article dict | reports listlengths 1 3.97k |
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{
"abstract": "Diaphragm flutter is a rare disorder defined by dyspnea and often thoracoabdominal pain associated with rapid rhythmic involuntary contractions of the diaphragm with no effective treatment. A 35-year-old woman's flutter was triggered by increasing the depth of breathing and by (electrical) stimulation of the diaphragm. Medical therapy, phrenic nerve crush, and diaphragm pacer stimulation were ineffective. Since increasing diaphragm activity was a trigger, resting the diaphragm was tried. A manual resuscitator and, subsequently, mouthpiece and nasal noninvasive ventilatory support (NVS) instantaneously halted the flutter for 3 months and almost instantaneously for another 6 months. For 16 months, it has continued to halt flutter with rare episodes when getting out of bed that resolve with up to 40 minutes of NVS. To our knowledge, this is the first case of idiopathic diaphragmatic flutter for which diaphragm rest was used as successful treatment with no adverse effects. This should be tried for future cases.",
"affiliations": "Department of Physical Medicine and Rehabilitation, Rutgers New Jersey Medical School, Newark, NJ.;Petrona Villegas de Cordero Hospital, San Fernando, Buenos Aires, Argentina.;Department of Physical Medicine and Rehabilitation, Rutgers New Jersey Medical School, Newark, NJ. Electronic address: bachjr@njms.rutgers.edu.;Department of Physical Medicine and Rehabilitation, Rutgers New Jersey Medical School, Newark, NJ.;Department of Physical Medicine and Rehabilitation, Rutgers New Jersey Medical School, Newark, NJ.",
"authors": "Chiou|Michael|M|;Herrero|María Victoria|MV|;Bach|John R|JR|;Cole|Jeffrey L|JL|;Gonzales|Enrique Luis|EL|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.chest.2017.01.034",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0012-3692",
"issue": "151(4)",
"journal": "Chest",
"keywords": "diaphragm pacing; diaphragmatic flutter; noninvasive ventilatory support; treatment",
"medline_ta": "Chest",
"mesh_terms": "D000328:Adult; D003937:Diagnosis, Differential; D003964:Diaphragm; D004576:Electromyography; D005260:Female; D005471:Fluoroscopy; D006801:Humans; D009207:Myoclonus; D010791:Phrenic Nerve; D012132:Respiratory Muscles",
"nlm_unique_id": "0231335",
"other_id": null,
"pages": "e69-e71",
"pmc": null,
"pmid": "28390638",
"pubdate": "2017-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Treatment of Idiopathic Diaphragm Flutter: A Case Study.",
"title_normalized": "treatment of idiopathic diaphragm flutter a case study"
} | [
{
"companynumb": "US-ACCORD-058111",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOBENZAPRINE"
},
"drugadditional": "3",
"... |
{
"abstract": "Autologous stem cell transplantation (ASCT), intensifying anti-leukemic effects without significant treatment-related mortality (TRM), is particularly appealing in AML with favorable genetic/molecular profile. This study retrospectively evaluated the outcomes of post-remission treatment in consecutive favorable-risk AML patients. Sixty-six patients were included: 32 had mutated NPM1/wild-type FLT-ITD, 16 had t(8:21) and 18 - inv(16). Forty patients received chemotherapy alone, 26 underwent ASCT upfront. In time-dependent analysis, the ASCT group demonstrated higher relapse-free (RFS) (p = .001) and overall survivals (OS) (p = .0007). The 1-year RFS and OS were 44.2% vs 88% and 71% vs 96% for chemotherapy and ASCT, respectively. The corresponding TRM was 4/40 (10.0%) and 0/26 (0%), with relapse rates of 70.0% and 19.2% (p = .0002). In multivariate analysis, ASCT was associated with superior OS and RFS. In conclusion, ASCT offers significantly superior RFS and OS in favorable-risk AML in first complete remission. These data support the recent resurgence of interest in ASCT for AML.",
"affiliations": "Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus , Haifa , Israel.;Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus , Haifa , Israel.;Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus , Haifa , Israel.;Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus , Haifa , Israel.;Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus , Haifa , Israel.;Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus , Haifa , Israel.;Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus , Haifa , Israel.;Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus , Haifa , Israel.;Department of Statistics, University of Haifa , Haifa , Israel.;Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus , Haifa , Israel.;Department of Human Genetics, Rambam Health Care Campus , Haifa , Israel.;Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus , Haifa , Israel.;Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus , Haifa , Israel.",
"authors": "Beyar-Katz|Ofrat|O|;Lavi|Noa|N|;Ringelstein-Harlev|Shimrit|S|;Henig|Israel|I|;Yehudai-Ofir|Dana|D|;Haddad|Nuhad|N|;Fineman|Riva|R|;Ofran|Yishai|Y|0000-0002-5521-1337;Nov|Yuval|Y|;Sahar|Dvora|D|;Moustafa-Hawash|Nivin|N|;Rowe|Jacob M|JM|;Zuckerman|Tsila|T|0000-0002-6204-977X",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1080/10428194.2019.1594214",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1026-8022",
"issue": "60(10)",
"journal": "Leukemia & lymphoma",
"keywords": "Acute myeloid leukemia (AML); NPM1 mutation; autologous SCT (ASCT); core-binding factor (CBF) translocation",
"medline_ta": "Leuk Lymphoma",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D003131:Combined Modality Therapy; D019468:Disease Management; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D060828:Induction Chemotherapy; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D000090243:Nucleophosmin; D011379:Prognosis; D012189:Retrospective Studies; D014182:Transplantation, Autologous; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9007422",
"other_id": null,
"pages": "2449-2456",
"pmc": null,
"pmid": "30943060",
"pubdate": "2019-10",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Superior outcome of patients with favorable-risk acute myeloid leukemia using consolidation with autologous stem cell transplantation.",
"title_normalized": "superior outcome of patients with favorable risk acute myeloid leukemia using consolidation with autologous stem cell transplantation"
} | [
{
"companynumb": "IL-PFIZER INC-2019481884",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYTARABINE"
},
"drugadditional": "3",
... |
{
"abstract": "Fungal prosthetic valve endocarditis (PVE) is rare and carries a high mortality rate. While uncommon, fungal endocarditis in transcatheter aortic valves has been reported. We present a unique case of Candida parapsilosis fungal PVE in a patient with a transcatheter pulmonary valve replacement.",
"affiliations": "Division of Cardiology, Department of Medicine, UCLA Medical Center, Los Angeles, CA, USA.;Division of Infectious Diseases, Department of Medicine, UCLA Medical Center, Los Angeles, CA, USA.;Division of Cardiology, Department of Medicine, UCLA Medical Center, Los Angeles, CA, USA.;Division of Cardiology, Department of Medicine, UCLA Medical Center, Los Angeles, CA, USA.",
"authors": "Tan|Weiyi|W|0000-0003-3509-322X;Dora|Amy|A|;Lluri|Gentian|G|;Aboulhosn|Jamil|J|",
"chemical_list": "D000935:Antifungal Agents; D000077336:Caspofungin",
"country": "United States",
"delete": false,
"doi": "10.1177/2150135119883624",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2150-1351",
"issue": "11(1)",
"journal": "World journal for pediatric & congenital heart surgery",
"keywords": null,
"medline_ta": "World J Pediatr Congenit Heart Surg",
"mesh_terms": "D000935:Antifungal Agents; D000074429:Candida parapsilosis; D002177:Candidiasis; D000077336:Caspofungin; D003937:Diagnosis, Differential; D004696:Endocarditis; D005260:Female; D019918:Heart Valve Prosthesis Implantation; D006801:Humans; D011183:Postoperative Complications; D016459:Prosthesis-Related Infections; D011666:Pulmonary Valve Stenosis; D018615:Ultrasonography, Doppler, Color; D055815:Young Adult",
"nlm_unique_id": "101518415",
"other_id": null,
"pages": "112-113",
"pmc": null,
"pmid": "31658874",
"pubdate": "2020-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Candida Parapsilosis Endocarditis Following Transcatheter Pulmonary Valve Implantation.",
"title_normalized": "candida parapsilosis endocarditis following transcatheter pulmonary valve implantation"
} | [
{
"companynumb": "US-009507513-2001USA005985",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CASPOFUNGIN ACETATE"
},
"drugadditional": nu... |
{
"abstract": "Vascular toxicity following the use of vinblastine, bleomycin, and cisplatin (VBP) combination chemotherapy has been described. This report gives details of five patients who suffered acute life-threatening vascular events following such a chemotherapy regimen for germ cell tumours. In three of the cases no evidence of tumour was found at autopsy. Both acute and long-term vascular toxicity were seen. Large artery vascular disease may result from synergistic toxicity of the drugs comprising the regimen. These cases, with an additional sixteen collected from the literature, suggest that major vascular disease is a significant side-effect of the VBP regimen.",
"affiliations": null,
"authors": "Samuels|B L|BL|;Vogelzang|N J|NJ|;Kennedy|B J|BJ|",
"chemical_list": "D001761:Bleomycin; D014747:Vinblastine; D002945:Cisplatin",
"country": "England",
"delete": false,
"doi": "10.1111/j.1365-2605.1987.tb00204.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0105-6263",
"issue": "10(1)",
"journal": "International journal of andrology",
"keywords": null,
"medline_ta": "Int J Androl",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001761:Bleomycin; D002318:Cardiovascular Diseases; D002945:Cisplatin; D006801:Humans; D008297:Male; D008875:Middle Aged; D009373:Neoplasms, Germ Cell and Embryonal; D009919:Orchiectomy; D013736:Testicular Neoplasms; D014747:Vinblastine",
"nlm_unique_id": "8000141",
"other_id": null,
"pages": "363-9",
"pmc": null,
"pmid": "2438227",
"pubdate": "1987-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Vascular toxicity following vinblastine, bleomycin, and cisplatin therapy for germ cell tumours.",
"title_normalized": "vascular toxicity following vinblastine bleomycin and cisplatin therapy for germ cell tumours"
} | [
{
"companynumb": "US-PFIZER INC-2021053524",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BLEOMYCIN SULFATE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nApproximately 10% of all Graves' disease cases are triiodothyronine (T3)-predominant. T3-predominance is characterized by higher T3 levels than thyroxine (T4) levels. Thyroid stimulating hormone receptor autoantibody (TRAb) levels are higher in T3-predominant Graves' disease cases than in non-T3-predominant Graves' disease cases. Treatment with oral drugs is difficult. Here, we report a case of fetal goiter in a pregnant woman with T3-predominant Graves' disease.\n\n\nMETHODS\nA 31-year-old woman had unstable thyroid function during the third trimester of pregnancy, making it impossible to reduce her dosage of antithyroid medication. She was admitted to our hospital at 34 weeks of gestation owing to hydramnios and signs of threatened premature labor, and fetal goiter (thyromegaly) was detected. The dose of her antithyroid medication was reduced, based on the assumption that it had migrated to the fetus. Subsequently, the fetal goiter decreased in size, and the hydramnios improved. The patient underwent elective cesarean delivery at 36 weeks and 5 days of gestation. The infant presented with temporary symptoms of hyperthyroidism that improved over time.\n\n\nCONCLUSIONS\nThe recommended perinatal management of Graves' disease is to adjust free T4 within a range from the upper limit of normal to a slightly elevated level in order to maintain the thyroid function of the fetus. However, in T3-predominant cases, free T4 levels may drop during the long-term course of the pregnancy owing to attempts to control the mother's symptoms of thyrotoxicosis. Little is known about the perinatal management and appropriate therapeutic strategy for T3-predominant cases and fetal goiter. Therefore, further investigation is necessary.",
"affiliations": "Department of Obstetrics and Gynecology, Akita University Hospital, 1-1-1 Hondo, Akita, 010-8543, Japan. fujishimaa@med.akita-u.ac.jp.;Department of Obstetrics and Gynecology, Akita University Hospital, 1-1-1 Hondo, Akita, 010-8543, Japan.;Department of Obstetrics and Gynecology, Akita University Hospital, 1-1-1 Hondo, Akita, 010-8543, Japan.;Department of Obstetrics and Gynecology, Akita University Hospital, 1-1-1 Hondo, Akita, 010-8543, Japan.;Department of Obstetrics and Gynecology, Akita University Hospital, 1-1-1 Hondo, Akita, 010-8543, Japan.;Department of Obstetrics and Gynecology, Akita University Hospital, 1-1-1 Hondo, Akita, 010-8543, Japan.;Department of Neonatal Medicine, Akita University Hospital, Akita, Japan.;Department of Diabetes and Endocrinology, Akita University Hospital, Akita, Japan.;Department of Obstetrics and Gynecology, Akita University Hospital, 1-1-1 Hondo, Akita, 010-8543, Japan.",
"authors": "Fujishima|Akiko|A|http://orcid.org/0000-0002-8609-484X;Sato|Akira|A|;Miura|Hiroshi|H|;Shimoda|Yuki|Y|;Kameyama|Saeko|S|;Ariake|Chika|C|;Adachi|Hiroyuki|H|;Fukuoka|Yuki|Y|;Terada|Yukihiro|Y|",
"chemical_list": "D013956:Antithyroid Agents; D014284:Triiodothyronine; D013974:Thyroxine",
"country": "England",
"delete": false,
"doi": "10.1186/s12884-020-03035-2",
"fulltext": "\n==== Front\nBMC Pregnancy Childbirth\nBMC Pregnancy Childbirth\nBMC Pregnancy and Childbirth\n1471-2393 BioMed Central London \n\n3035\n10.1186/s12884-020-03035-2\nCase Report\nFetal goiter identified in a pregnant woman with triiodothyronine-predominant graves’ disease: a case report\nhttp://orcid.org/0000-0002-8609-484XFujishima Akiko fujishimaa@med.akita-u.ac.jp 1 Sato Akira 12 Miura Hiroshi 1 Shimoda Yuki 1 Kameyama Saeko 1 Ariake Chika 1 Adachi Hiroyuki 3 Fukuoka Yuki 4 Terada Yukihiro 1 1 grid.411403.30000 0004 0631 7850Department of Obstetrics and Gynecology, Akita University Hospital, 1-1-1 Hondo, Akita, 010-8543 Japan \n2 Perinatal Medical Center, Japanese Red Cross Akita Hospital, Akita, Japan \n3 grid.411403.30000 0004 0631 7850Department of Neonatal Medicine, Akita University Hospital, Akita, Japan \n4 grid.411403.30000 0004 0631 7850Department of Diabetes and Endocrinology, Akita University Hospital, Akita, Japan \n3 6 2020 \n3 6 2020 \n2020 \n20 34426 2 2020 25 5 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nApproximately 10% of all Graves’ disease cases are triiodothyronine (T3)-predominant. T3-predominance is characterized by higher T3 levels than thyroxine (T4) levels. Thyroid stimulating hormone receptor autoantibody (TRAb) levels are higher in T3-predominant Graves’ disease cases than in non-T3-predominant Graves’ disease cases. Treatment with oral drugs is difficult. Here, we report a case of fetal goiter in a pregnant woman with T3-predominant Graves’ disease.\n\nCase presentation\nA 31-year-old woman had unstable thyroid function during the third trimester of pregnancy, making it impossible to reduce her dosage of antithyroid medication. She was admitted to our hospital at 34 weeks of gestation owing to hydramnios and signs of threatened premature labor, and fetal goiter (thyromegaly) was detected. The dose of her antithyroid medication was reduced, based on the assumption that it had migrated to the fetus. Subsequently, the fetal goiter decreased in size, and the hydramnios improved. The patient underwent elective cesarean delivery at 36 weeks and 5 days of gestation. The infant presented with temporary symptoms of hyperthyroidism that improved over time.\n\nConclusions\nThe recommended perinatal management of Graves’ disease is to adjust free T4 within a range from the upper limit of normal to a slightly elevated level in order to maintain the thyroid function of the fetus. However, in T3-predominant cases, free T4 levels may drop during the long-term course of the pregnancy owing to attempts to control the mother’s symptoms of thyrotoxicosis. Little is known about the perinatal management and appropriate therapeutic strategy for T3-predominant cases and fetal goiter. Therefore, further investigation is necessary.\n\nKeywords\nTriiodothyronine-predominant graves’ diseaseFetal goiterPerinatal managementAntithyroid drugBlock-replace therapyCase reportissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nFetal goiter is a diffuse enlargement of the fetal thyroid gland that can occur regardless of the status of the thyroid’s function. However, it has been reported that a fetal goiter is often associated with a change in thyroid function [1]. Fetal goiter is an extremely rare condition that affects one out of 30,000–50,000 pregnancies [2]. In pregnant women with Graves’ disease, the antithyroid drug or thyroid stimulating hormone (TSH) receptor autoantibody (TRAb) migrates across the placenta, increasing the fetus’ risk of goiter and thyroid dysfunction. This dysfunction can carry over into the neonatal period. Antithyroid drugs administered during pregnancy have a stronger suppressive effect on the fetus’ thyroid function than on the mother’s thyroid function. As a result, both the Graves’ Disease Guidelines (Japan Thyroid Association) [3] and the Guidelines of the American Thyroid Association [4] recommend that the mother’s free thyroxine (FT4) levels be adjusted to a range within the upper limit of normal to slightly elevated compared to those in a non-pregnant woman. However, in the case of triiodothyronine (T3)-predominant Graves’ disease, which accounts for approximately 10% of all Graves’ disease cases, if the FT4 levels are controlled as described above, then the free triiodothyronine (FT3) levels become elevated, thus preventing suppression of the mother’s hyperthyroidism symptoms. It is difficult to achieve remission with oral medication in women with T3-predominant Graves’ disease; the recommended treatment is either isotope therapy or surgery [5].\n\nIn suspected cases of fetal thyroid dysfunction, the antithyroid drug dose administered to the mother is increased when the results of percutaneous umbilical blood sampling (PUBS) and/or fetal ultrasound indicate fetal hyperthyroidism. However, for fetal hypothyroidism, it is useful to decrease the mother’s antithyroid dose, and administer levothyroxine in the amniotic fluid [6, 7].\n\nHere, we report the case of a pregnant woman with T3-predominant Graves’ disease that was challenging to manage and resulted in fetal goiter.\n\nCase presentation\nA 31-year-old woman (G1, P0) had been diagnosed with Graves’ disease at 16 years of age. She discontinued treatment at her own discretion but was advised to resume treatment when she expressed her desire to become pregnant. At the time treatment had resumed, her TRAb (second generation) level was 211 IU/L (normal range: < 1.75 IU/L). Her family history was negative.\n\nHistory of current disease\nThe patient became pregnant naturally, at a time when her thyroid function was not satisfactorily controlled by a high dose of propylthiouracil (PTU). An alternative treatment (isotope therapy or surgery) was being considered. Because of hyperemesis gravidarum, oral medications were no longer an option, resulting in her thyroid function deteriorating during week 13 of her pregnancy. Her TRAb level was 43.6 IU/L at that time, and a daily dose of 50 mg potassium iodide (KI) was administered. As a result, her thyroid function was under control, and KI administration was discontinued at week 17. The patient’s FT3 level fluctuated between normal and elevated, whereas her FT4 and TSH levels were low. Her TRAb level gradually declined but was still high at week 33 (18.4 IU/L).\n\nAt 33 weeks and 5 days of gestation, the amniotic pocket and the cervical lengths were 8.1 and 2.6 cm, respectively, indicating worsening hydramnios and threatened premature labor. A blood test showed that the patient’s TSH level had increased to within the normal range. Because pre-pregnancy reduction in her antithyroid medication caused sudden worsening of her thyroid function, she was prescribed a daily supplementary course of 25 μg levothyroxine. At 34 weeks of gestation, she was admitted for hydramnios management and prevention of threatened premature labor.\n\nProgress of post-admission therapy\nOn admission, blood sampling showed an increased TSH level; thus, her thyroid function had improved. Because she was experiencing frequent uterine contractions, we consulted the Department of Diabetes and Endocrinology at our hospital and initiated a continuous drip of ritodrine hydrochloride under careful monitoring for aggravation of hyperthyroidism. At 34 weeks and 4 days of gestation, a transabdominal ultrasound indicated enlargement of the fetal thyroid. It showed a transverse diameter and circumference of 58.4 and 178 mm, respectively (mean values at the 35th week of pregnancy: 18.9 mm and 51.1 mm respectively [8]) (Fig. 1a). The blood flow was diffusely increased (Fig. 1b), and hydramnios was observed. In addition, the epiphyseal nucleus of the distal femur could not be confirmed. The fetus was in face presentation (Fig. 2a). We assumed that the cause of the hydramnios was the inability to swallow the amniotic fluid due to the size of the thyroid. We suspected that the PTU had crossed the placenta and migrated to the fetus, causing fetal goiter; therefore, we initiated a reduced dose of antithyroid medication for the mother at 34 weeks and 5 days of gestation. After reducing the PTU dose from 200 to 100 mg/day, neither the mother nor the fetus showed signs of hyperthyroidism. The dose of PTU was gradually reduced to 50 mg/day, while the levothyroxine dose was increased to 100 μg/day. The fetal thyroid showed a shrinking tendency, as magnetic resonance imaging (MRI) performed at 36 weeks and 3 days of gestation showed a 3-cm fetal thyroid transverse diameter (transverse section; Fig. 2b). The next day, an ultrasound indicated that the AFI had decreased from 24 to 15 cm, and that the fetus’ thyroid blood flow had returned to normal (restricted to the thyroid margins). The fetus had moved into a normal flexion position.\nFig. 1 Fetal ultrasound images. Both images are taken at 34 weeks and 4 days of gestation. a: An image of the transverse section of the fetal neck. The transverse diameter and circumference of the fetal thyroid were 58.4 and 178 mm, respectively. b: An image of the transverse section of the fetal neck obtained with an ultrasonic Doppler blood flowmeter. The blood flow was diffusely increased\n\nFig. 2 Fetal MRI images. Left: T2-weighted sagittal section of the fetus, Middle: T1-weighted sagittal section of the fetus, Right: T1-weighted transverse section of the fetus. a: Images taken at 34 weeks and 5 days of gestation. The anterior side of the cervical region of the fetus is swollen and protruding, and the fetus is in face presentation. The cervical region of the fetus shows a mass with left-right symmetry. T1-weighted images are hyperechoic and T2-weighted images are hypoechoic (△). b: Images taken at 36 weeks and 3 days of gestation. The cervical mass of the fetus (▲) shows no change in the MRI intensity, although it does show slight tendency toward shrinkage. The fetus is in a normal, flexed presentation, and the volume of amniotic fluid has decreased. A T2-weighted sagittal section of the fetus confirms the fetal airway (⇧)\n\n\n\nBecause of the goiter, we were unable to confirm that there would be a patent airway after delivery. Therefore, we speculated that a tracheotomy would be necessary. After consultation with both the Department of Neonatal Medicine and the Department of Pediatric Surgery, an elective cesarean delivery was performed at 36 weeks and 5 days of gestation. On day 7 after delivery, the mother showed signs of hyperthyroidism, which necessitated an increase in her PTU dose.\n\nA diagram describing the therapeutic course from pre-pregnancy to postpartum is shown in Fig. 3.\nFig. 3 Maternal thyroid function and therapeutic course. During pregnancy, the maternal thyroid function was unstable; therefore, it was difficult to decrease the dosage of the antithyroid medication. Between the first and second trimesters, FT3 levels were normal to high, FT4 levels were low, and TSH levels were low. Elevated TSH levels were detected starting from week 33, along with a fetal goiter. Thus, the antithyroid medication dose was reduced and maintained until delivery. After delivery, hyperthyroidism was diagnosed, and the antithyroid medication dose was increased\n\n\n\nNeonatal progress\nThe infant was a male, weighing 2817 g, with Apgar scores of 8 and 9 at 1 and 5 min, respectively. His umbilical aortic blood pH was 7.26. The anterior cervical region had a transverse diameter of 40 mm, indicating an enlarged thyroid gland (Fig. 4). Crying was normal, and no resuscitation was necessary. The infant was admitted to the neonatal intensive care unit (NICU) immediately after birth because of premature delivery and goiter. No bradycardia was observed, and other than the goiter, no external deformities that would suggest congenital hypothyroidism, such as megaloglossia or umbilical hernia, were observed.\nFig. 4 Photographs of the neonate’s neck region. The anterior cervical region has a transverse diameter of 40 mm, indicating thyroid gland enlargement\n\n\n\nA sonography indicated that the thyroid gland had a left-to-right transverse diameter of 41.4 mm (normal range [mean ± 2SD]: 13.9 ± 4.0 mm [9]) and an isthmus of 5.2 mm, indicating enlargement. An ultrasound showed no increased blood flow. Radiographs indicated no epiphyseal nucleus of the distal femur, which showed that fetal bone maturation was delayed because of the fetal hypothyroidism.\n\nThyroid function tests were conducted using the umbilical blood at delivery, and the results were as follows: FT3, 1.7 pg/mL (normal range [mean ± SD]: 1.70 ± 0.034 pg/ml); FT4, 1.6 ng/dL (normal: 1.17 ± 0.14 ng/dl); and TSH, 25.18 μIU/mL (normal: 10.27 ± 6.31 μIU/mL) [10]. The TRAb level was 17.4 IU/L. No treatment was given until 5 days of age, when thyroid function tests indicated a tendency toward hyperthyroidism, (FT3 = 3.5 pg/mL, FT4 = 2.7 ng/dL, and TSH = 2.56 μIU/mL). The infant was administered a course of thiamazole (MMI) (0.5 mg/kg/day). No major changes in the size of the infant’s thyroid gland were observed during the hospital stay. Because of neonatal jaundice, the infant was treated with 24-h phototherapy starting at 4 days of age. His progress was stable, and he was discharged at 18 days of age, weighing 3.1 kg. Following discharge, the MMI dose was gradually decreased as TRAb levels dropped, and it was discontinued at 51 days of age. At 10 months of age, the infant’s thyroid function was normal, despite persistent goiter. There was no evidence of any developmental delays. Currently, the infant is under the continuous care of the Department of Pediatrics.\n\nDiscussion and conclusions\nIn this study, we report a case of a fetal goiter in a pregnant woman with T3-predominant Graves’ disease. Pregnant women with Graves’ disease, which can cause fetal goiter, are relatively common. Graves’ disease is found in 0.1–0.4% of all pregnant women [11]. In a previous case series summarizing 11 cases involving pregnant women with Graves’ disease, two cases (19%) of fetal goiter were reported [12]. Therefore, there is a need to carefully manage such cases.\n\nIn the present case, during the 13th week of pregnancy, the patient’s TRAb level was 43.6 IU/L, indicating a high risk of fetal Graves’ disease. T3-predominant Graves’ disease is known to promote the activity of the thyroxine 5′-deiodinase (T45’D) in the thyroid gland [5], resulting in T4–to–T3 conversion within the thyroid gland. Thus, during treatment with antithyroid drugs, the T4 blood level is adjusted within the normal range, but the T3 blood level remains elevated. Remission is unsuccessful through the use of oral medications, resulting in surgery in many cases [5]. Additionally, hyperthyroidism is known to be a risk of premature delivery [13]. In the present case, because of the risk of premature birth, attempts were made to adjust the FT3 levels within the normal range. As a result, the mother’s FT4 during pregnancy was maintained at a low level. When thyroid function cannot be controlled, even with high doses of antithyroid medications, surgery is an alternative treatment. The second trimester is the optimum timing for such surgery; however, our patient expressed an aversion to surgery during pregnancy. After the 33rd week, we added levothyroxine therapy to compensate for the FT4 levels to prevent fetal hypothyroidism. However, because antithyroid medication migrates to the fetus from the mother more predominantly than T4 [14, 15], the fetus developed fetal goiter.\n\nEither fetal hyperthyroidism or hypothyroidism can be present with a fetal goiter. A sampling of umbilical blood through PUBS is a useful technique for definitive diagnosis; however, it is known that PUBS is associated with an increased risk of fetal mortality [16]. Because the patient was already in the 35th week of pregnancy when the fetal goiter was detected, we chose not to conduct an invasive procedure, but instead opted to perform ultrasound, a minimally invasive method for assessing fetal thyroid function [17]. The ultrasound indicated increased, diffuse blood flow in the thyroid, suggesting hyperthyroidism. Nevertheless, we strongly suspected hypothyroidism on the basis of delayed development of the femur, absence of fetal tachycardia, and normal fetal movement. The use of T1-weighted MRI images in the assessment of fetal thyroid function has been reported [18]. In brief, this report assessed the thyroid-to-muscle signal intensity ratio (SIR) and showed that SIR values were significantly lower in cases of fetal hypothyroidism than in euthyroid cases. In the present case, the results suggested that thyroid function was between normal and low, and the possibility of fetal hyperthyroidism was considered low. Because we suspected fetal hypothyroidism, we reduced the dose of the antithyroid medication, which led to fetal thyroid shrinkage and a decrease in the volume of amniotic fluid.\n\nIn conclusion, fetal thyroid function in perinatal management of pregnancy with T3-predominant Graves’ disease can be tested using ultrasonography and MRI. Further research is needed to develop a standard of care for pregnant women and their fetuses when maternal Graves’ disease with T3 toxicosis is present.\n\nAbbreviations\nAFIAmniotic fluid index\n\nCIConfidence interval\n\nFT3Free triiodothyronine\n\nFT4Free thyroxine\n\nIU/LInternational Units/Liter\n\nMmThiamazole\n\nMRIMagnetic resonance imaging\n\nNICUNeonatal intensive care unit\n\npHPotential hydrogen\n\nPTUPropylthiouracil\n\nPUBSPercutaneous umbilical blood sampling\n\nT3Triiodothyronine\n\nT4Thyroxine\n\nT45’DThyroxine 5′-deiodinase\n\nTRAbTSH receptor autoantibody\n\nTSHThyroid stimulating hormone\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nWe would like to acknowledge our clinical team for their role in the management of this challenging case.\n\nAuthors’ contributions\nAF, AS, CA, SK, YS and HM were the treating obstetricians. HA served as a pediatric consultant and YF as an endocrine consultant. AF carried out the retrospective review of the case, and participated in the design, writing, and organization of the manuscript. AS and YT conceived the study and its design. All authors read and approved the final manuscript.\n\nFunding\nNo funding was used to support this study.\n\nAvailability of data and materials\nThe datasets used and/or analyzed during the current consent study are available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\nWritten informed consent was obtained from the mother for both herself and her child, and this study was approved by the ethical board of Akita University Graduate School of Medicine and Faculty of Medicine. (approval number:2392).\n\nConsent for publication\nWritten informed consent was obtained from the mother for both herself and her child for the procedure, publication of this case report and accompanying images.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Fisher DA Dussault JH Foley TP Jr Klein AH LaFranchi S Larsen PR Screening for congenital hypothyroidism: results of screening one million north American infants J Pediatr 1979 94 700 705 10.1016/S0022-3476(79)80133-X 87512 \n2. Fisher DA Klein AH Thyroid development and disorders of thyroid function in the newborn N Engl J Med 1981 304 702 712 10.1056/NEJM198103193041205 6258072 \n3. Japan Thyroid Association Guidelines for the Diagnosis of Graves' Disease 2019 2019 Tokyo Nankodo 161 163 \n4. Alexander EK Pearce EN Brent GA Brown RS Chen H Dosiou C Guidelines of the American Thyroid Association for the diagnosis and Management of Thyroid Disease during pregnancy and the postpartum Thyroid. 2017 27 315 389 10.1089/thy.2016.0457 28056690 \n5. Takamatsu J Sugawara M Kuma K Kobayashi A Matsuzuka F Mozai T Ratio of serum triiodothyronine to thyroxine and the prognosis of triiodothyronine-predominant Graves' disease Ann Intern Med 1984 100 372 375 10.7326/0003-4819-100-3-372 6546484 \n6. Hashimoto H Hashimoto K Suehara N Successful in utero treatment of fetal goitrous hypothyroidism: case report and review of the literature Fetal Diagn Ther 2006 21 360 365 10.1159/000092466 16757912 \n7. Ribault V Castanet M Bertrand AM Guibourdenche J Vuillard E Luton D Experience with intraamniotic thyroxine treatment in nonimmune fetal goitrous hypothyroidism in 12 cases J Clin Endocrinol Metab 2009 94 3731 3739 10.1210/jc.2008-2681 19737924 \n8. Bernardes LS Ruano R Sapienza AD Maganha CA Zugaib M Nomograms of fetal thyroid measurements estimated by 2-dimensional sonography J Clin Ultrasound 2008 36 193 199 10.1002/jcu.20434 18286516 \n9. Vade A Gottschalk ME Yetter EM Subbaiah P Sonographic measurements of the neonatal thyroid gland J Ultrasound Med 1997 16 395 399 10.7863/jum.1997.16.6.395 9315183 \n10. Mehari A Challa F Gebreyesus G Alemayehu D Seifu D Establishment of reference intervals of thyroid function tests from cord blood of neonates in two selected hospitals, Addis Ababa, Ethiopia BMC Pediatr 2016 16 118 10.1186/s12887-016-0654-2 27484127 \n11. De Groot L Abalovich M Alexander EK Amino N Barbour L Cobin RH Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline J Clin Endocrinol Metab 2012 97 2543 2565 10.1210/jc.2011-2803 22869843 \n12. Volumenie JL Polak M Guibourdenche J Oury JF Vuillard E Sibony O Management of fetal thyroid goitres: a report of 11 cases in a single perinatal unit Prenat Diagn 2000 20 799 806 10.1002/1097-0223(200010)20:10<799::AID-PD925>3.0.CO;2-V 11038457 \n13. Davis LE Lucas MJ Hankins GD Roark ML Cunningham FG Thyrotoxicosis complicating pregnancy Am J Obstet Gynecol 1989 160 63 70 10.1016/0002-9378(89)90088-4 2912104 \n14. Abraham P, Avenell A, McGeoch SC, Clark LF, Bevan JS. Antithyroid drug regimen for treating Graves' hyperthyroidism. Cochrane Database Syst Rev. 2010. 10.1002/14651858.CD003420.pub4.\n15. Laurberg P, Bournaud C, Karmisholt J, Orgiazzi J. Management of Graves' hyperthyroidism in pregnancy: focus on both maternal and foetal thyroid function, and caution against surgical thyroidectomy in pregnancy. Eur J Endocrinol. 2009. 10.1530/EJE-08-0663.\n16. Berry SM Stone J Norton ME Johnson D Berghella V Fetal blood sampling Am J Obstet Gynecol 2013 209 170 180 10.1016/j.ajog.2013.07.014 23978246 \n17. Huel C Guibourdenche J Vuillard E Ouahba J Piketty M Oury JF Use of ultrasound to distinguish between fetal hyperthyroidism and hypothyroidism on discovery of a goiter Ultrasound Obstet Gynecol 2009 33 412 420 10.1002/uog.6315 19306478 \n18. Fujii S Nagaishi J Mukuda N Kaneda S Inoue C Fukunaga T Evaluation of fetal thyroid with 3D gradient Echo T1-weighted MR imaging Magn Reson Med Sci 2017 16 203 208 10.2463/mrms.mp.2015-0157 28025468\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2393",
"issue": "20(1)",
"journal": "BMC pregnancy and childbirth",
"keywords": "Antithyroid drug; Block-replace therapy; Case report; Fetal goiter; Perinatal management; Triiodothyronine-predominant graves’ disease",
"medline_ta": "BMC Pregnancy Childbirth",
"mesh_terms": "D000328:Adult; D013956:Antithyroid Agents; D005260:Female; D006042:Goiter; D006111:Graves Disease; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D011247:Pregnancy; D011248:Pregnancy Complications; D011295:Prenatal Care; D013974:Thyroxine; D014284:Triiodothyronine; D016216:Ultrasonography, Prenatal",
"nlm_unique_id": "100967799",
"other_id": null,
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"pmc": null,
"pmid": "32493403",
"pubdate": "2020-06-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19306478;18286516;28025468;22869843;9315183;87512;20091544;11038457;18849306;23978246;28056690;27484127;16757912;6546484;19737924;6258072;2912104",
"title": "Fetal goiter identified in a pregnant woman with triiodothyronine-predominant graves' disease: a case report.",
"title_normalized": "fetal goiter identified in a pregnant woman with triiodothyronine predominant graves disease a case report"
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"abstract": "Recently, cancer therapies have been supplemented by vascular endothelial growth factor (VEGF) inhibitors as anti-angiogenic agents. However, kidney-related adverse reactions associated with these agents clinically manifest as hypertension and proteinuria, the most severe form being thrombotic microangiopathy (TMA). We present the spectrum of pathological features in VEGF inhibitor-associated kidney disease. Clinicopathological findings of kidney disease were retrospectively studied in 5 cancer patients treated with anti-VEGF agents. Although 4 cases received bevacizumab (anti-VEGF-A), one was given sorafenib (small molecule tyrosine kinase inhibitor affecting VEGF-R2). All patients presented with acute kidney injury, hypertension, and/or proteinuria. All kidney biopsies showed recent and chronic endothelial injury of varying severity and vascular sclerosis, including 2 with typical active features of TMA. Furthermore, acute tubular injury with focal necrosis was seen in all cases. While administration of VEGF inhibitor was discontinued in 4 cases, it was resumed for 5 more doses, following steroid therapy in 1 case. Cessation of VEGF inhibitor therapy was successful in reversing anemia and led to improvement of hypertension and proteinuria in 4 of the 5 cases. One case with TMA progressed to end-stage renal disease. A range of renal pathologic lesions secondary to endothelial injury are noted often accompanied by acute tubular damage following anti-VEGF therapy, the most severe being TMA. While most of the clinical manifestations are reversible with discontinuation of therapy, the role of other nephrotoxic chemotherapeutic agents in enhancing renal injury including severe TMA and other host factors with possible poor outcome should be considered.",
"affiliations": "Department of Pathology, Weill Cornell Medical College, Cornell University, New York, New York, 10065; Department of Nephrology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, 305-8575, Japan.;Renal Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, 10065.;Department of Pathology, Weill Cornell Medical College, Cornell University, New York, New York, 10065.;Nephrology Division, Department of Medicine, St. Joseph's Regional Medical Center, Paterson, New Jersey, 07503.;Renal Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, 10065.;Department of Pathology, Weill Cornell Medical College, Cornell University, New York, New York, 10065. Electronic address: svs2002@med.cornell.edu.",
"authors": "Usui|Joichi|J|;Glezerman|Ilya G|IG|;Salvatore|Steven P|SP|;Chandran|Chandra B|CB|;Flombaum|Carlos D|CD|;Seshan|Surya V|SV|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D042461:Vascular Endothelial Growth Factor A; D009536:Niacinamide; D000068258:Bevacizumab; D000077157:Sorafenib",
"country": "United States",
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"issue": "45(9)",
"journal": "Human pathology",
"keywords": "Acute tubular injury; Proteinuria; Renal failure; Thrombotic microangiopathy; Vascular endothelial growth factor inhibitor",
"medline_ta": "Hum Pathol",
"mesh_terms": "D058186:Acute Kidney Injury; D000368:Aged; D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000068258:Bevacizumab; D005260:Female; D006801:Humans; D007668:Kidney; D007674:Kidney Diseases; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D009536:Niacinamide; D010671:Phenylurea Compounds; D011507:Proteinuria; D012189:Retrospective Studies; D000077157:Sorafenib; D057049:Thrombotic Microangiopathies; D042461:Vascular Endothelial Growth Factor A",
"nlm_unique_id": "9421547",
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"pages": "1918-27",
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"pubdate": "2014-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": null,
"title": "Clinicopathological spectrum of kidney diseases in cancer patients treated with vascular endothelial growth factor inhibitors: a report of 5 cases and review of literature.",
"title_normalized": "clinicopathological spectrum of kidney diseases in cancer patients treated with vascular endothelial growth factor inhibitors a report of 5 cases and review of literature"
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"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
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"abstract": "Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare malignancy-related respiratory complication, showing rapid progression of respiratory dysfunction and pulmonary hypertension (PH). Accumulating evidence suggests that imatinib, a platelet-derived growth factor (PDGF) receptor-tyrosine kinase inhibitor, might be effective and improve severe PH in patients with PTTM associated with gastric cancer. However, its efficacy in PTTM with breast cancer is generally believed as very limited. We experienced a rare case of PTTM associated with metastatic breast cancer, a rare case who were treated with imatinib, exhibiting significant improvement of respiratory dysfunction and PH.",
"affiliations": "Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine.;Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine.;Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine.;Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine.;Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine.;Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine.",
"authors": "Yoshikawa|Sachiko|S|;Hara|Tetsuya|T|;Suzuki|Masataka|M|;Fujioka|Miyu|M|;Taniguchi|Yu|Y|;Hirata|Ken-Ichi|KI|",
"chemical_list": "D000970:Antineoplastic Agents; D000068877:Imatinib Mesylate",
"country": "Japan",
"delete": false,
"doi": "10.1536/ihj.19-556",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1349-2365",
"issue": "61(3)",
"journal": "International heart journal",
"keywords": "Cardio-oncology; Heart failure; Malignancy",
"medline_ta": "Int Heart J",
"mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D001943:Breast Neoplasms; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary; D000068877:Imatinib Mesylate; D057049:Thrombotic Microangiopathies",
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"pmid": "32350209",
"pubdate": "2020-05-30",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Imatinib Dramatically Improved Pulmonary Hypertension Caused by Pulmonary Tumor Thrombotic Microangiopathy (PTTM) Associated with Metastatic Breast Cancer.",
"title_normalized": "imatinib dramatically improved pulmonary hypertension caused by pulmonary tumor thrombotic microangiopathy pttm associated with metastatic breast cancer"
} | [
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"companynumb": "NVSJ2020JP006714",
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"activesubstancename": "IMATINIB MESYLATE"
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... |
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"abstract": "Angiomatosis is a term for multiple, gradually proliferating hemangiomas (angiodysplasia), affecting multiple organs or tissues at the same time. We describe a 12-year course of treatment of a patient with multiple hemangiomas located in the abdomen, retroperitoneum, oesophagus, mediastinum and also in vertebrae. The diagnosis was made in 2005 within probatory laparotomy, at the age of 28 years. The treatment was commenced right after making the diagnosis with interferon α. Due to its adverse effects (fatigue, anorexia), the use of interferon α was limited to the first year, after which the interferon dose was gradually being reduced until it was discontinued completely. From 2006 to 2011 the treatment was based on thalidomide and temporarily also on lenalidomide. By the end of the year 2011 the patient was stabilized through the effect of these drugs, without a need of repeated blood transfusions. In 2012 his condition got worse again, which required several transfusions in one month. We tested metronomic administration of cyclophosphamide and further administration of propranolol, however neither of them improved the patients situation. Injections of octreotide (Sandostatin 0.1 mg twice a day) helped reduce losses during bleeding into the alimentary tract. Still the patient continued to depend on blood transfusions. Therefore, in 2013, bevacizumab was added to the therapy (7.5 mg/kg in 3-week intervals). This treatment stabilized the patient, it reduced the use of transfusions for a period of 2 years, however after 2 years of a successful therapy with bevacizumab there was disease progression shown on CT imaging and hemorrhagic pleural effusion was also detected. After the treatment of hemorrhagic effusion, early in 2015 we transferred to the administration of aflibercept, at first at the dose of 4 mg/kg in 14-day intervals. Arising of massive proteinuria led to the dose reduction to 2 mg/kg while maintaining 14-day intervals. While receiving this dose, the patient tolerates aflibercept thera-py without significant adverse effects. At the time of publication, the patient has been treated with aflibercept for 24 months already, of that for the last ten months he has been fully independent of transfusions. Just before commencement of treatment with aflibercept his conditions required several transfusions in a week. This description demonstrates that the efficiency of individual medications for multiple angiomatosis is always time-limited and newly developed and more efficient drugs are needed to manage the disease. Bevacizumab and aflibercept are beneficial for patients with serious forms of multiple angiomatosis.Key words: aflibercept - angiomatosis - angiodysplasia - bevacizumab - hemangiomas.",
"affiliations": null,
"authors": "Brančíková|Dagmar|D|;Ostřížková|Lenka|L|;Adam|Zdeněk|Z|;Nebeský|Tomáš|T|;Pour|Luděk|L|;Král|Zdeněk|Z|;Mayer|Jiří|J|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D011993:Recombinant Fusion Proteins; C533178:aflibercept; D000068258:Bevacizumab; D040262:Receptors, Vascular Endothelial Growth Factor",
"country": "Czech Republic",
"delete": false,
"doi": null,
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"issn_linking": "0042-773X",
"issue": "63(10)",
"journal": "Vnitrni lekarstvi",
"keywords": null,
"medline_ta": "Vnitr Lek",
"mesh_terms": "D000328:Adult; D020533:Angiogenesis Inhibitors; D000798:Angiomatosis; D000068258:Bevacizumab; D006801:Humans; D008297:Male; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins",
"nlm_unique_id": "0413602",
"other_id": null,
"pages": "672-678",
"pmc": null,
"pmid": "29127751",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The benefit of new angiogenesis (bevacizumab and aflibercept) inhibitors for multiple angiomatosis therapy: a case report.",
"title_normalized": "the benefit of new angiogenesis bevacizumab and aflibercept inhibitors for multiple angiomatosis therapy a case report"
} | [
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"companynumb": "PHHY2017CZ178851",
"fulfillexpeditecriteria": "1",
"occurcountry": "CZ",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EPINEPHRINE"
},
"drugadditional": "3",
"drug... |
{
"abstract": "BACKGROUND\nChronic lung allograft dysfunction (CLAD) is the leading cause of mortality after the first year of transplantation and treatments can have little impact on CLAD progression in some cases. The objective of this study was to evaluate the effectiveness and safety of antithymocyte globulin (ATG) in lung transplant recipients with CLAD.\n\n\nMETHODS\nWe reviewed all patients from our center that had undergone a lung transplant between 2008 and 2019 and selected those with CLAD who were treated with ATG. The closest lung function (forced expiratory volume in the first second) to the ATG administration was recorded, as well as the values 3, 6, and 12 months before and after treatment. We followed and recorded survival during the 12 months after treatment.\n\n\nRESULTS\nA total of 13 patients with CLAD received ATG treatment. A favorable positive response to treatment (improvement or stabilization on lung function) was achieved in half of the patients. Most patients (71%) who responded well to ATG were in CLAD stage 1 to 2. The fall slope of forced expiratory volume in the first second is better after treatment. The median survival was 27 months, and we found a trend toward better survival in early CLAD stages 1 to 2. There were also differences in survival between rapid decliners and nonrapid decliners.\n\n\nCONCLUSIONS\nATG treatment could play a role in patient with CLAD who do not respond to conventional therapies. The effect of cytolytic therapy with ATG is clearly better in those patients in early stages, with little effect in those in CLAD stage 3.",
"affiliations": "Lung Transplantation Unit, Pneumology Department, Hospital Universitario 12 de Octubre, Madrid, Spain. Electronic address: juanmargalloi@gmail.com.;Lung Transplantation Unit, Pneumology Department, Hospital Universitario 12 de Octubre, Madrid, Spain.;Lung Transplantation Unit, Pneumology Department, Hospital Universitario 12 de Octubre, Madrid, Spain.;Lung Transplantation Unit, Pneumology Department, Hospital Universitario 12 de Octubre, Madrid, Spain.;Lung Transplantation Unit, Pneumology Department, Hospital Universitario 12 de Octubre, Madrid, Spain.;Lung Transplantation Unit, Pneumology Department, Hospital Universitario 12 de Octubre, Madrid, Spain.;Lung Transplantation Unit, Pneumology Department, Hospital Universitario 12 de Octubre, Madrid, Spain.",
"authors": "Margallo Iribarnegaray|Juan|J|;De Pablo Gafas|Alicia|A|;Alonso Moralejo|Rodrigo|R|;Quezada Loaiza|Carlos Andrés|CA|;Revuelta Salgado|Fernando|F|;Pina Maíquez|Isabel|I|;Pérez González|Virginia Luz|VL|",
"chemical_list": "D000961:Antilymphocyte Serum",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2021.08.039",
"fulltext": null,
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"issn_linking": "0041-1345",
"issue": "53(9)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D064591:Allografts; D000961:Antilymphocyte Serum; D006801:Humans; D008168:Lung; D016040:Lung Transplantation; D012189:Retrospective Studies; D066027:Transplant Recipients",
"nlm_unique_id": "0243532",
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"pmid": "34593251",
"pubdate": "2021-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Antithymocyte Globulin Treatment for Chronic Lung Allograft Dysfunction in Lung Transplant Recipients: Experience From a National Reference Transplant Center.",
"title_normalized": "antithymocyte globulin treatment for chronic lung allograft dysfunction in lung transplant recipients experience from a national reference transplant center"
} | [
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"companynumb": "ES-SA-2021SA328503",
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"actiondrug": "6",
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"activesubstancename": "LAPINE T-LYMPHOCYTE IMMUNE GLOBULIN"
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"drugadditio... |
{
"abstract": "Pericarditis should be considered in any patient complaining of chest pain and/or dyspnea who is taking a product that contains mesalamine or sulfasalazine. A 41-year-old woman was taking mesalamine 800 mg 3 times/day for 3 weeks before hospital admission. She complained of sharp, pleuritic chest pain that radiated down both arms and increased in intensity when lying down. She was diagnosed with pericarditis based on clinical presentation and electrocardiogram findings. Differential diagnoses for myocardial infarction, systemic lupus erythematosus, and viral or bacterial causes were ruled out based on subjective and objective data. Mesalamine-induced pericarditis was considered on hospital day 2, and the drug was discontinued at discharge on day 3. Clinicians should be aware of this potential drug-related complication, as the relationship between mesalamine or sulfasalazine and pericarditis has been reported rarely in the literature.",
"affiliations": "Department of Pharmacy Practice, Nesbitt School of Pharmacy, Wilkes University, Wilkes-Barre, Pennsylvania 18766, USA.",
"authors": "Waite|Robert A|RA|;Malinowski|Jennifer M|JM|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D019804:Mesalamine",
"country": "United States",
"delete": false,
"doi": "10.1592/phco.22.5.391.33188",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-0008",
"issue": "22(3)",
"journal": "Pharmacotherapy",
"keywords": null,
"medline_ta": "Pharmacotherapy",
"mesh_terms": "D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002637:Chest Pain; D003092:Colitis; D005260:Female; D006801:Humans; D019804:Mesalamine; D010493:Pericarditis",
"nlm_unique_id": "8111305",
"other_id": null,
"pages": "391-4",
"pmc": null,
"pmid": "11898896",
"pubdate": "2002-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Possible mesalamine-induced pericarditis: case report and literature review.",
"title_normalized": "possible mesalamine induced pericarditis case report and literature review"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2022-02504",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MESALAMINE"
},
"druga... |
{
"abstract": "We present the case of a 29-year-old male with a history of Mizuho hemolytic anemia, a rare form of unstable hemoglobinopathy, who presented with congestive heart failure secondary to recurrent valve thrombosis despite appropriate oral anticoagulation. He subsequently required mitral and aortic valve replacement. Pathologic examination revealed extensive nonbacterial thrombotic endocarditis. Due to recurrent thrombosis despite therapeutic anticoagulation, we elected to treat him with red blood cell exchange transfusions and hydroxyurea. He has remained free of symptoms for almost two years with this treatment regimen without side effects. <Learning objective: The management of nonbacterial thrombotic endocarditis (NBTE) is well described in the literature. However, the treatment for refractory NBTE in aggressive forms of unstable hemoglobinopathy remains difficult. The use of hydroxyurea and serial red blood cell exchange, in addition to the usual therapies, may be useful in the treatment of refractory NBTE.>.",
"affiliations": "The Congenital Heart Center, University of Florida Shands Children's Hospital, Gainesville, FL, USA.;The Congenital Heart Center, University of Florida Shands Children's Hospital, Gainesville, FL, USA.;The Congenital Heart Center, University of Florida Shands Children's Hospital, Gainesville, FL, USA.;The Congenital Heart Center, University of Florida Shands Children's Hospital, Gainesville, FL, USA.",
"authors": "Brock|Michael A|MA|;Bleiweis|Mark S|MS|;Reid|Jana|J|;Moguillanksy|Diego|D|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1016/j.jccase.2018.01.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-5409",
"issue": "17(5)",
"journal": "Journal of cardiology cases",
"keywords": "Anticoagulation; Aortic valve replacement; Endocarditis; Mitral valve replacement",
"medline_ta": "J Cardiol Cases",
"mesh_terms": null,
"nlm_unique_id": "101549579",
"other_id": null,
"pages": "175-177",
"pmc": null,
"pmid": "30279885",
"pubdate": "2018-05",
"publication_types": "D002363:Case Reports",
"references": "7059307;3548296;1726094;19880774;11761501",
"title": "Recurrent nonbacterial thrombotic endocarditis: A novel therapeutic approach.",
"title_normalized": "recurrent nonbacterial thrombotic endocarditis a novel therapeutic approach"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-196444",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "WARFARIN"
},
"drugad... |
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"abstract": "Dural metastases are uncommon in cancer patients, but can have as much of an effect on the lives of patients as brain metastases. Dural metastases are most commonly associated with primary cancers of the breast, prostate, and lung, and it is rare that the primary site of the tumor is unknown. In this study, we encountered a 51-year-old woman who had developed multiple bone tumors, with no known primary cancer lesion. A tumor biopsy of the sacral bone revealed non-keratinizing squamous cell carcinoma; the patient was therefore diagnosed as having multiple bone metastases of an unknown primary cancer. Magnetic resonance imaging revealed cranial metastases and partial thickening of the dura with suspected dura metastases. Platinum-based chemotherapy reduced the bone metastases and the thickened dura. However, as resistance to chemotherapy developed, invasions progressed rapidly and diffusely throughout the dura. This was accompanied by the development of dysarthria, visual impairments, and delirium. The patient died 10 months after being diagnosed with dural metastases. This report provides information on the clinical course and prognosis of patients with dural metastases of unknown primary cancer. Furthermore, it may help to construct a treatment strategy for dural metastases.",
"affiliations": "Department of Clinical Oncology, Yamagata University Faculty of Medicine, Yamagata, Japan.;Department of Pathological Diagnostics, Yamagata University Faculty of Medicine, Yamagata, Japan.;Department of Clinical Oncology, Yamagata University Faculty of Medicine, Yamagata, Japan.;Department of Clinical Oncology, Yamagata University Faculty of Medicine, Yamagata, Japan.;Department of Clinical Oncology, Yamagata University Faculty of Medicine, Yamagata, Japan.;Department of Clinical Oncology, Yamagata University Faculty of Medicine, Yamagata, Japan.;Department of Clinical Oncology, Yamagata University Faculty of Medicine, Yamagata, Japan.",
"authors": "Takeda|Hiroyuki|H|;Ohe|Rintaro|R|;Fukui|Tadahisa|T|;Suzuki|Shuhei|S|;Nakamura|Sho|S|;Watanabe|Kaname|K|;Yoshioka|Takashi|T|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000502416",
"fulltext": "\n==== Front\nCase Rep OncolCase Rep OncolCROCase Reports in Oncology1662-6575S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH-4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000502416cro-0012-0666Case ReportRapid Progression of Intracranial Dural Metastases in a Patient with Carcinoma of Unknown Primary Site Takeda Hiroyuki a*Ohe Rintaro bFukui Tadahisa aSuzuki Shuhei aNakamura Sho acWatanabe Kaname aYoshioka Takashi aaDepartment of Clinical Oncology, Yamagata University Faculty of Medicine, Yamagata, JapanbDepartment of Pathological Diagnostics, Yamagata University Faculty of Medicine, Yamagata, JapancCancer Prevention and Control Division, Kanagawa Cancer Center Research Institute, Yokohama, Japan*Hiroyuki Takeda, Department of Clinical Oncology, Yamagata University Faculty of Medicine, 2–2-2 Iida-Nishi, Yamagata City, Yamagata 990–9585 (Japan), E-Mail hiroyuki.tkd@med.id.yamagata-u.ac.jpMay-Aug 2019 16 8 2019 16 8 2019 12 2 666 670 22 7 2019 23 7 2019 2019 Copyright © 2019 by S. Karger AG, Basel2019This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Dural metastases are uncommon in cancer patients, but can have as much of an effect on the lives of patients as brain metastases. Dural metastases are most commonly associated with primary cancers of the breast, prostate, and lung, and it is rare that the primary site of the tumor is unknown. In this study, we encountered a 51-year-old woman who had developed multiple bone tumors, with no known primary cancer lesion. A tumor biopsy of the sacral bone revealed non-keratinizing squamous cell carcinoma; the patient was therefore diagnosed as having multiple bone metastases of an unknown primary cancer. Magnetic resonance imaging revealed cranial metastases and partial thickening of the dura with suspected dura metastases. Platinum-based chemotherapy reduced the bone metastases and the thickened dura. However, as resistance to chemotherapy developed, invasions progressed rapidly and diffusely throughout the dura. This was accompanied by the development of dysarthria, visual impairments, and delirium. The patient died 10 months after being diagnosed with dural metastases. This report provides information on the clinical course and prognosis of patients with dural metastases of unknown primary cancer. Furthermore, it may help to construct a treatment strategy for dural metastases.\n\nKeywords\nDural metastasesCarcinoma of unknown primary sitePrognosisChemotherapy\n==== Body\nIntroduction\nIntracranial metastases are common in cancer patients, most often of the brain, but meningeal and dural metastases can also occur [1]. Dural metastases are found in approximately 9% of cancer patients on autopsy [2, 3]. However, symptomatic dural metastases have only been reported retrospectively and therefore their rate of occurrence is still unclear. Dural metastases may cause headaches, cranial nerve symptoms, visual impairments, mental symptoms and convulsions [1]. Dural metastases are thought to be caused by direct invasion from cranial or hematogenous metastases. The primary cancers most often associated with dural metastases are breast, prostate and lung cancers [1]. Cancers of an unknown primary site (metastatic tumors from an unidentified primary site) that cause dural metastases are rare [4]. To the best of the authors knowledge, there have been no case reports of unknown primary cancers in which dural metastases contributed to symptoms and prognosis. The worsening of dural metastases with cancer of an unknown primary site is therefore a largely an uncharacterized process. In this study, we report a patient with an unknown primary cancer whose symptoms worsened due to rapid progression of dural metastases.\n\nCase Presentation\nA 51-year-old woman was admitted with back pain, dysuria, and dyschezia. Her medical history included salivary gland pleomorphic adenoma, parathyroid adenoma, and ovarian dermoid cyst. Spinal magnetic resonance imaging (MRI) showed multiple bone metastases including sacral metastases which were implicated in cauda equina syndrome. Computed tomography (CT) and positron emission tomography (PET) showed no primary tumor lesions other than bones of the whole body. Various screening examinations were performed, including urinalysis, esophagogastroscopy, colonoscopy, and mammography, but the primary tumor could not be identified. The sacral tumor biopsy results indicated non-keratinized squamous cell carcinoma based on positive immunohistochemical staining of the tumor cells for CK 5/6 and CK 7, and negative staining for CK 20, ER, PgR, p40, TTF-1, and GCDFP-15 (Fig. 1). Cephalic MRI detected partial thickening of the dura membrane adjacent to the calvarial metastases and to the masses protruding from the cranial base to the middle cranial fossa (Fig. 2a). There were no brain parenchyma metastases or leptomeningeal metastases. Whilst tumor markers CA125 and CYFRA were elevated, soluble interleukin-2 receptor and other tumor markers were not. We therefore concluded that the patient had carcinoma of an unknown primary site with no visceral metastases but multiple bone and dural metastases.\n\nThe patient received platinum-based chemotherapy (carboplatin 5 AUC and paclitaxel 175 mg/m2, every 3 weeks), and palliative radiotherapy (30 Gy/10 fr) for the sacral tumors [5]. One month after treatment, the thickened dura became thinner and back pain and bladder rectal disorder improved to some extent. Unfortunately, paclitaxel allergy occurred during the second cycle of chemotherapy, so paclitaxel was changed to docetaxel (60 mg/m2, every 3 weeks) [6]. However, she also developed docetaxel allergy during the second cycle. Therefore, docetaxel was changed to S-1 (tegafur-gimeracil-oteracil, 80 mg/ m2 on day 1–14, every 3 weeks) [7]. After four cycles of the carboplatin plus S-1 regimen, CT and MRI examinations showed progression of bone metastases and middle cranial fossa masses. Consequently, a single gemcitabine treatment was administered for palliative chemotherapy. After two months, the patient experienced dysarthria and nausea, at which point cranial MRI detected diffuse thickening of the dura membrane which indicated rapid progression of the dural metastases (Fig. 2b). To alleviate symptoms, whole brain irradiation was started. Immediately after the start of irradiation, the patient experienced visual loss and delirium; thus, it became difficult to continue the treatment. The patient was transferred to a palliative care unit at another hospital and died within a month. The survival time from diagnosis of dural metastases was 10 months.\n\nDiscussion\nThe case of an unknown primary cancer patient whose symptoms have worsened due to dural invasion from the skull metastases is discussed here. The dural metastases in this case started with partial dural thickening at the site consistent with skull metastases, and was followed by a rapid process of progression. Therefore, it is considered that the deterioration of dural metastasis determined the prognosis of this patient.\n\nDural metastases are caused by hematogenous metastases or direct invasion from the cranial metastases [1, 3]. The process of deterioration in cases of dural metastases includes local exacerbation and progression of lesions to distant dura, cerebral parenchyma, and leptomeninges [1]. In addition, cases of subdural hemorrhage from dural metastases have also been reported [3, 8]. The dural metastases in our patient began with a partial thickening of the dura and developed diffusely throughout the dura within 2 months after developing resistance to chemotherapy. Simultaneously, symptoms of dysarthria, visual impairment, and delirium appeared. Thus, the cancer in our patient was thought to have rapidly progressed to the leptomeninges and cerebral parenchyma by direct invasion from cranial metastases.\n\nThe survival time from the diagnosis of dural metastases in this patient was 10 months. In a report summarizing patients with dural metastases in various cancer types, the median survival time was 9.5 months [1]. On the contrary, the median survival time of patients with carcinomas of an unknown primary site, which have poor prognosis, is approximately 6 months [4, 9]. However, for squamous cell carcinomas of an unknown primary site, the median survival time is reported to be 10 months [10]. Thus, the prognosis of our patient was similar to that reported in these previous reports. The patient had a similar prognosis as that of other cancers of an unknown primary site because of the effect of chemotherapy, as the dural metastases were not affected by the blood-brain barrier [11]. Therefore, we believe that it is possible to use published prognostic data to predict the prognosis of patients with carcinomas of an unknown primary site with dural metastases.\n\nAlthough the utility of radiation therapy in cases of dural metastases has not yet been proven, several reports have suggested its usefulness. A retrospective review of 122 patients with dural metastases reported that although not statistically significant, radiation therapy tended to prolong the survival of patients [1]. Additionally, in a report of eight breast cancer patients with dural metastases who received whole-brain irradiation, no deterioration was observed in any of the patients [12]. In our patient, chemotherapy was given priority over radiotherapy since the dural metastases were partial and there were no symptoms of the central nervous system being affected at the time of diagnosis. However, radiation therapy commenced after the onset of symptoms and could not be completed; the patient died without gaining any benefit from radiation therapy. Since both chemotherapy and radiation therapy can be effective for dural metastases, treatment management should be conducted so that the patients do not miss any treatment opportunities.\n\nThis case report shows the rapid progression of dural metastases in a patient with carcinoma of an unknown primary site. The fact that dural metastases may indicate rapid progression emphasizes the importance of developing a therapeutic strategy that does not miss the optimal timing for treatment. The treatment strategy should include aggressive chemotherapy and radiotherapy prior to the development of neurological symptoms of dural metastases. We believe that this case report will help in understanding the clinical course of dural metastases in carcinoma of an unknown primary site or possibly other cancers, and will contribute to the improvement in survival time and quality of life of patients.\n\nStatement of Ethics\nEthical approval for disclosure was obtained from the patient.\n\nDisclosure Statement\nThe authors have no conflicts of interest to disclose.\n\nFunding Sources\nThe authors received no financial support for this study.\n\nFig. 1 Pathological images are shown. In hematoxylin-eosin staining, proliferation of poorly differentiated cells with a high nuclear-cytoplasmic ratio is observed. Immunostaining for CK 5/6 is positive.\n\nFig. 2 Brain MR images, (a) when the patient was diagnosed with dural metastases and (b) when the patient developed dysarthria and was hospitalized. Dural metastases indicated diffuse progression in a short period of time.\n==== Refs\nReferences\n1 Nayak L Abrey LE Iwamoto FM Intracranial dural metastases Cancer 2009 5 115 (9) 1947 53 19241421 \n2 Meyer PC Reah TG Secondary neoplasms of the central nervous system and meninges Br J Cancer 1953 12 7 (4) 438 48 13126386 \n3 Laigle-Donadey F Taillibert S Mokhtari K Hildebrand J Delattre JY Dural metastases J Neurooncol 2005 10 75 (1) 57 61 16215816 \n4 Pavlidis N Pentheroudakis G Cancer of unknown primary site Lancet 2012 4 379 (9824) 1428 35 22414598 \n5 Briasoulis E Kalofonos H Bafaloukos D Samantas E Fountzilas G Xiros N Carboplatin plus paclitaxel in unknown primary carcinoma: a phase II Hellenic Cooperative Oncology Group Study J Clin Oncol 2000 9 18 (17) 3101 7 10963638 \n6 Greco FA Erland JB Morrissey LH Burris HA 3rd Hermann RC Steis R Carcinoma of unknown primary site: phase II trials with docetaxel plus cisplatin or carboplatin Ann Oncol 2000 2 11 (2) 211 5 10761758 \n7 Tsuya A Kurata T Tamiya A Okamoto I Ueda S Sakai D A phase II study of cisplatin /S-1 in patients with carcinomas of unknown primary site Invest New Drugs 2013 12 31 (6) 1568 72 23975509 \n8 Bergmann M Puskas Z Kuchelmeister K Subdural hematoma due to dural metastasis: case report and review of the literature Clin Neurol Neurosurg 1992 94 (3) 235 40 1327614 \n9 Losa F Soler G Casado A Estival A Fernández I Giménez S SEOM clinical guideline on unknown primary cancer (2017) Clin Transl Oncol 2018 1 20 (1) 89 96 29230692 \n10 Hemminki K Bevier M Hemminki A Sundquist J Survival in cancer of unknown primary site: population-based analysis by site and histology Ann Oncol 2012 7 23 (7) 1854 63 22115926 \n11 Oechsle K Lange-Brock V Kruell A Bokemeyer C de Wit M Prognostic factors and treatment options in patients with leptomeningeal metastases of different primary tumors: a retrospective analysis J Cancer Res Clin Oncol 2010 11 136 (11) 1729 35 20204406 \n12 Sakaguchi M Maebayashi T Aizawa T Ishibashi N Whole-brain Radiation Therapy for Breast Cancer Patients with Dural Metastasis Without Concomitant Brain Metastasis and Leptomeningeal Metastasis Anticancer Res 2018 11 38 (11) 6405 11 30396965\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "12(2)",
"journal": "Case reports in oncology",
"keywords": "Carcinoma of unknown primary site; Chemotherapy; Dural metastases; Prognosis",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "666-670",
"pmc": null,
"pmid": "31572156",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "30396965;1327614;10761758;22414598;13126386;16215816;19241421;23975509;29230692;22115926;10963638;20204406",
"title": "Rapid Progression of Intracranial Dural Metastases in a Patient with Carcinoma of Unknown Primary Site.",
"title_normalized": "rapid progression of intracranial dural metastases in a patient with carcinoma of unknown primary site"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2019RR-225468",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GEMCITABINE"
},
"dru... |
{
"abstract": "OBJECTIVE\nWe assessed the problems and efficacy of glecaprevir + pibrentasvir (GLE/PIB) therapy for patients infected with hepatitis C virus (HCV) in the real world.\n\n\nMETHODS\nA total of 423 patients infected with HCV who started treatment at eight different centers in Japan were enrolled in the study. Glecaprevir (300 mg) and pibrentasvir (120 mg) were given once daily for 8 weeks to 246 non-cirrhotic direct-acting antiviral (DAA)-naive patients with HCV genotype (GT)-1 or -2, and for 12 weeks to patients who: were DAA-naive cirrhotic (n = 55), had experienced DAA failure (n = 78), were cirrhotic and had DAA failure (n = 37), and were other GT-1/2 (n = 7). Anti-HCV efficacy was defined as a sustained virologic response 12 weeks post-treatment (SVR12). The evaluation was undertaken in an intention-to-treat (ITT) population and in patients who were assessed at SVR12 (modified ITT population).\n\n\nRESULTS\nIn the ITT population, 220 (89%) patients on the 8-week regimen and 164 (93%) patients on the 12-week regimen achieved SVR12. The 30 dropout patients were predominantly men and with GT-2. All other DAA-naive GT-1 patients achieved SVR12. The 12-week regimen resulted in 100% SVR12 in 41 GT-2 patients. Nine patients did not achieve SVR12: two DAA naive with GT-2a, two GT-3b patients, two GT-1 patients with discontinuation, and three other GT-1 patients with a history of DAA failure. Four of seven patients who discontinued treatment due to severe adverse effects were more than 75 years old.\n\n\nCONCLUSIONS\nGlecaprevir + pibrentasvir had a remarkable anti-HCV effect in GT-1 and GT-2 patients, but not in GT-3b patients. Although this therapy was reasonably safe, it is necessary to carefully consider elderly and dropout patients.",
"affiliations": "Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan.;Department of Gastroenterology, Showa University, Yokohama, Japan.;Department of Gastroenterology, Tokai University, Isehara, Japan.;Department of Gastroenterology, Kagawa Prefectural Central Hospital, Takamatsu, Japan.;Department of Gastroenterology, Okayama City General Medical Center, Okayama, Japan.;Department of Gastroenterology, Okayama University, Okayama, Japan.;Aiseikai Yamashina Hospital, Kyoto, Japan.;Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan.;Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan.;Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan.",
"authors": "Tamori|Akihiro|A|https://orcid.org/0000-0001-9119-4864;Inoue|Kazuaki|K|;Kagawa|Tatehiro|T|;Takaguchi|Koichi|K|;Nouso|Kazuhiro|K|;Iwasaki|Yoshiaki|Y|;Minami|Masahito|M|;Hai|Hoang|H|;Enomoto|Masaru|M|;Kawada|Norifumi|N|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1111/hepr.13410",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1386-6346",
"issue": "49(12)",
"journal": "Hepatology research : the official journal of the Japan Society of Hepatology",
"keywords": "direct-acting antiviral therapy; dropout; hepatitis C virus; intention-to-treat; sustained virologic response",
"medline_ta": "Hepatol Res",
"mesh_terms": null,
"nlm_unique_id": "9711801",
"other_id": null,
"pages": "1365-1373",
"pmc": null,
"pmid": "31323165",
"pubdate": "2019-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Intention-to-treat assessment of glecaprevir + pibrentasvir combination therapy for patients with chronic hepatitis C in the real world.",
"title_normalized": "intention to treat assessment of glecaprevir pibrentasvir combination therapy for patients with chronic hepatitis c in the real world"
} | [
{
"companynumb": "JP-ABBVIE-20K-087-3262781-00",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "GLECAPREVIR\\PIBRENTASVIR"
},
"drugadditio... |
{
"abstract": "BACKGROUND\nDiabetic striatopathy (DS) is a rare complication of diabetes mellitus (DM). The syndrome appears in patients with uncontrolled DM and is characterized by abrupt onset of movement disorder, mainly hemichorea and accompanied by specific findings on brain imaging. It is believed that DS is unique to the Asian population and affects mainly elderly women with uncontrolled DM.\n\n\nMETHODS\nIn order to define existence and characterization of DS in Western population, we reviewed the medical records of all patients admitted to the Chaim Sheba Medical Center between 2004 and 2014 and identified those with documented elevated HbA1c (>10%). The charts and imaging studies of those with elevated HbA1c and undiagnosed neurological symptoms were reviewed to diagnose DS.\n\n\nRESULTS\nOut of 697 patients with HbA1c>10%, 328 patients had unknown neurological diagnosis. Among them, we identified 4 patients (3 women, mean age 73 and mean HbA1c of 14.8%) with hemichorea or choreoathetosis and brain imaging findings compatible with the diagnosis of DS. Only one out of the 4 patients was diagnosed during hospitalization with DS. All patients were treated with insulin with improvement of their symptoms during hospitalization. However, there was a recurrence in 2 of them and 1 died during the second episode.\n\n\nCONCLUSIONS\nDiabetic striatopathy exists but underdiagnosed in the Western population. It is important to increase the awareness for this clinical syndrome in order to treat those patients properly.",
"affiliations": "Internal Medicine D, the Chaim Sheba Medical Center, Tel-Hashomer, Israel(1).;Radiology Department, the Chaim Sheba Medical Center, Tel-Hashomer, Israel(1).;Internal Medicine D, the Chaim Sheba Medical Center, Tel-Hashomer, Israel(1).;Internal Medicine D, the Chaim Sheba Medical Center, Tel-Hashomer, Israel(1). Electronic address: Avshalom.Leibowitz@sheba.health.gov.il.",
"authors": "Shafran|Inbal|I|;Greenberg|Gahl|G|;Grossman|Ehud|E|;Leibowitz|Avshalom|A|",
"chemical_list": "D006442:Glycated Hemoglobin A; D007328:Insulin",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.ejim.2016.05.026",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0953-6205",
"issue": "35()",
"journal": "European journal of internal medicine",
"keywords": "Basal ganglia; Chorea; Diabetes mellitus; Diabetic striatopathy; Hyperglycemia",
"medline_ta": "Eur J Intern Med",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D001479:Basal Ganglia; D002819:Chorea; D003924:Diabetes Mellitus, Type 2; D005260:Female; D006442:Glycated Hemoglobin A; D006801:Humans; D006943:Hyperglycemia; D007328:Insulin; D007557:Israel; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D062606:Tertiary Care Centers",
"nlm_unique_id": "9003220",
"other_id": null,
"pages": "51-54",
"pmc": null,
"pmid": "27296589",
"pubdate": "2016-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Diabetic striatopathy-Does it exist in non-Asian subjects?",
"title_normalized": "diabetic striatopathy does it exist in non asian subjects"
} | [
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"companynumb": "PHHY2016IL081205",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nGingival tissue enlargement is a common side effect of antiepileptic medications (e.g. phenytoin and sodium valproate), immunosuppressing drugs (e.g. cyclosporine) and calcium channel blockers (e.g. nifedipine, verapamil, amlodipine) (Murakami et al. 2018, Clin Periodontol 45:S17-S27, 2018). The clinical and histological appearances of lesions caused by these drugs are indistinguishable from one another (Murakami et al. 2018, Clin Periodontol 45:S17-S27, 2018). Drug-induced gingival enlargement is rarely seen in edentulous patients.\n\n\nMETHODS\nThis case presents a 72-year-old female with a history of squamous cell carcinoma of the floor of the mouth treated with surgical excision and fibula-free flap reconstruction. Following the uncovering of osseointegrated implants placed in the fibular-free flap, the patient developed gingival enlargement of the floor of the mouth. Cessation of amlodipine and switching to an alternative medication lead to a resolution of the enlarged tissue.\n\n\nCONCLUSIONS\nThis case illustrates that gingival enlargement can occur around dental implants, most notably in rehabilitation cases in patients who have had head and neck cancer. Clinicians should be aware of the risk of gingival enlargement in hypertensive patients taking calcium channel blockers prior to implant placement.",
"affiliations": "Department of Restorative Dentistry, Royal Sussex County Hospital, Brighton, UK. henry.quach@nhs.net.;Department of Restorative Dentistry, Royal Sussex County Hospital, Brighton, UK.",
"authors": "Quach|Henry|H|http://orcid.org/0000-0002-8372-3647;Ray-Chaudhuri|Arijit|A|",
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"country": "Germany",
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"doi": "10.1186/s40729-020-00242-6",
"fulltext": "\n==== Front\nInt J Implant Dent\nInt J Implant Dent\nInternational Journal of Implant Dentistry\n2198-4034 Springer Berlin Heidelberg Berlin/Heidelberg \n\n242\n10.1186/s40729-020-00242-6\nCase Report\nCalcium channel blocker induced gingival enlargement following implant placement in a fibula free flap reconstruction of the mandible: a case report\nhttp://orcid.org/0000-0002-8372-3647Quach Henry henry.quach@nhs.net Ray-Chaudhuri Arijit arijit.ray-chaudhuri@nhs.net grid.416225.60000 0000 8610 7239Department of Restorative Dentistry, Royal Sussex County Hospital, Brighton, UK \n18 8 2020 \n18 8 2020 \n12 2020 \n6 4719 3 2020 30 6 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/.Background\nGingival tissue enlargement is a common side effect of antiepileptic medications (e.g. phenytoin and sodium valproate), immunosuppressing drugs (e.g. cyclosporine) and calcium channel blockers (e.g. nifedipine, verapamil, amlodipine) (Murakami et al. 2018, Clin Periodontol 45:S17–S27, 2018). The clinical and histological appearances of lesions caused by these drugs are indistinguishable from one another (Murakami et al. 2018, Clin Periodontol 45:S17–S27, 2018). Drug-induced gingival enlargement is rarely seen in edentulous patients.\n\nCase presentation\nThis case presents a 72-year-old female with a history of squamous cell carcinoma of the floor of the mouth treated with surgical excision and fibula-free flap reconstruction. Following the uncovering of osseointegrated implants placed in the fibular-free flap, the patient developed gingival enlargement of the floor of the mouth. Cessation of amlodipine and switching to an alternative medication lead to a resolution of the enlarged tissue.\n\nConclusions\nThis case illustrates that gingival enlargement can occur around dental implants, most notably in rehabilitation cases in patients who have had head and neck cancer. Clinicians should be aware of the risk of gingival enlargement in hypertensive patients taking calcium channel blockers prior to implant placement.\n\nKeywords\nGingival enlargementCalcium channel blockerAmlodipineImplantissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nDrug-induced gingival enlargement around natural teeth in patients on calcium channel blocker (CCB) therapy is widely reported in the literature, but fewer reports exist for effects of CCBs on the gingivae around dental implants. It was first reported in 1984 by Lederman et al. [1] and subsequently reported prevalence range from 14 [2] to 83% [3]. Nifedipine is the most commonly associated drug [4] with the prevalence lower for amlodipine [5] or verapamil [6]. Amlodipine belongs to the dihydropyridine class of CCBs along with nifedipine [5]. CCBs are the eighth most prescribed drug in the USA, and the most frequently prescribed CCB is amlodipine [7].\n\nCCBs prevent calcium ion influx by binding to L-type calcium channels on vascular smooth muscles. This causes relaxation and vasodilation and reduction in heart rate. This in turn decreases systemic vascular resistance which as a result reduces arterial blood pressure [8]. CCBs are widely used to manage hypertension, angina and cardiac arrythmias.\n\nGingival enlargement can present as an increased gingival mass and volume. It can range from mild to severe enlargement of papillary or marginal gingival tissues. It more commonly affects the anterior teeth than the posterior teeth and the buccal gingivae than the lingual/palatal gingivae [9, 10]. The enlargement can cause aesthetic and functional issues as well as harbour bacterial biofilm that can lead to periodontal disease.\n\nCase presentation\nPatient description\nThe patient is a 72-year-old Caucasian female with history of T4 N0 M0 squamous cell carcinoma (SCC) of the right floor of mouth and mandible.\n\nCase history\nThe patient had a right segmental mandibulectomy and fibula-free flap reconstruction 4 years prior to the events of this case report (Fig. 1). Three years following reconstructive surgery, the patient received restorative dental treatment in the form of mandibular dental implants to support an implant retained denture. The implant placement was carried out without incident.\nFig. 1 Panoramic radiograph showing segmental mandibulectomy and reconstruction\n\n\n\nPresentation\nThe patient presented with extensive gingival enlargement in the floor of the mouth and lingual gingival tissues (Fig. 2). The firm mass extended bilaterally and partially covered the healing abutments of the implants. The buccal gingivae around the implants were not as severely affected. As the mass presented in the same region as the previous SCC, a biopsy was arranged urgently.\nFig. 2 After implant exposure, placement of healing abutments and soft tissue surgery around the dental implants (all done simultaneously). Extensive gingival enlargement of the floor of mouth and lingual gingival tissue\n\n\n\nThe initial overgrowth was subsequently excised under local anaesthetic which leads to a recurrence 4 months later. This recurrence presented as a firm nodular enlargement over the mandibular ridge (Fig. 3). This was also subsequently biopsied to rule out malignancy.\nFig. 3 Firm nodular gingival enlargement over the mandibular ridge\n\n\n\nResults of pathological tests and other investigations\nThe patient underwent a series of biopsies to determine the cause for the gingival enlargement. An incisional biopsy was taken from the floor of the mouth (Fig. 4). The floor of mouth biopsy showed mucosa with overlying fibrin and neutrophil polymorphs. The underlying stroma contained a proliferation of thin-walled vessels and fibrosis and neutrophil polymorphs permeating through the depth of the biopsy. In particular, there was no convincing evidence of residual squamous cell carcinoma either morphologically or on immunohistochemistry. This biopsy came to the conclusion of granulation tissue with inflammation. Gingival enlargement is characterised by excess extracellular matrix proteins, non-collagenous proteins and chronic inflammatory infiltrate dominated by plasma cells.\nFig. 4 Biopsy floor of the mouth (AE in A1, × 20 magnification)\n\n\n\nThe second biopsy incisional biopsy (4 months following the first) was taken from the overlying mucosa of the mandibular ridge. This biopsy showed heavily inflamed connective tissue with prominent exuberant granulation tissue. There was no dysplasia or malignancy identified. The overall findings were granulation tissue with inflammation.\n\nA magnetic resonance imaging (MRI) scan was also requested following the second biopsy. The MRI scan found no abnormal signal at the resection/reconstruction site, and there were no enlarged lymph nodes. The radiologist concluded that there was no convincing MRI evidence for disease recurrence.\n\nTreatment\nAdvice was sought from specialists in oral medicine. It was concluded that the proliferative growth was induced by the patient’s use of amlodipine. The patient’s general medical practitioner was informed and asked to change the patient’s antihypertensive medication. It was then arranged for the remaining enlarged soft tissue mass to be excised under local anaesthetic by the maxillofacial surgeon.\n\nOutcome\nThe growth was excised uneventfully and without reoccurrence. Implant treatment was recommenced shortly after. The overgrown tissue was removed as it was obstructive for the patient and reduced her ability to undertake adequate oral hygiene around the dental implants. There was an expectation that non-surgical peri-implant therapy would be required, but due to the complete resolution of the gingival overgrowth after excision and alteration of her medication, this was not required. The patient required multiple appointments of oral hygiene instruction to allow the healing abutments to become visible and useable (Fig. 5).\nFig. 5 Resolution of gingival enlargement around healing abutments\n\n\n\nAt the implant-retained wax rim and wax try-in stage, the occlusion was initially prescribed as a class 1 incisal relationship with bilateral buccal overjets (Fig. 6). However, this did not provide sufficient lower lip support and tooth display for the patient to be satisfied, especially on her right hand side (Fig. 7). This tooth position was also uncomfortable lingually for the patient due to a reduced tongue space.\nFig. 6 Mandibular implant-retained wax try-in stage and pre-existing maxillary complete denture\n\nFig. 7 Wax try-in stage showing insufficient lip support and tooth display\n\n\n\nThus, the patient and dentist agreed to accept an altered occlusion. The new prescribed occlusion was balanced with simultaneous contacts anteriorly and posteriorly and mild lingual imbrication to provide the patient a more natural appearance (Fig. 8). This additional lip support was also pleasing to the patient.\nFig. 8 Definitive implant-retained mandibular denture and pre-existing complete denture showing new prescribed occlusion\n\n\n\nDiscussion\nIt is thought that CCBs limit the production of active collagenase leading to a reduction in collagen degradation and causes an increase in collagen accumulation [9]. Other pathways suggest that pro-inflammatory cytokines have an enhancing effect on gingival fibroblasts leading to increased collagen synthesis [11]. CCBs also cause elevated levels of androgens such as testosterone which may act on the gingival cells to cause overgrowth [12].\n\nAmlodipine is less commonly associated with gingival enlargement compared to nifedipine [5]. The prevalence of amlodipine-induced gingival enlargement is 1.7–3.3% compared to nifedipine (14–83%) [2, 3]. Both drugs have a similar structure but nifedipine is highly lipophilic and enters the cell membranes more quickly than amlodipine [8]. Amlodipine also has a higher high life (34 h) than nifedipine (7.5 h) and has a higher volume which means the drug does not circulate in the blood as the drug remains tissue bound and inactive [13].\n\nIt is accepted that oral plaque biofilms are a necessary risk factor in CCB-induced gingival enlargement. Enlarged gingival tissue is often confined to dentate areas where the influence of the biofilm exacerbates the effect of the CCB [14]. The placement of an implant may create an area of biofilm formation that was not otherwise present in a previously edentulous patient. Therefore, the implant itself may be a trigger for gingival overgrowth. Alternatively, as described in this case, the gingival enlargement may not manifest until the implants are exposed to the oral environment with the placement of trans-mucosal abutments.\n\nEffective treatment should initially begin with discontinuation of the CCB, after consultation with the general medical practitioner, and switching to an alternative antihypertensive medication class such as angiotensin-converting-enzyme (ACE) inhibitors, diuretics or beta-blockers [15].\n\nNon-surgical periodontal treatment can be effective for mild to moderate gingival enlargement [8]. The mechanical removal of the biofilm can reduce the inflammatory factors that contribute to the disease process [8]. Improved oral hygiene with regular periodontal treatment can help to control milder cases [16]. For moderate to severe cases, surgical treatment is recommended. Excess tissue can be excised (gingivectomy) using scalpels or electrosurgery; however, the latter should not be used around dental implants. However, without alteration to the patient’s medication, recurrence has been reported to occur in up to 40% of patients [17].\n\nFibula-free flaps are the most commonly used bone-containing free flap in maxillofacial reconstructive surgery [18]. The fibula-free flap provides a consistent bone volume that is suitable for rehabilitation with dental implants [19]. Osseointegration of implants into fibula-free grafts has been shown to be safe and predictable [19, 20]. Gurlek et al. found no significant difference between implants placed in the mandibular bone compared with those in vascularized fibula grafts [21]. However, for patients who have undergone postoperative radiation therapy, there are reduced success rates of implants placed in fibula grafts [22].\n\nThe incidence of SCC next to implants is low. It is reported that a history of previous SCC is a risk factor for peri-implant carcinoma. The most common clinical presentation is an exophytic mass around the implant [23]. It is not possible to determine if there is a causal relationship between the presence of implants and the development of SCC around implants [24]. However, studies have shown that SCC is more likely to arise around implants in patients with a previous history of oral cancer [25]. There should be a high level of suspicion for exophytic masses around implants placed for dental rehabilitation in head and neck cancer patients. These masses should be biopsied to exclude SCC recurrence.\n\nConclusions\nCCB-induced gingival enlargement is a rare presentation in edentulous patients and can be triggered by placement of dental implants to allow for oral rehabilitation or their exposure. This potential complication may be overlooked by dentists and surgeons when informing patients of potential risks. Clinicians should be aware of the presentation of this condition and its management through cessation of the CCB and non-surgical or surgical periodontal treatment if indicated.\n\nAbbreviations\nCCBCalcium channel blocker\n\nMRIMagnetic resonance imaging\n\nSCCSquamous cell carcinoma\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nMr. Mike Monteiro, Consultant Oral & Maxillofacial Surgeon. Dr. Kimberley Allan, Consultant Pathologist.\n\nAuthors’ contributions\nARC is the treating restorative dentistry consultant. HQ drafted the manuscript. All authors read and approved the final manuscript.\n\nFunding\nNo sources of funding to declare.\n\nAvailability of data and materials\nNot applicable.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nConsent for publication obtained from patient.\n\nCompeting interests\nHenry Quach and Arijit Ray-Chaudhuri declare that they have no competing interests.\n==== Refs\nReferences\n1. Lederman D Lumerman H Reuben S Freedman PD Gingival hyperplasia associated with nifedipine therapy: report of a case Oral Surg Oral Med Oral Pathol 1984 55 620 622 10.1016/0030-4220(84)90283-4 \n2. Barak S Engelberg IS Hiss J Gingival hyperplasia caused by nifedipine. Histopathologic findings J Periodontol 1987 58 639 642 10.1902/jop.1987.58.9.639 3477631 \n3. Fattore L Stablein M Bredfeldt G Semla T Moran M Doherty-Greenberg JM Gingival hyperplasia: a side effect of nifedipine and diltiazem Spec Care Dent 1991 11 107 109 10.1111/j.1754-4505.1991.tb00828.x \n4. Butler RT Kalkwarf KL Kaldahl WB Drug-induced gingival hyperplasia: phenytoin, cyclosporine, and nifedipine J Am Dent Assoc 1987 114 56 60 10.14219/jada.archive.1987.0050 3468168 \n5. Jorgensen MG Prevalence of amlodipine-related gingival hyperplasia J Periodontol 1997 68 676 678 10.1902/jop.1997.68.7.676 9249639 \n6. Miller CS Damm DD Incidence of verapamil-induced gingival hyperplasia in a dental population J Periodontol 1992 63 453 456 10.1902/jop.1992.63.5.453 1527689 \n7. Kaufman DW Kelly JP Rosenberg L Anderson TE Mitchell AA Recent patterns of medication use in the ambulatory adult population of the United States: The Slone Survey JAMA. 2002 287 337 344 10.1001/jama.287.3.337 11790213 \n8. Livada R Shiloah J Calcium channel blocker-induced gingival enlargement J Hum Hypertens 2014 28 10 14 10.1038/jhh.2013.47 23739159 \n9. Marshall RI Bartold PM A clinical review of drug induced gingival overgrowth Aust Dent J 1999 44 219 232 10.1111/j.1834-7819.1999.tb00224.x 10687229 \n10. Murakami S Mealey BL Mariotti A Chapple ILC Dental plaque–induced gingival conditions J Clin Periodontol 2018 45 Suppl 20 S17 S27 29926503 \n11. Seymour RA Thomason JM Ellis JS The pathogenesis of drug-induced gingival overgrowth J Clin Periodontol 1996 23 165 175 10.1111/j.1600-051X.1996.tb02072.x 8707974 \n12. Sooriyamoorthy M Gower D Hormonal influences on gingival tissue: relationship to periodontal disease J Clin Periodontol 1989 16 4 201 208 10.1111/j.1600-051X.1989.tb01642.x 2654195 \n13. Ishida H Kondoh T Kataoka M Nishikawa S Nakagawa T Morisaki I Factors influencing nifedipine induced gingival overgrowth in rats J Periodontol 1995 66 345 350 10.1902/jop.1995.66.5.345 7623253 \n14. Lucas RM Howell LP Wall BA Nifedipine-induced gingival hyperplasia. A histochemical and ultrastructural study J Periodontol 1985 56 4 211 215 10.1902/jop.1985.56.4.211 3858503 \n15. Torpet LA Kragelund C Reibel J Nauntofte B Oral adverse drug reactions to cardiovascular drugs Crit Rev Oral Biol Med 2004 15 28 46 10.1177/154411130401500104 14761898 \n16. Mavrogiannis M Ellis JS Thomason JM Seymour RA The management of drug induced gingival overgrowth J Clin Periodontol 2006 33 434 439 10.1111/j.1600-051X.2006.00930.x 16677333 \n17. Ilgenli T Atilla G Baylas H Effectiveness of periodontal therapy in patients with drug induced gingival overgrowth. Long-term results J Periodontol 1999 70 967 972 10.1902/jop.1999.70.9.967 10505798 \n18. Kramer FJ Dempf R Bremer B Efficacy of dental implants placed into fibula-free flaps for orofacial reconstruction Clin Oral Implants Res 2005 16 1 80 88 10.1111/j.1600-0501.2004.01040.x 15642034 \n19. Wu YQ Huang W Zhang ZY Zhang ZY Zhang CP Sun J Clinical outcome of dental implants placed in fibula-free flaps for orofacial reconstruction Chin Med J 2008 121 19 1861 1865 10.1097/00029330-200810010-00002 19080114 \n20. Attia S Wiltfang J Pons-Kühnemann J Wilbrand JF Streckbein P Kähling C Howaldt HP Schaaf H Survival of dental implants placed in vascularised fibula free flaps after jaw reconstruction J Cranio-Maxillofac Surg 2018 46 8 1205 1210 10.1016/j.jcms.2018.05.008 \n21. Gürlek A Miller MJ Jacob RF Lively JA Schusterman MA Functional results of dental restoration with osseointegrated implants after mandible reconstruction Plast Reconstr Surg 1998 101 3 650 659 10.1097/00006534-199803000-00011 9500381 \n22. Urken ML Buchbinder D Costantino PD Oromandibular reconstruction using microvascular composite flaps: report of 210 cases Arch Otolaryngol Head Neck Surg 1998 124 1 46 55 10.1001/archotol.124.1.46 9440780 \n23. Moergel M Karback J Kunkel M Wagner W Oral squamous cell carcinoma in the vicinity of dental implants Clin Oral Investig 2014 18 277 284 10.1007/s00784-013-0968-5 \n24. Salgado-Paralvo AO Arriba-Fuente L Mateos-Moreno MV Salgado-Garcia A Is there an association between dental implants and squamous cell carcinoma? BDJ. 2016 221 645 649 10.1038/sj.bdj.2016.863 27857102 \n25. Javed F Al-Askar M Qayyum F Wang HL Al-Hezaimi K Oral squamous cell carcinoma arising around osseointegrated dental implants Implant Dent 2012 21 4 280 286 10.1097/ID.0b013e31824cde85 22814551\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2198-4034",
