous emphysema (Figure 1). A diagnosis of Boerhaave´s syndrome was made about 24 hours after presentation. The blood count showed relative neutrophilia and the d-dimer was elevated. Other investigations done including, erythrocyte sedimentation rate, troponin T, SARS-CoV-2 test and electrocardiography were normal (Table 1).\n\nFigure 1 chest CT scan: axial view showing pneumomediastinum and subcutaneous emphysema\n\nFigure 2 chest CT scan: axial view showing pneumomediastinum and a thin rim of pneumothorax\n\nFigure 3 chest CT scan: coronal view showing air pneumomediastinum and discontinuity in the oesophageal wall about 2cm from the gastroesophageal junction\n\nTable 1 laboratory results\n\nParameter\tValue\tReference range\t\nComplete blood count\t\t\t\nHemoglobin (g/dl)\t15.8\t13.4 - 17.5\t\nTotal white cell count (x106/L)\t9,300\t3,900 - 10,400\t\nNeutrophil %\t90.1%\t32 - 76%\t\nLymphocytes %\t7.2%\t18 - 56%\t\nPlatelet count (x109/L)\t120\t150 - 400\t\nE/U/Cr\t\t\t\nSodium (mmol/L)\t140\t135 - 145\t\nPotassium (mmol/L)\t4.6\t3.0 - 5.2\t\nChloride (mmol/L)\t94\t95 - 105\t\nBicarbonate (mmol/L)\t25\t20 - 30\t\nUrea (mg/dl)\t17\t15 - 50\t\nCreatinine (mg/dl)\t1.0\t0.5 - 1.2\t\nErythrocyte sedimentation rate (mm/hr)\t23\t<30\t\nD-dimer (ng/ml)\t1760\t0 - 500\t\nTroponin-T (ng/l)\t<50\t<50\t\nSARS-CoV-2 PCR\tNegative\t\t\n\nBy the second day of admission the subcutaneous emphysema was clinically apparent on the anterior chest wall, extending to the supraclavicular fossa and lower neck. However, his respiratory rate and chest pain score were improving. He was managed conservatively with intravenous antibiotics, nil per oral, intravenous fluids, total parenteral nutrition and supplemental oxygen. By day 4, his symptoms were mostly resolved with mild residual retrosternal pain. He had a barium swallow on day 7 of admission which did not show any leakage from the oesophagus (Figure 4). Graded oral feeding was started on day 8 and he was discharged to ambulatory care. The subcutaneous emphysema resolved after two weeks.\n\nFigure 4 barium swallow (eighth day) anteroposterior and lateral views showing no barium spillage from the oesophagus\n\nDiscussion\n\nMajority of oesophageal perforations are iatrogenic, with only about 15% being spontaneous [4]. While Booerhave's syndrome is often described as a “spontaneous” rupture, it is due to a rise in the intraluminal pressure of the oesophagus. The classic triad includes forceful vomiting, chest pain and subcutaneous emphysema. Only about three cases are reported per million persons per year with most being middle-aged persons and above. Our case is unusual as it is uncommon in children and adolescents. The typical triggers are excessive alcohol consumption and large intake of meals. Medication-induced vomiting causing Boerhaave´s syndrome is quite uncommon and no previous report for pentazocine was found in the literature. The commonest location of the tear is at the left posterolateral wall of the lower third of the esophagus 2-3cm proximal to the GEJ along the longitudinal wall. The intrathoracic perforation can lead to chemical mediastinitis, necrosis and bacterial infection. It is unclear why our patient did not develop significant mediastinitis and could be managed conservatively. Possible reasons include: minimal length of the tear; the stomach was relatively empty due to poor feeding preceding the vomiting; it was not preceded by alcohol intake or binge eating; steroids were used to treat the supposed “asthma exacerbation” which could have inadvertently limited any inflammation.\n\nThe clinical manifestations of Boerhaave syndrome depends on the location of the rupture, the extent and the time from onset of rupture. The symptoms are often non-specific and diagnosis is often missed or delayed like in our patient. The history of vomiting preceding chest symptoms can be suggestive, although hematemesis is only occasionally present. Subcutaneous emphysema is observed within the first 24 hours in 28-60% of cases [5], though in our patient it was only noticed after 48 hours. Auscultation may also reveal a crackling sound heard with the heart beats (Hamman crunch) that signifies pneumomediastinum which is reported in about 20% of cases [5]. This was absent in our patient, despite the large amount of pneumomediastinum on CT scan. Chest finding are more often on the left because 90% of the tears are in the left posterolateral wall of the oesophagus, which communicates with the left pleural cavity in most cases [3]. The suspicion of pneumothorax in our patient was due to the sudden clinical presentation and finding of hyper-resonant percussion notes.\n\nSudden onset shortness of breath and chest pain in someone with asthma should make one think of a spontaneous pneumothorax; which was the main reason for urgent imaging in this patient. However, other differential diagnosis should be considered, especially when the usual clinical signs of acute severe asthma were not present like in our patient. Booerhave´s syndrome has also been misdiagnosed as acute aortic syndrome, pericarditis, pulmonary embolism or spontaneous pneumothorax [6] in other reports. Chest X-ray is usually the initial imaging modality which is abnormal in majority of patients. The usual abnormalities reported include left-sided pleural effusion, pneumothorax, subcutaneous emphysema and pneumomediastinum which manifests as V-sign described by Naclerio [5]. Chest CT scan was the initial modality used in this case in view of the higher diagnostic yield and the severity of symptoms.\n\nUnenhanced chest CT scan findings may include the aforementioned findings, additionally peri-oesophageal air collections, intramural hematoma and oesophageal wall thickening amongst others [7]. The most consistent findings are peri-oesophageal air collection, pneumomediastinum and subcutaneous emphysema which were present in our patient. CT scan is however limited in precisely defining the tear compared to oesophagography. Esophagogram is performed using barium or gastrograffin and it typically shows contrast extravasation at a supradiaphragmatic level. However, this was delayed in this patient as the diagnosis was already made from the CT scan and we believed the risk associated with extravasation of contrast medium was avoidable. It was normal on the eight day, indicating that healing has occurred. The negative test was reassuring in recommencement of oral feeding. It is noteworthy that false negative tests has been reported in contrast studies for oesophageal perforation [8].\n\nThe traditional management of Booerhaves syndrome is surgical. But there are several reports of successful conservative (non-operative) management [9-11]. The factors which support conservative management as suggested by Cameron et al. includes: oesophageal disruption well contained in the mediastinum; any cavity should be well drained back into the oesophagus; minimal symptoms, and minimum evidence of sepsis [12]. These were met in this patient. Conservative management in this patient included nil by mouth, intravenous fluids and antibiotics. Nasogastric tube drainage and thoracostomy are also components of conservative care, but was not necessary in this patient as mediastinal leakage was mostly air and inflammatory symptoms were minimal.\n\nConclusion\n\nMedication induced vomiting may be complicated by oesophageal tear and a high index of suspicion is required in patients that develop sudden onset chest pain and dyspnoea after such vomiting. The differential diagnosis of chest pain and dyspnoea is vast and imaging is critical for establishing a diagnosis in ambiguous cases. Conservative management of mild cases of Booerhave´s syndrome is possible with early diagnosis and prompt treatment.\n\nAcknowledgments\n\nWe acknowledge the patient, family members and nursing staff of Cardiocare Hospital for their contributions.\n\nCompeting interests\n\nThe authors declare no competing interests.\n\nAuthors' contributions\n\nAll authors were involved in the patient management and writing; Awofisoye conceived the case report and did most of the writing; Olalekan, Franklin and Anumenechi contributed to the writing, editing and proof-reading of the report. All the authors have read and agreed to the final manuscript.\n\nCite this article: Oyindamola Ibukun Awofisoye et al. Boerhaave’s syndrome after pentazocine-induced vomiting in a 21-year-old male with asthma: a case report. Pan African Medical Journal. 2021;38(74). 10.11604/pamj.2021.38.74.27031\n==== Refs\n1 Spapen J De Regt J Nieboer K Verfaillie G Honoré PM Spapen H Boerhaave's syndrome: still a diagnostic and therapeutic challenge in the 21st century Case Rep Crit Care 2013 2013 161286 24829816\n2 Bouma HR Scheer MLJ Mackler's triad: Boerhaave syndrome Netherlands Journal of Critical Care 2016 24 1 28\n3 Granel-Villach L Fortea-Sanchis C Martínez-Ramos D Paiva-Coronel G Queralt-Martín R Villarín-Rodríguez A et al Boerhaave's syndrome: a review of our experience over the last 16 years Rev Gastroenterol Mex 2014 79 1 67 70 24656512\n4 Brinster CJ Singhal S Lee L Marshall MB Kaiser LR Kucharczuk JC Evolving options in the management of esophageal perforation Ann Thorac Surg 2004 77 4 1475 83 15063302\n5 Marinis A Rizos S Boerhaave's syndrome or spontaneous perforation of the oesophagus Hellenic Journal of Surgery 2011 83 5 258 62\n6 Carrozza F Dragean C Spontaneous esophageal rupture or Boerhaave's syndrome J Belg Soc Radiol 2020 104 1 1 31976387\n7 Ghanem N Altehoefer C Springer O Furtwängler A Kotter E Schäfer O et al Radiological findings in Boerhaave's syndrome Emerg Radiol 2003 10 1 8 13 15290523\n8 Buecker A Wein BB Neuerburg JM Guenther RW Esophageal perforation: comparison of use of aqueous and barium-containing contrast media Radiology 1997 202 3 683 6 9051016\n9 Anwuzia-Iwegbu C Al Omran Y Heaford A Against all odds: conservative management of Boerhaave's syndrome BMJ Case Rep 2014 2014 bcr2013200485\n10 Vogel SB Rout WR Martin TD Abbitt PL Esophageal perforation in adults: aggressive, conservative treatment lowers morbidity and mortality Ann Surg 2005 241 6 1016 21 discussion 1021-3 15912051\n11 Griffin SM Lamb PJ Shenfine J Richardson DL Karat D Hayes N Spontaneous rupture of the oesophagus Br J Surg 2008 95 9 1115 20 18655213\n12 Cameron JL Kieffer RF Hendrix TR Mehigan DG Baker RR Selective nonoperative management of contained intrathoracic esophageal disruptions Ann Thorac Surg 1979 27 5 404 8 110275\n\n",
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"mesh_terms": "D000701:Analgesics, Opioid; D000900:Anti-Bacterial Agents; D001249:Asthma; D002637:Chest Pain; D004417:Dyspnea; D004939:Esophageal Perforation; D006801:Humans; D008297:Male; D008477:Mediastinal Diseases; D010102:Oxygen Inhalation Therapy; D010423:Pentazocine; D014057:Tomography, X-Ray Computed; D014839:Vomiting; D055815:Young Adult",
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"title": "Boerhaave's syndrome after pentazocine-induced vomiting in a 21-year-old male with asthma: a case report.",
"title_normalized": "boerhaave s syndrome after pentazocine induced vomiting in a 21 year old male with asthma a case report"
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"abstract": "The highest postmortem metformin concentrations are recorded utilizing a sensitive and specific analytical procedure. The peripheral blood metformin concentration was 240 mg/L, the liver concentration was 240 mg/kg and the gastric concentration was 1,700 mg. Additionally, an antemortem blood sample collected shortly after admission revealed a metformin concentration of 210 mg/L. These data, revealing a liver to peripheral blood ratio of 1.0, provide additional support that metformin is not subject to postmortem redistribution. Intentional self-poisonings with metformin can result in death, despite multiple medical interventions.",
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"abstract": "Nasopharyngeal carcinoma (NPC), an uncommon malignancy in Western Countries and Radiotherapy, remains an effective treatment. Its side effects are classified as either immediate or late; postradiation necrosis is as an important late side effect with a strong impact on the prognosis in patients with NPC. We report the case of 65-year-old Caucasian man presenting with a deep necrotic ulcer of the nasopharynx and osteoradionecrosis of the skull base that appeared 3 months after radiotherapy for nasopharyngeal carcinoma. Conservative treatment was applied with surgical management of the ulcer. Clinical and radiological outcomes are presented. Radiotherapy remains a good treatment option with varying degrees of side effects, in particular, postradiation necrosis and ulcer. Multiple options of treatment have been described. However, the surgical management could be indicated in cases of deep ulcer with life-threatening prognosis.",
"affiliations": "Otorhinolaryngology, Hospital of Sion, Sion, Switzerland bassel2004@hotmail.com.;Otorhinolaryngology, Hospital of Sion, Sion, Switzerland.;Radiology, Hospital Sion, Sion, Switzerland.;Otorhinolaryngology, Hospital of Sion, Sion, Switzerland.",
"authors": "Hallak|Bassel|B|;Morrison|Miranda|M|;Kohler|Romain|R|;Bouayed|Salim|S|",
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"doi": "10.1136/bcr-2019-230700",
"fulltext": "\n==== Front\nBMJ Case RepBMJ Case RepbmjcrbmjcasereportsBMJ Case Reports1757-790XBMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR bcr-2019-23070010.1136/bcr-2019-230700Reminder of Important Clinical Lesson15061524641333289304Case reportDeep radiation-induced ulcer following nasopharyngeal carcinoma: surgical management Hallak Bassel 1Morrison Miranda 1Kohler Romain 2Bouayed Salim 1\n1 \nOtorhinolaryngology, Hospital of Sion, Sion, Switzerland\n\n2 \nRadiology, Hospital Sion, Sion, Switzerland\nCorrespondence to Dr Bassel Hallak; bassel2004@hotmail.com2019 5 11 2019 5 11 2019 12 11 e23070017 10 2019 © BMJ Publishing Group Limited 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.2019This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.Nasopharyngeal carcinoma (NPC), an uncommon malignancy in Western Countries and Radiotherapy, remains an effective treatment. Its side effects are classified as either immediate or late; postradiation necrosis is as an important late side effect with a strong impact on the prognosis in patients with NPC. We report the case of 65-year-old Caucasian man presenting with a deep necrotic ulcer of the nasopharynx and osteoradionecrosis of the skull base that appeared 3 months after radiotherapy for nasopharyngeal carcinoma. Conservative treatment was applied with surgical management of the ulcer. Clinical and radiological outcomes are presented. Radiotherapy remains a good treatment option with varying degrees of side effects, in particular, postradiation necrosis and ulcer. Multiple options of treatment have been described. However, the surgical management could be indicated in cases of deep ulcer with life-threatening prognosis.\n\nimaging and managementnasopharyngeal carcinomanecrosisosteoradionecrosisradiotherapyulcerspecial-featureunlocked\n==== Body\nBackground\nNasopharyngeal carcinoma (NPC) is rare in the Western Countries and more common in Southeast Asia.1 Radiotherapy remains a treatment option for NPC. However, side effects induced by radiation could be acute or late. Late side effects develop after several months or years and could include both the bones and soft tissues of the neck and nasopharynx.2\n\n\nRadiation-induced necrosis of the nasopharynx, as its name suggests, is necrosis of the tissues of the nasopharynx, such as the mucosa, muscles, parapharyngeal tissues and skull base.3 Due to the anatomy of the nasopharynx and the approximately of the internal carotid artery (ICA), This necrosis could induced an erosion of the ICA with the risk of rupture and becomes life threatening.\n\nTraditionally, postradiation nasopharyngeal ulcers (PRNUs) are divided into mucosal ulcers induced by radiation and tumour necrosis-induced ulcers.4\n\n\nThe management of radiation-induced necrosis and ulcers of the nasopharynx depend on the severity of the UPRNN and varies from conservative medical treatment to surgical debridement.\n\nWe report a case of radiation-induced deep ulcer of the nasopharynx associated with skull base osteoradionecrosis and clivus bone exposure. Surgical management by using multiple grafts followed by a customised medical treatment was applied. Clinical, endoscopic and radiological outcomes are presented below.\n\nCase presentation\nA 65-year-old Caucasian man presented in January 2018, following the appearance since 3 months of a unilateral left-sided nasal obstruction associated with permeant pulsatile tinnitus of the left ear. His medical background showed an adenocarcinoma of the prostate staged pT2 cN0 M0 treated surgically in 2016. The fibroendoscopic examination of the nose showed an exophytic lesion in the nasopharynx on the left side. The examination of the left ear showed a retraction of the tympanic membrane with a signs of a retrotympanic effusion. The rest of the clinical examination was normal.\n\nMultiple biopsies of the left-sided nasopharyngeal mass were done, and the histology confirmed the diagnosis of an undifferentiated Epstein-Barr virus (EBV) positive carcinoma of the nasopharynx. An initial radiological evaluation with CT and positron emission tomography (PET)-CT were performed that revealed a hypermetabolic lesion in the nasopharynx on the left side (standardised uptake volume (SUV) max at 17.5) with suspicious hypermetabolic cervical and retropharyngeal lymph nodes on both sides (SUV max at 14.2 and 12.3), without evidence of a distant metastasis (figure 1A). The disease was staged as cT2 cN2 cM0, and the patient was treated by radiotherapy with a total dose of 69.96 Gy on the tumour side and 52.8 Gy on the lymph nodes bilaterally with concomitant chemotherapy (weekly carboplatin 2 area under the curve, 90 mg intravenously with Taxol 50 mg/m²).\n\nFigure 1 (A) Pretreatment PET-CT image shows the hypermetabolic mass on the left side of the nasopharynx. (B) Axial CT image (bony window) shows the osteoradionecrosis of the skull base with the erosion of the clivus bone on the left side. (C) Axial MRI T1 image after injection of gadolinium shows the presence of wide cavity, loss of the soft tissues and exposure of the left-sided ICA to the nasopharynx air. (D) Intraoperative endoscopic view shows an important purulent discharge at the level of the nasopharynx on the left side. (E) Intraoperative endoscopic view shows a deep ulcer and necrosis on the posterior wall of the nasopharynx with erosion of the clivus bone on the left side. ICA, internal carotid artery; PET, positron emission tomography.\n\nRadiological evaluation by PET-CT 3 months after the end of the treatment showed a complete response at the level of the cervical lymph nodes on both sides but persistence of mild hypermetabolic activity in the nasopharynx; on the left side that was considered as an inflammatory reaction induced by radiation therapy.\n\nThe patient presented 4 months following treatment completion, sever left-sided otalgia with hemicranial pain. The fibroendoscopic examination of the nose showed a large ulcer with mucosal necrosis and purulent discharge on the posterior wall of the nasopharynx. Radiological evaluation by CT (figure 1B) showed erosions of the clivus bone that were compatible with osteitis associated with diffuse inflammation in the retropharyngeal space and the skull base. Additionally, there was a large abscess causing a compression of the internal carotid artery on the left side.\n\nAn intravenous antibiotic (piperacillin (Tazobac)—4.5 g three times per day) was applied, and the patient underwent a surgical debridement with drainage of the abscess by an intranasal endoscopic approach (figure 1D and E). The bacterial biological analysis of the discharge taken from the fluid of the abscess showed S\ntaphylococcus aureus and anaerobic germs. Biopsies of the ulcer and the surrounding tissues confirmed eradication of tumour. The antibiotic was changed to intravenous coamoxicillin (1 g two times per day) and followed for an additional 6 weeks associated with daily nasal wash with saline solution. The follow-up at 3 weeks postsurgical debridement showed a marked decrease in the inflammatory signs and biological parameters.\n\nRadiological evaluation with an MRI (figure 1C) 2 months after the conservative treatment was performed and showed the persistence of a deep ulcer on the posterior wall of the nasopharynx, exposure of the clivus bone, the deep extension of the necrosis of the soft tissues and the threat of rupture of the internal carotid artery, a surgical closure of the defect of the nasopharynx was performed.\n\nThe surgical procedure was done by a transnasal endoscopic approach; the edges of the ulcer have been cleaned, fat grafts have been harvested from the periumbilical region and a fascia lata graft was taken from the region of the lateral thigh on the left side. A first layer of fascia lata was applied on the clivus bone and the deep part of the ulcer, the cavity of the defect was filled by the fat grafts and a second layer of fascia lata was applied on the surface. This was then fixed to the surrounding mucosa using the adhesive tissues (figure 2A–D).\n\nFigure 2 The second surgical procedure. (A) Intraoperative endoscopic view shows the regression of the inflammatory signs with the persistence of a deep ulcer of the nasopharynx on the left side. (B) Endoscopic view shows the application of the first layer of fascia lata in the deep part of the cavity of the ulcer. (C) Endoscopic view shows the application of the fat grafts to filled the cavity of the ulcer. (D) Endoscopic view shows the application of the second layer of fascia lata on the surface of the mucosa of the posterior wall of the nasopharynx. (E) Endoscopic view 4 months after the surgery shows a good healing and integration of the grafts with a compete closure of the defect of the nasopharynx on the left side.\n\nThe postoperative care was simple; it included regular nose cleansing and use of intravenous antibiotics. The patient was discharged 2 weeks after the surgery; the antibiotic was changed to oral clindamycin (dose of 600 mg three times per day) and followed for additional 3 months.\n\nThe follow-up at 4 months after the surgery showed absence of any complications, good healing with complete integration of the grafts, complete closure of the defect of the nasopharynx and total regression of the inflammatory signs (figure 2E).\n\nOutcome and follow-up\nRadiological evaluation by PET-CT 3 months after the radiochimiotherapy showed a complete response at the level of the cervical lymph nodes on both side, persistence of mild hypermetabolic activity in the nasopharynx on the left side.\n\nFollow- up at 4 months showed the development of radiation-induced deep ulcer and necrosis of the nasopharynx with osteoradionecrosis and abscess of the skull base without histological evidence of tumour recurrence. The management was included surgical debridement associated with medical treatment and surgical procedure to cover and protect the internal carotid artery.\n\nFollow-up at 4 months showed a total regression of the inflammatory signs and parameters, absence of complications and complete closure of the defect of the nasopharynx.\n\nDiscussion\nThe radiotherapy is the mainstay of treatment for NPC. However, radical radiation can both significantly improve survival and cause consequential late effects. Of these late effects, postradiation nasopharyngeal necrosis results in poor quality of life and poor prognosis. If osteoradionecrosis appears, the bone and internal carotid artery lose soft tissue coverage and are exposed to the air cavity.\n\nRadiation-induced necrosis of the nasopharynx is as a process with three stages4: the early stage, occurs at the level of the mucosa, including local denaturalisation and discontinuation; the second stage includes both the mucosa and the muscle and could extend to the tendon of the nasopharynx with more important defects in the paraphyrngeal space. The osteoradionecrosis of the skull base is seen in the third stage of necrosis and usually causes refractory headache.\n\nHaemorrhage, a fatal event, is closely associated with radiation-induced nasopharyngeal necrosis. Weakening of the wall of postradiated vessels may result in dissection or rupture and produce a pseudoaneurysm. Without immediate treatment, rupture can be fatal because of the anatomy of the nasopharynx.\n\nMing et a\nl\n5 reported a series of 67 nasopharyngeal carcinoma patients with postradiation necrosis treated at Sun Yat-sen University cancer Center in China. In this series, 18 patients (26,9%) died of acute haemorrhage within 2 years of being diagnosed with nasopharyngeal necrosis. In the clinical series reported by Fengqin et al\n6 of 53 ulcers of postradiation nasopharyngeal necrosis in patients with nasopharyngeal carcinoma, 5 patients succumbed to mortality due to a massive bleeding. In both these two series witch are presented the largest number of cases of radiation-induced deep nasopharyngeal ulcer and necrosis, the management was varied from conservative treatment to surgical debridement. According to our knowledge, the use of a different grafts to cover the cavity of the ulcer and to protect the ICA has not been reported yet in the literature.\n\nThe exact mechanism of PRNU is unknown; the infection was reported to play an important role in the process of nasopharyngeal necrosis.7 Infection of a local nasopharyngeal region may increase the energy demand by local tissues as well as oxygen and other metabolic demands, which leads to collagen destruction and cell death. Hypoxia and radiation factors such as dosage and dose rate also play an important role.8 Other factors such as the neoadjuvant chemotherapy, anaemia and malnutrition, T stage and the invasion of muscle have also an important role in the development of PRNU.\n\nThe treatment of PRNU is diverse and varies from conservative medical treatment to surgical endoscopic debridement. The choice of the treatment depends on the stage and the severity of the PRNU.\n\nOur patient presented a deep PRNU classified as stage 3. The possibility of local tumour recurrence was ruled out. He underwent a conservative treatment for a period of 2 months which included intravenous and oral antibiotics associated with daily nasal rinçages and endoscopic debridement of the nasopharyngeal ulcer. The evolution of the local infection was favourable with a significant decrease in the inflammatory parameters. But due to the persistence of a wide cavity on the posterior wall of the nasopharynx and loss of the soft tissues with a high risk of rupture of the ICA and massive bleeding, we completed the conservative treatment with surgical closing of the cavity of the ulcer by using different grafts to protect the ICA and reduce the risk of rupture. According to our knowledge, a similar procedure in the management of PRNU has never been reported in the literature.\n\nLearning points\nNasopharyngeal carcinoma is a common malignancy in Southeast Asia but a very rare entity in Western Countries.\n\nRadiotherapy remains a good treatment option but may cause both acute and late side effects.\n\nRadiation-induced nasopharyngeal necrosis and ulcer could be life threatening.\n\nManagement should be immediate and adapted depending on the stage of the ulcer and the extension of the necrosis.\n\nCoverage and protection of the internal carotid artery is very important to avoid fatal bleeding and death.\n\nContributors: BH was responsible for the reporting. MM was coauthor and responsible for the acquisition of data. RK was coauthor, responsible for the acquisition of data and design. SB was coauthor and also responsible for reporting.\n\nFunding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.\n\nCompeting interests: None declared.\n\nPatient consent for publication: Obtained.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n1 \nYu MC , Yuan J-M \nEpidemiology of nasopharyngeal carcinoma . Semin Cancer Biol \n2002 ;12 :421 –9 .12450728 \n2 \nLee AW , Law SC , Ng SH , et al \nRetrospective analysis of nasopharyngeal carcinoma treated during 1976-1985: late complications following megavoltage irradiation . Br J Radiol \n1992 ;65 :918 –28 . 10.1259/0007-1285-65-778-918 \n1422667 \n3 \nHua Y-J , Chen M-Y , Hong M-H , et al \n[Short-term efficacy of endoscopy-guided debridement on radiation-related nasopharyngeal necrosis in 20 nasopharyngeal carcinoma patients after radiotherapy] . Ai Zheng \n2008 ;27 :729 –33 .18606066 \n4 \nHua Y-J , Chen M-Y , Qian C-N , et al \nPostradiation nasopharyngeal necrosis in the patients with nasopharyngeal carcinoma . Head Neck \n2009 ;31 :807 –12 . 10.1002/hed.21036 \n19340873 \n5 \nMing YC , Hai QM , Rui S , et al \nClinical findings and imaging features of 67 nasopharyngeal carcinoma patients with postradiation nasopharyngeal necrosis .\n6 \nFengqin Y , Zhimin YE , FangzhengW LW , et al \nClinical and imaging characteristics of 53 ulcers of post-radiation nasopharyngeal necrosis in patients with nasopharyngeal carcinoma .\n7 \nHao SP , Chen HC , Wei FC , et al \nSystematic management of osteoradionecrosis in the head and neck . Laryngoscope \n1999 ;109 :1324 –7 . 10.1097/00005537-199908000-00027 \n10443843 \n8 \nHuang X-M , Zheng Y-Q , Zhang X-M , et al \nDiagnosis and management of skull base osteoradionecrosis after radiotherapy for nasopharyngeal carcinoma . Laryngoscope \n2006 ;116 :1626 –31 . 10.1097/01.mlg.0000230435.71328.b9 \n16954993\n\n",
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"issn_linking": "1757-790X",
"issue": "12(11)",
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"keywords": "imaging and management; nasopharyngeal carcinoma; necrosis; osteoradionecrosis; radiotherapy; ulcer",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D004724:Endoscopy; D006801:Humans; D008297:Male; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms; D009305:Nasopharynx; D010025:Osteoradionecrosis; D011832:Radiation Injuries; D019291:Skull Base; D016896:Treatment Outcome; D014456:Ulcer",
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"pubdate": "2019-11-05",
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"title": "Deep radiation-induced ulcer following nasopharyngeal carcinoma: surgical management.",
"title_normalized": "deep radiation induced ulcer following nasopharyngeal carcinoma surgical management"
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"abstract": "To examine methylphenidate extended-release chewable tablets (MPH ERCT) dose patterns, attention-deficit/hyperactivity disorder (ADHD) symptom scores, and safety during the 6-week, open-label (OL) dose-optimization period of a phase 3, laboratory classroom study.\n\n\n\nBoys and girls (6-12 years) diagnosed with ADHD were enrolled. MPH ERCT was initiated at 20 mg/day; participants were titrated in 10-20 mg/day increments weekly based on efficacy and tolerability (maximum dose, 60 mg/day). Dose-optimization period efficacy assessments included the ADHD Rating Scale (ADHD-RS-IV), analyzed by week in a post hoc analysis using a mixed-effects model for repeated measures with final optimized dose (20, 30/40, or 50/60 mg), visit, final optimized dose and visit interaction, and baseline score as terms. Adverse events (AEs) and concomitant medications were collected throughout the study.\n\n\n\nMean MPH ERCT daily dose increased weekly from 29.4 mg/day after the first dose adjustment at week 1 (n = 90) to 42.8 mg/day after the final adjustment at week 5 (n = 86). Final optimized MPH ERCT dose ranged from 20 to 60 mg/day. Mean final optimized MPH ERCT dose ranged from 40.0 mg/day in 6-8 year-old participants to 44.8 mg/day for 11-12 year-old participants. There was a progressive decrease in mean (standard deviation) ADHD-RS-IV total score from 40.1 (8.72) at baseline to 12.4 (7.88) at OL week 5, with similar improvement patterns for hyperactivity/impulsivity and inattentiveness subscale scores. Participants optimized to MPH ERCT 50/60 mg/day had a significantly higher mean (standard error) ADHD-RS-IV score at baseline compared with participants optimized to MPH ERCT 20 mg/day (42.4 [1.34] vs. 35.1 [2.55]; p = 0.013). Treatment-emergent AEs were reported by 65/90 (72.2%) participants in the dose-optimization period.\n\n\n\nDose-optimization period results describing relationships between change in ADHD symptom scores and final optimized MPH ERCT dose will be valuable for clinicians optimizing MPH ERCT dose.",
"affiliations": "1 University of California Irvine , Irvine, California.;2 Center for Psychiatry and Behavioral Medicine, Inc. , Las Vegas, Nevada.;3 Pfizer Inc. , New York, New York.;3 Pfizer Inc. , New York, New York.;4 Pfizer Inc. , Groton, Connecticut.;3 Pfizer Inc. , New York, New York.;3 Pfizer Inc. , New York, New York.;5 Pfizer Inc. , Collegeville, Pennsylvania.;3 Pfizer Inc. , New York, New York.",
"authors": "Wigal|Sharon B|SB|;Childress|Ann|A|;Berry|Sally A|SA|;Belden|Heidi W|HW|;Chappell|Phillip|P|;Wajsbrot|Dalia B|DB|;Nagraj|Praneeta|P|;Abbas|Richat|R|;Palumbo|Donna|D|",
"chemical_list": "D000697:Central Nervous System Stimulants; D003692:Delayed-Action Preparations; D013607:Tablets; D008774:Methylphenidate",
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"fulltext": "\n==== Front\nJ Child Adolesc PsychopharmacolJ Child Adolesc PsychopharmacolcapJournal of Child and Adolescent Psychopharmacology1044-54631557-8992Mary Ann Liebert, Inc. 140 Huguenot Street, 3rd FloorNew Rochelle, NY 10801USA 10.1089/cap.2017.013810.1089/cap.2017.0138Original ArticlesOptimization of Methylphenidate Extended-Release Chewable Tablet Dose in Children with ADHD: Open-Label Dose Optimization in a Laboratory Classroom Study Wigal Sharon B. PhD1Childress Ann MD2Berry Sally A. MD, PhD3Belden Heidi W. PharmD3Chappell Phillip MD, MBA4Wajsbrot Dalia B. MSc3Nagraj Praneeta PharmD3Abbas Richat PhD5Palumbo Donna PhD31 University of California Irvine, Irvine, California.2 Center for Psychiatry and Behavioral Medicine, Inc., Las Vegas, Nevada.3 Pfizer Inc., New York, New York.4 Pfizer Inc., Groton, Connecticut.5 Pfizer Inc., Collegeville, Pennsylvania.Address correspondence to:Sharon B. Wigal, PhDDepartment of PediatricsClinical Professor in Pediatrics and Psychiatry and Human BehaviorUniversity of California Irvine19722 MacArthur BoulevardIrvine, CA 92612E-mail:drsharon@avidainc.com01 6 2018 01 6 2018 01 6 2018 28 5 314 321 © Sharon B. Wigal et al. 2018; Published by Mary Ann Liebert, Inc.2018This Open Access article is distributed under the terms of the Creative Commons Attribution Noncommercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are cited.Abstract\nObjective: To examine methylphenidate extended-release chewable tablets (MPH ERCT) dose patterns, attention-deficit/hyperactivity disorder (ADHD) symptom scores, and safety during the 6-week, open-label (OL) dose-optimization period of a phase 3, laboratory classroom study.\n\nMethods: Boys and girls (6–12 years) diagnosed with ADHD were enrolled. MPH ERCT was initiated at 20 mg/day; participants were titrated in 10–20 mg/day increments weekly based on efficacy and tolerability (maximum dose, 60 mg/day). Dose-optimization period efficacy assessments included the ADHD Rating Scale (ADHD-RS-IV), analyzed by week in a post hoc analysis using a mixed-effects model for repeated measures with final optimized dose (20, 30/40, or 50/60 mg), visit, final optimized dose and visit interaction, and baseline score as terms. Adverse events (AEs) and concomitant medications were collected throughout the study.\n\nResults: Mean MPH ERCT daily dose increased weekly from 29.4 mg/day after the first dose adjustment at week 1 (n = 90) to 42.8 mg/day after the final adjustment at week 5 (n = 86). Final optimized MPH ERCT dose ranged from 20 to 60 mg/day. Mean final optimized MPH ERCT dose ranged from 40.0 mg/day in 6–8 year-old participants to 44.8 mg/day for 11–12 year-old participants. There was a progressive decrease in mean (standard deviation) ADHD-RS-IV total score from 40.1 (8.72) at baseline to 12.4 (7.88) at OL week 5, with similar improvement patterns for hyperactivity/impulsivity and inattentiveness subscale scores. Participants optimized to MPH ERCT 50/60 mg/day had a significantly higher mean (standard error) ADHD-RS-IV score at baseline compared with participants optimized to MPH ERCT 20 mg/day (42.4 [1.34] vs. 35.1 [2.55]; p = 0.013). Treatment-emergent AEs were reported by 65/90 (72.2%) participants in the dose-optimization period.\n\nConclusions: Dose-optimization period results describing relationships between change in ADHD symptom scores and final optimized MPH ERCT dose will be valuable for clinicians optimizing MPH ERCT dose.\n\nKeywords: \nmethylphenidatepharmaceutical formulationdose–response relationshipdrugattention-deficit/hyperactivity disordersymptoms\n==== Body\nIntroduction\nThe American Academy of Pediatrics (AAP) strongly recommends pharmacotherapy and/or evidence-based behavior therapy (preferably both) for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children aged 6–11 years, and treatment with US Food and Drug Administration (FDA)-approved medication for ADHD is strongly recommended for adolescents (12–18 years) with ADHD (American Academy of Pediatrics 2011). Methylphenidate (MPH)- and amphetamine-based psychostimulants are considered the standard of care for ADHD pharmacotherapy (Pliszka 2007). Most clinicians who treat ADHD patients with MPH- and amphetamine-based medications prescribe a long-acting medication, alone or with an immediate-release formulation for afternoon dosing when coverage with an extended-release (ER) drug is not adequate (Fullerton et al. 2012; Lachaine et al. 2012; Briars and Todd 2016; Hauck et al. 2017).\n\nAn ER chewable tablet (ERCT) formulation of MPH (QuilliChew ER®) has been approved by the US FDA for the treatment of ADHD in patients aged 6 years and older (QuilliChew ER package insert 2016). The MPH ERCTs formulation offers a child-friendly alternative for patients or parents who are not satisfied with the available formulation options, and especially for those individuals who cannot or prefer not to swallow tablets or capsules. MPH ERCT is available in a range of dosage strengths for individualizing treatment, including 20-, 30-, and 40-mg tablets, and the 20- and 30-mg tablets are functionally scored for additional dosing options of 10 and 15 mg, respectively (QuilliChew ER package insert 2016).\n\nAs with other ADHD medications, the clinician should optimize MPH ERCT dose for the individual patient (Pliszka 2007; American Academy of Pediatrics 2011; QuilliChew ER package insert 2016). AAP treatment guidelines emphasize that although ADHD symptom improvements may be seen at lower doses, increasing dose may yield greater improvement in the individual patient (American Academy of Pediatrics 2011), as demonstrated in dose-response curves for ADHD symptoms (Greenhill et al. 1996). Adverse effects also increase with dose, however (Greenhill et al. 2001), and guidelines state that medication dose should be titrated to achieve maximum benefit with minimum adverse effects (American Academy of Pediatrics 2011). Each patient has their own therapeutic window and optimal dose (Pliszka 2007; Huss et al. 2014), and both ADHD symptoms and drug tolerability should be monitored over a titration period and throughout treatment (Pliszka 2007).\n\nEfficacy and safety of MPH ERCT (20–60 mg) has been demonstrated in children with ADHD in a phase 3 study using the laboratory classroom design (Wigal et al. 2017), in which MPH ERCT treatment significantly improved ADHD symptoms compared with placebo based on average postdose Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Rating Scale-Combined scores (Wigal et al. 2017). The study design for that trial included a 6-week, open-label (OL), dose-optimization period followed by a double-blind laboratory classroom evaluation. Information collected during the dose-optimization period, including MPH ERCT dose and efficacy changes over time, may inform clinicians in making dosing decisions for this formulation. The objective of this analysis, therefore, was to examine MPH ERCT dose patterns, ADHD symptom scores, and safety outcomes during the OL dose-optimization period preceding the laboratory classroom evaluation.\n\nMethods\nThis was a secondary analysis of a phase 3, laboratory classroom study carried out at six U.S. sites (Wigal et al. 2017). The study was conducted in accordance with the International Council for Harmonisation Guideline for Good Clinical Practice (International Council for Harmonisation 1998) and other applicable regulatory requirements. The protocol, consent and assent forms, and the investigator's brochure received institutional review board approval before initiation of the study. Parents/guardians provided written informed consent, and children gave assent, before participation and before any study procedures being performed.\n\nStudy design\nThe study included a 6-week OL, dose-optimization treatment period followed by a 1-week randomized, double-blind, placebo-controlled period. Participants received MPH ERCT at a starting dose of 20 mg once daily at baseline. The dose could be titrated up or down in 10–20 mg/day increments weekly at week 1 through 5 visits to optimize efficacy and tolerability. Dose adjustments were made at the weekly visit after efficacy and safety assessments were completed. No adjustments were made at the last OL dose-optimization period visit (week 6). Participants who could not tolerate the 20-mg dose were discontinued; the maximum dose was 60 mg/day. In the double-blind treatment period, participants were randomly assigned to receive 1 week of MPH ERCT at their final individually optimized dose or matching placebo, followed by a laboratory classroom evaluation.\n\nParticipants\nBoys and girls 6–12 years of age diagnosed with ADHD, who were deemed to have the need for pharmacological treatment for ADHD in the judgment of the investigator, were eligible. Diagnosis was determined by a psychiatrist, developmental pediatrician, pediatrician, or licensed allied health professional, and confirmed at screening by Schedule for Affective Disorders and Schizophrenia for School Age Children (K-SADS) semistructured diagnostic interview (Kaufman et al. 1997). Eligible participants also had an investigator-administered Clinical Global Impressions-Severity (CGI-S) score of 3 (mildly ill) or greater at screening, and an ADHD Rating Scale (ADHD-RS-IV) home version score at or above 90th percentile for gender and age on hyperactive–impulsive subscale, inattentive subscale, and/or total score at screening or baseline.\n\nExclusion criteria and prohibited medications were described previously (Wigal et al. 2017). Briefly, they included presence of significant anxiety, depression, or other psychiatric disorder; substance abuse; personal or family history of Tourette's syndrome; seizure disorder; clinically significant or severe medical illness or condition; history of HIV or hepatitis B or C infections; use of psychotropic agents (sedative hypnotics at a stable dose for at least 30 days before baseline allowed as a sleep aid); history of hypersensitivity or lack of efficacy to MPH; or positive test for illicit drug use at screening. Individuals were also excluded from participating if they had severe hypertension, known structural cardiac disorders, serious cardiac conditions, serious arrhythmias, cardiomyopathy, coronary artery disease, or clinically significant abnormal electrocardiogram or abnormal cardiac findings on physical examination (including presence of a pathologic murmur); review and approval by the medical monitor were required for participation of any individual who had an immediate family history of sudden cardiac death. Pharmacologic treatment for ADHD, including stimulant medications for the control of ADHD (noninvestigational), was allowed until 24 hours before baseline measurements.\n\nAssessments\nThe ADHD-RS-IV and CGI-S were administered by study investigators at screening, baseline, and weekly visits during the OL period, and the CGI-Improvement (CGI-I) scale was administered weeks 1 through 6. The Conners' Parent Rating Scale (CPRS) (Conners et al. 1998) was administered weekly by a parent or guardian. Endpoints derived from the ADHD-RS-IV included ADHD-RS-IV total score, hyperactivity/impulsivity and inattentiveness subscale scores, and treatment response (defined as ≥50% improvement from baseline in ADHD-RS-IV total score). CPRS endpoints included CPRS factor scores (oppositional, cognitive problems/inattention, hyperactivity, anxious-shy, perfectionism, social problems, and psychosomatic) and scale scores (ADHD index, Global index: restless-impulse, Global index: emotional lability, Global index total score, and Diagnostic and Statistical Manual for Mental Disorders, fourth edition [DSM-IV] inattentive, DSM-IV hyperactive/impulsive, and DSM-IV total score) (Conners 1998).\n\nSafety assessments at weekly visits throughout the OL period included adverse event (AE) collection, vital sign measurements, and administration of the Columbia-Suicide Severity Rating Scale (C-SSRS). Height and weight were measured at screening, baseline, follow-up, and/or early termination. Physical examination, clinical laboratory tests, and electrocardiogram recordings were performed at screening.\n\nStatistical analysis\nThe enrolled safety population was defined as all enrolled participants who received at least one dose of OL study medication and had at least one postbaseline safety assessment.\n\nFinal optimized MPH ERCT dose was defined as the assigned dose at the final dose-optimization period visit (week 6). Final optimized dose (in mg and in mg/kg) and number (%) of participants optimized at each dose level (20, 30, 40, 50, and 60 mg) were summarized overall and by sex, age (6–8, 9–10, 11–12 years), weight (<60 lb [27.2 kg], ≥60 lb) groups, and baseline ADHD-RS-IV total score using descriptive statistics. An ADHD-RS-IV total score of 42 was used as a cutoff for moderate (<42) versus marked (≥42) severity of symptoms at baseline based on an analysis linking ADHD-RS-IV total and CGI-S scores in children (6–12 years) with ADHD (Goodman et al. 2010). The number (%) of participants at each dose level and number (%) of participants whose MPH ERCT dose was increased, decreased, or maintained were summarized by time point.\n\nChange from baseline in ADHD-RS-IV total score, ADHD-RS-IV hyperactivity/impulsivity and inattentiveness subscale scores, and CGI-S score was summarized by time point using descriptive statistics; CGI-I score was summarized by time point. In a post hoc analysis, ADHD-RS-IV total score was analyzed by week using a mixed-effects model for repeated measures with terms for final optimized dose (using three groups: 20, 30/40, or 50/60 mg), visit, interaction of final optimized dose and visit, and baseline score. CPRS factor and scale scores and the proportion of responders based on ADHD-RS-IV total score were determined for the final OL visit (week 6).\n\nResults\nNinety participants were enrolled in the study and 85 completed dose optimization. Of the five participants who discontinued during the OL period, one discontinued due to an AE (dysgeusia, bad taste of medicine [last assigned dose, 40 mg]), three withdrew consent (one each: unhappy with treatment/dose [last assigned dose, 50 mg], inability to attend weekly appointments [last assigned dose, 30 mg], and lack of clinical benefit [last assigned dose, 50 mg]), and one was lost to follow-up (last assigned dose, 50 mg). No children were discontinued due to an inability to tolerate the 20-mg dose. The mean (standard deviation [SD]) age of enrolled participants was 9.5 (1.73) years; 55 participants were boys (Table 1). In the enrolled safety population, 25.6% of patients were diagnosed as inattentive type ADHD, 0% as hyperactive/impulsive, and 74.4% as combined.\n\nTable 1. Baseline Demographics and Clinical Characteristics, Enrolled Safety Population\n\n \tMPH ERCT (n = 90)\t\nGender, n (%)\t\n Male\t55 (61.1)\t\n Female\t35 (38.9)\t\nMean ± SD age, years\t9.5 (1.73)\t\nAge categories, (%)\t\n 6–7 years\t16 (17.8)\t\n 8–10 years\t47 (52.2)\t\n 11–12 years\t27 (30.0)\t\nRace, n (%)\t\n White\t52 (57.8)\t\n Black/African American\t32 (35.6)\t\n Asian\t1 (1.1)\t\n Other\t5 (5.6)\t\nEthnicity, n (%)\t\n Hispanic/Latino\t13 (14.4)\t\n Non-Hispanic/Latino\t77 (85.6)\t\nADHD type, n (%)\t\n Inattentive\t23 (25.6)\t\n Hyperactive/impulsive\t0\t\n Combined\t67 (74.4)\t\nADHD, attention-deficit/hyperactivity disorder; ADHD-RS-IV, attention-deficit/hyperactivity disorder rating scale; MPH ERCT, methylphenidate extended-release chewable tablets; SD, standard deviation.\n\nDose optimization\nAll participants received MPH ERCT 20 mg/day through the first study week. Mean MPH ERCT daily dose then increased weekly, from 29.4 mg/day (median, 30 mg/day) after the first postassessment adjustment at week 1 (n = 90) to 42.8 mg/day (median, 40 mg/day) after the final adjustment at week 5 (n = 86); at week 6, the mean optimized dose for the 85 subjects who completed the OL period was 42.7 mg/day (median, 40 mg/day). Dose shifts over the course of the optimization period are summarized in Table 2, and the distribution of the individual participants' MPH ERCT daily dose is shown by week in Figure 1. The first adjustments to doses greater than 30 mg/day were made later in the optimization period for participants aged 6–8 compared with the 9–10 and 11–12 year-old groups. Some of the participants in the older two groups had their dose titrated up to 40 mg after 1 week of treatment (at the week 1 visit), and then to 60 mg after 2 weeks. The earliest any child in the 6–8 year-old group received the 40-mg dose was after 2 weeks of treatment. No children in the youngest age group had their dose adjusted to 50 mg/day before 3 weeks of treatment had been completed or to 60 mg/day dose before 4 weeks were completed.\n\nFIG. 1. Distribution of individual MPH ERCT daily dose by week. aDose adjustment was not allowed at week 6. MPH ERCT, methylphenidate extended-release chewable tablets.\n\nTable 2. Dose Titration During the Open-Label Period; Adjustments by Weeka\n\n \tTitration of MPH ERCT during OL period\t\nOL week\tIncreased n (%)\tDecreased n (%)\tMaintained n (%)\tTotal n\t\n1\t72 (80.0)\t0\t18 (20.0)\t90\t\n2\t64 (71.9)\t0\t25 (28.1)\t89\t\n3\t31 (35.2)\t2 (2.3)\t55 (62.5)\t88\t\n4\t18 (20.7)\t5 (5.7)\t64 (73.6)\t87\t\n5\t3 (3.5)\t2 (2.3)\t81 (94.2)\t86\t\n6\t0\t0\t85 (100)\t85\t\na Dose adjustments were made following efficacy assessment; adjustment was not allowed at the week 6 visit.\n\nMPH ERCT, methylphenidate extended-release chewable tablets; OL, open label.\n\nThe final daily MPH ERCT dose at the end of dose optimization was 20 mg for 11 participants, 30 mg for 14 participants, 40 mg for 25 participants, 50 mg for 21 participants, and 60 mg for 19 participants (mean final dose, 42.6 mg; n = 90). Mean (SD) final optimized dose in mg/kg/day was 1.19 (0.506), ranging from 0.38 to 2.45 mg/kg for all participants. Mean final optimized daily dose is shown by baseline demographic characteristics in Table 3. Mean dose at the end of the OL period was numerically highest for children aged 11–12 years (44.8 mg/day) and lowest for those aged 6–8 years (40.0 mg/day), with mean dose for 9–10-year olds in between (42.8 mg/day); the median final dose was 40 mg for all 3 age groups. Mean final dose was similar for participants weighing less than 60 lb (n = 19; 42.1 mg [1.76 mg/kg]) compared with participants weighing 60 lb or greater (n = 71; 42.7 mg [1.04 mg/kg]). Participants with baseline ADHD-RS-IV total scores of 42 or greater (n = 45) had a mean (SD) final optimized MPH ERCT dose of 45.8 (12.52) mg/day, while those with baseline ADHD-RS-IV total scores less than 42 had a mean (SD) of 39.3 (12.68) mg/day (n = 45).\n\nTable 3. Final Optimized Methylphenidate Extended-Release Chewable Tablets Dosea\n\n \t \tMPH ERCT dose in mg\tMPH ERCT dose in mg/kg\t\n \tN\tMean (SD)\tMedian (min, max)\tMean (SD)\tMedian (min, max)\t\nOverall\t90\t42.6 (12.94)\t40 (20, 60)\t1.19 (0.506)\t1.07 (0.38, 2.45)\t\nSex\t\n Male\t55\t42.7 (13.53)\t40 (20, 60)\t1.20 (0.571)\t1.01 (0.38, 2.45)\t\n Female\t35\t42.3 (12.15)\t40 (20, 60)\t1.19 (0.393)\t1.09 (0.52, 2.01)\t\nAge\t\n 6–8 years\t27\t40.0 (13.87)\t40 (20, 60)\t1.41 (0.519)\t1.38 (0.67, 2.45)\t\n 9–10 years\t36\t42.8 (12.79)\t40 (20, 60)\t1.18 (0.544)\t1.06 (0.38, 2.35)\t\n 11–12 years\t27\t44.8 (12.21)\t40 (20, 60)\t0.99 (0.342)\t0.94 (0.54, 1.65)\t\nWeight\t\n <60 lb\t19\t42.1 (15.48)\t50 (20, 60)\t1.76 (0.577)\t1.90 (0.74, 2.45)\t\n ≥60 lb\t71\t42.7 (12.30)\t40 (20, 60)\t1.04 (0.361)\t1.01 (0.38, 2.01)\t\nBaseline ADHD-RS-IV scoreb\t\n <42\t45\t39.3 (12.68)\t40 (20, 60)\t1.15 (0.478)\t1.04 (0.38, 2.30)\t\n ≥42\t45\t45.8 (12.52)\t50 (20, 60)\t1.24 (0.536)\t1.09 (0.56, 2.45)\t\na At OL week 6 or last assessment.\n\nb Based on the third quartile of children who were moderately ill (CGI-S = 4) in Goodman et al. 2010.\n\nCGI-S, Clinical Global Impressions-Severity scale; MPH ERCT, methylphenidate extended-release chewable tablets; ADHD-RS-IV, Attention-Deficit/Hyperactivity Disorder Rating Scale; SD, standard deviation; OL, open label.\n\nADHD symptoms\nOver the course of MPH ERCT dose optimization, there was a progressive decrease in mean (SD) ADHD-RS-IV total score from 40.1 (8.72) at baseline visit to 12.4 (7.88) at week 5 (Fig. 2A). There was little change in ADHD-RS-IV total score between week 5 and the last dose of OL treatment at week 6 (12.5 [7.80]), when few dose adjustments were made (dosage was maintained in 81/86 [94%] participants). Mean (SD) change from baseline in ADHD-RS-IV total score at week 6 was −27.5 (9.69). Improvement in ADHD-RS-IV hyperactivity/impulsivity and inattentiveness subscale scores showed a similar pattern of progressive improvement over the dose-optimization period (Fig. 2B); at week 6, mean (SD) change from baseline in hyperactivity/impulsivity subscale score was −13.7 (5.92) and in inattentiveness subscale score was −13.8 (5.36). A total of 74/85 (87.1%) participants had achieved ADHD-RS-IV response (≥50% improvement from baseline) at the final dose-optimization period visit, week 6. The pattern of improvement in ADHD symptoms during dose optimization was also reflected in a shift in the distribution of CGI-S and CGI-I scores over the 6-week period (Supplementary Fig. S1A, B; Supplementary Data are available online at www.liebertpub.com/cap). Changes from baseline to week 6 in CPRS factor and scale scores are reported in Supplementary Table S1.\n\nFIG. 2. Mean (SD) ADHD-RS-IV scores by dose-optimization period open-label week, intent-to-treat population. (A) ADHD-RS-IV total score. (B) ADHD-RS-IV subscale scores. ADHD-RS-IV, Attention-Deficit/Hyperactivity Disorder Rating Scale; SD, standard deviation.\n\nIn the analysis of ADHD-RS-IV total score by visit, there was a significant interaction between final optimized dose and study visit (p < 0.001), indicating that the pattern of improvement in symptoms over the course of the dose-optimization period differed for participants optimized to final daily doses of 20, 30/40, and 50/60 mg MPH ERCT (Fig. 3). Least squares mean (standard error) ADHD-RS-IV total score at baseline was significantly higher for participants with a final optimized MPH ERCT dose of 50/60 mg/day (42.4 [1.34]) compared with those optimized to the 20 mg/day dose (35.1 [2.55]; p = 0.013). The 30/40 mg/day (39.8 [1.36]) and 20 mg/day final optimized dose groups did not differ significantly at baseline. Differences in mean ADHD-RS-IV total score were observed between final optimized dose groups during the optimization period (weeks 1–4); however, all dosage groups reach a similar mean ADHD-RS-IV total score by the end of the dose optimization period (week 5; Fig. 3).\n\nFIG. 3. Mean (SD) ADHD-RS-IV total score by dose-optimization period open-label week, by final optimized dose. ADHD-RS scores were analyzed using a mixed-effects model for repeated measures with terms for week, final optimized dose (20, 30/40, and 50/60 mg), and the interaction between visit and final optimized dose. ap < 0.05 versus 20 mg final optimized dose.\n\nThe trajectory of symptom improvement observed over the course of dose optimization for age, sex, weight, and treatment/naive versus experienced subgroups is shown in Supplementary Figure S2.\n\nSafety\nTreatment-emergent AEs (TEAEs) were reported by 65/90 (72.2%) participants in the OL period. OL period TEAEs reported by at least 5% of participants in either the ADHD medication-naive or previous ADHD medication group are listed in Table 4.\n\nTable 4. Treatment-Emergent Adverse Events With an Incidence ≥5% in the Dose-Optimization Period by Previous Attention-Deficit/Hyperactivity Disorder Medication Treatment; Safety Population, n (%)\n\n \tTreatment naive\t \t\nTEAE, n (%)\tYes (n = 56)\tNo (n = 34)\tTotal (N = 90)\t\nAny TEAE\t40 (71.4)\t25 (73.5)\t65 (72.2)\t\nDecreased appetite\t22 (39.3)\t11 (32.4)\t33 (36.7)\t\nUpper abdominal pain\t8 (14.3)\t5 (14.7)\t13 (14.4)\t\nIrritability\t8 (14.3)\t4 (11.8)\t12 (13.3)\t\nMood swings\t9 (16.1)\t3 (8.8)\t12 (13.3)\t\nInsomnia\t7 (12.5)\t3 (8.8)\t10 (11.1)\t\nUpper respiratory tract infection\t7 (12.5)\t3 (8.8)\t10 (11.1)\t\nDysgeusia\t6 (10.7)\t2 (5.9)\t8 (8.9)\t\nHeadache\t5 (8.9)\t3 (8.8)\t8 (8.9)\t\nInitial insomnia\t4 (7.1)\t0\t4 (4.4)\t\nVomiting\t4 (7.1)\t0\t4 (4.4)\t\nViral infection\t3 (5.4)\t1 (2.9)\t4 (4.4)\t\nNausea\t3 (5.4)\t0\t3 (3.3)\t\nGastroenteritis\t1 (1.8)\t2 (5.9)\t3 (3.3)\t\nTic\t1 (1.8)\t2 (5.9)\t3 (3.3)\t\nExcoriation\t0\t3 (8.8)\t3 (3.3)\t\nContusion\t0\t2 (5.9)\t2 (2.2)\t\nTEAE, treatment-emergent adverse event.\n\nThe greatest severity of TEAEs reported was mild (19/90 [21.1%] participants) or moderate (46/90 [51.1%]); no severe TEAEs were reported during the dose-optimization period (or at any time during the study). Participants with cardiovascular-related TEAEs reported during the dose-optimization period included one child with syncope (moderate) and tachycardia (mild) and a second child with tachycardia (mild), both treatment naive; increased systolic blood pressure (114 mm Hg, +20 mm Hg from baseline) was reported as a TEAE in one participant whose prior medications included mixed amphetamine salts (resolved by following visit). No serious AEs were reported at any time during the study. Based on the C-SSRS, no suicidal thoughts or behaviors were reported during the OL period.\n\nChanges from baseline in vital signs at week 6 are summarized in Table 5. A total of 42/90 participants had at least one blood pressure value during the dose-optimization period considered by the sponsor to be potentially clinically significant; 20/90 participants had 1 or more potentially clinically significant pulse rate values during the dose-optimization period (Table 5).\n\nTable 5. Vital Sign Measures and Potentially Clinically Significant Results\n\n \tSystolic BP, mm Hg\tDiastolic BP, mm Hg\tPulse rate, bpm\t\nBaseline, mean (SD)\t103.6 (9.08)\t63.6 (6.19)\t82.6 (11.02)\t\nWeek 6, mean (SD)\t105.7 (10.28)\t65.6 (7.39)\t81.8 (9.89)\t\nChange from baseline, mean (SD)\t1.9 (8.97)\t2.0 (7.76)\t–0.7 (12.12)\t\nPCS value,an/N\t13/90\t8/90\t5/90\t\nPCS increase,bn/N\t6/90\t36/90\t15/90\t\na PCS values defined by sponsor: blood pressure value greater than the 95th percentile for age and sex or pulse rate greater than 110 bpm.\n\nb Systolic BP increase ≥20 mm Hg, diastolic BP increase ≥10 mm Hg, or pulse rate increase ≥25 bpm.\n\nBP, blood pressure; PCS, potentially clinically significant.\n\nDiscussion\nAlthough ADHD treatment guidelines emphasize the importance of optimizing stimulant medication dose (Pliszka 2007; American Academy of Pediatrics 2011), there are few published reports assessing response to ADHD medication during dose titration in clinical trials (Greenhill et al. 1996, 2001; Huss et al. 2014). The MPH ERCT dose and ADHD symptom data collected over the course of the initial 6-week OL period of a laboratory classroom study provide insight into how investigators adjusted ADHD medication dosage during optimization at treatment onset. Overall, the final optimized daily MPH ERCT dose for the enrolled population ranged from 20 to 60 mg (the minimum and maximum doses allowed in the study), with a mean of 42.6 mg (1.19 mg/kg; n = 90). Previous laboratory classroom studies of stimulants for the treatment of children with ADHD that used dose optimization have similarly shown that the range of doses to which individual patients were optimized included all available study doses (Wigal et al. 2009, 2013; Murray et al. 2011; Wigal et al. 2014; Childress et al. 2015, 2017).\n\nApproximately 70%–80% of participants had MPH ERCT dose increases after efficacy and safety assessments at the week 1 and 2 visits. The majority of participants were judged by investigators to have reached their individual optimal dose by the end of week 3; 63% and 74% of patients had no dose increased at the end of weeks 3 and 4, respectively. Few dose reductions were reported during the dose-optimization period. Adjustments to the highest allowable doses were made more slowly for younger children (6–8 years) compared with older children (9–10 and 11–12 years); shifts to the 60-mg dose were observed as early as the end of week 2 in older children, but not until the end of week 4 for those 6–8 years of age. Mean final optimized daily dose of MPH ERCT generally increased with age: numerically lowest for children aged 6–8 years and highest for those aged 11–12 years, with the mean dose for 9–10-year olds in between. However, the median dose was the same across age groups (40 mg).\n\nOverall, the severity of ADHD symptoms, based on mean ADHD-RS-IV total score, diminished progressively over the course of dose optimization as mean MPH ERCT dose increased, in line with previous reports showing dose-optimization period results or dose–response relationships for ADHD patients treated in clinical trials (Stein et al. 2003; Childress et al. 2015). The week-by-week improvement found in both hyperactive–impulsive and inattentive subscale scores was similar to that observed for ADHD-RS-IV total score. The pattern of improvement in ADHD-RS-IV total score during dose optimization was generally similar between age, sex, weight, and previous treatment experience subgroups.\n\nDifferences in pattern of symptom improvement over the course of the dose-optimization period were observed between participants who were optimized to high (50/60 mg) versus low (20 mg) MPH ERCT final daily doses. However, by the end of the dose-optimization period, mean ADHD-RS-IV total scores were similar for participants at each final optimized dose (20, 30–40, and 50–60 mg/day). On average, participants with more severe symptoms at baseline, based on an ADHD-RS-IV total score of 42 or greater, were optimized to a numerically higher mean final MPH ERCT dose compared with participants with less severe symptoms, consistent with the significantly higher mean baseline ADHD-RS-IV total score observed for participants who were optimized to highest (50/60 mg) versus lowest (20 mg) daily doses of MPH ERCT.\n\nThere were several limitations of the analysis. Measures of clinical response used in this analysis were secondary efficacy endpoints in the original study protocol. The original study was designed to examine the efficacy of MPH ERCT primarily in the double-blind, placebo-controlled laboratory classroom evaluation. In addition, the dose-optimization period was OL, which could have biased ADHD-RS-IV, CGI, and CPRS scoring, and did not include a placebo control. Dose was not randomly assigned in this study, and therefore dose–response inferences cannot be made based on these results. The objective of this analysis was to present descriptively the MPH ERCT dose pattern during the optimization period. Finally, restriction of participation in the study to children without significant comorbid psychiatric or medical conditions may limit the generalizability of these findings.\n\nConclusions\nBecause each individual has their own therapeutic window for efficacy and safety of ADHD medication and a therapeutic plasma or blood range for MPH has not been established, dose optimization is an important step in dose selection both in the clinic and in ADHD trials (Kimko et al. 1999; Swanson and Volkow 2002; Pliszka 2007; American Academy of Pediatrics 2011). A dose-optimization period preceding a randomized, double-blind testing period (for example, in laboratory classroom studies) is a commonly used study design for ADHD clinical trials (McGough et al. 2006; Wigal et al. 2009, 2013; Murray et al. 2011; Wigal et al. 2014; Childress et al. 2015, 2017). Several studies have reported efficacy, safety, or dosing data collected during dose optimization (Huss et al. 2014; Childress et al. 2015, 2017). However, the current analysis is one of the few analyses that have explored in detail how ADHD medication dose was adjusted over the optimization period, together with changes in ADHD symptoms as dose was optimized. The results of this analysis provide information about the relationship between change in ADHD symptom scores and final optimized MPH ERCT dose and patient subgroup comparisons, which will be valuable for clinicians optimizing MPH ERCT dose in practice.\n\nClinical Significance\nIn the 6-week, OL dose-optimization period of this laboratory classroom study, ADHD symptom severity progressively decreased as MPH ERCT dose increased from an initial dose of 20 mg/day to a mean of 42.8 mg/day after final adjustment at week 5. Children optimized to higher doses had a significantly higher mean ADHD-RS-IV score at baseline compared with those optimized to the lowest MPH ERCT dose. Understanding relationships between change in ADHD symptom scores and final optimized MPH ERCT dose overall and in subgroups in this study will help clinicians optimize MPH ERCT dose in their own patients.\n\nSupplementary Material\nSupplemental data\n Supplemental data\n Supplemental data\n Acknowledgments\nThis research was sponsored by NextWave Pharmaceuticals, a wholly owned subsidiary of Pfizer Inc. Medical writing support was provided by Kathleen M. Dorries, PhD, Peloton Advantage, and was funded by Pfizer Inc.\n\nAuthor Contributions\nStudy design: S.A.B. and S.B.W.; Study investigator: S.B.W.; Enrolled patients: S.B.W.; Collection and assembly of data: S.B.W.; Data analysis: D.B.W.; Data interpretation: all authors; Article preparation: S.B.W. and D.B.W.; Article review and revisions: all authors; Final approval of article: all authors.\n\nDisclosures\nS.B.W. receives or has received research support, acted as a consultant, been an advisory board member, and/or served on a speakers bureau for Addrenex Pharmaceuticals, Akili, Arbor, Eli Lilly and Company, Forest Pharmaceuticals, Ironshore, McNeil Consumer and Specialty Pharmaceuticals, Neos, Neurovance, NextWave Pharmaceuticals, NIMH, NLS, Noven, NuTec Pharma, Otsuka, Pfizer, Purdue, Quintiles, Rho, Rhodes Pharmaceuticals, Shionogi, Shire US, Sunovion, Taisho Pharmaceutical, and Tris Pharma. A.C. receives or has received research support, acted as a consultant, been an advisory board member, and/or served as a speaker for Shire Pharmaceuticals, Pfizer, Noven, NextWave Pharmaceuticals, Lilly USA, Forest Research Institute, Otsuka, Sunovion, Ironshore, Rhodes, Theravance, Neurovance, Neos, Arbor, Tris Pharma, Purdue, Lundbeck, Pearson, and Alcobra. S.A.B. and H.W.B. were paid consultants for Pfizer Inc. in connection with the development of this article. P.N. is a former employee of Pfizer Inc. P.C., D.B.W., R.A., and D.P. are employees of Pfizer Inc. P.C. and D.B.W. hold Pfizer stock and stock options.\n==== Refs\nReferences\nAmerican Academy of Pediatrics : ADHD: Clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents . Pediatrics \n128 :1007 –1022 , 2011 22003063 \nBriars L , Todd T : A review of pharmacological management of attention-deficit/hyperactivity disorder . 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Can J Psychiatry \n62 :393 –402 , 2017 28103079 \nHuss M , Ginsberg Y , Arngrim T , Philipsen A , Carter K , Chen CW , Gandhi P , Kumar V : Open-label dose optimization of methylphenidate modified release long acting (MPH-LA): A post hoc analysis of real-life titration from a 40-week randomized trial . Clin Drug Investig \n34 :639 –649 , 2014 \nInternational Council for Harmonisation: ICH harmonised tripartite guideline: Statistical principles for clinical trials E9. \nInternational Conference on Harmonisation \n1998 ; www.ich.org/products/guidelines/efficacy/efficacy-single/article/statistical-principles-for-clinical-trials.html (accessed 4 16 , 2017 )\nKaufman J , Birmaher B , Brent D , Rao U , Flynn C , Moreci P , Williamson D , Ryan N : Schedule for affective disorders and schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL): Initial reliability and validity data . J Am Acad Child Adolesc Psychiatry \n36 :980 –988 , 1997 9204677 \nKimko HC , Cross JT , Abernethy DR : Pharmacokinetics and clinical effectiveness of methylphenidate . Clin Pharmacokinet \n37 :457 –470 , 1999 10628897 \nLachaine J , Beauchemin C , Sasane R , Hodgkins PS : Treatment patterns, adherence, and persistence in ADHD: A Canadian perspective . Postgrad Med \n124 :139 –148 , 2012 22691908 \nMcGough JJ , Wigal SB , Abikoff H , Turnbow JM , Posner K , Moon E : A randomized, double-blind, placebo-controlled, laboratory classroom assessment of methylphenidate transdermal system in children with ADHD . J Atten Disord \n9 :476 –485 , 2006 16481664 \nMurray DW , Childress A , Giblin J , Williamson D , Armstrong R , Starr HL : Effects of OROS methylphenidate on academic, behavioral, and cognitive tasks in children 9 to 12 years of age with attention-deficit/hyperactivity disorder . Clin Pediatr (Phila) \n50 :308 –320 , 2011 21436147 \nPliszka S : Practice parameter for the assessment and treatment of children and adolescents with attention-deficit/hyperactivity disorder . J Am Acad Child Adolesc Psychiatry \n46 :894 –921 , 2007 17581453 \nQuilliChew ER \n[package insert] : New York, NY , NextWave Pharmaceuticals, Inc. , 2016 \nStein MA , Sarampote CS , Waldman ID , Robb AS , Conlon C , Pearl PL , Black DO , Seymour KE , Newcorn JH : A dose-response study of OROS methylphenidate in children with attention-deficit/hyperactivity disorder . Pediatrics \n112 :e404 –e413 , 2003 14595084 \nSwanson JM , Volkow ND : Pharmacokinetic and pharmacodynamic properties of stimulants: Implications for the design of new treatments for ADHD . Behav Brain Res \n130 :73 –78 , 2002 11864720 \nWigal S , Childress A , Berry S , Belden H , Walters F , Chappell P , Sherman N , Orazem J , Palumbo D : Efficacy and safety of a chewable methylphenidate extended-release tablet in children with attention-deficit/hyperactivity disorder . J Child Adolesc Psychopharmacol \n27 :690 –699 , 2017 28557548 \nWigal SB , Childress AC , Belden HW , Berry SA : NWP06, an extended-release oral suspension of methylphenidate, improved attention-deficit/hyperactivity disorder symptoms compared with placebo in a laboratory classroom study . J Child Adolesc Psychopharmacol \n23 :3 –10 , 2013 23289899 \nWigal SB , Greenhill LL , Nordbrock E , Connor DF , Kollins SH , Adjei A , Childress A , Stehli A , Kupper RJ : A randomized placebo-controlled double-blind study evaluating the time course of response to methylphenidate hydrochloride extended-release capsules in children with attention-deficit/hyperactivity disorder . J Child Adolesc Psychopharmacol \n24 :562 –569 , 2014 25470572 \nWigal SB , Kollins SH , Childress AC , Squires L : A 13-hour laboratory school study of lisdexamfetamine dimesylate in school-aged children with attention-deficit/hyperactivity disorder . Child Adolesc Psychiatry Ment Health \n3 :17 , 2009 19508731\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1044-5463",
"issue": "28(5)",
"journal": "Journal of child and adolescent psychopharmacology",
"keywords": "attention-deficit/hyperactivity disorder; dose–response relationship; drug; methylphenidate; pharmaceutical formulation; symptoms",
"medline_ta": "J Child Adolesc Psychopharmacol",
"mesh_terms": "D001289:Attention Deficit Disorder with Hyperactivity; D000697:Central Nervous System Stimulants; D002648:Child; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008774:Methylphenidate; D013607:Tablets; D016896:Treatment Outcome",
"nlm_unique_id": "9105358",
"other_id": null,
"pages": "314-321",
"pmc": null,
"pmid": "29641237",
"pubdate": "2018-06",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "22003063;8885584;25470572;21436147;16481664;11211366;28557548;22691908;25692608;10628897;9700518;19508731;9680050;25015027;28103079;9204677;17581453;27183299;27453697;22302327;11864720;14595084;23289899",
"title": "Optimization of Methylphenidate Extended-Release Chewable Tablet Dose in Children with ADHD: Open-Label Dose Optimization in a Laboratory Classroom Study.",
"title_normalized": "optimization of methylphenidate extended release chewable tablet dose in children with adhd open label dose optimization in a laboratory classroom study"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2021-03828",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPHENIDATE HYDROCHLORIDE"
... |
{
"abstract": "Bullous pemphigoid (BP) is an autoimmune disorder which is usually chronic, with blistering that predominantly affects the skin and occasionally the mucosa, and which includes several different types. One of them is a very rare dyshidrosiform type which is localized on the hands and feet with small or large blisters on the palmoplantar surfaces. BP resulting from a drug reaction is a relatively rare occurrence, and so far more than 50 different medications have been identified as triggers. The aim of this article was to present the case of a paraplegic patient who developed this rare dyshidrosiform type of BP while he was being neurologically treated with baclofen. In spite of therapy with systemic and topical corticosteroids and other measures, successful treatment was achieved only after eliminating baclofen from the patient's regimen. His general state of health was seriously endangered due to nasal and skin methicillin-resistant Staphylococcus aureus (MRSA), urinary infection, and oral mycosis (soor), and he was at high risk of sepsis and a fatal outcome. Through our efforts, however, we managed to achieve an excellent outcome. According to our knowledge, this was the first case of baclofen-induced dyshidrosiform BP.",
"affiliations": "Professor Liborija Lugović Mihić, MD, PhD, Department of Dermatovenereology, Sestre milosrdnice University Hospital Center, Vinogradska cesta 29, 10 000 Zagreb, Croatia; liborija@gmail.com.",
"authors": "Lugović-Mihić|Liborija|L|;Duvančić|Tomislav|T|;Pavić|Ivana|I|;Gverić-Grginić|Ana|A|;Šitum|Mirna|M|;Dediol|Iva|I|",
"chemical_list": "D009125:Muscle Relaxants, Central; D001418:Baclofen",
"country": "Croatia",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1330-027X",
"issue": "27(3)",
"journal": "Acta dermatovenerologica Croatica : ADC",
"keywords": null,
"medline_ta": "Acta Dermatovenerol Croat",
"mesh_terms": "D001418:Baclofen; D006801:Humans; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus; D008875:Middle Aged; D009125:Muscle Relaxants, Central; D010264:Paraplegia; D010391:Pemphigoid, Bullous; D013203:Staphylococcal Infections; D014552:Urinary Tract Infections",
"nlm_unique_id": "9433781",
"other_id": null,
"pages": "184-187",
"pmc": null,
"pmid": "31542063",
"pubdate": "2019-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Baclofen-Induced Dyshidrosiform Bullous Pemphigoid in a Paraplegic Patient Complicated by Methicillin-Resistant Staphylococcus aureus (MRSA) and Urinary Infection.",
"title_normalized": "baclofen induced dyshidrosiform bullous pemphigoid in a paraplegic patient complicated by methicillin resistant staphylococcus aureus mrsa and urinary infection"
} | [
{
"companynumb": "HR-SAOL THERAPEUTICS-2019SAO00405",
"fulfillexpeditecriteria": "1",
"occurcountry": "HR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "WARFARIN"
},
"drugadditional": null,... |
{
"abstract": "OBJECTIVE\nTo compare the efficacy of dolutegravir plus lamivudine dual therapy (DT) with that of dolutegravir plus two NRTIs triple therapy (TT) as switch strategies.\n\n\nMETHODS\nA multicentre cohort of HIV-positive, HBsAg-negative patients with viral suppression (HIV-RNA ≤50 copies/mL) switching to DT or TT was retrospectively selected from the ARCA database. The effect of DT versus TT on virological failure (VF; defined as two consecutive HIV-RNA values >50 copies/mL or one HIV-RNA value ≥200 copies/mL) was evaluated by multivariable Cox regression models, overall and after stratifying for the presence of NRTI resistance-associated mutations (RAMs).\n\n\nRESULTS\nFrom December 2014 to June 2020, 628 patients were eligible: 118 (18.8%) started tenofovir/emtricitabine/dolutegravir, 306 (48.7%) abacavir/lamivudine/dolutegravir and 204 (32.5%) lamivudine/dolutegravir. The DT group had significantly higher nadir and baseline CD4 counts, a higher duration of viral suppression and a lower prevalence of RAMs at historical genotype. Overall, 41 VF occurred after a median of 1.7 years of follow-up, with a lower, but not statistically significant, rate for DT [versus TT, adjusted HR (aHR) = 0.58, 95% CI = 0.25-1.34]. However, DT was associated with less VF in the absence of RAMs when compared with tenofovir-based TT (aHR = 0.20, 95% CI = 0.06-0.67), but not with abacavir-based TT (aHR = 0.43, 95% CI = 0.17-1.11). Conversely, in the setting of pre-existing M184V/I, DT showed a trend to increased risk of VF (versus tenofovir-based TT, aHR = 137.50, 95% CI = 4.24-4464.06; versus abacavir-based TT, aHR = 33.88, 95% CI = 1.75-656.47).\n\n\nCONCLUSIONS\nLamivudine/dolutegravir maintenance DT showed similar efficacy to dolutegravir-based TT; however, past M184V/I may favour VF.",
"affiliations": "Fondazione Policlinico Universitario A. Gemelli IRCCS, UOC Malattie Infettive, Rome, Italy.;Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy.;Università Cattolica del Sacro Cuore, Dipartimento di Sicurezza e Bioetica Sezione Malattie Infettive, Rome, Italy.;Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy.;Clinica Malattie Infettive e Tropicali, Azienda Ospedaliero Universitaria di Modena, Modena, Italy.;Department of Medical Biotechnologies, University of Siena, Siena, Italy.;Fondazione Policlinico Universitario A. Gemelli IRCCS, UOC Malattie Infettive, Rome, Italy.",
"authors": "Borghetti|A|A|;Alkhatib|M|M|;Dusina|A|A|;Duca|L|L|;Borghi|V|V|;Zazzi|M|M|;Di Giambenedetto|S|S|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/jac/dkab429",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0305-7453",
"issue": null,
"journal": "The Journal of antimicrobial chemotherapy",
"keywords": null,
"medline_ta": "J Antimicrob Chemother",
"mesh_terms": null,
"nlm_unique_id": "7513617",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34849981",
"pubdate": "2021-11-28",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Virological outcomes with dolutegravir plus either lamivudine or two NRTIs as switch strategies: a multi-cohort study.",
"title_normalized": "virological outcomes with dolutegravir plus either lamivudine or two nrtis as switch strategies a multi cohort study"
} | [
{
"companynumb": "IT-ViiV Healthcare Limited-IT2021GSK255665",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOLUTEGRAVIR"
},
"drugadditi... |
{
"abstract": "We sought to determine the rate of incident neutropenia and identify potential clinical factors associated with incident neutropenia among patients treated with long courses of ceftaroline.\n\n\n\nWe retrospectively identified adult patients who received ceftaroline for ≥7 days consecutively at two large academic medical centres in Boston, USA between November 2010 and March 2015. Clinical characteristics (age, gender, medication allergies, baseline renal function, duration of ceftaroline exposure, total daily ceftaroline dose, body mass-adjusted ceftaroline dose and development of rash and neutropenia) were recorded and the rate of incident neutropenia was calculated. The Naranjo probability scale was used to assess whether ceftaroline exposure was associated with neutropenia. We assessed whether clinical factors were associated with neutropenia.\n\n\n\nThe overall rate of incident neutropenia was 10%-14% with ≥2 weeks and 21% with ≥3 weeks of ceftaroline exposure. The median duration of ceftaroline exposure [26 days (IQR 22-44; range 13-68) in patients who developed neutropenia and 15 days (IQR 9-29; range 7-64) in patients without neutropenia] was associated with incident neutropenia (P = 0.048). The median total number of ceftaroline doses received [63 (IQR 44-126; range 36-198) by neutropenic patients and 32 (IQR 22-63; range 14-180) by non-neutropenic patients] was also associated with incident neutropenia (P = 0.023).\n\n\n\nThe overall rate of neutropenia was high and associated with duration of ceftaroline exposure and total number of doses received. Close laboratory monitoring is warranted with long-term ceftaroline use.",
"affiliations": "School of Pharmacy, Northeastern University, Boston, MA, USA Department of Pharmacy, Brigham and Women's Hospital, Boston, MA, USA kfurtek@gmail.com.;Department of Pharmacy, Brigham and Women's Hospital, Boston, MA, USA.;Department of Pharmacy, Brigham and Women's Hospital, Boston, MA, USA.;Department of Pharmacy, Massachusetts General Hospital, Boston, MA, USA.;Division of Infectious Diseases, Brigham and Women's Hospital, Boston, MA, USA Harvard Medical School, Boston, MA, USA.;Division of Infectious Diseases, Brigham and Women's Hospital, Boston, MA, USA Harvard Medical School, Boston, MA, USA.",
"authors": "Furtek|Kari J|KJ|;Kubiak|David W|DW|;Barra|Megan|M|;Varughese|Christy A|CA|;Ashbaugh|Cameron D|CD|;Koo|Sophia|S|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002511:Cephalosporins; C490727:T 91825",
"country": "England",
"delete": false,
"doi": "10.1093/jac/dkw062",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0305-7453",
"issue": "71(7)",
"journal": "The Journal of antimicrobial chemotherapy",
"keywords": null,
"medline_ta": "J Antimicrob Chemother",
"mesh_terms": "D000046:Academic Medical Centers; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D001900:Boston; D002511:Cephalosporins; D005260:Female; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009503:Neutropenia; D012189:Retrospective Studies; D012307:Risk Factors; D055815:Young Adult",
"nlm_unique_id": "7513617",
"other_id": null,
"pages": "2010-3",
"pmc": null,
"pmid": "27076105",
"pubdate": "2016-07",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D052061:Research Support, N.I.H., Extramural",
"references": "14614681;23590618;22797874;10090118;26037689;2338421;25147169;7249508;22311935;24807197;25282169",
"title": "High incidence of neutropenia in patients with prolonged ceftaroline exposure.",
"title_normalized": "high incidence of neutropenia in patients with prolonged ceftaroline exposure"
} | [
{
"companynumb": "US-FRI-1000087647",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DOXYCYCLINE"
},
"drugadditional": null,
"d... |
{
"abstract": "Prototheca is a genus of achlorophyllic algae present ubiquitously in the environment. Human infections are rare affecting immunocompromised individuals. We report a case of fatal algaemia caused by Prototheca zopfii in a patient who underwent liver transplant. Tissue diagnosis is mandatory for diagnosing rare entities in seriously ill, immunocompromised individuals.",
"affiliations": "Department of Infectious Diseases, Apollo Hospitals, Chennai, Tamil Nadu, India.;Department of Microbiology, Apollo Hospitals, Chennai, Tamil Nadu, India.;Department of Infectious Diseases, Apollo Hospitals, Chennai, Tamil Nadu, India.;Department of Infectious Diseases, Apollo Hospitals, Chennai, Tamil Nadu, India.",
"authors": "Rao|Polati Vishnu|PV|;Sethuraman|Nandini|N|;Ramanathan|Yamunadevi|Y|;Gopalakrishnan|Ram|R|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/jgid.jgid_55_17",
"fulltext": "\n==== Front\nJ Glob Infect DisJ Glob Infect DisJGIDJournal of Global Infectious Diseases0974-777X0974-8245Medknow Publications & Media Pvt Ltd India JGID-10-22810.4103/jgid.jgid_55_17Case ReportDisseminated Protothecosis Caused by Prototheca zopfii in a Liver Transplant Recipient Rao Polati Vishnu Sethuraman Nandini 1Ramanathan Yamunadevi Gopalakrishnan Ram Department of Infectious Diseases, Apollo Hospitals, Chennai, Tamil Nadu, India1 Department of Microbiology, Apollo Hospitals, Chennai, Tamil Nadu, IndiaAddress for correspondence: Dr. Nandini Sethuraman, Department of Microbiology, Apollo Hospitals, No. 21, Greams Lane, Off Greams Road, Chennai - 600 006, Tamil Nadu, India. E-mail: drnandinipgi@gmail.comOct-Dec 2018 10 4 228 229 Copyright: © 2018 Journal of Global Infectious Diseases2018This 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.Prototheca is a genus of achlorophyllic algae present ubiquitously in the environment. Human infections are rare affecting immunocompromised individuals. We report a case of fatal algaemia caused by Prototheca zopfii in a patient who underwent liver transplant. Tissue diagnosis is mandatory for diagnosing rare entities in seriously ill, immunocompromised individuals.\n\nKeywords:\nAlgaedisseminatedfatal outcomeliver transplantationPrototheca\n==== Body\nINTRODUCTION\nHuman protothecosis is an infection caused by members of the genus Prototheca. These organisms are achlorophyllic, unicellular, spherical, 3–30 mm algae that are ubiquitous in nature and exist in the environment as detritus inhabitants and contaminants of various substrates.[12] Human infections are rare. We hereby report a case.\n\nCASE REPORT\nA 36-year-old male underwent deceased donor liver transplantation for alcoholic liver disease. He had acute cellular rejection 2-month posttransplant, for which he received intravenous immunoglobulin and plasmapheresis. Eighteen months posttransplant, he had an episode of late cellular rejection and was treated with plasmapheresis, rituximab, and antithymocyte globulin, followed by maintenance immunosuppression with sirolimus, tacrolimus, and prednisolone 5 mg. He was on prophylaxis with valganciclovir and trimethoprim/sulfamethoxazole (TMP-SMX).\n\nHe presented 20-month posttransplant with right leg cellulitis, persistent cough, and chest pain. The patient could not recollect a traumatic event to his leg. Blood cultures grew a sensitive strain of Klebsiella pneumonia and computed tomography (CT) chest was suggestive of septic emboli. He was treated with intravenous ceftriaxone and discharged on oral ciprofloxacin. He was readmitted 1 month later with right-sided facial weakness, altered mental status, and hemiparesis. Hemogram and chest X-ray were normal. Creatinine was 1.9 mg/dl, bilirubin – 35.6 mg/dl, aspartate transaminase (AST) – 118 IU/L, alanine transaminase (ALT) – 65 IU/L, albumin – 2.4 mg/dl, and gamma-glutamyl transpeptidase-129 IU/L. Magnetic resonance imaging brain showed multiple enhancing lesions. Brain biopsy could not be done in view of elevated prothrombin time and activated partial thromboplastin time. He was started on empiric meropenem, TMP-SMX, liposomal amphotericin-B, and fluconazole. CSF analysis showed no cells with normal sugar and proteins. CSF cryptococcal antigen, XpertMtb, Gram-stain, Ziehl–Neelsen stain and fungal stains were negative. Blood cultures (BacTALERT, bioMerieux, Marcy L'Etoile, France) and mini-bronchoalveolar lavage, on subculture, grew cream colored, nonmucoid “Candida-like” colonies on sheep blood agar (bioMerieux), and Sabouraud's Dextrose Agar [Figure 1]. Gram stain of the colony showed Gram-positive large spherical cells of varied sizes. The organism was identified as Prototheca zopfii by MALDI-TOF (Vitek MS, bioMerieux,) and Vitek 2 Compact (bioMerieux). A diagnosis of disseminated protothecosis was made and amphotericin-B and fluconazole were continued. However, the patient's mental status and oxygenation progressively worsened and he expired 7 days after admission.\n\nFigure 1 Blood agar showing medium-sized cream colored, nonmucoid colonies of Prototheca zopfii\n\nDISCUSSION\nProtothecosis typically occurs in cattle as bovine mastitis. Even though the first description of human infection was given by Davies et al. as early as 1964,[3] human infections are extremely rare and difficult to suspect clinically. P. zopfii and Prototheca wickerhamii are the two species incriminated in human infections although most human infections are caused by P. wickerhamii.[1] Most infections are probably caused by traumatic inoculation into subcutaneous tissues.\n\nClinically, human protothecosis can present in three forms; cutaneous lesions, olecranon bursitis, and disseminated infection.[4] Olecranon bursitis and localized cutaneous infections are more commonly seen in immunocompetent patients, whereas dissemination and visceral involvement are associated with compromised host immunity.[4] Disseminated protothecosis occurs in individuals undergoing cancer chemotherapy,[5] or immunosuppression related to solid organ transplantation (SOT),[67] or in those with advanced AIDS.[8] The organs most commonly affected in dissemination are the skin, subcutaneous tissue, gut, peritoneum, blood, and spleen. Our patient presented with septic pulmonary emboli and multiple ring-enhancing lesions in the brain following cellulitis in the background of severe T-cell immunosuppression. The route of entry may have been the right leg cellulitis site. The presence of severe immunosuppression for underlying rejection appears to be the key reason for dissemination of disease.\n\nPreviously, 12 cases have been reported in the literature of protothecosis following SOT.[7] Of these, 6 were localized and 6 were disseminated infections. Most common organ transplanted was kidney (in 7 out of 12 cases). Only one each of liver and combined liver/kidney transplant recipients has been reported to have protothecosis previously.[67] The present case is the 13th case of protothecosis in SOT and third case associated with liver transplant in published literature. It is also the first case of disseminated P. zopfii in SOT recipients.\n\nMortality rates are as high as 75% overall and 100% in disseminated protothecosis in SOT recipients even with appropriate therapy with amphotericin B.[7] The underlying immunosuppression along with coinfections contributes to the increased mortality, as was seen in our patient who had an associated Klebsiella bacteremia.\n\nThere are no standard guidelines for treatment, but most Prototheca have in vitro sensitivity to amphotericin B and variable sensitivity to azoles. Amphotericin B therapy is recommended as the first-line therapy in cases of dissemination and for patients with severe underlying illness or with immunosuppression.[4]\n\nOrganism identification was done by Vitek 2 Compact (bioMerieux) and confirmed by MALDI-TOF (Vitek MS, bioMerieux). Molecular identification was not feasible in our setup. However, MALDI-TOF has been shown to be a robust tool for highly confident identification of this organism.[9] Our case illustrates the importance of obtaining a tissue diagnosis and cultures in seriously ill immune-compromised patients, to diagnose rare entities like protothecosis.\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Lass-Flörl C Mayr A Human protothecosis Clin Microbiol Rev 2007 20 230 42 17428884 \n2 Huerre M Ravisse P Solomon H Ave P Briquelet N Maurin S Human protothecosis and environment Bull Soc Pathol Exot 1993 86 484 8 7819807 \n3 Davies RR Spencer H Wakelin PO A case of human protothecosis Trans R Soc Trop Med Hyg 1964 58 448 51 14206703 \n4 Mayorga J Barba-Gómez JF Verduzco-Martínez AP Muñoz-Estrada VF Welsh O Protothecosis Clin Dermatol 2012 30 432 6 22682193 \n5 Torres HA Bodey GP Tarrand JJ Kontoyiannis DP Protothecosis in patients with cancer: Case series and literature review Clin Microbiol Infect 2003 9 786 92 14616698 \n6 Narita M Muder RR Cacciarelli TV Singh N Protothecosis after liver transplantation Liver Transpl 2008 14 1211 5 18668655 \n7 Ramírez I Nieto-Ríos JF Ocampo-Kohn C Aristizábal-Alzate A Zuluaga-Valencia G Muñoz Maya O Protothecal bursitis after simultaneous kidney/liver transplantation: A case report and review Transpl Infect Dis 2016 18 266 74 26779785 \n8 Kaminski ZC Kapila R Sharer LR Kloser P Kaufman L Meningitis due to prototheca wickerhamii in a patient with AIDS Clin Infect Dis 1992 15 704 6 1420686 \n9 von Bergen M Eidner A Schmidt F Murugaiyan J Wirth H Binder H Identification of harmless and pathogenic algae of the genus prototheca by MALDI-MS Proteomics Clin Appl 2009 3 774 84 21136986\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0974-777X",
"issue": "10(4)",
"journal": "Journal of global infectious diseases",
"keywords": "Algae; Prototheca; disseminated; fatal outcome; liver transplantation",
"medline_ta": "J Glob Infect Dis",
"mesh_terms": null,
"nlm_unique_id": "101521436",
"other_id": null,
"pages": "228-229",
"pmc": null,
"pmid": "30581267",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "14206703;1420686;14616698;17428884;18668655;21136986;22682193;26779785;7819807",
"title": "Disseminated Protothecosis Caused by Prototheca zopfii in a Liver Transplant Recipient.",
"title_normalized": "disseminated protothecosis caused by prototheca zopfii in a liver transplant recipient"
} | [
{
"companynumb": "IN-MYLANLABS-2019M1005109",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "Objective Rectal lymphoid follicular aphthous (LFA) lesions are related to ulcerative colitis (UC) and can be initial lesions of UC. We investigated the clinical course and prognosis of rectal LFA lesions. Methods This is a retrospective analysis of the clinical records at a single center. Patients Thirteen consecutive cases with LFA lesions treated at Hiroshima University Hospital between 1998 and 2015 were evaluated. Another 49 consecutive cases with ulcerative proctitis treated in the same period were enrolled as the control group. The clinical course and prognosis of both groups were evaluated. Results The group with LFA lesions included 9 women and 4 men with a median age of 39.9 years (range, 21-70 years). A total of 11 cases progressed to typical UC at 5-51 months. Proximal extension of these typical UC lesions was observed in 7 (53.8%) cases, which was significantly higher than in the control group (10 cases, 20.8%). Three cases (5-year accumulation incidence rate, 27.3%) progressed to steroid-intractable UC, a significantly higher incidence than that of the control group (3 cases; 5-year accumulation incidence rate, 6.9%). Conclusion Rectal LFA lesions frequently progress to typical UC with proximal extension, some of which become intractable to corticosteroid treatment.",
"affiliations": "Department of Endoscopy, Hiroshima University Hospital, Japan.;Department of Endoscopy, Hiroshima University Hospital, Japan.;Department of Endoscopy, Hiroshima University Hospital, Japan.;Department of Gastroenterology and Metabolism, Hiroshima University Hospital, Japan.;Department of Gastroenterology and Metabolism, Hiroshima University Hospital, Japan.;Department of Gastroenterology and Metabolism, Hiroshima University Hospital, Japan.;Department of Gastroenterology and Metabolism, Hiroshima University Hospital, Japan.;Department of Gastroenterology and Metabolism, Hiroshima University Hospital, Japan.;Department of Gastroenterology and Metabolism, Hiroshima University Hospital, Japan.;Department of Gastroenterology and Metabolism, Hiroshima University Hospital, Japan.",
"authors": "Hayashi|Ryohei|R|;Ueno|Yoshitaka|Y|;Tanaka|Shinji|S|;Wakai|Masaki|M|;Kumada|Junko|J|;Fujita|Akira|A|;Nomura|Motonobu|M|;Oka|Shiro|S|;Ito|Masanori|M|;Chayama|Kazuaki|K|",
"chemical_list": "D005938:Glucocorticoids",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.1635-18",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 3033341210.2169/internalmedicine.1635-18Original ArticleRectal Lymphoid Follicle Aphthous Lesions Frequently Progress to Ulcerative Colitis with Proximal Extension Hayashi Ryohei 1Ueno Yoshitaka 1Tanaka Shinji 1Wakai Masaki 2Kumada Junko 2Fujita Akira 2Nomura Motonobu 2Oka Shiro 2Ito Masanori 2Chayama Kazuaki 2\n1 Department of Endoscopy, Hiroshima University Hospital, Japan\n2 Department of Gastroenterology and Metabolism, Hiroshima University Hospital, JapanCorrespondence to Dr. Yoshitaka Ueno, yueno@hiroshima-u.ac.jp\n\n17 10 2018 1 3 2019 58 5 625 631 2 6 2018 24 7 2018 Copyright © 2019 by The Japanese Society of Internal Medicine2019The Internal Medicine is an Open Access journal 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/).Objective \nRectal lymphoid follicular aphthous (LFA) lesions are related to ulcerative colitis (UC) and can be initial lesions of UC. We investigated the clinical course and prognosis of rectal LFA lesions. \n\nMethods \nThis is a retrospective analysis of the clinical records at a single center. \n\nPatients \nThirteen consecutive cases with LFA lesions treated at Hiroshima University Hospital between 1998 and 2015 were evaluated. Another 49 consecutive cases with ulcerative proctitis treated in the same period were enrolled as the control group. The clinical course and prognosis of both groups were evaluated. \n\nResults \nThe group with LFA lesions included 9 women and 4 men with a median age of 39.9 years (range, 21-70 years). A total of 11 cases progressed to typical UC at 5-51 months. Proximal extension of these typical UC lesions was observed in 7 (53.8%) cases, which was significantly higher than in the control group (10 cases, 20.8%). Three cases (5-year accumulation incidence rate, 27.3%) progressed to steroid-intractable UC, a significantly higher incidence than that of the control group (3 cases; 5-year accumulation incidence rate, 6.9%). \n\nConclusion \nRectal LFA lesions frequently progress to typical UC with proximal extension, some of which become intractable to corticosteroid treatment. \n\naphthous lesionsproctitisproximal extensionulcerative colitis\n==== Body\nIntroduction\nUlcerative colitis (UC) is a chronic inflammatory disorder of the colon characterized by colonic mucosal ulceration (1). In patients with UC, the inflamed mucosa starts at the anorectal verge and extends proximally. Endoscopic images show characteristically granular and erythematous appearance with friability and reduced vascular pattern. In moderate cases, multiple erosions and ulcers occur (1). In recent years, with remarkable progress in endoscopic technology and the popularization of colonoscopy, it has become possible to detect small lesions and some atypical lesions, such as inflamed lesion of the appendiceal orifice, skip lesions, and aphthous lesions (2). Rectal aphthous lesions with a lymphoid follicular elevated hemispherical appearance, so-called lymphoid follicular aphthous (LFA) lesions, are particularly rare, but several reports have shown that they sometimes progress to typical UC (3,4). However, the clinical course and prognosis of these cases remain undefined.\n\nIn the present study, we evaluated the clinical course and prognosis of cases with LFA lesions.\n\nMaterials and Methods\nStudy design and patients\nThis report was a retrospective single-center cohort study covering an 18-year period between January 1, 1998, and December 31, 2015. Thirteen consecutive cases with LFA lesions and 49 consecutive cases with ulcerative proctitis treated in Hiroshima University Hospital were evaluated. The diagnosis of UC was made according to the clinical symptoms (sustained or repeated hematochezia), characteristic endoscopic findings (faded/absent vascular pattern, fine granular appearance, vulnerability of the mucosa, and mucosal erosion/ulcer), and histological features compatible with UC (infiltrates of lymphocytes, plasma cells, and granulocytes; crypt abscesses; goblet cell depletion; and distorted crypt architecture). Ulcerative proctitis data were obtained from the medical and endoscopic records of all UC patients encountered during the period in our hospital. Ulcerative proctitis was diagnosed by colonoscopy with characteristic findings of UC only in the rectum, with no extended findings beyond the rectosigmoid junction, and the presence of histological features compatible with UC in only rectal specimens. Patients who did not undergo total colonoscopy (reached at cecum) during the diagnosis of ulcerative proctitis or follow-up colonoscopy to evaluate proximal extension were excluded.\n\nThe clinical activity was evaluated using a partial Mayo score (stool frequency, rectal bleeding, physician's global assessment). Clinical remission was defined as a partial Mayo score ≤2 and rectal bleeding score of 0; clinical efficacy was defined as reduction of the partial Mayo score by ≥2 after treatment; and a clinical response was defined as the achievement of clinical efficacy but not clinical remission.\n\nSteroid-intractable UC was defined as steroid-resistant UC or steroid-dependent UC. Steroid-resistant UC was defined as unresponsiveness to oral or intravenous corticosteroid therapy (daily prednisolone dose of more than 1 mg/kg) over at least 1 week, and steroid-dependent UC was defined as relapse during the tapering of steroids.\n\nDefinition of rectal LFA\nLFA was defined as 1) a dense granular lesion with erosion on its apex, 2) granule size of ≤5 mm, 3) exclusion of chlamydial proctitis (negative of serum IgA for Chlamydia trachomatis and/or polymerase chain reaction of rectal swab for C. trachomatis) and presence of extranodal marginal zone lymphoma of the mucosa-associated lymphoid tissue (MALT) lymphoma type, 4) exclusion of characteristic endoscopic findings of UC, and 5) pathological findings of acute inflammation (Fig. 1). All cases with LFA were diagnosed at Hiroshima University Hospital.\n\nFigure 1. Endoscopic and histological findings of LFA lesions. a: Endoscopic findings of LFA showing lymphoid follicles with an elevated hemispherical appearance (like salmon caviar) restricted to the rectum. b, c: Chromoendoscopic findings of LFA showing dense granular deposits with erosion on the apex. d: Histological appearance of the biopsy specimen showing acute inflammatory cells in the lamina propria of the mucosa, superficial ulceration, crypt distortion, and large lymphoid follicular hyperplasias. LFA: lymphoid follicular aphtha\n\nThe progression to typical UC was defined as flattening of LFA lesions and appearance of characteristic endoscopic findings of UC. Proximal extension was defined as inflammation extending proximally from proctitis to left-sided or extensive colitis.\n\nStatistical analyses\nStudent's t-test for unpaired data and Fisher's exact test were used to compare the characteristics between the two groups. To evaluate the long-term prognosis, the survival times were evaluated using the Kaplan-Meier method, and statistical analyses were evaluated via the log-rank test. Fisher's exact test was used to evaluate the clinical responses to treatment. p values <0.05 were considered statistically significant.\n\nResults\nClinical characteristics of LFA\nThe clinical characteristics of patients with LFA lesions are shown in Table 1. There were 9 women and 4 men, with an average age of 39.9 years (range, 21-70 years). All patients underwent total colonoscopy for bloody stool symptoms, and the lesions were only found in the rectum. In total, 12 cases were treated with 5-aminosalicylic acid (5-ASA): oral 5-ASA, 7 cases; oral and topical 5-ASA, 3 cases; and oral 5-ASA with topical steroid, 2 cases.\n\nTable 1. Clinical Characteristics of Cases with Lymphoid Follicular Aphthous Lesions.\n\nCase\t\tAge*\t\tGender\t\tSymptom\t\tFirst treatment\t\tResponse to first treatment\t\tProgress to \ntypical UC\t\tProximal \nextension\t\nat 4 weeks\t\tat 8 weeks\t\n1\t\t24\t\tM\t\tbloody stool, diarrhea\t\toral 5-ASA\t\tnot effective\t\tremission\t\t(+)\t\t(+)\t\n2\t\t22\t\tF\t\tbloody stool, nausea\t\toral & topical 5-ASA\t\tremission\t\tremission\t\t(+)\t\t(-)\t\n3\t\t24\t\tF\t\tbloody stool\t\toral 5-ASA\t\tnot effective\t\tnot effective\t\t(+)\t\t(-)\t\n4\t\t61\t\tF\t\tbloody stool\t\toral 5-ASA\t\tremission\t\tremission\t\t(+)\t\t(+)\t\n5\t\t59\t\tF\t\tbloody stool\t\toral 5-ASA\t\tnot effective\t\tremission\t\t(+)\t\t(+)\t\n6\t\t38\t\tF\t\tbloody stool, diarrhea\t\toral 5-ASA\t\tremission\t\tremission\t\t(+)\t\t(+)\t\n7\t\t36\t\tM\t\tbloody stool\t\toral 5-ASA & topical steroid\t\tnot effective\t\tnot effective\t\t(+)\t\t(+)\t\n8\t\t21\t\tF\t\tbloody stool\t\toral & topical 5-ASA\t\tresponded\t\tresponded\t\t(+)\t\t(+)\t\n9\t\t31\t\tF\t\tbloody stool\t\toral 5-ASA & topical steroid\t\tnot effective\t\tresponded\t\t(+)\t\t(+)\t\n10\t\t64\t\tM\t\tbloody stool (temporal)\t\tnone\t\t\t\t\t\t(-)\t\t(-)\t\n11\t\t38\t\tF\t\tbloody stool\t\toral & topical 5-ASA\t\tnot effective\t\tremission\t\t(+)\t\t(-)\t\n12\t\t70\t\tM\t\tbloody stool\t\toral 5-ASA\t\tremission\t\tremission\t\t(+)\t\t(-)\t\n13\t\t31\t\tF\t\tbloody stool\t\toral 5-ASA\t\tnot effective\t\tnot effective\t\t(-)\t\t(-)\t\n*Age in years, M: male, F: female, UC: ulcerative colitis, 5-ASA: 5-aminosalicylic acid\n\nLFA frequently progress to typical UC\nA total of 11 (84.6%) cases progressed to typical UC lesions at 2-51 months [mean±standard deviation (SD), 15.5±14.0 months] (Fig. 2a). In case 5, the LFA lesions became flattened, and typical UC lesions appeared after two months of treatment with oral 5-ASA (Fig. 2b).\n\nFigure 2. Progress to typical UC and the proximal extension of UC lesion in LFA cases. a, b: Proportion of cases with lesions that progressed to typical UC. In case 5, the lymphoid follicle with an elevated hemispherical appearance became flattened and typical of UC lesions after two months. c, d: The overall cumulative rate of proximal extension in the LFA group and the control (ulcerative proctitis) group. In case 9, proximal extension into the transverse colon was observed at 30 months after the diagnosis. LFA: lymphoid follicular aphtha, UC: ulcerative colitis\n\nProximal extension of UC lesions in cases with LFA\nWe compared the clinical characteristics of the proximal extension rate of rectal LFA lesions (LFA group) with those of ulcerative proctitis (control group). The clinical details are shown in Table 2. In the LFA group, 7 (53.8%) cases exhibited proximal extension of the UC lesion at 17-78 months (mean±SD, 42.7±21.3 months). In 5 (71.4%) of 7 cases, typical UC lesions of the rectum appeared before the appearance of proximal extension. In 2 (28.6%) of 7 cases, typical UC lesions of the rectum and proximal extension appeared at the same time as colonoscopy. In the control group, 10 (20.4%) cases had proximal extension at 3-135 months (mean±SD: 34.9±47.0 months). The overall cumulative rate of proximal extension in the LFA group was significantly higher than that of the control group (67.9% vs. 17.1% at 5 years and 84.0% vs. 23.0% at 10 years, respectively; p<0.01) (Fig. 2c, d). In the LFA group, 3 cases progressed to left-sided UC (Montreal classification of inflammatory bowel disease E2) (5), and 4 progressed to extensive UC (Montreal classification E3). In the control group, 5 cases progressed to left-sided UC (E2), and 5 progressed to extensive UC (E3).\n\nTable 2. Clinical Characteristics of Lymphoid Follicular Aphthous Lesions Group and Control Group.\n\n\t\tLFA group \nn=13\t\tControl group \nn=49\t\tp value\t\nMean Age\t\t39.9 (21-70)\t\t41.7 (16-81)\t\tn.s.\t\n[average (range), y.o.]\t\t\t\t\t\t\t\nGender\t\t\t\t\t\t\t\nMale\t\t4\t\t26\t\tn.s.\t\nFemale\t\t9\t\t23\t\t\t\nSurveillance period\t\t82.2 (13-177)\t\t86.0 (8-203)\t\tn.s.\t\n[average (range), months]\t\t\t\t\t\t\t\nLocation of disease\t\t\t\t\t\t\t\n(Montreal score)\t\t\t\t\t\t\t\nRectum (E1)\t\t13\t\t49\t\tn.s.\t\nLeft-sided (E2)\t\t0\t\t0\t\t\t\nPancolitis (E3)\t\t0\t\t0\t\t\t\nApendiceal orifice inflammation\t\t2\t\t9\t\tn.s.\t\npMayo score (mean±SD)\t\t3.4±1.6\t\t4.7±1.8\t\tn.s.\t\nFirst treatment\t\t\t\t\t\t\t\noral mesalazine\t\t12\t\t46\t\tn.s.\t\ntopical mesalazine\t\t3\t\t6\t\t\t\ntopical steroid\t\t2\t\t10\t\t\t\nnon-therapy\t\t1\t\t1\t\t\t\ny.o.: year-old, pMayo score: partial Mayo score, n.s.: not significant, SD: standard deviation\n\nPatients with LFA tended to have steroid-intractable UC\nIn both groups, the initial treatment for the majority of the cases was oral 5-ASA or oral 5-ASA with topical therapy (5-ASA or steroid). The steroid-free survival rates were 74.6% in the LFA group versus 88.1% in the control group at 5 years (Fig. 3a). In addition, 3 cases (5-year accumulation incidence rate, 26.2%) had steroid-intractable UC in the LFA group, which was a significantly higher frequency than in the control group (3 cases; 5-year accumulation incidence rate, 6.9%) (Fig. 3b). Cases in the LFA group were more likely to be intractable to steroid therapy. The clinical flowchart is shown in Fig. 4.\n\nFigure 3. Steroid treatment for LFA lesions and ulcerative proctitis. a: The steroid-free survival rate of the LFA and control (ulcerative proctitis) groups. b: The overall cumulative steroid-intractable rate of the LFA and control groups. LFA: lymphoid follicular aphtha\n\nFigure 4. Clinical flowchart of the LFA and control groups. LFA: lymphoid follicular aphtha\n\nTreatment for steroid-intractable cases\nIn total, there were 3 cases each of steroid-intractable UC in the LFA and control groups. All cases showed proximal extension before becoming steroid-intractable. In the LFA group, one case was treated with anti-tumor necrosis factor α (TNFα) agents, and two cases were treated with tacrolimus when their lesions became steroid-intractable. Although these 2 cases were treated with tacrolimus and improved temporarily, their symptoms became exacerbated within 60 months after tacrolimus therapy was withdrawn. Subsequently, these two cases were treated with anti-TNFα agents; eventually, all three steroid-intractable cases in the LFA group received anti-TNFα agents. The efficacy rate of anti-TNFα agents for these cases was 33.3% at 8 weeks.\n\nDiscussion\nIntestinal aphthous lesions are observed in some diseases, such as intestinal Behçet's disease, infectious enterocolitis, drug-induced enterocolitis, Crohn's disease, and UC. The regions and forms of aphthous lesions differ depending on the disease (6). In the rectum, lymphoid follicles with an elevated hemispherical appearance resembling salmon caviar have been observed in chlamydial proctitis, rectal MALT lymphoma, and so-called lymphoid follicular proctitis (LFP), as proposed by Flejou et al. (7). In addition, rectal LFA lesions have recently been reported to have a relationship with UC and may be initial lesions of UC. Indeed, several previous reports have shown that patients with LFA-like lesions progress to typical UC (3,4).\n\nIn the present report, we focused on the lymphoid follicular aphthous lesions with an elevated hemispherical appearance that were localized to the rectum. This is the first report to define LFA lesions and evaluate the prognosis of patients with LFA lesions in relation to UC. In addition, as patients with LFA lesions are very rare, we feel that this report will prove very valuable despite the small number of cases.\n\nAlthough LFA resembles LFP endoscopically, the pathological findings are different. LFP is characterized by congested and granular mucosa with no ulceration, well-defined and large follicles, reactive germinal centers and preserved mantle zones, scanty or absent neutrophils and eosinophils, and no evidence of hyperplastic or atrophic changes in the crypt (7). In contrast, LFA lesions have acute inflammatory cells in the lamina propria of the mucosa, and the endoscopic findings are characterized by granules and erosion on its apex, indicating that LFA is accompanied by acute inflammation. The existence of ulcerative proctitis with lymphoid follicles might indicate the progression to UC through LFA. Case 5 exhibited such progression, with typical UC lesions appearing two months after the diagnosis (Fig. 2b), but some lymphoid follicles also remained. If initial colonoscopy had been performed at that time, this case might have been diagnosed as ulcerative proctitis with lymphoid follicles.\n\nOur results showed that the patients had a high probability of progressing to typical UC from LFA with long-term observation. Notably, one patient progressed to typical UC more than four years after the diagnosis. As Flejou et al. (7) reported, so-called LFP is unrelated to ulcerative proctitis or UC limited to the rectum; LFA may be a phenotypically different disease from LFP.\n\nPrevious reports have found that the proximal extension rate of ulcerative proctitis was 20-37% at 5 years and 30-54% at 10 years (8-13). In our case series, the LFA group showed significantly higher proximal extension rates than the control group. Furthermore, this rate was higher than that of ulcerative proctitis in previous reports as well. Although a previous report showed that appendiceal orifice inflammation is associated with proximal extension of UC lesions (14), there were only two cases of LFA accompanied by appendiceal orifice in the present report, and neither showed proximal extension.\n\nThe majority of patients in both groups were treated with oral 5-ASA, and some were treated with topical drugs. The patients with LFA lesions tended to become steroid-intractable after proximal extension of the UC lesion. Three cases in the LFA group needed tacrolimus and/or anti-TNFα agents, but the efficacy of these therapies was limited.\n\nGiven the high rate of proximal extension and the intractability to medical therapies, LFA might have the potential to progress to a more severe inflammatory disorder than typical ulcerative proctitis. However, this report is limited because of its retrospective design. In addition, the control group might have included LFA lesions, as these lesions might have no longer been detectable when initial colonoscopy was performed. The accumulation of further reports will be required to resolve these points.\n\nThe present findings suggest that rectal LFA lesions frequently progress to typical UC with proximal extension, and some become intractable to corticosteroids. Further studies in more cases with careful follow-up will be needed in order to prove this point.\n\n\nOur study protocol conformed to the ethical standards of the responsible committees on human experimentation (institutional and national) and with the 1964 Declaration of Helsinki and later versions and was approved by the Institutional Review Board. Informed consent was obtained from all patients included in this report.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. \nDanese S , Fiocchi C \nUlcerative colitis . N Engl J Med \n365 : 1713 -1725 , 2011 .22047562 \n2. \nOkawa K , Aoki T , Sano K , Harihara S , Kitano A , Kuroki T \nUlcerative colitis with skip lesion at the mouth of the appendix . Am J Gatroenterol \n93 : 2405 -2410 , 1998 .\n3. \nMatsumoto T , Kubokura N , Yada S , et al \nAphthous lesions of the colon as a precursor of ulcerative colitis . I to Cho (Stomach and Intestine) \n44 : 1514 -1521 , 2009 (in Japanese, Abstract in English).\n4. \nYokoyama J , Watanabe K , Ajioka Y , et al \nAphthous lesions of the colorectum-clinical significance of the initial lesion of ulcerative colitis . I to Cho (Stomach and Intestine) \n44 : 1523 -1533 , 2009 (in Japanese, Abstract in English).\n5. \nSatsangi J , Silverberg MS , Vermeire S , Columbel JF \nThe Montreal classification of inflammatory bowel disease: controversies, consensus, and implications . Gut \n55 : 749 -753 , 2006 .16698746 \n6. \nIida M , Hizawa K , Aoyagi K , et al \nRadiographic differential diagnosis of aphthoid lesions of the colon: focused on Crohn's disease with aphthoid lesions alone . I to Cho (Stomach and Intestine) \n28 : 397 -410 , 1992 (in Japanese, Abstract in English).\n7. \nFlejou JF , Potet F , Bogomoletz WV , et al \nLymphoid follicular proctitis. A condition different from ulcerative proctitis? \nDig Dis Sci \n33 : 314 -320 , 1988 .3342723 \n8. \nHiwatashi N , Yamazaki H , Kimura M , Morimoto T , Watanabe H , Toyota T \nClinical course and long-term prognosis of Japanese patients with ulcerative colitis . Gastroenterol Jpn \n26 : 312 -318 , 1991 .1889689 \n9. \nSiproudhis L , Vilotte J , Bonfils S , Mignon M \nIdiopathic ulcerative colitis. Clinical presentation and endoscopic outcome . Gastroenterol Clin Biol \n15 : 315 -321 , 1991 .2060743 \n10. \nMeucci G , Vecchi M , Astegiano M , et al \nThe natural history of ulcerative proctitis: a multicenter, retrospective study. Gruppo di Studio per le Malattie Infiammatorie Intestinali (GSMII) . Am J Gastroenterol \n95 : 469 -473 , 2000 .10685752 \n11. \nPica R , Paoluzi OA , Iacopini F , et al \nOral 5-ASA (5-ASA) treatment may protect against proximal extension of mucosal inflammation in ulcerative proctitis . Inflamm Bowel Dis \n10 : 731 -736 , 2004 .15626890 \n12. \nPark SH , Kim YM , Yang SK , et al \nClinical features and natural history of ulcerative colitis in Korea . Inflamm Bowel Dis \n13 : 278 -283 , 2007 .17206722 \n13. \nAlkim C , Alkim H , Dağli U , Parlak E , Ulker A , Sahın B \nExtension of ulcerative colitis . Turk J Gastroenterol \n22 : 382 -387 , 2011 .21948568 \n14. \nAnzaki H , Hata K , Kishikawa J , et al \nAppendiceal orifice inflammation is associated with proximal extension of disease in patients with ulcerative colitis . Colorectal Dis \n18 : O278 -O282 , 2016 .27354363\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "58(5)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "aphthous lesions; proctitis; proximal extension; ulcerative colitis",
"medline_ta": "Intern Med",
"mesh_terms": "D000328:Adult; D000368:Aged; D003093:Colitis, Ulcerative; D018450:Disease Progression; D004351:Drug Resistance; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D000072281:Lymphadenopathy; D008297:Male; D008875:Middle Aged; D011349:Proctitis; D011351:Proctoscopy; D011379:Prognosis; D012002:Rectal Diseases; D012189:Retrospective Studies; D055815:Young Adult",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "625-631",
"pmc": null,
"pmid": "30333412",
"pubdate": "2019-03-01",
"publication_types": "D016428:Journal Article",
"references": "10685752;15626890;16698746;17206722;1889689;2060743;21948568;22047562;27354363;3342723;9860400",
"title": "Rectal Lymphoid Follicle Aphthous Lesions Frequently Progress to Ulcerative Colitis with Proximal Extension.",
"title_normalized": "rectal lymphoid follicle aphthous lesions frequently progress to ulcerative colitis with proximal extension"
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"companynumb": "JP-MYLANLABS-2019M1046568",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
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"activesubstancename": "MESALAMINE"
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"abstract": "To analyze whether magnesium has a neuroprotective effect during episodes that indicate a critical brain perfusion after aneurysmal subarachnoid hemorrhage (SAH).\n107 patients with aSAH were randomized to continuously receive intravenous magnesium sulfate with target serum levels of 2.0 - 2.5 mmol/l (n = 54) or isotonic saline (n = 53). Neurological examination and transcranial Doppler sonography (TCD) were performed daily, Perfusion-CT (PCT) was acquired in 3-day intervals, angiography in case of suspected vasospasm. The primary endpoint was the development of secondary infarction following episodes of delayed ischemic neurological deficit (DIND), elevated mean flow velocity (MFV) in TCD or pathological findings in PCT.\nIn the magnesium group, 9 episodes of DIND were registered, none was followed by secondary infarction. In the control group, 23 episodes of DIND were registered, 9 were followed by secondary infarction (p < 0.05). In the magnesium group, 114 TCD-measurements showed an elevated MFV(> 140 cm/s). 7 were followed by new infarction. In control patients, 135 measurements showed elevated MFV, 32 were followed by new infarction (p < 0.05). 10 of 117 abnormal PCT-findings were followed by new infarction, compared to 30 of 122 in the control-group (p < 0.05).\nDIND, elevated MFV in TCD and abnormal PCT are findings which are associated with an increased risk to develop delayed secondary infarction. The results of this analysis suggest that magnesium-treatment may reduce the risk to develop infarction in a state of critical brain perfusion.",
"affiliations": "Department of Neurosurgery, University Hospital Wuerzburg, Josef-Schneider-Str. 11, 97080, Wuerzburg, Germany.;Department of Neurosurgery, University Hospital Wuerzburg, Josef-Schneider-Str. 11, 97080, Wuerzburg, Germany.;Department of Neurosurgery, University Hospital Wuerzburg, Josef-Schneider-Str. 11, 97080, Wuerzburg, Germany.;Department of Neurosurgery, University Hospital Wuerzburg, Josef-Schneider-Str. 11, 97080, Wuerzburg, Germany.;Department of Neurosurgery, University Hospital Wuerzburg, Josef-Schneider-Str. 11, 97080, Wuerzburg, Germany.",
"authors": "Kunze|Ekkehard|E|;Lilla|Nadine|N|;Stetter|Christian|C|;Ernestus|Ralf-Ingo|RI|;Westermaier|Thomas|T|",
"chemical_list": null,
"country": "Germany",
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"doi": "10.1515/tnsci-2018-0016",
"fulltext": "\n==== Front\nTransl NeurosciTransl NeuroscitnscitnsciTranslational Neuroscience2081-38562081-6936De Gruyter tnsci-2018-001610.1515/tnsci-2018-0016Regular ArticlesMagnesium Protects in Episodes of Critical Perfusion after Aneurysmal SAH Kunze Ekkehard 1Lilla Nadine 1Stetter Christian 1Ernestus Ralf-Ingo 1Westermaier Thomas *11 Department of Neurosurgery, University Hospital Wuerzburg, Josef-Schneider-Str. 11, 97080, Wuerzburg, Germany* E-mail: Westermaie_T@ukw.de01 9 2018 2018 9 99 105 20 10 2017 20 2 2018 © 2018 Ekkehard Kunze et al., published by De Gruyter2018Ekkehard Kunze, Nadine Lilla, Christian Stetter, Ralf-Ingo Ernestus, Thomas Westermaier, published by De GruyterThis work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License.Abstract\nBackground\nTo analyze whether magnesium has a neuroprotective effect during episodes that indicate a critical brain perfusion after aneurysmal subarachnoid hemorrhage (SAH).\n\nMethods\n107 patients with aSAH were randomized to continuously receive intravenous magnesium sulfate with target serum levels of 2.0 – 2.5 mmol/l (n = 54) or isotonic saline (n = 53). Neurological examination and transcranial Doppler sonography (TCD) were performed daily, Perfusion-CT (PCT) was acquired in 3-day intervals, angiography in case of suspected vasospasm. The primary endpoint was the development of secondary infarction following episodes of delayed ischemic neurological deficit (DIND), elevated mean flow velocity (MFV) in TCD or pathological findings in PCT.\n\nResults\nIn the magnesium group, 9 episodes of DIND were registered, none was followed by secondary infarction. In the control group, 23 episodes of DIND were registered, 9 were followed by secondary infarction (p < 0.05). In the magnesium group, 114 TCD-measurements showed an elevated MFV(> 140 cm/s). 7 were followed by new infarction. In control patients, 135 measurements showed elevated MFV, 32 were followed by new infarction (p < 0.05). 10 of 117 abnormal PCT-findings were followed by new infarction, compared to 30 of 122 in the control-group (p < 0.05).\n\nConclusion\nDIND, elevated MFV in TCD and abnormal PCT are findings which are associated with an increased risk to develop delayed secondary infarction. The results of this analysis suggest that magnesium-treatment may reduce the risk to develop infarction in a state of critical brain perfusion.\n\nKeywords\nsubarachnoid hemorrhagemagnesiumneuroprotectiondelayed cerebral infarction\n==== Body\nIntroduction\nThe data on beneficial effects of magnesium-treatment in patients who suffered aneurysmal subarachnoid hemorrhage (SAH) is conflicting. Experimental results in cerebral ischemia [1, 2, 3, 4] and early clinical data in stroke patients [5, 6] supported the idea that magnesium may act as a neuroprotective agent in cerebral ischemia and SAH. In the last two decades, several clinical studies have shown beneficial effects of magnesium in SAH [7, 8, 9, 10, 11, 12, 13, 14]. However, two large multicenter trials failed to confirm a reduced incidence of delayed cerebral ischemia and an improvement of clinical recovery by intravenous administration of magnesium sulfate [15, 16] and caused some disillusionment. However, the results of these two large studies may have been influenced by the co-medication. In both trials nimodipine was co-administered as a standard medication to magnesium-treated patients as well as to patients of the control-groups. Similar to nimodipine, magnesium predominantly acts as a calcium antagonist. This co-treatment resembles a combination therapy consisting of two similarly acting substances which is, from a pharmacological point of view, unlikely to exert synergistic effects. From the database of a clinical trial, which we previously reported on [14], we conducted this analysis focusing on the potential neuroprotective effects of continuous high-dose administration of magnesium sulfate during episodes of neurological deterioration, arterial vessel narrowing, or abnormalities in perfusion imaging suggesting a critical brain perfusion.\n\nMaterials and Methods\nThe study was approved by the local ethics committee. Informed consent was obtained from the patient or from a permanent or temporary legal guardian. This is a post-hoc analysis from a randomized clinical trial comparing the effects of intravenous magnesium sulfate versus control in patients after aneurysmal SAH [14]. For this purpose, critical events in terms of delayed ischemic neurological deterioration (DIND), angiographic delayed vasospasm, abnormal findings in Perfusion-CT (PCT) and elevated mean flow velocities (MFV) in transcranial Doppler sonography (TCD) were analyzed. While a patient-based analysis has been published previously [14], this is an event-based analysis investigating whether patients in the magnesium or control group, respectively, developed secondary infarction after these episodes of critical brain perfusion or not.\n\nInclusion- and exclusion-criteria\nPatients were included if they had suffered aneurysmal SAH within 96 hours before admission and no history of prior bleeding. In- and exclusion criteria have previously been described in detail [14]. All patients were admitted to the neurosurgical intensive care unit of a university hospital. All patients underwent early digital subtraction angiography (DSA) and early endovascular coiling or microsurgical clipping of the ruptured aneurysm within 48 hours after SAH.\n\nStandard management\nClinical assessment included the Glasgow Coma Scale (GCS) score, World Federation of Neurological Societies (WFNS) score and the Hunt/Hess score. Patients were intubated and mechanically ventilated if their GCS score was below 9 points. An external ventricular drainage was implanted if there were signs of hydrocephalus in CT-scans. Care was taken that mean arterial blood pressure did not fall below 80 mmHg in order to prevent episodes of hypotension. Substances used included Ringer’s solution, albumin and hydroxyethyl starch (HES 6%) and catecholamines [17]. In case of delayed ischemic neurological deterioration (DIND), elevated mean flow velocities (MFV) in transcranial Doppler sonography (TCD) or signs of perfusion deficits in Perfusion-CT (PCT) maps, patients received hyperdynamic therapy with an optimization of hematocrit (30 – 35%), central venous pressure (10 – 12 mmHg) and induced hypertension.\n\nRandomization and Magnesium dosage\nPatients included into the study were randomized to either receive intravenous magnesium sulfate or serve as controls after SAH was diagnosed by CT or lumbar puncture and an aneurysm was demonstrated either by digital subtraction angiography (DSA) or CT-Angiography (CTA). The latest time of occlusion was 96 hours after SAH. In the magnesium group, a loading dose of 16 mmol MgSO4 over half an hour was administered and followed by a continuous infusion of 8 mmol/h. In the following days, the infusion speed was adjusted according to magnesium serum levels in order to keep the latter at 2.0 – 2.5 mmol/l. In the control group, an equal volume of saline was administered. Intravenous magnesium was discontinued at day 10 if there were no signs of clinical deterioration or ultrasonographic vasospasm as measured by TCD and if PCT maps did not show any abnormal patterns. In case of clinical vasospasm, elevated MFV in TCD (over 140 cm/s) or abnormal PCT maps, intravenous magnesium was continued until these findings had normalized. Independent of the study procedures, patients were dismissed or transferred to rehabilitation units if their clinical condition was stable and no more danger for secondary ischemic deterioration was believed to be present.\n\nAssessment of study parameters\nNeurological assessment was conducted three times a day following a standard examination protocol including the GCS, deficits of awareness (person, place, time, situation) and cranial nerves, motor, sensory and coordination deficits of the upper and lower extremities, visual field defects, and speech abnormalities. DIND was defined as a secondary neurological deterioration in the absence of another cause.\n\nA TCD examination was conducted once a day and included the middle and anterior cerebral arteries and internal carotid artery (MCA, ACA, ICA) and the basilar artery. “Ultrasonographic vasospasm” was defined as a MFV >140 cm/s in the anterior circulation and > 90 cm/s in the basilar artery.\n\nA two-slice PCT was obtained after native CT in 3-day intervals (Somatom Plus 4 Volume Zoom, Siemens, Erlangen, Germany) For PCT analysis, a commercially available software was used (Perfusion CT, Siemens). Color maps were visually assessed for side asymmetries or clear bilateral defects indicating a decrease in Cerebral Blood Flow (CBF) or Cerebral Blood Volume (CBV), or an increase in Time-To-Peak (TTP) [18]. All study parameters were assessed by personnel not aware of the patient’s study allocation.\n\nIn case DIND, elevated MFV in TCD or new deficits in PCT, patients received DSA. Angiographic vasospasm was defined as a reduction of the vessel diameter of more than 50%. In this case, the spasm was treated endovascularly by a balloon catheter or – if not accessible - by a local infusion of nimodipine in a dose of 2 – 4 mg/h for 30 – 60 minutes.\n\nTarget parameters\nThe target parameter was secondary infarction on native CT within the following three days after episodes that suggest critical brain perfusion:\n\nAn episode of DIND,\n\nAngiographic vasospasm,\n\nElevated flow velocities in TCD (MFV > 140 cm/s) and\n\nPathological findings in PCT.\n\nCT-scans were analyzed for new hypodensities. Secondary infarction on plain CT-scans were defined as described by von Kummer et al. [19].\n\nData analysis\nA Fisher exact test was used to analyze incidences. An ROC analysis was performed for trancranial Doppler values to determine the cut-off limit for the value “ultrasonographic vasospasm”. This analysis confirmed the inflection point of the ROC curve to be at 140 cm/s. Statistical analysis was performed using GraphPad Prism 4 Statistical Software (GraphPad Software, San Diego, CA). Differences were considered significant at p < 0.05. Values are given as mean ± standard deviation for parametric data. For non-parametric data, median values (and mean values) are given.\n\nResults\nPatient characteristics\n107 patients were included in the study (66 female, 41 male). 54 patients were assigned to receive magnesium, 53 to the control group. The mean age was 50 ± 12 years in the magnesium group and 52 ± 13 years in the control group (p = 0.15). The median WFNS score was 3 (mean 2.63 ± 1.61) in the magnesium group and 2 (mean 2.46 ± 1.64) in the control group. The median Hunt/Hess Score was 3 in both groups (mean 2.88 ± 1.24 in the magnesium group and 2.66 ± 1.30 in the control group). The median Fisher Score was 3 in both groups. Patients in the magnesium group were hospitalized 21,9 ± 7.8 days, patients in the control group were hospitalized 20.1 ± 8.2 days. Neurological outcome was assessed by the GOS score after 6 months. The median GOS score was 5 (mean 3.92 ± 1.34) in the magnesium group and 4 (mean 3.45 ± 1.46) in the control group.\n\nSide effects\nPotential side effects of parenteral magnesium treatment are electrocardiographic changes, particularly bradycardic arrhythmias and a newly appearing atrioventricular block, hypocalcemic tetany and arterial hypotension. We found a tendency towards a slightly lower heart rate in magnesium-treated patients, several cases with facial flushing and one case with hypocalcemic tetany at serum levels above the target range which was successfully treated by dose-reduction. No further relevant side effects were observed, especially no life-threatening bradycardia and no hemodynamically relevant hypotension. In no case, therapy had to be stopped due to side effects of magnesium sulfate.\n\nAcquisition of Target Parameters\nIn the entire patient collective, 613 native CT-scans were obtained between admission and discharge. Of these, 484 were obtained at day three after admission or later. Following the study protocol, 414 PCTs were performed. 89 invasive angiographies (DSA) were performed due to suspected vasospasm in 53 of 107 patients. (Table 1)\n\nTable 1 Incidence of vasospasm and secondary infarction Incidence of vasospasm as determined by clinical examination (DIND), angiography (narrowing of vessel diameter > 50 %), TCD (MFV > 140 cm/s), and PCT (asymmetry or clear bilateral deficit). The incidence of DIND was reduced in magnesium-treated patients (32/54 patients in the magnesium group and 29/53 patients in the control group were neurologically assessable through the largest part of their hospital stay). There was no risk-reduction to develop arterial narrowing (DSA, TCD) or pathological perfusion patterns in PCT by magnesium-treatment. The risk to develop secondary infarction, however, was markedly reduced in magnesium-treated patients in conditions of arterial narrowing (DSA, TCD) and pathological findings in PCT. (Fisher Exact Test, DIND = delayed ischemic neurological deficit, DSA = digital subtraction angiography, TCD = transcranial Doppler sonography, PCT = perfusion-CT, MgSO4 = magnesium sulfate)\n\n\tNumber of patients/exams\tSigns of Vasospasm\tp-level\tSecondary infarction\tp-level\t\nDIND\tMgSO4 32 pats\nControl 29 pats\tMgSO4 9/32\nControl 23/29\tp = 0.03\tMgSO4 0/9\nControl 9/23\tp = 0.167\t\nDSA\tMgSO4 40 exams\nControl 49 exams\tMgSO4 26/40\nControl 32/49\tp = 1.00\tMgSO4 2/26\nControl 17/32\tp = 0.007\t\nTCD\tMgSO4 234 exams\nControl 246 exams\tMgSO4 114/234\nControl 135/246\tp = 0.48\tMgSO4 7/114\nControl 32/135\tp = 0.001\t\nPCT\tMgSO4 210 exams\nControl 196 exams\tMgSO4 117/210\nControl 122/196\tp = 0.51\tMgSO4 10/117\nControl 30/122\tp = 0.006\t\nNeurological assessment\n61 of 107 patients (32 in the magnesium group, 29 in the control group) were amenable to neurological assessment throughout the hospital stay except for episodes in which they needed anesthesia or sedation (surgery, endovascular aneurysm treatment, reangiography for suspected vasospasm) In magnesium-treated patients, 9 episodes of DIND were registered. None was followed by secondary infarction within the following 3 days. In the control-group, 23 episodes of DIND were found. 9 were followed by secondary infarction (p = 0.31).\n\nAngiography\nOver all, 89 DSA were performed in 53 patients due to suspected vasospasm. In 27 patients, DSA was conducted more than once (Table 1). 40 digital subtraction angiographies (DSA) were performed in the magnesium group due to suspected vasospasm. 26 showed relevant arterial narrowing, 25 were treated by angioplasty, one by a local intraarterial nimodipine infusion. 2 of 26 were followed by secondary infarction within the following 3 days. In the control-group, 49 DSA were performed, 32 showed relevant arterial vasospasm, 27 were treated by angioplasty, 5 by intraarterial nimodipine infusion. 17 of 32 developed secondary infarction (p = 0.007).\n\nTranscranial Doppler Sonography (TCD)\nIn the magnesium group, 114 TCD measurements showed elevated MFV. Of those, 7 were followed by secondary infarction. In the control-group, 135 TCD-measurements showed elevated MFV, 32 were followed by secondary infarction (p = 0.0009).\n\nPerfusion-CT (PCT)\nIn all but 2 cases, Flow-Perfusion maps and Blood Volume maps showed defects which correlated with already demarcated infarction in native CT. In the magnesium group, 117 Time-To-Peak (TTP) maps showed abnormal findings. 10 of those were followed by secondary infarction within the following 3 days. In the control-group, 122 TTP maps showed pathological findings. 30 of those were followed by secondary infarction within the following 3 days (p = 0.006). If differentiated by days after SAH, the differences in occurrence of DIND, ultrasonographic vasospasm and PCT were not statistically significant due to the limited number of patients and events for each respective day.\n\nDiscussion\nThe data of the present analysis show that continuous intravenous treatment with magnesium sulfate significantly reduces the risk to develop secondary cerebral infarction in case of angiographic vasospasm, elevated flow velocities in TCD and pathological findings in PCT. Even in case of DIND, the risk of eventual infarction was reduced.\n\nPromising results in experimental studies have raised high expectations that magnesium might be a valuable drug for the treatment of ischemic diseases of the brain, most of all in stroke patients. Several groups investigated the protective efficacy in experimental studies of permanent focal ischemia and consistently found reduced infarct volumes [1, 2, 20]. Likewise, a reduction of infarct volumes and improved neurological outcome was reported in animal models of temporary ischemia after intravenous administration of magnesium [3, 21]. However, after promising results of small clinical trials [5, 6], a large multicenter trial failed to show improved outcome after embolic stroke (IMAGES - Intravenous Magnesium Efficacy in Stroke Trial [22]). The authors concluded from their data that one of the most important reasons for the failure of the IMAGES-trial may have been the mean delay of 7 hours from onset of symptoms to beginning of treatment as neuroprotective efficacy decreases the longer administration is delayed [23].\n\nIn SAH, in turn, the prerequisites for a neuroprotective treatment are different. Delayed vasospasm of subarachnoid vessels appears in a high percentage of SAH patients within the first 2 weeks after SAH. Subarachnoid vessels become increasingly spastic and cerebral blood flow (CBF) may fall below ischemic thresholds [24]. This much-feared complication affects 20 – 30 % of SAH patients and may result in cerebral infarction, permanent morbidity or death. Delayed cerebral vasospasm after SAH is self-limiting after several days or weeks and, therefore, resembles a form of transient focal ischemia. On the other hand, this course of events bears the opportunity to undertake neuroprotective measures prior to the onset of ischemia. In an animal model of temporary middle cerebral artery occlusion (MCAO), a dose-finding study has demonstrated that the intra- and postischemic maintainance of serum concentrations between 2.0 and 2.5 mmol/l offered the highest neuroprotection [4]. Consequently, this dose was used in our clinical trial. We previously reported the absence of relevant side effects during the continuous long-term administration of magnesium sulfate in this dose and the prevention of secondary infarction [14]. Recently, the topic of magnesium has been re-caught and in an intraoperative setting during aneurysm surgery, the CBF-increasing properties been demonstrated [25]. In addition, further experimental [26] and clinical data [27, 28, 29] has been published suggesting a dose-dependent neuroprotective effect of parenteral magnesium.\n\nIn the face of these new activities in the topic, this post-hoc analysis was conducted specifically focussing on the neuroprotective property under conditions of critical brain perfusion after aneurysmal SAH. Our analysis shows that the incidence of pathological findings in TCD and PCT – parameters of arterial narrowing – are not overwhelmingly different between the two trial-groups indicating that the effect of magnesium in this concentration as a vasodilator may be secondary. Our finding that only 9 of 32 patients who were neurologically assessable in the magnesium group developed DIND while 23 of 29 in the control group developed DIND suggests that the ischemic tolerance may be increased by magnesium treatment. The findings that magnesium treatment decreases the incidence of infarction, once DIND has occurred, points into the same direction. Elevated flow velocities in TCD measurements and pathological findings in PCT are surrogate parameters which indicate arterial narrowing and reduced brain perfusion, respectively. The incidence of secondary infarction following these conditions was significantly reduced as well. Our results strongly suggest a neuroprotective effect of magnesium treatment after SAH.\n\nThe question arises why two large clinical trials have failed to show a beneficial effect in SAH-patients [15, 16]. Wong et al. reported about 327 patients that were randomized to receive a daily dose of 80 mmol/l MgSO4 or placebo. The authors reported no significant benefit of magnesium-treatment regarding clinical outcome after 6 months or clinical vasospasm [15]. The results of the largest clinical trial have been published by Mees and coworkers. In this multicenter study, 1,204 patients with aneurysmal SAH were enrolled and assigned to one of two study arms to either receive 64 mmol MgSO4 per day or serve as controls. The administration of MgSO4 did not improve clinical outcome assessed 3 months after SAH [16].\n\nThis data requires a critical analysis. In both trials, all patients – treatment and control group – were co-treated with nimodipine. This pyrrolopyrimidine-type calcium antagonist, has been intensively tested in various clinical studies in the 1980s and 1990s. Analyzing the pooled data for nimodipine trials, a Cochrane review revealed an advantage of nimodipine treatment, so that this treatment is routinely used in many centers. The review concludes, however, that the evidence for nimodipine was not beyond any doubt since the benefit of treatment is largely determined by one trial [30, 31]. The magnesium doses used in both trials were markedly lower than in our study in which 140 ± 51 mmol/d were administered to maintain the target serum parameters. In fact, dose regimens were used in those trials that had previously failed to prove a neuroprotective effect in stroke patients [32] and were neither tested in experimental settings nor in earlier clinical trials before launching the randomized trial. It is well known that magnesium has clear dose dependent effects [33]. New experimental data emphasizes that a neuroprotective action may not be exerted below a certain concentration [26]. Therefore, plasma concentrations need to be high enough. Our study used higher doses than other trials (Table 2) and – although it is a monocenter study – is the only one to investigate a dosing schedule that was a) controlled by serum levels, and b) tested for its neuroprotective efficacy in a preclinical experimental setting.\n\nTable 2 Randomized clinical studies investigating the therapeutic effect of intravenous magnesium to prevent delayed vasospasm and secondary ischemic events and to improve outcome after aneurysmal subarachnoid hemorrhage. The results are not unequivocal. The beneficial effect might depend on the dose-regimen and comedication.\n\nAuthor\tStudy setup\tTreatment arms and comedication\tIndividuals\tResults\t\nLuo et al., 1996 [9]\tRandomized, patient-blinded\tMgSO4 (approx. 100 – 200 mmol per day for 2 – 3 weeks) vs. placebo\t52 patients\tSignificant reduction of secondary neurological deterioration, reduction of delayed cerebral infarction\t\nVeyna et al., 2002 [8]\tRandomized, patient-blinded\tNimodipine vs. nimodipine + MgSO4 (25 mmol + 192 mmol/day for 10 days)\t36 patients\tSafe use of magnesium. Non-significant trend to improved clinical outcome\t\nVan den Bergh et al., 2005 [37]\tRandomized, double-blinded\tNimodipine vs. nimodipine + MgSO4 (64 mmol/day for 14 days)\t283 patients\tReduction of delayed cerebral ischemia and trend to better neurological outcome\t\nSchmid-Elsaesser et al., 2007 [12]\tRandomized, double-blinded\tNimodipine vs. MgSO4 (10mg/kg + 30mg/kg/day for 7 days)\t104 patients\tNo significant difference between magnesium and nimodipine\t\nMuroi et al., 2008 [10]\tRandomized, patient-blinded\tNimodipine vs. nimodipine + MgSO4 (16 mmol + 64 mmol/24h, maximum serum concentration 2.0 mmil/l)\t58 patients\tTrend to better clinical outcome after 3 and 12 months. Treatment was stopped in 16 patients due to hypotension, arrhythmias, respiratory arrest and myocardial infarction\t\nWong et al., 2010 [15]\tRandomized, double blinded\tNimodipine vs. nimodipine + MgSO4 (20 mmol + 80 mmol/day for 14 days)\t327 patients\tNo reduction of secondary ischemia or outcome\t\nWestermaier et al., 2010 [14]\tRandomized, double-blinded\tMgSO4 (141 ± 51 mmol – target serum level 2.0 – 2.5 mmol/l) vs. placebo\t107 patients\tSignificant reduction of secondary infarction and ultrasonographic/angiographic vasospasm. Non-significant reduction of neurological outcome and mortality\t\nMees et al., 2012 [16]\tRandomized, double-blinded\tNimodipine vs. nimodipine + MgSO4 (64 mmol/day)\t1207 patients\tNo improvement of clinical outcome\t\nOur serum-level targeted dose-regimen was chosen on the basis of previous experimental studies that offered the highest neuroprotective effect in a model of temporary cerebral ischemia. On the other side, the co-treatment with nimodipine and magnesium is a simultaneous treatment with two calcium antagonists offering similar modes of action. Again, experimental studies have to be looked at and suggest that the neuroprotective effect of nimodipine may not be enhanced by combination therapies [34]. Schmid-Elsaesser et al. compared nimodipine treatment to magnesium treatment and found no marked and significant difference in the incidence of vasospasm and clinical outcome [12].\n\nIn the present study, 107 patients were randomized to either receive a placebo infusion or to receive a variable dose of intravenous MgSO4 in order to maintain serum concentrations of 2.0 – 2.5 mmol/l for 10 days or – if there was clinical, angiographic and/or ultrasonographic vasospasm – until the signs of vasospasm had disappeared or to receive a placebo infusion without other calcium antagonists [14].\n\nThe fact that it resembles an incident-related rather than a patient-related analysis is a limitation of this study. A patient-related analysis has been reported previously [14]. It was, therefore, our purpose to investigate the tissue-protective effect of the compound once a sign of critical brain perfusion has appeared. The incidence-related assessment takes into account that a patient may have more than one episode of critical brain perfusion in the course of the disease and may react in a different way each time. However, it disregards that there may be a different degree of ischemic tolerance in each patient which may influence the risk of infarction and neurological recovery and make the analysis less precise. The choice of parameters that possibly indicate critical brain perfusion is another limitation of this analysis. Apart from clinical deterioration (DIND), all other parameters of this study indicating threatened brain perfusion (TCD, PCT, DSA) are surrogate parameters. We did not use absolute measures of CBF like thermodilution or Xenon-CT or single photon emission tomography in the daily routine, nor was it part of the study protocol. Although it is known today, that vasospasm is not the sole determinant of delayed ischemic deficits and infarction, it is widely accepted that reduced brain perfusion is a clear risk factor [35, 36]. All parameters used in this analysis are validated to indicate arterial narrowing or altered flow and tissue supply and perfusion at risk. Therefore, the results of this analysis suggest that, under these circumstances and if administered in an appropriate dose, magnesium can be neuroprotective in conditions of critical brain perfusion.\n\nConflict of Interest None of the authors has a conflict of interest to declare.\n\nFunding This publication was funded by the German Research Foundation (DFG) and the University of Wuerzburg in the funding programme Open Access Publishing.\n==== Refs\nReferences\n[1] Izumi Y Roussel S Pinard E Seylaz J Reduction of infarct volume by magnesium after middle cerebral artery occlusion in rats J Cereb Blood Flow Metab 1991 11 1025 1030 1939380 \n[2] Lee EJ Ayoub IA Harris FB Hassan M Ogilvy CS Maynard KI Mexiletine and magnesium independently, but not combined, protect against permanent focal cerebral ischemia in Wistar rats J Neurosci Res 1999 58 442 448 10518118 \n[3] Marinov MB Harbaugh KS Hoopes PJ Pikus HJ Harbaugh RE Neuroprotective effects of preischemia intraarterial magnesium 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evaluation of therapeutic window of post-ischemia treatment with magnesium sulfate in embolic stroke model of rat Neurosci Lett 2000 285 119 122 10793241 \n[24] Jones TH Morawetz RB Crowell RM Marcoux FW FitzGibbon SJ DeGirolami U et al Thresholds of focal cerebral ischemia in awake monkeys J Neurosurg 1981 54 773 782 7241187 \n[25] Sommer B Weidinger CS Wolf D Buchfelder M Schmitt H Intraoperative continuous cerebral microcirculation measurement in patients with aneurysmal subarachnoid hemorrhage: preliminary data on the early administration of magnesium sulfate BMC Anesthesiol 2017 17 143 0435 29041920 \n[26] Itoh K Maki T Shindo A Egawa N Liang AC Itoh N et al Magnesium sulfate protects oligodendrocyte lineage cells in a rat cell-culture model of hypoxic-ischemic injury Neurosci Res 2016 106 66 69 26699082 \n[27] Pearce A Lockwood C van den Heuvel C Pearce J The use of therapeutic magnesium for neuroprotection during global cerebral ischemia associated with cardiac arrest and cardiac surgery in adults: a systematic review JBI Database System Rev Implement Rep 2017 15 86 118 \n[28] Zhang LW Warrington JP Magnesium Sulfate Prevents Placental Ischemia-Induced Increases in Brain Water Content and Cerebrospinal Fluid Cytokines in Pregnant Rats Front Neurosci 2016 10 561 28008305 \n[29] Chakkarapani E Chau V Poskitt KJ Synnes A Kwan E Roland E et al Low plasma magnesium is associated with impaired brain metabolism in neonates with hypoxic-ischaemic encephalopathy Acta Paediatr 2016 105 1067 1073 27336238 \n[30] Pickard JD Murray GD Illingworth R Shaw MD Teasdale GM Foy PM et al Effect of oral nimodipine on cerebral infarction and outcome after subarachnoid haemorrhage: British aneurysm nimodipine trial BMJ 1989 298 636 642 2496789 \n[31] Dorhout MS Rinkel GJ Feigin VL Algra A van den Bergh WM Vermeulen M et al Calcium antagonists for aneurysmal subarachnoid haemorrhage Cochrane Database Syst Rev 2007 CD000277 17636626 \n[32] Dorhout MS Algra A Wong GK Poon WS Bradford CM Saver JL et al Early Magnesium Treatment After Aneurysmal Subarachnoid Hemorrhage: Individual Patient Data Meta-Analysis Stroke 2015 46 3190 3193 26463689 \n[33] Mohr K Therapeutic drugs Magnesium, Dtsch Med Wochenschr 1994 119 1669 1670 7988368 \n[34] Zausinger S Westermaier T Plesnila N Steiger HJ Schmid-Elsaesser R Neuroprotection in transient focal cerebral ischemia by combination drug therapy and mild hypothermia: comparison with customary therapeutic regimen Stroke 2003 34 1526 1532 12730554 \n[35] Pluta RM Hansen-Schwartz J Dreier J Vajkoczy P Macdonald RL Nishizawa S et al Cerebral vasospasm following subarachnoid hemorrhage: time for a new world of thought Neurol Res 2009 31 151 158 19298755 \n[36] Frontera JA Fernandez A Schmidt JM Claassen J Wartenberg KE Badjatia N et al Defining vasospasm after subarachnoid hemorrhage: what is the most clinically relevant definition? Stroke 2009 40 1963 1968 19359629 \n[37] van den Bergh WM Algra A van Kooten F Dirven CM van Gijn J Vermeulen M et al Magnesium sulfate in aneurysmal subarachnoid hemorrhage: a randomized controlled trial Stroke 2005 36 1011 1015 15790946\n\n",
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"title": "Magnesium Protects in Episodes of Critical Perfusion after Aneurysmal SAH.",
"title_normalized": "magnesium protects in episodes of critical perfusion after aneurysmal sah"
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"abstract": "Wernick's Encephalopathy (WE) is an acute neuropsychiatric syndrome caused by thiamine deficiency post hematopoietic stem cell transplant (HSCT). WE is associated with high mortality and morbidity rates, but due to its rare occurrence, it is rarely considered in patients submitted to this procedure. Considering that, the manuscript reports the clinical characteristics and the possible factors that predisposed the occurrence of WE in a patient with non-Hodgkin's lymphoma post-Autologous HSCT. We conclude that WE should be considered in patients submitted to autologous HSCT associated with prolonged use of TPN and malnutrition.",
"affiliations": "Doctor, Residence in Hematology, Bone Marrow Transplantation Service at Walter Cantidio University Hospital - Fortaleza (CE), Brasil.;Ph.D. in Pharmacy, Professor of Hematology, Federal University of Ceará - Fortaleza (CE), Brasil.;Ph.D. in Pharmaceutical Sciences, Federal University of Ceará - Fortaleza (CE), Brasil.;Doctor, Residence in Hematology, Bone Marrow Transplantation Service at Walter Cantidio University Hospital - Fortaleza (CE), Brasil.;Doctor, Residence in Hematology, Bone Marrow Transplantation Service at Walter Cantidio University Hospital - Fortaleza (CE), Brasil.;Doctor, Residence in Hematology, Bone Marrow Transplantation Service at Walter Cantidio University Hospital - Fortaleza (CE), Brasil.;Ph.D. in Pharmaceutical Sciences, Federal University of Ceará - Fortaleza (CE), Brasil.;Ph.D. in Pharmaceutical Sciences, Federal University of Ceará - Fortaleza (CE), Brasil.;Doctor, Residency in Radiology and Diagnostic Imaging of Walter Cantídio University Hospital - Fortaleza (CE), Brasil.;Ph.D. in Surgery, Chief of Bone Marrow Transplantation Service at Walter Cantidio University Hospital - Fortaleza (CE), Brasil.",
"authors": "Leitão|João Paulo de Vasconcelos|JPV|;Lemes|Romélia Pinheiro Gonçalves|RPG|;Barbosa|Maritza Cavalcante|MC|;Araújo|Beatriz Stela Gomes de Souza Pitombeira|BSGSP|;Barroso|Karine Sampaio Nunes|KSN|;Kaufman|Jacques|J|;Santos|Talyta Ellen de Jesus Dos|TEJD|;Moura|Anna Thawanny Gadelha|ATG|http://orcid.org/0000-0001-6582-7867;Barreto|André Rodrigues Façanha|ARF|;Duarte|Fernando Barroso|FB|",
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"doi": "10.1590/1806-9282.64.10.882",
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"issue": "64(10)",
"journal": "Revista da Associacao Medica Brasileira (1992)",
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"medline_ta": "Rev Assoc Med Bras (1992)",
"mesh_terms": "D000328:Adult; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008228:Lymphoma, Non-Hodgkin; D012307:Risk Factors; D013832:Thiamine Deficiency; D014182:Transplantation, Autologous; D014899:Wernicke Encephalopathy",
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"pubdate": "2018-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Wernicke's encephalopathy in a patient with non-Hodgkin's lymphoma post-Autologous HSCT.",
"title_normalized": "wernicke s encephalopathy in a patient with non hodgkin s lymphoma post autologous hsct"
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"abstract": "Carbamazepine and oxcarbazepine are used for behavioral disorders following organic diseases. After severe acquired brain injury, patients may develop frontal symptoms. In our neurological rehabilitation routine, oxcarbazepine is used for better safety over carbamazepine, although its efficacy is not clarified. We aimed to improve knowledge on this use of oxcarbazepine, by probing clinical factors associated with response. We retrospectively examined the clinical records of our patients, collecting clinical variables and outcomes of efficacy, both clinician-rated and caregiver/self-rated. We described the distribution of clinical variables and examined their associations via logistic regressions. Patients in our cohort were predominantly pediatric, with frontal lobe damage and irritable/reactive. With an oxcarbazepine median dose of 975 mg, almost half of patients improved. We found several clinical factors associated with clinician-rated efficacy: absence of frontal damage and absence of irritability/reactivity symptoms; clinical factors associated with caregivers/patients-rated efficacy were: higher DRS score at baseline and higher patient age. In this retrospective study, we observed that oxcarbazepine was differentially efficacious in patients with specific characteristics. Our study could not examine drug therapy separately from neuropsychological therapy, nor the influence of dose. Our associative results should be verified experimentally, also assessing causality and establishing dose-related efficacy and safety.",
"affiliations": "Scientific Institute IRCCS Eugenio Medea, 23842 Bosisio Parini, Italy.;Scientific Institute IRCCS Eugenio Medea, 23842 Bosisio Parini, Italy.;Scientific Institute IRCCS Eugenio Medea, 23842 Bosisio Parini, Italy.;Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences L. Sacco, \"Luigi Sacco\" University Hospital, Università di Milano, 20157 Milan, Italy.;Scientific Institute IRCCS Eugenio Medea, 23842 Bosisio Parini, Italy.;Scientific Institute IRCCS Eugenio Medea, 23842 Bosisio Parini, Italy.",
"authors": "Pozzi|Marco|M|0000-0002-3800-5697;Avantaggiato|Paolo|P|;Pastore|Valentina|V|;Carnovale|Carla|C|;Clementi|Emilio|E|;Strazzer|Sandra|S|0000-0001-8414-6565",
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"fulltext": "\n==== Front\nBrain Sci\nBrain Sci\nbrainsci\nBrain Sciences\n2076-3425\nMDPI\n\n10.3390/brainsci11070949\nbrainsci-11-00949\nArticle\nOxcarbazepine for Behavioral Disorders after Brain Injury: Factors Influencing Efficacy\nhttps://orcid.org/0000-0002-3800-5697\nPozzi Marco 1†\nAvantaggiato Paolo 1†\nPastore Valentina 1\nCarnovale Carla 2\nClementi Emilio 12\nhttps://orcid.org/0000-0001-8414-6565\nStrazzer Sandra 1*\nNakajima Shinichiro Academic Editor\n1 Scientific Institute IRCCS Eugenio Medea, 23842 Bosisio Parini, Italy; marco.pozzi@lanostrafamiglia.it (M.P.); avantaggiato74@yahoo.it (P.A.); valentina.pastore@lanostrafamiglia.it (V.P.); emilio.clementi@unimi.it (E.C.)\n2 Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences L. Sacco, “Luigi Sacco” University Hospital, Università di Milano, 20157 Milan, Italy; carla.carnovale@unimi.it\n* Correspondence: sandra.strazzer@lanostrafamiglia.it; Tel.: +39-031-877853; Fax: +39-031-877499 (ext. 855)\n† These authors contributed equally to the manuscript.\n\n19 7 2021\n7 2021\n11 7 94915 6 2021\n16 7 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nCarbamazepine and oxcarbazepine are used for behavioral disorders following organic diseases. After severe acquired brain injury, patients may develop frontal symptoms. In our neurological rehabilitation routine, oxcarbazepine is used for better safety over carbamazepine, although its efficacy is not clarified. We aimed to improve knowledge on this use of oxcarbazepine, by probing clinical factors associated with response. We retrospectively examined the clinical records of our patients, collecting clinical variables and outcomes of efficacy, both clinician-rated and caregiver/self-rated. We described the distribution of clinical variables and examined their associations via logistic regressions. Patients in our cohort were predominantly pediatric, with frontal lobe damage and irritable/reactive. With an oxcarbazepine median dose of 975 mg, almost half of patients improved. We found several clinical factors associated with clinician-rated efficacy: absence of frontal damage and absence of irritability/reactivity symptoms; clinical factors associated with caregivers/patients-rated efficacy were: higher DRS score at baseline and higher patient age. In this retrospective study, we observed that oxcarbazepine was differentially efficacious in patients with specific characteristics. Our study could not examine drug therapy separately from neuropsychological therapy, nor the influence of dose. Our associative results should be verified experimentally, also assessing causality and establishing dose-related efficacy and safety.\n\noxcarbazepine\npsychomotor agitation\nsevere acquired brain injury\nneurological rehabilitation\n==== Body\n1. Introduction\n\nFollowing severe acquired brain injury (sABI), many patients continue to experience major cognitive and behavior problems after physical recovery; these in turn affect rehabilitation negatively and have social consequences [1].\n\nIn cases that require pharmacological treatment, options include psychiatric drugs, from antipsychotics to mood stabilizing anticonvulsant and sedatives, used off-label and hence not thoroughly tested for efficacy and safety [2].\n\nAmong these drugs, anticonvulsants have gained momentum as alternatives and adjuncts to antipsychotics and lithium in the treatment of behavior disorders due to affective/schizoaffective disorders. Anticonvulsants can have a lithium-like clinical efficacy profile on behavior, yet they carry less risk for adverse effects, leading to greater manageability and patient compliance [3,4]. Most notably, carbamazepine was effective at improving endogenous mania in patients with organic psychoses and appeared more effective in patients with mixed mania, rapid cycling, and “non-classical” bipolar disorders [4,5]. Carbamazepine appears to be a drug of choice in the treatment of personality disorder [6,7] especially when symptoms of aggressive or impulsive behavior are present [8,9]. Carbamazepine has been used successfully in small cohorts of patients with agitation due to brain injury [10,11], and, more recently, a treatment guideline for behavioral disorders after traumatic brain injury indicated carbamazepine and valproic acid as first line medications over adrenergic antagonists and antipsychotics [12]. The clinical utility of carbamazepine is also limited by multiple drug interactions and adverse reactions. Regarding interactions, carbamazepine is a strong inducer of CYP3A4 and an inducer of glucuronyltransferase [13]. In the clinical setting of brain injury rehabilitation, typical concomitant therapies include drugs with a narrow therapeutic index metabolized by the two above enzymes, such as antibacterial chemotherapies, oral anticoagulants, drugs used for cardiovascular protection, other anticonvulsants, and glucocorticoids. Adverse reactions to carbamazepine itself include hyponatremia, cognitive impairment, hepatic toxicity, anemia, and immune system activation with potentially fatal outcomes [14]. Oxcarbazepine [15] is a derivative of carbamazepine that has the same main mechanism of action, as they both prolong the inactivation phase of voltage-gated sodium channels. However, oxcarbazepine is a weak inducer of CYP3A4 and of glucuronyltransferase, such that the concomitant therapies typical of patients with sABI would not need a dose adjustment [16], which represents a considerable added therapeutic value. The adverse reactions profile of carbamazepine and oxcarbazepine is almost identical. Better tolerance of oxcarbazepine stems from its increased manageability when drug combinations are frequent and inevitable, as in the case of patients with sABI. A lessened impact on the alterations of plasma levels of other drugs directly leads to reduced occurrence of adverse reactions and indirectly translates into better tolerance of oxcarbazepine and easier clinical management. Several studies suggest that oxcarbazepine has effects similar to those of carbamazepine in bipolar disorders [17]. In small active comparative studies, oxcarbazepine was as effective as lithium, haloperidol, and valproate in the treatment of acute mania [18,19]. In recent years, several authors have reported on cases with a long history of bipolar II disorder and violent behavior that showed an improvement in mood stabilization following treatment with oxcarbazepine [20,21,22]. Others have described cases of reduction in acute manic symptoms after oxcarbazepine [23]. There are also negative reports, as oxcarbazepine has been tested without success in a trial on patients with aggression due to dementia [24], and a recent meta-analysis on agitation due to dementia found no efficacy of oxcarbazepine [25]. It is important to note that patients examined in the studies above were not comparable to young or adult patients who incurred brain injury; thus results, both negative and positive, should be considered provisional. More recently, a Cochrane Review has concluded that, although numerous drugs have been tried in the management of aggressive behavior in acquired brain injury, no firm evidence of their efficacy has been found, except for propranolol [7]. Oxcarbazepine and valproate efficacy is likewise unsupported by a sufficient level of evidence [7]. A recent randomized controlled trial demonstrated that carbamazepine was efficacious in controlling aggression after traumatic brain injury [26], adding higher quality evidence to the field. In this context of unclear but possible efficacy, it is most important to choose drugs with few side effects and monitor their effects over time. Studies with a pediatric focus should also be conducted, as there is currently no evidence base on the use of carbamazepine and its derivatives for the control of behavior after brain injury in pediatric patients.\n\nIn our clinical practice we regularly use oxcarbazepine as pharmacotherapy for behavioral disorders after brain injury [27], making it possible to analyze its use on a fair number of patients. The objectives of this study were: (1) to describe the efficacy of oxcarbazepine on the containment of symptoms of conduct disorder and oppositional defiant disorder in our clinical population; (2) to verify whether oxcarbazepine efficacy was associated with differences in any clinical variables. The results of our analysis provide indications that distinct groups of patients may benefit more or less from oxcarbazepine; we described also its adverse effects.\n\n2. Materials and Methods\n\n2.1. Data Source and Extraction\n\nThis retrospective study evaluated for inclusion the clinical records of all patients admitted to the sABI unit of our rehabilitation institute during the last 20 years. Inclusion criteria for this study were: (1) having incurred sABI (GCS < 8); (2) being admitted to our institute for rehabilitation; (3) having results from magnetic resonance imaging performed prior to admittance to rehabilitation; (4) having a diagnosis of behavioral disorders formulated by staff neuropsychologists. This diagnosis followed the presence of the criteria that by the DSM-IV-TR lead to the diagnosis of conduct disorder or oppositional-defiant disorder. However, due to the presence of a brain injury not fully recovered, a formal diagnosis of conduct disorder or oppositional-defiant disorder was not made until discharge; the details of behavioral disorders were reported on clinical files and monitored; (5) having a Clinical Global Impression-Improvement (CGI-I) rating of behavioral symptoms (including but not limited to irritability, agitation, escaping, disruption, aggression), by which improvement is defined as CGI-I less than 3 on a scale of 1 (extremely improved) to 7 (extremely worsened); (6) having the referring physician opt for pharmacological treatment of behavioral disorders with oxcarbazepine. Exclusion criteria comprised: (1) having a psychiatric diagnosis before incurring sABI; (2) using psychotropic drugs before incurring sABI; (3) using oxcarbazepine as an anticonvulsant. Once in rehabilitation, all patients received the same standard treatments, as required by their injury (neurological and physical, kinesiotherapy, speech therapy). Psychological support and therapy are included for patients with a level of functioning sufficient to allow interaction; in the present group of patients, cognitive/behavioral psychological therapy was administered to everyone, following clinical protocols previously published [28]. For all included patients, we recorded the following variables: sex (m/f); date of birth; date of admittance to rehabilitation; brain injury etiology (trauma, stroke, anoxic brain damage, other); GCS score (the earliest available); GOS score at admittance to rehabilitation; duration of coma (days). From results of magnetic resonance imaging (MRI), we recorded the presence (yes/no) of damage to areas that may be involved with behavior and impulse control: frontal lobe, callous body, thalamus, or diffuse axonal injury. From results of psychological assessments (including, where applicable: Wechsler Intelligence Scale for Children, Leiter-R, Vineland Adaptive Behavior Scales, Child Behavior Checklists, Adult Behavior Checklist), we recorded the presence (yes/no) of behavioral disorders, subdividing them by distinct types of internalizing or externalizing disorders, in partial accordance with previous work [29]: oppositional behavior or non-compliance; hyperactivity or impulsivity; uninhibition or recklessness; confabulation or perseveration; irritability or over-reaction; aggression; mood disorders. We also recorded the use of concomitant drugs, classifying them as antidepressant or nootropic; antipsychotic or mood stabilizing; antispastic. We registered the dose of oxcarbazepine used for maintenance therapy and the occurrence and type of adverse drug reactions (ADRs) to oxcarbazepine, with details on actions taken to manage them and their outcomes. We collected the scores of the Disability Rating Scale (DRS) [30] and Functional Independence Measure (FIM—Subscale social function) [31] at admittance and at discharge from rehabilitation. For patients who had it administered, we collected scores of two behavior scoring scales. The Agitated Behavior Scale (ABS) rated by caregivers [32] and the Strengths and Difficulties questionnaire (SDQ) self-rated [33] were collected (where available) at two time points, before and after oxcarbazepine administration, which corresponded to admittance and discharge from rehabilitation. If two ABS or SDQ measures were not available, the patient was only evaluated following clinician-rated CGI-I.\n\n2.2. Data Analysis\n\nVariables were tested for normality by Kolmogorov–Smirnov or Wilcoxon Tests, as relevant. We described continuous variables as means with standard deviation (if normally distributed), or as medians with first and third quartile; categorical variables were reported as numbers and percentages. The cohort was described subdividing it between patients who responded or not. Variables were compared between responders and non-responders for descriptive purposes, by means of chi squared or the Kruskal–Wallis test or ANOVA as applicable. To define responders and non-responders, we used the main study outcome, i.e., CGI-I scale rated by clinicians 1 to 2 indicated responders, and scores of 3 or more indicated non-responders. Regarding caregiver- and patient-rated scales (ABS and SDQ), we calculated the Reliable Change Index (RCI) [34] using normative data [35,36], and used the RCI as a secondary study outcome. Patients who had a RCI < −1.96 were considered as responders. To assess the association between clinical variables and the clinician-rated response to oxcarbazepine on the CGI-I, we built a logistic regression model with a stepwise approach (p-in < 0.05; p-out > 0.1). The overall fit, adjusted R2, and lack-of-fit were reported; significant predictors were expressed with p-values and with odds ratios (OR). To assess the association between clinical variables and caregiver/patient-rated responses to oxcarbazepine on the ABS/SDQ, we built a linear regression model with a stepwise approach (p-in < 0.05; p-out > 0.1). The overall fit and adjusted R2 were reported; significant predictors were expressed with p-values and beta parameters. The full list of variables tested for associations was: Glasgow Coma Score (GCS) at injury; duration of coma (days); Glasgow Outcome Score (GOS) at admittance to rehabilitation; Disability Rating Scale (DRS) at admittance to rehabilitation and at discharge; Functional Independence Measure (FIM) at admittance to rehabilitation and at discharge; age at start of oxcarbazepine administration (years); oxcarbazepine titrated dose administered (mg/day); damage evidenced by MRI to the frontal lobe/callous body/thalamus/diffuse axonal damage (each yes/no); presence at neuropsychological evaluation of opposition, noncompliance/of hyperactivity, impulsivity/of uninhibition, recklessness/of confabulation, perseveration/of irritability, reactivity/of aggression/of disordered mood (each yes/no); concomitant use of antidepressant or nootropic drugs/of antipsychotic or mood stabilizing drugs/of anticonvulsant or antispastic drugs (each yes/no). Analyses were conducted by SPSS v.22 (IBM, Chicago, IL, USA).\n\n3. Results\n\n3.1. Cohort Description\n\nThrough a chart review, we assembled a retrospective cohort of 46 patients treated with oxcarbazepine for behavioral disorders; of these, 12 were children, 18 adolescents, and 16 adults. The most frequent cause of brain injury was trauma (73.9%), and the median GCS at injury was 5.75. Lesion sites, as described by MRI, were heterogeneous: damage was reported for 58.7% patients in the frontal lobe, 32.6% in the callous body, 30.4% in the thalamus; 45.7% patients had diffuse axonal injury. Behavioral symptoms were also variable; 58.7% patients were irritable and reactive, 47.8% aggressive, 41.3% oppositional or non-compliant, 34.8% hyperactive/impulsive, 32.6% uninhibited and reckless, and 19.6% perseverant/confabulatory; 39.1% of patients had mood disorders. Considering drug therapy, oxcarbazepine was used at a median daily dose of 975 mg; 30.4% patients used also antipsychotic/mood stabilizing drugs, 15.2% antidepressant or nootropic drugs, 13% antispastic drugs. A complete description of the demographic and clinical characteristics collected is shown in Table 1, in which the cohort is split among patients who either improved or not.\n\nFollowing the clinician-rated CGI-I, 21 (45.7%) patients were rated as having improved (CGI-I 2 or less), 25 (54.3%) as not (13 slightly improved, 7 unchanged, 1 worsened). On the caregiver-rated behavioral scales, considering RCI values, eight patients (50%) had significant improvements, and eight (50%) showed no significant change (7 improved slightly, 1 worsened slightly).\n\n3.2. Variables Associated with Improvement\n\nOn the whole dataset (n = 46), we performed a stepwise logistic regression analysis probing the association between clinician-rated improvement on the CGI-I and the clinical variables we collected. We found (model p = 0.005, pseudo-R2 = 0.40, lack of fit p = 0.591) two variables associated with non-efficacy: the presence of a frontal lobe damage, OR = 0.078 (95% C.I. 0.008–0.749, p = 0.027) and the presence of symptoms of irritability/reactivity OR= 0.094 (95% C.I. 0.010–0.893, p = 0.040). We analyzed further the subpopulation of patients who had a behavior scoring scale, either ABS or SDQ, filled out by caregivers or self-rated, respectively, both before and after the introduction of oxcarbazepine. On the RCIs from these data (n = 16), we could perform a linear regression analysis in search of associations between the reliable change index of the scale available for each patient and the clinical variables we collected. We observed (model p = 0.001, R2 = 0.25) that a higher DRS at baseline (β = −0.356, p = 0.010) and a higher patient age (β = −0.327, p = 0.017) were associated with a lower RCI (which means more improvement).\n\n3.3. Adverse Effects\n\nEight patients (17.4%) experienced adverse reactions considered by the treating physicians as possibly related to the use of oxcarbazepine: hyponatremia (3 patients; 6.5%), drowsiness or asthenia (2; 4.3%), psychiatric reactions (2; 4.3%), and one allergic reaction (2.1%). All adverse reactions were resolved at the time of discharge from rehabilitation, which required oxcarbazepine withdrawal in four cases and dose reduction in two; in two cases, the ADR was resolved by adding drugs or supplements. Details of ADRs are reported in Table 2.\n\n4. Discussion\n\nCarbamazepine and oxcarbazepine have been demonstrated as variably efficacious for the treatment of behavioral disorders in the context of psychiatric and neurological illness [25,37,38,39]. Given its lower potential for drug-drug interactions, we are using oxcarbazepine on patients in rehabilitation from brain injury in our clinical routine. Since the efficacy of oxcarbazepine has not been systematically assessed in brain-injured patients [7], any information on its effects, or on factors that may modulate them, is highly valuable from a clinical perspective. Regarding the composition of our study sample, there were predominantly pediatric patients; the majority of them had suffered brain trauma. In the literature, there is no clear indication of the efficacy of oxcarbazepine in such a population, with an exception made for some case-reports; thus, it is hard to compare our results with previous work.\n\nFollowing clinician ratings and parent/self-ratings alike, around half of the patients who received oxcarbazepine improved their behavioral disorders. We could find significant roles for some clinical variables that were associated with the responder status.\n\nRegarding clinician-rated CGI-I, we observed that the presence of a frontal lobe damage diagnosed by MRI and the presence of symptoms of irritability/reactivity were associated with non-response. Damage to the frontal lobe may indicate conditions that are connected with a “frontal lobe syndrome”, a generic definition for an organic behavioral disorder characterized by thought disorganization and personality changes including impulsivity, disinhibition, and aggression [31,40]. Symptoms of irritability and hyper-reactivity are the primary target of antipsychotic therapies used for the control of behavior, especially in young patients [41]; thus, it is not surprising that oxcarbazepine may be scantly efficacious at treating them, given its particular mechanism of action of suppressing neuronal hyperactivation. In fact, oxcarbazepine has been often used for mania, aggression, and mood swings in the context of bipolar disorders [23]. Of note, however, the presence of aggressive symptoms in our patients was not a factor associated with oxcarbazepine efficacy. It may be speculated that the presence of damage to the frontal lobe resembles a cognitive impairment; whether primary or degenerative, cognitive impairment is frequently the base of inappropriate comprehension of the environment (and relation with the environment) leading to frustration and irritability and eventually to abnormal behavior. Oxcarbazepine’s efficacy does not include cognitive improvement. On the caregiver/self-rated behavioral scales, higher DRS at baseline and higher patient age were associated with larger improvement. These results can be connected with a biased subjective perception of improvement. Indeed, parents of patients who are more severe at admittance to rehabilitation usually tend to overestimate their recovery; this bias effect can be even bigger when patients are asked to self-evaluate. Indeed, a qualitative result that emerged from several clinical records was that patients had the incapacity of perceiving their own behavioral issues and disability, possibly as part of an organic psychiatric illness. Indeed, a minority of patients reported complaints about their status, and they were those who developed depressive mood disorders after brain injury. The role of age may thus be involved with the fact that older patients are administered self-evaluations, with more positive bias, while children are evaluated by caregivers, with less bias. Moreover, age has been previously associated with the severity of behavioral disturbances in children [42]; following results of the present study, it may be hypothesized that younger patients incur deeper personality and behavior changes, as compared to older patients. Another important role of patients’ age regards the metabolism of oxcarbazepine. In the liver, oxcarbazepine is metabolized to its 10-monohydroxymetabolite, which is mostly responsible for psychopharmacological effects. The clearance of this metabolite decreases from childhood to adulthood. According to product labels for oxcarbazepine, 10-monohydroxymetabolite exposure in children up to 12 years is on average 40% higher than that of adults.\n\nOf note, the response was not associated with any variable regarding pharmacological treatment: this is an expected finding in the context of a non-interventional retrospective study. In support of this interpretation, the dose of oxcarbazepine at titration was lower in the responder group as compared to the non-responder group. This also suggests that if a response could be achieved, it was achieved with oxcarbazepine doses of around 1 g/day. In general, the need for oxcarbazepine doses higher than 1–1.2 g/day for this use might be considered as a proxy of non-response. However, it is impossible to distinguish in a retrospective work the beneficial effects of oxcarbazepine from those of rehabilitation therapy, including cognitive-behavioral therapy that was administered to all patients in the study. Randomized, double-blind studies should be conducted to demonstrate the efficacy of oxcarbazepine in the treatment of behavioral disorders in brain-injured patients. Such studies are difficult to perform due to the heterogeneity of patients’ characteristics, involving different degrees of physical injuries, as well as sensory, motor, and cognitive disturbances and language disorders, all aspects that affect profoundly social interactions and behavior, together with organic psychiatric symptoms. Furthermore, patients recovering from brain injury usually require multiple drug therapies that must be tailored, rendering a standard clinical trial hardly feasible. In this view, more observational studies, possibly prospective, may also provide useful insight. The lack of high-quality studies on behavioral disorders following brain injury currently limits any conclusion on the efficacy of proposed drug therapies [7]. Clinical decisions should thus be based on safety and lack of drug-drug interactions, properties for which oxcarbazepine would be a suitable candidate [15]. In the present study, we have in fact found a significant occurrence of adverse drug reactions, including hyponatremia (known to occur [43]), as well as asthenia and psychiatric reactions. These adverse reactions should not be underestimated as they can compromise the precarious course of recovery of patients undergoing rehabilitation from brain injury. In particular, asthenia may impair physical rehabilitation, and psychiatric reactions may be mistaken for genuine psychiatric disorders requiring drug treatment. Future prospective studies should perform a thorough evaluation of adverse reactions to oxcarbazepine.\n\nThe generalizability of our results is limited by the composition of our study sample, which was small and predominantly of pediatric patients and brain traumatized patients. Whereas patients’ age may be an important factor limiting generalizability, the traumatic etiology would be less limiting as it is the most frequent cause of brain injury. A technical limitation of our work regards the grouping of symptoms that we chose post-hoc; however, we tried to follow groups of symptoms that were previously described for the frontal syndrome [29] and that were included in the DSM-IV-TR classifications for conduct disorder and oppositional defiant disorder. We explored different groupings for symptoms and found irritability/over-reactivity was a significant factor only when taken on its own. Another limitation regards the limited sample size of the caregiver/self-evaluation sample, due to the absence of scoring scales in the clinical charts. In addition, the caregiver/self-evaluation questionnaires were not entirely equivalent and interchangeable. Future studies should thoroughly implement behavior rating scales such as the ABS and administer them only to caregivers, to minimize bias. In addition, the consistency between clinician- and caregiver-rated efficacy judgments should be verified, a task that we could not carry out due to the low sample size.\n\n5. Conclusions\n\nWe have investigated retrospectively which clinical factors may be associated with responses to oxcarbazepine in behavioral disorders, in the setting of rehabilitation from brain injury. We found possible roles for the presence of frontal lobe damage, of a diagnosis of irritability/hyper-reactivity, of lower patient age, and of lower disability ratings at baseline, in association with non-response. Given the nature of this study, it was expected that pharmacological factors could be not associated with the responder status. Future studies should implement experimental protocols or at least prospective observational protocols, in order to investigate the efficacy of oxcarbazepine. Such studies may be hard to conduct, given the need of patients for multiple drug, physical, and psychological therapies.\n\nAuthor Contributions\n\nConceptualization, M.P., P.A., and S.S.; methodology, M.P. and S.S.; formal analysis, M.P. and C.C.; investigation, P.A. and V.P.; data curation, M.P. and E.C.; writing—original draft preparation, M.P. and P.A.; writing—review and editing, M.P., P.A., E.C., S.S.; supervision, E.C., S.S. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis work was funded by the Italian Ministry of Health (Ricerca Corrente, to M.P., V.P., and S.S.) and by the Regional Center of Pharmacovigilance of Lombardy (to E.C.) and the Italian Medicines Agency, Agenzia Italiana del Farmaco (AIFA, to E.C.), which are gratefully acknowledged. The funding public institutions had no role in any part of the work.\n\nInstitutional Review Board Statement\n\nFollowing the Italian law, retrospective chart studies on anonymized data do not require ethical approval. The work described in clinical records has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.\n\nInformed Consent Statement\n\nNot applicable.\n\nData Availability Statement\n\nData are available from the corresponding author upon request.\n\nConflicts of Interest\n\nThe authors declare no conflict of interest.\n\nbrainsci-11-00949-t001_Table 1 Table 1 Description of demographic and clinical characteristics of the study sample.\n\n\t\tNot Improved on CGI-I (n = 21)\tImproved on CGI-I (n = 25)\tp Value *\t\nClinical characteristics\tBrain injury etiology\tTrauma\t14\t20\t0.059\t\nStroke\t1\t4\t\nAnoxia\t4\t0\t\nOther\t2\t1\t\nAge (years)\tMedian\t17.2\t17.4\t0.589\t\n1st–3rd q\t12.8–20.7\t15.0–26.6\t\nGCS at injury\tMedian\t5.75\t5.75\t0.761\t\n1st–3rd q\t5–6.5\t4.5–6.5\t\nGOS at admittance to rehabilitation\tMedian\t3\t3\t0.789\t\n1st–3rd q\t3–4\t3–3.5\t\nComa duration (days)\tMedian\t0\t0\t0.366\t\n1st–3rd q\t0–16\t0–9\t\nBrain damage as seen through MRI\tFrontal lobe\tYes\t15\t12\t0.108\t\nNo\t6\t13\t\nCallous body\tYes\t6\t9\t0.592\t\nNo\t15\t16\t\nThalamus\tYes\t5\t9\t0.371\t\nNo\t16\t16\t\nDiffuse axonal injury\tYes\t10\t11\t0.806\t\nNo\t11\t14\t\nBehavioral symptoms at baseline\tOppositional/noncompliant\tYes\t9\t10\t0.845\t\nNo\t12\t15\t\nHyperactive/impulsive\tYes\t7\t9\t0.850\t\nNo\t14\t16\t\nUninhibited/reckless\tYes\t8\t7\t0.467\t\nNo\t13\t18\t\nConfabulatory/perseverative\tYes\t4\t5\t0.935\t\nNo\t17\t20\t\nIrritable/reactive\tYes\t13\t14\t0.685\t\nNo\t8\t11\t\nAggressive\tYes\t11\t11\t0.571\t\nNo\t10\t14\t\nDisordered mood\tYes\t7\t11\t0.460\t\nNo\t14\t14\t\nDrug treatment\tOxcarbazepine daily dose (mg)\tMedian\t1200\t900\t0.238\t\n1st–3rd q\t725–1650\t675–1200\t\nAntidepressant/nootropic\tYes\t3\t4\t0.872\t\nNo\t18\t21\t\nAntipsychotic/other mood stabilizer\tYes\t8\t6\t0.301\t\nNo\t13\t19\t\nAntispastic\tYes\t2\t4\t0.673\t\nNo\t19\t21\t\nDisability and rehabilitation aspects\tDRS at admittance to rehabilitation\tMedian\t16.25\t16.25\t0.798\t\n1st–3rd q\t11–22\t14.5–20.5\t\nDRS after rehabilitation\tMedian\t5.5\t5.5\t0.247\t\n1st–3rd q\t4.5–7\t3–6\t\nFIM social subscale at admittance to rehabilitation\tMedian\t3\t3\t0.841\t\n1st–3rd q\t1–5\t1–5\t\nFIM social subscale after rehabilitation\tMedian\t3\t5\t0.482\t\n1st–3rd q\t2.5–6.5\t3–6\t\nLegend. 1st–3rd q: first and third quartiles; GCS: Glasgow Coma Score; GOS: Glasgow Outcome Score; MRI: Magnetic Resonance Imaging; DRS: Disability Rating Scale; FIM: Functional Independence Measure. * p-values reported regard: for categorical variables, Chi-square and/or Fisher’s exact tests, as applicable; for continuous variables, Mann–Whitney U tests.\n\nbrainsci-11-00949-t002_Table 2 Table 2 Description of adverse events attributed to oxcarbazepine.\n\nSex\tAge\tADR\tDose (mg)\tManagement\tOutcome\t\nM\t29.4\tAllergic reaction\tNot titrated\tOxcarbazepine withdrawal\tResolved\t\nM\t18.5\tDrowsiness\t1050 BID\tDose reduction (750 BID)\tResolved\t\nM\t37.4\tSevere asthenia\t450 BID\tDose reduction, then withdrawal\tResolved only by withdrawal\t\nM\t18.6\tHyponatremia (134 mEq/L)\t600 TID\tSodium supplementation\tResolved\t\nF\t20.9\tHyponatremia (132 mEq/L)\t600 TID\tDose reduction (300 BID + 600)\tResolved\t\nF\t27.5\tSevere hyponatremia (117 mEq/L), seizures\t600 BID\tHospitalization, oxcarbazepine withdrawal, antiepileptic prophylaxis\tResolved\t\nM\t17.2\tPsychotic behavior, derealization, mutism\t300 BID\tRisperidone add-on\tImproved\t\nM\t8.8\tBehavior worsened (increased agitation, aggression, screaming)\t300 BID\tOxcarbazepine withdrawn, re-administered causing the same ADR, then permanently withdrawn\tResolved\t\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. 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Berghuis B.d.H.G.J. van den Broek M.P. Sander J.W. Lindhout D. Koeleman B.P. Epidemiology, pathophysiology and putative genetic basis of carbamazepine- and oxcarbazepine-induced hyponatremia Eur. J. Neurol. 2016 23 1393 1399 10.1111/ene.13069 27333872\n\n",