"issue": "6(1)",
"journal": "International journal of implant dentistry",
"keywords": "Amlodipine; Calcium channel blocker; Gingival enlargement; Implant",
"medline_ta": "Int J Implant Dent",
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"nlm_unique_id": "101676532",
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"pages": "47",
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"pmid": "32808200",
"pubdate": "2020-08-18",
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"title": "Calcium channel blocker induced gingival enlargement following implant placement in a fibula free flap reconstruction of the mandible: a case report.",
"title_normalized": "calcium channel blocker induced gingival enlargement following implant placement in a fibula free flap reconstruction of the mandible a case report"
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"abstract": "OBJECTIVE\nTo describe a case of Epstein-Barr virus (EBV)-associated acute retinal necrosis (ARN) in an immunocompetent patient and to summarize the clinical features of published molecularly confirmed EBV-ARN cases.\n\n\nMETHODS\nCase report and literature review.\n\n\nRESULTS\nAn 83-year-old immunocompetent woman with unilateral ARN presented with visual acuity of light perception. Oral valacyclovir was started. One week later, vitrectomy was conducted for worsening inflammation. Intraoperatively, a severe confluent necrotizing retinitis and occlusive vasculitis involving all four quadrants of posterior and peripheral retina were noted. Vitreous polymerase chain reaction was exclusively positive for EBV. Other autoimmune, infective, and hematological work-up was negative. The retinitis resolved 3 months later, but with significant macular and generalized retinal atrophy, visual acuity remained light perception. From the literature, there are four EBV-ARN cases (six eyes) diagnosed based on polymerase chain reaction or fluorescence in-situ hybridization of vitreous or retinal samples. All patients were immunocompromised or on immunosuppressive treatment. Presenting visual acuity was light perception or worse in 3/6 eyes. Three patients received systemic acyclovir-based therapy. Vitrectomy was performed in 4/6 eyes between 4 and 8 weeks from disease onset. All cases had involvement of the posterior and peripheral retina. Retinal detachment occurred in 2/6 eyes, and final visual acuity was no light perception in 3/6 eyes.\n\n\nCONCLUSIONS\nThis case expands the clinical spectrum of EBV-ARN to include infection in immunocompetent hosts. Epstein-Barr virus-ARN seems to be characterized by a global peripheral and posterior fulminant retinitis, with adverse visual acuity outcomes despite systemic acyclovir-based therapy. The benefits of adjunctive intravitreal foscarnet, systemic steroids, and early vitrectomy may warrant further investigation.",
"affiliations": "Department of Ophthalmology, Jewish General Hospital, Montreal, Quebec, Canada.;Department of Ophthalmology, Jewish General Hospital, Montreal, Quebec, Canada.;Montreal Retina Institute, Montreal, Quebec, Canada; and.;Department of Ophthalmology, Jewish General Hospital, Montreal, Quebec, Canada.",
"authors": "Chan|Errol W|EW|;Sun|Vincent|V|;Eldeeb|Mohab|M|;Kapusta|Michael A|MA|",
"chemical_list": "D000998:Antiviral Agents; D000212:Acyclovir",
"country": "United States",
"delete": false,
"doi": "10.1097/ICB.0000000000000819",
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"issn_linking": "1935-1089",
"issue": "15(4)",
"journal": "Retinal cases & brief reports",
"keywords": null,
"medline_ta": "Retin Cases Brief Rep",
"mesh_terms": "D000212:Acyclovir; D000369:Aged, 80 and over; D000998:Antiviral Agents; D020031:Epstein-Barr Virus Infections; D005260:Female; D006801:Humans; D007121:Immunocompetence; D015882:Retinal Necrosis Syndrome, Acute",
"nlm_unique_id": "101298744",
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"pages": "412-416",
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"pubdate": "2021-07-01",
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"title": "EPSTEIN-BARR VIRUS ACUTE RETINAL NECROSIS IN AN IMMUNOCOMPETENT HOST.",
"title_normalized": "epstein barr virus acute retinal necrosis in an immunocompetent host"
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"abstract": "We report a case of urethritis in a 17-year-old non-sexually active male that developed after starting isotretinoin treatment for his acne. Clinicians must be vigilant about this adverse effect and elicit a thorough medication history prior to administering antibiotics in patients taking isotretinoin treatment for acne.",
"affiliations": "Dartmouth Geisel School of Medicine, One Rope Ferry Road, Hanover, NH, 03755, USA.;Section of Urology, Department of Surgery, Dartmouth-Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH, 03766, USA.;Section of Urology, Department of Surgery, Dartmouth-Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH, 03766, USA.",
"authors": "Paredes-Bhushan|Vivian|V|;Rezaee|Michael E|ME|;Chavez|David R|DR|",
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"doi": "10.1016/j.eucr.2019.101109",
"fulltext": "\n==== Front\nUrol Case RepUrol Case RepUrology Case Reports2214-4420Elsevier S2214-4420(19)30457-710.1016/j.eucr.2019.101109101109PediatricsIsotretinoin induced urethritis: A case report & review of the literature Paredes-Bhushan Vivian vivian.paredes.bhushan.med@dartmouth.edua∗Rezaee Michael E. bChavez David R. ba Dartmouth Geisel School of Medicine, One Rope Ferry Road, Hanover, NH, 03755, USAb Section of Urology, Department of Surgery, Dartmouth-Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH, 03766, USA∗ Corresponding author. Dartmouth Geisel School of Medicine, One Rope Ferry Road, Hanover, NH, 03755, USA. vivian.paredes.bhushan.med@dartmouth.edu23 12 2019 3 2020 23 12 2019 29 1011097 11 2019 17 12 2019 20 12 2019 © 2019 The Authors2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).We report a case of urethritis in a 17-year-old non-sexually active male that developed after starting isotretinoin treatment for his acne. Clinicians must be vigilant about this adverse effect and elicit a thorough medication history prior to administering antibiotics in patients taking isotretinoin treatment for acne.\n\nKeywords\nIsotretinoinUrethritisMeatitis\n==== Body\nIntroduction\nIsotretinoin is a highly regarded drug for severe nodulocystic acne and is commonly used in pediatric and young adults. Isotretinoin has mucocutaneous and systemic effects including xerosis, cheilitis, skin fragility, palmoplantar desquamation, epistaxis, and fetal retinoid syndrome among childbearing women.1 Although teratogenicity and common side effects of oral retinoids have been widely studied, little is known about isotretinoin as a cause of urological symptoms. We present a case of urethritis/meatitis that developed in a pediatric patient after starting isotretinoin treatment for his acne.\n\nCase presentation\nA 17-year-old non-sexually active male with acne on twice-daily isotretinoin 30 mg was referred to a Urology clinic for evaluation of possible urethral web. He initially presented to a dermatology appointment with a two-week history of “urine stream issues”. He had been on isotretinoin for approximately five weeks when he noticed a scab at the urethral tip that prevented him from urinating. This occurred twice before while on isotretinoin. He manually opened his urethra to allow for urination which worked until five days prior to presentation. He denied any sexual history, prior hematuria, or issues with his urinary stream. He was noted to have a rash on his hands and lips. No penile discharge was noted, although signs of meatal mucosal irritation were present. He was prescribed topical halobetasol 0.05% twice-daily for one week as needed while on isotretinoin. His symptoms were adequately managed with this regimen. The patient remained on isotretinoin for a total of five months, stopping medication after five months of treatment. In his subsequent follow-up visits to his dermatologist, he did not report the return of urological symptoms.\n\nDiscussion\nIsotretinoin is a rare cause of urethritis with multiple mechanisms at play. One proposed mechanism is the interaction of retinoids with their skin-specific receptors, RARγ and RXRα, resulting in stratum corneum thinning and increased transepithelial water loss. Keratolysis is another, which alters skin structure through desmosomal loss.1,2 The increase in skin fragility and dehydration of the urogenital mucosa from these mechanisms predisposes the area to infection and inflammation contributing to the symptoms of urethritis/meatitis observed in our patient.\n\nReview of the literature suggests that these mucocutaneous side effects are dose-dependent. Kellock et al. described cases of isotretinoin-induced urethritis improved by dose reduction. The first, a 30-year-old male who presented with dry cracked lips, dry eyes, epistaxis, penile discomfort, and bloody urethral discharge two weeks after initiating isotretinoin 100 mg daily. After a negative workup, he was treated with antibiotics without improvement. Symptom resolution occurred after reducing isotretinoin to 50 mg.3 In another case, a 25-year-old male on 60 mg daily of isotretinoin for three months had a one-week history of dry and painful urethral meatus suspected of penile candidiasis. He was treated with clotrimazole cream and antibiotics with no improvement in symptoms. Workup for infectious causes was unremarkable, and he was given a provisional diagnosis of nonspecific urethritis. Symptoms spontaneously resolved during the fourth month of treatment with no symptom recurrence following completion of isotretinoin treatment.3 Similarly, Alli et al. described a 23-year-old male presenting with dysuria and meatitis on isotretinoin 40 mg daily for four months. After a negative workup, he was diagnosed with retinoid dermatitis affecting the external urethral meatus. Symptom resolution occurred two weeks after dosage reduction and use of topical corticosteroids and dexpanthenol.1,2 Ballout et al. described a 28-year-old male with urethritis, clear penile discharge, and meatitis, whose isotretinoin dose was increased to 60 mg from 40 mg daily, five days before presentation. His dose was reduced back to 40 mg after a negative workup, with symptom resolution afterward.4\n\nAdditionally, urethritis is known to resolve within days to weeks after discontinuation of isotretinoin. Kellock et al. described a 20-year-old male with a two-week history of dysuria and urethral discharge on 60 mg isotretinoin for the past six weeks. The patient was subsequently treated with doxycycline for 14 days, requiring cessation of isotretinoin. He re-presented with similar symptoms one month later, noting his symptoms completely resolved while on a drug holiday from isotretinoin. Edwards et al. described two cases of urethritis that resolved with isotretinoin cessation. The first, a 23-year-old male who presented with meatal soreness and clear discharge upon initiation of a second course of isotretinoin. In another case, a 35-year-old male, presented with three days of urethral discharge one week after starting isotretinoin, reporting similar symptoms one year ago when previously on isotretinoin. Both patients were treated with a tetracycline, with symptom resolution upon isotretinoin cessation.5 While our 17-year-old patient was not treated with antibiotics, his symptoms resolved with isotretinoin cessation. Isotretinoin's pharmacokinetics, which has a half-life of 10–20 hours, best supports the resolution of these side effects.3,5\n\nThese studies demonstrate the correlation between isotretinoin usage or discontinuation and the presence or resolution of symptoms of urethritis, respectively. In contrast to other cases, where infectious workup was performed, no extensive workup to exclude infectious causes of urethritis/meatitis was performed for our patient. It was through review of his medication history, where we realized that his presentation may be an adverse effect of his isotretinoin treatment.\n\nThe case presented highlights the link between isotretinoin use and urethritis. This is critical in the pediatric and young adult population, as isotretinoin is commonly prescribed for acne treatment. This case underscores the importance of a thorough history and examination, particularly of the patient's medication history. In addition to eliciting a thorough review of medications, clinicians should be aware of this adverse effect and manage accordingly whether by dosage reduction or cessation of treatment altogether. Antibiotics or antivirals should be avoided in these patients in the absence of an immunocompromised state, positive STD workup, or positive urine culture.\n\nConclusion\nThough uncommon, isotretinoin has been shown to present with urethritis which is often overlooked. This is a diagnosis of exclusion and can be treated by dose reduction or cessation of isotretinoin. Clinicians must be vigilant about this adverse effect and elicit a thorough medication history prior to administering antibiotics or antivirals in patients on isotretinoin treatment for acne.\n\nFunding\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nDeclaration of competing interest\nThe authors declare that there is no conflict of interest regarding the publication of this article.\n\nAcknowledgements\nNone.\n==== Refs\nReferences\n1 Orfanos C.E. Zouboulis C.C. Almond-Roesler B. Geilen C.C. Current use and future potential role of retinoids in dermatology Drugs 53 3 1997 358 388 9074840 \n2 Alli N. Yorulmaz A. An unusual side effect of isotretinoin: retinoid dermatitis affecting external urethral meatus Cutan Ocul Toxicol 34 2 2015 176 177 24964168 \n3 Kellock D. Parslew R. Mendelsohn S. O'Mahony C. Non-specific urethritis-possible association with isotretinoin therapy Int J STD AIDS 7 2 1996 135 136 8737340 \n4 Ballout R.A. Maatouk I. Isotretinoin-induced urethritis versus non-gonococcal urethritis in a man who has sex with men: an open debate Int J STD AIDS 29 10 2018 1024 1026 29512421 \n5 Edwards S. Sonnex C. Urethritis associated with isotretinoin therapy Acta Derm Venereol 77 4 1997 330-330\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-4420",
"issue": "29()",
"journal": "Urology case reports",
"keywords": "Isotretinoin; Meatitis; Urethritis",
"medline_ta": "Urol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101626357",
"other_id": null,
"pages": "101109",
"pmc": null,
"pmid": "31908966",
"pubdate": "2020-03",
"publication_types": "D002363:Case Reports",
"references": "29512421;9228237;8737340;24964168;9074840",
"title": "Isotretinoin induced urethritis: A case report & review of the literature.",
"title_normalized": "isotretinoin induced urethritis a case report review of the literature"
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"abstract": "Renal infarction is an uncommon condition resulting from an acute disruption of renal blood flow and it is potentially life-threatening disease. The cause and outcome of renal infarction is not well established and is frequently misdiagnosed or diagnosed late. Melanotan II is a non-selective melanocortin-receptor agonist and its effect on humans is an increasing of skin pigmentation, producing of spontaneous penile erection and sexual stimulation. Melanotan II inducing rhabdomyolysis and renal failure have been described previously. We present a review of Melanotan II and the possible effects of this drug on the kidneys by including a case of a renal infarction most likely attributed to Melanotan II. In the mechanism of renal injury with Melanotan II, thrombotic pharmacological influence and possible direct toxic effect on renal parenchyma must be considered.",
"affiliations": "Department of Nephrology, Skaraborg Hospital, 541 85, Skövde, Sweden. bjorn.peters@vgregion.se.;Department of Nephrology, Skaraborg Hospital, 541 85, Skövde, Sweden.;Department of Nephrology, Skaraborg Hospital, 541 85, Skövde, Sweden.;Department of Nephrology, Skaraborg Hospital, 541 85, Skövde, Sweden.",
"authors": "Peters|Björn|B|0000-0003-1199-8948;Hadimeri|Henrik|H|;Wahlberg|Rebecka|R|;Afghahi|Henri|H|",
"chemical_list": "D000806:Angiotensin-Converting Enzyme Inhibitors; D006495:Heparin, Low-Molecular-Weight; D010456:Peptides, Cyclic; D044101:Receptors, Melanocortin; C079282:melanotan-II; D000521:alpha-MSH",
"country": "Japan",
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"doi": "10.1007/s13730-020-00447-z",
"fulltext": null,
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"issn_linking": "2192-4449",
"issue": "9(2)",
"journal": "CEN case reports",
"keywords": "Barbie drug; Kidney injury; Melanotan II; Renal infarction",
"medline_ta": "CEN Case Rep",
"mesh_terms": "D058186:Acute Kidney Injury; D000806:Angiotensin-Converting Enzyme Inhibitors; D003951:Diagnostic Errors; D006495:Heparin, Low-Molecular-Weight; D006801:Humans; D006973:Hypertension; D007238:Infarction; D007668:Kidney; D008297:Male; D008875:Middle Aged; D010410:Penile Erection; D010456:Peptides, Cyclic; D044101:Receptors, Melanocortin; D012206:Rhabdomyolysis; D000083942:Sexual Arousal; D012880:Skin Pigmentation; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D000521:alpha-MSH",
"nlm_unique_id": "101636244",
"other_id": null,
"pages": "159-161",
"pmc": null,
"pmid": "31953620",
"pubdate": "2020-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "16564787;15342973;19380666;30142729;17366315;19575725;11035391;20545686;23121206;2847615;16889574;1516719;1658407;1325670;10360502;19482364;28479851;18652274;4304587;16176587",
"title": "Melanotan II: a possible cause of renal infarction: review of the literature and case report.",
"title_normalized": "melanotan ii a possible cause of renal infarction review of the literature and case report"
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"abstract": "Introduction. Congenital long QT syndrome type 2 (LQTS2) is a rare inherited cardiac abnormality resulting in increased risk of polymorphic ventricular tachycardia (PVT). Case Description. A 21-year-old postpartum female presented with syncopal episode after phone alarm. She was noted to have PVT on telemetry monitoring in the emergency department. EKG revealed QTc of 530. The patient's only medication was medroxyprogesterone. She ultimately received a dual chamber pacemaker with ICD. Discussion. LQTS2 is associated with alarm sounds as a precipitating factor. Postpartum hormonal shifts as well as medroxyprogesterone have significant effect on native QTc duration.",
"affiliations": "Internal Medicine Residency Program, Rutgers New Jersey Medical School, Rutgers University, 150 Bergen Street, UH-I248, Newark, NJ 07101, USA.;Internal Medicine Residency Program, Rutgers New Jersey Medical School, Rutgers University, 150 Bergen Street, UH-I248, Newark, NJ 07101, USA.;Hackensack University Medical Center, 30 Prospect Avenue, Hackensack, NJ 07601, USA.;Internal Medicine Residency Program, Rutgers New Jersey Medical School, Rutgers University, 150 Bergen Street, UH-I248, Newark, NJ 07101, USA.",
"authors": "Kern|John|J|0000-0001-5904-2334;Duffy|Margaret|M|;Kern|Corinne|C|;Mazza|Victor|V|",
"chemical_list": null,
"country": "United States",
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"doi": "10.1155/2014/676080",
"fulltext": "\n==== Front\nCase Rep CardiolCase Rep CardiolCRICCase Reports in Cardiology2090-64042090-6412Hindawi Publishing Corporation 10.1155/2014/676080Case ReportLong QTc Syndrome Type 2 Presenting in a Postpartum Patient on Medroxyprogesterone http://orcid.org/0000-0001-5904-2334Kern John \n1\n\n*\nDuffy Margaret \n1\nKern Corinne \n2\nMazza Victor \n1\n1Internal Medicine Residency Program, Rutgers New Jersey Medical School, Rutgers University, 150 Bergen Street, UH-I248, Newark, NJ 07101, USA2Hackensack University Medical Center, 30 Prospect Avenue, Hackensack, NJ 07601, USA*John Kern: johnkerndo@gmail.comAcademic Editor: Gianluca Di Bella\n\n2014 21 10 2014 2014 67608010 7 2014 5 10 2014 Copyright © 2014 John Kern et al.2014This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nIntroduction. Congenital long QT syndrome type 2 (LQTS2) is a rare inherited cardiac abnormality resulting in increased risk of polymorphic ventricular tachycardia (PVT). Case Description. A 21-year-old postpartum female presented with syncopal episode after phone alarm. She was noted to have PVT on telemetry monitoring in the emergency department. EKG revealed QTc of 530. The patient's only medication was medroxyprogesterone. She ultimately received a dual chamber pacemaker with ICD. Discussion. LQTS2 is associated with alarm sounds as a precipitating factor. Postpartum hormonal shifts as well as medroxyprogesterone have significant effect on native QTc duration.\n==== Body\n1. Introduction\nCongenital long QT syndrome type 2 (LQTS2) is a rare inherited cardiac abnormality resulting in QT prolongation associated with the risk of polymorphic ventricular tachycardia. This patient's risk of having a cardiac event was increased due to her postpartum state.\n\n2. Case Description\nA 21-year-old, two-month postpartum female presented following a three-day history of syncopal episodes. The first occurred when her son set off her cell phone alarm and the second with her son playing a loud video game. She was placed on telemetry monitoring in the emergency department just prior to a “syncopal” episode and was found to be in polymorphic ventricular tachycardia (PVT). EKG revealed a QTc of 530 msec. The patient was also found to be hypokalemic. Her QT interval remained prolonged following repletion. The patient's only medication was medroxyprogesterone acetate. She has no family history of sudden cardiac death. She failed therapy with beta blockade and on the fourth day of admission a dual chamber pacemaker with ICD was placed for secondary prevention of sudden cardiac death. She had no further telemetry events and was discharged home to follow up with outpatient electrophysiology.\n\n3. Discussion\nLQTS2 is associated with alarm sounds as a precipitating factor, as it was in this case. The hormonal impacts have been recently described. Estrogen results in QTc prolongation while progesterone results in QTc shortening [1]. The dramatic shifts in estrogen/progesterone levels in the postpartum state have resulted in the initial cardiac presentation of LQTS2 in several patients. While endogenous progesterone provides protection via activation of endothelial nitrogen oxide synthetase, synthetic medroxyprogesterone acetate does not have this protective mechanism [2]. Therefore it could be implied that the use of medroxyprogesterone acetate could precipitate arrhythmias in a patient predisposed to such events. LQTS2 is a rare syndrome that should be considered in the differential when assessing postpartum patients with complaints of syncope.\n\nLQTS2 exacerbation postpartum has been well described in literature. There have been recent implications of the potential exacerbation of LQTS2 by the use of medroxyprogesterone acetate. The hormonal effects on QT length have been described in both animal and human models. Hormonal effects in females as they reach puberty were shown in a study by Locati et al., which highlighted the QTc changes in women from age 15 to 50 and correlated with a 10–20 ms shift in the average QTc, thought secondary to increased estrogen production [1]. In a large retrospective study by Rashba et al. the postpartum risk of cardiac events was increased specifically in LQTS2 [3]. Nakamura et al. highlighted the role of progesterone in shortening QT interval and its protective nature regarding the prevention of cardiac arrhythmias in this context [4]. Additionally progesterone levels, which are increased during pregnancy, resulted in a decrease in arrhythmogenic potential. The mechanism of progesterone is related to the activation of endothelial nitric oxide synthetase. While medroxyprogesterone acetate functions in a manner similar to endogenous progesterone it does not activate endothelial nitric oxide synthetase, thus conferring no cardiac protection or QT shortening [2]. In our patient this lack of peripartum cardiac protection increased her risk of experiencing a cardiac event.\n\nFemales with LQTS2 are at increased risk of developing arrhythmias when compared to males of the same age group. In a risk analysis it was shown that patients with LQTS2 and QTc greater than 498 msec carry with them a relative risk of a cardiac event by age 40 of 8.36. Furthermore there is a 50% likelihood of experiencing a cardiac event before age 40 in the absence of treatment [5]. This case highlights the importance of evaluation of syncope in the postpartum patient and the careful consideration of contraception choice in patients with LQTS2.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n==== Refs\n1 Locati E. H. Zareba W. Moss A. J. Schwartz P. J. Michael Vincent G. Lehmann M. H. Towbin J. A. Priori S. G. Napolitano C. Robinson J. L. Andrews M. Timothy K. Hall W. J. Age- and sex-related differences in clinical manifestations in patients with congenital long-QT syndrome: findings from the international LQTS registry Circulation 1998 97 22 2237 2244 10.1161/01.CIR.97.22.2237 2-s2.0-0032499656 9631873 \n2 Hermsmeyer R. K. Thompson T. L. Pohost G. M. Kaski J. C. Cardiovascular effects of medroxyprogesterone acetate and progesterone: a case of mistaken identity? Nature Clinical Practice Cardiovascular Medicine 2008 5 7 387 395 10.1038/ncpcardio1234 2-s2.0-46649108526 \n3 Rashba E. J. Zareba W. Moss A. J. Jackson Hall W. Robinson J. Locati E. H. Schwartz P. J. Andrews M. Influence of pregnancy on the risk for cardiac events in patients with hereditary long QT syndrome Circulation 1998 97 5 451 456 10.1161/01.CIR.97.5.451 2-s2.0-0032502041 9490239 \n4 Nakamura H. Kurokawa J. Bai C. X. Asada K. Xu J. Oren R. V. Zhu Z. I. Clancy C. E. Isobe M. Furukawa T. Progesterone regulates cardiac repolarization through a nongenomic pathway: an in vitro patch-clamp and computational modeling study Circulation 2007 116 25 2913 2922 10.1161/CIRCULATIONAHA.107.702407 2-s2.0-37349125566 18056530 \n5 Priori S. G. Schwartz P. J. Napolitano C. Risk stratification in the long-QT syndrome The New England Journal of Medicine 2003 348 19 1866 1874 10.1056/NEJMoa022147 2-s2.0-0038415858 12736279\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6404",
"issue": "2014()",
"journal": "Case reports in cardiology",
"keywords": null,
"medline_ta": "Case Rep Cardiol",
"mesh_terms": null,
"nlm_unique_id": "101576452",
"other_id": null,
"pages": "676080",
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"pmid": "25386366",
"pubdate": "2014",
"publication_types": "D016428:Journal Article",
"references": "9631873;9490239;18056530;12736279;18521110",
"title": "Long QTc Syndrome Type 2 Presenting in a Postpartum Patient on Medroxyprogesterone.",
"title_normalized": "long qtc syndrome type 2 presenting in a postpartum patient on medroxyprogesterone"
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"abstract": "BACKGROUND\nExtrauterine Endometrial Stromal Sarcoma (EESS) is an extremely rare mesenchymal tumour that simulates other pathologies, and therefore poses a diagnostic challenge. This report outlines a case of EESS arising from the greater omentum mimicking a colonic tumour, with review of literature.\n\n\nMETHODS\nA 47-year-old woman, with history of hysterectomy for menorrhagia and hormone replacement therapy (HRT), presented with right sided abdominal pain and localized peritonism. On exploratory laparoscopy an omental tumour, suspected to arise from the transverse colon was identified and biopsied. The histological features suggested an EESS. Colonoscopy ruled out colonic lesion. A laparoscopic tumour resection and bilateral salpingo-oophorectomy (BSO) was performed. Immunohistochemistry confirmed the diagnosis. No additional lesions or associated endometriosis were found. Resection was followed by adjuvant medroxyprogesterone-acetate therapy.\n\n\nCONCLUSIONS\nWe reviewed 20 cases of EESS originating from extragenital abdominopelvic organs reported since 1990. Acute presentation is rare, as well as upper abdominal occurrence. Isolated omental involvement was previously reported in only one case. Endometriosis is a risk factor for development of EESS and history and/or histological evidence for endometriosis is usually present. HRT is another acknowledged risk factor, mostly on the background of endometriosis. To our knowledge, this is the only report of EESS occurring in a woman on HRT treatment without background of endometriosis.\n\n\nCONCLUSIONS\nEESS can occur without endometriosis and HRT may be an aetiological factor. The condition can mimic a chronic or acute abdominal pathology and laparoscopic core biopsy is the best way to achieve a diagnosis and formulate management.",
"affiliations": "Upper Gastorintestinal and Hepatobiliary Unit, Department of Surgery, The Queen Elizabeth Hospital, Adelaide, Australia. Electronic address: Vered.Buchholz@sa.gov.au.;Upper Gastorintestinal and Hepatobiliary Unit, Department of Surgery, The Queen Elizabeth Hospital, Adelaide, Australia.;Upper Gastorintestinal and Hepatobiliary Unit, Department of Surgery, The Queen Elizabeth Hospital, Adelaide, Australia.;Upper Gastorintestinal and Hepatobiliary Unit, Department of Surgery, The Queen Elizabeth Hospital, Adelaide, Australia.",
"authors": "Buchholz|Vered|V|;Kiroff|George|G|;Trochsler|Markus|M|;Kanhere|Harsh|H|",
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"doi": "10.1016/j.ijscr.2017.04.017",
"fulltext": "\n==== Front\nInt J Surg Case RepInt J Surg Case RepInternational Journal of Surgery Case Reports2210-2612Elsevier S2210-2612(17)30194-310.1016/j.ijscr.2017.04.017Case ReportAn unexpected diagnosis of primary omental endometrial stromal sarcoma in a patient with acute right abdominal pain: A case report and review of literature Buchholz Vered Vered.Buchholz@sa.gov.auveredbuch@gmail.com⁎1Kiroff George Trochsler Markus Kanhere Harsh Upper Gastorintestinal and Hepatobiliary Unit, Department of Surgery, The Queen Elizabeth Hospital, Adelaide, Australia⁎ Corresponding author at: Upper Gastrointestinal and Hepatobiliary Unit, Department of Surgery, The Queen Elizabeth Hospital, 28 Woodville Road, Woodville South, SA 5011, Australia. Vered.Buchholz@sa.gov.auveredbuch@gmail.com1 Present address: Upper Gastrointestinal and Hepatobiliary Unit, Department of Surgery, The Lyell McEwin Hospital, Haydown Rd, Elizabeth Vale, SA 5112, Australia.\n\n19 4 2017 2017 19 4 2017 36 8 14 2 1 2017 7 4 2017 12 4 2017 © 2017 The Authors2017This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• Only case in literature without history of endometriosis, on Hormone replacement therapy.\n\n• Only the second case with isolated omental lesion.\n\n• Extrauterine Endometrial Stromal Sarcoma (EESS) is an extremely rare mesenchymal tumour.\n\n• This condition can simulate chronic or acute abdominal pathologies.\n\n• The tumour can occur without preceding endometriosis, and in upper abdominal location.\n\n• Biopsy showing typical immunohistochemistry markers is the best way to achieve diagnosis.\n\n• Hormone replacement therapy may be an independent risk factor for EESS occurrence.\n\n\n\nIntroduction\nExtrauterine Endometrial Stromal Sarcoma (EESS) is an extremely rare mesenchymal tumour that simulates other pathologies, and therefore poses a diagnostic challenge. This report outlines a case of EESS arising from the greater omentum mimicking a colonic tumour, with review of literature.\n\nPresentation of case\nA 47-year-old woman, with history of hysterectomy for menorrhagia and hormone replacement therapy (HRT), presented with right sided abdominal pain and localized peritonism. On exploratory laparoscopy an omental tumour, suspected to arise from the transverse colon was identified and biopsied. The histological features suggested an EESS. Colonoscopy ruled out colonic lesion. A laparoscopic tumour resection and bilateral salpingo-oophorectomy (BSO) was performed. Immunohistochemistry confirmed the diagnosis. No additional lesions or associated endometriosis were found. Resection was followed by adjuvant medroxyprogesterone-acetate therapy.\n\nDiscussion\nWe reviewed 20 cases of EESS originating from extragenital abdominopelvic organs reported since 1990. Acute presentation is rare, as well as upper abdominal occurrence. Isolated omental involvement was previously reported in only one case. Endometriosis is a risk factor for development of EESS and history and/or histological evidence for endometriosis is usually present. HRT is another acknowledged risk factor, mostly on the background of endometriosis. To our knowledge, this is the only report of EESS occurring in a woman on HRT treatment without background of endometriosis.\n\nConclusion\nEESS can occur without endometriosis and HRT may be an aetiological factor. The condition can mimic a chronic or acute abdominal pathology and laparoscopic core biopsy is the best way to achieve a diagnosis and formulate management.\n\nKeywords\nEndometrial stromal sarcomaExtrauterineOmentumHormone replacement therapy\n==== Body\n1 Introduction\nEndometrial stromal sarcoma (ESS) is a rare mesenchymal tumour of the uterus. It may also arise as a primary extrauterine endometrial sarcoma (EESS), mainly on the background of endometriosis, with predominant gonadal involvement as a result. Very rarely does EESS arise primarily in the gastrointestinal or extra-gastrointestinal tract organs outside the pelvis, or evolve without preceding endometriosis [1]. In these cases, the non-specific presentation and the unexpected location pose a diagnostic challenge [2], [3], and often another abdominal pathology is first suspected. A case of primary EESS arising from omentum mimicking a colonic primary is presented, with review of the literature. This report is line with the SCARE criteria [4].\n\n2 Presentation of case\nA 47-year-old female, presented to the Emergency Department with right sided and central abdominal pain. Her medical history included hysterectomy 10 years earlier for menorrhagia, and HRT with oestradiol patch. She reported vague, generalized abdominal pain, mainly central, which later migrated to the right lower abdomen. On examination she was tender along the right and upper central abdomen with localized peritonism. WBC and CRP were elevated (12.1 × 109/L, 16 mg/L respectively). Sonography demonstrated a hypoechoic, ovoid, irregular lesion with blind end, and sonographic probe induced tenderness above it. Given the acute presentation, and the high suspicion for an inflammatory lesion, the patient was taken for an exploratory laparoscopy. At surgery, a firm irregular omental mass was found, located above the proximal transverse colon, near the hepatic flexure. The lesion seemed to extend from the colon. The Appendix was normal. Prior hysterectomy was noted, right ovary and tube were normal, however optimal view of the left adnexa was impossible due to pelvic small bowel adhesions. No other pathology was found. A partially necrotic omental nodule adjacent to the larger eccentric mass was biopsied. The specimen consisted of an 18 × 15 × 12 mm nodule, with extensive haemorrhagic necrosis. The residual tissue was comprised of monomorphic ovoid to spindle-shaped cells with high nuclear to cytoplasmic ratio. The morphology suggested a mesenchymal-type lesion, but immunohistochemistry with a panel of antibodies, raised the possibility of endometrial stromal sarcoma.\n\nGiven the rarity of this diagnosis without previous ESS and endometriosis, the past hysterectomy slides were reviewed and confirmed as benign without any evidence of ESS. The current and previous slides were sent for a second external review which supported the diagnosis of primary EESS. A systemic workup was then undertaken. Chest, abdomen and pelvis computed tomography demonstrated a 28 × 15 mm ovoid mass arising from the transverse colon, without evidence for distant metastasis or nodal disease (Fig. 1). Tumour markers (CA19.9, CA-125, CEA, AFP) were negative. Colonoscopy excluded primary or secondary colon involvement. The patient was discussed by the Surgical and Gynae-Oncology multidisciplinary teams. The decision was to proceed with laparoscopic excision of the tumour together with BSO by joint surgical and gynaecology teams. A two centimetre omental lesion was found next to the hepatic flexure and resected. Pelvic small bowel loops were adhesiolysed and normal looking ovaries and tubes were resected. No peritoneal spread or other metastatic lesions were identified. The post-operative recovery was uneventful and the patient was discharged on day one post surgery.Fig. 1 (Greyscale and colour). Contrast enhancement coronal computed tomography showing showing ovoid mass in proximity to transverse colon.\n\nFig. 1\n\nThe omental lesion contained a firm nodule measuring 21 mm in maximal dimension. The mass was characterized by multiple foci of ovoid to spindle–shaped cells forming irregular tongues dissecting through markedly fibroblastic stroma (Fig. 2a). The cells were uniform with rare mitotic figures. Small capillary-sized blood vessels were found within the proliferative cells (Fig. 2b). The tumour cells stained strongly for CD10 (Fig. 2c), oestrogen receptor, progesterone receptor, vimentin, WT-1 and Bcl-2. There was no reaction for c-Kit, CD34, desmin, or smooth muscle actin. Both ovaries and fallopian tubes were normal. The morphology and immunoprofile were compatible with the diagnosis of primary extrauterine low grade ESS originating from the omentum. HRT was ceased and the patient was put on adjuvant hormonal therapy with medroxyprogesterone acetate and was scheduled for regular follow-up.Fig. 2 (Colour image). (A) Islands of spindle-shaped tumour cells infiltrating into omental fat. (B) Uniform population of spindle small with embedded prominent capillary-sized vessels/or arterioles. (C) Strong immunoreaction of cells for CD10.\n\nFig. 2\n\n3 Discussion\nExtrauterine endometrial sarcoma involving an extra-genital site is an extremely rare condition. It is even more rare to find it in the upper abdomen and without any clinical evidence of endometriosis. Even fewer cases of upper abdominal ESS without clinical evidence of endometriosis have been described in the literature. All 20 reported cases (including the present case) reported since 1990 were reviewed. These are summarized in Table 1.Table 1 Clinical features of extaruterine extraovarian abdominopelvic ESS.\n\nTable 1Authors\tAge (yr)\tPast History/HRT\tPresenting symptoms\tAbdominal Site\tGross Findings\tDissemination\tAssociated Endometriosis (specimen)\tTreatment\tFollow up\t\nSon et al. [5]\t52\tNone\tConstipation,\nabdominal pain and hematochezia (1 mo)\tSigmoid colon\t3.5 × 2.8 cm polypoid mass involving whole layers of colonic wall to pericolic fat\tLocal (pelvic, peritoneum, ovaries)\tNo\tLaparoscopic LAR\nTAH, BSO (2mo later)\tNED,\n4 mo\t\nWang et al. [6]\t40\tTAH (leiomyoma)\nRt. Ovarian cystectomy\tChange in bowel habits and hematochezia\n(1 yr)\tRectosigmoid, mesentery, intestinal wall\tMultiple 1–3 cm nodular masses involving intestinal wall and mesentery\tDistant (multiple mesentery and abdominal metastasis)\tYes\tIntraoperative chemotherapy, palliative transverse loop colostomy\tDOD,\n18 mo\t\nGhosal et al. [15]\t42\tNone\tPalpable mass (1 mo)\tTransverse and sigmoid colon mesentery, peritoneum\tMultiple 0.7–2.8 cm nodular masses involving mesentery and peritoneum\tDistant (multiple abdominal metastasis, para-aortic LNs)\tYes\tTAH, BSO, resection of abdominal nodules, and pelvic and para-aortic nodes\tNA\t\nAyuso et al. [7]\t80\tTAH, BSO (endometriosis/abnormal bleeding)\nHRT\tHematochesia\nChronic discharge\tSigmoid colon\t5 cm pelvic mass involving mucosa, muscularis and adjacent peritoneum\tLocal (peritoneum)\tNo\tLaparoscopic AR\n- > Hormonal therapy\tNED\n4 y\t\nBiliatis et al. [2]\t56\tNone\tIncidental finding of a pelvic mass at pelvic US\tTerminal ileum, cecum\t8 × 7 × 6 cm mass invading serosa\tNone\tYes\tRt. Hemicolectomy, TAH, BSO, bilateral pelvic node resection, omentectomy\n- > Chemotherapy\n- > Hormonal therapy\tNED\n38 mo\t\nRosca et al. [11]\t51\tRemoval of endometriosis\nimplants from ovaries and rectum\tNA\tSigmoid,\nAppendix (2 m later)\t5 cm mass\n3 cm peri-appnedicular mass\tLocal\tYes\tResection\nDetails NA\tRecurrence\n2 mo\nLong term − NA\t\nDoghri et al. [13]\t45\tNone\tAbdominal discomfort\n(6 mo)\tOmentum\t35 × 28 × 18 cm mass involving omentum\tNone\tYes\tTumourectomy and omentectomy\tNA\t\nZemlyak et al. [12]\t70\tTAH, BSO (leiomyoma)\nEndometriosis\nHRT\tAbdominal pain and increased urinary frequency\tSigmoid colon, terminal ileum\t15.8 × 13 × 8.9 cm mass adherent to both bowel segments and left ureter\tNone\tYes\tSigmoidectomy and segmental resection of terminal ileum\tNED\n3 yr\t\nKim et al. [1]\t75\tTAH, BSO (leiomyomas)\tAbdominal pain and palpable mass (1 yr)\tJejunum, mesentery and omentum\t7 cm mass adherent to jejunal serosa.\n4.5 cm mass in jejunal lumen.\n03.-0.5 cm nodules on mesentery and omentum.\tLocal (mesentery,omentum)\tNo\tSegmental resection of jejunum and omentectomy\nRefused chemotherapy\tRecurrence\n5 mo\nrepeated surgery, no further F/U\t\nChen et al. [8]\t42\tNon-small cell lung cancer, chemotherapy Treatment\n(5 yr)\tDifficult defecation and hematochezia\n(1 mo)\tSigmoid colon and omentum\t1–3 cm nodular masses involving bowel wall from mucosa to peri-colic fat\tLocal (omentum, ovary, fallopian tubes)\tYes\tRectosigmoidectomy, TAH, BSO, partial omentectomy\n-> Radiotherapy\tNED\n12 mo\t\nKovac et\nal. [22]\t45\tTAH, RSO (leiomyoma, normal adnexa)\tSymptoms of stenosing process\tRectosigmoid and omentum\t6 cm mass infiltrating all layers of bowel wall and multiple omental nodules\tLocal (omentum, ovary)\tYes\tTumourectomy, colon resection, LSO, omentectomy\tNED\n11 mo\t\nRojas et al. [10]\t42\tNone\tDiarrhea (2 yr) Acute abdominal pain, small bowel obstruction (1 d)\tSmall bowel, mesentery\t2.5–3.5 cm multiple nodules\tDistant (bowel mesentery)\tYes\tLaparoscopy, 3 nodules resected for histology. No definite surgery described.\tNA\t\nCho et al. [9]\t48\tSubtotal hysterectomy (leiomyoma)\nTAH, BSO (endometriosis)\tDifficult defecation and tenesmus\tSigmoid colon\t1–3 cm multi-multinodular masses involving all layer of bowel wall\tLocal (bowel, bladder, ureter)\tYes\tSegmental sigmoid resection, regional LNs dissection\tDIC post surgery\nNED\n4 mo\t\nBosincu et al. [14]\t42\tNone\tAbdominal pain and fever\tRectosigmoid\tMultiple polypoid ulcerated masses with transmural infiltration of bowel wall (size NA)\tLocal (omentum, peritoneum, parametrium, paracolic LNs)\tYes\tAR, appendectomy, omentectomy, TAH, BSO\n-> Chemotherapy\tNED\n20 mo\t\nMourra et al. [17]\t61\tHRT\tEpigastric pain (portal vein thrombosis on US)\tRectosigmoid\t2.7 cm polypoid tumour with lumen stenosis, involving all layers of bowel wall\tNone\tYes\tLAR\tNED\n30 mo\t\nYantiss et al. [18]\t63\tNA\tNA\tRectum\t2 cm polypoid mass involving all layers of bowel wall with lumen stenosis\tNone\tYes\tRectal resection (not specified)\tRecurrence 3y.\nNED at 6y following radiotherapy\t\nFukunaga et al. [23]\t43\tNone\tAbdominal distention\n(1 mo)\tRectum, bladder\t14 × 12 × 10 cm ill-circumscribed mass adherent to rectum and bladder wall\tNone\tYes\tTumourectomy, partial resection of rectal wall, TAH, BSO\tNED\n39 mo\t\nFukunaga et al. [23]\t50\tNone\tAbdominal distension\tOmentum, transverse colon mesentery\t20 cm omental mass, 10 cm mesocolon mass\tLocal (mesentery)\tNo\tTumourectomy, partial resection of transverse colon\tNED\n18 mo\t\nBaiocchi et al. [16]\t38\tOvarian Cystectomy (endometriosis)\nTAH, BSO (menorrhagia)\tAbdominal and back pain\n(6 mo)\tTransverse and ascending colon, terminal ileum\tLarge multilobular mass adherent to colon and ileum, with scattered implants (size NA)\tDistant (falciform ligament, gastrocolic ligament mesentery, pelvis)\tYes\tColectomy (ascending and transverse colon), partial ileum resection\n-> Chemotherapy\n-> Hormonal therapy\tNED\n2y\t\nPresent case\t47\tTAH\n(menorrhagia)\nHRT\tAcute RLQ abdominal pain\tOmentum\t2.1 cm tumour embedded in omentum\tNone\tNo\tLaparoscopic resection of tumour, BSO\n-> Hormonal therapy\tNED\n6 mo\t\nTAH, total abdominal hysterectomy; BSO, bilateral salpingo-oophorectomy; RSO, rt. salpingo-oophorectomy; HRT, hormonal replacement therapy; NA, not available; NED, no evidence of disease; DOD, dead of disease.\n\n\n\nPatient ages ranges between 38–80 years (median, 47.5 years). More than half of the patients were in their fifth decade or early menopause years (11/20) as previously reported [3]. The clinical presentation was ambiguous in most instances. The commonest complaint was abdominal pain (9 cases). Other complaints included hematochezia (4 cases) [5], [6], [7], [8], change in bowel habits (4 cases) [5], [6], [8], [9], and tenesmus (1 case) [9]. Only 2 cases, including the current one, presented acutely and were diagnosed following an emergent surgical intervention [10]. Associated foci of endometriosis was found in proximity to the tumour in 16 out of 20 patients, but only 3 of the 16 had documented history of endometriosis [9], [11], [12]. One patient had past endometriosis but none was found near the tumour [7]. The rectosigmoid was the most common site for primary EESS (12/20). Solitary involvement of the omentum is rare and was reported only in one case report prior to ours [13]. Lesions in the gastrointestinal tract may involve the serosa (9 cases) or invade bowel wall to create polypoid lesions [14], with resulting carcinoma-like obstructive symptoms (8 cases). Only four patients presented with disseminated disease [6], [10], [15], [16], while localised lesion or local spread comprised the majority of cases (9 and 7 cases respectively). Eight women had previous hysterectomy for benign pathologies, and four received unopposed hormonal therapy at the time of diagnosis, including the present case [7], [12], [17].\n\nThe association of EESS with endometriosis provides a clue for the pathogenesis of this tumour. Malignant transformation of endometriosis is a rare but recognised phenomenon, and was demonstrated by Yantiss et al. who reviewed 17 cases of pre-malignant and malignant transformation of gastrointestinal endometriosis [18]. Most malignant tumours were endometrial adenocarcinomas (8 cases), with one case of EESS. The high prevalence of concomitant endometriosis may have a bearing on the transformation pathway for EESS [3]. The pathogenesis of EESS in the absence of ectopic endometrial stroma is more obscure. Possible explanations include gland-poor endometriosis foci (stromal endometriosis) or complete replacement by the tumour [3]. Another theory is de-novo malignant transformation of peritoneum or coelomic multipotential epithelial cells [1], [3], [19].\n\nUnopposed hormonal therapy is associated with endometrial carcinomatosis and is related to EESS as well [18]. Masand et al. found that the majority of postmenopausal women diagnosed with EESS and associated endometriosis were on long standing HRT [3]. In the present review four women received HRT, including the present case. Associated endometrial foci were found in two of those cases. No endometriosis was found in the third case, although there was a clinical history of endometriosis. The present case had neither past endometriosis nor pathological evidence of it in the resected specimen. This is the only reported case with EESS on the background of prolonged HRT without history or clinical presence of endometriosis. These findings suggest that HRT may be an independent risk factor for development and/or progression of EESS [3], [18].\n\nDiagnosis of primary EESS needs exclusion of a uterine primary. In women with previous hysterectomy for benign pathologies, it is crucial to review previous specimens and rule out a missed uterine primary. The main differential diagnosis for EESS when arising from bowel is some other mesenchymal tumours, especially gastrointestinal stromal tumours (GISTs). Spindle cells in EESS are characterised by monotonous arrangement, compared with sheets or fascicles arrangement in GIST. Proliferation of small arterioles, resembling spiral arterioles of the endometrium, is also typical of EESS. However, the final diagnosis, especially in cases of unusual tumour location and absence of endometriosis, depends on immunohistochemistry. Positive labelling for CD10, PR and ER with no reactivity for CD117 and CD34 confirms the diagnosis [1], [3], [20].\n\nAlthough EESS was previously believed to have worse prognosis than its uterine counterpart [21], accumulating evidence, does not support this. Most cases reviewed had multifocal disease, with either local or distant dissemination, while only one death was reported for a patient with unresectable low grade EESS [6]. The clinical behaviour of EESS is similar to low grade uterine ESS. Mitotic index, size, multifocality, and vascular invasion, the known predictors for worse prognosis, do not affect the patients’ outcomes. The only feature that may predict poorer prognosis is high grade histologic features namely de-differentiation or cytologic atypia. This includes loss of typical vascular pattern, pleomorphic spindle or epitheloid cells, in concurrence with brisk mitotic activity [3].\n\nGiven the rarity of EESS, the treatment is usually based on the guidelines for uterine ESS. Surgical resection with or without debulking is the cornerstone of EESS treatment. Total abdominal hysterectomy and BSO is often added in order to rule out uterine or ovarian primary. The value of adjuvant therapy is not clear, as no prospective studies exist. Treatment options include observation only, hormonal therapy, chemotherapy, radiotherapy, or combined modality treatment. Hormonal therapy is the most prevalent treatment, and was also the chosen treatment for the present case [3], [12], [20].\n\n4 Conclusion\nEESS can occur without endometriosis and HRT may be an independent aetiological factor. The condition can mimic a chronic or acute abdominal pathology and laparoscopic core biopsy is the best way to achieve a diagnosis and formulate management.\n\nConflicts of interest\nNo conflicts of interest.\n\nFunding\nThis Research did no receive and specific grant form funding agencies in the public, commercial, or not-for-profit sectors.\n\nEthical approval\nThe paper is a case report, and therefore does not require ethics approval.\n\nConsent\nInformed consent has been obtained from the patient, and all identifying details have been omitted.\n\nAuthor contributions\nVered Buchholz – Conception of study, acquisition of data, analysis and interpretation of data, drafting the article\n\nGeorge Kiroff – Acquisition of data, management of case, revision of article.\n\nMarkus Trochsler – Acquisition of data, management of case, revision of article.\n\nHarsh Kanhere – Analysis of data, revision of article, final approval of the version to be submitted.\n\nGuarantor\nDr. Harsh Kanhere.\n==== Refs\nReferences\n1 Kim L. Choi S.J. Park I.S. Han J.Y. Kim J.M. Chu Y.C. Kim K.R. Endometrial stromal sarcoma of the small bowel Ann. Diagn. Pathol. 12 2008 128 133 18325474 \n2 Biliatis I. Akrivos N. Sotiropoulou M. Rodolakis A. Simou M. Antsaklis A. Endometrial stromal sarcoma arising from endometriosis of the terminal ileum: the role of immunohistochemistry in the differential diagnosis J. Obstet. Gynaecol. Res. 38 2012 899 902 22413936 \n3 Masand R.P. Euscher E.D. Deavers M.T. Malpica A. Endometrioid stromal sarcoma: a clinicopathologic study of 63 cases Am. J. Surg. Pathol. 37 2013 1635 1647 24121169 \n4 Agha R.A. Fowler A.J. Saeta A. Barai I. Rajmohan S. Orgill D.P. SCARE Group The SCARE statement: consensus-based surgical case report guidelines Int. J. Surg. Lond. Engl. 34 2016 180 186 \n5 Son H.-J. Kim J.-H. Kang D.-W. Lee H.-K. Park M.-J. Lee S.Y. Primary extrauterine endometrial stromal sarcoma in the sigmoid colon Ann. Coloproctol. 31 2015 68 73 25960975 \n6 Wang Q. Zhao X. Han P. Endometrial stromal sarcoma arising in colorectal endometriosis: a case report and review of the literature Case Rep. Obstet. Gynecol. 2015 2015 534273 \n7 Ayuso A. Fadare O. Khabele D. A case of extrauterine endometrial stromal sarcoma in the colon diagnosed three decades after hysterectomy for benign disease Case Rep. Obstet. Gynecol. 2013 202458 2013 \n8 Chen C.-W. Ou J.-J. Wu C.-C. Hsiao C.-W. Cheng M.-F. Jao S.-W. High-grade endometrial stromal sarcoma arising from colon endometriosis Int. J. Colorectal Dis. 22 2007 1551 1553 17262201 \n9 Cho H.-Y. Kim M.-K. Cho S.-J. Bae J.-W. Kim I. Endometrial stromal sarcoma of the sigmoid colon arising in endometriosis: a case report with a review of literatures J. Korean Med. Sci. 17 2002 412 414 12068150 \n10 Rojas H. Wang J. Chase D. Wang J. Pathologic quiz case: a 46-year-old woman with 1-day history of abdominal pain and intestinal obstruction. Extrauterine low-grade endometrial stromal sarcoma Arch. Pathol. Lab. Med. 129 2005 e44 e46 15679447 \n11 Roşca E. Venter A. Muţiu G. Drăgan A. Coroi M. Roşca D.M. Endometrial stromal sarcoma developed on outer endometriosis foci Rom. J. Morphol. Embryol. Rev. 52 2011 489 492 \n12 Zemlyak A. Hwang S. Chalas E. Pameijer C.R.J. Primary extrauterine endometrial stromal cell sarcoma: a case and review J. Gastrointest. Cancer 39 2008 104 106 19333789 \n13 Doghri R. Mrad K. Driss M. Sassi S. Abbes I. Dhouib R. Hechiche M. Romdhane K.B. Endometrial stromal sarcoma presenting as a cystic abdominal mass Pathologica 101 2009 93 96 19886556 \n14 Bosincu L. Massarelli G. Cossu Rocca P. Isaac M.A. Nogales F.F. Rectal endometrial stromal sarcoma arising in endometriosis: report of a case Dis. Colon Rectum 44 2001 890 892 11391154 \n15 Ghosal T. Roy A. Kurian S. Primary extrauterine endometrial stromal sarcoma: located in pelvic and abdominal tissue and arising in endometriosis Indian J. Pathol. Microbiol. 57 2014 447 449 25118742 \n16 Baiocchi G. Kavanagh J.J. Wharton J.T. Endometrioid stromal sarcomas arising from ovarian and extraovarian endometriosis: report of two cases and review of the literature Gynecol. Oncol. 36 1990 147 151 2403959 \n17 Mourra N. Tiret E. Parc Y. de Saint-Maur P. Parc R. Flejou J.F. Endometrial stromal sarcoma of the rectosigmoid colon arising in extragonadal endometriosis and revealed by portal vein thrombosis Arch. Pathol. Lab. Med. 125 2001 1088 1090 11473465 \n18 Yantiss R.K. Clement P.B. Young R.H. Neoplastic and pre-neoplastic changes in gastrointestinal endometriosis: a study of 17 cases Am. J. Surg. Pathol. 24 2000 513 524 10757398 \n19 Katre R. Morani A.K. Prasad S.R. Surabhi V.R. Choudhary S. Sunnapwar A. Tumors and pseudotumors of the secondary müllerian system: review with emphasis on cross-sectional imaging findings AJR Am J. Roentgenol. 195 2010 1452 1459 21098209 \n20 Rauh-Hain J.A. del Carmen M.G. Endometrial stromal sarcoma: a systematic review Obstet. Gynecol. 122 2013 676 683 23921879 \n21 Chang K.L. Crabtree G.S. Lim-Tan S.K. Kempson R.L. Hendrickson M.R. Primary extrauterine endometrial stromal neoplasms: a clinicopathologic study of 20 cases and a review of the literature Int. J. Gynecol. Pathol. 12 1993 282 296 8253545 \n22 Kovac D. Gasparović I. Jasic M. Fuckar D. Dobi-Babić R. Haller H. Endometrial stromal sarcoma arising in extrauterine endometriosis: a case report Eur. J. Gynaecol. Oncol. 26 2005 113 116 15755017 \n23 Fukunaga M. Ishihara A. Ushigome S. Extrauterine low-grade endometrial stromal sarcoma: report of three cases Pathol. Int. 48 1998 297 302 9648159\n\n",
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"issn_linking": "2210-2612",
"issue": "36()",
"journal": "International journal of surgery case reports",
"keywords": "Endometrial stromal sarcoma; Extrauterine; Hormone replacement therapy; Omentum",
"medline_ta": "Int J Surg Case Rep",
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"nlm_unique_id": "101529872",
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"pages": "8-14",
"pmc": null,
"pmid": "28494324",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": "19886556;25960975;11391154;12068150;23710389;24121169;8253545;25118742;17262201;15755017;11473465;19333789;25648532;23921879;2403959;21098209;27613565;22413936;9648159;18325474;21424099;15679447;10757398",
"title": "An unexpected diagnosis of primary omental endometrial stromal sarcoma in a patient with acute right abdominal pain: A case report and review of literature.",
"title_normalized": "an unexpected diagnosis of primary omental endometrial stromal sarcoma in a patient with acute right abdominal pain a case report and review of literature"
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"abstract": "In patients with mechanical aortic and mitral valves and left ventricular (LV) tachycardia (VT), catheter ablation is technically challenging due to the limited access to the LV. Promising new alternatives to radiofrequency ablation include pulsed-field electroporation, percutaneous or surgical sympathetic neuromodulation, and noninvasive stereotactic radioablation therapy (SBRT). We herein describe the effect of SBRT as a bailout therapy on the management of a challenging VT case in the presence of double left-sided mechanical valves.",
"affiliations": "Department of Cardiology, University of Health Sciences, Ankara City Hospital, Ankara, Turkey.;Department of Radiation Oncology, University of Health Sciences, Ankara City Hospital, Ankara, Turkey.;Department of Nuclear Medicine, University of Health Sciences, Ankara City Hospital, Ankara, Turkey.;Department of Cardiovascular Surgery, University of Health Sciences, Ankara City Hospital, Ankara, Turkey.;Department of Cardiology, University of Health Sciences, Ankara City Hospital, Ankara, Turkey.;Department of Cardiology, University of Health Sciences, Ankara City Hospital, Ankara, Turkey.;Department of Nuclear Medicine, University of Health Sciences, Ankara City Hospital, Ankara, Turkey.;Department of Cardiology, University of Health Sciences, Ankara City Hospital, Ankara, Turkey.;Department of Cardiology, University of Health Sciences, Ankara City Hospital, Ankara, Turkey.;Department of Cardiology, University of Health Sciences, Ankara City Hospital, Ankara, Turkey.;Department of Cardiology, University of Health Sciences, Ankara City Hospital, Ankara, Turkey.;Department of Radiation Oncology, University of Health Sciences, Ankara City Hospital, Ankara, Turkey.",
"authors": "Aras|Dursun|D|;Ozturk|Huseyin Furkan|HF|;Ozdemir|Elif|E|;Kervan|Umit|U|;Kara|Meryem|M|;Cay|Serkan|S|;Coskun|Nazim|N|;Ozcan|Firat|F|;Korkmaz|Ahmet|A|;Ozeke|Ozcan|O|;Topaloglu|Serkan|S|;Tezcan|Yilmaz|Y|",
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"doi": "10.19102/icrm.2021.120902",
"fulltext": "\n==== Front\nJ Innov Card Rhythm Manag\nJ Innov Card Rhythm Manag\nJICRM\nThe Journal of Innovations in Cardiac Rhythm Management\n2156-3977\n2156-3993\nMediaSphere Medical United States\n\nicrm.2021.120902\n10.19102/icrm.2021.120902\nCase Report\nUse of Stereotactic Radioablation Therapy as a Bailout Therapy for Refractory Ventricular Tachycardia in a Patient with a No-entry Left Ventricle\nAras Dursun MD 1\nOzturk Huseyin Furkan MD 2\nOzdemir Elif MD 3\nKervan Umit MD 4\nKara Meryem MD 1\nCay Serkan MD 1\nCoskun Nazim MD 3\nOzcan Firat MD 1\nKorkmaz Ahmet MD 1\nOzeke Ozcan MD 1\nTopaloglu Serkan MD 1\nTezcan Yilmaz MD 2\n1Department of Cardiology, University of Health Sciences, Ankara City Hospital, Ankara, Turkey\n2Department of Radiation Oncology, University of Health Sciences, Ankara City Hospital, Ankara, Turkey\n3Department of Nuclear Medicine, University of Health Sciences, Ankara City Hospital, Ankara, Turkey\n4Department of Cardiovascular Surgery, University of Health Sciences, Ankara City Hospital, Ankara, Turkey\nAddress correspondence to: Ozcan Ozeke, MD, Sağlık Bilimleri Üniversitesi, Ankara Şehir Hastanesi, Kardiyoloji Klinigi, Bilkent, Ankara 06800, Turkey. Email: ozcanozeke@gmail.com.\nThe authors report no conflicts of interest for the published content.\n\n15 9 2021\n9 2021\n12 9 46714675\n06 12 2020\n25 1 2021\nCopyright: © 2021 Innovations in Cardiac Rhythm Management\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nIn patients with mechanical aortic and mitral valves and left ventricular (LV) tachycardia (VT), catheter ablation is technically challenging due to the limited access to the LV. Promising new alternatives to radiofrequency ablation include pulsed-field electroporation, percutaneous or surgical sympathetic neuromodulation, and noninvasive stereotactic radioablation therapy (SBRT). We herein describe the effect of SBRT as a bailout therapy on the management of a challenging VT case in the presence of double left-sided mechanical valves.\n\nMechanical aortic and mitral valve\nno-entry left ventricle\nrefractory ventricular tachycardia\nSBRT\nstereotactic radioablation therapy\n==== Body\npmcIntroduction\n\nIn patients with mechanical aortic and mitral valves and left ventricular (LV) tachycardia (VT), catheter ablation is technically challenging due to the limited access to the LV. Several operators have reported on the application of non-conventional techniques for VT ablation, including transventricular septal puncture, transmechanical valve, transcoronary venous, and transapical approaches.1–5 Promising alternatives to radiofrequency ablation include percutaneous or surgical sympathetic neuromodulation, alcohol ablation from the coronary arterial or venous system, direct current or pulsed-field electroporation, and noninvasive stereotactic radioablation therapy (SBRT) in critically ill patients.6–9 We herein describe the effect of SBRT as a bailout therapy on the management of a challenging VT case with two mechanical valve prostheses in aortic and mitral positions.2\n\nCase presentation\n\nA 58-year-old man with two mechanical valves in mitral and aortic positions was referred after multiple appropriate implantable cardioverter-defibrillator shocks despite oral amiodarone and mexiletine therapies. He had nonischemic, valvular, dilated cardiomyopathy with an LV ejection fraction of 15% and had undergone implantation of a cardiac resynchronization therapy (CRT) device 10 years prior. His documented monomorphic VT suggested a lateral mid-LV exit (Figure 1). Due to his previous double valve surgery, we planned and performed an epicardial VT ablation via a lateral thoracotomy (Figure 2A). Electroanatomic mappings (CARTO® 3; Biosense Webster, Diamond Bar, CA, USA) showed scar regions containing local abnormal ventricular activities (LAVAs) in the inferolateral wall of the LV (Figure 2B). Despite epicardial LAVA ablation, after five months, recurrent VT episodes with similar exit sites from previously delineated scar regions recurred under amiodarone, mexiletine, and sotalol therapies. We also transiently switched off the CRT device to exclude the possible lead-related VT, as there are some controversial data concerning the proarrhythmic or antiarrhythmic potential of CRT therapy.10 As all available cardiologic therapeutic strategies failed to free the patient from VT recurrence, we decided to implement SBRT as a therapy of last resort after discussions in our group and with the patient and his relatives. In the next step, positron-emission tomography-computed tomography (PET-CT) showed hypometabolic scar areas in the inferolateral walls corresponding with previous electroanatomic maps (Figure 2C). A four-dimensional (4D) CT scan (General Electric Healthcare, Milwaukee, WI, USA) with 10 respiratory phases was performed for radiotherapy planning using an alpha cradle and a chest board for immobilization after an eight-hour fast. After transferring the CT images to the radiotherapy planning system (Eclipse™; Varian Medical Systems, Palo Alto, CA, USA), an average-phase CT (avgCT) was created to evaluate cardiac and respiratory movements. After the fusion of PET-CT and avgCT images using the RT planning software (Varian Medical Systems) (Figures 2C–2F), an inferolateral hypometabolic scar region with the guidance of electroanatomic mapping was created as the internal gross target volume (IGTV). To overcome any uncertainties during positioning, motion, and therapy, a 5-mm safety margin was added to the IGTV for obtaining the final planned target volume (PTV) (Figure 3). Before treatment delivery, re-imaging with cone-beam CT was performed for comparison and alignment of images with simulation images. All treatment procedures were handled by a team of electrophysiologists, radiation oncologists, nuclear medicine specialists, and radiation physicists. Radiotherapy was given using a linear accelerator device (TrueBeam®; Varian Medical). A total dose of 25 Gy was delivered in a single fraction to the PTV in 7.5 minutes to be targeted by at least 95% of the given dose. Despite rare hemodynamically stable slow VT episodes responding to antitachycardia pacing, a significant reduction in VT episodes was observed within the first eight months after radioablation therapy (Figure 2G). No abnormal device parameters nor acute or chronic adverse effects were detected at 10 months. At present, the patient is being followed up with at the outpatient clinic.\n\nDiscussion\n\nThe growing burden of ventricular arrhythmias and their significant morbidity and mortality rates demand new effective therapeutic approaches based on a given patient’s triggers, comorbidities, and underlying pathology. Mechanical prosthetic aortic and mitral valves impede either a retrograde aortic or transseptal approach to the LV endocardium. SBRT, delivered in a single dose of 25 Gy, may serve as an alternative or palliative therapy for otherwise untreatable patients with refractory VT and electrical storm who are otherwise ineligible for catheter ablation,6,11–13 potentially keeping ventricular arrhythmias quiescent while awaiting heart transplantation,14 as was done in the current case. Because of its high precision and target conformity, it can deliver a high dose of radiation to a specific area in tissue without significantly affecting the nearby tissues.15–18 Indeed, the radiobiology of this treatment when applied to noncancer myocytes is limited, but endothelial vacuolization is a well-described effect of radiation.19 There have been studies that have investigated single-fraction whole-heart irradiation in animal models, and these demonstrated dose-dependent myocardial degeneration and fibrosis progressing from the epicardial tissue to full transmurality in the months after irradiation at doses of 20 Gy and higher.20,21 Histopathologic findings in the human myocardium after SBRT for recalcitrant VT have also provided radiobiological mechanisms of acute cellular injury during SBRT for VT, which may have an antiarrhythmic effect before the onset of fibrosis.22 These data suggest that SBRT can also be used as a relatively acute antiarrhythmic palliation in patients with electrical storm.21 Nonetheless, the optimal dose regimen has yet to be elucidated, and the long-term efficacy and toxicity of SBRT remain unsettled. Before more data on efficacy and safety are obtained, it could be offered as a “bailout” procedure after failed endo- and/or epicardial catheter ablation.12,23 The current case suggested that the noninvasive SBRT was applicable as a potential salvage treatment option for patients with double mechanical valves with dosage at 25 Gy providing the safest short-term profile. A recent systematic literature review summarized that VT was targeted with reduction in the number of episodes beyond 85% during follow-up, with an encouraging short-term safety profile.24 Nevertheless, the same analysis revealed significant heterogeneity in the available study designs, limiting the clinical evidence on the efficacy and safety of SBRT.24 Moving forward, randomized clinical trials will be essential to establish the safety, efficacy, and comparative effectiveness of this new and promising modality.23\n\nFigure 1: Twelve-lead electrocardiogram showing the patient’s clinical VT suggesting the exit of tachycardia at the left mid-ventricular inferolateral area.\n\nFigure 2: After a mini-thoracotomy (A), three-dimensional mapping (B) with images of PET-CT (C) and 4D CT (D–F) were used to detect the target substrate. The noninvasive SBRT (red arrow) was applied successfully in March 2020 (G). FVT, fascicular ventricular tachycardia; LAVAs, local abnormal ventricular activities; LV, left ventricular; SBRT, stereotactic radioablation therapy; VF, ventricular fibrillation; VT, ventricular tachycardia.\n\nFigure 3: Treatment plan by the isodose distribution of SBRT in axial (A), coronal (C), and sagittal (D) orientation is shown with PTV (B). Color lines delineate areas with the same dose (isodose lines). CT, computed tomography; PTV, planned target volume; SBRT, stereotactic radioablation therapy.\n==== Refs\nReferences\n\n1. Aras D Topaloglu S Ozeke O Ozcan F Cay S Golbasi Z Percutaneous interventricular septal access guided by subcostal echocardiography and fluoroscopy for ventricular tachycardia ablation in a patient with aortic and mitral mechanical valves J Innov Card Rhythm Manag 2019 10 7 3719 3721 [CrossRef][PubMed] 32477738\n2. Ozeke O Cay S Ozcan F Topaloglu S Aras D The reentry circuit and route in no entry left ventricle situations for ventricular tachycardia ablations Pacing Clin Electrophysiol 2018 41 6 678 [CrossRef][PubMed] 29656452\n3. Vurgun VK Altin AT Kilickap M Candemir B Akyurek O Percutaneous transapical approach and transcatheter closure for ventricular tachycardia ablation Pacing Clin Electrophysiol 2018 41 6 680 [CrossRef][PubMed] 29635829\n4. Yorgun H Canpolat U Nof E Transapical left ventricular access for ventricular tachycardia ablation in patients with mechanical aortic and mitral valve prosthesis Circ Arrhythm Electrophysiol 2020 13 10 e008893 [CrossRef][PubMed] 32921133\n5. Santangeli P Hyman MC Muser D Callans DJ Shivkumar K Marchlinski FE Outcomes of percutaneous trans-right atrial access to the left ventricle for catheter ablation of ventricular tachycardia in patients with mechanical aortic and mitral valves JAMA Cardiol 2020 6 3 1 6 [CrossRef][PubMed]\n6. Robinson CG Samson PP Moore KMS Phase I/II trial of electrophysiology-guided noninvasive cardiac radioablation for ventricular tachycardia Circulation 2019 139 3 313 321 [CrossRef][PubMed] 30586734\n7. Kim EJ Davogustto G Stevenson WG John RM Non-invasive cardiac radiation for ablation of ventricular tachycardia: a new therapeutic paradigm in electrophysiology Arrhythm Electrophysiol Rev 2018 7 1 8 10 [CrossRef][PubMed] 29636967\n8. Cuculich PS Schill MR Kashani R Noninvasive cardiac radiation for ablation of ventricular tachycardia N Engl J Med 2017 377 24 2325 2336 [CrossRef][PubMed] 29236642\n9. Aksu T Guler TE Bozyel S Yalin K Gopinathannair R Potential therapeutic effects of electrogram-guided cardioneuroablation in long QT syndrome: case series J Interv Card Electrophysiol 2020 7 23 [Epub ahead of print]. [CrossRef][PubMed]\n10. Kawamura M Arai S Yoshikawa K Association left ventricular lead and ventricular arrhythmias after upgrade to cardiac resynchronization therapy in patients with implantable cardioverter defibrillators Clin Cardiol 2019 42 7 670 677 [CrossRef][PubMed] 31056759\n11. Lloyd MS Wight J Schneider F Clinical experience of stereotactic body radiation for refractory ventricular tachycardia in advanced heart failure patients Heart Rhythm 2020 17 3 415 422 [CrossRef][PubMed] 31585181\n12. Jumeau R Ozsahin M Schwitter J Rescue procedure for an electrical storm using robotic non-invasive cardiac radio-ablation Radiother Oncol 2018 128 2 189 191 [CrossRef][PubMed] 29753550\n13. Jumeau R Ozsahin M Schwitter J Stereotactic radiotherapy for the management of refractory ventricular tachycardia: promise and future directions Front Cardiovasc Med 2020 7 108 [CrossRef][PubMed] 32671101\n14. Lyle M Lloyd M Higgins K Stereotactic body radiation for refractory ventricular tachycardia in patients with left ventricular assist devices J Heart Lung Transplant 2020 39 4 S349 10.1016/j.healun.2020.01.402\n15. Refaat MM Zakka P Youssef B Zeidan YH Geara F Al-Ahmad A Noninvasive cardioablation Card Electrophysiol Clin 2019 11 3 481 485 [CrossRef][PubMed] 31400872\n16. Weidlich GA Hacker F Bellezza D Maguire P Gardner EA Ventricular tachycardia: a treatment comparison study of the cyberknife with conventional linear accelerators Cureus 2018 10 10 e3445 [CrossRef][PubMed] 30555760\n17. John RM Shinohara ET Price M Stevenson WG Radiotherapy for ablation of ventricular tachycardia: assessing collateral dosing Comput Biol Med 2018 102 376 380 [CrossRef][PubMed] 30126615\n18. Kelsey KL Kubicek LN Bacon NJ Torres T Robertson SA Neuromuscular blockade and inspiratory breath hold during stereotactic body radiation therapy for treatment of heart base tumors in four dogs J Am Vet Med Assoc 2017 250 2 199 204 [CrossRef][PubMed] 28058956\n19. Shim S Lee JG Bae CH Claudin-3 expression in radiation-exposed rat models: a potential marker for radiation-induced intestinal barrier failure Biochem Biophys Res Commun 2015 456 1 351 354 [CrossRef][PubMed] 25475725\n20. Kruse JJ Zurcher C Strootman EG Structural changes in the auricles of the rat heart after local ionizing irradiation Radiother Oncol 2001 58 3 303 311 [CrossRef][PubMed] 11230892\n21. Lauk S Kiszel Z Buschmann J Trott KR Radiation-induced heart disease in rats Int J Radiat Oncol Biol Phys 1985 11 4 801 808 [CrossRef][PubMed] 3980275\n22. Kiani S Kutob L Schneider F Higgins KA Lloyd MS Histopathologic and ultrastructural findings in human myocardium after stereotactic body radiation therapy for recalcitrant ventricular tachycardia Circ Arrhythm Electrophysiol 2020 13 11 e008753 [CrossRef][PubMed] 33031001\n23. Neuwirth R Cvek J Knybel L Stereotactic radiosurgery for ablation of ventricular tachycardia Europace 2019 21 7 1088 1095 [CrossRef][PubMed] 31121018\n24. van der Ree MH Blanck O Limpens J Cardiac radioablation-A systematic review Heart Rhythm 2020 17 8 1381 1392 [CrossRef][PubMed] 32205299\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2156-3977",
"issue": "12(9)",
"journal": "The Journal of innovations in cardiac rhythm management",
"keywords": "Mechanical aortic and mitral valve; SBRT; no-entry left ventricle; refractory ventricular tachycardia; stereotactic radioablation therapy",
"medline_ta": "J Innov Card Rhythm Manag",
"mesh_terms": null,
"nlm_unique_id": "101589872",
"other_id": null,
"pages": "4671-4675",
"pmc": null,
"pmid": "34595050",
"pubdate": "2021-09",
"publication_types": "D002363:Case Reports",
"references": "31400872;29656452;32671101;32205299;32477738;30555760;33031001;30126615;32997112;11230892;31056759;3980275;32921133;31121018;29753550;32700129;29236642;25475725;29636967;29635829;28058956;31585181;30586734",
"title": "Use of Stereotactic Radioablation Therapy as a Bailout Therapy for Refractory Ventricular Tachycardia in a Patient with a No-entry Left Ventricle.",
"title_normalized": "use of stereotactic radioablation therapy as a bailout therapy for refractory ventricular tachycardia in a patient with a no entry left ventricle"
} | [
{
"companynumb": "TR-SUN PHARMACEUTICAL INDUSTRIES LTD-2022RR-326677",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMIODARONE"
},
"drug... |
{
"abstract": "There is a lack of knowledge regarding the incidence of serious adverse drug reactions (ADR) to the oral iron chelator deferiprone in Chinese children with transfusion-dependent thalassaemia. In this retrospective population-based cohort study, paediatric thalassaemia patients in Hong Kong were screened for serious and medically important adverse events related to deferiprone therapy using diagnosis codes, laboratory data and hospital admissions. Potential ADRs were assessed by reviewing concomitant medications, diagnoses and laboratory data and evaluated using standardised causality assessment. Eighty-seven patients contributing 169.8 person-years were included. Thirty ADRs were identified in 21 patients. Most ADRs (56.0%) occurred in the first three months of therapy. Neutropenia occurred in 11 patients (12.6%; incidence rate 6.5 per 100 patient-years) and severe neutropenia (agranulocytosis) was observed in 5 patients (5.7%, incidence rate 2.9 per 100 patient-years). Other identified ADRs involve severe arthropathy, elevated liver enzymes and mild thrombocytopenia. In conclusion, the safety profile of DFP therapy in Chinese children suffering from transfusion-dependent thalassaemia is in line with previous studies of non-Chinese children. However, unlike previous studies, we observed a relatively high incidence of agranulocytosis and neutropenia in patients with simultaneous combined therapy. Hence close monitoring for white blood cell counts is advised in Chinese children under combined iron chelation therapy. Further prospective clinical and pharmacogenetic studies are required to better evaluate this important safety signal.\n\n\nCONCLUSIONS\n• Half of the identified ADRs related to deferiprone therapy occurred during the first three months of treatment. • A relatively high incidence of agranulocytosis and neutropenia. Hence close monitoring for white blood cell counts is advised in Chinese children under combined iron chelation therapy.",
"affiliations": "Research Department of Practice & Policy, University College London, School of Pharmacy, 29-39 Brunswick Square, London, UK. i.wong@ucl.ac.uk.",
"authors": "Botzenhardt|Sebastian|S|;Sing|Chor W|CW|;Wong|Ian C K|IC|;Chan|Godfrey Chi-Fung|GC|;Wong|Lisa Y L|LY|;Felisi|Mariagrazia|M|;Rascher|Wolfgang|W|;Ceci|Adriana|A|;Neubert|Antje|A|",
"chemical_list": "D007502:Iron Chelating Agents; D011728:Pyridones; D000077543:Deferiprone",
"country": "United Arab Emirates",
"delete": false,
"doi": "10.2174/1574886310666150930113957",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1574-8863",
"issue": "11(2)",
"journal": "Current drug safety",
"keywords": null,
"medline_ta": "Curr Drug Saf",
"mesh_terms": "D000284:Administration, Oral; D000293:Adolescent; D016907:Adverse Drug Reaction Reporting Systems; D000380:Agranulocytosis; D001803:Blood Transfusion; D002648:Child; D002675:Child, Preschool; D002681:China; D015331:Cohort Studies; D000077543:Deferiprone; D005260:Female; D006801:Humans; D007502:Iron Chelating Agents; D008297:Male; D009503:Neutropenia; D011159:Population Surveillance; D011728:Pyridones; D012189:Retrospective Studies; D013789:Thalassemia",
"nlm_unique_id": "101270895",
"other_id": null,
"pages": "137-44",
"pmc": null,
"pmid": "26419768",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Safety Profile of Oral Iron Chelator Deferiprone in Chinese Children with Transfusion-Dependent Thalassaemia.",
"title_normalized": "safety profile of oral iron chelator deferiprone in chinese children with transfusion dependent thalassaemia"
} | [
{
"companynumb": "DE-APOPHARMA-2015AP015658",
"fulfillexpeditecriteria": "1",
"occurcountry": "HK",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASCORBIC ACID"
},
"drugadditional": null,
... |
{
"abstract": "In this case report we discuss changes in hospital-based abortion care due to the COVID-19 pandemic. We highlight our experience with exposure to an asymptomatic COVID-19 positive patient. We hope early lessons from the United States epicenter will guide clinicians providing abortion care during this and future pandemics.",
"affiliations": "Columbia University Irving Medical Center, Department of Obstetrics and Gynecology, Division of Family Planning and Preventive Services, 622 West 168th St, PH 16-69, New York, NY 10032, United States. Electronic address: nf2466@cumc.columbia.edu.;Columbia University Irving Medical Center, Department of Obstetrics and Gynecology, Division of Family Planning and Preventive Services, 622 West 168th St, PH 16-69, New York, NY 10032, United States.;Columbia University Irving Medical Center, Department of Obstetrics and Gynecology, Division of Family Planning and Preventive Services, 622 West 168th St, PH 16-69, New York, NY 10032, United States.",
"authors": "Fang|Nancy Z|NZ|;Castaño|Paula M|PM|;Davis|Anne|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.contraception.2020.05.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0010-7824",
"issue": "102(2)",
"journal": "Contraception",
"keywords": "Abortion; COVID-19; Pandemic",
"medline_ta": "Contraception",
"mesh_terms": "D000028:Abortion, Induced; D000328:Adult; D000755:Anemia, Sickle Cell; D058345:Asymptomatic Infections; D000073640:Betacoronavirus; D000086382:COVID-19; D018352:Coronavirus Infections; D054810:Deep Sedation; D018450:Disease Progression; D005260:Female; D006760:Hospitalization; D006801:Humans; D007902:Length of Stay; D058873:Pandemics; D011024:Pneumonia, Viral; D011247:Pregnancy; D011250:Pregnancy Complications, Hematologic; D011251:Pregnancy Complications, Infectious; D000086402:SARS-CoV-2; D061665:Time-to-Treatment",
"nlm_unique_id": "0234361",
"other_id": null,
"pages": "137-138",
"pmc": null,
"pmid": "32416144",
"pubdate": "2020-08",
"publication_types": "D002363:Case Reports",
"references": "32292903;32305073",
"title": "A hospital-based COVID-19 abortion case in the early phase of the pandemic.",
"title_normalized": "a hospital based covid 19 abortion case in the early phase of the pandemic"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-258624",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXYCYCLINE"
},
"dru... |
{
"abstract": "Eruptive epidermoid cysts are a rare adverse event of imiquimod treatment for basal cell carcinoma. Up to date, 8 cases have been described in the literature. We present the case of a 75-year-old Caucasian woman with recurrent basal cell carcinoma on the nose. After multiple excisions and treatment with vismodegib, imiquimod 5% cream was administered 5 times per week over 6 weeks. Two months after the end of treatment, the patient presented with eruptive epidermoid cysts.",
"affiliations": "Univ.-Augenklinik, Medizinische Universität Graz, Auenbruggerplatz 4, 8036, Graz, Österreich. n.woltsche@medunigraz.at.;Univ.-Klinik für Dermatologie & Venerologie, Medizinische Universität Graz, Graz, Österreich.;Univ.-Klinik für Dermatologie & Venerologie, Medizinische Universität Graz, Graz, Österreich.;Univ.-Klinik für Dermatologie & Venerologie, Medizinische Universität Graz, Graz, Österreich.;Kennedy Institut für Rheumatologie, Universität Oxford, Oxford, Großbritannien.;Univ.-Klinik für Dermatologie & Venerologie, Medizinische Universität Graz, Graz, Österreich.;Abteilung für Dermatologie & Venerologie, Klinik Maggiore, Triest, Italien.",
"authors": "Woltsche|Nora|N|;El-Shabrawi-Caelen|Laila|L|;Deinlein|Teresa|T|;Kupsa|Romana|R|;Gschwandtner|Martha|M|;Hofmann-Wellenhof|Rainer|R|;Zalaudek|Iris|I|",
"chemical_list": "D000634:Aminoquinolines; D000970:Antineoplastic Agents; D000077271:Imiquimod",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00105-019-4359-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0017-8470",
"issue": "70(5)",
"journal": "Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandte Gebiete",
"keywords": "Adverse event; Excision; Immunomodulators; Infundibular cysts; Skin cancer",
"medline_ta": "Hautarzt",
"mesh_terms": "D000368:Aged; D000634:Aminoquinolines; D000970:Antineoplastic Agents; D002280:Carcinoma, Basal Cell; D004814:Epidermal Cyst; D005260:Female; D006801:Humans; D000077271:Imiquimod; D012878:Skin Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "0372755",
"other_id": null,
"pages": "363-366",
"pmc": null,
"pmid": "30694354",
"pubdate": "2019-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16029707;17911995;18991155;22652500;24575881;25695444;27230691;27377695;27387373;27765414",
"title": "Eruptive epidermoid cysts after imiquimod treatment of recurrent basal cell carcinoma : A case report.",
"title_normalized": "eruptive epidermoid cysts after imiquimod treatment of recurrent basal cell carcinoma a case report"
} | [
{
"companynumb": "AT-TOLMAR, INC.-TOLG20190060",
"fulfillexpeditecriteria": "1",
"occurcountry": "AT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IMIQUIMOD"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nDual antiplatelet therapy has been adopted as the standard of care for intracranial stenting, including flow diversion of cerebral aneurysms, to reduce the risk of acute and delayed ischemic complications.\n\n\nMETHODS\nThis is a report of 2 cases in which patients who underwent flow diversion of unruptured internal carotid artery aneurysms were treated with aspirin monotherapy. Neither patient tolerated dual antiplatelet therapy, one because of nosebleeds due to hereditary hemorrhagic telangiectasia and one because of an unnamed bleeding disorder. The lesions-a previously coiled, recanalizing dorsal internal carotid artery aneurysm and a small superior hypophyseal aneurysm-were each treated with a single Pipeline Flex embolization device and were completely occluded with normal-appearing parent vessel on 12-month follow-up digital subtraction angiography.\n\n\nCONCLUSIONS\nThis is the first report of patients electively treated with flow diversion using Pipeline Flex embolization device on aspirin monotherapy in the literature.",
"affiliations": "Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York, USA. Electronic address: matthew_bender@urmc.rochester.edu.;Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.;Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.;Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.;Department of Neurosurgery, University of California Irvine, Orange, California, USA.;Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.;Department of Neurosurgery, University of California Los Angeles, Los Angeles, California, USA.;Department of Neurosurgery, Carondelet Neurological Institute, Tucson, Arizona, USA.",
"authors": "Bender|Matthew T|MT|;Zarrin|David A|DA|;Jiang|Bowen|B|;Campos|Jessica K|JK|;Lin|Li-Mei|LM|;Young|Robert W|RW|;Colby|Geoffrey P|GP|;Coon|Alexander L|AL|",
"chemical_list": "D001241:Aspirin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.wneu.2019.06.161",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-8750",
"issue": "134()",
"journal": "World neurosurgery",
"keywords": "Aspirin; Flow diversion; Pipeline embolization device; Single-antiplatelet therapy",
"medline_ta": "World Neurosurg",
"mesh_terms": "D015901:Angiography, Digital Subtraction; D001241:Aspirin; D002340:Carotid Artery Diseases; D002343:Carotid Artery, Internal; D002533:Cerebral Angiography; D004621:Embolization, Therapeutic; D005260:Female; D006801:Humans; D002532:Intracranial Aneurysm; D016896:Treatment Outcome",
"nlm_unique_id": "101528275",
"other_id": null,
"pages": "580-583",
"pmc": null,
"pmid": "31254705",
"pubdate": "2020-02",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Aspirin Monotherapy in Flow Diversion of Selected Internal Carotid Artery Aneurysms.",
"title_normalized": "aspirin monotherapy in flow diversion of selected internal carotid artery aneurysms"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-335405",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadd... |
{
"abstract": "Anti-glomerular basement membrane (anti-GBM) glomerulonephritis is a rare disease caused by autoantibodies against the glomerular basement membrane. Atypical anti-GBM nephritis is clinically less aggressive and characterized by the absence of circulating autoantibodies to the basement membrane. A previously healthy 53-year-old white woman presented with a rising creatinine over a short observation period. Renal biopsy, urinary sediment, and laboratory testing confirmed the diagnosis of atypical anti-GBM disease. She received plasmapheresis, steroids, and cyclophosphamide. She developed hemorrhagic cystitis early in the treatment from oral cyclophosphamide and mycophenolate mofetil was substituted as a first-line drug. She responded favorably and continued on mycophenolate mofetil without evidence of relapse. Despite the absence of circulating autoantibodies, a diagnosis of atypical anti-GBM nephritis should not be excluded if a high index of clinical suspicion exists. Early renal biopsy should be considered. Mycophenolate mofetil may be a reasonable replacement for oral cyclophosphamide in the treatment of atypical anti-GBM disease when cyclophosphamide is contraindicated.",
"affiliations": "Department of Medicine, Orlando Regional Healthcare, Orlando, Florida, USA.;Department of Medicine, Orlando Regional Healthcare, Orlando, Florida, USA.;Department of Medicine, Orlando Regional Healthcare, Orlando, Florida, USA.;Division of Nephrology, Orlando Regional Healthcare, Orlando, Florida, USA.;Department of Medicine, Orlando Regional Healthcare, Orlando, Florida, USA.;Division of Academic Affairs and Research, Orlando Regional Healthcare, Orlando, Florida, USA.",
"authors": "Olivier|Maxim|M|;Watson|Harold|H|;Lee|Danielle|D|;Mohanlal|Viresh|V|;Madruga|Mario|M|;Carlan|Steven|S|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000498844",