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"issue": "11(7)",
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"title": "Oxcarbazepine for Behavioral Disorders after Brain Injury: Factors Influencing Efficacy.",
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"abstract": "Cerebral vasculitis is a serious complication of bacterial meningitis that can cause significant morbidity and mortality due to stroke. Currently, there are no treatment guidelines or safety and efficacy studies on the management of cerebral vasculitis in this context. Herein, we report a case of a previously well 11-year-old girl who presented with acute otitis media that progressed to mastoiditis and fulminant meningitis. Group A Streptococcus was found in blood and ear-fluid cultures (lumbar puncture was unsuccessful). Her decreased level of consciousness persisted despite appropriate antimicrobial treatment, and repeat MRI revealed extensive large vessel cerebral vasculitis. Based on expert opinion and a presumed inflammatory mechanism, her cerebral vasculitis was treated with 7 days of pulse intravenous methylprednisolone followed by oral prednisone taper. She was also treated with intravenous heparin. Following these therapies, she improved clinically and radiographically with no adverse events. She continues to undergo rehabilitation with improvement.",
"affiliations": "Division of Infectious Diseases, Immunology and Allergy, Department of Pediatrics, University of Ottawa Faculty of Medicine, Ottawa, Ontario, Canada bhummel@cheo.on.ca.;Département de Microbiologie et Immunologie, University of Montreal Faculty of Medicine, Montreal, Quebec, Canada.;Division of Infectious Diseases, Immunology and Allergy, Department of Pediatrics, University of Ottawa Faculty of Medicine, Ottawa, Ontario, Canada.;Division of Neurology, Department of Pediatrics, University of Ottawa Faculty of Medicine, Ottawa, Ontario, Canada.",
"authors": "Hummel|Brian Alexander|BA|http://orcid.org/0000-0003-2801-3949;Blackburn|Julie|J|;Pham-Huy|Anne|A|;Muir|Katherine|K|",
"chemical_list": "D000900:Anti-Bacterial Agents; D006493:Heparin",
"country": "England",
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"doi": "10.1136/bcr-2020-239618",
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"issue": "14(2)",
"journal": "BMJ case reports",
"keywords": "infection (neurology); meningitis; neurology (drugs and medicines); stroke",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000900:Anti-Bacterial Agents; D002648:Child; D003937:Diagnosis, Differential; D003952:Diagnostic Imaging; D004359:Drug Therapy, Combination; D005260:Female; D006493:Heparin; D006801:Humans; D016920:Meningitis, Bacterial; D013290:Streptococcal Infections; D013297:Streptococcus pyogenes; D020293:Vasculitis, Central Nervous System",
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"pmid": "33563670",
"pubdate": "2021-02-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "High-dose steroid and heparin: a novel therapy for cerebral vasculitis associated with presumed group A Streptococcus meningitis.",
"title_normalized": "high dose steroid and heparin a novel therapy for cerebral vasculitis associated with presumed group a streptococcus meningitis"
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"abstract": "Organising pneumonia (OP) in rheumatoid arthritis (RA) may be part of pulmonary manifestation (disease related) or disease-modifying antirheumatic drugs (DMARDs) related. We report a case series of RA patients with DMARDs related OP. A 65-year-old woman developed OP 3 weeks after initiation of methotrexate (MTX). High-resolution CT (HRCT) scan of the thorax revealed bilateral consolidations in the lung bases. She had complete radiological resolution 6 months after corticosteroid therapy with cessation of MTX. The second case was of a 60-year-old woman on MTX with recent addition of leflunomide due to flare of RA. She developed worsening cough 4 months later and HRCT scan revealed consolidation in the left upper lobe with biopsy proven OP. She responded within 6 months of corticosteroid therapy with clinical and radiological resolution. This case series highlights that OP may developed with low-dose MTX (as early as 3 weeks) and leflunomide and the diagnosis requires a high index of suspicion.",
"affiliations": "Respiratory Unit, Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Cheras, Kuala Lumpur, Malaysia.;Respiratory Unit, Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Cheras, Kuala Lumpur, Malaysia.;Respiratory Unit, Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Cheras, Kuala Lumpur, Malaysia.;Respiratory Unit, Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Cheras, Kuala Lumpur, Malaysia andreaban@gmail.com.",
"authors": "Faisal|Mohamed|M|http://orcid.org/0000-0002-7526-361X;Roslan|Asyraf|A|;Nik Abeed|Nik Nuratiqah|NN|http://orcid.org/0000-0002-3283-649X;Ban Yu-Lin|Andrea|A|",
"chemical_list": "D018501:Antirheumatic Agents; D000077339:Leflunomide; D008727:Methotrexate",
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"keywords": "interstitial lung disease; respiratory medicine; rheumatoid arthritis; rheumatology",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D018549:Cryptogenic Organizing Pneumonia; D005260:Female; D006801:Humans; D000077339:Leflunomide; D008168:Lung; D008727:Methotrexate; D008875:Middle Aged; D014057:Tomography, X-Ray Computed",
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"title": "Disease-modifying antirheumatic drugs and organising pneumonia.",
"title_normalized": "disease modifying antirheumatic drugs and organising pneumonia"
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"abstract": "BACKGROUND\nIn children, paracetamol overdose due to deliberate self-poisoning, accidental exposure or medication errors can lead to paediatric acute liver failure and death. In Australia and New Zealand, the nature of ingestion and outcomes of paracetamol-associated paediatric acute liver failure have not been described.\n\n\nOBJECTIVE\nTo describe the nature and outcomes of paracetamol-associated paediatric acute liver failure.\n\n\nMETHODS\nRetrospective analysis of paracetamol-associated paediatric acute liver failure cases presenting 2002-2012.\n\n\nMETHODS\nNew Zealand and Queensland Paediatric Liver Transplant Services.\n\n\nRESULTS\n14 of 54 cases of paediatric acute liver failure were attributed to paracetamol, the majority were secondary to medication errors. 12 of the 14 children were under the age of 5 years. Seven children received doses in excess of 120 mg/kg/day. Many of the other children received either a double dose, too frequent administration, coadministration of other medicines containing paracetamol or regular paracetamol for up to 24 days. Three children underwent transplant. One of these and one other child died.\n\n\nCONCLUSIONS\nIn Australia and New Zealand, paracetamol overdose secondary to medication errors is the leading cause of paediatric acute liver failure. A review of regional safety practices surrounding paracetamol use in children is indicated.",
"affiliations": "Department of Paediatric Gastroenterology, Hepatology and Nutrition, Starship Children's Hospital, Auckland, New Zealand.;Department of Paediatric Gastroenterology, Hepatology and Nutrition, Starship Children's Hospital, Auckland, New Zealand.;Department of Paediatric Gastroenterology, Hepatology and Nutrition, Royal Children's Hospital, Brisbane, Australia.;Department of Paediatric Gastroenterology, Hepatology and Nutrition, Starship Children's Hospital, Auckland, New Zealand.",
"authors": "Rajanayagam|J|J|;Bishop|J R|JR|;Lewindon|P J|PJ|;Evans|Helen M|HM|",
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"keywords": "Analgesia; Drug Abuse; Hepatology; Mortality; Toxicology",
"medline_ta": "Arch Dis Child",
"mesh_terms": "D000082:Acetaminophen; D000293:Adolescent; D018712:Analgesics, Non-Narcotic; D001315:Australia; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D017114:Liver Failure, Acute; D008297:Male; D008508:Medication Errors; D009520:New Zealand; D012189:Retrospective Studies",
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"title": "Paracetamol-associated acute liver failure in Australian and New Zealand children: high rate of medication errors.",
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"abstract": "A 63-year-old man with pharyngeal cancer had been prescribed pilocarpine hydrochloride for xerostomia after concomitant chemoradiotherapy. After 6 months of taking pilocarpine hydrochloride, he was referred to our hospital due to gradually developing renal insufficiency. The patient underwent detailed urinalysis, blood chemistry analysis, immune-serology testing. A renal biopsy was also performed. He was diagnosed with chronic tubulointerstitial nephritis (TIN) caused by lymphocytic infiltration of the interstitium, tubular atrophy, and interstitial fibrotic changes. Infections, autoimmune diseases, and genetic factors were ruled out as causes of TIN; a drug-induced lymphocyte stimulation test confirmed that he had high stimulation index scores for pilocarpine hydrochloride and a normal range stimulation score for other supplements. These results indicated that the TIN could have been induced by pilocarpine hydrochloride. Drug discontinuation partly improved his renal function and tubule marker levels. To our knowledge, this is the first report of TIN following administration of pilocarpine hydrochloride. This finding could contribute to future treatment decisions for patients with TIN and those using pilocarpine hydrochloride.",
"affiliations": "Division of Nephrology, Department of Medicine, Tokyo Metropolitan Komagome Hospital, 3-18-22, Honkomagome, Bunkyo-Ku, Tokyo, 113-0021, Japan. terubassist@hotmail.co.jp.;Division of Nephrology, Department of Medicine, Tokyo Metropolitan Komagome Hospital, 3-18-22, Honkomagome, Bunkyo-Ku, Tokyo, 113-0021, Japan.;Division of Nephrology, Department of Medicine, Tokyo Metropolitan Komagome Hospital, 3-18-22, Honkomagome, Bunkyo-Ku, Tokyo, 113-0021, Japan.;Division of Pathology, Department of Medicine, Tokyo Metropolitan Komagome Hospital, 3-18-22, Honkomagome, Bunkyo-Ku, Tokyo, 113-0021, Japan.;Division of Pathology, Department of Medicine, Tokyo Metropolitan Komagome Hospital, 3-18-22, Honkomagome, Bunkyo-Ku, Tokyo, 113-0021, Japan.;Division of Nephrology, Department of Medicine, Tokyo Metropolitan Komagome Hospital, 3-18-22, Honkomagome, Bunkyo-Ku, Tokyo, 113-0021, Japan.;Department IV, Internal Medicine, Tokyo Women's Medical University, 8-1, Kawadacho, Shinjuku-Ku, Tokyo, 162-8666, Japan.",
"authors": "Fujii|Teruhiro|T|0000-0002-6498-5668;Kawasoe|Kentaro|K|;Nishizawa|Yuki|Y|;Kashima|Jumpei|J|;Tonooka|Akiko|A|;Ohta|Akihito|A|;Nitta|Kosaku|K|",
"chemical_list": "D018721:Muscarinic Agonists; D010862:Pilocarpine",
"country": "Japan",
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"doi": "10.1007/s13730-019-00401-8",
"fulltext": "\n==== Front\nCEN Case RepCEN Case RepCEN Case Reports2192-4449Springer Singapore Singapore 40110.1007/s13730-019-00401-8Case ReportA suspected case of drug-induced tubulointerstitial nephritis by pilocarpine hydrochloride http://orcid.org/0000-0002-6498-5668Fujii Teruhiro +81-3-3823-2101terubassist@hotmail.co.jp 13Kawasoe Kentaro 13Nishizawa Yuki 1Kashima Jumpei 2Tonooka Akiko 2Ohta Akihito 1Nitta Kosaku 31 grid.415479.aDivision of Nephrology, Department of Medicine, Tokyo Metropolitan Komagome Hospital, 3-18-22, Honkomagome, Bunkyo-Ku, Tokyo, 113-0021 Japan 2 grid.415479.aDivision of Pathology, Department of Medicine, Tokyo Metropolitan Komagome Hospital, 3-18-22, Honkomagome, Bunkyo-Ku, Tokyo, 113-0021 Japan 3 grid.410818.40000 0001 0720 6587Department IV, Internal Medicine, Tokyo Women’s Medical University, 8-1, Kawadacho, Shinjuku-Ku, Tokyo, 162-8666 Japan 10 5 2019 10 5 2019 11 2019 8 4 246 251 19 2 2019 2 5 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.A 63-year-old man with pharyngeal cancer had been prescribed pilocarpine hydrochloride for xerostomia after concomitant chemoradiotherapy. After 6 months of taking pilocarpine hydrochloride, he was referred to our hospital due to gradually developing renal insufficiency. The patient underwent detailed urinalysis, blood chemistry analysis, immune-serology testing. A renal biopsy was also performed. He was diagnosed with chronic tubulointerstitial nephritis (TIN) caused by lymphocytic infiltration of the interstitium, tubular atrophy, and interstitial fibrotic changes. Infections, autoimmune diseases, and genetic factors were ruled out as causes of TIN; a drug-induced lymphocyte stimulation test confirmed that he had high stimulation index scores for pilocarpine hydrochloride and a normal range stimulation score for other supplements. These results indicated that the TIN could have been induced by pilocarpine hydrochloride. Drug discontinuation partly improved his renal function and tubule marker levels. To our knowledge, this is the first report of TIN following administration of pilocarpine hydrochloride. This finding could contribute to future treatment decisions for patients with TIN and those using pilocarpine hydrochloride.\n\nKeywords\nPharyngeal cancerPilocarpineTubulointerstitial nephritisissue-copyright-statement© Japanese Society of Nephrology 2019\n==== Body\nIntroduction\nPilocarpine hydrochloride, a cholinergic agonist, is used for treating xerostomia associated with radiotherapy for head and neck cancer and for Sjögren’s syndrome [1–3]. Common side effects include miosis, hyperhidrosis, nausea, liver dysfunction, diarrhea, frequent urination; serious side effects include interstitial pneumonia and loss of consciousness [4]. However, nephrotoxicity by pilocarpine hydrochloride has to date, not been reported. Tubulointerstitial nephritis (TIN) is a renal histologic lesion characterized by the presence of inflammatory infiltrates and edema within the tubulointerstitial compartment, which usually does not affect the glomerular and vascular compartments [5]. Any drug can cause TIN; hence, clinical and laboratory findings, including renal biopsy, are important for diagnosis [6]. We report, herein, a rare instance of pilocarpine hydrochloride-induced TIN.\n\nCase report\nA 63-year-old man was admitted to the Tokyo Metropolitan Komagome Hospital because of renal insufficiency. The patient had received insulin treatment since the age of 40 years for type 2 diabetes mellitus. He was treated with external beam radiation 70 Gy radiation therapy along with concomitant chemotherapy consisting of 100 mg/m2 cisplatin once every 3 weeks three times in total for pharyngeal carcinoma since the age of 62 years. He had no history of allergies or any other significant medical history.\n\nFollowing concomitant chemotherapy, he had been prescribed pilocarpine hydrochloride for xerostomia associated with radiotherapy for head and neck cancer. In addition, he was taking four types of supplements (zinc, vitamin E, branched-chain amino acids, and docosahexaenoic acid) every day since the age of 61. When pilocarpine hydrochloride therapy commenced, the patient’s creatinine (Cr) level was 1.0 mg/dL. Subsequently, renal dysfunction gradually developed, and his Cr rose to 2.05 mg/dL after 6 months of treatment. The patient was hospitalized for intensive examination and to treat his renal insufficiency.\n\nUpon admission, the patient weight and height were 63 kg and 177 cm, respectively. The patient’s blood pressure was 139/86 mmHg, pulse rate was 58 beats/min, and body temperature was 36.3 °C. Chest, heart, and abdominal findings were unremarkable. Ophthalmological examination indicated no uveitis, and no superficial lymphadenopathies or rashes were observed. The electrocardiogram showed no significant abnormal findings. Ultrasonography revealed an enlarged kidney. There were no findings suggestive of a post-renal lesion on computed tomography. However, gallium scintigraphy and positron emission tomography were not performed due to their low specificity.\n\nLaboratory findings on admission are shown in Table 1. Urinary findings indicated the absence of proteinuria or hematuria but the presence of leukocyturia [10–19 white blood cells/high-power field (HPF)], and urinary excretion of β2-microglobulin (β2MG) was 1542 μg/gCr. The white blood cell (WBC) count and hemoglobin (Hb) level were 5100 cells/μL and 11.5 g/dL, respectively. Blood eosinophils accounted for 3.9% of circulating lymphocytes. The results of blood biochemistry tests indicated that blood urea nitrogen (BUN) was 30.4 mg/dL, and Cr was 2.05 mg/dL. Electrolyte and liver function tests were normal. Blood sugar levels and hemoglobin A1c (HbA1c) were under control. Immunological tests for C-reactive protein (CRP), myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA), proteinase 3 antineutrophil cytoplasmic antibody (PR3-ANCA), antinuclear antibody (ANA), anti-SS-A/Ro antibodies, and anti-SS-B/La antibodies were all negative.Table 1 Laboratory findings on admission\n\nUrinalysis\tBlood chemistry\tImmuno-serology\t\n Urinometry\t1.011\t\t TP\t6.6\tg/dL\t CRP\t0.06\tmg/dL\t\n pH\t5.0\t\t Alb\t4.1\tg/dL\t IgG\t862\tmg/dL\t\n Protein\t–\t\t BUN\t30.4\tmg/dL\t IgA\t126\tmg/dL\t\n Occult blood\t–\t\t Cr\t2.05\tmg/dL\t IgM\t63\tmg/dL\t\n β2MG\t1542\tμg/gCr\t UA\t8.4\tmEq/L\t C3\t85\tmg/dL\t\n NAG\t26.1\tIU/gCr\t Na\t140\tmEq/L\t C4\t33.5\tmg/dL\t\n\t\t\t K\t4.3\tmEq/L\t CH50\t55.8\tU/mL\t\nUrine sediment\t Cl\t109\tmEq/L\t ANA\t< 40 ×\t\t\n RBC\t<1/HPF\t\t Ca\t9.1\tmg/dL\t Anti-SS-A antibody\tNegative\t\t\n WBC\t10-19/HPF\t\t iP\t3.4\tmg/dL\t Anti-SS-B antibody\tNegative\t\t\n Cast\t–\t\t AST\t26\tIU/L\t MPO-ANCA\t< 1.0\tU/mL\t\n\t\t\t ALT\t23\tIU/L\t PR3-ANCA\t< 1.0\tU/mL\t\nHematology\t\t\t LDH\t193\tIU/L\t\t\t\t\n WBC\t5100\t/μL\t ALP\t206\tIU/L\tDLST\tSI\tNormal range (< 180%)\t\n Neutrophil\t76.6\t%\t Glu\t88\tmg/dL\t Supplement 1 (zinc)\t49%\t\t\n Eosinophil\t3.9\t%\t HbA1c\t6.2\t%\t Supplement 2 (vitamin E)\t135%\t\t\n Monocytes\t11.7\t%\t\t\t\t Supplement 3 (branched-chain amino acids)\t78%\t\t\n Lymphocytes\n\n Hb\n\n\t7.6\n\n11.5\n\n\t%\n\ng/dL\n\n\t\t\t\t Supplement 4 (docosahexaenoic acid)\t158%\t\t\n Plt\t21.5 × 104\t/μL\t\t\t\t Pilocarpine hydrochloride\t290%\t\t\nβ2MG, β2-microglobulin; NAG, N-acetyl-β-d-glucosaminidase; RBC, red blood cell; WBC, white blood cell; HPF, high power field; Hb, hemoglobin; Plt, platelet; TP, total protein; Alb, albumin; BUN, blood urea nitrogen; Cr, creatinine; UA, uric acid; Na, sodium; K, potassium; Cl, chloride; Ca, calcium; iP, inorganic-phosphate; AST, aspartate transaminase; ALT, alanine transaminase; LDH, lactate dehydrogenase; ALP, alkaline phosphatase; Glu, glucose; HbA1c, hemoglobin A1c; IgG, immunoglobulin G; IgA, immunoglobulin A; IgM, immunoglobulin M; C3, complement 3; C4, complement 4; CH50, complement hemolytic activity; ANA, anti-nuclear autoantibody; anti-SS-A antibody, anti-Sjögren’s syndrome-A antibody; anti-SS-B antibody, anti-Sjögren’s syndrome-B antibody; MPO-ANCA, myeloperoxidase antineutrophil cytoplasmic antibody; PR3-ANCA, proteinase 3 antineutrophil cytoplasmic antibody; DLST, drug lymphocyte stimulation test; SI, stimulation index\n\n\n\nA renal biopsy was performed to assess renal insufficiency. The sample of renal cortex contained fourteen glomeruli, three of which showed global sclerosis, and the remaining eleven glomeruli were borderline normal. Moderate tubular injury, mild interstitial inflammation, and thinning of renal tubular epithelium were observed (Fig. 1). Tubular atrophy and interstitial fibrotic changes were notable, along with dilatation of some tubules, mild infiltration of lymphocyte, and very few tubular casts (Fig. 2). Immunofluorescent staining for IgG, IgA, IgM, C3, and C1q yielded negative results. Immunohistochemical analysis showed CD3 expression in the interstitium and tubular epithelial infiltration, indicating tubulitis (Fig. 3a). In contrast, CD20 and CD68 staining was not as prominent as CD3 staining, demonstrating lower expression (Fig. 3b, c). CD68 was expressed mildly in the interstitium. CD4 and CD8 were equally expressed (Fig. 3d, e). These findings were consistent with those of chronic TIN. A drug-induced lymphocyte stimulation test (DLST) confirmed that the patient had a negative stimulation index (SI) score for the four supplements, whereas he had a high SI score of 290% for pilocarpine hydrochloride (the cut off value for DLST positivity is 180%). Drug-induced TIN, especially pilocarpine hydrochloride-induced TIN was suspected, due to the lack of suggestive findings of ocular disease by ophthalmological screening in addition to the laboratory and pathological results, and the patient’s clinical history. The patient, therefore, discontinued pilocarpine hydrochloride. After drug discontinuation, his Cr level partly recovered from 2.05 to 1.47 mg/dL and his tubule marker level also improved (Fig. 4), and the kidney returned to normal size.Fig. 1 Light microscopic findings of renal biopsy. Renal biopsy demonstrates interstitial inflammatory infiltration and thinning of renal tubular epithelium (hematoxylin/eosin stain)\n\nFig. 2 Tubular atrophy and interstitial fibrotic changes were notable, along with dilatation of some tubules, mild infiltration of mononuclear cells, and very few tubular casts (periodic acid–Schiff stain)\n\nFig. 3 Immunohistochemistry showed CD3 expression in interstitium and arrow shows the infiltration in the tubular epithelia. CD20 and CD68 staining did not show infiltration compared to CD3 staining (a–c). CD4 and CD8 were equally expressed (d, e)\n\nFig. 4 Clinical course of the patient over a period of 12 months. X represents the point of renal biopsy. BW, body weight; Cr, creatinine; CDDP, cisplatin; β2MG, β2-microglobulin; mo, month\n\n\n\nDiscussion\nTIN is a renal histologic lesion characterized by the presence of inflammatory infiltrates and edema within the tubulointerstitial compartment but usually does not affect the glomerular and vascular compartments [5]. TIN can be caused by medications; infections including bacteria, fungi, and viruses; systemic diseases (Sjögren’s syndrome, TIN with uveitis syndrome, immunoglobulin G4-related diseases); and idiopathic forms of diseases. Drug-induced TIN accounts for most cases and antibiotics represent the most common class of drug used for responding to TIN followed by proton-pump inhibitors and non-steroidal anti-inflammatory drugs (NSAIDs). However, a wide variety of other medications have been implicated. The clinical presentation is highly varied with the classic triad of fever, rash and eosinophilia occurring in a small minority of patients. Thus, renal biopsy is required for a definitive diagnosis [7].\n\nThe clinical diagnosis of drug-induced TIN is quite challenging since numerous types of medications have been implicated in causing TIN. However, the diagnosis of TIN may be aided by laboratory examinations and these can include DLST, which measures the proliferation of T cells induced by an agent in vitro, leading to suspicion of previous sensitization in vivo. DLST has been regarded as a useful diagnostic procedure for drug hypersensitivity, including drug-induced TIN [8]. Although, there are diseases and drugs that tend to cause low sensitivity and/or false positives [9], DLST may be effective when diagnosing drug-induced interstitial nephritis with less well-known drugs and patients with autoimmune diseases that cause interstitial nephritis [10].\n\nOur patient was ruled out as having an infection or any systemic diseases; dehydration due to body weight variations (Fig. 4) was also ruled out. However, the patient showed high scores for pilocarpine hydrochloride in the DLST and as such, we ascribed his renal dysfunction to drug-induced TIN. We also considered the possibility of CDDP nephrotoxicity as chronic use of CDDP can cause tubular atrophy and interstitial fibrosis [11]. However, CDDP is not known to cause interstitial nephritis [12] and, in our case, the usage period was short and probably not sufficient to induce those histological changes. There is no standard approach for treating drug-induced TIN. The consensus is to withdraw the responsible medication as soon as possible [13]; any delay in drug withdrawal can adversely affect kidney function recovery. The role of steroids in treating TIN is not clear and there are no randomized controlled studies to guide therapy [14]. Several studies have reported that steroids appear to have some beneficial role, but Muriithi et al. found increased amounts of interstitial fibrosis and tubular atrophy with smaller kidneys evident on ultrasound, correlated with a poor response to steroids [15]. Steroids should be avoided in patients with advanced fibrosis, particularly in those with diabetes and labile blood glucose. In our case, we did not opt for steroid therapy due to interstitial fibrosis evident in renal biopsy and the risk of detrimentally affecting of glycemic control.\n\nKidney function in our case was only partly recovered. Two reasons can be considered for the only partial improvements in renal function. First, drug-induced TIN was diagnosed 6 months after the introduction of pilocarpine hydrochloride. The long delay between pilocarpine hydrochloride introduction and TIN diagnosis could explain the partial recovery of kidney functionality. Second, our patient had mild renal dysfunction before developing renal dysfunction. When he was initially treated with cisplatin for pharyngeal cancer, his renal function deteriorated temporarily. After chemotherapy, his Cr slightly worsened to 1.0 mg/dL (baseline 0.8 mg/dL) by cisplatin nephrotoxicity.\n\nThis is the first reported case of TIN induced by pilocarpine hydrochloride. A thorough assessment including the assessment of medication history, DLST, and renal biopsy was helpful in establishing the diagnosis in our patient who had a complex past renal history.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nCompliance with Ethical Standards\nConflict of interest\nThe authors have declared that no conflict of interest exists.\n\nHuman and animal rights\nThis article does not contain any studies with human participants or animals performed by any of the authors.\n\nInformed consent\nInformed consent was obtained from all individual participants included in the study.\n==== Refs\nReferences\n1. Ma SJ Rivers CI Serra LM Singh AK Long-term outcomes of interventions for radiation-induced xerostomia: a review World J Clin Oncol. 2019 10 1 13 10.5306/wjco.v10.i1.1 30627521 \n2. Margaix-Muñoz M Bagán JV Poveda R Jiménez Y Sarrión G Sjögren’s syndrome of the oral cavity. Review and update Med Oral Patol Oral Cir Bucal 2009 14 E325 E330 19300364 \n3. Gil-Montoya JA Silvestre FJ Barrios R Silvestre-Rangil J Treatment of xerostomia and hyposalivation in the elderly: a systematic review Med Oral Patol Oral Cir Bucal. 2016 21 e355 e366 10.4317/medoral.20969 27031061 \n4. Cheng CQ Xu H Liu L Wang RN Liu YT Li J Zhou XK Efficacy and safety of pilocarpine for radiation-induced xerostomia in patients with head and neck cancer: a systematic review and meta-analysis J Am Dent Assoc 2016 147 236 243 10.1016/j.adaj.2015.09.014 26563850 \n5. Raghavan R Eknoyan G Acute interstitial nephritis—a reappraisal and update Clin Nephrol 2014 82 149 162 10.5414/CN108386 25079860 \n6. Praga M González E Acute interstitial nephritis Kidney Int 2010 77 956 961 10.1038/ki.2010.89 20336051 \n7. Krishnan N Perazella MA Drug-induced acute interstitial nephritis: pathology, pathogenesis, and treatment Iran J Kidney Dis. 2015 9 3 13 25599729 \n8. Pichler WJ Tilch J The lymphocyte transformation test in the diagnosis of drug hypersensitivity Allergy 2004 59 809 820 10.1111/j.1398-9995.2004.00547.x 15230812 \n9. Eisenthal A Eytan K Brazowski E Gitstein G Greenberg R Skornick Y Effects of 5-FU on DNA synthesis and cytotoxicity of human lymphocytes induced by IL-2, TGF-beta3 and PGE2 Anticancer Res 2009 29 3925 3930 19846930 \n10. Joh K Aizawa S Yamaguchi Y Inomata I Shibasaki T Sakai O Hamaguchi K Drug-induced hypersensitivity nephritis: lymphocyte stimulation testing and renal biopsy in 10 cases Am J Nephrol 1990 10 222 230 10.1159/000168085 2382683 \n11. Tanaka H Ishikawa E Teshima S Shimizu E Histopathological study of human cisplatin nephropathy Toxicol Pathol 1986 14 247 257 10.1177/019262338601400215 3764321 \n12. Vickers AE Rose K Fisher R Saulnier M Sahota P Bentley P Kidney slices of human and rat to characterize cisplatin-induced injury on cellular pathways and morphology Toxicol Pathol 2004 32 577 590 10.1080/01926230490508821 15603542 \n13. Perazella MA Markowitz GS Drug-induced acute interstitial nephritis Nat Rev Nephrol. 2010 6 461 470 10.1038/nrneph.2010.71 20517290 \n14. Moledina DG Perazella MA Drug-induced acute interstitial nephritis Clin J Am Soc Nephrol 2017 12 2046 2049 10.2215/CJN.07630717 28893923 \n15. Muriithi AK Leung N Valeri AM Cornell LD Sethi S Fidler ME Nasr SH Biopsy-proven acute interstitial nephritis, 1993–2011: a case series Am J Kidney Dis 2014 64 558 566 10.1053/j.ajkd.2014.04.027 24927897\n\n",
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"title": "A suspected case of drug-induced tubulointerstitial nephritis by pilocarpine hydrochloride.",
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"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PILOCARPINE HYDROCHLORIDE"
},
"drugadditional": "1",
... |
{
"abstract": "Purpose: Multiple myeloma is an insidious haematological malignancy characterised by monoclonal proliferation of plasma cells in the bone marrow. Extramedullary plasmacytoma is a rare manifestation of multiple myeloma and usually occurs in the upper respiratory tract. Orbital involvement is particularly uncommon, but may be associated with devastating visual impairment and poor clinical outcomes. Therefore, this article aims to highlight the need for multidisciplinary management of orbital extramedullary plasmacytoma. Methods: This is a retrospective observational case series of five patients. All presented to the authors for management of orbital extramedullary plasmacytomas from 2004 to 2015 at Prince of Wales and Mater Hospitals in Sydney, Australia. Medical records were reviewed for pertinent information including demographics, disease features, management strategy, and clinical progress. The study met Medical Ethics Board standards and is in accordance with the Helsinki Agreements. Results: This case series of five patients underscores the poor prognosis of orbital extramedullary plasmacytoma. Despite aggressive multidisciplinary management, four of these five patients succumbed to their illness during the study period. However, multidisciplinary management did manage to minimise symptoms and preserve quality of life. Conclusions: On a case-by-case basis, patients may derive palliative benefit from orbital surgery in conjunction with radiotherapy and chemotherapy. Orbital surgeons are encouraged to work within a multidisciplinary framework of medical specialists, including haematologists and radiation oncologists, when determining the optimal management plan in cases of orbital extramedullary plasmacytoma.",
"affiliations": "a Faculty of Medicine , University of New South Wales , Sydney, Australia.;b Sydney Medical School , University of Sydney , Sydney, Australia.;a Faculty of Medicine , University of New South Wales , Sydney, Australia.;b Sydney Medical School , University of Sydney , Sydney, Australia.;c Department of Haematology , Mater Hospital , Sydney , Australia.;c Department of Haematology , Mater Hospital , Sydney , Australia.;a Faculty of Medicine , University of New South Wales , Sydney, Australia.",
"authors": "Wang|Samuel S Y|SSY|;Lee|Mitchell B|MB|;George|Adarsh|A|;Wang|Sarah B|SB|;Blackwell|Jonathan|J|;Moran|Steve|S|;Francis|Ian C|IC|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/01676830.2018.1490437",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0167-6830",
"issue": "38(3)",
"journal": "Orbit (Amsterdam, Netherlands)",
"keywords": "Extramedullary; multiple myeloma; orbital mass; orbital surgery; plasmacytoma",
"medline_ta": "Orbit",
"mesh_terms": "D000368:Aged; D001706:Biopsy; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009918:Orbital Neoplasms; D010348:Patient Care Team; D010954:Plasmacytoma; D012189:Retrospective Studies",
"nlm_unique_id": "8301221",
"other_id": null,
"pages": "218-225",
"pmc": null,
"pmid": "29985709",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Five cases of orbital extramedullary plasmacytoma: diagnosis and management of an aggressive malignancy.",
"title_normalized": "five cases of orbital extramedullary plasmacytoma diagnosis and management of an aggressive malignancy"
} | [
{
"companynumb": "PHHY2019AU165141",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ZOLEDRONIC ACID"
},
"drugadditional": "3",
"... |
{
"abstract": "Case 1 was a 70-year-old man, and case 2 was a 65-year-old woman. Both were diagnosed with type 2 advanced HER2-positive gastric cancer. Capecitabine, cisplatin, and trastuzumab (HXP therapy) were administered to both patients. However, both patients developed peritonitis caused by gastric cancer perforation during HXP therapy on day 38 for case 1 and day 8 for case 2. Emergency omentum filling and gastric segmental resection were performed for both patients. The same chemotherapy regimen was continued after the surgery, and partial response was observed in both patients. Because most advanced HER2-positive gastric cancers are ulcers, we should always consider the risk of gastric cancer perforation while administering HXP therapy, which has a high cytoreductive effect. Good convalescence can be expected by continuing chemotherapy after emergency surgery due to gastric cancer perforation.",
"affiliations": "Department of Gastroenterology, National Hospital Organization, Fukuyama Medical Center.",
"authors": "Matsueda|Katsunori|K|;Toyokawa|Tatsuya|T|;Ueda|Yuya|Y|;Endo|Shinya|S|;Sakata|Masahiro|M|;Fujita|Isao|I|;Horii|Jouichiro|J|;Murakami|Takako|T|",
"chemical_list": "D000069287:Capecitabine; C508053:ERBB2 protein, human; D018719:Receptor, ErbB-2; D000068878:Trastuzumab; D002945:Cisplatin",
"country": "Japan",
"delete": false,
"doi": "10.11405/nisshoshi.114.59",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0446-6586",
"issue": "114(1)",
"journal": "Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology",
"keywords": null,
"medline_ta": "Nihon Shokakibyo Gakkai Zasshi",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069287:Capecitabine; D002945:Cisplatin; D005260:Female; D006801:Humans; D007416:Intestinal Perforation; D008297:Male; D018719:Receptor, ErbB-2; D013270:Stomach; D013272:Stomach Diseases; D013274:Stomach Neoplasms; D000068878:Trastuzumab; D016896:Treatment Outcome",
"nlm_unique_id": "2984683R",
"other_id": null,
"pages": "59-68",
"pmc": null,
"pmid": "28070095",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Two cases of unresectable advanced HER2-positive gastric cancer perforation during chemotherapy with trastuzumab.",
"title_normalized": "two cases of unresectable advanced her2 positive gastric cancer perforation during chemotherapy with trastuzumab"
} | [
{
"companynumb": "JP-MYLANLABS-2017M1005947",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": "1",
... |
{
"abstract": "The present study reported a case of portopulmonary hypertension (POPH) that was secondary to underlying liver cirrhosis in a 58-year-old woman, who was successfully treated with low-dose tolvaptan. The patient had suffered from refractory peripheral edema and electrolyte abnormalities, including severe hypokalemia, under the combination therapy of sildenafil, ambrisentan, furosemide and spironolactone. Subsequent to the initiation of low-dose tolvaptan at 3.75 mg/day with concurrent de-escalation of the dose of furosemide, the daily urine volume increased, peripheral edema improved and the serum potassium level increased immediately. In addition, plasma renin activity, plasma aldosterone concentration and plasma brain natriuretic peptide level decreased within 1 week after the initiation of tolvaptan therapy. Hemodynamic assessments using a right heart catheter revealed that the pulmonary vascular resistance decreased by ~20%. Finally, chronic combination therapy with spironolactone and low-dose tolvaptan without loop diuretics achieved adequate fluid management. In conclusion, the findings of the present study suggest that low-dose tolvaptan may be a promising therapeutic option for liver cirrhosis-associated POPH in patients with an electrolyte abnormality due to liver cirrhosis and conventional diuretics.",
"affiliations": "Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan.;Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan.;Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan.;Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan.;Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan.;Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan.;Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan.;Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan.",
"authors": "Ogihara|Yoshito|Y|;Yamada|Norikazu|N|;Dohi|Kaoru|K|;Matsuda|Akimasa|A|;Ota|Satoshi|S|;Ishikura|Ken|K|;Nakamura|Mashio|M|;Ito|Masaaki|M|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": "10.3892/etm.2016.3945",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1792-0981",
"issue": "13(1)",
"journal": "Experimental and therapeutic medicine",
"keywords": "electrolyte abnormality; hepatic edema; liver cirrhosis; portopulmonary hypertension; tolvaptan",
"medline_ta": "Exp Ther Med",
"mesh_terms": null,
"nlm_unique_id": "101531947",
"other_id": null,
"pages": "269-272",
"pmc": null,
"pmid": "28123500",
"pubdate": "2017-01",
"publication_types": "D016428:Journal Article",
"references": "23551935;19713419;6339312;22099507;17338936;9731583;15121411;23457185;23321196;4541913;23111998;23530991",
"title": "Effects of low-dose tolvaptan on electrolyte abnormality and hemodynamic parameters in a liver cirrhosis-associated portopulmonary hypertension patient: A case report.",
"title_normalized": "effects of low dose tolvaptan on electrolyte abnormality and hemodynamic parameters in a liver cirrhosis associated portopulmonary hypertension patient a case report"
} | [
{
"companynumb": "JP-TEVA-735077ISR",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BOSENTAN"
},
"drugadditional": "1",
"drugad... |
{
"abstract": "Enoxaparin sodium is a heparin of low molecular weight with antithrombotic properties that acts by inhibiting factor Xa. We present a 59-year-old woman who developed heparin-related bullous hemorrhagic dermatosis, at sites distant from the injections, one month after starting treatment with enoxaparin.",
"affiliations": "Hospital Universitario de La Princesa. mjconchg@gmail.com.",
"authors": "Concha-Garzon|Mj|M|;Sotomayor-Lopez|E|E|;Solano-Lopez|G|G|;Fraga|J|J|;De Argila|D|D|",
"chemical_list": "D017984:Enoxaparin; D005343:Fibrinolytic Agents",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1087-2108",
"issue": "20(10)",
"journal": "Dermatology online journal",
"keywords": null,
"medline_ta": "Dermatol Online J",
"mesh_terms": "D017984:Enoxaparin; D005260:Female; D005343:Fibrinolytic Agents; D006470:Hemorrhage; D006801:Humans; D007267:Injections; D012872:Skin Diseases, Vesiculobullous; D013479:Superior Vena Cava Syndrome",
"nlm_unique_id": "9610776",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "25526009",
"pubdate": "2014-10-15",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "Bullous hemorrhagic dermatosis distant from the site of heparin injection.",
"title_normalized": "bullous hemorrhagic dermatosis distant from the site of heparin injection"
} | [
{
"companynumb": "PHHY2014ES146842",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "ENOXAPARIN SODIUM"
},
"drugadditional": null,
... |
{
"abstract": "Gummy formulations are widely available with estimated 65% marketed for children. Currently, there are few studies describing children ingesting gummy formulated medications. The aim of this study was to quantify and identify the type of ingestions due to gummy formulated medications, evaluate their clinical significance as defined by adverse outcomes: associated symptoms, emergency department (ED) visits, and hospitalizations.\nRetrospective study in children aged 0-19 exposed to gummy formulated medications from 2015 to 2017 as identified by calls made to the Regional Poison Control Center (RPCC). A list of potentially toxic gummy formulated medications was compiled and reviewed by medical and clinical toxicologists. We categorized medications into vitamins, minerals and supplements, melatonin, and other. Data collected included: medication name, number of units, age, sex, symptoms described, ED visit, hospitalization, and unintentional or intentional ingestion.\nOf the 66,059 pediatric exposures received by RPCC, 1143 (1.7%) involved gummy formulated medications of which 1098 were analyzed. Median age was 3 years, 57.7% were males and 7% were symptomatic. Seventy-four percent exposures involved vitamins and 24% melatonin. In comparison to other gummy exposures, those who ingested melatonin had 8.4 times higher odds of being symptomatic (OR: 8.4, 95% CI: 5.1, 14) and 4.8 times higher odds of visiting ED (OR: 4.8, 95% CI: 2.5, 9). The predominant symptoms reported were drowsiness, gastrointestinal upset, and hyperactivity. Two patients were hospitalized who ingested multiple medications, one was unintentional, and one was intentional as a suicide attempt thus admitted for psychiatric stabilization.\nGummy formulated medications comprised <2% of the total pediatric calls to the RPCC. Although, the occurrence of symptoms is rare, these medications especially those containing melatonin should be safely stored.",
"affiliations": "Pediatric Emergency Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.;Pediatric Emergency Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.;Children's of Alabama, Birmingham, AL, USA.;Pediatric Emergency Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.;Children's of Alabama, Birmingham, AL, USA.",
"authors": "Crawford|Erika Bishop|EB|;Coco|Teresa|T|;Gaines|LaDonna|L|;Shah|Nipam|N|;Slattery|Ann|A|",
"chemical_list": "D008903:Minerals; D014815:Vitamins; D008550:Melatonin",
"country": "England",
"delete": false,
"doi": "10.1080/15563650.2020.1822532",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-3650",
"issue": "59(5)",
"journal": "Clinical toxicology (Philadelphia, Pa.)",
"keywords": "Pediatric; gummy medication; ingestion; poisonings; retrospective cohort",
"medline_ta": "Clin Toxicol (Phila)",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000407:Alabama; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D019587:Dietary Supplements; D004339:Drug Compounding; D004636:Emergency Service, Hospital; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008550:Melatonin; D008903:Minerals; D011039:Poison Control Centers; D012189:Retrospective Studies; D014815:Vitamins; D055815:Young Adult",
"nlm_unique_id": "101241654",
"other_id": null,
"pages": "440-444",
"pmc": null,
"pmid": "33021391",
"pubdate": "2021-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Pediatric ingestions with gummy formulated medications: a retrospective study.",
"title_normalized": "pediatric ingestions with gummy formulated medications a retrospective study"
} | [
{
"companynumb": "US-HETERO-HET2021US01613",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VITAMINS"
},
"drugadditional": "3",
... |
{
"abstract": "Fungal pathogens can be the source of serious and sometimes fatal infections following organ transplantation. To the best of our knowledge, we present the first case of cutaneous blastomycosis in a renal allograft recipient in India, a country outside the known endemic regions. This case, with the very rare and unexpected diagnosis of blastomycosis, not only reflects the tremendous diversity of infections in transplant recipients but also emphasizes the utility of serological methods even in the immunosuppressed host.",
"affiliations": "Department of Nephrology and Clinical Transplantation, G.R. Doshi and K.M. Mehta Institute of Kidney Diseases and Research Centre-Dr. H. L. Trivedi Institute of Transplantation Sciences (ITS), Civil Hospital Campus, Ahmedabad, India.",
"authors": "Patel|Himanshu V|HV|;Kute|Vivek B|VB|;Vanikar|Aruna V|AV|;Shah|Pankaj R|PR|;Gumber|Manoj R|MR|;Trivedi|Hargovind L|HL|",
"chemical_list": "D000935:Antifungal Agents; D007166:Immunosuppressive Agents",
"country": "Saudi Arabia",
"delete": false,
"doi": "10.4103/1319-2442.139934",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1319-2442",
"issue": "25(5)",
"journal": "Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia",
"keywords": null,
"medline_ta": "Saudi J Kidney Dis Transpl",
"mesh_terms": "D000328:Adult; D000935:Antifungal Agents; D001706:Biopsy; D001758:Blastomyces; D001759:Blastomycosis; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D007194:India; D016030:Kidney Transplantation; D008297:Male; D009894:Opportunistic Infections; D012867:Skin; D016896:Treatment Outcome",
"nlm_unique_id": "9436968",
"other_id": null,
"pages": "1042-5",
"pmc": null,
"pmid": "25193904",
"pubdate": "2014-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Blastomyces dermatitidis in a renal transplant recipient.",
"title_normalized": "blastomyces dermatitidis in a renal transplant recipient"
} | [
{
"companynumb": "PHHY2015IN116734",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
"drug... |
{
"abstract": "Severe thrombocytopenia with impairment of the activity of platelets and impairment of blood clotting occurs in dengue hemorrhagic fever (DHF). Continuation of dual antiplatelet therapy in such patients can result in life-threatening hemorrhages. On the other hand, withholding of antiplatelets in a patient undergone coronary stenting lately can lead to stent thrombosis, resulting in myocardial infarctions and sudden cardiac death. There are no guidelines on management of DHF in patients with coronary stents. Here, we discuss about several divergent factors that need to be considered and balanced when managing such patients. We describe a case as an example to illustrate how we balanced the risk of serious bleeding versus the risk of stent thrombosis successfully according to evolution of the disease process, by temporary withholding of antiplatelets in such a patient.",
"affiliations": "The Teaching (General) Hospital - Kandy, Kandy, Sri Lanka.;The Teaching (General) Hospital - Kandy, Kandy, Sri Lanka.;The Teaching (General) Hospital - Kandy, Kandy, Sri Lanka.;The Teaching (General) Hospital - Kandy, Kandy, Sri Lanka.",
"authors": "Ehelepola|N D B|NDB|;Athurupana|A A S D|AASD|;Bowatte|P G C S|PGCS|;Dissanayake|Wasantha P|WP|",
"chemical_list": "D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D001241:Aspirin",
"country": "United States",
"delete": false,
"doi": "10.4269/ajtmh.19-0512",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9637",
"issue": "102(1)",
"journal": "The American journal of tropical medicine and hygiene",
"keywords": null,
"medline_ta": "Am J Trop Med Hyg",
"mesh_terms": "D001241:Aspirin; D000077144:Clopidogrel; D023921:Coronary Stenosis; D054855:Drug-Eluting Stents; D000080903:Dual Anti-Platelet Therapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors; D019595:Severe Dengue",
"nlm_unique_id": "0370507",
"other_id": null,
"pages": "17-19",
"pmc": null,
"pmid": "31701855",
"pubdate": "2020-01",
"publication_types": "D016428:Journal Article",
"references": "19098345;17874007;20170869;23890510;7608308;22268852;20109979;27826219;29385613;26417060;30546678;22315266;22880140;23323902;26712948;11560568",
"title": "Continuation of Dual Antiplatelet Therapy in a Patient with a Coronary Artery Stent with Dengue Hemorrhagic Fever: A Clinical Conundrum.",
"title_normalized": "continuation of dual antiplatelet therapy in a patient with a coronary artery stent with dengue hemorrhagic fever a clinical conundrum"
} | [
{
"companynumb": "LK-GENUS_LIFESCIENCES-USA-POI0580202000208",
"fulfillexpeditecriteria": "1",
"occurcountry": "LK",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CLOPIDOGREL BISULFATE"
},
"... |
{
"abstract": "Procalcitonin (PCT), a marker of the inflammatory response during infections, can be elevated by diabetic ketoacidosis (DKA). A male patient in his 50s with diabetic nephropathy on hemodialysis presented with vomiting and a reduced level of consciousness and was diagnosed with DKA. His PCT level was markedly elevated, but bacterial cultures (blood, urine, and stool) were negative. The PCT level decreased after DKA improvement. In this patient, DKA probably enhanced the PCT levels. As DKA can increase the PCT levels, an elevation of the PCT levels in DKA patients may not be indicative of infectious diseases, and non-infectious causes of DKA should therefore be considered.",
"affiliations": "Department of Internal Medicine IV, Shimane University Faculty of Medicine, Japan.;Department of Internal Medicine IV, Shimane University Faculty of Medicine, Japan.;Department of Internal Medicine IV, Shimane University Faculty of Medicine, Japan.;Department of Internal Medicine IV, Shimane University Faculty of Medicine, Japan.;Department of Internal Medicine IV, Shimane University Faculty of Medicine, Japan.;Department of Internal Medicine IV, Shimane University Faculty of Medicine, Japan.;Department of Internal Medicine IV, Shimane University Faculty of Medicine, Japan.;Department of Urology, Shimane University Faculty of Medicine, Japan.;Department of Internal Medicine IV, Shimane University Faculty of Medicine, Japan.;Department of Internal Medicine IV, Shimane University Faculty of Medicine, Japan.",
"authors": "Fukunaga|Shohei|S|;Hoshino|Yuki|Y|;Sonoda|Hirotaka|H|;Kawanishi|Miharu|M|;Yamauchi|Asuka|A|;Kato|Shiho|S|;Yoshikane|Kaori|K|;Shiina|Hiroaki|H|;Tanabe|Kazuaki|K|;Ito|Takafumi|T|",
"chemical_list": "D015415:Biomarkers; D000077740:Procalcitonin",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.5841-20",
"fulltext": "\n==== Front\nIntern Med\nIntern Med\nInternal Medicine\n0918-2918\n1349-7235\nThe Japanese Society of Internal Medicine\n\n33229806\n10.2169/internalmedicine.5841-20\nCase Report\nA Remarkable Elevation in the Procalcitonin Levels Due to Diabetic Ketoacidosis in a Hemodialysis Patient\nFukunaga Shohei 1\nHoshino Yuki 1\nSonoda Hirotaka 1\nKawanishi Miharu 1\nYamauchi Asuka 1\nKato Shiho 1\nYoshikane Kaori 1\nShiina Hiroaki 2\nTanabe Kazuaki 1\nIto Takafumi 1\n1 Department of Internal Medicine IV, Shimane University Faculty of Medicine, Japan\n2 Department of Urology, Shimane University Faculty of Medicine, Japan\nCorrespondence to Dr. Shohei Fukunaga, fukunaga@med.shimane-u.ac.jp\n\n23 11 2020\n15 4 2021\n60 8 12311235\n11 7 2020\n23 9 2020\nCopyright © 2021 by The Japanese Society of Internal Medicine\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ The Internal Medicine is an Open Access journal 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/).\nProcalcitonin (PCT), a marker of the inflammatory response during infections, can be elevated by diabetic ketoacidosis (DKA). A male patient in his 50s with diabetic nephropathy on hemodialysis presented with vomiting and a reduced level of consciousness and was diagnosed with DKA. His PCT level was markedly elevated, but bacterial cultures (blood, urine, and stool) were negative. The PCT level decreased after DKA improvement. In this patient, DKA probably enhanced the PCT levels. As DKA can increase the PCT levels, an elevation of the PCT levels in DKA patients may not be indicative of infectious diseases, and non-infectious causes of DKA should therefore be considered.\n\nprocalcitonin\ndiabetic ketoacidosis\nhemodialysis\n==== Body\nIntroduction\n\nDiabetic ketoacidosis (DKA) is one of the most serious complications of diabetes mellitus (DM). It often manifests in type 1 and type 2 DM. Infections are the most common triggers of DKA. Several studies have reported that DKA enhances cytokine production (1-3). The procalcitonin (PCT) levels increase in bacterial infections/sepsis and they are used as markers of bacterial infection (4). However, they can also increase in conditions that elevate the cytokine levels, such as burns, trauma, surgery, and pancreatitis (5). A few studies have reported that PCT can increase in DKA. However, the mechanism by which DKA leads to elevated PCT levels remains unknown. To the best of our knowledge, only one report has quantified the PCT levels in DKA (6). Understanding the transition in the PCT level is important for elucidating the relationship between PCT and DKA. In this case report, we measured the PCT levels twice (during and after DKA). Importantly, this is the first report on the relationship between PCT and DKA in patients on hemodialysis (HD). Specifically, we herein present the case of a patient on HD with DKA who had markedly elevated PCT levels, and we assessed the relationship between PCT and DKA.\n\nCase Report\n\nA male patient in his 50s presented to our hospital with vomiting, a reduced level of consciousness, and malaise that had developed 2 days prior to admission. He had been receiving treatment for type 1 DM for 34 years and HD for end-stage kidney disease due to diabetic nephropathy for 6 years. He had received online-hemodiafiltration (HDF) 2 days before admission. He was on insulin therapy (insulin glargine: 10 U at bedtime; insulin aspart: 6 U at breakfast, lunch, and dinner time), although he stopped the insulin therapy the day before admission. His regular medications were rabeprazole sodium, precipitated calcium carbonate, bixalomer, alfacalcidol, amitriptyline hydrochloride, and atorvastatin calcium hydrate. The initial physical examination showed a blood pressure of 100/51 mmHg, a heart rate of 80 beats/min, and an oxygen saturation of 99% (room air). His height, body weight, and body mass index were 163 cm, 57.6 kg, and 21.7 kg/m2, respectively. His respiratory sounds were clear, and no abnormal abdominal findings were noted. Blood investigations (Table 1) showed severe metabolic acidosis, hyperkalemia, hyponatremia, high PCT levels (62.84 ng/mL), hyperglycemia (767 mg/dL), and elevated 3-hydroxybutyric acid levels. Therefore, we diagnosed him with DKA, attributed to the cessation of insulin therapy. An electrocardiogram showed normal P and inverted T waves. Chest X-ray imaging (Fig. 1) showed no pneumonia, whereas chest computed tomography (CT) showed a very mild frosted glass image on the ventral side of the right lung (in S1). Therefore, we diagnosed him as having slight pneumonia.\n\nTable 1. Laboratory Investigation.\n\nHematology\tBlood chemistry\t\t\t\tBlood gas (arterial blood)\t\nWBC\t14,530\t/μL\tTP\t6.8\tg/dL\tNa\t124\tmmol/L\tpH\t7.019\t\t\nNeut\t95.5\t%\tAlb\t3.6\tg/dL\tK\t7.8\tmmol/L\tPCO2\t26.4\tmmHg\t\nLynph\t0.5\t%\tT-bil\t0.1\tmg/dL\tCl\t88\tmmol/L\tPO2\t82.1\tmmHg\t\nMono\t4\t%\tAST\t24\tU/L\tCa\t8.9\tmg/dL\tHCO3-\t8.0\tmmol/L\t\nRBC\t391\t×104/μL\tALT\t17\tU/L\tP\t6.2\tmg/dL\tLac\t4.8\tmEq/L\t\nHb\t12.0\tg/dL\tLDH\t238\tU/L\tCRP\t6.38\tmg/dL\t\t\t\t\nPlt\t10.5\t×104/μL\tγ-GTP\t7\tU/L\tPCT\t62.84\tng/mL\t\t\t\t\nCoagulation\tAlp\t319\tU/L\tPG\t767\tmg/dL\t\t\t\t\nPT-INR\t1.00\t\tBUN\t100.9\tmg/dL\t3-OHBA\t4.3\tmmol/L\t\t\t\t\nAPTT\t29.4\ts\tCrea\t12.46\tmg/dL\tCPR\t<0.01\tng/mL\t\t\t\t\nFib\t646\tmg/dL\t\t\t\t\t\t\t\t\t\t\nD dimer\t0.6\tμg/mL\t\t\t\t\t\t\t\t\t\t\n3-OHBA: 3-Hydroxybutyric acid, Alb: albumin, Alp: alkaline phosphatase, ALT: alanine aminotransferase, APTT: activated partial thromboplastin time, AST: aspartate aminotransferase, BUN: blood urea nitrogen, CPR: C-peptide immunoreactivity, Crea: creatinine, CRP: C-reactive protein, Fib: fibrinogen, Hb: hemoglobin, Lac: lactate, LDH: lactate dehydrogenase, Lymph: lymphocytes, Mono: monocytes, Neut: neutrophils, PCT: procalcitonin, PG: plasma glucose, Plt: platelet, PT-INR: prothrombin time international normalized ratio, RBC: red blood cells, T-bil: total-bilirubin, TP: total protein, WBC: white blood cells, γ-GTP: γ-glutamyl transpeptidase\n\nFigure 1. Chest X-ray and computed tomography.\n\nCalcium gluconate hydrate (1,700 mg) was injected intravenously, glucose insulin therapy was started, and emergency HD [polyethersulfone (PES) membrane; membrane surface area, 1.5 m2; blood flow, 150 mL/min; dialysis time, 4 h] was urgently performed to manage hyperkalemia. Maintenance hemodialysis (offline-HDF; PES membrane; membrane surface area, 2.1 m2; blood flow, 200 mL/min; dialysis time, 4 h) was started on the 2nd day. The continuous intravenous administration of insulin was initiated for managing DKA but was discontinued because of appetite improvement 3 days after admission. Subsequently, intensive insulin therapy was initiated.\n\nA high inflammatory response [C-reactive protein (CRP) levels, 6.38 mg/dL; PCT levels, 62.84 ng/mL] was observed (Fig. 2). However, chest CT showed only a slight frosted glass image, and cultures for blood, urine, and stool were negative. We could not perform a sputum culture due to the absence of respiratory symptoms. The intravenous administration of tazobactam/piperacillin 4.5 g twice daily had been started at admission, but was discontinued on the 4th day; instead, oral sultamicillin 375mg once daily was initiated. CRP levels rapidly decreased, although his general condition improved. Therefore, we judged that the infection had resolved, and the antibiotics were discontinued on the 10th day. The PCT levels decreased to 29.6 ng/mL on the 8th day. The patient's blood glucose levels stabilized, and his general condition improved; therefore, he was discharged on the 12th day. After discharge, he did not develop any infectious disease and did not experience a recurrence of DKA.\n\nFigure 2. Clinical course of the patient on HD admitted with DKA. CRP: C-reactive protein, CVII: continuous venous insulin infusion, DKA: diabetic ketoacidosis, HD: Hemodialysis, HDF: Hemodiafiltration, Neut: neutrophils, PCT: procalcitonin, SBTPC: sultamicillin, TAZ/PIPC: tazobactam/piperacillin, WBC: white blood cells\n\nDiscussion\n\nPCT has higher sensitivity and specificity than CRP for distinguishing between infectious and non-infectious diseases. The PCT levels can help to differentiate between bacterial and viral infections with a high sensitivity (92%) (4). PCT is normally synthesized in thyroid C cells, as a precursor of calcitonin (7). However, in severe infections caused by bacteria, parasites, and fungi, inflammatory cytokines are produced by the action of bacterial cells and toxins. These cytokines act on organs, such as lungs, kidneys, liver, adipose tissue, and muscles, promoting PCT production (8).\n\nHowever, serious trauma, surgical invasion, and severe burns, Plasmodium infection, acute respiratory distress syndrome (ARDS) can also lead to elevated PCT levels, and caution is required when interpreting PCT findings in such cases (5). Several studies have reported that DKA enhances cytokine production (1-3). Moreover, hyperglycemia also enhances cytokine production (9). Hence, DKA leads to the production of inflammatory cytokines and an increase in the PCT levels.\n\nIvaska et al. reported that when children with type 1 DM develop DKA, the PCT levels are high despite the absence of infection (10). Two studies have reported a PCT elevation after DKA in adults with type 1 DM (10, 11). Information regarding these eight previously reported cases is presented in Table 2. Except for our case, all cases of PCT elevation due to DKA were reported in women, and the median age of the patients was 34 years (range, 14-73 years), which was relatively low. This is likely because women have a stronger immune response than men do (12), and younger individuals in general show higher cytokine production. It is also widely considered that DKA is more likely to occur in young people (13).\n\nTable 2. Comparison of the Present Case with Previously Reported DKA Patient with High PCT Level.\n\nSex\tAge\n(year)\tPlasma glucose\n(mg/dL)\tpH\tLactate\n(mEq/L)\tWBC\n(/L)\tCRP\n(mg/dL)\tPCT\n(ng/mL)\tReference\t\nF\t14\t633\t7.04\t3.3\t25,800\t8.4\t82.94\t9\t\nF\t15\t601\t7.00\t4.3\t24,600\t5.5\t13.13\t9\t\nF\tN/A\t522\tN/A\tN/A\tN/A\tN/A\t1.72\t10\t\nF\t34\t539\t6.91\t2.1\t21,800\t0.06\t12.4\t11\t\nF\t42\t1,177\t6.94\t4.6\t19,910\t0.31\t30.47\t11\t\nF\t32\t623\t6.80\t1.6\t26,510\t0.25\t8.81\t11\t\nF\t73\t1,044\t7.06\t2.8\t18,900\t2.08\t6.87\t11\t\nM\t59\t767\t7.019\t4.8\t14,530\t6.38\t62.84\tThe present case\t\nCRP: C-reactive protein, DKA: diabetic ketoacidosis, PCT: procalcitonin, WBC: white blood cells\n\nThe CRP levels were slightly elevated at 3.28±3.17 mg/dL, but the PCT levels were very high at 26.29±26.57 ng/mL. However, the level of inflammatory cytokines has not been examined in any previous studies, and it was not possible to prove that DKA enhances PCT production via inflammatory cytokines. Moreover, the number of reported cases is small, and many more cases should be examined and analyzed to elucidate the relationship between inflammatory cytokines and DKA.\n\nIn addition, the standard threshold for PCT is slightly higher in patients undergoing HD. Kubo et al. reported that the median PCT level before dialysis in such patients was 0.23 ng/mL, which was higher than that in healthy participants (14). Trimarchi et al. reported that the 95th percentile of PCT levels in 45 uninfected patients on HD was 0.8 ng/mL, which is the upper limit of the reference value (15). While the PCT level in such patients can be slightly higher than that in healthy individuals, the PCT levels in our case were markedly high at 62.84 ng/mL, and no serious bacterial infection was observed. Although candidiasis and aspergillosis antigen tests were not performed, the two conditions were deemed unlikely because the clinical course and findings were not in accordance with either of the two conditions. Moreover, β-D-glucan was negative (5.2 pg/mL), and there were no characteristic findings on CT. Since the patient did not have respiratory distress, and pulmonary edema was not detected on chest CT, ARDS was excluded. With no history of overseas travel, Plasmodium infection was unlikely. Although non-severe pneumonia may raise the PCT levels, DKA was strongly suspected to be the main cause of the PCT elevation. In addition, it has been reported that PCT decreases with an improvement in acute hyperglycemia (16); however, the transition trajectory of the PCT levels among DKA patients has not been clarified. In our case, the improvement of DKA was also associated with a reduction in the PCT levels to 29.6 ng/mL, further supporting their DKA-dependent increase. In contrast, Cipriano et al. reported that “PCT returned to normal values (＜0.5 ng/mL) after 3 days of hospitalization, thus reflecting the half-life of the protein.” (6). The decline in the PCT level was slow in our case. Meisner et al. suggested that plasma clearance of PCT may be delayed in patients with renal dysfunction (17). While HD will gradually eliminate PCT, our patient could not attain the urinary excretion of procalcitonin because he was anuric. It was suggested that the rate of PCT elimination was slow by HD and offline-HDF alone.\n\nThe PCT removal rate was found to be 53.7% in a single HD using PES membrane (14). Nevertheless, there are no reports of PCT removal rates of HDF. The molecular weight of PCT is approximal 13 kDa, which is similar to that of β2 microglobulin. Online HDF can achieve a 46% higher β2-microglobulin removal rate when compared with HD (18) suggesting that the first has a better PCT removal rate than the latter. However, he received offline-HDF, and the PCT removal rate was not as high as that of the online-HDF, indicating that the decline in the PCT level was slow. One limitation associated with this report was that the cause of PCT elevation was not only DKA, but pneumonia was also slightly involved.\n\nConclusion\n\nBacterial infections often cause DKA which may elevate the PCT levels. However, DKA in the absence of bacterial infection can also increase the PCT levels. Therefore, in DKA, it is necessary to carefully determine whether PCT is elevated because of bacterial infection or due to DKA itself. In patients on HD, the rate of PCT decline is slower. Further studies are thus needed to determine the transition of PCT in DKA patients on HD.\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. Dalton RR , Hoffman WH , Passmore GG , Martin SL . Plasma C-reactive protein levels in severe diabetic ketoacidosis. Ann Clin Lab Sci 33 : 435-442, 2003.14584758\n2. Hoffman WH , Burek CL , Waller JL , Fisher LE , Khichi M , Mellick LB . Cytokine response to diabetic ketoacidosis and its treatment. Clin Immunol 108 : 175-181, 2003.14499240\n3. Karavanaki K , Karanika E , Georga S , et al . Cytokine response to diabetic ketoacidosis (DKA) in children with type 1 diabetes (T1DM). Endocr J 58 : 1045-1053, 2011.22033476\n4. Simon L , Gauvin F , Amre DK , Saint-Louis P , Lacroix J . Serum procalcitonin and C-reactive protein levels as markers of bacterial infection: a systematic review and meta-analysis. Clin Infect Dis 39 : 206-217, 2004.15307030\n5. Christ-Crain M , Müller B . Procalcitonin in bacterial infections--hype, hope, more or less? Swiss Med Wkly 135 : 451-460, 2005.16208582\n6. Cipriano A , Rebelos E , Park N , Santini M . Moderate increase of serum levels of procalcitonin in diabetic ketoacidosis. Neth J Med 76 : 454, 2018.30569896\n7. Becker KL , Nylén ES , White JC , Müller B , Snider RH Jr . Clinical review 167: Procalcitonin and the calcitonin gene family of peptides in inflammation, infection, and sepsis: a journey from calcitonin back to its precursors. J Clin Endocrinol Metab 89 : 1512-1525, 2004.15070906\n8. Linscheid P , Seboek D , Nylen ES , et al . In vitro and in vivo calcitonin I gene expression in parenchymal cells: a novel product of human adipose tissue. Endocrinology 144 : 5578-5584, 2003.12960010\n9. Jafar N , Edriss H , Nugent K . The effect of short-term hyperglycemia on the innate immune system. Am J Med Sci 351 : 201-211, 2016.26897277\n10. Ivaska L , Elenius V , Mononen I , Ruuskanen O , Peltola V . Discrepancies between plasma procalcitonin and C-reactive protein levels are common in acute illness. Acta Paediatr 105 : 508-513, 2016.26644355\n11. Anno T , Shigemoto R , Kawasaki F , et al . Marked elevation of plasma procalcitonin levels in patients with diabetic ketoacidosis: a possible useful diagnostic biomarker. Diabetes Metab 46 : 504-505, 2020.31178365\n12. Chrousos GP . Stress and sex versus immunity and inflammation. Sci Signal 3 : pe36, 2010.20940425\n13. Wolfsdorf JI , Glaser N , Agus M , et al . ISPAD Clinical Practice Consensus Guidelines 2018: Diabetic ketoacidosis and the hyperglycemic hyperosmolar state. Pediatr Diabetes 19 : 155-177, 2018.29900641\n14. Kubo S , Iwasaki M , Horie M , et al . Biological variation of procalcitonin levels in hemodialysis patients. Clin Exp Nephrol 23 : 402-408, 2019.30196520\n15. Trimarchi H , Dicugno M , Muryan A , et al . Pro-calcitonin and inflammation in chronic hemodialysis. Medicina (B Aires) 73 : 411-416, 2013.24152395\n16. Aksu NM , Aksoy DY , Akkaş M , et al . 25-OH-Vitamin D and procalcitonin levels after correction of acute hyperglycemia. Med Sci Monit 19 : 264-268, 2013.23580106\n17. Meisner M , Lohs T , Huettemann E , Schmidt J , Hueller M , Reinhart K . The plasma elimination rate and urinary secretion of procalcitonin in patients with normal and impaired renal function. Eur J Anaesthesiol 18 : 79-87, 2001.11270029\n18. Lornoy W , Becaus I , Billiouw JM , Sierens L , van Malderen P . remarkable removal of beta-2-microglobulin by on-line hemodiafiltration. Am J Nephrol 18 : 105-108, 1998.9569951\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "60(8)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "diabetic ketoacidosis; hemodialysis; procalcitonin",
"medline_ta": "Intern Med",
"mesh_terms": "D015415:Biomarkers; D016883:Diabetic Ketoacidosis; D006801:Humans; D008297:Male; D000077740:Procalcitonin; D006435:Renal Dialysis",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "1231-1235",
"pmc": null,
"pmid": "33229806",
"pubdate": "2021-04-15",
"publication_types": "D016428:Journal Article",
"references": "14499240;15070906;14584758;9569951;16208582;12960010;15307030;26644355;30196520;29900641;22033476;11270029;30569896;20940425;26897277;23580106;24152395;31178365",
"title": "A Remarkable Elevation in the Procalcitonin Levels Due to Diabetic Ketoacidosis in a Hemodialysis Patient.",
"title_normalized": "a remarkable elevation in the procalcitonin levels due to diabetic ketoacidosis in a hemodialysis patient"
} | [
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"companynumb": "JP-NOVOPROD-855576",
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"abstract": "Early severe preeclampsia with changes consistent with the Hemolysis elevated liver enzymes low platelet count (HELLP) variant and severe fetal growth restriction rarely resolves prior to delivery. Established clinical disease is preceded by endothelial dysfunction and inflammation. Endothelial activation is reported in vitro to be raised in the presence of necrotic trophoblastic debris which is deported into the maternal circulation in preeclampsia. We report on an early severe preeclamptic patient admitted at 24 weeks gestation. Maternal serum was taken at day 2, 16, 30 of admission and 45 days postpartum. 20% maternal serum or trophoblastic debris from first trimester placental explants that had been cultured with 10% maternal serum was exposed to endothelial cells. Endothelial cell activation was quantified by the cell surface ICAM-1 expression and U937 monocyte adhesion assay. The clinical condition of this patient improved including the blood pressure, liver function, and platelet count by the 3rd day after antihypertensive treatment and remained normal until delivery at 37 weeks. ICAM-1 expression and U937 moncyte adhesion assay of endothelial cells was significantly increased following exposure of the endothelial cells to the maternal serum or trophoblastic debris from placentae treated with maternal serum drawn on day 2. However, ICAM-1 expression and the monocyte adhesion assay were significantly reduced following exposure of endothelial cells to maternal serum or trophoblastic debris from placenta treated with maternal serum drawn on day 16 or 30. Our data suggest unknown factor(s) in the maternal serum triggered endothelial cell activation when the clinical symptoms were present. The improvement in the clinical condition occurred along with the changes in endothelial cell activation.",
"affiliations": "a Department of Obstetrics & Gynaecology , The University of Auckland , Auckland , New Zealand.;c Maternal Fetal Medicine, Auckland City Hospital , Auckland , New Zealand.;c Maternal Fetal Medicine, Auckland City Hospital , Auckland , New Zealand.;a Department of Obstetrics & Gynaecology , The University of Auckland , Auckland , New Zealand.;a Department of Obstetrics & Gynaecology , The University of Auckland , Auckland , New Zealand.",
"authors": "Chen|Q|Q|;Sousa|J De|JD|;Snowise|S|S|;Chamley|L|L|;Stone|P|P|",
"chemical_list": "D018799:Intercellular Adhesion Molecule-1",
"country": "England",
"delete": false,
"doi": "10.3109/10641955.2015.1100309",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1064-1955",
"issue": "35(1)",
"journal": "Hypertension in pregnancy",
"keywords": "Antihypertensive; endothelial cell activation; preeclampsia; preeclamptic serum; trophoblastic debris",
"medline_ta": "Hypertens Pregnancy",
"mesh_terms": "D000328:Adult; D042783:Endothelial Cells; D005260:Female; D006801:Humans; D018799:Intercellular Adhesion Molecule-1; D010920:Placenta; D011225:Pre-Eclampsia; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D012720:Severity of Illness Index",
"nlm_unique_id": "9421297",
"other_id": null,
"pages": "32-41",
"pmc": null,
"pmid": "26852788",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Reduction in the severity of early onset severe preeclampsia during gestation may be associated with changes in endothelial cell activation: A pathological case report.",
"title_normalized": "reduction in the severity of early onset severe preeclampsia during gestation may be associated with changes in endothelial cell activation a pathological case report"
} | [
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"companynumb": "NZ-MYLANLABS-2016M1018156",
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"activesubstance": {
"activesubstancename": "METHYLDOPA"
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"abstract": "Aspergillus fumigatus can cause a variety of pulmonary syndromes including allergic bronchopulmonary aspergillosis (ABPA), chronic pulmonary aspergillosis and invasive pulmonary aspergillosis (IPA). Occurrence of IPA and ABPA in the same patient is rare as the risk factors for ABPA and IPA are different. We describe a 45-year-old male with ABPA treated with oral methylprednisolone and itraconazole, who developed acute respiratory failure secondary to IPA, a month later. The patient subsequently improved after systemic antifungal therapy. Presumably, itraconazole by inhibiting CYP3A4 enzyme caused an increase in plasma methylprednisolone levels. This probably led to a profound immunosuppressed state, which predisposed to the development of IPA. We performed a systematic review and identified nine cases of IPA following ABPA. The disease course is fulminant, and only three of the nine patients survived. Physicians treating ABPA patients should be aware of this potentially fatal overlap. Clinical suspicion and early diagnosis are crucial to improve the patient outcomes.",
"affiliations": "Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research, Sector-12, Chandigarh, 160012, India.",
"authors": "Maturu|Venkata Nagarjuna|VN|;Agarwal|Ritesh|R|",
"chemical_list": "D000935:Antifungal Agents; D007166:Immunosuppressive Agents; D017964:Itraconazole; D008775:Methylprednisolone",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s11046-015-9907-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0301-486X",
"issue": "180(3-4)",
"journal": "Mycopathologia",
"keywords": null,
"medline_ta": "Mycopathologia",
"mesh_terms": "D000935:Antifungal Agents; D001229:Aspergillosis, Allergic Bronchopulmonary; D001232:Aspergillus fumigatus; D006801:Humans; D007166:Immunosuppressive Agents; D055744:Invasive Pulmonary Aspergillosis; D017964:Itraconazole; D008297:Male; D008775:Methylprednisolone; D008875:Middle Aged",
"nlm_unique_id": "7505689",
"other_id": null,
"pages": "209-15",
"pmc": null,
"pmid": "26045286",
"pubdate": "2015-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review; D000078182:Systematic Review",
"references": "7426370;18462102;23210682;12065367;22457034;5680235;23889240;8165040;19211274;11422002;25478929;25367472;8956126;21881144;9797792;8417908;1089377;19265090;7709000;8092014;7351446;12783174;10853878",
"title": "Acute Invasive Pulmonary Aspergillosis Complicating Allergic Bronchopulmonary Aspergillosis: Case Report and Systematic Review.",
"title_normalized": "acute invasive pulmonary aspergillosis complicating allergic bronchopulmonary aspergillosis case report and systematic review"
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"companynumb": "IN-MYLANLABS-2015M1043021",
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"activesubstancename": "METHYLPREDNISOLONE"
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"drugadditional": null... |
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"abstract": "In an effort to maintain high primary response rates against multiple myeloma and without serious toxicity, we assessed 3 different bortezomib combinations in small numbers of patients, with combinations that included cyclophosphamide and lenalidomide in modest doses and for short courses. Remissions occurred in approximately 90% of patients, with rare episodes of serious drug-related adverse effects.\n\n\nBACKGROUND\nRecent bortezomib combinations have induced remission in approximately 90% of patients newly diagnosed, with moderate frequency of adverse effects.\n\n\nMETHODS\nIn an attempt to reduce adverse effects, and to prepare qualified patients for early intensification, we assessed the antimyeloma effect and toxicity of 3 different bortezomib combinations in small numbers of patients.\n\n\nMETHODS\nWith reduced doses and short durations of exposure, we combined bortezomib with (a) cyclophosphamide/dexamethasone, (b) lenalidomide/dexamethasone/liposomal doxorubicin, and (c) cyclophosphamide/dexamethasone/lenalidomide.\n\n\nRESULTS\nResponse rates were high, with rare episodes of severe drug-related toxicity.\n\n\nCONCLUSIONS\nFurther study of similar combinations of effective drugs given in limited doses and for short durations would be useful.",
"affiliations": "Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA. ralexani@mdanderson.org",
"authors": "Alexanian|Raymond|R|;Delasalle|Kay|K|;Wang|Michael|M|",
"chemical_list": "D001897:Boronic Acids; D011719:Pyrazines; D013792:Thalidomide; D000069286:Bortezomib; D003907:Dexamethasone; D004317:Doxorubicin; D003520:Cyclophosphamide; D000077269:Lenalidomide",
"country": "United States",
"delete": false,
"doi": null,
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"fulltext_license": null,
"issn_linking": "2152-2669",
"issue": "13(2)",
"journal": "Clinical lymphoma, myeloma & leukemia",
"keywords": null,
"medline_ta": "Clin Lymphoma Myeloma Leuk",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D001897:Boronic Acids; D000069286:Bortezomib; D003520:Cyclophosphamide; D003907:Dexamethasone; D004317:Doxorubicin; D005260:Female; D006801:Humans; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D009367:Neoplasm Staging; D011719:Pyrazines; D013792:Thalidomide; D016896:Treatment Outcome",
"nlm_unique_id": "101525386",
"other_id": null,
"pages": "119-22",
"pmc": null,
"pmid": "23260599",
"pubdate": "2013-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "High frequencies of response after limited primary therapy for multiple myeloma.",
"title_normalized": "high frequencies of response after limited primary therapy for multiple myeloma"
} | [
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"activesubstancename": "DOXORUBICIN"
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... |
{
"abstract": "We experienced rocuronium-induced anaphylaxis in a 62-year-old man who was scheduled for laparoscopic ileocecal excision for cecal cancer under general anes- thesia. The patient did not have a preoperative history and examinations suggestive of heart disease, or pre- disposing factors for myocardial infarction. Just after induction of anesthesia, we noticed abnormally low blood pressure and ST segment elevation on his elec- trocardiogram. The surgery was postponed and percu- taneous coronary intervention was performed to treat coronary artery stenosis. Re-operation was planned 73-days after the first operation. The patient suffered cardiac arrest just after induction of general anesthesia At the same time, we noticed systemic erythema all over his body, which led to the diagnosis of anaphy- laxis. Cardiopulmonary resuscitation was performed and the surgery was postponed once again. Cardiovas- cular agents, including adrenaline, noradrenaline, atro- pine and amiodarone, improved his hemodynamics. In addition, steroids and anti-histamines were also admin- istered to treat anaphylaxis. We advised him to undergo skin tests to determine the causative agent of anaphylaxis, but he declined. Instead, a basophil activa- tion test was performed, which showed a positive reac- tion to rocuronium. Therefore, we planned general anesthesia without using muscle relaxants such as rocuronium for the third attempt at surgery. The sur- gery was performed safely with this protocol. It is likely that his symptoms in the first general anesthesia were caused by Kounis syndrome. We conclude that the basophil activation test seems to be valuable in determining the causative agent of anaphylaxis, partic- ularly when a patient does not agree to undergo skin tests.",