"fulltext": "\n==== Front\nCase Rep Nephrol DialCase Rep Nephrol DialCNDCase Reports in Nephrology and Dialysis2296-9705S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000498844cnd-0009-0008Case ReportMonotypic IgG1-kappa Atypical Anti-Glomerular Basement Membrane Nephritis: A Case Report Olivier Maxim aWatson Harold aLee Danielle aMohanlal Viresh cMadruga Mario aCarlan Steven b*aDepartment of Medicine, Orlando Regional Healthcare, Orlando, Florida, USAbDivision of Academic Affairs and Research, Orlando Regional Healthcare, Orlando, Florida, USAcDivision of Nephrology, Orlando Regional Healthcare, Orlando, Florida, USA*Steven Carlan, 1401 Lucerne Terrace, 2nd floor, Orlando, FL 32806 (USA), E-Mail stevecarlan@gmail.comJan-Apr 2019 28 2 2019 28 2 2019 9 1 8 14 19 9 2018 9 2 2019 2019 Copyright © 2019 by S. Karger AG, Basel2019This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Anti-glomerular basement membrane (anti-GBM) glomerulonephritis is a rare disease caused by autoantibodies against the glomerular basement membrane. Atypical anti-GBM nephritis is clinically less aggressive and characterized by the absence of circulating autoantibodies to the basement membrane. A previously healthy 53-year-old white woman presented with a rising creatinine over a short observation period. Renal biopsy, urinary sediment, and laboratory testing confirmed the diagnosis of atypical anti-GBM disease. She received plasmapheresis, steroids, and cyclophosphamide. She developed hemorrhagic cystitis early in the treatment from oral cyclophosphamide and mycophenolate mofetil was substituted as a first-line drug. She responded favorably and continued on mycophenolate mofetil without evidence of relapse. Despite the absence of circulating autoantibodies, a diagnosis of atypical anti-GBM nephritis should not be excluded if a high index of clinical suspicion exists. Early renal biopsy should be considered. Mycophenolate mofetil may be a reasonable replacement for oral cyclophosphamide in the treatment of atypical anti-GBM disease when cyclophosphamide is contraindicated.\n\nKey Words\nRenal failureAtypical anti-glomerular basement membraneNephritisMycophenolate mofetil\n==== Body\nIntroduction\nAnti-glomerular basement membrane (GBM) antibody nephritis is a rare autoimmune disorder characterized by the presence of circulating anti-GBM antibodies and diffuse linear staining for immunoglobulins along the GBM detected through immunofluorescence microscopy [1]. Classic anti-GBM disease typically presents with rapidly progressive glomerulonephritis and most cases are dialysis dependent on diagnosis or have a fast progression to end-stage renal disease despite intensive immunosuppressive therapy and plasmapheresis [2]. Pulmonary involvement can occur in up to half of the cases of classic anti-GBM disease and usually presents with pulmonary hemorrhage. Recently, atypical forms of the disease have been reported with a more indolent clinical course and no pulmonary involvement. Absent detectable circulating autoantibodies but intact linear deposition and staining of the GBM for immunoglobulin G (IgG) through immunofluorescence technique is the hallmark of the diagnosis for atypical cases [3, 4].\n\nEarly detection through renal biopsy is critical since aggressive therapy is likely to preserve renal function long-term and delay or decrease the need for maintenance dialysis. The proposed treatment strategy for both classic and atypical anti-GBM disease has remained unchanged for decades and consists of intensive plasmapheresis combined with prednisone and cyclophosphamide [5]. There is no established second-line treatment, only rare reports of success with mycophenolate mofetil in place of cyclophosphamide [6].\n\nWe present a case of indolent atypical anti-GBM disease with no detectable circulating anti-GBM antibody diagnosed by an early renal biopsy and characterized by a contraindication to cyclophosphamide use resulting in mycophenolate mofetil selection as the primary immunosuppressant.\n\nCase\nA 53-year-old white female with a past medical history of hypothyroidism was referred to a nephrologist after detecting a serum creatinine of 1.8 mg/dL on routine lab work. Initially this finding was thought to be transient; however, labs the following month showed serum creatinine increased to 2.4 mg/dL. Her only medications included levothyroxine (0.088 mg, once daily) and an occasional over-the-counter nonsteroidal anti-inflammatory drug, which she was advised to discontinue. She denied any symptoms including dysuria, increased urinary frequency, hematuria, rashes, ulcers, or joint pains or recent respiratory infections. She denied hemoptysis, cough, or dyspnea. Physical examination was unremarkable without evidence of pulmonary pathology. Laboratory studies on admission 2 weeks later showed the following values: serum creatinine of 1.89 mg/dL; albumin, 3.6 g/dL; hemoglobin, 9.8 g/dL; white blood cell count, 8.8 × 103/µL; platelet count, 225 × 103/µL. Urine studies revealed 3+ occult blood, 11–30 red blood cells, and a protein/creatinine ratio of 655 mg/g creatinine (normal, 0–200). The glomerular filtration rate was 28 mL/min/SA (surface area). In addition, tests for complements, anti-DNA (deoxyribonucleic acid) antibody, ANA (antinuclear antibody), MPO (myeloperoxidase), c-ANCA (cytoplasmic antineutrophil cytoplasmic antibodies), p-ANCA (perinuclear antineutrophil cytoplasmic antibodies) (typical and atypical), anti-proteinase 3 antibody and SPEP (serum protein electrophoresis), and UPEP (urine protein electrophoresis) were all normal. Her GBM IgG antibody was negative and no monoclonal bands were detected on urine or serum IFE (immunofixation electrophoresis). Hepatitis B surface antigen and hepatitis C antibody were both negative. Because of the rapid deterioration of renal function, screening renal ultrasound was considered redundant and thus cancelled. Kidney biopsy revealed linear staining along the GBMs by monotypic IgG1-kappa (Fig. 1) with numerous red blood cell casts (Fig. 2), interstitial fibrosis, tubular atrophy, moderate arteriosclerosis, and moderate arteriolar hyalinosis of moderate chronicity. Electron microscopic examination of the glomerulus (Fig. 3) revealed widespread effacement of the foot processes and absence of any immune complex electron dense deposits. These microscopic findings along with serological results were diagnostic for atypical anti-GBM disease.\n\nShe was started on a 3-day regimen of intravenous methylprednisolone 500 mg daily for 3 days then switched to oral prednisone 60 mg/day, 150 mg oral cyclophosphamide daily, and 5 sessions of plasmapheresis. Repeat serology was still negative. Pulmonary exams were consistently clear to auscultation without abnormalities and there were never any upper respiratory symptoms such as cough, hemoptysis, sputum production, or rhinitis. Thus, no chest imaging was done as it was not warranted. She was discharged from the hospital and 10 days into the treatment course, she developed hemorrhagic cystitis. Oral cyclophosphamide was discontinued and prednisone was reduced to 40 mg/day. Mycophenolate mofetil 500 mg twice daily by mouth was added. Three months after discharge, she was asymptomatic on mycophenolate mofetil 1,500 mg twice per day and prednisone 20 mg/day but had developed mild essential hypertension treated with losartan 25 mg/day. Her blood pressure on her last clinic visit was 113/75. Her 3-month follow-up labs showed improvement of the serum creatinine to 1.38 mg/dL, estimated glomerular filtration rate 45 mL/min/1.73 (normal > 59), and random protein/creatinine 374 mg/g creatinine.\n\nResults\nThis case is notable for three reasons. First, atypical anti-GBM nephritis is extremely rare, with less than 30 cases reported, and consequently requires a high level of clinical suspicion to diagnose [4]. The disease process is a result of autoantibodies to alpha-3 chain of type IV collagen in the basement membrane of the glomerulus [7]. Around 50% of cases will also have lung involvement and that condition is known as Goodpasture's disease [8]. The features of the atypical presentation of anti-GBM disease include absence of both the lung involvement and undetectable circulating anti-GBM antibody. The lack of detectable offending antibodies is curious and there are several listed theories. Two possible explanations include the pathogenic antibodies produced by the patient are directed against an antigen other than the basement membrane collagen, or secondly, there is lower or transient antibody production making it undetectable by standard tests [9].\n\nRegardless of the cause, however, using positive serologic antibody screening is not possible to rule in the disease. In fact, serologic testing is not completely reliable to make a rapid diagnosis. Since early diagnosis of the disease is important to begin treatment that could maintain renal function, an aggressive position on early renal biopsy is prudent. That is what happened in our case. The patient originally was thought to have temporary elevation of serum creatinine secondary to nonsteroidal use, but the clinical suspicion of an alternative cause resulted in recommendation of an early renal biopsy. The biopsy findings in our case were consistent with the clinical suspicion of atypical disease.\n\nThe second reason this case is unique is the approach to treatment modification that was necessary secondary to contraindications to cyclophosphamide. She was offered the standard treatment for classic anti-GBM nephritis. This choice was considered since, to date, there is no standardized therapeutic protocol for the treatment of atypical anti-GBM nephritis. Most cases of atypical anti-GBM nephritis are managed in a similar fashion as classic anti-GBM nephritis with a combination of aggressive plasmapheresis combined with steroids and cyclophosphamide. However, there are three reports of initial management with mycophenolate mofetil rather than cyclophosphamide. One case reported complete remission and the other two reported residual renal dysfunction. The clinical outcome probably represents the stage of disease at the beginning of treatment rather than the specific agent itself [8]. Mycophenolate mofetil is an immunosuppressive agent that was initially developed as an antirejection drug and has a much more favorable toxicity profile than cyclophosphamide [6]. It has been used successfully to treat Goodpasture's disease and may be, as shown in this case, an agent that can be used as both an initial drug and a long-term immunosuppressant. How long immunosuppression should continue appears to be dependent on the level of renal disease and the antibody profile from the immunofluorescence microscopy. Those with extensive, irreversible disease should be weaned off immunosuppression as soon as possible, while those with ongoing active disease and salvageable renal function should maintain aggressive suppression [8]. Based on the clinical findings and biopsy results, we elected to recommend continued immunosuppression with mycophenolate mofetil while following her labs. Another drug that has been used to treat anti-GBM disease is rituximab. When it became apparent that the cyclophosphamide was no longer an option, our patient was counseled about this agent but declined. Rituximab is an antineoplastic agent that is reported to be useful in the treatment of anti-GBM nephritis, but there are serious reported reactions to the drug [10].\n\nThe third unique feature of this case is the antibody profile from the immunofluorescence microscopy. We found 2+ linear staining along the GBM with antibodies against IgG and kappa. All other stains including lambda were negative and there was no significant extraglomerular staining. Additional sections were incubated with antibodies specific for the subclasses of IgG, revealing 2+ linear staining with antibodies against IgG1 and no significant staining with antibodies against IgG2, lgG3, or lgG4. This is unusual because IgG1-kappa anti-GBM nephritis has been reported only three previous times [9]. Two of the reported IgG1-kappa anti-GBM nephritis cases were treated initially with cyclophosphamide and two were relapsing [4, 10]. There were no data on the initial treatment regimen or pathogenicity for the third case [4], and our case would be the fourth. Although data are limited, atypical IgG1-kappa anti-GBM nephritis appears to be characterized as a relapsing disease [11]. This is important in determining how to chronically manage the patient. Her notable non-dialysis-dependent level of renal involvement and her antibody profile from the immunofluorescence microscopy suggests she should be offered long-term mycophenolate mofetil both as a primary agent and as a steroid-sparing agent for maintenance immunosuppression.\n\nConclusion\nThis report describes a case of atypical IgG1-kappa anti-GBM nephritis that was diagnosed early by renal biopsy. The treatment was modified secondary to toxicity and early follow-up indicates there is no relapse yet. Early renal biopsy is critical in this condition. Determining the method of chronic management and length of treatment should reflect the likelihood of relapse.\n\nStatement of Ethics\nThe authors have no ethical conflicts to disclose.\n\nDisclosure Statement\nThere are no potential conflicts of interest for any of the authors with products or techniques discussed in the paper.\n\nFunding Sources\nThere is no funding information to report.\n\nAuthor Contributions\nStudy design: A; data collection: B; statistical analysis: C; data interpretation: D; manuscript preparation: E; literature search: F; funds collection: G (no funds were collected).\n\nMaxim Olivier: A, B, D, E, F; Harold Watson: B, F; Danielle Lee: A, F; Viresh Mohanlal: B, D, F; Mario Madruga: B, D, E; Steve J. Carlan: A, E, F.\n\nAcknowledgements\nNo acknowledgements, financial supports, or grants to report.\n\nFig. 1. Immunofluorescence shows 2+ linear stating along the glomerular basement membrane with antibodies against IgG (a) and kappa (b). All other stains including lambda (c) and albumin (d) were negative. IgG1 subclass shows 2+ linear staining of glomerular basement membrane (e). Staining for IgG subclasses IgG2, IgG3, and IgG4 was negative (not shown).\n\nFig. 2. H&E staining on light microscopy shows RBC casts of varying ages in the tubular lumens.\n\nFig. 3. Electron microscopic examination of glomerulus reveals widespread effacement of the foot processes (black arrows) and absence of any immune complex electron dense deposits.\n==== Refs\nReferences\n1 Salama AD Levy JB Lightstone L Pusey CD Goodpasture's disease Lancet 2001 358 917 9 11567730 \n2 Cui Z Zhao MH Xin G Wang HY Characteristics and prognosis of Chinese patients with anti-glomerular basement membrane disease Nephron Clin Pract 2005 99 (2) c49 55 15637429 \n3 Troxell ML Houghton DC Atypical anti-glomerular basement membrane disease Clin Kidney J 2016 4 9 (2) 211 21 26985371 \n4 Nasr SH Collins AB Alexander MP Schraith DF Herrera Hernandez L Fidler ME The clinicopathologic characteristics and outcome of atypical anti-glomerular basement membrane nephritis Kidney Int 2016 4 89 (4) 897 908 26994577 \n5 Levy JB Turner AN Rees AJ Pusey CD Long-term outcome of anti-glomerular basement membrane antibody disease treated with plasma exchange and immunosuppression Ann Intern Med 2001 6 134 (11) 1033 42 11388816 \n6 Mori M Nwaogwugwu U Akers GR McGill RL Anti-glomerular basement membrane disease treated with mycophenolate mofetilcorticosteroids, and plasmapheresis Clin Nephrol 2013 7 80 (1) 67 71 23803597 \n7 Pedchenko V Bondar O Fogo AB Vanacore R Voziyan P Kitching AR Molecular architecture of the Goodpasture autoantigen in anti-GBM nephritis N Engl J Med 2010 7 363 (4) 343 54 20660402 \n8 L'Imperio V Ajello E Pieruzzi F Nebuloni M Tosoni A Ferrario F Clinicopathological characteristics of typical and atypical anti-glomerular basement membrane nephritis J Nephrol 2017 8 30 (4) 503 9 28382508 \n9 Syeda UA Singer NG Magrey M Anti-glomerular basement membrane antibody disease treated with rituximab: A case-based review Semin Arthritis Rheum 2013 6 42 (6) 567 72 23352254 \n10 Bahrainwala JZ Stokes MB Hannani AK Hogan JJ Atypical antiglomerular basement membrane disease with IgG1-κ staining Kidney Int Rep 2016 8 2 (1) 80 3 29142944 \n11 Coley SM Shirazian S Radhakrishnan J D'Agati VD Monoclonal IgG1κ anti-glomerular basement membrane disease: a case report Am J Kidney Dis 2015 2 65 (2) 322 6 25446021\n\n",
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"keywords": "Atypical anti-glomerular basement membrane; Mycophenolate mofetil; Nephritis; Renal failure",
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"title": "Monotypic IgG1-kappa Atypical Anti-Glomerular Basement Membrane Nephritis: A Case Report.",
"title_normalized": "monotypic igg1 kappa atypical anti glomerular basement membrane nephritis a case report"
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"abstract": "A 76-year-old man complicated with end-stage renal disease had latent tuberculosis infection (LTBI), and isoniazid (INH) 300 mg daily was started to prevent reactivation of LTBI before using biologic agents for rheumatoid arthritis. On the 8th day after administration of INH, he presented with a fever, petechiae, and myalgia. Serological studies revealed elevated myogenic enzymes and creatinine level. Based on the exclusion of other etiologies, rapid improvement with cessation of INH, and the recurrence of the fever and myalgia with re-administration of a reduced dose of INH, we diagnosed him with INH-induced rhabdomyolysis. Physicians should be aware of rhabdomyolysis induced by INH at a therapeutic dose as an infrequent but potentially fatal adverse drug reaction.",
"affiliations": "Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Japan.;Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Japan.;Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Japan.;Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Japan.",
"authors": "Komai|Toshihiko|T|;Sumitomo|Shuji|S|;Teruya|Shuzo|S|;Fujio|Keishi|K|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000995:Antitubercular Agents; D007538:Isoniazid",
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"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2952695610.2169/internalmedicine.0463-17Case ReportRhabdomyolysis Induced by Isoniazid in a Patient with Rheumatoid Arthritis and End-stage Renal Disease: A Case Report and Review of the Literature Komai Toshihiko 1Sumitomo Shuji 1Teruya Shuzo 1Fujio Keishi 1\n1 Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, JapanCorrespondence to Dr. Shuji Sumitomo, sumitos-tky@umin.ac.jp\n\n9 3 2018 15 8 2018 57 16 2413 2416 5 11 2017 28 12 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/).A 76-year-old man complicated with end-stage renal disease had latent tuberculosis infection (LTBI), and isoniazid (INH) 300 mg daily was started to prevent reactivation of LTBI before using biologic agents for rheumatoid arthritis. On the 8th day after administration of INH, he presented with a fever, petechiae, and myalgia. Serological studies revealed elevated myogenic enzymes and creatinine level. Based on the exclusion of other etiologies, rapid improvement with cessation of INH, and the recurrence of the fever and myalgia with re-administration of a reduced dose of INH, we diagnosed him with INH-induced rhabdomyolysis. Physicians should be aware of rhabdomyolysis induced by INH at a therapeutic dose as an infrequent but potentially fatal adverse drug reaction. \n\nlatent tuberculosis infectionrhabdomyolysisisoniazidrheumatoid arthritisend-stage renal disease\n==== Body\nIntroduction\nBiologic agents have become a part of the mainstream therapy for rheumatoid arthritis (RA); however, the blockade of pro-inflammatory cytokines increases the risk of reactivation of intracellular pathogens, especially Mycobacterium tuberculosis (TB). To avoid the reactivation of latent TB infection (LTBI), appropriate screening and therapy for LTBI is necessary for patients with RA who plan to start biologic therapy (1).\n\nIsoniazid (INH) is recommended for the standard treatment of LTBI (2) and is known to have a high efficacy for preventing the progression to active TB (3, 4). INH reduces active TB by approximately 85% in RA patients treated with biologic agents (1). INH is metabolized and cleared predominantly in the liver (5); well-known adverse drug reactions include neuropathy (6) and hepatotoxicity (7).\n\nWe herein report a rare case of rhabdomyolysis induced by INH at a therapeutic dose. Written informed consent for the publication was obtained from the patient.\n\nCase Report\nA 76-year-old Japanese man had a 17-year history of seropositive RA. He also had a history of chronic kidney disease (stage G5A3) with a glomerular filtration rate <15 mL/min due to nephrosclerosis. He had a history of treatment with methotrexate, sulfasalazopyridine, bucillamine, and tacrolimus, but the efficacy was limited. Subsequently, he was treated with prednisolone (5 mg daily) and lobenzarit (40 mg daily), but the disease activity remained high. Therefore, the use of biologic agents was considered. He had fibronodular changes in the upper lobes bilaterally and a positive tuberculin skin test. Therefore, LTBI was diagnosed. INH (300 mg daily) was started to prevent reactivation of LTBI before starting biologic agents.\n\nOn the 8th day after the administration of INH, he developed a fever, petechiae in the lower extremities, and intermittent myalgia in the thighs. A physical examination revealed tenderness in the thighs without muscle weakness. Serologic studies showed the following: creatine kinase, 11,253 U/L [reference value (RV), 59-248 U/L]; myoglobin, 13,900 ng/mL (RV, <154.9 ng/mL); and creatinine, 3.8 mg/dL (RV, 0.65-1.07 mg/dL; Table 1). The urine myoglobin level was also elevated to 21,850 ng/mL (RV, <10 ng/mL). Based on a detailed medical interview, prior trauma, muscle compression, heat stroke, and infection were excluded. All bacterial cultures were negative, and viral antibody tests excluded a viral infection. Thyroid function tests were within normal limits, and autoantibodies against Jo-1 and aminoacyl tRNA synthetase were not detected. All drugs, except for INH, had been taken for a long period of time, and statins were not included. The serum concentrations of INH at 3 and 24 hours after the last INH administration were 2.93 and 0.58 μg/mL, respectively, which was consistent with a previous pharmacokinetic study (8). The cessation of INH and intravenous hydration significantly ameliorated the rhabdomyolysis and acute kidney injury within 7 days (Table 1). The re-administration of INH at a reduced dose to 200 mg every other day was planned 1 month after his complete recovery of rhabdomyolysis under hospitalization with detailed informed consent. He developed a fever and systemic myalgia with a single-dose administration of 200 mg INH, although his serum creatine kinase (CK) level was not elevated.\n\nTable 1. Time Courses of Laboratory Findings.\n\n\tBaseline\t8 Days after INH Intake\t7 Days after INH Cessation\tRV\t\nWBC (103 cells/μL)\t12.6\t7.0\t12.9\t3.3 - 8.6\t\nNeutrophil (%)\t84.1\t82.2\t62.7\t44 - 74\t\nLymphocyte (%)\t9.1\t10.4\t28.0\t30 - 40\t\nMonocyte (%)\t5.0\t4.9\t5.6\t2 - 10\t\nEosinophil (%)\t1.4\t2.4\t3.3\t0 - 5\t\nBasophil (%)\t0.4\t0.1\t0.4\t0 - 2\t\nHb (g/dL)\t10.6\t9.4\t9.0\t13.7 - 16.8\t\nPlatelet (104 cells/μL)\t23.6\t14.9\t37.0\t15.8 - 34.8\t\nProcalcitonin (ng/mL)\tnot evaluated\t2.49\tnot evaluated\t0 - 0.49\t\nCK (U/L)\t70\t11,253\t23\t59 - 248\t\nCK-MB (U/L)\tnot evaluated\t13\t7\t0 - 12\t\nBUN (mg/dL)\t36.5\t43.0\t36.5\t8.0 - 20.0\t\nCr (mg/dL)\t2.30\t3.80\t2.40\t0.65 - 1.07\t\nAST (U/L)\t15\t182\t19\t13 - 30\t\nALT (U/L)\t9\t14\t32\t10 - 42\t\nCRP (mg/dL)\t0.28\t13.72\t0.86\t0.0 - 0.3\t\nINH: isoniazid, RV: reference value, WBC: white blood cell, Hb: hemoglobin, CK: creatine kinase, BUN: blood urea nitrogen, Cr: creatinine, Mb: myoglobin, AST: aspartate transaminase, ALT: alanine transaminase, CRP: C-reactive protein\n\nDiscussion\nRhabdomyolysis is a life-threating condition resulting from the breakdown of muscles and leakage of muscle cell contents (9). Medications are a potential cause of this condition, and lipid-modifying agents, including hydroxymethylglutaryl (HMG)-CoA reductase inhibitors, antipsychotics, and anesthetic agents, are frequently reported to the US Food and Drug Administration (FDA) as causes of drug-associated rhabdomyopathy (10). Although rhabdomyolysis induced by an overdose of more than 2.4 g INH has been reported (11-13), there are quite a few case reports of rhabdomyolysis induced by INH at therapeutic doses (14, 15) (Table 2). Our case differs from these reports in that rhabdomyolysis occurred only several days after the INH intake, but the clinical course implied that INH induced rhabdomyolysis as an adverse drug reaction based on the two causality assessment systems proposed by Naranjo (16) (Table 3) and the World Health Organization Uppsala Monitoring Centre (WHO-UMC) (17) (Table 4). Dose adjustment of INH for renal impairment is usually unnecessary because INH is metabolized and cleared predominantly in the liver, and our patient did not have a significant elevation in the serum concentration of INH. However, decreased isoniazid acetylation in chronic renal failure (18) can cause the accumulation of hydrazine, a metabolite of INH, as the concentration of hydrazine is predicted to be high in slow acetylators (19). Further pharmacokinetic analyses of INH and its metabolites in end-stage renal failure are awaited.\n\nTable 2. Literature Review of Isoniazid-induced Rhabdomyolysis.\n\nCase\tAge\tSex\tEthnicity\tApplication of INH\tDosage of INH\tComorbidities and risks\tMaximal CK levels\tReference No.\t\n1\t17\tF\tn.d.\tPositive PPD test\t10.8 g (intoxication)\tSeizure, Hepatitis\t88,000 U/L (RV<390)\t12\t\n2\t16\tM\tn.d.\tTuberculosis prophylaxis\t6.0 g (intoxication)\tSeizure, Usage of intramuscular pyridoxine\t22,673 U/L (RV; n.d.)\t13\t\n3\t25\tF\tBlacks\tPositive PPD test\t300 mg daily for 4 months (poor compliance)\tPreceding viral infection\t168,000 U/L (RV; n.d.)\t14\t\n4\t56\tM\tChinese\tTreatment of pulmonary TB\t300 mg daily for 5 months\tDilated cardiomyopathy Chronic heart failure\t14,781 U/L (RV<306)\t15\t\n5\t76\tM\tJapanese\tPrevention for LTBI\t300 mg daily for 8 days\tRheumatoid arthritis End-stage renal disease\t11,253 U/L (RV<248)\tPresent case\t\nINH: isoniazid, TB: tuberculosis, LTBI: latent TB infection, CK: creatine kinase, RV: reference value, PPD: purified protein derivative, n.d.: not demonstrated\n\nTable 3. Systematic Causality Assessment by Naranjo’s Algorithm.\n\nQuestionnaire\tScore\tScore of Our Case\t\n1. Are there previous conclusive reports on this reaction?\tYES=+1\nNO=0\nDo not know or not done=0\t0\t\n2. Did the adverse event appear after the suspected drug was administered?\tYES=+2\nNO=-1\nDo not know or not done=0\t+2\t\n3. Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered?\tYES=+1\nNO=0\nDo not know or not done=0\t+1\t\n4. Did the adverse reaction reappear after the drug was readministered?\tYES=+2\nNO=-1\nDo not know or not done=0\t+2\t\n5. Are there alternative causes (other than the drug) that could on their own have caused the reaction?\tYES=-1\nNO=+2\nDo not know or not done=0\t+2\t\n6. Did the reaction reappear when a placebo was given?\tYES=-1\nNO=+1\nDo not know or not done=0\t0\t\n7. Was the drug detected in the blood (or other fluids) in concentrations known to be toxic?\tYES=+1\nNO=0\nDo not know or not done=0\t0\t\n8. Was the reaction more severe when the dose was increased, or less severe when the dose was decreased?\tYES=+1\nNO=0\nDo not know or not done=0\t+1\t\n9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure?\tYES=+1\nNO=0\nDo not know or not done=0\t0\t\n10. Was the adverse event confirmed by any objective evidence?\tYES=+1\nNO=0\nDo not know or not done=0\t+1\t\nScoring:\t>8=definite ADR, 5-8=probable ADR \n1-4=possible ADR, 0=Doubtful ADR\t\tTotal score: 9\t\nADR: adverse drug reaction\n\nTable 4. Systematic Causality Assessment by World Health Organization Uppsala Monitoring Centre.\n\nAssessment Criteria of Causality ’Probable/Likely’\tOur Case\t\n· Event of laboratory test abnormality, with reasonable time relationship to drug intake\tYes\t\n· Unlikely to be attributed to disease or other drugs\tYes\t\n· Response to withdrawal clinically reasonable\tYes\t\n· Rechallenge not required\t\t\nOur patient's rapid development of recurrent adverse events on the re-administration of INH suggests an allergic mechanism. However, in contrast to the previous reports of rhabdomyolysis and hypersensitivity syndrome (20-25), our case did not present with typical skin rashes or a fever and myalgia, suggesting that other etiologies may have induced the adverse events.\n\nOne of the mechanisms suspected to underlie rhabdomyolysis is the depletion of ATP within myocytes (9). Recently, statin-induced myopathy has been reported to be caused by the inhibition of mitochondrial respiration and ATP production (26). In addition, INH induces mitochondrial dysfunction and ATP depletion, which results in hepatocellular injury (27). INH can inhibit the mitochondrial function and cause rhabdomyolysis via a mechanism similar to that of statin-induced rhabdomyolysis. Our case indicates that INH at a therapeutic dose can induce rhabdomyolysis, and caution should therefore be practiced when prescribing INH.\n\n\nAuthor's disclosure of potential Conflicts of Interest (COI).\n\nToshihiko Komai: Patent royalties, Chugai Pharmaceutical. Shuji Sumitomo: Honoraria, AbbVie, Eisai, Chugai Pharmaceutical, Takeda, Bristol-Myers Squibb, Astrazeneca and UCB. Keishi Fujio: Patent royalties, Chugai Pharmaceutical; Honoraria, Bristol-Myers Squibb, Chugai Pharmaceutical, Pfizer, AbbVie, Eli Lilly, Astellas Pharma, Daiichi-Sankyo, Mitsubishi Tanabe Pharma, Santen, Takeda, Eisai, Taisho Toyama, UCB, Janssen and Nippon Kayaku; Research funding, Takeda Pharmaceutical, Chugai Pharmaceutical, Bristol-Myers Squibb, Mitsubishi Tanabe Pharma, Eli Lilly and Astellas Pharma.\n==== Refs\n1. Winthrop KL , Chiller T \nPreventing and treating biologic-associated opportunistic infections . Nat Rev Rheumatol \n5 : 405 -410 , 2009 .19568254 \n2. McClintock AH , Eastment M , McKinney CM , et al \nTreatment completion for latent tuberculosis infection: a retrospective cohort study comparing 9 months of isoniazid, 4 months of rifampin and 3 months of isoniazid and rifapentine . BMC Infect Dis \n17 : 146 , 2017 .28196479 \n3. Targeted tuberculin testing and treatment of latent tuberculosis infection . Am J Respir Crit Care Med \n161 : S221 -S247 , 2000 .10764341 \n4. Stagg HR , Zenner D , Harris RJ , Muñoz L , Lipman MC , Abubakar I \nTreatment of latent tuberculosis infection . Ann Intern Med \n161 : 419 , 2014 .25111745 \n5. Wang P , Pradhan K , Zhong X , Ma X \nIsoniazid metabolism and hepatotoxicity . Acta Pharm Sin B \n6 : 384 -392 , 2016 .27709007 \n6. Vilholm OJ , Christensen AA , Zedan AH , Itani M \nDrug-induced peripheral neuropathy . Basic Clin Pharmacol Toxicol \n115 : 185 -192 , 2014 .24786912 \n7. Nolan CM , Goldberg SV , Buskin SE \nHepatotoxicity associated with isoniazid preventive therapy: a 7-year survey from a public health tuberculosis clinic . JAMA \n281 : 1014 -1018 , 1999 .10086436 \n8. Peloquin CA , Jaresko GS , Yong CL , Keung ACF , Bulpitt AE , Jelliffe RW \nPopulation pharmacokinetic modeling of isoniazid, rifampin, and pyrazinamide . Antimicrob Agents Chemother \n41 : 2670 -2679 , 1997 .9420037 \n9. Bosch X , Poch E , Grau JM \nRhabdomyolysis and acute kidney injury . N Engl J Med \n361 : 62 -72 , 2009 .19571284 \n10. Oshima Y \nCharacteristics of drug-associated rhabdomyolysis: analysis of 8,610 cases reported to the U.S. Food and Drug Administration . Intern Med \n50 : 845 -853 , 2011 .21498932 \n11. Panganiban LR , Makalinao IR , Corte-Maramba NP \nRhabdomyolysis in isoniazid poisoning . J Toxicol Clin Toxicol \n39 : 143 -151 , 2001 .11407500 \n12. Blowey DL , Johnson D , Verjee Z \nIsoniazid-associated rhabdomyolysis . Am J Emerg Med \n13 : 543 -544 , 1995 .7662061 \n13. Eyüboğlu T , Derinöz O \nRhabdomyolysis due to isoniazid poisoning resulting from the use of intramuscular pyridoxine . Turk J Pediatr \n55 : 328 -330 , 2013 .24217082 \n14. Cronkright PJ , Szymaniak G \nIsoniazid and rhabdomyolysis . Ann Intern Med \n110 : 945 , 1989 .\n15. Liu P , Zheng H , Yuan W , Nie R , Wang J \nIsoniazid-induced rhabdomyolysis in a patient with chronic heart failure: a case report . Chin Med J (Engl) \n123 : 502 -504 , 2010 .20193494 \n16. Naranjo CA , Busto U , Sellers EM , et al \nA method for estimating the probability of adverse drug reactions . Clin Pharmacol Ther \n30 : 239 -245 , 1981 .7249508 \n17. Varallo FR , Planeta CS , Herdeiro MT , Mastroianni P de C \nImputation of adverse drug reactions: causality assessment in hospitals . PLoS One \n12 : e0171470 , 2017 .28166274 \n18. Kim YG , Shin JG , Shin SG , et al \nDecreased acetylation of isoniazid in chronic renal failure . Clin Pharmacol Ther \n54 : 612 -620 , 1993 .8275616 \n19. Federico P , Rosanna M , Missimo B , Giovanni T , Mario F \nIsoniazid and its hydrazine metabolite in patients with tuberculosis . Clin Drug Investig \n17 : 145 -154 , 1999 .\n20. Arnold PA , Guglielmo BJ , Hollander H \nSevere hypersensitivity reaction upon rechallenge with trimethoprim-sulfamethoxazole in a patient with AIDS . Drug Intell Clin Pharm \n22 : 43 -45 , 1988 .2965002 \n21. Compton MR , Crosby DL \nRhabdomyolysis associated with azathioprine hypersensitivity syndrome . Arch Dermatol \n132 : 1254 -1255 , 1996 .\n22. Rahman Z , Weinberg J , Scheinfeld N \nMinocycline hypersensitivity syndrome manifesting with rhabdomyolysis . Int J Dermatol \n41 : 530 -531 , 2002 .12207780 \n23. Kong Q , Sang H , Zhang M , et al \nRhabdomyolysis associated with roxithromycin hypersensitivity syndrome . Indian J Dermatol Venereol Leprol \n78 : 197 -199 , 2012 .22421658 \n24. Huang LY , Lin CM , Chiou CC , Lin WS , Cheng SM \nRhabdomyolysis as a potential complication of carbamazepine-induced toxic epidermal necrolysis . Clin Biochem \n45 : 1531 -1532 , 2012 .22728955 \n25. Kellett S , Cock C \nA case of drug reaction with eosinophilia and systemic symptoms . Case Rep Med \n2012 : 705190 , 2012 .22966234 \n26. Schirris TJJ , Renkema GH , Ritschel T , et al \nStatin-induced myopathy is associated with mitochondrial complex III inhibition . Cell Metab \n22 : 399 -407 , 2015 .26331605 \n27. Lee KK , Fujimoto K , Zhang C , et al \nIsoniazid-induced cell death is precipitated by underlying mitochondrial complex i dysfunction in mouse hepatocytes . Free Radic Biol Med \n65 : 584 -594 , 2013 .23911619\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "57(16)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "end-stage renal disease; isoniazid; latent tuberculosis infection; rhabdomyolysis; rheumatoid arthritis",
"medline_ta": "Intern Med",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D000995:Antitubercular Agents; D001172:Arthritis, Rheumatoid; D006801:Humans; D007538:Isoniazid; D007676:Kidney Failure, Chronic; D055985:Latent Tuberculosis; D008297:Male; D012206:Rhabdomyolysis; D016896:Treatment Outcome",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "2413-2416",
"pmc": null,
"pmid": "29526956",
"pubdate": "2018-08-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "10086436;22728955;27709007;11407500;24217082;28166274;8275616;25111745;7662061;19571284;2965002;22966234;9420037;19568254;10764341;23911619;7249508;8859049;26331605;24786912;28196479;21498932;12207780;22421658;20193494;2719433",
"title": "Rhabdomyolysis Induced by Isoniazid in a Patient with Rheumatoid Arthritis and End-stage Renal Disease: A Case Report and Review of the Literature.",
"title_normalized": "rhabdomyolysis induced by isoniazid in a patient with rheumatoid arthritis and end stage renal disease a case report and review of the literature"
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"abstract": "Non-tuberculous mycobacterial adenitis is getting more common in our environment. Epidemiologic studies and clinical trials published nowadays are limited. We present a 2-years-old boy diagnosed of Mycobacterium intracellulare adenitis and severe neutropenia as side effect of combined treatment with oral azythromycin and rifabutin, which recovers after suspending the second one. Liver metabolism of macrolide seems to increase other drugs toxicity, in this case, rifabutin. The patient eventually needed surgery due to persistence of the adenitis despite treatment with antibiotics.",
"affiliations": null,
"authors": "Ruíz del Olmo|Ignacio|I|;Romera|Beatriz|B|;Guerrero|Carmelo|C|;Burgués|Pedro|P|;Bustillo|Matilde|M|",
"chemical_list": "D000900:Anti-Bacterial Agents; D017828:Rifabutin; D017963:Azithromycin",
"country": "Chile",
"delete": false,
"doi": null,
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"issn_linking": "0716-1018",
"issue": "32(5)",
"journal": "Revista chilena de infectologia : organo oficial de la Sociedad Chilena de Infectologia",
"keywords": null,
"medline_ta": "Rev Chilena Infectol",
"mesh_terms": "D000900:Anti-Bacterial Agents; D017963:Azithromycin; D002675:Child, Preschool; D004359:Drug Therapy, Combination; D006801:Humans; D008199:Lymphadenitis; D008297:Male; D009165:Mycobacterium Infections, Nontuberculous; D009503:Neutropenia; D017828:Rifabutin; D012720:Severity of Illness Index",
"nlm_unique_id": "9305754",
"other_id": null,
"pages": "584-7",
"pmc": null,
"pmid": "26633119",
"pubdate": "2015-10",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Severe neutropenia as side effect of medical treatment in nontuberculous mycobacterial adenitis.",
"title_normalized": "severe neutropenia as side effect of medical treatment in nontuberculous mycobacterial adenitis"
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"companynumb": "ES-PFIZER INC-2015441863",
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"abstract": "Nivolumab shows promising efficacy against metastatic melanoma. However, immune-related adverse events are of great concern. We herein report a case of persistent colitis that developed during nivolumab monotherapy and nivolumab readministration. An 82-year-old Japanese woman with recurrent melanoma developed Grade 3 colitis after 6 cycles of nivolumab. She was treated with corticosteroid for 28 days. Follow-up by computed tomography and colonoscopy after corticosteroid treatment revealed persistent pancolitis. Her symptoms ameliorated spontaneously in two months. Given the amelioration, nivolumab was restarted and resulted in the maintenance of stable disease for 21 months without recurrence of colitis. Even in cases of persistent colitis over several months, nivolumab readministration should be considered.",
"affiliations": "Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Japan.;Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Japan.;Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Japan.;Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Japan.;Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Japan.;Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Japan.;Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Japan.",
"authors": "Fujii|Yosuke|Y|;Nishikawa|Yoshitaka|Y|;Nomura|Motoo|M|;Miyamoto|Shin'ich|S|;Uneno|Yu|Y|;Horimatsu|Takahiro|T|;Muto|Manabu|M|",
"chemical_list": "D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000077594:Nivolumab",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.8910-17",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2926964010.2169/internalmedicine.8910-17Case ReportReadministration of Nivolumab after Persistent Immune-related Colitis in a Patient with Recurrent Melanoma Fujii Yosuke 1Nishikawa Yoshitaka 12Nomura Motoo 1Miyamoto Shin'ich 3Uneno Yu 1Horimatsu Takahiro 1Muto Manabu 1\n1 Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Japan\n2 Department of Health Informatics, School of Public Health, Kyoto University, Japan\n3 Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, JapanCorrespondence to Dr. Yoshitaka Nishikawa, ynishikawa-tky@umin.ac.jp\n\n21 12 2017 15 4 2018 57 8 1173 1176 3 2 2017 19 8 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/).Nivolumab shows promising efficacy against metastatic melanoma. However, immune-related adverse events are of great concern. We herein report a case of persistent colitis that developed during nivolumab monotherapy and nivolumab readministration. An 82-year-old Japanese woman with recurrent melanoma developed Grade 3 colitis after 6 cycles of nivolumab. She was treated with corticosteroid for 28 days. Follow-up by computed tomography and colonoscopy after corticosteroid treatment revealed persistent pancolitis. Her symptoms ameliorated spontaneously in two months. Given the amelioration, nivolumab was restarted and resulted in the maintenance of stable disease for 21 months without recurrence of colitis. Even in cases of persistent colitis over several months, nivolumab readministration should be considered. \n\nPD-1 inhibitorimmune-related adverse eventreadministrationcolitismelanoma\n==== Body\nIntroduction\nNivolumab, a programmed cell death protein 1 (PD-1) inhibitor, shows promising efficacy in patients with metastatic melanoma and other solid tumors. However, systemic immune-related adverse events (irAEs), such as interstitial lung disease, liver dysfunction, hypothyroidism, and colitis, are of great concern (1). Approximately 30% of patients develop nivolumab-associated colitis (Common Terminology Criteria for Adverse Events v4.0; CTCAE, any Grade), and less than 10% of patients have severe colitis (Grade 3 or 4). Nivolumab-associated colitis generally occurs one to three months after starting nivolumab therapy (2). As irAEs can occasionally be lethal, the readministration of nivolumab after a severe irAE has been controversial. We herein report a case of restarting nivolumab after recovery from nivolumab-associated colitis.\n\nCase Report\nAn 82-year-old Japanese woman was admitted to our hospital with intermittent severe abdominal pain. She had a history of malignant rectal melanoma treated with transanal tumor resection and 6 subsequent cycles of adjuvant chemotherapy (dacarbazine, nimustine, and vincristine: DAV) 15 years earlier. Four years after the first episode, relapse of the primary rectal lesion was found. With transanal tumor resection and DAV therapy, periodical gallium scintigraphy confirmed no tumor residue. She had been followed-up for three years after the relapse and had finished her periodical checkups seven years earlier.\n\nFour months before admission, she noticed bloody stool. Colonoscopy revealed the recurrence of rectal melanoma at the primary site with pathological confirmation, and computed tomography (CT) detected multiple lesions of para-aortic lymph nodes, lung, liver, and the first lumbar vertebra. We detected no other malignancy. Given the recurrence at the rectal primary site and simultaneous multiple lesions on CT, she was diagnosed with recurrent melanoma with multiple metastasis to the liver, lung, para-aortic lymph node, and first lumbar vertebra. Her Eastern Cooperative Oncology Group performance status was 0. She was administered nivolumab (2 mg/kg) every 3 weeks. After completing six cycles of nivolumab, she developed severe abdominal pain and loose bloody stool twice per day and was referred to our hospital.\n\nShe had a sudden onset of a fever (38.1℃) the day before admission to our institution. A physical examination revealed abdominal tenderness from the left hypochondriac to the lower quadrant region. Laboratory findings showed an increased white blood cell count (12,400/mm3, neutrophils 87%), C-reactive protein level (CRP, 23.0 mg/dL) and decreased hemoglobin (9.7 g/dL). Nuclear antibodies and antineutrophil cytoplasmic antibodies were negative. Contrast-enhanced CT on the day of admission showed that the colonic wall from the cecum to the transverse colon was markedly edematous and thickened (Fig. 1A), which is not consistent with ischemic colitis, as this typically occurs in a localized region, such as the splenic curvature, due to a reduced blood supply from the major arteries. We excluded infectious colitis due to the following clinical findings: Both blood and stool cultures were negative for pathogenic bacteria, and serum testing of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) were negative. These clinical findings and the history of nivolumab therapy suggested an association between colitis and nivolumab therapy. Colonoscopy could not be performed because of severe abdominal pain and the risk of perforation at that time. Colonoscopy was therefore planned after the amelioration of her symptoms.\n\nFigure 1. CT image. (A) The cecal wall was markedly thickened (arrowheads) at the onset of colitis on the day of admission. (B) The thickened cecal wall was improved on day 21 of corticosteroid treatment. (C) Recurrence of thickened cecal wall three weeks after corticosteroid treatment was discontinued.\n\nThe patient discontinued nivolumab and was immediately treated with intravenous prednisolone 2 mg/kg/day combined with antibiotics according to the manufacturer's management guidelines (1). Her abdominal tenderness was relieved in the next day and completely ameliorated after one week. The blood in her stool was resolved, and loose stool once a day was observed until six days after admission. Her hemoglobin level improved from 9.7 g/dL to her baseline level (12 g/dL) after1 week without blood transfusion. Prednisolone was gradually tapered every three days. As her symptoms were ameliorated, colonoscopy was performed on day 9 after admission, revealing pancolitis from the ilium to the descending colon with reddish, edematous erythematous mucosa. Histopathology revealed interstitial edema and inflammatory infiltration of lymphocytes, plasma cells, eosinophils, and neutrophils. The typical findings of ischemic colitis, such as ghost outlines and atrophy of crypt and interstitial eosinophilic deposition, were absent. We confirmed the diagnosis of nivolumab-associated colitis. Three weeks after starting prednisolone treatment, CT revealed that the thickened cecal wall was ameliorated (Fig. 1B). She was discharged on day 22 of hospitalization with prednisolone reduced to 5 mg/day. Corticosteroid treatment was continued for 28 days.\n\nThree weeks after the discontinuation of corticosteroid treatment, she still complained of loose stool. Follow-up CT on day 50 after the first admission revealed recurrent edematous and thickened cecal wall (Fig. 1C). Colonoscopy on day 59 after the first admission showed pancolitis from the ilium to the descending colon with reddish, edematous erythematous mucosa, and a loss of normal vascularity (3,4) (Fig. 2). A histopathological examination of the biopsy specimen revealed mild inflammation with eosinophilic infiltration in the cecal mucosa (3,4) and reconfirmed no evidence of pathogens, including CMV and Mycobacterium tuberculosis. These findings were consistent with recurrence of irAE colitis. To relieve discomfort, the rectal recurrent lesion was endoscopically dissected, confirming the diagnosis of recurrent melanoma without a v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutation.\n\nFigure 2. Colonoscopy images after the discontinuation of corticosteroid treatment. Erythematous mucosa and dilated small vessels (inset).\n\nCareful observation was carried out without reintroduction of corticosteroids (Fig. 3). Follow-up colonoscopy on day 80 after admission confirmed persistent pancolitis with edematous erythematous mucosa. The CRP level remained slightly elevated at around 1.5 mg/dL. It gradually decreased to 0.3 mg/dL, and her loose stool improved spontaneously 2 months after the discontinuation of corticosteroids. With stable clinical symptoms and a normal CRP level, nivolumab was restarted on day 99 after admission. Her condition has remained stable for 21 months without recurrence of irAE colitis or progression of the disease (more than 20% increase in tumor volume or new metastatic lesions).\n\nFigure 3. The clinical course of this patient. CT: computed tomography, CS: colonoscopy, PSL: prednisolone\n\nDiscussion\nTo our knowledge, this is the first case of nivolumab-associated colitis with successfully restarted nivolumab after the recovery from colitis. In the present case, colitis lasted more than three months, including corticosteroid tapering, which was longer than the one month stated in the guidelines (1).\n\nOur patient was followed up carefully after the development of Grade 3 irAE colitis with nivolumab monotherapy. Discontinuation of nivolumab and immunosuppressive therapy (corticosteroid) successfully relieved her symptoms. Corticosteroid administration was gradually tapered over one month. The CT and colonoscopy findings were more severe than the clinical symptoms (i.e. loose stool and abdominal pain) and CRP elevation (<1.5 mg/dL). This case suggests that periodical visits, an in-depth history taking, and careful CRP monitoring combined with CT imaging can assist in the early detection and follow-up of irAE colitis in the clinical setting.\n\nThe persistence of colonic inflammation in this 82-year-old patient suggested that colitis could last for over 3 months. For irAE colitis, the management guidelines recommend continuing steroids until recovery to Grade 1 and then tapering the dose over at least one month (1). Previous clinical studies have reported that irAE colitis was sustained for less than 1 month [median 0.7 weeks (5) and 4.0 weeks (6)]. While some factors have been reported to be associated with the clearance of nivolumab, further investigation is needed to ensure the safe administration of nivolumab.\n\nThe readministration of nivolumab was performed in this case after recovery from severe irAE colitis. With careful observation of clinical symptoms and laboratory data, the patient has maintained a stable condition for 21 months without recurrence of colitis. The readministration of nivolumab after irAEs has been controversial. A previous study reported that 7 out of 20 patients who developed irAE pneumonitis restarted nivolumab, and 5 patients successfully continued without recurrence of irAE pneumonitis (7). With regard to ipilimumab, an early approved immune-checkpoint inhibitor of cytotoxic T-lymphocyte antigen 4 (CTLA4), the accumulation of informative clinical data has indicated that ipilimumab-associated colitis is more frequently observed than nivolumab-associated colitis (8). A previous study reported the successful use of nivolumab after ipilimumab-induced colitis for 11 unresectable metastatic melanoma cases (3 Grade 2, 7 Grade 3, and 1 Grade 4) (9). Another study reported 67 advanced melanoma patients with a history of ipilimumab-induced irAE, and 47 cases of colitis (5 Grade2, 37 Grade 3, and 5 Grade 4) treated with nivolumab attained an average progression-free survival (PFS) of 7.2 months. It was also reported that recurrence of the same irAE was rare (3%, 2/67 cases), even in patients with severe colitis (10). Although molecular immunological evidence was not available in previous reports and this case, the clinical findings suggest that recurrence of irAE at the same organ is not common (10). Thus, readministration can be considered under careful observation. In the present case, restarting nivolumab was the only treatment option, as cytotoxic drugs had already been administered and there was no BRAF mutation.\n\nWith the readministration of nivolumab, our patient successfully maintained stable disease status for 21 months. The present case suggests that the readministration of nivolumab may be a feasible treatment option, even in cases of persistent irAE colitis over a few months.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n\nFinancial Support\nThis study was supported by a grant from the Promotion Plan for the Platform of Human Resource Development for Cancer by Ministry of Education, Culture, Sports, Science and Technology, Japan.\n\nAcknowledgement\nThe authors express sincere gratitude to Dr. Tetsuya Tanimoto (Navitas Clinic, Tokyo, Japan) for his insightful suggestions on drug approval systems in Japan.\n==== Refs\n1. \nOPDIVO Immune-Mediated Adverse Reactions Management Guide. [Internet]. [cited 2017 Jan. 1]. Available from:\nhttp://www.opdivohcp.bmscustomerconnect.com/servlet/servlet.FileDownload?file=00Pi000000Hj19REAR\n\n2. \nVilladolid J , Amin A \nImmune checkpoint inhibitors in clinical practice: update on management of immune-related toxicities . Transl Lung Cancer Res \n4 : 560 -575 , 2015 .26629425 \n3. \nYanai S , Nakamura S , Matsumoto T \nNivolumab induced colitis treated by infliximab . Clin Gastroenterol Hepatol \n15 : e80 -e81 , 2017 (Epub ahead of print).27664866 \n4. \nKubo K , Kato M , Mabe K \nNivolumab-associated colitis mimicking ulcerative colitis . Clin Gastroenterol Hepatol \n15 : A35 -A36 , 2017 (Epub ahead of print).\n5. \nRobert C , Long GV , Brady B , et al \nNivolumab in previously untreated melanoma without BRAF Mutation . N Engl J Med \n372 : 320 -330 , 2015 .25399552 \n6. \nLarkin J , Chiarion-Sileni V , Gonzalez R , et al \nCombined nivolumab and ipilimumab or monotherapy in untreated melanoma . N Engl J Med \n373 : 23 -34 , 2015 .26027431 \n7. \nNishino M , Ramaiya NH , Awad MM , et al \nPD-1 inhibitor-related pneumonitis in advanced cancer patients: Radiographic patterns and clinical course . Clin Cancer Res \n58 : 7250 -7257 , 2016 .\n8. \nJeryl V , Asim A \nImmune checkpoint inhibitors in clinical practice: update on management of immune-related toxicities . Transl Lung Cancer Res \n4 : 560 -575 , 2015 .26629425 \n9. \nGutzmer R , Koop A , Meier F , et al \nProgrammed cell death protein-1 (PD-1) inhibitor therapy in patients with advanced melanoma and preexisting autoimmunity or ipilimumab-triggered autoimmunity . Eur J Cancer \n75 : 24 -32 , 2017 .28214654 \n10. \nMenzies AM , Johnson DB , Ramanujam S , et al \nAnti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab . Ann Oncol \n28 : 368 -376 , 2017 (Epub ahead of print).27687304\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "57(8)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "PD-1 inhibitor; colitis; immune-related adverse event; melanoma; readministration",
"medline_ta": "Intern Med",
"mesh_terms": "D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D003092:Colitis; D005260:Female; D006801:Humans; D008545:Melanoma; D009364:Neoplasm Recurrence, Local; D000077594:Nivolumab",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "1173-1176",
"pmc": null,
"pmid": "29269640",
"pubdate": "2018-04-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "27535979;27664866;26629425;28351793;25399552;28214654;27687304;26027431",
"title": "Readministration of Nivolumab after Persistent Immune-related Colitis in a Patient with Recurrent Melanoma.",
"title_normalized": "readministration of nivolumab after persistent immune related colitis in a patient with recurrent melanoma"
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"drugaddi... |
{
"abstract": "BACKGROUND\nIn Japan, S-1, an oral fluoropyrimidine, plus cisplatin is a standard regimen for advanced gastric cancer, whereas nab-paclitaxel is a treatment option. We aimed to evaluate the tolerance, pharmacokinetics, safety, and clinical efficacy of S-1 combined with nab-paclitaxel in patients with advanced gastric cancer in a phase 1 study.\n\n\nMETHODS\nThe primary objective was to determine the maximum tolerated dose (MTD) and recommended dose (RD) of S-1 plus nab-paclitaxel. The study was designed in accordance with a standard 3 + 3 method. Patients received 3-week cycles of treatment. S-1 was administered orally at 80 mg/m2 twice daily for 14 days, and nab-paclitaxel was administered as an intravenous infusion at 180, 220, or 260 mg/m2 on day 1 or 8.\n\n\nRESULTS\nAmong the 16 patients enrolled, dose-limiting toxicity was observed in one patient at level 2a (S-1 80 mg/m2 twice daily plus nab-paclitaxel 220 mg/m2 on day 1). The MTD was not obtained, but the RD was established as level 3a (S-1 80 mg/m2 twice daily plus nab-paclitaxel 260 mg/m2 on day 1). The most common grade 3-4 toxicity was neutropenia (62.5 %). The overall response rate was 54.5 %. The pharmacokinetic profiles of coadministered S-1 and paclitaxel were comparable to those of nab-paclitaxel or S-1 alone.\n\n\nCONCLUSIONS\nBased on the present results, the RD was determined as level 3a (S-1 80 mg/m2 twice daily plus nab-paclitaxel 260 mg/m2 on day 1). This combination therapy was well tolerated and showed antitumor efficacy in patients with advanced gastric cancer.",
"affiliations": "Department of Gastroenterology, Kanagawa Cancer Center, 2-3-2 Nakao, Asahi-ku, Yokohama, Kanagawa, 241-0815, Japan. norisuke@kcch.jp.;Department of Gastroenterology, Kitasato University School of Medicine, Kanagawa, Japan.;Department of Gastroenterology, Cancer Institute Hospital, Tokyo, Japan.;Department of Gastroenterology, Kanagawa Cancer Center, 2-3-2 Nakao, Asahi-ku, Yokohama, Kanagawa, 241-0815, Japan.;Department of Gastroenterology, Kitasato University School of Medicine, Kanagawa, Japan.;Department of Gastroenterology, Cancer Institute Hospital, Tokyo, Japan.;Department of Gastroenterology, Kanagawa Cancer Center, 2-3-2 Nakao, Asahi-ku, Yokohama, Kanagawa, 241-0815, Japan.;Department of Gastroenterology, Kitasato University School of Medicine, Kanagawa, Japan.;Department of Gastroenterology, Cancer Institute Hospital, Tokyo, Japan.;Department of Gastroenterology, Kitasato University School of Medicine, Kanagawa, Japan.",
"authors": "Nakayama|Norisuke|N|;Ishido|Kenji|K|;Chin|Keisho|K|;Nishimura|Ken|K|;Azuma|Mizutomo|M|;Matsusaka|Satoshi|S|;Inokuchi|Yasuhiro|Y|;Tanabe|Satoshi|S|;Kumekawa|Yosuke|Y|;Koizumi|Wasaburo|W|",
"chemical_list": "C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D004338:Drug Combinations; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; D017239:Paclitaxel",
"country": "Japan",
"delete": false,
"doi": "10.1007/s10120-016-0614-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1436-3291",
"issue": "20(2)",
"journal": "Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association",
"keywords": "Gastric cancer; Nab-paclitaxel; S-1",
"medline_ta": "Gastric Cancer",
"mesh_terms": "D000368:Aged; D000418:Albumins; D000971:Antineoplastic Combined Chemotherapy Protocols; D004338:Drug Combinations; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008113:Liver Neoplasms; D008175:Lung Neoplasms; D008207:Lymphatic Metastasis; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D010094:Oxonic Acid; D017239:Paclitaxel; D010534:Peritoneal Neoplasms; D011379:Prognosis; D013274:Stomach Neoplasms; D015996:Survival Rate; D005641:Tegafur",
"nlm_unique_id": "100886238",
"other_id": null,
"pages": "350-357",
"pmc": null,
"pmid": "27189323",
"pubdate": "2017-03",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D016448:Multicenter Study",
"references": "25220842;24190112;20133335;17133268;12506170;15547687;25240821;18282805;16319513;15505626;8862723;16006754;25516635;20946314;24716542;25786335;16163539;19818685",
"title": "A phase I study of S-1 in combination with nab-paclitaxel in patients with unresectable or recurrent gastric cancer.",
"title_normalized": "a phase i study of s 1 in combination with nab paclitaxel in patients with unresectable or recurrent gastric cancer"
} | [
{
"companynumb": "JP-CELGENEUS-JPN-2015072081",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GIMERACIL\\OTERACIL\\TEGAFUR"
},
"drugaddit... |
{
"abstract": "Zoledronic acid (ZA), an intravenous bisphosphonate, has been widely used for the treatment of osteoporosis. ZA is generally well tolerated, and ZA-related hepatotoxicity is rare. We report a case of hepatotoxicity after ZA infusion in an elderly male patient with primary osteoporosis. The patient had femoral neck and vertebral fractures, and 3 days after ZA 5-mg infusion, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) increased 23.4- and 15.3-fold, respectively, compared with pre-treatment values. Hepatoprotective agents were administered, and liver enzymes were back to near normal range 9 days later. This case report shows the possible hepatic adverse effects related to ZA infusion. The mechanism of hepatotoxicity caused by ZA is not clear. Acute-phase reaction after ZA infusion may play a role in hepatotoxicity, which should be taken into consideration, especially for the elderly.",
"affiliations": null,
"authors": "Chen|Wenjun|W|;Zhu|Mingjin|M|",
"chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D004364:Pharmaceutical Preparations; D000077211:Zoledronic Acid",
"country": "Germany",
"delete": false,
"doi": "10.5414/CP203987",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0946-1965",
"issue": "59(11)",
"journal": "International journal of clinical pharmacology and therapeutics",
"keywords": null,
"medline_ta": "Int J Clin Pharmacol Ther",
"mesh_terms": "D000368:Aged; D050071:Bone Density Conservation Agents; D056486:Chemical and Drug Induced Liver Injury; D004164:Diphosphonates; D006801:Humans; D008297:Male; D010024:Osteoporosis; D004364:Pharmaceutical Preparations; D000077211:Zoledronic Acid",
"nlm_unique_id": "9423309",
"other_id": null,
"pages": "721-724",
"pmc": null,
"pmid": "34423770",
"pubdate": "2021-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Drug-induced hepatotoxicity linked to zoledronic acid in the treatment of an elderly man with primary osteoporosis.",
"title_normalized": "drug induced hepatotoxicity linked to zoledronic acid in the treatment of an elderly man with primary osteoporosis"
} | [
{
"companynumb": "CN-ACCORD-237989",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ZOLEDRONIC ACID"
},
"drugadditional": "3",
"... |
{
"abstract": "This article discusses a case of antipsychotic-induced, focal lingual dystonia causing airway obstruction that was managed completely in the out-of-hospital environment by emergency medical services (EMS) providers. With the ever-increasing use of antipsychotic medications by the general population, it is important for EMS providers and emergency medicine physicians to be aware of rare presentations of dystonic reactions that can sometimes be life-threatening when they involve the lingual, pharyngeal, or laryngeal musculature. This article identifies the medications most likely to induce dystonic reactions, risk factors that predispose individuals to the development of dystonia, and the pathophysiology behind these adverse reactions. It also discusses differential diagnoses to consider, and emergent treatment options.",
"affiliations": "Emergency Department, Truman Medical Center, Kansas City, Missouri 64108, USA. ryan.jacobsen@tmcmed.org",
"authors": "Jacobsen|Ryan C|RC|",
"chemical_list": "D018926:Anti-Allergic Agents; D014150:Antipsychotic Agents; D001993:Bronchodilator Agents; D004155:Diphenhydramine; D009241:Ipratropium; D018967:Risperidone; D000420:Albuterol",
"country": "England",
"delete": false,
"doi": "10.3109/10903127.2011.598612",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1090-3127",
"issue": "15(4)",
"journal": "Prehospital emergency care : official journal of the National Association of EMS Physicians and the National Association of State EMS Directors",
"keywords": null,
"medline_ta": "Prehosp Emerg Care",
"mesh_terms": "D000328:Adult; D000402:Airway Obstruction; D000420:Albuterol; D018926:Anti-Allergic Agents; D014150:Antipsychotic Agents; D001993:Bronchodilator Agents; D003937:Diagnosis, Differential; D004155:Diphenhydramine; D004359:Drug Therapy, Combination; D020821:Dystonic Disorders; D004632:Emergency Medical Services; D006801:Humans; D009241:Ipratropium; D008297:Male; D009330:Nebulizers and Vaporizers; D018967:Risperidone; D012563:Schizophrenia, Paranoid; D013525:Surgical Instruments; D014059:Tongue",
"nlm_unique_id": "9703530",
"other_id": null,
"pages": "537-40",
"pmc": null,
"pmid": "21823929",
"pubdate": "2011",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Out-of-hospital lingual dystonia resulting in airway obstruction.",
"title_normalized": "out of hospital lingual dystonia resulting in airway obstruction"
} | [
{
"companynumb": "US-RANBAXY-2012US-53981",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"drugadditional": null,
... |
{
"abstract": "Mutations at HIV-1 reverse transcriptase (RT) codon 184 such as M184V confer resistance to two nucleos(t)ide RT inhibitors (NRTI), lamivudine (3TC) and emtricitabine (FTC). The prevalence of mutations at HIV-1 RT codon 184 was evaluated using three independent RT sequence databases from treatment-experienced (TE) and treatment-naïve (TN) individuals. Data were collected retrospectively from three centers: one in Italy and two in France between 1997 and 2016. In order to highlight the role of these mutations in conferring drug resistance, structural and thermodynamic analyses were conducted by means of computational approaches. Among 32,440 RT sequences isolated from TE and 12,365 isolated from TN patients, the prevalence of HIV-1 RT codon 184 substitutions in each group was 31.21% and 0.72%, respectively. The mutations M184L and M184T have been observed only in TE patients. In all cases but four, M184L and M184T mutations were present during NRTI treatment. Molecular recognition studies on M184L and M184T structures showed both FTC and 3TC thermodynamic profiles unfavorable in comparison with the wild-type sequence, corroborated by molecular dynamic simulations (MDS). In this study, we highlighted two new resistance mutations in vivo for NRTI resistance. The low frequency of this pathway can be related to high impairment of replicative capacity mediated by these mutations.",
"affiliations": "UPMC Univ Paris 06-UMR_S 1136, Pierre Louis Institute of Epidemiology and Public Health, Sorbonne Universités, Paris, France.;Department of Experimental Medicine and Surgery, University of Rome \"Tor Vergata\", Rome, Italy.;IAME, UMR 1137-Université Paris Diderot, Sorbonne Paris Cité, INSERM, Paris, France.;Department of Experimental Medicine and Surgery, University of Rome \"Tor Vergata\", Rome, Italy.;Department of Health Sciences, University \"Magna Grӕcia\" of Catanzaro, Catanzaro, Italy.;Department of Health Sciences, University \"Magna Grӕcia\" of Catanzaro, Catanzaro, Italy.;Department of Health Sciences, University \"Magna Grӕcia\" of Catanzaro, Catanzaro, Italy.;Infectious Diseases Division, National Institute for Infectious Diseases L. Spallanzani, IRCCS, Rome, Italy.;UPMC Univ Paris 06-UMR_S 1136, Pierre Louis Institute of Epidemiology and Public Health, Sorbonne Universités, Paris, France.;Antiretroviral Drugs Monitoring Unit, National Institute for Infectious Diseases L. Spallanzani, IRCCS, Rome, Italy.;Department of Health Sciences, University \"Magna Grӕcia\" of Catanzaro, Catanzaro, Italy.;UPMC Univ Paris 06-UMR_S 1136, Pierre Louis Institute of Epidemiology and Public Health, Sorbonne Universités, Paris, France.;IAME, UMR 1137-Université Paris Diderot, Sorbonne Paris Cité, INSERM, Paris, France.;UPMC Univ Paris 06-UMR_S 1136, Pierre Louis Institute of Epidemiology and Public Health, Sorbonne Universités, Paris, France.;Department of Experimental Medicine and Surgery, University of Rome \"Tor Vergata\", Rome, Italy.;UPMC Univ Paris 06-UMR_S 1136, Pierre Louis Institute of Epidemiology and Public Health, Sorbonne Universités, Paris, France.",
"authors": "Pouga|Lydia|L|0000-0002-2574-0254;Santoro|Maria Mercedes|MM|;Charpentier|Charlotte|C|;Di Carlo|Domenico|D|;Romeo|Isabella|I|;Artese|Anna|A|;Alcaro|Stefano|S|;Antinori|Andrea|A|;Wirden|Marc|M|;Perno|Carlo Federico|CF|;Ambrosio|Francesca Alessandra|FA|;Calvez|Vincent|V|;Descamps|Diane|D|;Marcelin|Anne-Geneviève|AG|;Ceccherini-Silberstein|Francesca|F|;Lambert-Niclot|Sidonie|S|",
"chemical_list": "D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D000068679:Emtricitabine",
"country": "England",
"delete": false,
"doi": "10.1111/cbdd.13378",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1747-0277",
"issue": "93(1)",
"journal": "Chemical biology & drug design",
"keywords": null,
"medline_ta": "Chem Biol Drug Des",
"mesh_terms": "D000328:Adult; D000368:Aged; D001665:Binding Sites; D024882:Drug Resistance, Viral; D000068679:Emtricitabine; D005260:Female; D054303:HIV Reverse Transcriptase; D015497:HIV-1; D006801:Humans; D019259:Lamivudine; D008297:Male; D008875:Middle Aged; D062105:Molecular Docking Simulation; D009154:Mutation; D017434:Protein Structure, Tertiary; D012189:Retrospective Studies; D018894:Reverse Transcriptase Inhibitors",
"nlm_unique_id": "101262549",
"other_id": null,
"pages": "50-59",
"pmc": null,
"pmid": "30103267",
"pubdate": "2019-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "New resistance mutations to nucleoside reverse transcriptase inhibitors at codon 184 of HIV-1 reverse transcriptase (M184L and M184T).",
"title_normalized": "new resistance mutations to nucleoside reverse transcriptase inhibitors at codon 184 of hiv 1 reverse transcriptase m184l and m184t"
} | [
{
"companynumb": "FR-MYLANLABS-2019M1016129",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LAMIVUDINE"
},
"drugadditional": "3",
... |
{
"abstract": "The endpoint in emergent management of acute massive pulmonary embolism (PE) has traditionally been with embolectomy through a standard median sternotomy. This approach is limited in both exposure and concomitant functional morbidity associated with sternotomy. In a previous publication, we described a novel minimally invasive, thoracoscopically assisted approach to pulmonary embolectomy. This approach utilized a small 5-cm left upper parasternal thoracotomy and femoral cardiopulmonary bypass to conduct thoracoscopically assisted surgical pulmonary embolectomy. The first publication featured three patients that had a massive pulmonary embolus that was treated with minimally invasive pulmonary embolectomy, and the initial data was positive and suggested that this approach is safe and feasible. We now broaden our experience with another two patients who underwent this approach, and highlight a number of technical and management modifications that have been made to optimize the procedure. These lessons learned will ideally benefit future surgeons as this approach is more heavily implemented in practice.",
"affiliations": "Department of Surgery, Division of Cardiothoracic Surgery, School of Medicine, Emory University, Atlanta, Georgia, USA.;Department of Surgery, Division of Cardiothoracic Surgery, School of Medicine, Emory University, Atlanta, Georgia, USA.;Department of Surgery, Division of Cardiothoracic Surgery, School of Medicine, Emory University, Atlanta, Georgia, USA.;School of Medicine, American University of Beirut, Beirut, Lebanon.;Department of Surgery, Division of Cardiothoracic Surgery, School of Medicine, Emory University, Atlanta, Georgia, USA.",
"authors": "Lattouf|Omar M|OM|https://orcid.org/0000-0003-3062-8934;Laan|Danuel|D|https://orcid.org/0000-0002-2356-8059;Zapata|David|D|;Assaf|Edwyn J|EJ|;Fallon|John|J|https://orcid.org/0000-0002-2709-6896",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/jocs.15357",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0886-0440",
"issue": "36(4)",
"journal": "Journal of cardiac surgery",
"keywords": "minimally invasive pulmonary embolectomy; pulmonary embolectomy; pulmonary embolism",
"medline_ta": "J Card Surg",
"mesh_terms": "D017128:Embolectomy; D006801:Humans; D011655:Pulmonary Embolism; D056346:Sternotomy; D013908:Thoracotomy; D016896:Treatment Outcome",
"nlm_unique_id": "8908809",
"other_id": null,
"pages": "1258-1263",
"pmc": null,
"pmid": "33538050",
"pubdate": "2021-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Lessons learned on a new procedure: Nonsternotomy minimally invasive pulmonary embolectomy.",
"title_normalized": "lessons learned on a new procedure nonsternotomy minimally invasive pulmonary embolectomy"
} | [
{
"companynumb": "US-FRESENIUS KABI-FK202110326",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "EPOPROSTENOL SODIUM"
},
"drugadditional"... |
{
"abstract": "The emergence of acquired anaplastic lymphoma kinase (ALK) resistant mutations is a common molecular mechanism underpinning disease progression during crizotinib treatment of ALK-positive (ALK+) non-small cell lung cancer (NSCLC) patients. Identifying acquired resistance mutations in ALK is paramount for tailoring future therapy with second generation ALK inhibitors and beyond. Comprehensive genomic profiling using hybrid-capture next generation sequencing has been successful in identifying acquired ALK resistance mutations. Here we described the emergence of an ALK F1245C mutation in an advanced ALK+ NSCLC patient (EML4-ALK variant 3a/b) who developed slow disease progression after a durable response to crizotinib. The patient was eventually switched to ceritinib with on-going clinical response. This is the first patient report that ALK F1245C is an acquired resistance mutation to crizotinib that can be overcome by ceritinib.",
"affiliations": "Greater Houston Cancer Clinic, 9201 Pinecroft, The Woodlands, TX77380, USA.;Foundation Medicine Inc., 150 Second Street, Cambridge, MA 02141, USA.;Foundation Medicine Inc., 150 Second Street, Cambridge, MA 02141, USA.;Foundation Medicine Inc., 150 Second Street, Cambridge, MA 02141, USA.;Foundation Medicine Inc., 150 Second Street, Cambridge, MA 02141, USA.;Foundation Medicine Inc., 150 Second Street, Cambridge, MA 02141, USA.;Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, CA 92868, USA.;Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, CA 92868, USA. Electronic address: ignatius.ou@uci.edu.",
"authors": "Kodityal|Sandeep|S|;Elvin|Julia A|JA|;Squillace|Rachel|R|;Agarwal|Nikita|N|;Miller|Vincent A|VA|;Ali|Siraj M|SM|;Klempner|Samuel J|SJ|;Ou|Sai-Hong Ignatius|SH|",
"chemical_list": "D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D013450:Sulfones; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; C586847:ceritinib",
"country": "Ireland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0169-5002",
"issue": "92()",
"journal": "Lung cancer (Amsterdam, Netherlands)",
"keywords": "ALK F1245C; ALK-positive NSCLC; Acquired anaplastic lymphoma kinase resistance mutation; Ceritinib; Comprehensive genomic profiling; Crizotinib; Next generation sequencing",
"medline_ta": "Lung Cancer",
"mesh_terms": "D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents; D002289:Carcinoma, Non-Small-Cell Lung; D000077547:Crizotinib; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009154:Mutation; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D020794:Receptor Protein-Tyrosine Kinases; D013450:Sulfones",
"nlm_unique_id": "8800805",
"other_id": null,
"pages": "19-21",
"pmc": null,
"pmid": "26775591",
"pubdate": "2016-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A novel acquired ALK F1245C mutation confers resistance to crizotinib in ALK-positive NSCLC but is sensitive to ceritinib.",
"title_normalized": "a novel acquired alk f1245c mutation confers resistance to crizotinib in alk positive nsclc but is sensitive to ceritinib"
} | [
{
"companynumb": "PHHY2016US007907",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "CERITINIB"
},
"drugadditional": null,
"druga... |
{
"abstract": "Hyponatremia is a known adverse effect of duloxetine, and it can lead to potentially life-threatening complications. Administration of thiazide diuretics also has been the cause of hyponatremia. We report a case of duloxetine-induced hyponatremia in an elderly patient treated with thiazide diuretics. An 86-year-old woman treated with the trichlormethiazide was admitted for vertebral compression fracture with disorientation and nausea on the 6(th) day of treatment with duloxetine. Laboratory findings revealed hyponatremia, hypo-osmolality, concentrated urine, and increased urine sodium. Syndrome of inappropriate antidiuretic hormone was considered, therefore, duloxetine, and trichlormethiazide was discontinued and treated with fluid restriction, furosemide and sodium chloride administered orally. Disorientation and nausea were improved after correction of hyponatremia. Health care practitioners should be aware of the possibility of duloxetine-induced hyponatremia, particularly in patients treated with thiazide diuretics.",
"affiliations": "Department of Pharmacy, Kuwana West Medical Center, Kuwana, Japan.;Department of Pharmacy, Kuwana West Medical Center, Kuwana, Japan.;Department of Pharmacy, Kuwana West Medical Center, Kuwana, Japan.;Department of Orthopaedic Surgery, Kuwana West Medical Center, Kuwana, Japan.;Department of Orthopaedic Surgery, Kuwana West Medical Center, Kuwana, Japan.",
"authors": "Mori|Miyu|M|;Koide|Tetsuro|T|;Imanishi|Yoshinori|Y|;Matsui|Yuriyo|Y|;Matsuda|Toru|T|",
"chemical_list": "D000928:Antidepressive Agents; D049993:Sodium Chloride Symporter Inhibitors; D013876:Thiophenes; D000068736:Duloxetine Hydrochloride; D014237:Trichlormethiazide",
"country": "India",
"delete": false,
"doi": "10.4103/0253-7613.144947",
"fulltext": "\n==== Front\nIndian J PharmacolIndian J PharmacolIJPharmIndian Journal of Pharmacology0253-76131998-3751Medknow Publications & Media Pvt Ltd India IJPharm-46-65710.4103/0253-7613.144947Drug WatchDuloxetine-induced hyponatremia in an elderly patient treated with thiazide diuretics Mori Miyu Koide Tetsuro Imanishi Yoshinori Matsui Yuriyo 1Matsuda Toru 1Department of Pharmacy, Kuwana West Medical Center, Kuwana, Japan1 Department of Orthopaedic Surgery, Kuwana West Medical Center, Kuwana, JapanCorrespondence to: Dr. Miyu Mori, E-mail: yakuzai.kch@kuwanacmc.or.jpNov-Dec 2014 46 6 657 659 11 5 2014 02 8 2014 28 10 2014 Copyright: © Indian Journal of Pharmacology2014This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Hyponatremia is a known adverse effect of duloxetine, and it can lead to potentially life-threatening complications. Administration of thiazide diuretics also has been the cause of hyponatremia. We report a case of duloxetine-induced hyponatremia in an elderly patient treated with thiazide diuretics. An 86-year-old woman treated with the trichlormethiazide was admitted for vertebral compression fracture with disorientation and nausea on the 6th day of treatment with duloxetine. Laboratory findings revealed hyponatremia, hypo-osmolality, concentrated urine, and increased urine sodium. Syndrome of inappropriate antidiuretic hormone was considered, therefore, duloxetine, and trichlormethiazide was discontinued and treated with fluid restriction, furosemide and sodium chloride administered orally. Disorientation and nausea were improved after correction of hyponatremia. Health care practitioners should be aware of the possibility of duloxetine-induced hyponatremia, particularly in patients treated with thiazide diuretics.\n\nKEY WORDS\nDrug interactionduloxetinesyndrome of inappropriate secretion of antidiuretic hormone syndrometrichlormethiazide\n==== Body\nIntroduction\nDuloxetine is a selective serotonin and noradrenaline reuptake inhibitor (SNRI), indicated for the treatment of major depressive disorder and diabetic peripheral neuropathy. In rare cases, hyponatremia associated with duloxetine has been reported in female patients.[1] Thiazide diuretics are among the most commonly prescribed antihypertensive medications, which have been implicated in multiple electrolyte abnormalities including hyponatremia.[2] We report a case of severe hyponatremia that developed after the duloxetine was added to thiazide diuretics therapy.\n\nCase Report\nAn 86-year-old woman with a history of hypertension, vertigo and insomnia was admitted to the orthopedic department complaining of low back pain, nausea and disorientation. Her height was 151 cm, and she weighed 48 kg. According to the information obtained from the patient and her family members, she complained of nausea and disorientation a few days before admission and fell down at that time. On admission, her magnetic resonance imaging of the thoracic-lumbar vertebra showed fresh compression fracture of the twelfth thoracic vertebra. She was prescribed trichlormethiazide 2 mg/day, Doxazosin 1 mg/day, tocopherol nicotinate 600 mg/day, oxybutynin 4 mg/day, diphenidol 75 mg/day, bethahistine 18 mg/day, domperidone 30 mg/day, triazolam 0.25 mg/day, lorazepam 0.5 mg/day and duloxetine 20 mg/day before admission. According to her medication history, duloxetine was started for depression 6 days before admission and trichlormethiazide was started more than 1-year before admission. At the time of admission, blood investigation showed serum sodium level of 116 mEq/L (normal range: 136–145 mEq/L). Other clinical laboratory findings were: Serum aspartate-amino transferase level - 26 IU/L (normal range: 10–35 IU/L), serum alanine transaminase level - 18 IU/L (10–35 IU/L), serum potassium level - 3.2 mEq/L (3.4–4.7 mEq/L), serum urea nitrogen level - 19.1 mg/dL (9.0–22.0 mg/dL) and serum creatinine level-0.7 mg/dL (0.4–0.8 mg/dL). Additional clinical laboratory investigations revealed serum osmolality of 239 mOsm/L (normal range: 276–292 mOsm/L), simultaneous urine osmolality of 385 mOsm/L (85–850 mOsm/L) and urine sodium of 32 mEq/L (<10 mEq/L). According to medical records from her primary care physician, serum sodium level was 142 mEq/L before 3 months. Other clinical laboratory findings were also within normal range. Her medications were not changed, except duloxetine. Hence based on laboratory reports, the diagnosis of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) was made. It was suspected that SIADH was associated with concurrent use of duloxetine and trichlormethiazide, which were, therefore, discontinued. The severe hyponatremia was treated with oral fluid restriction (600 ml/day), oral furosemide (20 mg/day) and oral sodium chloride (6 g/day). On the third day after admission, serum sodium concentration increased to 123 mEq/L. On the next day, disorientation and nausea improved remarkably. On the 7th day after admission, serum sodium concentration returned to the normal range (137 mEq/L). Liver and renal functions also remained normal [Table 1]. Oral fluid restriction and oral sodium chloride were stopped a week later. After that serum sodium concentration remained in normal range.\n\nTable 1 Serial laboratory findings in the patient\n\nDiscussion\nHyponatremia is defined as a low serum sodium level <136 mEq/L.[3] Patients with mild hyponatremia whose serum sodium levels are >125 mEq/L are usually asymptomatic.[3] Symptoms of hyponatremia include lethargy, anorexia, headache, fatigue, nausea, and muscle cramps. If sodium levels continue to decrease, symptoms may progress to confusion, seizure, coma and irreversible brain damage, which are noted with serum sodium levels <120 mEq/L.[3]\n\nIn our case, symptoms of hyponatremia included nausea and disorientation, which seemed to be relatively modest. However, her serum sodium level was 116 mEq/L, which could lead to severe symptoms. If appropriate treatments were not conducted at an early stage, patient might have developed permanent neurological complications.\n\nThe exact mechanism of hyponatremia associated with thiazide is unclear. Some proposed mechanisms involve impairment of the urinary diluting ability, stimulation of the antidiuretic hormone (ADH) secretion, urinary sodium loss and intracellular potassium depletion by inhibiting sodium chloride reabsorption in the distal convoluted tubule. Furthermore, increased water ingestion due to dipsogenic effect of thiazides can develop more severe hyponatremia.[2]\n\nThe mechanism of SNRI-related hyponatremia is also unclear. Animal experiments suggest that both norepinephrine and serotonin can stimulate ADH secretion.[4] Duloxetine inhibits the reuptake of both serotonin and norepinephrine, which may explain why our patient developed hyponatremia. Hyponatremia associated with selective serotonin reuptake inhibitors (SSRIs) developed a few weeks after initiation of SSRIs, while duloxetine-induced hyponatremia developed a few days following the start of duloxetine,[1] which also occurred in our patient.\n\nAccording to Horn's drug interaction probability scale,[5] hyponatremia was probably related to concomitant use of duloxetine and trichlormethiazide (score 6). Furthermore, according to the Naranjo adverse drug reaction probability scale,[6] hyponatremia was also probably related to the use of these drugs (score 7). Serum sodium level before and after the initiation of duloxetine were 142 mEq/L and 116 mEq/L, respectively. The risk factors for hyponatremia include advanced age, female, lower body weight, lower baseline serum sodium.[4] Our patient had these risk factors except lower baseline serum sodium. All previous cases of duloxetine-related hyponatremia had lower baseline sodium levels.[2] Our case suggests that the rapid decrease in serum sodium level developed due to coadministration of SNRI with thiazides through complementary and synergistic manners. Our report has two limitations. First, serum sodium level immediately before the initiation of duloxetine was unclear. Second, the role of thiazide in the rapid decrease of serum sodium level is unclear because thiazide was started >1-year before the initiation of duloxetine.\n\nThis case highlights the development of severe hyponatremia in elderly female patient treated with duloxetine and thiazide diuretics concurrently. Although the exact mechanism is unclear, SIADH is suspected as a contributing cause based on the clinical findings (normal renal function, low serum osmolality, concentrated urine and high level of urine sodium). The combination of duloxetine and thiazide may result in a rapid decrease of serum sodium level. When SNRI and thiazide diuretics are prescribed concurrently, health care practitioners should be aware of the possibility of hyponatremia. Careful monitoring of serum electrolytes within a week of the initiation of these medications is recommended.\n\nSource of Support: Nil.\n\nConflict of Interest: No.\n==== Refs\n1 Safdieh JE Rudominer R A case of hyponatremia induced by duloxetine J Clin Psychopharmacol 2006 26 675 6 17110834 \n2 Friedman E Shadel M Halkin H Farfel Z Thiazide-induced hyponatremia. Reproducibility by single dose rechallenge and an analysis of pathogenesis Ann Intern Med 1989 110 24 30 2491733 \n3 Adrogué HJ Madias NE Hyponatremia N Engl J Med 2000 342 1581 9 10824078 \n4 Kirby D Ames D Hyponatraemia and selective serotonin re-uptake inhibitors in elderly patients Int J Geriatr Psychiatry 2001 16 484 93 11376464 \n5 Horn JR Hansten PD Chan LN Proposal for a new tool to evaluate drug interaction cases Ann Pharmacother 2007 41 674 80 17389673 \n6 Naranjo CA Busto U Sellers EM Sandor P Ruiz I Roberts EA A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 239 45 7249508\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0253-7613",
"issue": "46(6)",
"journal": "Indian journal of pharmacology",
"keywords": "Drug interaction; duloxetine; syndrome of inappropriate secretion of antidiuretic hormone syndrome; trichlormethiazide",
"medline_ta": "Indian J Pharmacol",
"mesh_terms": "D000369:Aged, 80 and over; D000928:Antidepressive Agents; D004347:Drug Interactions; D000068736:Duloxetine Hydrochloride; D005260:Female; D006801:Humans; D007010:Hyponatremia; D049993:Sodium Chloride Symporter Inhibitors; D013876:Thiophenes; D014237:Trichlormethiazide",
"nlm_unique_id": "7902477",
"other_id": null,
"pages": "657-9",
"pmc": null,
"pmid": "25538343",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10824078;11376464;17389673;2491733;17110834;7249508",
"title": "Duloxetine-induced hyponatremia in an elderly patient treated with thiazide diuretics.",
"title_normalized": "duloxetine induced hyponatremia in an elderly patient treated with thiazide diuretics"
} | [
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"companynumb": "JP-LUPIN PHARMACEUTICALS INC.-2014-01900",
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"activesubstance": {
"activesubstancename": "DOXAZOSIN\\DOXAZOSIN MESYLATE"
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{
"abstract": "Bisphosphonates are widely used both in the multidisciplinary management of bone metastases, especially osteolytic lesions from solid tumors or multiple myeloma, and of osteoporosis.Aseptic osteonecrosis, especially of the jaw, is among the well-known, although uncommon, side effects of bisphosphonates. Osteonecrosis of other bones has been very rarely reported with the use of bisphosphonates.We describe a rare case of osteonecrosis of the distal femur associated with the use of bisphosphonates in a 74 years old female patient with metastatic breast cancer.",
"affiliations": "Institute of Oncology of Southern Switzerland (IOSI), Lugano, Switzerland.;Institute of Oncology of Southern Switzerland (IOSI), Lugano, Switzerland.;Institute of Oncology of Southern Switzerland (IOSI), Lugano, Switzerland.;Institute of Oncology of Southern Switzerland (IOSI), Lugano, Switzerland.",
"authors": "Rossi|Lorenzo|L|;Lascio|Simona Di|SD|;Kouros|Michail|M|;Pagani|Olivia|O|",
"chemical_list": "D000970:Antineoplastic Agents; D050071:Bone Density Conservation Agents; D004164:Diphosphonates",
"country": "Netherlands",
"delete": false,
"doi": "10.3233/BD-150410",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0888-6008",
"issue": "35(3)",
"journal": "Breast disease",
"keywords": "Bisphosphonates; knee osteonecrosis; metastatic breast cancer",
"medline_ta": "Breast Dis",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D019645:Arthroplasty, Replacement, Knee; D001201:Ascites; D050071:Bone Density Conservation Agents; D001943:Breast Neoplasms; D004164:Diphosphonates; D005260:Female; D005271:Femur Head Necrosis; D006801:Humans; D008408:Mastectomy; D009367:Neoplasm Staging; D010024:Osteoporosis; D010537:Peritoneum; D016896:Treatment Outcome; D000069584:Unilateral Breast Neoplasms",
"nlm_unique_id": "8801277",
"other_id": null,
"pages": "203-6",
"pmc": null,
"pmid": "26406544",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A rare avascolar osteonecrosis of the knee related to biphosphonate treatment in a patient with metastatic breast cancer.",
"title_normalized": "a rare avascolar osteonecrosis of the knee related to biphosphonate treatment in a patient with metastatic breast cancer"
} | [
{
"companynumb": "PHHY2015CH101025",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
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"activesubstancename": "ZOLEDRONIC ACID"
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"abstract": "Medication shortages are a clinical reality that force changes in practice patterns leading to unintended consequences. Potential solutions to any drug shortage require a thoughtful, multidisciplinary and often creative approach. Here, we report a case of unintentional epinephrine overdose leading to an unstable cardiac arrhythmia and our subsequent development of a visual cue system to prevent future errors. A 56-year-old man with a history of rectal adenocarcinoma presented for low anterior resection and creation of diverting loop ileostomy. Epidural placement was requested by the surgical team, and following administration of a second test dose (created by the physician), the patient experienced supraventricular tachycardia with heart rates of 200-210 BPM for approximately 2 minutes. This rhythm then converted to atrial fibrillation with rapid ventricular response with heart rate of 150-170 BPM. The patient was stabilized after cardioversion. Later evaluation of medication administration revealed that the second epidural test dose inadvertently contained 100 mcg epinephrine instead of the intended 10 mcg dose. The test dose had to be created because the original ampule with the kit had been utilized. Since this time, our kits have no test dose, and this shortage is concerning for increased provider error. We suggest a novel visual cue system that may prevent unintentional epinephrine overdoses in the setting of regional anesthesia.",
"affiliations": "Department of Anesthesiology, UW School of Medicine and Public Health, Madison, Wisconsin, United States.;Department of Anesthesiology, UW School of Medicine and Public Health, Madison, Wisconsin, United States.;Department of Anesthesiology, UW School of Medicine and Public Health, Madison, Wisconsin, United States.;Department of Anesthesiology, UW School of Medicine and Public Health, Madison, Wisconsin, United States.",
"authors": "Borden|Shelly B|SB|;Groose|Molly K|MK|;Robitaille|Mark J|MJ|;Schroeder|Kristopher M|KM|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/sja.SJA_218_19",