"affiliations": null,
"authors": "Sakamoto|Shinya|S|;Horiuchi|Tatsuo|T|;Takazawa|Tomonori|T|;Hoshino|Yutaka|Y|;Takahashi|Kenichiro|K|;Saito|Shigeru|S|",
"chemical_list": "D000077123:Rocuronium",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0021-4892",
"issue": "66(4)",
"journal": "Masui. The Japanese journal of anesthesiology",
"keywords": null,
"medline_ta": "Masui",
"mesh_terms": "D000707:Anaphylaxis; D000768:Anesthesia, General; D001063:Appendiceal Neoplasms; D001491:Basophils; D006801:Humans; D000074962:Kounis Syndrome; D008297:Male; D008875:Middle Aged; D000077123:Rocuronium",
"nlm_unique_id": "0413707",
"other_id": null,
"pages": "424-430",
"pmc": null,
"pmid": "30382647",
"pubdate": "2017-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Rocuronium-induced Anaphylaxis in a Man with Kounis Syndrome in which Basophil Activation Test was Valuable in Determining the Causative Agent.",
"title_normalized": "a case of rocuronium induced anaphylaxis in a man with kounis syndrome in which basophil activation test was valuable in determining the causative agent"
} | [
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"companynumb": "JP-MYLANLABS-2019M1010764",
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"activesubstancename": "REMIFENTANIL"
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{
"abstract": "A 46-year-old man with a history of paranoid schizophrenia was admitted with a recurrence of psychotic symptoms. Improvement was noted after the initiation of clozapine. After 2 weeks of clozapine therapy, chest pressure and abnormal cardiac biomarkers (in the presence of a normal coronary angiogram) raised suspicion of myocarditis. That diagnosis was confirmed by means of cardiac magnetic resonance imaging. Discontinuation of the clozapine led to resolution of the cardiac symptoms. Clozapine-induced myocarditis is rare and can be missed for lack of specific clinical findings. In order to prevent disease progression and a possibly fatal outcome, early recognition of the condition and prompt discontinuation of clozapine are necessary.",
"affiliations": null,
"authors": "Hatton|Jennifer L|JL|;Bhat|Pradeep K|PK|;Gandhi|Sanjay|S|",
"chemical_list": "D014150:Antipsychotic Agents; D003024:Clozapine",
"country": "United States",
"delete": false,
"doi": "10.14503/THIJ-13-3633",
"fulltext": null,
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"issn_linking": "0730-2347",
"issue": "42(2)",
"journal": "Texas Heart Institute journal",
"keywords": "Antipsychotic agents/adverse effects; cardiac magnetic resonance imaging; clozapine; myocarditis/chemically induced; schizophrenia/drug therapy",
"medline_ta": "Tex Heart Inst J",
"mesh_terms": "D014150:Antipsychotic Agents; D003024:Clozapine; D006801:Humans; D007089:Image Enhancement; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009205:Myocarditis; D012563:Schizophrenia, Paranoid",
"nlm_unique_id": "8214622",
"other_id": null,
"pages": "155-7",
"pmc": null,
"pmid": "25873829",
"pubdate": "2015-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11476122;14993139;9885782;15936612;22113154;17194170;10584719;17980265;19389557;15936613",
"title": "Clozapine-induced myocarditis: recognizing a potentially fatal adverse reaction.",
"title_normalized": "clozapine induced myocarditis recognizing a potentially fatal adverse reaction"
} | [
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"companynumb": "PHHY2015US052244",
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"occurcountry": "US",
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"activesubstancename": "CLOZAPINE"
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{
"abstract": "BACKGROUND Acute intermittent porphyria is an inherited disease caused by a defect in heme biosynthesis, with accumulation of neurotoxic metabolites leading to acute neurovisceral symptoms. Some patients develop long-term neurological and renal damage after the acute episodes, many of them requiring hemodialysis. Since heme production in the human body occurs predominantly in the bone marrow and liver, liver transplantation has been shown to significantly reduce the production of neurotoxic metabolites, effectively controlling the disease. Patients with severe acute intermittent porphyria who have chronic kidney failure may benefit from combined kidney and liver transplant. Only 2 uses of this approach have been previously reported in the literature. CASE REPORT We report here the case of a 19-year-old male patient who received a combined liver and kidney transplant for the treatment of acute intermittent porphyria. He presented the first symptoms of the disease 4 years before the procedure, with abdominal pain and significant neurological impairment, with weakness requiring prolonged mechanical ventilation. He also had chronic kidney failure secondary to the porphyria. A combined liver and kidney transplant was performed, with no intraoperative complications. The explanted liver showed light siderosis, as well as portal and perisinusoidal fibrosis at microscopy. At 3.5 years of follow-up, he remains clinically well, with normal hepatic and renal function, had had no further acute porphyria episodes, and shows progressive neurological recovery. CONCLUSIONS This case demonstrates that combined liver and kidney transplant can be a curative treatment for patients with severe acute intermittent porphyria associated with end-stage renal failure. The patient shows satisfactory long-term function of both grafts, with no clinical or biochemical signs of porphyria recurrence.",
"affiliations": "Department of Liver Transplantation, Institute of Cardiology of the Federal District (ICDF), Brasília, Brazil.;Department of Nephrology, University Hospital of Brasília (HUB), Brasília, Brazil.;Department of Kidney Transplantation, Institute of Cardiology of the Federal District (ICDF), Brasília, Brazil.;Department of Liver Transplantation, Institute of Cardiology of the Federal District (ICDF), Brasília, Brazil.;Department of Kidney Transplantation, Institute of Cardiology of the Federal District (ICDF), Brasilia, Brazil.;Department of Kidney Transplantation, Institute of Cardiology of the Federal District (ICDF), Brasília, Brazil.;Department of Kidney Transplantation, Institute of Cardiology of the Federal District (ICDF), Brasília, Brazil.;Department of Kidney Transplantation, Institute of Cardiology of the Federal District (ICDF), Brasília, Brazil.;School of Medicine, Catholic University of Brasília, Brasília, Brazil.;School of Medicine, Catholic University of Brasília, Brasília, Brazil.;School of Medicine, Catholic University of Brasília, Brasília, Brazil.;School of Medicine, Universidade Catolica de Brasilia, Brasilia, Brazil.",
"authors": "de Sousa Arantes Ferreira|Gustavo|G|;Claudio de Oliveira|Livia|L|;Roberto de Sousa Ulisses|Luiz|L|;Luis Conde Watanabe|Andre|A|;Medeiros|Isabela Novais|IN|;Souto Siqueira Cardoso|Helen|H|;Creão da Costa Alves|Inara|I|;Martins de Almeida|Tiago|T|;Viana de Lima|Laura|L|;Fontoura|Renata Pereira|RP|;Resende Sousa E Silva|Eduardo|E|;de Araújo|Pollyana Lopes|PL|",
"chemical_list": null,
"country": "United States",
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"doi": "10.12659/AJCR.927832",
"fulltext": "\n==== Front\nAm J Case Rep\nAm J Case Rep\namjcaserep\nThe American Journal of Case Reports\n1941-5923 International Scientific Literature, Inc. \n\n33203827\n10.12659/AJCR.927832\n927832\nArticles\nCombined Liver and Kidney Transplant in Acute Intermittent Porphyria: A Case Report\nde Sousa Arantes Ferreira Gustavo ABCDEF1 de Oliveira Livia Claudio ABE2 de Sousa Ulisses Luiz Roberto AE3 Watanabe Andre Luis Conde AD1 Medeiros Isabela Novais D3 Cardoso Helen Souto Siqueira CD3 Alves Inara Creão da Costa CD3 de Almeida Tiago Martins BC3 de Lima Laura Viana ABF4 Fontoura Renata Pereira BC4 Silva Eduardo Resende Sousa e CDF4 de Araújo Pollyana Lopes CDF4 \n1 Department of Liver Transplantation, Institute of Cardiology of the Federal District (ICDF), Brasília, Brazil\n\n2 Department of Nephrology, University Hospital of Brasília (HUB), Brasília, Brazil\n\n3 Department of Kidney Transplantation, Institute of Cardiology of the Federal District (ICDF), Brasília, Brazil\n\n4 School of Medicine, Catholic University of Brasília, Brasília, Brazil\nCorresponding Author: Gustavo de Sousa Arantes Ferreira, e-mail: gustferr@ufmg.brAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\n\n2020 \n18 11 2020 \n21 e927832-1 e927832-5\n04 8 2020 17 9 2020 05 10 2020 © Am J Case Rep, 20202020This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Male, 19-year-old\n\nFinal Diagnosis: Acute intermittent porphyria\n\nSymptoms: Abdominal pain • dark color urine • weakness\n\nMedication: —\n\nClinical Procedure: Kidney transplantation • liver transplantation\n\nSpecialty: Gastroenterology and Hepatology • Hematology • Nephrology • Surgery • Transplantology\n\nObjective:\nRare disease\n\nBackground:\nAcute intermittent porphyria is an inherited disease caused by a defect in heme biosynthesis, with accumulation of neurotoxic metabolites leading to acute neurovisceral symptoms. Some patients develop long-term neurological and renal damage after the acute episodes, many of them requiring hemodialysis. Since heme production in the human body occurs predominantly in the bone marrow and liver, liver transplantation has been shown to significantly reduce the production of neurotoxic metabolites, effectively controlling the disease. Patients with severe acute intermittent porphyria who have chronic kidney failure may benefit from combined kidney and liver transplant. Only 2 uses of this approach have been previously reported in the literature.\n\nCase Report:\nWe report here the case of a 19-year-old male patient who received a combined liver and kidney transplant for the treatment of acute intermittent porphyria. He presented the first symptoms of the disease 4 years before the procedure, with abdominal pain and significant neurological impairment, with weakness requiring prolonged mechanical ventilation. He also had chronic kidney failure secondary to the porphyria. A combined liver and kidney transplant was performed, with no intraoperative complications. The explanted liver showed light siderosis, as well as portal and perisinusoidal fibrosis at microscopy. At 3.5 years of follow-up, he remains clinically well, with normal hepatic and renal function, had had no further acute porphyria episodes, and shows progressive neurological recovery.\n\nConclusions:\nThis case demonstrates that combined liver and kidney transplant can be a curative treatment for patients with severe acute intermittent porphyria associated with end-stage renal failure. The patient shows satisfactory long-term function of both grafts, with no clinical or biochemical signs of porphyria recurrence.\n\nMeSH Keywords:\nHematologic DiseasesKidney TransplantationLiver TransplantationPorphyria, Acute IntermittentPorphyriasRenal Insufficiency\n==== Body\nBackground\nAcute intermittent porphyria (AIP) is an inherited disease caused by a defect in heme biosynthesis, leading to acute neurovisceral symptoms. Heme is an iron-based molecule that functions as an essential cofactor for a number of proteins in the human body, such as hemoglobin, myoglobin, and cytochromes P-450. Heme is synthetized in many different tissues, but most of the production occurs in the bone marrow and the liver [1]. AIP is one of the 4 acute hepatic porphyrias, a group of diseases that comprises: 5-aminolevulinic acid dehydratase deficiency porphyria, AIP, hereditary coproporphyria, and variegate porphyria [1]. AIP is both the most severe and the most common of them, with an estimated prevalence of 5 in 1600 people for the mutation, of which only 2% will develop symptoms during their lifetime, reflecting a key role of environmental factors and, possibly, genetic modifiers [1,2].\n\nA genetic mutation in the hydroxymethylbilane synthesis gene causes a partial deficiency in activity of the porphobilinogen deaminase enzyme, leading to the accumulation of the neurotoxic upstream metabolites aminolevulinic acid (ALA) and porphobilinogen [2–4].\n\nSymptomatic disease is more common in females, and usually manifests between 15 and 50 years of age. Acute episodes are characterized by diffuse abdominal pain, usually of a colicky nature, associated with constipation, nausea, vomiting, and weakness [1,2]. Other common symptoms are hypertension, tachycardia, and dark-colored urine. Freshly voided urine in patients with AIP appears unremarkable, as ALA and porphobilinogen are colorless. However, if exposed to light, it will slowly assume a dark color, as the oxidation of porphobilinogen in urine leads to the formation of a dark brown pigment [1,2,4]. Neurological symptoms consist mostly of proximal weakness and hyperesthesia, but seizures, bulbar paralysis, dysphagia, and dysarthria may also occur. Neuropsychiatric manifestations are attributed to the structural similarities between ALA and gamma-aminobutyric acid, a major neurotransmitter, and also to a direct toxic effect of ALA [1,2]. AIP can be diagnosed by the measurement of urinary ALA and porphobilinogen, which remain elevated for several days after an acute attack [1]. Common triggers for acute porphyria attacks include infections, prolonged fasting, progesterone, alcohol intake, physical or emotional distress, and certain drugs (e.g., sulfonamides, benzodiazepines, and valproate) [1,2].\n\nThe initial treatment of acute AIP episodes includes carbohydrate administration (usually intravenous 10% dextrose), analgesics, and intravenous hematin infusion. Heme infusion works by a negative feedback mechanism, reducing the activity of the defective enzymes in the heme synthesis process and thereby decreasing the production of toxic metabolites [2]. Patients with frequent symptoms may receive weekly prophylactic hematin infusions.\n\nRenal pathology in AIP is caused mainly by ALA, which is particularly nephrotoxic, causing oxidative damage to the mitochondrial membrane of convoluted proximal tubule cells and leading to chronic tubule-interstitial nephropathy and focal cortical atrophy [4–6]. Hypertension during the acute episodes can also contribute to kidney damage. Arteriolopathy can also play a role, as both ALA and porphobilinogen are apoptosis inducers and show in vitro vascular toxicity [7,8]. Some patients progress to chronic kidney failure after having acute porphyria attacks [4–8]. There are reports that hemodialysis can worsen neuropathy symptoms in these patients, as ALA and porphobilinogen levels can increase after dialysis [9,10]. Kidney transplant has been successfully used to treat patients with chronic renal failure secondary to AIP [11–13]. While there is some concern in the choice of immunosuppressive drugs in patients with AIP after the kidney transplant, the use of calcineurin inhibitors, such as cyclosporine and tacrolimus, is generally considered to be safe [11].\n\nStudies show a marked increase in the risk of hepatocellular carcinoma in patients with AIP, particularly after 50 years of age [4,14,15]. It is possible that heme deficiency and the increase in ALA levels lead to the production of reactive oxygen species in the liver, creating a carcinogenic microenvironment [14].\n\nSince the liver is one of the major sites of heme production in the human body, liver transplantation leads to a significant reduction in the synthesis of toxic metabolites in patients with AIP, neutralizing the risk of acute porphyria attacks [16]. Patients with severe, intractable, and disabling attacks that are refractory to hematin infusion can therefore be considered for orthotopic liver transplantation, which has been shown to be a curative procedure in AIP [1,2,17].\n\nTwo cases of combined liver and kidney transplant in patients with AIP were reported in Sweden. Both patients had chronic kidney failure secondary to AIP, and showed excellent recovery after the transplant [9].\n\nCase Report\nA male patient had acute episodes of diffuse abdominal pain, associated with nausea and vomiting, lasting from 12 h to 2 days, occurring approximately every 3–6 months, and improving after medication with intravenous analgesics. The symptoms started when he was 15 years old. The patient had no significant comorbidities. His past medical history was uneventful, with no past surgeries or hospital admissions. He had no family history of kidney or liver disease. He presented several times to the emergency room of a hospital in his home city in the northeastern region of Brazil, where he was discharged every time after his symptoms improved with intravenous medication. Initial laboratory and radiologic exams were normal, and he received no definite diagnosis for the cause his symptoms. Two years after the onset of the symptoms, he had a new episode of fever, odynophagia, abdominal pain, and dark-colored urine. He had laboratorial markers of acute kidney failure and was admitted to the hospital. He was transferred to a tertiary hospital in a different part of the country, and hemodialysis was initiated due to progressive worsening of his renal function. The patient had not used any potentially nephrotoxic medication, such as nonsteroidal anti-inflammatory drugs, in the 6 months prior to this episode. Screening for possible causes of kidney injury included testing for rheumatoid factor, antinuclear antibodies, complement components (C3 and C4), thyroid stimulating hormone, anti-cyclic citrullinated peptide, anti-cardiolipins, lupus anticoagulant, anti-neutrophil cytoplasmic antibody, and anti-Ro and anti-La antibodies, all of which yielded unremarkable results.\n\nAfter being prescribed diazepam to reduce anxiety during dialysis, he developed peripheral muscle weakness, with progressive deterioration leading to involvement of the respiratory muscles. Endotracheal intubation and mechanical ventilation were necessary due to respiratory failure. Due to prolonged endotracheal intubation, a gastrostomy and a tracheostomy were performed. Acute intermittent porphyria was suspected, and a urine sample was positive for porphobilinogen and showed elevated levels of ALA, with 6.7 mg per gram of creatinine (the maximum reference level is 4.5 mg/g creatinine). After the suspension of all drugs that could possibly act as a trigger for AIP attacks (metoclopramide, benzodiazepines, and phenytoin), the patient showed slow improvement of his weakness, with successful weaning from mechanical ventilation, and a return to oral feeding and ambulation. He remained hospitalized for 183 days, with 110 days of those being in the intensive care unit. He showed no improvement of his renal function, however, and hemodialysis on alternate days in an outpatient clinic was necessary. A second urinary exam for ALA and porphobilinogen was performed, with results similar to the first one. Genetic testing of the patient and his immediate family revealed an IVS9–1G >A intronic mutation in the PBGD gene in the patient and his father, who was asymptomatic. This mutation has a significant association with AIP.\n\nHe consulted in a liver and kidney transplant unit 1 year after hospital discharge, with persistent weakness and chronic kidney failure. While he had no further episodes of abdominal pain or infection during this 1-year period, there were no signs of kidney function recovery, with persistently elevated urea and creatinine levels and minimal diuresis. The first symptoms of AIP had started 3 years before his referral, and he was receiving hemodialysis for 18 months.\n\nAt examination, the patient showed proximal and distal weakness in all 4 limbs, was unable to write or perform other tasks requiring fine motor skills, and had a characteristic myopathic gait and moderate dysarthria, causing a reduction in speech intelligibility. He had no increase in aminotransferases or any clinical or laboratorial signs of hepatic dysfunction, and a model for end-stage liver disease (MELD) score of 21, largely due to his elevated creatinine (5.1 mg/dl). An ultrasound of the liver with Doppler evaluation of the hepatic and iliac vessels was obtained, with normal results.\n\nAfter being on the waitlist for 6 months, at age 19 he received a combined liver and kidney transplant from a cadaveric donor. The donor was a 13-year-old male who suffered brain death due to hypoxic injury secondary to an asthma attack. An orthotopic liver transplant was performed, with simultaneous portal and hepatic artery reperfusion of the graft, and a total ischemia time of 313 min. A kidney transplant was performed immediately afterwards, with a cold ischemia time of 478 min. There were no intraoperative complications, and the patient received no blood product transfusion. He received induction immunosuppressive therapy with 3 mg/kg of thymoglobulin, administered on the 2 first post-operative days (POD). On the first POD he also started using 100 mg of methylprednisolone, with gradual tapering of the dose, 8 mg of tacrolimus, 1440 mg of mycophenolate mofetil, and prophylactic subcutaneous heparin. He received 4 sessions of hemodialysis, from the first to the fifth POD, after which he demonstrated a progressive increase in diuresis and a decrease in creatinine and urea levels. He was discharged from the hospital in the ninth POD, using prophylactic acetylsalicylic acid.\n\nNineteen days after the procedure, a new urinary sample was obtained and tested for porphobilinogen, which was negative, and ALA levels, which had decreased to 0.8 mg/g creatinine. Microscopy of the explanted liver showed light siderosis, as well as portal and perisinusoidal fibrosis. At 1 and 5 months after the transplant, he had 2 episodes of cytomegalovirus reactivation detected by antigenemia and treated with ganciclovir and reduction of the immunosuppressive regimen. He currently attends a rehabilitation program and showed significant improvement of his muscular weakness, being able to write, walk normally, and speak with greater intelligibility. At 42 months after the procedure, he remains with adequate function of both liver and kidney grafts, has had no episodes of rejection or further acute AIP attacks, and receives a triple immunosuppressive drug regimen consisting of tacrolimus, everolimus, and prednisone.\n\nDiscussion\nDiagnosis of AIP can be challenging, with patients often suffering multiple acute episodes before adequate treatment is initiated. Clinical treatment consists in the avoidance of common triggers for porphyria attacks, and in the infusion of intravenous hematin. Hematin treatment can be costly, and phlebitis of peripheral vessels or the requirement for a central venous catheter causes a negative long-term impact in the quality of life of these patients. Approximately 5–10% of patients show no adequate response to hematin therapy, and disease progression in those cases may lead to significant neurological and renal damage [17]. Liver transplantation is a curative treatment for AIP, restoring normal excretion of ALA and porphobilinogen, preventing acute porphyria attacks, and preventing the development of further disabilities, and should be considered in those patients who do not respond or adapt adequately to hematin treatment [17–20].\n\nMore than a dozen liver transplants for patients with severe AIP have been reported, with clinical and biochemical remission in all cases and normalization of ALA and porphobilinogen levels within 72 h [16,18]. Survival is similar to that of liver transplantation performed for other indications [16,19,20]. Some studies report an increase in the occurrence of hepatic artery thrombosis in patients who received liver transplantation for the treatment of AIP [19]. This may be related to the administration of hematin before the procedure, since hematin can cause platelet aggregation after its infusion [4]. The use of anticoagulation or antiplatelet therapy is generally recommended after liver transplantation for AIP [18,21]. The explanted livers are usually unremarkable, except for moderate siderosis and steatosis, but detailed studies have described the presence of nodular regenerative hyperplasia and focal incomplete septal cirrhosis in some cases, suggesting that even patients with no clinical or laboratory markers of liver disease may have a greater amount of liver damage than previously imagined [22].\n\nIn patients with chronic kidney failure secondary to AIP, kidney transplantation offers a cure for the renal dysfunction, but has no impact on the natural history of AIP. The patients remain at risk for new porphyria attacks, with possible worsening of neurological symptoms and deterioration of graft function.\n\nCombined liver and kidney transplant is a particularly beneficial treatment option in these patients, as it not only restores kidney function, but also protects the patient from new acute episodes of AIP. In the 2 cases previously reported in the literature, 2 female patients (a 55-year-old and a 24-year-old) had complete remission of AIP symptoms and adequate liver and kidney graft function in a follow-up period of 16 months [9].\n\nSince normalization of ALA and porphobilinogen levels occurs shortly after the patient receives the liver transplant, we saw no need for withholding the use of drugs that commonly act as triggers for AIP attacks, such as sulfamethoxazole or corticosteroids, in the post-operative management of this patient.\n\nTo reduce the risk of hepatic artery thrombosis that has been described in other reports of liver transplant in AIP, we did not administer intravenous hematin immediately before the procedure. We also administered heparin prophylaxis during in-patient care, substituted by acetylsalicylic acid at the time of hospital discharge. Despite having normal laboratory markers of liver function before the transplant, the liver explanted from our patient showed portal and perisinusoidal fibrosis, which raises concern for the potential use of organs obtained from AIP patients in sequential domino liver transplants. In the present case, we have observed the potential for long-term recovery of neurological symptoms such as weakness and dysarthria after the transplant.\n\nConclusions\nCombined liver and kidney transplant is a safe and effective treatment for patients with chronic kidney failure secondary to AIP. It should be considered as an alternative when there is no satisfactory response to first-line treatments such as hematin therapy. It can prevent further episodes of porphyria attacks, restore kidney function, and allow progressive recovery from previous neurological damage.\n\nConflicts of interest\n\nNone.\n==== Refs\nReferences:\n1. Wang B Rudnick S Cengia B Bonkovsky HL Acute hepatic porphyrias: Review and recent progress Hepatol Commun 2019 3 2 193 207 30766957 \n2. Spiritos Z Salvador S Mosquera D Wilder J Acute intermittent porphyria: Current perspectives and case presentation therapeutics and clinical risk management 2019 15 1443 51 31908464 \n3. Dhital R Basnet S Poudel DR Bhusal KR Acute intermittent porphyria: A test of clinical acumen J Community Hosp Intern Med Perspect 2017 7 2 100 2 28638573 \n4. Bissell DM Anderson KE Bonkovsky HL Porphyria N Engl J Med 2017 377 9 862 73 28854095 \n5. El-Haggan W Lobbedez T Ryckelynck JP Ligny BH Sirolimus tolerability in a kidney transplant recipient with acute intermittent porphyria Nephrol Dial Transplant 2002 17 1147 12032218 \n6. Marsden JT Chowdhury P Wang J Acute intermittent porphyria and chronic renal failure Clin Nephrol 2008 69 5 339 46 18538096 \n7. Andersson C Wikberg A Stegmayr B Lithner F Renal symptomatology in patients with acute intermittent porphyria. A population-based study J Intern Med 2000 248 319 25 11086643 \n8. Pallet N Mami I Schmitt C High prevalence of and potential mechanisms for chronic kidney disease in patients with acute intermittent porphyria Kidney Int 2015 88 386 95 25830761 \n9. Wahlin S Harper P Sard E Combined liver and kidney transplantation in acute intermittent porphyria Transpl Int 2010 23 e18 21 20028496 \n10. Unzu C Sampedro A Sardh E Renal failure affects the enzymatic activities of the three first steps in hepatic heme biosynthesis in the acute intermittent porphyria mouse PLos One 2012 7 3 e32978 22412963 \n11. Warholm C Wilczek H Renal transplantation in a case of acute intermittent porphyria J Clin Pharmacol 2003 43 1158 60 14517198 \n12. Alfano G Ventura P Fontana F Rhodococcus equi pneumonia in kidney transplant recipient affected by acute intermittent porphyria: A case report Transplant Proc 2019 51 1 229 34 30661897 \n13. Warholm C Wilczek H Renal transplantation in a case of acute intermittent porphyria J Clin Pharmacol 2003 43 10 1158 60 14517198 \n14. Sardh E Wahlin S Bjornstedt M Harper P Andersson DEH High risk of primary liver cancer in a cohort of 179 patients with Acute Hepatic Porphyria J Inherit Metab Dis 2013 36 1063 71 23344888 \n15. Andant C Puy H Bogard C Hepatocellular carcinoma in patients with acute hepatic porphyria: frequency of occurrence and related factors J Hepatol 2000 32 933 39 10898313 \n16. Singal AK Parker C Bowden C Liver transplantation in the management of porphyria Hepatology 2014 60 3 1082 90 24700519 \n17. Soonawalla ZF Orug T Badminton MN Liver transplantation as a cure for acute intermittent porphyria Lancet 2004 363 705 6 15001330 \n18. Malinzak EB Kudsen NW Udani AD Perioperative challenges in liver transplantation for a patient with acute intermittent porphyria J Cardiothorac Vasc Anesth 2017 32 6 2716 20 29306617 \n19. Downman JK Gunson BK Mirza DF Liver transplantation for acute intermittent porphyria is complicated by a high rate of hepatic artery thrombosis Liver Transplantation 2012 18 195 200 21618697 \n20. Seth AK Badminton MN Mirza D Liver transplantation for porphyria: Who, when, and how? Liver Transpl 2007 13 1219 27 17763398 \n21. Kappus MR Summers BB Byrns JS Liver transplantation for the management of acute intermittent porphyria: A case report Journal of Hepatology and Gastrointestinal Disorders 2017 3 1 1000141 \n22. Yasuda M Erwin AL Liu LU Liver transplantation for acute intermittent porphyria: Biochemical and pathologic studies of the explanted liver Mol Med 2015 21 487 95 26062020\n\n",
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"mesh_terms": "D000328:Adult; D006801:Humans; D016030:Kidney Transplantation; D016031:Liver Transplantation; D008297:Male; D009364:Neoplasm Recurrence, Local; D017118:Porphyria, Acute Intermittent; D055815:Young Adult",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "28638573;29306617;30661897;22412963;24700519;25830761;21618697;18538096;12032218;17763398;15001330;11086643;20028496;30766957;28854095;10898313;14517198;26062020;31908464;23344888",
"title": "Combined Liver and Kidney Transplant in Acute Intermittent Porphyria: A Case Report.",
"title_normalized": "combined liver and kidney transplant in acute intermittent porphyria a case report"
} | [
{
"companynumb": "BR-NUVO PHARMACEUTICALS INC-2107242",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
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"activesubstance": {
"activesubstancename": "PHENYTOIN"
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{
"abstract": "BACKGROUND\nAripiprazole is a third generation antipsychotic approved by the US Food and Drug Administration (FDA) for the treatment of schizophrenia. Aripiprazole is available as oral and long-acting injectable (LAI) depot formulations, with a unique mechanism of action comprising partial D2 and serotonin 5-HT1A agonism and antagonism at serotonin 5-HT2A receptors.\nWe review short-and-long-term clinical trials, meta-analyses of clinical trials and product information pertaining to the safety and efficacy of aripiprazole in adults with schizophrenia. Formulations of aripiprazole reviewed include oral aripiprazole, Aripiprazole monohydrate LAI (Abilify Maintena©) and Aripiprazole lauroxil LAI (Aristada©). Clinical studies and product information were collected from PubMed, Psychinfo, Embase, and other web sources.\nAripiprazole is a generally well-tolerated third-generation antipsychotic with low rates of motor side effects and metabolic adverse effects that occur commonly with several alternative antipsychotics. Akathisia and tremor appear to occur at higher rates with aripiprazole compared to placebo but are still generally uncommon with incidences of 10-11% or less. Uniquely, aripiprazole treatment is associated with reduced serum prolactin levels and QTc interval. A variety of LAI options with dosing intervals as infrequent as every 8 weeks provide a compelling reason to select aripiprazole in patients with limited oral treatment adherence.",
"affiliations": "Department of Psychiatry and Human Behavior, UC Irvine Medical Center , Orange, CA, USA.;Department of Psychiatry and Human Behavior, UC Irvine Medical Center , Orange, CA, USA.",
"authors": "Preda|Adrian|A|https://orcid.org/0000-0003-3373-2438;Shapiro|Bryan B|BB|",
"chemical_list": "D014150:Antipsychotic Agents; D003692:Delayed-Action Preparations; D000068180:Aripiprazole; D011388:Prolactin",
"country": "England",
"delete": false,
"doi": "10.1080/14740338.2020.1832990",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1474-0338",
"issue": "19(12)",
"journal": "Expert opinion on drug safety",
"keywords": "Antipsychotic; adverse event; aripiprazole; neuroleptic; safety; tolerability",
"medline_ta": "Expert Opin Drug Saf",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D000068180:Aripiprazole; D003692:Delayed-Action Preparations; D004334:Drug Administration Schedule; D006801:Humans; D055118:Medication Adherence; D011388:Prolactin; D012559:Schizophrenia",
"nlm_unique_id": "101163027",
"other_id": null,
"pages": "1529-1538",
"pmc": null,
"pmid": "33064050",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "A safety evaluation of aripiprazole in the treatment of schizophrenia.",
"title_normalized": "a safety evaluation of aripiprazole in the treatment of schizophrenia"
} | [
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"companynumb": "US-OTSUKA-2020_026401",
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"occurcountry": "US",
"patient": {
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
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"drugadditional": "3",
... |
{
"abstract": "Data regarding ceftaroline use for meticillin-resistant Staphylococcus aureus bacteraemia (MRSAB) are lacking. Here we review the outcomes of 31 patients with MRSAB treated with ceftaroline, including 9 patients with endocarditis. Clinical success was observed in 23 patients (74.2%). Adverse events associated with prolonged therapy were rare and included eosinophilic pneumonia, rash and diarrhoea. We conclude that ceftaroline can be used for MRSAB.",
"affiliations": "Wright State University Boonshoft School of Medicine, Miami Valley Hospital, 128 East Apple Street, Weber CHE 2nd Floor, Dayton, OH 45409, USA. Electronic address: haralampie1909@gmail.com.",
"authors": "Polenakovik|Hari M|HM|;Pleiman|Craig M|CM|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002511:Cephalosporins; C490727:T 91825",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0924-8579",
"issue": "42(5)",
"journal": "International journal of antimicrobial agents",
"keywords": "Bacteraemia; Ceftaroline; Endocarditis; MRSA; Meticillin-resistant Staphylococcus aureus",
"medline_ta": "Int J Antimicrob Agents",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D016470:Bacteremia; D002511:Cephalosporins; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus; D008875:Middle Aged; D013203:Staphylococcal Infections; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9111860",
"other_id": null,
"pages": "450-5",
"pmc": null,
"pmid": "23993067",
"pubdate": "2013-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Ceftaroline for meticillin-resistant Staphylococcus aureus bacteraemia: case series and review of the literature.",
"title_normalized": "ceftaroline for meticillin resistant staphylococcus aureus bacteraemia case series and review of the literature"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2017SP003872",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
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{
"abstract": "Myasthenia gravis (MG), a neuromuscular junction autoimmune disease, sometimes complicates second malignancies; however, T-cell lymphoproliferative disorders have rarely been reported. A 55-year-old man, who received oral tacrolimus and prednisolone for MG for 16 years after thymectomy, presented with left abdominal pain, lymphadenopathy, and splenomegaly. A lymph node biopsy revealed peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS). This is the first report of oral tacrolimus leading to a T-cell lymphoproliferative disorder in patient without a history of transplantation. Physicians should be aware of the possibility of rare T-cell lymphoproliferative disorders, such as PTCL-NOS, occurring as complications in MG patients on immunosuppressive regimens after thymectomy.",
"affiliations": "Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Japan.;Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Japan.;Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Japan.;Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Japan.;Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Japan.;Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Japan.;Department of Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Japan.;Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Japan.;Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Japan.;Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Japan.",
"authors": "Ohara|Masahiro|M|;Ozaki|Kokoro|K|;Ohkubo|Takuya|T|;Yamada|Akane|A|;Numasawa|Yoshiyuki|Y|;Tanaka|Keisuke|K|;Tomii|Shohei|S|;Ishibashi|Satoru|S|;Sanjo|Nobuo|N|;Yokota|Takanori|T|",
"chemical_list": "D007166:Immunosuppressive Agents; D016559:Tacrolimus",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.9167-17",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2926964410.2169/internalmedicine.9167-17Case ReportMyasthenia Gravis Complicated with Peripheral T-cell Lymphoma, Not Otherwise Specified (PTCL-NOS), Following Thymectomy and Longstanding Tacrolimus Therapy Ohara Masahiro 1Ozaki Kokoro 1Ohkubo Takuya 1Yamada Akane 1Numasawa Yoshiyuki 1Tanaka Keisuke 2Tomii Shohei 3Ishibashi Satoru 1Sanjo Nobuo 1Yokota Takanori 1\n1 Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Japan\n2 Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Japan\n3 Department of Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, JapanCorrespondence to Dr. Kokoro Ozaki, k-oznuro@tmd.ac.jp\n\n21 12 2017 15 2 2018 57 4 601 604 15 3 2017 22 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/).Myasthenia gravis (MG), a neuromuscular junction autoimmune disease, sometimes complicates second malignancies; however, T-cell lymphoproliferative disorders have rarely been reported. A 55-year-old man, who received oral tacrolimus and prednisolone for MG for 16 years after thymectomy, presented with left abdominal pain, lymphadenopathy, and splenomegaly. A lymph node biopsy revealed peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS). This is the first report of oral tacrolimus leading to a T-cell lymphoproliferative disorder in patient without a history of transplantation. Physicians should be aware of the possibility of rare T-cell lymphoproliferative disorders, such as PTCL-NOS, occurring as complications in MG patients on immunosuppressive regimens after thymectomy. \n\nmyasthenia gravislymphomaPTCL-NOStacrolimusthymectomy\n==== Body\nIntroduction\nMyasthenia gravis (MG) is an autoimmune disease that disrupts the function of the neuromuscular junction through autoantibodies against the acetylcholine receptor (AChR) or muscle-specific tyrosine kinase (MuSK) (1). Peripheral T-cell lymphomas (PTCLs) represent 10-15% of non-Hodgkin lymphomas, and are classified into 23 different entities, encompassing various heterogeneous diseases (2). Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is the second most prevalent variant of PTCL; the coexistence of MG with T-cell non-Hodgkin lymphoma is very rare and only a few case reports have been reported. Among the cases complicated with a thymoma, most suffered from T-lymphoblastic leukemia/lymphoma (3). We herein report the case of a patient undergoing long-term treatment with a calcineurin inhibitor for MG who developed PTCL-NOS 16 years after thymectomy. We discuss the causal relationship among MG, oral tacrolimus (TAC) and PTCL-NOS in the current case, with reference to previous cases.\n\nCase Report\nA 55-year-old man was hospitalized for left abdominal pain. The patient had previously been diagnosed with MG (MGFA classIIa) and had undergone thymectomy at 39 years of age. The thymus was pathologically normal. He had since been treated with oral TAC and prednisolone (PSL) for 16 years. On admission, a physical examination revealed tenderness in the left upper abdomen, a palpable spleen and bilateral lymphadenopathy in the neck, left submandibular region, and right groin that were associated with spiking fever and night sweats. A neurological examination revealed bilateral ptosis and diplopia. Laboratory tests revealed the following: a normal white blood cell count (5,400 /μL; reference range, 3,600-9,300 /μL); a decreased platelet count (9.3×104/μL; reference range, 12-41×104/μL), elevated lactate dehydrogenase (432 U/L; reference range, 109-210 U/L), anti-AChR antibody positivity (0.6 nmol/L; reference range, ＜0.2 nmol/L); an extremely elevated serum soluble interleukin 2 receptor level (16,600 U/mL; reference range, ＜145 U/mL). Systemic computed tomography (CT) revealed right inguinal lymphadenopathy and low-density areas in the enlarged spleen. Because these findings suggested malignant lymphoma, a right inguinal lymph node biopsy was conducted; the diffuse proliferation of atypical small- or medium-sized lymphoid cells was observed, and immunostaining revealed that the proliferating cells expressed CD3, CD5, CD4＜8, with the diminished expression of CD7. The proliferating cells did not express CD20/CD79a (Figure). A clinical staging examination of the bone marrow showed hypercellular marrow with infiltrating lymphoma cells that were positive for CD3. Flow cytometry of the marrow aspirate demonstrated an abnormal T-cell population that expressed CD2, CD3, CD4, CD5, CD7, and CD8. Myeloid and B-cell markers, as well as CD1a, CD16, CD25, CD56, and TdT, were absent. Although the differential diagnosis of CD4-positive/CD8-positive T-cell lymphoma includes T-lymphoblastic leukemia/lymphoma, T-cell prolymphocytic leukemia, and PTCL-NOS, the overall morphologic, immunophenotypic, and cytogenetic findings were most consistent with PTCL-NOS. Epstein-Barr virus (EBV) was not identified in the tumor cells by EBV-encoded RNA in situ hybridization. The patient's serum was negative for human T-cell leukemia virus types 1 and 2. We discontinued TAC to allow the recovery of the antitumor immune responses and started combined chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP therapy), which elicited a partial response.\n\nFigure. The histological findings of an inguinal lymph node biopsy specimen. Diffuse proliferation of atypical small- or medium-sized lymphoid cells were shown on Hematoxylin-Eosin staining sections (A; original magnification, 200 ×). These cells were positive for CD3 (B; 200 ×), but the expression of CD7 was diminished (C; 200 ×).\n\nDiscussion\nWe treated a patient with MG who developed PTCL-NOS after thymectomy and subsequent long-term oral immunosuppressive treatment. There are very few previous reports of MG complicating T-cell lymphoma; this is the second report of MG with PTCL-NOS. Although Cory et al. reported a case of concurrent MG, thymoma, and PTCL-NOS (3), this report presents the first case of PTCL-NOS occurring after long-term immunosuppressive treatment for non-thymomatous MG after thymectomy. There could be several explanations for the pathogenic etiology and mechanisms of PTCL-NOS in our case.\n\nFirst, one plausible explanation is that longstanding immunosuppressive treatment for 16 years may have weakened the antitumor immune responses, resulting in the occurrence of PTCL-NOS. TAC binds to the FK-binding protein (FKBP) in helper T cells (4); this complex acts on intracellular phosphatase calcineurin, and subsequently inhibits the activation of nuclear factor of activated T cells (NFAT), resulting in the suppression of cytokine production (e.g., TL-2, IL-5, and IL-6) and immune reactions (4). Immunological responses, especially the activity of natural killer cells and cytotoxic T-cells, against cancerous tumor cells are weakened by the suppression of cytokine production, sometimes resulting in the development of malignancy (4). Thus, it is proposed that oral TAC may cause malignant lymphomas in post-transplantation patients (5-8). The association between oral TAC and malignant lymphomas without a history of transplantation has only been reported in 3 cases; however, it is possible that oral TAC generally leads to the development of lymphoproliferative disorders (Table 1) (9-11). These cases all involved B-cell lymphomas. The present study is the first report describing the development of PTCL-NOS in an MG patient on longstanding oral TAC treatment. Cyclosporine, another calcineurin inhibitor, is also known to cause B-cell lymphomas, but very rarely T-cell lymphomas (16,17). There is only one case in which primary cutaneous CD30+ large T-cell lymphoma was reported to have developed after cyclosporine treatment for psoriasis (Table 1) (12). In addition, it was reported that the experimental use of oral pimecrolimus, a calcineurin inhibitor, increased the incidence of pleomorphic or malignant lymphomas in CD-1 mice (18,19). Thus, it is likely that longstanding immunosuppression by TAC induced PTCL-NOS in this case.\n\nTable 1. Case Reports of Lymphoproliferative Disorders after Oral Calcineurin Inhibitors Use without History of Transplantation.\n\nReferences\tAge/Sex\tType of lymphoproliferative disorders\tType of calcineurin inhibitors\tOral calcineurin inhibitors dose/Administration period\tPrimary disease\tEBV infection\t\n12\t61/F\tLTCL\tCsA\t3 mg/kg/day, 8 years\tPsoriasis\tN.A.\t\n13\t67/M\tBL\tCsA\t5 mg/kg/day, 8 months\tPsoriasis\tN.A.\t\n14\t58/M\tBL\tCsA\t2.5-5 mg/kg/day, 4 years\tRA\tpositive\t\n15\t37/M\tCD30+large cell lymphoma\tCsA\t2.5-4 mg/kg/day, 1 year\tAD\tN.A.\t\n16\t70/M\tNHL\tCsA\t3.3 mg/kg/day, 21 months\tRefractory anemia\tnegative\t\n17\t33/M\tNHL\tCsA\t200 mg/day, 4 years\tUC\tN.A.\t\n9\t69/F\tDLBCL\tTAC\t3 mg/day, 14 months\tSS/MCTD\tnegative\t\n10\t74/F\tBL\tTAC\tN.A., 32 months\tRA\tN.A.\t\n11\t73/M\tLPL\tTAC\tN.A., 10 months\tMG\tN.A.\t\nThe present case\t55/M\tPTCL-NOS\tTAC\t3 mg/day, 16 years\tMG\tnegative\t\nM: male, F: female, SS: Sjögren’s syndrome, MCTD: mixed connective tissue disease, RA: rheumatoid arthritis, MG: myasthenia gravis, AD: atopic dermatitis, UC: ulcerative colitis, N.A.: not available, TAC: tacrolimus, CsA: cyclosporine, DLBCL: diffuse large B-cell lymphoma, BL: Burkitt lymphoma, LPL: lymphoplasmacytic lymphoma, LTCL: large T-cell lymphoma, NHL: non-Hodgkin’s lymphoma, PTCL-NOS: peripheral T-cell lymphoma: not otherwise specified\n\nMoreover, the sustained stimulation of lymphocytes by autoantigens may drive cellular proliferation and result in the development of malignant lymphoma. Some autoimmune diseases are known to lead to malignancies long after their diagnosis, and chronic autoimmune diseases such as rheumatoid arthritis, Sjögren's syndrome, and systemic lupus erythematosus increase the risk of developing malignant disease, especially malignant lymphoma (20). In these diseases, it is proposed that mechanisms underlying sustained autoantigen stimulation drive lymphocytic proliferation (21,22). Colon cancer, breast cancer, and malignant lymphoma are extrathymic malignancies that are frequently reported in MG (23); there have been only 6 reports on complications of T-cell lymphoproliferative disorders in the literature (Table 2) (3,24-28). In 3 of these cases, chemotherapy for T-cell lymphoblastic lymphoma (T-LBL) was also effective against MG; in 2 of them, the complete remission of MG and T-LBL was achieved (24-26). In these cases, MG may have presented as one of the paraneoplastic neurological syndromes induced by lymphoma. In contrast, in our case a paraneoplastic etiology is unlikely because MG was diagnosed as long as 16 years before PTCL-NOS. Interestingly, however, there is an argument that MG may be protective against second cancers. Owe et al. observed that patients with MG showed a lower incidence of cancer in comparison to the normal population (29). Thus, it is controversial whether MG causes second malignancies, particularly lymphoid malignancy. Large and controlled studies should be performed to assess whether longstanding MG predisposes patients to lymphoid malignancies.\n\nTable 2. Case Reports of MG with T-cell Lymphoproliferative Disorders.\n\nReferences\tAge/Sex\tLymphoma/ Leukemia type\tWhen T-cell lymphoproliferative disorders diagnosed\tTreatment of T-cell lymphoproliferative disorders/ Response of MG to the treatment\t\n24\t51/F\tT-LBL\t1 year after MG diagnosis\tCT/ Complete remission of lymphoma and MG for 1 year\t\n25\t51/F\tT-LBL\t2-3 months after MG diagnosis\tCT/ Complete remission of lymphoma and MG for 2 years\t\n26\t38/M\tT-LBL\t1 year after MG diagnosis\tCT/ Remission of lymphoma and MG initially, but relapse of MG and lymphoma 5 and 6 years after initial diagnosis\t\n27\t26/M\tT-LBL\ta few months before MG diagnosis\tCT/ Death due to progressive lymphoma\t\n28\t43/M\tT-cell lymphoblastic leukemia\t6 years after MG diagnosis\tCT/ Death due to progressive lymphoma\t\n3\t59/F\tPTCL-NOS\tSimultaneous\tCT/ Death due to infection during CT\t\nThe present case\t55/M\tPTCL-NOS\t16 years after MG diagnosis\tCT/ Partially remission of lymphoma, but no improvement of MG symptoms\t\nM: male, F: female, T-LBL: T-cell lymphoblastic lymphoma, PTCL-NOS: Peripheral T-cell lymphoma: not other specified, MG: myasthenia gravis, CT: chemotherapy\n\nThe present case suggests that it is possible that longstanding oral TAC treatment and sustained autoantigen stimulation drove lymphocytic proliferation.\n\nConclusion\nA case of MG was complicated by PTCL-NOS following long-term oral TAC treatment after thymectomy. The association between MG and PTCL-NOS is complex, and the long-term use of immunosuppressive therapy as well as sustained autoantigen stimulation may have affected the development of PTCL-NOS in the present case.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. \nRomi F , Gilhus NE , Aarli JA \nMyasthenia gravis: clinical, immunological and therapeutic advances . Acta Neurol Scand \n111 : 134 -141 , 2005 .15644074 \n2. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues . 4th Ed \nSteven H , Swerdlow EC , Harris NL et al , Eds. International Agency for Research on Cancer , Lyon, France , 2008 .\n3. \nCory RF , Rios C , Kaya K , et al \nComposite lymphocyte-rich thymoma and peripheral T-cell lymphoma not otherwise specified: case report and literature review . Lab Med \n43 : 4 -8 , 2012 .\n4. \nAzzi JR , Sayegh MH , Mallat SG \nCalcineurin inhibitor: 40 years later, can't live without... \nJ Immunol \n191 : 5785 -5791 , 2013 .24319282 \n5. \nDharnidharka VR , Sullivan EK , Stablein DM , Tejani AH , Harmon WE \nNorth American Pediatric Renal Transplant Cooperative Study (NAPRTCS): Risk factors for posttransplant lymphoproliferative disorder (PTLD) in pediatric kidney transplantation: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) . Transplantation \n71 : 1065 -1068 , 2001 .11374404 \n6. \nYounes BS , McDiarmid SV , Martin MG , et al \nThe effect of immunosuppression on posttransplant lymphoproliferative disease in pediatric liver transplant patients . Transplantation \n70 : 94 -99 , 2000 .10919581 \n7. \nEllis D , Jaffe R , Green M , et al \nEpstein-Barr virus-related disorders in children undergoing renal transplantation with tacrolimus-based immunosuppression . Transplantation \n68 : 997 -1003 , 1999 .10532541 \n8. \nCox KL , Lawrence-Miyasaki LS , Garcia-Kennedy R , et al \nAn increased incidence of Epstein-Barr virus infection and lymphoproliferative disorder in young children on FK506 after liver transplantation . Transplantation \n59 : 524 -529 , 1995 .7533344 \n9. \nSekiguchi Y , Shimada A , Imai H , et al \nEpstein-Barr virus-negative, CD5-positive diffuse large B-cell lymphoma developing after treatment with oral tacrolimus for mixed connective tissue disease: a case report and review of the literature . J Clin Exp Hematopathol \n52 : 211 -228 , 2012 .\n10. \nMiseki T , Sugata H , Kubo Y , et al \nA case in which RA was not exacerbated during rituximab treatment of BL that occurred during FK506 use . Nihon Gan Chiryo Gakkai Shi \n45 : 966 , 2010 (in Japanese, Abstract in English).\n11. \nMinami N , Fujiki N , Doi S , et al \nA case of myasthenia gravis in which a variety of tumors developed during the clinical course . Neurol Therap \n24 : 360 , 2007 (in Japanese, Abstract in English).\n12. \nCorazza M , Zampino MR , Montanari A , et al \nPrimary cutaneous CD30+ large T-cell lymphoma in a patient with psoriasis treated with cyclosporine . Dermatology \n206 : 330 -333 , 2003 .12771475 \n13. \nKoo JY , Kadonaga JN , Wintroub BV , et al \nThe development of B-cell lymphoma in a patient with psoriasis treated with cyclosporine . J Am Acad Dermatol \n26 : 836 -840 , 1992 .1613146 \n14. \nZijlmans JM , Rijthoven AW , Kluin PM , et al \nEpstein-Barr virus-associated lymphoma in a patient with rheumatoid arthritis treated with cyclosporine . N Engl J Med \n326 : 1363 , 1992 .\n15. \nMougel F , Dalle S , Balme B , et al \nAggressive CD30 large cell lymphoma after cyclosporine given for putative atopic dermatitis . Dermatology \n213 : 239 -241 , 2006 .17033176 \n16. \nOgata M , Kikuchi H , Ono K , et al \nSpontaneous remission of Epstein-Barr virus-negative non-Hodgkin's lymphoma after withdrawal of cyclosporine in a patient with refractory anemia . Int J Hematol \n79 : 161 -164 , 2004 .15005345 \n17. \nShibahara T , Miyazaki K , Sato D , et al \nRectal malignant lymphoma complicating ulcerative colitis treated with long-term cyclosporine A . J Gastroenterol Hepatol \n21 : 336 -338 , 2006 .16460502 \n18. \nUS Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Elidel NDA 21-302 pharmacology review [Internet]. 2001 Nov. 6 [cited 2017 Feb. 1]; Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2001/21-302_ELIDEL_pharmr_P2.pdf\n\n19. \nPediatric Advisory Committee presentation from Barbara Hill, Division of Dermatologic and Dental Drug Products, FDA Center for Drug Evaluation and Research. Topical immunosuppressants (calcineurin inhibitors)-animal toxicology [Internet]. 2005 Feb. 15 [cited 2017 Feb. 1]; Available from: http://www.fda.gov/ohrms/dockets/ac/05/slides/2005-4089s2_01_06_Hill.ppt\n20. \nNaschitz JE , Rosner I \nMusculoskeletal syndromes associated with malignancy (excluding hypertrophic osteoarthropathy) . Curr Opin Rheumatol \n20 : 100 -105 , 2008 .18281865 \n21. \nZintzaras E , Voulgarelis M , Moutsopoulos HM \nThe risk of lymphoma development in autoimmune diseases: a meta-analysis . Arch Intern Med \n165 : 2337 -2344 , 2005 .16287762 \n22. \nMackay IR , Rose NR \nAutoimmunity and lymphoma: tribulations of B cells . Nat Immunol \n2 : 793 -795 , 2001 .11526388 \n23. \nLevin N , Abramsky O , Lossos A , et al \nExtrathymic malignancies in patients with myasthenia gravis . J Neurol Sci \n237 : 39 -43 , 2005 .15990114 \n24. \nBowen JD , Kidd P \nMyasthenia gravis associated with T helper cell lymphoma . Neurology \n37 : 1405 -1408 , 1987 .2956532 \n25. \nMortimer JE , Kidd P \nMyasthenia gravis and lymphoblastic lymphoma antiacetylcholine receptor antibody as a tumor marker-a case report . Cancer Invest \n7 : 327 -331 , 1989 .2686813 \n26. \nStrauchen JA \nIndolent T-lymphoblastic proliferation: report of a case with an 11-year history and association with myasthenia gravis . Am J Surg Pathol \n25 : 411 -415 , 2001 .11224614 \n27. \nUner AH , Abali H , Engin H , et al \nMyasthenia gravis and lymphoblastic lymphoma involving the thymus: a rare association . Leuk Lymphoma \n42 : 527 -531 , 2001 .11699420 \n28. \nNishioka R , Nakajima S , Morimoto Y , et al \nT-cell acute lymphoblastic leukemia with transient pure red cell aplasia associated with myasthenia gravis and invasive thymoma . Intern Med \n34 : 127 -130 , 1995 .7727878 \n29. \nOwe JF , Daltveit AK , Gilhus NE \nDoes myasthenia gravis provide protection against cancer? \nActa Neur Scand \n113 : 33 -36 , 2006 .\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "57(4)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "PTCL-NOS; lymphoma; myasthenia gravis; tacrolimus; thymectomy",
"medline_ta": "Intern Med",
"mesh_terms": "D003131:Combined Modality Therapy; D006801:Humans; D007166:Immunosuppressive Agents; D016411:Lymphoma, T-Cell, Peripheral; D008297:Male; D008875:Middle Aged; D009157:Myasthenia Gravis; D016559:Tacrolimus; D013934:Thymectomy",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "601-604",
"pmc": null,
"pmid": "29269644",
"pubdate": "2018-02-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11526388;11699420;2686813;15990114;15005345;1613146;17033176;23269082;24319282;10532541;12771475;11224614;16637926;10919581;16460502;16287762;7727878;11374404;7533344;18281865;15644074;1565156;2956532",
"title": "Myasthenia Gravis Complicated with Peripheral T-cell Lymphoma, Not Otherwise Specified (PTCL-NOS), Following Thymectomy and Longstanding Tacrolimus Therapy.",
"title_normalized": "myasthenia gravis complicated with peripheral t cell lymphoma not otherwise specified ptcl nos following thymectomy and longstanding tacrolimus therapy"
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"abstract": "Patients with chronic kidney disease (CKD) are commonly at high risk of tuberculosis (TB). Conversely, TB rarely causes tubulointerstitial nephritis. A 75-year-old Japanese man who was undergoing periodic follow-ups for CKD stage G3aA3 with membranous nephropathy was diagnosed with acute kidney injury (AKI) (estimated glomerular filtration rate [eGFR]: 15 mL/min/1.73 m2) without prerenal AKI. He reported developing recent-onset cough 3 weeks prior to presenting to us. Renal biopsy revealed acute tubulointerstitial nephritis along with known membranous nephropathy. CD4+ helper T cells comprised most lymphocytes in the tubulointerstitium. Results of the interferon-gamma release assay, sputum smear test, polymerase chain reaction (PCR), and culture test were positive for TB. Chest computed tomography revealed thickening of the left bronchial wall; therefore, a diagnosis of early bronchial TB was made; his urine culture and PCR were negative for TB. At four months after TB treatment with no immunosuppressive therapy, his eGFR improved to 50 mL/min/1.73 m2, and based on this progress, the AKI was diagnosed as tuberculosis-associated tubulointerstitial nephritis (TATIN). Although TATIN typically occurs with chronic or miliary tuberculosis, it is very rare in early bronchial TB. Identification of TATIN is important in kidney diseases of unknown etiology, and treatment with anti-TB drugs is necessary.",
"affiliations": "Department of Hypertension and Nephrology, NTT Medical Centre Tokyo, 5-9-22, Higashi-Gotanda, Shinagawa-ku, Tokyo 141-8625, Japan. Electronic address: furuto19761006@yahoo.co.jp.;Department of Diagnostic Pathology, NTT Medical Centre Tokyo, 5-9-22, Higashi-Gotanda, Shinagawa-ku, Tokyo 141-8625, Japan.;Department of Hypertension and Nephrology, NTT Medical Centre Tokyo, 5-9-22, Higashi-Gotanda, Shinagawa-ku, Tokyo 141-8625, Japan.;Department of Hypertension and Nephrology, NTT Medical Centre Tokyo, 5-9-22, Higashi-Gotanda, Shinagawa-ku, Tokyo 141-8625, Japan.;Department of Hypertension and Nephrology, NTT Medical Centre Tokyo, 5-9-22, Higashi-Gotanda, Shinagawa-ku, Tokyo 141-8625, Japan.;Department of Hypertension and Nephrology, NTT Medical Centre Tokyo, 5-9-22, Higashi-Gotanda, Shinagawa-ku, Tokyo 141-8625, Japan.;Department of Hypertension and Nephrology, NTT Medical Centre Tokyo, 5-9-22, Higashi-Gotanda, Shinagawa-ku, Tokyo 141-8625, Japan.;Department of Hypertension and Nephrology, NTT Medical Centre Tokyo, 5-9-22, Higashi-Gotanda, Shinagawa-ku, Tokyo 141-8625, Japan.;Department of Diagnostic Pathology, NTT Medical Centre Tokyo, 5-9-22, Higashi-Gotanda, Shinagawa-ku, Tokyo 141-8625, Japan.;Department of Hypertension and Nephrology, NTT Medical Centre Tokyo, 5-9-22, Higashi-Gotanda, Shinagawa-ku, Tokyo 141-8625, Japan.",
"authors": "Furuto|Yoshitaka|Y|;Hashimoto|Hirotsugu|H|;Kawamura|Mariko|M|;Yamashita|Jumpei|J|;Yoshikawa|Takahiro|T|;Namikawa|Akio|A|;Isshiki|Rei|R|;Takahashi|Hiroko|H|;Morikawa|Teppei|T|;Shibuya|Yuko|Y|",
"chemical_list": null,
"country": "Singapore",
"delete": false,
"doi": "10.1016/j.jfma.2021.07.010",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0929-6646",
"issue": null,
"journal": "Journal of the Formosan Medical Association = Taiwan yi zhi",
"keywords": "Acute kidney injury; Glomerulonephritis; Mycobacterium tuberculosis; Nephrotic syndrome tubulointerstitial nephritis",
"medline_ta": "J Formos Med Assoc",
"mesh_terms": null,
"nlm_unique_id": "9214933",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34301423",
"pubdate": "2021-07-20",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Acute tubulointerstitial nephritis in a patient with early bronchial tuberculosis.",
"title_normalized": "acute tubulointerstitial nephritis in a patient with early bronchial tuberculosis"
} | [
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"companynumb": "JP-DSJP-DSJ-2022-106788",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
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"abstract": "BACKGROUND\nMinocycline-induced pigmentation of bone (black bone) is well described in tooth-bearing intra-oral bone, but is less known in periarticular bone in patients who have undergone total joint arthroplasty. On a retrospective basis, we investigated the short-term clinico-radiological results of total joint arthroplasties in which the patient developed minocycline-induced periarticular black bone.\n\n\nMETHODS\nWe found 5 cases (0.08%), in 4 patients, of periarticular bone pigmentation revealed during total joint arthroplasties (2 hips, 2 knees, and 1 ankle) in our series of total joint surgeries (6,548 cases) over a 10-year time period in our 3 institutes. Their mean age was 56 years at surgery. All patients had received long-term minocycline treatment. Mean dosage and duration of minocycline was 160 mg/day and 2.2 years, respectively. Minocycline had been prescribed for reactive arthritis (one), rheumatoid arthritis (two) and late infection after total joint arthroplasty (two patients). Mean follow-up period was 3.4 years after the surgeries.\n\n\nRESULTS\nAll cases had black or brown pigmentation in the periarticular bones during the surgery. There was no pigmentation in the cartilage or soft tissues of the joints. The mean Japanese Orthopaedic Association (JOA) score or Japanese Society for Surgery of the Foot (JSSF) scale for rheumatoid arthritis foot and ankle joints at latest follow-up (case 1, 66; case 2, 87; case 3, 77; case 4, 77; case 5, 80) improved compared to those of pre-surgery (case 1, 47; case 2, 45; case 3, 55; case 4, 34; case 5, 55). No implant loosening was noted on radiographic examination during the follow-up period. No abnormal bone formation, bone necrosis, hemosiderin deposition, malignancy or metallic debris was found on histological examination.\n\n\nCONCLUSIONS\nNo clinico-radiological symptoms of total joint arthroplasties showed in the patients with minocycline-induced periarticular black bone in the short-term. Systemic minocycline treatment has the potential to induce significant black pigmentation of many tissues. In particular, minocycline-induced pigmentation of periarticular bone may be accelerated by inflammation due to rheumatic or pyogenic arthritis. Surgeons should recognize the risk of bone pigmentation in inflamed joints due to the systemic treatment of minocycline and explore its influence on periarticular bone and total joint arthroplasty in the long-term.",
"affiliations": "Department of Orthopedic Surgery, Yamagata University School of Medicine, Yamagata, Japan. yangsuran@gmail.com",
"authors": "Yang|Suran|S|;Takakubo|Yuya|Y|;Kobayashi|Shinji|S|;Asano|Tamon|T|;Sasaki|Akiko|A|;Sasaki|Kan|K|;Ohki|Hiroharu|H|;Tamaki|Yasunobu|Y|;Takagi|Michiaki|M|",
"chemical_list": "D000900:Anti-Bacterial Agents; D008911:Minocycline",
"country": "Korea (South)",
"delete": false,
"doi": "10.4055/cios.2012.4.3.181",
"fulltext": "\n==== Front\nClin Orthop SurgClin Orthop SurgCIOSClinics in Orthopedic Surgery2005-291X2005-4408The Korean Orthopaedic Association 10.4055/cios.2012.4.3.181Original ArticleMinocycline-induced Periarticular Black Bones in Inflamed Joints Which Underwent Arthroplastic Reconstruction Yang Suran MD*Takakubo Yuya MD*†Kobayashi Shinji MD*Asano Tamon MD*‡Sasaki Akiko MD*Sasaki Kan MD*Ohki Hiroharu MD*Tamaki Yasunobu MD*§Takagi Michiaki MD** Department of Orthopedic Surgery, Yamagata University School of Medicine, Yamagata, Japan.† Department of Medicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.‡ Department of Orthopedic Surgery, Sanyudo Hospital, Yonezawa, Japan.§ Department of Orthopedic Surgery, Yamagata Saisei Hospital, Yamagata, Japan.\nCorrespondence to: Suran Yang, MD. Department of Orthopaedic Surgery, Yamagata University School of Medicine, 2-2-2 Iida Nishi, Yamagata 990-9585, Japan. Tel: +81-23-628-5355, Fax: +81-23-628-5357, yangsuran@gmail.com9 2012 14 8 2012 4 3 181 187 16 1 2012 27 3 2012 Copyright © 2012 by The Korean Orthopaedic Association2012This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\nMinocycline-induced pigmentation of bone (black bone) is well described in tooth-bearing intra-oral bone, but is less known in periarticular bone in patients who have undergone total joint arthroplasty. On a retrospective basis, we investigated the short-term clinico-radiological results of total joint arthroplasties in which the patient developed minocycline-induced periarticular black bone.\n\nMethods\nWe found 5 cases (0.08%), in 4 patients, of periarticular bone pigmentation revealed during total joint arthroplasties (2 hips, 2 knees, and 1 ankle) in our series of total joint surgeries (6,548 cases) over a 10-year time period in our 3 institutes. Their mean age was 56 years at surgery. All patients had received long-term minocycline treatment. Mean dosage and duration of minocycline was 160 mg/day and 2.2 years, respectively. Minocycline had been prescribed for reactive arthritis (one), rheumatoid arthritis (two) and late infection after total joint arthroplasty (two patients). Mean follow-up period was 3.4 years after the surgeries.\n\nResults\nAll cases had black or brown pigmentation in the periarticular bones during the surgery. There was no pigmentation in the cartilage or soft tissues of the joints. The mean Japanese Orthopaedic Association (JOA) score or Japanese Society for Surgery of the Foot (JSSF) scale for rheumatoid arthritis foot and ankle joints at latest follow-up (case 1, 66; case 2, 87; case 3, 77; case 4, 77; case 5, 80) improved compared to those of pre-surgery (case 1, 47; case 2, 45; case 3, 55; case 4, 34; case 5, 55). No implant loosening was noted on radiographic examination during the follow-up period. No abnormal bone formation, bone necrosis, hemosiderin deposition, malignancy or metallic debris was found on histological examination.\n\nConclusions\nNo clinico-radiological symptoms of total joint arthroplasties showed in the patients with minocycline-induced periariticular black bone in the short-term. Systemic minocycline treatment has the potential to induce significant black pigmentation of many tissues. In particular, minocycline-induced pigmentation of periarticular bone may be accelerated by inflammation due to rheumatic or pyogenic arthritis. Surgeons should recognize the risk of bone pigmentation in inflamed joints due to the systemic treatment of minocycline and explore its influence on periarticular bone and total joint arthroplasty in the long-term.\n\nJointPeriarticular boneBlack boneMinocyclineTotal joint arthroplasty\n==== Body\nMinocycline, 7-dimethylamino-6-demethyl-6-deoxytetracycline, a semi-synthetic broad-spectrum tetracycline antimicrobial agent, has been used since 1967.1) Because minocycline has distinct advantages over other tetracyclines because of its high lipid solubility, better absorption, minimal phototoxicity, and superior antimicrobial activity,1-4) minocycline has been used extensively in the treatment of acne rosacea, acne vulgaris, chronic respiratory diseases, and Gram-positive or -negative infections. Minocycline binds to the 30S subunits of bacterial ribosomes and specifically inhibits the binding of aminoacyl-tRNA to the ribosomal acceptor site, in this way inhibiting protein synthesis in susceptible microorganisms.5,6) In addition, this drug is used in the treatment of rheumatoid arthritis because of its potent anti-inflammatory properties.5,7) Although long-term minocycline therapy is safe for most patients, the most frequently reported adverse reaction is cutaneous pigmentation.8) Pigmentation caused by minocycline has been reported not only in the skin, but in other soft tissues including the thyroid gland, mucosa, and eyes;5,9-11) in the breast milk secretions,2) and in hard tissues, including teeth, nails and bones.2-5,8,10)\n\nOver twenty published reports have described bone pigmentation and/or discoloration induced by minocycline in the oral cavity, variously calling it intra-oral \"black bone\" with \"black or green roots\" of the teeth.2,6) However, to our knowledge, there have been only 6 previous reports regarding minocycline-induced bone pigmentation that is not in the oral cavity. These have included one case of affected parietal bone and costal cartilage found at autopsy,10) one of the clavicle discovered during surgery to treat a bone cyst,12) one of the acromion during surgery for subacromial impingement,3) one of the thoracic vertebrae during surgery for sever lumbago,13) one of the ends of the femur and tibia at total knee arthroplasty (TKA) for osteoarthritis,14) and one of the diaphysis of the femur at revision surgery for late infection after primary surgical reduction of a fracture.4) In particular, only one case of periarticular bone pigmentation observed at the surgical site during total join arthroplasty has been reported and that follow-up period was one year after surgery.14) Although it is still unclear whether minocycline-induced pigmentation of periarticular bones have an effect on the clinical and/or radiological result of their total joint arthroplasties, minocycline, which is a semi-synthetic tetracycline, is known to cause dysosteogenesis of oral bone, in particular in children.2,6) They are expected to have a potent of effect to the bone around total joint arthroplasty like a effect for oral bone in children.\n\nIn this retrospective study on data from a 10-year period, we investigated minocycline-induced periarticular black bone and the short-term clinico-radiological results in our patients who had undergone total joint arthroplasty.\n\nMETHODS\nPatient Characteristics\nWe investigated in our series of total joint arthroplasty (total 6,548 cases) patients of 10 years (2001-2010) that had been treated at one of our 3 institutions and found 5 cases (0.08%), in 4 patients, of minocycline-induced pigmentation of periarticular bone observed at the surgical site during one of the following surgeries summarized in Table 1: one total ankle arthroplasty (TAA; Fine total ankle, Nakashima, Okayama, Japan), one primary total hip arthroplasty (THA; ZCA cup, CPT Stem, Zimmer, Warsaw, IN, USA), one revision THA (KT-plate, JMM, Kyoto, Japan; ZCA cup, CPT Stem, Zimmer), one TKA (Vanguard, Biomet, Warsaw, IN, USA), and one revision TKA (NexGen LCCK, Zimmer). The primary disease was reactive arthritis (case 1), rheumatoid arthritis (RA, cases 2 and 3), sarcoidosis (case 4) and osteoarthritis (case 5). Minocycline had been prescribed for reactive arthritis (case 1), RA (cases 2 and 3) and late infection after total joint arthroplasty (cases 4 and 5). In case 1, the patient was prescribed low dose prednisolone combined with minocycline for reactive arthritis; in cases 2 and 3 in patients using combination therapy with methotrexate, salazosulfapyridine and prednisolone with minocycline for RA; in case 4, the patient was prescribed a moderate dose of prednisolone for his sarcoidosis.\n\nClinical Analyses\nFor clinical estimation, the Japanese Orthopaedic Association (JOA) hip15) and knee16) scores, and Japanese Society for Surgery of the Foot (JSSF) scale for RA foot and ankle joints17) were analyzed at the preoperation and at latest follow-up. X-rays were estimated for radiological assessments at the preoperation and latest follow-up by two observers blindly. In addition, skin pigmentation by minocycline was investigated in each case. The mean follow-up period was 3.4 years (range, 2.0 to 4.6 years). We did not perform a statistical analysis because the numbers were very small in each category.\n\nEvaluation of Pathological Findings\nHematoxylin-eosin and Berlin-blue-stained sections were used for pathological analyses.\n\nRESULTS\nOperative Findings\nAll cases were observed to have black or brown pigmentation in the periarticular anatomy during total joint arthroplasty. We show a representative example (case 1) who was affected on her right ankle by reactive arthritis, which included black pigmentation of the periarticular bone (Fig. 1A and 1C). No pigmentation was found in any other tissue, cartilage or soft tissues, such as the synovial tissue in the joint.\n\nRadiological Evaluation\nRadiographic examination showed no implant loosening and abnormal findings during the postoperative follow-up in all cases. We show the representative X-ray at the pre-surgery and the latest follow-up (case 1) (Fig. 1A and 1B).\n\nClinical Evaluation (Table 2)\nAll JOA scores, or JSSF scale scores, in each case at the last follow-up were compared to those of the pre-surgery. In case 1, the patient was able to walk, but was experiencing slight arthritic joint pain because of the arthritis in her ankle at the most recent follow-up. In cases 2, 3, and 4, they were able to walk and undertake daily activities with no hip or knee pain. In case 5, his JOA score was used for to estimate the necessity to be confinement to bed, because unfortunately the patient developed severe multiple cerebral infarctions and aspiration pneumonia, 24 months after the revision surgery.\n\nPathological Findings\nHistological examination of the removed tissue at the operation revealed no bone necrosis, hemosiderin, malignancy, or other specific changes. No abnormal bone formation, bone necrosis, hemosiderin deposition, malignancy or metallic debris, were found on histological examination in all cases (Fig. 1D).\n\nSkin Pigmentation (Table 1)\nSkin pigmentation had been observed in 4 of our cases (80%) for a mean duration of 13 months (range, 2 to 22 months) after receiving minocycline. In 3 of the 4 cases, their skin pigmentation had decreased and had cleared gradually after quitting minocycline (Fig. 2).\n\nDISCUSSION\nIn this retrospective study, we presented the short-term clinico-radiological results of total joint arthroplasties in 5 cases, in which the patients had minocycline-induced periarticular black bone at the surgical site.\n\nIt is well known that periarticular bone pigmentation or discoloration in joints are caused by several pathological factors, including ochronosis,18) hemophilic arthropathy,19) pigmented villonodular synovitis,20) metallosis after joint arthroplasty,21) and rarely drugs, such as tetracycline antibiotics.6) Ochronosis, which is a result of deposition of black homogentisic acid in the bone, cartilage and synovial membrane of joints is most often associated with alkaptonuria, a recessive hereditary disease caused by a complete defect of homogentisic acid oxidase.18) In hemophilic arthropathy and pigmented villonodular synovitis, hemosiderin deposition causes brownish discoloration, the hemosiderin being derived from phagocytosis of red blood cells after joint hematomas caused by intra-articular bleeding.19,20) In metallosis, micro metallic abrasion after joint arthroplasty causes black discoloration of the bone surface, synovium, and articular cartilage in the joints.21) In fact, metallosis after joint arthroplasty dose not show pigmentation of internal bone, but only discoloration/pigmentation of bone surface and soft tissue in the joint, except occult massive osteolysis in acetabulum where titanium debris was carried into the cancellous structure, and remodeling of bone occur involving the small metal particle into the bone matrix.22,23) Tetracycline antibiotics were first found to cause intra-oral bone pigmentation and discoloration of teeth in the 1950s.6)\n\nIn 1979, Ragucci24) suggested the possibility that minocycline-caused pigmentation in alveolar bone. Fredrich and Brookes25) reported minocycline-induced black pigmentation of alveolar bone in 1984. Over 20 published reports have described pigmentation and discoloration induced by minocycline in intra-oral bone.2,6,7,24-26) However, to our knowledge, only 6 previous articles have reported minocycline-induced pigmentation of bone outside the oral cavity.3,4,10,12-14) In particular, only one case of periarticular bone pigmentation observed during total joint arthroplasty has previously been reported; in this case, black or green pigmentation was found in the distal end of the femur and proximal end of the tibia during TKA for osteoarthritis (Table 3)14).\n\nBlack pigmentation of bone by minocycline is thought to occur through ferric iron being bound to the oxidized drug in developing bone, and via the accumulation of insoluble quinine from degradation of the aromatic ring of the drug in mature bone.1,7,27) However, deposition of iron and/or hemosiderin has not been observed in all cases. In the present study, common histological examination of the removed tissue at the surgery revealed no evidence of bone necrosis, hemosiderin, malignancy, or other specific changes, but some authors have elicited fluorescence, indicating the presence of minocycline-stained bone, by ultraviolet microscopy.3,26) One author has reported pigmentation of cartilage,10) however no discoloration of cartilage or soft tissue in the joints was observed in our cases. The mechanism of black bone pigmentation is not yet completely understood.3,7,14)\n\nMinocycline-induced pigmentation in skin is considered to be dose-dependent, the reported incidence being 2% in patients taking the drug over 2 months, 10% over one year, and 20% over 2 years.2,26) In addition, the incidence of skin pigmentation in patients treated for rheumatoid arthritis (range, 40% to 70%) is reportedly higher than that in patients treated for acne (range, 0.4% to 15%).7,28) In our 5 cases, the bone pigmentation was seen during surgery on joints where there was active inflammation due to rheumatic or pyogenic arthritis. This suggests that pigmentation of bone is influenced by inflammation in joints, such inflammation possibly accelerating the oxidization of minocycline, the process that is believed to cause skin pigmentation.1,7,27) In addition, in 4 of our cases (80%) skin pigmentation had been observed for a mean duration of 13 months (range, 2 to 22 months) after receiving minocycline. In previous reports regarding minocycline-induced pigmentation of bone outside the oral cavity, associated skin pigmentation was observed in 5 of the cases (83%). The occurrence of skin pigmentation might be strongly correlated with that of bone pigmentation. If so, it would allow prediction of bone pigmentation prior to surgery.\n\nOn the other hand, the time to resolution of black pigmentation and/or discoloration of bone after discontinuation of the drug is unknown. Most reported cases of minocycline/tetracycline-induced black pigmentation or discoloration of intra-oral bone have failed to resolve.6,7,26) In an animal model, Bowels29) demonstrated that an antioxidant, such as ascorbic acid (vitamin C), can inhibit minocycline-induced pigment deposition.\n\nTo our knowledge, there have been no reports describing the prevalence of minocycline induced-black bone and its potential adverse events with/without any implants in the long-term. McCleskey and Littleton14) reported good physiological and radiographic results of TKA one year after surgery for osteoarthritis in a patient who had taken minocycline for 2 years to treat acne rosacea. With the exception of case 5, who had severe multiple cerebral infarctions and aspiration pneumonia after his surgery, our 4 cases had satisfactory results from total joint arthroplasty, their clinical results (JSSF scale and JOA score) being improved and their implants being stable on radiographic examination at the most recent follow-up. However, our study population is extremely small (5 cases) and the mean duration of postoperative follow-up was only 3.4 years (range, 2.0 to 4.6 years). The large cases are needed with paired-matched control group for a long duration and statistical analysis in the next study. In addition, tetracycline is contraindicated in children because it causes dysosteogenesis and enamel hypoplasia; these adverse events occur with minocycline, which is a semi-synthetic tetracycline.2,6,26) It is speculated minocycline has potent influence on the clinical and/or radiological result of the bone around total joint arthroplasty. The adverse effects of minocycline-induced bone pigmentation and/or discoloration in regard to loosening of implants should be carefully assessed in the long term and patients informed of this adverse effect of minocycline before they receive the drug, because the influence of minocycline on bone quality and bone metabolism in vivo is still unknown in long term. We believe that not only rheumatologists, but orthopedic surgeons should know about black bone and minocycline-induced bone discoloration/pigmentation in the joint. It would be possible that surgeons may encounter metallic debris deposition combined with minocycline-induced bone discoloration/pigmentation, struggle to determine the degree to which the area should be removed during revision surgery.\n\nIn conclusion, we have presented the short-term results of total joint surgeries in 5 cases that had minocycline-induced black pigmentation of the periarticular bone. In cases with minocycline-induced bone pigmentation, surgeons should examine carefully for implant loosening and adverse effects of bone quality around implants in the long term.\n\nACKNOWLEDGEMENTS\nWe sincerely thank a lot Ms. Eiko Saito and Dr. Taku Nakajima for their skilful technical support in histological analysis and clinical data gathering. Yuya Takakubo was supported by the Excellent Young Researchers Overseas Visit Program, the Japan Society for the Promotion of Science (21-8117).\n\nNo potential conflict of interest relevant to this article was reported.\n\nFig. 1 Case 1: A 75-year-old woman had received 200 mg/day minocycline for 2 years to treat reactive arthritis. (A) Anteroposterior radiographic views of the right ankle preoperatively and (B) at the last follow-up. Preoperatively, her right ankle shows end-stage osteoarthritic changes. (C) Black pigmentation and discoloration of the distal part of the tibia and talus (indicated by arrows) were observed during total ankle arthroplasty; this was due to long-term minocycline medication. (D) Hematoxylin-eosin-stained microphotograph of the black bone removed from the distal end of the tibia shows normal bone structure; there were no bone necrosis, deposition of hemosiderin, malignancy, or abnormalities of bone matrix (×200).\n\nFig. 2 Case 4: A 33-year-old man had received 200 mg/day minocycline for 7 months for infection of his total hip arthroplasty. Photographic views of minocycline-induced skin hyperpigmentation on the lower legs (A) at pre-revision surgery and (B) 37 months after discontinuing minocycline. Note the resolution of skin pigmentation after discontinuation of minocycline.\n\nTable 1 Clinical Data for the Five Cases of Black Periarticular Bone Pigmentation\n\nRA: rheumatoid arthritis, TAA: total ankle arthroplasty, THA: total hip arthroplasty, TKA: total knee arthroplasty.\n\nTable 2 JOA Hip and Knee Score and JSSF Scale for RA Foot and Ankle Joints at the Preoperation and Latest Follow-up\n\nJOA: Japanese Orthopaedic Association, JSSF: Japanese Society for Surgery of the Foot, RA: rheumatoid arthritis.\n\nTable 3 Clinical Data for the Six Previous Reports of Black Bone Pigmentation Excluding Bone in the Oral Cavity\n\nMRSA: methicillin-resistant Staphylococcus aureus, TKA: total knee arthroplasty.\n==== Refs\n1 Kelly RG Kanegis LA Metabolism and tissue distribution of radioisotopically labelled minocycline Toxicol Appl Pharmacol 1967 11 1 171 183 6056150 \n2 Eisen D Hakim MD Minocycline-induced pigmentation. Incidence, prevention and management Drug Saf 1998 18 6 431 440 9638388 \n3 Pandit S Hadden W Black pigmentation of bone due to long-term minocycline use Surgeon 2004 2 4 236 237 15570834 \n4 Hepburn MJ Dooley DP Hayda RA Minocycline-induced black bone disease Orthopedics 2005 28 5 501 502 15945609 \n5 Treister NS Magalnick D Woo SB Oral mucosal pigmentation secondary to minocycline therapy: report of two cases and a review of the literature Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2004 97 6 718 725 15184854 \n6 Sanchez AR Rogers RS 3rd Sheridan PJ Tetracycline and other tetracycline-derivative staining of the teeth and oral cavity Int J Dermatol 2004 43 10 709 715 15485524 \n7 LaPorta VN Nikitakis NG Sindler AJ Reynolds MA Minocycline-associated intra-oral soft-tissue pigmentation: clinicopathologic correlations and review J Clin Periodontol 2005 32 2 119 122 15691339 \n8 Angeloni VL Salasche SJ Ortiz R Nail, skin, and scleral pigmentation induced by minocycline Cutis 1987 40 3 229 233 3652731 \n9 Benitz KF Roberts GK Yusa A Morphologic effects of minocycline in laboratory animals Toxicol Appl Pharmacol 1967 11 1 150 170 4964321 \n10 Attwood HD Dennett X A black thyroid and minocycline treatment Br Med J 1976 2 6044 1109 1110 990789 \n11 Sabroe RA Archer CB Harlow D Bradfield JW Peachey RD Minocycline-induced discolouration of the sclerae Br J Dermatol 1996 135 2 314 316 8881683 \n12 Wolfe ID Reichmister J Minocycline hyperpigmentation: skin, tooth, nail, and bone involvement Cutis 1984 33 5 457 458 6478869 \n13 Rumbak MJ Pitcock JA Palmieri GM Robertson JT Black bones following long-term minocycline treatment Arch Pathol Lab Med 1991 115 9 939 941 1718240 \n14 McCleskey PE Littleton KH Minocycline-induced blue-green discoloration of bone: a case report J Bone Joint Surg Am 2004 86 1 146 148 14711958 \n15 Ueno R Staging of osteoarthritis of the hip joint according to the roentgenographic findings J Jpn Orthop Assoc 1971 45 10 826 828 \n16 Koshino T Japanese Orthopaedic Association knee scoring system J Jpn Orthop Assoc 1988 62 8 900 902 \n17 Niki H Aoki H Inokuchi S Development and reliability of a standard rating system for outcome measurement of foot and ankle disorders II: interclinician and intraclinician reliability and validity of the newly established standard rating scales and Japanese Orthopaedic Association rating scale J Orthop Sci 2005 10 5 466 474 16193357 \n18 Takagi M Ida H Kobayashi S Ishii M Osanai T Konttinen YT Ochronotic spondylarthropathy: two case reports of progressive destructive changes in the hip Mod Rhumatol 2003 13 1 81 86 \n19 Kelley SS Lachiewicz PF Gilbert MS Bolander ME Jankiewicz JJ Hip arthroplasty in hemophilic arthropathy J Bone Joint Surg Am 1995 77 6 828 834 7782355 \n20 Goldman AB DiCarlo EF Pigmented villonodular synovitis: diagnosis and differential diagnosis Radiol Clin North Am 1988 26 6 1327 1347 2845469 \n21 Iida H Kaneda E Takada H Uchida K Kawanabe K Nakamura T Metallosis due to impingement between the socket and the femoral neck in a metal-on-metal bearing total hip prosthesis: a case report J Bone Joint Surg Am 1999 81 3 400 403 10199279 \n22 Khan RJ Wimhurst J Foroughi S Toms A The natural history of metallosis from catastrophic failure of a polyethylene liner in a total hip J Arthroplasty 2009 24 7 1144.e1 1144.e4 18848419 \n23 Huber M Reinisch G Zenz P Zweymuller K Lintner F Postmortem study of femoral osteolysis associated with metal-on-metal articulation in total hip replacement: an analysis of nine cases J Bone Joint Surg Am 2010 92 8 1720 1731 20660235 \n24 Ragucci BD Green bones and tooth roots: minocycline? Schoch Lett 1979 29 1 3 \n25 Fendrich P Brooke RI An unusual case of oral pigmentation Oral Surg Oral Med Oral Pathol 1984 58 3 288 289 6592526 \n26 Westbury LW Najera A Minocycline-induced intraoral pharmacogenic pigmentation: case reports and review of the literature J Periodontol 1997 68 1 84 91 9029456 \n27 Cockings JM Savage NW Minocycline and oral pigmentation Aust Dent J 1998 43 1 14 16 9583219 \n28 Roberts G Capell HA The frequency and distribution of minocycline induced hyperpigmentation in a rheumatoid arthritis population J Rheumatol 2006 33 7 1254 1257 16758512 \n29 Bowles WH Protection against minocycline pigment formation by ascorbic acid (vitamin C) J Esthet Dent 1998 10 4 182 186 9893512\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2005-291X",
"issue": "4(3)",
"journal": "Clinics in orthopedic surgery",
"keywords": "Black bone; Joint; Minocycline; Periarticular bone; Total joint arthroplasty",
"medline_ta": "Clin Orthop Surg",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D019072:Antibiotic Prophylaxis; D001168:Arthritis; D019643:Arthroplasty, Replacement; D001842:Bone and Bones; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008911:Minocycline; D012189:Retrospective Studies; D012867:Skin; D012880:Skin Pigmentation",