"fulltext": "\n==== Front\nSaudi J AnaesthSaudi J AnaesthSJASaudi Journal of Anaesthesia1658-354X0975-3125Wolters Kluwer - Medknow India SJA-13-24910.4103/sja.SJA_218_19Case ReportCardiac arrhythmia from epinephrine overdose in epidural test dose Borden Shelly B. Groose Molly K. Robitaille Mark J. Schroeder Kristopher M. Department of Anesthesiology, UW School of Medicine and Public Health, Madison, Wisconsin, United StatesAddress for correspondence: Dr. Shelly B. Borden, Department of Anesthesiology, UW School of Medicine and Public Health, 600 Highland Ave B6/319 CSC, Madison, Wisconsin 53792-3727, United States. E-mail: bagga@wisc.eduJul-Sep 2019 13 3 249 252 Copyright: © 2019 Saudi Journal of Anesthesia2019This 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.Medication shortages are a clinical reality that force changes in practice patterns leading to unintended consequences. Potential solutions to any drug shortage require a thoughtful, multidisciplinary and often creative approach. Here, we report a case of unintentional epinephrine overdose leading to an unstable cardiac arrhythmia and our subsequent development of a visual cue system to prevent future errors. A 56-year-old man with a history of rectal adenocarcinoma presented for low anterior resection and creation of diverting loop ileostomy. Epidural placement was requested by the surgical team, and following administration of a second test dose (created by the physician), the patient experienced supraventricular tachycardia with heart rates of 200-210 BPM for approximately 2 minutes. This rhythm then converted to atrial fibrillation with rapid ventricular response with heart rate of 150-170 BPM. The patient was stabilized after cardioversion. Later evaluation of medication administration revealed that the second epidural test dose inadvertently contained 100 mcg epinephrine instead of the intended 10 mcg dose. The test dose had to be created because the original ampule with the kit had been utilized. Since this time, our kits have no test dose, and this shortage is concerning for increased provider error. We suggest a novel visual cue system that may prevent unintentional epinephrine overdoses in the setting of regional anesthesia.\n\nDrug shortagemedication errorregional anesthesiology\n==== Body\nIntroduction\nOver the recent years, medication shortages have become commonplace in both inpatient and outpatient healthcare settings around the world. Despite legislation in the United States enacted in 2012 requiring manufacturers to notify the Food and Drug Administration “of any change in production that is reasonably likely to lead to reduction in supply”, shortages continue to be a reality.[1] The often-cited reasons for such shortages include manufacturing and quality problems, delays, and discontinuations. However, what is arguably more important than their etiology, is that these medication shortages are driving changes in patient care leading to unintended consequences. Below, we report a case of unintentional epinephrine overdose leading to an unstable cardiac arrhythmia and our subsequent development of a visual cue system to prevent future errors.\n\nCase\nA 56-year-old man with a history of rectal adenocarcinoma presented for low anterior resection and creation of diverting loop ileostomy. The surgical service requested epidural analgesia for assistance with post-operative pain management. Following uneventful thoracic epidural placement and negative catheter aspiration, a test dose of 1.5% lidocaine with 5 mcg/ml epinephrine was administered. This resulted in a transient increase in heart rate from approximately 80 beats per minute (BPM) to 115 BPM. There was no change in non-invasive blood pressure measurement and the patient remained asymptomatic. Attempts to aspirate blood through the epidural catheter failed to demonstrate any return of any fluid. Given the transient rise in heart rate, lack of change in blood pressure, negative aspiration, and lack of symptoms reported by the patient, a repeat test dose created by the provider was administered. Following administration of a second test dose, the patient experienced supraventricular tachycardia with heart rates of 200-210 BPM for approximately 2 minutes. This rhythm then converted to atrial fibrillation with rapid ventricular response with heart rate of 150-170 BPM. Initial conservative treatment with esmolol boluses was ineffective and the patient's blood pressure decreased from approximately 140/70 mm Hg to approximately 90/50 mm Hg. He denied chest pressure or other cardiac symptoms, but 12 lead ECG revealed marked ST segment depression in the lateral leads. The patient was sedated with 1 mg midazolam and 30 mg propofol prior to 120 joule synchronized cardioversion at the bedside in the preoperative area. The patient returned to sinus rhythm and ST depression resolved. Later, evaluation of medication administration revealed that the second epidural test dose inadvertently contained 100 mcg epinephrine instead of the intended 10 mcg dose.\n\nThe surgeon and patient's family were updated, and surgery was postponed to allow for a formal cardiology evaluation. The patient received a transthoracic echocardiogram which revealed normal heart structure and function. The patient returned 3 days later and underwent an uneventful low anterior resection with diverting loop ileostomy. He declined pre-operative epidural placement but consented to post-operative bilateral quadratus lumborum blockade. The patient's post-operative course was complicated by ileus, but he had no further cardiac complications. He was discharged 8 days post the operation. Written informed consent for treatment and patient's approval for the publication of results were obtained.\n\nDiscussion\nMedication shortages have unfortunately become a clinical reality. Within the practice of regional anesthesia and pain medicine, rolling shortages of opioids, ketamine and local anesthetics have become commonplace and provisions have been required to ensure that high quality care continues to be provided. Recently, a shortage of epinephrine led to the exclusion of epidural test dose solution (1.5% lidocaine with 5 mcg/ml epinephrine) from epidural kits. While the kit in this case contained one ampule of test dose, subsequent kits from the manufacturer did not. Obviously, the epidural test dose is an important component of ensuring the correct location of an epidural catheter via its ability to rule out inadvertent intravascular or intrathecal catheter placement. Therefore, the shortage of this pre-prepared test dose solution requires the practitioner to fashion a test dose of their own.\n\nUnfortunately, epinephrine is a medication with a long history of inadvertent overdoses and other administration errors. In fact, previous studies have demonstrated that when utilized for anaphylaxis, recognized potentially life-threatening dosing errors occur with epinephrine in approximately 2.4% of cases. It is possible that dosing errors occur with an even greater frequency but are missed because the effect of epinephrine is transient or because dosing errors are not considered in unstable patients.[2] Likely, part of this risk is related to the narrow therapeutic window for epinephrine and the potential for serious adverse events to occur with dosing miscalculations. In addition, the nomenclature for reporting epinephrine concentration can be incredibly confusing to even experienced providers. For example, epinephrine concentration can variably be reported in mcg/ml, percentage and/or as a dilution ratio. This variety in concentration nomenclature and the small volume/mass of normally administered doses presents a legitimate opportunity for error. In fact, a previous study demonstrated that 40% of physicians may make incorrect calculations when converting drug doses from percentage to mass calculations.[3] Further studies have demonstrated the danger of presenting epinephrine dosing in ratios where it was found that medication errors with that form of concentration occurred much more frequently than when dosing was reported with mass labels.[4] In addition to dosing errors, epinephrine may be administered via the incorrect route or may be confused with other agents (i.e., ephedrine).[5]\n\nComplications of epinephrine overdoses have been reported a number of times in the published literature and can include arrhythmia, hypertension, chest pain, tremor, anxiety, paleness, headache, peripheral vasoconstriction and nausea/vomiting.[67] Reported severe complications associated with iatrogenic epinephrine overdosages have included ventricular dysfunction, myocardial infarction, cardiac arrest, pulmonary edema and renal failure.[891011] Adverse events tend to be more severe in older patients that receive high doses of epinephrine via the intravenous routes.[712] Laboratory findings of excessive epinephrine dosing may include hyperglycemia, leukocytosis and hypokalemia. Treatment of epinephrine overdose is generally supportive in nature and targeted at specific symptom management.[6]\n\nIn the event of medication shortages of this nature, it is incumbent upon the faculty at any given institution to develop practices and guidelines to minimize the occurrence of adverse events related to medication administration errors. In the case of epinephrine shortages for epidural test dose, there are other considerations that may include the potential infectious complications that could arise from obtaining epinephrine from multi-dose vials or preparing the test dose under non-sterile conditions. There are also potential concerns related to selecting the correct local anesthetic for the epidural test dose and ensuring that it is preservative-free.\n\nPotential solutions to any drug shortage require a thoughtful, multidisciplinary and often creative approach. In the case of epidural test dose shortages, pharmacy preparation of test dose supplies could occur in a sterile hood and may reduce the opportunity for physician error. Education is clearly needed, but should be performed frequently enough to reinforce vital concepts and may require competency assessments to identify areas of weakness. Visual point of care labeling clues have been successfully implemented in an emergency department setting where they have been utilized to guide decision making for anaphylaxis versus cardiac arrest dosing.[2] In response to this adverse cardiac event following and overdose of local anesthetic our institution decided upon a multi-faceted approach to ensuring that this does not occur again. First, all faculty and nurses were educated regarding the nature of the dosing error and how to subsequently avoid similar errors in the future. Visual cues were then plastered about our work area and epidural test dose dilution instructions were affixed to the “block cart.” Finally, epidural test dose solution instructions were affixed to all epidural kits that were found to be missing a pre-packaged test dose [Figure 1]. An effort was made to both convey the intent of this project to all providers and create visual cues that were informative and highly visible [Figure 2].\n\nFigure 1 Epidural kit used with sticker (novel cue) reminder that the epidural kit does not include a premade by the manufacturer test dose\n\nFigure 2 Bright sticker created by the author's acute pain team that clearly emphasizes the lack of test dose by the manufacturer. (Publish in color requested)\n\nWe therefore present a case of epinephrine overdose related to an inadvertently high dose of epinephrine being administered as part of an epidural test dose that was prepared by a member of the regional anesthesia team because of an ongoing medication shortage. Further work is required to validate a novel visual cue system to prevent epinephrine dosing errors in the context of regional anesthesia and pain management.\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\n1 Food and Drug Administration Safety and Innovation Act. Pub. L. No. 112-144, § 1001, 126 Stat. 993, 1099 (2012) (codified at 21 U.S.C § 356c) \n2 Kanwar M Irvin CB Frank JJ Weber K Rosman H Confusion about epinephrine dosing leading to iatrogenic overdose: A life-threatening problem with a potential solution Ann Emerg Med 2010 55 341 4 20031267 \n3 Rolfe S Harper NJ Ability of hospital doctors to calculate drug doses BMJ 1995 310 1173 4 7767153 \n4 Wheeler DW Carter JJ Murray LJ Degnan BA Dunling CP Salvador R The effect of drug concentration expression on epinephrine dosing errors: A randomized trial Ann Intern Med 2008 148 11 4 18166759 \n5 Paparella SF Epinephrine: A potpourri of potential medication safety risks J Emerg Nurs 2013 39 151 3 23369771 \n6 Levine RD Orkin LR Epinephrine overdose N Y State J Med 1981 81 1669 70 6945502 \n7 Cardona V Ferré-Ybarz L Guilarte M Moreno-Pérez N Gómez-Galán C Alcoceba-Boras E Safety of adrenaline use in anaphylaxis: A multicentre register Int Arch Allergy Immunol 2017 173 171 7 28793302 \n8 Budhwani N Bonaparte KL Cuyjet AB Saric M Severe reversible left ventricular systolic and diastolic dysfunction due to accidental iatrogenic epinephrine overdose Rev Cardiovasc Med 2004 5 130 3 15188772 \n9 Dybvik T Halvorsen P Steen PA Accidental intravenous administration of 50 mg of racemic adrenaline in a 2-year old boy Eur J Anaesthesiol 1995 12 181 3 7781638 \n10 Woodard ML Brent LD Acute renal failure, anterior myocardial infarction, and atrial fibrillation complicating epinephrine abuse Pharmacotherapy 1998 18 656 8 9620120 \n11 Liu HP Wu KC Lu PP Lin WR Wang YL Li AH Delayed-onset epinephrine-induced pulmonary edema Anesthesiology 1999 91 1169 70 10519519 \n12 Campbell RL Bellolio F Knutson BD Bellamkonda VR Fedko MG Nestler DM Epinephrine in anaphylaxis: Higher risk of cardiovascular complications and overdose after administration of intravenous bolus epinephrine compared with intramuscular epinephrine J Allergy Clin Immunol Pract 2015 3 76 80 25577622\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": null,
"issue": "13(3)",
"journal": "Saudi journal of anaesthesia",
"keywords": "Drug shortage; medication error; regional anesthesiology",
"medline_ta": "Saudi J Anaesth",
"mesh_terms": null,
"nlm_unique_id": "101500601",
"other_id": null,
"pages": "249-252",
"pmc": null,
"pmid": "31333374",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "10519519;15188772;18166759;20031267;23369771;25577622;28793302;6945502;7767153;7781638;9620120",
"title": "Cardiac arrhythmia from epinephrine overdose in epidural test dose.",
"title_normalized": "cardiac arrhythmia from epinephrine overdose in epidural test dose"
} | [
{
"companynumb": "US-TEVA-2019-US-1087255",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LIDOCAINE"
},
"drugadditional": "3",
... |
{
"abstract": "West Syndrome is characterized by infantile spasms, a hypsarrhythmic electroencephalogram (EEG) pattern, and a poor neurodevelopmental prognosis. First-line treatments include adrenocorticotrophic hormone (ACTH) and vigabatrin, but adverse effects often limit their use. CPP-115 is a high-affinity vigabatrin analogue developed to increase therapeutic potency and to limit retinal toxicity. Here, we present a child treated with CPP-115 through an investigational new drug protocol who experienced a marked reduction of seizures with no evidence of retinal dysfunction. Given the potential consequences of ongoing infantile spasms and the limitations of available treatments, further assessment of CPP-115 is warranted.",
"affiliations": "New York University School of Medicine, Comprehensive Epilepsy Center, 223 East 34th Street, New York, NY 10016, USA.;New York University School of Medicine, Comprehensive Epilepsy Center, 223 East 34th Street, New York, NY 10016, USA.;New York University School of Medicine, Comprehensive Epilepsy Center, 223 East 34th Street, New York, NY 10016, USA.;New York University School of Medicine, Comprehensive Epilepsy Center, 223 East 34th Street, New York, NY 10016, USA.;New York University School of Medicine, Comprehensive Epilepsy Center, 223 East 34th Street, New York, NY 10016, USA.",
"authors": "Doumlele|Kyra|K|;Conway|Erin|E|;Hedlund|Julie|J|;Tolete|Patricia|P|;Devinsky|Orrin|O|",
"chemical_list": null,
"country": "United States",
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"doi": "10.1016/j.ebcr.2016.08.002",
"fulltext": "\n==== Front\nEpilepsy Behav Case RepEpilepsy Behav Case RepEpilepsy & Behavior Case Reports2213-3232Elsevier S2213-3232(16)30039-110.1016/j.ebcr.2016.08.002Case ReportA case report on the efficacy of vigabatrin analogue (1S, 3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (CPP-115) in a patient with infantile spasms Doumlele Kyra kyra.doumlele@nyumc.org⁎Conway Erin Hedlund Julie Tolete Patricia Devinsky Orrin New York University School of Medicine, Comprehensive Epilepsy Center, 223 East 34th Street, New York, NY 10016, USA⁎ Corresponding author at: NYULMC Comprehensive Epilepsy Center, 223 East 34th Street, New York, NY 10016, USA.NYULMC Comprehensive Epilepsy Center223 East 34th StreetNew YorkNY10016USA kyra.doumlele@nyumc.org21 8 2016 2016 21 8 2016 6 67 69 15 6 2016 5 8 2016 © 2016 The Authors2016This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).West Syndrome is characterized by infantile spasms, a hypsarrhythmic electroencephalogram (EEG) pattern, and a poor neurodevelopmental prognosis. First-line treatments include adrenocorticotrophic hormone (ACTH) and vigabatrin, but adverse effects often limit their use. CPP-115 is a high-affinity vigabatrin analogue developed to increase therapeutic potency and to limit retinal toxicity. Here, we present a child treated with CPP-115 through an investigational new drug protocol who experienced a marked reduction of seizures with no evidence of retinal dysfunction. Given the potential consequences of ongoing infantile spasms and the limitations of available treatments, further assessment of CPP-115 is warranted.\n\nKeywords\nWest SyndromeInfantile spasmsEpileptic spasmsEpilepsyCPP-115\n==== Body\n1 Introduction\nWest Syndrome is an infantile-onset epileptic encephalopathy characterized by the following: 1) clusters of flexor, extensor, or mixed spasms (infantile spasms); 2) cognitive and/or psychomotor disability; and 3) hypsarrhythmia on electroencephalogram (EEG). West Syndrome can result from diverse genetic and acquired causes, and in many cases, the etiology remains unknown [1], [2]. Patients typically develop spasms in the first year of life which often resolve by four years of age. Spasms are often accompanied or followed by other seizure types. Further, the combination of the underlying disorder, abundant interictal epileptiform activity, and seizures often causes severe intellectual and motor deficits [3], [4].\n\nEarly and effective treatment intervention may reduce or prevent developmental delays associated with West Syndrome [5], [6]. The FDA-approved treatments are limited by tolerability and efficacy [4]. Adrenocorticotropic hormone (ACTH) and (RS)-4-aminohex-5-enoic acid (vigabatrin) are effective in many cases but have potentially serious adverse effects [3], [4]. The ACTH can lead to immunosuppression and infections, hypertension, metabolic abnormalities, and renal impairment and is rarely fatal [7]. Vigabatrin can cause progressive and potentially irreversible visual field loss from retinal toxicity. Despite the risks associated with vigabatrin, its efficacy makes it the first line treatment for some etiologies of infantile spasms, especially tuberous sclerosis [8]. There is a need for safer and more effective therapies.\n\nVigabatrin inactivates GABA aminotransferase (GABA-AT), an intracellular enzyme that degrades GABA, increasing synaptic GABA concentrations [9]. (1S, 3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (CPP-115) is a high-affinity vigabatrin analogue. CPP-115 was developed to produce greater therapeutic potency than vigabatrin without retinal toxicity [10], [11]. The molecular structure prevents formation of the reactive metabolite implicated in retinal toxicity [10]. Mechanism-based inhibition assays demonstrated that CPP-115 design increased its ability to inactivate GABA-AT to 187 times that of vigabatrin [11].\n\nAnimal studies support increased efficacy and decreased retinal toxicity associated with CPP-115. Administration of CPP-115 in a multiple-hit rat model of infantile spasms significantly reduced spasms and normalized the EEG. Results were significant at a dose 400 times lower than that of vigabatrin, with effects lasting two to three times as long [12]. Rats treated with CPP-115 had reduced retinal toxicity compared with those treated with vigabatrin [13]. In humans treated with CPP-115 for one week, there were significantly increased GABA concentrations on 1H magnetic resonance spectroscopy (MRS) in the supplementary motor area and parietal–occipital cortex [14].\n\nThe FDA has granted CPP-115 orphan drug designation for the treatment of infantile spasms. The potential safety and efficacy of CPP-115 led us to treat a child with pharmacologically resistant infantile spasms in an open-label investigational new drug protocol.\n\n2 Case report\nThe boy presented at one year of age with episodes of head-nodding and shoulder/arm shrugs upon waking. After an EEG recorded episodic electrodecremental responses associated with motor paroxysms and hypsarrhythmia, infantile spasms were diagnosed. Magnetic resonance imaging (MRI) showed a mild decreased cerebral volume, dysmeylination, and an atrophic corpus callosum. Genetic testing, including whole exome sequencing of the child and parents, was negative. The patient also had cortical blindness, bilateral sensory hearing loss, hypotonia, and global developmental delay. Over the next two years, spasms continued despite various treatment combinations of ACTH, clonazepam, zonisamide, vigabatrin, valproic acid, ketogenic diet, topiramate, clobazam, felbatol, intravenous solumedrol, and lamotrigine. Seizure cessation was achieved only during the first month of treatment with vigabatrin. An EEG five months prior to CPP-115 initiation recorded several tonic spasms seizures on one day and 71 parental pushbuttons within a separate 16-hour period, of which ~ 50% were myoclonic jerks without EEG correlates and ~ 50% were spasms with ictal correlates.\n\nThis patient began taking CPP-115 at age 3 years as an FDA-authorized investigational drug with institutional review board approval. His current antiseizure drugs were clobazam 1.8 mg/kg daily and vigabatrin 157.5 mg/kg, and he was on the ketogenic diet. Vigabatrin was reduced to 118.1 mg/kg with CPP-115 treatment initiation. CPP-115 is a powder prepared in 5 mL of sterile water and administered as a liquid via syringe. It was mixed with a noncarbonated, artificially sweetened beverage. CPP-115 titrations followed a dosing protocol provided by Catalyst Pharmaceutical Partners, the drug manufacturer. CPP-115 titrations started at 0.2 mg/kg with planned increases of 0.2 mg/kg per week as tolerated up to a maximum daily dose of 1.2 mg/kg. CPP-115 reached maximal dosing in 6 weeks as per protocol. However, the dose was reduced to 1.1 mg/kg ~ 2 months later because of concerns over decreased appetite and fatigue, both of which resolved within 1 year of CPP-115 initiation. His seizure frequency increased with the reduction of the CPP-115 dose. At the time of the dose reduction, the patient was also taking 83.3 mg/kg vigabatrin. Vigabatrin was completely weaned within 1 year of CPP-115 initiation (Fig. 1). Mood and cognitive improvement were noted with the cessation of vigabatrin, but an increase in seizure frequency persisted for ~ 5 months. During the vigabatrin weaning period, CPP-115 was increased by 0.03 mg/kg. Clobazam was also reduced to 0.83 mg/kg daily within the same year.\n\nThe patient's seizure frequency went from ~ 100 seizures per day before CPP-115 to ~ 25–30 seizures per day after 1.5 years on CPP-115 (Fig. 1). The greatest reduction in seizures was reported during the two months that he was on ~ 83.3 mg/kg vigabatrin and the maximal dose of CPP-115 (1.2 mg/kg or 14.4 mg). During this time, his seizures were initially reduced to 5–10/day, and he went four weeks without observed seizures. After the weaning of the vigabatrin, tiagabine was introduced to control a relative increase in reported seizure frequency and demonstrated some seizure control, but gagging, insomnia, and decreased appetite led to discontinuation of tiagabine. During treatment with CPP-115, electroretinograms (ERGs), complete blood count, and comprehensive metabolic panel were obtained every 3–6 months with no abnormalities. A recent 18-hour, 24-channel EEG study showed the absence of normal wake and sleep state features, moderate generalized slowing, increased beta activity, bilateral multifocal epileptiform discharges, and generalized discharges. The report noted improvement because of a complete lack of electrodecremental responses or seizures. The events classified as myoclonic seizures by the parents, were milder in intensity than before CPP-115, and were not associated with EEG changes. Currently, the patient continues to experience reduced myoclonic seizures, ~ 25–30 per day according to parental report, on CPP-115 at 1.2 mg/kg or 13.9 mg per day, clobazam 0.4 mg/kg daily, and the ketogenic diet.\n\nClinically, with the addition of CPP-115, his parents and therapists observed improved environmental interaction, attention, and motor function.\n\n3 Discussion\nThis case study suggests sustained efficacy and tolerability of CPP-115 in treating epileptic spasms. Prior to CPP-115 treatment, this patient's seizures had failed ten drugs and the ketogenic diet, and this patient had approximately 100 seizures per day. One year after starting CPP-115 and tapering off of clobazam and vigabatrin, his reported seizure frequency decreased by more than 50%, and his cognition and behavior improved. An 18-hour EEG at age five revealed resolution of electrographic seizures and reduction of interictal discharges by more than 50%. The patient had no evidence of retinal damage seen on regular ERGs, which is consistent with a potentially increased safety profile with CPP-115 versus vigabatrin [10], [11], [13]. The cognitive and behavioral improvement observed by parents and therapists could have been due to reduced seizure frequency and interictal epileptiform discharges or other factors.\n\nAs an open-label, single subject case report, this evidence is limited by several factors. The discrepancy between the seizure-free 18-hour EEG and parental report of 25–30 seizures per day suggests some inaccuracies in parental reporting of seizure frequency. Many of his ‘myoclonic seizures’ may be nonepileptic or seizures that are not associated with an EEG change. Notably, the baseline parental reports of ~ 100 seizures per day were associated with > 35 electrographic seizures per day on an EEG, and an additional equal number of events reported by the family were myoclonic jerks lacking ictal correlates. Parental reports of reduced seizure frequency and duration were concordant with the improvement observed in the EEG. While the reduction in reported seizure frequency and improvement in EEG could represent the natural clinical progression of his disorder, his seizure frequency had remained constant except for a one-month cessation during initial vigabatrin therapy. Despite ten antiepileptic drugs and dietary therapy, his seizures remained drug-resistant. Another limitation was that CPP-115 was not administered in a blinded setting but in tandem with other antiseizure medications. The patient was treated simultaneously with vigabatrin during the first year of treatment, during which time the therapy exhibited the most marked apparent reduction in seizure frequency. This could reflect a synergistic effect that warrants further investigation. However, vigabatrin was weaned and has not been reinitiated in the last year, during which time the patient has continued to have improved seizure control. Finally, we cannot exclude long-term retinal toxicity in this child. Never the less, regular ERGs are considered sensitive to detect vigabatrin-associated retinal toxicity and meet current clinical safety guidelines to detect retinal dysfunction in infants and other patients who cannot perform perimetry [15].\n\n4 Conclusion\nDespite the appreciable limitations of the available data, the reported reduction in seizure frequency and documented improvements in the interictal and ictal EEG temporally associated with CPP-115 initiation in this patient are noteworthy. In the context of infantile spasms and associated morbidity, mortality, and poor neurodevelopmental outcomes, CPP-115 presents a promising alternative to vigabatrin therapy, albeit one requiring further comprehensive analysis in a controlled setting.\n\nConflict of interest\nNone of the authors has any conflict of interest to disclose.\n\nFig. 1 Patient's estimated daily seizure frequency as reported by his parents and concurrent vigabatrin (VGB) and CPP-115 dosages (mg/kg).\n\nFig. 1\n==== Refs\nReferences\n1 Pellock J.M. Hrachovy R. Shinnar S. Baram T. Bettis D. Dlugos D. Infantile spasms: a US consensus report Epilepsia 51 2010 2175 2189 20608959 \n2 Pavone P. Striano P. Falsaperla R. Pavone L. Ruggieri M. Infantile spasms syndrome, West syndrome and related phenotypes: what we know in 2013 Brain Dev 36 2014 739 751 24268986 \n3 Nelson G.R. Management of infantile spasms Transl Pediatr 4 2015 260 270 26835388 \n4 Go C.Y. Mackay M.T. Weiss S.K. Stephens D. Adams-Webber T. Ashwal S. Evidence-based guideline update: medical treatment of infantile spasms. Report of the guideline development subcommittee of the American Academy of Neurology and the practice committee of the Child Neurology Society Neurology 78 2012 1974 1980 22689735 \n5 Riikonen Favourable prognostic factors with infantile spasms Eur J Paediatr Neurol 14 2010 13 18 19362867 \n6 Bombardieri R. Pinci M. Moavero R. Cerminara C. Curatolo Early control of seizures improves long-term outcome in children with tuberous sclerosis complex Eur J Paediatr Neurol 14 2010 146 149 19369101 \n7 Shumiloff N.A. Lam W.M. Manasco K.B. Adrenocorticotropic hormone for the treatment of West Syndrome in children Ann Pharmacother 47 2013 744 754 23606552 \n8 Faulkner M.A. Tolman J.A. Safety and efficacy of vigabatrin for the treatment of infantile spasms J Cent Nerv Syst Dis 3 2011 199 207 23861649 \n9 Pesaturo K.A. Spooner L.M. Belliveau P. Vigabatrin for infantile spasms Pharmacotherapy 31 2011 298 311 21361740 \n10 Lee H. Doud E.H. Wu R. Sanishvili R. Juncosa J.I. Liu D. Mechanism of inactivation of γ-aminobutyric acid aminotransferase by (1S,3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (CPP-115) J Am Chem Soc 137 2015 2628 2640 25616005 \n11 Silverman R.B. The 2011 E. B. Hershberg Award for important discoveries in medicinally active substances: (1S,3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (CPP-115), a GABA aminotransferase inactivator and new treatment for drug addiction and infantile spasms J Med Chem 55 2012 567 575 22168767 \n12 Briggs S.W. Mowrey W. Hall C.B. Galanopoulou A.S. CPP-115, a vigabatrin analogue, decreases spasms in the multiple-hit rat model of infantile spams Epilepsia 55 2014 94 102 24321005 \n13 Pan Y. Gerasimov M.R. Kvist T. Wellendorph P. Madsen K.K. Pera E. (1S, 3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (CPP-115), a potent gamma-aminobutyric acid aminotransferase inactivator for the treatment of cocaine addiction J Med Chem 55 2012 357 366 22128851 \n14 Data provided by Catalyst Pharmaceuticals, Inc. Catalyst Study CPP-115-00002 2016.\n15 Sergott R.C. Wheless J.W. Smith M.C. Westall C.A. Kardon R.H. Arnold A. Evidence-based review of recommendations for visual function testing in patients treated with vigabatrin J Neuroophthalmol 34 2010 20 35\n\n",
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"issn_linking": "2213-3232",
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"journal": "Epilepsy & behavior case reports",
"keywords": "CPP-115; Epilepsy; Epileptic spasms; Infantile spasms; West Syndrome",
"medline_ta": "Epilepsy Behav Case Rep",
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"pubdate": "2016",
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"references": "23861649;22689735;26835388;21361740;22168767;25616005;20608959;22128851;19362867;19369101;24321005;24268986;23606552",
"title": "A case report on the efficacy of vigabatrin analogue (1S, 3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (CPP-115) in a patient with infantile spasms.",
"title_normalized": "a case report on the efficacy of vigabatrin analogue 1s 3s 3 amino 4 difluoromethylenyl 1 cyclopentanoic acid cpp 115 in a patient with infantile spasms"
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"abstract": "Immune checkpoint inhibitors have emerged as a novel treatment in a wide variety of malignancies; however, it is associated with a distinctive array of side effects known as immune-related adverse events. Hyperprogression is defined as an accelerated growth of disease burden in patients treated with immunotherapy. Limited literature is available regarding hyperprogression in hepatocellular cancer. We report a case of a 36-year-old male with no past medical history who presented with nausea, vomiting, and abdominal pain and was diagnosed with unresectable hepatocellular cancer and thereby started on atezolizumab and bevacizumab. The patient got only 1 cycle of treatment and unfortunately had hyperprogression of disease.",
"affiliations": "Saint Joseph's University Medical Center, Paterson, NJ, USA.;Saint Joseph's University Medical Center, Paterson, NJ, USA.;Saint Joseph's University Medical Center, Paterson, NJ, USA.",
"authors": "Singh|Balraj|B|0000-0001-7986-6031;Kaur|Parminder|P|;Maroules|Michael|M|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; C000594389:atezolizumab",
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"fulltext": "\n==== Front\nJ Investig Med High Impact Case Rep\nJ Investig Med High Impact Case Rep\nHIC\nsphic\nJournal of Investigative Medicine High Impact Case Reports\n2324-7096\nSAGE Publications Sage CA: Los Angeles, CA\n\n33787380\n10.1177/2324709621992207\n10.1177_2324709621992207\nCase Report\nHyperprogression in a Patient With Hepatocellular Cancer Treated With Atezolizumab and Bevacizumab: A Case Report and Review of Literature\nhttps://orcid.org/0000-0001-7986-6031\nSingh Balraj MD 1\nKaur Parminder MD 1\nMaroules Michael MD 1\n1 Saint Joseph’s University Medical Center, Paterson, NJ, USA\nBalraj Singh, MD, Saint Joseph’s University Medical Center, 703 Main Street, Paterson, NJ 07503, USA. Email: bsriar9@gmail.com\n31 3 2021\nJan-Dec 2021\n9 23247096219922072 12 2020\n3 1 2021\n6 1 2021\n© 2021 American Federation for Medical Research\n2021\nAmerican Federation for Medical Research\nThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).\nImmune checkpoint inhibitors have emerged as a novel treatment in a wide variety of malignancies; however, it is associated with a distinctive array of side effects known as immune-related adverse events. Hyperprogression is defined as an accelerated growth of disease burden in patients treated with immunotherapy. Limited literature is available regarding hyperprogression in hepatocellular cancer. We report a case of a 36-year-old male with no past medical history who presented with nausea, vomiting, and abdominal pain and was diagnosed with unresectable hepatocellular cancer and thereby started on atezolizumab and bevacizumab. The patient got only 1 cycle of treatment and unfortunately had hyperprogression of disease.\n\nhepatocellular carcinoma\nhyperprogression\nimmunotherapy\npseudo progression\ntumor growth rate\natezolizumab\nanti-PD-1\nimmune checkpoint inhibitors\ncover-dateJanuary-December 2021\ntypesetterts1\n==== Body\nIntroduction\n\nHepatocellular carcinoma (HCC) is one of the major causes of cancer-related mortality worldwide.1 Risk factors include viral hepatitis B and C infections, alcohol abuse, and metabolic disorders.2 The prognosis of HCC is poor despite availability of many treatment modalities including surgical resection, transplantation, locoregional treatment (radiofrequency ablation, transcatheter arterial chemoembolization), and systemic therapy (tyrosine kinase inhibitors). In recent years, immune checkpoint inhibitors (ICIs) have expanded as an emerging treatment for HCC. Current approved treatment for advanced HCC includes atezolizumab (anti-PD-L1) with bevacizumab approved as first-line treatment option and pembrolizumab (anti-PD-1) and nivolumab (anti-PD-1) with or without ipilimumab (anti-CTLA4) approved as second-line therapy.3\n\nCase Presentation\n\nA 36-year-old male with no past medical history presented to emergency department (ED) for nausea, vomiting, and abdominal pain of 8 weeks duration. The patient had another emergency department visit 4 weeks prior to this presentation for similar complaints; imaging was done (Figure 1) and he was discharged from the ED to follow-up in oncology clinic. The patient was seen in the oncology clinic and plan was to do biopsy of the liver mass; however, due to worsening of his symptoms, he came to the ED and was admitted. Review of system was positive for weight loss of 20 pounds over 6 weeks and negative for blood in stools, fever, shortness of breath, cough, chest pain, and night sweats. The patient denies any smoking or drug abuse and admitted to 1 to 2 beers sometimes over the weekend. No history of blood transfusion. Physical examination was normal. Initial laboratory evaluation showed complete blood count and basic metabolic profile within normal limits. Other blood work was as follows: lactate dehydrogenase 168 U/L (reference: 140-271 U/L), alkaline phosphatase 90 U/L (reference: 34-104 U/l), aspartate transaminase 35 U/L (reference: 13-39 U/L), alanine transaminase 58 U/L (reference: 7-52U/L), bilirubin 0.6 mg/dL (reference: 0.3-1.1 mg/dL), prothrombin time 13.4 seconds (reference: 12.2-14.9 seconds), international normalized ratio 1 (reference: <1), partial thromboplastin time 27.7 seconds (reference: 21.3-35.1 seconds), calcium 9.7 mg/dL (reference: 8.6-10.3 mg/dL), albumin 4.5 mg/dL (reference: 3.5-5.0 mg/dL), α-fetoprotein 5037 ng/mL (reference: 0.5-9 ng/mL), and des gamma carboxy prothrombin 149.3 ng/mL (reference: 0-7.5 ng/mL). HIV, hepatitis B and C profile was negative. Computed tomography (CT) of the abdomen and pelvis with intravenous contrast showed large heterogeneous mass in the left lobe of the liver measuring 11 × 10 × 10 cm (Figure 2). The patient underwent CT-guided biopsy of the liver mass, and pathology was consistent with HCC. A hepatobiliary surgical consult was placed, and the patient underwent diagnostic laparoscopy, which showed left lobe mass involving segments 2 and 3, nodular lesion on the peritoneum overlying segment 2 of the liver (frozen pathology revealed the specimen sample was too small for evaluation, piece of peritoneum was removed in the same area and was sent as specimen), nodular area on the anterior surface of segment 4 (frozen pathology revealed carcinoma), and wedge resection of the posterior surface of segment 4 (3.0 × 2.2 × 1.7 cm). Final pathology of the wedge resection of segment 4 showed 3 separate nodules consistent with HCC and peritoneum biopsy was negative. The patient was discharged and seen at an outpatient clinic and started on atezolizumab and bevacizumab given unresectable disease. The patient got treatment on October 5, 2020. Three weeks later, the patient came to the ED for abdominal pain and CT chest/abdomen/pelvis with contrast showed multiple bilateral lumg nodules (all size less than 1 cm), large (21 × 10.9 × 16.5 cm) heterogeneously enhancing mass in the left lobe of the liver, and interval development of additional small multiple hypodense lesions in the right lobe of the liver suggesting multicentric HCC (Figures 3 and 4). The imaging findings of the patient were consistent with hyperprogressive disease (HPD). Summary of the patient’s course from presentation to HPD is provided in Figure 5. The patient performance status had declined to ECOG 3-4 (Eastern Cooperative Oncology Group). Palliative care was recommended and the patient went to his home country Peru.\n\nFigure 1. Computed tomography scan of the abdomen and pelvis showing 9.5 cm mass in the left lobe of the liver (initial emergency department visit on July 17, 2020).\n\nFigure 2. Computed tomography scan of the abdomen and pelvis on admission (August 21, 2020) showing 11 × 10 × 10 cm mass in the left lobe of the liver.\n\nFigure 3. Computed tomography scan of the abdomen and pelvis (cross-sectional view) on readmission (October 26, 2020) showing large 21 × 10.9 × 16.5 cm mass in the left lobe and additional small multiple hypodense lesions in the right lobe of the liver.\n\nFigure 4. Computed tomography scan of the abdomen and pelvis (coronal view) on readmission (October 26, 2020) showing large 21 × 10.9 × 16.5 cm mass in the left lobe.\n\nFigure 5. Summary of the patient’s course from presentation to hyperprogressive disease (HPD).\n\nDiscussion\n\nCheckpoint inhibition–based immunotherapy has become a primary treatment option in the management of wide range of malignancies and is associated with a distinctive array of side effects known as immune-related adverse events and can affect almost any organ in the human body. The most common adverse effects reported are pneumonitis, colitis, hepatitis, adrenocorticotropic hormone insufficiency, hypothyroidism, type 1 diabetes, acute kidney injury, and myocarditis.4\n\nHyperprogression is characterized by accelerated growth in disease burden in patients treated with ICIs and is usually associated with a deteriorating clinical course. In reported literature hyperprogression incidence varied between 4% and 29% and has been reported with different types of cancer (head and neck squamous cell carcinoma, gastric cancer, non–small cell lung cancer, and melanoma).5 Limited literature is available regarding hyperprogression in HCC. HPD defining criteria, predictors, and mechanisms of hyperprogression are not completely understood at present. To define HPD, the following different criteria have been used in the literature: tumor growth kinetics, tumor growth rate, and time-to-treatment-failure.6 For the evaluation of HPD in our patient, we used Lo Russo and colleagues7 recommended criteria (diagnosis of HPD requires at least 3 of the following criteria): (1) time-to-treatment failure, which is defined as the time between the start and the discontinuation of immunotherapy of less than 2 months; (2) a ≥50% increase in the sum of the major diameters of the target lesions between baseline and first radiologic assessment; (3) the emergence of at least 2 new lesions in an already involved organ during the first radiologic assessment; (4) the involvement of a new organ revealed by the first radiologic assessment; and (5) an ECOG performance status score of ≥2 within the first 2 months of start of immunotherapy treatment.7 Furthermore, our patient met all the criteria.\n\nKim and colleagues8 reported an incidence of 12.7% (24/189) in advanced HCC patients treated with nivolumab. Furthermore, HPD patients had worse progression-free survival and overall survival compared with patients with progressive disease without HPD, and more than 90% of HPD patients did not receive subsequent cancer treatment due to rapid decline of clinical status. Poor prognostic feature associated with HPD included elevated neutrophil-to-lymphocyte ratio (>4.125).8 In a retrospective study of 47 patients who got nivolumab as second- or third-line treatment, HPD was observed in 3 patients (6%) with metastatic HCC, metastatic lung adenocarcinoma, and metastatic urothelial transitional carcinoma.9 Wong and colleagues10 reported a case series of 6 patients with advanced HCC treated with ICIs who developed HPD. The immunotherapy drugs used were anti-PD-1 (nivolumab and durvalumab) and anti-CTLA4 (tremelimumab).Wang and colleagues11 reported HPD by serial F-fluorodeoxyglucose positron emission tomography in a patient with metastatic HCC patient during combined immunotherapy (pembrolizumab-ipilimumab-lenvatinib).\n\nVascular endothelial growth factor (VEGF-A) promotes tumor progression via angiogenesis and exhaustion of effector T-cells in the tumor microenvironment.12 Kim and colleagues8 analyzed 95 patients with advanced HCC treated with regorafenib (anti-VEGF therapy; along with 189 patients treated with immunotherapy) and observed that HPD occurred exclusively in patients treated with immunotherapy, thereby suggesting possible protective effect of anti-VEGF therapy against HPD. However, our patient received bevacizumab (anti-VEGF therapy) along with atezolizumab and still developed HPD. Further studies are needed regarding this aspect. As immunotherapy is being widely used for different types of cancer, it is of paramount importance to improve the knowledge of this novel phenomenon.\n\nConclusion\n\nIn conclusion, we report a patient with HCC treated with atezolizumab and bevacizumab for 1 cycle and developed HPD. Our case and review of literature suggest that health care providers should maintain a high index of suspicion to recognize HPD (accelerated progression with immunotherapy), and once the diagnosis is confirmed, immunotherapy should be stopped immediately.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nEthics Approval: Our institution does not require ethical approval for reporting individual cases.\n\nInformed Consent: Verbal informed consent was obtained from the patient for their anonymized information to be published in this article.\n\nORCID iD: Balraj Singh https://orcid.org/0000-0001-7986-6031\n==== Refs\nReferences\n\n1 Jemal A Ward EM Johnson CJ , et al . Annual report to the nation on the status of cancer, 1975-2014, featuring survival. J Natl Cancer Inst. 2017;109 :djx030.\n2 Park JW Chen M Colombo M , et al . Global patterns of hepatocellular carcinoma management from diagnosis to death: the BRIDGE study. Liver Int. 2015;35 :2155-2166.25752327\n3 Bonilla CM McGrath NA Fu J Xie C . Immunotherapy of hepatocellular carcinoma with infection of hepatitis B or C virus. Hepatoma Res. 2020;6 :68.33134550\n4 Bajwa R Cheema A Khan T , et al . Adverse effects of immune checkpoint inhibitors (programmed death-1 inhibitors and cytotoxic T-lymphocyte-associated protein-4 inhibitors): results of a retrospective study. J Clin Med Res. 2019;11 :225-236.30937112\n5 Camelliti S Le Noci V Bianchi F , et al . Mechanisms of hyperprogressive disease after immune checkpoint inhibitor therapy: what we (don’t) know. J Exp Clin Cancer Res. 2020;39 :236.33168050\n6 Han XJ Alu A Xiao YN Wei YQ Wei XWfx . Hyperprogression: a novel response pattern under immunotherapy. Clin Transl Med. 2020;10 :e167.\n7 Lo Russo G Moro M Sommariva M , et al . Antibody-Fc/FcR interaction on macrophages as a mechanism for hyperprogressive disease in non-small cell lung cancer subsequent to PD-1/PD-L1 blockade. Clin Cancer Res. 2019;25 :989-999.30206165\n8 Kim CG Kim C Yoon SE , et al . Hyperprogressive disease during PD-1 blockade in patients with advanced hepatocellular carcinoma. J Hepatol. 2021;74 :350-359.32810553\n9 Petrioli R Mazzei MA Giorgi S , et al . Hyperprogressive disease in advanced cancer patients treated with nivolumab: a case series study. Anticancer Drugs. 2020;31 :190-195.31850916\n10 Wong DJ Lee J Choo SP Thng CH Hennedige T . Hyperprogressive disease in hepatocellular carcinoma with immune checkpoint inhibitor use: a case series. Immunotherapy. 2019;11 :167-175.30730278\n11 Wang J Wang X Yang X Zhao H Huo L . FDG PET findings of hyperprogression during immunotherapy in a patient with hepatocellular carcinoma. Clin Nucl Med. 2020;45 :92-93.31789917\n12 Kim CG Jang M Kim Y , et al . VEGF-A drives TOX-dependent T cell exhaustion in anti–PD-1–resistant microsatellite stable colorectal cancers. Sci Immunol. 2019;4 :eaay0555.\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2324-7096",
"issue": "9()",
"journal": "Journal of investigative medicine high impact case reports",
"keywords": "anti-PD-1; atezolizumab; hepatocellular carcinoma; hyperprogression; immune checkpoint inhibitors; immunotherapy; pseudo progression; tumor growth rate",
"medline_ta": "J Investig Med High Impact Case Rep",
"mesh_terms": "D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D006528:Carcinoma, Hepatocellular; D006801:Humans; D008113:Liver Neoplasms; D008297:Male",
"nlm_unique_id": "101624758",
"other_id": null,
"pages": "2324709621992207",
"pmc": null,
"pmid": "33787380",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "31850916;30206165;33168050;32997401;31789917;30937112;33134550;30730278;25752327;31704735;32810553;28376154",
"title": "Hyperprogression in a Patient With Hepatocellular Cancer Treated With Atezolizumab and Bevacizumab: A Case Report and Review of Literature.",
"title_normalized": "hyperprogression in a patient with hepatocellular cancer treated with atezolizumab and bevacizumab a case report and review of literature"
} | [
{
"companynumb": "US-AMGEN-USASP2021054113",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ATEZOLIZUMAB"
},
"drugadditional": null,
... |
{
"abstract": "We reported that epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor re-administration (TKI-R) might be salvage therapy in patients with advanced non-small cell lung cancer after recovery from EGFR-TKI-induced interstitial lung disease (ILD). Here we retrospectively evaluated whether chemotherapy re-administration (CT-R) was effective in patients after chemotherapy-induced ILD. After providing their informed consent due to the risk of severe ILD, five patients received CT-R and six received TKI-R with oral administration of 0.5 mg/kg prednisolone. The overall survival (OS) from the occurrence of drug-induced ILD was shorter in CT-R cases than that in TKI-R cases (7.3 months vs. 25.4 months, p=0.003). The median duration of OS, however, was 7.3 months in cases with CT-R and 1.9 months in cases without CT-R. Multivariate analysis showed that CT-R as well as TKI-R tended to reduce the risk of mortality. CT-R might be salvage therapy in such patients, although the benefit of CT-R was smaller than that of TKI-R.",
"affiliations": "Department of Respiratory Medicine, Kumamoto Regional Medical Center, Kumamoto, Japan kskkswbr@krmc.or.jp.;Department of Respiratory Medicine, Kumamoto Regional Medical Center, Kumamoto, Japan.;Department of Respiratory Medicine, Kumamoto Regional Medical Center, Kumamoto, Japan.;Department of Respiratory Medicine, Kumamoto Regional Medical Center, Kumamoto, Japan.",
"authors": "Kashiwabara|Kosuke|K|;Semba|Hiroshi|H|;Fujii|Shinji|S|;Tsumura|Shinsuke|S|",
"chemical_list": "D047428:Protein Kinase Inhibitors; C512478:EGFR protein, human; D066246:ErbB Receptors",
"country": "Greece",
"delete": false,
"doi": "10.21873/invivo.11319",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0258-851X",
"issue": "32(4)",
"journal": "In vivo (Athens, Greece)",
"keywords": "Drug-induced interstitial lung disease; EGFR-TKI; chemotherapy; corticosteroid; re-administration",
"medline_ta": "In Vivo",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D002289:Carcinoma, Non-Small-Cell Lung; D018572:Disease-Free Survival; D064420:Drug-Related Side Effects and Adverse Reactions; D066246:ErbB Receptors; D005260:Female; D006801:Humans; D017563:Lung Diseases, Interstitial; D008297:Male; D008875:Middle Aged; D009154:Mutation; D047428:Protein Kinase Inhibitors; D012189:Retrospective Studies; D016879:Salvage Therapy",
"nlm_unique_id": "8806809",
"other_id": null,
"pages": "851-857",
"pmc": null,
"pmid": "29936470",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": "27565912;20581579;18344641;15340374;23225454;25473530;22114570;23171837;17998366;15062597;20035424;27022112;15316202;25750330;23410901;28258422;18252919;22896776;25667495;15340376;21623280;22579408;20581580;15340375;18021415",
"title": "Re-administration of Chemotherapy in Patients with Advanced Non-small Cell Lung Cancer Who Recovered from Chemotherapy-induced Interstitial Lung Disease.",
"title_normalized": "re administration of chemotherapy in patients with advanced non small cell lung cancer who recovered from chemotherapy induced interstitial lung disease"
} | [
{
"companynumb": "JP-MYLANLABS-2018M1061748",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nThe drug-drug interactions between pitavastatin and darunavir/ritonavir (DRV/r) as well as pitavastatin and efavirenz (EFV) were examined in an open-label, parallel-arm, pharmacokinetic (PK) study in HIV-uninfected healthy volunteers.\n\n\nMETHODS\nSubjects received a pitavastatin dose of 2 mg for 4 days, followed by either EFV 600 mg (n = 14) or DRV/r 800/100 mg (n = 14) daily for 10 days, and pitavastatin 2 mg coadministered with EFV 600 mg or DRV/r 800/100 mg for 4 days. Full PK profiles were determined for pitavastatin and its lactone metabolite on days 4 and 18 and for EFV or DRV on days 14 and 18.\n\n\nRESULTS\nIn the EFV arm, the geometric mean area under the concentration time curve (AUC0-τ) and Cmax of pitavastatin were 85.3 ng·h·mL and 15.6 ng/mL, respectively, when given alone, versus 76 ng·h·mL and 18.8 ng/mL when coadministered with EFV. The geometric mean ratio for pitavastatin with EFV versus alone was 0.89 [90% confidence interval (CI): 0.73 to 1.09] for AUC0-τ and 1.20 (90% CI: 0.79 to 1.83) for Cmax. In the DRV/r arm, AUC0-τ and Cmax were 62.8 ng·h·mL and 24.0 ng/mL, respectively, when pitavastatin was administered alone, versus 56.9 ng·h·mL and 23.2 ng/mL when coadministered with DRV/r. The geometric mean ratio for pitavastatin with DRV/r versus alone was 0.91 (90% CI: 0.78 to 1.06) for AUC0-τ and 0.93 (90% CI: 0.72 to 1.19) for Cmax.\n\n\nCONCLUSIONS\nThere were no significant PK interactions between pitavastatin and EFV or DRV/r. No significant safety issues or lipid changes were noted.",
"affiliations": "*Division of Infectious Disease, Department of Medicine, New York University School of Medicine, New York, NY; †Division of Infectious Disease, Department of Medicine, Ohio State University Medical Center, Columbus, OH; ‡FACES Program, Nationwide Children's Hospital, Columbus, OH; §Translational Pharmacology Research Core, New York State Center of Excellence in Bioinformatics and Life Sciences, Buffalo, NY; ‖Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY; and ¶Division of Infectious Disease, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.",
"authors": "Malvestutto|Carlos D|CD|;Ma|Qing|Q|;Morse|Gene D|GD|;Underberg|James A|JA|;Aberg|Judith A|JA|",
"chemical_list": "D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D017320:HIV Protease Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011804:Quinolines; D013449:Sulfonamides; C098320:efavirenz; C108475:pitavastatin; D019438:Ritonavir; D000069454:Darunavir",
"country": "United States",
"delete": false,
"doi": "10.1097/QAI.0000000000000333",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1525-4135",
"issue": "67(4)",
"journal": "Journal of acquired immune deficiency syndromes (1999)",
"keywords": null,
"medline_ta": "J Acquir Immune Defic Syndr",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D000069454:Darunavir; D004347:Drug Interactions; D005260:Female; D017320:HIV Protease Inhibitors; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008297:Male; D008875:Middle Aged; D011804:Quinolines; D019438:Ritonavir; D013449:Sulfonamides; D055815:Young Adult",
"nlm_unique_id": "100892005",
"other_id": null,
"pages": "390-6",
"pmc": null,
"pmid": "25202920",
"pubdate": "2014-12-01",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "16778721;24176465;16595711;24235263;19442037;19884908;23819752;16863456;15980690;22174437;17304157;19234366;16514303;23703578;12410494;11873000;20102298;22627182;17177112",
"title": "Lack of pharmacokinetic interactions between pitavastatin and efavirenz or darunavir/ritonavir.",
"title_normalized": "lack of pharmacokinetic interactions between pitavastatin and efavirenz or darunavir ritonavir"
} | [
{
"companynumb": "US-JNJFOC-20141101814",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DARUNAVIR"
},
"drugadditional": null,
"... |
{
"abstract": "BACKGROUND\nThere have been previous cases of medication-induced hyponatremia with various causative agents reported. Severe hyponatremia, a common medical emergency, can vary widely in its presentation, ranging from seizures and comas to no clinical manifestations.\n\n\nMETHODS\nAn 81-year-old female patient presented to the Emergency Department with history of a fall. She had a known case of hypertension and was recently started on hydrochlorothiazide. When evaluated at the hospital, her sodium level was measured as 106 mmol/L and her clinical symptoms were unremarkable. She was simultaneously diagnosed with a urinary tract infection, for which she was treated with intravenous ciprofloxacin. A few hours after administration, her sodium level fell even further, and she quickly developed symptoms of hyponatremia. After discontinuation of ciprofloxacin and treatment with hypertonic saline (3% NS), she improved and made a full recovery. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: We present an unusual case of minimally symptomatic, severe consecutive multi-medication-induced hyponatremia. As hyponatremia can present asymptomatically, routinely checking sodium levels is recommended, especially when caring for patients who recently experienced a fall or started a thiazide diuretic.",
"affiliations": "University of California at San Diego Medical Center, San Diego, California.;University of California at San Diego Medical Center, San Diego, California.;University of California at San Diego Medical Center, San Diego, California.",
"authors": "Vilke|Gary M|GM|;Akeely|Yahia|Y|;Lin|Lucia C|LC|",
"chemical_list": "D004232:Diuretics; D012462:Saline Solution, Hypertonic; D006852:Hydrochlorothiazide",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jemermed.2019.11.048",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-4679",
"issue": "58(3)",
"journal": "The Journal of emergency medicine",
"keywords": "ciprofloxacin; diuretic; severe hyponatremia; thiazide",
"medline_ta": "J Emerg Med",
"mesh_terms": "D000369:Aged, 80 and over; D004232:Diuretics; D005260:Female; D006801:Humans; D006852:Hydrochlorothiazide; D006973:Hypertension; D007010:Hyponatremia; D012462:Saline Solution, Hypertonic",
"nlm_unique_id": "8412174",
"other_id": null,
"pages": "e137-e140",
"pmc": null,
"pmid": "32205001",
"pubdate": "2020-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Sequential Drug-Induced Severe Hyponatremia in a Minimally Symptomatic, 81-Year-Old Patient.",
"title_normalized": "sequential drug induced severe hyponatremia in a minimally symptomatic 81 year old patient"
} | [
{
"companynumb": "US-RISING PHARMACEUTICALS, INC.-2020RIS00141",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SODIUM CHLORIDE"
},
"drug... |
{
"abstract": "Necrotizing fasciitis is an infection of the soft tissue that is characterized by rapidly spreading inflammation and subsequent necrosis. It is a rare complication of peripheral nerve blocks. We report a rare case of necrotizing fasciitis after placement of a peripheral nerve catheter.\n\n\n\nA 58-year-old woman presented for an elective right second metatarsal resection and received a sciatic nerve catheter for postoperative pain control. On postoperative day 7, clinical examination and imaging supported the diagnosis of necrotizing fasciitis.\n\n\n\nMultiple reports have been published of necrotizing fasciitis after single-shot peripheral nerve block injections, neuraxial anesthesia, and intramuscular injections. This case highlights the potential for the rare complication of necrotizing fasciitis after peripheral nerve catheter placement.",
"affiliations": "From the Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN.",
"authors": "Dott|Daltry|D|;Canlas|Christopher|C|;Sobey|Christopher|C|;Obremskey|William|W|;Thomson|Andrew Brian|AB|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1097/AAP.0000000000000482",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1098-7339",
"issue": "41(6)",
"journal": "Regional anesthesia and pain medicine",
"keywords": null,
"medline_ta": "Reg Anesth Pain Med",
"mesh_terms": "D057785:Catheters; D019115:Fasciitis, Necrotizing; D005260:Female; D006801:Humans; D007273:Injections, Intramuscular; D008875:Middle Aged; D019637:Orthopedic Procedures; D012584:Sciatic Nerve",
"nlm_unique_id": "9804508",
"other_id": null,
"pages": "728-730",
"pmc": null,
"pmid": "27662064",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Necrotizing Fasciitis as a Complication of a Continuous Sciatic Nerve Catheter Using the Lateral Popliteal Approach.",
"title_normalized": "necrotizing fasciitis as a complication of a continuous sciatic nerve catheter using the lateral popliteal approach"
} | [
{
"companynumb": "US-UCBSA-2017011447",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DIPHENHYDRAMINE HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "To characterise a sample of patients with inflammatory choroidal neovascularization (I-CNV), including clinical profile, underlying aetiology and its course, treatments performed, associated clinical response, and visual prognosis.\nRetrospective analysis of patients with a diagnosis of I-CNV followed at the Ophthalmology Department of Centro Hospitalar Universitário de São João (CHUSJ). Clinical and visual outcomes were classified according to the difference in visual acuity after treatment.\nTwenty eyes from 17 patients were analysed (11 female and 6 male patients, mean age 41.90 ± 16.457 years at CNV diagnosis). Punctate inner choroidopathy/multifocal choroiditis was the predominant inflammatory aetiology (10 patients, 58.82%). Median follow-up time was 46 months (range 10 to 188 months). Neovascularization was treated with intravitreal anti-VEGF injections (bevacizumab, aflibercept, and ranibizumab), and inflammation with anti-inflammatory/immunosuppressive therapy (oral, intravenous, and/or intravitreal corticosteroids; oral cyclosporine or methotrexate). Intravitreal anti-VEGF agents had a median number of 7.00 injections (IQR, 4.25 to 29.00). Visual acuity among 20 eyes had a mean gain of 15.10 ± 12.998 ETDRS letters after anti-VEGF treatment (p=0.000051). According to our classification, 16 had an improved outcome (80.00%), 3 had a stable outcome (15.00%), and 1 had a worsened visual outcome (5.00%). In addition, 13 eyes (65.00%) had a final VA equal to or greater than 65 letters. Recurrence was seen in 3 eyes (15.00%). Complications included cataract (6 patients) and ocular hypertension (4 patients).\nA combined approach with anti-VEGF agents and anti-inflammatory therapy was effective in I-CNV treatment, and an overall good visual prognosis was attainable. Intensive follow-up was fundamental in the management of both the primary inflammatory and secondary neovascular conditions.",
"affiliations": "Faculty of Medicine, University of Porto, Porto, Portugal.;Department of Ophthalmology, São João Hospital University Centre, Porto, Portugal.;Department of Ophthalmology, São João Hospital University Centre, Porto, Portugal.;Department of Ophthalmology, São João Hospital University Centre, Porto, Portugal.;Department of Ophthalmology, São João Hospital University Centre, Porto, Portugal.",
"authors": "Carrola|Gonçalo|G|https://orcid.org/0000-0001-8961-0101;Lima-Fontes|Mário|M|https://orcid.org/0000-0002-9126-3505;Falcão-Reis|Fernando|F|;Figueira|Luís|L|;Carneiro|Ângela|Â|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2021/9982883",
"fulltext": "\n==== Front\nJ Ophthalmol\nJ Ophthalmol\nJOPH\nJournal of Ophthalmology\n2090-004X\n2090-0058\nHindawi\n\n10.1155/2021/9982883\nResearch Article\nInflammatory Choroidal Neovascular Membranes: Clinical Profile, Treatment Effectiveness, and Visual Prognosis\nhttps://orcid.org/0000-0001-8961-0101\nCarrola Gonçalo goncaloesmacarrola@gmail.com\n1\nhttps://orcid.org/0000-0002-9126-3505\nLima-Fontes Mário 2\nFalcão-Reis Fernando 2 3\nFigueira Luís 2 4 5\nCarneiro Ângela 2 3\n1Faculty of Medicine, University of Porto, Porto, Portugal\n2Department of Ophthalmology, São João Hospital University Centre, Porto, Portugal\n3Departments of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal\n4Department of Pharmacology and Therapeutics, Faculty of Medicine of the University of Porto, Porto, Portugal\n5Centre for Drug Discovery and Innovative Medicines (MedInUP), University of Porto, Porto, Portugal\nAcademic Editor: Masaru Takeuchi\n\n2021\n23 7 2021\n2021 998288328 3 2021\n22 6 2021\n16 7 2021\nCopyright © 2021 Gonçalo Carrola et al.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nPurpose\n\nTo characterise a sample of patients with inflammatory choroidal neovascularization (I-CNV), including clinical profile, underlying aetiology and its course, treatments performed, associated clinical response, and visual prognosis.\n\nMethods\n\nRetrospective analysis of patients with a diagnosis of I-CNV followed at the Ophthalmology Department of Centro Hospitalar Universitário de São João (CHUSJ). Clinical and visual outcomes were classified according to the difference in visual acuity after treatment.\n\nResults\n\nTwenty eyes from 17 patients were analysed (11 female and 6 male patients, mean age 41.90 ± 16.457 years at CNV diagnosis). Punctate inner choroidopathy/multifocal choroiditis was the predominant inflammatory aetiology (10 patients, 58.82%). Median follow-up time was 46 months (range 10 to 188 months). Neovascularization was treated with intravitreal anti-VEGF injections (bevacizumab, aflibercept, and ranibizumab), and inflammation with anti-inflammatory/immunosuppressive therapy (oral, intravenous, and/or intravitreal corticosteroids; oral cyclosporine or methotrexate). Intravitreal anti-VEGF agents had a median number of 7.00 injections (IQR, 4.25 to 29.00). Visual acuity among 20 eyes had a mean gain of 15.10 ± 12.998 ETDRS letters after anti-VEGF treatment (p=0.000051). According to our classification, 16 had an improved outcome (80.00%), 3 had a stable outcome (15.00%), and 1 had a worsened visual outcome (5.00%). In addition, 13 eyes (65.00%) had a final VA equal to or greater than 65 letters. Recurrence was seen in 3 eyes (15.00%). Complications included cataract (6 patients) and ocular hypertension (4 patients).\n\nConclusion\n\nA combined approach with anti-VEGF agents and anti-inflammatory therapy was effective in I-CNV treatment, and an overall good visual prognosis was attainable. Intensive follow-up was fundamental in the management of both the primary inflammatory and secondary neovascular conditions.\n\nOphthalmology Department of CHUSJ\n==== Body\n1. Introduction\n\nInflammatory choroidal neovascularization (I-CNV) is characterised by the pathologic growth of blood vessels from the choroid to the subretinal and/or subretinal pigment epithelium spaces due to an inflammatory cause [1, 2]. In fact, inflammation represents the third most common cause of choroidal neovascularization (CNV), behind age-related macular degeneration (AMD) and pathologic myopia [1]. Regardless of the aetiology, what these entities have in common is a disruption in Bruch's membrane combined with an inflammatory and angiogenic cascade [3]. Endothelial and inflammatory cell invasion leads to the formation of neovascular membranes with associated leakage and haemorrhage and, consequently, a variable degree of vision loss [1, 3].\n\nInflammatory causes of CNV can be mainly divided into infectious and noninfectious uveitis (Table 1) [1].\n\nNevertheless, the risk of developing CNV in patients with these conditions varies considerably [4]. I-CNV is better documented in noninfectious than in infectious etiologies [1]. In addition, specific morphologic syndromes appear to be more correlated to this complication in comparison with eyes with nonsyndromic panuveitis or posterior uveitis [4]. Punctate inner choroidopathy, multifocal choroiditis, and Vogt–Koyanagi–Harada disease are some of those syndromes with higher incidences of CNV [4].\n\nEven though CNV is a relatively rare complication of inflammatory diseases, it can result in severe vision loss and it has a big impact on patients' work ability and productivity, since it happens commonly during active years [4–6]. This correlates with the incidence of uveitis, which also tends to affect a younger population [4]. Usual presenting symptoms are distortion and metamorphopsia, which can be accompanied by decreased visual acuity or scotoma [1]. Yet, many patients are asymptomatic, so new-onset neovascular membranes are often diagnosed by imaging techniques during follow-up of their inflammatory condition [4].\n\nDiagnosis still remains a challenge, but prompt treatment initiation is essential in order to avoid possibly rapid and irreversible visual loss [1, 6, 7]. Traditional fluorescein angiography and indocyanine green angiography coupled with optical coherence tomography have been crucial to not only ensure an accurate and early diagnosis but also to monitor disease progression and treatment response. Optical coherence tomography angiography is a recently used complementary imaging modality, also useful in the diagnosis and management of this condition [1, 7].\n\nManagement of inflammatory choroidal neovascularization has had massive progress in recent years/decades. Introduction of antivascular endothelial growth factor (VEGF) intravitreal therapies seems to be a major determinant decreasing neovascularization and, consequently, improving visual acuity [8, 9]. Such evidence agrees with the practically consensual understanding of VEGF as a key mediator in CNV pathogenesis [3]. In fact, in I-CNV, there are two disease processes we aim to control: neovascularization itself and the underlying inflammatory cause. It is consensual nowadays that a combined approach with both local and systemic therapies results in better disease control and overall visual prognosis. Accordingly, intravitreal anti-VEGF agents, such as bevacizumab, aflibercept, and ranibizumab, in association with systemic immunosuppressive/anti-inflammatory drugs, with or without corticosteroids, are now the standard of care for these patients. As a matter of fact, directly addressing the inflammatory environment, which is itself the root of I-CNV formation, will probably terminate the angiogenic drive, therefore leading to better outcomes [1, 5]. Other therapies, such as photodynamic therapy (PDT) with verteporfin, can also be used to manage the disease [1].\n\nAnti-VEGF therapy seems promising treating I-CNV, as reported by several small sample size studies. However, there is a paucity of clinical trials regarding this theme and no well-accepted anti-VEGF treatment algorithm for I-CNV [5].\n\nIn this sense, the purpose of this study is to characterise a sample of patients followed at Centro Hospitalar Universitário de São João (CHUSJ) with inflammatory choroidal neovascularization including clinical profile, underlying aetiology of I-CNV and its course, treatments performed and associated clinical response, and visual prognosis.\n\n2. Methods\n\n2.1. Study Design\n\nAn observational retrospective case series was conducted in a tertiary care centre group of patients.\n\n2.2. Study Population\n\nPatients with a diagnosis of inflammatory choroidal neovascularization followed at the Ophthalmology Department of CHUSJ were identified as described in Figure 1.\n\nA list of patients followed at the Ocular Inflammation Clinic since January 2008 until November 2020 was generated. From the 3076 patients obtained, 202 were submitted to intravitreal treatments and were selected for medical records analysis.\n\nCriteria for inclusion were as follows:Diagnosis of CNV established by fundoscopy, optical coherence tomography, fluorescein angiography, and indocyanine green angiography\n\nDiagnosis of an underlying inflammatory eye/systemic condition\n\nPatients without CNV or with CNV secondary to other causes were excluded.\n\nThus, our final population included 17 patients. They were numerically ordered according to CNV diagnosis, from oldest to most recent (P1 to P17).\n\nData were collected retrospectively from medical records, including age, sex, past medical history, regular medication, refractive errors, underlying inflammatory disease characterisation (aetiology, symptoms/signs, and date of diagnosis), CNV characterisation (affected eyes, symptoms/signs, and date of diagnosis), complications, recurrence, other eye diseases/problems, imaging exam descriptions, treatments (directed to the inflammatory cause and CNV), and visual acuity.\n\nCurrently, no agreement exists in respect to punctate inner choroidopathy (PIC) and multifocal choroiditis (MFC) classification as separate entities or belonging to the same spectrum of disease [10–12]. Therefore, and because they are difficult to differentiate, we classified these entities as a common aetiology group in our study: PIC/MFC.\n\n2.3. Treatment\n\nTreatment of neovascularization in our care centre included photodynamic therapy with verteporfin until 2006. Afterwards, CNV was addressed with intravitreal anti-VEGF agents: bevacizumab, aflibercept, and ranibizumab.\n\nInflammation was treated with anti-inflammatory/immunosuppressive agents according to disease severity and patient's response to treatment. Anti-inflammatory therapy included oral, intravenous, and/or intravitreal corticosteroids, and immunosuppressants used were cyclosporine or methotrexate.\n\n2.4. Outcome Definition\n\nBest-corrected visual acuity (BCVA) was determined using the Early Treatment Diabetic Retinopathy Study (ETDRS) charts. Four visual acuities were defined for each patient:Baseline VA: at primary inflammatory/infectious disease presentation or beginning of follow-up\n\nPretreatment VA (pre-Tx VA): at CNV presentation, prior to the beginning of intravitreal anti-VEGF therapy\n\nPosttreatment VA (post-Tx VA): after intravitreal anti-VEGF therapy suspension and VA stabilisation\n\nFinal VA: last available VA during follow-up (until November 2020)\n\nWhenever both primary inflammatory and CNV presentations/diagnosis were simultaneous, baseline VA was equal to pretreatment VA. When patients maintained intravitreal anti-VEGF treatment at the last evaluation, final VA was the same as posttreatment VA.\n\nVisual outcome was characterised according to the difference in visual acuity after intravitreal anti-VEGF treatment. For this purpose, a new variable called deltaVA (ΔVA) representing the difference between posttreatment VA and pretreatment VA was created (difference in absolute number of letters).\n\nAn outcome higher than or equal to 5 letters was considered improved, an outcome between −4 and 4 letters was counted as stable, and an outcome equal to or lower than −5 letters was classified as worsened.\n\n2.5. Statistical Analysis\n\nDescriptive statistics were performed to describe clinical data (mean, standard deviation (SD), median, interquartile range (IQR), and frequency).\n\nSeveral nonparametric Mann–Whitney U tests were performed when comparing categorical variables (cataract, PIC/MFC, infectious or noninfectious inflammatory aetiology, CNV recurrence, and anti-VEGF treatment suspension) and nonnormally distributed quantitative variables (total number of anti-VEGF injections). The mentioned categorical variables were also compared with normally distributed quantitative variables (age, pretreatment VA, posttreatment VA, and deltaVA) using several independent T-tests.\n\nQuantitative variables (spherical equivalent, pretreatment VA, posttreatment VA, and deltaVA) were analysed using Pearson's correlation coefficient. Categorical variables were analysed using chi-square tests.\n\nStatistical analysis was performed using IBM SPSS Statistics for Windows, version 27.0 (IBM Corp., Armonk, NY), and statistical significance was defined with a p value inferior to 0.05.\n\n2.6. Ethics Statement\n\nThis study, including all the applied methodology, was approved by the Ethics Committee of CHUSJ/FMUP in October 2020.\n\n3. Results\n\n3.1. Sample Description\n\nIn this study, 17 patients were included. The majority, 14 patients, had only one eye affected with CNV (82.35%), and 3 had both eyes affected (P5, P11, and P12; 17.65%). Thus, a total of 20 affected eyes were analysed. From those with unilateral involvement, 8 were on the right side and 6 on the left side.\n\nOur study population was predominantly female, accounting for 11 female patients (64.71%) and 6 male patients (35.29%). The mean age of patients at CNV diagnosis among the 20 affected eyes was 41.90 ± 16.457 years, ranging between 20 and 69 years. Specific epidemiological details are summed up in Table 2.\n\nAdditionally, 7 patients (P2, P3, P4, P5, P8, P11, and P12) had concomitant high myopia, defined as spherical equivalent ≤ -6.00 dioptres. Because P5, P11, and P12 had bilateral I-CNV, a total of 10 eyes were highly myopic.\n\nBaseline spherical equivalent was not possible to obtain for patients P6 and P9, due to previous refractive surgery in other healthcare facilities (phacoemulsification with intraocular lens implantation and LASIK surgery, respectively). Median spheric equivalent of the remaining selected eyes was −9.50 dioptres.\n\nOther eye pathology, general history, and baseline eye refraction history are seen in Supplementary Table 1 (see Supplementary Material).\n\n3.2. CNV Aetiology\n\nCNV was secondary to a noninfectious aetiology in 15 patients (88.24%) and to an infectious cause in 2 patients (11.76%).\n\nThe noninfectious group comprehended 10 patients with the entity punctate inner choroidopathy/multifocal choroiditis (58.82%), 2 patients with sarcoidosis (11.76%), 1 patient with an ambiguous diagnosis between multifocal choroiditis and serpiginous choroiditis (5.88%), 1 patient with serpiginous choroiditis (5.88%), and 1 patient with Vogt–Koyanagi–Harada disease (5.88%).\n\nThe infectious aetiology subgroup comprehended 1 patient with toxoplasmosis (5.88%) and 1 patient with nocardiosis (5.88%).\n\nAetiology information is summed up in Table 2.\n\nFrom 15 noninfectious patients, most were female: 11 females versus 4 males. In contrast, the 2 infectious cases were both male.\n\nSince punctate inner choroidopathy/multifocal choroiditis was by far the predominant I-CNV cause (10 out of 17 patients), patients with this aetiology were compared with the remainder. The mean age at CNV presentation was inferior in PIC/MFC patients than in other patients (39.46 ± 15.554 versus 46.43 ± 18.356; p=0.381). The proportion of female patients with PIC/MFC was also higher when compared to the remaining patients (70.00% vs. 57.14%, p=0.644).\n\n3.3. Presentation and Follow-Up\n\nMost patients presented with typical CNV symptoms, such as metamorphopsia, vision loss, and scotoma (17 out of 20 eyes, 85.00%). The other 3 eyes were only diagnosed with CNV due to suggestive imaging findings, despite patients being asymptomatic (eyes E5.2, E6, and E17, 15.00%).\n\nFor instance, P5 was previously diagnosed with symptomatic CNV secondary to PIC/MFC on the right eye in 2010 (E5.1). During follow-up, in 2017, OCT examination showed evidence of new-onset neovascular membrane in the contralateral eye (E5.2; left), despite having no symptoms. P6 had a history of bilateral posterior uveitis secondary to sarcoidosis and was being followed at the Ocular Inflammation Clinic. His visual acuity before CNV diagnosis was low (35 letters). New symptoms were not reported by the patient, and CNV was only found over examination using OCT. Finally, P17 was diagnosed with retinochoroiditis due to Nocardia infection (Nocardia abscessus). During follow-up, OCT showed new-onset CNV membrane on the left eye without reported symptoms.\n\nAll patients except P14 had a posterior uveitis at presentation. P14 presented with an intermediate uveitis, but later developed posterior manifestations.\n\nNeovascular membranes were also classified according to location as subfoveal, juxtafoveal, or peripapillary (Table 2). Lesions were mostly subfoveal, affecting 12 eyes (60.00%), followed by juxtafoveal location, with 7 eyes (35 00%), and only 1 eye with peripapillary CNV location (5.00%).\n\nMedian follow-up time since CNV diagnosis was approximately 46 months (45.50 (IQR, 40.00 to 111.25)), ranging between 10 and 188 months. Two patients had a previous I-CNV diagnosis and follow-up in another care centre (P9 and P13). They then continued treatment and follow-up in our medical centre. Only one patient lost follow-up after treatment (P10). Nevertheless, posttreatment visual acuity was available on medical records and was stabilised before the patient discontinued the consultations, so the anti-VEGF effect in his eye was analysed.\n\n3.4. Local Therapy: PDT and Anti-VEGF\n\nTwo patients were previously treated with photodynamic therapy (PDT), specifically P1 and P2, both in 2005. PDT was used in our care centre before anti-VEGF treatment, and these two patients were the first diagnosed with I-CNV among our sample.\n\nAll patients were treated with intravitreal anti-VEGF injections at some point. Anti-VEGF agents used in CHUSJ included bevacizumab, aflibercept, and ranibizumab. The total number of intravitreal injections differed considerably, from 2 to 111, and had a median of 7.00 (IQR, 4.25 to 29.00) among the twenty included eyes. Most eyes, 12 specifically, were only treated with bevacizumab, 5 eyes were treated with two different anti-VEGF agents (bevacizumab and aflibercept in 4 eyes; bevacizumab and ranibizumab in 1 eye), and 3 eyes were treated with all three agents (bevacizumab, aflibercept, and ranibizumab). Therefore, bevacizumab was used in all 20 eyes, aflibercept in 7 eyes, and ranibizumab in 4 eyes. Specific anti-VEGF and number of injections for each eye are shown in Table 3.\n\nAt the end of the study, 6 patients maintained intravitreal treatment with anti-VEGF (35.29%). P5 maintained treatment in both eyes, so 7 eyes were still on anti-VEGF treatment (Table 3).\n\nA significant statistical association was found between the development of cataract and the median number of anti-VEGF intravitreal injections (35.00 injections in patients with cataract (IQR, 6.00 to 42.00) versus 7.00 injections in patients without cataract (IQR, 3.00 to 8.50), p=0.031).\n\nThe median total of anti-VEGF injections was equal between the noninfectious and the infectious aetiology groups, both having a median of 7.00 injections. Median total anti-VEGF injections between eyes with and without PIC/MFC also did not differ, respectively (7.00 (IQR, 3.50 to 36.00) versus 7.00 (IQR, 6.00 to 10.00), p=0.661).\n\n3.5. Systemic Treatment\n\nFrom all 17 patients, 10 received oral corticosteroids (58.82%).\n\nOnly one patient had intravenous corticosteroids (P16, 5.88%). He had oral and intravenous prednisolone in Brazil to treat Vogt–Koyanagi–Harada disease. One patient (P8, 5.88%) was treated with intravitreal CCTs (triamcinolone) to help control PIC/MFC activity.\n\nOral immunosuppressive therapy was used in 6 patients (35.29%): 5 (P4, P8, P11, P12, and P13) had cyclosporin and 1 (P14) had methotrexate. P4 changed immunosuppressive treatment from cyclosporin to azathioprine because of cyclosporine adverse effects. He afterwards initiated treatment with biologic therapy using adalimumab due to severe refractory disease and high risk of central vision loss. He was the only patient in our study receiving biologic therapy.\n\nAbsence of systemic treatment can be explained, on the one hand, because the inflammatory condition stayed inactive during follow-up in some patients. On the other hand, in patients belonging to the infectious group, direct treatment of infection would almost certainly control the inflammatory process. In fact, none of the two patients (P15 and P17) belonging to the infectious aetiology subgroup were treated with corticosteroids.\n\nRegarding the infectious etiologies, P15 did not receive specific therapy to treat toxoplasmosis, since this condition was inactive at presentation and during follow-up. In contrast, P17 presented with a recrudescence from a previous Nocardia infection, this time with eye involvement. An anti-Nocardia therapy was used, specifically a combined therapy of trimethoprim-sulfamethoxazole (TMP-SMX) and a beta-lactam antibiotic. The patient was hospitalised for systemic study, so he underwent intravenous treatment with TMP-SMX and a carbapenem firstly and ceftriaxone secondly. Oral treatment was then continued for 12 months with TMP-SMX and cefixime.\n\nAll therapeutic measures are summed up in Table 3.\n\n3.6. Visual Outcome\n\nThe mean deltaVA among the 20 eyes was +15.10 ± 12.998 (p=0.000051 (range: −8 to +49)). In other words, patients had a mean gain of approximately 15 letters in their visual acuity. Mean pretreatment visual acuity was 50.85 ± 19.148 letters, and mean posttreatment visual acuity was 65.95 ± 19.168. Posttreatment VA had a significant positive strong correlation to the pretreatment VA (Pearson correlation coefficient = 0.770, p=0.000072). These results are shown in Table 4.\n\nAccording to our classification, 16 eyes had an improved outcome (80,00%), 3 had a stable outcome (15.00%), and 1 had a worsened visual outcome (E13, 5.00%). In addition, 13 eyes (65.00%) had a final VA equal to or greater than 65 letters.\n\nThe mean baseline VA was 62.15 ± 22.203 letters, and the mean final VA was 63.45 ± 21.508 letters. Individual visual acuities and deltaVA are described in Table 5.\n\nWhen analysing visual outcomes in accordance with the aetiology group, the mean deltaVA was +15.00 ± 13.668 letters in the noninfectious subgroup and +16.00 ± 5.657 letters in the infectious subgroup (p=0.921). No associations were also found for pre-Tx VA (p=0.961) and post-Tx VA (p=0.908) between the abovementioned subgroups.\n\nNo significant statistical differences were found when comparing pre-Tx VA (p=0.813), post-Tx VA (p=0.975), and deltaVA (p=0.763) between eyes of patients with PIC/MFC and those with other etiologies.\n\n3.7. Recurrence and Complications\n\nRecurrence of I-CNV pathology was seen in 3 eyes (E2, E5.1, and E15; 15.00%). Management of these cases was made using further anti-VEGF treatment with bevacizumab. Other 5 eyes, although not classified as recurrent, maintained active I-CNV during all follow-up period, not being able to suspend anti-VEGF treatment (E1, E4, E5.2, E13, and E17; 25.00%). DeltaVA was not significantly related to CNV recurrence (p=0.436) or treatment suspension (p=0.408).\n\nPatient 17 had only 10 months of follow-up, so more time would be needed to evaluate the possibility to discontinue treatment if stabilisation was achieved. Follow-up time was longer than 3 years in the other four cases (E1, E4, E5.2, and E13 with 188, 126, 46, and 45 months, respectively). However, neovascular membranes were still active, and anti-VEGF treatment suspension was not possible.\n\nComplications included cataract and ocular hypertension. Cataract was seen in 6 patients (P1, P3, P5, P6, P13, and P14). Five had bilateral cataract and one (P13) had unilateral on the left side. Three patients underwent phacoemulsification with intraocular lens implantation (P5, P6, and P14).\n\nFour patients (P4, P6, P11, and P14) developed ocular hypertension. All were treated using topical medication. P16 also underwent trabeculectomy and cyclophotocoagulation.\n\nDetails about CNV recurrence, treatment suspension, and complications are described in Supplementary Tables 2 and 3 (see Supplementary Material).\n\n4. Discussion\n\nInflammatory choroidal neovascularization is an uncommon yet sight-threatening complication of ocular inflammatory diseases. It represents a diagnostic and treatment challenge, due to the heterogeneity in associated etiologies, array of presentations and disease courses, and difficulty in differentiating between inflammatory choroidal lesions and choroidal neovascularization. In contrast with neovascular AMD, there are no long-term studies reporting treatment efficacy and visual prognosis in I-CNV. Therefore, research studies aiming to describe and analyse patients with this condition are fundamental to understand the best clinical approach and management.\n\nHere we described a group of 17 patients with a total of 20 eyes affected with I-CNV and compared their clinical profiles, treatments performed, and visual outcomes. Our sample was young at I-CNV presentation (mean age of approximately 40 years), predominantly female (approximately 65%), and highly myopic (median refractive error of −9.50 D). In accordance with these features, punctate inner choroidopathy/multifocal choroiditis was the most common inflammatory aetiology for CNV. Other studies have reported a higher incidence of PIC/MFC in a young myopic female population [10, 13]. Other noninfectious CNV causes found in our study were sarcoidosis, serpiginous choroiditis, and Vogt–Koyanagi–Harada disease.\n\nIn contrast, we described two cases of infectious CNV, one secondary to toxoplasmosis and the other to nocardiosis, both being male. Some studies have suggested the existence of geographical variation in inflammatory conditions leading to I-CNV, especially regarding infectious causes [1, 14]. Therefore, specific studies are important to understand the local range of I-CNV etiologies.\n\nPractically all patients, except for one, presented with posterior uveitis. Other studies have reported CNV occurring more commonly in posterior and panuveitis [4]. Choroidal neovascularization had a predominant subfoveal location (12 eyes), followed by juxtafoveal (7 eyes) and peripapillary locations (1 eye).\n\nI-CNV had a symptomatic presentation in the majority of the affected eyes (85%). Reported symptoms in our patients were compatible with typical CNV symptoms, for instance, metamorphopsia, vision loss, and scotoma [1]. This high incidence of CNV-related symptoms may be associated with the predominant subfoveal location of the neovascular membranes, in addition to the low mean age of the sample and alleged good previous visual acuities. Nevertheless, some eyes with I-CNV were only found through ancillary imaging, while they were being followed either for their primary inflammatory condition or for CNV in the contralateral eye. As a matter of fact, an active inflammatory state and a prior CNV diagnosis in the contralateral eye have been reported as increasing risk factors for CNV development [4]. Therefore, patients with ocular inflammatory conditions or already with I-CNV in the contralateral eye must have a tight follow-up to guarantee prompt diagnosis and treatment.\n\nAdequate individualised treatment prevents disease progression and additional visual loss [5]. In fact, if choroidal neovascularization is adequately and opportunistically addressed and inflammatory pathology is concomitantly managed, it is possible to stabilise or even improve patient's visual acuity from their nadir at the time of CNV presentation/decompensation [5, 8]. In our study, CNV was approached with intravitreal anti-VEGF injections and uveitis was treated with anti-inflammatory/immunosuppressive agents (i.e., corticosteroids and cyclosporin). Several studies have shown the benefit of intravitreal anti-VEGF therapy in patients with CNV secondary to various inflammatory aetiologies. For instance, a retrospective multicentre case series of patients with I-CNV was one of the early and largest studies demonstrating the benefit of bevacizumab in CNV regression and significant visual improvement. In this study, from 76 eyes with I-CNV, 58 improved, 15 registered no change, and 3 worsened their visual acuities after intravitreal bevacizumab. Additionally, visual improvement was significant in punctate inner choroidopathy, multifocal choroiditis, and Vogt–Koyanagi–Harada disease [15].\n\nThere are few clinical trials regarding I-CNV and no well-established anti-VEGF treatment algorithm. The phase 3 Minerva study, a 12-month double-masked randomized clinical study for ranibizumab efficacy and safety in patients with CNV secondary to uncommon causes, including inflammation, showed clinically significant visual improvement of ranibizumab against placebo at month 2. Even though the study comprehended a wide variety of etiologies, with few patients with an inflammatory cause, it suggested that ranibizumab is effective and safe in CNV secondary to causes other than AMD and myopia, regardless of the primary aetiology [16].\n\nWe found a wide variation in the number of performed intravitreal anti-VEGF injections (range: 2 to 111, median: 7 injections). Some patients were able to stabilise the disease with a smaller number of injections, whereas others needed a substantially greater number. I-CNV recurrence was seen in 15% of eyes. This percentage seems to be lower than in myopic CNV or neovascular AMD [17–20]. In fact, since CNV was secondary to an inflammatory aetiology, managing the primary disease with an anti-inflammatory/immunosuppressive approach allows better disease control, reducing recurrence and need for anti-VEGF injections. In comparison, in a previous retrospective study of CNV secondary to PIC, the authors compared 14 eyes treated with ranibizumab monotherapy with 10 eyes treated with a combination of corticosteroids and ranibizumab. Patients treated with a combined approach received fewer ranibizumab injections, had a greater mean visual acuity improvement, and never recurred, compared with the ranibizumab monotherapy group [21].\n\nAdditionally, 25% of eyes maintained treatment during all follow-up period, never suspending anti-VEGF therapy. In one of these cases, I-CNV had been diagnosed only 10 months before, so we can speculate that more time would be needed to achieve CNV remission. All the other 4 cases had more than 3 years of follow-up. This significant variability between patient's responses to treatment emphasises the importance of an individual on demand approach, which had also been proven effective in other studies [8, 9, 22].\n\nFollow-up in our care centre required frequent consultation with continuous patient evaluation. This allowed detection and immediate management of active CNV through patients de novo symptoms and suggestive imaging findings. Median follow-up time was 46 months, ranging from 10 to 188 months.\n\nOur results reinforce that a combined approach with anti-VEGF agents and anti-inflammatory therapy is effective in I-CNV treatment. In fact, in our study, most patients had a favourable visual outcome. Among the twenty included eyes, an approximate mean gain of 15 letters after anti-VEGF treatment (+15.10) was observed. Also, according to our classification, most had an improved visual acuity, with 16 eyes having gained 5 or more letters. Other 3 eyes maintained a stable visual outcome, with visual acuity not varying more than 4 letters (either a gain or a loss) from the pretreatment to the posttreatment stages. Additionally, 65% of eyes had a visual acuity equal to or greater than 65 letters at the end of the study, suggesting that the combined treatment approach is effective in maintaining visual improvement in the long term. Mansour et al. noted that a median of 3 injections of bevacizumab was able to sustain significant visual improvement in 8 eyes with I-CNV refractory to standard therapy at a 5-year interval [23].\n\nOnly 1 eye had an outcome classified as worsened (patient 13), with a loss of 8 letters. However, this individual had already been previously treated and followed in another medical centre. CNV was diagnosed in 2013 in his left eye and was treated with 5 injections until 2015. Before starting follow-up in our medical centre in January 2017, he had 3 other injections of aflibercept in June, October, and December 2016. Therefore, the pretreatment visual acuity measured in our medical centre does not represent the true pretreatment visual acuity of this patient. As a result, the difference in letters obtained in our study could potentially underestimate his real visual outcome and wrongly interpret the benefit of the instituted treatment measures.\n\nVisual acuities did not differ between the infectious and the noninfectious subgroups. However, it is important to pinpoint the small number of cases belonging to the infectious subgroup (2 eyes), when compared with the noninfectious subgroup (18 eyes). This could explain the absence of statistical significance.\n\nComplications seen in our sample were cataract and ocular hypertension. Cataract development correlated with a higher mean number of anti-VEGF intravitreal injections (35 versus 7, p=0.031).\n\nIn sum, our results show a favourable visual outcome for patients with I-CNV. However, we must emphasise the importance of regular screening. Intensive follow-up of both the inflammatory disease and the choroidal neovascular membrane is key to successively manage these conditions with the appropriate treatment, in order to promote a better visual prognosis and improve quality of life.\n\n5. Strengths and Limitations\n\nSince it is a retrospective study, we were able to observe the natural history and development of inflammatory choroidal neovascularization. This is essential since our aim was to describe a sample of patients, regarding their clinical characteristics, the treatments they underwent, and the evolution of both the disease itself and the corresponding visual acuity. Besides, due to the considerably extensive follow-up time, such characterisation was possible, and we could witness long-term phenomena such as recurrence and complications as well as the correspondent appropriate therapeutic manoeuvres.\n\nSince we underwent an intensive search among virtually all inflammatory cases in our care centre (3076 cases in the initial list), we were able to positively ascertain that probably all I-CNV cases were included. Nevertheless, since it is an uncommon pathology and difficult to identify, we found only 17 patients, which is similar to peer case series studies regarding this theme.\n\nLimitations were related to access and quality of gathered clinical data, pertaining to the retrospective nature of our study. However, it was possible to get the majority of the expected clinical information.\n\n6. Conclusion\n\nA combined treatment approach with anti-VEGF agents and systemic anti-inflammatory treatment was effective in the management of inflammatory choroidal neovascularization among eyes with various etiologies: punctate inner choroidopathy/multifocal choroiditis, sarcoidosis, serpiginous choroiditis, Vogt–Koyanagi–Harada disease, toxoplasmosis, and nocardiosis. Patients had an overall good visual prognosis, with improved or stable visual acuities after anti-VEGF treatment and prompt systemic immunomodulation. Rigorous follow-up was fundamental in the management of both the primary inflammatory and secondary neovascular conditions.\n\nAcknowledgments\n\nPublication-related costs were supported by the Ophthalmology Department of CHUSJ.\n\nData Availability\n\nAll the data used to support the findings of this study are included within the article.\n\nDisclosure\n\nThis work was developed under Dr. Gonçalo Carrola master thesis project at São João Hospital University Centre and can be found on its institutional page.\n\nConflicts of Interest\n\nThe authors declare that there are no conflicts of interest regarding the publication of this study.\n\nSupplementary Materials\n\nSupplementary Materials Supplementary Table 1: medical history. Supplementary Table 2: recurrence and treatment suspension. Supplementary Table 3: complications. .\n\nClick here for additional data file.\n\nFigure 1 Process of patient's selection.\n\nTable 1 Infectious and noninfectious inflammatory choroidal neovascularization aetiologies.\n\nInflammatory choroidal neovascularization aetiologies\t\nNoninfectious\tMultifocal choroiditis\t\nSerpiginous choroiditis\t\nPunctate inner choroidopathy\t\nAcute multifocal placoid pigment epitheliopathy\t\nBirdshot chorioretinitis\t\nMultiple evanescent white dot syndrome\t\nVogt–Koyanagi–Harada syndrome\t\nSympathetic ophthalmia\t\nBehcet's disease\t\nSarcoidosis\t\nMultifocal choroiditis with panuveitis\t\nIdiopathic panuveitis\t\nTubulointerstitial nephritis and uveitis\t\n\t\nInfectious\tTuberculosis\t\nToxoplasmosis\t\nWest Nile virus\t\nRubella retinopathy\t\nCandida albicans\t\nHistoplasma capsulatum\t\nCryptococcus neoformans\t\nAspergillus fumigatus\t\nToxocara\t\nEndophthalmitis\t\nNote. Adapted from [1].\n\nTable 2 Sample description.\n\nP\tAgea\tSex\tInflammatory aetiology\tI or NI\tInflammatory diagnosis date\tCNV eyes\tCNV location\tCNV diagnosis date\tFollow-up timeb (months)\t\nP1\t62\tF\tMFC/SERP\tNI\tMarch 16, 2005\tL\tSF\tMarch 16, 2005\t188\t\nP2\t27\tF\tPIC/MFC\tNI\tApril 5, 2005\tR\tSF\tApril 5, 2005\t186\t\nP3\t36\tF\tPIC/MFC\tNI\tMay 7, 2012\tR\tSF\tDecember 18, 2007\t141\t\nP4\t32\tM\tPIC/MFC\tNI\tNovember 18, 2011\tR\tSF\tNovember 5, 2009\t126\t\nP5\t57\tF\tPIC/MFC\tNI\tMarch 9, 2012\tR\nL\tSF\nJF\tJuly 13, 2010\nJanuary 4, 2017\t123\n46\t\nP6\t69\tF\tSARC\tNI\t1984\tR\tSF\tAugust 23, 2012\t76\t\nP7\t20\tM\tSERP\tNI\tNovember 1, 2013\tR\tJF\tNovember 13, 2013\t70\t\nP8\t28\tF\tPIC/MFC\tNI\tMarch 18, 2011\tL\tSF\tJune 18, 2014\t71\t\nP9\t69\tM\tPIC/MFC\tNI\t2013c (another centre)\tL\tPP\t2013c CHUSJd: July 7, 2015\t61\t\nP10\t53\tF\tPIC/MFC\tNI\tAugust 2015\tR\tSF\tMarch 31, 2016\t13e\t\nP11\t32\tF\tPIC/MFC\tNI\tJune 12, 2015\tL\nR\tJF\nJF\tAugust 16, 2016\nSeptember 15, 2016\t44\n43\t\nP12\t22\tF\tPIC/MFC\tNI\tOctober 1, 2016\tL\nR\tSF\nSF\tNovember 9, 2016\nMay 24, 2019\t40\n9\t\nP13\t37\tM\tPIC/MFC\tNI\t2013c (another centre)\tL\tSF\t2013c CHUSJd: January 18, 2017\t45\t\nP14\t57\tF\tSARC\tNI\tSeptember 7, 2010\tL\tJF\tMarch 22, 2017\t42\t\nP15\t41\tM\tTOXO\tI\tNovember 2010\tR\tJF\tJune 6, 2017\t40\t\nP16\t26\tF\tVKHD\tNI\tJanuary 2016 (Brazil)\tR\tJF\tFebruary 8, 2018\t23\t\nP17\t50\tM\tNOC\tI\tFebruary 2016 (Germany)\tL\tSF\tDecember 13, 2019\t10\t\nP: patient number; I: infectious aetiology; NI: noninfectious aetiology; F: female sex; M: male sex; PIC/MFC: punctate inner choroidopathy/multifocal choroiditis; SERP: serpiginous choroiditis; SARC: sarcoidosis; TOXO: toxoplasmosis; VKHD: Vogt–Koyanagi–Harada disease; NOC: nocardiosis; SF: subfoveal location; JF: juxtafoveal location; PP: peripapillary location. aAge of CNV diagnosis; bfrom CNV diagnosis until last examination; cprevious diagnosis and follow-up in another medical centre; dbeginning of follow-up in CHUSJ in cases previously diagnosed; elost to follow-up: last consultation on May 2, 2017.\n\nTable 3 Treatment.\n\nEye\tCNV eye\tTotal anti-VEGF injections\tAnti-VEGF agentsa (number of injections)\tAnti-VEGF statusb\tSystemic treatment\tTreatment for TB\tTopic treatments\t\nE1\tL\t111\tR (24)\nB (68)\nA (19)\tM\tPDT\nCCTs (p.o.)\tHRZE\tCCTs\t\nE2\tR\t2\tB (2)\tE\tPDT\nCCTs (p.o.)\tNo\tNo\t\nE3\tR\t6\tB (6)\tE\t—\tNo\tCCTs\nNSAIDs\t\nE4\tR\t38\tR (3)\nB (35)\tM\tCCTs (p.o.)\nCyclosporin\nAzathioprine\nAdalimumab\tIsoniazid (prophylaxis before biologic therapy)\tCCTs\nNSAIDs\nFor OHTN\t\nE5.1\tR\t35\tR (5)\nB (18)\nA (12)\tM\t—\tHRZE\tCCTs\nNSAIDs\t\nE5.2\tL\t42\tB (30)\nA (12)\tM\t—\tHRZE\tCCTs\nNSAIDs\t\nE6\tR\t10\tB (10)\tE\tCCTs (p.o.)\tNo\tCCTs\nNSAIDs\nFor OHTN\t\nE7\tR\t3\tB (3)\tE\t—\tNo\tNo\t\nE8\tL\t2\tB (2)\tE\tCCTs (p.o. and intravitreal: triamcinolone)\nCyclosporin\tNo\tCCTs\nNSAIDs\t\nE9\tL\t5\tA (2)\nB (3)\tE\t—\tNo\tNo\t\nE10\tR\t11\tB (3)\nA (3)\nR (5)\tE\t—\tNo\tNo\t\nE11.1\tL\t7\tB (7)\tE\tCCTs (p.o.)\nCyclosporin\tNo\tFor OHTN\t\nE11.2\tR\t7\tB (7)\tE\tCCTs (p.o.)\nCyclosporin\tNo\tFor OHTN\t\nE12.1\tL\t4\tB (4)\tE\tCCTs (p.o.)\nCyclosporin\tNo\tCCTs\nNSAIDs\t\nE12.2\tR\t3\tB (3)\tE\tCCTs (p.o.)\nCyclosporin\tNo\tNo\t\nE13\tL\t37\tB (5)\nA (3)\nB (29)\tM\tCCTs (p.o.)\nCyclosporin\tNo\tNo\t\nE14\tL\t6\tB (6)\tE\tCCTs (p.o.)\nMethotrexate\tNo\tCCTs\nFor OHTN\t\nE15\tR\t7\tB (7)\tM\t—\tNo\tNo\t\nE16\tR\t10\tB (10)\tE\tCCTs (p.o. and intravenous)\tNo\tNo\t\nE17\tL\t7\tB (4)\nA (3)\tM\tTMP-SMX + β-lactam\tNo\tNo\t\naOrdered from oldest to most recent agent used in each eye; banti-VEGF status at final data collection (November 2020): M: maintained anti-VEGF treatment or E: ended anti-VEGF treatment; R: right; L: left; B: bevacizumab; A: aflibercept; R: ranibizumab; PDT: photodynamic therapy; OHTN: ocular hypertension; CCTs: corticosteroids; NSAIDs: nonsteroidal anti-inflammatory drugs; p.o.: per os; TMP-SMX: trimethoprim-sulfamethoxazole; TB: tuberculosis; HRZE: isoniazid (H) + rifampicin (R) + pyrazinamide (Z) + ethambutol (E).\n\nTable 4 Visual outcomes.\n\n \tPre-Tx VA\tPost-Tx VA\tΔVA\tp\t\nMean\t50.85\t65.95\t+15.10\t0.000051\t\nSD\t19.148\t19.168\t12.998\t\n\nTable 5 Visual acuities and visual outcomes.\n\nEye\tAgea\tSex\tInflammatory aetiology\tCNV eye\tBaseline VA\tPre-Tx VA\tPost-Tx VA\tFinal VA\tΔVA\tVisual outcomed\t\nE1\t62\tF\tMFC/SERP\tL\t65\t38\t38c\t38c\t0\tStable\t\nE2\t27\tF\tPIC/MFC\tR\t55\t58\t59\t58\t1\tStable\t\nE3\t36\tF\tPIC/MFC\tR\t30\t53\t82\t82\t29\tImproved\t\nE4\t32\tM\tPIC/MFC\tR\t65b\t65b\t76\t30\t11\tImproved\t\nE5.1\t57\tF\tPIC/MFC\tR\t19b\t19b\t68c\t68c\t49\tImproved\t\nE5.2\t63\tF\tPIC/MFC\tL\t74\t37\t68c\t68c\t31\tImproved\t\nE6\t69\tF\tSARC\tR\t35\t33\t50\t45\t17\tImproved\t\nE7\t20\tM\tSERP\tR\t85\t72\t84\t83\t12\tImproved\t\nE8\t28\tF\tPIC/MFC\tL\t80\t52\t74\t81\t22\tImproved\t\nE9\t69\tM\tPIC/MFC\tL\t50b\t50b\t62\t70\t12\tImproved\t\nE10\t53\tF\tPIC/MFC\tR\t35\t31\t30\t30\t−1\tStable\t\nE11.1\t32\tF\tPIC/MFC\tL\t70\t50\t76\t75\t26\tImproved\t\nE11.2\t32\tF\tPIC/MFC\tR\t26\t15\t20\t15\t5\tImproved\t\nE12.1\t22\tF\tPIC/MFC\tL\t85\t67\t85\t84\t18\tImproved\t\nE12.2\t25\tF\tPIC/MFC\tR\t85\t70\t80c\t80c\t10\tImproved\t\nE13\t37\tM\tPIC/MFC\tL\t84b\t84b\t76c\t76c\t−8\tWorsened\t\nE14\t57\tF\tSARC\tL\t80\t54\t73\t67\t19\tImproved\t\nE15\t41\tM\tTOXO\tR\t85\t73\t85c\t85c\t12\tImproved\t\nE16\t26\tF\tVKHD\tR\t70\t66\t83\t84\t17\tImproved\t\nE17\t50\tM\tNOC\tL\t65\t30\t50c\t50c\t20\tImproved\t\nF: female sex; M: male sex; R: right; L: left; PIC/MFC: punctate inner choroidopathy/multifocal choroiditis; SERP: serpiginous choroiditis; SARC: sarcoidosis; TOXO: toxoplasmosis; VKHD: Vogt–Koyanagi–Harada disease; NOC: nocardiosis. aAge of CNV diagnosis; bbaseline VA was equal to pretreatment VA in patients when primary inflammatory and I-CNV presentations were simultaneous; cfinal VA was equal to posttreatment VA in patients that maintained intravitreal anti-VEGF treatment at the last evaluation; dan outcome higher than or equal to 5 letters was considered improved, an outcome between −4 and 4 letters was counted as stable, and an outcome equal to or lower than −5 letters was classified as worsened.\n==== Refs\n1 Agarwal A. Invernizzi A. Singh R. B. An update on inflammatory choroidal neovascularization: epidemiology, multimodal imaging, and management Journal of Ophthalmic Inflammation and Infection 2018 8 1 p. 13 10.1186/s12348-018-0155-6 2-s2.0-85053260672\n2 Weber M. L. Heier J. S. Choroidal neovascularization secondary to myopia, infection and inflammation Developments in Ophthalmology 2016 55 167 175 10.1159/000431194 2-s2.0-84947243180 26501802\n3 Campa C. Costagliola C Incorvaia C Inflammatory mediators and angiogenic factors in choroidal neovascularization: pathogenetic interactions and therapeutic implications Mediators of Inflammation 2010 2010 10.1155/2010/546826 2-s2.0-77957899993\n4 Baxter S. L. Pistilli M. Pujari S. S. Risk of choroidal neovascularization among the uveitides American Journal of Ophthalmology 2013 156 3 468 477 10.1016/j.ajo.2013.04.040 2-s2.0-84882259786 23795984\n5 Cerquaglia A. Fardeau C. Cagini C. Fiore T. LeHoang P. Inflammatory choroidal neovascularization: beyond the intravitreal approach Ocular Immunology and Inflammation 2018 26 7 1047 1052 10.1080/09273948.2017.1311923 2-s2.0-85018283436 28471283\n6 Bansal R. Bansal P. Gupta A. Diagnostic challenges in inflammatory choroidal neovascular membranes Ocular Immunology and Inflammation 2017 25 4 554 562 10.3109/09273948.2016.1160128 2-s2.0-84963857350 27082010\n7 Astroz P. Miere A. Mrejen S. Optical coherence tomography angiography to distinguish choroidal neovascularization from macular inflammatory lesions IN multifocal choroiditis Retina 2018 38 2 299 309 10.1097/iae.0000000000001617 2-s2.0-85017031433 28368976\n8 Dʼsouza P. Ranjan R Babu U Kanakath A. V Saravanan V. R Inflammatory choroidal neovascular membrane: long-term visual and anatomical outcomes after intravitreal anti-vascular endothelial growth factor therapy Retina (Philadelphia, Pa.) 2018 38 7 1307 1315 10.1097/IAE.0000000000001710 2-s2.0-85049994703\n9 Arevalo J. F. Adan A. Berrocal M. H. Intravitreal bevacizumab for inflammatory choroidal neovascularization Retina 2011 31 2 353 363 10.1097/iae.0b013e3181ed8cec 2-s2.0-79551508522 20890239\n10 Ahnood D. Madhusudhan S. Tsaloumas M. D. Waheed N. K. Keane P. A. Denniston A. K. Punctate inner choroidopathy: a review Survey of Ophthalmology 2017 62 2 113 126 10.1016/j.survophthal.2016.10.003 2-s2.0-85007089909 27751823\n11 Amer R. Lois N. Punctate inner choroidopathy Survey of Ophthalmology 2011 56 1 36 53 10.1016/j.survophthal.2010.03.009 2-s2.0-78650226306 21056447\n12 Essex R. W. Wong J. Jampol L. M. Dowler J. Bird A. C. Idiopathic multifocal choroiditis Retina 2013 33 1 1 4 10.1097/iae.0b013e3182641860 2-s2.0-84872095088 23026849\n13 Peng Y. Zhang X. Mi L. Efficacy and safety of conbercept as a primary treatment for choroidal neovascularization secondary to punctate inner choroidopathy BMC Ophthalmology 2017 17 1 p. 87 10.1186/s12886-017-0481-8 2-s2.0-85020441720 28606070\n14 Cohen S. Y. Laroche A. Leguen Y. Soubrane G. Coscas G. J. Etiology of choroidal neovascularization in young patients Ophthalmology 1996 103 8 1241 1244 10.1016/s0161-6420(96)30515-0 2-s2.0-0029811777 8764794\n15 Mansour A. M. Mackensen F Arevalo J. F Intravitreal bevacizumab in inflammatory ocular neovascularization American Journal of Ophthalmology 2008 146 3 410 416 10.1016/j.ajo.2008.05.024 2-s2.0-49949094774 18619571\n16 Lai T. Y. Y. Staurenghi G. Lanzetta P. Efficacy and safety of ranibizumab for the treatment of choroidal neovascularization due to uncommon cause Retina 2018 38 8 1464 1477 10.1097/iae.0000000000001744 2-s2.0-85023769575 28704254\n17 Kang H. M. Koh H. J. Ocular risk factors for recurrence of myopic choroidal neovascularization Retina 2013 33 8 1613 1622 10.1097/iae.0b013e318285cc24 2-s2.0-84883741007 23591527\n18 Moon B. G. Cho A. R. Lee J. Improved visual outcome and low recurrence with early treatment with intravitreal anti-vascular endothelial growth factor in myopic choroidal neovascularization Ophthalmologica 2017 237 3 128 138 10.1159/000458160 2-s2.0-85015670512 28278507\n19 Adrean S. D. Chaili S. Grant S. Pirouz A. Recurrence rate of choroidal neovascularization in neovascular age-related macular degeneration managed with a treat-extend-stop protocol Ophthalmology Retina 2018 2 3 225 230 10.1016/j.oret.2017.07.009 2-s2.0-85048313316 31047590\n20 Kim J. H. Chang Y. S. Lee D. W. Kim C. G. Kim J. W. Incidence and timing of the first recurrence in neovascular age-related macular degeneration: comparison between ranibizumab and aflibercept Journal of Ocular Pharmacology and Therapeutics 2017 33 6 445 451 10.1089/jop.2016.0098 2-s2.0-85022327162 28384009\n21 Wu W. Li S Xu H Treatment of punctate inner choroidopathy with choroidal neovascularization using corticosteroid and intravitreal ranibizumab BioMed Research International 2018 2018 7 1585803 10.1155/2018/1585803 2-s2.0-85054013851\n22 Kramer M. Axer-Siegel R. Jaouni T. Bevacizumab for choroidal neovascularization related to inflammatory diseases Retina 2010 30 6 938 944 10.1097/iae.0b013e3181c96a00 2-s2.0-77953336820 20168273\n23 Mansour A. Mackensen F. Khairallah fnm Mahendradas fnm Lai T. Bashshur Five-year visual results of intravitreal bevacizumab in refractory inflammatory ocular neovascularization Clinical Ophthalmology 2012 6 1233 1237 10.2147/opth.s34294 2-s2.0-84930474484 22927733\n\n",
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"title": "Inflammatory Choroidal Neovascular Membranes: Clinical Profile, Treatment Effectiveness, and Visual Prognosis.",
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"abstract": "A 7-month-old boy with a novel mutation in ATP6V1A gene is described. The ATP6V1A gene has been recently identified to be associated with epileptic encephalopathies. Clinical features in this patient are different from cases reported so far, thus broadening the spectrum of ATP6V1A-associated epileptic encephalopathy.",
"affiliations": "Department of Pediatric Neurology, Ankura Hospital for Women and Children, Hyderabad, Telangana, India.",
"authors": "Kadwa|Razia A|RA|0000-0001-9792-0804",
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"title": "Novel Mutation in ATP6V1A Gene with Infantile Spasms in an Indian Boy.",
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"abstract": "When advising a pregnant patient who has previously had a cesarean section about the risks of trial of labor, it is important to explain the risk of uterine rupture. Subjective symptoms of abdominal pain or objective findings of non-reassuring fetal status and loss of fetal station are often indicative of this disease process, which most commonly is caused by a defect on the uterus from the cesarean delivery. Any uterine surgical intervention (myomectomy, for example) is the leading risk factor for uterine rupture. This case report presents a patient who had no such history. However, the maternal and fetal clinical status rapidly deteriorated and required emergency cesarean delivery, at which point a complete uterine rupture was diagnosed. Low suspicion for rare occurrences such as uterine rupture in an unscarred uterus can delay diagnosis, with increased likelihood of fetal and maternal morbidity and mortality.",
"affiliations": "Department of Obstetrics & Gynecology, Ascension Providence Hospital, Affiliation with Michigan State University, 16001 W Nine Mile Road, Southfield, MI, 48075, United States.;Department of Obstetrics & Gynecology, Ascension Providence Hospital, Affiliation with Michigan State University, 16001 W Nine Mile Road, Southfield, MI, 48075, United States.;Department of Obstetrics & Gynecology, Ascension Providence Hospital, Affiliation with Michigan State University, 16001 W Nine Mile Road, Southfield, MI, 48075, United States.",
"authors": "Halassy|S D|SD|;Eastwood|J|J|;Prezzato|J|J|",
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"doi": "10.1016/j.crwh.2019.e00154",
"fulltext": "\n==== Front\nCase Rep Womens HealthCase Rep Womens HealthCase Reports in Women's Health2214-9112Elsevier S2214-9112(19)30135-310.1016/j.crwh.2019.e00154e00154ArticleUterine rupture in a gravid, unscarred uterus: A case report Halassy S.D. shalassy@gmail.com⁎Eastwood J. Prezzato J. Department of Obstetrics & Gynecology, Ascension Providence Hospital, Affiliation with Michigan State University, 16001 W Nine Mile Road, Southfield, MI, 48075, United States⁎ Corresponding author. shalassy@gmail.com17 10 2019 10 2019 17 10 2019 24 e0015431 8 2019 8 10 2019 11 10 2019 © 2019 Published by Elsevier B.V.2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• The risk of uterine rupture in a gravid, unscarred uterus is largely unknown.\n\n• The risk factors for uterine rupture, when summed, can accumulate to a devastating and unforeseen end-result, such as fetal and maternal demise.\n\n• Low suspicion for rare occurrences such as uterine rupture in an unscarred uterus can delay diagnosis, with increased likelihood of fetal and maternal morbidity and mortality.\n\n\n\nWhen advising a pregnant patient who has previously had a cesarean section about the risks of trial of labor, it is important to explain the risk of uterine rupture. Subjective symptoms of abdominal pain or objective findings of non-reassuring fetal status and loss of fetal station are often indicative of this disease process, which most commonly is caused by a defect on the uterus from the cesarean delivery. Any uterine surgical intervention (myomectomy, for example) is the leading risk factor for uterine rupture. This case report presents a patient who had no such history. However, the maternal and fetal clinical status rapidly deteriorated and required emergency cesarean delivery, at which point a complete uterine rupture was diagnosed. Low suspicion for rare occurrences such as uterine rupture in an unscarred uterus can delay diagnosis, with increased likelihood of fetal and maternal morbidity and mortality.\n\nKeywords\nUterine ruptureGravidUnscarred uterusCesarean hysterectomyExternal cephalic versionAdvanced maternal ageInduction of labor\n==== Body\n1 Introduction\nUterine rupture in pregnancy is a life-threatening situation for both mother and fetus. It is a rare complication and is usually associated with a trial labor after cesarean delivery. Any previous uterine defect, such as from a myomectomy or other surgical intervention, is a known and important risk factor. Other risk factors, though even rarer and less well characterized, include a shortened inter-delivery interval, gestational age greater than 40 weeks, and a birth weight greater than 4000 g [1]. According to one study from the Netherlands, the incidence is between 0.7 and 5.1 per 10,000 deliveries in unscarred and scarred uteri, respectively [2]. Uterine rupture is an extremely rare event in a patient with a history of spontaneous vaginal deliveries and no obvious risk factors [2,3].\n\n2 Case\nA 40-year-old gravida 5, para 4 woman presented at 36 weeks and 2 days of pregnancy for evaluation after an office visit at which she had complained of headaches and spots in her vision. The patient had had a previous diagnosis of pre-eclampsia without severe features prior to presentation. Upon arrival, the patient was noted to have normal blood pressure (126/67 mmHg). However, she reported having a persistent headache, despite acetaminophen administration. She described the headache as left-sided and retro-orbital in location, and graded it as 2 out of 10 in severity (on a severity scale from 1 to 10, with 10 being the most severe). She denied any history of migraines, chronic headaches, or other neurologic disability. The patient also complained of “white spots” in her vision that appeared to be floating. She denied having any chest pain, shortness of breath, right upper quadrant pain, or bilateral upper extremity or facial swelling. Serum and urine tests for pre-eclampsia were repeated and no change from her previous baseline was noted. As such, the decision was initially made to re-administer acetaminophen with re-evaluation for possible relief of the headache.\n\nDespite the acetaminophen, the patient continued to report visual disturbances and a persistent headache. After consultation with the maternal-fetal medicine department, the decision was made to proceed with induction of labor. Magnesium sulfate was started for seizure prophylaxis. A bedside ultrasound scan was performed prior to commencement of the induction, and the fetus was found to be in breech position. As the patient had had 4 vaginal deliveries in the past and was currently stable, she was deemed a good candidate for an external cephalic version (ECV). The alternative option, namely cesarean delivery, along with risks and benefits of the procedure were explained and the patient consented to an attempt at ECV. The ECV was performed successfully after administration of terbutaline and an epidural for pain management.\n\nShortly thereafter, the induction of labor was started with misoprostol for cervical dilation of 1 cm. In total, the patient received 2 timed doses of misoprostol. The induction was then continued with Foley bulb placement, along with oxytocin for augmentation, as per institutional protocol. With incremental increases in oxytocin, the patient had intermittent episodes of tachysystole, for which the oxytocin was appropriately titrated. The overall fetal status was reassuring during this course.\n\nWhile initial blood pressures were within normal ranges, the patient did experience severe episodes of abnormal blood pressure requiring IV administration of both labetalol and hydralazine. Blood pressures did return to baseline. After 26 h of induction, the fetal status became progressively less reassuring, with decreasing variability and multiple variable decelerations on fetal heart tone monitoring. This persisted despite supportive measures. At this time, the patient reported that she was in severe pain and she urgently requested epidural bolus.\n\nExamination revealed a 6-centimeter dilated cervix that was edematous on palpation. There was then an abrupt, prolonged fetal deceleration that was not amenable to resuscitative measures (such as positional changes, supplemental oxygen, discontinuation of oxytocin, and administration of terbutaline sulfate). A further cervical examination demonstrated an anterior lip dilation. The decision was made to urgently proceed to the operating room for fetal delivery. While in the operating room, fetal heart tones were measured and noted to have returned to baseline and were reassuring. Thus, vacuum-assisted delivery was attempted. Despite two pulls of the vacuum, there was no change in fetal station. An emergency cesarean delivery was performed under general anesthesia.\n\nUpon entry into the abdomen, a large amount of blood was evacuated. Suction to the uterus revealed a thin serosal layer overlying the uterus and an obvious uterine rupture (Fig. 1, Fig. 2), with the fetus noted to be floating within the serosal sac. This was entered with blunt dissection of the surgeon’s digit. The fetus was delivered without a fetal heart tone and was passed to the neonatologist, who successfully resuscitated the baby.Fig. 1 Gross specimen of ruptured, left sidewall of the uterus after cesarean supracervical hysterectomy.\n\nFig. 1Fig. 2 Intra-operative image demonstrating complete uterine rupture of the anterior, left sidewall of the uterus. The surgeon’s hand demonstrates the site of rupture extending fully to the posterior segment of the uterine wall.\n\nFig. 2\n\nUterine rupture was once again confirmed, with complete obliteration of the left side of the uterus into the uterine artery. There was extensive blood loss that required massive transfusion. The patient became hypotensive and required IV fluid and blood product resuscitation. Unfortunately, the uterine anatomy was severely distorted and the uterus could not be repaired. A supracervical hysterectomy was performed. Left salpingo-oophorectomy was also performed due to extensive bleeding from the uterine artery, which had dissected through the infundibulopelvic ligament and into the sidewall of the pelvis. Hemostasis was eventually achieved after transfusion of blood products.\n\nAfter surgery, the patient remained under general anesthesia and was transferred to the intensive care unit for further monitoring and stabilization.\n\n3 Discussion\nThe prevalence of uterine rupture in developed countries in women with previous cesarean sections has been reported to be as low as 1%. However, it is exceedingly rare in women without any history of cesarean section or other gynecological surgery [4]. In patients who have an unscarred uterus, there are reported risk factors that, though rare, can lead to possible rupture. These include macrosomia, shorter interval between deliveries, post-date pregnancies, and advanced maternal age. Women over 30 years of age have been reported to have two to three times the risk of uterine rupture for women who are younger than 30 years [1]. Other reported risk factors for rupture of an unscarred uterus include any uterine anomalies, grand multiparity, cephalopelvic disproportion, and uterine trauma, including version maneuvers and oxytocin stimulation [5]. However, there continues to be a debate on whether ECV is an independent risk factor for uterine rupture. One recent cohort study failed to demonstrate any association between the two [6]. Of note, the American College of Obstetricians and Gynecologists (ACOG) states that ECV itself is not contraindicated in a woman with a previous low-transverse uterine incision [7]. Uterine distension from multiple gestations is another association with uterine rupture [8,9].\n\nAs uterine rupture is a rare complication, few large studies have examined this disease process. However, one study examining women who gave birth in Norway from 1967 to 2008 sought to examine specific risk factors for uterine rupture. The researchers discovered that, among women with an unscarred uterus, those aged over 35 years, having a parity of at least 3, being born in a non-Western country, and having a previous miscarriage before 12 weeks put them at a particularly high risk for rupture. Of greatest significance, they found that oxytocin has a higher odds ratio for rupture than induction with prostaglandins (6.5 and 4.5, respectively), and that the sequential use of prostaglandins and oxytocin had an odds ratio of 48 [10].\n\nOur patient had a history of four uncomplicated spontaneous vaginal deliveries and denied any previous gynecological procedures that would have increased her risk for uterine rupture. During labor, the non-reassuring fetal status and severe abdominal pain led to the decision to proceed immediately to the operating room. At this time, placental abruption was originally thought to be the cause of her symptoms. There was a low suspicion for uterine rupture at the time and it was diagnosed only after her abdomen was entered surgically. Most ruptures occur in the lower uterine segment [11]. However, this patient’s rupture was located on the left, lateral wall of the uterus and into the uterine artery, eventually requiring cesarean hysterectomy.\n\n4 Conclusion\nRupture of the unscarred uterus can be a catastrophic event that results in maternal and fetal morbidity and mortality [4]. This was demonstrated in a case-control study comparing the outcomes of 20 cases of unscarred uterine rupture with 120 cases of scarred uterine rupture. The authors discovered that primary uterine rupture cases (those of the unscarred uterus) had a “greater maternal morbidity, greater mean blood loss, a higher rate of blood transfusion, and a higher frequency of peripartum hysterectomy” than rupture of a scarred uterus [12]. Similar to our case, most patients presenting with uterine rupture have non-reassuring fetal status and severe abdominal pain [1,13]. It is imperative to have increased suspicion and distinguish these symptoms from other occurrences in the intrapartum period, such as placental abruption or intrauterine infection. The risk for maternal and neonatal morbidity and mortality is higher in cases involving unscarred uteri because there can be delayed awareness [1,12] of the rupture due to typical labor pains and lack of obvious risk factors [1,12]. Our patient’s advanced maternal age, fourth pregnancy, external cephalic version to correct for breech position, and sequential use of misoprostol and oxytocin are all individual factors that could have led to her rupture. Although an exceedingly rare complication, her risk factors compounded each other and resulted in this unfavorable outcome.\n\nThis case serves as an educational example of a detrimental outcome in an apparently low-risk situation. Heightened awareness, close supervision, and low threshold for intervention would enable obstetrical teams to achieve a better outcome when presented with a similar situation.\n\nAuthor’s contribution\nS.D. Halassy drafted and revised the manuscript.\n\nJ. Eastwood performed the literature search and revised the draft manuscript.\n\nJ. Prezzato revised the draft manuscript.\n\nFunding\nNo funding from an external source supported the publication of this case report.\n\nPatient consent\nObtained.\n\nProvenance and peer review\nThis case report was peer reviewed.\n\nDeclaration of Competing Interest\nThe authors declare that they have no conflict of interest regarding the publication of this case report.\n==== Refs\nReferences\n1 You S.H. Chang Y.L. Yen C.F. Rupture of the scarred and unscarred gravid uterus: outcomes and risk factors analysis Taiwan. J. Obstet. Gynecol. 57 2 2018 248 254 29673669 \n2 Zwart J.J. Uterine rupture in the Netherlands: a nationwide population-based cohort study BJOG 116 8 2009 1069 1078 discussion 1078-80 19515148 \n3 Vernekar M. Rajib R. Unscarred uterine rupture: a retrospective analysis J. Obstet. Gynaecol. India 66 Suppl. 1 2016 51 54 27651577 \n4 Hofmeyr G.J. Say L. Gülmezoglu A.M. WHO systematic review of maternal mortality and morbidity: the prevalence of uterine rupture BJOG 112 9 2005 1221 1228 16101600 \n5 Langton J. Spontaneous rupture of an unscarred gravid uterus at 32 weeks gestation Hum. Reprod. 12 9 1997 2066 2067 9363731 \n6 Impey O.R.E. Greenwood C.E.L. Impey L.W.M. External cephalic version after previous cesarean section: a cohort study of 100 consecutive attempts Eur. J. Obstet. Gynecol. Reprod. Biol. 231 2018 210 213 30412904 \n7 ACOG Practice Bulletin No. 205: vaginal birth after cesarean delivery Obstet. Gynecol. 133 2 2019 e110 e127 30681543 \n8 Tarney C.M. Rupture of an unscarred uterus in a quadruplet pregnancy Obstet. Gynecol. 121 2 Pt. 2 Suppl. 1 2013 483 485 23344417 \n9 Sakr R. Unscarred uterine rupture—case report and literature review Clin. Exp. Obstet. Gynecol. 34 3 2007 190 192 17937100 \n10 Al-Zirqi I. Daltveit A.K. Vangen S. Maternal outcome after complete uterine rupture Acta Obstet. Gynecol. Scand. 98 8 2019 1024 1031 30762871 \n11 Islam A. A two-year analysis of uterine rupture in pregnancy J. Ayub Med. Coll. Abbottabad 30 Suppl. 1 (4) 2018 S639 S641 30838822 \n12 Gibbins K.J. Maternal and fetal morbidity associated with uterine rupture of the unscarred uterus Am. J. Obstet. Gynecol. 213 3 2015 p. 382.e1-6 \n13 Andonovová V. Uterine rupture during pregnancy and delivery: risk factors, symptoms and maternal and neonatal outcomes—restrospective cohort Ceska Gynekol. 84 2 2019 121 128 31238682\n\n",
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"issn_linking": "2214-9112",
"issue": "24()",
"journal": "Case reports in women's health",
"keywords": "Advanced maternal age; Cesarean hysterectomy; External cephalic version; Gravid; Induction of labor; Unscarred uterus; Uterine rupture",
"medline_ta": "Case Rep Womens Health",
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"pmid": "31709158",
"pubdate": "2019-10",
"publication_types": "D002363:Case Reports",
"references": "31238682;23344417;30762871;26026917;30681543;29673669;16101600;30412904;19515148;9363731;27651577;17937100;30838822",
"title": "Uterine rupture in a gravid, unscarred uterus: A case report.",
"title_normalized": "uterine rupture in a gravid unscarred uterus a case report"
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"abstract": "Soft tissue infections occur in over 30% of patients with chemotherapy-induced neutropenia. Gram-positive bacterial infections predominate early in neutropenia, and likelihood of infection by resistant bacteria and fungi increases with prolonged neutropenia. Prior infections and exposures influence the risk of rare pathogens. A 55-year-old woman with chemotherapy-induced neutropenia was scratched on her forearm by a dog. She cleaned the wound with isopropanol and was treated empirically with amoxicillin-clavulanate. Over the next 4 days, she developed fever along with erythema, edema, and mild tenderness of the forearm without purulence or crepitus. She was hospitalized and received empiric treatment with intravenous vancomycin, piperacillin-tazobactam, tobramycin, and voriconazole. Despite therapy, her fevers persisted and the cellulitis progressed for over a week. After 10 days of hospitalization, her neutrophil count began to recover and a bulla developed at the wound site. Culture of the bullous fluid grew Serratia marcescens, and antibiotics were switched to cefepime based on susceptibility. She defervesced and showed substantial improvement of cellulitis within 48 hours and was discharged on oral ciprofloxacin. Serratia marcescens skin infections are rare, and this may be the first report of Serratia cellulitis associated with trauma from dog contact. This case highlights the need to consider unusual pathogens based on exposure history and immune status and to obtain cultures from fluid collections or tissue in cases of treatment-resistant soft tissue infections.",
"affiliations": "1 Medical College of Georgia, Augusta University, Augusta, GA, USA.;1 Medical College of Georgia, Augusta University, Augusta, GA, USA.;2 Madigan Army Medical Center, Joint Base Lewis-McChord, WA, USA.;1 Medical College of Georgia, Augusta University, Augusta, GA, USA.",
"authors": "Pithadia|Deeti J|DJ|;Weathers|Erena N|EN|;Colombo|Rhonda E|RE|;Baer|Stephanie L|SL|",
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"doi": "10.1177/2324709619832330",
"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 10.1177/232470961983233010.1177_2324709619832330Case ReportSevere and Progressive Cellulitis Caused by Serratia\nmarcescens Following a Dog Scratch Pithadia Deeti J. BS1Weathers Erena N. BS1Colombo Rhonda E. MD2Baer Stephanie L. MD131 Medical College of Georgia, Augusta\nUniversity, Augusta, GA, USA2 Madigan Army Medical Center, Joint Base\nLewis-McChord, WA, USA3 Charlie Norwood Veterans Affairs Medical\nCenter, Augusta, GA, USAStephanie L. Baer, MD, Charlie Norwood VA\nMedical Center, 1 Freedom Way (235), Augusta, GA 30904, USA. Email:\nstephanie.baer@va.gov01 4 2019 Jan-Dec 2019 7 23247096198323305 1 2019 7 1 2019 13 1 2019 © 2019 American Federation for Medical\nResearch2019American Federation for Medical\nResearchThis article is distributed under the terms of the Creative Commons\nAttribution 4.0 License (http://www.creativecommons.org/licenses/by/4.0/) which\npermits any use, reproduction and distribution of the work without further\npermission provided the original work is attributed as specified on the SAGE\nand Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Soft tissue infections occur in over 30% of patients with chemotherapy-induced\nneutropenia. Gram-positive bacterial infections predominate early in\nneutropenia, and likelihood of infection by resistant bacteria and fungi\nincreases with prolonged neutropenia. Prior infections and exposures influence\nthe risk of rare pathogens. A 55-year-old woman with chemotherapy-induced\nneutropenia was scratched on her forearm by a dog. She cleaned the wound with\nisopropanol and was treated empirically with amoxicillin-clavulanate. Over the\nnext 4 days, she developed fever along with erythema, edema, and mild tenderness\nof the forearm without purulence or crepitus. She was hospitalized and received\nempiric treatment with intravenous vancomycin, piperacillin-tazobactam,\ntobramycin, and voriconazole. Despite therapy, her fevers persisted and the\ncellulitis progressed for over a week. After 10 days of hospitalization, her\nneutrophil count began to recover and a bulla developed at the wound site.\nCulture of the bullous fluid grew Serratia marcescens, and\nantibiotics were switched to cefepime based on susceptibility. She defervesced\nand showed substantial improvement of cellulitis within 48 hours and was\ndischarged on oral ciprofloxacin. Serratia marcescens skin\ninfections are rare, and this may be the first report of\nSerratia cellulitis associated with trauma from dog\ncontact. This case highlights the need to consider unusual pathogens based on\nexposure history and immune status and to obtain cultures from fluid collections\nor tissue in cases of treatment-resistant soft tissue infections.\n\nSerratia marcescenscellulitisdog scratchskin infectionimmunocompromisedcover-dateJanuary-December 2019\n==== Body\nIntroduction\nSkin and soft tissue infections comprise approximately 30% of infections in patients\nwith chemotherapy-induced neutropenia.1Gram-positive and antibiotic-susceptible gram-negative bacterial infections\npredominate in patients who are neutropenic for less than 7 days. The risk of\ninfection by resistant bacteria, yeasts, and molds increases with prolonged neutropenia.2 Gram-positive cutaneous infections generally begin as focal regions of\ntenderness progressing to cellulitis, while gram-negative skin infections have\ndiverse presentations including cellulitis, erythematous maculopapular lesions, and nodules.3 Past infections and exposures influence the risk of rare pathogens causing\ninfection in immunocompromised patients.\n\nWe report a case of severe and progressive cellulitis following a dog scratch on the\nforearm of a patient who was profoundly neutropenic following chemotherapy.\n\nCase\nA 55-year-old Caucasian female receiving chemotherapy for primary central nervous\nsystem lymphoma was scratched by a dog on her right forearm. She cleaned the wound\nwith isopropanol and presented to the emergency department at a community hospital.\nShe was discharged on oral amoxicillin-clavulanate, which she took as prescribed.\nThree days later, she was seen in oncology clinic for scheduled follow-up and was\nnoted to have erythema surrounding the scratch site. The wound contacted tap water\nin the shower, but she denied other environmental exposures. Over the next 24 hours,\nshe developed a fever and increased erythema, edema, and tenderness around the\nscratch site. She was subsequently admitted to our medical center.\n\nHer history was significant for primary central nervous system lymphoma diagnosed 6\nmonths prior. She completed consolidation chemotherapy 3 days prior to the dog\nscratch; a right-sided chest port remained in place. She had no prior history of\nimmunocompromised state. She had no prior skin infections, significant trauma, or\nsurgeries to the affected arm. She smoked 1 pack daily for many years but quit\nfollowing her cancer diagnosis. The dog was up-to-date on vaccinations. Her\noutpatient medications included prophylactic acyclovir, fluconazole, and\ntrimethoprim/sulfamethoxazole per standard chemotherapy protocol.\n\nOn admission to our medical center, she denied purulence, drainage, crepitus, or\nsignificant pain at the scratch site. She denied chest pain, dyspnea, abdominal\npain, nausea, vomiting, diarrhea, or dysuria. She had a fever of 39.3°C and\ntachycardia at 110 beats per minute. Her respiratory rate, blood pressure, and\noxygen saturation were within normal limits. She was awake, alert, and fully\noriented. Her cardiac, pulmonary, and abdominal examinations were unremarkable.\nThere was no erythema, purulence, or tenderness around her right-sided chest port. A\n10-cm, well-circumscribed patch of erythema with a 1-cm central, darkly pigmented\ncrust was present on her right forearm. The erythema had expanded from its earlier\nsize denoted by an outline drawn 3 days earlier. The region was warm and mildly\ntender. She had 2+ radial and brachial pulses bilaterally and 5/5 motor strength of\nthe bilateral upper extremities. No pain on flexion or extension of elbows, wrists,\nor fingers. Sensation was unaffected throughout the right upper extremity. Her\nlaboratory findings were significant for undetectable white blood cell count.\nHemoglobin was 11.7 g/dL, hematocrit was 34.0%, and platelet count was 19\n000/mm3.\n\nAmoxicillin/clavulanate was discontinued, and vancomycin intravenous (IV) and\npiperacillin/tazobactam IV were begun at admission. Cultures of blood from her chest\nport and urine were found to grow Pseudomonas aeruginosa with\nidentical susceptibilities, including to piperacillin/tazobactam and cefepime.\nCulture of blood taken at the same time from a peripheral site was negative, and all\nsubsequent blood cultures during hospitalization were negative. Despite the empiric\nbroad-spectrum antibiotic therapy, the cellulitis worsened. The borders of erythema\nbecame more sharply demarcated by hospital day 5 (Figure 1), and the patient experienced daily\nfevers with maximum temperature of 39.2°C. Clindamycin IV was added for its\nantitoxin effect on day 5. By hospital day 7, the erythematous patch became less\nwell-circumscribed (Figure\n2), and she developed increased pain and decreased strength (4/5) on flexion\nof the right wrist and digits. Ultrasound of the right arm showed soft tissue edema.\nSubsequent magnetic resonance imaging showed an elbow joint effusion and myositis\nwithout pyomyositis or abscess (Figure 3). Voriconazole IV was added on day 7 for empiric antifungal\ncoverage. The patient’s chest port was removed on day 8 of hospitalization and was\nculture-negative.\n\nFigure 1. Appearance of patient’s arm on day 5 of hospitalization. The ulcerated region\nwas the location of the dog scratch, and the drawn circle denoted the\nborders of erythema marked 3 days following the incident and 1 day prior to\nhospitalization. Borders of erythema were sharply demarcated, and edema was\nmild.\n\nFigure 2. Appearance of patient’s arm on day 7 of hospitalization. Borders of erythema\nbecame less poorly demarcated and spread into the arm and medial forearm.\nThe edema had extended into the hand and digits.\n\nFigure 3. Magnetic resonance imaging study of right forearm on day 9 of\nhospitalization, ordered due to concern for compartment syndrome. The study\ndemonstrated diffuse soft tissue cellulitis without abscess as well as\nmyositis without pyomyositis.\n\nOn hospital day 10, the patient’s leukocyte count recovered to 3400/mm3\n(neutrophils 2800/mm3, lymphocytes 400/mm3, monocytes\n200/mm3) and a bulla developed adjacent to the site of the dog\nscratch. Serous fluid from the bulla was drained using sterile technique and grew\nSerratia marcescens on culture. Cefepime IV was initiated based\non susceptibility results, and piperacillin/tazobactam and voriconazole were\ndiscontinued. She defervesced and experienced substantial improvement in the\ncellulitis over 48 hours. The patient was discharged home after 15 days of\nhospitalization on oral ciprofloxacin to complete a 14-day course of targeted\nantibiotic therapy. She was advised to keep her arm elevated to promote drainage of\nedema.\n\nAt follow-up, the patient continued to be afebrile after completing her antibiotic\ncourse. She received wound care at a community hospital. The wound healed completely\nwithin 2 months.\n\nDiscussion\nCellulitis is infection of the dermis and subcutaneous fat most frequently caused by\nintroduction of Streptococcus or Staphylococcus\nspecies into the skin through abrasions.4 Cellulitis secondary to traumatic contact, including scratches and bites, by\ndomestic mammals is most commonly due to Pasteurella\nmultocida.5,6\nIn patients with contaminated water exposure, Aeromonas hydrophila, Vibrio\nvulnificus, and Pseudomonas aeruginosa have been\nreported as culprits.7,8\nPseudomonas aeruginosa also is a common cause of skin infections\nand osteomyelitis in individuals suffering from puncture wounds.9\n\nDue to the patient’s history of a penetrating wound with subsequent tap water contact\nin the setting of neutropenia, the eschar-like lesion on the arm resembling ecthyma\ngangrenosum, and the blood and urine culture results, Pseudomonas\naeruginosa was initially believed to be the cause of cellulitis.\nFailure to respond to piperacillin/tazobactam, despite in vitro susceptibility,\nprompted further investigation. Although bullous cellulitis secondary to\ngram-negative septicemia is rare, Pseudomonas aeruginosa, which\nclassically presents in the skin as ecthyma gangrenosum, has been documented as a\ncause in numerous case reports.10\n\nSerratia marcescens is a gram-negative, motile, facultative\nanaerobic Bacillus that is pervasive in soil, water, and other damp\nenvironments. Prior to the mid-to-late 20th century, Serratia\nmarcescens was not considered to be a human pathogen11; since then, our understanding of its potential as a pathogen has transformed\nsignificantly. It is now known to be associated with opportunistic nosocomial\ninfections such as catheter-associated urinary tract infections,\nventilator-associated pneumonia, and central line–associated bacteremia.11\nSerratia may also cause severe infections following penetrating\ntrauma, such as endocarditis following IV drug use,12 meningitis following spinal anesthesia,13 and spinal epidural abscess following acupuncture.14\n\nSerratia skin and soft tissue infections are uncommon, and most\ncases occur in immunocompromised patients. Presentations include isolated plaques,15 bullous cellulitis,16 papillovesicular eruptions,17 abscesses,18,19 nodules,20,21 granulomatous\nlesions,22,23 and necrotizing cellulitis.24 Cases have been reported in the extremities of patients with uncontrolled diabetes25 and end-stage renal disease,26 as well as those who have undergone splenectomy27 and chemotherapy.17 Infections associated with immunocompromised state frequently disseminate and\nlead to life-threatening sepsis. In healthy, immunocompetent patients,\nSerratia skin and soft tissue infections are generally\nlocalized and associated with direct trauma or chronic vascular disease. Infections\nin patients with venous insufficiency have presented as nodules, purulent ulcers,\nand cellulitis.18,20,21,28\n\nTo better understand the risk factors and potential etiologies for infection in our\npatient, we conducted a review of reported cases of Serratia\nmarcescens skin and soft tissue infections associated with inoculation\ninjury or trauma (Table\n1). Twenty-five individual patient cases were found. Skin and soft tissue\nmanifestations included cellulitis (11 cases), necrotizing fasciitis (6 cases),\ncellulitis progressing to necrotizing fasciitis (3 cases), abscesses (2 cases),\nulcers (2 cases), and inflamed nodule (1 case). Thirteen cases were reported in\nimmunocompetent patients, 11 were in immunocompromised patients, and 1 did not\nspecify. Two cases were in patients who were immunocompromised from\nchemotherapy.\n\nTable 1. Cases of Serratia marcescens Skin and Soft Tissue Infections\nFollowing External Trauma.\n\nCase\tPatient Demographic\tPreceding Traumatic Insult\tDistribution\tImmunocompromised\tSkin/Soft Tissue Manifestation\tManagement\tOutcome\t\nBrenner and Lookingbill45\t51-year-old male\tIntravenous catheter placement\tThigh\tNo\tCellulitis\tNafcillin, gentamicin\tDeath from hepatic and renal failure 7 days after catheter\nplacement\t\nBornstein et al26\t37-year-old female\tHemodialysis, fistula-site needle penetration\tAxilla, breast, thorax\tYes; end-stage renal disease\tCellulitis\tSurgical debridement, amikacin, ciprofloxacin\tResolution\t\nBonner and Meharg44\t60-year-old male\tMuscle and nerve biopsy\tFoot\tNo\tCellulitis\tCefoxitin\tResolution\t\nCooper et al25\t69-year-old female\tIngrown toenail surgery\tFoot\tYes; type 2 diabetes mellitus\tBullous cellulitis\tAmputation\tResolution\t\nPereira et al33\t21-year-old female\tFinger amputations caused by steel door; reconstructive surgery;\nleech application\tThird and fourth digits on hand\tNo\tCellulitis\tAmputation of reconstructed fingertip, ciprofloxacin\tResolution\t\nHsieh and Babl29\t8-year-old male\tIguana bite\tIndex finger\tNo\tCellulitis\tIncision and drainage, ampicillin/sulbactam, gentamicin,\namoxicillin/clavulanate\tResolution\t\nHuang et al43\t40-year-old male\tSkin biopsy\tFoot\tYes; prednisolone therapy for systemic lupus erythematosus\tNecrotizing fasciitis\tSurgical debridement, ceftazidime\tResolution\t\nCurtis et al34\t51-year-old male\tScraping legs on rocks while fishing in river\tLeg\tYes; end-stage renal disease\tNecrotizing fasciitis\tSurgical debridement, vancomycin, ciprofloxacin, clindamycin,\naztreonam\tResolution\t\nGrim et al16\t54-year-old male\tIguana bite\tPosterior calf\tNo\tBullous cellulitis\tTrimethoprim/sulfamethoxazole\tResolution\t\nGrim et al16\t25-year-old male\tIguana bite\tAnkle\tNo\tBullous cellulitis\tTrimethoprim/sulfamethoxazole\tResolution\t\nMotsitsi31\t37-year-old male\tHuman bite\tForearm\tNo\tNecrotizing fasciitis\tSurgical debridement\tDeath 2 days after admission\t\nPark and Seo47\t62-year-old female\tDermal filler injection\tUpper face\tNo\tInflamed nodule\tTrimethoprim/sulfamethoxazole\tResolution\t\nPrelog et al46\t15-year-old female\tVenous access port implantation\tAxilla\tYes; active chemotherapy for acute lymphoblastic leukemia\tNecrotizing fasciitis\tSurgical debridement\tResolution\t\nSubramani et al30\t50-year-old female\tSnake bite\tHand\tNo\tBullous cellulitis and necrotizing fasciitis\tSurgical debridement, ciprofloxacin,\npiperacillin/tazobactam\tResolution\t\nSharma et al32\t11-month-old female\tInsect bite\tUpper chest\tNo\tAbscess followed by ulceration\tCeftazidime, amikacin, amoxicillin/clavulanate\tResolution\t\nVano-Galvan et al48\t57-year-old female\tMinor trauma of unspecified origin\tThigh\tYes; chemotherapy for chronic lymphocytic leukemia, type 2\ndiabetes mellitus\tBullous cellulitis and necrotizing fasciitis\tLinezolid, piperacillin/tazobactam\tDeath 2 hours after presentation\t\nGarcía et al38\t32-year-old male\tTattoo\tElbow\tNo\tAbscess\tIncision and drainage, ertapenem, ciprofloxacin\tResolution\t\nLakhani et al41\t51-year-old female\tBifemoral bypass and left distal femoral aneurysm repair\nsurgeries\tAbdomen and groin\tYes; type 2 diabetes mellitus\tNecrotizing fasciitis\tCiprofloxacin\tResolution\t\nMajumdar and Crum-Cianflone42\t54-year-old female\tSkin biopsy\tLeg\tYes; end-stage renal disease, type 2 diabetes mellitus\tBullous cellulitis and necrotizing fasciitis\tSurgical debridement, vancomycin, piperacillin/tazobactam,\nlevofloxacin, clindamycin\tResolution\t\nRoth39\t54-year-old female\tTransobturator sling surgery\tThigh\tNot specified\tCellulitis\tSurgical debridement, ciprofloxacin\tResolution\t\nHagiya et al36\t64-year-old male\tUntreated burn\tLeg\tYes; liver cirrhosis\tNecrotizing fasciitis\tPenicillin G, meropenem, clindamycin\tDeath from septic shock 25 hours after presentation\t\nKyvernitakis et al40\t71-year-old female\tMastectomy and sentinel node biopsy\tBreast\tNo\tCellulitis with underlying seroma\tAspiration, ciprofloxacin\tResolution\t\nVeraldi and Nazzaro37\t75-year-old male\tScratch from bush\tLeg\tNo\tUlcer\tCeftriaxone\tResolution\t\nVeraldi and Nazzaro37\t75-year-old female\tScratch from rose thorn\tLeg\tYes; type 1 diabetes mellitus\tUlcer\tLevofloxacin\tResolution\t\nMarin et al35\t50-year-old male\tDropping of piece of drywall to affected area\tFoot\tYes; type 2 diabetes mellitus\tBullous cellulitis, liquefactive necrosis, necrotic eschar\tIncision and drainage; discharged against medical advice before\nantibiotic treatment\tLost to follow-up\t\nFive of the reports were associated with bite trauma, including 3 iguana\nbites,16,29 1 snake bite,30 1 human bite,31 and 1 insect bite.32 One case followed exposure to leeches.33 Six of the cases had preceding accidental trauma or burns.33-35 Three of the cases involved\noutdoor contact, including scrapes by rocks, bushes,36 and a rose thorn.37 One case of an abscess caused by a tattoo was reported.38 There are 12 reports of occurrences subsequent to iatrogenic trauma,\nincluding 5 that occurred after surgery.25,33,39-41 Other iatrogenic-associated\ncases followed skin or muscle biopsies,42-44 IV catheter\nplacement,45,46 arteriovenous fistula,26 and dermal filler injection.47 One patient was described to have “minor trauma” of unspecified origin.48 Most of these infections were managed successfully with antibiotics or\nsurgical debridement, though 4 were fatal.\n\nBased on our review, this may be the first report of Serratia\nmarcescens skin infection associated with traumatic break in the skin\ncaused by a dog scratch. The source of Serratia in our patient is\nunclear, but it may have been introduced into the wound by the dog scratch, while\ncleaning the wound with contaminated isopropanol, or while taking a shower. Risk\nfactors included her profoundly neutropenic state on presentation and her exposure\nto prophylactic antibiotics during and after chemotherapy. Her chest port, which was\nlocated on the same side as her affected arm, was also considered a potential nidus\nfor infection leading to secondary cellulitis. This is less likely given the absence\nof Serratia bacteremia and negative culture of port following\nremoval.\n\nConclusion\nWe report a case of Serratia marcescens cellulitis following a dog\nscratch in a neutropenic patient. This case highlights the need for clinicians to\nconsider unusual pathogens based on exposure history in cases of treatment-resistant\nsoft tissue infections in immunocompromised patients. It also emphasizes the\nimportance of obtaining cultures from drainable lesions or tissue to establish a\nmicrobiologic diagnosis and allow for targeted therapy.\n\nAuthors’ Note: This work was presented at the previously presented at the American Federation\nfor Medical Research Southern Regional Meeting (February 2018, New Orleans, LA)\nand previously published in abstract form (J Investig Med.\n2018;66(2):467). The contents of this article do not represent the views of the\nDepartment of Veterans Affairs or the US government.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the\nresearch, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or\npublication of this article.\n\nEthics Approval: Our institution does not require ethical approval for reporting individual cases\nor case series.\n\nInformed Consent: Verbal informed consent was obtained from the patient(s) for their anonymized\ninformation to be published in this article.\n==== Refs\nReferences\n1 \nElting LS Rubenstein EB Rolston KV Bodey GP. \nOutcomes of bacteremia in patients with cancer and neutropenia:\nobservations from two decades of epidemiological and clinical\ntrials . 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Clin Microbiol Rev .\n2011 ;24 :755 -791 .21976608 \n12 \nMills J Drew D. \nSerratia marcescens endocarditis: a regional\nillness associated with intravenous drug abuse . Ann\nIntern Med .\n1976 ;84 :29 -35 .1106290 \n13 \nYang CW Hsu SN Liu JS Hueng DY. \nSerratia marcescens spinal epidural abscess\nformation following acupuncture . Intern\nMed .\n2014 ;53 :1665 -1668 .25088883 \n14 \nErsoz G Uguz M Aslan G Horasan ES Kaya A. \nOutbreak of meningitis due to Serratia\nmarcescens after spinal anaesthesia . J\nHosp Infect .\n2014 ;87 :122 -125 .24814159 \n15 \nYoshida R Takae Y Fujio Y Tanaka M Ohyama M. \nCutaneous Serratia marcescens infection on the\nface of a healthy female . J Eur Acad Dermatol\nVenereol .\n2009 ;23 :1213 -1215 .19220644 \n16 \nGrim KD Doherty C Rosen T. \nSerratia marcescens bullous cellulitis after\niguana bites . J Am Acad Dermatol .\n2010 ;62 :1076 -1076 .20466190 \n17 \nBahadir A Erduran E. \nSerratia marcescens infection presenting with\npapillovesicular rash similar to varicella zoster infection: a case\nreport . North Clin Istanb .\n2015 ;2 :55 -58 .28058340 \n18 \nLangrock ML Linde HJ Landthaler M Karrer S. \nLeg ulcers and abscesses caused by Serratia\nmarcescens . Eur J Dermatol .\n2008 ;18 :705 -707 .18955204 \n19 \nFriedman ND Peterson NB Sumner WT Alexander BD. \nSpontaneous dermal abscesses and ulcers as a result of\nSerratia marcescens . J Am Acad\nDermatol . 2003 ;49 (2 suppl case\nreports):S193 -S194 .12894121 \n20 \nJoão AM Serrano PN Cachão MP Bártolo EA Brandão FM. \nRecurrent Serratia marcescens cutaneous\ninfection manifesting as painful nodules and ulcers .\nJ Am Acad Dermatol .\n2008 ;58 (2\nsuppl ):S55 -S57 .18191713 \n21 \nNieves DS James WD. \nPainful red nodules of the legs: a manifestation of chronic\ninfection with gram-negative organisms . 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Infection .\n2016 ;44 :371 -377 .26498285 \n43 \nHuang JW Fang CT Hung KY Hsueh PR Chang SC Tsai TJ. \nNecrotizing fasciitis caused by Serratia\nmarcescens in two patients receiving corticosteroid\ntherapy . J Formos Med Assoc .\n1999 ;98 :851 -854 .10634026 \n44 \nBonner MJ Meharg JG Jr. \nPrimary cellulitis due to \nSerratia marcescens. JAMA .\n1983 ;250 :2348 -2349 .6355524 \n45 \nBrenner DE Lookingbill DP. \nSerratia marcescens cellulitis .\nArch Dermatol .\n1977 ;113 :1599 -1600 .337905 \n46 \nPrelog T Jereb M Cuček I Jazbec J. \nNecrotizing fasciitis caused by Serratia\nmarcescens after venous access port implantation in a child\nwith acute lymphoblastic leukemia . J Pediatr Hematol\nOncol .\n2012 ;34 :e246 -e248 .22584779 \n47 \nPark KY Seo SJ. \nCutaneous Serratia marcescens infection in an\nimmunocompetent patient after filler injection . 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"fulltext_license": "CC BY",
"issn_linking": "2324-7096",
"issue": "7()",
"journal": "Journal of investigative medicine high impact case reports",
"keywords": "cellulitis; dog scratch; immunocompromised; skin infection",
"medline_ta": "J Investig Med High Impact Case Rep",
"mesh_terms": "D000818:Animals; D000900:Anti-Bacterial Agents; D001733:Bites and Stings; D002481:Cellulitis; D002939:Ciprofloxacin; D004285:Dogs; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D016868:Serratia Infections; D012706:Serratia marcescens",
"nlm_unique_id": "101624758",
"other_id": null,
"pages": "2324709619832330",
"pmc": null,
"pmid": "30929475",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10209471;10426919;10452669;10634026;1106290;12894121;1489009;15550150;15869138;15962544;16483663;16844533;18191713;18955204;1918497;19220644;19484589;20466189;21469761;21724683;21976608;22513504;22584779;22640271;23416662;23975584;24814159;25088883;25185597;26294949;26356072;26498285;26778253;27052490;27079487;27433413;28058340;28650753;28663809;28966913;3295825;337905;4567039;6355524;9332520;9831674;9887159",
"title": "Severe and Progressive Cellulitis Caused by Serratia marcescens Following a Dog Scratch.",
"title_normalized": "severe and progressive cellulitis caused by serratia marcescens following a dog scratch"
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"abstract": "BACKGROUND\nInvasive fungal pneumonia is a severe infectious disease with high mortality in immunocompromised patients. However, the clinical diagnosis of the pathogen(s) remains difficult since microbiological evidence is difficult to acquire.\n\n\nMETHODS\nHere, we report a case of pulmonary fungal infection detected by next-generation sequencing (NGS) of bronchoalveolar lavage fluid (BALF) in a 61-year-old male with corticosteroid-treated dermatomyositis. Cytomegalovirus and influenza A virus infections were confirmed by nucleic acid detection and treated with antiviral medicine. The patient had been diagnosed with severe pneumonia and treated with empiric broad-spectrum antibacterial and antifungal drugs before bronchoscopy was performed. The patient responded poorly to those empiric treatments. Three fungi were found by NGS in the BALF, namely, Pneumocystis jirovecii, Aspergillus fumigatus and Rhizopus oryzae. After adjusting the patient's treatment plan according to the NGS results, he improved significantly.\n\n\nCONCLUSIONS\nThis case highlights the combined application of NGS and traditional tests in the clinical diagnosis of pulmonary invasive fungal disease. NGS is proposed as an important adjunctive diagnostic approach for identifying uncommon pathogens.",
"affiliations": "Department of Infectious Diseases, the First Hospital, Jilin University, Changchun, 130021, Jilin, China.;Department of Infectious Diseases, the First Hospital, Jilin University, Changchun, 130021, Jilin, China.;Department of Infectious Diseases, the First Hospital, Jilin University, Changchun, 130021, Jilin, China.;Department of Infectious Diseases, the First Hospital, Jilin University, Changchun, 130021, Jilin, China. wyang@jlu.edu.cn.",
"authors": "Zhang|Kaiyu|K|;Yu|Chen|C|;Li|Yuxiang|Y|;Wang|Yang|Y|http://orcid.org/0000-0001-8055-9522",
"chemical_list": "D000935:Antifungal Agents; D004271:DNA, Fungal",
"country": "England",
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"doi": "10.1186/s12879-020-05341-8",
"fulltext": "\n==== Front\nBMC Infect Dis\nBMC Infect. Dis\nBMC Infectious Diseases\n1471-2334 BioMed Central London \n\n5341\n10.1186/s12879-020-05341-8\nCase Report\nNext-generation sequencing technology for detecting pulmonary fungal infection in bronchoalveolar lavage fluid of a patient with dermatomyositis: a case report and literature review\nZhang Kaiyu zhangky2000@aliyum.com 1 Yu Chen 191985540@qq.com 1 Li Yuxiang yuxiangli2@aliyun.com 1 http://orcid.org/0000-0001-8055-9522Wang Yang wyang@jlu.edu.cn 12 1 grid.430605.4Department of Infectious Diseases, the First Hospital, Jilin University, Changchun, 130021 Jilin China \n2 grid.266902.90000 0001 2179 3618Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104 USA \n17 8 2020 \n17 8 2020 \n2020 \n20 60818 3 2020 11 8 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\nInvasive fungal pneumonia is a severe infectious disease with high mortality in immunocompromised patients. However, the clinical diagnosis of the pathogen(s) remains difficult since microbiological evidence is difficult to acquire.\n\nCase presentation\nHere, we report a case of pulmonary fungal infection detected by next-generation sequencing (NGS) of bronchoalveolar lavage fluid (BALF) in a 61-year-old male with corticosteroid-treated dermatomyositis. Cytomegalovirus and influenza A virus infections were confirmed by nucleic acid detection and treated with antiviral medicine. The patient had been diagnosed with severe pneumonia and treated with empiric broad-spectrum antibacterial and antifungal drugs before bronchoscopy was performed. The patient responded poorly to those empiric treatments. Three fungi were found by NGS in the BALF, namely, Pneumocystis jirovecii, Aspergillus fumigatus and Rhizopus oryzae. After adjusting the patient’s treatment plan according to the NGS results, he improved significantly.\n\nConclusions\nThis case highlights the combined application of NGS and traditional tests in the clinical diagnosis of pulmonary invasive fungal disease. NGS is proposed as an important adjunctive diagnostic approach for identifying uncommon pathogens.\n\nKeywords\nNext-generation sequencingBronchoalveolar lavage fluidPneumoniahttp://dx.doi.org/10.13039/501100001809National Natural Science Foundation of China81801972Wang Yang issue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nDermatomyositis (DM) is a rare chronic autoimmune disease primarily affecting skeletal muscle and the skin, with characteristic cutaneous findings and varying amounts of systemic involvement [1]. It is still a poorly understood multisystem disease. DM treatment usually involves corticosteroids and immunosuppressants, but the course of these treatments is very long [2]. Following treatment with corticosteroids, the incidence of invasive infection increases, especially pulmonary invasive infection [3]. The causative agents of these invasive infections are difficult to identify because many of the pathogens are ‘unculturable’ or ‘difficult to culture’. Multiple methods of detection, such as specific antigen or antibody detection, PCR amplification, inflammatory indexes and imaging examinations, have been utilized in clinical work, but we occasionally still cannot draw a correct conclusion according to these tests. However, next-generation sequencing (NGS), a highly sensitive method for analyzing the microbiome, could provide additional valuable information for diagnosis and treatment.\n\nHere, we report one patient with DM who developed severe pneumonia and was infected with multiple pathogens, including viruses and three different fungi, and pulmonary fungi were revealed by NGS of bronchoalveolar lavage fluid (BALF).\n\nCase presentation\nA 61-year-old male presented to the infectious disease department of the First Hospital, Jilin University, with fever for 7 days. This patient had been diagnosed with DM 2 months prior. He was prescribed oral methylprednisolone therapy (morning dose 40 mg, night dose 24 mg, daily) without antibiotic prophylaxis after his diagnosis. He came to the hospital because he had a fever with a temperature up to 38.8 °C for 7 days. He also complained of intermittent productive cough with pale sputum associated with chest heaviness, pectoralgia and dyspnea at rest.\n\nThe laboratory results were as follows: white blood cell count 11.98 × 109/L, with a neutrophil ratio of 93%; hemoglobin 133 g/L; and platelet count 139 × 109/L. Inflammatory marker levels were increased significantly: C-reactive protein (CRP) 174.1 mg/L; erythrocyte sedimentation rate (ESR) 72 mm/h; and procalcitonin 0.05 ng/mL. Arterial blood gas analysis (with O2 5 L/min via nasal catheter) showed pH 7.51; pCO2 37 mmHg; pO2 60 mmHg; HCO3− 29.5 mmol/L; BE 6.1 mmol/L; lactate 1.9 mmol/L; and O2 saturation 93%. Blood biochemical index results showed that creatine kinase content increased to 746 U/L, creatine kinase isoenzyme content increased to 86.2 U/L, lactate dehydrogenase content increased to 682 U/L, and ɑ-hydroxybutyrate dehydrogenase content increased to 528 U/L. Nucleic acid detection of common respiratory pathogens (including Mycoplasma pneumoniae, Chlamydia pneumoniae, adenovirus, respiratory syncytial virus, parainfluenza virus, and influenza A and B) was performed, and nucleic acid detection of influenza A virus was positive. Nucleic acid detection of cytomegalovirus showed 4.5 × 104 copies/mL. A computed tomography (CT) scan showed bronchitis and inflammation in the right lung lobes, the left ligule lobe and the left lower lobe (Fig. 1a). All of the blood culture, urine culture and sputum culture results were negative. Both the 1,3-beta-D-glucan test (G test) result (15 pg/ml) and galactomannan test (GM test) result (0.33 μg/L) were negative. We also sent the sputum sample to perform Gomori-Grocott methenamine silver nitrate staining (GMS) for Pneumocystis jirovecii detection and obtained a negative result. The diagnosis of this patient included pneumonia, influenza A virus infection and cytomegalovirus infection.\nFig. 1 CT scan of the lung. a On the 1st day, a CT scan showed bronchitis and inflammation in the right lung lobes, the left ligule lobe and the left lower lobe. b: On the 9th day, a CT scan showed that some of the inflammation was alleviated, but inflammation in most lung lobes was worse\n\n\n\nConsidering the treatment with methylprednisolone and the results of the tests, moxifloxacin (400 mg, QD, iv. D), piperacillin/tazobactam (4.5, Q8H, iv. D) and voriconazole (200 mg, Q12H, iv. D) were used after he was hospitalized (Fig. 2a). Oseltamivir (75 mg, Q12H, orally, for 5 days) was given after the positive result of the nucleic acid detection of influenza A virus was received. After 2 days of treatment with voriconazole, the patient developed visual hallucinations and confusion, and the antifungal treatment was changed to micafungin (50 mg, Q12H, iv. D) (Fig. 2a). Ganciclovir (0.25, Q12H, iv. D) was given to him after receiving the positive nucleic acid detection of cytomegalovirus. On the 6th day after admission to the hospital, his body temperature decreased to below 38.5 °C but did not decrease to normal levels (Fig. 2b). Meanwhile, his cough and dyspnea were obviously relieved. His arterial blood gas analysis (without an O2 nasal catheter) showed pO2 80 mmHg and O2 saturation 95%. On the 9th day after admission to the hospital, the patient underwent a second CT scan test, and the results showed that some of the inflammation was alleviated, but the inflammation in most lung lobes was worse (Fig. 1b). The G test and GM test results remained negative. Blood biochemical index results showed that the creatine kinase content decreased to 441 U/L, creatine kinase isoenzyme content decreased to 47.5 U/L, lactate dehydrogenase content increased to 505 U/L, and ɑ-hydroxybutyrate dehydrogenase content increased to 395 U/L. To verify pathogen-induced pneumonia, the patient underwent bronchoscopy examination with collection of BALF specimens, and these samples were sent to BGI Diagnosis Co. (Shenzhen, China) for an NGS test on the 12th day after admission to the hospital. We also sent the BALF samples to perform GMS for Pneumocystis jirovecii detection, and this time, we obtained a positive result. In addition, another portion of the BALF was sent to the laboratory for traditional culture and T-SPOT, which were reported as negative. Two days later, NGS results showed that three fungi were in the BALF, namely, Pneumocystis jirovecii, Aspergillus fumigatus and Rhizopus oryzae (Table 1). The other microorganisms detected by NGS are listed in Fig. 3, but they were not regarded as responsible for the invasive lung infection. The antifungal therapy was changed to posaconazole (75 mg, Q12H, orally) and trimethoprim/sulfamethoxazole (TMP/SMX, TMP 0.24/SMX 1.2, Q6H, orally, for 3 weeks). The patient improved significantly, and his body temperature decreased to normal levels 4 days after adjusting the treatment plan (Fig. 2b). Then, he was treated with ganciclovir, posaconazole and TMP/SMX at home (Fig. 2a).\nFig. 2 Timeline of the patient’s clinical manifestations and treatment. a Timeline of the patient’s tests and treatment. MP, methylprednisolone; MOX, moxifloxacin; PIP-TAZ, piperacillin/tazobactam; OST, oseltamivir; VORI, voriconazole; MCFG, micafungin; GCV, ganciclovir; PCZ, posaconazole; TMP-SMX, trimethoprim/sulfamethoxazole; G test, 1,3-β-D-glucan test; GM test, galactomannan test. b Timeline of the patient’s body temperature\n\nTable 1 NGS report of the microorganism in BALF\n\nGenus\tSpecies\t\nName\tSequence numbera\tName\tSequence numbera\t\nPneumocystis\t66\tPneumocystis jirovecii\t66\t\nAspergillus\t45\tAspergillus fumigatus\t11\t\nRhizopus\t22\tRhizopus oryzae\t11\t\naThe sequence number of the strict comparison of the microorganism detected at the level of genus/species\n\nFig. 3 Other microorganisms found by NGS. a Bacteria found by NGS. Megasphaera micronuciformis: 6358 reads; Megasphaera elsdenii: 4 reads; Cardiobacterium hominis: 4660 reads; Cardiobacterium valvarum: 71 reads; Leptotrichia trevisanii: 339 reads; Leptotrichia buccalis: 238 reads; others: 360412 reads. b Viruses found by NGS. Human betaherpesvirus 5: 35 reads; Human alphaherpesvirus 1: 15 reads; others: 5 reads\n\n\n\nThe patient’s body temperature remained normal, and no significant symptoms were observed (Fig. 2b). On the 30th day, he underwent nucleic acid detection for cytomegalovirus. The result was negative, and ganciclovir was discontinued. On the 35th day, TMP/SMX was discontinued because its course of treatment was long enough. The latest lung CT scan was taken on the 86th day, and the results showed that the inflammation of the lung lobes had dissipated well. Posaconazole was eventually discontinued (Fig. 2a). Blood biochemical index results were slightly higher than the normal levels but were much better than those before treatment.\n\nDiscussion and conclusions\nCorticosteroids are frequently used to treat rheumatic diseases. Their use comes with a number of well-established risks, including glaucoma, avascular necrosis, osteoporosis and diabetes. Corticosteroid treatment could inhibit the host immune system, and immunocompromised patients are easily infected with various opportunistic pathogens [4]. Many studies have suggested that high-dose (> 20 mg/day prednisone) corticosteroids might lead to an increased risk of serious infections, and this increased risk is dose dependent [4]. This patient with DM had been treated with a high-dose corticosteroid for 2 months (methylprednisolone, morning dose 40 mg, night dose 24 mg, daily, orally) before acquiring pneumonia.\n\nIt is known that several viruses with different replication mechanisms contribute to oncogenesis in immunosuppressed subjects, both directly and indirectly. Among these viruses, the main ones are as follows: Epstein-Barr virus (EBV), human papillomavirus (HPV), Kaposi sarcoma herpesvirus (KSHV), human T-cell leukemia virus type 1 (HTLV-1), and Merkel cell polyoma virus (MCV) [5]. Worldwide, human cytomegalovirus (CMV) infection is very common, with seroprevalence rates ranging from 40 to nearly 100%. Primary infection is usually subclinical in healthy adults due to a complex antiviral immune response. However, patients receiving immunosuppressive medication are a high-risk group [6]. CMV is the most common infection among immunocompromised patients and has a major impact on morbidity, mortality and graft survival [7]. It has been reported that CMV and other respiratory viral infections are common between 1 and 3 months after immune suppression [8]. In the present study, nucleic acid detection was cytomegalovirus positive, and approximately 4 weeks of ganciclovir therapy was given until the test became negative. Nucleic acid detection of influenza A virus was also positive. The population is generally susceptible to influenza A virus, and this patient did not receive the influenza A virus vaccine. He took oseltamivir for 5 days, with decreasing body temperature.\n\nInfection secondary to corticosteroid therapy could be from bacteria, such as Mycobacterium tuberculosis, or fungi [4]. In the present study, the patient’s inflammatory markers were increased significantly; however, the lung CT characteristics did not show specific changes to help us verify the pathogens. The results of blood culture and sputum culture were negative. We used broad-spectrum antibacterials (moxifloxacin and piperacillin/tazobactam) that could kill or inhibit most gram-positive and gram-negative bacteria and atypical respiratory pathogens [9]. In our case, all blood culture, sputum culture, G test and GM test results for this patient were negative. However, invasive fungal infections are generally encountered in immunocompromised patients treated with steroids. Aspergillus is a common agent among invasive fungal pathogens, with high mortality, and Aspergillus infections most commonly involve the lungs [10]. Aspergillus fumigatus is most ubiquitous in the environment and is the major cause of the disease [11]. Considering that voriconazole is the preferred antifungal agent for the primary therapy of invasive Aspergillus and is considered the first-line treatment for invasive aspergillosis [12], we chose this medicine even though there was no direct evidence of fungal infection. After the side effects of voriconazole were evident, micafungin was used instead, which is a fungistatic echinocandin and represents an alternative therapy [13]. Pneumocystis jirovecii is an opportunistic fungus that can cause interstitial pneumonia in an immunocompromised host. Most reported Pneumocystis jirovecii pneumonia (PCP) cases are among HIV-positive or transplant recipients and patients who have hematological malignancies requiring T cell-depleting agents. However, in recent years, PCP has also been found in some patients with autoimmune disease on high-dose glucocorticoids [14, 15]. The diagnosis of PCP depends on a GMS test of sputum to detect cysts and trophic forms of Pneumocystis jirovecii and/or nucleic acid detection [16]. These two tests are not regular tests and are not available in most hospitals. These tests are required only in HIV-positive patients, and samples need be sent to a commercial company or laboratory. Microscopic detection of Pneumocystis jirovecii in respiratory secretions is simple and useful but may underestimate Pneumocystis jirovecii infection. Nucleic acid detection of Pneumocystis jirovecii has become increasingly important in recent years [17]. Prophylaxis is highly effective and should be given to all patients at moderate to high risk of PCP [18]. Unfortunately, this patient did not receive prophylaxis for PCP. TMP/SMX remains the drug of choice for prophylaxis and treatment of PCP. Rhizopus oryzae exists broadly in the environment and can also be an opportunistic fungus. Rhizopus oryzae is one of the causes of mucormycosis [19]. Reported cases of Rhizopus oryzae infection are rare, but there have been cases in patients receiving corticosteroid therapy. Among those cases of Rhizopus oryzae infection, only one case was related to pulmonary infection [20]. The diagnosis of Rhizopus oryzae infection usually depends on fungal culture and lesional biopsy. Posaconazole is a second-generation triazole agent with potent and broad antifungal activity. Posaconazole could be used to treat invasive Aspergillus and Rhizopus infection. We modified the therapeutic strategies as soon as we obtained the results of NGS and achieved good outcomes.\n\nNGS can be used to sequence the entire DNA/RNA of a sample. The NGS platform we utilized (the BGISEQ-50 sequencing platform) can simultaneously detect a broad range of bacterial, viral, fungal or parasitic DNA/RNA sequences with high accuracy and within less than 30 h [21]. DNA and RNA were extracted from BALF samples. Complementary DNA (cDNA) was generated from an RNA template by reverse transcription. Then, DNA libraries were constructed through DNA fragmentation, end repair, adapter ligation and PCR amplification. Quality qualified libraries were sequenced by using the BGISEQ-50 platform. High-quality sequencing data were generated by removing low-quality and short (length < 35 bp) reads, followed by computational subtraction of human host sequences mapped to the human reference genome (hg19) using Burrows-Wheeler Alignment. The remaining data obtained by removal of low-complexity reads were classified by simultaneous alignment to four microbial genome databases consisting of viruses, bacteria, fungi, and parasites [22, 23]. In recent years, the cost of NGS has decreased, and most patients can afford it. Traditional ‘gold standard’ sample culture requires a much longer time with much lower sensitivity. For the diagnosis of invasive fungal infection, the results of some promising tests (G test and/or GM test) are not specific, and their sensitivity is not satisfactory. In the present case, none of the results of these kinds of tests verified fungal infection. We could only give empiric treatment according to the patient’s medical history, clinical manifestations and examination results until the NGS of BALF result was received; then, the antipathogen therapy was changed to a targeted treatment. NGS can provide direct clues and assist in accurately diagnosing complex infections [24]. Regarding the high mortality associated with severe pneumonia, NGS should be considered a regular test [25]. However, not all microorganisms determined by NGS are associated with disease; for example, NGS can identify colonizing bacteria within the host body. Collectively, clinicians should identify the actual causative agent(s) according to NGS results, the characteristics of the detected pathogen(s) and other examinations results.\n\nNGS is currently not the best choice for fungal identification. However, the diagnosis of invasive fungal infection is very difficult, and NGS in BALF has become increasingly important and is regarded as an important adjunctive diagnostic approach for uncommon pathogens. This case report highlights the feasibility of deploying NGS of BALF as a rapid and sensitive diagnostic assay for severe pneumonia among immunocompromised patients, especially those patients treated with corticosteroids. This method may help clinicians make an accurate diagnosis of invasive pathogens and apply the most appropriate therapy.\n\nAbbreviations\nBALFBronchoalveolar lavage fluid\n\ncDNAComplementary DNA\n\nCMVCytomegalovirus\n\nCRPC-reactive protein\n\nCTComputed tomography\n\nDMDermatomyositis\n\nEBVEpstein-Barr virus\n\nESRErythrocyte sedimentation rate\n\nG test1,3-beta-D-glucan test\n\nGCVGanciclovir\n\nGM test Galactomannan test\n\nGMSGomori-Grocott methenamine silver nitrate staining\n\nHPV Human papillomavirus\n\nHTLV-1Human T-cell leukemia virus type 1\n\nKSHVKaposi sarcoma herpesvirus\n\nMCFGMicafungin\n\nMCVMerkel cell polyoma virus\n\nMOXMoxifloxacin\n\nMPMethylprednisolone\n\nNGS Next-generation sequencing\n\nOST Oseltamivir\n\nPCP Pneumocystis jirovecii pneumonia\n\nPCZ Posaconazole\n\nPIP-TAZPiperacillin/tazobactam\n\nTMP/SMXTrimethoprim/sulfamethoxazole\n\nVORIVoriconazole\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nThe authors thank the radiological technicians and neurosurgeons for their efforts in the clinical diagnosis and management of this patient.\n\nAuthors’ contributions\nKZ, YL and YW treated the patient and collected clinical data; CY sent samples to perform the NGS. This manuscript was initially drafted by KZ and CY, then revised by YW. All authors approved the final manuscript.\n\nFunding\nThis study was funded by National Natural Science Foundation of China (NSFC 81801972). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\n\nAvailability of data and materials\nThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\nNot Applicable.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case and any accompanying images report. A copy of the written consent is available for review by the Editor of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Cobos GA, Femia A, Vleugels RA. Dermatomyositis: an update on diagnosis and treatment. Am J Clin Dermatol. 2020. 10.1007/s40257-020-00502-6.\n2. Waldman R DeWane ME Lu J Dermatomyositis: diagnosis and treatment J Am Acad Dermatol 2020 82 2 283 296 10.1016/j.jaad.2019.05.105 31279813 \n3. Iannella H Luna C Waterer G Inhaled corticosteroids and the increased risk of pneumonia: what's new? A 2015 updated review Ther Adv Respir Dis 2016 10 3 235 255 10.1177/1753465816630208 26893311 \n4. Youssef J Novosad SA Winthrop KL Infection risk and safety of corticosteroid use Rheum Dis Clin N Am 2016 42 1 157 176 10.1016/j.rdc.2015.08.004 \n5. Pierangeli A Antonelli G Gentile G Immunodeficiency-associated viral oncogenesis Clin Microbiol Infect 2015 21 11 975 983 10.1016/j.cmi.2015.07.009 26197213 \n6. Fonseca Brito L, Brune W, Stahl FR. Cytomegalovirus (CMV) Pneumonitis: Cell Tropism, Inflammation, and Immunity. Int J Mol Sci. 2019;20(16). 10.3390/ijms20163865.\n7. Kotton CN CMV: prevention, diagnosis and therapy Am J Transplant 2013 13 Suppl 3 24 40 10.1111/ajt.12006 23347212 \n8. Mikulska M Viscoli C Orasch C Livermore DM Averbuch D Cordonnier C Aetiology and resistance in bacteraemias among adult and paediatric haematology and cancer patients J Inf Secur 2014 68 4 321 331 10.1016/j.jinf.2013.12.006 \n9. Watkins RR Lemonovich TL Diagnosis and management of community-acquired pneumonia in adults Am Fam Physician 2011 83 11 1299 1306 21661712 \n10. Rudramurthy SM, Paul RA, Chakrabarti A, Mouton JW, Meis JF. Invasive Aspergillosis by Aspergillus flavus: Epidemiology, Diagnosis, Antifungal Resistance, and Management. J Fungi (Basel). 2019;5(3). 10.3390/jof5030055.\n11. Sugui JA Kwon-Chung KJ Juvvadi PR Latgé JP Steinbach WJ Aspergillus fumigatus and related species Cold Spring Harb Perspect Med 2014 5 2 a019786 10.1101/cshperspect.a019786 25377144 \n12. Eckerle I Ebinger D Gotthardt D Eberhardt R Schnabel PA Stremmel W Invasive Aspergillus fumigatus infection after plasmodium falciparum malaria in an immuno-competent host: case report and review of literature Malar J 2009 8 167 10.1186/1475-2875-8-167 19619319 \n13. Aruanno M, Glampedakis E, Lamoth F. Echinocandins for the Treatment of Invasive Aspergillosis: from Laboratory to Bedside. Antimicrob Agents Chemother. 2019;63(8). 10.1128/AAC.00399-19.\n14. Chew LC Maceda-Galang LM Tan YK Chakraborty B Thumboo J Pneumocystis jirovecii pneumonia in patients with autoimmune disease on high-dose glucocorticoid J Clin Rheumatol 2015 21 2 72 75 10.1097/RHU.0000000000000215 25710857 \n15. Jagannathan M The infectious danger of corticosteroids: a fatal case of Pneumocystis Jirovecii pneumonia in a non-HIV patient following corticosteroid use with prophylaxis Cureus. 2019 11 10 e5874 10.7759/cureus.5874 31763097 \n16. Li Y Ghannoum M Deng C Gao Y Zhu H Yu X Pneumocystis pneumonia in patients with inflammatory or autoimmune diseases: usefulness of lymphocyte subtyping Int J Infect Dis 2017 57 108 115 10.1016/j.ijid.2017.02.010 28223177 \n17. Song Y Ren Y Wang X Li R Recent advances in the diagnosis of Pneumocystis pneumonia Med Mycol J 2016 57 4 E111 E116 10.3314/mmj.16-00019 27904052 \n18. Cooley L Dendle C Wolf J Teh BW Chen SC Boutlis C Consensus guidelines for diagnosis, prophylaxis and Management of Pneumocystis Jirovecii Pneumonia in patients with Haematological and solid malignancies, 2014 Intern Med J 2014 44 12b 1350 1363 10.1111/imj.12599 25482745 \n19. Najafi N Kermani F Gholinejad Ghadi N Aghili SR Seifi Z Roilides E Fatal rhinocerebral mucormycosis in a patient with ulcerative colitis receiving azathioprine and corticosteroid Curr Med Mycol 2019 5 1 37 41 10.18502/cmm.5.1.536 31049457 \n20. Gerlach MM Lippmann N Kobelt L Petzold-Quinque S Ritter L Kiess W Possible pulmonary Rhizopus oryzae infection in a previously healthy child after a near-drowning incident Infection. 2016 44 3 361 364 10.1007/s15010-015-0839-x 26365402 \n21. Long Y Zhang Y Gong Y Sun R Su L Lin X Diagnosis of Sepsis with cell-free DNA by next-generation sequencing technology in ICU patients Arch Med Res 2016 47 5 365 371 10.1016/j.arcmed.2016.08.004 27751370 \n22. He BC Liu LL Chen BL Zhang F Su X The application of next-generation sequencing in diagnosing invasive pulmonary aspergillosis: three case reports Am J Transl Res 2019 11 4 2532 2539 31105860 \n23. Yamairi K Ido K Nakamura S Niki M Imoto W Shibata W Successful treatment of invasive pulmonary aspergillosis caused by Aspergillus felis, a cryptic species within the Aspergillus section Fumigati: a case report J Infect Chemother 2019 25 4 307 310 10.1016/j.jiac.2018.10.016 30503017 \n24. Yohe S Thyagarajan B Review of clinical next-generation sequencing Arch Pathol Lab Med 2017 141 11 1544 1557 10.5858/arpa.2016-0501-RA 28782984 \n25. Boers SA Jansen R Hays JP Understanding and overcoming the pitfalls and biases of next-generation sequencing (NGS) methods for use in the routine clinical microbiological diagnostic laboratory Eur J Clin Microbiol Infect Dis 2019 38 6 1059 1070 10.1007/s10096-019-03520-3 30834996\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2334",
"issue": "20(1)",
"journal": "BMC infectious diseases",
"keywords": "Bronchoalveolar lavage fluid; Next-generation sequencing; Pneumonia",
"medline_ta": "BMC Infect Dis",
"mesh_terms": "D000935:Antifungal Agents; D001232:Aspergillus fumigatus; D001992:Bronchoalveolar Lavage Fluid; D004271:DNA, Fungal; D003882:Dermatomyositis; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008168:Lung; D008172:Lung Diseases, Fungal; D008297:Male; D008875:Middle Aged; D045363:Pneumocystis carinii; D012233:Rhizopus; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "100968551",
"other_id": null,
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"pmc": null,
"pmid": "32807082",
"pubdate": "2020-08-17",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "31279813;27904052;26611557;26893311;30503017;31105860;24370562;32096127;31266196;31763097;31398860;19619319;28782984;23347212;26365402;30834996;25377144;28223177;25710857;25482745;31138565;21661712;31049457;27751370;26197213",
"title": "Next-generation sequencing technology for detecting pulmonary fungal infection in bronchoalveolar lavage fluid of a patient with dermatomyositis: a case report and literature review.",
"title_normalized": "next generation sequencing technology for detecting pulmonary fungal infection in bronchoalveolar lavage fluid of a patient with dermatomyositis a case report and literature review"
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"companynumb": "CN-PFIZER INC-2020442958",
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"abstract": "Bacterial parotitis is a common childhood disease with a favorable outcome. Staphylococcus aureus is the most frequently involved pathogen. Clinical presentation in adult patients can be misleading, Onset occurs in patients with multiple comorbidities, making diagnosis difficult--particularly in ICU. Different pathogens are found in adults with worse outcomes observed. We report here the case of a critically ill patient and discuss diagnosis and management of bacterial parotitis.",
"affiliations": "Service d'anesthésie-réanimation, université de Lyon, CHU Lyon-Sud, 415, chemin du grand-Revoyet, 69495 Pierre-Bénite, France. Electronic address: olivia.vassal@gmail.com.",
"authors": "Vassal|O|O|;Bernet|C|C|;Wallet|F|F|;Friggeri|A|A|;Piriou|V|V|",
"chemical_list": "D000900:Anti-Bacterial Agents; D007166:Immunosuppressive Agents; D016559:Tacrolimus",
"country": "France",
"delete": false,
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"issn_linking": "0750-7658",
"issue": "32(9)",
"journal": "Annales francaises d'anesthesie et de reanimation",
"keywords": "Antibiotherapy; Antibiothérapie; Bacterial parotitis; Parotidite bactérienne aiguë; Pseudomonas aeruginosa",
"medline_ta": "Ann Fr Anesth Reanim",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D003422:Critical Care; D004569:Electroencephalography; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D008279:Magnetic Resonance Imaging; D008297:Male; D008826:Microbial Sensitivity Tests; D010306:Parotid Gland; D010309:Parotitis; D011552:Pseudomonas Infections; D011550:Pseudomonas aeruginosa; D013203:Staphylococcal Infections; D016559:Tacrolimus",
"nlm_unique_id": "8213275",
"other_id": null,
"pages": "615-7",
"pmc": null,
"pmid": "23948025",
"pubdate": "2013-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bacterial parotitis in an immunocompromised patient in adult ICU.",
"title_normalized": "bacterial parotitis in an immunocompromised patient in adult icu"
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"companynumb": "PHHY2014FR122904",
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"occurcountry": "FR",
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"activesubstancename": "UNSPECIFIED INGREDIENT"
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{
"abstract": "BACKGROUND\nDermatomyositis, an inflammatory myopathy with cutaneous involvement, is associated with malignancy and often manifests paraneoplastically. While co-occurrence with small cell carcinoma is well attested, primary lung adenocarcinoma, which may present as focal ground-glass opacification on computed tomography of the thorax, is less frequently coincident.\n\n\nMETHODS\nWe report the case of a 72-year-old female patient with dermatomyositis - treated with a combination of prednisone, methotrexate, and intravenous immunoglobulin - and an indolent, subsolid, non-hypermetabolic pulmonary lesion, which was determined to be invasive primary lung adenocarcinoma. Supporting a paraneoplastic basis, immunosuppressive therapy was discontinued following tumor excision without relapse of signs or symptoms of dermatomyositis.\n\n\nCONCLUSIONS\nWhile dermatomyositis prodromal to lung adenocarcinoma is not without precedent, association with an indolent, subsolid lesion has, to the best of our knowledge, not been reported. The case described herein illustrates the importance of maintaining a high index of suspicion for malignancy in the setting of dermatomyositis.",
"affiliations": "Stanford University School of Medicine, Stanford, USA.;Division of Thoracic Surgery, Stanford University School of Medicine, Falk Building, 300 Pasteur Drive, Stanford, 94305, USA.;Division of Oncology, Stanford University School of Medicine / Stanford Cancer Institute, Stanford, USA.;Division of Hospital Medicine, Stanford University School of Medicine, Stanford, USA.;Division of Thoracic Surgery, Stanford University School of Medicine, Falk Building, 300 Pasteur Drive, Stanford, 94305, USA. natalielui@stanford.edu.",
"authors": "Beel|Andrew J|AJ|;Demos|David S|DS|;Chung|Alfred|A|;Liao|Charles|C|;Lui|Natalie S|NS|http://orcid.org/0000-0002-6602-6372",
"chemical_list": null,
"country": "England",
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"doi": "10.1186/s13019-018-0705-x",