"nlm_unique_id": "101505087",
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"pages": "181-7",
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"pmid": "22949948",
"pubdate": "2012-09",
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"references": "20660235;16758512;10199279;6592526;24387122;15945609;8881683;18848419;6478869;9893512;14711958;9638388;7782355;6056150;9583219;990789;3652731;16193357;1718240;2845469;15570834;9029456;4964321;15691339;15485524;15184854",
"title": "Minocycline-induced periarticular black bones in inflamed joints which underwent arthroplastic reconstruction.",
"title_normalized": "minocycline induced periarticular black bones in inflamed joints which underwent arthroplastic reconstruction"
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"abstract": "OBJECTIVE\nTo expand the adverse events associated with metronidazole to include nonconvulsive status epilepticus (NCSE).\n\n\nMETHODS\nObservational single case report of a rare association.\n\n\nMETHODS\nHospitalized lung transplant recipient treated with metronidazole for prevention of infection.\n\n\nMETHODS\nA 56-year-old man with systemic symptoms, peripheral neuropathy, generalized seizure, and a subsequent acute deterioration of mental status due to NCSE.\n\n\nMETHODS\nAdministration of midazolam was successful in terminating status epilepticus.\n\n\nMETHODS\nAbrupt termination of NCSE was evident on continuous bedside electroencephalogam associated with clinical resolution of mental status.\n\n\nRESULTS\nRecovery occurred from NCSE eventually deteriorating to a fatal outcome.\n\n\nCONCLUSIONS\nMetronidazole may be associated with successfully treated NCSE.",
"affiliations": "Santa Casa de Misericórdia de Itatiba, Itatiba, Brazil.",
"authors": "Cantador|A A|AA|;Meschia|J F|JF|;Freeman|W D|WD|;Tatum|W O|WO|",
"chemical_list": null,
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"doi": "10.1177/1941874412470667",
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"issue": "3(4)",
"journal": "The Neurohospitalist",
"keywords": "EEG; encephalopathy; metronidazole; nonconvulsive status epilepticus; organ transplant",
"medline_ta": "Neurohospitalist",
"mesh_terms": null,
"nlm_unique_id": "101558199",
"other_id": null,
"pages": "185-9",
"pmc": null,
"pmid": "24198899",
"pubdate": "2013-10",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "7898724;11267444;20067388;10082092;11778010;21881470;10871017;19589454;11673700;21996645;7436193;17885234",
"title": "Nonconvulsive status with metronidazole.",
"title_normalized": "nonconvulsive status with metronidazole"
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"companynumb": "BR-PFIZER INC-2014179020",
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"abstract": "Bipolar disorder is associated with a high risk of suicide attempts and suicide deaths. The suicide mortality of people with bipolar disorder is approximately 25 times higher than the general population. No approved pharmacological strategies for suicidal thoughts and attempts in bipolar disorder have been introduced so far, and lithium remains as the first-line treatment for suicidal subjects. Clozapine is also a potentially good candidate for this indication. This case series represents three treatment-resistant bipolar patients with severe suicidal ideation who responded to low-dose clozapine treatment.",
"affiliations": "Department of Psychiatry, Medical University of Gdańsk, Gdańsk, Poland.;Department of Psychiatry, Medical University of Gdańsk, Gdańsk, Poland.;Department of Psychiatry, Medical University of Gdańsk, Gdańsk, Poland.",
"authors": "Wilkowska|Alina|A|;Wiglusz|Mariusz S|MS|;Cubała|Wiesław J|WJ|",
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"country": "Switzerland",
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"doi": "10.3389/fpsyt.2019.00520",
"fulltext": "\n==== Front\nFront PsychiatryFront PsychiatryFront. PsychiatryFrontiers in Psychiatry1664-0640Frontiers Media S.A. 10.3389/fpsyt.2019.00520PsychiatryCase ReportClozapine in Treatment-Resistant Bipolar Disorder With Suicidality. Three Case Reports Wilkowska Alina \n*\nWiglusz Mariusz S. Cubała Wiesław J. Department of Psychiatry, Medical University of Gdańsk, Gdańsk, PolandEdited by: Edoardo Spina, University of Messina, Italy\n\nReviewed by: Alessandro Serretti, University of Bologna, Italy; Maurizio Pompili, Sapienza University of Rome, Italy\n\n*Correspondence: Alina Wilkowska, ali.wilkowska@gmail.com\nThis article was submitted to Psychopharmacology, a section of the journal Frontiers in Psychiatry\n\n19 7 2019 2019 10 52028 5 2019 02 7 2019 Copyright © 2019 Wilkowska, Wiglusz and Cubała2019Wilkowska, Wiglusz and CubałaThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Bipolar disorder is associated with a high risk of suicide attempts and suicide deaths. The suicide mortality of people with bipolar disorder is approximately 25 times higher than the general population. No approved pharmacological strategies for suicidal thoughts and attempts in bipolar disorder have been introduced so far, and lithium remains as the first-line treatment for suicidal subjects. Clozapine is also a potentially good candidate for this indication. This case series represents three treatment-resistant bipolar patients with severe suicidal ideation who responded to low-dose clozapine treatment.\n\nclozapinebipolar disordersuicidal ideationbipolar depressiontreatment resistanceGdański Uniwersytet Medyczny10.13039/501100010609\n==== Body\nBackground\nDespite growing evidence for the effectiveness of new pharmacological strategies in bipolar disorder (BD), the number of studies on pharmacotherapy of treatment-resistant cases is scarce. One of the medications used for this indication is clozapine. Although clozapine lacks regulatory approval for use in any phase of BD, it has been shown to be useful in treatment-resistant BD (TRBD), decreasing the number of hospitalizations (1) and is associated with symptomatic and functional improvement (2). Clozapine probably reduces aggressive behavior in young patients with TRBD (3), and it seems to be effective in reducing the number of hospitalizations and emergency room (ER) visits, including the ones due to self-harm and overdose (4). One case report presents its antidepressant effect (5) and another its anti-suicidal effect (6).\n\nSuicidal ideation and behaviors in BD consist a significant clinical problem (7, 8). Suicide accounts for 15% to 20% of deaths among BD patients (9, 10). The ratio of suicidal attempts among BD patients is much lower (∼ −3:1) than that in the general population (∼30:1); however, it has a high lethality (11). Suicidal acts appear mostly in association with severe depressive or mixed states. For today, there are no approved pharmacological interventions for suicidality in BD. Clozapine has been shown to have specific anti-suicidal properties in patients with schizophrenia (12–14). Some authors have suggested that clozapine’s anti-suicidal properties could extend beyond schizophrenia to BD (8, 13).\n\nThis case series represents three bipolar patients with severe suicidal ideation who responded to clozapine as an add-on treatment.\n\nCase 1\nA 26-year-old single Caucasian female was admitted to an inpatient psychiatry unit. She was diagnosed with BD manic episodes with psychotic symptoms according to Diagnostic and Statistical Manual of Mental Disorders, 5th Edition. She had a 5-year history of BD with three hospitalizations due to manic episodes, including one involuntary. She also had four episodes of depression and one mixed episode. In the course of her illness, she hardly had any remissions.\n\nOn admission, she presented an elevated mood, increased energy and motor activity, loud and aggressive behavior, flights of ideas, tangentiality, delusions of grandiosity, and a decrease in sleep and appetite. She had to be restrained because of self-aggression (banging her head against the wall). She had quit her treatment (olanzapine, lithium, fluoxetine, and lorazepam) a few months earlier without consulting her psychiatrist. Initially, she was treated with haloperidol intramuscularly (up to 20 mg) and olanzapine intramuscularly (up to 20 mg), then zuclopenthixol 50 mg intramuscularly and aripiprazole up to 30 mg with no satisfactory effects. Next, she was treated with valproic acid intravenously up to 3,200 mg with a good antimanic effect, but the drug had to be withdrawn due to thrombocytopenia. Moreover, the patient refused to take lithium carbonate due to the “bad taste of the drug” (in Poland, available lithium carbonate tablets are not coated). Subsequently, she was treated with olanzapine 20 mg together with aripiprazole 30 mg that caused a remission of the manic symptoms, but after about 2 weeks, the patient’s mood had worsened; she became extremely irritable and revealed suicidal thoughts.\n\nAt this time, clozapine 100 mg was introduced, and the dose was increased to 200 mg the next day. We observed the resolution of the suicidal thoughts and mood normalization during the first 2 days of clozapine treatment. Unfortunately, there was no improvement as far as her insight, and after a few days, the patient refused to take any medication and was discharged at her own demand.\n\nCase 2\nA 26-year-old Caucasian female was admitted to the inpatient psychiatry unit due to severe bipolar I depression with comorbid borderline personality disorder and epilepsy. During the course of her illness, she was hospitalized four times due to depressive episodes and had two manic episodes without hospitalization. The current depressive episode lasted 6 months prior to admission. She had a low mood and extreme lack of energy, anhedonia, psychomotor retardation, reduced sleep, and suicidal thoughts. She was treated with valproate at a maximum of 1,300 mg/day for 9 weeks (serum level 70 mg/l), but the drug was withdrawn due to hair loss and tremor and lack of effect. Aripiprazole at a max of 30 mg/day for 6 weeks that also did not cause any improvement was administered, and then, we used quetiapine at a max of 550 mg/day that caused partial mood stabilization and also severe constipation causing withdrawal. Additionally, the patient was taking lamotrigine 400 mg/day and lithium carbonate 1,000 mg/day during the whole hospitalization. During treatment with lithium carbonate, we introduced eight intravenously ketamine doses (0.5 mg/kg) that caused an immediate mood improvement lasting about a week. Next, we used risperidone 4 mg without any clinical effect. We added topiramate at a max of 400 mg hoping for a further mood stabilizing effect and weight reduction (the patient had gained 10 kg during the year before hospitalization, and it was a significant problem for her). Next, we introduced fluoxetine at a max of 60 mg/day plus 5-mg olanzapine for 10 weeks—which was associated with a mild antidepressant effect.\n\nFinally, we used clozapine at a max of 100 mg for 8 weeks that caused gradual mood and energy normalization and the withdrawal of suicidal thoughts. The patient was discharged on lamotrigine 400 mg, lithium carbonate 750 mg, clozapine 100 mg, and topiramate 400 mg. During the whole time of her hospitalization, the patient had psychodynamic psychotherapy twice a week and continued it after discharge.\n\nCase 3\nA 42-year-old Caucasian female was admitted to the inpatient psychiatry unit due to a severe depressive episode in the course of BD. Before admission, she had quarreled with her husband, and under the influence of ethanol, she had tried to commit suicide by cutting her wrist. She had never been hospitalized in a psychiatric unit before. During hospitalization, she was treated with venlafaxine 375 mg, lamotrigine 200 mg, and quetiapine 200 mg with a small improvement of her depressive symptoms but no effect on her suicidal ideations. The patient stayed at the hospital for 10 days, subsequently withdrawing consent for further hospitalization—claiming her mental state had much improved. The next day, she came to our outpatient clinic still presenting active suicidal thoughts and depressive symptoms. She refused to be hospitalized but agreed to take medication at home with the close supervision of her family and frequent ambulatory visits (three times a week). The patient had been diagnosed with BD type I 21 years ago. During her illness, she had three episodes of major depression, two manic episodes, and one mixed episode. The current depressive episode lasted 2 months before admission and was related to a relationship crisis due to her marital relations. She had a low mood and anhedonia, psychomotor retardation, reduced sleep, and active, persistent suicidal thoughts that were the leading cause of her concern at the moment.\n\nShe agreed to be treated with clozapine up to 100 mg as an add-on treatment to previous drugs. During the next two weeks, the patient improved significantly, with the most prominent anti-suicidal effect after 10 days of clozapine treatment. Although she was still depressed, she did not express any suicidal thoughts, and this effect was present as long as the clozapine was subscribed. Two months later, due to sedation, she tried to decrease the dose of clozapine to 25 mg/day, but suicidal thoughts returned. Since then (2 years), she has been taking clozapine as an add-on treatment with a good clinical effect.\n\nThe previously discussed cases constitute the part of the clozapine registry approved by the independent ethics committee of the Medical University of Gdansk (approval number NKEBN/355/2016). The previously mentioned cases are presented according to guidelines for disguising case material.\n\nDiscussion\nThis case series presents the anti-suicidal effect of clozapine in three TRBP patients (\nTable 1\n). Clozapine is an effective anti-suicide agent approved in schizophrenia (12–14). Data on the pharmacotherapy of suicidal thoughts and behaviors in BD are very sparse, but it is suggested that clozapine can be effective in BD patients experiencing suicidal ideation (8). No approved strategies for treating suicidal thoughts and behaviors in BD have been introduced so far. These mechanisms seem to be independent of that which provides psychotic symptom relief. Interestingly, psychotic symptoms do not predict a better response to clozapine in bipolar patients compared with those in schizophrenic patients (15), and the doses required for optimal effect in BD may be less than those used for treatment-resistant schizophrenia (16). This subject demands further study.\n\nTable 1 Clinical characteristics of the case series.\n\nNo.\tAge\tGender\tEducation\tMarital\nstatus\tCurrent episode\tCourse of BD\tCon-meds\tSmoker\tClozapine dose\t\n1\t26 years\tF\t12 years\tsingle\tSevere depression with psychotic symptoms\tBD type I manic = depressive\t–\tYes\t200 mg\t\n2\t26 years\tF\t17 years\tsingle\tSevere depression without psychotic symptoms\tBD type I manic < depressive\tLamotrigine 400 mg, lithium carbonicum 750 mg, and topiramate 400 mg\tNo\t100 mg\t\n3\t42 years\tF\t17 years\tmarried\tSevere depression without psychotic symptoms\tBP type I\nManic < depressive\tLamotrigine 200 mg, wenlafaxine 375 mg, bupropion 300 mg, and quetiapine XR 200 mg\tNo\t100 mg\t\nClozapine’s clinical efficacy in TRBD has been previously demonstrated (17). The unique and complex pharmacology of this drug is responsible for its effectiveness in the treatment of resistant patients (18).\n\nAccording to British guidelines, clozapine is worth considering as a treatment option in cases of resistant BD, including rapid cycling (19). It is also recommended for TRBD in the latest version of The World Federation of Societies of Biological Psychiatry Guidelines for the Biological Treatment of Bipolar Disorders (20). The latest Canadian guidelines for the treatment of BD suggest using clozapine as the third-line treatment for acute mania and as an additional agent for the maintenance treatment of bipolar I, treatment-resistant mania (21).\n\nDespite being the first drug to demonstrate a reduction in suicidal behavior in a large RCT, clozapine is used in only 1.5% of bipolar patients (4, 22), suggesting a substantial underutilization of this valuable and relatively inexpensive drug. This is most probably caused by the side effects of clozapine: hematological, cardiovascular, metabolic, neurological, but also sedation, cognition, and the need for frequent monitoring of white blood cells. The risk-benefit profile in long-term treatment of BD needs to be assessed carefully.\n\nPossible mechanisms of reducing suicidal thoughts and behaviors with clozapine probably involve the simultaneous modulation of dopamine, norepinephrine, and serotonin (13), regulation of the hormone system (pregnenolone, cortisol) (23, 24), and intracellular systems—dependent modulation of N-methyl-D-aspartate receptor expression, brain-derived neurotrophic factor upregulation, and regulation of the arachidonic acid cascade (24, 25). The decrease in impulsivity and aggression connected with elevated plasma noradrenalin levels in patients treated with clozapine may be another mechanism responsible for the anti-aggressive/anti-suicidal activity of clozapine (26). Impulsivity and aggressive behavior increase the risk of suicidal acts, and mood stabilizers seem to reduce these symptoms (27). According to Youssef, pregnenolone alterations may be relevant to the neurobiology of suicide in schizophrenia and BD and may constitute a common path for the anti-suicidal effect for clozapine and lithium (28). There are few interesting studies suggesting that newer atypical antipsychotics like quetiapine and asenapine could also reduce suicidal ideation in BD, and they, just like clozapine, should definitely be studied further (29).\n\nLimitations\nClozapine serum level measurements were not performed. No psychometric scales were reported. Concomitant medications could interfere with the effect of clozapine. The case series does not reflect the wider population nor a causative relationship, and thus, replication in a proof of concept study is warranted in a larger population. Longer follow-up might be warranted.\n\nConclusions\nDespite the limitations, this case series presents the effectiveness of low-dose clozapine in reducing suicidal thoughts in three TRBD patients. The strategy described did not cause any serious adverse events and is relatively safe, especially in the clinical inpatients setting. Considering a lack of approved treatment for suicidal thoughts and behaviors in TRBD, there is a definite need for further studies in this field. A randomized controlled trial of effectiveness and tolerability in TRBD is warranted. Clozapine provides much promise for the treatment of suicidal thoughts and behaviors in this group of patients, and it seems to be effective, safe, and well tolerated.\n\nEthics Statement\nThe studies involving human participants were reviewed and approved by the Independent Ethics Committee of the Medical University of Gdansk (approval number NKEBN/355/2016). The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\nAW contributed to the manuscript draft, patient management, and research on the topic. MW contributed to the patient management, conceptualized the study, and corrected the manuscript. WC corrected the manuscript and conceptualized the study.\n\nConflict of Interest Statement\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n==== Refs\nReferences\n1 \nZarate CA JrTohen M Baldessarini RJ \nClozapine in severe mood disorders . J Clin Psychiatry (1995 ) 56 :411–7.\n2 \nSuppes T Webb A Paul B Carmody T Kraemer H Rush AJ \nClinical outcome in a randomized 1-year trial of clozapine versus treatment as usual for patients with treatment-resistant illness and a history of mania . Am J Psychiatry (1999 ) 156 :1164–9.\n3 \nKowatch R Suppes T Gilfillan SK Fuentes RM Grannemann BD Emslie GJ \nClozapine treatment of children and adolescents with bipolar disorder and schizophrenia: a clinical case series . J Child Adolesc Psychopharmacol (1995 ) 5 :241–53. 10.1089/cap.1995.5.241 \n\n4 \nNielsen J Kane JM Correll CU \nReal-world effectiveness of clozapine in patients with bipolar disorder: results from a 2-year mirror-image study . Bipolar Disord (2012 ) 14 :863–9. 10.1111/bdi.12018 \n\n5 \nBanov MD Zarate CA JrTohen M Scialabba D Wines JD JrKolbrener M \nClozapine therapy in refractory affective disorders: polarity predicts response in long-term follow-up . J Clin Psychiatry (1994 ) 55 :295 –300 .8071290 \n6 \nVangala VR Brown ES Suppes T \nClozapine associated with decreased suicidality in bipolar disorder: a case report . Bipolar Disord (1999 ) 1 :123–4. 10.1034/j.1399-5618.1999.010210.x \n\n7 \nSchaffer A Isometsä ET Tondo L Moreno D Turecki G Reis C \nInternational society for bipolar disorders task force on suicide: meta-analyses and meta-regression of correlates of suicide attempts and suicide deaths in bipolar disorder . Bipolar Disord (2015 ) 17 :1 –16 . 10.1111/bdi.12271 \n\n8 \nCarter TD Mundo E Parikh SV Kennedy JL \nEarly age at onset as a risk factor for poor outcome of bipolar disorder . J Psychiatr Res (2003 ) 37 :297 –303 . 10.1016/S0022-3956(03)00052-9 \n12765852 \n9 \nBaldessarini RJ Pompili M \nTondo L Bipolar Disorder . In: Simon HI Hales RE , editors. American Psychiatric Publishing Textbook of Suicide Assessment and Management . American Psychiatric Publishing (2006 ). p. 277–99.\n10 \nGoodwin FK Jamison KR \nManic-Depressive Illness . New York, NY : Oxford University Press (1990 ).\n11 \nBaldessarini RJ Pompili M Tondo L \nSuicide in bipolar disorder: risks and management . CNS Spectr (2006 ) 11 (6 ):465–71. 10.1017/S1092852900014681 \n\n12 \nCalabrese JR Kimmel SE Woyshville MJ Rapport DJ Faust CJ Thompson PA \nClozapine for treatment-refractory mania . J Psychiatry (1996 ) 153 :759–64. 10.1176/ajp.153.6.759 \n\n13 \nMeltzer HY Alphs L Green AI Altamura AC Anand R Bertoldi A \nClozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT) . Arch Gen Psychiatry (2003 ) 60 :82 –91 . 10.1001/archpsyc.60.1.82 \n12511175 \n14 \nHennen J Baldessarini RJ \nReduced suicidal risk during treatment with clozapine: meta-analysis . Schizophre Res (2005 ) 73 :139–45. 10.1016/j.schres.2004.05.015 \n\n15 \nCiapparelli A Dell’Osso L Pini S Chiavacci MC Fenzi M Cassano GB \nClozapine for treatment-refractory schizophrenia, schizoaffective disorder, and psychotic bipolar disorder: a 24-month naturalistic study . J Clin Psychiatry (2000 ) 61 :329–34. 10.4088/JCP.v61n0502 \n\n16 \nFehr BS Ozcan ME Suppes T \nLow doses of clozapine may stabilize treatment-resistant bipolar patients . Eur Arch Psychiatry Clin Neurosci (2005 ) 255 :10–4. 10.1007/s00406-004-0528-8 \n\n17 \nLi X-B Tang Y-L Wang C-Y de Leon J \nClozapine for treatment resistant bipolar disorder: a systematic review . Bipolar Disord (2015 ) 17 :235–47. 10.1111/bdi.12272 \n\n18 \nGriffiths JJ Zarate CA JrRasimas JJ \nExisting and novel biological therapeutics in suicide prevention . Am J Prev Med (2014 ) Sep47(3 Suppl 2 ):S195 –203 . 10.1016/j.amepre.2014.06.012 \n25145739 \n19 \nGoodwin GM \nConsensus Group of the British Association for Psychopharmacology. Evidence-based guidelines for treating bipolar disorder: revised second edition-recommendations from the British Association for Psychopharmacology . J Psychopharmacol (2009 ) 23 (4 ):346–88. 10.1177/0269881109102919 \n\n20 \nGrunze H Vieta E Goodwin GM Bowden C Licht RW Moller HJ \nThe World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of bipolar disorders: update 2012 on the long term treatment of bipolar disorder . World J Biol Psychiatry (2013 ) 14 :154 –219 . 10.3109/15622975.2013.770551 \n23480132 \n21 \nYatham LN Kennedy SH Schaffer A Parikh SV Beaulieus S O'Donovan C \nCanadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2009 . Bipolar Disord (2009 ) 11 :225–55. 10.1111/j.1399-5618.2009.00672.x \n\n22 \nNielsen J Dahm M Lublin H Taylor D \nPsychiatrists’ attitude towards and knowledge of clozapine treatment . J Psychopharmacol (2010 ) 24 :965–71. 10.1177/0269881108100320 \n\n23 \nMeltzer HY Anand R Alphs L \nReducing suicide risk in schizophrenia: focus on the role of clozapine . CNS Drugs (2000 ) 14 :355–65. 10.2165/00023210-200014050-00003 \n\n24 \nMarx CE Shampine LJ Duncan GE Van Doren MJ Grobin AC Massing MW \nClozapine markedly elevates pregnenolone in rat hippocampus, cerebral cortex, and serum: candidate mechanism for superior efficacy ? Pharmacol Biochem Behav (2006 ) 84 :598 –608 . 10.1016/j.pbb.2006.07.026 \n16962649 \n25 \nLeveque JC Macías W Rajadhyaksha A Carlsson RR Barczak A Kang S \nIntracellular modulation of NMDA receptor function by antipsychotic drugs . J Neurosci (2000 ) 20 :4011–20. 10.1523/JNEUROSCI.20-11-04011.2000 \n\n26 \nSpivak B Shabash E Sheitman B Weizman A Mester R \nThe effects of clozapine vs. haloperidol on measures of impulsive aggression and suicidality in chronic schizophrenia patients: an open, nonrandomized, 6-month study . J Clin Psychiatry (2003 ) 64 :755–60. 10.4088/JCP.v64n0703 \n\n27 \nPompili M Innamorati M Raja M Falcone I Ducci G Angeletti G \nSuicide risk in depression and bipolar disorder: do impulsiveness-aggressiveness and pharmacotherapy predict suicidal intent ? Neuropsychiatr Dis Treat (2008 ) 4 (1 ):247–55. 10.2147/NDT.S2192 \n\n28 \nYoussef NA Bradford DW Kilts JD Szabo ST Naylor JC Allen TB \nExploratory investigation of biomarker candidates for suicide in schizophrenia and bipolar disorder . Crisis (2015 ) 36 :46 –54 . 10.1027/0227-5910/a000280 \n25410258 \n29 \nPompili M Baldessarini RJ Forte A Erbuto D Serafini G Fiorillo A \nDo atypical antipsychotics have antisuicidal effects? a hypothesis-generating overview . Int J Mol Sci (2016 ) 17 (10 ):1700 . 10.3390/ijms17101700\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1664-0640",
"issue": "10()",
"journal": "Frontiers in psychiatry",
"keywords": "bipolar depression; bipolar disorder; clozapine; suicidal ideation; treatment resistance",
"medline_ta": "Front Psychiatry",
"mesh_terms": null,
"nlm_unique_id": "101545006",
"other_id": null,
"pages": "520",
"pmc": null,
"pmid": "31379632",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "10450255;10818136;10847306;11252659;12511175;12765852;12934974;15538596;15653256;16816785;16962649;18728807;19164499;19329543;19419382;23107278;23480132;25145739;25329791;25346322;25410258;27727180;7665540;8071290;8633686",
"title": "Clozapine in Treatment-Resistant Bipolar Disorder With Suicidality. Three Case Reports.",
"title_normalized": "clozapine in treatment resistant bipolar disorder with suicidality three case reports"
} | [
{
"companynumb": "PL-ALEMBIC PHARMACUETICALS LIMITED-2019SCAL000586",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "OLANZAPINE"
},
"druga... |
{
"abstract": "Early neonatal meningitis with non-fermenting Gram negative bacilli (NFGNB) is rare, and whenever it occurrs, inanimate environment is usually implicated as the source. The authors report a case of neonatal meningitis and sepsis with Chryseobacterium indologenes, a rare non fermenting Gram negative bacterium with unusual antimicrobial susceptibility. Despite resistance to all the beta lactams, carbapenems and aminoglycosides, therapy with ciprofloxacin led to a favorable outcome.",
"affiliations": "Department of Microbiology, Kasturba Medical College, Manipal University, Manipal, Udupi, Karnataka, 576104, India, vandanake@gmail.com.",
"authors": "Eshwara|Vandana Kalwaje|VK|;Sasi|Arun|A|;Munim|Frenil|F|;Purkayastha|Jayashree|J|;Lewis|Leslie Edward|LE|;Mukhopadhyay|Chiranjay|C|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002939:Ciprofloxacin",
"country": "India",
"delete": false,
"doi": "10.1007/s12098-013-1040-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0019-5456",
"issue": "81(6)",
"journal": "Indian journal of pediatrics",
"keywords": null,
"medline_ta": "Indian J Pediatr",
"mesh_terms": "D000900:Anti-Bacterial Agents; D045247:Chryseobacterium; D002939:Ciprofloxacin; D024881:Drug Resistance, Bacterial; D005260:Female; D045826:Flavobacteriaceae Infections; D006801:Humans; D007231:Infant, Newborn; D016920:Meningitis, Bacterial; D012074:Remission Induction; D018805:Sepsis",
"nlm_unique_id": "0417442",
"other_id": null,
"pages": "611-3",
"pmc": null,
"pmid": "23681831",
"pubdate": "2014-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "8818879;15947433;21235776;17596816;21654125;14715802;15794973;8879779;19729329;17326034",
"title": "Neonatal meningitis and sepsis by Chryseobacterium indologenes: a rare and resistant bacterium.",
"title_normalized": "neonatal meningitis and sepsis by chryseobacterium indologenes a rare and resistant bacterium"
} | [
{
"companynumb": "IN-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295809",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CIPROFLOXACIN"
},
"d... |
{
"abstract": "Gemcitabine (Gemzar) is the only chemotherapeutic agent approved by the U.S. Food and Drug Administration (FDA) for the treatment of advanced pancreatic cancer. Thromboembolism requiring anticoagulation is a common paraneoplastic complication in these patients. We report a case of patient with pancreatic cancer, complicated by gastrointestinal bleeding following therapy with concomitant gemcitabine-warfarin (Coumadin).The patient was a 65-year-old male with medical history notable for atrial fibrillation for which he was taking warfarin 57.5 mg/week (international normalized ratio [INR] 1.94). He received capecitabine-radiotherapy for locally advanced pancreatic cancer. Later, he developed multiple liver metastases. The patient was started on gemcitabine. At the end of first cycle, he experienced bright red blood per rectum. His platelet count was normal, but his INR was noted to be significantly elevated at 8.00. Esophagogastroduodenoscopy (EGD) revealed 2 antral ulcers and a duodenal ulcer. The patient was stabilized and recovered without further incident.Patients with pancreatic cancer who receive warfarin and gemcitabine should be monitored for any potential drug interactions. Weekly prothrombin time (PT)/INRs for anticoagulated patients receiving gemcitabine is suggested.",
"affiliations": "Section of Medical Oncology, Yale University School of Medicine, New Haven, Connecticut.",
"authors": "Saif|M Wasif|MW|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1537-064X",
"issue": "5(3)",
"journal": "The journal of applied research",
"keywords": null,
"medline_ta": "J Appl Res",
"mesh_terms": null,
"nlm_unique_id": "101132979",
"other_id": null,
"pages": "434-437",
"pmc": null,
"pmid": "19829753",
"pubdate": "2005-01-01",
"publication_types": "D016428:Journal Article",
"references": "9117804;8075055;10555940;9196156;3542339;12147431;11821446",
"title": "Interaction between Gemcitabine and Warfarin Causing Gastrointestinal Bleeding in a Patient with Pancreatic Cancer.",
"title_normalized": "interaction between gemcitabine and warfarin causing gastrointestinal bleeding in a patient with pancreatic cancer"
} | [
{
"companynumb": "US-PFIZER INC-2019357324",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nPatients with moderate to severe psoriasis may not respond adequately to single systemic agent and may require combination systemic therapy.\n\n\nOBJECTIVE\nTo evaluate the prevalence, indications, and response to combination systemic therapy with ustekinumab for psoriasis in a tertiary referral center.\n\n\nMETHODS\nThis retrospective study comprised 102 psoriasis patients treated with ustekinumab at a single tertiary care center. Data was collected pertaining to history of psoriasis, past and current therapies including use of concomitant psoriasis agents, response to therapy, and side effects while on ustekinumab.\n\n\nRESULTS\nTwenty-two of 102 (22%) patients were identified as receiving combination systemic treatment involving ustekinumab and at least one additional agent. The most common indication for combination therapy was psoriatic arthritis (35%), followed by bridging therapy (26%), inadequate psoriasis control (13%), prevention of non-melanoma skin cancers (17%), and control of palmoplantar disease (9%). Methotrexate was the additional agent in 12 patients, cyclosporine in 7 patients, acitretin in 5 patients, and 1 patient received a second biologic agent, first etanercept and then adalimumab. Overall, the reduction in body surface area (BSA) was 80% for patients on combination therapy. For those patients on combination therapy for psoriatic arthritis, 75% had resolution or stabilization of their symptoms. Only one patient, receiving cyclosporine, discontinued combination therapy due to adverse side effects.\n\n\nCONCLUSIONS\nCombination systemic therapy with ustekinumab can be effective and well tolerated for patients who cannot be adequately treated with ustekinumab alone.",
"affiliations": null,
"authors": "Heinecke|Gillian M|GM|;Luber|Adam J|AJ|;Levitt|Jacob O|JO|;Lebwohl|Mark G|MG|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D001688:Biological Products; D003879:Dermatologic Agents; D007166:Immunosuppressive Agents; D012176:Retinoids; D016572:Cyclosporine; D000069549:Ustekinumab; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-9616",
"issue": "12(10)",
"journal": "Journal of drugs in dermatology : JDD",
"keywords": null,
"medline_ta": "J Drugs Dermatol",
"mesh_terms": "D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D001688:Biological Products; D016572:Cyclosporine; D003879:Dermatologic Agents; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D011565:Psoriasis; D012176:Retinoids; D012189:Retrospective Studies; D062606:Tertiary Care Centers; D000069549:Ustekinumab",
"nlm_unique_id": "101160020",
"other_id": null,
"pages": "1098-102",
"pmc": null,
"pmid": "24085044",
"pubdate": "2013-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Combination use of ustekinumab with other systemic therapies: a retrospective study in a tertiary referral center.",
"title_normalized": "combination use of ustekinumab with other systemic therapies a retrospective study in a tertiary referral center"
} | [
{
"companynumb": "US-APOTEX-2015AP010270",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": null,
... |
{
"abstract": "The usual age range of acute lymphoblastic malignancies (acute lymphoblastic leukemia and advanced-stage lymphoblastic lymphoma) includes teenagers and young adults (<22 years of age) and coincides with the age of fertility. Concurrence of acute lymphoblastic malignancy with pregnancy is therefore most likely to happen during the younger childbearing ages. However, the therapeutic challenges posed by the dual diagnosis of lymphoblastic malignancy and pregnancy have not specifically been studied in the context of age, and management guidelines for pregnant young patients are lacking. Inconsistency in defining the legal decision-making rights of pregnant teenaged patients adds a further level of complexity in this age group. Management of this challenging combination in the young patient therefore entails unique ethical considerations. Here we present two illustrative cases of teenage pregnancy complicated by acute lymphoblastic malignancy, review the available literature, and offer suggestions for the therapeutic management of such cases in adolescent and young adult patients. Importantly, practical management recommendations are provided in the context of clinical ethics principles that are universally applicable, including in developing countries, where the highest incidence of adolescent pregnancies has been documented.",
"affiliations": "International Outreach Program, St. Jude Children's Research Hospital , Memphis, Tennessee. ; Department of Oncology, St. Jude Children's Research Hospital , Memphis, Tennessee.;Department of Oncology, St. Jude Children's Research Hospital , Memphis, Tennessee.;Division of General and Health Studies, Baptist College of Health Sciences , Memphis, Tennessee.;Department of Pediatric Hematology and Oncology, Hospital Infantil Dr. Robert Reid Cabral , Santo Domingo, Dominican Republic .;Department of Pediatric Hematology and Oncology, St. Jude Tri-Cities Affiliate , Johnson City, Tennessee.;Department of Pediatric Hematology and Oncology, Texas Children's Hospital , Houston, Texas.;Department of Oncology, St. Jude Children's Research Hospital , Memphis, Tennessee.",
"authors": "Zaidi|Alia|A|;Johnson|Liza-Marie|LM|;Church|Christopher L|CL|;Gomez-Garcia|Wendy C|WC|;Popescu|Marcela I|MI|;Margolin|Judith F|JF|;Ribeiro|Raul C|RC|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1089/jayao.2014.0014",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2156-5333",
"issue": "3(4)",
"journal": "Journal of adolescent and young adult oncology",
"keywords": "acute lymphoblastic leukemia; chemotherapy; lymphoma; pregnancy; teenager; teratogenicity",
"medline_ta": "J Adolesc Young Adult Oncol",
"mesh_terms": null,
"nlm_unique_id": "101543508",
"other_id": null,
"pages": "160-175",
"pmc": null,
"pmid": "25538861",
"pubdate": "2014-12-01",
"publication_types": "D016454:Review",
"references": "22511239;6337330;11800526;18712595;22851372;19762005;11476351;15912518;18285545;22326925;15327608;1546920;12185292;23015469;12684890;22508540;19841323;19745695;22325663;18690355;20018452;18355783;18472198;14679135;16272162;19807918;22880883;21733678;16310676;15120665;22463835;3340063;21444030;16421910;23182070;11779294;5690454;22119057;16326099;8628623;11378574;14716752;24269956;16310674;23889312;3046546;18040902;16328314;22296338;21239787;15370205;22488718;19844988;19463109;2351317;18322153;9565431;23198190;23725710;1707227;18291591;1985762",
"title": "Management of Concurrent Pregnancy and Acute Lymphoblastic Malignancy in Teenaged Patients: Two Illustrative Cases and Review of the Literature.",
"title_normalized": "management of concurrent pregnancy and acute lymphoblastic malignancy in teenaged patients two illustrative cases and review of the literature"
} | [
{
"companynumb": "US-APOTEX-2017AP018796",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DAUNORUBICIN"
},
"drugadditional": null,
... |
{
"abstract": "Reactivation of hepatitis B virus (HBV) is a serious complication of immunosuppressive therapy and cytotoxic chemotherapy. The optimal duration of HBV-DNA monitoring for at-risk patients depends on the clinical features of reactivation, especially the range of potency from therapies to reactivation. We present a case of very late reactivation after chemotherapy for lymphoma and review previous reports of late reactivation cases. We also underscore the significance of developing an indicator for anti-HBV immunity which can be used to determine the optimal monitoring period.",
"affiliations": "Department of Hematology, Gifu Prefectural Medical Center, Japan.",
"authors": "Yamada|Toshiki|T|;Nannya|Yasuhito|Y|;Suetsugu|Atsushi|A|;Shimizu|Shogo|S|;Sugihara|Junichi|J|;Shimizu|Masahito|M|;Seishima|Mitsuru|M|;Tsurumi|Hisashi|H|",
"chemical_list": "D000970:Antineoplastic Agents; D006514:Hepatitis B Surface Antigens",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.56.7468",
"fulltext": "\n==== Front\nIntern MedIntern. Med10.2169/internalmedicine.56.7468Internal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 28049989Case ReportLate Reactivation of Hepatitis B Virus after Chemotherapies for Hematological Malignancies: A Case Report and Review of the Literature Yamada Toshiki 1Nannya Yasuhito 23Suetsugu Atsushi 2Shimizu Shogo 4Sugihara Junichi 4Shimizu Masahito 2Seishima Mitsuru 35Tsurumi Hisashi 21 Department of Hematology, Gifu Prefectural Medical Center, Japan2 First Department of Internal Medicine, Gifu University School of Medicine, Japan3 Department of Transfusion Medicine, Gifu University School of Medicine, Japan4 Department of Gastroenterology, Gifu Prefectural Medical Center, Japan5 Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, JapanCorrespondence to Dr. Hisashi Tsurumi, htsuru@gifu-u.ac.jp\n\n1 1 2017 56 1 115 118 25 3 2016 13 5 2016 The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).Reactivation of hepatitis B virus (HBV) is a serious complication of immunosuppressive therapy and cytotoxic chemotherapy. The optimal duration of HBV-DNA monitoring for at-risk patients depends on the clinical features of reactivation, especially the range of potency from therapies to reactivation. We present a case of very late reactivation after chemotherapy for lymphoma and review previous reports of late reactivation cases. We also underscore the significance of developing an indicator for anti-HBV immunity which can be used to determine the optimal monitoring period. \n\nde novo hepatitishepatitis B virusrituximab\n==== Body\nIntroduction\nReactivation of hepatitis B virus (HBV) is a serious complication of immunosuppressive therapy and cytotoxic chemotherapy (1). Carriers of HBV (HBsAg-positive) are at higher risk of reactivation than non-carriers, and prophylaxis with anti-viral therapy is applied during and after these treatments (2). While patients who recovered from past HBV infection (HBsAg-negative and HBcAb-positive and/or HBsAb-positive) are at lower risk, they still carry a definite risk of reactivation and usually receive either prophylaxis or preemptive therapy, according to the viral load. Hepatitis in these patients is referred to as de novo hepatitis and poses a high risk of progressing to the fulminant form of hepatitis, which is associated with nearly 100% mortality once developed.\n\nA recently developed scheme for managing HBV reactivation has been shown to be highly effective, with a significant suppression rate of de novo hepatitis (3). However, sporadic cases of late reactivation, tentatively defined as those that take place more than 12 months after immunosuppressive therapies, have been reported under this management scheme, highlighting unresolved issues that are mainly due to the lack of any way of determining the optimal period for monitoring the viral load after chemotherapy. We herein report a case of very late reactivation of HBV following rituximab-containing therapy for malignant lymphoma and discuss this issue with a review of the literature regarding late HBV reactivation.\n\nCase Report\nA 77-year-old man was diagnosed with diffuse large B cell lymphoma stage IIA at low-intermediate risk according to the international prognostic index in July of Year X. A routine examination before treatment revealed positive HBsAb and HBcAb and negative HBsAg and HBV-DNA; we therefore concluded that this patient had previously had an HBV infection and started periodical monitoring of HBV-DNA according to the recommended management scheme in Japan. Six courses of R-CHOP therapy successfully induced complete remission.\n\nSince the patient remained negative for HBV-DNA for 20 months after R-CHOP therapy, we suspended further monitoring in November of Year X+2. We continued measuring ALT/AST as a routine laboratory test at outpatient visits. Nineteen months later (June of Year X+4; 33 months after the last session of R-CHOP therapy), this patient presented with increased levels of liver enzymes (ALT 104 IU/L, AST 97 IU/L) that had been within normal ranges one month prior. A further examination revealed reverse seroconversion of HBs (HBsAg 111 IU/mL, HBsAb ＜10 mIU/mL), and given that the patient had no history of blood transfusions and was sexually inactive, we diagnosed him with de novo hepatitis. The lymphocyte counts in the peripheral blood and serum IgG level were within normal limits. Entecavir was started, and the hepatitis resolved promptly leading to rapid suppression of HBV-DNA and HBsAg and recovery of HBsAb (32.1 mIU/mL) within two months. The clinical course of HBV-related markers is shown in Table 1. A further examination revealed that the patient had HBV-DNA genotype B, with a mixed precore mutation (nt1894, 10% mutated and 90% wild) and a wild type core promotor region (nt1972 and nt1974).\n\nTable 1. Clinical Profile of HBV Associated Markers.\n\ntime (year/month)\tX/Jula\tX+1/Marb\tX+2/Novc\tX+4/Jund\tX+4/Jul\tX+4/Aug\t\nHBsAg (IU/mL)\t0\t\t\t111\t0\t0\t\nHBsAb (mIU/mL)\t52.9\t\t\t<10\t\t32.1\t\nHBcAb\t9.9\t\t\t11.18\t10.19\t\t\nIgM HBcAb\t\t\t\t0.1\t\t\t\nHBeAg\t\t\t\t350\t0.4\t\t\nHBeAb (%)\t\t\t\t0.1\t90\t\t\nHBV-DNA (log copies/mL)\tnegative\tnegative\tnegative\t6.2\t<2.1\t\t\nHBcrAg\t\t\t\t>7.0\t4.7\t3.9\t\nAbbreviations: HBsAg: hepatitis B surface antigen, HBsAb: antibody against hepatitis B surface antigen, HBsAb: antibody against hepatitis B core antigen, HBeAg: hepatitis B e antigen, HBeAb: antibody against hepatitis B e antigen, HBcrAg: hepatitis B core related antigen\n\na DLBCL was diagnosed.\n\nb Six courses of R-CHOP finished.\n\nc HBV-DNA monitoring was suspended.\n\nd Hepatitis occurred and entecavir was administered.\n\nDiscussion\nHBV reactivation and de novo hepatitis is a serious condition associated with high mortality and morbidity usually encountered after chemotherapy or immunosuppressive therapy for patients with past HBV infection or HBV carriers (4). In endemic areas of HBV such as Japan, management guidelines are available to prevent de novo hepatitis in patients who are to receive therapies that entail immunosuppression (5); this preemptive approach is recommended for HBV non-carrier patients without a detectable viral load (HBV-DNA <2.1 log copies/mL); patients undergo monthly monitoring for HBV-DNA and begin anti-viral therapy when the HBV-DNA titer increases to ≥2.1 log copies/mL, and a prospective study in Japan has demonstrated the efficacy of this strategy in completely suppressing hepatitis (3). However, the success of this preemptive approach depends on the optimal setting of cutoff values for judging reactivation, because a similar approach in Taiwan applying distinct cut-off criteria resulted in the occurrence of 7 de novo hepatitis cases out of 150 enrollments (6).\n\nOur case of de novo hepatitis that occurred three years after the completion of chemotherapy is striking in that the present preemptive strategy was not able to completely prevent HBV reactivation-related hepatitis. We detected no early signs of reactivation, probably because we stopped HBV-DNA monitoring 18 months after chemotherapy, but this raises a significant issue regarding how long and in whom we should continue measuring viral load over the generally recommended duration of one year, which was tentatively determined based on the observation that most cases of HBV reactivation occurred within one year (7,8).\n\nIn practice, the duration of HBV monitoring for each patient is left to the discretion of each physician. While HBV reactivation has been widely acknowledged recently and the prevalence of the preemptive strategy has significantly suppressed de novo hepatitis, sporadic reports of late reactivation (defined as those taking place one year after the final therapy session) have gradually accumulated. However, integrative information such as the incidence and clinical characteristics of late reactivation are lacking, limiting the utility of these reports for enacting effective countermeasures.\n\nA more practical and economically less burdensome solution is to identify those patients who need an extended monitoring period, instead of continuing to monitor the viral load in all patients indefinitely. We therefore searched the PubMed database for late reactivation cases in hematological patients and reviewed them (7-13). The incidence of late reactivation in a prospective cohort under the routine monitoring policy is relatively low, ranging from 0% to 1.1% according to reports [Japanese cohort: 2/269 (3), Taiwanese cohort: 0/150 (6), Hong Kong cohort 3/263 (13)]. However, it would be inappropriate to ignore late reactivation based on its rarity, because de novo hepatitis is prone to progressing to fulminant hepatitis, which has a mortality of nearly 100% (4).\n\nHematopoietic stem cell transplantation is distinct from conventional chemotherapies, in that it involves much deeper immunological suppression and the need for immunosuppressing agents for a long period after allogeneic transplantation. These patients tend to have a much higher incidence of reactivation, and the reactivation time tends to be later than with conventional therapies (12). In such situations, a longer follow up period is recommended and justified. Therefore, we excluded transplant cases from the review, leaving a total of 14 cases (Table 2).\n\nTable 2. Cases of Late Reactivatio of HBV after Hemtological Chemotherapies (Transplantation Excluded).\n\n\t\t\t\t\t\t\tstatus at reactivation\t\t\t\t\nsex\tage\tdisease\ttreatment\tcylcles\tHBV status before treatment\tinterval from chemotherapy to reactivation\tliver enzymes and serostatus of HBV\tHBV genotype and mutation\tHBV-DNA\toutcome\ttreatment of reactivation\treferences\t\nFemale\t53\tDLBCL\tR-CEOP\t8\tHBsAg-, HBsAb+, HBcAb+, HBV-DNA<10 mIU/mL\t100 weeks\tALT 28 IU/L, HBsAg-, HBsAb+\tND\t310 IU/mL\trecovered\tentecavir\tSeto [13]\t\nFemale\t84\tLPL\tR\t4\tHBsAg-, HBsAb-, HBcAb+, HBV-DNA<10 mIU/mL\t80 weeks\tALT 19 IU/L, HBsAg-, HBsAb-\tND\t71 IU/mL\trecovered\tentecavir\tSeto [13]\t\nFemale\t68\tDLBCL\tR-CVP\t4\tHBsAg-, HBsAb+, HBcAb+, HBV-DNA<10 mIU/mL\t72 weeks\tALT 14 IU/L, HBsAg-, HBsAb+\tND\t82 IU/mL\trecovered\tentecavir\tSeto [13]\t\nFemale\t77\tlow grade B cell lymphoma\tR, R-Flu\t9 for R\tHBsAg-, HBsAb+, HBcAb-\t18 months\tAST 1740 IU/L, ALT 1904 IU/L, HBsAg+, HBsAb-HBcAb+, HBeAg+, HBeAb-\tgenotype D, sT118K\t230000 IU/mL\tND\tlamivudine\tCeccarelli [11]\t\nFemale\t78\tcutaneous follicular center B cell lymphoma\tR\t4\tHBsAg+, HBsAb-, HBcAb+, HBeAg-. HBeAb+\t12 months\tALT 1624 IU/L, HBsAg+, HBsAb-, HBcAb+, HBeAg+, HBeAb-\tND\t200000 copies/mL\tdead\tlamivudine\tPerceau [10]\t\nFemale\t68\tDLBCL\tR-CHOP\t6\tND\t1 year\tAST 109 IU/L, ALT 88 IU/L, HBsAb+, HBeAg-, HBeAb-*\tND\tND\tdead\tlamivudine\tGarcia [7]\t\nFemale\t50\tmalignant lymphoma\tR-CV\tND\tHBsAg+, HBsAb-, HBcAb+\t441 days\tAST/ALT elevation\tND\t6.9 log copies/mL\trecoverd\tentecavir\tTakahashi [9]\t\nFemale\t53\tmalignant lymphoma\tR-CHOP +MTX (IT)\tND\tHBsAg+, HBsAb-, HBcAb+\t539 days\tAST/ALT elevation\tND\t5.3 log copies/mL\tdead\tlamivudine\tTakahashi [9]\t\nMale\t84\tmalignant lymphoma\tR-THP-COP\tND\tHBsAg+\t1210 days\tND\tND\t8.8 log copies/mL\trecovered\tentecavir\tTakahashi [9]\t\nFemale\t87\tMM\tMP\tND\tHBsAg-, HBsAb+, HBcAb+, HBV-DNA<1.8 log copies/mL\t553 days\tHBsAg+\tND\t8.5 log copies/mL\trecovered\tentecavir\tTakahashi [9]\t\nND\telderly\tDLBCL\tR-CVP\t6\tHBsAg-, HBcAb+\t1 year\tAST 116 IU/L, ALT 139 IU/L, HBsAg-,\tgenotype D, G415R, T126T/I, T131A, C139Y, E/D144G\t1.7×107 IU/mL\trecovered\tlamivudine\tZoppoli [8]\t\nMale\t70\tDLBCL\tR-CHOP\t6\tHBsAb+, HBcAb+, HBV-DNA-\t21 months\tND\tND\t432 IU/mL\trecovered\tentecavir\tKusumoto [3]\t\nMale\t77\tDLBCL\tR-CHOP\t6\tHBsAb+, HBcAb+, HBV-DNA-\t13 months\tND\tno mutation\t14 IU/mL\trecovered\tentecavir\tKusumoto [3]\t\nMale\t77\tDLBCL\tR-CHOP\t6\tHBsAg-, HBsAb+, HBcAb+, HBV-DNA-\t33 months\tAST 104 IU/L, ALT 97 IU/L, HBsAg+, HBsAb-, HBcAb+, HBeAg+, HBeAb-\tgenotype B, nt1894\t6.2 log copies/mL\trecovered\tentecavir\tour case\t\nAbbreviations: ND, no data; DLBC, diffuse large B cell lymphoma; LPL, lymphoplasmacytic lymphoma; R, rituximab; Flu, fludarabine; CEOP, cyclophophamide, epirubicin, vincristine, prednisone; CV, cyclophophamide, vincristine; CVP, cyclophophamide, vincristine, prednisone; CHOP, cyclophophamide, doxorubicin, vincristine, prednisone; THP-COP, pirarubicin, cyclophophamide, vincristine, prednisone; MTX, methotrexate; IT, intrathecal; MP, melphalan, predonisone;\n* later, converted to HBsAg+ and HBeAg\n\nThese 14 patients were characterized by advanced age, lymphoid malignancies, and treatment with multiple courses of rituximab-containing therapies. Of note, some of these patients received less intensive or mild therapies, but even rituximab monotherapy and MP (melphalan and prednisolone) therapy caused late reactivation (10,13), suggesting that the intensity of treatments has little association with the risk of late reactivation. Discrete follow-up of patients with advanced age, lymphoid malignancies, and rituximab-containing therapies is warranted; however, these features are apparently unsatisfactory for the proper characterization of patients at high risk of late reactivation.\n\nNotably, though: whether or not late reactivation is a distinct disease state from typical de novo hepatitis remains controversial, as the clinical outcomes differ. Indeed, all 14 of the patients reviewed here received nucleoside analogues (5 lamivudine and 9 entecavir), and 10 were successfully treated, while typical de novo hepatitis has a much higher mortality rate. In addition, there are cases of spontaneous reactivation of HBV without any chemotherapies or immunosuppressive therapies who responded to anti-viral therapy promptly (14). These cases hamper determination of the clinical entity of late reactivation. However, it would be prudent to have a discrete follow-up policy in place until the clinical characteristics of late reactivation are clarified.\n\nAlternatively, judgements regarding when to finish monitoring the viral load might be best made based on the immunological status against HBV. This approach seems realistic, considering the difficulties in making an assessment of late reactivation by therapy-associated factors, as discussed above. HBV reactivation is the result of impaired anti-HBV immunity that allows the proliferation of HBV, which is subsequently attacked by the host's immune system when it recovers later. Therefore, it is assumed that we can safely stop monitoring HBV-DNA if we are able to detect the adequate recovery of anti-HBV immunity before an increase in the HBV titer. HBs-Ab is a potent candidate marker for assessing the recovery status of anti-HBV immunity due to its protective nature, and a low HBs-Ab titer is strongly associated with reactivation risk (15). Regarding the optimal threshold of HBs-Ab titer indicating adequate recovery of anti-HBV immunity, 50 mIU/mL has been suggested as a candidate based on prospective observations, where 18 of 19 reactivated cases showed an HBs-Ab titer below 50 mIU/mL at the time of reactivation (13). We believe we can safely stop HBV-DNA monitoring once the HBs-Ab values in cancer patients who have received immunosuppressive chemotherapies exceed this threshold. Clear determination of the recovery phase of immunity will require serial measurements of the markers, and clinical trials are needed to prove this concept.\n\nIn conclusion, we experienced a case of HBV reactivation over three years after R-CHOP therapy and discussed potential strategies for coping with late reactivation by reviewing similar previous cases. Our report highlights significant issues regarding the adequate monitoring period after chemotherapies for hematological diseases. The accumulation of cases to clarify the shared features is imperative for predicting and coping with late reactivation. The establishment of a reliable marker indicating the sufficient recovery of anti-HBV immunity will be useful as a guide for when to stop monitoring HBV-DNA for preemptive therapy.\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. \nYeo W , Chan PK , Zhong S , et al \nFrequency of hepatitis B virus reactivation in cancer patients undergoing cytotoxic chemotherapy: a prospective study of 626 patients with identification of risk factors . J Med Virol \n62 : 299 -307 , 2000 .11055239 \n2. \nYeo W , Zee B , Zhong S , et al \nComprehensive analysis of risk factors associating with Hepatitis B virus (HBV) reactivation in cancer patients undergoing cytotoxic chemotherapy . Br J Cancer \n90 : 1306 -1311 , 2004 .15054446 \n3. \nKusumoto S , Tanaka Y , Suzuki R , et al \nMonitoring of hepatitis B virus (HBV) DNA and risk of HBV reactivation in B-Cell lymphoma: a prospective observational study . Clin Infect Dis \n61 : 719 -729 , 2015 .25935551 \n4. \nUmemura T , Tanaka E , Kiyosawa K , Kumada H ; Japan de novo Hepatitis BRG . Mortality secondary to fulminant hepatic failure in patients with prior resolution of hepatitis B virus infection in Japan . Clin Infect Dis \n47 : e52 -e56 , 2008 .18643758 \n5. \nKusumoto S , Tanaka Y , Mizokami M , Ueda R \nReactivation of hepatitis B virus following systemic chemotherapy for malignant lymphoma . Int J Hematol \n90 : 13 -23 , 2009 .19544079 \n6. \nHsu C , Tsou HH , Lin SJ , et al \nChemotherapy-induced hepatitis B reactivation in lymphoma patients with resolved HBV infection: a prospective study . Hepatology \n59 : 2092 -2100 , 2014 .24002804 \n7. \nGarcia-Rodriguez MJ , Canales MA , Hernandez-Maraver D , Hernandez-Navarro F \nLate reactivation of resolved hepatitis B virus infection: an increasing complication post rituximab-based regimens treatment? \nAm J Hematol \n83 : 673 -675 , 2008 .18528824 \n8. \nZoppoli G , Bruzzone B , Caligiuri P , et al \nFrom a medical mistake to a clinical warning: the case of HBV mutant virus reactivation in haematological patients . Br J Haematol \n144 : 969 -970 , 2009 .19120363 \n9. \nTakahashi H , Ikeda M , Kumada T , et al \nMulticenter cooperative case survey of hepatitis B virus reactivation by chemotherapeutic agents . Hepatol Res \n45 : 1220 -1227 , 2015 .25627550 \n10. \nPerceau G , Diris N , Estines O , Derancourt C , Levy S , Bernard P \nLate lethal hepatitis B virus reactivation after rituximab treatment of low-grade cutaneous B-cell lymphoma . Br J Dermatol \n155 : 1053 -1056 , 2006 .17034541 \n11. \nCeccarelli L , Salpini R , Sarmati L , et al \nLate hepatitis B virus reactivation after lamivudine prophylaxis interruption in an anti-HBs-positive and anti-HBc-negative patient treated with rituximab-containing therapy . J Infect \n65 : 180 -183 , 2012 .22138369 \n12. \nHammond SP , Borchelt AM , Ukomadu C , Ho VT , Baden LR , Marty FM \nHepatitis B virus reactivation following allogeneic hematopoietic stem cell transplantation . Biol Blood Marrow Transplant \n15 : 1049 -1059 , 2009 .19660717 \n13. \nSeto WK , Chan TS , Hwang YY , et al \nHepatitis B reactivation in patients with previous hepatitis B virus exposure undergoing rituximab-containing chemotherapy for lymphoma: a prospective study . J Clin Oncol \n32 : 3736 -3743 , 2014 .25287829 \n14. \nKamitsukasa H , Iri M , Tanaka A , et al \nSpontaneous reactivation of hepatitis B virus (HBV) infection in patients with resolved or occult HBV infection . J Med Virol \n87 : 589 -600 , 2015 .25612181 \n15. \nYeo W , Chan TC , Leung NW , et al \nHepatitis B virus reactivation in lymphoma patients with prior resolved hepatitis B undergoing anticancer therapy with or without rituximab . J Clin Oncol \n27 : 605 -611 , 2009 .19075267\n\n",
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"issue": "56(1)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": null,
"medline_ta": "Intern Med",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D019337:Hematologic Neoplasms; D006509:Hepatitis B; D006514:Hepatitis B Surface Antigens; D006515:Hepatitis B virus; D006801:Humans; D008223:Lymphoma; D008297:Male; D014775:Virus Activation",
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"title": "Late Reactivation of Hepatitis B Virus after Chemotherapies for Hematological Malignancies: A Case Report and Review of the Literature.",
"title_normalized": "late reactivation of hepatitis b virus after chemotherapies for hematological malignancies a case report and review of the literature"
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"abstract": "Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a well-characterized oral complication of systemic therapy with bisphosphonates. Pseudoepitheliomatous hyperplasia was observed in some of the lesions. Because podoplanin expression has been linked to malignant lesions of the oral mucosa, we aimed to investigate podoplanin expression in the pseudoepitheliomatous hyperplasia. We analyzed archival paraffin- and plastic-embedded specimens from BRONJ using both conventional and immunohistochemical (AE1/AE3, D2-40) staining methods. Eleven out of seventeen BRONJ cases showed pseudoepitheliomatous hyperplasia. All these cases were positive for AE1/AE3 and pseudoepitheliomatous hyperplasia displayed a strong basal and parabasal reaction against podoplanin. The podoplanin expression in pseudoepitheliomatous hyperplasia in BRONJ specimens should not be considered a sign of malignancy. We discuss the current and possible future roles of surgical pathologists in diagnosing morphological changes associated with the development and therapy of BRONJ lesions.",
"affiliations": "Institute of Pathology, University Medical Centre Hamburg Eppendorf, Martinistr.52, 20246 Hamburg, Germany. j.zustin@uke.uni-hamburg.de.",
"authors": "Zustin|Jozef|J|;Reske|Dennis|D|;Zrnc|Tomislav A|TA|;Heiland|Max|M|;Scheuer|Hanna A|HA|;Assaf|Alexandre T|AT|;Friedrich|Reinhard E|RE|",
"chemical_list": "D004164:Diphosphonates; D008562:Membrane Glycoproteins; C117468:PDPN protein, human",
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"issue": "28(1)",
"journal": "In vivo (Athens, Greece)",
"keywords": "BRONJ; D2-40; Pseudoetheliomatous hyperplasia; bisphosphonate; podoplanin",
"medline_ta": "In Vivo",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw; D004164:Diphosphonates; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D006965:Hyperplasia; D007568:Jaw; D007573:Jaw Neoplasms; D008297:Male; D008562:Membrane Glycoproteins; D008875:Middle Aged; D016612:Paraffin Embedding; D011859:Radiography",
"nlm_unique_id": "8806809",
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"title": "Pseudoepitheliomatous hyperplasia associated with bisphosphonate-related osteonecrosis of the jaw.",
"title_normalized": "pseudoepitheliomatous hyperplasia associated with bisphosphonate related osteonecrosis of the jaw"
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"abstract": "A 27-year-old male patient presented with a maculopapular eruption on the flexural areas and buttocks after using oral ketoconazole. The patient was diagnosed with drug-induced baboon syndrome based on his history, which included prior sensitivity to topical ketoconazole, a physical examination, and histopathological findings. Baboon syndrome is a drug- or contact allergen-related maculopapular eruption that typically involves the flexural and gluteal areas. To the best of our knowledge, this is the first reported case of ketoconazole-induced baboon syndrome in the English literature.",
"affiliations": "Department of Dermatology, Duzce Medical Faculty , Duzce , Turkey.",
"authors": "Gulec|Ali Ihsan|AI|;Uslu|Esma|E|;Başkan|Elife|E|;Yavuzcan|Gizem|G|;Aliagaoglu|Cihangir|C|",
"chemical_list": "D000935:Antifungal Agents; D007654:Ketoconazole",
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"journal": "Cutaneous and ocular toxicology",
"keywords": "Baboon syndrome; SDRIFE; ketoconazole",
"medline_ta": "Cutan Ocul Toxicol",
"mesh_terms": "D000287:Administration, Topical; D000328:Adult; D000935:Antifungal Agents; D002081:Buttocks; D003875:Drug Eruptions; D004890:Erythema; D006801:Humans; D007654:Ketoconazole; D008297:Male; D012867:Skin; D013577:Syndrome; D014008:Tinea Pedis",
"nlm_unique_id": "101266892",
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"pubdate": "2014-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Baboon syndrome induced by ketoconazole.",
"title_normalized": "baboon syndrome induced by ketoconazole"
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"abstract": "The use of pharmacogenomics has become more prevalent over the past several years in treating many disease states. Several cytochrome P450 enzymes play a role in the metabolism of many pain medications including opioids and antidepressants. Noncytochrome P450 enzymes such as methylenetetrahydrofolate reductase (MTHFR) and catechol-O-methyl transferase (COMT) also play a role in the explanation of opioid dosage requirements as well as in response to certain antidepressants. We present the case of a patient with reduced COMT and MTHFR expression treated with leucovorin 10 mg daily for the management of chronic pain. The use of leucovorin in this patient decreased pain scores, which were clinically significant and increased functionality. This case demonstrates the importance of pharmacogenetics testing in patients, as this can help direct providers to better therapeutic options for their patients.",
"affiliations": "Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.;Department of Pharmacy, Albany Stratton VA Medical Center, Albany, NY, USA.;Research and Network Development, Boston Pain Care, Waltham, MA, USA.;Department of Pharmacy, Albany Stratton VA Medical Center, Albany, NY, USA.",
"authors": "Dragic|Lisa Lynn|LL|;Wegrzyn|Erica L|EL|;Schatman|Michael E|ME|;Fudin|Jeffrey|J|",
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"fulltext": "\n==== Front\nJ Pain ResJ Pain ResJournal of Pain ResearchJournal of Pain Research1178-7090Dove Medical Press 10.2147/JPR.S144560jpr-11-037Case ReportPharmacogenetic guidance: individualized medicine promotes enhanced pain outcomes Dragic Lisa Lynn 1Wegrzyn Erica L 2Schatman Michael E 345Fudin Jeffrey 26\n1 Central Arkansas Veterans Healthcare System, Little Rock, AR, USA\n2 Department of Pharmacy, Albany Stratton VA Medical Center, Albany, NY, USA\n3 Research and Network Development, Boston Pain Care, Waltham, MA, USA\n4 Public Health and Community Medicine, Tufts University School of Medicine, Boston, MA, USA\n5 Department of Public Health and Community Medicine, Tufts University School of Medicine, Boston, MA, USA\n6 Scientific and Clinical Affairs, Remitigate, LLC, Delmar, NY, USACorrespondence: Jeffrey Fudin, Scientific and Clinical Affairs, Remitigate LLC, 357 Delaware Avenue, #124, Delmar, NY 12054, USA, Tel +1 518 558 5651, Email jeffrey.fudin@remitigate.com2018 22 12 2017 11 37 40 © 2018 Dragic et al. This work is published and licensed by Dove Medical Press Limited2018The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.The use of pharmacogenomics has become more prevalent over the past several years in treating many disease states. Several cytochrome P450 enzymes play a role in the metabolism of many pain medications including opioids and antidepressants. Noncytochrome P450 enzymes such as methylenetetrahydrofolate reductase (MTHFR) and catechol-O-methyl transferase (COMT) also play a role in the explanation of opioid dosage requirements as well as in response to certain antidepressants. We present the case of a patient with reduced COMT and MTHFR expression treated with leucovorin 10 mg daily for the management of chronic pain. The use of leucovorin in this patient decreased pain scores, which were clinically significant and increased functionality. This case demonstrates the importance of pharmacogenetics testing in patients, as this can help direct providers to better therapeutic options for their patients.\n\nKeywords\npharmacogeneticdepressionpainMTHFRCOMTmethyl tetrahydrofolate reductasecatechol-O-methyltransferase\n==== Body\nIntroduction\nPharmacogenetics (PGT) plays an important role in several disease states including pain management and mental health disorders. The use of pharmacogenomics has become more prevalent over the past several years in treating various disease states, and over 150 drug manufacturers’ inserts include statements on dosing depending on these parameters. Several cytochrome (CYP) P450 enzymes play a role in the metabolism of many pain medications, including opioids and antidepressants. Genetic phenotypes vary among worldwide populations and even within populations.1 This phenomenon is known as polymorphism. Aside from CYP450 polymorphisms, there are many important genetic factors that affect response to and side effects of various medications that are commonly used in pain patients. This is especially important in patients with long-term pain when considering that various mental health disorders are common.2 Examples of nonCYP450 polymorphisms include methylenetetrahydrofolate reductase (MTHFR) and catechol-O-methyl-transferase (COMT), both of which play an important role in opioid and antidepressant response. We present a unique and interesting case of a patient with reduced COMT and MTHFR genes and the impact of initiating leucovorin. Ethical considerations for including PGT in the differential are discussed in terms of cost justification and outcomes.\n\nBackground\nPT is a 48-year-old man with a past medical history significant for attention-deficit hyperactivity disorder (ADHD), obstructive sleep apnea, fibromyalgia, posttraumatic stress disorder, and chronic low-back pain. The patient presented in October 2016 with worsening fibromyalgia pain and previous extreme sensitivity to antidepressants as outlined later. Prior to the patient’s visit to a comprehensive pain clinic, the patient was started on duloxetine, and after 5 days the patient reported a “debilitating headache and hangover effect.” The patient also reported similar side effects to venlafaxine, citalopram, sertraline, bupropion, and mirtazapine.\n\nBecause of the patient’s reactions to multiple medications, PT was sent for a PGT by saliva swab. PT was tested for 2C19, 2D6, 3A4/5, MTHFR, and COMT, all of which are responsible for the metabolism of many medications.3,4 For a summary of results, see Table 1.\n\nPGT results\nPGT testing yielded the following: COMT – reduced activity, MTHFR – reduced activity, CYP3A4 and CYP3A5 – intermediate metabolizer, CYP2C19 – normal metabolizer CYP2D6 – normal metabolizer, and UGT2B15 – normal metabolizer.\n\nRole of COMT and MTHFR\nThe patient exhibited reduced COMT activity, specifically the expression of the VAL158MET genotype. COMT is an enzyme that is responsible for the breakdown of serotonin, dopamine, norepinephrine, and other common neuroamines within neuronal junctions.5–7 The VAL158Met allele is associated with low COMT activity, which corresponds to increased concentrations of dopamine and norepinephrine in the cortical region.5–7 PT was also receiving methylphenidate, which blocks the reuptake of norepinephrine and dopamine into presynaptic neurons, resulting in increased dopaminergic and noradrenergic activity in the prefrontal cortex. We note that PT also exhibited reduced MTHFR activity, specifically the 677T and A1298C genotypes. MTHFR is responsible for converting 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, and 5-methyltetrahydrofolate is the predominant circulating form of folate.8\nMTHFR C677T polymorphism is associated with a reduction in the bioavailability of folate and folate metabolites. Thus, we expected PT to demonstrate a decreased ability to convert folic acid to its active form, essentially mimicking low dietary folate intake.8 Not only have reduced folate levels been linked to depression, but also to attention deficit disorder.8–10\n\nAt PT’s subsequent pain management visit in October 2016, he reiterated his extreme sensitivity to antidepressants and insufficient response to methylphenidate both for depression and ADHD. Theoretically, PT should have exhibited an increased response to methylphenidate due to reduced COMT activity; however, there is a possibility that the patient may have uncontrolled attention deficit disorder despite treatment due to reduced levels of usable folate. MTHFR activity is associated with poor or limited response to antidepressants, pain medications, and methylphenidate.10 Therefore, we hypothesized that PT could benefit from the addition of folate supplementation such as l-methylfolate or lecuovorin for pain, depression, and perhaps ADHD.10\n\nFolate supplementation\nl-Methylfolate is the active form of folate, and is the only form of folate that crosses the blood–brain barrier.10 Studies suggest that the use of l-methylfolate as an adjunctive agent to specific serotonin reuptake inhibitor and serotonin norepinephrine reuptake inhibitor treatment is associated with improved depression treatment outcomes.10 Additionally, supplementation of l-methylfolate may provide increased efficacy of methylphenadiate.10\n\nSince l-methylfolate was not a formulary item within the institution at which PT was being treated, the patient was started on leucovorin (folinic acid) 10 mg PO each morning for folate supplementation in November 2016. Leucovorin is the active form of folate and does not require MTHFR for activation. Possible side effects of leucovorin include neuropathic pain and zinc depletion; therefore, we provided him with zinc sulfate 220 mg PO every evening.\n\nPrior to initiation of leucovorin, PT reported a pain level of 9 out of 10 on a visual analog scale of 0–10, with 0 signifying no pain and 10 representing the worst pain possible. Just 1 week following the initiation of leucovorin, the patient reported his pain level to be 2–3 out of 10. He reported feeling “much better than before and was sharing his positive results with his friends in the medical field and was very grateful for the genetics testing.” Eight months later, he remains stable with regard to his pain, depression, and ADHD. He also reported increased functioning with daily activities.\n\nAlthough the clinical implications of this case are quite evident, the ethical issues associated with it are both obvious and subtle. First, and perhaps foremost, PGT should be performed in all cases in which patients demonstrate a combination of both nonresponsiveness and hypersensitivity to numerous medications. Unfortunately, in the United States, PGT is underutilized, with much of this failure to regularly use such technology due to insurers’ refusal to cover its costs. This failure has been empirically demonstrated to reduce patients’ willingness to utilize PGT, irrespective of their interest in such tests.11 Fortunately, the Veterans’ Affairs Medical System through which PT was treated has the wisdom to recognize that cost containment is not necessarily synonymous with cost efficiency.\n\nSecond, while CYP450 polymorphisms seem to receive considerable attention due to their formidable impact on opioid response, clinicians (and payers) need to recognize that a broad range of potential polymorphisms should not be ignored. In the case of PT, he was determined to be a normal metabolizer of CYP2D6 – the most common CYP P450 polymorphism.12 “Simple” PGT testing is not necessarily “thorough” PGT, with this case serving as evidence that numerous potential polymorphisms should be considered when patients are nonresponsive or hypersensitive to multiple therapeutic agents.\n\nFinally, PT’s good fortune to be treated by open-minded clinicians should not be underestimated. As a sufferer of long-term pain, many hospitals would not have done their due diligence by providing him with a comprehensive PGT panel. Patients with chronic pain, for myriad unfortunate reasons, are expected to respond positively to whatever pharmacologic intervention is initially provided. Those who do not do so are often stigmatized and provided with pejorative labels such as “drug-seekers.”13 We posit that although all patients with disease states deserve precision medicine approaches such as that received by PT, the stigmatization and marginalization of patients with the disease of chronic pain and criticism for random morphine equivalent daily dose limits in this unfortunate era of frank opiophobia make consideration of the comprehensive use of PGT even more crucial if their condition is to be treated from an optimally ethical perspective.\n\nConsent\nThe patient has provided written informed consent for the case details to be published.\n\nDisclosure\n\nDr Schatman would like to disclose that he is a consultant for Depomed. Dr Fudin discloses the following: Astra Zeneca (Speakers Bureau), Daiichi Sankyo (Advisory Board), Egalet (consultant, Advisory Board), Quest Labs (Advisory Board), Remitigate, LLC (Owner). The authors report no other conflicts of interest in this work.\n\nTable 1 Examples of medications\tEnzyme\tMetabolite\t\nCitalopram\t2C19, 3A4, 2D6\tDesmethylcitalopram\t\nVenlafaxine\t2D6\tO-desmethylvenlafaxine\t\nBupropion\t2B6\tHydroxybupropion\n==== Refs\nReferences\n1 Kirsh KL Ehlenberger E Huskey A Strickland J Egan City K Passik SD Exploring rates of abnormal pharmacogenetic findings in a pain practice J Pain Palliat Care Pharmacother 2014 28 1 28 32 24601730 \n2 Velly AM Mohit S Epidemiology of pain and relation to psychiatric disorders Prog Neuropsychopharmacol Biol Psychiatry Epub 2017 5 15 \n3 Kapur BM Lala PK Shaw JL Pharmacogenetics of chronic pain management Clin Biochem 2014 47 13–14 1169 1187 24912048 \n4 Ciraulo DA Pharmacotherapy of Depression Humana Press Totowa, NJ 2004 \n5 Matthews N Vance A Cummins TD The COMT Val158 allele is associated with impaired delayed-match-to-sample performance in ADHD Behav Brain Funct 2012 8 25 22640745 \n6 Cheon KA Jun JY Cho DY Association of the catechol-O-methyltransferase polymorphism with methylphenidate response in a classroom setting in children with attention-deficit hyperactivity disorder Int Clin Psychopharmacol 2008 23 5 291 298 18703939 \n7 Bonvicini C Faraone SV Scassellati C Attention-deficit hyperactivity disorder in adults: a systematic review and meta-analysis of genetic, pharmacogenetic and biochemical studies Mol Psychiatry 2016 21 11 1643 27502472 \n8 Gokcen C Kocak N Pekgor A Methylenetetrahydrofolate reductase gene polymorphisms in children with attention deficit hyperactivity disorder Int J Med Sci 2011 8 7 523 528 21897766 \n9 Young SN Folate and depression—a neglected problem J Psychiatr Neurosci 2007 32 2 80 82 \n10 Papakostas GI Shelton RC Zajecka JM L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials Am J Psychiatry 2012 169 12 1267 1274 23212058 \n11 Gibson ML Hohmeier KC Smith CT Pharmacogenomics testing in a community pharmacy: patient perceptions and willingness-to-pay Pharmacogenomics 2017 18 3 227 233 28112585 \n12 Yee MM Josephson C Hill CE Cytochrome P450 2D6 polymorphisms and predicted opioid metabolism in African American children with sickle cell disease J Pediatr Hematol Oncol 2013 35 7 e301 e305 23619115 \n13 Gazzaniga D Brenton A Meshkin B A precision medicine approach to a patient with unresolved pain following orthopedic surgery: a case report J Med Case Rep 2017 11 1 50 28231802\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1178-7090",
"issue": "11()",
"journal": "Journal of pain research",
"keywords": "COMT; MTHFR; catechol-O-methyltransferase; depression; methyl tetrahydrofolate reductase; pain; pharmacogenetic",
"medline_ta": "J Pain Res",
"mesh_terms": null,
"nlm_unique_id": "101540514",
"other_id": null,
"pages": "37-40",
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"pmid": "29317847",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "28522289;22640745;24601730;27502472;18703939;28231802;23619115;24912048;17353937;21897766;28112585;23212058",
"title": "Pharmacogenetic guidance: individualized medicine promotes enhanced pain outcomes.",
"title_normalized": "pharmacogenetic guidance individualized medicine promotes enhanced pain outcomes"
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"abstract": "Cholestatic liver disease has long been associated with childhood rickets, secondary to impaired absorption of fat-soluble vitamin D. Elevated serum levels of fibroblast growth factor 23 (FGF23), secondary to genetic defects or tumor-induced osteomalacia, causes hypophosphatemic rickets in childhood. We present 2 infants with end-stage liver disease due to biliary atresia (BA) who developed hypophosphatemia with renal phosphate wasting. Serum FGF23 levels were elevated more than 8 times the upper limit of normal, and the older infant showed radiographic evidence of rickets. Both infants required large supplements of phosphate in addition to calcitriol. Following liver transplantation, FGF23 normalized in both patients and phosphate and calcitriol supplementation were discontinued. Immunohistochemistry revealed ectopic overexpression of FGF23 by hepatocytes in the BA liver. These observations highlight a unique cause of hypophosphatemic rickets in childhood and suggest the need for further investigation into the relationship between BA and other cholestatic disorders, and bone metabolism.",
"affiliations": "Divisions of Endocrinology, Halley.wasserman@cchmc.org.;Divisions of Endocrinology.;Gastroenterology, Hepatology, and Nutrition, and.;Gastroenterology, Hepatology, and Nutrition, and.;Pathology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio.;Divisions of Endocrinology.",
"authors": "Wasserman|Halley|H|;Ikomi|Chijioke|C|;Hafberg|Einar T|ET|;Miethke|Alexander G|AG|;Bove|Kevin E|KE|;Backeljauw|Philippe F|PF|",
"chemical_list": "C000717427:FGF23 protein, human; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
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"issn_linking": "0031-4005",
"issue": "138(2)",
"journal": "Pediatrics",
"keywords": null,
"medline_ta": "Pediatrics",
"mesh_terms": "D001656:Biliary Atresia; D053098:Familial Hypophosphatemic Rickets; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors; D006801:Humans; D007223:Infant; D008297:Male",
"nlm_unique_id": "0376422",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "27462066",
"pubdate": "2016-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Two Case Reports of FGF23-Induced Hypophosphatemia in Childhood Biliary Atresia.",
"title_normalized": "two case reports of fgf23 induced hypophosphatemia in childhood biliary atresia"
} | [
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"companynumb": "US-STRIDES ARCOLAB LIMITED-2017SP001384",
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"abstract": "Recommendations on lithium dosing around delivery vary, with several guidelines suggesting that lithium should be discontinued prior to delivery. We aimed to evaluate the validity of these recommendations by investigating 1) maternal lithium blood level changes following delivery, and 2) the association between neonatal lithium blood levels at delivery and neonatal outcomes.\n\n\n\nIn this retrospective observational cohort study, we included women with at least one lithium blood level measurement during the final week of pregnancy and the first postpartum week. For aim 2, we included a subcohort of women with neonates for whom neonatal lithium blood levels (obtained from the umbilical cord or a neonatal vein puncture within 24 hours of delivery) were available.\n\n\n\nThere were a total of 233 maternal lithium blood level measurements; 55 (23.6%) in the week before delivery and 178 (76.4%) in the week after. There was no association between time and lithium blood level/dose ratio (Pearson correlation coefficient -0.03, P = .63). Additionally, we included a total of 29 neonates for whom a lithium measurement was performed within 24 hours postpartum. Maternal and neonatal lithium blood levels were strongly correlated. We observed no associations between neonatal lithium blood levels at delivery and neonatal outcomes.\n\n\n\nBased on our findings, we do not recommend lowering the dosage or discontinuation of lithium prior to delivery. Stable dosing can prevent subtherapeutic lithium serum levels, which is especially important in the postpartum period when relapse risks are highest.",
"affiliations": "Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.;Department of Psychiatry, Erasmus Medical Center, Rotterdam, The Netherlands.;Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.;Department of Psychiatry, Erasmus Medical Center, Rotterdam, The Netherlands.;Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.",
"authors": "Molenaar|Nina M|NM|0000-0003-2531-9467;Poels|Eline M P|EMP|;Robakis|Thalia|T|;Wesseloo|Richard|R|0000-0003-0298-3728;Bergink|Veerle|V|",
"chemical_list": "D008094:Lithium",
"country": "Denmark",
"delete": false,
"doi": "10.1111/bdi.12955",