"fulltext": "\n==== Front\nJ Cardiothorac SurgJ Cardiothorac SurgJournal of Cardiothoracic Surgery1749-8090BioMed Central London 70510.1186/s13019-018-0705-xCase ReportGround-glass opacity heralding invasive lung adenocarcinoma with prodromal dermatomyositis: a case report Beel Andrew J. beelaj@stanford.edu 1Demos David S. ddemosmd@outlook.com 2Chung Alfred alfchung@stanford.edu 3Liao Charles cliao9@stanford.edu 4http://orcid.org/0000-0002-6602-6372Lui Natalie S. natalielui@stanford.edu 21 0000000419368956grid.168010.eStanford University School of Medicine, Stanford, USA 2 0000000419368956grid.168010.eDivision of Thoracic Surgery, Stanford University School of Medicine, Falk Building, 300 Pasteur Drive, Stanford, 94305 USA 3 0000000419368956grid.168010.eDivision of Oncology, Stanford University School of Medicine / Stanford Cancer Institute, Stanford, USA 4 0000000419368956grid.168010.eDivision of Hospital Medicine, Stanford University School of Medicine, Stanford, USA 7 2 2018 7 2 2018 2018 13 208 11 2017 24 1 2018 © The Author(s) 2018Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nDermatomyositis, an inflammatory myopathy with cutaneous involvement, is associated with malignancy and often manifests paraneoplastically. While co-occurrence with small cell carcinoma is well attested, primary lung adenocarcinoma, which may present as focal ground-glass opacification on computed tomography of the thorax, is less frequently coincident.\n\nCase presentation\nWe report the case of a 72-year-old female patient with dermatomyositis — treated with a combination of prednisone, methotrexate, and intravenous immunoglobulin — and an indolent, subsolid, non-hypermetabolic pulmonary lesion, which was determined to be invasive primary lung adenocarcinoma. Supporting a paraneoplastic basis, immunosuppressive therapy was discontinued following tumor excision without relapse of signs or symptoms of dermatomyositis.\n\nConclusions\nWhile dermatomyositis prodromal to lung adenocarcinoma is not without precedent, association with an indolent, subsolid lesion has, to the best of our knowledge, not been reported. The case described herein illustrates the importance of maintaining a high index of suspicion for malignancy in the setting of dermatomyositis.\n\nKeywords\nDermatomyositisLung adenocarcinomaSubsolidGround-glass opacityhttp://dx.doi.org/10.13039/100000002National Institutes of HealthT32-GM007365issue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nIdiopathic inflammatory myopathies are a group of diseases of uncertain but presumed autoimmune etiology characterized by weakness and inflammation of the proximal musculature, and include polymyositis (PM), dermatomyositis (DM), sporadic inclusion body myositis, and necrotizing autoimmune myopathy. The best characterized among them, PM and DM, effect insidious dysfunction of the proximal musculature in a symmetric fashion, the progression of which may produce such complications as dysphagia and respiratory failure. Despite their similarities, DM distinguishes itself from PM through a plethora of cutaneous manifestations, including “Gottron’s papules” on the dorsal aspects of the phalangeal joints, the periorbital heliotrope eruption, and rashes distributed characteristically over the back (“shawl sign”), chest (“V sign”), or thighs (“holster sign”) [1]. Since the diagnostic codification of DM and PM by Bohan and Peter [2], many proposals for systematizing the diagnosis of these disorders have been advanced (e.g., [3]). In addition to clinical features, elevations in serum enzyme levels, and histologic and electromyographic evidence, diagnosis is commonly supported by the presence of characteristic autoantibodies, the nature of which may connote a particular disease subtype or impart prognostic significance [4]. Therapy is normally directed toward immunosuppression, by high-dose corticosteroids alone or in conjunction with steroid-sparing agents such as methotrexate and azathioprine, with addition of further agents (e.g., rituximab, intravenous immunoglobulin (IVIG)) as required for refractory illness. Given the association of malignancy with both PM and DM, particularly the latter [5, 6], a thorough diagnostic work-up for its presence is inevitably prompted by a diagnosis of either condition. In many cases, an occult neoplasm is detected at an early stage and with a higher likelihood of successful treatment. While the lung is a frequent site for primary, myositis-associated malignancy, presentation as a subsolid lesion has not been previously reported. We describe herein a case in which DM was the presenting manifestation of invasive adenocarcinoma of the lung, detected by thin-section computed tomography as an indolent nodule with predominantly ground-glass attenuation.\n\nCase presentation\nA 72-year-old woman with a history of Graves’ disease treated by radioiodine ablation and no smoking history presented with subacute proximal muscle weakness, accompanied by myalgia and a rash. Dermatologic examination was significant for non-pruritic, macular erythema over the posterior arms; discrete papules on the second and fourth distal interphalangeal joints of the left hand; dusky, reticulated erythema involving the proximal, lateral thighs (evoking the “holster sign” [7]); and linear, erythematous plaques extending inferiorly from the nape. Elevations were noted in the levels of creatine kinase (CK), aldolase, lactate dehydrogenase (LDH), aspartate transaminase (AST), and alanine transaminase (ALT). Suspicion for dermatomyositis prompted initiation of high-dose prednisone (1 mg/kg) on hospital day 2, in spite of which symptoms failed to improve and enzyme levels continued to rise, peaking on hospital day 8 (cf. Fig. 1; peak values were as follows: CK 3108 U/L, aldolase 25.9 U/L, LDH 594 U/L, AST 252 U/L, ALT 344 U/L). Immune serology studies, encompassing general and myositis-specific antibodies, were uniformly negative (ANA, Jo-1, PL-12, PL-7, EJ, OJ, Mi-2, SRP, Ku, U2 snRNP, PM/Scl). Electromyography revealed fibrillations and positive sharp waves, indicative of an irritative myopathic process affecting the proximal muscles. Muscle biopsy demonstrated immune myopathy with perimysial pathology (IMPP). Given the presumptive diagnosis of dermatomyositis, a malignancy work-up was initiated, and computed tomography (CT) of the thorax revealed a 2.1-cm subsolid nodule in the right middle lobe. Relative to a CT scan acquired four years earlier, the nodule was stable in size but had progressed in fractional solidity from 15% (i.e., predominantly ground-glass opacified) to 90% (Fig. 2). PET/CT showed minimal 18F-fluorodeoxyglucose (FDG) avidity (standardized uptake value (SUV) 1.3) in the right middle lobe lesion, consistent with its indolent nature, and no evidence of lymph node or metastatic disease. Given the refractoriness of symptoms to high-dose corticosteroids and biopsy evidence of a DM-spectrum process (IMPP), methotrexate (gradually dose-escalated from 7.5 to 15 mg weekly) and IVIG (2 g/kg monthly) were initiated on hospital day 11. Despite the indolence of the pulmonary lesion, the heightened risk of malignancy in the setting of presumed DM prompted thoracoscopic right middle lobectomy and mediastinal lymph node dissection, which the patient underwent on hospital day 16, after spirometry and diffusion capacity testing demonstrated satisfactory pulmonary function. Histopathologic analysis revealed a 2.1-cm, moderately differentiated, invasive adenocarcinoma, arranged in papillary (60%), acinar (30%), micropapillary (5%), and lepidic (5%) proliferative patterns. There was one intraparenchymal node involved by direct extension; level 4R, 7, and 11 lymph nodes were negative for malignancy. Her stage was pT1cN1M0 or IIB (AJCC 7th edition [8]). Molecular studies of the tumor (specifically, short-read sequencing of a target-enriched library of 130 genes that are frequently mutated in solid tumors) disclosed a constitutively activating mutation of EGFR (c.2156G>C; p.G719A) and a mutation of β-catenin (CTNNB1) within the GSK3 β (GSK3B) phosphorylation region (c.97T>C, p.S33P), with variant allele fractions of 23.5 and 8.6%, respectively. Following surgical excision of the lung tumor, the patient experienced a dramatic improvement in muscle strength and disappearance of the rash. Deltoid and hip-flexor strength increased from 5/10 at the time of surgery to 8/10 within a week. Her enzyme levels continued to decline and were all within the normal range at the time of discharge on hospital day 29. Upon discharge, the corticosteroid dose was tapered from 1 to 0.083 mg/kg/d over a one-month period and the methotrexate discontinued, without relapse of dermatomyositis symptoms; the corticosteroid and IVIG were both discontinued approximately one month thereafter. At the time of writing, the patient continued to show improvements in functional status, and had recently discontinued adjuvant chemotherapy with carboplatin and pemetrexed owing to toxicities.\nFig. 1 Serum creatine kinase levels are displayed with respect to the duration of hospitalization. The upper limit of normal (200 U/L) is indicated by the dashed horizontal line, while the onset of an intervention is indicated by a dashed vertical line. High-dose prednisone (1 mg/kg/d) was started on hospital day 2; methotrexate (MTX, 7.5 mg/week) and intravenous immunoglobulin (IVIG, 2 g/kg/mo) began on hospital day 11; and right middle lobectomy and mediastinal lymph node dissection took place on hospital day 16. Not shown are escalations of the methotrexate dose to 10 mg/week (hospital day 18) and 15 mg/week (hospital day 25), as well as discharge and commencement of the steroid taper, which coincided on hospital day 29\n\n\nFig. 2 Slices from chest CT scans acquired four years prior to (left) and at the time of presentation (right), demonstrating an indolent, subsolid lesion in the right middle lobe, the solid fraction of which evolved from 15% (left) to 90% (right)\n\n\n\nDiscussion\nAlthough the etiology of DM remains to be elucidated, both innate and adaptive arms of the immune system are thought to play important roles, and autoantibodies — classified as either nonspecific, myositis-associated, or myositis-specific — are found in as many as 80% of patients with PM or DM [9]. Numerous myositis-specific autoantigens have been described, including the signal recognition particle (SRP), the helicase Mi-2, and a battery of aminoacyl tRNA synthetases (e.g., histidyl [Jo-1], threonyl [PL-7], alanyl [PL-12], isoleucyl [OJ], glycyl [EJ]), and autoantibodies directed against each are thought to define distinct myositis syndromes: antisynthetase syndrome, for instance, is strongly associated with interstitial lung disease, while Mi-2 autoantibodies are thought to confer reduced risk for a myositis-associated malignancy [10]. Assaying serum for a set of autoantibodies representing the three aforementioned classes was uniformly negative in the patient described in this report. As a putative autoimmune disease, DM has also been found in association with other autoimmune conditions, including Graves’ disease [11, 12], an association observed in the present case.\n\nThe incidence of malignancy is elevated in the setting of DM, an association first recognized in 1916 [13, 14] and confirmed by many retrospective analyses, with standardized incidence ratios (SIRs) typically ranging from 3 to 6 [15–18]. The temporal association of diagnoses of DM and malignancy [16, 18, 19], and the tendency for resolution of DM symptoms upon treatment of the underlying malignancy [6, 20] are consistent with the notion that malignancy-associated DM is a paraneoplastic phenomenon. While the mechanism underlying the association remains ill-defined, tumoral expression of myositis autoantigens has been proposed as a link whereby an immune-response directed against cancer cells leads to inflammatory destruction of antigenically similar muscle tissue [21]. The association of DM with cancer is broad, comprising many histologic types and tissues of origin, the latter of which tends to reflect the anatomic distribution of cancers observed in a population [22]. Accordingly, the lung is a common site of DM-associated cancer among western populations [15]. A review of 24 cases of coincident PM/DM and primary lung cancer spanning the period 1947–2000 found small cell and squamous cell carcinomas to be the most common histologic types [23]. Since then, myriad reports of DM-associated lung cancer have appeared in the literature [24–53]. Combining these reports with those of Fujita et al. [23] gives nearly 50 cases of dermatomyositis-associated, histologically determined lung cancer over the past 70 years, the aggregate analysis of which is presented in Table 1 (many more cases of DM-associated lung cancer have been reported without histologic characterization, e.g., [22]). The most commonly reported histologic type of lung cancer associated with DM is small cell carcinoma (approximately 44%), which is followed by squamous cell carcinoma and adenocarcinoma, each of which account for approximately 17% of reported cases. Given the small, non-systematic sample and the possibility of reporting bias, these frequencies should not be misconstrued as an accurate reflection of the association of lung-cancer histology with dermatomyositis. Among these cases, a history of smoking is common, and in several, including the present one, paraneoplasticity is suggested by the remission of DM shortly after treatment of the associated lung cancer [32, 33, 44, 47].\nTable 1 Summary of histologic classification of DM-associated lung malignancies reported in the literature (1947–2017) [23–53]\n\nHistology\tCases\tFrequency\t\nSmall cell carcinoma\t21\t43.8%\t\nSquamous cell carcinoma\t8\t16.7%\t\nAdenocarcinoma\t8\t16.7%\t\nNeuroendocrine\t3\t6.3%\t\nUndifferentiated\t2\t4.2%\t\nOther\t6\t12.5%\t\nTotal\t48\t100.0%\t\nThe category “other” comprises mixed histology (e.g., adenosquamous), anaplastic cell carcinoma, alveolar cell carcinoma, giant cell carcinoma, and non-small cell carcinoma not otherwise specified\n\n\n\nWhile previous studies have documented the association between histologic types of lung cancer and DM, little attention has been paid to its association with the molecular basis of malignancy. Genetic analysis of the primary tumor in the present case revealed mutation of the gene encoding EGFR, an event reported to occur in about 10% of cases of non-small cell lung cancer [54]. Point mutations of the codon for G719 account for about 3% of all EGFR mutations in lung cancer; are more common among non-smokers, females, and East Asians [55]; and predict sensitivity to EGFR tyrosine kinase inhibitors [56]. In addition, a mutation was found in the GSK3B phosphorylation region of β-catenin (S33P, which leads to constitutive transactivation of T-cell factor and lymphoid enhancer factor target genes). While β-catenin has been reported to be rarely subject to mutation in lung cancer [57], recent evidence suggests an important role for Wnt/ β-catenin signaling in the progression from lung adenoma to adenocarcinoma [58]. No mutations were found in various other genes implicated in lung adenocarcinoma, including KRAS, ALK, MET, RET, CCND1, TP53, KEAP1, MAP2K1, RIT1, PIK3CA, U2AF1, MDM2, and SETD2 [59]. Whether mutations such as the ones observed bear any relation to paraneoplastic DM remains to be determined.\n\nFinally, the attenuation characteristics of the lesion observed in this case deserve remark inasmuch as an association thereof with paraneoplastic DM is, to our knowledge, without precedent. Ground-glass opacification (GGO) describes an increase in X-ray attenuation which, unlike consolidation, does not obscure underlying vascular and bronchial architecture [60]. Although the finding is generally non-specific, persistence and focality together suggest malignancy, particularly adenocarcinoma or its precursors, the histologic type with which circumscribed subsolid lesions are almost exclusively associated [61, 62]. As a category, subsolid lesions comprise both pure ground-glass-opacified nodules and those with a solid component (part-solid); the GGO component is thought to signify preinvasive growth (atypical adenomatous hyperplasia and adenocarcinoma in situ), and the solid component a nucleus of invasive adenocarcinoma [63]. The consolidation-to-tumor-ratio (CTR), typically defined as the ratio of the maximum linear extents of the solid fraction of the tumor and of the tumor itself, may be used to predict the invasiveness and likelihood of progression of a subsolid lesion [64]. Despite prior claims of association between GGO and EGFR mutation status, a recent meta-analysis found statistically significant association of EGFR mutation status not with pure GGO lesions but with part-solid ones [65]. The majority of subsolid lesions are stable in size; those that grow do so indolently, with reported volume doubling times of 600–900 and 300–500 days for pure GGO and part-solid lesions, respectively [63]. Their typically languorous course explains observations of insignificant FDG uptake [66] — on account of which SUVmax thresholds must be adjusted for proper interpretation [62] — and moreover demands prolonged (three to five years) surveillance by CT [67, 68]. Indeed, among a cohort of 218 patients with subsolid nodules that had been stable for 3 years, 14 (6.4%) experienced subsequent growth [69], underscoring the need for vigilance. PET/CT, biopsy, and resection should be pursued for nodules having solid components greater than 8 mm in length, expanding consolidation, or other concerning features [68]. Although sublobar resection has been demonstrated to be equally effective to lobectomy for subsolid nodules [67], the higher recurrence rate for part-solid lesions [70] should be taken into consideration when determining surgical management. In the present case, an indolent GGO lesion evolved within four years to EGFR-mutated, non-hypermetabolic, invasive adenocarcinoma, and is, to our knowledge, the first case of a GGO-predominant pulmonary lesion manifesting as DM.\n\nConclusions\nThe case described herein illustrates the importance of maintaining a high index of suspicion for malignancy in the setting of dermatomyositis. The occurrence of a subsolid, indolent, non-hypermetabolic pulmonary lesion, approximately stable in size over a period of four years, in a lifetime nonsmoker may have seemed an unlikely trigger for dermatomyositis, and misapprehension of its significance would have delayed definitive treatment.\n\nAbbreviations\nALTAlanine transaminase\n\nASTAspartate transaminase\n\nCKCreatine kinase\n\nCTComputed tomography\n\nCTRConsolidation-tumor ratio\n\nDMDermatomyositis\n\nEGFREpidermal growth factor receptor\n\nFDG18F-fluorodeoxyglucose\n\nGGOGround-glass opacity\n\nIMPPImmune myopathy with perimysial pathology\n\nIVIGIntravenous immunoglobulin\n\nLDHLactate dehydrogenase\n\nPETPositron emission tomography\n\nPMPolymyositis\n\nSIRStandardized incidence ratio\n\nSUVStandardized uptake value\n\nAcknowledgements\nNone declared.\n\nFunding\nThe study was supported by Stanford Medical Scientist Training Program NIH grant T32-GM007365 (AJB).\n\nAvailability of data and materials\nData sharing is not applicable to this article as no datasets were generated or analyzed during the current study.\n\nAuthors’ contributions\nAJB, DSD, and NLS contributed to design, data collection and analysis, and drafting of the manuscript. All authors contributed to revision of the manuscript. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nInformed consent for publication was obtained and is available for review by the editor.\n\nCompeting interests\nNone declared.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1 Callen JP Cutaneous manifestations of dermatomyositis and their management Curr Rheumatol Rep 2010 12 3 192 7 10.1007/s11926-010-0100-7 20425525 \n2 Bohan A Peter JB Polymyositis and dermatomyositis (first of two parts) N Engl J Med 1975 292 7 344 7 10.1056/NEJM197502132920706 1090839 \n3 Dalakas MC Hohlfeld R Polymyositis and dermatomyositis Lancet 2003 362 9388 971 82 10.1016/S0140-6736(03)14368-1 14511932 \n4 Targoff IN Humoral immunity in polymyositis/dermatomyositis J Invest Dermatol 1993 100 1 S116 23 10.1038/jid.1993.34 \n5 Sigurgeirsson B Lindelof B Edhag O Allander E Risk of cancer in patients with dermatomyositis or polymyositis. 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development: EGFR gene and cancer FEBS J 2010 277 2 301 8 10.1111/j.1742-4658.2009.07448.x 19922469 \n56 Lynch TJ Bell DW Sordella R Gurubhagavatula S Okimoto RA Brannigan BW Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib N Engl J Med 2004 350 21 2129 39 10.1056/NEJMoa040938 15118073 \n57 Shigemitsu K Sekido Y Usami N Mori S Sato M Horio Y Genetic alteration of the beta-catenin gene (CTNNB1) in human lung cancer and malignant mesothelioma and identification of a new 3p21.3 homozygous deletion Oncogene 2001 20 31 4249 57 10.1038/sj.onc.1204557 11464291 \n58 Tammela T Sanchez-Rivera FJ Cetinbas NM Wu K Joshi NS Helenius K A Wnt-producing niche drives proliferative potential and progression in lung adenocarcinoma Nature 2017 545 7654 355 9 10.1038/nature22334 28489818 \n59 Network CGAR Comprehensive molecular profiling of lung adenocarcinoma Nature 2014 511 7511 543 50 10.1038/nature13385 25079552 \n60 Hansell DM Bankier AA MacMahon H McLoud TC Muller NL Remy J Fleischner Society: glossary of terms for thoracic imaging Radiology 2008 246 3 697 722 10.1148/radiol.2462070712 18195376 \n61 Seki N Sawada S Nakata M Inoue T Nishimura R Segawa Y Lung cancer with localized ground-glass attenuation represents early-stage adenocarcinoma in nonsmokers J Thorac Oncol 2008 3 5 483 90 10.1097/JTO.0b013e31816a4994 18449000 \n62 Ichinose J Kohno T Fujimori S Harano T Suzuki S Fujii T Invasiveness and malignant potential of pulmonary lesions presenting as pure ground-glass opacities Ann Thorac Cardiovasc Surg 2014 20 5 347 52 10.5761/atcs.oa.13-00005 24088912 \n63 Kobayashi Y Mitsudomi T Management of ground-glass opacities: should all pulmonary lesions with ground-glass opacity be surgically resected? Transl Lung Cancer Res 2013 2 5 354 63 25806254 \n64 Asamura H Hishida T Suzuki K Koike T Nakamura K Kusumoto M Radiographically determined noninvasive adenocarcinoma of the lung: survival outcomes of Japan Clinical Oncology Group 0201 J Thorac Cardiovasc Surg 2013 146 1 24 30 10.1016/j.jtcvs.2012.12.047 23398645 \n65 Cheng Z Shan F Yang Y Shi Y Zhang Z CT characteristics of non-small cell lung cancer with epidermal growth factor receptor mutation: a systematic review and meta-analysis BMC Med Imaging 2017 17 1 5 10.1186/s12880-016-0175-3 28068946 \n66 Sim HJ Choi SH Chae EJ Kim HR Kim YH Kim DK Surgical management of pulmonary adenocarcinoma presenting as a pure ground-glass nodule Eur J Cardiothorac Surg 2014 46 4 632 6 10.1093/ejcts/ezu007 24566849 \n67 Callister ME Baldwin DR Akram AR Barnard S Cane P Draffan J British Thoracic Society guidelines for the investigation and management of pulmonary nodules Thorax 2015 70 Suppl 2 ii1 54 10.1136/thoraxjnl-2015-207168 26082159 \n68 MacMahon H Naidich DP Goo JM Lee KS Leung AN Mayo JR Guidelines for management of incidental pulmonary nodules detected on CT images: from the Fleischner Society Radiology 2017 284 1 228 43 10.1148/radiol.2017161659 28240562 \n69 Cho J Kim ES Kim SJ Lee YJ Park JS Cho YJ Long-term follow-up of small pulmonary ground-glass nodules stable for 3 years: implications of the proper follow-up period and risk factors for subsequent growth J Thorac Oncol 2016 11 9 1453 9 10.1016/j.jtho.2016.05.026 27287413 \n70 Cho JH Choi YS Kim J Kim HK Zo JI Shim YM Long-term outcomes of wedge resection for pulmonary ground-glass opacity nodules Ann Thorac Surg 2015 99 1 218 22 10.1016/j.athoracsur.2014.07.068 25440277\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1749-8090",
"issue": "13(1)",
"journal": "Journal of cardiothoracic surgery",
"keywords": "Dermatomyositis; Ground-glass opacity; Lung adenocarcinoma; Subsolid",
"medline_ta": "J Cardiothorac Surg",
"mesh_terms": "D000230:Adenocarcinoma; D000077192:Adenocarcinoma of Lung; D000368:Aged; D003882:Dermatomyositis; D005260:Female; D006801:Humans; D008168:Lung; D008175:Lung Neoplasms; D009364:Neoplasm Recurrence, Local; D010257:Paraneoplastic Syndromes; D014057:Tomography, X-Ray Computed",
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"pages": "20",
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"pmid": "29415746",
"pubdate": "2018-02-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Ground-glass opacity heralding invasive lung adenocarcinoma with prodromal dermatomyositis: a case report.",
"title_normalized": "ground glass opacity heralding invasive lung adenocarcinoma with prodromal dermatomyositis a case report"
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"abstract": "The abnormal allocation of nodules of grey matter in areas of the brain or spinal cord that should physiologically be occupied by white matter characterizes a neural defect called Grey Matter Heterotopia (GMH). The improvement of MRI techniques has enabled a deeper understanding of the neuropathological bases and epidemiology of such a condition. Among its major manifestations, there is the onset of epileptic seizures, mild intellectual disability, impairments in executive functioning, neurodevelopmental disorders; less frequently GMH has been found associated with depression, anxiety, and schizophrenia. Despite the clinical interest in GMH, no studies have considered the possible forensic and criminological implications of this condition. In the current study, we present a case of GMH in a young male defendant accused of having seriously injured a schoolmate as a reaction to bullying behavior. Neuropsychological and instrumental evidence converge in showing prevalence for the defendant's adoption of repressive responses to stressors, and difficulties to inhibit undesirable behavior at the long run. In the case at hand, the massive stress induced by the exposition to bullying behavior undermined inhibitory control, hence an impulsive and disproportionate reaction took place. Without appropriate therapeutic control, this reactive behavior might take place again. As a consequence, the forensic assessment recommended that the defendant was held partially liable only but that there was likelihood of recidivism. We discuss this single-case evidence for a possible role of GMH in the adoption of dyscontrolled responses to stressors, and the relevance of GMH diagnosis in forensic proceedings.",
"affiliations": "Department of Education, Psychology, Communication, University of Bari \"Aldo Moro\", Bari, Italy.;Department of Basic Medical Science, Neuroscience and Sense Organs University of Bari \"Aldo Moro\", Bari, Italy.",
"authors": "Curci|Antonietta|A|;Rampino|Antonio|A|",
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"doi": "10.3389/fpsyt.2020.00261",
"fulltext": "\n==== Front\nFront Psychiatry\nFront Psychiatry\nFront. Psychiatry\nFrontiers in Psychiatry\n1664-0640 Frontiers Media S.A. \n\n10.3389/fpsyt.2020.00261\nPsychiatry\nCase Report\nGrey Matter Heterotopia and Criminal Responsibility in a Case of Personal Injury Defense\nCurci Antonietta 1* Rampino Antonio 2 1Department of Education, Psychology, Communication, University of Bari \"Aldo Moro\", Bari, Italy\n2Department of Basic Medical Science, Neuroscience and Sense Organs University of Bari “Aldo Moro”, Bari, Italy\n\nEdited by: Johann Brink, University of British Columbia, Canada\n\nReviewed by: Claudio de'Sperati, Vita-Salute San Raffaele University, Italy; Stefano Ferracuti, Sapienza University of Rome, Italy\n\n*Correspondence: Antonietta Curci, antonietta.curci@uniba.itThis article was submitted to Forensic Psychiatry, a section of the journal Frontiers in Psychiatry\n\n\n01 4 2020 \n2020 \n11 26104 7 2019 17 3 2020 Copyright © 2020 Curci and Rampino2020Curci and RampinoThis 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.The abnormal allocation of nodules of grey matter in areas of the brain or spinal cord that should physiologically be occupied by white matter characterizes a neural defect called Grey Matter Heterotopia (GMH). The improvement of MRI techniques has enabled a deeper understanding of the neuropathological bases and epidemiology of such a condition. Among its major manifestations, there is the onset of epileptic seizures, mild intellectual disability, impairments in executive functioning, neurodevelopmental disorders; less frequently GMH has been found associated with depression, anxiety, and schizophrenia. Despite the clinical interest in GMH, no studies have considered the possible forensic and criminological implications of this condition. In the current study, we present a case of GMH in a young male defendant accused of having seriously injured a schoolmate as a reaction to bullying behavior. Neuropsychological and instrumental evidence converge in showing prevalence for the defendant's adoption of repressive responses to stressors, and difficulties to inhibit undesirable behavior at the long run. In the case at hand, the massive stress induced by the exposition to bullying behavior undermined inhibitory control, hence an impulsive and disproportionate reaction took place. Without appropriate therapeutic control, this reactive behavior might take place again. As a consequence, the forensic assessment recommended that the defendant was held partially liable only but that there was likelihood of recidivism. We discuss this single-case evidence for a possible role of GMH in the adoption of dyscontrolled responses to stressors, and the relevance of GMH diagnosis in forensic proceedings.\n\nGrey Matter Heterotopianeurodevelopmental disorderepilepsyinhibitory controlimpulsivity\n==== Body\nBackground\nGrey Matter Heterotopia (GMH) is a neural defect due to an anomalous development of the cerebral cortex. It is characterized by the presence of small or extended portions of grey matter in areas of the brain or spinal cord that should physiologically be occupied by white matter. Subependymal (periventricular) heterotopia consists of an abnormal allocation of nodules of grey matter within the wall of lateral ventricles in a sub-ependymal position. Studies demonstrate that genetic and epigenetic factors may contribute to the aetiology of this condition. The first include mutations of the X-linked FNLA gene (Xq28), coding for the Filamin, an actin-binding protein that crosslinks actin filaments and links actin filaments to membrane glycoproteins. Glycoproteins are involved in remodeling of the cytoskeleton and effect changes in cell shape and migration. Rare mutations or microdeletion of autosomal genes (1, 2) may result further in syndromic disorders. Among epigenetic factors, perinatal stressors, such as hypoxic-ischemic events occurring during migration of neuroblasts, at 7-16 weeks of fetal development, may play a crucial role in the etiopathogenesis of GMH (3).\n\nNeuroimaging techniques have enabled a deeper understanding of the neuropathological bases of GMH, while the epidemiology of such a condition has been widely underestimated in pre-MRI era. For example, rather surprisingly, MRI methodologies have demonstrated that about 15% of brain cortical malformations due to alteration of cortical development are due to GMH and more than 2% of epileptic patients may suffer from GMH (4). Indeed, the major clinical manifestation of GMH is epilepsy. Likely, such a condition emerges from the cytoarchitectural modification that heterotopic migration of neurons determines in grey matter, predictably resulting in a number of electrophysiological modification, including the new formation of epileptogenic foci (5). Along with epilepsy, further manifestations of GMH are represented by mild intellectual disability (ID) and dyslexia, involving impairments in reading ability, processing speed, and executive functioning (4, 6). Moreover, because of the potentially disruptive impact of heterotopic neuronal migration, a number of neurodevelopmental disorders, such as autism (7) and ADHD (8), are associated with GMH. Less frequently, reports of depression (9), anxiety (6), and schizophrenia (1, 10) have been found in comorbidity with GMH (see Table 1 for a detailed description of the possible neurological and psychiatric comorbidities of GMH).\n\nTable 1 List of principal neurological and psychiatric conditions associated with GMH) (1, 4, 5).\n\nPRINCIPAL NEUROLOGICAL CONDITIONS ASSOCIATED WITH GMH\t\n\nEpilepsy\n\nPartial, complex, atypical absence\n\nDrop attacks\n\nMotor skill loss\n\n\t\nPRINCIPAL PSYCHIATRIC CONDITIONS ASSOCIATED WITH GMH\t\n\nDelirium\n\nSchizophrenia\n\nSchizoaffective Disorder\n\nBipolar Disorder\n\nMajor Depressive Disorder\n\nAutism Spectrum Disorder\n\nAttention-Deficits Hyperactivity Disorder\n\nIntellectual Disability\n\n\t\nTo our knowledge, so far none of GMH clinical manifestations has been investigated for its possible associations with forensic and criminological outcomes. However, in children and adolescents with ADHD and other neurodevelopmental disorders, externalizing and antisocial behavioral manifestations might occur, which seldom anticipate more serious criminal behavior in adulthood (11–13). The lack of impulse control that characterizes many of these behaviors poses a challenge for the forensic expert in the evaluation of the criminal liability of an offender and the possible strategies for preventing recidivism in specific cases.\n\nHere we present a case of GMH in a young male defendant (E.L.) accused of having seriously injured a schoolmate after receiving some bullying behavior. We will show here the diagnostic difficulties in the clinical history of E.L. with respect to behavioral and neuropsychiatric manifestations of GMH. We will discuss how these manifestations are related with the committed injury as an issue for the forensic evaluation of the defendant's accountability in criminal trial and prevention of possible recidivism.\n\nCase Presentation\nE.L. is an 18-year-old Caucasian male, who is accused of having severely wounded another student in a scuffle after school two years earlier. Due to the physical conflict, E.L.'s schoolmate reported an injury of his left eyeball, and E.L. was charged with causing serious personal injuries.\n\nE.L. has a complex clinical history. Born at term of natural childbirth, he was artificially fed, and his development followed regular phases until the age of 2. In the course of subsequent months, first symptoms of a delay in language development emerged, and, at the age of 4, E.L. was diagnosed with an Autism Spectrum Disorder (ASD). While attending the first years of primary school, he showed good interactions with peers, though experiencing significant learning difficulties. According to his parents' accounts and consistent with school reports, sometimes E.L. appeared restless and hyperactive. Clinical assessment identified mild cognitive disability associated with language disorder, subsequently revised as learning disability associated with affective immaturity and scarce tolerance to frustrations. At the age of 8, E.L. was hospitalized for re-assessment of his diagnosis, which was indeed revised as a developmental mixed disorder with a major impairment of linguistic capacity. In the same period, E.L. experienced epileptiform seizures. At the age of 9, following a MRI, he was diagnosed with Grey Matter Heterotopia, while first problems of socialization appeared alongside: E.L. became a target of his peer social pressure and bullying to the extent that he decided to move school the year after.\n\nE.L. has a mild and submissive temperament, particularly wishful to establish meaningful friendship relationships, a trait of his personality that has paradoxically backfired with him becoming the object of bad jokes and mistreatments by his classmates and acquaintances. He has a very supportive family, with parents thoughtfully caring for his health and social concerns. Over the years, E.L. has undergone further diagnostic refinements, which progressively evidenced depressive tendencies and social withdrawal along with linguistic and cognitive disabilities and developmental emotional disorder. In medical records, the condition of E.L. is described as characterized by attention and memory lability especially in the school context, motor instability, affective immaturity, and difficulty in emotion regulation and inhibition (F80.8, F81.9, F93 ICD10). Within the overall picture, however, the clinical implications of GMH are left almost completely unconsidered except for their role in the emergence of epileptic seizures.\n\nThe troubles in adaptation and socialization led E.L. to experience severe episodes of social rejection and bullying, which made him feel profoundly sad and worthless. As an aggravation of this psychological condition, at the age of 16, seven months before the dispute with his schoolmate, he engaged in a suicidal attempt by ingesting an overdose of sleeping pills. He was hospitalized with the diagnosis of depression in a passive-dependent personality and thought disorders, started on antipsychotic treatment (aripiprazole, 10 ml per day). The therapeutic program increased his behavioral control, but negatively affected personal interests, energy, and socialization, so that the antipsychotic dosage was progressively reduced until complete discontinuation, which was reached a couple of months before the criminal conduct he was later charged with. On the day of the alleged offence, E.L. had a verbal dispute with one of his classmates for a trivial reason, and received verbal abuse in return. On leaving the school, E.L. found that girl along with her boyfriend and other schoolmates, waiting for him beyond the school gate threateningly staring at him. Frightened by the scene, E.L. tried to escape running as fast as he could, but he was intercepted and stopped by the boyfriend of his classmate who roughly blamed him for the dispute he had had with the girl few hours before. A scuffle ensued, and the two boys fell to the ground, with E.L. punching blindly a break through and free himself from people around him. Following the fight, E.L. reported small facial and knee injuries while his antagonist was diagnosed with an outbreak of his left eyeball. Shocked by the unpredictable evolution of the events, E.L. became progressively more aware of the severity of the injuries he had inflicted. Very soon, he started to feel guilty and became regretful. He repeatedly declared he had never intended to harm his mate so severely and explained his exclusive aim had been to escape the frightened situation he had found himself in. Rather interestingly, he also displayed an almost complete amnesia for the event and his running off.\n\nE.L. is submitted to expert examination following a Court order to establish his criminal liability at the time of the facts and the actual risk of recidivism. The psycho-forensic assessment included clinical interviews and test administration, the results of which are displayed in Table 1. Furthermore, E.L. underwent a structural Magnetic Resonance Imaging (sMRI) scan to ascertain the presence of a previously reported area of heterotopic grey matter in E.L.'s brain. MRI was performed on a GE Signa 3T scanner (GE Healthcare).\n\nAs Table 2 shows, E.L. appears to have a normal level of intelligence with mild impairment in processing speed and receptive linguistic capacities. He appears suspicious, with persistent persecutory thought contents, phobic ideas, and obsessive worries regarding the future. E.L. preferably adopts a defensive modality of coping with anger expression, with a dominance of repressive and avoidant tendencies. His affective state is dysphoric and characterized by high levels of anxiety. The neuropsychological assessment reveals a poor executive capacity of inhibiting dominant responses, set shifting, planning, and strategic control. However, E.L. appears able to choose and manage effective problem solving strategies, which do not imply space or time constraints. Finally, a low risk propensity is observed. The psychometric conclusions are consistent with evidence obtained through the clinical interviews.\n\nTable 2 Psychometric evaluation of E.L.\n\nTest\tScore\t\nTROG-2 (standard scores)\t95\t\nWAIS-IV (standard scores)\tIQ = 90; VC = 74; PR = 112; WM = 103; PS = 81\t\nMMPI-2 (T-scores)\tPa = 68; Pt = 68; Hs = 63; D = 60\t\nSTAI-Y (T-scores)\tY-1 = 90\nY-2 = 70\t\nSTAXI (T-scores)\tS-Anger = 49; T-Anger < 34; AX/In = 44; Ax/Out = 44; Ax/Con = 57; Ax/EX = 37\t\nBDI-II\t15\t\nFF (cut-off = 6)\t2.7\t\nTMT A-B\n(cut-off: A = 45”, B = 122”)\tA = 62”, B = 145”\t\nP-M (cut-off = 15.5”)\t86”\t\nToL (cut-off = 29)\t14\t\nEPMT (standard scores)\t113.8\t\nWCST (standard scores)\t100-108\t\nBART (cut-off: Orange = 3.5; Yellow = 12.3; Blue = 33.3)\tOrange = 2.77; Yellow = 3.67; Blue = 7.7\t\nStandard scores, T-scores, and cut-off were set-up according to Italian norms, when available. TROG-2, Test for Reception of Grammar-2 (14); WAIS-IV, Wechsler Adult Intelligence Scale IV; VC, Verbal Comprehension; PR, Perceptual Reasoning; WM, Working Memory; PS, Processing Speed (15); MMPI-2, Minnesota Multiphasic Personality Inventory 2 (16); STAI-Y, State-Trait Anxiety Inventory (17); STAXI, State-Trait Anger Inventory (18); BDI-II, Beck Depression Inventory-II (19); FF, Phonemic Fluency (20); TMT A-B, Trail Making Test A and B (21); P-M, Plus-Minus Test (22); ToL, Tower of London (23); EPMT, Elithorn Perceptual Maze Test (24); WCST, Wisconsin Card Sorting Test (25); BART, Balloon Analogue Risk Task (26).\n\nThe outcome of sMRI scanning confirms previous evidence of a sub-ependymal GMH in E.L.'s brain, excluding the presence of other morphological and/or structural abnormalities (Figure 1).\n\nFigure 1 MRI scan sections of the patient's brain reporting the presence of GMH (indicated by arrows and circles). (A) T2W – coronal section; (B) T1W- assial section; (C) T1W – sagittal section. Arrows indicate areas of subependimal alterated signal (bilateral and asymmetrical PNH—Periventricular Nodular Heterotopia—with heterotopic grey matter stretching all along the ventricular walls, maximum diameter = 5 mm). Note that the shade of grey is the same as that of the cortical grey matter (the same signal intensity), which confirms that it is grey matter—the pathognomonic finding in GMH.\n\nDiscussion\nFollowing the clinical and instrumental examination, the expert opinion in the criminal proceeding recommended partial liability of the defendant: E.L. appears able to understand the real implications and moral wrongfulness of his action against his schoolmate. In fact, he asks for forgiveness to the victim. His cognitive capacity is intact, as long as his problem solving ability when in absence of space or time constraints. However, relevant impairments result in his executive capacities, in that he appears unable to inhibit emotionally overwhelming and compelling responses, with difficulties in set shifting, planning, and strategic control. As a consequence, under particular circumstances, E.L.'s behavior is driven by impulsivity to the extent that, once started, it cannot readily be stopped. From the clinical point of view, anxiety and phobias are the affective responses to external overwhelming pressure. Overall, the clinical and neuropsychological pattern emerging from the examination of E.L. appears compatible with the clinical manifestations of GMH (4).\n\nDuring the course of his development, E.L. has learnt to adjust to his executive impairment, by adopting a behavioral risk control. In other words, being somewhat aware of his executive deficits, he prevents fatal consequences through low engagement in defiance and challenges. The dispute in the classroom and the ensuing consequences with the schoolmates are some of those particular circumstances in which E.L. could have experienced a failure in impulse control. In an attempt to desperately run from the threatening situation, he engaged in a sequence of actions that exceeded the limits of a reasonable reaction. Although able to understand the inappropriateness of his conduct, E.L. is unable to exert a full control on it. At the time of the alleged offence, E.L. had suspended the therapeutic treatment. The action flowed unwillingly, without restraints, so that E.L. cannot be considered completely responsible for that (27).\n\nAnamnestic data suggest that E.L. has a mild and submissive temperament, and psychometric assessment indicates a prevalent adoption of repressive modalities of response to stressors. In other words, E.L. appears usually able to inhibit and control undesirable behavior. However, inhibition is a resource-consuming process, highly vulnerable when self-regulatory capacity is reduced by prior exertion of self-control. Ego-depletion theory postulates that the self has a limited amount of resources, used for a wide range of tasks, such as emotion regulation, reasoning, decision making, impulse control, behavioral performance, and so on (28). In case of a low availability of executive resources, a massive stress can induce a significant impairment on inhibitory control, hence concomitant actions can develop in all their disruptiveness. Although auto-directed, the suicidal behavior that E.L. manifested a few months before the scuffle is indicative of such a failure.\n\nPossible Role of GMH in E.L. Behavior\nBrain morphological (MRI) assessments on E.L. were performed in three different stages of his life: once during his early childhood, once during his teenage years, and last time during the forensic assessment. All assessments concluded for the presence of a GMH area within the wall of one lateral ventricule in E.L.'s brain.\n\nWith regard for the events that brought E.L. to be accused of severe injuries against his schoolmate, the MRI findings may be of critical relevance. In fact, while studies have reported that GMH is associated with seizure emergence, that is also observed in the case for E.L., there is consistent evidence that epilepsy, in turn, is associated with impulsive and potentially harmful behaviors. In fact, studies report that aggression and impulsivity are observed in a minority of people with epilepsy, sometimes occurring as a part of a more complex psychiatric comorbidity, sometimes also emerging as a side effect of anticonvulsant agents. In line with these reports, other studies have shown that epilepsy and impulsive behavior share common neurotransmitter systems and brain regions, including the GABA, glutamate, serotonin, dopamine, and noradrenaline systems and the hippocampus, amygdala, prefrontal cortex, anterior cingulate cortex, and temporal lobes (29). On the other hand, there are studies supporting the evidence that GMH per se is associated with impulsivity and aggressive behaviors. In particular, heterotopic grey matter presence is found associated with aggression, impulsive violence, inability to control anger and lack of remorse violent acts (1, 6, 30, 31).\n\nIn the case we here report, it is possible that psychological features above described interact with brain structure and electrophysiological alteration in reducing impulse control and increasing intolerance to emotionally overwhelming stimulation, resulting in the overall inability to establish appropriate and effective behavioral responses. These responses are instead substituted with chaotic and aggressive behavioral patterns. The present considerations, although non-definitive on a causal role of GMH on the pathogenesis of criminal behavior, might be useful when evaluating the defendant's impulsivity in forensic contexts. More generally, the present case exemplifies the need to implement neuroscientific evidence in forensic assessment of violent and dyscontrolled behavior of forensic relevance. The presence of a neural substrate for a psychopathological condition contributes to explain the difficulties of some forensic patients in inhibiting impulsive criminal acts, so that their responsibility is diminished. Neuroscientific assessment – following the Daubert's standards (Daubert v. Merrell Dow Pharmaceuticals, 509 U.S. 579, 1993) –can thus contribute to the legal decision of judges and juries on the criminal responsibility of defendants under the BARD (Beyond-Any-Reasonable-Doubt) criteria (32). Additionally, the convergence between neuropsychological and instrumental evidence has implications on prevention of recidivism in cases similar to that here described, by suggesting that, under acute pressure and without adequate therapeutic control, impulsive and disproportionate reactions to hostile actions might take place again.\n\nData Availability Statement\nThe data sets generated for this study are available on request to the corresponding author.\n\nEthics Statement\nEthical approval was not provided for this study because data were collected following a request of a Criminal Court of providing an expert opinion on a case of personal injury defense. Written informed consent was obtained from the participant for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\nAC wrote the second, third, and fourth paragraphs of Background; Case Presentation except the last two paragraphs; Discussion except Possible Role of GMH in E.L. Behavior, and set up Table 2. AR wrote the first paragraph of Background, the last two paragraphs of Case Presentation, Possible Role of GMH in E.L. Behavior, and set up Table 1 and Figure 1. Both authors have made substantial, direct, and intellectual contributions to the work, and approved it for publication.\n\nFunding\nPublication of the study was supported by grant no. 86602-VIII/2 of the University of Bari \"Aldo Moro\".\n\nConflict of Interest\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\nAcknowledgments\nThe authors gratefully acknowledge the help of Dr. Andrea Salvati from “F. Miulli” Hospital, Acquaviva delle Fonti (BA), for his help in MRI rendering.\n==== Refs\nReferences\n1 \nFry AE Kerr MP Gibbon F Turnpenny PD Hamandi K Stoodley N \nNeuropsychiatric disease in patients with periventricular heterotopia\n. J Neuropsychiatry Clin Neurosci (2013 ) 25 (1 ):26 –31\n. 10.1176/appi.neuropsych.11110336 \n23487190 \n2 \nRezazadeh A Bercovici E Kiehl TR Chow EW Krings T Bassett AS \nPeriventricular nodular heterotopia in 22q11. 2 deletion and frontal lobe migration\n. Ann Clin Trans Neurol (2018 ) 5 (11 ):1314–22. 10.1002/acn3.641 \n\n3 \nBadrfam R Zandifar A Abhari SAA \nSubependymal Heterotopia With Psychosis and Imperforate Anus in a Female Patent\n. Case Rep Clin Pract (2018 ) 3 (4 ):113–7. 10.16966/2471-4925.172 \n\n4 \nLippi G \nNeuropsychiatric symptoms and diagnosis of grey matter heterotopia: a case-based reflection\n. South Afr J Psychiatry (2017 ) 23 (1 ):1 –6\n. 10.4102/sajpsychiatry.v23i0.923 \n\n5 \nWatrin F Manent JB Cardoso C Represa A \nCauses and consequences of gray matter heterotopia\n. CNS Neurosci Ther (2015 ) 21 (2 ):112–22. 10.1111/cns.12322 \n\n6 \nFelker MV Walker LM Sokol DK Edwards-Brown M Chang BS \nEarly cognitive and behavioral problems in children with nodular heterotopia\n. Epilepsy Behav (2011 ) 22 (3 ):523–6. 10.1016/j.yebeh.2011.08.010 \n\n7 \nBlackmon K Ben-Avi E Wang X Pardoe HR Di Martino A Halgren E \nPeriventricular white matter abnormalities and restricted repetitive behavior in autism spectrum disorder\n. NeuroImage Clin (2016 ) 10 :36 –45\n. 10.1016/j.nicl.2015.10.017 \n26693400 \n8 \nNopoulos P Berg S Castellenos FX Delgado A Andreasen NC Rapoport JL \nDevelopmental brain anomalies in children with attention-deficit hyperactivity disorder\n. J Child Neurol (2000 ) 15 (2 ):102–8. 10.1177/088307380001500208 \n\n9 \nMaruyama Y Onishi H Miura T Kosaka K \nA case of depressive disorder with neuronal heterotopia\n. Psychiatry Clin Neurosci (1998 ) 52 (3 ):361–2. 10.1046/j.1440-1819.1998.00385.x \n\n10 \nNopouulos PC Flaum M Andreasen NC Swayze VW \nGray matter heterotopias in schizophrenia\n. Psychiatry Res (1995 ) 61 (1 ):11–4. 10.1016/0925-4927(95)02573-G \n\n11 \nBeauchaine TP Hinshaw SP Pang KL \nComorbidity of attention-deficit/hyperactivity disorder and early-onset conduct disorder: biological, environmental, and developmental mechanisms\n. Clin Psychol Sci Pract (2010 ) 17 (4 ):327–36. 10.1111/j.1468-2850.2010.01224.x \n\n12 \nMordre M Groholt B Kjelsberg E Sandstad B Myhre AM \nThe impact of ADHD and conduct disorder in childhood on adult delinquency: a 30 years follow-up study using official crime records\n. BMC Psychiatry (2011 ) 11 (1 ):57 . 10.1186/1471-244X-11-57 \n21481227 \n13 \nMouridsen SE Rich B Isager T Nedergaard NJ \nPervasive developmental disorders and criminal behaviour: a case control study\n. Int J Offender Ther Comp Criminol (2008 ) 52 (2 ):196 –205\n. 10.1177/0306624X07302056 \n17615427 \n14 \nBishop DVM \nTROG-2. Test for Reception of Grammar. Version 2 . Oxford : Pearson (2003 ).\n\n15 \nWechsler D \nWechsler Adult Intelligence Scale . 4th ed. \nSan Antonio, TX : Pearson Assessment (2008 ).\n\n16 \nButcher JN Dahlstrom WG Graham JR Tellegen AM Kaemmer B \nMinnesota Multiphasic PersonalityInventory-2 (MMPI-2): manual for administration and scoring . Minneapolis : University of Minnesota Press (1989 ).\n\n17 \nSpielberger CD \nManual for the State-Trait Anxiety Inventory STAI (Form Y) . Palo Alto, CA : Consulting Psychologists Press (1983 ).\n\n18 \nSpielberger CD \nProfessional Manual for the State-Trait Anger Expression Inventory (STAXI) . Odessa, FX : Psychological Assessment Resource (1988 ).\n\n19 \nBeck AT Steer RA Brown GK \nManual for Beck Depression Inventory-II . San Antonio, TX : Psychological Corporation (1996 ).\n\n20 \nLezak MD \nNeuropsychological Assessment . 2nd \nNew York : Oxford University Press (1995 ).\n\n21 \nTombaugh TN \nTrail Making Test A and B: normative data stratified by age and education\n. Arch Clin Neuropsychol (2004 ) 19 (2 ):203–14. 10.1016/S0887-6177(03)00039-8 \n\n22 \nMiyake A Friedman NP Emerson MJ Witzki AH Howerter A Wager TD \nThe unity and diversity of executive functions and their contributions to complex “frontal lobe” tasks: A latent variable analysis\n. Cogn Psychol (2000 ) 41 (1 ):49 –100\n. 10.1006/cogp.1999.0734 \n10945922 \n23 \nShallice T \nSpecific Impairment of Planning\n. Philos Trans R Soc (1982 ) 298 :199 –209\n. 10.1098/rstb.1982.0082 \n\n24 \nElithorn A \nA preliminary report on a perceptual maze test sensitive to brain damage\n. J Neurol Neurosurg Psychiatry (1955 ) 18 :287–92. 10.1136/jnnp.18.4.287 \n\n25 \nHeaton RK \nThe Wisconsin Card Sorting Test manual . Odessa : Psychological Assessment Resources Inc. (1981 ).\n\n26 \nLejuez CW Read JP Kahler CW Richards JB Ramsey SE Stuart GL \nEvaluation of a behavioral measure of risk taking: the Balloon Analogue Risk Task (BART)\n. J Exp Psychol Appl (2002 ) 8 :75 –84\n. 10.1037/1076-898X.8.2.75 \n12075692 \n27 \nPenney S \nImpulse control and criminal responsibility: Lessons from neuroscience\n. Int J Law Psychiatry (2012 ) 35 :99 –103\n. 10.1016/j.ijlp.2011.12.004 \n22261322 \n28 \nBaumeister RF \nSelf-regulation, ego depletion, and inhibition\n. Neuropsychologia (2014 ) 65 :313–9. 10.1016/j.neuropsychologia.2014.08.012 \n\n29 \nBrodie MJ Besag F Ettinger AB Mula M Gobbi G Comai S \nEpilepsy, antiepileptic drugs, and aggression: an evidence-based review\n. Pharmacol Rev (2016 ) 68 (3 ):563 –602\n. 10.1124/pr.115.012021 \n27255267 \n30 \nPridmore S McInerney G Rybak M Archer S \nPsychotic disorder NOS with heterotopia\n. J Psychiatr Intensive Care (2006 ) 2 (2 ):118–21. 10.1017/S1742646407000386 \n\n31 \nLivingston JH Aicardi J \nUnusual MRI appearance of diffuse subcortical heterotopia or” double cortex” in two children\n. J Neurol Neurosurg Psychiatry (1990 ) 53 (7 ):617–20. 10.1136/jnnp.53.7.617 \n\n32 \nCurci A Lanciano T Curtotti D Sartori G \nLessons for the courtroom from the study of Flashbulb memory: an integrative review\n. Memory (2020 ) 28 (3 ), 441 –449\n. 10.1080/09658211.2020.1727522 \n32046596\n\n",
"fulltext_license": "CC BY",
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"issue": "11()",
"journal": "Frontiers in psychiatry",
"keywords": "Grey Matter Heterotopia; epilepsy; impulsivity; inhibitory control; neurodevelopmental disorder",
"medline_ta": "Front Psychiatry",
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"pages": "261",
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"title": "Grey Matter Heterotopia and Criminal Responsibility in a Case of Personal Injury Defense.",
"title_normalized": "grey matter heterotopia and criminal responsibility in a case of personal injury defense"
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"abstract": "Hepatitis E virus (HEV) can induce chronic infections in the case of immunosuppression, which are sometimes not cured with ribavirin. Furthermore, sofosbuvir is a highly potent inhibitor of HCV polymerase and was shown to inhibit HEV genotype-3 replication in vitro. We report here the outcome of sofosbuvir/ribavirin therapy on a chronic HEV infection in a heart transplant recipient non-responder to ribavirin. After 24 weeks, the regimen failed to cure the persistent HEV infection, highlighting the need of therapeutic options for HEV-infected immunosuppressed patients.",
"affiliations": "Sorbonne Universités, UPMC Univ Paris 06, INSERM, Institut Pierre Louis d'épidémiologie et de Santé Publique (IPLESP UMRS 1136), Paris, France.;APHP, Hôpital Pitié-Salpêtrière, Unité Médicale de Transplantation Hépatique, Hépato-Gastro-Enterologie, UPMC Paris VI, Boulevard de l'Hôpital, Paris, France.;Department of Virology, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.;CHU Toulouse, Hôpital Purpan, Laboratoire de virologie, National Reference Center for Hepatitis E, Toulouse, France.;Groupe Hospitalier Pitié Salpêtrière APHP, Paris, France Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938 and Institute of Cardiometabolism and Nutrition (ICAN), INSERM, Paris, France.;AP-HP, Hôpital Paul Brousse, Virologie, Univ Paris-Sud, INSERM U1193, Villejuif, France.;Pharmaco-Toxicology Department, Bichat-Claude Bernard Hospital, APHP, Paris, France.;Sorbonne Universités, UPMC Univ Paris 06, INSERM, Institut Pierre Louis d'épidémiologie et de Santé Publique (IPLESP UMRS 1136), Paris, France.;APHP, Hôpital Pitié-Salpêtrière, Unité Médicale de Transplantation Hépatique, Hépato-Gastro-Enterologie, UPMC Paris VI, Boulevard de l'Hôpital, Paris, France.;Université René Descartes, Service de Chirurgie Cardio-Vasculaire, Assistance Publique-hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France.;Unité Fonctionnelle de Transplantation Thoracique, Pole Cardiovasculaire - Néphrologie - Hypertension - Diabète, Assistance Publique - Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France.;APHP, Hôpital Pitié-Salpêtrière, Unité Médicale de Transplantation Hépatique, Hépato-Gastro-Enterologie, UPMC Paris VI, Boulevard de l'Hôpital, Paris, France.",
"authors": "Todesco|Eve|E|;Mazzola|Alessandra|A|;Akhavan|Sepideh|S|;Abravanel|Florence|F|;Poynard|Thierry|T|;Roque-Afonso|Anne-Marie|AM|;Peytavin|Gilles|G|;Marcelin|Anne-Geneviève|AG|;Calmus|Yvon|Y|;Lecuyer|Lucien|L|;Guillemain|Romain|R|;Conti|Filomena|F|",
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"nlm_unique_id": "9815705",
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"references": null,
"title": "Chronic hepatitis E in a heart transplant patient: sofosbuvir and ribavirin regimen not fully effective.",
"title_normalized": "chronic hepatitis e in a heart transplant patient sofosbuvir and ribavirin regimen not fully effective"
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"abstract": "A 45-year-old man with a new diagnosis of low grade glioma was started on an escalating dose of levetiracetam (Lev) for seizure management. He gradually developed intractable nausea/vomiting and a high creatinine concentration due to acute renal failure which was attributed to Lev-induced interstitial nephritis. The medication was changed and his renal function rapidly improved to his baseline.",
"affiliations": "Department of Neurosciences, Moores Cancer Center, University of California San Diego, 3855 Suite 3336, Health Sciences Drive, La Jolla, California 92093-0819, USA.",
"authors": "Mahta|Ali|A|;Kim|Ryan Y|RY|;Kesari|Santosh|S|",
"chemical_list": "D000927:Anticonvulsants; D000077287:Levetiracetam; D010889:Piracetam",
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"mesh_terms": "D058186:Acute Kidney Injury; D000927:Anticonvulsants; D001254:Astrocytoma; D001932:Brain Neoplasms; D006801:Humans; D000077287:Levetiracetam; D008297:Male; D008875:Middle Aged; D009395:Nephritis, Interstitial; D010889:Piracetam; D012640:Seizures",
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"title": "Levetiracetam-induced interstitial nephritis in a patient with glioma.",
"title_normalized": "levetiracetam induced interstitial nephritis in a patient with glioma"
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"abstract": "Porto-sinusoidal vascular liver disease (PSVD) is a disorder that can cause portal hypertension without liver cirrhosis. TAFRO syndrome is a systemic inflammatory disorder with a background of immunological abnormalities. We report a case of TAFRO syndrome complicated by PSVD with portal hypertension. A 39-year-old man developed refractory ascites and esophageal varices. Lymph node histology revealed multicentric Castleman disease-like features. Intravenous methylprednisolone and tocilizumab therapy improved ascites and renal dysfunction, but the patient developed severe infections. The diagnosis of TAFRO syndrome in patients complicated by PSVD with portal hypertension encourages the consideration of appropriate treatment for these patients.",
"affiliations": "Department of Gastroenterology, Fukushima Medical University, 1 Hikarigaoka, Fukushima, 960-1295, Japan. m884884@fmu.ac.jp.;Department of Gastroenterology, Fukushima Medical University, 1 Hikarigaoka, Fukushima, 960-1295, Japan.;Department of Gastroenterology, Fukushima Medical University, 1 Hikarigaoka, Fukushima, 960-1295, Japan.;Department of Rheumatology, Fukushima Medical University, Fukushima, Japan.;Department of Rheumatology, Fukushima Medical University, Fukushima, Japan.;Department of Rheumatology, Fukushima Medical University, Fukushima, Japan.;Department of Rheumatology, Fukushima Medical University, Fukushima, Japan.;Department of Rheumatology, Fukushima Medical University, Fukushima, Japan.;Department of Rheumatology, Fukushima Medical University, Fukushima, Japan.;Department of Rheumatology, Fukushima Medical University, Fukushima, Japan.;Department of Rheumatology, Fukushima Medical University, Fukushima, Japan.;Department of Rheumatology, Fukushima Medical University, Fukushima, Japan.;Department of Gastroenterology, Fukushima Medical University, 1 Hikarigaoka, Fukushima, 960-1295, Japan.;Department of Gastroenterology, Fukushima Medical University, 1 Hikarigaoka, Fukushima, 960-1295, Japan.;Department of Diagnostic Pathology, Fukushima Medical University, Fukushima, Japan.;Department of Diagnostic Pathology, Fukushima Medical University, Fukushima, Japan.;Department of Gastroenterology, Fukushima Medical University, 1 Hikarigaoka, Fukushima, 960-1295, Japan.;Department of Gastroenterology, Fukushima Medical University, 1 Hikarigaoka, Fukushima, 960-1295, Japan.;Department of Pathology, School of Medicine, Iwate Medical University, Iwate, Japan.;Department of Diagnostic Pathology, Fukushima Medical University, Fukushima, Japan.;Department of Rheumatology, Fukushima Medical University, Fukushima, Japan.;Department of Gastroenterology, Fukushima Medical University, 1 Hikarigaoka, Fukushima, 960-1295, Japan.",
"authors": "Hayashi|Manabu|M|http://orcid.org/0000-0002-2213-3918;Wada|Jun|J|;Fujita|Masashi|M|;Asano|Tomoyuki|T|;Matsuoka|Naoki|N|;Fujita|Yuya|Y|;Temmoku|Jumpei|J|;Matsumoto|Haruki|H|;Yashio-Furuya|Makiko|M|;Sato|Shuzo|S|;Kobayashi|Hiroko|H|;Watanabe|Hiroshi|H|;Ryoichiro|Kobashi|K|;Waragai|Yuichi|Y|;Suzuki|Erina|E|;Kiko|Yuichiro|Y|;Abe|Kazumichi|K|;Takahashi|Atsushi|A|;Masuda|Tomoyuki|T|;Hashimoto|Yuko|Y|;Migita|Kiyoshi|K|;Ohira|Hiromasa|H|http://orcid.org/0000-0003-4331-0634",
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"keywords": "Ascites; Idiopathic noncirrhotic portal hypertension; Porto-sinusoidal vascular liver disease; TAFRO syndrome; Tocilizumab",
"medline_ta": "Clin J Gastroenterol",
"mesh_terms": "D000328:Adult; D005871:Castleman Disease; D006801:Humans; D006975:Hypertension, Portal; D008103:Liver Cirrhosis; D008297:Male; D014652:Vascular Diseases",
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"title": "TAFRO syndrome complicated by porto-sinusoidal vascular liver disease with portal hypertension: a case report.",
"title_normalized": "tafro syndrome complicated by porto sinusoidal vascular liver disease with portal hypertension a case report"
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"abstract": "Barriers to sustainable virologic suppression (VS) of HIV-infected adolescents and young adults include drug resistance mutations (DRMs) and limited treatment options, which may impact the outcome of second-line antiretroviral therapy (ART). We sequenced plasma viral RNA from 74 adolescents and young adults (16-24 years) failing first-line ART at Newlands Clinic, Zimbabwe between October 2015 and December 2016. We evaluated first-line nucleoside reverse transcriptase inhibitor (NRTI) susceptibility scores to first- and second-line regimens. Boosted protease inhibitor (bPI)-based ART was provided and viral load (VL) monitored for ≥48 weeks. Fisher's exact test was used to evaluate factors associated with VS on second-line regimens, defined as VL <1,000 copies/mL (VS1,000) or <50 copies/mL (VS50). The 74 participants on first-line ART had a median [interquartile range (IQR)] age of 18 (16-21) years and 42 (57%) were female. The mean (±standard deviation) duration on ART was 5.5 (±3.06) years and the median (IQR) log10 VL was 4.26 (3.78-4.83) copies/mL. After switching to a second-line PI regimen, 88% suppressed to <1,000 copies/mL and 76% to <50 copies/mL at ≥48 weeks. A new NRTI was associated with increased VS50 (p = .031). These 74 adolescents and young adults failing first-line ART demonstrated high levels (97%) of DRMs, despite enhanced adherence counseling. Switching to new NRTIs in second-line improved VS. With the widespread adoption of generic dolutegravir, lamivudine and tenofovir combinations in Africa, genotyping to determine NRTI susceptibility, may be warranted.",
"affiliations": "Department of Medicine, College of Health Sciences, University of Zimbabwe, Harare, Zimbabwe.;Department of Molecular Biology, Biomedical Research and Training Institute, Harare, Zimbabwe.;Newlands Clinic, Newlands, Harare, Zimbabwe.;Division of Epidemiology and Biostatistics, University of Stellenbosch, Stellenbosch, South Africa.;Newlands Clinic, Newlands, Harare, Zimbabwe.;Newlands Clinic, Newlands, Harare, Zimbabwe.;Department of Medical Microbiology, College of Health Sciences, University of Zimbabwe, Harare, Zimbabwe.;Department of Molecular Biology, Biomedical Research and Training Institute, Harare, Zimbabwe.",
"authors": "Kouamou|Vinie|V|;Varyani|Bhavini|B|;Shamu|Tinei|T|;Mapangisana|Tichaona|T|;Chimbetete|Cleophas|C|;Mudzviti|Tinashe|T|;Manasa|Justen|J|;Katzenstein|David|D|",
"chemical_list": "D019380:Anti-HIV Agents; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors",
"country": "United States",
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"issue": "36(7)",
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"keywords": "HIV drug resistance; Zimbabwe; adherence; adolescents and young adults",
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"mesh_terms": "D000293:Adolescent; D019380:Anti-HIV Agents; D023241:Antiretroviral Therapy, Highly Active; D024882:Drug Resistance, Viral; D005260:Female; D015658:HIV Infections; D015497:HIV-1; D006801:Humans; D008297:Male; D009154:Mutation; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D000072230:Sustained Virologic Response; D017211:Treatment Failure; D019562:Viral Load; D055815:Young Adult; D015030:Zimbabwe",
"nlm_unique_id": "8709376",
"other_id": null,
"pages": "566-573",
"pmc": null,
"pmid": "32138527",
"pubdate": "2020-07",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Drug Resistance Among Adolescents and Young Adults with Virologic Failure of First-Line Antiretroviral Therapy and Response to Second-Line Treatment.",
"title_normalized": "drug resistance among adolescents and young adults with virologic failure of first line antiretroviral therapy and response to second line treatment"
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"abstract": "We have treated 25 patients, 7 with breast cancer and 18 with non-Hodgkin's lymphoma, with recombinant alpha 2 interferon. In 5 patients we observed cardiac arrhythmias that were unexpected and required treatment. No deaths have occurred that we can attribute to interferon, though 1 patient had to be resuscitated. Age, prior cardiac disease, prior treatment with doxorubicin, and interferon dose appear to be predisposing factors for this toxicity.",
"affiliations": null,
"authors": "Martino|S|S|;Ratanatharathorn|V|V|;Karanes|C|C|;Samal|B A|BA|;Sohn|Y H|YH|;Rudnick|S A|SA|",
"chemical_list": "D007370:Interferon Type I; D011994:Recombinant Proteins",
"country": "Germany",
"delete": false,
"doi": "10.1007/BF00397722",
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"issue": "113(4)",
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"mesh_terms": "D000368:Aged; D001145:Arrhythmias, Cardiac; D001943:Breast Neoplasms; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D007370:Interferon Type I; D008228:Lymphoma, Non-Hodgkin; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins",
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"references": "6482933;7352018;6690072;6182613;6357102;431720;6315898;6163151;6323641",
"title": "Reversible arrhythmias observed in patients treated with recombinant alpha 2 interferon.",
"title_normalized": "reversible arrhythmias observed in patients treated with recombinant alpha 2 interferon"
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"abstract": "Extraintestinal infections due to Clostridium difficile are uncommon. When such infections occur, extraintestinal C. difficile isolates are usually identical to fecal isolates. We present a rare case of a large postoperative abscess caused by C. difficile infection, in which different C. difficile strains were isolated from the abscess and from feces of the patient. An 82-year-old woman with cutaneous polyarteritis nodosa developed pain, skin ulcers, and extensive necrosis of the right leg. Above-knee amputation was performed without stopping antiplatelet therapy, leading to postoperative hematoma. Six weeks after surgery, a large femoral abscess was detected and C. difficile was isolated. Repeat amputation of the thigh was required to remove the abscess. C. difficile was also cultured from feces despite the lack of intestinal symptoms. However, genetic analysis confirmed that the C. difficile isolates from the abscess and feces were different strains. Thus, C. difficile can cause postoperative infection of a hematoma and the extraintestinal and fecal C. difficile isolates are not necessarily identical in the same patient.",
"affiliations": "Department of Orthopaedic Surgery, Tonan Hospital, 3-8 Kita-4-jo Nishi-7-chome, Chuo-ku, Sapporo, Hokkaido 060-0004, Japan. Electronic address: ona27@ruby.ocn.ne.jp.;Department of Infection Control and Laboratory Diagnostics, Internal Medicine, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi Prefecture 980-8574, Japan.;Department of Orthopaedic Surgery, Tonan Hospital, 3-8 Kita-4-jo Nishi-7-chome, Chuo-ku, Sapporo, Hokkaido 060-0004, Japan.;Department of Orthopaedic Surgery, Tonan Hospital, 3-8 Kita-4-jo Nishi-7-chome, Chuo-ku, Sapporo, Hokkaido 060-0004, Japan.;Department of Rheumatology, Tonan Hospital, 3-8 Kita-4-jo Nishi-7-chome, Chuo-ku, Sapporo, Hokkaido 060-0004, Japan.;Department of Rheumatology, Tonan Hospital, 3-8 Kita-4-jo Nishi-7-chome, Chuo-ku, Sapporo, Hokkaido 060-0004, Japan.",
"authors": "Onada|Yoshihiro|Y|;Endo|Shiro|S|;Umemoto|Takahisa|T|;Kajino|Tomomichi|T|;Amasaki|Yoshiharu|Y|;Furusaki|Akira|A|",
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"doi": "10.1016/j.anaerobe.2017.05.018",
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"issn_linking": "1075-9964",
"issue": "47()",
"journal": "Anaerobe",
"keywords": "Clostridium difficile; Extraintestinal infection; Hematoma; Pulsed-field gel electrophoresis",
"medline_ta": "Anaerobe",
"mesh_terms": "D000038:Abscess; D000369:Aged, 80 and over; D016360:Clostridioides difficile; D003015:Clostridium Infections; D016521:Electrophoresis, Gel, Pulsed-Field; D005243:Feces; D005260:Female; D006406:Hematoma; D006801:Humans; D010488:Polyarteritis Nodosa; D011183:Postoperative Complications; D021521:Ribotyping; D013848:Thigh",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Extraintestinal Clostridium difficile infection due to a ribotype different from that isolated from the feces of the patient: A case report.",
"title_normalized": "extraintestinal clostridium difficile infection due to a ribotype different from that isolated from the feces of the patient a case report"
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"abstract": "OBJECTIVE\nThe purpose of this study was to report the case of a patient who underwent vitrectomy for bilateral rhegmatogenous retinal detachment caused by cytomegalovirus (CMV) retinitis while undergoing steroid and immunosuppressant therapy for systemic lupus erythematosus (SLE).\n\n\nMETHODS\nWe report on a 29-year-old female who was undergoing steroids and immunosuppressants treatment for SLE at Osaka Medical College Hospital, Takatsuki City, Japan. Examination of the patient due to prolonged and worsening diarrhea revealed positive test results for C7-HRP, and she was diagnosed with CMV colitis. She was subsequently admitted to the hospital and started on intravenous ganciclovir for treatment. Approximately 1.5 months later, her primary complaint was deterioration of the upper visual field in her left eye, and she was then referred to the Department of Ophthalmology. Numerous granular exudative spots were found around the lower retinal area of her left eye with retinal breaks that had developed in an area of retinal necrosis that resulted in retinal detachment. After time was allowed for the patient's general condition to improve, a vitrectomy was performed on that eye. The patient subsequently developed a similar retinal detachment in her right eye, for which she underwent a vitrectomy. Although the patient required multiple surgeries on both eyes, her retinas currently remain reattached and the inflammation has subsided.\n\n\nCONCLUSIONS\nThe findings of this study show that strict attention must be paid to SLE patients on immunosuppressive therapy due to the possible association of CMV retinitis.",
"affiliations": "Department of Ophthalmology, Osaka Medical College, Takasuki City, Japan.;Department of Ophthalmology, Osaka Medical College, Takasuki City, Japan.;Department of Ophthalmology, Osaka Medical College, Takasuki City, Japan.;Department of Ophthalmology, Osaka Medical College, Takasuki City, Japan.;Department of Ophthalmology, Osaka Medical College, Takasuki City, Japan.;Department of Ophthalmology, Osaka Medical College, Takasuki City, Japan; Takeda Eye Clinic, Osaka City, Japan.;Department of Ophthalmology, Osaka Medical College, Takasuki City, Japan; Tada Eye Clinic, Ikeda City, Japan.;Department of Ophthalmology, Osaka Medical College, Takasuki City, Japan; Maruyama Eye Clinic, Takatsuki City, Japan.;Department of Ophthalmology, Osaka Medical College, Takasuki City, Japan.;Department of Ophthalmology, Osaka Medical College, Takasuki City, Japan.",
"authors": "Haze|Masaya|M|;Kobayashi|Takatoshi|T|;Kakurai|Keigo|K|;Shoda|Hiromi|H|;Takai|Nanae|N|;Takeda|Sayako|S|;Tada|Rei|R|;Maruyama|Kouichi|K|;Kida|Teruyo|T|;Ikeda|Tsunehiko|T|",
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"fulltext": "\n==== Front\nCase Rep OphthalmolCase Rep OphthalmolCOPCase Reports in Ophthalmology1663-2699S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000446391cop-0007-0303Case ReportBilateral Cytomegalovirus Retinitis in a Patient with Systemic Lupus Erythematosus Haze Masaya aKobayashi Takatoshi aKakurai Keigo aShoda Hiromi aTakai Nanae aTakeda Sayako abTada Rei acMaruyama Kouichi adKida Teruyo aIkeda Tsunehiko a*aDepartment of Ophthalmology, Osaka Medical College, Takasuki City, JapanbTakeda Eye Clinic, Osaka City, JapancTada Eye Clinic, Ikeda City, JapandMaruyama Eye Clinic, Takatsuki City, Japan*Tsunehiko Ikeda, MD, Department of Ophthalmology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki City, Osaka 569-8686 (Japan), E-Mail tikeda@osaka-med.ac.jpMay-Aug 2016 2 6 2016 2 6 2016 7 2 303 308 17 2 2016 23 4 2016 Copyright © 2016 by S. Karger AG, Basel2016This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Purpose\nThe purpose of this study was to report the case of a patient who underwent vitrectomy for bilateral rhegmatogenous retinal detachment caused by cytomegalovirus (CMV) retinitis while undergoing steroid and immunosuppressant therapy for systemic lupus erythematosus (SLE).\n\nCase Report\nWe report on a 29-year-old female who was undergoing steroids and immunosuppressants treatment for SLE at Osaka Medical College Hospital, Takatsuki City, Japan. Examination of the patient due to prolonged and worsening diarrhea revealed positive test results for C7-HRP, and she was diagnosed with CMV colitis. She was subsequently admitted to the hospital and started on intravenous ganciclovir for treatment. Approximately 1.5 months later, her primary complaint was deterioration of the upper visual field in her left eye, and she was then referred to the Department of Ophthalmology. Numerous granular exudative spots were found around the lower retinal area of her left eye with retinal breaks that had developed in an area of retinal necrosis that resulted in retinal detachment. After time was allowed for the patient's general condition to improve, a vitrectomy was performed on that eye. The patient subsequently developed a similar retinal detachment in her right eye, for which she underwent a vitrectomy. Although the patient required multiple surgeries on both eyes, her retinas currently remain reattached and the inflammation has subsided.\n\nConclusion\nThe findings of this study show that strict attention must be paid to SLE patients on immunosuppressive therapy due to the possible association of CMV retinitis.\n\nKeywords\nSystemic lupus erythematosusCytomegalovirus retinitisRetinal detachmentVitrectomy\n==== Body\nIntroduction\nCytomegalovirus (CMV) is a DNA virus of the Herpesviridae family that commonly affects individuals during childhood [1]. In fact, 50–85% of adults in the United States have CMV antibodies, and the virus is said to latently infect mononuclear cells in bone marrow and peripheral blood. Generally, CMV infections are opportunistic infections that commonly develop in immunocompromised patients, such as patients with acquired immunodeficiency syndrome (AIDS), malignant tumors, and those that have recently undergone organ transplantation [2, 3]. In recent years, however, there have been scattered reports of CMV infections appearing in patients with both connective tissue and blood diseases [4, 5, 6, 7, 8]. In this study, we report the case of a patient who underwent vitrectomy for bilateral rhegmatogenous retinal detachment caused by CMV retinitis while undergoing steroid and immunosuppressant therapy for systemic lupus erythematosus (SLE).\n\nCase Report\nWe report the case of a 29-year-old female patient who presented with deterioration of the upper visual field in the left eye.\n\nThe patient was diagnosed with SLE at the age of 22 years and was undergoing oral administration of immunosuppressants such as dexamethasone, tacrolimus, and mycophenolate mofetil for treatment. Family history included rheumatoid arthritis in the patient's grandmother.\n\nHistory of Present Condition\nDue to prolonged and worsening diarrhea, the patient was admitted to the Department of Internal Medicine and Connective Tissue Disorders at Osaka Medical College Hospital, Takatsuki City, Japan, in mid-July 2010 to undergo further tests. A blood sample obtained from the patient tested positive on a CMV pp65 antigen test (hereafter referred to as ‘C7-HRP’), and she was diagnosed with CMV colitis. Subsequently, the patient was administered intravenous ganciclovir in parallel with the immunosuppressant and steroid treatment for SLE. The patient's C7-HRP eventually tested negative and the intravenous ganciclovir was temporarily stopped; however, she later occasionally tested positive for C7-HRP and was administered intravenous ganciclovir each time for treatment. While still hospitalized in late August 2010, the patient suddenly became aware of a deterioration of the upper visual field in her left eye and was sent to the Department of Ophthalmology for examination.\n\nFindings on Initial Examination\nUpon initial examination, the patient's visual acuity (VA) was 0.05 (1.2 × S-5.0D = C-2.75DA × 5°) OD and 0.04 (1.2 × S-5.5D = C-1.75 DA × 180°) OS. Intraocular pressure was 13 mm Hg in both eyes. Mild iritis in the anterior segment was observed in her left eye. Rhegmatogenous retinal detachment was found in the lower second quadrant of her left eye with obstructions of the blood vessels in the lower area of that eye, thus resulting in retinal thinning and necrosis (fig. 1b). Yellowish-white granular exudate was also found in the retina around an area of necrosis. Yellowish-white granular exudate was also found in the retinal area of the right eye, yet with no retinal detachment (fig. 1a). The patient was diagnosed with bilateral CMV retinitis based on the observations of her overall condition and ocular fundus findings.\n\nClinical Course\nAlthough the retinal detachment in the patient's left eye was encroaching on the macular area, internal medical treatment took priority, and we planned to perform a vitrectomy after the patient's overall condition had improved. Pars plana lensectomy and pars plana vitrectomy were performed on the patient's left eye on September 14, 2010, as the retinal detachment had already reached the macular area. The posterior vitreous had not yet detached and the vitreoretinal adhesion in the lower CMV retinitis area was robust. We therefore created an artificial posterior vitreous detachment using bimanual techniques (fig. 2). Pneumatic retinal reattachment surgery, intraocular laser photocoagulation, a peripheral encircling procedure, and a silicone oil tamponade were later performed to complete the operation. Polymerase chain reaction (PCR) testing of the vitreous fluid obtained during surgery revealed CMV DNA.\n\nIn July 2011, the patient experienced rhegmatogenous retinal detachment in her right eye, and as with that for the left eye, pars plana lensectomy and pars plana vitrectomy, along with a silicone oil tamponade, were performed for treatment. A macular pucker formed in the patient's left eye, and in September 2011, she underwent silicone oil removal and secondary insertion of an intraocular lens (IOL), removing the macular pucker at the same time. However, the retinal detachment reoccurred after surgery, and in October 2011, the IOL was removed and silicone oil was once again injected. Silicone oil removal and secondary insertion of an IOL were performed on the patient's right eye in January 2012, and her postoperative progress has been favorable. As of March 2015, the patient's corrected VA was 0.8 OD and 0.15 OS.\n\nDiscussion\nCMV retinitis commonly manifests in patients who are in an immunocompromised state, such as patients with AIDS, malignant tumors, or those who have recently undergone organ transplantation [1, 2, 3]. However, there have been scattered reports in recent years of CMV retinitis developing in patients suffering from connective tissue diseases, such as SLE and chronic rheumatoid arthritis, while on immunosuppressive therapy [4, 5, 6, 7, 8]. Compromised immunity arises from pancytopenia stemming from SLE itself along with the side effects of steroid and immunosuppressant therapy, often accompanied by infectious diseases. There have been numerous reports of CMV infections such as pneumonia and nephritis associated with SLE [9, 10]. Although reports of retinitis have been few in comparison, it has been on the rise in recent years. There have been numerous past reports of CMV retinitis associated with SLE due to treatment with multiple steroids and immunosuppressants, such as in the present case [5, 6, 7, 8]. Although there are reports from other institutions investigating CMV infections occurring in patients with connective tissue disorders including, most notably, SLE [4], there have been no extensive reports on cases of patients exhibiting CMV retinitis. Thus, we await the findings of future research on this topic.\n\nIn many cases, CMV retinitis can be diagnosed from characteristic observations in the ocular fundus. It can be categorized as fulminant, in which case it develops in the posterior fundus and is often accompanied by retinal bleeding, or granular, in which case the retinitis develops in surrounding regions and often progresses slowly. In the case shown in this present study, there was a high likelihood that progression of the infection was steady, as the granular surrounding area of the lesion was the primary agent, and although retinal detachment occurred in the course of the infection, the patient was not examined by an ophthalmologist until she became aware of the loss in her field of vision, thus leading to the delayed diagnosis.\n\nDry eye, scleritis, and retinopathy are known to be among the ocular complications associated with SLE [11, 12]. Retinopathy is characterized by soft exudate and bleeding and may be associated with obstruction of the retinal blood vessels. If vasculitis progresses, it may be accompanied by proliferative retinopathy or neovascular glaucoma. CMV retinitis is generally characterized by granular exudate and bleeding along the blood vessels, however, and in the initial stages, it can be difficult to distinguish from SLE retinitis. PCR testing using aqueous humor from the anterior chamber is a simple and effective method for diagnosing CMV retinitis.\n\nIf CMV retinitis is discovered, the patient should be started on systemic administration of antiviral drugs. Even after the retinitis subsides, necrosis may develop in the outer layer of the retina, commonly leading to thinning of the retina. It has also been reported that the adhesion between the retina and vitreous body strengthens after the inflammation subsides [13], which necessitates a vitrectomy if it progresses into rhegmatogenous retinal detachment accompanied by the advance of posterior vitreous detachment. In the case presented in this study, the creation of an artificial posterior vitreous detachment on the site of the lesion was a challenge. As the retinal detachment in the left eye was delayed in this case, the patient's corrected vision remains at 0.15. However, we were able to operate on the retinal detachment in the patient's right eye which developed during the course of the infection at an early stage, thus allowing us to be able to maintain a relatively favorable VA of 0.8. In terms of the prognosis for retinal detachment with CMV retinitis, the recovery rate is approximately 80%; i.e., a very positive prognosis [14]. Had the patient undergone an eye test at the time she was diagnosed with CMV colitis, the chances are high that the CMV retinitis would have been discovered at an earlier stage.\n\nSLE patients who undergo long-term treatment with steroids and immunosuppressants, such as in the present case, should be observed with great care over the course of the illness, and there should be an awareness that such patients are at high risk for opportunistic CMV infections.\n\nStatement of Ethics\nThis case study has been approved by the Ethics Committee of the Osaka Medical College.\n\nDisclosure Statement\nThe authors have no conflicts of interest to report.\n\nAcknowledgements\nThe authors wish to thank John Bush for editing the manuscript.\n\nFig. 1 Preoperative fundus photographs obtained on initial examination. a Right eye. b Left eye. a Yellowish-white granular exudate was found in the retinal area of the right eye, even though no retinal detachment had occurred. b Image showing the occurrence of rhegmatogenous retinal detachment in the lower second quadrant of the patient's left eye, with obstruction of the blood vessels in the lower area of that eye, thus resulting in retinal thinning and necrosis.\n\nFig. 2 Intraoperative findings in the patient's left eye. The vitreoretinal adhesion in the lower cytomegalovirus retinitis area was robust. Hence, an artificial posterior vitreous detachment was created with the use of a bimanual technique.\n==== Refs\nReferences\n1 Wiegand TW Young LH Cytomegalovirus retinitis Int Ophthalmol Clin 2006 46 91 110 16770157 \n2 Jeon S Lee WK Lee Y Lee DG Lee JW Risk factors for cytomegalovirus retinitis in patients with cytomegalovirus viremia after hematopoietic stem cell transplantation Ophthalmology 2012 119 1892 1898 22657564 \n3 Bhat V Joshi A Sarode R Chavan P Cytomegalovirus infection in the bone marrow transplant patient World J Transplant 2015 5 287 291 26722656 \n4 Takizawa Y Inokuma S Tanaka Y Saito K Atsumi T Hirakata M Kameda H Hirohata S Kondo H Kumagai S Tanaka Y Clinical characteristics of cytomegalovirus infection in rheumatic diseases: multicentre survey in a large patient population Rheumatology 2008 47 1373 1378 18577548 \n5 Kelkar A Kelkar J Kelkar S Bhirud S Biswas J Cytomegalovirus retinitis in a seronegative patient with systemic lupus erythematosus on immunosuppressive therapy J Ophthalmic Inflamm Infect 2011 1 129 132 21484181 \n6 Lee JJ Teoh SC Chua JL Tien MC Lim TH Occurrence and reactivation of cytomegalovirus retinitis in systemic lupus erythematosus with normal CD4(+) counts Eye 2006 20 618 621 15920561 \n7 Shahnaz S Choksi MT Tan IJ Bilateral cytomegalovirus retinitis in a patient with systemic lupus erythematosus and end-stage renal disease Mayo Clin Proc 2003 78 1412 1415 14601702 \n8 Schlingemann RO Wertheim-van Dillen P Kijlstra A Bos PJ Meenken C Feron EJ Bilateral cytomegalovirus retinitis in a patient with systemic lupus erythematosus Br J Ophthalmol 1996 80 1109 1110 9059280 \n9 Gutsche M Rosen GD Swigris JJ Connective tissue disease-associated interstitial lung disease: s review Curr Respir Care Rep 2012 1 224 232 23125954 \n10 Koutsokeras T Healy T Systemic lupus erythematosus and lupus nephritis Nat Rev Drug Discov 2014 13 173 174 24525782 \n11 Davies JB Rao PK Ocular manifestations of systemic lupus erythematosus Curr Opin Ophthalmol 2008 19 512 518 18998618 \n12 Giorgi D Pace F Giorgi A Bonomo L Gabrieli CB Retinopathy in systemic lupus erythematosus: pathogenesis and approach to therapy Hum Immunol 1999 60 688 696 10439314 \n13 Brar M Kozak I Freeman WR Oster SF Mojana F Yuson RM Vitreoretinal interface abnormalities in healed cytomegalovirus retinitis Retina 2010 30 1262 1266 20517176 \n14 Mathur G Ratra D Bhuibhar SS Roy R Clinical outcomes of retinal detachment surgery following cytomegalovirus retinitis in patients on highly active anti-retroviral therapy for acquired immune deficiency syndrome Ocul Immunol Inflamm 2015 23 400 404 26221740\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1663-2699",
"issue": "7(2)",
"journal": "Case reports in ophthalmology",
"keywords": "Cytomegalovirus retinitis; Retinal detachment; Systemic lupus erythematosus; Vitrectomy",
"medline_ta": "Case Rep Ophthalmol",
"mesh_terms": null,
"nlm_unique_id": "101532006",
"other_id": null,
"pages": "303-8",
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"title": "Bilateral Cytomegalovirus Retinitis in a Patient with Systemic Lupus Erythematosus.",
"title_normalized": "bilateral cytomegalovirus retinitis in a patient with systemic lupus erythematosus"
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"abstract": "BACKGROUND\nRhabdomyosarcoma (RMS), a malignant tumour of mesenchymal origin which can occur at various sites in the body, is one of the most common soft tissue sarcomas in both children and adolescents, but is rare in adults with a prevalence of less than 1 %. The alveolar subtype of rhabdomyosarcoma (ARMS) is typically characterized by a specific reciprocal chromosomal translocation involving the PAX3 and FKHR or PAX7 and FKHR genes, respectively. ARMS is most frequently seen in childhood, and typically affects the sinuses and soft tissue of the extremities, with approximately 23 % exhibiting metastasis to the marrow. Non-invasive F-18-fluorodeoxyglucose positron-emission tomography (FDG-PET) scans have a high ability to detect lymph nodes, bone, and bone marrow involvement in patients with metastatic RMS, often with higher sensitivity and specificity compared with conventional modalities.\n\n\nMETHODS\nHere, we report an unusual case of ARMS confined to the bone marrow in an older adult that lacked an identifiable primary tumour using FDG-PET/CT and mimicked a haematological disease with pancytopenia but without abnormal findings by FDG-PET/CT. The patient was initially treated with topotecan/cyclophosphamide and subsequently switched to vinorelbine. Due to severe toxicity the treatment was discontinued, however after 7-months follow-up, the patient is still alive with an improved general state of health and only a mild pancytopenia with no need for blood transfusions.\n\n\nCONCLUSIONS\nRhabdomyosarcoma can be limited to the bone marrow with no identifiable primary tumour. This case shows that the use of a bone marrow biopsy in suspected malignancies affecting the bone marrow is irreplaceable.",
"affiliations": "Department of Oncology, Haematology and Stem Cell transplantation, University Hospital of Hamburg Eppendorf, Hamburg, Germany.;Department of Oncology, Haematology and Stem Cell transplantation, University Hospital of Hamburg Eppendorf, Hamburg, Germany.;Department of Oncology, Haematology and Stem Cell transplantation, University Hospital of Hamburg Eppendorf, Hamburg, Germany.;Department of Radiology and Nuclear Medicine, University Hospital of Hamburg Eppendorf, Hamburg, Germany.;Gerhard-Domagk-Institute of Pathology, University Hospital of Muenster, Muenster, Germany.;Institute of Pathology, University Hospital of Schleswig- Holstein, Kiel, Germany.;Department of Oncology, Haematology and Stem Cell transplantation, University Hospital of Hamburg Eppendorf, Hamburg, Germany.;Institute of Pathology, University Hospital of Schleswig- Holstein, Kiel, Germany.;Gerhard-Domagk-Institute of Pathology, University Hospital of Muenster, Muenster, Germany.;Department of Oncology, Haematology and Stem Cell transplantation, University Hospital of Hamburg Eppendorf, Hamburg, Germany.",
"authors": "Karagiannis|Panagiotis|P|;Guth|Nina|N|;Thoennissen|Gabriela B|GB|;Bern|Christina|C|;Sperveslage|Jan|J|;Oschlies|Ilske|I|;Bokemeyer|Carsten|C|;Klapper|Wolfram|W|;Wardelmann|Eva|E|;Thoennissen|Nils H|NH|",
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"fulltext": "\n==== Front\nClin Sarcoma ResClin Sarcoma ResClinical Sarcoma Research2045-3329BioMed Central London 3910.1186/s13569-015-0039-6Case ReportAlveolar rhabdomyosarcoma confined to the bone marrow with no identifiable primary tumour using FDG-PET/CT Karagiannis Panagiotis +49-40-7410-18104p.karagiannis@uke.de Guth Nina n.guth@uke.de Thoennissen Gabriela B. g.thoennissen@uke.de Bern Christina c.bern@uke.de Sperveslage Jan sperveslage@ukmuenster.de Oschlies Ilske ioschlies@path.uni-kiel.de Bokemeyer Carsten c.bokemeyer@uke.de Klapper Wolfram wklapper@path.uni-kiel.de Wardelmann Eva eva.wardelmann@ukmuenster.de Thoennissen Nils H. n.thoennissen@uke.de Department of Oncology, Haematology and Stem Cell transplantation, University Hospital of Hamburg Eppendorf, Hamburg, Germany NIHR Biomedical Research Centre at Guy’s and St. Thomas’s Hospitals and King’s College London, London, United Kingdom Department of Radiology and Nuclear Medicine, University Hospital of Hamburg Eppendorf, Hamburg, Germany Gerhard-Domagk-Institute of Pathology, University Hospital of Muenster, Muenster, Germany Institute of Pathology, University Hospital of Schleswig- Holstein, Kiel, Germany 19 11 2015 19 11 2015 2015 5 2423 9 2015 2 11 2015 © Karagiannis et al. 2015\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nRhabdomyosarcoma (RMS), a malignant tumour of mesenchymal origin which can occur at various sites in the body, is one of the most common soft tissue sarcomas in both children and adolescents, but is rare in adults with a prevalence of less than 1 %. The alveolar subtype of rhabdomyosarcoma (ARMS) is typically characterized by a specific reciprocal chromosomal translocation involving the PAX3 and FKHR or PAX7 and FKHR genes, respectively. ARMS is most frequently seen in childhood, and typically affects the sinuses and soft tissue of the extremities, with approximately 23 % exhibiting metastasis to the marrow. Non-invasive F-18-fluorodeoxyglucose positron-emission tomography (FDG-PET) scans have a high ability to detect lymph nodes, bone, and bone marrow involvement in patients with metastatic RMS, often with higher sensitivity and specificity compared with conventional modalities.\n\nCase presentation\nHere, we report an unusual case of ARMS confined to the bone marrow in an older adult that lacked an identifiable primary tumour using FDG-PET/CT and mimicked a haematological disease with pancytopenia but without abnormal findings by FDG-PET/CT. The patient was initially treated with topotecan/cyclophosphamide and subsequently switched to vinorelbine. Due to severe toxicity the treatment was discontinued, however after 7-months follow-up, the patient is still alive with an improved general state of health and only a mild pancytopenia with no need for blood transfusions.\n\nConclusion\nRhabdomyosarcoma can be limited to the bone marrow with no identifiable primary tumour. This case shows that the use of a bone marrow biopsy in suspected malignancies affecting the bone marrow is irreplaceable.\n\nKeywords\nRhabdomyosarcomaBone marrowTopotecan/cyclophosphamideVinorelbineAlveolar rhabdomyosarcomaFDG-PETissue-copyright-statement© The Author(s) 2015\n==== Body\nBackground\nRhabdomyosarcoma (RMS), a malignant tumour of mesenchymal origin which can occur at various sites in the body, is one of the most common soft tissue sarcomas in both children and adolescents, but is rare in adults with a prevalence of less than 1 % [1]. The alveolar subtype of rhabdomyosarcoma (ARMS) is typically characterized by a specific reciprocal chromosomal translocation involving the PAX3 and FKHR or PAX7 and FKHR genes, respectively [2]. ARMS is most frequently seen in childhood, and typically affects the sinuses and soft tissue of the extremities, with approximately 23 % exhibiting metastasis to the marrow [2, 3]. Non-invasive F-18-fluorodeoxyglucose positron-emission tomography (FDG-PET) scans have a high ability to detect lymph nodes, bone, and bone marrow involvement in patients with metastatic RMS, often with higher sensitivity and specificity compared with conventional modalities [4–6]. Here, we report an unusual case of ARMS confined to the bone marrow in an older adult that lacked an identifiable primary tumour using FDG-PET/CT and mimicked a haematological disease with pancytopenia but without abnormal findings by FDG-PET/CT.\n\nCase presentation\nA 61-year-old Caucasian female presented to an external hospital with a 2 month history of shortness of breath, anorexia and fatigue. She had pre-diagnosed obesity, liver cirrhosis (non-alcoholic fatty liver disease; Child-Pugh A), severe osteoporosis and peripheral edema due to chronic heart disease. On admission, the patient had no fever and no signs of infection, bleeding, haemolysis or acute decompensated heart failure. First laboratory assessments revealed a pancytopenia grade 2–3 including microcytic anaemia with haemoglobin of 7.6 g/dl, white blood cells of 1.7 billion/l and platelets of 74 billion/l, as well as reduced levels of iron, ferritin and vitamin B12. The differential leukocyte count revealed a slight left shift, but absence of blasts. Furthermore, electrolytes, lactatdehydrogenase (LDH), and serum markers for liver and kidney function were in normal ranges. Initial symptomatic treatment management mainly included blood transfusions leading to a fast recovery of the patient. To rule out a suspected haematological disease a bone marrow aspiration was performed, which demonstrated no evidence of malignancy. However, since adequate supplementation of iron and vitamin B12 did not improve the pancytopenia, and other medical reasons known to cause pancytopenia were excluded (e.g. medications, infections) bone marrow aspiration was repeated, this time including a biopsy. The bone marrow aspiration showed no sign of malignancy. Surprisingly, the immunohistological assessment revealed an infiltration (up to 35 %) of the bone marrow with ARMS (Fig. 1a top panel left) with strong positivity for desmin, CD56 and MyF4 (Fig. 1a bottom panel) and negativity in particular for NGFR, TLE1, Melan-A, MITF, HMB45, and S100 (data not shown). In addition, genetic analysis of the biopsy by reverse transcriptase-polymerase chain reaction (Fig. 1a top panel right) and Sanger sequencing (Fig. 1a top panel right) detected the PAX3-FKHR gene fusion. The patient was immediately referred to our university clinic for further evaluation.Fig. 1 \na Histological and genetic characteristics of bone marrow infiltrating cells. Top left Infiltration of the bone marrow by medium to large atypical cells (×40), right top corner (×100); top right Gelelectrophoresis of PAX/FKHR RT-PCR including positive and negative controls for PAX7- und PAX3-FKHR fusions in two dilutions (neat and 1:50), below results of Sanger sequencing; bottom panel the atypical cells express desmin, CD56 and MyF4. b\nLeft panel Whole body positron emission tomography (PET-CT); top right panel PET-CT indicating one single increased uptake in the right thyroid gland revealing follicular neoplasia; bottom right panel haemangioma in the 9th thoracic vertebrae\n\n\n\nStaging and work up of the occult primary tumour via whole body FDG-PET (Fig. 1b panel left) showed a single site of increased uptake in the right thyroid gland with absence of a corresponding lesion in the integrated computerised tomography (Fig. 1b top panel right). Histological investigation by fine needle aspiration of the respective thyroid gland revealed follicular neoplasia. Furthermore, adenoma of the right adrenal gland and haemangiomas in the 9th and 12th thoracic vertebrae (Fig. 1b bottom panel right) were diagnosed via FDG-PET/CT and were confirmed by magnetic resonance imaging (MRI). Otherwise, whole body FDG-PET/CT and MRI of the spine and head showed no suspicious uptake and/or lesions. In addition, upper gastrointestinal endoscopy and colonoscopy were performed without pathological findings. In summary, diagnosis of an ARMS confined to the bone marrow with no identifiable primary by FDG-PET/CT and which caused insufficient haematopoiesis with the need for regular blood transfusions was made.\n\nDue to co-morbidities and a reduced Eastern Cooperative Oncology Group (ECOG) performance status of three, we started the patient on topotecan 0.75 mg/m2/day (days 1–5) and cyclophosphamide 250 mg/m2/day (days 1–5) intravenously (i.v.). Chemotherapy-induced side effects included increased anorexia, fatigue with ECOG 4, and haematological toxicity with pancytopenia Common Terminology Criteria for Adverse Events (CTCAE) grade 3–4. Temporary, increased rates of transfusion (red blood cells and platelets) were necessary, as well as the application of iv. antibiotics and granulocyte-colony stimulating factor (G-CSF) due to recurrent fever-in-neutropenia. After the third cycle of chemotherapy, bone marrow aspiration and biopsy were repeated showing maturing trilineage haematopoiesis with no signs of RMS tumour cells. Due to the significant level of high-grade toxicities related to the applied combination chemotherapy and the significant response already achieved we decided to apply monotherapeutic vinorelbine 30 mg/m2/d d1 + d8 i.v. (max 60 mg abs./d; q3w) as a consolidation therapy. After the first cycle of vinorelbine, the patient developed muscle and joint pain, nausea/emesis, as well as autonomic neuropathy causing severe constipation. Subsequently, the acute side effects were treated adequately, and follow-up care was introduced.\n\nAt present, after a 7-months follow-up, the patient is still alive with an improved general state of health and only a mild pancytopenia with no need for blood transfusions.\n\nConclusion\nRhabdomyosarcoma is an aggressive type of sarcoma arising in the soft tissues of the body, like muscles, tendons, and connective tissues [1, 3]. A multimodal treatment including multiagent chemotherapy, radiotherapy, and surgery, is standard of care for this disease, and can lead to a relatively high rate of cure in young patients with local or regional RMS [1, 3, 7]. Improvements in risk stratifications have allowed the treatment assignment of pediatric patients in different therapeutic trials, leading to an increase of up to 70 % in 5 year survival [1, 3, 7]. However, for adult patients, in great part due to rarity of the disease and the lack of clear guidelines for standard treatment, as well as increased prevalence of advanced presentations, clinical outcome is still dismal. The presence of metastases is one of the most adverse prognostic factor in RMS, and bone marrow is a frequent site of tumour dissemination, especially in ARMS [8]. Therefore, with FDG-PET/CT the treatment algorithm has improved through more accurate staging including greater precision in detecting lymph node disease and distant metastases compared with anatomic imaging alone [4–6]. Moreover this case illustrates that frequently bone marrow smears alone are not sufficient to diagnose tumour infiltrations of the bone marrow and therefore a trephine is necessary in any unexplained pancytopenia and will not be replaced by bone marrow aspiration/cytology alone. Furthermore recent emerging data show that new techniques such as whole body diffusion weight (DW)-MRI alongside with molecular and genetic analysis could lead the way to further guide clinical decisions [9].\n\nTo the best of our knowledge, we present the first case of an adult patient with ARMS limited to the bone marrow with no identifiable primary tumour by FDG-PET/CT scan. We report this case for its rarity, occurrence in an adult with complete absence of a primary of ARMS, and to increase awareness in the diagnostic, as well as in the staging evaluation for the irreplaceable use of a bone marrow biopsy in suspected malignancies affecting the bone marrow.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.\n\n\nAbbreviations\nARMSalveolar subtype of rhabdomyosarcoma\n\nCTCAECommon Terminology Criteria for Adverse Events\n\nECOGEastern Cooperative Oncology Group\n\nFDGPET- F-18-fluorodeoxyglucose positron-emission tomography\n\nG-CSFgranulocyte-colony stimulating factor\n\nLDHlactatdehydrogenase\n\nMRImagnetic resonance imaging\n\nRMSrhabdomyosarcoma\n\nPanagiotis Karagiannis and Nina Guth contributed equally\n\nAuthors’ contributions\nPK, NG, NHT were involved in the clinical management of the patient. JS, IO, WK, EW contributed pathology review. CB contributed to radiological assessment and review. CB, GBT PK NHT wrote and reviewed the manuscript. All authors read and approved the final manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Meza JL Anderson J Pappo AS Meyer WH Analysis of prognostic factors in patients with nonmetastatic rhabdomyosarcoma treated on intergroup rhabdomyosarcoma studies III and IV: The Children’s Oncology Group J Clin Oncol 2006 24 24 3844 3851 10.1200/JCO.2005.05.3801 16921036 \n2. Sorensen PH Lynch JC Qualman SJ Tirabosco R Lim JF Maurer HM PAX3-FKHR and PAX7-FKHR gene fusions are prognostic indicators in alveolar rhabdomyosarcoma: a report from The Children’s Oncology Group J Clin Oncol 2002 20 11 2672 2679 10.1200/JCO.2002.03.137 12039929 \n3. Weiss AR Lyden ER Anderson JR Hawkins DS Spunt SL Walterhouse DO Histologic and clinical characteristics can guide staging evaluations for children and adolescents with rhabdomyosarcoma: a report from the children’s oncology group soft tissue sarcoma committee J Clin Oncol 2013 31 26 3226 3232 10.1200/JCO.2012.44.6476 23940218 \n4. Tateishi U Hosono A Makimoto A Nakamoto Y Kaneta T Fukuda H Comparative study of FDG PET/CT and conventional imaging in staging rhabdomyosarcoma Ann Nucl Med 2009 23 2 155 161 10.1007/s12149-008-0219-z 19225939 \n5. Völker T Denecke T Steffen I Misch D Schönberger S Plotkin M Positron emission tomography for staging of pediatric sarcoma patients: results of a prospective multicenter trial J Clin Oncol 2007 25 34 5435 5441 10.1200/JCO.2007.12.2473 18048826 \n6. Norman G Fayter D Lewis-Light K Chisholm J McHugh K Levine D An emerging evidence base for PET-CT in the management of childhood rhabdomyosarcoma: systematic review BMJ Open 2015 5 1 e006030 10.1136/bmjopen-2014-006030 25573522 \n7. Egas-Bejar D Huh WW Rhabdomyosarcoma in adolescent and young adult patients: current perspectives Adolesc Health Med Ther 2014 5 115 125 24966711 \n8. Ruymann FB Newton WA Jr Ragab AH Donaldson MH Foulkes M Bone marrow metastases at diagnosis in children and adolescents with rhabdomyosarcoma. A report from the intergroup rhabdomyosarcoma study Cancer 1984 53 2 368 373 10.1002/1097-0142(19840115)53:2<368::AID-CNCR2820530233>3.0.CO;2-3 6546301 \n9. Messiou C Kaiser M Whole body diffusion weighted MRI—a new view of myeloma Br J Haematol 2015 171 1 29 37 10.1111/bjh.13509 26013304\n\n",
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"journal": "Clinical sarcoma research",
"keywords": "Alveolar rhabdomyosarcoma; Bone marrow; FDG-PET; Rhabdomyosarcoma; Topotecan/cyclophosphamide; Vinorelbine",
"medline_ta": "Clin Sarcoma Res",
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"title": "Alveolar rhabdomyosarcoma confined to the bone marrow with no identifiable primary tumour using FDG-PET/CT.",
"title_normalized": "alveolar rhabdomyosarcoma confined to the bone marrow with no identifiable primary tumour using fdg pet ct"
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"abstract": "BACKGROUND\nSeizures of autoimmune etiology may occur independent of or predate syndromes of encephalitis. We report a child with \"pure\" autoimmune epilepsy followed up for 7 years to highlight long-term effects of this epilepsy and the importance of early initiation and appropriate escalation of immunosuppression to achieve a good long-term outcome.\n\n\nMETHODS\nA previously healthy 5-year-old Sri Lankan boy presented with acute, frequent, brief focal seizures of temporal-lobe semiology without clinical and investigatory findings suggestive of central nervous system infection, tumor, structural abnormality, or metabolic causes. His epilepsy showed poor response to increasing doses and combinations of antiseizure medications. Further investigations detected N-methyl-D-aspartate receptor antibodies in serum, but not cerebrospinal fluid. Treatment with intravenous methyl prednisolone and maintenance on mycophenolate resulted in a rapid reduction, with seizure freedom achieved within 5-6 weeks. He relapsed when immunotherapy and anti seizure medications were reduced after seizure freedom for 24 months. This, and subsequent relapses, showed poor response to modification of anti-seizure medications, but treatment with immunotherapy (methyl prednisolone and rituximab) achieved complete seizure freedom. At 7-years of follow-up, he remains free of seizure for over 3 years, and has average academic performance and satisfactory quality of life.\n\n\nCONCLUSIONS\nAutoimmune epilepsy is a recognized independent entity. Diagnostic criteria have been suggested for its early recognition and confirmation of diagnosis. Early diagnosis and initiation of immunosuppression, with prompt escalation of treatment when necessary, remains key to good patient outcome.",
"affiliations": "Department of Paediatrics, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka. jithangi@gmail.com.;Department of Clinical Medicine, University of Colombo, Colombo, Sri Lanka.",
"authors": "Wanigasinghe|Jithangi|J|http://orcid.org/0000-0002-9413-8363;Chang|Thashi|T|",
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"doi": "10.1186/s13256-021-03117-5",
"fulltext": "\n==== Front\nJ Med Case Rep\nJ Med Case Rep\nJournal of Medical Case Reports\n1752-1947\nBioMed Central London\n\n3117\n10.1186/s13256-021-03117-5\nCase Report\nAutoimmune epilepsy due to N-methyl-d-aspartate receptor antibodies in a child: a case report\nhttp://orcid.org/0000-0002-9413-8363\nWanigasinghe Jithangi jithangi@gmail.com\n\n1\nChang Thashi thashichang@gmail.com\n\n2\n1 grid.8065.b 0000000121828067 Department of Paediatrics, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka\n2 grid.8065.b 0000000121828067 Department of Clinical Medicine, University of Colombo, Colombo, Sri Lanka\n20 10 2021\n20 10 2021\n2021\n15 51613 4 2020\n18 9 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nIntroduction\n\nSeizures of autoimmune etiology may occur independent of or predate syndromes of encephalitis. We report a child with “pure” autoimmune epilepsy followed up for 7 years to highlight long-term effects of this epilepsy and the importance of early initiation and appropriate escalation of immunosuppression to achieve a good long-term outcome.\n\nCase presentation\n\nA previously healthy 5-year-old Sri Lankan boy presented with acute, frequent, brief focal seizures of temporal-lobe semiology without clinical and investigatory findings suggestive of central nervous system infection, tumor, structural abnormality, or metabolic causes. His epilepsy showed poor response to increasing doses and combinations of antiseizure medications. Further investigations detected N-methyl-d-aspartate receptor antibodies in serum, but not cerebrospinal fluid. Treatment with intravenous methyl prednisolone and maintenance on mycophenolate resulted in a rapid reduction, with seizure freedom achieved within 5–6 weeks. He relapsed when immunotherapy and anti seizure medications were reduced after seizure freedom for 24 months. This, and subsequent relapses, showed poor response to modification of anti-seizure medications, but treatment with immunotherapy (methyl prednisolone and rituximab) achieved complete seizure freedom. At 7-years of follow-up, he remains free of seizure for over 3 years, and has average academic performance and satisfactory quality of life.\n\nConclusions\n\nAutoimmune epilepsy is a recognized independent entity. Diagnostic criteria have been suggested for its early recognition and confirmation of diagnosis. Early diagnosis and initiation of immunosuppression, with prompt escalation of treatment when necessary, remains key to good patient outcome.\n\nKeywords\n\nAutoimmune epilepsy\nNMDAR antibodies\nRituximab\nSri Lanka\nissue-copyright-statement© The Author(s) 2021\n==== Body\npmcBackground\n\nAntibodies targeting neuronal surface proteins (NSAbs) are increasingly recognized in autoimmune central nervous system (CNS) disorders in which seizures are the main or an important feature. N-methyl-d-aspartate receptor (NMDAR) encephalitis and NSAb-associated limbic encephalitis are the two leading syndromes within this group [1]. However, it has been increasingly recognized that seizures of autoimmune etiology may occur independent of or predate syndromes of encephalitis [2, 3]. It is considered specifically in those with drug-resistant epilepsies and epilepsies of unknown etiology [4]. The International League Against Epilepsy (ILAE) in their 2017 classification identified autoimmunity as one of the etiological subcategories of epilepsy [5]. The potential for effective treatment with immune therapy calls for its consideration in all patients presenting with poorly controlled epilepsy without a known etiology or a recognized epilepsy syndrome. We reported the first case of NMDAR-antibody encephalitis in Sri Lanka in 2012 [6] and now report the first case of autoimmune epilepsy (AEp) from Sri Lanka, a resource-restricted setting. We discuss the initial presentation and subsequent long-term epilepsy and neurocognitive outcome over the 7-year follow-up. We wish to highlight the importance of early recognition and treatment, and document the need for prolonged therapy in some patients.\n\nCase history\n\nA 5-year-old, previously well, Sri Lankan boy presented in 2014 with recurrent seizures manifesting as staring episodes with behavioral arrest, progressively increasing from 10 to about 40 seizures a day. Some of the seizures were associated with autonomic features such as retching, vomiting, and tachycardia. In between seizures, his behavior fluctuated between normalcy, irritability, and increased sleepiness. Apart from two bouts of loose stools at the start of the illness, he remained afebrile without features of meningeal irritation such as neck stiffness or Kernig’s sign of papilledema. His cranial nerves, motor and sensory system, and cerebellar examination was normal. Glasgow Coma Scale score was 15/15. He did not have any abnormal movements or psychiatric manifestations. In between seizures, his pulse rate ranged from 90 to 100 beats per minute and blood pressure was 90/60 mmHg. His hematological and biochemical tests included full blood count (11.3 × 103 μ/L) with normal differential), C-reactive proteins (< 5.0 mg/L), erythrocyte sedimentation rate (10 mm/hour), calcium (9.2 mg/dL), magnesium (1.9 mg/dL), and serum sodium (136 mmol/L) and potassium (4.3 mmol/L). Renal, liver, and thyroid functions [serum glutamic pyruvic transaminase (SGPT) 14 U/L, serum glutamic oxaloacetic transaminase (SGOT) 33 U/L, and blood urea 14 U/L], serum creatinine (36 μmol/L), triiodothyronine (T3) (3.44 ng/dL), and thyroxine (T4) (1.2 ng/dL) were normal. In his very first electroencephalogram, only intermittent slowing with theta and delta activity over right temporal and occipital region was noted. Subsequent video monitoring identified seizures with staring, grimace, and versive head movements. Ictal recording showed bilateral attenuation of background, evolving to fast activity and rhythmic theta over temporal, and then frontal region over the right side. No delta brush was noted in these records. Computerized tomography and subsequent magnetic resonance imaging (MRI) of the brain were normal. Although he was afebrile, a lumbar puncture was performed considering the possibility of a CNS infection. Cerebrospinal fluid (CSF) analysis did not show a pleocytosis, and protein level was within normalcy (22/mm3 lymphocytes, 1/mm3 polymorphs, sugar of 3.9 mmol/L, and protein of 30 mg/dL); bacterial antigens were negative, and culture yielded no growth. Herpes simplex viral screen was negative. Stool analysis and culture were negative for infection. The initial electroencephalogram revealed intermittent slow background activity, particularly in the temporal and occipital regions. No focal or generalized epileptic discharges were recorded. No extreme delta brush was noted. He was the firstborn, with birth weight of 3.45 kg at 38 weeks. He did not have any major illness prior to this admission. There was no significant family history of note. He was only attending mainstream school in grade 2 at the time of onset of his illness.\n\nHe was initially treated with cefotaxime (50 mg/kg/dose 6-hourly) and aciclovir (250 mg/m2 8-hourly), which were discontinued when the CSF findings were normal, including herpes simplex virus 1 (HSV-1= viral polymerase chain reaction (PCR) in CSF. He was commenced simultaneously on intravenous followed by multiple oral antiseizure medications (ASMs). These were phenobarbitone given intravenously (20 mg/kg) and levetiracetam, carbamazepine, and clobazam given in escalating doses gradually via oral route. The dosages were 30 mg/kg/day, 18 mg/kg/day, and 5 mg/day, respectively, the seizures progressively reduced in frequency and duration to 10–15 brief seizures per day. He was discharged from hospital after 2 weeks on three ASMs, albeit with infrequent seizure recurrences.\n\nAlthough ASMs were increased in dose and in different combinations, there was no improvement in seizure control. Within the next 4 weeks, escalation up to 30–40 brief seizures per day, both with and without altered consciousness was noted. His serology at this point was negative for antinuclear, thyroglobulin, and thyroid peroxidase antibodies. Serum lactate level was 1.2 mmol/L. Facilities for advanced metabolic screening or genetic panels for epilepsy were unavailable. A repeat CSF analysis showed normal lactate and glucose values. However, examination of paired serum and CSF revealed presence of N-methyl-d-aspartate receptor (NMDAR) antibodies in serum but not in CSF (live cell-based assay, Oxford, UK). At this point, on retrospective analysis, we note that he fulfilled Antibody Prevalence in Epilepsy and Encephalopathy (APE2) score of 4 in the proposed autoimmune epilepsy diagnostic criteria described in 2017, in which a score of ≥ 4 predicts has a sensitivity of 98% and a specificity of 85% for prediction of neural specific antibody seropositivity [7].\n\nHe was treated with intravenous methylprednisolone 30 mg/kg/day for 3 days, which resulted in significant reduction of seizure frequency after the first pulse, followed by complete freedom of seizures after the second pulse a month later. He was maintained on oral prednisolone (2 mg/kg/day), followed by transition to mycophenolate mofetil (MMF) at a starting dosage of 600 mg/m2 twice daily. Serial ultrasonography excluded a testicular teratoma. On retrospective analysis, he can be considered to have demonstrated a Response to Immunotherapy in Epilepsy and Encephalopathy (RITE2) score of 8, which confirms his condition to be a definite autoimmune epilepsy.\n\nHe remained seizure free for 3 years and continued schooling with no concerns, and his behavior continued to be normal. Subsequent two electroencephalograms done annually showed no abnormality. However, he relapsed when attempting to tail off ASMs and MMF (March 2017). The repeat MRI of brain reviewed carefully remained normal without evidence of focal cortical dysplasia, and cortical or subcortical hyperintensities. The temporal lobes remained unchanged in hyperintensity or in size. Intensified treatment with levetiracetam (gradually up to 50 mg/kg/day), carbamazepine (20 mg/kg/day), and clobazam (10 mg/day) was ineffective, but pulsed intravenous steroids (methyl prednisolone 30 mg/kg/day for 3 days) given two times with 1-month interval resulted in complete resolution of seizures. One year later, while on regular MMF and ASMs, he relapsed with similar seizures (August 2018). Electroencephalography (EEG) at this point showed interictal epileptic activity over the right pericentral (C4) region and brief subclinical ictal activity consisting of rhythmic theta over the F4, Fz, and C4 region. Repeat serum and CSF examination detected persistence of NMDAR antibodies in low titers in the serum. Seizure resolution was achieved once again with pulsed high-dose intravenous steroids. To achieve longer remission, he was treated with rituximab (August 2019) given as four weekly doses of 375 mg/m2. Currently, he is 12 years old and has remained seizure-free for more than 2 years since last relapse in 2018 (Fig. 1). He schools in an age-appropriate grade with average academic performance comparable to his peers in school. His quality of life, assessed using the Sri Lankan Health Related Quality of Life Index for school children (SLHRQ-S), an age-specific, primary caregiver proxy rated, validated questionnaire for Sri Lankan children with epilepsy [8], demonstrated a mean score of 84.13. Individual scores were 83.3 (physical), 80.8 (psychological), and 88.3 (social) for the respective domains. These were within normal range of the validation scores.Fig. 1 The temporal profile of seizure frequency since presentation and its response to immunotherapy. The x-axis indicates the time course from presentation (red arrow) to last review (red star) with time points of relapses. Time points of immunotherapy (black arrows, intravenous methylprednisolone; orange arrow, rituximab) are indicated above the graph\n\nDiscussion\n\nThis report narrates the progression of a child with poorly controlled epilepsy, subsequently confirmed a definitive diagnosis of autoimmune epilepsy without encephalopathy, treated with progressive courses of immunotherapy resulting in normal childhood and intellectual growth with satisfactory quality of life. Early institution of immunotherapy and its timely escalation to achieve long-term remission is emphasized.\n\nIn the 2017 ILAE concept paper, “Epilepsy of immune aetiology” was considered for persons in whom “epilepsy was directly from an immune disorder in which the seizures are a core symptom of the disorder” [5]. Criteria and supportive features to diagnose AEp are presented in Table 1 [9]. Those with supportive criteria for AEp are divided into four groups: “definite,” “possible,” “probable,” and “unlikely” [10], which was subsequently modified to include a fifth category as “unknown AEp” [2]. In our patient, the diagnosis fulfilled “definite” criteria. Subsequent description of a predictive model in 2017 aided diagnosis, treatment, and prognostication of autoimmune epilepsy [11]. In this, an RITE2 score of ≥ 7 is associated with definite diagnosis of autoimmune epilepsy, with sensitivity of 88% and specificity of 84%; our patient had scored 8.Table 1 Diagnostic criteria for autoimmune epilepsy (AEp) [2]\n\nDiagnosis of AEp requires the presence of the following two clinical criteria:\t\n 1. Acute or subacute (< 12 weeks) onset of symptoms, and\t\n 2. Exclusion of other causes (CNS infection, trauma, toxic, tumor, metabolic, previous CNS disease)\t\nThe presence of at least one of the following supportive features would strengthen the suspicion of AEp:\t\n 1. The presence of a well-defined clinical syndrome such as NMDAR or limbic encephalitis;\t\n 2. CNS inflammation manifested by at least one of the following:\t\n a. CSF pleocytosis (defined as > 5 white cells/mm3) or presence of oligoclonal bands, elevated IgG index, or elevated neopterin (defined as > 30 nM);\t\n b. MRI abnormality compatible with an inflammatory or autoimmune encephalitis including increased signal in the mesio-temporal lobe (LE-like syndrome); or\t\n c. Inflammatory neuropathology on biopsy\t\n 3. History of other antibody-mediated conditions (for example myasthenia gravis), organ-specific autoimmunity, or other autoimmune disorders; or\t\n 4. Response to immunotherapy\t\nAEp Autoimmune epilepsy, CNS Central Nervous System, NMDAR N-methyl-D-aspartate receptor, CSF Cerebrospinal fluid, IgG Immunoglobulin, MRI Magnetic Resonance Imaging, LE Limbic encephalitis\n\nThe role of immunity in epileptogenesis is related to different types of immunity [12]. A specific role has been shown for innate immunity, where activation of glial cells occurs owing to release of inflammatory molecules in brain injury, convulsive events, and some genetic epilepsies [13]. Similarly, the peripheral immune system mediated by lymphocytes has been shown to play a role in disruption of the blood–brain barrier [14]. Additionally, an increasing number of clinical and neuropathological observations have shown that activation of inflammatory processes occurs in a variety of focal epilepsies without infectious or immune-mediated etiology [12].\n\nIn our patient, it is the adoptive immunity that plays a role in epileptogenicity. There has been a massive expansion of knowledge, particularly over the past two decades, with demonstration of causality between autoimmunity and several seizure-related diseases [13, 15]. Antibodies described in AEp include antibodies directed against intracellular proteins, such as glutamic acid decarboxylase 65-kilodalton isoform (GAD65), and NSAb directed against voltage-gated potassium channel (VGKC)-complex proteins, glutamate [NMDA and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)], and gamma-amino butyric acid-A (GABAA) and gamma-amino butyric acid-B (GABAB) receptors [13, 16]. Antibody-negative AEp has been reported in about 36% of patients [17]. AEp was initially described as part of a syndrome of encephalitis, but has now been recognized as an entity of its own, as seen in our patient who did not develop encephalitis over a period of 7 years of follow-up. It could be argued that early initiation of immunotherapy may have prevented the progression to encephalitis, but this appears less likely given the long follow-up and quiescent disease during periods of waning immunotherapy.\n\nImmunotherapy-responsive, CSF-negative but serum-positive NMDAR-antibody encephalitides have been previously reported, with the observation that serum antibodies were always higher than CSF in paired samples, and that, with time, previously present CSF antibodies may diminish with preserved serum antibodies [18, 19]. Indeed, this may have been the case in our patient, in whom NMDAR antibodies were tested late during the first presentation, while in the second presentation the serum antibody response being of low titer may have had a paired CSF titer that was not detectable. Furthermore, it has been hypothesized that immunoprecipitation of the antibody at the blood–brain barrier may account for this discrepancy of seropositive but CSF-negative autoimmune encephalitis in some patients [20].\n\nFeatures that would suggest an autoimmune etiology in epilepsy include young age at onset, previous normal health, multiple focal seizures occurring several times a day, temporal lobe semiology, and some specific seizure semiologies such as faciobrachial dystonia and paroxysmal dizzy spells, poor response to ASM, and negative brain imaging [17, 21]. Seizure semiologies suggesting AEp include usually brief, focal seizures, with or without retained awareness, rapid recovery with minimal post-ictal features, and occur with higher frequency in sleep. They may be multifocal and may have changing semiologies [21]. Other factors to suspect AEp include personal or family history of autoimmune disorders, or recent or past neoplasia [21]. Literature on specifics of treatment of AEp and its long-term outcome are rare but immunotherapy, if instituted early, has shown to result in good outcomes in epilepsies associated with NSAbs [21]. Type of therapy is mostly guided by recommendations available for autoimmune encephalitis, that is, steroids, plasmapheresis, and intravenous immunoglobulins as first-line immunotherapy; rituximab, cyclophosphamide, MMF, and azathioprine as second line; and tocilizumab and bortezomib as third-line therapy [22]. Treatment strategies for new-onset refractory status epilepticus (NORSE) have been described. Prospective studies are needed for establishing treatment algorithms specific for autoimmune epilepsy. Initiation of immune therapy early for AEp (within 6 months of disease onset) is shown to result in favorable seizure control [11]. This was the case in our patient. Larger reports of long-term outcomes will be useful to understand the disease evolution and its behavior with immune therapy.\n\nConclusion\n\nOur case report highlights the importance of early diagnosis of AEp, early treatment with immunotherapy, long-term clinical follow-up, and timely escalation and continuation of immunotherapy in achieving a good patient outcome, retaining intellectual development, and quality of life.\n\nAcknowledgements\n\nWe thankfully acknowledge Prof. Angela Vincent, Professor of Immunology, Nuffield Department of Clinical Neurosciences, University of Oxford, UK, for facilitating the immunodiagnostic assays.\n\nAuthors’ contributions\n\nJW—pediatric neurologist responsible for diagnosis and follow-up of the patient and writing up the case history. TC—neurologist contributed towards the follow-up of the patient and writing up the case history. Both the authors read and approved the final manuscript.\n\nFunding\n\nNone.\n\nAvailability of data and materials\n\nNot applicable.\n\nDeclarations\n\nEthics approval and consent to participate\n\nNot applicable.\n\nConsent for publication\n\nWritten informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\n\nBoth the authors declare that they have no competing interests.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Graus F Titulaer MJ Balu R Benseler S Bien CG Cellucci T Cortese I Dale RC Gelfand JM Geschwind M A clinical approach to diagnosis of autoimmune encephalitis Lancet Neurol 2016 15 4 391 404 10.1016/S1474-4422(15)00401-9 26906964\n2. Suleiman J Brilot F Lang B Vincent A Dale RC Autoimmune epilepsy in children: case series and proposed guidelines for identification Epilepsia 2013 54 6 1036 1045 10.1111/epi.12142 23551014\n3. Thompson J Bi M Murchison AG Makuch M Bien CG Chu K Farooque P Gelfand JM Geschwind MD Hirsch LJ The importance of early immunotherapy in patients with faciobrachial dystonic seizures Brain 2018 141 2 348 356 10.1093/brain/awx323 29272336\n4. Iorio R Assenza G Tombini M Colicchio G Della Marca G Benvenga A Damato V Rossini PM Vollono C Plantone D The detection of neural autoantibodies in patients with antiepileptic-drug-resistant epilepsy predicts response to immunotherapy Eur J Neurol 2015 22 1 70 78 10.1111/ene.12529 25112548\n5. Scheffer IE Berkovic S Capovilla G Connolly MB French J Guilhoto L Hirsch E Jain S Mathern GW Moshe SL ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology Epilepsia 2017 58 4 512 521 10.1111/epi.13709 28276062\n6. Wanigasinghe J Chang T Vincent A Treatment-responsive, reversible, autoimmune encephalitis in a child Ceylon Med J 2012 57 2 90 91 10.4038/cmj.v57i2.4466 22772791\n7. Dubey D Pittock SJ McKeon A Antibody prevalence in epilepsy and encephalopathy score: increased specificity and applicability Epilepsia 2019 60 2 367 369 10.1111/epi.14649 30727035\n8. Murugupillai R Wanigasinghe J Muniyandi R Arambepola C Development of a pilot health related quality of life tool for Sri Lankan children with epilepsy Sri Lanka J Child Health 2016 45 3 163 10.4038/sljch.v45i3.8024\n9. Suleiman J Brenner T Gill D Brilot F Antony J Vincent A Lang B Dale RC VGKC antibodies in pediatric encephalitis presenting with status epilepticus Neurology 2011 76 14 1252 1255 10.1212/WNL.0b013e3182143552 21464429\n10. Zuliani L Graus F Giometto B Bien C Vincent A Central nervous system neuronal surface antibody associated syndromes: review and guidelines for recognition J Neurol Neurosurg Psychiatry 2012 83 6 638 645 10.1136/jnnp-2011-301237 22448032\n11. Dubey D Singh J Britton JW Pittock SJ Flanagan EP Lennon VA Tillema JM Wirrell E Shin C So E Predictive models in the diagnosis and treatment of autoimmune epilepsy Epilepsia 2017 58 7 1181 1189 10.1111/epi.13797 28555833\n12. Vezzani A Lang B Aronica E Immunity and inflammation in epilepsy Cold Spring Harb Perspect Med 2015 6 2 a022699 10.1101/cshperspect.a022699 26684336\n13. Geis C Planaguma J Carreno M Graus F Dalmau J Autoimmune seizures and epilepsy J Clin Invest 2019 129 3 926 940 10.1172/JCI125178 30714986\n14. Wright S Vincent A Pediatric autoimmune epileptic encephalopathies J Child Neurol 2017 32 4 418 428 10.1177/0883073816685505 28056633\n15. McKnight K Jiang Y Hart Y Cavey A Wroe S Blank M Shoenfeld Y Vincent A Palace J Lang B Serum antibodies in epilepsy and seizure-associated disorders Neurology 2005 65 11 1730 1736 10.1212/01.wnl.0000187129.66353.13 16344514\n16. Irani SR Bien CG Lang B Autoimmune epilepsies Curr Opin Neurol 2011 24 2 146 153 10.1097/WCO.0b013e3283446f05 21358545\n17. Lv RJ Ren HT Guan HZ Cui T Shao XQ Seizure semiology: an important clinical clue to the diagnosis of autoimmune epilepsy Ann Clin Transl Neurol 2018 5 2 208 215 10.1002/acn3.520 29468181\n18. Zandi MS Paterson RW Ellul MA Jacobson L Al-Diwani A Jones JL Cox AL Lennox B Stamelou M Bhatia KP Clinical relevance of serum antibodies to extracellular N-methyl-d-aspartate receptor epitopes J Neurol Neurosurg Psychiatry 2015 86 7 708 713 10.1136/jnnp-2014-308736 25246644\n19. Warren N Swayne A Siskind D O'Gorman C Prain K Gillis D Blum S Serum and CSF Anti-NMDAR antibody testing in psychiatry J Neuropsychiatry Clin Neurosci 2020 32 2 154 160 10.1176/appi.neuropsych.19030079 31530118\n20. Castillo-Gomez E Kastner A Steiner J Schneider A Hettling B Poggi G Ostehr K Uhr M Asif AR Matzke M The brain as immunoprecipitator of serum autoantibodies against N-methyl-d-aspartate receptor subunit NR1 Ann Neurol 2016 79 1 144 151 10.1002/ana.24545 26505629\n21. Quek AM Britton JW McKeon A So E Lennon VA Shin C Klein C Watson RE Jr Kotsenas AL Lagerlund TD Autoimmune epilepsy: clinical characteristics and response to immunotherapy Arch Neurol 2012 69 5 582 593 10.1001/archneurol.2011.2985 22451162\n22. Stingl C Cardinale K Van Mater H An update on the treatment of pediatric autoimmune encephalitis Curr Treatm Opt Rheumatol 2018 4 1 14 28 10.1007/s40674-018-0089-z 29780690\n\n",
"fulltext_license": "CC BY",
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"issue": "15(1)",
"journal": "Journal of medical case reports",
"keywords": "Autoimmune epilepsy; NMDAR antibodies; Rituximab; Sri Lanka",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D060426:Anti-N-Methyl-D-Aspartate Receptor Encephalitis; D001323:Autoantibodies; D002648:Child; D002675:Child, Preschool; D004660:Encephalitis; D004827:Epilepsy; D006801:Humans; D008297:Male; D011788:Quality of Life; D016194:Receptors, N-Methyl-D-Aspartate; D012640:Seizures",
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"title": "Autoimmune epilepsy due to N-methyl-D-aspartate receptor antibodies in a child: a case report.",
"title_normalized": "autoimmune epilepsy due to n methyl d aspartate receptor antibodies in a child a case report"
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"abstract": "BACKGROUND\nRituximab has greatly improved the outcomes of ABO-incompatible living donor liver transplantation (ABO-I LDLT). To clarify the optimal regimen for rituximab in adult ABO-I LDLT, a multicenter study was conducted in Japan.\n\n\nMETHODS\nClinical data of 33 adult patients undergoing ABO-I LDLT at 15 centers in 2013 were retrospectively corrected.\n\n\nRESULTS\nThe targeted blood type was A1 in 18, B in 14, and AB in one patient. Rituximab was administered at 7 to 48 days before LT, at a dose of 375 mg/m2 in 12 patients, 500 mg in 15 patients, 300 mg in five patients, and 100 mg in one patient. Adverse effects of rituximab were tolerable. Overall 1-year patient survival was 81%; antibody-mediated rejection (AMR) occurred in three patients (9%), two of whom died. Rituximab dose was significantly lower in patients with AMR (P < 0.001, 137 ± 61 vs. 307 ± 66 mg/m2 ). Among rituximab dose (n = 28), local infusion (n = 11), splenectomy (n = 23), prophylactic intravenous immunoglobulins (n = 12), preoperative tacrolimus (n = 9), preoperative antimetabolites (n = 21), and plasmapheresis (n = 23), only rituximab dose was a significantly favorable factor for AMR (P < 0.001).\n\n\nCONCLUSIONS\nThe use of rituximab at sufficient doses is recommended in adult ABO-I LDLT.",
"affiliations": "Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan.;Department of Surgery, Osaka University, Osaka, Japan.;Department of Surgery, Kyoto University, Kyoto, Japan.",
"authors": "Egawa|Hiroto|H|;Umeshita|Koji|K|;Uemoto|Shinji|S|",
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"keywords": "Antibody-mediated rejection; Desensitization; Patient survival",
"medline_ta": "J Hepatobiliary Pancreat Sci",
"mesh_terms": "D000328:Adult; D001787:Blood Group Incompatibility; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007155:Immunologic Factors; D016031:Liver Transplantation; D019520:Living Donors; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D000069283:Rituximab",
"nlm_unique_id": "101528587",
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"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Optimal dosage regimen for rituximab in ABO-incompatible living donor liver transplantation.",
"title_normalized": "optimal dosage regimen for rituximab in abo incompatible living donor liver transplantation"
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"abstract": "Methimazole is a widely used antithyroid agent. Although methimazole is generally well tolerated, rare but severe cholestatic jaundice may occur. We described a 74-year-old woman who had a 10-year history of type 2 diabetes had developed severe jaundice and itching 1 month after receiving methimazole (10 mg tid) and propranolol (10 mg tid) for the treatment of hyperthyroidism. Clinical investigations revealed no evidence of any mechanical obstruction in the common bile duct or other obvious causes of hepatic injury, and the diagnosis methimazole-induced cholestasis was made on the basis of the temporal relationship between initiation of methimazole and onset of cholestasis. Methimazole was hence discontinued. However, the patient experienced a progressive worsening in cholestasis after receiving 2 weeks of ursodeoxycholic acid (UDCA) therapy. Prednisone therapy was then attempted. Liver function tests eventually improved with combination of glucocorticoids and ursodeoxycholic acid therapy. This case clearly showed that glucocorticoids could be a possible additional way of treatment for some cases of drug-induced cholestatic jaundice even in diabetic patients.",
"affiliations": "Department of Endocrinology, First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.",
"authors": "Zhang|Mei|M|;Zhou|Hongwen|H|;He|Ronghua|R|;Di|Fusong|F|;Yang|Liu|L|;Yang|Tao|T|",
"chemical_list": "D013956:Antithyroid Agents; D007004:Hypoglycemic Agents; D013256:Steroids; D008713:Methimazole",
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"journal": "Endocrine",
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"medline_ta": "Endocrine",
"mesh_terms": "D000368:Aged; D013956:Antithyroid Agents; D003924:Diabetes Mellitus, Type 2; D005260:Female; D006801:Humans; D006980:Hyperthyroidism; D007004:Hypoglycemic Agents; D041781:Jaundice, Obstructive; D008713:Methimazole; D012720:Severity of Illness Index; D013256:Steroids",
"nlm_unique_id": "9434444",
"other_id": null,
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"pubdate": "2010-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18386249;16720710;16845245;11821593;7714072;14982270;12904107;9773944;8876856;17872349",
"title": "Steroids for the treatment of methimazole-induced severe cholestatic jaundice in a 74-year-old woman with type 2 diabetes.",
"title_normalized": "steroids for the treatment of methimazole induced severe cholestatic jaundice in a 74 year old woman with type 2 diabetes"
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"abstract": "Rituximab-induced lung disease (R-ILD) is a rare entity that should be considered in patients treated with rituximab who present with dyspnea, fever, and cough, but no clear evidence of infection. A variety of pathologic findings have been described in this setting. Bronchiolitis obliterans organizing pneumonia (BOOP) is the most common clinicopathologic diagnosis, followed by interstitial pneumonitis, acute respiratory distress syndrome (ARDS), and hypersensitivity pneumonitis. Prompt diagnosis and treatment with corticosteroids are essential as discussed by Wagner et al. (2007). Here we present a case of an 82-year-old man who was treated with rituximab for recurrent marginal zone lymphoma. After the first infusion of rituximab, he reported fever, chills, and dyspnea. On computed tomography imaging, he was found to have bilateral patchy infiltrates, consistent with BOOP on biopsy. In our patient, BOOP was caused by single-agent rituximab, in the first week after the first infusion of rituximab. We reviewed the relevant literature to clarify the different presentations and characteristics of R-ILD and raise awareness of this relatively overlooked entity.",
"affiliations": "Department of Medicine, Fairview Hospital, Cleveland, OH 44111, USA.",
"authors": "Ergin|Ahmet B|AB|;Fong|Nancy|N|;Daw|Hamed A|HA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2012/680431",
"fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIMCase Reports in Medicine1687-96271687-9635Hindawi Publishing Corporation 10.1155/2012/680431Case ReportRituximab-Induced Bronchiolitis Obliterans Organizing Pneumonia Ergin Ahmet B. \n1\n*Fong Nancy \n2\nDaw Hamed A. \n3\n1Department of Medicine, Fairview Hospital, Cleveland, OH 44111, USA2Department of Pathology, Cleveland Clinic Cancer Center, Fairview Hospital, Cleveland, OH 44111, USA3Moll Pavilion, Fairview Hospital, Cleveland, OH 44111, USA*Ahmet B. Ergin: bahadirergin@gmail.comAcademic Editor: Bruno Megarbane\n\n2012 19 6 2012 2012 6804313 4 2012 10 5 2012 16 5 2012 Copyright © 2012 Ahmet B. Ergin et al.2012This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Rituximab-induced lung disease (R-ILD) is a rare entity that should be considered in patients treated with rituximab who present with dyspnea, fever, and cough, but no clear evidence of infection. A variety of pathologic findings have been described in this setting. Bronchiolitis obliterans organizing pneumonia (BOOP) is the most common clinicopathologic diagnosis, followed by interstitial pneumonitis, acute respiratory distress syndrome (ARDS), and hypersensitivity pneumonitis. Prompt diagnosis and treatment with corticosteroids are essential as discussed by Wagner et al. (2007). Here we present a case of an 82-year-old man who was treated with rituximab for recurrent marginal zone lymphoma. After the first infusion of rituximab, he reported fever, chills, and dyspnea. On computed tomography imaging, he was found to have bilateral patchy infiltrates, consistent with BOOP on biopsy. In our patient, BOOP was caused by single-agent rituximab, in the first week after the first infusion of rituximab. We reviewed the relevant literature to clarify the different presentations and characteristics of R-ILD and raise awareness of this relatively overlooked entity.\n==== Body\n1. Introduction\nRituximab, a mouse/human chimeric anti-CD20 antibody human monoclonal antibody has been effectively used to treat lymphoma since 1997. It has also been used for immune thrombocytopenic purpura, systemic lupus erythematous, rheumatoid arthritis, and autoimmune hemolytic anemia. Rituximab has been associated with infusion-related self-limited symptoms including fever, chills, and rigor [1]. Recently more severe lung pathologies were described. We prefer rituximab-induced lung disease (R-ILD) for this group of complications rather than rituximab-induced interstitial lung disease due to the variety of pathologic diagnoses seen in this setting. Here, we report a case of BOOP occurring in the first week of rituximab treatment and review the relevant literature.\n\n2. Case Report\nThe patient was an 82-year-old male with recurrent nodal marginal zone B-cell stage 4 lymphoma, mostly involving abdominal lymph nodes. His past medical history included IgG kappa monoclonal gammopathy, congestive heart failure, sick sinus syndrome, and hypertension. The patient presented to the hospital complaining of chills, fever, and dyspnea for two days, 4 days after receiving his first infusion of rituximab therapy (375 mg/m2) with a premedication including acetaminophen and diphenhydramine but not steroids. No history of recent upper respiratory infection, chest pain, acute blood loss, or new medications was reported. The patient was admitted to the hospital and started on broad-spectrum antibiotics. His routine blood counts, liver function test, renal function test, and D-dimer were normal. His shortness of breath progressively worsened over the course of 3 days. The patient developed hypoxic respiratory failure. On physical examination, he was tachypneic and tachycardic. Lung auscultation revealed bibasilar inspiratory crackles. Oxygen saturation was 90% on nonrebreather mask and arterial blood gas revealed a PO2 of 54 mmHg on 100% FiO2. CT of the chest showed bilateral diffuse patchy infiltrates involving 3/4 of the lung parenchyma (Figure 1). The patient had a previous PET CT one month ago which showed mild bilateral fibrous changes in the periphery of the lungs.\n\nThe patient was intubated and placed on mechanical ventilation. A two-dimensional echocardiogram (2D-Echo) showed left ventricular ejection fraction (EF) of 55%, stage 1-diastolic function and no valvular disease. BNP level was 95 pg/mL. Bronchoscopy with bronchoalveolar lavage and transbronchial biopsies was performed. Bacterial, viral, and fungal cultures were negative. BAL was negative for Pneumocystis jirovecii and malignant cells. Biopsy showed pulmonary parenchyma with patchy fibroblastic proliferation, suggestive of BOOP with no malignant or atypical cells (Figure 2).\n\nAntibiotics were discontinued and the patient was extubated, but continued to require high oxygen flow. Methylprednisolone 40 mg IV every 8 hours was started with a gradual improvement in his oxygen saturation over the next few days. Follow-up CT scan of the chest two weeks after starting steroids showed improvement in the bilateral pulmonary infiltrates. He was switched to oral prednisone at a dose 60 mg daily with a weaning plan over the next few months. After discharge to home, he no longer required oxygen.\n\n3. Discussion\nTwo aspects are remarkable in this case report. First, BOOP presentation was early in the first week following rituximab treatment, which has not been reported before. Second, this is one of the initial reports of BOOP following single-agent rituximab treatment.\n\nRituximab was approved by the FDA in 1997 for lymphoma treatment. Patients are given one to six infusions at intervals depending on the type of lymphoma. Rituximab is given as a single agent or in combination regimens. It is overall a well-tolerated drug [2–5], with lung toxicity rate of less than 0.03% among 540,000 patients [2].\n\nNotwithstanding, many life-threatening pulmonary side effects were reported [1, 6–13]. A prospective Korean study described 107 patients with non-Hodgkin lymphoma treated with a rituximab-containing regimen. Among these patients, 9 (8%) developed interstitial pneumonitis during rituximab therapy [12], suggesting a higher incidence of R-ILD than previously considered. Many factors may account for the limited number of R-ILD reported cases. The first factor is reporting bias due to poor outcomes; the second is the failure to recognize this complication by attributing symptoms to infections or to the underlying disease; and the third is the common use of corticosteroids for suspected reactive airway disease which may treat R-ILD in some patients [1].\n\nAlthough presentation and clinical features are very similar, there is some variation regarding pathologic descriptions of R-ILD. Among reported cases in which pathology reports were available, the predominant finding was BOOP [8, 10, 14–19]. Interstitial pneumonia/pneumonitis with or without interstitial fibrosis was the second most common diagnosis [1, 10, 20–22]. Five ARDS cases were identified as infusion reactions to rituximab [23]. Hypersensitivity pneumonitis was reported in 3 case reports [15, 19, 21] which were also biopsy proven. In 2 cases, R-ILD was complicated by alveolar hemorrhage [15, 21].\n\nR-ILD is a diagnosis of exclusion. Differential diagnoses includes lymphoma progression, infection, cardiogenic edema, radiation pneumonitis, pulmonary hemorrhage, and allergies. There is no clear consensus in regards to criteria for rituximab causality. Our criteria were the following.\n\n3.1. Clinical Manifestation\nClinical findings of R-ILD consist of dyspnea (85%), fever (62%), and cough (43%) [23]. High-resolution CT of the chest demonstrates diffuse interstitial pattern (ground glass opacities) (34%), focal alveolar pattern (54%), and diffuse alveolar pattern (8.5%) [23]. The predominant abnormalities on pulmonary function test when performed, associates a restrictive pattern with a reduction in the diffusion capacity of CO (DLCO) [24–26]. Additionally, a bronchoscopy with bronchoalveolar lavage is required to rule out an infectious aetiology while biopsy can demonstrate interstitial fibrosis or alveolitis. We did not perform a pulmonary function test due to the rapid deterioration of our patient.\n\n3.2. Rechallenge\nRechallenge has its own limitations given the possibility of fatal outcome. In a study with Lioté et al. [23], rechallenge, either intentional or unintentional, gave positive results in 4 patients with rituximab alone [10, 25, 27, 28] and in eight patients with rituximab combination therapy [10, 12, 15, 20, 26, 28]. Rechallenge gave negative results in 3 patients who also took concomitant steroid treatment [23]. \n\n3.3. Time to Onset\nLioté et al. [23] reported a mean time of symptom onset of 3 months with a peak after the fourth cycle of treatment. There was a significant variance in timing, even with similar pathologic findings. Delay from the last rituximab infusion to the onset of respiratory manifestations was about 15 days in their review. Our patient reported symptoms on the 5th day after rituximab treatment.\n\n3.4. Exclusion of Other Medications\nRituximab has been given as a single agent in 7 patients with reported R-ILD [8, 18, 19, 24, 25, 27]. In other cases, rituximab was given as part of a chemotherapy regimen, most often combined with CHOP (cyclophosphamide, vincristine, doxorubicin, and prednisone). Cyclophosphamide and bleomycin are known to cause early onset pneumonitis. Among 107 patients treated with R-CHOP regimen, 9 patients developed interstitial pneumonitis when compared to none of the 66 patients treated with CHOP alone [12].\n\nPathogenesis of R-ILD is largely unknown [1]. Rituximab acts by binding CD20+ B cells. Toxicity and efficacy are related to events after binding, which include B-cell signaling, complement activation, direct apoptosis, and antibody-dependent cellular cytotoxicity [29]. Complement activation and cytokine secretion, in particular, seems to be the causative factors associated with rituximab infusion reactions [24, 29, 30]. TNF-α has been postulated to be the major inflammatory mediator in ILD pathogenesis by inducing chemokines, other inflammatory cytokines, and angiogenic factors [31]. Interestingly, serum levels of TNF-α, interferon gamma, and interleukin-4 were elevated only in the R-ILD patient where they were checked [32].\n\nCorticosteroids are the cornerstone of treatment. We found 8 case reports in which patients with R-ILD expired despite steroid treatment [1, 7–13]. There was only one BOOP patient which was not biopsy-proven who died while on steroids [6]. On the basis of the proposed pathophysiology of the lung injury, anti-TNF-a directed therapy infliximab might have a role in severe cases and patients whose clinical condition worsens despite corticosteroids.\n\nIn conclusion, we presented a patient with clinical and pathological features of BOOP consistent with R-ILD. This is the first case of such an early presentation (in first week after the first infusion) and the second case report of BOOP after single-agent rituximab therapy. The patient responded well to steroids supporting its efficacy. Because symptoms at presentation are nonspecific, physicians should maintain a high index of suspicion to recognize this complication. Awareness of R-ILD is of utmost importance in order to prevent severe morbidity and mortality.\n\nFigure 1 Computed tomography (CT) of the chest at the initial presentation of patient on the fifth day following rituximab treatment (a) and 20 days after initiation of steroid treatment (b). Arrows show bilateral pulmonary patchy infiltrates.\n\nFigure 2 Transbronchial biopsy of the lung. Arrows point at myxoid fibroblastic plugs of bronchiolitis obliterans organizing pneumonia (BOOP).\n==== Refs\n1 Wagner SA Mehta AC Laber DA Rituximab-induced interstitial lung disease American Journal of Hematology 2007 82 10 916 919 2-s2.0-34848909646 17597477 \n2 Kimby E Tolerability and safety of rituximab (MabThera) Cancer Treatment Reviews 2005 31 6 456 473 2-s2.0-27544508559 16054760 \n3 Solal-Céligny P Safety of rituximab maintenance therapy in follicular lymphomas Leukemia Research 2006 30 1 S16 S21 2-s2.0-33745912498 16750674 \n4 Cvetković RS Perry CM Rituximab: a review of its use in non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia Drugs 2006 66 6 791 820 2-s2.0-33646894910 16706552 \n5 Mohrbacher A B cell non-Hodgkin’s lymphoma: rituximab safety experience Arthritis Research and Therapy 2005 7 3 S19 S25 2-s2.0-21644469786 15960818 \n6 Davis TA White CA Grillo-López AJ Single-agent monoclonal antibody efficacy in bulky non-Hodgkin’s lymphoma: results of a phase II trial of rituximab Journal of Clinical Oncology 1999 17 6 1851 1857 2-s2.0-0033067232 10561225 \n7 Hainsworth JD Litchy S Lamb MR Rodriguez GI Scroggin C Jr. Greco FA First-line treatment with brief-duration chemotherapy plus rituximab in elderly patients with intermediate-grade Non-Hodgkin’s lymphoma: phase II trial Clinical Lymphoma 2003 4 1 36 42 2-s2.0-0038015602 12837153 \n8 Leon RJ Gonsalvo A Salas R Hidalgo NC Rituximab-induced acute pulmonary fibrosis Mayo Clinic Proceedings 2004 79 7 949 953 2-s2.0-3042853058 15244399 \n9 Ghesquieres H Severe interstitial pneumonitis following rituximab and bleomycin-containing combination chemotherapy Annals of Oncology 2005 16 8 p. 1399 2-s2.0-23844534141 \n10 Herishanu Y Polliack A Leider-Trejo L Grieff Y Metser U Naparstek E Fatal interstitial pneumonitis related to rituximab-containing regimen Clinical Lymphoma and Myeloma 2006 6 5 407 409 2-s2.0-33646565355 16640819 \n11 Wu SJ Chou WC Ko BS Tien HF Severe pulmonary complications after initial treatment with rituximab for the Asian-variant of intravascular lymphoma Haematologica 2007 92 1 141 142 2-s2.0-33846916924 17229654 \n12 Liu X Hong XN Gu YJ Wang BY Luo ZG Cao J Interstitial pneumonitis during rituximab-containing chemotherapy for non-Hodgkin lymphoma Leukemia and Lymphoma 2008 49 9 1778 1783 2-s2.0-52349097837 18798110 \n13 Montero AJ McCarthy JJ Chen G Rice L Acute respiratory distress syndrome after rituximab infusion International Journal of Hematology 2005 82 4 324 326 2-s2.0-33644664959 16298824 \n14 Feenstra JFE Hickey BP Blackwell EA Acute respiratory failure associated with cladribine pneumonitis Internal Medicine Journal 2004 34 9-10 583 584 2-s2.0-8344289044 15482276 \n15 Alexandrescu DT Dutcher JP O’Boyle K Albulak M Oiseth S Wiernik PH Fatal intra-alveolar hemorrhage after rituximab in a patient with non-Hodgkin lymphoma Leukemia and Lymphoma 2004 45 11 2321 2325 2-s2.0-8644274721 15512824 \n16 Macartney C Burke E Elborn S Bronchiolitis obliterans organizing pneumonia in a patient with non-Hodgkin’s lymphoma following R-CHOP and pegylated filgrastim Leukemia and Lymphoma 2005 46 10 1523 1526 2-s2.0-26944446202 16194900 \n17 Mian M Rass C Hutarew G Kofler B Fiegl M Greil R Extensive organizing pneumonia during chemo-immunotherapy containing rituximab and G-CSF in a patient with diffuse large B-cell lymphoma: case report and review of the literature Leukemia and Lymphoma 2006 47 8 1683 1685 2-s2.0-33748569810 16966286 \n18 Biehn SE Kirk D Rivera MP Martinez AE Khandani AH Orlowski RZ Bronchiolitis obliterans with organizing pneumonia after rituximab therapy for non-Hodgkin’s lymphoma Hematological Oncology 2006 24 4 234 237 2-s2.0-33845927593 16948177 \n19 Tonelli AR Lottenberg R Allan RW Sriram PS Rituximab-induced hypersensitivity pneumonitis Respiration 2009 78 2 225 229 2-s2.0-68549088877 18843175 \n20 Byrd JC Peterson BL Morrison VA Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from cancer and leukemia group B 9712 (CALGB 9712) Blood 2003 101 1 6 14 2-s2.0-0037220152 12393429 \n21 Heresi GA Farver CF Stoller JK Interstitial pneumonitis and alveolar hemorrhage complicating use of rituximab: case report and review of the literature Respiration 2008 76 4 449 453 2-s2.0-56649087902 17596682 \n22 Kim KM Kim HC Jeon KN Rituximab-CHOP induced interstitial pneumonitis in patients with disseminated extranodal marginal zone B cell lymphoma Yonsei Medical Journal 2008 49 1 155 158 2-s2.0-41949127888 18306483 \n23 Lioté H Lioté F Séroussi B Mayaud C Cadranel J Rituximab-induced lung disease: a systematic literature review European Respiratory Journal 2010 35 3 681 687 2-s2.0-77951158777 19608586 \n24 Burton C Kaczmarski R Jan-Mohamed R Benyunes MC Multani PS Saunders A Interstitial pneumonitis related to rituximab therapy The New England Journal of Medicine 2003 348 26 2690 2691 2-s2.0-0038309767 12826649 \n25 Swords R Power D Fay M O’Donnell R Murphy PT Interstitial pneumonitis following rituximab therapy for immune thrombocytopenic purpura (ITP) American Journal of Hematology 2004 77 1 103 104 2-s2.0-4243132721 \n26 Lee Y Kyung SY Choi SJ Two cases of interstitial pneumonitis caused by rituximab therapy Korean Journal of Internal Medicine 2006 21 3 183 186 2-s2.0-37849188122 17017668 \n27 Kanelli S Ansell SM Habermann TM Inwards DJ Tuinstra N Witzig TE Rituximab toxicity in patients with peripheral blood malignant B-cell lymphocytosis Leukemia and Lymphoma 2001 42 6 1329 1337 2-s2.0-0035697071 11911416 \n28 Nieuwenhuizen L Verzijlbergen FJ Wiltink E Grutters JC Biesma DH A possible role of 18F-FDG positron-emission tomography scanning in the early detection of rituximab-induced pneumonitis in patients with non-Hodgkin’s lymphoma Haematologica 2008 93 8 1267 1269 2-s2.0-48749097315 18556403 \n29 Smith MR Rituximab (monoclonal anti-CD20 antibody): mechanisms of action and resistance. Oncogene 2003 22 47 7359 7368 2-s2.0-0642312825 14576843 \n30 Bienvenu J Chvetzoff R Salles G Tumor necrosis factor α release is a major biological event associated with rituximab treatment Hematology Journal 2001 2 6 378 384 2-s2.0-0035677256 11920277 \n31 Alho HS Maasilta PK Harjula ALJ Hämmäinen P Salminen J Salminen US Tumor necrosis factor-α in a porcine bronchial model of obliterative bronchiolitis Transplantation 2003 76 3 516 523 2-s2.0-0042968643 12923437 \n32 Hiraga J Kondoh Y Taniguchi H Kinoshita T Naoe T A case of interstitial pneumonia induced by rituximab therapy International Journal of Hematology 2005 81 2 169 170 2-s2.0-13944264955 15765788\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "2012()",
"journal": "Case reports in medicine",
"keywords": null,
"medline_ta": "Case Rep Med",
"mesh_terms": null,
"nlm_unique_id": "101512910",
"other_id": null,
"pages": "680431",
"pmc": null,
"pmid": "22778751",
"pubdate": "2012",
"publication_types": "D016428:Journal Article",
"references": "15512824;12826649;12393429;17597477;17596682;11911416;16966286;16194900;16750674;16054760;15960818;12923437;16298824;17017668;16948177;14576843;15482276;18306483;18843175;15307117;16706552;18798110;17229654;15244399;15857843;19608586;15765788;10561225;16640819;12837153;11920277;18556403",
"title": "Rituximab-induced bronchiolitis obliterans organizing pneumonia.",
"title_normalized": "rituximab induced bronchiolitis obliterans organizing pneumonia"
} | [
{
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"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
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{
"abstract": "BACKGROUND\nNeuroendocrine tumors are uncommon tumors that are histopathologically and biologically heterogeneous and include the multiple endocrine neoplasia (MEN) 1 and 2 syndromes. The morbidity of MEN-1 and MEN-2 is often due to the symptomatology of the endocrine hormones produced, and the mortality mainly occurs from hepatic dysfunction incurred by liver metastases. At present, there is essentially no effective cure once the tumor has metastasized to the liver.\n\n\nMETHODS\nWe present a patient with progressive, metastatic MEN-1 with the classic '3 P's' triad of neuroendocrine tumor of the pancreas, parathyroid adenoma and a pituitary adenoma.\n\n\nRESULTS\nAfter progression on high-dose Sandostatin LAR (60 mg/month) and multiple surgeries, the patient had a partial response (40% decrease) to a novel regimen of capecitabine and temozolomide (CAPTEM) and progression-free survival of 18 months. He had minor grade 1 toxicities and no grade 2, 3 or 4 toxicities.\n\n\nCONCLUSIONS\nThe history and treatment options for MEN-1/2 cancers are reviewed, as well as the data behind our novel regimen, CAPTEM.\n\n\nCONCLUSIONS\nThe CAPTEM regimen is a tolerable, safe, easy to administer oral regimen with possible efficacy for MEN-1 tumors.",
"affiliations": "Experimental Therapeutics Program, Division of Medical Oncology, New York Presbyterian-Columbia University Medical Center, New York, N.Y., USA.",
"authors": "Gulati|Anthony P|AP|;Krantz|Benjamin|B|;Moss|Rebecca A|RA|;Moyal|Wendy N|WN|;Tsushima|Dawn A|DA|;Mowatt|Kelley B|KB|;Schreibman|Stephen|S|;Fine|Robert L|RL|",
"chemical_list": "D003841:Deoxycytidine; D000069287:Capecitabine; D003606:Dacarbazine; D005472:Fluorouracil; D000077204:Temozolomide",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000342961",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0030-2414",
"issue": "84(3)",
"journal": "Oncology",
"keywords": null,
"medline_ta": "Oncology",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D000069287:Capecitabine; D003606:Dacarbazine; D003841:Deoxycytidine; D005472:Fluorouracil; D006801:Humans; D008297:Male; D008875:Middle Aged; D018761:Multiple Endocrine Neoplasia Type 1; D018813:Multiple Endocrine Neoplasia Type 2a; D011379:Prognosis; D012196:Review Literature as Topic; D000077204:Temozolomide; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "0135054",
"other_id": null,
"pages": "127-34",
"pmc": null,
"pmid": "23235517",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Treatment of multiple endocrine neoplasia 1/2 tumors: case report and review of the literature.",
"title_normalized": "treatment of multiple endocrine neoplasia 1 2 tumors case report and review of the literature"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2015US-97624",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
"dr... |
{
"abstract": "Pseudotumor cerebri, an uncommon complication following BMT, has been generally associated with cyclosporin A neurotoxicity. However, it has not previously been reported as a clinical presentation of sinusitis in spite of its high incidence after BMT. We report a case of pseudotumor cerebri secondary to sinusitis in a child with acute lymphoblastic leukemia and who underwent unrelated bone marrow transplantation.",
"affiliations": "Department of Pediatric Hematology-Oncology, Niño Jesús Children Hospital, Madrid, Spain.",
"authors": "González Vicent|M|M|;Díaz|M A|MA|;Madero|L|L|",
"chemical_list": "D007166:Immunosuppressive Agents; D016572:Cyclosporine",
"country": "Germany",
"delete": false,
"doi": "10.1007/s002770000262",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0939-5555",
"issue": "80(4)",
"journal": "Annals of hematology",
"keywords": null,
"medline_ta": "Ann Hematol",
"mesh_terms": "D016026:Bone Marrow Transplantation; D002051:Burkitt Lymphoma; D002648:Child; D016572:Cyclosporine; D005260:Female; D005334:Fever; D006801:Humans; D007166:Immunosuppressive Agents; D009682:Magnetic Resonance Spectroscopy; D011559:Pseudotumor Cerebri; D012852:Sinusitis; D014057:Tomography, X-Ray Computed; D014184:Transplantation, Homologous",
"nlm_unique_id": "9107334",
"other_id": null,
"pages": "236-7",
"pmc": null,
"pmid": "11401091",
"pubdate": "2001-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "\"Pseudotumor cerebri\" following allogeneic bone marrow transplantation (BMT).",
"title_normalized": "pseudotumor cerebri following allogeneic bone marrow transplantation bmt"
} | [
{
"companynumb": "ES-PFIZER INC-2020406103",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHOTREXATE"
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"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nNeuropsychiatric side effects of oseltamivir occur occasionally, especially in infants and young patients, but nothing is known about possible contributory factors.\n\n\nMETHODS\nWe report a case of a 15-year-old Japanese female with influenza infection who developed abnormal psychiatric symptoms after administration of standard doses of oseltamivir. She had no history of neurological illness, had never previously taken oseltamivir, and had not developed psychiatric reactions during previous influenza infection. Her delirium-like symptoms, including insomnia, visual hallucinations, and a long-term memory deficit, disappeared after cessation of oseltamivir and administration of benzodiazepine. Detailed assessment was performed, including neurological examination (electroencephalogram, brain magnetic resonance imaging, single photon emission computed tomography with 99mTc-ethyl cysteinate dimer and with (123)I-iomazenil, cerebrospinal fluid analysis and glutamate receptor autoantibodies), drug level determination and simulation, and genetic assessment (OAT1, OAT3, CES1, Neu2).\n\n\nCONCLUSIONS\nAbnormal slowing in the electroencephalogram, which is characteristic of influenza-associated encephalopathy, was not observed in repeated recordings. The serum level determination of active metabolite Ro 64-0802 determined at 154 h after final dosing of oseltamivir was higher than the expected value, suggesting delayed elimination of Ro 64-0802. Thus, abnormal exposure to Ro 64-0802 might have contributed, at least in part, to the development of neuropsychiatric symptoms in this patient. The score on Naranjo's adverse drug reaction probability scale was 6. Mutation of c.122G > A (R41Q) in the sialidase Neu2 gene, increased CSF glutamate receptor autoantibodies, and limbic GABAergic dysfunction indicated by SPECT with (123)I-iomazenil were found as possible contributory factors to the CNS side effects.",
"affiliations": "Department of Pharmacology, Graduate School, Takasaki University of Health and Welfare, 60 Nakaorui-machi, Takasaki-city, Gunma, Japan. morimoto@tohoku-pharm.ac.jp.;Department of General Pediatrics and Interdisciplinary Medicine, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan. nagaoka-k@khe.biglobe.ne.jp.;Department of General Pediatrics and Interdisciplinary Medicine, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan. nagai-ak@ncchd.go.jp.;Division of Neurology, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan. kashii-tky@umin.ac.jp.;Faculty of Pharmaceutical Sciences, Chiba Institute of Science, 15-8 Shiomi-cho, Choshi-city, Chiba, Japan. masakiyo@cis.ac.jp.;Department of Pediatrics, National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Urushiyama 886, Aoi-ku, Shizuoka, 420-8688, Japan. yukito@hosp.go.jp.;Department of Pharmacology, Graduate School, Takasaki University of Health and Welfare, 60 Nakaorui-machi, Takasaki-city, Gunma, Japan. togihara@takasaki-u.ac.jp.;Division of Neurology, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan. mkmegped@opal.plala.or.jp.",
"authors": "Morimoto|Kaori|K|;Nagaoka|Kei|K|;Nagai|Akira|A|;Kashii|Hirofumi|H|;Hosokawa|Masakiyo|M|;Takahashi|Yukitoshi|Y|;Ogihara|Takuo|T|;Kubota|Masaya|M|",
"chemical_list": "D000998:Antiviral Agents; D053139:Oseltamivir",
"country": "England",
"delete": false,
"doi": "10.1186/s12883-015-0393-2",
"fulltext": "\n==== Front\nBMC NeurolBMC NeurolBMC Neurology1471-2377BioMed Central London 39310.1186/s12883-015-0393-2Case ReportAnalysis of a child who developed abnormal neuropsychiatric symptoms after administration of oseltamivir: a case report Morimoto Kaori morimoto@tohoku-pharm.ac.jp Nagaoka Kei nagaoka-k@khe.biglobe.ne.jp Nagai Akira nagai-ak@ncchd.go.jp Kashii Hirofumi kashii-tky@umin.ac.jp Hosokawa Masakiyo masakiyo@cis.ac.jp Takahashi Yukitoshi yukito@hosp.go.jp Ogihara Takuo togihara@takasaki-u.ac.jp Kubota Masaya +3-3416-0181mkmegped@opal.plala.or.jp Department of Pharmacology, Graduate School, Takasaki University of Health and Welfare, 60 Nakaorui-machi, Takasaki-city, Gunma Japan Department of Drug Absorption and Pharmacokinetics, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai-city, Miyagi Japan Department of General Pediatrics and Interdisciplinary Medicine, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535 Japan Division of Neurology, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535 Japan Faculty of Pharmaceutical Sciences, Chiba Institute of Science, 15-8 Shiomi-cho, Choshi-city, Chiba Japan Department of Pediatrics, National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Urushiyama 886, Aoi-ku, Shizuoka 420-8688 Japan 5 8 2015 5 8 2015 2015 15 1308 4 2015 28 7 2015 © Morimoto et al. 2015\nOpen Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nNeuropsychiatric side effects of oseltamivir occur occasionally, especially in infants and young patients, but nothing is known about possible contributory factors.\n\nCase presentation\nWe report a case of a 15-year-old Japanese female with influenza infection who developed abnormal psychiatric symptoms after administration of standard doses of oseltamivir. She had no history of neurological illness, had never previously taken oseltamivir, and had not developed psychiatric reactions during previous influenza infection. Her delirium-like symptoms, including insomnia, visual hallucinations, and a long-term memory deficit, disappeared after cessation of oseltamivir and administration of benzodiazepine. Detailed assessment was performed, including neurological examination (electroencephalogram, brain magnetic resonance imaging, single photon emission computed tomography with 99mTc-ethyl cysteinate dimer and with 123I-iomazenil, cerebrospinal fluid analysis and glutamate receptor autoantibodies), drug level determination and simulation, and genetic assessment (OAT1, OAT3, CES1, Neu2).\n\nConclusions\nAbnormal slowing in the electroencephalogram, which is characteristic of influenza-associated encephalopathy, was not observed in repeated recordings. The serum level determination of active metabolite Ro 64-0802 determined at 154 h after final dosing of oseltamivir was higher than the expected value, suggesting delayed elimination of Ro 64-0802. Thus, abnormal exposure to Ro 64-0802 might have contributed, at least in part, to the development of neuropsychiatric symptoms in this patient. The score on Naranjo’s adverse drug reaction probability scale was 6. Mutation of c.122G > A (R41Q) in the sialidase Neu2 gene, increased CSF glutamate receptor autoantibodies, and limbic GABAergic dysfunction indicated by SPECT with 123I-iomazenil were found as possible contributory factors to the CNS side effects.\n\nElectronic supplementary material\nThe online version of this article (doi:10.1186/s12883-015-0393-2) contains supplementary material, which is available to authorized users.\n\nKeywords\nOseltamivirNeuropsychiatric symptomsSerum concentrationissue-copyright-statement© The Author(s) 2015\n==== Body\nBackground\nOseltamivir is a prodrug of the neuraminidase inhibitor [3R,4R,5S]-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid (Ro 64-0802), which targets the influenza virus. Despite good tolerance of this drug by most patients, there have been reports of neuropsychiatric side effects, especially in infants and young patients [1]. However, contributory factors to the development of neuropsychiatric reactions after administration of oseltamivir are presently unknown.\n\nCase presentation\nThis previously healthy 15-year-old Japanese girl developed fever and was diagnosed with influenza A virus infection based on a positive result with a rapid detection kit in 2009, during the pandemic influenza (H1N1) period. She had not previously taken oseltamivir, and had not developed neuropsychiatric symptoms in her previous influenza infection; this was her first admission to a neurological ward. The day after oseltamivir was started, her fever subsided, but the family noticed unusual behavior, such as doing her makeup at midnight and littering her room. She took 5 doses of 2 mg/kg (150 mg/day, b.i.d., 36 kg in weight) of oseltamivir every twelve hours and concomitantly took dihydrocodeine, ambroxol, benproperine, azithromycin and clarithromycin. There is no report of neuropsychiatric symptoms associated with these concomitant medications, except clarithromycin (clarithromycin occasionally induces altered mental status accompanied with electroencephalogram (EEG) abnormality, mostly in adults with psychiatric illness [2]). The symptoms did not fluctuate according to oseltamivir dosing times. After 3 days, she suddenly left her home and was found standing in front of an unknown apartment. Her family discontinued oseltamivir at that point. Because her bizarre behaviors continued after cessation of oseltamivir (for example, she complained of hearing voices of strange men), she was admitted to our hospital with suspected influenza encephalopathy. She developed delirium-like symptoms, such as insomnia, disorientation, visual hallucinations, a long-term memory deficit, abnormal behaviors (e.g., persistent ritual sneezing) and delusion (e.g., insisting that she was pregnant), but showed normal responses intermittently, especially during benzodiazepine infusion (diazepam or midazolam). Midazolam infusion (1 mg) enabled her to give correct verbal responses to questions about her name, her friends’ names, her age, and her address, as well as to perform mental calculations (additions and subtractions). Seizures were not observed and abnormal slowing in the EEG, which is characteristic of influenza-associated encephalopathy, was not observed in repeated recordings. Cerebrospinal fluid (CSF) study and repeated brain MRIs showed no abnormality. SPECT with 99mTc-ethyl cysteinate dimer showed no abnormal cerebral perfusion, while SPECT with 123I-iomazenil (performed 3 days after discontinuation of benzodiazepine) showed decreased benzodiazepine receptor binding in the right medial temporal area (Fig. 1).Fig. 1 SPECT with 123I-iomazenil 10 days after admission revealed decreased benzodiazepine receptor binding in the right medial temporal area (arrows)\n\n\n\nGlutamate receptor autoantibodies (GluRAbs), including GluRε2-NT2, GluRε2-CT1, GluRδ2-NT and GluRδ2-CT, were within normal limits in serum, but were increased in CSF (Additional file 1: Table S1).\n\nFinally, she completely recovered within 2 weeks after cessation of oseltamivir and administration of benzodiazepine (oral nitrazepam or lorazepam, with continuous midazolam infusion for 5 days in the middle). Naranjo’s adverse drug reaction probability scale [3] gave a score of 6.\n\nDrug level determination and simulation\nAt 154 h after final dosing of oseltamivir, blood and cerebrospinal fluid (CSF) were taken for drug level determination and genetic assessment. The serum level of oseltamivir was under the detection limit (0.5 ng/mL) and that of its active metabolite Ro 64-0802 was 1.30 ng/mL. CSF levels of oseltamivir and Ro 64-0802 were both under the detection limit (0.5 ng/mL). The observed serum level of Ro 64-0802 in this patient was higher than the expected level of Ro 64-0802 based on the pharmacokinetic parameters of age-matched healthy subjects, suggesting delayed excretion of Ro 64-0802 (Fig. 2a). The pharmacokinetics of oseltamivir in patients with influenza is qualitatively similar to that in healthy subjects [4].Fig. 2 Simulations of serum concentrations of oseltamivir and Ro 64-0802. a Simulation with normal parameters. Closed circle (arrow), observed Ro 64-0802 concentration; dotted line, simulated oseltamivir concentration; solid line, simulated Ro 64-0802 concentration. b Simulations of Ro 64-0802 and oseltamivir concentrations. Closed circle (arrow), observed Ro 64-0802 concentration; dotted lines, oseltamivir; solid lines, Ro 64-0802. Thin lines indicate simulation results using an elimination rate of Ro 64-0802 of one-half of the normal value. Bold lines indicate simulation results using a conversion rate of oseltamivir to Ro 64-0802 of one-tenth of the normal value\n\n\n\nOseltamivir is exclusively converted by hepatic carboxylesterase CES1 to Ro 64-0802, which is excreted into urine by glomerular filtration and tubular secretion via organic anion transporter OAT1 and/or OAT3 [5, 6]. Delayed excretion of Ro 64-0802 could be due either to decreased conversion of oseltamivir to Ro 64-0802 or to decreased elimination of Ro 64-0802 itself. Simulation studies indicated that the observed serum concentration of Ro 64-0802 at 154 h after final dosing was consistent with a decrease to one-tenth of normal in the conversion rate of oseltamivir to Ro 64-0802 or with a decrease to one-half in the elimination rate of Ro 64-0802 (Fig. 2b, Additional file 2: Table S2 and Additional file 3: Table S3). The former case, but not the latter, would also result in increased concentrations of oseltamivir, though in both cases, the oseltamivir concentration would have been at an undetectable level by 154 h after the final dose. The patient’s renal function was normal. The patient was not receiving any drugs known to inhibit OAT1, OAT3 or CES1.\n\nGenetic assessment\nGene sequencing of OAT1 and OAT3 and diplotype analysis of CES1 failed to explain her abnormal exposure to Ro 64-0802. Examination of the single nucleotide polymorphism of c.122G > A(R41Q) in the human sialidase Neu2 gene showed that the patient was a heterozygous carrier of this variation [7].\n\nDiscussion and conclusions\nAs far as we know, this is the first case report that includes the results of a comprehensive examination of the underlying mechanisms of psychiatric reactions associated with oseltamivir. The results of drug level determination and simulation suggested that enhanced exposure to either Ro 64-0802 alone or to both oseltamivir and Ro 64-0802 might have occurred in this case. Although influenza encephalopathy itself causes similar symptoms, and it was ethically unacceptable to examine the effect of re-administration of oseltamivir, this neuropsychiatric reaction appears to have been drug-induced, because EEG changes characteristic of influenza-associated encephalopathy was not observed and the symptoms disappeared after drug cessation. A previous report indicated that oseltamivir up to 450 mg twice daily is well-tolerated in healthy volunteers, and no drug-related psychiatric symptoms were observed [8]. However, the safety and pharmacokinetics of oseltamivir and Ro 64-0802 in subjects with severe influenza infection are presently unknown. In our patient, repeated measurements of the same samples and simulation studies clearly demonstrated enhanced exposure to Ro 64-0802, although the precise reason for this was not established. The brain concentration of oseltamivir and/or Ro 64-0802 is likely to be the key determinant of neuropsychiatric side effects. Although oseltamivir and Ro 64-0802 were not detected in CSF, it is considered that enhanced brain exposure to oseltamivir and/or Ro-64-0802 would have occurred, because brain-to-plasma ratios were reported to be linear up to 100 mg/kg (with values of 0.1 for oseltamivir and 0.005–0.02 for Ro 64-0802) in mice [9]. Efflux transport of oseltamivir is mediated by P-glycoprotein (ABCB1) at the blood–brain barrier, and therefore reduced P-glycoprotein activity due to factors such as genetic polymorphism [10] and inhibition by pro-inflammatory cytokines [11] or concomitant drugs could result in an increased brain concentration of oseltamivir. For example, our patient concomitantly received azithromycin, which may inhibit P-glycoprotein [12]. Although Ro 64-0802 is not a substrate of P-glycoprotein, animal studies indicate that it undergoes active efflux at the BBB mediated by transporter(s) such as OAT3 [13]. Therefore, reduced efflux transport of Ro 64-0802 is another possibility, although no genetic abnormality of OAT3 was found in our patient.\n\nBased on the neuropsychiatric symptoms following influenza A infection and the increase in CSF GluRAb, our patient's clinical course could be categorized as non-herpetic limbic encephalitis [14], but the precise nosological position remains inconclusive. Our patient’s clinical course somewhat resembled that of autoimmune limbic encephalitis, but differed in disease duration (much longer in autoimmune limbic encephalitis), the efficacy of benzodiazepine, the absence of abnormal EEG and CSF findings, and the absence of seizures and movement disorders during the clinical course (seizures and movement disorders are often observed in patients with typical autoimmune limbic encephalitis according to Dalmau’s group [15, 16]). Further, our GluRAbs were different from Dalmau’s NR1/NR2 heteromers of N-methyl-Daspartate receptor (NMDAR), and the disease sensitivity of our GluRAbs appeared to be low.\n\nLimbic GABAergic dysfunction might be involved in the pathogenesis, considering the transience of the symptoms and the later persistent efficacy of benzodiazepine in our patient. This idea is further supported by the 123I-IMZ SPECT findings, which suggested a decrease in the right medial temporal benzodiazepine/GABA-A receptors. Usami et al. [17] reported that oseltamivir and its active metabolite enhanced neuronal synchronization and induced population burst events of rat hippocampal CA3 networks in a concentration-dependent manner. They suggested that the oseltamivir-induced population bursts may be shaped by the phasic activity of inhibitory interneurons, rather than pyramidal cells. Thus, GABAergic inhibitory interneurons might be an action target of oseltamivir.\n\nThe genetic polymorphism of c.122G > A (R41Q) in the Neu2 gene of our patient resides near the active site of this enzyme and has the effect of increasing the binding affinity of Ro 64-0802, making the enzyme more sensitive to inhibition by Ro 64-0802 in vitro [4]. We speculate that oseltamivir induced excessive population bursts, which were further enhanced by the Neu2 gene SNP, resulting in down-regulation of GABAergic receptor, leading to the SPECT change. Because of the similarity between the neuropsychiatric reaction to oseltamivir and the symptoms of human sialidase-related disorders (epilepsy [18], seizures [19], mental deterioration [20], impaired intelligence [20]) and the role of sialidases in neuronal excitation [21, 22] and synaptic plasticity [23], we speculate that possession of this variant may play a role in the occurrence of severe adverse reactions to oseltamivir. Further clinical investigation will be needed to test this idea.\n\nIn conclusion, abnormal exposure to oseltamivir and/or Ro 64-0802 probably contributed to the development of neuropsychiatric symptoms in this patient, at least in part. Factors that might increase the risk of CNS side effects after administration of oseltamivir include Neu2 mutation, exclusively observed in Asians, and increased CSF GluRAbs. GABAergic inhibitory neurons may play an important role in the pathogenesis of the psychiatric symptoms.\n\nConsent\nInformed consent was obtained from the patient and her parents after oral or written explanation, according to the ethical principles of the Declaration of Helsinki. A copy of the written consent is available for review by the Editor of this journal.\n\nAdditional files\nAdditional file 1: Table S1. Measurements of glutamate receptor autoantibodies (OD values with ELISA method) in our patient. (DOCX 29 kb)\n\nAdditional file 2: Table S2. Simulated serum concentrations of oseltamivir and Ro 64-0802 in our patient. (DOCX 30 kb)\n\nAdditional file 3: Table S3. Pharmacokinetic parameters used for the simulation of plasma concentration - time curve in our patient. (DOCX 30 kb)\n\n\n\nAbbreviations\nEEGElectroencephalogram\n\nCSFCerebrospinal fluid\n\nGluRAbsGlutamate receptor autoantibody\n\nOATOrganic anion transporter\n\nCESCarboxylesterase\n\nNeu2Neuraminidase 2\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nKM and MK wrote the manuscript. MK, KN, AN, and HK performed the medical assessment. KM and TO performed pharmacokinetic analysis. KM, MK, MH and TO performed genetic analysis. YT performed glutamate receptor autoantibody assessment. All authors read and approved the final manuscript.\n==== Refs\nReferences\n1. Toovey S Prinssen EP Rayner CR Thakrar BT Dutkowski R Koerner A Chu T Sirzen-Zelenskaya A Britschgi M Bansod S Donner B Post-marketing assessment of neuropsychiatric adverse events in influenza patients treated with oseltamivir: an updated review Adv Ther 2012 29 826 848 10.1007/s12325-012-0050-8 23054689 \n2. Poggio MB Anfosso S Audenino D Primavera A Clarithromycin-induced neurotoxicity in adults J Clin Neurosci 2011 18 313 318 10.1016/j.jocn.2010.08.014 21269833 \n3. Naranjo CA Busto U Sellers EM Sandor P Ruiz I Roberts EA Janecek E Domecq C Greenblatt DJ A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 239 245 10.1038/clpt.1981.154 7249508 \n4. He G Massarella J Ward P Clinical pharmacokinetics of the prodrug oseltamivir and its active metabolite Ro 64-0802 Clin Pharmacokinet 1999 3 471 484 10.2165/00003088-199937060-00003 10628898 \n5. Shi D Yang J Yand D LeCluyse EL Black C You L Akhlaghi F Yan B Anti-influenza prodrug oseltamivir is activated by carboxylesterase human carboxylesterase 1, and the activation is inhibited by antiplatelet agent clopidogrel J Pharmacol Exp Ther 2006 319 1477 1484 10.1124/jpet.106.111807 16966469 \n6. Hill G Chilar T Oo C Ho ES Prior K Wiltshire H Barrett J Liu B Ward P The anti-influenza drug oseltamivir exhibits low potential to induce pharmacokinetic drug interactions via renal secretion-correlation of in vivo and in vitro studies Drug Metab Dispos 2002 30 13 19 10.1124/dmd.30.1.13 11744606 \n7. Li CY Yu Q Ye ZQ Sun Y He Q Li XM Zhang W Luo J Gu X Zheng X Wei L A nonsynonymous SNP in human cytosolic sialidase in a small Asian population results in reduced enzyme activity: potential link with severe adverse reactions to oseltamivir Cell Res 2007 17 357 362 10.1038/cr.2007.27 17426694 \n8. Dutkowski R Smith JR Davis BE Safety and pharmacokinetics of oseltamivir at standard and high dosages Int J Antimicob Agents 2010 35 461 467 10.1016/j.ijantimicag.2009.12.023 \n9. Morimoto K Nakakariya M Shirasaka Y Kakinuma C Fujita T Tamai I Ogihara T Oseltamivir (Tamiflu) efflux transport at the blood–brain barrier via P-glycoprotein Drug Metab Dispos 2008 36 6 9 10.1124/dmd.107.017699 17940134 \n10. L'Huillier AG Ing Lorenzini K Crisinel PA Rebsamen MC Fluss J Korff CM Barbe RP Siegrist CA Dayer P Posfay-Barbe KM Desmeules JA ABCB1 polymorphisms and neuropsychiatric adverse events in oseltamivir-treated children during influenza H1N1/09 pandemia Pharmacogenomics 2011 12 1493 1501 10.2217/pgs.11.91 21902503 \n11. Roberts DJ Goralski KB A critical overview of the influence of inflammation and infection on P-glycoprotein expression and activity in the brain Expert Opin Drug Metab Toxicol 2008 4 1245 1264 10.1517/17425255.4.10.1245 18798696 \n12. Yoshindo Co. Ltd. Basic product information of azithromycin, 1st edition; 2013.\n13. Ose A Ito M Kusuhara H Yamatsugu K Kanai M Shibasaki M Hosokawa M Schuetz JD Sugiyama Y Limited brain distribution of [3R,4R,5S]-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate (Ro 64-0802), a pharmacologically active form of oseltamivir, by active efflux across the blood–brain barrier mediated by organic anion transporter 3 (Oat3/Slc22a8) and multidrug resistance-associated protein 4 (Mrp4/Abcc4) Drug Metab Dispos 2009 37 315 21 10.1124/dmd.108.024018 19029202 \n14. Mochizuki Y Mizutani T Isozaki E Ohtake T Takahashi Y Acute limbic encephalitis: a new entity? Neurosci Lett 2006 394 5 8 10.1016/j.neulet.2005.08.070 16364542 \n15. Dalmau J Lancaster E Martinez-Hernandez E Rosenfeld MR Balice-Gordon R Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis Lancet Neurol 2011 10 63 74 10.1016/S1474-4422(10)70253-2 21163445 \n16. Bigi S Hladio M Twilt M Dalmau J Benseler SM The growing spectrum of antibody-associated inflammatory brain diseases in children Neurol Neuroimmunol Neuroinflamm 2015 2 10.1212/NXI.0000000000000092 25909091 \n17. Usami A Sasaki T Satoh N Akiba T Yokoshima S Fukuyama T Yamatsugu K Kanai M Shibasaki M Matsuki N Ikegaya Y Oseltamivir enhances hippocampal network synchronization J Pharmacol Sci 2008 106 659 62 10.1254/jphs.SC0070467 18403897 \n18. Harzer K Cantz M Sewell AC Dhareshwar SS Roggendorf W Heckl RW Schofer O Thumler R Peiffer J Schlote W Normomorphic sialidosis in two female adults with severe neurologic disease and without sialyl oligosacchariduria Hum Genet 1986 74 209 214 10.1007/BF00282535 3096875 \n19. Spranger JW Wiedemann HR Tolksdorf M Graucob E Caesar R Lipomucopolysaccharidose: eine neue Speicherkrankheit Z Kinderheilk 1968 103 285 306 10.1007/BF00439910 4235073 \n20. Winter RM Swallow DM Baraitser M Purkiss P Sialidosis type 2 (acid neuramindase deficiency): clinical and biochemical features of a further case Clin Genet 1980 18 203 210 10.1111/j.1399-0004.1980.tb00873.x 6777097 \n21. Isaeva E Lushnikova I Savrasova A Skibo G Holmes GL Isaev D Blockade of endogenous neuraminidase leads to an increase of neuronal excitability and activity-dependent synaptogenesis in the rat hippocampus Eur J Neurosci 2010 32 1889 96 10.1111/j.1460-9568.2010.07468.x 21044183 \n22. Isaev D Isaeva E Shatskih T Zhao Q Smits NC Shworak NW Khazipov R Holmes GL Role of extracellular sialic acid in regulation of neuronal and network excitability in the rat hippocampus J Neurosci 2007 27 11587 11594 10.1523/JNEUROSCI.2033-07.2007 17959801 \n23. Becker CG Artola A Gerardy-Schahn R Becker T Welzl H Schachner M The polysialic acid modification of the neural cell adhesion molecule is involved in spatial learning and hippocampal long-term potentiation J Neurosci Res 1996 45 143 152 10.1002/(SICI)1097-4547(19960715)45:2<143::AID-JNR6>3.0.CO;2-A 8843031\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2377",
"issue": "15()",
"journal": "BMC neurology",
"keywords": null,
"medline_ta": "BMC Neurol",
"mesh_terms": "D000293:Adolescent; D000998:Antiviral Agents; D005260:Female; D006212:Hallucinations; D006801:Humans; D007251:Influenza, Human; D008569:Memory Disorders; D001523:Mental Disorders; D053139:Oseltamivir; D007319:Sleep Initiation and Maintenance Disorders",
"nlm_unique_id": "100968555",
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"pages": "130",
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"pmid": "26242979",
"pubdate": "2015-08-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21044183;20189775;11744606;21269833;16364542;19029202;17426694;6777097;23054689;16966469;25909091;21163445;21902503;18403897;7249508;17959801;18798696;8843031;10628898;3096875;17940134;4235073",
"title": "Analysis of a child who developed abnormal neuropsychiatric symptoms after administration of oseltamivir: a case report.",
"title_normalized": "analysis of a child who developed abnormal neuropsychiatric symptoms after administration of oseltamivir a case report"
} | [
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"companynumb": "JP-WATSON-2016-09407",
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"abstract": "Posterior reversible encephalopathy syndrome, an infrequent neurotoxicity associated with the use of tacrolimus, was first described in 1996, as a reversible syndrome manifested by headache, altered mental function, seizures, and visual disturbances. We describe the case of a 37-year-old woman who developed neurologic symptoms consistent with encephalopathy after treatment with tacrolimus, which was prescribed to maintain immunosuppression after orthotopic heart transplantation. This report also discusses the imaging methods used in the diagnosis of posterior reversible encephalopathy and highlights the difficulty of maintaining immunosuppression and managing medication-related adverse effects, while taking into account the risk of acute rejection after transplantation.",
"affiliations": null,
"authors": "Kapoor|Aniruddh|A|;Birks|Emma|E|;Lenneman|Andrew|A|;McCants|Kelly|K|",
"chemical_list": "D007166:Immunosuppressive Agents; D020123:Sirolimus; D016559:Tacrolimus",
"country": "United States",
"delete": false,
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"issue": "44(3)",
"journal": "Texas Heart Institute journal",
"keywords": "Brain diseases/diagnostic imaging; drug therapy, combination; graft rejection/heart transplantation/adverse effects; immunosuppressive agents/therapeutic use; nervous system diseases/chemically induced; tacrolimus/adverse effects/therapeutic use; treatment outcome",
"medline_ta": "Tex Heart Inst J",
"mesh_terms": "D000328:Adult; D038524:Diffusion Magnetic Resonance Imaging; D057915:Drug Substitution; D005260:Female; D006084:Graft Rejection; D006085:Graft Survival; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents; D054038:Posterior Leukoencephalopathy Syndrome; D020123:Sirolimus; D016559:Tacrolimus; D016896:Treatment Outcome",