"fulltext": "\n==== Front\nBipolar Disord\nBipolar Disord\n10.1111/(ISSN)1399-5618\nBDI\nBipolar Disorders\n1398-5647 1399-5618 John Wiley and Sons Inc. Hoboken \n\n32526071\n10.1111/bdi.12955\nBDI12955\nOriginal Article\nOriginal Articles\nManagement of lithium dosing around delivery: An observational study\nMOLENAAR ET AL.Molenaar Nina M. https://orcid.org/0000-0003-2531-9467\n1\n\n2\nnina.molenaar@mssm.edu Poels Eline M. P. \n2\n Robakis Thalia \n1\n Wesseloo Richard https://orcid.org/0000-0003-0298-3728\n2\n\n3\n Bergink Veerle \n1\n\n2\n\n4\n \n1 \nDepartment of Psychiatry\nIcahn School of Medicine at Mount Sinai\nNew York City\nNew York\nUSA\n\n\n2 \nDepartment of Psychiatry\nErasmus Medical Center\nRotterdam\nThe Netherlands\n\n\n3 \nDepartment of Psychiatry\nGGZ Delftland\nDelft\nThe Netherlands\n\n\n4 \nDepartment of Obstetrics, Gynecology and Reproductive Science\nIcahn School of Medicine at Mount Sinai\nNew York City\nNew York\nUSA\n\n* Correspondence\n\nNina M. Molenaar, Icahn School of Medicine at Mount Sinai, New York, NY.\n\nEmail: nina.molenaar@mssm.edu\n\n30 6 2020 \n2 2021 \n23 1 10.1111/bdi.v23.149 54\n© 2020 The Authors. Bipolar Disorders published by John Wiley & Sons LtdThis is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nObjectives\nRecommendations on lithium dosing around delivery vary, with several guidelines suggesting that lithium should be discontinued prior to delivery. We aimed to evaluate the validity of these recommendations by investigating 1) maternal lithium blood level changes following delivery, and 2) the association between neonatal lithium blood levels at delivery and neonatal outcomes.\n\nMethods\nIn this retrospective observational cohort study, we included women with at least one lithium blood level measurement during the final week of pregnancy and the first postpartum week. For aim 2, we included a subcohort of women with neonates for whom neonatal lithium blood levels (obtained from the umbilical cord or a neonatal vein puncture within 24 hours of delivery) were available.\n\nResults\nThere were a total of 233 maternal lithium blood level measurements; 55 (23.6%) in the week before delivery and 178 (76.4%) in the week after. There was no association between time and lithium blood level/dose ratio (Pearson correlation coefficient −0.03, P = .63). Additionally, we included a total of 29 neonates for whom a lithium measurement was performed within 24 hours postpartum. Maternal and neonatal lithium blood levels were strongly correlated. We observed no associations between neonatal lithium blood levels at delivery and neonatal outcomes.\n\nConclusion\nBased on our findings, we do not recommend lowering the dosage or discontinuation of lithium prior to delivery. Stable dosing can prevent subtherapeutic lithium serum levels, which is especially important in the postpartum period when relapse risks are highest.\n\ndeliveryinfantlithiumneonatepostpartumpregnancythe Netherlands Organization for Scientific ResearchBlavatnik Women's Health Institute source-schema-version-number2.0cover-dateFebruary 2021details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.7 mode:remove_FC converted:18.02.2021\n\n\nMolenaar \nNM \n, \nPoels \nEMP \n, \nRobakis \nT \n, \nWesseloo \nR \n, \nBergink \nV \n. Management of lithium dosing around delivery: An observational study\n. Bipolar Disord .2021 ;23 :49 –54\n. 10.1111/bdi.12955 \n32526071\n==== Body\n1 INTRODUCTION\nWomen with bipolar disorder are at high risk of relapse in the postpartum period.\n1\n, \n2\n Especially women without prophylactic pharmacotherapy are at elevated risk of postpartum relapse, with a reported pooled prevalence rate of 66%.\n1\n Effective treatment with pharmacotherapy is therefore of critical importance. Lithium is an effective mood stabilizer and is widely used as a first‐line treatment for bipolar disorder.\n3\n Some women choose to start lithium prophylaxis immediately after delivery, but for other women, continuation of lithium during pregnancy is the best option, despite associated risks.\n4\n Lithium use during the first trimester of pregnancy is associated with a dose dependent increased risk of congenital malformations.\n5\n, \n6\n An increased risk could not be found for lithium use during the second and third trimester.\n\nDosing of lithium can be challenging as a result of normal physiological adaptations of renal function throughout pregnancy.\n7\n Lithium blood levels decrease gradually in the first and second trimester, returning to their preconception level in the third trimester.\n8\n, \n9\n As a consequence, there is a risk of subtherapeutic lithium levels in the first and second trimester, which might lead to an increase in the dose by clinicians. This, in turn, could lead to an increased risk of lithium intoxication in the third trimester and the postpartum period. Frequent monitoring of lithium blood levels during pregnancy is therefore recommended and dosage should be adjusted in order to remain within the therapeutic window (0.5 mmol/L to 1.2 mmol/L).\n4\n, \n8\n, \n10\n, \n11\n\n\n\nSeveral reviews and guidelines have provided clinical advice on dosing strategy during pregnancy and the postpartum, including strategies for dosing around delivery to minimize the risk of both maternal and neonatal complications. Some suggest dose reduction by 30%‐50% upon first signs of labor or immediately after delivery,\n9\n, \n12\n, \n13\n, \n14\n, \n15\n and others recommend to stop lithium prior to delivery.\n16\n, \n17\n, \n18\n The underlying rationale is two‐fold: 1) blood lithium levels may rise due to a decrease in lithium clearance and vascular volume following delivery, and 2) a previous study found an association between lithium blood levels around delivery and neonatal complications, suggesting that a lower dosage could reduce the complication rate.\n19\n\n\n\nIn the current study we aimed to evaluate the validity of the recommendations around delivery by further investigating maternal lithium blood level changes following delivery (aim 1) and by examining the association between neonatal lithium blood levels at delivery and neonatal outcomes (aim 2).\n\n2 PATIENTS AND METHODS\nThis retrospective observational cohort study was part of a larger study for which all women referred to the psychiatric and obstetric out‐patient clinics of Erasmus Medical Center and Leiden University Medical Center between January 2003 and May 2018 were eligible.\n8\n Women were included in the current study if they used lithium during pregnancy and at least one lithium blood level measurement was obtained during the final week of pregnancy and the first postpartum week (aim 1). From the medical records, we extracted demographic, psychiatric and obstetric data, lithium blood level measurements, daily lithium dose, dosing alterations, and the dosing frequency. For aim 2, we included a subcohort of women with neonates for whom neonatal lithium blood levels were available. Clinical protocols in the Erasmus Medical Center recommend clinical observation of all lithium exposed neonates during the first 5 days after birth. Neonatal lithium blood levels were obtained from the umbilical cord or a neonatal vein puncture within 24 hours of delivery. From the medical records, we extracted information on neonatal outcomes and complications, including mild and transient complications. Extracted neonatal outcomes included: preterm birth, birth weight, Apgar scores, cord blood pH‐values, cord blood Base Excess values, and admission to medium/high care. We extracted information of all reported complications, ranging from mild to severe, and categorized them by organ system: respiratory, circulatory, hematological, gastro‐intestinal, metabolic, neurological, and immune system (infections).\n\nThe study was approved by the medical ethical review board of Erasmus University Medical Centre (MEC‐2013‐319).\n\n2.1 Statistical analysis\nFor aim 1, we calculated the lithium blood level/dose ratio for each measurement, and visualized (scatterplot) and tested (R‐squared) the correlation between time (−7 to +7 days of delivery date) and lithium blood level/dose ratio. Lithium citrate (Litarex 564mg = 6mmol lithium) dosages were multiplied by 0.395 in order to obtain lithium carbonate prescription equivalents (400 mg = 10.8 mmol lithium).\n\nFor our second aim, we first visualized (scatterplot) and tested (R‐squared) the correlation between maternal and neonatal lithium blood levels surrounding delivery. Sensitivity analyses (two sample t‐test and Mann‐Whitney U test) were used to assess whether mean neonatal blood levels differed between umbilical cord and neonatal vein puncture measurements. We then used linear and binary logistic univariate regression to examine the association between neonatal lithium blood levels and neonatal outcome measures (preterm birth, birthweight, Apgar scores, cord blood pH‐ and BE‐values, admission to medium/high care, and neonatal complications). No multivariate regression analysis was performed due to the limited number of pregnancies included. The Statistical Package for Social Sciences (SPSS) version 25.0 was used for data analyses and the significance level was set at 0.05, two sided.\n\n3 RESULTS\n3.1 Lithium blood level changes following delivery (Aim 1)\nWe identified 78 women with a total of 100 pregnancies who were referred to the specialized out‐patient university clinics of Rotterdam (n = 57) and Leiden (n = 21). The most common psychiatric diagnosis was bipolar spectrum disorder (n = 68, 87.2%), while the remaining women (n = 10, 12.8%) were diagnosed with schizoaffective disorder, depressive disorder, or borderline personality traits. Median parity of all pregnancies was 1 (range 0‐6) and mean age at delivery 34.6 years (SD 4.3).\n\nThere were a total of 233 lithium blood level measurements: 55 (23.6%) in the week before delivery and 178 (76.4%) in the week after. Mean lithium dosage was 1071 mg (SD 368) in the week before delivery and 1016mg (SD 284) in the week after delivery. Mean lithium blood level was 0.73 mmol/L in the week before delivery and 0.70 mmol/L in the week after delivery. The course of the lithium blood level/dose ratio before and after delivery can be seen in Figure 1. There was no association between time and ratio (Pearson correlation coefficient −0.03, P = .63). Lithium blood levels not normalized to dose can be found in Supplementary Figure 1.\n\nFIGURE 1 Course of lithium blood level/dose ration around delivery\n\n3.2 Lithium blood levels and neonatal complications (Aim 2)\nWe included a total of 29 neonates for which a lithium measurement was performed within 24 hours postpartum (20 umbilical cord, 9 neonatal vein puncture). Cohort characteristics are represented in Table 1. While approximately half of the neonates had a complication, the majority of reported neonatal complications were mild and transient. One term neonate with fetal distress had complications in all seven organ systems, while having a neonatal lithium blood level of 0.72 mmol/L, and a birth weight of 4360 grams. A full overview of complications per neonate with additional lithium blood level can be found in Supplementary Table 1. All neonates with medium/high care admission were discharged in good medical condition, except for one neonate that was transferred to another hospital for further recovery from a respiratory infection.\n\nTABLE 1 Maternal and neonatal characteristics of the sub cohort (aim 2)\n\nMaternal characteristics\tAll (N = 29)\t\nLithium dosage in mg/day, mean (SD)\na\n\n\t1142.82 (350.74)\t\nLithium blood level in mmol/L, mean (SD)\t0.67 (0.23)\t\nComplications during delivery, n (%)\nb\n\n\t16 (55.2)\t\nNeonatal characteristics\t\nLithium blood level in mmol/L, mean (SD)\t0.61 (0.31)\t\nPreterm (<37 weeks), n (%)\t3 (10.3)\t\nBirth weight in grams, mean (SD)\t3589.14 (457.16)\t\nApgar score 1 minute, median (IQR)\t8 (2)\t\nApgar score 5 minutes, median (IQR)\t9 (2)\t\npH‐value cord blood, mean (SD)\t7.24 (0.10)\t\nBase Excess value cord blood, mean (SD)\t−4.50 (5.12)\t\nAdmission medium/high care, n (%)\t13 (44.8)\t\nDuration admission medium/high care in days, median (IQR)\t3 (4)\t\nAny complication (including mild/transient), n (%)\nc\n\n\t14 (48.3)\t\nNeurological complications, n (%)\t5 (17.2)\t\nRespiratory complications, n (%)\t5 (17.2)\t\nCirculatory complications, n (%)\t1 (3.4)\t\nGastro‐intestinal complications, n (%)\t1 (3.4)\t\nInfectious complications, n (%)\t4 (13.8)\t\nHematological complications, n (%)\t1 (3.4)\t\nMetabolic complications, n (%)\t7 (24.1)\t\na Lithium dosage closest to delivery.\n\nb Observed complications: fetal distress (n = 7), postpartum hemorrhage (n = 5), prolonged rupture of the membranes (n = 5), increased duration second stage of labor (n = 3), preterm birth (n = 3), shoulder dystocia (n = 1), retained placenta (n = 1), meconium amniotic fluid (n = 1).\n\nc Details of complications: neurological – hypotonia (n = 3), tremors (n = 1), irritability (n = 1); respiratory – asphyxia with no spontaneous breathing after birth (n = 1), dyspnea (n = 1), cyanosis (n = 1), decreased oxygen saturation due to vomiting (n = 1), impaired breathing coordination (n = 1); circulatory – bradycardia (n = 1); gastro‐intestinal – cholestasis (n = 1); infectious – pneumonia (n = 1), observation/treatment for suspected infection (n = 3); hematological – disseminated intravascular coagulation (n = 1); metabolic – hyperbilirubinemia (n = 6), transient abnormal thyroid levels (n = 1).\n\nJohn Wiley & Sons, LtdThere was a strong positive correlation between maternal and neonatal lithium blood levels (Pearson correlation coefficient 0.703, P < .001), which is visualized in Figure 2. Sensitivity analyses showed no significant difference in mean neonatal blood levels between umbilical cord and neonatal vein puncture measurements (two sample t‐test, P = .288; Mann‐Whitney U test, P = .390).\n\nFIGURE 2 Correlation between maternal and neonatal lithium blood levels around delivery. Maternal lithium blood levels were obtained between 2 days prior to delivery and 6 days after delivery. Neonatal blood levels were obtained from the umbilical cord (n = 20) or neonatal vein puncture within 24 hours after delivery (n = 9)\n\nUnivariate linear and logistic regression analysis showed no associations between neonatal lithium blood levels and complications during delivery (B = 11.8, 95% CI 0.8;181.1, P = .1), preterm birth (B = 8.2, 95% CI 0.1;746.7, P = .4), birth weight (B = 79.8, 95% CI −496.1;655.7, P = .8), Apgar score at 1 minute (B=−1.2, 95% CI −3.9;1.4, P = .4) and 5 minutes (B = −0.8, 95% CI −2.8;1.1, P = .4), cord blood pH‐value (B = −0.1, 95% CI −0.2;0.0, P = .2), cord blood BE‐value (B = −6.2, 95% CI −12.7;0.4, P = .1), admission to medium/high care (B = 1.8, 95% CI 0.2;20.1, P = .6), and neonatal complications (B = 1.2, 95% CI 0.1;12.9, P = .9).\n\n4 DISCUSSION\nIn this retrospective observational cohort study, we found no maternal lithium blood level fluctuations surrounding delivery. Maternal and neonatal lithium blood levels were strongly correlated. We observed no association between neonatal lithium blood levels at delivery and neonatal outcomes.\n\nSeveral guidelines recommend, out of caution, lowering or discontinuing lithium prior to labor to avoid high plasma lithium levels.\n13\n, \n14\n, \n15\n, \n16\n, \n17\n, \n18\n Blood levels are assumed to rise due to a decrease in lithium clearance and contraction of fluid volume following delivery, possibly reaching toxic levels. These recommendations are primarily based on reviews and case studies rather than on observational data of the target population, as cohort studies are sparse due to methodological difficulties. Our data indicates that lithium plasma levels do not increase during labor after correcting for the prescribed lithium dose.\n\nA second argument for decreasing or discontinuing lithium treatment just before labor is the belief that a lower neonatal lithium blood level at time of delivery reduces the risks of lithium side‐effects in the neonate. This argument is based on the important study by Newport et al,\n19\n in which lithium concentrations and obstetrical outcomes were available for 10 neonates, plus for another 14 neonates identified from published reports. Infants were grouped into a low and high lithium exposure group (cut‐off of 0.64 meq/L). They found that the high lithium exposure group had a higher rate of complications compared to the low lithium group, including central nervous system and neuromuscular complications, longer duration of infant hospital stay, and lower 1‐minute Apgar scores. In our sample of 29 neonates, we did not find a significant association between neonatal lithium blood levels and neonatal outcomes. A potential explanation for these contrasting findings is that neonatal blood level range differed substantially between our sample and the sample of Newport et al.\n19\n The high lithium exposure group in Newport's study was predominantly composed of the neonates from previous case reports, who often had a lithium blood level higher than 0.7 and with some neonates classified as being within the toxic range (>1.2 mmol/L). Their low lithium exposure group existed mainly of women who had suspended their lithium treatment before delivery, and lithium levels were mostly subtherapeutic (<0.5 mmol/L). In our sample, most women were within the therapeutic window and no toxic levels were observed. Neonatal lithium levels might be associated with neonatal complication rate only if high (toxic) lithium dosages are used. Moreover, in the Newport paper, the overall complication rate of 100% in the high exposure group was driven by case reports on this topic for which publication bias is likely. Case studies are in origin a tool to disseminate information on unusual clinical syndromes, disease associations, or unusual side effects to therapy,\n20\n and therefore in this case more likely to be published if neonatal complications were present with high lithium levels.\n\nThe high rate of neonatal complications (48.3%) in our study sample should be interpreted keeping in mind that lithium use during pregnancy is an indication for neonatal observation during the first five days following birth. Due to this observation period and the knowledge of lithium exposure during pregnancy, several mild complications might have been detected and recorded that otherwise would have gone unnoticed. Fortunately, even though the rate of complications was high, most complications were mild and transient.\n\nThis study is not without limitations. Statistical power was limited for examining the association between neonatal lithium levels and neonatal outcomes, even though we report on the largest sample thus far. In addition, neonatal lithium levels are not routinely assessed in clinical settings. Selective sampling might have contributed to relatively high neonatal lithium levels, as well as to a high complication rate.\n\nLithium dosing during pregnancy can be challenging due to changes in clearance throughout the trimesters. Relapse risk during pregnancy is not elevated and some authors even suggest that pregnancy is protective for relapse.\n21\n Lithium levels in the lower range are often accepted, especially during the first trimester, in which there is a dose dependent increased risk for congenital malformations.\n22\n In general, we recommend to monitor lithium levels frequently until 34 weeks of pregnancy, for example once every three weeks, followed by weekly monitoring until delivery. Lithium levels should not exceed therapeutic levels during pregnancy, as this may cause harm to the pregnant woman and her developing child. Based on the results of this study, we do not recommend to lower the dosage or discontinue lithium prior to delivery when lithium is used within the therapeutic window, unless this is warranted by special circumstances such as severe dehydration or renal dysfunction. Lowering the lithium dosage prior to delivery could lead to a subtherapeutic blood level and, as a consequence, insufficient protection against maternal relapse in the postpartum period, when relapse risks are highest.\n23\n Instead, we recommend to carefully monitor lithium blood levels around delivery, and secure adequate fluid management. After delivery, we recommend lithium blood levels be obtained once at day 2 postpartum, followed again by (bi‐)weekly monitoring, and dosage adjustments when necessary. A high target therapeutic lithium blood level (eg 0.8‐1.0 mmol/L) immediately after delivery and during the first month postpartum is recommended to optimize relapse prevention.\n\n5 DECLARATIONS\n\nEthics approval and consent to participate: The study was approved by the medical ethical review board of Erasmus University Medical Centre (MEC‐2013‐319). Due to the retrospective nature of the study, the need for consent was waived.\n\nSupporting information\nSupplementary Material\n\nClick here for additional data file.\n\n ACKNOWLEDGEMENTS\nVB is supported by the Netherlands Organization for Scientific Research (the NWO Innovational Research Incentives Scheme), and the Blavatnik Women's Health Institute. The funding body did not have a role in the design of the study and collection, analysis, interpretation of the data, or in writing the manuscript.\n\nDATA AVAILABILITY STATEMENT\nThe data that support the findings of this study are available on request from the corresponding author. The data are not publicly available as they contain information that could compromise research participant privacy.\n==== Refs\nREFERENCES\n1 \n\nWesseloo \nR \n, \nKamperman \nAM \n, \nMunk‐Olsen \nT \n, \nPop \nVJM \n, \nKushner \nSA \n, \nBergink \nV \n. Risk of postpartum relapse in bipolar disorder and postpartum psychosis: a systematic review and meta‐analysis\n. Am J Psychiatry . 2016 ;173 (2 ):117 ‐127\n. 10.1176/appi.ajp.2015.15010124 \n26514657 \n2 \n\nSalim \nM \n, \nSharma \nV \n, \nAnderson \nKK \n. Recurrence of bipolar disorder during pregnancy: a systematic review\n. Arch Womens Ment Health . 2018 ;21 (4 ):475 ‐479\n. 10.1007/s00737-018-0831-4 \n29549439 \n3 \n\nGeddes \nJR \n, \nMiklowitz \nDJ \n. Treatment of bipolar disorder\n. Lancet . 2013 ;381 (9878 ):1672 ‐1682\n. 10.1016/S0140-6736(13)60857-0 \n23663953 \n4 \n\nPoels \nEMP \n, \nBijma \nHH \n, \nGalbally \nM \n, \nBergink \nV \n. Bergink V. Lithium during pregnancy and after delivery: a review\n. Int J Bipolar Disord . 2018 ;6 (1 ). 10.1186/s40345-018-0135-7 \n\n5 \n\nMunk‐Olsen \nT \n, \nLiu \nX \n, \nViktorin \nA \n, et al. Maternal and infant outcomes associated with lithium use in pregnancy: an international collaborative meta‐analysis of six cohort studies\n. Lancet Psychiatry . 2018 ;5 (8 ):644 ‐652\n. 10.1016/S2215-0366(18)30180-9 \n29929874 \n6 \n\nPatorno \nE \n, \nHuybrechts \nKF \n, \nBateman \nBT \n, et al. Lithium use in pregnancy and the risk of cardiac malformations\n. N Engl J Med . 2017 ;376 (23 ):2245 ‐2254\n. 10.1056/NEJMoa1612222 \n28591541 \n7 \n\nDeligiannidis \nKM \n, \nByatt \nN \n, \nFreeman \nMP \n. Pharmacotherapy for mood disorders in pregnancy: a review of pharmacokinetic changes and clinical recommendations for therapeutic drug monitoring\n. J Clin Psychopharmacol . 2014 ;34 (2 ):244 ‐255\n. 10.1097/JCP.0000000000000087 \n24525634 \n8 \n\nWesseloo \nR \n, \nWierdsma \nAI \n, \nvan Kamp \nIL \n, et al. Lithium dosing strategies during pregnancy and the postpartum period\n. Br J Psychiatry . 2017 ;211 (1 ):31 ‐36\n. 10.1192/bjp.bp.116.192799 \n28673946 \n9 \n\nKhan \nSJ \n, \nFersh \nME \n, \nErnst \nC \n, \nKlipstein \nK \n, \nAlbertini \nES \n, \nLusskin \nSI \n. Bipolar disorder in pregnancy and postpartum: principles of management\n. Curr Psychiatry Rep . 2016 ;18 (2 ):1 ‐11\n. 10.1007/s11920-015-0658-x \n26685903 \n10 \n\nGraham \nRK \n, \nTavella \nG \n, \nParker \nGB \n. Is there consensus across international evidence‐based guidelines for the psychotropic drug management of bipolar disorder during the perinatal period?\n\nJ Affect Disord . 2018 ;228 :216 ‐221\n. 10.1016/j.jad.2017.12.022 \n29274567 \n11 \n\nAustgulen Westin \nA \n, \nBrekke \nM \n, \nMolden \nE \n, \nSkogvoll \nE \n, \nAadal \nM \n, \nSpigset \nO \n. Changes in drug disposition of lithium during pregnancy: a retrospective observational study of patient data from two routine therapeutic drug monitoring services in Norway\n. BMJ Open . 2017 ;7 (3 ):e015738. doi: 10.1136/bmjopen-2016-015738 .\n12 \n\nThomson \nM \n, \nSharma \nV \n. Weighing the risks: the management of bipolar disorder during pregnancy\n. Curr Psychiatry Rep . 2018 ;20 (3 ):20 \n10.1007/s11920-018-0882-2 \n29549608 \n13 \n\nHirschfeld \nRMA \n. Practice guideline for the treatment of patients with bipolar disorder\n. APA Practice Guidelines . 2002 .\n14 \n\nMalhi \nGS \n, \nBassett \nD \n, \nBoyce \nP \n, et al. Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders\n. Aust N Z J Psychiatry . 2015 ;49 (12 ):1087 ‐1206\n. 10.1177/0004867415617657 \n26643054 \n15 \n\nGoodwin \nGM \n, \nHaddad \nPM \n, \nFerrier \nIN \n, et al. Evidence‐based guidelines for treating bipolar disorder: Revised third edition recommendations from the British Association for Psychopharmacology\n. J Psychopharmacol . 2016 ;30 (6 ):495 ‐553\n. 10.1177/0269881116636545 .26979387 \n16 \nThe Management of Bipolar Disorder Working Group \n. VA/DoD Clinical Practice Guideline for Management of Bipolar Disorders in Adults. Washington, DC ; 2010 .\n17 \nNVVP \n. Richtlijn Bipolaire Stoornis [Bipolar Disorder Guideline]\n. VA/DoD ; 2014 .\n18 \nNational Institutes of Excellence (NICE) \n. Antenatal and Postnatal Mental Health: Clinical Management and Service Guidance\n; 2014 .\n19 \n\nNewport \nDJ \n, \nViguera \nAC \n, \nBeach \nAJ \n, \nRitchie \nJC \n, \nCohen \nLS \n, \nStowe \nZN \n. Lithium placental passage and obstetrical outcome: implications for clinical management during late pregnancy\n. Am J Psychiatry . 2005 ;162 (11 ):2162 ‐2170\n. 10.1176/appi.ajp.162.11.2162 \n16263858 \n20 \n\nGopikrishna \nV \n. A report on case reports\n. J Conserv Dent . 2010 ;13 (4 ):265 \n10.4103/0972-0707.73375 \n21217956 \n21 \n\nGrof \nP \n, \nRobbins \nW \n, \nAlda \nM \n, et al. Protective effect of pregnancy in women with lithium‐responsive bipolar disorder\n. J Affect Disord . 2000 ;61 (1–2 ):31 ‐39\n. 10.1016/S0165-0327(99)00197-4 \n11099738 \n22 \n\nFornaro \nM \n, \nMaritan \nE \n, \nFerranti \nR \n, et al. Lithium exposure during pregnancy and the postpartum period: A systematic review and meta‐analysis of safety and efficacy outcomes\n. Am J Psychiatry . 2020 ;177 (1 ):76 ‐92\n. 10.1176/appi.ajp.2019.19030228 \n31623458 \n23 \n\nWesseloo \nR \n, \nLiu \nX \n, \nClark \nCT \n, \nKushner \nSA \n, \nMunk‐Olsen \nT \n, \nBergink \nV \n. Risk of postpartum episodes in women with bipolar disorder after lamotrigine or lithium use during pregnancy: a population‐based cohort study\n. J Affect Disord . 2017 ;218 :394 ‐397\n. 10.1016/j.jad.2017.04.070 \n28501739\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1398-5647",
"issue": "23(1)",
"journal": "Bipolar disorders",
"keywords": "delivery; infant; lithium; neonate; postpartum; pregnancy",
"medline_ta": "Bipolar Disord",
"mesh_terms": "D001714:Bipolar Disorder; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008094:Lithium; D049590:Postpartum Period; D011247:Pregnancy; D012189:Retrospective Studies",
"nlm_unique_id": "100883596",
"other_id": null,
"pages": "49-54",
"pmc": null,
"pmid": "32526071",
"pubdate": "2021-02",
"publication_types": "D016428:Journal Article; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": "26514657;29274567;26979387;26781551;24525634;29929874;28591541;28501739;11099738;30506447;32526071;26643054;21217956;23663953;28249852;16263858;28673946;29549608;31623458;29549439",
"title": "Management of lithium dosing around delivery: An observational study.",
"title_normalized": "management of lithium dosing around delivery an observational study"
} | [
{
"companynumb": "US-ALEMBIC PHARMACUETICALS LIMITED-2020SCAL000307",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LITHIUM CARBONATE"
},
... |
{
"abstract": "BACKGROUND\nSystemic sclerosis is a complex disorder that requires systematic screening. Our objective is to report the European Scleroderma Trials and Research group centre affiliation and its impact in our clinical practice.\n\n\nMETHODS\nThe European Scleroderma Trials and Research group affiliation process, database update and current patient evaluation, with respect to demographic and clinical features. Cumulative mortality was analysed.\n\n\nRESULTS\nWe identified 19 female patients (which met all the American College of Rheumatology/ European League Against Rheumatism 2013 criteria for systemic sclerosis) under current follow-up, divided according to the LeRoy classification into diffuse cutaneous (n = 5), limited cutaneous (n = 11) and limited (n = 3) types, followed for a median period of 5, 12 and 6 years, respectively. Raynaud´s phenomenon and abnormal nailfold capillaries were universally present. Interstitial lung disease was absent in the limited cutaneous form but present in 100% of the diffuse subtype. Pitting scars were more common in the diffuse form. Active disease was also more frequent in the diffuse form, and most patients with active disease were treated with anti-endothelin receptor antagonists. Over 21 years (from 1994 to 2015) the mortality rate was 55% (n = 23/42). Age at time of death was significantly lower in the diffuse subtype.\n\n\nCONCLUSIONS\nOur single centre cohort shares many features with larger and international reports and more specifically is in accordance with patient characteristics described in the European Scleroderma Trials and Research group registries.\n\n\nCONCLUSIONS\nThe European Scleroderma Trials and Research group registration motivated our systematic patient characterization and may be used as a tool for homogenous disease registries.",
"affiliations": "Serviço de Medicina Interna. Hospital do Divino Espírito Santo de Ponta Delgada. São Miguel.;Serviço de Radiologia. Hospital de Santa Marta. Centro Hospitalar de Lisboa Central. Lisboa. Portugal.;Unidade de Doenças Auto-Imunes/Serviço Medicina 7.2. Hospital de Curry Cabral. Centro Hospitalar de Lisboa Central. Lisboa. Portugal.;Unidade de Doenças Auto-Imunes/Serviço Medicina 7.2. Hospital de Curry Cabral. Centro Hospitalar de Lisboa Central. Lisboa. Portugal.;Unidade de Doenças Auto-Imunes/Serviço Medicina 7.2. Hospital de Curry Cabral. Centro Hospitalar de Lisboa Central. Lisboa. Portugal.;Laboratório de Imunologia. Centro Hospitalar de Lisboa Central. Lisboa. Portugal.;Unidade de Doenças Auto-Imunes/Serviço Medicina 7.2. Hospital de Curry Cabral. Centro Hospitalar de Lisboa Central. Lisboa. Portugal.;Unidade de Doenças Auto-Imunes/Serviço Medicina 7.2. Hospital de Curry Cabral. Centro Hospitalar de Lisboa Central. Lisboa. Portugal.;Unidade de Doenças Auto-Imunes/Serviço Medicina 7.2. Hospital de Curry Cabral. Centro Hospitalar de Lisboa Central. Lisboa. Portugal.;Serviço de Medicina Interna. Hospital do Divino Espírito Santo de Ponta Delgada. São Miguel. Portugal.",
"authors": "Vidal|Carolina|C|;Ruano|Carina|C|;Bernardino|Vera|V|;Lavado Carreira|Pedro|P|;Lladó|Ana|A|;Santos|Maria Céu|MC|;Gruner|Heidi|H|;Panarra|António|A|;Riso|Nuno|N|;Moraes-Fontes|Maria Francisca|MF|",
"chemical_list": null,
"country": "Portugal",
"delete": false,
"doi": "10.20344/amp.10658",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0870-399X",
"issue": "31(6)",
"journal": "Acta medica portuguesa",
"keywords": "Databases, Factual; Scleroderma, Systemic; Severity of Illness Index",
"medline_ta": "Acta Med Port",
"mesh_terms": "D000368:Aged; D005060:Europe; D005260:Female; D006801:Humans; D008875:Middle Aged; D012042:Registries; D012595:Scleroderma, Systemic; D015996:Survival Rate; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "7906803",
"other_id": null,
"pages": "312-320",
"pmc": null,
"pmid": "30020876",
"pubdate": "2018-06-29",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical Presentation and Long-Term Outcomes of Systemic Sclerosis Portuguese Patients from a Single Centre Cohort: A EUSTAR Registration Initiative.",
"title_normalized": "clinical presentation and long term outcomes of systemic sclerosis portuguese patients from a single centre cohort a eustar registration initiative"
} | [
{
"companynumb": "PT-ACTELION-A-CH2018-175219",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BOSENTAN"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nValproate is a first-line antiepileptic agent and is also used in the treatment of bipolar disorder and migraine. It is a known human teratogen. The objective of the study was to evaluate the teratogenic risk of valproate.\n\n\nMETHODS\nAll callers who contacted the Israeli Teratology Information Service (TIS) between 1994 and 2004 for information about gestational exposure to valproate were enrolled in the study. After the expected date of delivery, these women were followed up by telephone interview about their pregnancy outcome using a structured questionnaire. Data obtained from women who contacted the TIS about valproate exposure during pregnancy were then compared with data obtained from callers who were counselled for nonteratogenic exposures over the same timeframe. The main outcome measure was the rate of major congenital anomalies.\n\n\nRESULTS\nThe outcomes of 154 valproate-exposed pregnancies (96.1% at least in the first trimester) were compared with those of 1315 pregnancies of women in the TIS database who were counselled for nonteratogenic exposures. The rate of major anomalies (some multiple) in the valproate group exposed in the first trimester was higher compared with controls after exclusion of genetic or cytogenetic anomalies (8 of 120 [6.7%] vs 31 of 1236 [2.5%], p = 0.018, relative risk [RR] = 2.66, 95% CI 1.25, 5.65). There were no cases of neural tube defect in the valproate-exposed group. Five of the eight major anomalies in the valproate group were cardiovascular, two of eight were mentally retarded, two of five male infants with major anomalies had hypospadias and three of eight were suspected of having fetal valproate syndrome. A daily dose > or =1000 mg was associated with the highest teratogenic risk (7 of 32 [21.9%] vs 31 of 1236 [2.5%], RR = 8.72, 95% CI 4.16, 18.30). In the subgroup exposed to polytherapy there was a 4-fold increase in the rate of major anomalies compared with controls. All major anomalies were in the group treated for epilepsy.\n\n\nCONCLUSIONS\nWhen valproate treatment cannot be avoided in the first trimester of pregnancy, the lowest effective dose should be prescribed, preferably as monotherapy, to minimize its teratogenic risk.",
"affiliations": "The Israeli Teratology Information Service, Israel Ministry of Health, Jerusalem, Israel.",
"authors": "Diav-Citrin|Orna|O|;Shechtman|Svetlana|S|;Bar-Oz|Benjamin|B|;Cantrell|Dana|D|;Arnon|Judy|J|;Ornoy|Asher|A|",
"chemical_list": "D018692:Antimanic Agents; D014635:Valproic Acid",
"country": "New Zealand",
"delete": false,
"doi": "10.2165/00023210-200822040-00004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1172-7047",
"issue": "22(4)",
"journal": "CNS drugs",
"keywords": null,
"medline_ta": "CNS Drugs",
"mesh_terms": "D000014:Abnormalities, Drug-Induced; D018692:Antimanic Agents; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D011247:Pregnancy; D011256:Pregnancy Outcome; D011297:Prenatal Exposure Delayed Effects; D018600:Teratology; D014635:Valproic Acid",
"nlm_unique_id": "9431220",
"other_id": null,
"pages": "325-34",
"pmc": null,
"pmid": "18336060",
"pubdate": "2008",
"publication_types": "D016428:Journal Article",
"references": "9988874;9579936;3125743;6815474;15046269;6127554;15491979;7845341;4743779;4116552;16157661;6401849;6102670;6772753;1574165;1574181;10882750;55587;3111880;6439041;16639967;7687042;15781808;16894099;11077457;8174516;10706358;3134192;11950853;6126782;6782218;12601095;15519862;14756581;15955936",
"title": "Pregnancy outcome after in utero exposure to valproate : evidence of dose relationship in teratogenic effect.",
"title_normalized": "pregnancy outcome after in utero exposure to valproate evidence of dose relationship in teratogenic effect"
} | [
{
"companynumb": "IL-VISTAPHARM, INC.-VER202001-000151",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VALPROIC ACID"
},
"drugadditional"... |
{
"abstract": "Pentoxifylline is an agent that improves red blood cell deformability (known as a hemorrheologic effect) and reduces blood viscosity. Here, we present a case of a patient with hemolytic anemia after continuous-flow left ventricular assist device (CF-LVAD) implantation that was successfully treated with pentoxifylline. Our case is a 64-year-old African American woman who was implanted with a HeartMate II device on August 6, 2010, as a bridge to transplant for end-stage heart failure. Her postoperative course was complicated by recurrent gastrointestinal bleeding and antiplatelet therapy was discontinued. On October 25, 2011, she was readmitted with anemia and hemoglobin of 6.6 mg/dl and no identifiable source of bleeding. Her lactate dehydrogenase (LDH) was 936 IU/L, indicating severe hemolysis. Due to her evidence of hemolytic anemia and her inability to tolerate antiplatelet therapy due to recurrent bleeding, she was discharged on pentoxifylline 400 mg thrice daily on October 27, 2011, with hemoglobin of 11.2 mg/dl after transfusion. After 60 days of pentoxifylline, her hemoglobin and LDH in clinic were 10.1 mg/dl and 223 IU/L, respectively. The patient was successfully bridged to transplant in June 2012. Additional analysis of pentoxifylline as a therapeutic modality to manage hemolytic anemia after CF-LVAD implantation may be warranted.",
"affiliations": "Pharmacy Services, Henry Ford Hospital, Detroit, Michigan, USA. djennin1@gmail.com",
"authors": "Jennings|Douglas L|DL|;Williams|Celeste T|CT|;Morgan|Jeffrey A|JA|",
"chemical_list": "D006454:Hemoglobins; D010975:Platelet Aggregation Inhibitors; D014665:Vasodilator Agents; D007770:L-Lactate Dehydrogenase; D010431:Pentoxifylline",
"country": "United States",
"delete": false,
"doi": "10.1097/MAT.0b013e31829f0eb1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1058-2916",
"issue": "59(5)",
"journal": "ASAIO journal (American Society for Artificial Internal Organs : 1992)",
"keywords": null,
"medline_ta": "ASAIO J",
"mesh_terms": "D000743:Anemia, Hemolytic; D009202:Cardiomyopathies; D005260:Female; D006471:Gastrointestinal Hemorrhage; D006333:Heart Failure; D016027:Heart Transplantation; D006353:Heart-Assist Devices; D006454:Hemoglobins; D006461:Hemolysis; D006801:Humans; D007770:L-Lactate Dehydrogenase; D008875:Middle Aged; D017202:Myocardial Ischemia; D010431:Pentoxifylline; D010975:Platelet Aggregation Inhibitors; D016896:Treatment Outcome; D014665:Vasodilator Agents",
"nlm_unique_id": "9204109",
"other_id": null,
"pages": "526-7",
"pmc": null,
"pmid": "23896772",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pentoxifylline for the treatment of hemolytic anemia in a patient who developed recurrent gastrointestinal bleeding while on continuous-flow left ventricular assist device support.",
"title_normalized": "pentoxifylline for the treatment of hemolytic anemia in a patient who developed recurrent gastrointestinal bleeding while on continuous flow left ventricular assist device support"
} | [
{
"companynumb": "PHHY2014US160285",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"drugadm... |
{
"abstract": "The XEN implant is a small hydrophilic stent designed to be implanted permanently for the treatment of glaucoma. As with other bleb-forming surgical procedures, needling is part of postoperative care. We describe 3 cases of XEN fracture of the subconjunctival portion that occurred during the needling procedure.\n\n\n\nThe purpose of this study was to describe the clinical and anatomic outcomes in 3 cases of XEN fracture caused by the needling procedure.\n\n\n\nIn our case series of XEN procedures (n=170), bleb needling has been performed in 98 cases (57.6%). In 3 cases (3.1%), we observed unintentional damage to the implant after the procedure.The mean distal segment length of the fractured XEN measured 0.83 (range: 0.7 to 1) mm. Despite the adverse event, the mean IOP changed from 25.0 (range: 21 to 30) mm Hg before needling to 12.0 (range: 10 to 14) after needling, with a mean follow-up of 15.3 (range: 11 to 18) months. No vision-threatening complications were recorded during the entire follow-up.\n\n\n\nXEN fracture related to the needling procedure should be considered as a possible adverse event of bleb management. Because XEN is composed of a soft and flexible gelatin material, it could be easily damaged by the needle. The fracture does not seem to impair the efficacy of the draining device. As a matter of fact, according to Poiseuille's laws, shortening of the implant's length decreases the resistance while increasing the flow rate. Despite our positive results, it is recommended to preserve the integrity of the implant.",
"affiliations": "Eye Clinic, DiNOGMI, University of Genoa.;Eye Clinic, DiNOGMI, University of Genoa.;Eye Clinic, DiNOGMI, University of Genoa.;Eye Clinic, DiNOGMI, University of Genoa.;Eye Clinic, DiNOGMI, University of Genoa.;Eye Clinic, DiNOGMI, University of Genoa.;Eye Clinic, DiNOGMI, University of Genoa.",
"authors": "Olivari|Sara|S|;Cutolo|Carlo A|CA|;Negri|Letizia|L|;Cappelli|Francesca|F|;Testa|Valeria|V|;Iester|Michele|M|;Traverso|Carlo E|CE|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/IJG.0000000000001360",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1057-0829",
"issue": "28(12)",
"journal": "Journal of glaucoma",
"keywords": null,
"medline_ta": "J Glaucoma",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000079245:Dry Needling; D005260:Female; D020327:Glaucoma Drainage Implants; D005902:Glaucoma, Open-Angle; D006068:Gonioscopy; D006801:Humans; D007429:Intraocular Pressure; D008875:Middle Aged; D018918:Phacoemulsification; D011475:Prosthesis Failure; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "9300903",
"other_id": null,
"pages": "1086-1089",
"pmc": null,
"pmid": "31478952",
"pubdate": "2019-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "XEN Implant Fracture During Needling Procedure.",
"title_normalized": "xen implant fracture during needling procedure"
} | [
{
"companynumb": "IT-BAUSCH-BL-2020-000922",
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"occurcountry": "IT",
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"activesubstancename": "DEXAMETHASONE\\TOBRAMYCIN"
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"abstract": ": The development of neutralizing antibodies is a rare complication of von Willebrand disease treatment. In major surgical procedures for severe forms of the disease, the recognition of ineffective therapy and alternative treatment protocols are lifesaving. We report the case of a 6-year-old girl with type 3 von Willebrand disease in whom inhibitors were sought due to ineffective haemostasis together with lower than expected von Willebrand factor (VWF) recoveries after a surgical procedure. Replacement therapy first with recombinant factor VIIa and then with high doses of recombinant factor VIII in continuous infusion successfully stopped the bleeding. A high level of anti-VWF antibodies was determined by the immunological method. A frameshift mutation associated with premature termination codon (c.2435delC, p.Pro812ArgfsTer31) was determined in our patient. Although the reports on association of this mutation with inhibitor risk are inconsistent, it represents an evidence-based diagnostic and management practice in recognition of high-risk VWF genotype.",
"affiliations": "Department of Haematology and Oncology, University Medical Centre Ljubljana, University Children's Hospital, Ljubljana, Slovenia.;Department of Clinical Chemistry, Malmö University Hospital, Malmö, Sweden.;Unity of Special Laboratory Diagnostic, University Medical Centre Ljubljana, University Children's Hospital.;Department of Haematology and Oncology, University Medical Centre Ljubljana, University Children's Hospital, Ljubljana, Slovenia.;Department of Haematology and Oncology, University Medical Centre Ljubljana, University Children's Hospital, Ljubljana, Slovenia.;National Haemophilia Centre, Ljubljana, Slovenia.;Unity of Special Laboratory Diagnostic, University Medical Centre Ljubljana, University Children's Hospital.",
"authors": "Faganel Kotnik|Barbara|B|;Strandberg|Karin|K|;Debeljak|Maruša|M|;Kitanovski|Lidija|L|;Jazbec|Janez|J|;Benedik-Dolničar|Majda|M|;Trampuš Bakija|Alenka|A|",
"chemical_list": "D007518:Isoantibodies",
"country": "England",
"delete": false,
"doi": "10.1097/MBC.0000000000000865",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0957-5235",
"issue": "31(1)",
"journal": "Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis",
"keywords": null,
"medline_ta": "Blood Coagul Fibrinolysis",
"mesh_terms": "D002648:Child; D005260:Female; D006801:Humans; D007518:Isoantibodies; D014842:von Willebrand Diseases",
"nlm_unique_id": "9102551",
"other_id": null,
"pages": "77-79",
"pmc": null,
"pmid": "31714257",
"pubdate": "2020-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "von Willebrand factor alloantibodies in type 3 von Willebrand disease.",
"title_normalized": "von willebrand factor alloantibodies in type 3 von willebrand disease"
} | [
{
"companynumb": "SI-BEH-2019109742",
"fulfillexpeditecriteria": "1",
"occurcountry": "SI",
"patient": {
"drug": [
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "HUMAN COAGULATION FACTOR VIII/VON WILLEBRAND FACTOR COMPLEX"
}... |
{
"abstract": "Clozapine has been associated with various adverse effects at both subtherapeutic and standard doses. These adverse effects are most commonly seen during the initiation of therapy in treatment-naïve patients. However, reports of intoxication in patients with long-term use of clozapine are yet to be documented. We highlight the case of a 42-year-old gentleman who had been on long-term clozapine use and presented with an altered mental status after being resumed on full standard doses without careful titration of clozapine after a short period of medication noncompliance. His workup in the hospital was largely unremarkable, and his presentation was attributed to the resumption of clozapine without medication titration. This is the first case to demonstrate the necessity of careful titration regardless of previous treatment history and highlights that patients should be started on clozapine at low levels to avoid the possibility of acute intoxication.",
"affiliations": "Internal Medicine, University of Massachusetts Medical School - Baystate, Springfield, USA.;Internal Medicine, Tufts University School of Medicine, Boston, USA.;Internal Medicine, University of Massachusetts Medical School - Baystate, Springfield, USA.",
"authors": "Khan|Zoha|Z|;Miller|Emily A|EA|;Pervaiz|Abdullah M|AM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.16578",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.16578\nInternal Medicine\nNeurology\nPsychiatry\nClozapine Intoxication in a Patient on Chronic Use With a Short-Term Noncompliance\nMuacevic Alexander\nAdler John R\nKhan Zoha 1\nMiller Emily A 2\nPervaiz Abdullah M 1\n1 Internal Medicine, University of Massachusetts Medical School - Baystate, Springfield, USA\n2 Internal Medicine, Tufts University School of Medicine, Boston, USA\nZoha Khan zoha.khanmd@baystatehealth.org\n23 7 2021\n7 2021\n13 7 e1657823 7 2021\nCopyright © 2021, Khan et al.\n2021\nKhan et al.\nhttps://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nThis article is available from https://www.cureus.com/articles/65122-clozapine-intoxication-in-a-patient-on-chronic-use-with-a-short-term-noncompliance\nClozapine has been associated with various adverse effects at both subtherapeutic and standard doses. These adverse effects are most commonly seen during the initiation of therapy in treatment-naïve patients. However, reports of intoxication in patients with long-term use of clozapine are yet to be documented. We highlight the case of a 42-year-old gentleman who had been on long-term clozapine use and presented with an altered mental status after being resumed on full standard doses without careful titration of clozapine after a short period of medication noncompliance. His workup in the hospital was largely unremarkable, and his presentation was attributed to the resumption of clozapine without medication titration. This is the first case to demonstrate the necessity of careful titration regardless of previous treatment history and highlights that patients should be started on clozapine at low levels to avoid the possibility of acute intoxication.\n\nclozapine\nintoxication\nchronic\npsychiatry\nencephalopathy\nThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\n\nClozapine has been shown to cause various adverse effects including life-threatening neutropenia, agranulocytosis, and sedation at subtherapeutic as well as standard doses. These adverse effects are most commonly seen during the initiation of therapy in treatment-naïve patients. Previous cases have reported clozapine intoxication in treatment-naïve patients [1,2]. However, with regards to patients with long histories of clozapine use at standard doses, reports of intoxication have not been documented. Here, we present a case of clozapine intoxication in a patient with a long history of clozapine use.\n\nCase presentation\n\nA 42-year-old man with a past medical history of schizophrenia was found outside a behavioral health facility and appeared groggy with slurring of speech. The patient was given naloxone by emergency medical services without improvement in his symptoms and was transported to the emergency department for further evaluation. On presentation, the patient was afebrile and hemodynamically stable. He was alert and oriented to person, place, and time; however, exhibited slurred speech and an inability to stay awake despite repeated stimulation. Lab work did not show electrolyte abnormalities, leukocytosis, or a deranged thyroid-stimulating hormone level (Table 1). Urine toxicology was negative for barbiturates, cannabinoids, cocaine, benzodiazepines, amphetamine, and opioids. His serum ethanol level was negative and his acetaminophen level was less than 5 µg/mL. His urinalysis was not indicative of infection. Clozapine level was noted to be 172 ng/mL (reference range: 350-650 ng/mL). Chest X-ray showed no acute cardiopulmonary abnormality. The patient reported that he was in his usual state of health the prior night when he restarted clozapine after approximately six weeks of medication noncompliance due to the inability to see his psychiatrist for a prescription. He stated that he took 300 mg of clozapine at the full dose the previous evening, and did not restart it with a taper. Medication history indicated that the patient had been prescribed haloperidol 5 mg daily and clozapine 100 mg in the morning and 300 mg in the evening for at least three years. He denied using any opioids or alcohol. He also reported no history of recent infection, shortness of breath, chest pain, or trauma. The following day, the patient was alert and oriented to person, place, and time, and was able to converse normally with no drowsiness or somnolence. He was evaluated by the psychiatry service, and his altered mental status was attributed to the resumption of clozapine at full dose after a period of medication noncompliance. The patient was restarted on clozapine at 25 mg twice daily with plans to increase slowly to therapeutic doses in the outpatient setting.\n\nTable 1 Lab workup obtained on admission which was unremarkable for leukocytosis, hypoglycemia, or electrolyte abnormalities.\n\nLab parameters\tValue\tReference range\t\nHemoglobin\t12.7\t13.7-17.1 g/dL\t\nWhite blood cell count\t9.6\t4-11 k/mm3\t\nSodium\t139\t133-145 mmol/L\t\nPotassium\t4.2\t3.6-5.2 mmol/L\t\nGlucose\t137\t70-99 mg/dL\t\nBlood urea nitrogen\t15\t6-20 mg/dL\t\nCreatinine\t1.2\t0.7-1.2 mg/dL\t\nCalcium\t9.3\t8.6-10.5 mg/dL\t\nMagnesium\t2.1\t1.6-2.3 mg/dL\t\nAlkaline phosphatase\t87\t40-129 U/L\t\nAspartate aminotransferase\t14\t0-38 U/L\t\nAlanine aminotransferase\t14\t0-41 U/L\t\nTroponin T\t<0.01\t0-0.09 ng/L\t\nAmmonia venous\t41\t16-60 µmol/L\t\nThyroid-stimulating hormone\t1.57\t0.4-4 mIU/mL\t\n\nDiscussion\n\nIn considering treatment for schizophrenia, both first- and second-generation antipsychotics are considered to be of equal clinical efficacy, with one exception. Clozapine, a second-generation antipsychotic, has been demonstrated to be of superior clinical efficacy in the treatment of schizophrenia. It is known to decrease mortality in treatment-resistant schizophrenia, mainly by reducing suicidal ideations [3]. However, due to its potential for severe, life-threatening side effects, clozapine is considered a second-line therapy, indicated only for patients with treatment-resistant schizophrenia/schizoaffective disorder and those with persistent self-injurious behaviors.\n\nClozapine has been shown to cause life-threatening neutropenia, agranulocytosis, and sedation at subtherapeutic as well as standard doses. Orthostatic hypotension, syncope, cardiac arrest, and myocarditis are additional known side effects of clozapine [4]. These adverse effects are most commonly seen during the initiation of therapy in treatment-naïve patients. As such, clozapine prescribing guidelines require doses to be titrated slowly to therapeutic levels with frequent patient monitoring. Previous cases have reported clozapine intoxication in treatment-naïve patients [1,2]. However, with regards to patients with long histories of clozapine use at standard doses with a brief period of noncompliance, reports of intoxication have not been documented. Our patient developed clozapine intoxication despite having a long history of clozapine use. The observed degree of sedation after restarting clozapine is not common in patients who have a history of previous clozapine treatment. However, we highlight the potential for adverse reactions to clozapine regardless of the duration of treatment and the necessity of tapers for all patients starting or restarting this medication.\n\nThe necessity of tapered dosing for clozapine-naïve patients is well-established. Multiple case reports have documented instances of acute intoxication in treatment-naïve patients, even at low doses [4,5]. Therapeutic dosing typically requires 300-600 mg per day; however, patients are typically started on 12.5-25 mg per day with gradual increases in dosages [6]. Little is known regarding clozapine intoxication in patients with previous clozapine treatment. Studies in pretreated patients have been limited to reports of intoxication in patients after large doses intended for suicide [2,7]. It has been suggested that previous treatment with clozapine can be protective against intoxication. Studies in animal models have supported this idea, suggesting a mechanism for clozapine tolerance [8].\n\nOur case is unique in that the patient presented with known signs of clozapine intoxication, notably sedation, altered mental status, and dysarthria after taking therapeutic doses of the medication [2]. Clozapine metabolism varies widely between patients due to inherent metabolic differences, drug interactions, and patient characteristics such as age [1,9,10]. While evidence supports the idea of clozapine tolerance, we demonstrate the necessity of careful titration regardless of the previous treatment history. Resumption of clozapine therapy requires caution and should be restarted at low levels to avoid the possibility of acute intoxication for all patients.\n\nConclusions\n\nWe highlight the potential for adverse reactions to clozapine regardless of the duration of treatment and the necessity of tapers for all patients starting or restarting this medication. While evidence supports the idea of clozapine tolerance, we demonstrate the necessity of careful titration regardless of the previous treatment history. This case highlights that when prescribing or dispensing clozapine therapy greater detail regarding prior medication compliance and treatment history should be taken into account. In addition, the resumption of clozapine therapy requires caution and should be restarted at low levels to avoid the possibility of acute intoxication for all patients.\n\nHuman Ethics\n\nThe authors have declared that no competing interests exist.\n\nConsent was obtained or waived by all participants in this study\n==== Refs\nReferences\n\n1 Covert clozapine overdose: clozapine toxicity in a naive patient Aust N Z J Psychiatry West S Jeffery-Smith A Brownlee W Kenedi C 1208 1209 47 2013 23817859\n2 Clozapine intoxication mimicking acute stroke Clin Pract Cases Emerg Med Lebin JA Villarreal JD Chen BC Hall MK 155 157 2 2018 29849223\n3 Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT) Arch Gen Psychiatry Meltzer HY Alphs L Green AI 82 91 60 2003 12511175\n4 Review and management of clozapine side effects J Clin Psychiatry Miller DD 14 17 61 Suppl 8 2000 https://www.psychiatrist.com/jcp/neurologic/neurology/review-management-clozapine-side-effects/\n5 Minimal dose for severe poisoning and influencing factors in acute human clozapine intoxication: a 13-year retrospective study Clin Neuropharmacol Krämer I Rauber-Lüthy C Kupferschmidt H Krähenbühl S Ceschi A 230 234 33 2010 20689404\n6 Response of patients with treatment-refractory schizophrenia to clozapine within three serum level ranges Am J Psychiatry VanderZwaag C McGee M McEvoy JP Freudenreich O Wilson WH Cooper TB 1579 1584 153 1996 8942454\n7 Delayed recovery associated with persistent serum concentrations after clozapine overdose J Emerg Med Thomas L Pollak PT 61 66 25 2003 12865111\n8 Effects of central activation of serotonin 5-HT2A/2C or dopamine D 2/3 receptors on the acute and repeated effects of clozapine in the conditioned avoidance response test Psychopharmacology (Berl) Feng M Gao J Sui N Li M 1219 1230 232 2015 25288514\n9 Pharmacokinetics and pharmacodynamics of clozapine Clin Pharmacokinet Jann MW Grimsley SR Gray EC Chang WH 161 176 24 1993 8453823\n10 Interactions between the cytochrome P450 system and the second-generation antipsychotics J Psychiatry Neurosci Prior TI Baker GB 99 112 28 2003 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC161731/ 12670127\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "13(7)",
"journal": "Cureus",
"keywords": "chronic; clozapine; encephalopathy; intoxication; psychiatry",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e16578",
"pmc": null,
"pmid": "34430174",
"pubdate": "2021-07",
"publication_types": "D002363:Case Reports",
"references": "20689404;8942454;25288514;12670127;12511175;29849223;23817859;10811238;12865111;8453823",
"title": "Clozapine Intoxication in a Patient on Chronic Use With a Short-Term Noncompliance.",
"title_normalized": "clozapine intoxication in a patient on chronic use with a short term noncompliance"
} | [
{
"companynumb": "US-ACCORD-237527",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "HALOPERIDOL"
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"abstract": "To report the induction of anti-Ma2 antibody-associated paraneoplastic neurologic syndrome (Ma2-PNS) in 6 patients after treatment with immune checkpoint inhibitors (ICIs). We also analyzed (1) patient clinical features compared with a cohort of 44 patients who developed Ma2-PNS without receiving ICI treatment and (2) the frequency of neuronal antibody detection before and after ICI implementation.\n\n\n\nRetrospective nationwide study of all patients with Ma2-PNS developed during ICI treatment between 2017 and 2018.\n\n\n\nOur series of patients included 5 men and 1 woman (median age, 63 years). The patients were receiving nivolumab (n = 3), pembrolizumab (n = 2), or a combination of nivolumab and ipilimumab (n = 1) for treatment of neoplasms that included lung (n = 4) and kidney (n = 1) cancers and pleural mesothelioma (n = 1). Clinical syndromes comprised a combination of limbic encephalitis and diencephalitis (n = 3), isolated limbic encephalitis (n = 2), and a syndrome characterized by ophthalmoplegia and head drop (n = 1). No significant clinical difference was observed between our 6 patients and the overall cohort of Ma2-PNS cases. Post-ICI Ma2-PNS accounted for 35% of the total 17 Ma2-PNS diagnosed in our center over the 2017-2018 biennium. Eight cases had been detected in the preceding biennium 2015-2016, corresponding to a 112% increase of Ma2-PNS frequency since the implementation of ICIs in France. Despite ICI withdrawal and immunotherapy, 4/6 patients died, and the remaining 2 showed a moderate to severe disability.\n\n\n\nWe show a clear association between ICI use and increased diagnosis of Ma2-PNS. Physicians need to be aware that ICIs can trigger Ma2-PNS because clinical presentation can be challenging.",
"affiliations": "From the Centre National de Référence pour les Syndromes Neurologiques Paranéoplasiques (A.V., M.F., B.J., G.P., V.R., A.-L.P., S.M.-C., F.D., V.D., J.H.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team, NeuroMyoGene Institute, INSERM U1217/CNRS UMR5310, Lyon, France; University Claude Bernard Lyon 1, Université de Lyon; Service de Pneumologie-Oncologie Thoracique-Soins Intensifs Respiratoires (M.R.), Centre Hospitalier Universitaire de Rouen; Service d'Oncologie Médicale (J.R.), Institut de Cancérologie de l'Ouest René Gauducheau, St. Herblain; Service de Pneumologie (C.D.), Centre Hospitalier de Saint-Quentin; Service de Neurologie et Unité Neuro-Vasculaire-Hôpital de La Cavale Blanche (L.G.), Brest; Service de Neurologie et Unité Neurovasculaire (M.P.-G.), Centre Hospitalier Régional d'Orléans; Service de Neurologie-Pathologies Inflammatoires (J.L.), Centre Hospitalier Universitaire de Lille; and AP-HP (D.P.), Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2-Mazarin et Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière (CRICM), UMRS 975; Inserm U 975, CNRS, UMR 7225; Centre de Compétence des Syndromes Neurologiques Paraneoplasiques et Encéphalites Autoimmunes, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.;From the Centre National de Référence pour les Syndromes Neurologiques Paranéoplasiques (A.V., M.F., B.J., G.P., V.R., A.-L.P., S.M.-C., F.D., V.D., J.H.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team, NeuroMyoGene Institute, INSERM U1217/CNRS UMR5310, Lyon, France; University Claude Bernard Lyon 1, Université de Lyon; Service de Pneumologie-Oncologie Thoracique-Soins Intensifs Respiratoires (M.R.), Centre Hospitalier Universitaire de Rouen; Service d'Oncologie Médicale (J.R.), Institut de Cancérologie de l'Ouest René Gauducheau, St. Herblain; Service de Pneumologie (C.D.), Centre Hospitalier de Saint-Quentin; Service de Neurologie et Unité Neuro-Vasculaire-Hôpital de La Cavale Blanche (L.G.), Brest; Service de Neurologie et Unité Neurovasculaire (M.P.-G.), Centre Hospitalier Régional d'Orléans; Service de Neurologie-Pathologies Inflammatoires (J.L.), Centre Hospitalier Universitaire de Lille; and AP-HP (D.P.), Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2-Mazarin et Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière (CRICM), UMRS 975; Inserm U 975, CNRS, UMR 7225; Centre de Compétence des Syndromes Neurologiques Paraneoplasiques et Encéphalites Autoimmunes, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.;From the Centre National de Référence pour les Syndromes Neurologiques Paranéoplasiques (A.V., M.F., B.J., G.P., V.R., A.-L.P., S.M.-C., F.D., V.D., J.H.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team, NeuroMyoGene Institute, INSERM U1217/CNRS UMR5310, Lyon, France; University Claude Bernard Lyon 1, Université de Lyon; Service de Pneumologie-Oncologie Thoracique-Soins Intensifs Respiratoires (M.R.), Centre Hospitalier Universitaire de Rouen; Service d'Oncologie Médicale (J.R.), Institut de Cancérologie de l'Ouest René Gauducheau, St. Herblain; Service de Pneumologie (C.D.), Centre Hospitalier de Saint-Quentin; Service de Neurologie et Unité Neuro-Vasculaire-Hôpital de La Cavale Blanche (L.G.), Brest; Service de Neurologie et Unité Neurovasculaire (M.P.-G.), Centre Hospitalier Régional d'Orléans; Service de Neurologie-Pathologies Inflammatoires (J.L.), Centre Hospitalier Universitaire de Lille; and AP-HP (D.P.), Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2-Mazarin et Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière (CRICM), UMRS 975; Inserm U 975, CNRS, UMR 7225; Centre de Compétence des Syndromes Neurologiques Paraneoplasiques et Encéphalites Autoimmunes, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.;From the Centre National de Référence pour les Syndromes Neurologiques Paranéoplasiques (A.V., M.F., B.J., G.P., V.R., A.-L.P., S.M.-C., F.D., V.D., J.H.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team, NeuroMyoGene Institute, INSERM U1217/CNRS UMR5310, Lyon, France; University Claude Bernard Lyon 1, Université de Lyon; Service de Pneumologie-Oncologie Thoracique-Soins Intensifs Respiratoires (M.R.), Centre Hospitalier Universitaire de Rouen; Service d'Oncologie Médicale (J.R.), Institut de Cancérologie de l'Ouest René Gauducheau, St. Herblain; Service de Pneumologie (C.D.), Centre Hospitalier de Saint-Quentin; Service de Neurologie et Unité Neuro-Vasculaire-Hôpital de La Cavale Blanche (L.G.), Brest; Service de Neurologie et Unité Neurovasculaire (M.P.-G.), Centre Hospitalier Régional d'Orléans; Service de Neurologie-Pathologies Inflammatoires (J.L.), Centre Hospitalier Universitaire de Lille; and AP-HP (D.P.), Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2-Mazarin et Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière (CRICM), UMRS 975; Inserm U 975, CNRS, UMR 7225; Centre de Compétence des Syndromes Neurologiques Paraneoplasiques et Encéphalites Autoimmunes, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.;From the Centre National de Référence pour les Syndromes Neurologiques Paranéoplasiques (A.V., M.F., B.J., G.P., V.R., A.-L.P., S.M.-C., F.D., V.D., J.H.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team, NeuroMyoGene Institute, INSERM U1217/CNRS UMR5310, Lyon, France; University Claude Bernard Lyon 1, Université de Lyon; Service de Pneumologie-Oncologie Thoracique-Soins Intensifs Respiratoires (M.R.), Centre Hospitalier Universitaire de Rouen; Service d'Oncologie Médicale (J.R.), Institut de Cancérologie de l'Ouest René Gauducheau, St. Herblain; Service de Pneumologie (C.D.), Centre Hospitalier de Saint-Quentin; Service de Neurologie et Unité Neuro-Vasculaire-Hôpital de La Cavale Blanche (L.G.), Brest; Service de Neurologie et Unité Neurovasculaire (M.P.-G.), Centre Hospitalier Régional d'Orléans; Service de Neurologie-Pathologies Inflammatoires (J.L.), Centre Hospitalier Universitaire de Lille; and AP-HP (D.P.), Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2-Mazarin et Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière (CRICM), UMRS 975; Inserm U 975, CNRS, UMR 7225; Centre de Compétence des Syndromes Neurologiques Paraneoplasiques et Encéphalites Autoimmunes, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.;From the Centre National de Référence pour les Syndromes Neurologiques Paranéoplasiques (A.V., M.F., B.J., G.P., V.R., A.-L.P., S.M.-C., F.D., V.D., J.H.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team, NeuroMyoGene Institute, INSERM U1217/CNRS UMR5310, Lyon, France; University Claude Bernard Lyon 1, Université de Lyon; Service de Pneumologie-Oncologie Thoracique-Soins Intensifs Respiratoires (M.R.), Centre Hospitalier Universitaire de Rouen; Service d'Oncologie Médicale (J.R.), Institut de Cancérologie de l'Ouest René Gauducheau, St. Herblain; Service de Pneumologie (C.D.), Centre Hospitalier de Saint-Quentin; Service de Neurologie et Unité Neuro-Vasculaire-Hôpital de La Cavale Blanche (L.G.), Brest; Service de Neurologie et Unité Neurovasculaire (M.P.-G.), Centre Hospitalier Régional d'Orléans; Service de Neurologie-Pathologies Inflammatoires (J.L.), Centre Hospitalier Universitaire de Lille; and AP-HP (D.P.), Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2-Mazarin et Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière (CRICM), UMRS 975; Inserm U 975, CNRS, UMR 7225; Centre de Compétence des Syndromes Neurologiques Paraneoplasiques et Encéphalites Autoimmunes, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.;From the Centre National de Référence pour les Syndromes Neurologiques Paranéoplasiques (A.V., M.F., B.J., G.P., V.R., A.-L.P., S.M.-C., F.D., V.D., J.H.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team, NeuroMyoGene Institute, INSERM U1217/CNRS UMR5310, Lyon, France; University Claude Bernard Lyon 1, Université de Lyon; Service de Pneumologie-Oncologie Thoracique-Soins Intensifs Respiratoires (M.R.), Centre Hospitalier Universitaire de Rouen; Service d'Oncologie Médicale (J.R.), Institut de Cancérologie de l'Ouest René Gauducheau, St. Herblain; Service de Pneumologie (C.D.), Centre Hospitalier de Saint-Quentin; Service de Neurologie et Unité Neuro-Vasculaire-Hôpital de La Cavale Blanche (L.G.), Brest; Service de Neurologie et Unité Neurovasculaire (M.P.-G.), Centre Hospitalier Régional d'Orléans; Service de Neurologie-Pathologies Inflammatoires (J.L.), Centre Hospitalier Universitaire de Lille; and AP-HP (D.P.), Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2-Mazarin et Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière (CRICM), UMRS 975; Inserm U 975, CNRS, UMR 7225; Centre de Compétence des Syndromes Neurologiques Paraneoplasiques et Encéphalites Autoimmunes, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.;From the Centre National de Référence pour les Syndromes Neurologiques Paranéoplasiques (A.V., M.F., B.J., G.P., V.R., A.-L.P., S.M.-C., F.D., V.D., J.H.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team, NeuroMyoGene Institute, INSERM U1217/CNRS UMR5310, Lyon, France; University Claude Bernard Lyon 1, Université de Lyon; Service de Pneumologie-Oncologie Thoracique-Soins Intensifs Respiratoires (M.R.), Centre Hospitalier Universitaire de Rouen; Service d'Oncologie Médicale (J.R.), Institut de Cancérologie de l'Ouest René Gauducheau, St. Herblain; Service de Pneumologie (C.D.), Centre Hospitalier de Saint-Quentin; Service de Neurologie et Unité Neuro-Vasculaire-Hôpital de La Cavale Blanche (L.G.), Brest; Service de Neurologie et Unité Neurovasculaire (M.P.-G.), Centre Hospitalier Régional d'Orléans; Service de Neurologie-Pathologies Inflammatoires (J.L.), Centre Hospitalier Universitaire de Lille; and AP-HP (D.P.), Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2-Mazarin et Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière (CRICM), UMRS 975; Inserm U 975, CNRS, UMR 7225; Centre de Compétence des Syndromes Neurologiques Paraneoplasiques et Encéphalites Autoimmunes, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.;From the Centre National de Référence pour les Syndromes Neurologiques Paranéoplasiques (A.V., M.F., B.J., G.P., V.R., A.-L.P., S.M.-C., F.D., V.D., J.H.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team, NeuroMyoGene Institute, INSERM U1217/CNRS UMR5310, Lyon, France; University Claude Bernard Lyon 1, Université de Lyon; Service de Pneumologie-Oncologie Thoracique-Soins Intensifs Respiratoires (M.R.), Centre Hospitalier Universitaire de Rouen; Service d'Oncologie Médicale (J.R.), Institut de Cancérologie de l'Ouest René Gauducheau, St. Herblain; Service de Pneumologie (C.D.), Centre Hospitalier de Saint-Quentin; Service de Neurologie et Unité Neuro-Vasculaire-Hôpital de La Cavale Blanche (L.G.), Brest; Service de Neurologie et Unité Neurovasculaire (M.P.-G.), Centre Hospitalier Régional d'Orléans; Service de Neurologie-Pathologies Inflammatoires (J.L.), Centre Hospitalier Universitaire de Lille; and AP-HP (D.P.), Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2-Mazarin et Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière (CRICM), UMRS 975; Inserm U 975, CNRS, UMR 7225; Centre de Compétence des Syndromes Neurologiques Paraneoplasiques et Encéphalites Autoimmunes, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.;From the Centre National de Référence pour les Syndromes Neurologiques Paranéoplasiques (A.V., M.F., B.J., G.P., V.R., A.-L.P., S.M.-C., F.D., V.D., J.H.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team, NeuroMyoGene Institute, INSERM U1217/CNRS UMR5310, Lyon, France; University Claude Bernard Lyon 1, Université de Lyon; Service de Pneumologie-Oncologie Thoracique-Soins Intensifs Respiratoires (M.R.), Centre Hospitalier Universitaire de Rouen; Service d'Oncologie Médicale (J.R.), Institut de Cancérologie de l'Ouest René Gauducheau, St. Herblain; Service de Pneumologie (C.D.), Centre Hospitalier de Saint-Quentin; Service de Neurologie et Unité Neuro-Vasculaire-Hôpital de La Cavale Blanche (L.G.), Brest; Service de Neurologie et Unité Neurovasculaire (M.P.-G.), Centre Hospitalier Régional d'Orléans; Service de Neurologie-Pathologies Inflammatoires (J.L.), Centre Hospitalier Universitaire de Lille; and AP-HP (D.P.), Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2-Mazarin et Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière (CRICM), UMRS 975; Inserm U 975, CNRS, UMR 7225; Centre de Compétence des Syndromes Neurologiques Paraneoplasiques et Encéphalites Autoimmunes, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.;From the Centre National de Référence pour les Syndromes Neurologiques Paranéoplasiques (A.V., M.F., B.J., G.P., V.R., A.-L.P., S.M.-C., F.D., V.D., J.H.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team, NeuroMyoGene Institute, INSERM U1217/CNRS UMR5310, Lyon, France; University Claude Bernard Lyon 1, Université de Lyon; Service de Pneumologie-Oncologie Thoracique-Soins Intensifs Respiratoires (M.R.), Centre Hospitalier Universitaire de Rouen; Service d'Oncologie Médicale (J.R.), Institut de Cancérologie de l'Ouest René Gauducheau, St. Herblain; Service de Pneumologie (C.D.), Centre Hospitalier de Saint-Quentin; Service de Neurologie et Unité Neuro-Vasculaire-Hôpital de La Cavale Blanche (L.G.), Brest; Service de Neurologie et Unité Neurovasculaire (M.P.-G.), Centre Hospitalier Régional d'Orléans; Service de Neurologie-Pathologies Inflammatoires (J.L.), Centre Hospitalier Universitaire de Lille; and AP-HP (D.P.), Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2-Mazarin et Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière (CRICM), UMRS 975; Inserm U 975, CNRS, UMR 7225; Centre de Compétence des Syndromes Neurologiques Paraneoplasiques et Encéphalites Autoimmunes, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.;From the Centre National de Référence pour les Syndromes Neurologiques Paranéoplasiques (A.V., M.F., B.J., G.P., V.R., A.-L.P., S.M.-C., F.D., V.D., J.H.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team, NeuroMyoGene Institute, INSERM U1217/CNRS UMR5310, Lyon, France; University Claude Bernard Lyon 1, Université de Lyon; Service de Pneumologie-Oncologie Thoracique-Soins Intensifs Respiratoires (M.R.), Centre Hospitalier Universitaire de Rouen; Service d'Oncologie Médicale (J.R.), Institut de Cancérologie de l'Ouest René Gauducheau, St. Herblain; Service de Pneumologie (C.D.), Centre Hospitalier de Saint-Quentin; Service de Neurologie et Unité Neuro-Vasculaire-Hôpital de La Cavale Blanche (L.G.), Brest; Service de Neurologie et Unité Neurovasculaire (M.P.-G.), Centre Hospitalier Régional d'Orléans; Service de Neurologie-Pathologies Inflammatoires (J.L.), Centre Hospitalier Universitaire de Lille; and AP-HP (D.P.), Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2-Mazarin et Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière (CRICM), UMRS 975; Inserm U 975, CNRS, UMR 7225; Centre de Compétence des Syndromes Neurologiques Paraneoplasiques et Encéphalites Autoimmunes, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.;From the Centre National de Référence pour les Syndromes Neurologiques Paranéoplasiques (A.V., M.F., B.J., G.P., V.R., A.-L.P., S.M.-C., F.D., V.D., J.H.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team, NeuroMyoGene Institute, INSERM U1217/CNRS UMR5310, Lyon, France; University Claude Bernard Lyon 1, Université de Lyon; Service de Pneumologie-Oncologie Thoracique-Soins Intensifs Respiratoires (M.R.), Centre Hospitalier Universitaire de Rouen; Service d'Oncologie Médicale (J.R.), Institut de Cancérologie de l'Ouest René Gauducheau, St. Herblain; Service de Pneumologie (C.D.), Centre Hospitalier de Saint-Quentin; Service de Neurologie et Unité Neuro-Vasculaire-Hôpital de La Cavale Blanche (L.G.), Brest; Service de Neurologie et Unité Neurovasculaire (M.P.-G.), Centre Hospitalier Régional d'Orléans; Service de Neurologie-Pathologies Inflammatoires (J.L.), Centre Hospitalier Universitaire de Lille; and AP-HP (D.P.), Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2-Mazarin et Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière (CRICM), UMRS 975; Inserm U 975, CNRS, UMR 7225; Centre de Compétence des Syndromes Neurologiques Paraneoplasiques et Encéphalites Autoimmunes, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.;From the Centre National de Référence pour les Syndromes Neurologiques Paranéoplasiques (A.V., M.F., B.J., G.P., V.R., A.-L.P., S.M.-C., F.D., V.D., J.H.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team, NeuroMyoGene Institute, INSERM U1217/CNRS UMR5310, Lyon, France; University Claude Bernard Lyon 1, Université de Lyon; Service de Pneumologie-Oncologie Thoracique-Soins Intensifs Respiratoires (M.R.), Centre Hospitalier Universitaire de Rouen; Service d'Oncologie Médicale (J.R.), Institut de Cancérologie de l'Ouest René Gauducheau, St. Herblain; Service de Pneumologie (C.D.), Centre Hospitalier de Saint-Quentin; Service de Neurologie et Unité Neuro-Vasculaire-Hôpital de La Cavale Blanche (L.G.), Brest; Service de Neurologie et Unité Neurovasculaire (M.P.-G.), Centre Hospitalier Régional d'Orléans; Service de Neurologie-Pathologies Inflammatoires (J.L.), Centre Hospitalier Universitaire de Lille; and AP-HP (D.P.), Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2-Mazarin et Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière (CRICM), UMRS 975; Inserm U 975, CNRS, UMR 7225; Centre de Compétence des Syndromes Neurologiques Paraneoplasiques et Encéphalites Autoimmunes, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.;From the Centre National de Référence pour les Syndromes Neurologiques Paranéoplasiques (A.V., M.F., B.J., G.P., V.R., A.-L.P., S.M.-C., F.D., V.D., J.H.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team, NeuroMyoGene Institute, INSERM U1217/CNRS UMR5310, Lyon, France; University Claude Bernard Lyon 1, Université de Lyon; Service de Pneumologie-Oncologie Thoracique-Soins Intensifs Respiratoires (M.R.), Centre Hospitalier Universitaire de Rouen; Service d'Oncologie Médicale (J.R.), Institut de Cancérologie de l'Ouest René Gauducheau, St. Herblain; Service de Pneumologie (C.D.), Centre Hospitalier de Saint-Quentin; Service de Neurologie et Unité Neuro-Vasculaire-Hôpital de La Cavale Blanche (L.G.), Brest; Service de Neurologie et Unité Neurovasculaire (M.P.-G.), Centre Hospitalier Régional d'Orléans; Service de Neurologie-Pathologies Inflammatoires (J.L.), Centre Hospitalier Universitaire de Lille; and AP-HP (D.P.), Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2-Mazarin et Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière (CRICM), UMRS 975; Inserm U 975, CNRS, UMR 7225; Centre de Compétence des Syndromes Neurologiques Paraneoplasiques et Encéphalites Autoimmunes, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.;From the Centre National de Référence pour les Syndromes Neurologiques Paranéoplasiques (A.V., M.F., B.J., G.P., V.R., A.-L.P., S.M.-C., F.D., V.D., J.H.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team, NeuroMyoGene Institute, INSERM U1217/CNRS UMR5310, Lyon, France; University Claude Bernard Lyon 1, Université de Lyon; Service de Pneumologie-Oncologie Thoracique-Soins Intensifs Respiratoires (M.R.), Centre Hospitalier Universitaire de Rouen; Service d'Oncologie Médicale (J.R.), Institut de Cancérologie de l'Ouest René Gauducheau, St. Herblain; Service de Pneumologie (C.D.), Centre Hospitalier de Saint-Quentin; Service de Neurologie et Unité Neuro-Vasculaire-Hôpital de La Cavale Blanche (L.G.), Brest; Service de Neurologie et Unité Neurovasculaire (M.P.-G.), Centre Hospitalier Régional d'Orléans; Service de Neurologie-Pathologies Inflammatoires (J.L.), Centre Hospitalier Universitaire de Lille; and AP-HP (D.P.), Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2-Mazarin et Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière (CRICM), UMRS 975; Inserm U 975, CNRS, UMR 7225; Centre de Compétence des Syndromes Neurologiques Paraneoplasiques et Encéphalites Autoimmunes, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.;From the Centre National de Référence pour les Syndromes Neurologiques Paranéoplasiques (A.V., M.F., B.J., G.P., V.R., A.-L.P., S.M.-C., F.D., V.D., J.H.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team, NeuroMyoGene Institute, INSERM U1217/CNRS UMR5310, Lyon, France; University Claude Bernard Lyon 1, Université de Lyon; Service de Pneumologie-Oncologie Thoracique-Soins Intensifs Respiratoires (M.R.), Centre Hospitalier Universitaire de Rouen; Service d'Oncologie Médicale (J.R.), Institut de Cancérologie de l'Ouest René Gauducheau, St. Herblain; Service de Pneumologie (C.D.), Centre Hospitalier de Saint-Quentin; Service de Neurologie et Unité Neuro-Vasculaire-Hôpital de La Cavale Blanche (L.G.), Brest; Service de Neurologie et Unité Neurovasculaire (M.P.-G.), Centre Hospitalier Régional d'Orléans; Service de Neurologie-Pathologies Inflammatoires (J.L.), Centre Hospitalier Universitaire de Lille; and AP-HP (D.P.), Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2-Mazarin et Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière (CRICM), UMRS 975; Inserm U 975, CNRS, UMR 7225; Centre de Compétence des Syndromes Neurologiques Paraneoplasiques et Encéphalites Autoimmunes, Groupe Hospitalier Pitié-Salpêtrière, Paris, France. jerome.honnorat@chu-lyon.fr.",
"authors": "Vogrig|Alberto|A|;Fouret|Marine|M|;Joubert|Bastien|B|;Picard|Géraldine|G|;Rogemond|Véronique|V|;Pinto|Anne-Laurie|AL|;Muñiz-Castrillo|Sergio|S|;Roger|Maxime|M|;Raimbourg|Judith|J|;Dayen|Charles|C|;Grignou|Laurianne|L|;Pallix-Guyot|Maud|M|;Lannoy|Julien|J|;Ducray|François|F|;Desestret|Virginie|V|;Psimaras|Dimitri|D|;Honnorat|Jérôme|J|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000951:Antigens, Neoplasm; D000074322:Antineoplastic Agents, Immunological; D007155:Immunologic Factors; D000074324:Ipilimumab; C119249:Ma2 antigen; D009419:Nerve Tissue Proteins; D000077594:Nivolumab; C582435:pembrolizumab",
"country": "United States",
"delete": false,
"doi": "10.1212/NXI.0000000000000604",
"fulltext": "\n==== Front\nNeurol Neuroimmunol NeuroinflammNeurol Neuroimmunol NeuroinflammnnnNEURIMMINFLNeurology® Neuroimmunology & Neuroinflammation2332-7812Lippincott Williams & Wilkins Hagerstown, MD NEURIMMINFL201902118810.1212/NXI.0000000000000604131132213221ArticleIncreased frequency of anti-Ma2 encephalitis associated with immune checkpoint inhibitors Vogrig Alberto MD*Scientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\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\nFouret Marine MD*Scientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\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\nJoubert Bastien MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\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:\nEuropean Academy of Neurology awarded the following grant: EAN Research Training Fellowship 2019\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\nPicard Géraldine MScScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\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\nRogemond Véronique PhDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\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\nPinto Anne-Laurie MScScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\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\nMuñiz‐Castrillo Sergio MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\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\nRoger Maxime MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\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\nRaimbourg Judith MD, PhDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\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\nDayen Charles MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\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\nGrignou Laurianne MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for travel or speaker honoraria:\n1) Train ticket and hotel for JNLF congress 2019, SANOFI 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:\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\nPallix-Guyot Maud MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\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\nLannoy Julien MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\n(1)Roche funding for travel AAN 2019 at Philadelphia (2)Sanofi Genzyme funding for travel ECTRIMS 2017 at Amsterdam\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\n(1)Lettre du Neurologue e-journal ECTRIMS 2018, writer\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\nDucray François MD, PhDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\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\nDesestret Virginie MD, PhDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\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\nPsimaras Dimitri MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\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\nHonnorat Jérôme MD, PhDScientific Advisory Boards:\nScientific advisory board for Bristol Meyers Squibb\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nreceives royalties from licensing fees to AthenaDiagnostics, Euroimmun, and ravo Diagnostika for a patentfor the use of CV2/CRMP5 as diagnostic tests.\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:\nResearch support from CSL Behring France\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\nFrom the Centre National de Référence pour les Syndromes Neurologiques Paranéoplasiques (A.V., M.F., B.J., G.P., V.R., A.-L.P., S.M.-C., F.D., V.D., J.H.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team, NeuroMyoGene Institute, INSERM U1217/CNRS UMR5310, Lyon, France; University Claude Bernard Lyon 1, Université de Lyon; Service de Pneumologie-Oncologie Thoracique-Soins Intensifs Respiratoires (M.R.), Centre Hospitalier Universitaire de Rouen; Service d'Oncologie Médicale (J.R.), Institut de Cancérologie de l'Ouest René Gauducheau, St. Herblain; Service de Pneumologie (C.D.), Centre Hospitalier de Saint-Quentin; Service de Neurologie et Unité Neuro-Vasculaire—Hôpital de La Cavale Blanche (L.G.), Brest; Service de Neurologie et Unité Neurovasculaire (M.P.-G.), Centre Hospitalier Régional d'Orléans; Service de Neurologie—Pathologies Inflammatoires (J.L.), Centre Hospitalier Universitaire de Lille; and AP-HP (D.P.), Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2-Mazarin et Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière (CRICM), UMRS 975; Inserm U 975, CNRS, UMR 7225; Centre de Compétence des Syndromes Neurologiques Paraneoplasiques et Encéphalites Autoimmunes, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.Correspondence Dr. Honnorat jerome.honnorat@chu-lyon.frGo to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.\n\n* These authors contributed equally to the manuscript.\n\nData access, responsibility, and analysis: The corresponding author had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.\n\nThe Article Processing Charge was funded by Institut Neuromyogène INSERM U1217 CNRS 5310.\n\n07 8 2019 11 2019 07 8 2019 6 6 e60424 4 2019 08 7 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 report the induction of anti–Ma2 antibody–associated paraneoplastic neurologic syndrome (Ma2-PNS) in 6 patients after treatment with immune checkpoint inhibitors (ICIs). We also analyzed (1) patient clinical features compared with a cohort of 44 patients who developed Ma2-PNS without receiving ICI treatment and (2) the frequency of neuronal antibody detection before and after ICI implementation.\n\nMethods\nRetrospective nationwide study of all patients with Ma2-PNS developed during ICI treatment between 2017 and 2018.\n\nResults\nOur series of patients included 5 men and 1 woman (median age, 63 years). The patients were receiving nivolumab (n = 3), pembrolizumab (n = 2), or a combination of nivolumab and ipilimumab (n = 1) for treatment of neoplasms that included lung (n = 4) and kidney (n = 1) cancers and pleural mesothelioma (n = 1). Clinical syndromes comprised a combination of limbic encephalitis and diencephalitis (n = 3), isolated limbic encephalitis (n = 2), and a syndrome characterized by ophthalmoplegia and head drop (n = 1). No significant clinical difference was observed between our 6 patients and the overall cohort of Ma2-PNS cases. Post-ICI Ma2-PNS accounted for 35% of the total 17 Ma2-PNS diagnosed in our center over the 2017–2018 biennium. Eight cases had been detected in the preceding biennium 2015–2016, corresponding to a 112% increase of Ma2-PNS frequency since the implementation of ICIs in France. Despite ICI withdrawal and immunotherapy, 4/6 patients died, and the remaining 2 showed a moderate to severe disability.\n\nConclusions\nWe show a clear association between ICI use and increased diagnosis of Ma2-PNS. Physicians need to be aware that ICIs can trigger Ma2-PNS because clinical presentation can be challenging.\n\nOPEN-ACCESSTRUE\n==== Body\nTherapy with monoclonal antibodies (Abs) targeting immune checkpoints, including cytotoxic T lymphocyte–associated antigen 4 (CTLA-4), the programmed death-1 receptor (PD-1), and its ligand PD-L1, has led to a paradigm shift in the treatment of numerous types of cancer.1 Their unprecedented results in controlling tumors at a metastatic stage have come at the expense of an increased risk of developing immune-related adverse events (irAEs), including severe neurologic complications.2–6 Given their mechanism of action, a possible association with the development of paraneoplastic neurologic syndromes (PNSs) has been predicted.3,7 Recently, the emergence of individual cases and small series of patients developing encephalitis and other neurologic manifestations has caused growing concern.4,5,8 Because an increasing number of patients will be exposed to immune checkpoint inhibitors (ICIs) in the forthcoming future, it is crucial to identify the main features of neurologic irAEs.\n\nPNS with Abs targeting the intracellular Ma2 antigen characterizes a peculiar form of encephalitis with prominent involvement of limbic, brainstem, and diencephalic structures, usually in association with testicular or lung cancer.9,10 Atypical manifestations including narcolepsy-cataplexy, weight gain, sexual dysfunction, and motor neuron syndrome were described and account for the difficulty in diagnosing anti–Ma2 antibody–associated PNS (Ma2-PNS).9–12\n\nWe herein report 6 patients who developed autoimmune encephalitis with anti-Ma2 Abs during treatment with ICIs. To assess the relevance of our findings, we analyzed (1) their clinical features compared with a cohort of 44 patients who had developed Ma2-PNS without receiving any ICI and (2) the impact of ICI use on the frequency of Ma2 detection in a national reference center.\n\nMethods\nPatient selection\nThis is a retrospective study of all patients with anti-Ma2-PNS observed after treatment with ICIs and diagnosed at the French National Reference Center for Paraneoplastic Neurological Syndromes in Lyon, France, between January 1, 2017, and December 31, 2018. All patients underwent a comprehensive laboratory examination for suspected PNS as recommended,13 including an initial assessment with immunohistochemistry on rat brain sections, followed by a second confirmatory test represented by dot blot analysis on recombinant proteins (Euroimmun, Lübeck, Germany, and/or RAVO Diagnostika, Freiburg, Germany) and/or cell-based assays (CBAs) (in-house techniques) for the presence of onconeuronal Abs. We systematically tested: anti-Hu, Yo, CV2/CRMP5, Ri, Ma2, amphiphysin, GAD65, AK5, NMDA receptor (NMDAR), AMPAR, GABAAR, GABABR, IgLON5, CASPR2, LGI1, and DPPX. Anti-Ma2 specificities14 were confirmed using in-house CBA and commercial dot blots (Euroimmun, Lubeck, Germany). Clinical and ancillary data were obtained by telephone or email at the time of diagnosis, based on the biological sample, and at least twice a year to assess clinical evolution. Immunotherapy treatment modalities and oncologic therapy were recorded. Outcomes were assessed using the modified Ranking Scale (mRS). The scale ranges from 0 (no symptoms) to 6 (death).\n\nClinical comparison between ICI-induced Ma2-PNS vs classic Ma2-PNS\nDemographic and clinical features of patients with Ma2-PNS triggered by ICIs were compared with those of the overall cohort of patients with Ma2-PNS unrelated to ICI treatment diagnosed in our center between 2002 and 2018 (n = 44).\n\nFrequency of ICI-related PNS\nTo assess the impact of ICI use on the development of PNS at a national level, we compared the frequency of the different Ab detections in our Reference Center in the biennium 2017–2018 to the biennium 2015–2016 when the use of ICIs in France was at its starting point. The proportion of Ab-positive cases that developed after ICI use was calculated for each Ab specificity.\n\nStatistical analysis\nDescriptive analysis is presented as frequencies and percentages for categorical variables and as the median and range for continuous variables. Categorical data were analyzed with the Fisher exact test (2 tailed) and numerical data with the Mann-Whitney U test. Statistical analyses were performed using IBM SPSS Statistics Software (Version 25.0; IBM Corp, Armonk, NY). p Values <0.05 were considered significant.\n\nStandard protocol approvals, registrations, and patient consents\nWritten consent was obtained from all patients, and the study was approved by the Institutional Review Board of the University Claude Bernard Lyon 1 and Hospices Civils de Lyon.\n\nData availability\nData reported in this manuscript are available within the article or its supplementary materials. More information regarding the data is available from the corresponding author on reasonable request.\n\nResults\nPatients with ICI-associated anti-Ma2 syndromes\nBetween 2002 and 2018, we identified 50 patients with Ma2-PNS in our center, 6 of which developed the syndrome after ICI treatment in the biennium 2017–2018. All the information on clinical and paraclinical results, together with associated treatments and outcomes of these 6 patients, is summarized in the table. Most of the patients were male (83%), with a median age of 63 years (range: 47–79 years). All were Caucasians. Four of them had an associated non–small-cell lung cancer, 1 a pleural mesothelioma, and the last one a renal clear cell carcinoma. At the time of ICI introduction—a median of 6.5 months (range: 0.5–25) after cancer diagnosis—all the patients except 1 (patient 2) had a metastatic disease, which included brain involvement in 2 cases (patients 1 and 3). ICIs used comprised nivolumab (3 cases), pembrolizumab (2 cases), and a combination of nivolumab and ipilimumab in 1 case. Median delay between ICI introduction and onset of the neurologic syndrome was 4 months (range: 2–8). When the neurologic syndrome ensued, the 2 patients with cerebral metastasis had stable or improved lesions on brain MRI, whereas the others showed no evidence of cancer dissemination in the CNS. Clinical syndromes included a combination of limbic encephalitis and diencephalitis (patients 1, 2, and 5), isolated limbic encephalitis (patients 3 and 6), and a syndrome characterized by ophthalmoplegia and motor neuron involvement (head drop) in patient 4. Onset of the neurologic symptoms was usually subacute (3 patients), whereas patient 5 had an acute onset and patient 1 a chronic/progressive course. All patients fulfilled the criteria for definite PNS.15 No statistically significant clinicodemographic differences (including sex, age at onset, cancer type, and main neurologic syndrome) were observed between our 6 patients and the overall cohort of 44 patients with anti-Ma2-PNS diagnosed in our center. Testicular cancer was present in 11/44 (25%) of the patients with “classic” anti-Ma2-PNS and in none of the post-ICI cases. It is noteworthy that patients with Ma2-PNS associated with testicular cancer (n = 11) were significantly younger than patients with ICI-induced Ma2 Ab syndrome (p = 0.003). Importantly, the timing of onset of the neurologic syndrome in relation to the discovery of cancer was clearly different in the cases triggered by ICIs (p = 0.004). Indeed, 77% of the patients in the overall Ma2 cohort manifested their neurologic syndrome before the oncologic diagnosis. On the contrary, all patients in the ICI group have, by definition, a cancer at the time of PNS onset. It is, however, interesting to note that the symptoms appear long after cancer diagnosis, a median of 10 months later (range: 5.5–28 months).\n\nTable Characteristics of patients with ICI-induced Ma2 antibody paraneoplastic syndrome\n\nAll the patients in the present study were investigated using brain MRI, which showed bilateral fluid-attenuated inversion recovery hyperintensity involving the mesial temporal lobes in 4 cases, including 1 with coexisting hyperintensity of the periventricular regions of the third ventricle and hypothalamus (figure 1). Contrast enhancement was not detected in any patient at the level of inflammatory lesions on T1-weighted sequences. CSF analysis revealed inflammatory alterations in all cases, with the most common abnormality being an increased protein content (5 cases), followed by pleocytosis (2 cases) and presence of CSF-exclusive oligoclonal bands in 1 patient. Patient 5 showed additional anti-Ma1 positivity; no other onconeural Abs were detected in the remainder of the patients. The neurologic syndrome was moderately severe with a median pretreatment mRS score of 4 (range: 0–6), characteristic of a patient unable to walk unassisted and to attend to own bodily needs. Treatment included ICI withdrawal and corticosteroids in all patients. Additional treatment was adopted in 4 patients: 2 received IV immunoglobulin, 1 was treated with plasmapheresis, and 1 with rituximab. Median follow-up was 4 months (range: 1–6 months). Despite all these measures, 4/6 patients died, and the remaining 2 showed a moderate to severe disability (mRS score: 3 and 4, respectively). The cause of death was directly related to the neurologic involvement or its associated complications in 3 patients, whereas in 1 case, it was attributed to the tumor progression. Of note, before ICI withdrawal, all patients except 1 (patient 4) showed a good response of cancer to immunotherapy, with stabilization or reduction of the neoplastic lesions. Intriguingly, for 1 case (patient 2), a serum sample was taken before ICI initiation and then stored in a biobank. The retrospective analysis of this sample revealed the presence of Ma2 Abs even before cancer immunotherapy onset. No antecedent serum sample was available for the other patients.\n\nFigure 1 Results of paraclinical studies in patients with anti-Ma2 encephalitis triggered by immune checkpoint inhibitors [ICIs]\nBrain MRI (fluid-attenuated inversion recovery sequences) in 2 patients with anti-Ma2 encephalitis triggered by ICIs. Note the prominent limbic (A, axial view) and diencephalic (B, sagittal view) involvement (arrowheads).\n\nImpact of ICI use on the frequency of Ma2-PNS\nWe questioned whether ICI use had an impact on the frequency of Ma2-PNS in our center. During the study period 2017–2018, a total of 17 patients with Ma2 Abs were diagnosed in our reference center. The 6 Ma2-PNS described herein representing 35% of all the cases. During the biennium 2015–2016, when the use of ICIs in France was at its starting point, we observed only 8 Ma2-PNS cases, meaning that a 112.5% increase was observed since ICI implementation in France. As a matter of fact, the annual number of anti-Ma2 positivities diagnosed in our national reference center was relatively stable over the last decade, with a median of 4 cases per year (range: 1–6 cases), and this observation is therefore unprecedented. No other onconeural Ab targeting intracellular antigens demonstrated a similar increment (figure 2). A lower increment was demonstrated for the recently implemented neural surface Abs (such as NMDAR, Lgi1, CASPR2, GABABR, and AMPAR), ranging from 30 to 50%, probably reflecting their relatively novel adoption in clinical practice if compared with the former group. Remarkably, only 1 case associated with neural surface antibody (CASPR2 positivity) developed after ICI initiation, accounting for 3% of all CASPR2 patients diagnosed in our center in the same period.\n\nFigure 2 Proportion of variation in antibody detection between 2017 and 2018 vs 2015 and 2016 at the French Reference Center for Paraneoplastic Neurological Syndromes\nNote the 112% increase in Ma2-associated paraneoplastic neurologic syndrome detection observed after immune checkpoint inhibitor introduction. No other onconeural antibody (Ab) targeting intracellular antigens demonstrated a similar increment. A lower increment is observed for the recently implemented neural surface Abs, ranging from 30% to 50%, probably reflecting their relatively novel adoption in clinical practice if compared with the former group.\n\nDiscussion\nWe describe here 6 patients who developed anti-Ma2-PNS after receiving ICI treatment. Their demographic, clinical, and paraclinical features were remarkably uniform. Most of them were male, middle-age/elderly adults who developed a neurologic syndrome characterized by prominent limbic and diencephalic involvement, mainly associated with lung cancer. This clinical presentation is in line with both the original descriptions of the Ma2 syndrome9,10,16,17 and the clinical features from the 44 remaining patients of our overall cohort. We, however, note 3 notable differences: (1) in the classic, paraneoplastic form, the neurologic syndrome is known to precede cancer diagnosis by several weeks to months. When the tumor is eventually found, it is usually detected at a limited disease stage. On the contrary, when the disease appeared as a complication of ICIs, patients already presented with metastasis and the neurologic syndrome manifested several months after cancer discovery. (2) Testicular cancer is a frequently associated neoplasia in Ma2-PNS, and patients with Ma2 autoimmunity in the context of testicular tumors tend to be younger. Because the current treatment of testicular cancer does not include ICIs, this could explain the older age at onset and higher percentage of lung cancer association observed herein. (3) Contrast enhancement of inflammatory brain alterations is usually detected in up to one-third of Ma2-PNS cases. However, this pattern was not observed in the cases elicited by ICI treatment.6\n\nDespite these differences, the inflammatory alterations detected by CSF analysis, the presence of well-characterized Abs, and the selective brain MRI involvement of the mesial temporal lobe and diencephalon structures strongly suggest an immune-mediated pathogenesis.18 We therefore consider that the ICI treatment elicited the autoimmune encephalitis in our patients.\n\nBecause the anti–Ma2-associated syndrome is characterized by atypical manifestations such as increased daytime sleepiness, hyperphagia, and weight gain,10–12 it is important for the clinician to recognize the prominent features of this disease to avoid diagnostic pitfalls. These symptoms are related to the diencephalic involvement and need to be promptly differentiated from the clinical correlate of primary hypothyroidism, which is a much more common irAE that shares a similar presentation.19–21 The latter misdiagnosis occurred in 1 patient that we present (patient 2). Clinical worsening despite thyroid hormone therapy prompted further investigations until a final diagnosis of polysomnography-proven narcolepsy-cataplexy was finally made, together with the discovery of low hypocretin levels in the CSF. Patients treated with cancer immunotherapy are also at an increased risk of developing hypophysitis, which is less frequent than primary hypothyroidism and more difficult to diagnose, presenting mainly with fatigue, hormonal disturbances, and headache.20\n\nDiagnostic delay could result in inappropriate continuation of ICI therapy and late introduction of immunosuppressants, with obvious repercussions on patients' status. Indeed, the clinical outcome of patients with Ma2 Ab was poor, with most of the patients dying due to the neurologic involvement, and the remainder being left severely disabled. To this matter, we would like to underline that (1) contrary to previous reports,2,8 we demonstrate that ICI-related encephalitis can develop beyond the first 4–8 weeks of treatment and (2) ICI withdrawal and administration of corticosteroids, which is the recommended course of treatment in this situation,19 is not sufficient for all patients; (3) the adoption of second-line immunosuppressants is probably warranted for refractory cases.22 As such, the use of drugs—such as natalizumab—that can act on brain inflammatory processes without hampering the immune reaction against systemic localizations of cancer, was recently suggested.23\n\nThe pathogenesis of neurologic irAEs due to ICI use remains to be elucidated, although several lines of evidence suggest that (1) ICIs act by blocking the signaling from certain molecules—CTLA-4, PD-1, and its ligands—that exert inhibitory regulatory effects on T-cell activation, thus promoting antitumor immunity1,3; (2) the antitumor immune response might in turn cross-react with CNS autoantigens leading to a PNS, as demonstrated in a preclinical model using CTLA-4 blockade24; and (3) CD8+ T cells, activated by ICIs, were found to play a major effector role in neuronal death in PNS.24 In agreement with this model, it has been previously shown that the pathologic substrate of post-ICI encephalitis is characterized by prominent CD8+ lymphocytic perivascular infiltration.25\n\nTwo previous cases of ICI-induced anti-Ma2 encephalitis have been described. One concerned a patient with pleural mesothelioma treated with the anti-CTLA-4 Ab tremelimumab,26 and the second was in a patient with kidney cancer treated with nivolumab.25 Including the present series, this brings the total of cases reported in the literature up to 8. The reason for the increase in susceptibility to anti-Ma2 autoimmune response among all other Ab-associated PNS remains unclear. We propose that it reflects the fact that non–small-cell lung cancer is one of the cancers in which ICIs are most extensively used,1 and this tumor is known to associate with Ma2-PNS.9,10,17 We therefore hypothesize that an analogous increment of anti-Yo and anti-Ri syndrome will be seen after the adoption of ICIs in breast cancer.24,27 The same will probably occur for anti-Hu or anti-CV2/CRMP5 PNS if their use is extended to small-cell lung cancer.28,29\n\nThe retrospective detection of Ma2 Ab in the serum of one of our patients taken before ICI administration is an intriguing finding that deserves further discussion. First, it should be considered that at the time, the sample was taken and stored in a biobank, and the patient was asymptomatic. Neurologic symptoms appeared only 5 months later, following treatment with the combination of ipilimumab-nivolumab. Second, the finding of a confirmed Ma2 positivity in a patient without neurologic syndrome is exceedingly rare,15 whereas other onconeural Abs, such as anti-Hu and anti-CV2/CRMP5, are detected in 16% and 9% of neurologically asymptomatic patients with SCLC, respectively.15 These Abs are known to be reliable biomarkers of an underlying cancer but are not pathogenic because a T cell–mediated response is advocated as the cause of the neurologic syndrome.15,30 We therefore hypothesize, similarly to what we have observed in patients with ovary cancer with Yo-Abs and paraneoplastic cerebellar ataxia,31 that the tumor (a pleural mesothelioma in this case) expressed aberrantly the Ma2 antigens and triggered the systemic Ab production. This event per se was not sufficient to elicit a PNS, but required a loss of self-tolerance as permitted by the use of ICIs. This hypothesis needs to be verified in prospective studies assessing the presence and titer of onconeural Abs over time, their relation to immunotherapy, and the development of an overt neurologic syndrome. Our practical recommendation is to test patients undergoing ICI treatment for onconeural Abs before initiation of immunotherapy, and to closely follow those with an Ab positivity, with special caution for Ma2-positive cases. Patients with preexisting Abs are probably at an increased risk of developing irAEs, as demonstrated for anti-acetylcholine receptor autoantibodies and subsequent myositis in patients treated with avelumab.32\n\nThe present study is limited by its retrospective nature, small sample size, and, possibly, referral bias toward more complex and/or treatment-refractory cases. Nevertheless, it represents the 2-year experience of a national reference center focused on the diagnosis and treatment of PNS.\n\nDiscussion\nWe showed a clear association between ICI use in France and an increased frequency of anti-Ma2-PNS. Although final arguments proving a causal relationship between ICI and PNS development are lacking, there are several findings suggesting that this syndrome is related to ICI. Middle-aged/elderly men with lung cancer appeared to be at particular risk of developing post-ICI anti-Ma2-PNS. Given the anticipated rise in the use of immunotherapy for oncologic practices, we highlight the importance of early detection of these immune-mediated neurotoxic effects, which can be severe or even fatal.\n\nAcknowledgment\nThe authors thank NeuroBioTec Hospices Civils de Lyon BRC (France, AC-2013-1867, NFS96-900) for banking sera and CSF samples. They also thank Dr. Pauline De L'Estang Du Rusquec, Dr. Youcef Douadi, Dr. Aurore Jourdain, Dr. Justin Le Tallec, and Dr Jerome Meunier who provided additional clinical data for the study. They gratefully acknowledge Véréna Landel, PhD, for English language editing (Direction de la Recherche Clinique, Hospices Civils de Lyon).\n\nStudy funding\nThis study is supported by research grants from Agence Nationale de la Recherche (ANR-14-CE15-0001-MECANO), Fondation pour la recherche médicale (DQ20170336751).\n\nDisclosure\nThe authors have no conflicts of interest to disclose. Go to Neurology.org/NN for full disclosures.\n\nAppendix Authors\n\n\nGlossary\nCBAcell-based assay\n\nCTLA-4cytotoxic T lymphocyte–associated antigen 4\n\nICIimmune checkpoint inhibitor\n\nirAEimmune-related adverse event\n\nMa2-PNSMa2 antibody–associated paraneoplastic neurologic syndrome\n\nmRSmodified Ranking Scale\n\nNMDARNMDA receptor\n\nPD-1programmed death-1 receptor\n==== Refs\nReferences\n1. Ribas A , Wolchok JD \nCancer immunotherapy using checkpoint blockade . Science \n2018 ;359 :1350 –1355 .29567705 \n2. Dalakas MC \nNeurological complications of immune checkpoint inhibitors: what happens when you ‘take the brakes off’ the immune system . Ther Adv Neurol Disord \n2018 ;11 :1756286418799864 .30245744 \n3. Yshii LM , Hohlfeld R , Liblau RS \nInflammatory CNS disease caused by immune checkpoint inhibitors: status and perspectives . Nat Rev Neurol \n2017 ;13 :755 –763 .29104289 \n4. Larkin J , Chmielowski B , Lao CD , et al \nNeurologic serious adverse events associated with nivolumab plus ipilimumab or nivolumab alone in advanced melanoma, including a case series of encephalitis . Oncologist \n2017 ;22 :709 –718 .28495807 \n5. Kao JC , Liao B , Markovic SN , et al \nNeurological complications associated with anti–programmed death 1 (PD-1) antibodies . JAMA Neurol \n2017 ;74 :1216 .28873125 \n6. Touat M , Talmasov D , Ricard D , Psimaras D \nNeurological toxicities associated with immune-checkpoint inhibitors . Curr Opin Neurol \n2017 ;30 :659 –668 .28938341 \n7. Graus F , Dalmau J \nParaneoplastic neurological syndromes in the era of immune-checkpoint inhibitors . Nat Rev Clin Oncol Epub 2019 Mar 12.\n8. Williams TJ , Benavides DR , Patrice KA , et al \nAssociation of autoimmune encephalitis with combined immune checkpoint inhibitor treatment for metastatic cancer . JAMA Neurol \n2016 ;73 :928 .27271951 \n9. Dalmau J \nClinical analysis of anti-Ma2-associated encephalitis . Brain \n2004 ;127 :1831 –1844 .15215214 \n10. Vogrig A , Joubert B , Maureille A , et al \nMotor neuron involvement in anti-Ma2-associated paraneoplastic neurological syndrome . J Neurol \n2019 ;266 :398 –410 .30498914 \n11. Dauvilliers Y , Bauer J , Rigau V , et al \nHypothalamic immunopathology in anti-Ma-associated diencephalitis with narcolepsy-cataplexy . JAMA Neurol \n2013 ;70 :1305 –1310 .23939463 \n12. Adams C , McKeon A , Silber MH , Kumar R \nNarcolepsy, REM sleep behavior disorder, and supranuclear gaze palsy associated with Ma1 and Ma2 antibodies and tonsillar carcinoma . Arch Neurol \n2011 ;68 :521 –524 .21482933 \n13. Waters P , Pettingill P , Lang B \nDetection methods for neural autoantibodies . Handb Clin Neurol \n2016 ;133 :147 –163 .27112676 \n14. Rosenfeld MR , Eichen JG , Wade DF , Posner JB , Dalmau J \nMolecular and clinical diversity in paraneoplastic immunity to Ma proteins . Ann Neurol \n2001 ;50 :339 –348 .11558790 \n15. Graus F , Delattre JY , Antoine JC , et al \nRecommended diagnostic criteria for paraneoplastic neurological syndromes . J Neurol Neurosurg Psychiatry \n2004 ;75 :1135 –1140 .15258215 \n16. Voltz R , Gultekin SH , Rosenfeld MR , et al \nA serologic marker of paraneoplastic limbic and brain-stem encephalitis in patients with testicular cancer . N Engl J Med \n1999 ;340 :1788 –1795 .10362822 \n17. Hoffmann LA , Jarius S , Pellkofer HL , et al \nAnti-Ma and anti-Ta associated paraneoplastic neurological syndromes: 22 newly diagnosed patients and review of previous cases . J Neurol Neurosurg Psychiatry \n2008 ;79 :767 –773 .18223018 \n18. Graus F , Titulaer MJ , Balu R , et al \nA clinical approach to diagnosis of autoimmune encephalitis . Lancet Neurol \n2016 ;15 :391 –404 .26906964 \n19. Haanen JBAG , Carbonnel F , Robert C , et al \nManagement of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up† . Ann Oncol \n2017 ;28 :iv119 –iv142 .28881921 \n20. Barroso-Sousa R , Barry WT , Garrido-Castro AC , et al \nIncidence of endocrine dysfunction following the use of different immune checkpoint inhibitor regimens: a systematic review and meta-analysis . JAMA Oncol \n2018 ;4 :173 –182 .28973656 \n21. Feldman AZ , Shrestha RT , Hennessey JV \nNeuropsychiatric manifestations of thyroid disease . Endocrinol Metab Clin North Am \n2013 ;42 :453 –476 .24011880 \n22. Hottinger AF \nNeurologic complications of immune checkpoint inhibitors . Curr Opin Neurol \n2016 ;29 :806 –812 .27653290 \n23. Hottinger AF , de Micheli R , Guido V , Karampera A , Hagmann P , Du Pasquier R \nNatalizumab may control immune checkpoint inhibitor–induced limbic encephalitis . Neurol Neuroimmunol Neuroinflamm \n2018 ;5 :e439 \ndoi: 10.1212/NXI.0000000000000439.30465016 \n24. Yshii LM , Gebauer CM , Pignolet B , et al \nCTLA4 blockade elicits paraneoplastic neurological disease in a mouse model . Brain \n2016 ;139 :2923 –2934 .27604307 \n25. Kopecký J , Kubeček O , Geryk T , et al \nNivolumab induced encephalopathy in a man with metastatic renal cell cancer: a case report . J Med Case Rep \n2018 ;12 :262 .30217214 \n26. Vogrig A , Ferrari S , Tinazzi M , Manganotti P , Vattemi G , Monaco S \nAnti-Ma-associated encephalomyeloradiculopathy in a patient with pleural mesothelioma . J Neurol Sci \n2015 ;350 :105 –106 .25661887 \n27. Santa-Maria CA , Nanda R \nImmune checkpoint inhibitor therapy in breast cancer . J Natl Compr Canc Netw \n2018 ;16 :1259 –1268 .30323094 \n28. Calles A , Aguado G , Sandoval C , Álvarez R \nThe role of immunotherapy in small cell lung cancer . Clin Transl Oncol Epub 2019 Jan 12.\n29. Graus F , Keime-Guibert F , Reñe R , et al \nAnti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients . Brain \n2001 ;124 :1138 –1148 .11353730 \n30. Honnorat J , Antoine JC \nParaneoplastic neurological syndromes . Orphanet J Rare Dis \n2007 ;2 :22 .17480225 \n31. Small M , Treilleux I , Couillault C , et al \nGenetic alterations and tumor immune attack in Yo paraneoplastic cerebellar degeneration . Acta Neuropathologica \n2018 ;135 :569 –579 .29299667 \n32. Mammen AL , Rajan A , Pak K , et al \nPre-existing antiacetylcholine receptor autoantibodies and B cell lymphopaenia are associated with the development of myositis in patients with thymoma treated with avelumab, an immune checkpoint inhibitor targeting programmed death-ligand 1 . Ann Rheum Dis \n2019 ;78 :150 –152 .30185415\n\n",
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"issue": "6(6)",
"journal": "Neurology(R) neuroimmunology & neuroinflammation",
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"mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D000951:Antigens, Neoplasm; D000074322:Antineoplastic Agents, Immunological; D004660:Encephalitis; D006801:Humans; D007155:Immunologic Factors; D000074324:Ipilimumab; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D009419:Nerve Tissue Proteins; D000077594:Nivolumab; D020361:Paraneoplastic Syndromes, Nervous System; D012189:Retrospective Studies",
"nlm_unique_id": "101636388",
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"pmid": "31454760",
"pubdate": "2019-11",
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"title": "Increased frequency of anti-Ma2 encephalitis associated with immune checkpoint inhibitors.",
"title_normalized": "increased frequency of anti ma2 encephalitis associated with immune checkpoint inhibitors"
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"companynumb": "FR-SHIRE-FR202013667",
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"abstract": "We report on a case of a 59-year-old female patient with atrial fibrillation who received edoxaban. She withdrew edoxaban before tooth extraction. She was brought to our emergency department due to acute onset of left-side weakness. Under the impression of acute ischemic stroke, edoxaban was replaced with aspirin. However, the patient suffered from recurrent cerebral embolism with conscious disturbance. Urgent mechanical thrombectomy was performed due to left internal carotid artery occlusion. Remarkable recovery was noted on the second day after thrombectomy. She was discharged with mild neurological deficit. We suggest that early recognition, assessment, and interventional treatment for patients with in-hospital strokes are favorable for stroke outcome.",
"affiliations": "Department of Neurology and Stroke Center, Linkou Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan, Taiwan.",
"authors": "Lee|Tsong-Hai|TH|",
"chemical_list": null,
"country": "Switzerland",
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"doi": "10.1159/000501001",
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"issue": "12(Suppl 1)",
"journal": "Case reports in neurology",
"keywords": "Atrial fibrillation; Cardioembolic stroke; In-hospital; Mechanical thrombectomy",
"medline_ta": "Case Rep Neurol",
"mesh_terms": null,
"nlm_unique_id": "101517693",
"other_id": null,
"pages": "22-26",
"pmc": null,
"pmid": "33505268",
"pubdate": "2020",
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"references": "29237321;29165556;30455404;30155739;29572080;25566339;23718166;29781063;30619054",
"title": "In-Hospital Mechanical Thrombectomy: A Case Report.",
"title_normalized": "in hospital mechanical thrombectomy a case report"
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"companynumb": "TW-DSJP-DSJ-2021-100355",
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"activesubstancename": "EDOXABAN TOSYLATE"
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"abstract": "BACKGROUND\nAlthough mitral valve repair is the preferred treatment for mitral regurgitation in neonates and infants, mitral valve replacement (MVR) is sometimes necessary.\n\n\nMETHODS\nFrom 1999 through 2013, 18 patients younger than 1 year underwent MVR with the smallest (16 mm) commercially available mechanical valve. At surgery, mean age was 4.0 ± 1.8 months (range, 4 days to 7 months), and mean body weight was 5.3 ± 1.6 kg (range, 3.2 to 8.3 kg). Prosthetic valves were implanted in the supra-annular position in 17 of the 18 patients.\n\n\nRESULTS\nAll patients were followed up, and the mean follow-up period was 4.5 ± 3.8 years (range, 0.2 to 14 years). The rates of overall survival and freedom from redo MVR at 10 years were 88.9% and 57.8%, respectively. The causes of redo MVR were pulmonary hypertension in patients with left ventricular outflow obstruction (n = 2), hemolysis (n = 1), and a stuck valve (n = 1). The estimated effective orifice area index (effective orifice area/body surface area) was significantly inversely correlated with peak transmitral pressure gradient (r = -0.784, p < 0.01). The rate of freedom from permanent pacemaker implantation at 10 years was 71.2%. Three of the 5 pacemaker implantation procedures were for postoperative sick sinus syndrome. Although intracranial hemorrhage developed in 3 infants, all neurologic sequelae resolved.\n\n\nCONCLUSIONS\nThe implanted valves were durable, and no premature increase in transmitral pressure gradient was observed. Complications included injury of the sinus node artery and hemorrhage related to anticoagulation therapy.",
"affiliations": "Department of Pediatric Cardiovascular Surgery, National Cerebral and Cardiovascular Center, Suita, Japan.;Department of Pediatric Cardiovascular Surgery, National Cerebral and Cardiovascular Center, Suita, Japan. Electronic address: thoashi@surg1.med.osaka-u.ac.jp.;Department of Pediatric Cardiovascular Surgery, National Cerebral and Cardiovascular Center, Suita, Japan.;Department of Pediatric Cardiology, National Cerebral and Cardiovascular Center, Suita, Japan.;Department of Pediatric Cardiology, National Cerebral and Cardiovascular Center, Suita, Japan.;Department of Pediatric Cardiovascular Surgery, National Cerebral and Cardiovascular Center, Suita, Japan.",
"authors": "Moon|Jiyong|J|;Hoashi|Takaya|T|;Kagisaki|Koji|K|;Kurosaki|Kenichi|K|;Shiraishi|Isao|I|;Ichikawa|Hajime|H|",
"chemical_list": null,
"country": "Netherlands",
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"issue": "99(2)",
"journal": "The Annals of thoracic surgery",
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"medline_ta": "Ann Thorac Surg",
"mesh_terms": "D005260:Female; D006350:Heart Valve Prosthesis; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008943:Mitral Valve; D008944:Mitral Valve Insufficiency; D011474:Prosthesis Design; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "15030100R",
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"pubdate": "2015-02",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article",
"references": null,
"title": "Clinical outcomes of mitral valve replacement with the 16-mm ATS advanced performance valve in neonates and infants.",
"title_normalized": "clinical outcomes of mitral valve replacement with the 16 mm ats advanced performance valve in neonates and infants"
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"companynumb": "JP-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2015-BI-23824GD",
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"abstract": "The present case report described a 61-year-old female patient who was diagnosed as Meige syndrome with double eyelid spasm, anxiety and insomnia. After she was treated with psychoactive drugs, it was found that clonazepam tablets in the benzodiazepine class and dopamine antagonist olanzapine tablets aggravated double eyelid spasm; while eszopiclone tablets as a specificity γ-aminobutyric acid receptor binding drug alleviated this condition. The present case suggests that psychoactive drugs have both positive and negative effects on treating Meige syndrome. As for the patients who also have emotion disorder, their conditions should be observed carefully when choosing which psychoactive drug to use. The specificity γ-aminobutyric acid receptor binding drugs should be the prime choice, such as eszopiclone.",
"affiliations": "Department of Psychiatry, Sir Run Run Shaw Hospital, Zhejiang University School of Medical, and the Collaborative Innovation Center for Brain Science, Hangzhou, Zhejiang, China.;Department of Psychiatry, Sir Run Run Shaw Hospital, Zhejiang University School of Medical, and the Collaborative Innovation Center for Brain Science, Hangzhou, Zhejiang, China.;Department of Psychiatry, Sir Run Run Shaw Hospital, Zhejiang University School of Medical, and the Collaborative Innovation Center for Brain Science, Hangzhou, Zhejiang, China.;Department of Psychiatry, Sir Run Run Shaw Hospital, Zhejiang University School of Medical, and the Collaborative Innovation Center for Brain Science, Hangzhou, Zhejiang, China.;Department of Psychiatry, Sir Run Run Shaw Hospital, Zhejiang University School of Medical, and the Collaborative Innovation Center for Brain Science, Hangzhou, Zhejiang, China.",
"authors": "Zhao|Shimiao|S|;Zhang|Yingchun|Y|;Xu|Luoyi|L|;Wei|Lili|L|;Chen|Wei|W|",
"chemical_list": null,
"country": "China",
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"doi": "10.11919/j.issn.1002-0829.216038",
"fulltext": "\n==== Front\nShanghai Arch PsychiatrySAPShanghai Archives of Psychiatry1002-0829Shanghai Municipal Bureau of Publishing 10.11919/j.issn.1002-0829.216038Case ReportA Case Report of Psychoactive Drugs Aggravating and Alleviating Meige Syndrome 精神药物加重及减轻美格综合征一例 ZHAO Shimiao 赵 世苗 12*ZHANG Yingchun 章 迎春 1XU Luoyi 许 洛伊 1WEI Lili 魏 丽丽 1CHEN Wei 陈 炜 1*1 Department of Psychiatry, Sir Run Run Shaw Hospital, Zhejiang University School of Medical, and the Collaborative Innovation Center for Brain Science, Hangzhou, Zhejiang, China2 The Seventh People’s Hospital, Shaoxing, Zhejing, China*No.3 East Qingchun Road, Hangzhou, Zhejiang, China. Postcode: 310016. srrcw@zju.edu.cn25 8 2016 25 8 2016 28 4 222 226 © Shanghai Municipal Bureau of Publishing2016This work is licensed under a Creative Commons Attribution-NonCommercial-Share Alike 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/Summary\nThe present case report described a 61-year-old female patient who was diagnosed as Meige syndrome with double eyelid spasm, anxiety and insomnia. After she was treated with psychoactive drugs, it was found that clonazepam tablets in the benzodiazepine class and dopamine antagonist olanzapine tablets aggravated double eyelid spasm; while eszopiclone tablets as a specificity γ-aminobutyric acid receptor binding drug alleviated this condition. The present case suggests that psychoactive drugs have both positive and negative effects on treating Meige syndrome. As for the patients who also have emotion disorder, their conditions should be observed carefully when choosing which psychoactive drug to use. The specificity γ-aminobutyric acid receptor binding drugs should be the prime choice, such as eszopiclone.\n\n概述\n本病例报告描述了一女性患者，61 岁，双眼睑 痉挛，诊断美格综合征(Meige syndrome)，伴焦虑失 眠症状，使用精神药物治疗时发现，苯二氮卓类药物 硝西泮片、多巴胺拮抗剂奥氮平片加重眼睑痉挛，特 异性γ- 氨基丁酸受体结合药物右佐匹克隆片则减轻眼 睑痉挛。本病例提示精神药物对美格综合征的影响存 在正面与负面的差异，对伴发情绪障碍的患者，在选 用精神药物治疗时应仔细观察评估病情，首选特异性γ- 氨基丁酸受体结合的药物，如右佐匹克隆。\n\nKey words\npsychoactive drugMeige syndromeclonazepameszopiclone\n==== Body\n1. Case history\nM. was a sixty-one-year-old housewife. She was accompanied by her daughter to the mental health ward of our hospital on 22nd September 2014 because she had discomfort in her eyes for two years and had trouble sleeping for two months. In the previous 2 years and without any obvious cause, she began to have foreign physical sensations in her eyes, photophobia, and blurred vision. However her eyes did not feel weak or dry. She was treated with eye drops and was diagnosed with xeroma during a visit to her local hospital, however her condition did not improve. After that, she was tested with the anti-nuclear antibody spectrum, tear film, Schirmer test, however xeroma was ruled out. In the meantime, she continued to receive treatment for xeroma, but the effect was not significant. One year ago, her eyes began to blink involuntarily. It happened occasionally at first, and then gradually became more frequent. At times it was accompanied by twitching her cheeks and mouth as well. This condition was relatively mild in morning, but the frequency increased in afternoon. Her MRI results showed no significant abnormalities, therefore, no exact diagnosis was given. She was prescribed Tiapride Hydrochloride tablets 100 mg per night for more than three months, but the blinking and twitching did not improve and she became frequently drowsy. Two months ago, she started having trouble falling asleep, and becoming agitated and anxious after she stopped taking Tiapride Hydrochloride tablets. At this point, her highest blood pressure reached 138/110mmHg, and her insomnia did not improve after two days of acupuncture treatment. The local department of mental health admitted her to the hospital for anxiety and she was treated with and intravenous infusion of clonazepam 0.5 mg per day, paroxetine tablets 30 mg per day, clonazepam tablets 0.5mg per night and haloperidol tablets 2mg per night. Her sleeping and anxiety conditions improved after treatment; however, the blinking became aggravated on the third or fourth day after she was admitted. Her eyes were like a small crack, and she could not open them for a long time. She left the hospital after more than 20 days. Shortly after she went home, her body started to shake, and she became restless and anxious. Later when she went to the local hospital’s mental health department, her treatment was changed to escitalopram (Lexapro) 10 mg per day and olanzapine (Zyprexa) 1.25-3.75 mg per night. Her restlessness and anxiety improved, however the blinking was not alleviated. During this period of time, she took olanzapine tablets for only a month due to her difficulty in tolerating the gastrointestinal side effects of escitalopram tablets. However, her issues with blinking and trouble opening her eyes did not improve. In the recent two months, the patient’s normal life has been compromised by the fact that she needs to pull her eyelids up with her hands when she walks. She was not able to ride a bike, cook or do other activities, and she is therefore also timid, agitated, easily worried, and negative. She wanted to get a botox injection at our outpatient facility to treat the eyelid spasm. But considering that her emotional distress may have been aggravating the eyelid spasm she was advised to first consult with a clinician in our hospitals psychology department.\n\nPast history: she received hemorrhoid surgery 20 years ago and recovered well. A gastroscopy in 2013 showed that she had duodenal ulcer, and she often had discomfort in her stomach.A colonoscopy showed rectal erosion. She denied any history of trauma to her head and face.\n\nPersonal history: Patient was the second child in her household, had a poor health condition in childhood, was outgoing and stubborn, had junior middle school education and was currently retired. Client was extremely sensitive to needles.\n\nObstetrical history: Client had menses at 15 (3-4/30) (menopause at 50), and had one one daughter. Patient was widowed 8 years ago, her husband died of liver cancer, and she denied any bereavement.\n\nFamily history: The patient’s father died of a myocardial infarction, but her mother and younger brother were healthy.\n\nExamination: Patient had double eyelid spasm, involuntary closing of eyes, paroxysmal double eyelid twitching, normal vision and visual field, no diplopia or strabismus, functional blindness. In addition she had twitching in the cheek and mouth, the left side was more obvious, but there were no significant positive symptoms.\n\nMental health examination: Patient had clear consciousness, normal orientation, coherent thinking, no delusions, and secondary anxiety which was mainly the concern for double eyelid spasm. She denied any concerns about the future. There was no significant abnormality in her behavior; while her social function was obviously impaired, but this was secondary to double eyelid spasm. Her insight was intact. After she was admitted into the hospital, the nurse noticed that the eyelid spasm was absent during her sleep. There was no significant abnormality of MRI and thyroid function results.\n\n2. Diagnosis analysis\nBased on the patients’ medical history and clinical characteristics (61 years old female; developed double eyelid spasm, twitches of mouth and cheek; no abnormal MRI of her head or thyroid dysfunction; no facial trauma history), the diagnosis was Meige syndrome, and the aggravation of the conditions were related to the psychoactive drugs. Differential diagnosis included: 1) Xeroma: xeroma was ruled out by immunological tests and eye examinations; moreover, the patient did not experience any dry sensation in her eyes, which suggested that the prerequisite of xeroma was absent. 2) Myasthenia gravis: the main symptoms are eyelid weakness and blepharoptosis. However the patients’ symptoms were muscle spasms in the eyelids and mouth, so we did not consider Myasthenia gravis. After three days in the hospital, the patient’s eyelid spasm was suddenly aggravated. Her condition developed more quickly than what is regularly seen in Meige’s syndrome. We considered the following other factors: 1) Generalized anxiety disorder: the patient was agitated and anxious, but anxiety was limited only to concerns about her medical condition. She wasn’t anxious about the future or unspecific issues. Therefore we did not consider generalized anxiety disorder. 2) Adverse drug reactions: The eyelid spasms were aggravated after three days in hospital, so we considered it related to drugs used.\n\n3. Treatment\nThe patient stopped taking olanzapine and escitalopram, and was started on eszopiclone 3 mg/qn after she was admitted. The eyelid spasm alleviated gradually, and was improved significantly after a week. The patient stated: “Basically, I don’t blink uncontrollably, and I am like how I was when I was normal.” But the patient was still midly anxious, and only got 4 to 5 hours of sleep a day. In order to improve her sleep, treatment was changed to clonazepam 10mg/qn because adding eszopiclone can have some risks for elderly patients. The patient felt blepharoptosis and had trouble opening her eyes the next day. So she was started on eszopiclone 3 mg/d again. Three days later, of the condition with her eyelids improved and five days later the condition had been completely alleviated. Afterwards the spasming was not as serious in the morning but still occurred in the afternoon though the degree was far less than before Her anxiety was completely relieved, therefore she was discharged from the hospital the 5th of October 2014. During a follow up visit a week later the eyelid spasms were not obvious and did not affect her life. However the outpatient clinic in the department of neurology did not recommend her taking a botox injection. She continued to take eszopiclone 3 mg/d for more than two months and did not have any more eyelid spasms, however she could not tolerate the nausea. After she stopped taking the eszopiclone, her eyelid spasm relapsed. In the local mental health hospital, she was prescribed with “lorazepam,flupentixol and melitracen” which did not improve her condition. Her condition aggravated, and she could barely open her eyes again. On the 27th July 2015, she went to our department of neurology to have the botox injection. She is currently not taking psychoactive drugs, such as “lorazepam,flupentixol and melitracen tablets”. Her blinking symptoms have resolved and she does not have any discomfort in her eyes. Also, she does not have remaining symptoms like anxiety and insomnia.\n\n4. Discussion\nMeige’s syndrome is a kind of focal dystonia disease, and it was first reported by French neurologist Meige in 1910. The main symptoms are double eyelid spasm and facial involuntary movements, and it is also called blepharospasm-oromandibular dystonia.[1] Marsdan[2] classified it into three types: (1) blepharospasm (BS): the symptoms are eyelid paroxysmal involuntary spasm or involuntary blinking. (2) blepharospasm with oromandilular dystonia (BS-OMD): the patients have eyelid spasming and also experience twitching in the cheeks and mouth which appear as pouting, pulling back of the lips, opening ones mouth, sticking the tongue out and involuntary twitches of the mouth and face. In addition patients have strange expressions. (3) oromandibular dystonia (OMD): the symptom is limited to the twitches of the mouth and cheeks.\n\nMeige’s syndrome usually starts to appear when people are 50 to 60 years old, but there are teenage patients as well. It is more common in females. The ratio of males to females with this condition is 1:3.[3-4] Double eyelid spasm is the most common symptom of this disease, and eyelid weakness and blepharoptosis are also quite common. A few patients’ first symptom is intense facial tension. Patients with severe conditions could have functional blindness. The patient in this case had become functionally blind with eyelid and lower facial muscle spasming. Therefore, the diagnosis was BS-OMD. However, the blinking condition disappearing after the botox injection supports the Meige’s syndrome diagnosis.\n\nWhen Meige’s syndrome’s initial symptoms are not typical, it should be differentiated from xeroma.[5-6] Patients with Xeroma are impaired by low secretion and poor stability in tears. It is easy to confuse xeroma with eyelid spasm, as xeroma’s symptoms are dry eyes, a burning sensation, increasing scardamyxis and so forth. Supplementary inspection methods include the break up time of tear film, Schirmer test and corneal fluorescein staining. Clinical inspection emphasizes the self-reported symptoms. The patient in this case did not suffer from dry eyes during her two year course of disease and the increasing scardamyxis was due to uncontrollable muscle twitches instead of dry eyes. Artificial tears can improve dry eyes and reduce scardamyxis, but the patient’s bilinking was not alleviated after being treated with artificial tears. Therefore, xeroma was not considered. This patient was misdiagnosed with xeroma at first, and was treated with ophthalmology methods after xeroma was ruled out and this led to the indiscreet use of psychoactive drugs. The nosology of primary Meige’s syndrome is unclear, whereas secondary Meige’s syndrome is related to the upper brain stem and abnormal basal ganglia dopamine receptor hypersensitivity, hyperactive cholinergic nervous system (e.g., basal ganglia), low Gamma-amino butyric Acid (GABA) function. However the syndrome is not simply due to function in dopamine, acetylcholine and GABA, but is also related to chemical imbalances. [7] One third of people with Meige’s syndrome have emotional disorder,[8] with main symptoms of anxiety, depression and sleep disorder. Moreover, the symptoms are aggravated when the patients are agitated therefore it is easy to misdiagnose. When emotional disorder is the focus of treatment, medications acting on the neurotransmitters described above should be considered and may by proxy improve the symptoms of Meige’s syndrome.\n\nCurrently, medications used to treat Meige’s syndrome include anticholinergics (e.g. Trihexyphenidyl), GABA receptor agonists (e.g. Benzodiazepine class of drugs), dopamine antagonist (e.g. Tiapride), antiepileptics (e.g. VPA) and so on. The majority are psychoactive drugs. Their effect is average, but they have many side effects.[9] Botox injection is applied extensively in the clinical treatment, and it has positive effects. But it also loses its effect gradually, and leads to antibody production and therapeutic resistance.[10] Stereotactic surgery is applied in neurosurgery, but it does not have ideal effects either.[11] Recent reports have mentioned that globus pallidus deep brain stimulation (GBS) is effective and has less side effects, but research with large samples and follow-ups is still needed.[12]\n\nThis patient was treated with the dopamine antagonist Tiapride, but it had no effect. After she stopped taking Tiapride, she began to have significant anxiety. Her eyelid spasm worsened after she started taking Clonazepam (i.e., GABA receptor agonist), Paroxetine (i.e., anti-acetylcholine) and Haloperidol (i.e., dopamine antagonist). The later treatment demonstrated that using Olanzapine and Escitalopram together or using Lorazepam and Deanxit together aggravated symptoms. It is possible that these drugs affect acetylcholine, GABA and dopamine and lead to the imbalance of acetylcholine, dopamine and serotonin. Even though it is uncertain which drug aggravates symptoms, it suggests that joint usage may aggravate the symptoms of Meige’s syndrome. The later treatment which used Nitrazepam or Olanzapine also only worsened eyelid spasming. The temporal relationship was clear, so Nitrazepam and Olanzapine were suspected to aggravate Meige’s syndrome. After the patient took Eszopiclone twice, her eyelid spasming were basically relieved. Her condition was easier to assess when she was not taking psychoactive drugs. After she stopped taking Eszopiclone, her eyelid spasming became worse. Therefore, Eszopiclone was assumed to be effective at treating this patient’s eyelid spasm.\n\nUsing antipsychotic drugs for a long period of time could cause eyelid spasming, which is secondary to Meige’s syndrome. It is possible that it is caused by hypersensitivity of the basal ganglia dopamine receptor. Increasing the dose of antipsychotics can alleviate symptoms. Despite eyelid spasming being caused by atypical antipsychotics is rarer than it being caused by typical antipsychotics, it has been reported that the usage of olanzapine can worsen eyelid spasming, and is most likely associated with the effects of the anti-DA and anti-cholinergic qualities of olanzapine on the basal ganglia.[13-14] It was reported that clonazepam activated GABA receptors could inhibit basal ganglia circuitry in the treatment of Meige’s syndrome.[15] Nitrazepam and clonazepam have similar mechanisms, and both displayed a worsening of eyelid spasming in this case patient. On the other hand, eszopiclone alleviates eyelid spasming. Eszopiclone reacts with benzodiazepines (ω1 and ω2 receptors) at the specific binding sites of the GABA receptor complex. Nitrazepam reacts on even more subunits of the benezodiaqepines receptors, predicting that activation of the ω1 and ω2 receptor could possibly alleviate the eyelid spasming, whereas activations of the other subunit could aggravate the symptoms. Patients with Meige syndrome that had no effects from the usage of clonazepam, benzhexol, baclofen, and intramuscular injection of botulinum toxin found zolpiden effective, as reported by Miyazaki. The highly selective binding nature of zolpiden to GABAω1 receptor might play a role in the effectiveness.\n\nAll in all, this case study suggests that specific GABA receptor activators can help alleviate symptoms of blepharospasm with oromandilular dystonia in Meige syndrome. One should be cautious when also taking psychotropics for the improvement of emotional symptoms. Nitrazepam and olanzapine are likely to aggravate eye spasming; therefore, one should use them cautiously with careful observation.\n\nAcknowledgement\nWe sincerely give our greatest gratitude to the reviewers of this case study.\n\nFunding\n\nThe study is funded by the Zhejiang Medical Technology Project (project number: 2016KYB3).\n\nConflict of interest\n\nThe authors declared no conflict of interest related to this manuscript.\n\nInformed consent\n\nThe participant and her legal guardian signed the informed consent allowing us to publish this case study.\n\nAuthor contributions\n\nThe correspondence author of this article is the lead physician of the patient, who was responsible for the diagnoses and treatments of the patients as well as the verification and revision of this article. The first author is the treating physician of the patient, who took up the work of data collection, follow-ups, and article writing. Yingchun Zhang, Luoyi Xu, and Lili Wei were also on the treatment team.\n\nShimiao Zhao graduated from the Department of Clinical Medicine, Wenzhou Medical University in 2005. Now she is in the Master’s program at Wenzhou Medical University. Since 2005, she has started to work at the Department of Psychiatry and Psychosomatic in the Seventh People’s Hospital, Shao Xin. Her research interest includes psychosomatic disorders.\n==== Refs\nReferences\n1. Meige H [Les convulsions de la face. Ue forme clinique de convulsion faciale bilaterale et mediane ]. Rev Neurol (Paris). \n1910 ; 21 : 437 –443 .Paris\n2. Marsden CD \nBlepharospasm-oromandibular dystonia syndrome (Brueghel’s Sysndrome). A variant of adult-onset torsion dystonia . Neurol Neurosurg Psychiatry. \n1976 ; 39 (12 ): 1204 -1209 \n3. Jankovic J \nClinical Features, Differential Diagnosis and Pathogenesis of Blepharospam and Cranial-Cervical Dystonia . Bosniak L , editor. Blepharospasm Advances in Ophthalmic Plastic Reconstructive Surgery. \nNew York : Pergamon Press ; 1998 p. 67 –82 \n4. Isaias IU Alterman RL Tagliati M. \nDeep brain stimulation for primary generalized dystonia: long-term outcomes . Arch Neurol. \n2009 ; 66 : 465 –470 . doi: http://dx.doi.org/10.1001/archneurol.2009.20 19364931 \n5. Du XG Liu MP Liu ZH Wu CY Geng JH [14 cases of clinical analysis of Meige syndrome and literature review ]. Zhongguo Shi Yong Shen Jing Ji Bing Za Zhi. \n2008 ; 11 (4 ): 131 -132 . Chinese. doi: http://dx.doi.org/10.3969/j.issn.1673-5110.2008.04.084 \n6. Tsubota K Fujihara T Kaido M Mori A Mimuri M Kato M. \nDry eye and Meige’s syndrome . Br J Ophthalmol. \n1997 ; 81 (6 ): 439 -442 9274405 \n7. Hallett M \nBlepharospasm: recent advances . Neurology. \n2002 ; 59 (5 ): 1306 -1312 12434791 \n8. Du W Wang KY Wang WZ [Analysis of seven diagnostic errors cases of blepharospasm Meige syndrome ]. Shen Jing Ji Bing Yu Jing Shen Wei Sheng. \n2012 ; 12 (1 ): 57 -59 . Chinese. doi: http://dx.doi.org/10.3969/j.issn.1009-6574.2012.01.019 \n9. LeDoux MS \nMeige syndrome: What’s in a name? \nParkinsonism Relat Disord. \n2009 ; 15 (7 ): 483 –489 . doi: http://dx.doi.org/10.1016/j.parkreldis.2009.04.006 19457699 \n10. Thenganatt MA Jankovic J. \nTreatment of dystonia . Neurotherapeutics. \n2014 ; 11 (1 ): 139 –152 . doi: http://dx.doi.org/10.1007/s13311-013-0231-4. 24142590 \n11. Dae-Woong Bae Byung-chul Son Joong-Seok Kim \nGlobus pallidus interna deep brain stimulation in a patient with medically intractable Meige Syndrome . J Mov Disord. \n2014 ; 7 (2 ): 92 –94 . doi: http://dx.doi.org/10.14802/jmd.14013 25360233 \n12. Barow E Neumann W Brücke C Huebl J Horn J Brown P \nDeep brain stimulation suppresses pallidal low frequency activity in patients with phasic dystonic movements . Brain . 2014 ; 137 (Pt 11 ): 3012 –3024 . doi: http://dx.doi.org/10.1093/brain/awu258 25212852 \n13. Aggarwal A Jain M Khandelwal A Jiloha RC \nTardive Meige’s syndrome associated with olanzapine . Ann Indian Acad Neurol. \n2011 ; 14 (2 ): 133 -134 . doi: http://dx.doi.org/10.4103/0972-2327.82808 21808480 \n14. Mendhekar DN War L. \nOlanzapine induced acute Meige’s syndrome . J Neuropsychiatry Clin Neurosci. \n2009 ; 21 (2 ): 225 \ndoi: http://dx.doi.org/10.1176/appi.neuropsych.21.2.225 \n15. Hattori H Yoshikawa F Sato H Fujimine T. \nSpasmodic dysphonia in Meige syndrome responding to clonazepam . Intern Med. \n2011 ; 50 (18 ): 2061 -2062 21921402 \n16. Miyazaki Y Sako W Asanuma K Izumi Y Miki T Kaji R. \nEfficacy of zolpidem for dystonia: a study among different subtypes . Front Neurol. \n2012 ; 3 : 58 \ndoi: http://dx.doi.org/10.3389/fneur.2012.00058 22529836\n\n",
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"keywords": "Meige syndrome; clonazepam; eszopiclone; psychoactive drug",
"medline_ta": "Shanghai Arch Psychiatry",
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"title": "A Case Report of Psychoactive Drugs Aggravating and Alleviating Meige Syndrome.",
"title_normalized": "a case report of psychoactive drugs aggravating and alleviating meige syndrome"
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"abstract": "Septic arthritis of the pubic symphysis is a rare but serious entity which can be difficult to distinguish from common pregnancy-related problems. The following highlights the risk factors and clinical features of this uncommon condition and describes its diagnosis and management. The patient is a 26-year-old gravida 2 para 1 (second pregnancy that lasted >20 weeks and one prior term delivery) who presented to the labour and delivery triage unit of a tertiary care centre at 23 weeks' gestation with pelvis and hip pain. The patient had elevated inflammatory markers and Staphylococcal bacteraemia. MRI demonstrated pubic symphyseal septic arthritis and osteomyelitis. The patient underwent two fluoroscopy-guided joint aspirations; synovial fluid contained abundant neutrophils and grew colonies of methicillin-susceptible Staphylococcus aureus She then completed 6 weeks of intravenous antibiotic therapy. Repeat MRI of the pelvis at 31 weeks' gestation was favourable. The patient underwent caesarean delivery at 39 weeks' gestation without complication. Pelvic pain is common in pregnancy. However, abnormal musculoskeletal exam findings, historical elements and elevated inflammatory markers may suggest septic arthritis or osteomyelitis of the pubic symphysis. Accurate microbial identification, aggressive source control and multidisciplinary treatment are essential to optimal maternal and pregnancy outcomes.",
"affiliations": "Obstetrics and Gynecology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA glenn.boyles@osumc.edu.;Obstetrics and Gynecology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.",
"authors": "Boyles|Glenn Patrick|GP|http://orcid.org/0000-0001-9648-9864;Costantine|Maged M|MM|",
"chemical_list": "D000900:Anti-Bacterial Agents",
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"issn_linking": "1757-790X",
"issue": "13(11)",
"journal": "BMJ case reports",
"keywords": "bone and joint infections; interventional radiology; obstetrics and gynaecology; pregnancy",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D001170:Arthritis, Infectious; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D011631:Pubic Symphysis; D013203:Staphylococcal Infections; D013211:Staphylococcus aureus",
"nlm_unique_id": "101526291",
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"pages": null,
"pmc": null,
"pmid": "33139358",
"pubdate": "2020-11-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Septic arthritis of the pubic symphysis in pregnancy.",
"title_normalized": "septic arthritis of the pubic symphysis in pregnancy"
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"abstract": "BACKGROUND\nRuptured abdominal aortic aneurysm (AAA) is a highly lethal condition which requires rapid identification and treatment to improve the chance of survival. Computed tomography is the diagnostic modality of choice for ruptured AAA though it is time-consuming and often requires movement of the patient out of the emergency department (ED). Point-of-care ultrasound in the ED has excellent sensitivity and specificity for the detection of AAA, though less is known about its use to diagnose AAA rupture. We report a case of ruptured AAA identified on ultrasound performed at the bedside in the ED.\n\n\nMETHODS\nA 77-year-old woman on warfarin with a known AAA presented to our ED with 2 days of epigastric abdominal pain. Point-of-care ultrasound revealed several findings suggestive of rupture of the AAA, which was confirmed on computed tomography. The patient was subsequently taken for emergent operative repair of the AAA and was later discharged from the hospital.\n\n\nCONCLUSIONS\nCharacteristics suggestive of AAA rupture may be seen on ultrasound. As ED physicians become more familiar with the use of point-of-care ultrasound in the evaluation of abdominal pain, identification of these characteristics may aid in the rapid diagnosis of AAA rupture.",
"affiliations": "Department of Emergency Medicine, University of Illinois at Chicago, College of Medicine, Room 469, COME 1819 West Polk St, Chicago, IL, 60612, USA.;Department of Emergency Medicine, University of Illinois at Chicago, College of Medicine, Room 469, COME 1819 West Polk St, Chicago, IL, 60612, USA. weilbert@uic.edu.",
"authors": "Diaz|Omar|O|;Eilbert|Wesley|W|",
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"country": "England",
"delete": false,
"doi": "10.1186/s12245-020-00279-9",
"fulltext": "\n==== Front\nInt J Emerg Med\nInt J Emerg Med\nInternational Journal of Emergency Medicine\n1865-1372 1865-1380 Springer Berlin Heidelberg Berlin/Heidelberg \n\n279\n10.1186/s12245-020-00279-9\nCase Report\nRuptured abdominal aortic aneurysm identified on point-of-care ultrasound in the emergency department\nDiaz Omar odiaz15@uic.edu Eilbert Wesley weilbert@uic.edu grid.185648.60000 0001 2175 0319Department of Emergency Medicine, University of Illinois at Chicago, College of Medicine, Room 469, COME 1819 West Polk St, Chicago, IL 60612 USA \n14 5 2020 \n14 5 2020 \n2020 \n13 2526 2 2020 14 4 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nRuptured abdominal aortic aneurysm (AAA) is a highly lethal condition which requires rapid identification and treatment to improve the chance of survival. Computed tomography is the diagnostic modality of choice for ruptured AAA though it is time-consuming and often requires movement of the patient out of the emergency department (ED). Point-of-care ultrasound in the ED has excellent sensitivity and specificity for the detection of AAA, though less is known about its use to diagnose AAA rupture. We report a case of ruptured AAA identified on ultrasound performed at the bedside in the ED.\n\nCase presentation\nA 77-year-old woman on warfarin with a known AAA presented to our ED with 2 days of epigastric abdominal pain. Point-of-care ultrasound revealed several findings suggestive of rupture of the AAA, which was confirmed on computed tomography. The patient was subsequently taken for emergent operative repair of the AAA and was later discharged from the hospital.\n\nConclusions\nCharacteristics suggestive of AAA rupture may be seen on ultrasound. As ED physicians become more familiar with the use of point-of-care ultrasound in the evaluation of abdominal pain, identification of these characteristics may aid in the rapid diagnosis of AAA rupture.\n\nKeywords\nAbdominal aortic aneurysmRuptured abdominal aortic aneurysmEmergency ultrasoundBedside ultrasoundPoint-of-care ultrasoundissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nRupture of an abdominal aortic aneurysm (AAA) is often lethal, with a mortality of 85-90% [1]. Delays in the diagnosis and treatment are known to be a major contributor to the lethality of this condition [2]. A palpable abdominal mass may be present on physical exam, though this finding has a wide range of sensitivity from 29-76% [3]. With point-of-care ultrasound part of the core emergency medicine curriculum in the United States, emergency physicians have become quite adept at using this imaging modality to diagnose AAA [4]. However, less is known about the use of point-of-care ultrasound to diagnose AAA rupture. We report a case of a ruptured AAA identified by point-of-care ultrasound in the emergency department (ED).\n\nCase presentation\nA 77-year-old woman presented to our ED complaining of non-radiating epigastric abdominal pain starting the previous day and becoming severe approximately 2 h before coming to the hospital. She had some associated non-bloody emesis. Her past medical history was significant for hypertension, peripheral vascular disease, coronary artery disease, chronic kidney disease, and chronic obstructive pulmonary disease with an extensive history of smoking. She was taking warfarin for protein S deficiency complicated by previous deep venous thromboses. She had a known infrarenal AAA measuring 4.4 cm in diameter seen on computed tomography (CT) 3 months earlier. The AAA had not changed in size over the previous 4 years. On arrival she appeared uncomfortable, though in no apparent distress. Her blood pressure was 142/113 mmHg, heart rate 60 bpm, respiratory rate 15 bpm, temperature 35.8 degrees Celsius, and pulse oximetry 97% on room air. She was noted to be tender to palpation in the epigastrium without guarding, and no masses were appreciated in her abdomen.\n\nA point-of-care ultrasound was performed revealing an AAA measuring approximately 6 cm in diameter (Fig. 1). There was an inhomogeneous appearance of the luminal thrombus of the aneurysm. A hypoechoic area was identified which caused a discontinuity of the aneurysm’s luminal thrombus and outer wall and extended into the para-aortic space, suggestive of aneurysmal rupture. Laboratory values were significant for creatinine 2.0 mg/dL, international normalized ratio 1.4, and hemoglobin 10.6 g/L. A review of her previous laboratory values noted her hemoglobin had been 13.0 g/L approximately 2 months prior. CT of the abdomen and pelvis was performed confirming the presence of an infrarenal AAA measuring 6.4 cm in diameter (Fig. 2). The CT also revealed a large right retroperitoneal hematoma adjacent to the AAA with attenuation suggesting subacute hemorrhage.\nFig. 1 Ultrasonographic transverse view of the abdominal aortic aneurysm with an inhomogeneous appearance of the luminal thrombus (star), a focal disruption of the luminal thrombus and the outer wall of the aneurysm (white arrow), and a para-aortic hypoechoic area (black arrow)\n\nFig. 2 Noncontrast computed tomography of the abdominal aortic aneurysm (black arrow) with an adjacent subacute retroperitoneal hemorrhage (white arrow)\n\n\n\nA transfusion of 2 units of packed red blood cells was started in the ED, and the vascular surgery service was consulted. The patient was taken emergently to the operating room where the ruptured AAA was repaired using a polyester graft. After a difficult postoperative course, the patient was eventually discharged to a rehabilitation facility 5 weeks later.\n\nDiscussion\nThe most commonly used definition of an AAA is a maximum infrarenal abdominal aortic diameter greater than 3 cm on ultrasound or CT imaging [5]. While rare under the age of 50, the prevalence of AAA over age 65 is 5-10% in men and 0.5-1.3% in women, with increasing prevalence with each decade of life [6, 7]. Risk factors for AAA include smoking, hypertension, white race, atherosclerotic disease, and a family history of the disorder [1]. The risk of rupture of AAAs less than 4 cm diameter is negligible; however, this risk increases exponentially after reaching a diameter of 5 cm to an annual rupture risk of 30-50% for those larger than 8 cm [8]. Unfortunately, most AAAs are asymptomatic until they rupture. It is estimated that ruptured AAA accounts for 1% of all deaths of men over age 65 and that 50% of patients with a ruptured AAA will die before reaching the hospital [9, 10].\n\nRapid identification and treatment of ruptured AAA is paramount to improving survival, though its diagnosis often remains elusive. It is estimated that only 30-50% of cases present with the classic triad of abdominal pain, hypotension, and pulsatile mass [3]. In 1992, Martin et al. found that 30% of cases were initially misdiagnosed, often as renal colic, diverticulitis, or gastrointestinal hemorrhage [11]. In 1994, Lederle et al. reported that the diagnosis of ruptured AAA was missed in 61% of cases presenting to internists and was only identified when hemodynamic compromise occurred [12].\n\nCT is the diagnostic modality of choice for ruptured AAA, though point-of-care ultrasound is more readily available in most EDs. ED ultrasound screening for ruptured AAA has been found to reduce the time to diagnosis and improve patient outcomes [13]. ED point-of-care ultrasound has a sensitivity of 99% and specificity of 98% for the detection of AAA, though it is much less useful in identifying rupture. This is due to the fact that most (88%) AAAs rupture into the retroperitoneal space, where ultrasound visualization is limited [3]. In 2005, Catalano et al. described 8 sonographic findings of AAA rupture in 29 patients (Table 1) [14]. Four of these findings were present in our patient. Catalano et al. also described a contrast-enhanced bedside ultrasound using an intravenous microbubble contrast agent to improve the accuracy of diagnosing ruptured AAAs [15]. Some authors have advocated immediate operative repair of AAAs if rupture is identified on bedside ultrasound, especially in hypotensive patients [16]. This practice would bypass the time-consuming task of CT scanning.\nTable 1 Sonographic findings with abdominal aortic aneurysm rupture\n\nDeformation of aneurysmal shape\t\nInhomogeneous appearance of the luminal thrombus\t\nFocal discontinuity of the thrombus layer\t\nA floating intraluminal thrombus layer\t\nFocal disruption of the outer aneurysmal wall\t\nA para-aortic hypoechoic area\t\nRetroperitoneal hematoma\t\nHemoperitoneum\t\n\n\nEmergent operative repair has been the traditional treatment of ruptured AAAs, though endovascular repair has become another treatment option, even in unstable patients [17]. Regardless of the method of repair chosen, rapid identification of this highly lethal condition is of utmost importance. As emergency physicians become increasingly proficient with the use of bedside ultrasound, its role in the diagnosis of ruptured AAA will likely increase.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nWe are indebted to Elizabeth Pearson and Joseph Eilbert for their assistance in the preparation of this manuscript.\n\nAuthors’ contributions\nOD provided the information for the case report, performed the preliminary literature search, and assisted in the writing of the manuscript. WE performed the definitive literature search and assisted in the writing of the manuscript. The authors read and approved the final manuscript.\n\nFunding\nNone.\n\nAvailability of data and materials\nData sharing not applicable to this article as no data sets were generated or analyzed during the current study.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nNot applicable.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Kent KC Clinical practice. Abdominal aortic aneurysms N Engl J Med 2014 371 22 2101 2108 25427112 \n2. Sebesta P Klika T Zdrahal P Kramar J Ruptured abdominal aortic aneurysm: role of initial delay on survival J Mal Vasc 1998 23 5 361 367 9894191 \n3. Lech C Swaminathan A Abdominal aortic emergencies Emerg Med Clin North Am 2017 35 4 847 867 28987432 \n4. Rubano E Mehta N Caputo W Paladino L Sinert R Systematic review: emergency department bedside ultrasonography for diagnosing suspected aortic aneurysm Acad Emerg Med 2013 20 2 128 138 23406071 \n5. Gollege J Abdominal aortic aneurysm: update on pathogenesis and medical treatments Nat Rev Cardiol 2019 16 4 225 242 30443031 \n6. Genovese EA Fonio P Floridi C Macchi M Maccaferri A Ianora AA Abdominal vascular emergencies: US and CT assessment Crit Ultrasound J 2013 5 Suppl 1 S10 23902665 \n7. Preventative Services Task Force US Screening for abdominal aortic aneurysm: recommendation statement Ann Intern Med 2005 142 3 198 202 15684208 \n8. Brewster DC Cronenwett JL Hallett JW Johnston KW Krupski WC Matsumura JS Guidelines for the treatment of abdominal aortic aneurysms. Report of a subcommittee of the Joint Council of the American Association of Vascular Surgery and Society for Vascular Surgery J Vasc Surg 2003 37 5 1106 1117 12756363 \n9. Howard DP Banerjee A Fairhead JF Handa A Silver LE Rothwell PM Age-specific incidence, risk factors and outcome of acute abdominal aneurysms in a defined population Br J Surg 2015 102 8 907 915 25955556 \n10. Lewiss RE Egan D Shreves A Vascular abdominal emergencies Emerg Med Clin N Am 2011 29 2 253 272 \n11. Marston WA Ahlquist R Johnson G Meyer AA Misdiagnosis of ruptured abdominal aortic aneurysms J Vasc Surg 1992 16 1 17 22 1619721 \n12. Lederle FA Parenti CM Chute EP Ruptured abdominal aortic aneurysm: the internist as a diagnostician Am J Med 1994 96 2 163 167 8109601 \n13. Plummer D Clinton J Matthew B Emergency department ultrasound improves time to diagnosis and survival in ruptured abdominal aortic aneurysm [Abstract] Acad Emerg Med 1998 5 5 417 \n14. Catalano O Siani A Ruptured abdominal aortic aneurysm. Categorization of sonographic findings and report of 3 new signs J Ultrasound Med 2005 24 8 1077 1083 16040822 \n15. Catalano O Lobianco R Cusati B Contrast-enhanced sonography for diagnosis of ruptured abdominal aortic aneurysm AJR Am J Roentgenol 2005 184 2 423 427 15671357 \n16. Bhatt S Dogra VS Catastrophes of abdominal aorta: sonographic evaluation Ultrasound Clin 2008 3 1 83 91 \n17. Spencer T Juyia R Parks R Case series of patients with ruptured abdominal aortic aneurysm West J Emerg Med 2015 16 3 367 371 25987908\n\n",
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"authors": "Mercier|Victor|V|;Bastides|Frédéric|F|;Bailly|Éric|É|;Garcia-Hermoso|Dea|D|;Miquelestorena-Standley|Elodie|E|;El Baz|Zaki|Z|;Marteau|Emilie|E|;Vermes|Emmanuelle|E|;De Muret|Anne|A|;Bernard|Louis|L|;Desoubeaux|Guillaume|G|http://orcid.org/0000-0001-7945-9890",
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"abstract": "Parathyroid carcinoma is an extremely rare endocrine malignancy that accounts for less than 1% of cases of primary hyperparathyroidism. We report a 44-year-old woman who presented with fatigue and diffuse bone pain. Laboratory findings revealed highly elevated serum calcium and parathyroid hormone (PTH) levels and a 4.5 × 3 × 2.5 cm cystic lesion in the lower pole of the right thyroid lobe that was shown histologically to be a parathyroid carcinoma. Ten years later, the patient developed brain and pulmonary metastases and recurrence of PTH-related hypercalcemia. Treatment of hypercalcemia along with localized radiotherapy and various chemotherapy regimens failed to induce a biochemical or radiological response. In conclusion, parathyroid carcinoma is a rare neoplasia that may develop metastases even after prolonged follow-up, for which there is no evidence-based treatment besides surgery. Different chemotherapeutic schemes did not prove to be of any benefit in our case highlighting the need for registering such patients to better understand tumor biology and develop specific treatment.\nMetastases can develop many years after parathyroid cancer diagnosis.Surgery is the only curative treatment for parathyroid carcinoma.Chemotherapy and radiotherapy prove to be ineffective in parathyroid cancer treatment.Patient registering is required in order to delineate underlining pathology and offer specific treatment.",
"affiliations": "Department of Pathophysiology, National and Kapodistrian University of Athens, Athens, Greece.;Department of Pathophysiology, National and Kapodistrian University of Athens, Athens, Greece.;Department of Histopathology, Evagelismos General Hospital, Athens, Greece.;Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.;Department of Pathophysiology, National and Kapodistrian University of Athens, Athens, Greece.",
"authors": "Tsoli|Marina|M|;Angelousi|Anna|A|;Rontogianni|Dimitra|D|;Stratakis|Constantine|C|;Kaltsas|Gregory|G|",
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"fulltext": "\n==== Front\nEndocrinol Diabetes Metab Case RepEndocrinol Diabetes Metab Case RepEDMEndocrinology, Diabetes & Metabolism Case Reports2052-0573Bioscientifica Ltd Bristol 10.1530/EDM-17-0106EDM170106Unique/Unexpected Symptoms or Presentations of a DiseaseAtypical manifestation of parathyroid carcinoma with late-onset distant metastases M Tsoli, A Angelousi and othersLate metastases in parathyroid cancerTsoli Marina 1*Angelousi Anna 1*Rontogianni Dimitra 2Stratakis Constantine 3Kaltsas Gregory 11 Department of Pathophysiology, National and Kapodistrian University of Athens, Athens, Greece\n2 Department of Histopathology, Evagelismos General Hospital, Athens, Greece\n3 Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA\nCorrespondence should be addressed to M Tsoli; Email: martso.mt@gmail.com* (M Tsoli and A Angelousi contributed equally to this work)\n\n28 10 2017 2017 2017 17-010610 9 2017 10 10 2017 © 2017 The authors2017The authors This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License.Parathyroid carcinoma is an extremely rare endocrine malignancy that accounts for less than 1% of cases of primary hyperparathyroidism. We report a 44-year-old woman who presented with fatigue and diffuse bone pain. Laboratory findings revealed highly elevated serum calcium and parathyroid hormone (PTH) levels and a 4.5 × 3 × 2.5 cm cystic lesion in the lower pole of the right thyroid lobe that was shown histologically to be a parathyroid carcinoma. Ten years later, the patient developed brain and pulmonary metastases and recurrence of PTH-related hypercalcemia. Treatment of hypercalcemia along with localized radiotherapy and various chemotherapy regimens failed to induce a biochemical or radiological response. In conclusion, parathyroid carcinoma is a rare neoplasia that may develop metastases even after prolonged follow-up, for which there is no evidence-based treatment besides surgery. Different chemotherapeutic schemes did not prove to be of any benefit in our case highlighting the need for registering such patients to better understand tumor biology and develop specific treatment.\n\nLearning points:\nMetastases can develop many years after parathyroid cancer diagnosis.\n\nSurgery is the only curative treatment for parathyroid carcinoma.\n\nChemotherapy and radiotherapy prove to be ineffective in parathyroid cancer treatment.\n\nPatient registering is required in order to delineate underlining pathology and offer specific treatment.\n\nPatient demographics\nAdultFemaleWhiteGreeceClinical overview\nParathyroidEndocrine-related cancerParathyroid hormoneParathyroid carcinomaMetastatic carcinomaDiagnosis & treatment\nBone painFatiguePolydipsiaPolyuriaMyasthaeniaHypercalcaemiaHypophosphataemiaMRIPTHHistopathologyCT scanSestamibi scanRadionuclide imagingUltrasound scanCalcium (serum)Phosphate (serum)Alkaline phosphataseFluid repletionParathyroidectomyThyroidectomyLymphadenectomyRadiotherapyTemozolomideFurosemidePamidronateBisphosphonatesCalcium carbonateZoledronic acidCinacalcetFluorouracilCapecitabineRelated disciplines\nOncologyPublication details\nUnique/unexpected symptoms or presentations of a diseaseOctober2017\n==== Body\nBackground\nParathyroid cancer is a rare endocrine disorder constituting less than 1% of parathyroid neoplasms. It is mainly a sporadic disease with a peak incidence in the fourth or fifth decade of life. Parathyroid carcinoma commonly presents with significantly elevated calcium levels due to high parathyroid hormone (PTH) levels and symptoms are related to severity of hypercalcemia. Distant metastases are developed in about 25% of patients, most commonly to lymph nodes, bone, lung and liver. It is usually difficult to diagnose malignant tumors pre-operatively or on histological examination and definitive diagnosis is made upon local recurrence or metastases development (1, 2). We report a female patient with parathyroid carcinoma who developed brain and pulmonary metastases ten years after the initial diagnosis. Different chemotherapeutic regimens and radiotherapy did not prove to be of any benefit.\n\nCase presentation\nA 44-year-old woman presented with one-month history of weakness, polydipsia, polyuria and diffuse bone pains. She had a past history of ureteral colic but no relevant familial history.\n\nInitial laboratory investigations revealed hypercalcemia (19.3 mg/dL; normal range 8.4–10.1 mg/dL), hypophosphatemia (2 mg/dL; 2.7–4.5 mg/dL) and significantly increased PTH (1084 pg/mL; 15–65 pg/mL) and alkaline phosphatase (ALP) (308 U/L; 48–141) levels. Creatinine, BUN and thyroid function were normal. The patient was treated with intravenous fluids, furosemide and pamidronate that led to substantial reduction of calcium levels and resolution of her symptoms. A neck ultrasound and computerized tomography (CT) scanning revealed a 4.5 × 3 × 2.5 cm cystic lesion adjacent to the lower pole of the right thyroid lobe that was shown to represent a single hyperfunctioning parathyroid lesion on sestamibi (MIBI) parathyroid scintigraphy. No enlarged or suspicious lymph nodes were noted. In addition, chest, abdominal and brain CT revealed no pathological findings.\n\nThe patient underwent a parathyroidectomy along with en bloc right thyroid lobectomy. Histological examination revealed anaplastic regions and giant cells with abundant cytoplasm and polymorphous nuclei consistent with parathyroid carcinoma. In addition, capsular and vascular invasion were observed, whereas the Ki-67 labeling index (LI) was approximately 10%. No invasion in the thyroid has been observed while resection margins were free. Postoperatively, calcium and PTH levels were substantially reduced, and replacement therapy with calcidiol and calcium carbonate was initiated (Fig. 1). Post-surgery ultrasound, magnetic resonance imaging (MRI) of the neck, chest and abdominal CT and whole-body MIBI scintigraphy did not reveal any evidence of residual or metastatic disease.\nFigure 1 PTH levels (pg/mL) at initial diagnosis and during different treatments.\n\n\n\n\nOne year later, laboratory investigations showed mildly raised PTH levels (91.4 pg/mL). Mediastinal MRI, abdominal CT and whole-body MIBI scintigraphy showed no evidence of distant metastatic disease, whereas a neck MRI revealed a 7–8 mm lesion behind the left thyroid lobe that was excised with concomitant right neck lymph node dissection. Histology revealed chief cell hyperplasia in the resected lesion, whereas all 15 lymph nodes excised were free of neoplastic disease. Postoperative calcium and PTH levels were normal. As the patient had no relevant family history neither fulfilled any criteria of a familial syndrome, she only underwent genetic analysis for CDC73 (cell division cycle 73) gene somatic and germline mutations that was negative.\n\nThe patient remained normocalcemic with normal neck ultrasonography and MRI during the following six years. Subsequently, a progressive increase of calcium levels was observed and a neck MRI revealed three 4–5 mm structures, one on the right and two on the left, in the anatomic region of parathyroid glands. During the following four years, serum calcium and PTH levels remained marginally raised while the abovementioned neck structures displayed no significant change (Fig. 1).\n\nTen years after initial diagnosis, the patient developed numbness and right upper limb weakness. Physical examination revealed diminished right upper limb muscle strength and increased deep tendon reflex.\n\nInvestigation\nA brain MRI showed a 37 mm left parietal lobe lesion that was entirely removed followed by radiotherapy (Fig. 2). Histopathology demonstrated positive immunostaining for PTH while the Ki-67 LI was 15%, confirming a parathyroid carcinoma metastasis (Fig. 3). A subsequent chest CT revealed a 7.5 cm solid lesion in the lower right lung lobe with satellite lesions and a further 8 mm lesion in the upper left lobe that all exhibited increased uptake to whole-body MIBI scintigraphy. There were no other MIBI avid lesions or any uptake on tectrotyd somatostatin receptor and bone scintigraphy. Biopsy of the lung lesion was suggestive of metastatic parathyroid carcinoma with a Ki-67 LI of 40% (Fig. 3).\nFigure 2 Brain MRI showing left parietal lobe metastatic lesion.\n\n\nFigure 3 (A) Ki-67 labeling index of lung metastatic lesion. (B) PTH immunostaining of brain lesion.\n\n\n\n\nTreatment\nAs the lung lesions were inoperable, and there is no specific therapeutic regimen for parathyroid carcinomas FOLFOX (folic acid, Fluorouracil, Oxaliplatin) chemotherapy was initiated. After three cycles, the patient was found to have stable disease that was regarded as a response, and further two FOLFOX cycles were administered. However, a subsequent chest CT revealed further increase of the right lower lung lesion that was extending into the right pulmonary artery also infiltrating the right lower pulmonary vein and left atrium. A heart MRI confirmed these findings.\n\nAlthough radiation treatment to pulmonary metastases followed by two cycles of chemotherapy with temozolomide and capecitabine (capecitabine: 1500 mg/m2: d1–d14, temozolomide: 200 mg/m2: d10–d14 every 28 days) was administered, there was further disease progression.\n\nOutcome and follow-up\nDespite treatment with different chemotherapeutic regimens and radiotherapy, the disease displayed continuous progression. Persistent hypercalcemia was treated with intravenous fluids, furosemide, zoledronic acid and cinacalcet, but the patient died twelve years after initial diagnosis.\n\nDiscussion\nParathyroid carcinoma is an extremely rare, slowly evolving malignancy that accounts for less of 1% of cases of primary hyperparathyroidism. It occurs equally in males and females with a peak incidence in the fourth or fifth decade of life. Most cases are sporadic but may also occur as part of hyperparathyroidism-jaw tumor syndrome (HJTS) or rarely multiple endocrine neoplasia (MEN) type 1 or 2A syndromes (1). Our case demonstrates the slow evolution and increasing malignant potential of an initially localized parathyroid carcinoma that developed brain and lung metastases ten years after initial diagnosis and proved to be resistant to any conventional therapy.\n\nMore than 90% of parathyroid carcinomas are functional and symptoms are related to the severity of hypercalcemia similar to our case. Physical examination commonly reveals a palpable neck mass in 40–70% of patients (1, 2). It is often difficult to distinguish between benign and malignant tumors pre-operatively or at histological examination, and definite diagnosis is made in the presence of local recurrences or development of metastases. However, the presence of some predictive markers could raise the suspicion of malignancy pre-operatively.\n\nBiochemically, parathyroid carcinoma presents with more severe hypercalcemia compared to benign disease, due to higher PTH levels. Alkaline phosphatase and α- and β-subunits of human chorionic gonadotropin (hCG) are particularly elevated in carcinomas (1, 2). Our patient was found to have significantly elevated serum alkaline phosphatase levels.\n\nHistological criteria still remain the most established predictive method of malignancy irrespective of whether old or revised criteria are used (3). There are two prognostic classification systems derived from a retrospective literature review of 330 patients (4). Stage III disease in Schulte’s staging system (lymph node metastases) and a high-risk score in the Schulte Risk Classification (vascular and lymph node invasion, vital organ or distant metastases) are associated with parathyroid carcinoma recurrence (5).\n\nInactivating mutations of the CDC73 gene have been identified in up to 70% of apparently sporadic parathyroid carcinomas and approximately one-third of which are germline mutations. Loss of parafibromin protein immunostaining has also been found in most parathyroid carcinomas. The combination of CDC73mutations and loss of parafibromin protein expression predicts a worse clinical outcome and a lower overall 5- and 10-year survival (3). In contrast, the increased expression of the proliferative marker Ki-67 has produced contradictory results (6).\n\nGenetic analyses should always be considered in parathyroid carcinomas. Except for CDC73gene, various genes have been found to be linked to parathyroid carcinomas including BRCA, p53, Rb and cyclin D1. However, no single molecular marker has proved to be reliable in distinguishing malignant from benign tumors (1, 2, 7). Our patient was not found to have a CDC73mutation, besides having an additional hyperplastic gland, neither had any clinical and/or biochemical stigmata of a familial syndrome.\n\nNeck ultrasound is the most commonly employed radiological modality for parathyroid disease. Large tumors, displaying hypoechogenicity, inhomogeneity, irregular borders and calcifications are more likely to be malignant. However, only invasion into adjacent tissues or presence of metastases allows the pre-operative diagnosis of parathyroid cancer. MIBI scintigraphy remains a valuable tool to assess the presence and localization of hyperfunctioning parathyroid tissue (1, 2, 8).\n\nSurgery is the only curative treatment for parathyroid carcinoma. Tumor resection en bloc with ipsilateral thyroidectomy is the procedure of choice. Surgery is also the treatment of choice in the presence of local recurrence or metastatic disease. However, neck reoperation is associated with a 3–5 times higher complication rate than the initial operation (2, 9, 10). Parathyroid carcinoma is considered resistant to radiotherapy, but recent case series suggest that adjuvant radiation therapy can be effective in preventing recurrence and extending disease-free survival (2).\n\nTherapeutic options for unresectable parathyroid carcinoma are limited. Chemotherapy is considered to be ineffective in parathyroid carcinomas as shown in our case. A few case reports describing monotherapy with dacarbazine and several regimens (nitrogen mustard, vincristine, cyclophosphamide and actinomycin D, adriamycin, cyclophosphamide and 5-fluorouracil and adriamycin alone) showed that all have been relatively ineffective (1, 2).\n\nIn case of metastatic carcinoma, the primary aim is to control hypercalcemia. Mitramycin, plicamycin, gallium nitrate, bisphosphonates, calcitonin and glucocorticoids have been used, but newer drugs such as the calcimimetic cinacalcet are probably more effective (2). Anti-parathyroid hormone immunotherapy has been experimentally used with promising results but is not yet available, while ethanol ablation, radiofrequency ablation and trans-arterial embolization present palliative treatment methods (2).\n\nRecurrence is very common in parathyroid carcinoma usually observed between 2.5 and 4.8 years after initial surgery but can occur even after 20 years (2). In our case, metastases developed 10 years after initial diagnosis. About 50% of patients develop local recurrence and 25% distant metastases, the most common being locoregional lymph nodes, lung, liver and bones (2). Five- and ten-year survival rates range from 76–85% to 49–77% respectively (1, 2). Local excision instead of en bloc resection at initial operation, high calcium levels and early recurrence are associated with 7-fold greater risk of mortality (5).\n\nIn conclusion, parathyroid carcinoma is an extremely rare endocrine malignancy that may develop metastases after prolonged follow-up. En bloc surgical resection with microscopically negative margins is the recommended treatment for cure, as these lesions are resistant to conventional chemotherapy and radiotherapy. International registries and inclusion of patients in experimental trials are required in order to develop tumor-oriented and specific therapies.\n\nDeclaration of interest\nThe authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.\n\nFunding\nThis research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.\n\nAuthor contribution statement\nProf. Kaltsas, Dr Angelousi and Dr Tsoli were responsible for patient’s care. Histopathological examination was performed by Dr Rontogianni and genetic analysis by Dr Stratakis. Dr Tsoli and Dr Angelousi contributed equally to the manuscript.\n==== Refs\nReferences\n1 McClenaghan F Qureshi YA \n2015 \nParathyroid cancer . Gland Surgery \n4 \n329 –338 . (10.3978/j.issn.2227-684X.2015.05.09 )26312219 \n2 Wei CH Harari A \n2012 \nParathyroid carcinoma: update and guidelines for management . Current Treatment Options in Oncology \n13 \n11 –23 . (10.1007/s11864-011-0171-3 )22327883 \n3 Cetani F Pardi E Marcocci C \n2016 \nUpdate on parathyroid carcinoma . Journal of Endocrinological Investigation \n39 \n595 –606 . (10.1007/s40618-016-0447-3 )27001435 \n4 Talat N Schulte KM \n2010 \nClinical presentation, staging and long-term evolution of parathyroid cancer . Annals of Surgical Oncology \n17 \n2156 –2174 . (10.1245/s10434-010-1003-6 )20221704 \n5 Xue S Chen H Lv C Shen X Ding J Liu J Chen X \n2016 \nPreoperative diagnosis and prognosis in 40 parathyroid carcinoma patients . Clinical Endocrinology \n85 \n29 –36 . (10.1111/cen.13055 )26939543 \n6 Farnebo F Auer G Farnebo LO Tech BT Twigg S Aspenblad U Thompson NW Grimelius L Larsson C Sandelin K \n1999 \nEvaluation of retinoblastoma and Ki-67 immunostaining as diagnostic markers of benign and malignant parathyroid disease . World Journal of Surgery \n23 \n68 –74 . (10.1007/s002689900567 )9841766 \n7 Fernandez-Ranvier GG Khanafshar E Tacha D Wong M Kebebew E Duh QY Clark OH \n2009 \nDefining a molecular phenotype for benign and malignant parathyroid tumors . Cancer \n115 \n334 –344 . (10.1002/cncr.24037 )19107770 \n8 Sidhu PS Talat N Patel P Mulholland NJ Schulte KM \n2011 \nUltrasound features of malignancy in the preoperative diagnosis of parathyroid cancer: a retrospective analysis of parathyroid tumours larger than 15 mm . European Radiology \n21 \n1865 –1873 . (10.1007/s00330-011-2141-3 )21556910 \n9 Harari A Waring A Fernandez-Ranvier G Hwang J Suh I Mitmaker E Shen W Gosnell J Duh QY Clark O \n2011 \nParathyroid carcinoma: a 43-year outcome and survival analysis . Journal of Clinical Endocrinology and Metabolism \n96 \n3679 –3686 . (10.1210/jc.2011-1571 )21937626 \n10 Kebebew E \n2001 \nParathyroid carcinoma . Current Treatment Options in Oncology \n2 \n347 –354 . (10.1007/s11864-001-0028-2 )12057115\n\n",
"fulltext_license": "CC BY-NC-ND",
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"journal": "Endocrinology, diabetes & metabolism case reports",
"keywords": "2017; Adult; Alkaline phosphatase; Bisphosphonates; Bone pain; CT scan; Calcium (serum); Calcium carbonate; Capecitabine; Cinacalcet; Endocrine-related cancer; Fatigue; Female; Fluid repletion; Fluorouracil; Furosemide; Greece; Histopathology; Hypercalcaemia; Hypophosphataemia; Lymphadenectomy; MRI; Metastatic carcinoma; Myasthaenia; October; Oncology; PTH; Pamidronate; Parathyroid; Parathyroid carcinoma; Parathyroid hormone; Parathyroidectomy; Phosphate (serum); Polydipsia; Polyuria; Radionuclide imaging; Radiotherapy; Sestamibi scan; Temozolomide; Thyroidectomy; Ultrasound scan; Unique/unexpected symptoms or presentations of a disease; White; Zoledronic acid",
"medline_ta": "Endocrinol Diabetes Metab Case Rep",
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"title": "Atypical manifestation of parathyroid carcinoma with late-onset distant metastases.",
"title_normalized": "atypical manifestation of parathyroid carcinoma with late onset distant metastases"
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"abstract": "OBJECTIVE\nTo report a case of hepatitis, rhabdomyolysis and multi-organ failure resulting from the use of statins.\n\n\nMETHODS\nA 70 year old Caucasian woman was admitted with general malaise, myalgia and jaundice. She was being treated with a statin for aortic stenosis, the dose of which had been increased approximately 6 months earlier. Investigations showed evidence of hepatitis and rhabdomyolysis resulting in multi-organ failure, eventually leading to her death.\n\n\nCONCLUSIONS\nStatins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and are commonly used for treatment of hypercholesterolaemia. The use of high dose statin is becoming increasingly common with emerging evidence suggesting improved outcomes in various conditions. Statins have transformed the care of patients with vascular disease. Statins generally have an excellent safety profile and low risk of adverse reactions, but cases of rhabdomyolysis and hepatitis resulting from their use have been reported.\n\n\nCONCLUSIONS\nWhile there is good evidence suggesting improved outcomes with use of high dose statins, the potential drug interactions and adverse effects need close attention. All patients started on statin therapy should be counselled regarding the signs and symptoms of muscle injury, particularly those who are on drugs that may have an interaction. In this patient the Naranjo probability scale revealed a probable adverse reaction associated with atorvastatin therapy.",
"affiliations": "St Helens and Knowsley Hospitals NHS Trust, Medicine-Gastro, Whiston Hospital, Warrington Prescot, L35 5DR, UK.",
"authors": "Rajaram|Muthuram|M|",
"chemical_list": null,
"country": "England",
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"issue": "2009()",
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"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101526291",
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"pmid": "21686823",
"pubdate": "2009",
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"title": "Hepatitis, rhabdomyolysis and multi-organ failure resulting from statin use.",
"title_normalized": "hepatitis rhabdomyolysis and multi organ failure resulting from statin use"
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"abstract": "OBJECTIVE\nIrinotecan-induced severe toxicities are possibly related to UGT1A1*6 and *28 genotypes. However, the correlation between UGT1A1 polymorphisms and the risk of toxicities induced by low-dose irinotecan plus platinum combination therapy still remains controversial. This prospective observational study aimed to examine the correlation between UGT1A1 genotypes and clinical outcomes of low-dose irinotecan (median 60 mg/m(2) , range 25-115 mg/m(2) ) plus platinum in Japanese patients with solid tumors.\n\n\nMETHODS\nToxicity profiles were compared between UGT1A1 SNP heterozygotes (hetero-group) and patients with homozygous SNP profile (*6/*6, *28/*28 and *6/*28). Logistic regression models were used to identify independent risk factors for these toxicities.\n\n\nRESULTS\nA total of 331 patients were enrolled: 84% with hetero-group and 16% with homo-group. Although the initial irinotecan dose was similar, the dose intensities during the three cycles were significantly lower in the homo-group (P < 0.01). Grade 3/4 hematological toxicities were significantly more frequent in the homo-group. Multivariable analysis identified UGT1A1 genotype (P < 0.01) as an independent factor for grade 4 hematological toxicity in the first treatment cycle.\n\n\nCONCLUSIONS\nUGT1A1 genotype has a major impact on the increased risk of severe hematological toxicities, even in low-dose irinotecan regimens. UGT1A1 genotypes are useful biomarkers for predicting severe hematological toxicities in patients treated with irinotecan plus platinum analog.",
"affiliations": "Department of Obstetrics and Gynecology, National Defense Medical College, Tokorozawa, Japan.;Department of Obstetrics and Gynecology, Sakai Hospital, Kinki University Faculty of Medicine, Sakai, Japan.;Department of Obstetrics and Gynecology, Mie University Graduate School of Medicine, Tsu, Japan.;Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.;Department of Respiratory Medicine, Kyorin University Hospital, Mitaka, Japan.;Department of Obstetrics and Gynecology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.;Department of Respiratory Medicine, Naga Municipal Hospital, Kinokawa, Japan.;Department of Obstetrics and Gynecology, Tottori University School of Medicine, Yonago, Japan.;Department of Thoracic Oncology, Kanagawa Cancer Center, Yokohama, Japan.;Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto, Japan.;Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Japan.;Pharmacovigilance Department, Daiichi Sankyo, Tokyo, Japan.;Clinical Data and Biostatistics Department, Daiichi Sankyo, Tokyo, Japan.;Department of Obstetrics and Gynecology, Iwate Medical University, Morioka, Japan.;Department of Integrated Science and Engineering for Sustainable Society, Chuo University, Tokyo, Japan.;CEO, Misawa City Hospital, Misawa, Japan.",
"authors": "Takano|Masashi|M|;Yamamoto|Kaichiro|K|;Tabata|Tsutomu|T|;Minegishi|Yuji|Y|;Yokoyama|Takuma|T|;Hirata|Eiji|E|;Ikeda|Takeshi|T|;Shimada|Muneaki|M|;Yamada|Kouzo|K|;Morita|Satoshi|S|;Ando|Yuichi|Y|;Hirata|Koji|K|;Sugihara|Masahiro|M|;Sugiyama|Toru|T|;Ohashi|Yasuo|Y|;Sakata|Yuh|Y|",
"chemical_list": "D009944:Organoplatinum Compounds; D000077146:Irinotecan; C418331:UGT1A1 enzyme; D014453:Glucuronosyltransferase; D002166:Camptothecin",
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"keywords": "UGT1A1; irinotecan plus platinum; toxicity",
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"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study",
"references": null,
"title": "Impact of UGT1A1 genotype upon toxicities of combination with low-dose irinotecan plus platinum.",
"title_normalized": "impact of ugt1a1 genotype upon toxicities of combination with low dose irinotecan plus platinum"
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"abstract": "The Japanese guidelines for the treatment of gastric cancer recommend nivolumab as third-line chemotherapy for metastatic gastric adenocarcinoma. We report a case in which long-term control of metastatic gastric adenocarcinoma was achieved with nivolumab after pseudoprogression. A man in his late 70s with advanced HER2-negative gastric cancer and liver metastasis underwent total gastrectomy to control tumor bleeding. He then underwent chemotherapy with S-1 plus oxaliplatin, followed by S-1 alone. After metastases in the liver and para-aortic and hilar lymph nodes regrew, the patient received ramucirumab plus paclitaxel as second-line chemotherapy, followed by third-line therapy with nivolumab. After four cycles of nivolumab, these metastases showed progression;however, the treatment was continued because levels of CA19-9 were decreased, and performance status was good. After five more cycles of nivolumab, the liver metastasis shrank, and CA19-9 levels decreased;therefore, we confirmed pseudoprogression. The patient suffered no immune-related adverse events and survived for 50 months after gastrectomy with 34 cycles of nivolumab treatment. Thus, at the beginning of treatment with an immune checkpoint inhibitor, oncologists must consider the possibility of pseudoprogression in cases of tumor growth associated with decreasing tumor marker levels and good performance status.",
"affiliations": "Department of Gastroenterological Surgery and Oncology, Tazuke Kofukai Medical Research Institute, Kitano Hospital.;Department of Gastroenterological Surgery and Oncology, Tazuke Kofukai Medical Research Institute, Kitano Hospital.",
"authors": "Okamoto|Tomohiro|T|;Ueda|Shugo|S|",
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"journal": "Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology",
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"medline_ta": "Nihon Shokakibyo Gakkai Zasshi",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D005743:Gastrectomy; D006801:Humans; D008198:Lymph Nodes; D008297:Male; D000077594:Nivolumab; D013274:Stomach Neoplasms",
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"pubdate": "2021",
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"title": "A case of metastatic gastric cancer showing long-term control with nivolumab after pseudoprogression.",
"title_normalized": "a case of metastatic gastric cancer showing long term control with nivolumab after pseudoprogression"
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"dru... |
{
"abstract": "New-onset psoriasis in patients receiving tumor necrosis factor inhibitors is well recognized in children and adults. We describe three children who underwent cardiac transplantation and developed an analogous form of paradoxic eczema occurring 2-48 months after starting systemic tacrolimus, a drug widely used topically to treat eczema. Anecdotal reports and our experience suggest that tacrolimus taper with alternative systemic antirejection immunosuppressant may lead to skin clearance. Pending additional insight, treatment should include optimizing skin barrier function, minimizing microbial and allergic triggers, and coordinating care to choose the best-tolerated systemic immunosuppressant regimen at the lowest effective dose.",
"affiliations": "Department of Dermatology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.;Department of Pediatric Dermatology, School of Medicine, Saint Louis University, St. Louis, MO, USA.",
"authors": "Jackson Cullison|Stephanie R|SR|http://orcid.org/0000-0002-5833-122X;Siegfried|Elaine C|EC|",
"chemical_list": "D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D016559:Tacrolimus",
"country": "United States",
"delete": false,
"doi": "10.1111/pde.13342",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-8046",
"issue": "35(1)",
"journal": "Pediatric dermatology",
"keywords": "eczema; genetic disease/mechanism; immunodeficiency; systemic therapy; topical therapy",
"medline_ta": "Pediatr Dermatol",
"mesh_terms": "D002648:Child; D002675:Child, Preschool; D004485:Eczema; D005938:Glucocorticoids; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents; D007223:Infant; D008297:Male; D012867:Skin; D016559:Tacrolimus",
"nlm_unique_id": "8406799",
"other_id": null,
"pages": "e29-e34",
"pmc": null,
"pmid": "29194735",
"pubdate": "2018-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Paradoxic eczema in infants after heart transplantation.",
"title_normalized": "paradoxic eczema in infants after heart transplantation"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2018-00572",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"druga... |
{
"abstract": "A 66-YEAR-OLD female requiring cardiac surgery had persisting anti-platelet factor 4 (PF4)/heparin antibodies (HIT-abs) 8 years after heparin-induced thrombocytopenia (HIT). In 2010, she developed thrombotic thrombocytopenic purpura (TTP) (ADAMTS-13 <5%, inhibitor at 1.0 BU/mL), which was treated successfully with corticotherapy, plasmapheresis, and intravenous heparin. While taking heparin, she developed HIT, as evidenced by a positive functional test. Her platelet count fully resolved without thrombotic complications with danaparoid treatment. In 2018, the preoperative titer of HIT-abs was still 0.38 U/mL by chemoluminescent immunoassay (CLIA), and positive by particle-gel agglutination immunoassay (PaGIA) with a titer of 2 and was strongly positive on an enzyme-linked immunosorbent assay (ELISA). The authors of the case report chose to use cangrelor combined with heparin during cardiopulmonary bypass (CPB). Cangrelor was used without increased postoperative bleeding or thrombotic complications. Postoperatively she exhibited a huge rise in HIT-abs (14.22 U/mL on postoperative day 11) with a positive functional assay. There was no recurrence of HIT, however. This case illustrates the importance of excluding the presence of persisting HIT-abs before CPB and ensuring close medical follow-up after even a single exposure to heparin.",
"affiliations": "Department of Anesthesiology, Lausanne University Hospital (CHUV), Lausanne, Switzerland; Division of Hematology and Central Hematology Laboratory, Lausanne University Hospital (CHUV), Lausanne, Switzerland. Electronic address: Emmanuelle.Scala@chuv.ch.;Department of Cardiac Surgery, Lausanne University Hospital (CHUV), Lausanne, Switzerland.;Department of Intensive Care, Lausanne University Hospital (CHUV), Lausanne, Switzerland.;Department of Cardiac Surgery, Lausanne University Hospital (CHUV), Lausanne, Switzerland.;Department of Cardiac Surgery, Lausanne University Hospital (CHUV), Lausanne, Switzerland; Faculty of Biology and Medicine, University of Lausanne (UNIL), Lausanne, Switzerland.;Department of Anesthesiology, Lausanne University Hospital (CHUV), Lausanne, Switzerland; Faculty of Biology and Medicine, University of Lausanne (UNIL), Lausanne, Switzerland.;Division of Hematology and Central Hematology Laboratory, Lausanne University Hospital (CHUV), Lausanne, Switzerland; Faculty of Biology and Medicine, University of Lausanne (UNIL), Lausanne, Switzerland.",
"authors": "Scala|Emmanuelle|E|;Pitta-Gros|Barbara|B|;Pantet|Olivier|O|;Iafrate|Manuel|M|;Kirsch|Matthias|M|;Marcucci|Carlo|C|;Alberio|Lorenzo|L|",
"chemical_list": "D000925:Anticoagulants; D010975:Platelet Aggregation Inhibitors; D010978:Platelet Factor 4; D000249:Adenosine Monophosphate; C117446:cangrelor; D006493:Heparin",
"country": "United States",
"delete": false,
"doi": "10.1053/j.jvca.2019.06.044",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1053-0770",
"issue": "33(11)",
"journal": "Journal of cardiothoracic and vascular anesthesia",
"keywords": "cangrelor; cardiac surgery; heparin-induced thrombocytopenia; platelet",
"medline_ta": "J Cardiothorac Vasc Anesth",
"mesh_terms": "D000249:Adenosine Monophosphate; D000925:Anticoagulants; D006348:Cardiac Surgical Procedures; D005260:Female; D005500:Follow-Up Studies; D005544:Forecasting; D006493:Heparin; D006801:Humans; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors; D010978:Platelet Factor 4; D011183:Postoperative Complications; D013921:Thrombocytopenia",
"nlm_unique_id": "9110208",
"other_id": null,
"pages": "3073-3077",
"pmc": null,
"pmid": "31420311",
"pubdate": "2019-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cardiac Surgery Successfully Managed With Cangrelor in a Patient With Persistent Anti-PF4/Heparin Antibodies 8 Years After Heparin-Induced Thrombocytopenia.",
"title_normalized": "cardiac surgery successfully managed with cangrelor in a patient with persistent anti pf4 heparin antibodies 8 years after heparin induced thrombocytopenia"
} | [
{
"companynumb": "CH-TEVA-2019-CH-1129234",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CANGRELOR"
},
"drugadditional": null,
... |
{
"abstract": "A safe, simple, effective, and pan-genotypic regimen to treat hepatitis C virus (HCV) infection in patients coinfected with human immunodeficiency virus type 1 (HIV-1) remains a medical need. We assessed the efficacy and safety of the NS5B polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir for HCV in patients coinfected with HIV-1.\nThis phase 3, open-label, single-arm study at 17 sites in the United States enrolled patients with HCV of any genotype and HIV-1 coinfection, including those with compensated cirrhosis. All patients received sofosbuvir-velpatasvir once daily for 12 weeks. The primary endpoint was sustained virologic response 12 weeks after treatment (SVR12). Efficacy and safety were assessed in all patients receiving at least 1 dose of treatment.\nOf 106 patients, 91 (86%) were men, 48 (45%) were black, and 19 (18%) had cirrhosis. SVR12 was achieved by 101 of 106 (95% [95% confidence interval {CI}, 89%-99%]) patients: 74 of 78 (95% [95% CI, 87%-99%]) with genotype 1; all 11 (100% [95% CI, 72%-100%]) with genotype 2; 11 of 12 (92% [95% CI, 62%-100%]) with genotype 3; and all 5 (100% [95% CI, 48%-100%]) with genotype 4. All 19 patients with cirrhosis had SVR12. Two patients relapsed, 2 were lost to follow-up, and 1 withdrew consent. Two discontinued treatment due to adverse events and 2 had serious adverse events. The most common adverse events were fatigue (25%), headache (13%), upper respiratory tract infection (8%), and arthralgia (8%).\nSofosbuvir-velpatasvir for 12 weeks was safe and provided high rates of SVR12 in patients coinfected with HCV and HIV-1.\nNCT02480712.",
"affiliations": "Division of Infectious Diseases, Denver Health and Hospital Authority, Colorado.;James J. Peters Veterans Affairs Medical Center, Bronx.;Institute of Human Virology, University of Maryland, Baltimore.;Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance.;Ruane Medical and Liver Health Institute, Los Angeles, California.;Emory University, Atlanta, Georgia.;University of California, San Francisco.;CORE Center, Cook County Health and Hospitals System and Rush University Medical Center, Chicago, Illinois.;Massachusetts General Hospital and Harvard Medical School, Boston.;Gilead Sciences, Foster City, California.;Gilead Sciences, Foster City, California.;Gilead Sciences, Foster City, California.;Gilead Sciences, Foster City, California.;Gilead Sciences, Foster City, California.;Gilead Sciences, Foster City, California.;Gilead Sciences, Foster City, California.;Duke University, Durham, North Carolina.;Johns Hopkins University School of Medicine, Baltimore, Maryland.",
"authors": "Wyles|David|D|;Bräu|Norbert|N|;Kottilil|Shyam|S|;Daar|Eric S|ES|;Ruane|Peter|P|;Workowski|Kimberly|K|;Luetkemeyer|Anne|A|;Adeyemi|Oluwatoyin|O|;Kim|Arthur Y|AY|;Doehle|Brian|B|;Huang|K C|KC|;Mogalian|Erik|E|;Osinusi|Anu|A|;McNally|John|J|;Brainard|Diana M|DM|;McHutchison|John G|JG|;Naggie|Susanna|S|;Sulkowski|Mark|M|;|||",
"chemical_list": "D000998:Antiviral Agents; D002219:Carbamates; D006576:Heterocyclic Compounds, 4 or More Rings; C000604171:velpatasvir; D000069474:Sofosbuvir",
"country": "United States",
"delete": false,
"doi": "10.1093/cid/cix260",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1058-4838",
"issue": "65(1)",
"journal": "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America",
"keywords": "ASTRAL-5; HCV-HIV coinfection; hepatitis C virus; sofosbuvir; velpatasvir",
"medline_ta": "Clin Infect Dis",
"mesh_terms": "D000328:Adult; D000368:Aged; D000998:Antiviral Agents; D002219:Carbamates; D060085:Coinfection; D005260:Female; D015658:HIV Infections; D006526:Hepatitis C; D006576:Heterocyclic Compounds, 4 or More Rings; D006801:Humans; D008297:Male; D008875:Middle Aged; D000069474:Sofosbuvir; D014481:United States",
"nlm_unique_id": "9203213",
"other_id": null,
"pages": "6-12",
"pmc": null,
"pmid": "28369210",
"pubdate": "2017-07-01",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article",
"references": "26740514;26571066;26196665;16352363;26569658;26575258;14679458;27296509;10498659;26196502;26248117;20851211",
"title": "Sofosbuvir and Velpatasvir for the Treatment of Hepatitis C Virus in Patients Coinfected With Human Immunodeficiency Virus Type 1: An Open-Label, Phase 3 Study.",
"title_normalized": "sofosbuvir and velpatasvir for the treatment of hepatitis c virus in patients coinfected with human immunodeficiency virus type 1 an open label phase 3 study"
} | [
{
"companynumb": "US-MYLANLABS-2017M1054005",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "ATAZANAVIR\\RITONAVIR"
},
"drugadditional": n... |
{
"abstract": "In the context of palliative medicine, spinal cord compression occurs in around 5% of patients with cancer. Ten per cent of patients with spinal metastases are affected; the commonest causes are breast, prostate, lung cancer and multiple myeloma. We describe a rare cause of spinal cord compression in a 29-year-old man resulting from a complication of long-term corticosteroid use. Spinal epidural lipomatosis is a complex disorder caused by hypertrophy of adipose tissue located in the spinal epidural space. Symptoms occur when the adipose tissue enlarges, encroaching on the spinal canal. In this case, the aetiology was long-term exogenous dexamethasone use.",
"affiliations": "ST5 Palliative Medicine, Community Palliative Care Team, Coventry, UK.",
"authors": "Clerici|Joanna|J|;MacLaran|Sarah|S|",
"chemical_list": "D005938:Glucocorticoids; D003907:Dexamethasone",
"country": "England",
"delete": false,
"doi": "10.1136/bmjspcare-2012-000394",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2045-435X",
"issue": "4(1)",
"journal": "BMJ supportive & palliative care",
"keywords": "Dexamethasone; Spinal Epidural Lipomatosis; Steroids; spinal cord compression",
"medline_ta": "BMJ Support Palliat Care",
"mesh_terms": "D000328:Adult; D003907:Dexamethasone; D003937:Diagnosis, Differential; D004824:Epidural Space; D017809:Fatal Outcome; D005938:Glucocorticoids; D006801:Humans; D008068:Lipomatosis; D008279:Magnetic Resonance Imaging; D008297:Male; D013117:Spinal Cord Compression",
"nlm_unique_id": "101565123",
"other_id": null,
"pages": "81-3",
"pmc": null,
"pmid": "24644776",
"pubdate": "2014-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A rare non-malignant cause of spinal cord compression in a young patient.",
"title_normalized": "a rare non malignant cause of spinal cord compression in a young patient"
} | [
{
"companynumb": "GB-FRESENIUS KABI-FK201503161",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,... |
{
"abstract": "High-dose chemotherapy with autologous hematopoietic stem cell transplantation improves event-free survival in patients with high-risk neuroblastoma. However, in heavily pretreated patients, poor marrow function can be an obstacle in the successful proceeding of therapy. Priming with plerixafor plus filgrastim is an option for effective mobilization and collection of stem cells. In addition, thrombopoietin agonist eltrombopag can improve the outcome of posttransplantation thrombocytopenia and poor graft function in the posttransplant setting. We describe a case of a child with high-risk neuroblastoma, for whom plerixafor and eltrombopag were used as an effective and safe supportive therapy.",
"affiliations": "Department of Pediatric Hematology and Oncology, Collegium Medicum, Nicolaus Copernicus University Torun, Antoni Jurasz University Hospital, Bydgoszcz, Poland.",
"authors": "Marjanska|Agata|A|;Czyzewski|Krzysztof|K|;Debski|Robert|R|;Krenska|Anna|A|;Wysocki|Mariusz|M|;Styczynski|Jan|J|",
"chemical_list": "D019380:Anti-HIV Agents; D001565:Benzoates; D001596:Benzylamines; D000080027:Cyclams; D006571:Heterocyclic Compounds; D006834:Hydrazines; D011720:Pyrazoles; C520809:eltrombopag; C088327:plerixafor",
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000001551",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "42(7)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D019380:Anti-HIV Agents; D001565:Benzoates; D001596:Benzylamines; D002675:Child, Preschool; D003131:Combined Modality Therapy; D000080027:Cyclams; D004359:Drug Therapy, Combination; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006571:Heterocyclic Compounds; D006801:Humans; D006834:Hydrazines; D009447:Neuroblastoma; D011379:Prognosis; D011720:Pyrazoles",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "e680-e682",
"pmc": null,
"pmid": "31306338",
"pubdate": "2020-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "The Successful Sequential Use of Plerixafor and Eltrombopag For Hematopoietic Cell Transplantation in a Child With High-risk Neuroblastoma.",
"title_normalized": "the successful sequential use of plerixafor and eltrombopag for hematopoietic cell transplantation in a child with high risk neuroblastoma"
} | [
{
"companynumb": "PL-TEVA-2021-PL-1874492",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"drugadditional": "3",
... |
{
"abstract": "An 11-month-old girl presented with dermatitis, boggy arthritis, and keratitis shortly after her hospitalization for bacterial pneumonia. A skin biopsy and genetic testing led to a diagnosis of Blau syndrome. Her symptoms persisted despite a stepwise increase in immune-modulating therapies. Her ocular findings advanced to include bilateral panuveitis, optic disk edema, and hypopigmented chorioretinitis. We speculate that the bacterial infection triggered an inflammatory reaction throughout her body that was facilitated by the pathogenic NOD2 variant.",
"affiliations": "Division of Ophthalmology, Department of Surgery, McMaster University, Hamilton, Ontario, Canada. Electronic address: sidiqiahm@gmail.com.;Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, British Columbia, Canada.",
"authors": "Sidiqi|Ahmad|A|;Pegado|Victor|V|",
"chemical_list": "D053473:Nod2 Signaling Adaptor Protein",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jaapos.2019.12.008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1091-8531",
"issue": "24(2)",
"journal": "Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus",
"keywords": null,
"medline_ta": "J AAPOS",
"mesh_terms": "D001168:Arthritis; D001424:Bacterial Infections; D005260:Female; D006801:Humans; D007223:Infant; D009154:Mutation; D053473:Nod2 Signaling Adaptor Protein; D012507:Sarcoidosis; D013585:Synovitis; D014605:Uveitis",
"nlm_unique_id": "9710011",
"other_id": null,
"pages": "118-120",
"pmc": null,
"pmid": "32045678",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Blau syndrome following a bacterial infection.",
"title_normalized": "blau syndrome following a bacterial infection"
} | [
{
"companynumb": "NVSC2020CA229129",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": "3",
"dr... |
{
"abstract": "BACKGROUND\nMinocycline-induced drug rash with eosinophilia and systemic symptoms (DRESS) may have a prolonged course, especially in African and African-American patients.\n\n\nOBJECTIVE\nTo determine if a prolonged course of minocycline-induced DRESS was associated with an accumulation of the culprit drug.\n\n\nMETHODS\nWe determined plasma and skin levels of minocycline in patients with minocycline-induced DRESS. We investigated the genetic polymorphisms of enzymes potentially involved in the detoxification of the drug, glutathione S-transferases and UDP-glucuronosyltransferases.\n\n\nCONCLUSIONS\nWe demonstrated the persistence of minocycline in the plasma and/or in the skin of 7 out of 9 patients with skin phototypes V-VI. As pigmented skin contains more melanin, this could promote the formation of a melanin-minocycline complex, which could explain the severe and prolonged DRESS which may occur in this subgroup of patients.",
"affiliations": "Department of Dermatology, Hôpital Henri-Mondor, Assistance Publique-Hôpitaux de Paris, Créteil, France.",
"authors": "Maubec|Eve|E|;Wolkenstein|Pierre|P|;Loriot|Marie-Anne|MA|;Wechsler|Janine|J|;Mulot|Claire|C|;Beaune|Philippe|P|;Revuz|Jean|J|;Roujeau|Jean-Claude|JC|",
"chemical_list": "D000900:Anti-Bacterial Agents; D008543:Melanins; D005982:Glutathione Transferase; D008911:Minocycline",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000112926",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1018-8665",
"issue": "216(3)",
"journal": "Dermatology (Basel, Switzerland)",
"keywords": null,
"medline_ta": "Dermatology",
"mesh_terms": "D000152:Acne Vulgaris; D000293:Adolescent; D000328:Adult; D000900:Anti-Bacterial Agents; D044383:Blacks; D002851:Chromatography, High Pressure Liquid; D004342:Drug Hypersensitivity; D004802:Eosinophilia; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005982:Glutathione Transferase; D006801:Humans; D008297:Male; D008543:Melanins; D008875:Middle Aged; D008911:Minocycline; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D017384:Sequence Deletion; D012867:Skin; D012880:Skin Pigmentation; D013577:Syndrome",
"nlm_unique_id": "9203244",
"other_id": null,
"pages": "200-4",
"pmc": null,
"pmid": "18182810",
"pubdate": "2008",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Minocycline-induced DRESS: evidence for accumulation of the culprit drug.",
"title_normalized": "minocycline induced dress evidence for accumulation of the culprit drug"
} | [
{
"companynumb": "FR-MYLANLABS-2020M1060693",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MINOCYCLINE HYDROCHLORIDE"
},
"drugadditional... |
{
"abstract": "Panniculitis is a rare complication of BRAF inhibitor therapy that is used to treat patients with BRAF-mutated metastatic melanoma. We present a clinicopathologic review of 9 patients who developed panniculitis while on BRAF inhibitor therapy. In 13% of patients on vemurafenib, 3% of patients on dabrafenib and 10% on combination of dabrafenib + trametinib, tender erythematous nodular lesions of panniculitis appeared on legs, arms and trunk. Histological evaluation of 8 biopsies from 7 patients showed predominantly neutrophilic infiltrate in 4, lymphocytic in 1, and mixed in 3. Lesions with neutrophilic infiltrate appeared in earlier stages of treatment than those with mixed or lymphocytic infiltrate. All biopsies showed lobular involvement and 5 also had a septal component. In addition, 1 biopsy had lichenoid inflammation in the epidermis and the other had evidence of vasculitis. Most patients responded to conservative medical management without the need to reduce or to stop BRAF inhibitor therapy. Panniculitis seems to be a rare class effect of BRAF inhibitors that is predominantly lobular and neutrophilic, although other patterns can be seen.",
"affiliations": "*Department of Dermatology, Westmead Hospital, Sydney, Australia; †Sydney Medical School, The University of Sydney, Sydney, Australia; and ‡Department of Tissue Pathology and Diagnostic Oncology, Pathology West, Institute of Clinical Pathology and Medical Research, Westmead, Sydney, Australia.",
"authors": "Choy|Bonita|B|;Chou|Shaun|S|;Anforth|Rachael|R|;Fernández-Peñas|Pablo|P|",
"chemical_list": "D007093:Imidazoles; D007211:Indoles; D010091:Oximes; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; D013449:Sulfonamides; D000077484:Vemurafenib; C560077:trametinib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C561627:dabrafenib",
"country": "United States",
"delete": false,
"doi": "10.1097/DAD.0000000000000023",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0193-1091",
"issue": "36(6)",
"journal": "The American Journal of dermatopathology",
"keywords": null,
"medline_ta": "Am J Dermatopathol",
"mesh_terms": "D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D007093:Imidazoles; D007211:Indoles; D008297:Male; D008545:Melanoma; D008875:Middle Aged; D010091:Oximes; D015434:Panniculitis; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; D011728:Pyridones; D011744:Pyrimidinones; D012878:Skin Neoplasms; D013449:Sulfonamides; D000077484:Vemurafenib",
"nlm_unique_id": "7911005",
"other_id": null,
"pages": "493-7",
"pmc": null,
"pmid": "24879511",
"pubdate": "2014-06",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Panniculitis in patients treated with BRAF inhibitors: a case series.",
"title_normalized": "panniculitis in patients treated with braf inhibitors a case series"
} | [
{
"companynumb": "AU-GLAXOSMITHKLINE-AU2015GSK083336",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DABRAFENIB"
},
"drugadditional": nul... |
{
"abstract": "A 41-year-old female presented with a large anterior mediastinal mass adjacent to the heart. Biopsy demonstrated lymphoma. Upon administration of chemotherapy, she developed cardiogenic shock requiring a 5-day course of extracorporeal membrane oxygenation (ECMO) as a bridge through her treatment. After one cycle of chemotherapy, ECMO was discontinued and the patient completed her course of chemotherapy and recovered to hospital discharge.",
"affiliations": null,
"authors": "Worku|Berhane|B|;DeBois|William|W|;Sobol|Irina|I|;Gulkarov|Iosif|I|;Horn|Evelyn M|EM|;Salemi|Arash|A|",
"chemical_list": "D014750:Vincristine; D003907:Dexamethasone; D004317:Doxorubicin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-1058",
"issue": "47(1)",
"journal": "The journal of extra-corporeal technology",
"keywords": null,
"medline_ta": "J Extra Corpor Technol",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D003131:Combined Modality Therapy; D003907:Dexamethasone; D004317:Doxorubicin; D015199:Extracorporeal Membrane Oxygenation; D005260:Female; D006801:Humans; D016393:Lymphoma, B-Cell; D008479:Mediastinal Neoplasms; D012120:Respiration Disorders; D016896:Treatment Outcome; D014750:Vincristine",
"nlm_unique_id": "0267637",
"other_id": null,
"pages": "52-4",
"pmc": null,
"pmid": "26390681",
"pubdate": "2015-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18045830;22647970;20386416;16885791;16551801;16236967;10617025;11251283",
"title": "Extracorporeal Membrane Oxygenation as a Bridge through Chemotherapy in B-Cell Lymphoma.",
"title_normalized": "extracorporeal membrane oxygenation as a bridge through chemotherapy in b cell lymphoma"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2016US-130964",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"dru... |
{
"abstract": "Salvage chemotherapy for recurrent chest wall lesions in breast cancer results in response rates of 20% to 30%. Preclinical studies showed significant disease regression could be induced in murine chest wall mammary cancers with a topical toll-like receptor (TLR)-7 agonist, imiquimod.\nTo evaluate the safety and objective response rate (ORR) of imiquimod in combination with systemic albumin bound paclitaxel in treatment-refractory breast cancer of the chest wall.\nA single arm phase 2 clinical trial of 15 patients with breast cancer previously treated in an academic medical center setting between 2009 and 2012 for chest wall disease that had recurred.\nImiquimod cream, 5%, was applied topically to a designated target lesion once per day for 4 consecutive days on days 1 through 4, 8 through 11, 15 through 18, and 22 through 25 of a 28-day cycle, for 12 weeks. Albumin bound paclitaxel, 100 mg/m2, was given intravenously on days 1, 8, and 15, and repeated every 28 days over the 12-week period.\nThe primary endpoint was safety and ORR. Secondary endpoints included the generation of tumor-infiltrating lymphocytes and modulation of immune cell populations.\nThe median age at baseline of the 15 study participants was 54 years (range, 46-92 years). Fourteen patients were evaluable. Combination therapy was associated with low-grade toxic effects. Of 358 adverse events 330 (92%) were grades 1 and 2. Five (36%) patients achieved a compete response and another 5 (36%) were partial responders for an overall response rate of 72% (10 of 14). The response duration was limited. Pretreatment levels of programmed death-1 (PD-1)+ peripheral blood T cells (PD-1+ cluster of differentiation [CD]4+; 95% CI, 2.68-6.63; P < .001 and PD-1+CD8+; 95% CI, 1.13-8.35; P = .01) and monocytic myeloid derived suppressor cells (mMDSC) (95% CI, 3.62-12.74; P = .001) greater than controls predicted suboptimal clinical response.\nChemoimmunomodulation with a TLR-7 agonist and albumin bound paclitaxel is effective in inducing disease regression in treatment-refractory breast cancer chest wall metastases but responses are short-lived. Preexisting levels of cells indicating either T-cell exhaustion or systemic immunosuppression may be markers of selection for responsive patients.\nclinicaltrials.gov Identifier: NCT00821964.",
"affiliations": "Tumor Vaccine Group, Center for Translational Medicine in Women's Health, University of Washington, Seattle.;Immune Design, Seattle, Washington.;Tumor Vaccine Group, Center for Translational Medicine in Women's Health, University of Washington, Seattle.;Tumor Vaccine Group, Center for Translational Medicine in Women's Health, University of Washington, Seattle.;Tumor Vaccine Group, Center for Translational Medicine in Women's Health, University of Washington, Seattle.;Tumor Vaccine Group, Center for Translational Medicine in Women's Health, University of Washington, Seattle.;Medical Oncology, City of Hope, Durante, California.;Department of Pathology, Stanford University, Stanford, California.;Tumor Vaccine Group, Center for Translational Medicine in Women's Health, University of Washington, Seattle.;Tumor Vaccine Group, Center for Translational Medicine in Women's Health, University of Washington, Seattle.",
"authors": "Salazar|Lupe G|LG|;Lu|Hailing|H|;Reichow|Jessica L|JL|;Childs|Jennifer S|JS|;Coveler|Andrew L|AL|;Higgins|Doreen M|DM|;Waisman|James|J|;Allison|Kimberly H|KH|;Dang|Yushe|Y|;Disis|Mary L|ML|",
"chemical_list": "C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D000634:Aminoquinolines; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D000077271:Imiquimod; D017239:Paclitaxel",
"country": "United States",
"delete": false,
"doi": "10.1001/jamaoncol.2016.6007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2374-2437",
"issue": "3(7)",
"journal": "JAMA oncology",
"keywords": null,
"medline_ta": "JAMA Oncol",
"mesh_terms": "D000279:Administration, Cutaneous; D061605:Administration, Intravenous; D000368:Aged; D000369:Aged, 80 and over; D000418:Albumins; D000634:Aminoquinolines; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D015496:CD4-Positive T-Lymphocytes; D018414:CD8-Positive T-Lymphocytes; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D000077271:Imiquimod; D016246:Lymphocytes, Tumor-Infiltrating; D008875:Middle Aged; D009000:Monocytes; D017239:Paclitaxel; D061026:Programmed Cell Death 1 Receptor; D016879:Salvage Therapy; D012878:Skin Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "101652861",
"other_id": null,
"pages": "969-973",
"pmc": null,
"pmid": "28114604",
"pubdate": "2017-07-01",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article",
"references": "27777769;16135470;25968455;23722543;24780756;27355489;20308630;11527294;14533438;21490155;17329192;24162107;22446942;19733657;27493241",
"title": "Topical Imiquimod Plus Nab-paclitaxel for Breast Cancer Cutaneous Metastases: A Phase 2 Clinical Trial.",
"title_normalized": "topical imiquimod plus nab paclitaxel for breast cancer cutaneous metastases a phase 2 clinical trial"
} | [
{
"companynumb": "US-CELGENEUS-USA-2017019650",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": "3",
... |
{
"abstract": "This post hoc study assessed the evidence-base for esketamine nasal spray for management of treatment-resistant depression (TRD) using number needed to treat (NNT), number needed to harm (NNH), and likelihood to be helped or harmed (LHH).\n\n\n\nData sources were four phase III randomized, double-blind studies including two positive studies (acute flexible-dose; maintenance) in patients with TRD. Key efficacy study outcomes: acute response (≥50% decrease from baseline on Montgomery-Asberg Depression Rating Scale [MADRS] total score), acute remission (MADRS scores ≤12). NNT, NNH were calculated for esketamine nasal spray+newly initiated oral antidepressant (esketamine+AD) vs. placebo+AD.\n\n\n\nIn the pivotal acute flexible-dose study, MADRS response (63.4% vs. 49.5%) and remission (48.2% vs. 30.3%) at 4 weeks resulted in NNT of 8 and 6 for esketamine+AD vs. placebo+AD. NNH values <10 included dissociation (26.1% vs. 3.7%), vertigo (26.1% vs. 2.8%), nausea (26.1% vs. 6.4%), dizziness (20.9% vs. 4.6%), and dysgeusia (24.3% vs. 11.9%). Discontinuation rates due to adverse events (AE) (7.0% vs. 0.9%) yielded NNH=17. LHH comparing MADRS remission vs. discontinuation due to AE was 17 vs. 6. Maintenance use of esketamine+AD demonstrated NNT values<10 for relapse and/or maintenance of remission. In maintenance study, discontinuation due to AE (2.6% vs. 2.1%) yielded NNH=178 (non-significant).\n\n\n\nOnly dichotomous outcomes were included.\n\n\n\nNNT<10 for efficacy outcomes suggests potential benefit of esketamine+AD for both acute and maintenance use. LHH was favorable: esketamine+AD was 3 times likely to result in acute remission vs. discontinuations due to AE.",
"affiliations": "Department of Psychiatry & Behavioral Sciences, New York Medical College, Valhalla, NY 10595, United States. Electronic address: citrome@cnsconsultant.com.;Janssen Research & Development, LLC, 1125 Trenton-Harbourton Road, Titusville, NJ 08560, United States.;Janssen Research & Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, United States.",
"authors": "Citrome|Leslie|L|;DiBernardo|Allitia|A|;Singh|Jaskaran|J|",
"chemical_list": "D059085:Nasal Sprays; C000629870:Esketamine; D007649:Ketamine",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jad.2020.03.106",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0165-0327",
"issue": "271()",
"journal": "Journal of affective disorders",
"keywords": "Esketamine nasal spray; Number needed to harm (NNH); Number needed to treat (NNT); Treatment-resistant depression",
"medline_ta": "J Affect Disord",
"mesh_terms": "D000328:Adult; D003863:Depression; D006801:Humans; D007649:Ketamine; D059085:Nasal Sprays; D016896:Treatment Outcome",
"nlm_unique_id": "7906073",
"other_id": null,
"pages": "228-238",
"pmc": null,
"pmid": "32479321",
"pubdate": "2020-06-15",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Appraising esketamine nasal spray for the management of treatment-resistant depression in adults: Number needed to treat, number needed to harm, and likelihood to be helped or harmed.",
"title_normalized": "appraising esketamine nasal spray for the management of treatment resistant depression in adults number needed to treat number needed to harm and likelihood to be helped or harmed"
} | [
{
"companynumb": "US-OTSUKA-2020_019474",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "We examined outcomes of haploidentical hematopoietic cell transplantation (haplo-HCT) using T-cell receptor αβ+ (TCRαβ+)/CD19+-depleted grafts (TCR group, 14 patients) in children with hemoglobinopathies. Patients received a preparative regimen consisting of busulfan, thiotepa, cyclophosphamide, and antithymocyte globulin preceded by fludarabine, hydroxyurea, and azathioprine. The median follow-up among surviving patients was 3.9 years. The 5-year probabilities of overall survival (OS) and disease-free survival (DFS) were 84% and 69%, respectively. The incidence of graft failure was 14%. We compared outcomes to a historical group of 40 patients with hemoglobinopathies who received CD34+-selected grafts (CD34 group). The median follow-up of surviving patients for the CD34 group was 7.5 years. The 5-year probabilities of OS and DFS were 78% and 39%, respectively. The CD34 group had a significantly higher incidence of graft failure (45%) than the TCR group (14%) (P = .048). The incidences of grades 2 to 4 acute graft-versus-host disease (GVHD) in the TCR and CD34 groups were 28% and 29%, respectively, and 21% and 10% (P = .1), respectively, for extensive chronic GVHD. Viral reactivation was common in both groups. The overall incidence of posttransplant lymphoproliferative disorders for the entire group was 16%. Among all patients, 5 developed autoimmune hemolytic anemia or thrombocytopenia, with the overall cumulative incidence of 11%. The 2 groups showed suboptimal CD4+ recovery within the first 6 months of transplantation with no significant difference between groups. These data demonstrate that TCRαβ+/CD19+-depleted grafts are associated with a reduced incidence of graft failure, but delayed immune reconstitution and associated morbidity and mortality remain a significant challenge.",
"affiliations": "International Center for Transplantation in Thalassemia and Sickle Cell Anemia, Mediterranean Institute of Hematology, Policlinico Tor Vergata, Rome, Italy.;International Center for Transplantation in Thalassemia and Sickle Cell Anemia, Mediterranean Institute of Hematology, Policlinico Tor Vergata, Rome, Italy.;Unità Operativa Complessa Internal Medicine and Hematology, Azienda Ospedaliera Ospedali Riuniti Marche Nord, Ospedale Santo Croce, Fano, Italy; and.;International Center for Transplantation in Thalassemia and Sickle Cell Anemia, Mediterranean Institute of Hematology, Policlinico Tor Vergata, Rome, Italy.;International Center for Transplantation in Thalassemia and Sickle Cell Anemia, Mediterranean Institute of Hematology, Policlinico Tor Vergata, Rome, Italy.;International Center for Transplantation in Thalassemia and Sickle Cell Anemia, Mediterranean Institute of Hematology, Policlinico Tor Vergata, Rome, Italy.;International Center for Transplantation in Thalassemia and Sickle Cell Anemia, Mediterranean Institute of Hematology, Policlinico Tor Vergata, Rome, Italy.;International Center for Transplantation in Thalassemia and Sickle Cell Anemia, Mediterranean Institute of Hematology, Policlinico Tor Vergata, Rome, Italy.;Servizio di Immunoematologia e Medicina Trasfusionale, Policlinico Tor Vergata Foundation, Rome, Italy.;International Center for Transplantation in Thalassemia and Sickle Cell Anemia, Mediterranean Institute of Hematology, Policlinico Tor Vergata, Rome, Italy.;Servizio di Immunoematologia e Medicina Trasfusionale, Policlinico Tor Vergata Foundation, Rome, Italy.;International Center for Transplantation in Thalassemia and Sickle Cell Anemia, Mediterranean Institute of Hematology, Policlinico Tor Vergata, Rome, Italy.",
"authors": "Gaziev|Javid|J|;Isgrò|Antonella|A|;Sodani|Pietro|P|;Paciaroni|Katia|K|;De Angelis|Gioia|G|;Marziali|Marco|M|;Ribersani|Michela|M|;Alfieri|Cecilia|C|;Lanti|Alessandro|A|;Galluccio|Tiziana|T|;Adorno|Gaspare|G|;Andreani|Marco|M|",
"chemical_list": "D018941:Antigens, CD19; D018952:Antigens, CD34; D016693:Receptors, Antigen, T-Cell, alpha-beta",
"country": "United States",
"delete": false,
"doi": "10.1182/bloodadvances.2017012005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2473-9529",
"issue": "2(3)",
"journal": "Blood advances",
"keywords": null,
"medline_ta": "Blood Adv",
"mesh_terms": "D000293:Adolescent; D018941:Antigens, CD19; D018952:Antigens, CD34; D002648:Child; D002675:Child, Preschool; D006084:Graft Rejection; D006085:Graft Survival; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006453:Hemoglobinopathies; D006801:Humans; D008212:Lymphocyte Depletion; D008297:Male; D016693:Receptors, Antigen, T-Cell, alpha-beta; D012189:Retrospective Studies; D016019:Survival Analysis; D000075442:Transplantation, Haploidentical; D016896:Treatment Outcome",
"nlm_unique_id": "101698425",
"other_id": null,
"pages": "263-270",
"pmc": null,
"pmid": "29431621",
"pubdate": "2018-02-13",
"publication_types": "D016428:Journal Article",
"references": "28293408;8807120;3307954;19264919;9731078;27519279;25054717;10204198;17917892;12796786;12463477;27000732;18039551;19855248;26039210;27088380;29296761;26878659;16338616;22955919;7581076;26187864;22491731;9780338;8639809;23208313;24869942;23416852;18489989;16769581;9028343;22914586;19897573;24274983;23993299;27625358;3011326",
"title": "Haploidentical HSCT for hemoglobinopathies: improved outcomes with TCRαβ+/CD19+-depleted grafts.",
"title_normalized": "haploidentical hsct for hemoglobinopathies improved outcomes with tcr cd19 depleted grafts"
} | [
{
"companynumb": "IT-ASPEN-GLO2018IT002977",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROXYUREA"
},
"drugadditional": "3",
... |
{
"abstract": "The role of mTOR inhibitors, such as EVL, has not been established for pediatric liver transplant recipients up to now, although data from adult solid organ graft transplantation are very promising. Major complications following pediatric liver transplantation in the long-term course include chronic graft rejection and CNI-derived nephrotoxicity. The purpose of our study was to report first results using EVL as a rescue therapy in pediatric liver transplant recipients for the following indications: chronic graft dysfunction n=12, suspected CNI toxicity n=3, hepatoblastoma n=2, and recurrence of primary sclerosing cholangitis post-Ltx n=1. Four patients with chronic graft dysfunction developed completely normal liver function tests using EVL, six patients showed partial improvement, and two patients did not respond at all. One patient with CNI-induced nephropathy showed a slightly improved GFR. Both patients with hepatoblastoma did not develop any metastasis post-Ltx. First experience with EVL in pediatric liver transplant recipients shows promising results in patients with chronic graft failure when standard immunosuppression has failed. The future role of EVL in immunosuppressive protocols for children post-Ltx has to be proven by controlled clinical trials.",
"affiliations": "Departments of General Pediatrics Pediatric Hepatology and Liver Transplantation Hepatobiliary Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.",
"authors": "Nielsen|Dirk|D|;Briem-Richter|Andrea|A|;Sornsakrin|Marijke|M|;Fischer|Lutz|L|;Nashan|Bjoern|B|;Ganschow|Rainer|R|",
"chemical_list": "D007166:Immunosuppressive Agents; D000068338:Everolimus; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus",
"country": "Denmark",
"delete": false,
"doi": "10.1111/j.1399-3046.2011.01515.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "15(5)",
"journal": "Pediatric transplantation",
"keywords": null,
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D000068338:Everolimus; D005260:Female; D005919:Glomerular Filtration Rate; D006084:Graft Rejection; D006085:Graft Survival; D018197:Hepatoblastoma; D006801:Humans; D007166:Immunosuppressive Agents; D007223:Infant; D008111:Liver Function Tests; D016031:Liver Transplantation; D008297:Male; D010372:Pediatrics; D011446:Prospective Studies; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "510-4",
"pmc": null,
"pmid": "21696525",
"pubdate": "2011-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The use of everolimus in pediatric liver transplant recipients: first experience in a single center.",
"title_normalized": "the use of everolimus in pediatric liver transplant recipients first experience in a single center"
} | [
{
"companynumb": "PHHY2011DE87665",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BASILIXIMAB"
},
"drugadditional": null,
"drug... |
{
"abstract": "OBJECTIVE\nThis retrospective case series study of the effectiveness of electroconvulsive therapy (ECT) augmentation on clozapine-resistant schizophrenia was conducted by EMR review.\n\n\nMETHODS\nClozapine-resistance was defined as persistent psychotic symptoms despite at least 12 weeks of clozapine administration with blood levels over 350 ng/mL in order to rule out pseudo-resistance. Seven in-patients who were taking clozapine and treated with ECT were selected. We analyzed the psychopathology and subscales changed by ECT.\n\n\nRESULTS\nThe average number of ECT sessions was 13.4 (±4.6). Total Positive and Negative Syndrome Scale (PANSS) score was significantly reduced by 17.9 (±12.8) points (p=0.0384) on average, which represented a reduction of 25.5% (±14.3). 71.4% (5/7) of patients were identified as clinical remission, with at least a 20% reduction in PANSS score. PANSS reduction was associated with number of ECT sessions, stimulus level in the final session, and blood clozapine levels before ECT. However, the negative subscale on the PANSS were not reduced by ECT in any patient. We did not observe any persistent adverse cognitive effects.\n\n\nCONCLUSIONS\nThis study supports that ECT augmentation on clozapine-resistant schizophrenia reveals clinically effective and safe. Further research should be done involving a larger number of patients to investigate the effectiveness of clozapine/ECT combination therapy.",
"affiliations": "Department of Psychiatry, Dongguk University International Hospital, Goyang, Republic of Korea.;Department of Psychiatry, Dongguk University International Hospital, Goyang, Republic of Korea.; Institute of Clinical Psychopharmacology, Dongguk University College of Medicine, Goyang, Republic of Korea.;Department of Psychiatry, Dongguk University International Hospital, Goyang, Republic of Korea.; Institute of Clinical Psychopharmacology, Dongguk University College of Medicine, Goyang, Republic of Korea.;Department of Psychiatry, Dongguk University International Hospital, Goyang, Republic of Korea.; Institute of Clinical Psychopharmacology, Dongguk University College of Medicine, Goyang, Republic of Korea.;Department of Anesthesia & Pain Medicine, Dongguk University International Hospital, Goyang, Republic of Korea.;Department of Anesthesia & Pain Medicine, Dongguk University International Hospital, Goyang, Republic of Korea.;Department of Psychiatry, Dongguk University International Hospital, Goyang, Republic of Korea.; Institute of Clinical Psychopharmacology, Dongguk University College of Medicine, Goyang, Republic of Korea.;Department of Psychiatry, Dongguk University International Hospital, Goyang, Republic of Korea.; Institute of Clinical Psychopharmacology, Dongguk University College of Medicine, Goyang, Republic of Korea.",
"authors": "Kim|Hye Sung|HS|;Kim|Se Hyun|SH|;Lee|Nam Young|NY|;Youn|Tak|T|;Lee|Jeoung Hyuk|JH|;Chung|Seunghyun|S|;Kim|Yong Sik|YS|;Chung|In Won|IW|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.4306/pi.2017.14.1.58",
"fulltext": "\n==== Front\nPsychiatry InvestigPsychiatry InvestigPIPsychiatry Investigation1738-36841976-3026Korean Neuropsychiatric Association 10.4306/pi.2017.14.1.58Original ArticleEffectiveness of Electroconvulsive Therapy Augmentation on Clozapine-Resistant Schizophrenia Kim Hye Sung 1Kim Se Hyun 12Lee Nam Young 12Youn Tak 12Lee Jeoung Hyuk 3Chung Seunghyun 3Kim Yong Sik 12Chung In Won 121 Department of Psychiatry, Dongguk University International Hospital, Goyang, Republic of Korea.2 Institute of Clinical Psychopharmacology, Dongguk University College of Medicine, Goyang, Republic of Korea.3 Department of Anesthesia & Pain Medicine, Dongguk University International Hospital, Goyang, Republic of Korea.Correspondence: In Won Chung, MD, PhD. Department of Psychiatry, Dongguk University International Hospital, 27 Dongguk-ro, Ilsandong-gu, Goyang 10326, Republic of Korea. Tel: +82-31-961-7231, Fax: +82-31-961-7236, ciw@duih.org1 2017 29 12 2016 14 1 58 62 07 12 2015 31 3 2016 11 4 2016 Copyright © 2017 Korean Neuropsychiatric Association2017This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Objective\nThis retrospective case series study of the effectiveness of electroconvulsive therapy (ECT) augmentation on clozapine-resistant schizophrenia was conducted by EMR review.\n\nMethods\nClozapine-resistance was defined as persistent psychotic symptoms despite at least 12 weeks of clozapine administration with blood levels over 350 ng/mL in order to rule out pseudo-resistance. Seven in-patients who were taking clozapine and treated with ECT were selected. We analyzed the psychopathology and subscales changed by ECT.\n\nResults\nThe average number of ECT sessions was 13.4 (±4.6). Total Positive and Negative Syndrome Scale (PANSS) score was significantly reduced by 17.9 (±12.8) points (p=0.0384) on average, which represented a reduction of 25.5% (±14.3). 71.4% (5/7) of patients were identified as clinical remission, with at least a 20% reduction in PANSS score. PANSS reduction was associated with number of ECT sessions, stimulus level in the final session, and blood clozapine levels before ECT. However, the negative subscale on the PANSS were not reduced by ECT in any patient. We did not observe any persistent adverse cognitive effects.\n\nConclusion\nThis study supports that ECT augmentation on clozapine-resistant schizophrenia reveals clinically effective and safe. Further research should be done involving a larger number of patients to investigate the effectiveness of clozapine/ECT combination therapy.\n\nClozapine-resistant schizophreniaElectroconvulsive therapyAugmentationDongguk Universityhttp://dx.doi.org/10.13039/501100002471S-2015-G0041-00058\n==== Body\nINTRODUCTION\nThough clozapine is the gold standard for the treatment of patients with antipsychotic-resistant schizophrenia, who represent as many as 20% to 30% of patients with schizophrenia,123 clinical symptoms persist in approximately 40 to 70% of clozapine users even after one year of medication.45 For clozapine-resistant schizophrenia, a variety of pharmacological and non-pharmacological approaches, including electroconvulsive therapy (ECT), have been tried as adjunct therapies.6 The reported advantages of various psychotropic drugs that is the most frequently attempted strategy have been known as modest or equivocal.56789 ECT augmentation has been continued ever since the re-introduction of clozapine in the 1990s10 and the effectiveness of ECT in patients on clozapine has been reported in two randomized controlled studies,411 as well as in case reports and open trials.51213141516171819 These studies consistently demonstrated favorable clinical effects and safety. In studies including a meta-analysis, 47.4-72.7% of patients with clozapine-resistant schizophrenia experienced clinical improvement after ECT.4202122 Further studies are required to validate the usefulness of ECT in clozapine-resistant schizophrenia.6\n\nClozapine resistance is defined as the persistence of psychotic symptoms even after at least 12 weeks of clozapine administration and despite a clozapine blood level of more than 350 ng/mL.45 Before examining the effects of ECT augmentation on clozapine resistance, pseudo-resistance arising from drug noncompliance, the effects of other medications, misdiagnosis, and adverse events must be ruled out.1 However, most studies did not provide information on dosages and blood levels of clozapine, which would be necessary to confirm the effects of ECT augmentation.2324 In order to clarify the effects of ECT augmentation on clozapine-resistant schizophrenia, we conducted a case series study that included only patients whose blood clozapine levels were maintained above 350 ng/mL for a sufficient period of time,4525 and analyzed the psychopathology and symptom domains changed by ECT procedures.\n\nMETHODS\nSubjects\nThe electronic medical record (EMR) of Dongguk University International Hospital was retrospectively reviewed to identify patients diagnosed with schizophrenia by DSM-IV-TR criteria who were treated with clozapine and ECT from December 2012 to April 2015. Patients whose psychotic symptoms were persistent or only partially responsive to 12 weeks or more of clozapine administration and who consistently had blood levels of clozapine greater than 350 ng/mL were eligible for the study. Patients with physical illnesses, substance addiction, or IQs less than 80 were excluded.\n\nMethods\nThe demographic characteristics, psychiatric history including clozapine administration, and clinical and laboratory findings of patients before and after ECT were collected. Psychotic symptoms were evaluated using the Positive and Negative Syndrome Scale (PANSS), in which each item was assessed on a score of 0-6 because the responses could possibly be underestimated when using a score of 1-7.26 A lower PANSS score indicates fewer symptoms. Changes in PANSS score following ECT are given as mean scores and percentage change. The symptom domains were also explored with Hwang's five factors model, which was derived from the Korean version of the PANSS; the symptom domains are positive, negative, activation, autistic preoccupation, and anxiety/depressive factors.27\n\nAdverse events after ECT were tallied using progress notes and the cognitive effects of ECT were assessed before and after the last ECT session using the Mini-Mental State Examination, Korean version of the Consortium (MMSE-KC).28 This study was approved by the Institutional Review Board of Dongguk University International Hospital.\n\nECT procedure\nECT was performed three times per week using bilateral electrode placement and brief pulse stimuli (800 mA; 1 ms) with a MECTA spECTrum 5000Q (MECTA Corp, Lake Oswego, OR, USA). ECT was begun at level 3 (80 millicouloumbs; mC) for men and at level 2 (42 mC) for women, according to Coffey et al.29 Glycopyrrolate (0.1–0.2 mg/Kg) was administered intravenously a few minutes before the patients were given anesthesia for ECT. Thiopental (2–4 mg/kg) was most often used for the general anesthesia. Succinylcholine (0.5–1 mg/kg) was injected to produce muscular relaxation, which was confirmed by fasciculation. Seizure was followed up with EEG, ECG, and visual observation.\n\nStatistical analysis\nNominal data, such as total and symptom domain PANSS scores, were analyzed with paired t-tests. Linear regression was used to explore the factors on the PANSS that changed after ECT. Statistical significance was set at p<0.05. All statistical analyses were performed using SPSS ver. 21.0 for Windows (SPSS, Inc., Chicago, IL, USA).\n\nRESULTS\nDemographic characteristics and clinical information\nThe mean age and length of education of the seven patients were 41.4 (±14.2) and 13.7 (±2.1) years, respectively. The mean durations of illness and clozapine administration were 15.0 (±8.6) and 3.9 (±13.4) years, respectively (Table 1).\n\nClozapine dosage and blood levels\nThe mean dosages of clozapine taken by the seven patients before and after ECT were 350.0 (±146.5) and 260.7 (±95.6) mg, respectively (p=0.048; t=2.471, df=6). The main reason for the reduction in mean dose was that one patient showed transient postictal delirious episodes late in the course of ECT, so her dosage was reduced. There were no statistical differences in clozapine dose during the course of ECT in the other six patients. The mean blood levels of clozapine and norclozapine were 637.9 (±141.3) ng/mL and 275.5 (±72.1) ng/mL before ECT and 574.7 (±244.5) ng/mL and 293.5 (±180.9) ng/mL after ECT, respectively. There were no statistical differences in blood levels over the ECT course (Table 2).\n\nECT and clinical efficacy\nThe main indication for ECT augmentation was insufficient clinical response to clozapine. The mean number of sessions and duration of ECT were 13.4 (±4.6) and 45.4 (±18.9) days, respectively (Table 3). The mean total PANSS scores before and after ECT were 70.1 (±17.9) and 52.3 (±17.9) points, respectively, using the 0-6 scoring system, which is a reduction in mean score of 17.9 (±12.8) points and a statistically significant decrease (p=0.0384). The mean percentage score reduction was 25.5% (±14.3). 71.4% (5/7) of patients were identified as being in clinical remission, as defined by a 20% reduction in PANSS score. In the other two patients, one experienced a reduction in symptoms of 19.3%, and the other experienced no change at all (case 2). In the linear regression analysis, the factors that were associated with a decrease in PANSS score were total number of ECT sessions (β=-0.722), stimulus level in the final session (β=1.182), and blood clozapine level before ECT (β=-0.600). In Hwang's five factor model of the PANSS, the positive factor (p=0.0090; t=3.7932, df=6), the activation factor (p=0.0139; t=3.4340, df=6), autistic preoccupation (p=0.0109; t=3.6332, df=6), and anxiety/depression (p=0.0437; t=2.5460, df=6) were reduced significantly, while the negative factor was not affected. No patient showed any persistent adverse cognitive effects as assessed by the MMSE-KC after ECT.\n\nCase briefings\nDuring the course of ECT, six of the seven patients were maintained on clozapine with no significant changes in dose, and their blood clozapine levels were consistently over 350 ng/mL. One patient (case 5) showed post-ECT irritability manifesting as transient disorientation of time and a mild delirious state, which seemed to occur at the high electrical dose, level 7 (432 mC) and was relieved by benzodiazepines. Reducing her dose of clozapine and the electrical stimulus level, and providing hyperventilation for a few minutes produced successful seizures without causing delirious events afterwards. Despite the difficulties she had, she responded well to ECT and experienced a reduction in PANSS score of 28.1%. Four patients (cases 1, 3, 4, and 6) complained of mild headaches and temporary disorientations of time which were easily relieved with painkillers and bed rest. Only one patient (case 2) did not respond at all to 12 sessions of ECT and had no change in PANSS score. His PANSS profile was the negative type put forward by Kay et al.,30 and his negative scale score was not changed by ECT. The total score on the PANSS is a trade-off between the positive and general psychopathology scales. The other six patients were all positive type.\n\nDISCUSSION\nThis study is a case series report using a retrospective EMR review that aimed to explore the efficacy and safety of ECT in patients with clozapine-resistant schizophrenia. We first ruled out the possibility of pseudo-resistance1 by ensuring that blood clozapine levels of patients were maintained above 350 ng/mL for a sufficient period of time.45 On average, the seven patients experienced clinical benefits from ECT, with a mean reduction of 25.5% on the PANSS, without serious adverse events. The clinical remission rate was 71.4%, which corresponds with the results of previous studies. Kho et al.18 reported a 30% reduction in PANSS score in 8 (72.7%) out of 11 patients with clozapine-resistant schizophrenia treated with ECT, and Petrides et al.4 showed a 20% reduction in PANSS score in 12 (60%) out of 20 patients. The present study provides further evidence for the benefits of ECT augmentation on patients with clozapine-resistant schizophrenia and shows that ECT causes no persistent adverse cognitive events,1 even though the mean dosages and blood levels of clozapine were not substantially changed during the course of ECT. Reductions in PANSS score were associated with total number of ECT sessions, the last stimulus level, and blood clozapine levels before ECT.\n\nIn this report, the negative subscale on the PANSS by Kay et al.,30 was not significantly reduced by ECT; one patient (case 2), who did not respond to ECT at all, was classified as the negative type. The average score on the negative subscale in all seven patients was not statistically reduced (data not shown). This is in agreement with other studies that showed that patients who responded to ECT were less likely to be negative type,313233 and that there is less of a reduction in the negative subscale compared with the positive and general subscales following ECT.34 However, the seven patients in this study had chronic schizophrenia and their psychotic symptoms were resistant to various antipsychotic medications, including clozapine, which they had taken for 3.9 (±3.4) years on average. It has been suggested that long-term treatment may be required to observe improvements in negative symptoms.35 Therefore, this study may have been insufficiently long to evaluate improvements in negative symptoms following a course of ECT as the average course of ECT took place over only 45.4 (±18.9) days.\n\nSome limitations to this study should be noted. First, this is a case series report with only seven patients, so the findings are not necessarily generalizable, although the findings of this study do avoid the crucial drawback, common to other studies, of patients possibly being underdosed with clozapine.6 A larger number of cases and studies with more participants are needed to validate the study findings. Second, this study also did not have controls such as sham ECT or combinations of other pharmacotherapies. Third, nearly half (3/7) of the patients were taking other antipsychotic drugs along with clozapine, which may have afffected the usefulness of clozapine. However, chlorpromazine-equivalent dosages were not statistically different before and after ECT. We will attempt to rule out the effects of other antipsychotic drugs in our next study. Fourth, this report did not trace clinical courses of patients for a long period of time after ECT. Further studies will be required to determine whether the effects of ECT augmentation will persist and prevent the recurrence of psychotic symptoms. Even though this was a retrospective study conducted by reviewing the EMR, our results strongly suggest that ECT augmentation could be a favorable strategy for the treatment of clozapine-resistant schizophrenia.\n\nAcknowledgments\nThis research was supported by Free Research Project (S-2015-G0041-00058), Dongguk University Medical Center and the Institute of Clinical Psychopharmacology, Dongguk University College of Medicine.\n\nTable 1 Demographic and clinical characteristics of the study subjects\nNumbers are mean±SD except marriage and positive family history\n\nTable 2 PANSS score and clozapine/norclozapine dosage and blood levels before and after ECT\n*p-value<0.05 by paired t-test. PANSS: Positive and Negative Syndrome Scale, ECT: electroconvulsive therapy\n\nTable 3 ECT parameters\n*mean duration. Stimulus levels: 3, 80 mC; 4, 128 mC; 5, 192 mC; 6, 288 mC. ECT: electroconvulsive therapy\n==== Refs\n1 Dold M Leucht S Pharmacotherapy of treatment-resistant schizophrenia: a clinical perspective Evid Based Ment Health 2014 17 33 37 24713315 \n2 Juarez-Reyes MG Shumway M Battle C Bacchetti P Hansen MS Hargreaves WA Effects of stringent criteria on eligibility for clozapine among public mental health clients Psychiatr Serv 1995 46 801 806 7583481 \n3 Meltzer HY Treatment-resistant schizophrenia--the role of clozapine Curr Med Res Opin 1997 14 1 20 9524789 \n4 Petrides G Malur C Braga RJ Bailine SH Schooler NR Malhotra AK Electroconvulsive therapy augmentation in clozapine-resistant schizophrenia: a prospective, randomized study Am J Psychiatry 2015 172 52 58 25157964 \n5 Remington G Saha A Chong SA Shammi C Augmentation strategies in clozapine-resistant schizophrenia CNS Drugs 2005 19 843 872 16185094 \n6 Miyamoto S Jarskog LF Fleischhacker WW New therapeutic approaches for treatment-resistant schizophrenia: a look to the future J Psychiatr Res 2014 58 1 6 25070124 \n7 Kerwin RW Bolonna A Management of clozapine-resistant schizophrenia Adv Psychiatr Treat 2005 11 101 106 \n8 Shiloh R Zemishlany Z Aizenberg D Radwan M Schwartz B Dorfman-Etrog P Sulpiride augmentation in people with schizophrenia partially responsive to clozapine. A double-blind, placebo-controlled study Br J Psychiatry 1997 171 569 573 9519099 \n9 Kerwin R From pharmacological profiles to clinical outcomes Int Clin Psychopharmacol 2000 15 Suppl 4 S1 S4 \n10 Fink M Clozapine and electroconvulsive therapy Arch Gen Psychiatry 1990 47 290 291 1968331 \n11 Masoudzadeh A Khalilian AR Comparative study of clozapine, electroshock and the combination of ECT with clozapine in treatment-resistant schizophrenic patients. Pakistan Journal of Biological Sciences Pak J Biol Sci 2007 10 4287 4290 19086588 \n12 Williams L Newton G Roberts K Finlayson S Brabbins C Clozapine-resistant schizophrenia: a positive approach Br J Psychiatry 2002 181 184 187 12204919 \n13 Friedel RO The combined use of neuroleptics and ECT in drug resistant schizophrenic patients Psychopharmacol Bull 1986 22 928 930 3797594 \n14 Safferman AZ Munne R Combining Clozapine with ECT Convuls Ther 1992 8 141 143 11941161 \n15 Benatov R Sirota P Megged S Neuroleptic-resistant schizophrenia treated with clozapine and ECT Convuls Ther 1996 12 117 121 8744173 \n16 Bhatia SC Bhatia SK Gupta S Concurrent administration of clozapine and ECT: a successful therapeutic strategy for a patient with treatment-resistant schizophrenia J ECT 1998 14 280 283 9871852 \n17 Kales HC Dequardo JR Tandon R Combined electroconvulsive therapy and clozapine in treatment-resistant schizophrenia Prog Neuropsychopharmacol Biol Psychiatry 1999 23 547 556 10378236 \n18 Kho KH Blansjaar BA de Vries S Babuskova D Zwinderman AH Linszen DH Electroconvulsive therapy for the treatment of clozapine nonresponders suffering from schizophrenia--an open label study Eur Arch Psychiatry Clin Neurosci 2004 254 372 379 15538604 \n19 Grover S Hazari N Kate N Combined use of clozapine and ECT: a review Acta Neuropsychiatr 2015 27 131 142 25697225 \n20 Havaki-Kontaxaki BJ Ferentinos PP Kontaxakis VP Paplos KG Soldatos CR Concurrent administration of clozapine and electroconvulsive therapy in clozapine-resistant schizophrenia Clin Neuropharmacol 2006 29 52 56 16518135 \n21 Kupchik M Spivak B Mester R Reznik I Gonen N Weizman A Combined electroconvulsive-clozapine therapy Clin Neuropharmacol 2000 23 14 16 10682225 \n22 Lally J Tully J Robertson D Stubbs B Gaughran F MacCabe JH Augmentation of clozapine with electroconvulsive therapy in treatment resistant schizophrenia: a systematic review and meta-analysis Schizophr Res 2016 171 215 224 26827129 \n23 Porcelli S Balzarro B Serretti A Clozapine resistance: augmentation strategies Eur Neuropsychopharmacol 2012 22 165 182 21906915 \n24 Muscatello MR Bruno A De Fazio P Segura-Garcia C Pandolfo G Zoccali R Augmentation strategies in partial responder and/or treatment-resistant schizophrenia patients treated with clozapine Expert Opin Pharmacother 2014 15 2329 2345 25284216 \n25 Buchanan RW Kreyenbuhl J Kelly DL Noel JM Boggs DL Fischer BA The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements Schizophr Bull 2010 36 71 93 19955390 \n26 Leucht S Kissling W Davis JM The PANSS should be rescaled Schizophr Bull 2010 36 461 462 20357133 \n27 Hwang SS Chang JS Lee KY Kim SH Ahn YM Kim YS Causal model of insight and psychopathology based on the PANSS factors: 1-year cross-sectional and longitudinal revalidation Int Clin Psychopharmacol 2009 24 189 198 19521247 \n28 Lee JH Lee KU Lee DY Kim KW Jhoo JH Kim JH Development of the Korean version of the Consortium to Establish a Registry for Alzheimer's Disease Assessment Packet (CERAD-K): clinical and neuropsychological assessment batteries J Gerontol B Psychol Sci Soc Sci 2002 57 P47 P53 11773223 \n29 Coffey CE Lucke J Weiner RD Krystal AD Aque M Seizure threshold in electroconvulsive therapy: I. Initial seizure threshold Biol Psychiatry 1995 37 713 720 7640326 \n30 Kay SR Flszbein A Opfer LA The Positive and Negative Syndrome Scale (PANSS) for schizophrenia Schizophr Bull 1987 13 261 276 3616518 \n31 Chanpattana W Chakrabhand MLS Kongsakon R Techakasem P Buppanharun W Short-term effect of combined ECT and neuroleptic therapy in treatment-resistant schizophrenia J ECT 1999 15 129 139 10378152 \n32 Chanpattana W Chakrabhand ML Combined ECT and neuroleptic therapy in treatment: prediction of outcome Psychiatry Res 2001 105 107 115 11740980 \n33 Payne NA Prudic J Electroconvulsive therapy: Part I. A perspective on the evolution and current practice of ECT J Psychiatr Pract 2009 15 346 368 19820553 \n34 Pawelczyk T Kołodziej-Kowalska E Pawełczyk A Rabe-Jabłon´ska J Augmentation of antipsychotics with electroconvulsive therapy in treatment-resistant schizophrenia patients with dominant negative symptoms: a pilot study of effectiveness Neuropsychobiology 2014 70 158 164 25358377 \n35 Schooler NR Buchanan RW Laughren T Leucht S Nasrallah HA Potkin SG Defining therapeutic benefit for people with schizophrenia: focus on negative symptoms Schizophr Res 2015 162 169 174 25579053\n\n",
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"issue": "14(1)",
"journal": "Psychiatry investigation",
"keywords": "Augmentation; Clozapine-resistant schizophrenia; Electroconvulsive therapy",
"medline_ta": "Psychiatry Investig",
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"nlm_unique_id": "101242994",
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"title": "Effectiveness of Electroconvulsive Therapy Augmentation on Clozapine-Resistant Schizophrenia.",
"title_normalized": "effectiveness of electroconvulsive therapy augmentation on clozapine resistant schizophrenia"
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"abstract": "A 63-year-old African American man was diagnosed with prostate cancer by biopsy for elevated prostrate-specific antigen. He was initially treated with radiation and then with intermittent androgen ablation because of biochemical relapse. He continued to have rising prostrate-specific antigen and he was thought to have hormone-resistant prostate cancer. So he received chemotherapy with docetaxel. He returned to the hospital within 3 days of the first cycle of treatment with fever, altered mental status, acute renal failure, anemia, and thrombocytopenia. He was started on empiric antibiotics but his cultures from most sites were negative. His platelets dropped from 119,000 to a nadir of 10,000 during hospital stay. Patient had microangiopathic hemolytic anemia suggested by elevated lactate dehydrogenase, decreased haptoglobin, increased indirect bilirubin, and schistocytes in peripheral smear. His coagulation profile was normal. A presumptive diagnosis of chemotherapy-related thrombotic thrombocytopenic purpura (TTP)-hemolytic uremic syndrome was made and patient was started on fresh frozen plasma infusion and hemodialysis for renal failure and steroids. Patient improved symptomatically, platelet count was stable, and lactate dehydrogenase was in a declining trend after 5 days of fresh frozen plasma infusion. The ADAMS TS-13 activity was 37% suggestive of chemotherapy-related TTP. Patient also had sickle cell beta thalassemia disease and glucose 6 phosphate dehydrogenase deficiency. Docetaxel, like some other vascular endothelial growth factor inhibiting chemotherapeutic drugs may cause TTP-hemolytic uremic syndrome.",
"affiliations": "Mount Sinai Hospital Medical Center/The Chicago Medical School at Rosalind Franklin University of Medicine and Science, Chicago, IL 60608, USA. shresthaanuj@yahoo.com",
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"title": "Docetaxel-induced thrombotic thrombocytopenic purpura/hemolytic uremic syndrome-related complex in a patient with metastatic prostate cancer?",
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"abstract": "Delayed recovery/awakening/ emergence can occur under anaesthesia and is multifactorial, could be drug or non drug related. Similarly, we report a case of delayed recovery in a 68-year-old patient, for laparoscopic cholecystectomy, a known case of hypertension, bronchial asthma and hypothyroidism. Preoperatively, she was optimised for her medical disorders; however, she had delayed recovery from general anaesthesia. The delayed recovery, often, would be expected in a case of hypothyroidism, however in our patient it was found to be associated with inadvertent hypokalemia.",
"affiliations": "Associate Professor, Department of Anaesthesiology, ESI PGI-MSR, MGM Hospital , Parel, Mumbai-12, Maharashtra, India .;Professor, Department of Anaesthesiology, ESI PGI-MSR, MGM Hospital , Parel, Mumbai-12, Maharashtra, India .;Senior Resident, Department of Anaesthesiology, ESI PGI-MSR, MGM Hospital , Parel, Mumbai-12, Maharashtra, India .;Junior Resident, Department of Anaesthesiology, ESI PGI-MSR, MGM Hospital , Parel, Mumbai-12, Maharashtra, India .",
"authors": "More|Preeti|P|;Laheri|Vandana V|VV|;Waigankar|Tejasi|T|;Wagh|Charchill|C|",
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"title": "Delayed recovery from anaesthesia in a patient with optimised hypothyroidism and incidental hypokalemia.",
"title_normalized": "delayed recovery from anaesthesia in a patient with optimised hypothyroidism and incidental hypokalemia"
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"abstract": "An 81-year-old man was admitted for evaluation of progressive dyspnea over the previous 4 weeks. He initially noticed dyspnea when walking briskly, but this progressed to dyspnea after only walking several feet. He also endorsed a dry cough without hemoptysis. Review of systems revealed a history of intermittent low-grade fevers, malaise, and nonexertional chest pain. He had been treated for a urinary tract infection twice over the past 3 weeks with prolonged courses of levofloxacin; while his urinary symptoms improved, his respiratory symptoms did not. Medical history was pertinent for lung adenocarcinoma stage IIIb status post right upper lobectomy 10 years prior with recurrence of lung adenocarcinoma in the right lower lobe and was recently diagnosed with stage 1 primary pancreatic adenocarcinoma. He had been a longstanding tobacco smoker but quit two decades ago. Treatment of his recurrent lung adenocarcinoma included four cycles of carboplatin-pemetrexed over the preceding 5 months and intensity-modulated radiation therapy totaling 60 Gy over 30 fractions to his right lower lobe 2 months prior to presentation. He also received stereotactic body radiation therapy totaling 45 Gy over five fractions to his pancreas.",
"affiliations": "Division of Pulmonary and Critical Care, University of Maryland School of Medicine, Baltimore, MD. Electronic address: atul.mehta@som.umaryland.edu.;Department of Medicine, University of Maryland School of Medicine, Baltimore, MD.;Division of Pulmonary and Critical Care, University of Maryland School of Medicine, Baltimore, MD.",
"authors": "Mehta|Atul K|AK|;Khan|Zulqarnain|Z|;Deepak|Janaki|J|",
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"mesh_terms": "D000230:Adenocarcinoma; D000369:Aged, 80 and over; D004417:Dyspnea; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D010190:Pancreatic Neoplasms; D017564:Radiation Pneumonitis; D050397:Radiotherapy, Intensity-Modulated; D014057:Tomography, X-Ray Computed",
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"pubdate": "2019-09",
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"title": "An 81-Year-Old Man With Shortness of Breath After Chemotherapy and Radiation Therapy for Lung Cancer.",
"title_normalized": "an 81 year old man with shortness of breath after chemotherapy and radiation therapy for lung cancer"
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... |
{
"abstract": "Ciprofloxacin and fluconazole combination therapy is frequently used as prophylaxis for, and treatment of, infections in patients with haematological malignancies. However, both drugs are known to prolong the heart rate-corrected QT (QTc) interval, which is a serious risk factor for torsade de pointes (TdP). Therefore, the aim of the current study was to assess the prevalence of QTc prolongation during ciprofloxacin and fluconazole use. The secondary objective was to determine associated risk factors of QTc prolongation in these patients.\n\n\n\nA prospective observational study was performed in patients admitted to the Erasmus University Medical Centre and treated with ciprofloxacin and fluconazole. A 12-lead electrocardiogram (ECG) was recorded at the estimated time to peak concentration (Tmax ) for the last added drug. The main outcome was the proportion of patients with QTc prolongation during treatment. Data on the following potential risk factors were collected: patient characteristics, serum electrolyte levels, dosage of ciprofloxacin and fluconazole, renal and liver function and concomitant use of other QTc-prolonging drugs and cytochrome P450 3A4 inhibitors.\n\n\n\nA total of 170 patients were included, of whom 149 (87.6%) were treated for haematological malignancies. The prevalence of QTc prolongation was 4.7%. No risk factors were found to be associated with QTc prolongation. The QTc interval increased by 10.7 ms [95% confidence interval (CI) 7.2, 14.1 ms] during ciprofloxacin and fluconazole combination therapy.\n\n\n\nThe prevalence of QTc prolongation in patients using ciprofloxacin and fluconazole is low compared with the prevalence in the general population, which varies from 5% to 11%. In addition, no risk factors were found. Given the low prevalence, routine ECG monitoring in patients on this therapy should be reconsidered.",
"affiliations": "Department of Hospital Pharmacy, Erasmus University Medical Centre, Rotterdam, The Netherlands.;Erasmus University, Rotterdam, The Netherlands.;Department of Cardiology, Erasmus University Medical Centre, Rotterdam, The Netherlands.;Department of Internal Medicine, IJsselland Hospital, Capelle a/d Ijssel, The Netherlands.;Department of Hospital Pharmacy, Erasmus University Medical Centre, Rotterdam, The Netherlands.;Pharmacy Foundation of Haarlem Hospitals, Haarlem, The Netherlands.;Department of Haematology, Erasmus University Medical Centre, Rotterdam, The Netherlands.;Department of Hospital Pharmacy, Erasmus University Medical Centre, Rotterdam, The Netherlands.;Department of Hospital Pharmacy, Erasmus University Medical Centre, Rotterdam, The Netherlands.",
"authors": "Berger|Florine A|FA|0000-0003-2723-8919;Monadian|Nico|N|;de Groot|Natasja M S|NMS|0000-0002-0259-6691;Santbergen|Bart|B|;van der Sijs|Heleen|H|;Becker|Matthijs L|ML|0000-0003-0054-7498;Broers|Annoek E C|AEC|;van Gelder|Teun|T|0000-0001-5980-6947;van den Bemt|Patricia M L A|PMLA|0000-0003-1418-5520",
"chemical_list": "D002939:Ciprofloxacin; D015725:Fluconazole",
"country": "England",
"delete": false,
"doi": "10.1111/bcp.13457",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0306-5251",
"issue": "84(2)",
"journal": "British journal of clinical pharmacology",
"keywords": "QTc prolongation; antibiotics; drug interactions; pharmacovigilance",
"medline_ta": "Br J Clin Pharmacol",
"mesh_terms": "D002939:Ciprofloxacin; D004359:Drug Therapy, Combination; D004562:Electrocardiography; D005260:Female; D015725:Fluconazole; D006339:Heart Rate; D006801:Humans; D008133:Long QT Syndrome; D008297:Male; D008875:Middle Aged; D008991:Monitoring, Physiologic; D015995:Prevalence; D011446:Prospective Studies; D012307:Risk Factors",
"nlm_unique_id": "7503323",
"other_id": null,
"pages": "369-378",
"pmc": null,
"pmid": "29057492",
"pubdate": "2018-02",
"publication_types": "D016428:Journal Article; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": "27896662;15208785;14999113;15888497;23229485;24827793;20142454;20297862;1542320;26745817;28275963;18319048;16869820;17109296;17251531;8522713;4758544;27150690;12505572;18598957;10754424;10560690;23716032;10577320;21258094;11765299;18462182;26650441;8690825;12495173;29057492;26920666;11922236;16357358;15136301;18454341;16554806;16628725;14638563;16148284;11302406;26464438;11994029",
"title": "QTc prolongation during ciprofloxacin and fluconazole combination therapy: prevalence and associated risk factors.",
"title_normalized": "qtc prolongation during ciprofloxacin and fluconazole combination therapy prevalence and associated risk factors"
} | [
{
"companynumb": "NL-MYLANLABS-2018M1003500",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CIPROFLOXACIN"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nA species of hawthorn, Crataegus mexicana (tejocote), has been marketed as a weight-loss supplement that is readily available for purchase online. While several hawthorn species have shown clinical benefit in the treatment of heart failure owing to their positive inotropic effects, little is known about hawthorn, and tejocote in particular, when consumed in excess. We describe a case of tejocote exposure from a weight-loss supplement resulting in severe cardiotoxicity.\n\n\nMETHODS\nA healthy 16-year-old girl presented to an emergency department after ingesting eight pieces of her mother's tejocote root weight-loss supplement. At arrival, she was drowsy, had active vomiting and diarrhea, and had a heart rate of 57 with normal respirations. Her initial blood chemistries were unremarkable, except for an elevated digoxin assay of 0.7 ng/mL (therapeutic range 0.5-2.0 ng/mL). All other drug screens were negative. She later developed severe bradycardia and multiple episodes of hypopnea that prompted a transfer to our institution, a tertiary pediatric hospital. Her ECG demonstrated a heart rate of 38 and Mobitz type 1 second-degree heart block. She was subsequently given two vials of Digoxin Immune Fab due to severe bradycardia in the setting of suspected digoxin-like cardiotoxicity after discussion with the regional poison control center. No clinical improvement was observed. Approximately 29 hours after ingestion, subsequent ECGs demonstrated a return to normal sinus rhythm, and her symptoms resolved.\n\n\nCONCLUSIONS\nTejocote root toxicity may cause dysrhythmias and respiratory depression. Similar to other species of hawthorn, tejocote root may cross-react with some commercial digoxin assays, resulting in a falsely elevated level.",
"affiliations": "Department of Emergency Medicine, University of Washington, 325 9th Avenue, Box 359702, Seattle, WA, 98104, USA. kgpalmer@uw.edu.;Department of Emergency Medicine, University of Washington, 325 9th Avenue, Box 359702, Seattle, WA, 98104, USA.;Pediatric Critical Care Medicine, Seattle Children's Hospital, University of Washington, 4800 Sand Point Way NE, Mailstop: FA.2.112, Seattle, WA, 98105, USA.;Division of Emergency Medicine, Seattle Children's Hospital, University of Washington, MB.7.520 - Emergency Medicine , 4800 Sand Point Way NE, Seattle, WA, 98105, USA.;Division of Emergency Medicine, Seattle Children's Hospital, University of Washington, MB.7.520 - Emergency Medicine , 4800 Sand Point Way NE, Seattle, WA, 98105, USA.",
"authors": "Palmer|Katherine G|KG|;Lebin|Jacob A|JA|;Cronin|Michael T|MT|;Mazor|Suzan S|SS|;Burns|Rebekah A|RA|",
"chemical_list": "D007140:Immunoglobulin Fab Fragments; D010936:Plant Extracts; D004077:Digoxin",
"country": "United States",
"delete": false,
"doi": "10.1007/s13181-019-00727-w",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-9039",
"issue": "15(4)",
"journal": "Journal of medical toxicology : official journal of the American College of Medical Toxicology",
"keywords": "Cardiovascular toxicity; Crataegus; Digoxin; Hawthorn; Tejocote",
"medline_ta": "J Med Toxicol",
"mesh_terms": "D000293:Adolescent; D066126:Cardiotoxicity; D027825:Crataegus; D019587:Dietary Supplements; D004077:Digoxin; D005260:Female; D006801:Humans; D007140:Immunoglobulin Fab Fragments; D010936:Plant Extracts; D018517:Plant Roots; D015431:Weight Loss",
"nlm_unique_id": "101284598",
"other_id": null,
"pages": "295-298",
"pmc": null,
"pmid": "31407210",
"pubdate": "2019-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12043949;10532672;16752934;29741399;19019730;17416888;28082789;29080984;18254076;20670141",
"title": "Crataegus mexicana (Tejocote) Exposure Associated with Cardiotoxicity and a Falsely Elevated Digoxin Level.",
"title_normalized": "crataegus mexicana tejocote exposure associated with cardiotoxicity and a falsely elevated digoxin level"
} | [
{
"companynumb": "US-BTG-201900157",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OVINE DIGOXIN IMMUNE FAB"
},
"drugadditional": "3",
... |
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