"nlm_unique_id": "8214622",
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"pages": "205-208",
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"pmid": "28761402",
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"references": "24814477;11884934;23331705;18403560;21572890;7501141;7520105;10401009;21216835;7523946;24949044;8559202;7645483;21963515;22217983;12050171;1721398;17698535",
"title": "Posterior Reversible Encephalopathy Syndrome after Heart Transplantation: Diagnosis and Immunosuppressive Therapy.",
"title_normalized": "posterior reversible encephalopathy syndrome after heart transplantation diagnosis and immunosuppressive therapy"
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"companynumb": "US-STRIDES ARCOLAB LIMITED-2017SP012220",
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"abstract": "We report two patients with drug-induced liver injury (DILI)-related acute liver failure (ALF) who were successfully treated with high-volume plasma exchange without liver transplantation. The first patient was a 66-year-old man admitted because of a perforated duodenal ulcer complicated with peritonitis and septic shock. After treatment with multiple antibiotics, the patient developed DILI and ALF. Grade 3 hepatic encephalopathy and profound jaundice were present. Symptoms and signs of ALF improved dramatically after initiation of plasma exchange. The patient was discharged uneventfully. The second patient was a 94-year-old man admitted for treatment of newly diagnosed pulmonary tuberculosis. DILI and ALF developed 5 days after initiation of anti-tuberculosis treatment. Grade 4 hepatic encephalopathy was present. After plasma exchange, the patient's level of consciousness improved dramatically, and he recovered from ALF. These 2 cases show the potential of plasma exchange in the treatment of DILI despite occurrence acute liver failure.",
"affiliations": "Division of Nephrology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.",
"authors": "Liu|Chung-Te|CT|;Chen|Tso-Hsiao|TH|;Cheng|Chung-Yi|CY|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000995:Antitubercular Agents; D006895:Hydroxyethyl Starch Derivatives; D010952:Plasma Substitutes",
"country": "United States",
"delete": false,
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"issue": "28(6)",
"journal": "Journal of clinical apheresis",
"keywords": "acute liver failure; artificial liver support; drug-induced liver injury; plasma exchange",
"medline_ta": "J Clin Apher",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D057868:Anastomotic Leak; D000900:Anti-Bacterial Agents; D000995:Antitubercular Agents; D056486:Chemical and Drug Induced Liver Injury; D003428:Cross Infection; D004381:Duodenal Ulcer; D017809:Fatal Outcome; D006501:Hepatic Encephalopathy; D006801:Humans; D006895:Hydroxyethyl Starch Derivatives; D017093:Liver Failure; D008297:Male; D010538:Peritonitis; D010949:Plasma; D010951:Plasma Exchange; D010952:Plasma Substitutes; D011014:Pneumonia; D012772:Shock, Septic; D014397:Tuberculosis, Pulmonary",
"nlm_unique_id": "8216305",
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"pubdate": "2013-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful treatment of drug-induced acute liver failure with high-volume plasma exchange.",
"title_normalized": "successful treatment of drug induced acute liver failure with high volume plasma exchange"
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"companynumb": "TW-MYLANLABS-2015M1008793",
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"patient": {
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ETHAMBUTOL HYDROCHLORIDE"
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"abstract": "Mechanical circulatory support is increasingly used and may bring about unique challenges. Most support systems require systemic anticoagulation and the need for anticoagulation must be balanced against the increased risk for bleeding. We report the case of a young man awaiting heart retransplantation, who was supported with a temporary extracorporeal ventricular assist device with the addition of an oxygenator. He developed hemoptysis that forced the cessation of anticoagulation exposing to increased thromboembolic risk. We discuss this distinct clinical scenario with no clearly defined solution and explore the risks and benefits of the different treatment options.",
"affiliations": "Department of Anesthesiology, Columbia University Medical Center, New York, New York.;Department of Anesthesiology, Columbia University Medical Center, New York, New York.;Department of Surgery, Division of Cardiothoracic Surgery, Columbia University Medical Center, New York, New York.;Department of Medicine, Division of Cardiology, Columbia University Medical Center, New York, New York.;Department of Anesthesiology, Columbia University Medical Center, New York, New York.",
"authors": "Wang|Amy L|AL|;Hittesdorf|Erin|E|;Takeda|Koji|K|;Colombo|Paolo C|PC|;Wagener|Gebhard|G|http://orcid.org/0000-0001-9420-0596",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/jocs.14161",
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"issn_linking": "0886-0440",
"issue": "34(10)",
"journal": "Journal of cardiac surgery",
"keywords": "hemoptysis; pulmonary hemorrhage; ventricular assist device",
"medline_ta": "J Card Surg",
"mesh_terms": "D000328:Adult; D001706:Biopsy; D020878:Device Removal; D015199:Extracorporeal Membrane Oxygenation; D006353:Heart-Assist Devices; D006469:Hemoptysis; D006801:Humans; D008297:Male; D019106:Postoperative Hemorrhage; D011650:Pulmonary Alveoli; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "8908809",
"other_id": null,
"pages": "1110-1113",
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"pmid": "31269305",
"pubdate": "2019-10",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Pulmonary alveolar hemorrhage in a patient with a temporary external ventricular assist device and extracorporeal membrane oxygenation.",
"title_normalized": "pulmonary alveolar hemorrhage in a patient with a temporary external ventricular assist device and extracorporeal membrane oxygenation"
} | [
{
"companynumb": "US-PFIZER INC-2019480757",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
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... |
{
"abstract": "There is a lack of consensus regarding the role and method of hematopoietic stem cell transplantation (HSCT) on patients with chronic granulomatous disease (CGD). Long-term follow-up after HSCT in these patient population is essential to know its potential complications and decide who will benefit the most from HSCT. We report the outcome of HSCT and long-term follow-up in 24 patients with CGD, transplanted in our center from either related (n = 6) or unrelated (n = 18) donors, over a 12-year period (2003 to 2015), using high-dose alemtuzumab in the preparative regimen. We evaluated the incidence and timing of adverse events and potential risk factors. We described in detailed the novel finding of increased autoimmunity after HSCT in patients with CGD. At a median follow-up of 1460 days, 22 patients were full donor chimeras, and 2 patients had stable mixed chimerism. All assessable patients showed normalization of their neutrophil oxidative burst test. None of the patients developed grades II to IV acute graft-versus-host disease, and no patient had chronic graft-versus-host disease. Twelve of 24 patients developed 17 autoimmune diseases (ADs). Severe ADs (cytopenia and neuropathy) occurred exclusively in the unrelated donor setting and mainly in the first year after HSCT, whereas thyroid AD occurred in the related donor setting as well and more than 3 years after HSCT. Two patients died due to infectious complications after developing autoimmune cytopenias. One additional patient suffered severe brain injury. The remaining 21 patients have long-term Lansky scores ≥ 80. The outcome of HSCT from unrelated donors is comparable with related donors but might carry an increased risk of developing severe AD. A lower dose of alemtuzumab may reduce this risk and should be tested in further studies.",
"affiliations": "Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital Cancer Center and Houston Methodist Hospital, Houston, Texas.;Section of Immunology Allergy and Rheumatology, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas.;Section of Immunology Allergy and Rheumatology, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas.;Section of Immunology Allergy and Rheumatology, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas.;Section of Immunology Allergy and Rheumatology, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas.;Section of Immunology Allergy and Rheumatology, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas.;Section of Immunology Allergy and Rheumatology, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas.;Section of Immunology Allergy and Rheumatology, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas.;Section of Immunology Allergy and Rheumatology, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas.;Section of Immunology Allergy and Rheumatology, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas.;Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital Cancer Center and Houston Methodist Hospital, Houston, Texas.;Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital Cancer Center and Houston Methodist Hospital, Houston, Texas.;Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital Cancer Center and Houston Methodist Hospital, Houston, Texas.;Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital Cancer Center and Houston Methodist Hospital, Houston, Texas.;Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital Cancer Center and Houston Methodist Hospital, Houston, Texas.;Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital Cancer Center and Houston Methodist Hospital, Houston, Texas.;Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital Cancer Center and Houston Methodist Hospital, Houston, Texas.;Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital Cancer Center and Houston Methodist Hospital, Houston, Texas.;Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital Cancer Center and Houston Methodist Hospital, Houston, Texas.;The Division of Biostatistics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.;The Division of Biostatistics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.;Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital Cancer Center and Houston Methodist Hospital, Houston, Texas.;Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital Cancer Center and Houston Methodist Hospital, Houston, Texas.;Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital Cancer Center and Houston Methodist Hospital, Houston, Texas.;Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital Cancer Center and Houston Methodist Hospital, Houston, Texas.;Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital Cancer Center and Houston Methodist Hospital, Houston, Texas. Electronic address: camartin@txch.org.",
"authors": "Yanir|Asaf D|AD|;Hanson|Imelda C|IC|;Shearer|William T|WT|;Noroski|Lenora M|LM|;Forbes|Lisa R|LR|;Seeborg|Feliz O|FO|;Nicholas|Sarah|S|;Chinn|Ivan|I|;Orange|Jordan S|JS|;Rider|Nicholas L|NL|;Leung|Kathryn S|KS|;Naik|Swati|S|;Carrum|George|G|;Sasa|Ghadir|G|;Hegde|Meenakshi|M|;Omer|Bilal A|BA|;Ahmed|Nabil|N|;Allen|Carl E|CE|;Khaled|Yassine|Y|;Wu|Meng-Fen|MF|;Liu|Hao|H|;Gottschalk|Stephen M|SM|;Heslop|Helen E|HE|;Brenner|Malcolm K|MK|;Krance|Robert A|RA|;Martinez|Caridad A|CA|",
"chemical_list": "D000074323:Alemtuzumab",
"country": "United States",
"delete": false,
"doi": "10.1016/j.bbmt.2018.03.029",
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"issn_linking": "1083-8791",
"issue": "24(8)",
"journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation",
"keywords": "Autoimmune disease; Chimerism; Chronic granulomatous disease; Hematopoietic stem cell transplantation; Immune reconstitution; Myeloablative conditioning; Unrelated donors",
"medline_ta": "Biol Blood Marrow Transplant",
"mesh_terms": "D000074323:Alemtuzumab; D001327:Autoimmune Diseases; D046528:Chimerism; D005500:Follow-Up Studies; D006105:Granulomatous Disease, Chronic; D020275:Guillain-Barre Syndrome; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015994:Incidence; D010198:Pancytopenia; D061349:Unrelated Donors",
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"pubdate": "2018-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "High Incidence of Autoimmune Disease after Hematopoietic Stem Cell Transplantation for Chronic Granulomatous Disease.",
"title_normalized": "high incidence of autoimmune disease after hematopoietic stem cell transplantation for chronic granulomatous disease"
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"abstract": "The use of atypical antipsychotic medication is increasing, with an increase in reported side-effects. The first reported case of quetiapine and citalopram-associated serotonin syndrome is discussed with reference to a Medline, Embase, and PsycINFO literature search. The putative aetiological mechanism is supersensitivity of 5-HT(1A) receptors (quetiapine) within an environment of increased synaptic available serotonin (citalopram). The symptom profile of serotonin syndrome overlaps with neuroleptic malignant syndrome, but can be reliably differentiated using a time and toxicity scale.",
"affiliations": "Tower Hamlets Early Intervention Service, Royal London Hospital, St Clement's, 2A Bow Road, Mile End, London E3 4LL, UK. karl.marlowe@elcmht.nhs.uk",
"authors": "Marlowe|Karl|K|;Schirgel|Dorothea|D|",
"chemical_list": "D014151:Anti-Anxiety Agents; D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D012702:Serotonin Antagonists; D017367:Serotonin Uptake Inhibitors; D015283:Citalopram; D000069348:Quetiapine Fumarate; D018967:Risperidone; D000525:Alprazolam",
"country": "New Zealand",
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"issue": "119(1237)",
"journal": "The New Zealand medical journal",
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"medline_ta": "N Z Med J",
"mesh_terms": "D000328:Adult; D000525:Alprazolam; D014151:Anti-Anxiety Agents; D014150:Antipsychotic Agents; D001714:Bipolar Disorder; D015283:Citalopram; D003987:Dibenzothiazepines; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D000069348:Quetiapine Fumarate; D018967:Risperidone; D012702:Serotonin Antagonists; D020230:Serotonin Syndrome; D017367:Serotonin Uptake Inhibitors; D016896:Treatment Outcome",
"nlm_unique_id": "0401067",
"other_id": null,
"pages": "U2058",
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"pmid": "16862204",
"pubdate": "2006-07-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Quetiapine and citalopram: aetiological significances in serotonin syndrome.",
"title_normalized": "quetiapine and citalopram aetiological significances in serotonin syndrome"
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"companynumb": "GB-ALKEM LABORATORIES LIMITED-GB-ALKEM-2022-02174",
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"abstract": "Cinacalcet, a calcimimetic drug, is considered a safe and valid option for the treatment of hypercalcemia in patients with primary hyperparathyroidism who are unable to undergo parathyroidectomy. Hypocalcemia and gastrointestinal adverse reactions are the main side effects reported in patients treated with cinacalcet. We present here the case of an 80-years-old patient with primary hyperparathyroidism treated with cinacalcet for 17 months who developed a severe and symptomatic episode of hypocalcemia requiring hospitalization 1 month after reaching a daily dose of 180 mg. Follow-up laboratory and imaging exams showed remission of primary hyperparathyroidism and disappearance of the parathyroid adenoma, suggesting a possible association between cinacalcet therapy and parathyroid infarction resulting in normalization of the elevated serum parathyroid hormone levels and severe hypocalcemia. No known cases of iatrogenic parathyroid apoplexy have thus far been described. We report here the first case of parathyroid apoplexy associated with the administration of cinacalcet in a patient with primary hyperparathyroidism. Parathyroid apoplexy features heterogeneous clinical manifestations ranging from relatively asymptomatic to potentially life-threatening cases. The occurrence of this complication should be carefully considered in patients with primary hyperparathyroidism in therapy with cinacalcet.",
"affiliations": "Unit of Endocrinology, Department of Medicine and Sciences of Aging and Ce.S.I.-Me.T., University of Chieti-Pescara, Chieti, Italy.;Unit of Endocrinology, Department of Medicine and Sciences of Aging and Ce.S.I.-Me.T., University of Chieti-Pescara, Chieti, Italy.;Unit of Endocrinology, Department of Medicine and Sciences of Aging and Ce.S.I.-Me.T., University of Chieti-Pescara, Chieti, Italy.",
"authors": "Di Dalmazi|Giulia|G|;Giuliani|Cesidio|C|;Napolitano|Giorgio|G|",
"chemical_list": null,
"country": "Switzerland",
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"doi": "10.3389/fendo.2018.00777",
"fulltext": "\n==== Front\nFront Endocrinol (Lausanne)Front Endocrinol (Lausanne)Front. Endocrinol.Frontiers in Endocrinology1664-2392Frontiers Media S.A. 10.3389/fendo.2018.00777EndocrinologyCase ReportParathyroid Apoplexy Following Cinacalcet Treatment in Primary Hyperparathyroidism Di Dalmazi Giulia Giuliani Cesidio *Napolitano Giorgio Unit of Endocrinology, Department of Medicine and Sciences of Aging and Ce.S.I.-Me.T., University of Chieti-Pescara, Chieti, ItalyEdited by: Giacomina Brunetti, Università degli Studi di Bari, Italy\n\nReviewed by: Sabrina Corbetta, University of Milan, Italy; Michaël R. Laurent, University Hospitals Leuven, Belgium\n\n*Correspondence: Cesidio Giuliani cesidio.giuliani@unich.itThis article was submitted to Bone Research, a section of the journal Frontiers in Endocrinology\n\n21 12 2018 2018 9 77727 9 2018 11 12 2018 Copyright © 2018 Di Dalmazi, Giuliani and Napolitano.2018Di Dalmazi, Giuliani and NapolitanoThis 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.Cinacalcet, a calcimimetic drug, is considered a safe and valid option for the treatment of hypercalcemia in patients with primary hyperparathyroidism who are unable to undergo parathyroidectomy. Hypocalcemia and gastrointestinal adverse reactions are the main side effects reported in patients treated with cinacalcet. We present here the case of an 80-years-old patient with primary hyperparathyroidism treated with cinacalcet for 17 months who developed a severe and symptomatic episode of hypocalcemia requiring hospitalization 1 month after reaching a daily dose of 180 mg. Follow-up laboratory and imaging exams showed remission of primary hyperparathyroidism and disappearance of the parathyroid adenoma, suggesting a possible association between cinacalcet therapy and parathyroid infarction resulting in normalization of the elevated serum parathyroid hormone levels and severe hypocalcemia. No known cases of iatrogenic parathyroid apoplexy have thus far been described. We report here the first case of parathyroid apoplexy associated with the administration of cinacalcet in a patient with primary hyperparathyroidism. Parathyroid apoplexy features heterogeneous clinical manifestations ranging from relatively asymptomatic to potentially life-threatening cases. The occurrence of this complication should be carefully considered in patients with primary hyperparathyroidism in therapy with cinacalcet.\n\nparathyroid apoplexycinacalcetprimary hyperparathyroidismhungry bone syndromehypocalcemia\n==== Body\nBackground\nPrimary hyperparathyroidism (PHPT) is a common endocrine disorder characterized biochemically by hypercalcemia and elevated or inappropriately normal levels of parathyroid hormone (PTH). PHPT is even more common in the elderly, with a prevalence of up to 2% (1).\n\nIt is caused in most cases (80%) by a single parathyroid adenoma, less frequently (15–20%) by a multiple gland disorder (such as multiple adenomas or multi-gland parathyroid hyperplasia), rarely (<1%) by a parathyroid carcinoma (2). In its classical form, rarely seen today, primary hyperparathyroidism features skeletal, renal, gastrointestinal, neurological, and psychiatric manifestation (2). Most patients nowadays are asymptomatic and discovered incidentally during routine laboratory testing. These asymptomatic subjects, however, may develop with time overt symptoms. Surgical removal of the parathyroid gland(s) is currently the only cure for primary hyperparathyroidism (3) but it cannot be used in a subset of patients (4) and is often deferred in elderly patients (5). For them, a valid treatment option is the administration of cinacalcet. Cinacalcet is an allosteric modulator of the calcium-sensing receptor (CaSR) that ultimately yields reduction of PTH. This drug was approved by the European Medicines Agency and the U.S. Food and Drug Administration for the treatment of hypercalcemia in hyperparathyroid patients who are unable to undergo parathyroidectomy (6).\n\nWe herein report a case of parathyroid adenoma apoplexy following cinacalcet treatment in a patient with primary hyperparathyroidism. Although spontaneous cases of parathyroid apoplexy have been previously described in primary hyperparathyroidism (7–9), this is the first case observed in association with cinacalcet treatment.\n\nCase Presentation\nAn 80-year-old white male was referred to our endocrinology outpatient clinic in December 2015 for a fracture of the left radial head, hypercalcemia (11.9 mg/dL; normal range 8.1–10.4 mg /dL), increased PTH (681 pg/ml; normal range 15–65 pg/mL), and increased alkaline phosphatase (375 U/L; normal range 40–130 U/L). Medical history was positive for hypertension and benign prostatic hyperplasia. Physical examination, including that of the cervical region, was overall normal but a 2-year history of bone pain, muscle weakness, and nephrolithiasis was noted. Renal (CKD-EPI 87, 1 ml/min/1.73 m2) and hepatic functions were normal (Table 1), as well as cardiovascular function. His medications included valsartan, alfuzosin, and cholecalciferol.\n\nTable 1 Main laboratory data at admission and during follow-up.\n\n\tCalcium, mg/dl\n\n(NR: 8.1–10.4)\tiPTH,\npg/mL\n\n(NR:15–65)\t25-OH Vit. D, ng/mL\n\n(NR: > 20)\tCreatinine, mg/dL\n\n(NR: 0.5–1.1)\tAlkaline Phosphatase, U/L\n\n(NR: 40–130)\t\nDecember 2015 (at admission)\t11.9\t681\tNA\t0.74\t375\t\nApril 2016\t11.8\t512\t26\tNA\tNA\t\nNovember 2016\t12.4\t751\t23\tNA\tNA\t\nFebruary 2017\t12.7\t798\tNA\t0.73\tNA\t\nJune 2017\t6.3\t53.6\t22\t0.93\t411\t\nNovember 2017\t9.2\t40.2\t28\t0.83\tNA\t\nMarch 2018\t9.0\t61.1\t26\t0.91\t79\t\nJuly 2018\t9.1\t61.9\tNA\t0.95\tNA\t\niPTH, intact parathyroid hormone, chemiluminescence immunoassay.\n\nNA, not available; NR, normal range.\n\nNeck ultrasound revealed a 9–mm, hypoechoic mass behind the right lobe of the thyroid gland (Figure 1A). Technetium 99m (99mTc)-sestamibi scintigraphy showed a focal area of increased uptake (Figure 1B), corresponding to the ultrasound finding, thus suggesting a parathyroid adenoma. A diagnosis of primary hyperparathyroidism due to a parathyroid adenoma was, therefore, established. A parathyroidectomy was offered to the patient, but refused. In January 2016 we thus began medical treatment with cinacalcet, starting at a dose of 30 mg twice a day. This dosage was gradually increased, in the following months, to 60 mg 3 times a day as to normalize the serum calcium levels (Figure 2, left panel; Table 1).\n\nFigure 1 Neck ultrasound and 99mTc-sestamibi scintigraphy performed on admission and 8 months after parathyroid apoplexy. (A) Baseline neck ultrasound showed a solid and hypoechoic 8 mm nodule located behind the right thyroid lobe (arrow). (B) Baseline 99mTc-sestamibi scintigraphy showed an area of increased uptake (arrow). (C) Follow-up neck ultrasound performed 8 months later notice the near complete disappearance of the nodule. (D) Follow-up 99mTc-sestamibi scintigraphy performed 8 months later showing a marked reduction of the uptake, although residual activity was still noticeable.\n\nFigure 2 Serum levels of total calcium and parathyroid hormone (PTH). The x-axis shows the calendar time and the boxes above the graph show the treatments. Assessments were made at several time points before, during and after cinacalcet treatment. Note the marked decline in PTH and total calcium (arrow) occurring about a month after cinacalcet reached the 180 mg/dl daily dosage.\n\nIn June 2017, 1 month after reaching a daily dose of 180 mg, the patient was admitted to the emergency room for tetany. Laboratory testing showed hypocalcemia (6.27 mg/dL), normal PTH (53.6 pg/mL), hypophosphatemia (2.7 mEq/L, normal range 3.5–5.5 mEq/L) and still increased alkaline phosphatase levels (411 U/L). Renal and hepatic functions were not impaired (Table 1). He was treated with intravenous calcium gluconate, and stopped cinacalcet treatment.\n\nSerum calcium, surprisingly, did not rise after cinacalcet cessation, remaining around values of 6 mg/dL for about 10 days (Figure 2, arrow). Neck ultrasound confirmed the presence of a hypoechoic, irregular mass behind the thyroid right lobe, this time 17 mm in diameter. An ultrasound-guided fine needle aspiration of this lesion was performed. Cytological examination revealed basophilic amorphous material, neutrophils (Figure 3, black arrow), macrophages (Figure 3, white arrow), and lymphocytes (Figure 3, arrowhead), consistent with necrosis and inflammation. The patient was given calcium supplement (calcium carbonate, 1,000 mg twice daily) and 1,25 dihydroxyvitamin D3 (calcitriol, 0.5 μg once per day). Three months later, serum calcium normalized and PTH remained normal (44.0 pg/ml) (Figure 2). Neck ultrasound performed at the same time no further identified the parathyroid lesion (Figure 1C). Repeated 99mTc-sestamibi scintigraphy showed a minute area of increased uptake, which we interpreted as a remnant adenoma, although a local inflammatory reaction could not be excluded (Figure 1D). We gradually decreased calcium treatment to a dosage of 500 mg/die and eventually stopped it in March 2018, whereas we continued calcitriol therapy (0.5 μg once per day). At the time of our latest assessment (July 2018), calcium (9.12 mg/dL), PTH (61.9 pg/mL), and alkaline phosphatase (79 U/L) were in the normal range (Table 1), clinical conditions were satisfactory except for the muscle weakness which did not improve significantly.\n\nFigure 3 Morphological appearance of the fine-needle aspirate of the patient's parathyroid nodule. Note the presence of necrotic debris and inflammatory cells mainly consisting in neutrophils (black arrow), macrophages (white arrow), and lymphocytes (arrowhead). Original magnification 20X.\n\nThe above described findings suggested that the remission of primary hyperparathyroidism was caused by the apoplexy of the parathyroid adenoma.\n\nDiscussion\nSpontaneous cases of parathyroid apoplexy, were firstly described in 1946 (7) and defined pathologically by the presence of hemorrhage or infarction within the adenoma (8). Spontaneous parathyroid apoplexy occurs rarely in primary hyperparathyroidism and features heterogeneous manifestations such as cervical pain, neck mass and compression symptoms, hematoma or ecchymosis, hypercalcemic crisis due to acute PTH release, and hypocalcemia with tetany or convulsions due to auto-parathyroidectomy (8). Asymptomatic cases and potentially life-threatening manifestations are also described (9). The pathogenesis of parathyroid apoplexy is considered secondary to an imbalance between the growth of the adenoma and its blood supply. No known cases of iatrogenic parathyroid apoplexy have thus far been described. We report here the first case of parathyroid adenoma apoplexy due to a glandular infarction, as suggested by the cytological and clinical features, induced by cinacalcet therapy given for primary hyperparathyroidism.\n\nOur patient had been given cinacalcet therapy for 17 months to control his classical symptoms of primary hyperparathyroidism. A dose of 180 mg/day was reached, since lower doses of cinacalcet failed to control the hypercalcemia (Figure 2 and Table 1). High doses of cinacalcet, although unusual, are sometimes necessary even in cases of primary hyperparathyroidism of benign etiology (10, 11). During this treatment, he developed an acute episode of severe hypocalcemia associated with drop in PTH concentration requiring hospitalization, drug discontinuation, and intravenous calcium replacement. Follow-up laboratory and imaging exams showed remission of primary hyperparathyroidism and disappearance of the parathyroid adenoma, possibly revealing an association between cinacalcet therapy and parathyroid infarction, resulting in a normalization of the elevated serum PTH levels and severe hypocalcemia. The sustained hypocalcemia, associated with the hypophosphatemia, suggested to us a mechanism akin to the “hungry bone syndrome,” which usually occurs in the context of prolonged PTH elevation followed by a marked and rapid PTH decline. Notably, the same mechanism has been described in patients with hyperparathyroidism secondary to end stage renal disease treated with cinacalcet (12).\n\nThe treatment of choice for spontaneous parathyroid apoplexy is surgery. In a few cases a conservative approach, with clinical and biochemical follow-up, is chosen. In our patient, surgery was not performed considering the favorable clinical outcome. Despite the lack of histological confirmation, an infarction of the parathyroid adenoma was strongly suggested by the acute onset of hypocalcemia, the rapid drop in serum PTH levels, and the cytological findings.\n\nThe neck ultrasound and 99mTc-sestamibi scintigraphy, further supported the occurrence of parathyroid infarction.\n\nIt is interesting to speculate on the cause of parathyroid apoplexy in our patient as it relates to the mechanism of action of cinacalcet. Cinacalcet is a calcimimetic, which, like extracellular calcium, activates the CaSR on parathyroid cells, ultimately leading to decreased synthesis and secretion of PTH. Randomized clinical trials and observational studies have shown the ability of cinacalcet to reduce PTH concentration and normalize serum calcium in patients with primary hyperparathyroidism and contraindications to surgery (13). It has been shown that cinacalcet does not improve bone mineral density or other PHPT-related symptoms, as recently reviewed by Leere et al. (13). On the contrary, bisphosphonates or denosumab protect against bone resorption (14, 15) and could have a role in the medical management of PHPT, especially in elderly patients with osteoporosis or at high risk of fracture. Cinacalcet has also shown effects on parathyroid cells proliferation. Imanishi et al. (16) demonstrated that cinacalcet suppress parathyroid cell proliferation without affecting apoptosis in a murine model of primary hyperparathyroidism. Conversely, increased parathyroid cells apoptosis has been described in glands surgically removed from secondary hyperparathyroidism patients treated with cinacalcet (17). Furthermore, in vitro experiments on human cultured parathyroid cells showed dose- and time-dependent increase of apoptotic cells by adding cinacalcet to the culture medium (17). Miller et al. (18) demonstrated that established parathyroid hyperplasia in uremic rats can be reversed by modulating CASR activity with cinacalcet. In addition, cinacalcet treatment in secondary hyperparathyroidism patients has been associated with a reduction in parathyroid hyperplastic volume documented by ultrasonography (19, 20).\n\nRecently Coloma et al. (21) reported a decrease in parathyroid glandular size, evaluated by 99mTc-sestamibi, occurring in associations with the reduction of PTH levels and serum calcium concentration in a patient with asymptomatic primary hyperparathyroidism in treatment with cinacalcet.\n\nA case of parathyroid hemorrhage after administration of cinacalcet in a patient with secondary hyperparathyroidism on hemodialysis requiring emergency surgery has been reported. Authors suggest that parathyroid hemorrhage was the consequence of a glandular degeneration caused by the administration of cinacalcet (22). Our case confirms and expands these findings by showing for the first time its occurrence in a patient with primary hyperparathyroidism.\n\nRecurrence of primary hyperparathyroidism following initial spontaneous remission has been described (23), therefore in cases in which a conservative approach is chosen, careful clinical and biochemical follow-up is necessary.\n\nConclusion\nWe report here the first case of parathyroid apoplexy associated with the administration of cinacalcet in a patient with primary hyperparathyroidism. The occurrence of this complication should be carefully considered in patients with primary hyperparathyroidism treated with cinacalcet. Long-term data about the management of patients with primary hyperparathyroidism treated with cinacalcet are desirable.\n\nEthics Statement\nThis study was exempt from ethical approval procedures being a case report that describes the clinical course and outcome of a single patient who was referred to our outpatient clinic. The patient provided written consent to have his case published for the purpose to improve the medical knowledge.\n\nAuthor Contributions\nGDD: clinical and endocrinological evaluation, contributions to the conception and design of the work, drafting the work, final approval of the version to be published, and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. CG: substantial contributions to the conception of the work, revising the work critically for important intellectual content, final approval of the version to be published, and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. GN: substantial contributions to the design of the work; revising the work critically for important intellectual content; final approval of the version to be published; and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.\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\nWe are grateful to Dr. Sandro Mosca MD for performing the cytopathological examination and providing us with the iconographic material, and to Dr. Patrizio Caturegli for critically reviewing the manuscript.\n==== Refs\nReferences\n1. Calo PG Medas F Loi G Pisano G Sorrenti S Erdas E . Parathyroidectomy for primary hyperparathyroidism in the elderly: experience of a single endocrine surgery center . Aging Clin Exp Res. (2017 ) 29 (Suppl. 1 ):15 –21 . 10.1007/s40520-016-0666-7 27837463 \n2. Bilezikian JP Bandeira L Khan A Cusano NE . Hyperparathyroidism . Lancet (2018 ) 391 :168 –78 . 10.1016/s0140-6736(17)31430-7 28923463 \n3. AACE/AAES \nThe American Association of Clinical Endocrinologists and the American Association of Endocrine Surgeons position statement on the diagnosis and management of primary hyperparathyroidism . Endocr Pract. (2005 ) 11 :49 –54 . 10.4158/ep.11.1.49 16033736 \n4. Bilezikian JP Brandi ML Eastell R Silverberg SJ Udelsman R Marcocci C . Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the Fourth International Workshop . J Clin Endocrinol Metab. (2014 ) 99 :3561 –9 . 10.1210/jc.2014-1413 25162665 \n5. Kebebew E Duh QY Clark OH . Parathyroidectomy for primary hyperparathyroidism in octogenarians and nonagenarians: a plea for early surgical referral . Arch Surg. (2003 ) 138 :867 –71 . 10.1001/archsurg.138.8.867 12912745 \n6. Khan A Bilezikian J Bone H Gurevich A Lakatos P Misiorowski W . Cinacalcet normalizes serum calcium in a double-blind randomized, placebo-controlled study in patients with primary hyperparathyroidism with contraindications to surgery . Eur J Endocrinol. (2015 ) 172 :527 –35 . 10.1530/eje-14-0877 25637076 \n7. Norris EH . Primary hyperparathyroidism; a report of five cases that exemplify special features of this disease (infarction of a parathyroid adenoma; oxyphil adenoma) . Arch Pathol . (1946 ) 42 :261 –73 . 20999926 \n8. Nylen E Shah A Hall J . Spontaneous remission of primary hyperparathyroidism from parathyroid apoplexy . J Clin Endocrinol Metab. (1996 ) 81 :1326 –8 . 10.1210/jcem.81.4.8636326 8636326 \n9. Garrahy A Hogan D O'Neill JP Agha A \nAcute airway compromise due to parathyroid tumour apoplexy: an exceptionally rare and potentially life-threatening presentation . BMC Endocr Disord. (2017 ) 17 :35 \n10.1186/s12902-017-0186-2 28637440 \n10. Marcocci C Chanson P Shoback D Bilezikian J Fernandez-Cruz L Orgiazzi J . Cinacalcet reduces serum calcium concentrations in patients with intractable primary hyperparathyroidism . J Clin Endocrinol Metab. (2009 ) 94 :2766 –72 . 10.1210/jc.2008-2640 19470620 \n11. Misiorowski W Zgliczynski W . Cinacalcet as symptomatic treatment of hypercalcaemia in primary hyperparathyroidism prior to surgery . Endokrynol Pol. (2017 ) 68 :306 –10 . 10.5603/ep.2017.0023 28660989 \n12. Koubar SH Qannus AA Medawar W Abu-Alfa AK . Hungry bone syndrome two weeks after starting cinacalcet: a call for caution . CEN Case Rep. (2018 ) 7 :21 –3 . 10.1007/s13730-017-0284-z 29124559 \n13. Leere JS Karmisholt J Robaczyk M Vestergaard P \nContemporary Medical Management of Primary Hyperparathyroidism: a systematic review . Front Endocrinol. (2017 ) 8 :79 \n10.3389/fendo.2017.00079 \n14. Eller-Vainicher C Palmieri S Cairoli E Goggi G Scillitani A Arosio M . Protective effect of denosumab on bone in older women with primary hyperparathyroidism . J Am Geriatr Soc. (2018 ) 66 :518 –24 . 10.1111/jgs.15250 29364518 \n15. Khan AA Bilezikian JP Kung AW Ahmed MM Dubois SJ Ho AY Schussheim D Rubin MR Shaikh AM Silverberg SJ Standish TI Syed Z Syed ZA . Alendronate in primary hyperparathyroidism: a double-blind, randomized, placebo-controlled trial . J Clin Endocrinol Metab (2004 ) 89 :3319 –25 . 10.1210/jc.2003-030908 15240609 \n16. Imanishi Y Kawata T Kenko T Wada M Nagano N Miki T . Cinacalcet HCl suppresses Cyclin D1 oncogene-derived parathyroid cell proliferation in a murine model for primary hyperparathyroidism . Calcif Tissue Int. (2011 ) 89 :29 –35 . 10.1007/s00223-011-9490-4 21541686 \n17. Tatsumi R Komaba H Kanai G Miyakogawa T Sawada K Kakuta T . Cinacalcet induces apoptosis in parathyroid cells in patients with secondary hyperparathyroidism: histological and cytological analyses . Nephron Clin Pract. (2013 ) 124 :224 –31 . 10.1159/000357951 24503607 \n18. Miller G Davis J Shatzen E Colloton M Martin D Henley CM . Cinacalcet HCl prevents development of parathyroid gland hyperplasia and reverses established parathyroid gland hyperplasia in a rodent model of CKD . Nephrol Dial Transl. (2012 ) 27 :2198 –205 . 10.1093/ndt/gfr589 22036941 \n19. Meola M Petrucci I Barsotti G . Long-term treatment with cinacalcet and conventional therapy reduces parathyroid hyperplasia in severe secondary hyperparathyroidism . Nephrol Dial Transl. (2009 ) 24 :982 –9 . 10.1093/ndt/gfn654 19181759 \n20. Ichii M Ishimura E Okuno S Chou H Kato Y Tsuboniwa N . Decreases in parathyroid gland volume after cinacalcet treatment in hemodialysis patients with secondary hyperparathyroidism . Nephron Clin Pract. (2010 ) 115 :c195 –202 . 10.1159/000313035 20413997 \n21. Coloma A Hernandez-Estrada S Bowles H Sanchez N Fuster D Torregrosa J . Primary hyperparathyroidism regression associated to cinacalcet therapy proved by 99mTc-MIBI scintigraphy . Rev Esp Med Nucl Imagen Mol. (2017 ) 36 :120 –1 . 10.1016/j.remn.2016.10.010 28011189 \n22. Nagasawa M Ubara Y Suwabe T Yamanouchi M Hayami N Sumida K . Parathyroid hemorrhage occurring after administration of cinacalcet in a patient with secondary hyperparathyroidism . Intern Med. (2012 ) 51 :3401 –4 . 10.2169/internalmedicine.51.8055 23257528 \n23. Cetani F Ambrogini E Faviana P Vitti P Berti P Pinchera A . Spontaneous short-term remission of primary hyperparathyroidism from infarction of a parathyroid adenoma . J Endocrinol Invest. (2004 ) 27 :687 –90 . 10.1007/bf03347505 15505996\n\n",
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"keywords": "cinacalcet; hungry bone syndrome; hypocalcemia; parathyroid apoplexy; primary hyperparathyroidism",
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"abstract": "Thyrotoxic periodic paralysis (TPP) and cardiomyopathy are two established complications of thyrotoxicosis. Emergent management is essential as TPP and cardiac events secondary to thyrotoxic cardiomyopathy can be fatal. We report a unique case of a patient with Graves' disease presenting with symptoms secondary to both these complications. A 34-year-old Hispanic male, diagnosed with Graves' disease, non-compliant with his medications, presented to the emergency room (ER) with complaints of generalized weakness, palpitations, chest pain and multiple episodes of nausea and vomiting for one day. On presentation, the patient was tachycardiac, had a systolic flow murmur and decreased motor strength in all extremities. Blood work showed a potassium of 1.8 millimoles per liter, cardiac troponin of 0.04 nanograms per milliliter and a thyroid panel consistent with hyperthyroidism. Electrocardiogram showed atrial flutter. In the ER, Propranolol, Propylthiouracil and Hydrocortisone were administered to prevent thyroid storm. Potassium was repleted, and the patient developed rebound hyperkalemia. He was given calcium gluconate, insulin, sodium polystyrene and admitted to the medical intensive care unit (MICU) for further management. Echocardiogram revealed severely decreased left ventricular systolic function and an ejection fraction of 26-30%. He was diagnosed with cardiomyopathy secondary to thyrotoxicosis. He was stabilized with Methimazole, Propranolol, Lisinopril and discharged on day nine with these medications and an outpatient follow-up appointment. Thyrotoxicosis can be life-threatening. This case shows a unique instance where a Hispanic patient presented with two complications of this phenomena. The pathogenesis of TPP involves increased responsiveness of the beta-adrenergic receptors, which leads to increased activity of the Sodium/Potassium (Na+/K+) ATPase pump and a transcellular shift of potassium into cells. The condition can resolve acutely with the administration of potassium. It is important to monitor the rate of potassium replacement as rebound hyperkalemia can occur, as this case demonstrates. Propranolol is an integral part of treatment as it is a beta-adrenergic receptor blocker and blocks the peripheral conversion of thyroxine (T4) to triiodothyronine (T3) in high doses. Thyrotoxic cardiomyopathy is one of the many cardiac complications that can be precipitated by Graves' disease. One probable cause is the chronic tachycardia that patients with hyperthyroidism develop. Treatment entails managing the hyperthyroidism by starting the patient on beta blockers and anti-thyroid drugs or radioactive iodine uptake. Diuretics can be started to manage patients with heart failure. It is important to identify and treat the condition immediately to prevent grave complications.",
"affiliations": "Internal Medicine, Maimonides Medical Center, Brooklyn, USA.;Critical Care, Maimonides Medical Center, Brooklyn, USA.;Critical Care, Maimonides Medical Center, Brooklyn, USA.;Critical Care, Maimonides Medical Center, Brooklyn, USA.;Critical Care, Maimonides Medical Center, Brooklyn, USA.",
"authors": "Abbasi|Anna A|AA|;Chandar|Prarthna|P|;Shankar|Shyam|S|;Gupta|Sushilkumar S|SS|;Kupfer|Yizhak|Y|",
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"fulltext": "\n==== Front\nCureusCureus2168-8184Cureus2168-8184Cureus Palo Alto (CA) 10.7759/cureus.2837CardiologyEndocrinology/Diabetes/MetabolismInternal MedicineThyrotoxic Periodic Paralysis and Cardiomyopathy in a Patient with Graves’ Disease Muacevic Alexander Adler John R Abbasi Anna A 1Chandar Prarthna 2Shankar Shyam 2Gupta Sushilkumar S 2Kupfer Yizhak 2\n1 \nInternal Medicine, Maimonides Medical Center, Brooklyn, USA \n2 \nCritical Care, Maimonides Medical Center, Brooklyn, USA \nAnna A. Abbasi anna.amjad.abbasi@gmail.com19 6 2018 6 2018 10 6 e283725 5 2018 19 6 2018 Copyright © 2018, Abbasi et al.2018Abbasi et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/11037-thyrotoxic-periodic-paralysis-and-cardiomyopathy-in-a-patient-with-graves-diseaseThyrotoxic periodic paralysis (TPP) and cardiomyopathy are two established complications of thyrotoxicosis. Emergent management is essential as TPP and cardiac events secondary to thyrotoxic cardiomyopathy can be fatal. We report a unique case of a patient with Graves’ disease presenting with symptoms secondary to both these complications. A 34-year-old Hispanic male, diagnosed with Graves’ disease, non-compliant with his medications, presented to the emergency room (ER) with complaints of generalized weakness, palpitations, chest pain and multiple episodes of nausea and vomiting for one day. On presentation, the patient was tachycardiac, had a systolic flow murmur and decreased motor strength in all extremities. Blood work showed a potassium of 1.8 millimoles per liter, cardiac troponin of 0.04 nanograms per milliliter and a thyroid panel consistent with hyperthyroidism. Electrocardiogram showed atrial flutter. In the ER, Propranolol, Propylthiouracil and Hydrocortisone were administered to prevent thyroid storm. Potassium was repleted, and the patient developed rebound hyperkalemia. He was given calcium gluconate, insulin, sodium polystyrene and admitted to the medical intensive care unit (MICU) for further management. Echocardiogram revealed severely decreased left ventricular systolic function and an ejection fraction of 26-30%. He was diagnosed with cardiomyopathy secondary to thyrotoxicosis. He was stabilized with Methimazole, Propranolol, Lisinopril and discharged on day nine with these medications and an outpatient follow-up appointment. Thyrotoxicosis can be life-threatening. This case shows a unique instance where a Hispanic patient presented with two complications of this phenomena. The pathogenesis of TPP involves increased responsiveness of the beta-adrenergic receptors, which leads to increased activity of the Sodium/Potassium (Na+/K+) ATPase pump and a transcellular shift of potassium into cells. The condition can resolve acutely with the administration of potassium. It is important to monitor the rate of potassium replacement as rebound hyperkalemia can occur, as this case demonstrates. Propranolol is an integral part of treatment as it is a beta-adrenergic receptor blocker and blocks the peripheral conversion of thyroxine (T4) to triiodothyronine (T3) in high doses. Thyrotoxic cardiomyopathy is one of the many cardiac complications that can be precipitated by Graves’ disease. One probable cause is the chronic tachycardia that patients with hyperthyroidism develop. Treatment entails managing the hyperthyroidism by starting the patient on beta blockers and anti-thyroid drugs or radioactive iodine uptake. Diuretics can be started to manage patients with heart failure. It is important to identify and treat the condition immediately to prevent grave complications.\n\nthyrotoxicosisthyrotoxic cardiomyopathythyrotoxic periodic paralysisicu managementThe 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\nThyrotoxic periodic paralysis (TPP) and cardiomyopathy are two established complications of thyrotoxicosis [1-3]. A patient suffering from thyrotoxicosis can present acutely with these complications. Presenting symptoms can include, but are not limited to chest pain, palpitations, dyspnea, tachycardia and generalized weakness [2, 4]. Emergent management is essential as TPP and cardiac events secondary to thyrotoxic cardiomyopathy can be life-threatening. We report a case of a patient with Graves’ disease presenting with symptoms secondary to these complications.\n\nCase presentation\nA 34-year-old Hispanic male, diagnosed with Graves’ Disease three years prior to presentation, non-compliant with his medications, presented to the emergency room (ER) with complaints of generalized weakness, palpitations, chest pain and multiple episodes of nausea and vomiting. The patient had been in his usual state of health till a day before admission. Vitals showed his blood pressure to be 137/83 mmHg and heart rate to be 119 beats per minute. Physical exam was significant for proptosis, a systolic flow murmur and upper and lower extremity weakness graded with a three out of five on the strength scale. Blood work showed a potassium of 1.8 millimoles per liter (mmol/l), thyroid stimulating hormone (TSH) 0.02 micro international units/milliliters (mcIU/ml), Free Triiodothyronine (T3) 25.14 picograms/milliliters (pg/ml) and Free Thyroxine (T4) 5.23 nanograms/deciliter (ng/dl). Cardiac troponin was 0.04 nanograms/milliliter (ng/ml). Electrocardiogram showed the patient to be in atrial flutter. In the ER, Propranolol was administered, along with Propylthiouracil and Hydrocortisone to prevent thyroid storm. Morphine was given to manage the pain and Ondansetron for the nausea and vomiting. A central line was placed through the Internal Jugular vein for rapid Potassium repletion. He developed rebound hyperkalemia with a potassium as high as 6.9 mmol/l. The patient was given calcium gluconate, insulin and sodium polystyrene. He was stabilized and admitted to the medical intensive care unit (MICU) for further management. In the MICU, the patient was switched from Propylthiouracil to Methimazole. Hydrocortisone was continued. He had an elevation in his cardiac troponin to 1.52 ng/ml, however, it trended down after the patient was hemodynamically stabilized. Echocardiogram revealed mild to moderately dilated left ventricle, mild to moderately dilated left atrium, severely decreased left ventricular systolic function and an ejection fraction of 26-30%. The patient was diagnosed with cardiomyopathy secondary to thyrotoxicosis. Management was continued with anti-thyroid drugs and Propranolol. On day two, the patient improved clinically, his weakness abated, he did not complain of any chest pain and he did not have any episodes of nausea and vomiting. Physical exam showed an increase in the upper and lower extremity muscle strength to five out of five. The patient's potassium was down to 4.2 mmol/l and thyroid function tests were repeated which showed the TSH, Free T3 and Free T4 trending down. The patient was downgraded to the regular medicine floor and discharged on day nine with Methimazole, Propranolol and Lisinopril, with an outpatient follow-up appointment.\n\nDiscussion\nTPP is a more common phenomenon in the Asian population [5], however, it has been reported in Hispanic males. It presents more often in men than women [5]. About 0.2% of the population affected by hyperthyroidism develops TPP [6]. Patients can present with generalized weakness (that affects the lower extremities more than the upper extremities), hyporeflexia and/or areflexia [2]. The pathogenesis involves increased responsiveness of the beta-adrenergic receptors, which in turn leads to increased activity of the Sodium/Potassium (Na+/K+) ATPase pump and a transcellular shift of potassium into cells [7]. Genetic mutations in the encoding of Kir2.6, a potassium channel in skeletal muscle that regulates membrane potential stability, make certain patients with Graves’ disease more susceptible to developing TPP [8]. The condition can resolve acutely with the administration of potassium, however, it is important to monitor the rate of potassium replacement as rebound hyperkalemia can occur in these patients, as this case demonstrates [5]. Rebound hyperkalemia develops when, upon the resolution of TPP the amount of potassium entering the extracellular fluid exceeds the renal potassium being excreted. During an episode of TPP, the overall stores of potassium in the body are not lowered [5]. Potassium is temporarily stored in cells due to the increased activity of the beta-adrenergic receptors. Propranolol is the other integral part of TPP treatment as it is a beta-adrenergic receptor blocker [5]. Administration of propranolol slows the activity of these receptors down, which along with potassium repletion can increase the serum potassium levels. In high doses propranolol blocks the conversion of T4 to T3 [9]. Thyrotoxic cardiomyopathy is one of the many cardiac complications that can be precipitated by Graves’ disease [3]. The mechanism of cardiomyopathy is not well understood, however, one probable cause is the chronic tachycardia that patients with hyperthyroidism develop [10]. Some other cardiac manifestations of hyperthyroidism include atrial fibrillation, congestive heart failure and pulmonary hypertension [3, 11]. The mortality from cardiogenic shock secondary to thyrotoxicosis is about 30% [12]. In most cases, the cardiovascular manifestations can be reversed by treating the hyperthyroidism [13]. Treatment entails starting the patient on beta blockers and anti-thyroid drugs or radioactive iodine uptake. Diuretics can be started to manage patients with heart failure [13]. Our patient was treated with and responded well to all these medications.\n\nConclusions\nThyrotoxicosis can cause grave complications. Our patient presented with two separate, life-threatening complications of thyrotoxicosis secondary to Graves’ disease. It is important to identify and treat the condition immediately to reduce morbidity and prevent mortality from the life-threatening complications that can occur.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 Heart failure in thyrotoxic cardiomopathy: extracorporeal membrane oxygenation treatment for Graves’ disease J Extra Corpor Technol Allencherril J Birnbaum I 231 232 47(4 47 2015 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4730167/ 26834286 \n2 Thyrotoxic hypokalemic periodic paralysis: an overlooked pathology in western countries Eur J Intern Med Pompeo A Nepa A Maddestra M Feliziani V Genovesi N 380 390 18(5 18 2007 17693226 \n3 Cardiovascular complications secondary to Graves’ disease: a prospective study from Ukraine Plos One Tsymbaliuk I Unukovych D Shvets N Dinets A 0 10 2015 \n4 Cardiovascular manifestations of hyperthyroidism before and after antithyroid therapy: a matched case-control study J Am Coll Cardiol Osman F Franklyn JA Holder RL Sheppard MC Gammage MD 71 81 49 2007 17207725 \n5 Clinical and metabolic features of thyrotoxic periodic paralysis in 24 episodes Arch Intern Med Manoukian MA Foote JA Crapo LM 601 606 159 1999 10090117 \n6 Thyrotoxic periodic paralysis: a case study and review of the literature J Community Hosp Intern Med Perspect Meseeha M Parsamehr B Kissell K Attiac M 103 106 7 2017 28638574 \n7 Case 4-2012 — a 37-year-old man with muscle pain, weakness, and weight loss N Engl J Med Rhee EP Scott JA Dighe AS 553 560 553-560; February 366 2012 22316449 \n8 Thyrotoxic periodic paralysis: an underdiagnosed and under-recognized condition Cureus Tella SH Kommalapati A 0 7 2015 \n9 The influence of beta-adrenoceptor blocking agents on plasma thyroxine and triiodothyronine J Clin Endocrinol Metab Wiersinga WM Touber JL 293 298 45 1977 885993 \n10 Tachycardia-induced cardiomyopathy secondary to thyrotoxicosis: a young man with previously unrecognized Graves' disease Thyroid Yu YH Bilezikian JP 923 927 10 2000 11081259 \n11 Reversible pulmonary hypertension, tricuspid regurgitation and right-sided heart failure associated with hyperthyroidism: case report and review of the literature Cardiol Rev Lozano HF Sharma CN 299 305 12 2004 15476566 \n12 Thyrotoxicosis and thyroid storm Endocrinol Metab Clin North Am Nayak B Burman K 663 686 35 2006 17127140 \n13 Thyroid disease and the heart Curr Probl Cardiol Klein I Danzi S 65 92 41 2016 26792255\n\n",
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"abstract": "A 15-year-old male admitted for Pott's puffy tumor developed recurrent episodes of fever, diffuse morbilliform rash, eosinophilia, and tubulointerstitial nephritis while on multiple antibiotics. Lymphocyte blast transformation (LBT), a method of detecting cellular immune response by measuring levels of interferon-γ (IFN-γ), was used to diagnose vancomycin hypersensitivity and guide antibiotic selection.",
"affiliations": "Allergy/Immunology, Le Bonheur Children's Hospital, Memphis, TN 38103, USA.",
"authors": "Tran|Nguyen P|NP|;Katcher|Jeremy|J|;Rohman|Erin|E|;Hall|Mary Francis|MF|;Michael|Christie F|CF|;Miyairi|Isao|I|;Lew|D Betty|DB|",
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"fulltext": "\n==== Front\nCase Rep PediatrCase Rep PediatrCRIM.PEDIATRICSCase Reports in Pediatrics2090-68032090-6811Hindawi Publishing Corporation 2260651610.1155/2011/562620Case ReportVancomycin Hypersensitivity Diagnosed by Lymphocyte Blast Transformation Tran Nguyen P. \n1\nKatcher Jeremy \n1\nRohman Erin \n1\nHall Mary Francis \n2\nMichael Christie F. \n1\nMiyairi Isao \n1\nLew D. Betty \n1\n*1Allergy/Immunology, Le Bonheur Children's Hospital, Memphis, TN 38103, USA2Diagnostic Immunology, Memphis Pathology Laboratories, Memphis, TN 38141, USA*D. Betty Lew: dlew@uthsc.eduAcademic Editors: R. Lazzarini and Y. P. Venkatesh\n\n2011 24 11 2011 2011 56262019 8 2011 21 9 2011 Copyright © 2011 Nguyen P. Tran et al.2011This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.A 15-year-old male admitted for Pott's puffy tumor developed recurrent episodes of fever, diffuse morbilliform rash, eosinophilia, and tubulointerstitial nephritis while on multiple antibiotics. Lymphocyte blast transformation (LBT), a method of detecting cellular immune response by measuring levels of interferon-γ (IFN-γ), was used to diagnose vancomycin hypersensitivity and guide antibiotic selection.\n==== Body\n1. Introduction\n Drug allergies have a significant impact on patient morbidity and overall cost of the practice of medicine. Anywhere from 10–20% of hospitalized patients will have an adverse drug reaction [1]. The most common clinical presentation of these reactions is cutaneous, such as urticaria and maculopapular eruptions [2]. Adverse drug reactions from vancomycin specifically can range from red man syndrome to leukocytoclastic vasculitis to anaphylaxis [3]. Less common reactions include exfoliative dermatitis, linear IgA bullous dermatosis, and delayed hypersensitivity reaction [4, 5].\n\n Currently, diagnostic methods for suspected allergic reaction to vancomycin are limited, and the diagnosis is often made based by history alone. Skin puncture testing with vancomycin results in frequent false positives secondary to direct degranulation of mast cells [6]. Polk et al. performed vancomycin skin testing on healthy volunteers and found that all subjects tested had a positive reaction at concentrations ≥10 μg/mL [7].\n\n We report a case of an adolescent patient who developed a morbilliform rash while on multiple antibiotics. Lymphocyte blast transformation (LBT) was performed to involve antibiotics to help determine the culprit. Although T-cell Rx test (CD69 upregulation) for vancomycin delayed hypersensitivity has become recently available [8], vancomycin hypersensitivity documented by LBT has not been previously reported.\n\n2. Case Report\nA 15-year-old male with a history of craniosynostosis and developmental delay presented to the Emergency Department with fever, headache, and swelling of the left forehead. A CT scan revealed left frontal sinusitis with extension of the inflammatory process through the left frontal bone into the subperiosteal region (Pott's puffy tumor) and subgaleal region. The patient also had evidence of metallic sutures and fenestrated plate to the superior margin of the left frontal sinus consistent with his past medical history of repaired craniosynostosis at 6 months of age. Family history and social history were unremarkable for drug reactions. The patient was started on vancomycin and ceftriaxone upon admission and underwent bifrontal craniotomy, exoneration of frontal sinuses with vascularized pericranial rotational graft, an endoscopic left-sided ethmoidectomy, and maxillary antrostomy. Gram stain of the purulent material obtained from the surgery revealed Gram-positive cocci in pairs, chains, and clusters while the culture grew rare anaerobic Gram-negative cocci, which we were unable to speciate. Given concerns of polymicrobial infection with potential foreign body involvement, his regimen was changed to vancomycin and meropenem. The patient defervesced, and his edema subsided. On hospital day 8–10, he developed a diffuse, erythematous morbilliform rash, fevers up to 40°C, and elevated blood pressures with systolic measurements to 160 mmHg. Laboratory examination revealed new onset eosinophilia (max. absolute eosinophil count 980/mm3), mild elevation of creatinine and 1−2+ proteinuria, consistent with drug associated hypersensitivity and tubulointerstitial nephritis. Vancomycin and meropenem were discontinued and changed to ceftriaxone and metronidazole on hospital day 10. The patient promptly defervesced with gradual improvement of the rash, but on hospital day 14 developed low-grade fevers (Tm 38.1°C) and recurrence of diffuse rash. Skin exam revealed widespread maculopapular erythematous rash, prominent on the arms, legs, and trunk, especially abdomen. No blisters or drainage were associated with the rash and there was no mucosal involvement. \n\nLBT was performed as described in the methods and results section. Lymphocytes incubated with vancomycin showed a robust response and those incubated with metronidazole showed an equivocal response (likely contributing to the recurrence of rash on hospital day 14). The remainder of the antibiotics tested did not show significant IFN-γ production. The patient tolerated a treatment regimen of ceftriaxone and clindamycin with resolution of rash and return to his baseline temperatures. He completed a total course of 4-weeks of antibiotics without any signs of relapse.\n\n3. Methods and Results\n Lymphocyte blast transformation is a method for detection of cellular immune response based upon the premise that stimulated or sensitized lymphocytes will revert to blast formation and produce detectable levels of IFN-γ, which are directly proportional to the level of sensitization. Testing was performed using the QuantiFERON-CMI testing kit (Cellestis, Victoria, Australia, http://www.cellestis.com/) [9]. Heparinized whole blood was collected, and ex vivo LBT was performed with phytohemagglutinin (PHA), pokeweed mitogen (PWM), concanavalin A (Con A) to evaluate the patient's baseline immune function. The patient's whole blood was incubated with antibiotics at varying dilutions designed to mimic actual serum concentration for 18 hours at 37°C in a 24-well tissue culture plate. Then using a pipette, 200–300 μL of plasma above the sedimented red cells was transferred to a new well plate (anti-human IFN-γ antibodies bound to the solid phase), and IFN-γ production was then quantitatively measured using enzyme-linked immunosorbent assay (ELISA) utilizing enzyme-labeled IFN-γ antibodies in solution. The interferon cutoff was set at 0.16 IU/mL, which was determined by plotting the optical density against a standard curve generated according to the manufacture's instructions.\n\n In our patient, his response to PWM, PHA, and the kit's mitogen positive control was within the expected ranges. The positive control included in the QuantiFERON-CMI testing kit generally elicits the greatest IFN-γ response for any given individual. The response to Con A was less than expected at 0.269 IU/mL (effective response >0.6). There was a remarkable concentration-dependant response to vancomycin, an equivocal response to metronidazole, and no response to ceftriaxone, amoxicillin, and meropenem; see Figure 1. Vancomycin hypersensitivity was diagnosed.\n\n4. Discussion\n Maculopapular eruptions are a common manifestation of nonimmediate allergic drug reactions and are mediated via drug-specific T cells. Drugs are low-molecular-weight chemicals that can interact with T cells, specifically their receptors, to activate an immune response. Once activated, the drug-specific T cells migrate into the skin and cause inflammatory damage with the release of various cytokines [10].\n\n One of the original methods of determining cell stimulation was via the lymphocyte transformation test, which is an in vitro assay that measures the rate of 3H-thymidine or bromodeoxyuridine uptake in replicating DNA [11]. Its clinical use has been discussed in the literature for detection of delayed hypersensitivity reactions to certain antibiotics, antiepileptics, antihypertensives, NSAIDS, anesthetics, and radiocontrast media [12]. LBT has the advantage over the lymphocyte transformation test of a quicker turn-around time (usually 24–48 hours) since there is no radioisotope or need to culture cells. Recently, Beeler et al. reported on the use of CD69 upregulation on T cells as an activation marker for delayed-type drug hypersensitivity [8]. In contrast, LBT is a functional assay for detecting IFN-γ production by sensitized T cells in response to specific antigen or mitogen [9]. There is no previously published report on the use of increased IFN-γ production to diagnose vancomycin hypersensitivity.\n\n The patient described in this paper demonstrates a common scenario encountered by consulting allergists and infectious diseases specialists. Due to the lack of specificity and sensitivity of skin testing for some medications, the patient history is often relied upon to determine which antibiotic is the causative agent in a drug reaction. Reliable diagnosis, though difficult, is necessary for safe and effective patient treatment. This patient had a complicated sinus infection requiring long-term broad-spectrum coverage, which was further complicated by recurrent episodes of fever and rash resulting in the use of multiple classes of antibiotics. His morbilliform rash was initially thought to be secondary to cephalosporins. However, we were able to determine that vancomycin and possibly metronidazole were likely to be responsible for the patient's fever and rash. In this case, LBT testing guided us in establishing an alternative regimen of ceftriaxone and clindamycin. \n\nThe marked INF-γ levels detected using the quantiFERON-CMI kit indicates the presence of a specific T-cell-mediated immune response against vancomycin, which is the immunologic basis for delayed-type hypersensitivity. Vancomycin concentrations used were within therapeutic levels and combined with the patient's clinical course indicate that LBT was useful in the diagnosis of vancomycin hypersensitivity in this patient. Since it is a cellular immune response, unsensitized individuals should show zero production of interferon. Clearly, larger studies are needed to determine its utility in various clinical scenarios. There was a mild response to metronidazole, which correlates with the relatively milder clinical manifestation observed during metronidazole therapy and possible metronidazole hypersensitivity. The results of a negative response to β-lactam agents were interpreted with caution, and clinical response was monitored.\n\nA potential limitation of LBT would be non-discriminatory IFN-γ production that may be seen in a scenario of multidrug hypersensitivity induced by superantigens. However, even in such a case, negative results can still be helpful. Results need to be reproduced in a larger sample size. Further evaluation is also needed to see if it can be used for hypersensitivity to other medications and if other cytokines may be more sensitive or specific for drug-related delayed-type hypersensitivity.\n\n5. Conclusions\nLymphoblast transformation is a useful test in confirming the etiology of vancomycin-induced delayed hypersensitivity reaction.\n\nConflict of Interests\nAll authors declare no conflict of interests. No funding was received for this project.\n\nFigure 1 Secreted fraction of INF-γ production by the patient's peripheral lymphocytes after 18 h stimulation with various concentrations of Vancomycin and Metronidazole. The patient did not produce any detectable levels of INF-γ with Ceftriaxone, Amoxicillin, and Meropenem stimulation at all drug concentrations (<0.16 IU/mL). Likewise, the levels of INF-γ production in Vancomycin-naïve control subject were below the threshold of detection (<0.16 IU/mL) at all Vancomycin concentrations.\n==== Refs\n1 Gomes ER Demoly P Epidemiology of hypersensitivity drug reactions Current Opinion in Allergy and Clinical Immunology 2005 5 4 309 316 15985812 \n2 Celik G Pichler W Adkinson NF Adkinson NF Bochner BS Busse W Drug allergy Middleton’s Allergy 2009 7th edition Philadelphia, Pa, USA Mosby 1205 1226 \n3 Felix-Getzik E Sylvia L Vancomycin-induced leukocytoclastic vasculitis Pharmacotherapy 2009 29 7 846 851 19558258 \n4 Bernstein E Schuster M Linear IgA bullous dermatosis associate with vancomycin Annals of Internal Medicine 1998 129 6 508 509 9735095 \n5 Marik PE Ferris N Delayed hypersensitivity reaction to vancomycin Pharmacotherapy 1997 17 6 1341 1344 9399623 \n6 Wazny L Daghigh B Desensitization protocols for vancomycin hypersensitivity Annals of Pharmacotherapy 2001 35 11 1458 1464 11724099 \n7 Polk RE Israel D Wang J Vancomycin skin tests and prediction of red man syndromein healthy volunteers Antimicrob Agents Chemother 1993 37 10 2139 2143 8257136 \n8 Beeler A Zaccaria L Kawabata T Gerber BO Pichler WJ CD69 upregulation on T cells as an in vitro marker for delayed-type drug hypersensitivity Allergy 2008 63 2 181 188 18005225 \n9 Mosmann TR Coffman RL TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties Annual Review of Immunology 1989 7 145 173 \n10 Rozieres A Vocanson M Said BB Nosbaum A Nicolas JF Role of T cells in nonimmediate allergic drug reactions Current Opinion in Allergy and Clinical Immunology 2009 9 4 305 310 19474707 \n11 Pichler WJ Tilch J The lymphocyte transformation test in the diagnosis of drug hypersensitivity Allergy 2004 59 8 809 820 15230812 \n12 Lochmatter P Zawodniak A Pichler WJ In Vitro tests in drug hypersensitivity diagnosis Immunology and Allergy Clinics of North America 2009 29 3 537 554 19563996\n\n",
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"title": "Vancomycin hypersensitivity diagnosed by lymphocyte blast transformation.",
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"abstract": "BACKGROUND\nTyrosine kinase inhibitors are widely prescribed in thoracic oncology and have excellent responses as a first-line treatment for locally advanced or metastatic lung cancer with epidermal growth factor receptor mutations. The side effects of tyrosine kinase inhibitors are mostly gastrointestinal and dermatological, and are usually resolved after symptomatic treatment. However, new complications have now arisen due to increased use of these drugs. Here we report a side effect of erlotinib that has not been described previously: that is, metastatic lung tumor nodules were transformed into cysts, which ruptured the pleura and were responsible for bilateral life-threatening pneumothorax.\n\n\nMETHODS\nWe report the case of a 35-year-old Caucasian woman with metastatic adenocarcinoma and a deletion in epidermal growth factor receptor exon 19 (del E746-A750). She was treated with erlotinib for metastatic lung adenocarcinoma. Treatment with erlotinib resulted in the replacement of pulmonary tumor nodules with air-containing cysts. These cysts ruptured in the pleura causing a life-threatening bilateral pneumothorax. To the best of our knowledge, this tumor-cystic response after erlotinib therapy has not been previously described.\n\n\nCONCLUSIONS\nTyrosine kinase inhibitors are widely prescribed in thoracic oncology, and managing toxicities must be optimal in order to improve adherence. Transformation of pulmonary nodules into cysts must be known and clinicians should be aware of this potential complication, which can lead to life-threatening pneumothorax.",
"affiliations": "Pôle thorax et vaisseaux, Unité d'oncologie thoracique, CHU Grenoble, BP217, 38043 Grenoble cedex 9, France. lsakhri@chu-grenoble.fr.",
"authors": "Sakhri|Linda|L|;Meynet|Elodie|E|;Ferrer|Léonie|L|;Pirvu|Augustin|A|;Ferretti|Gilbert|G|;Moro-Sibilot|Denis|D|",
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"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central 1752-1947-8-3352530132310.1186/1752-1947-8-335Case ReportAtypical response to erlotinib in a patient with metastatic lung adenocarcinoma: a case report Sakhri Linda 1lsakhri@chu-grenoble.frMeynet Elodie 1emeynet@chu-grenoble.frFerrer Léonie 1lferrer@chu-grenoble.frPirvu Augustin 2apirvu@chu-grenoble.frFerretti Gilbert 3gferretti@chu-grenoble.frMoro-Sibilot Denis 1dmoro-sibilot@chu-grenoble.fr1 Pôle thorax et vaisseaux, Unité d’oncologie thoracique, CHU Grenoble, BP217, 38043 Grenoble cedex 9, France2 Service de chirurgie thoracique, vasculaire et endocrinienne, CHU Grenoble, BP217, 38043 Grenoble cedex 9, France3 Service de radiologie, CHU Grenoble, 38043 Grenoble cedex 9, France2014 9 10 2014 8 335 335 4 5 2014 8 8 2014 Copyright © 2014 Sakhri et al.; licensee BioMed Central Ltd.2014Sakhri et al.; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Introduction\nTyrosine kinase inhibitors are widely prescribed in thoracic oncology and have excellent responses as a first-line treatment for locally advanced or metastatic lung cancer with epidermal growth factor receptor mutations. The side effects of tyrosine kinase inhibitors are mostly gastrointestinal and dermatological, and are usually resolved after symptomatic treatment. However, new complications have now arisen due to increased use of these drugs. Here we report a side effect of erlotinib that has not been described previously: that is, metastatic lung tumor nodules were transformed into cysts, which ruptured the pleura and were responsible for bilateral life-threatening pneumothorax.\n\nCase presentation\nWe report the case of a 35-year-old Caucasian woman with metastatic adenocarcinoma and a deletion in epidermal growth factor receptor exon 19 (del E746-A750). She was treated with erlotinib for metastatic lung adenocarcinoma.\n\nTreatment with erlotinib resulted in the replacement of pulmonary tumor nodules with air-containing cysts. These cysts ruptured in the pleura causing a life-threatening bilateral pneumothorax.\n\nTo the best of our knowledge, this tumor–cystic response after erlotinib therapy has not been previously described.\n\nConclusions\nTyrosine kinase inhibitors are widely prescribed in thoracic oncology, and managing toxicities must be optimal in order to improve adherence. Transformation of pulmonary nodules into cysts must be known and clinicians should be aware of this potential complication, which can lead to life-threatening pneumothorax.\n\nBilateral pneumothoraxEGFR mutationErlotinibPulmonary adenocarcinomaPulmonary cystsTyrosine kinase inhibitors\n==== Body\nIntroduction\nTargeted therapies in thoracic oncology are starting to compete with ‘classic’ chemotherapies due to their better clinical tolerance and easier mode of administration. However, we are now faced with a new complication because of their increased usage. Tyrosine kinase inhibitors (TKIs) are now widely prescribed in thoracic oncology: thus, managing any toxicity should be optimal to improve adherence. Here we report a case in which erlotinib caused transformation of pulmonary nodules into cysts; this has not been described previously in the literature.\n\nCase presentation\nA 35-year-old Caucasian woman and former cigarette smoker presented with dyspnea and neck pain. A computed tomography (CT) scan revealed bilateral round opacities in both lungs (Figure 1A, C), hepatic metastases, osteolysis of her second cervical vertebra (C2) (Figure 2A), and two cerebral metastases. A percutaneous biopsy of the hepatic metastasis showed lung adenocarcinoma with a deletion in the epidermal growth factor receptor exon 19 (del E746-A750).Treatment with erlotinib was started. After 2 months she was hospitalized in our intensive care unit for an acute respiratory distress syndrome, secondary to a bilateral and spontaneous pneumothorax, which required placement of a chest tube. A thoracic CT scan revealed the replacement of diffuse parenchymatous nodules by cystic lesions (Figure 1B, D). Because of prolonged air leakage but also a good response to oncological treatment, a two-stage thoracoscopic bilateral talc poudrage was performed. Her postoperative course was uneventful and the drains were removed at 3 weeks after surgery.\n\nFigure 1 Thoracic computed tomography scan. (A) (C) Initial thoracic computed tomography scan showing multiple pulmonary metastases. (B) (D) Thoracic computed tomography scan after 2 months of treatment with erlotinib, showing a partial thoracic response with the appearance of pulmonary cysts and a partially drained bilateral pneumothorax.\n\nFigure 2 Computed tomography scan of the neck. (A) revealing C2 osteolysis as indicated by the arrow. (B) showing osteocondensation (as indicated by the arrow) in the location of the initial lysis of the C2 vertebrae after 2 months of treatment with erlotinib.\n\nThe cancer progressed within the next 9 months. A second-line treatment of cisplatin, pemetrexed, and bevacizumab followed by a maintenance therapy of bevacizumab, was given. After 6 months of chemotherapy, the tumor had progressed and erlotinib was reintroduced. This therapy was associated with a cerebral infarction in the context of paraneoplastic syndrome. The patient died 18 months later from disease progression.\n\nDiscussion\nIn this patient, erlotinib gave an excellent initial response; there was complete disappearance of the cerebral metastases, and the osteocondensation of the C2 vertebrae (Figure 2B). However, lysis of the subpleural metastases (Figure 1B, C) could explain the occurrence of the cystic lesions and pneumothorax.\n\nWe have recently reported a case in which there was transformation of pulmonary nodules into pulmonary cysts in a 40-year-old woman who was a non-cigarette smoker with multi-metastatic pulmonary adenocarcinoma, an EML4-ALK gene rearrangement, and who was successfully treated with crizotinib [1].\n\nThe phenomenon of cyst formation is caused by parenchymal necrosis as a result of targeted therapy, but which also increases the risk of a pneumothorax. Tumor necrosis has previously been described in connection with the lysis of some chemosensitive tumors, such as germinal tumors, lymphomas, and sarcomas [2,3], with a 1% risk of a pneumothorax occurring within 2 to 7 days following the start of chemotherapy [4].\n\nTransformation of tumor lesions into cysts is also a difficulty in Response Evaluation Criteria in Solid Tumours assessments. The solid tumors initially retain the same diameter as the newly formed cysts.\n\nTKIs are prescribed as a first-line therapy in the context of sensitive mutations, and produce a response rate of 50 to 90% and progression-free survival times of 9.7 to 13.1 months; this is compared to 4.6 to 5.2 months in patients treated with a platinum-based chemotherapy [5].\n\nHere we report the unusual response of the lung after erlotinib therapy, in which the lung nodules were transformed into cysts via a mechanism that was probably associated with necrosis.\n\nConclusions\nThe association between lysis of a lung tumor and its replacement by a cyst seemed to be caused by erlotinib treatment: thus, this should be borne in mind, as the rupture of a cyst in the pleura can result in a life-threatening pneumothorax.\n\nConsent\nWritten informed consent was obtained from the patient's next of kin for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nDMS declares that he is on the advisory board and consults for Roche, Astra Zeneca, Pfizer and Lilly Laboratories. GF declares that he received honorarium and travel expenses to speak to professional groups, travel accommodations and meeting expenses (Roche and Guerbet laboratories), and payment for lectures including service on speakers bureaus (Lilly, Boehringer, Actelion, Astra Zeneca, Roche). All other authors have no conflicts to declare.\n\nAuthors’ contributions\nLS wrote the manuscript and helped manage the patient while in the hospital. EM helped manage the patient while in the hospital and was a major contributor in writing the manuscript. LF helped manage the patient while in the hospital and was a major contributor in writing the manuscript. AP was the surgeon of the patient and a major contributor in writing the manuscript. GF interpreted the radiologic data and was a major contributor in writing the manuscript. DMS helped manage the patient while in the hospital and was a major contributor in writing the manuscript. All authors read and approved the final manuscript\n\nAcknowledgement\nThe sources of funding for all authors: none.\n==== Refs\nAlbahary MV Ferretti G Lantuejoul S Mc Leer Florin A Pop O Toffart AC Melis A Goncalves A Moro-Sibilot D Cavitating nodules in a 40-year-old non-smoking woman: a very particular tumour Rev Mal Respir 2012 29 916 919 10.1016/j.rmr.2012.03.007 22980554 \nStein ME Shklar Z Drumea K Goralnik L Ben-Arieh Y Haim N Chemotherapy induced spontaneous pneumothorax in a patient with bulky mediastinal lymphoma: a rare oncologic emergency Oncology 1997 54 15 18 8978586 \nHsu JR Chang SC Perng RP Pneumothorax following cytotoxic chemotherapy in malignant lymphoma Chest 1990 98 1512 1513 10.1378/chest.98.6.1512 1700945 \nMorgan C Tillett T Braybrooke J Ajithkumar T Management of uncommon chemotherapy-induced emergencies Lancet Oncol 2011 12 806 814 10.1016/S1470-2045(10)70208-4 21276754 \nRosell R Carcereny E Gervais R Vergnenegre A Massuti B Felip E Palmero R Garcia-Gomez R Pallares C Sanchez JM Porta R Cobo M Garrido P Longo F Moran T Insa A De Marinis F Corre R Bover I Illiano A Dansin E de Castro J Milella M Reguart N Altavilla G Jimenez U Provencio M Moreno MA Terrasa J Muñoz-Langa J Erlotinib versus standard chemotherapy as first line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial Lancet Oncol 2012 13 239 246 10.1016/S1470-2045(11)70393-X 22285168\n\n",
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"mesh_terms": "D000230:Adenocarcinoma; D000077192:Adenocarcinoma of Lung; D000328:Adult; D003560:Cysts; D000069347:Erlotinib Hydrochloride; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D009362:Neoplasm Metastasis; D011030:Pneumothorax; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D012422:Rupture, Spontaneous",
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"title": "Atypical response to erlotinib in a patient with metastatic lung adenocarcinoma: a case report.",
"title_normalized": "atypical response to erlotinib in a patient with metastatic lung adenocarcinoma a case report"
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"abstract": "Receptor for advanced glycation end-products (RAGE), a receptor for amyloids, is constitutively expressed in lungs and generally observed to be downregulated in lung cancer tissues. However, increasing levels of RAGE or serum amyloids is associated with poor outcome in lung cancer patients. We report a rare case of primary systemic amyloid light-chain (AL) amyloidosis in biopsy-proven multiple organs with early-stage non-small cell lung cancer (NSCLC) that displayed strong staining for RAGE in the tumour tissue. Interestingly, compared with randomly selected lung cancer biopsy samples, including all representative histological subtypes of NSCLC and small-cell lung cancer, only the NSCLC in the present case showed strong expression for RAGE that can bind amyloids.\n\n\n\nA 71-year-old woman was admitted to our hospital for comprehensive investigation of nephrotic syndrome. Computed tomography showed a small nodule in the right upper lung lobe with hilar mediastinal lymph node enlargement. Pathological examination of transbronchial biopsy samples of the nodule yielded a diagnosis of lung adenocarcinoma. Furthermore, the pathological detection of amyloid deposition in biopsy samples of a subcarinal lymph node, gastric and duodenal mucosa, cardiac muscle, and bone marrow led to a diagnosis of primary systemic AL amyloidosis with nephrotic syndrome and cardiomyopathy. In addition, RAGE was detected in lung tumour tissues surrounded by normal lung tissues with amyloid deposition.\n\n\n\nThe RAGE positivity of the lung cancer cells in this case suggests an interaction between amyloid-containing tissues and RAGE-expressing cancer cells. Lung adenocarcinoma with RAGE expression may be a complication of underlying amyloidosis.",
"affiliations": "Department of Respiratory Medicine, Juntendo University School of Medicine & Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.;Department of Respiratory Medicine, Juntendo University School of Medicine & Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan. shinsaku@juntendo.ac.jp.;Junior Resident of Juntendo University Hospital, Tokyo, Japan.;Department of Respiratory Medicine, Juntendo University School of Medicine & Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.;Department of Respiratory Medicine, Juntendo University School of Medicine & Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.;Department of Respiratory Medicine, Juntendo University School of Medicine & Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.;Department of Respiratory Medicine, Juntendo University School of Medicine & Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.;Department of Pathology, Labor Health and Welfare Organization Kanto Rosai Hospital, Kanagawa, Japan.;Department of Respiratory Medicine, Juntendo University School of Medicine & Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.",
"authors": "Okamoto|Shouichi|S|;Togo|Shinsaku|S|;Nagata|Ichiro|I|;Shimizu|Kazue|K|;Koinuma|Yoshika|Y|;Namba|Yukiko|Y|;Ito|Jun|J|;Uekusa|Toshimasa|T|;Takahashi|Kazuhisa|K|",
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"fulltext": "\n==== Front\nBMC CancerBMC CancerBMC Cancer1471-2407BioMed Central London 300910.1186/s12885-016-3009-3Case ReportLung adenocarcinoma expressing receptor for advanced glycation end-products with primary systemic AL amyloidosis: a case report and literature review Okamoto Shouichi sho-okamoto@juntendo.ac.jp 12Togo Shinsaku shinsaku@juntendo.ac.jp 12Nagata Ichiro nagata@juntendo.ac.jp 3Shimizu Kazue kshimizu@juntendo.ac.jp 1Koinuma Yoshika ymatsuda@juntendo.ac.jp 12Namba Yukiko yknanba@juntendo.ac.jp 12Ito Jun moisture@juntendo.ac.jp 12Uekusa Toshimasa uekusatoshimasa@kantoh.rofuku.go.jp 4Takahashi Kazuhisa kztakaha@juntendo.ac.jp 121 Department of Respiratory Medicine, Juntendo University School of Medicine & Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421 Japan 2 Research Institute for Diseases of Old Ages, Juntendo University Graduate School of Medicine, Tokyo, Japan 3 Junior Resident of Juntendo University Hospital, Tokyo, Japan 4 Department of Pathology, Labor Health and Welfare Organization Kanto Rosai Hospital, Kanagawa, Japan 5 1 2017 5 1 2017 2017 17 2211 8 2016 15 12 2016 © The Author(s). 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nReceptor for advanced glycation end-products (RAGE), a receptor for amyloids, is constitutively expressed in lungs and generally observed to be downregulated in lung cancer tissues. However, increasing levels of RAGE or serum amyloids is associated with poor outcome in lung cancer patients. We report a rare case of primary systemic amyloid light-chain (AL) amyloidosis in biopsy-proven multiple organs with early-stage non-small cell lung cancer (NSCLC) that displayed strong staining for RAGE in the tumour tissue. Interestingly, compared with randomly selected lung cancer biopsy samples, including all representative histological subtypes of NSCLC and small-cell lung cancer, only the NSCLC in the present case showed strong expression for RAGE that can bind amyloids.\n\nCase presentation\nA 71-year-old woman was admitted to our hospital for comprehensive investigation of nephrotic syndrome. Computed tomography showed a small nodule in the right upper lung lobe with hilar mediastinal lymph node enlargement. Pathological examination of transbronchial biopsy samples of the nodule yielded a diagnosis of lung adenocarcinoma. Furthermore, the pathological detection of amyloid deposition in biopsy samples of a subcarinal lymph node, gastric and duodenal mucosa, cardiac muscle, and bone marrow led to a diagnosis of primary systemic AL amyloidosis with nephrotic syndrome and cardiomyopathy. In addition, RAGE was detected in lung tumour tissues surrounded by normal lung tissues with amyloid deposition.\n\nConclusion\nThe RAGE positivity of the lung cancer cells in this case suggests an interaction between amyloid-containing tissues and RAGE-expressing cancer cells. Lung adenocarcinoma with RAGE expression may be a complication of underlying amyloidosis.\n\nKeywords\nAmyloidosisCase reportLung adenocarcinomaRAGEissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nThe incidence of systemic amyloidosis in patients with cancer is very rare and has been estimated to be between 0.1% and 0.4% among all cancers [1]. Increasing serum amyloid A (SAA) level in a patient with non-small cell lung cancer (NSCLC) is considered a predictive biomarker of poor prognosis [2]. Receptor for advanced glycation end-products (RAGE) is a transmembrane receptor of the immunoglobulin superfamily and binds structurally diverse molecules, including amyloids. RAGE is constitutively expressed in lungs and observed to be downregulated in lung cancer patients. RAGE associates with survival and metastatic spread of cancers [3, 4]. Herein, we report on a rare case of primary systemic amyloid light-chain (AL) amyloidosis in biopsy-proven multiple organs with early-stage NSCLC that displayed strong staining for RAGE in the tumour tissue.\n\nCase presentation\nA 71-year-old Japanese woman, non-smoker, with a history of cholelithiasis, hypertension, and dyslipidaemia, was referred to our hospital for evaluation of nephrotic syndrome. The patient had been diagnosed with hypertrophic cardiomyopathy 6 months previously.\n\nOn physical examination, the patient was 155.0 cm tall. She weighed 46.0 kg and showed a systolic ejection murmur from the left sternal border to the apex and pitting leg oedema. The remainder of the examination was unremarkable. On blood analysis, hypoalbuminemia (1.7 g/dL), proteinuria (4.5 g/gCr), and serum IgG M-protein were detected. Serum free light chain (SFLC) assay showed an increase in free lambda chain with a decreased kappa/lambda ratio (kappa SFLC: 7.8 mg/L, normal 3.3–19.4 mg/L; lambda SFLC: 70.5 mg/L, normal 5.7–26.3 mg/L; kappa/lambda ratio: 0.11, normal 0.3–1.3). On the other hand, SAA (5.6 μg/mL) and immunoglobulin were within normal limits. Creatinine (0.8 mg/dL), brain natriuretic peptide (325.8 pg/mL), and carcinoembryonic antigen (6.4 ng/mL) were elevated. Chest radiography showed a nodule, 2.1 cm in diameter, in the right upper lung field. Computed tomography revealed a nodule with marginal irregularity and bronchodilatation in the right upper lobe, hilar mediastinal lymph node enlargement, slight bilateral pleural effusion, pericardial effusion, and ascites (Fig. 1).Fig. 1 Computed tomography (CT) images. a Chest CT scan showing the nodule with marginal irregularity and bronchodilatation in the right upper lobe. b CT scan in the mediastinal window showing mediastinal lymph node enlargement and bilateral pleural effusion\n\n\n\n\nPathological examination of transbronchial biopsy samples of the lung nodule yielded a diagnosis of adenocarcinoma (Fig. 2a). In addition, interstitial deposition of amorphous material that stained positively for Congo red with apple-green birefringence in the polarized view, and an amyloid P component was found in the tissues surrounding the tumour and in the subcarinal lymph node (Fig. 2f, j: lung; g, k: subcarinal lymph node). Enlargement of the subcarinal lymph node was not due to cancer metastasis. In addition, biopsy samples of gastric and duodenal mucosa, bone marrow, and cardiac muscle stained positively for Congo red with apple-green birefringence in the polarized view, and amyloid P component (Fig. 2h, l: duodenal mucosa; i, m: bone marrow). Only the subcarinal lymph node and the cardiac muscle stained positively for anti-lambda light chain antibodies. Furthermore, positive staining for RAGE was detected only in the lung tumour cells (Fig. 2b-e). The bone marrow demonstrated a normal population of plasma cells with slight atypia.Fig. 2 Microphotographs of the present case. a-b The lung adenocarcinoma (a, b: arrowheads): a haematoxylin and eosin staining (bar = 100 μm); b receptor for advanced glycation end-products (RAGE) staining (bar = 100 μm). Positive staining for RAGE is seen. c-e RAGE staining of other tissues (bar = 100 μm): c subcarinal lymph node; d duodenal mucosa; e bone marrow. None of these tissues show positive staining for RAGE. f-i Congo red staining (bar = 200 μm): f lung tissue surrounding the adenocarcinoma; g subcarinal lymph node; h duodenal mucosa; i bone marrow. Amorphous deposition was found in the tissues surrounding the tumour (f: arrowheads). j-m Amyloid P component staining (bar = 200 μm): j lung tissue surrounding the adenocarcinoma; k subcarinal lymph node; l duodenal mucosa; m bone marrow. All amorphous material shows positive staining for Congo red with apple-green birefringence in the polarized view, and amyloid P component\n\n\n\n\nFinally, the case was diagnosed as lung adenocarcinoma, Stage IA (cT1bN0M0), and primary systemic AL amyloidosis with nephrotic syndrome and cardiomyopathy.\n\nBecause the patient displayed rapidly worsening edema and cardiac amyloidosis with elevated brain natriuretic peptide, she was given a poor prognosis rather than that expected with early-stage lung adenocarcinoma and was treated with dexamethasone (20 mg/day) and diuretics. The oedema, mainly due to the nephrotic syndrome with severe proteinuria, pleural effusion, and brain natriuretic peptide levels were not responsive to treatment. The patient died after 3 months despite dexamethasone and bortezomib treatment in another hospital.\n\nDiscussion\nRAGE is a multiligand receptor that binds structurally diverse molecules, including high mobility group box 1, S100 family of proteins, some species of advanced glycation end-products, and β-sheet fibrillar material (e.g., amyloid-β and SAA). RAGE is constitutively expressed at high levels in alveolar-type cells and at relatively low levels in vascular endothelial cells, inflammatory cells, and neurons [4–6]. RAGE and its ligands are highly upregulated in cancer tissue (e.g., pancreatic, colon, and prostate cancer) [7]. By contrast, both RAGE and serum soluble RAGE (sRAGE) levels are downregulated in smokers and lung cancer patients [7–9].\n\nInterestingly, RAGE that can bind amyloids showed strong expression in primary lung adenocarcinoma tissue in the early stages (Fig. 2b) and negative expression in other amyloid-positive tissues without metastasis such as the subcarinal lymph node, duodenal mucosa, and bone marrow (Fig. 2c, d, e). We confirmed RAGE staining in lung cancer tissues without comorbidity of amyloidosis by applying immunohistochemical analysis in randomly selected biopsy samples of lung cancer, including all representative histological subtypes of NSCLC and small-cell lung cancer; these samples were used as the negative control (Fig. 3a-f).Fig. 3 Immunohistochemical staining for receptor for advanced glycation end-products (RAGE) in control lung cancers: a solid adenocarcinoma; b acinar adenocarcinoma; c papillary adenocarcinoma; d lepidic adenocarcinoma; e squamous cell carcinoma; f small-cell carcinoma. All controls stained negatively for RAGE (bar = 100 μm)\n\n\n\n\nPrevious studies have reported that expression levels of RAGE and its ligands are associated with clinical outcome in patients with NSCLC. Upregulated RAGE expression and activity are associated with tumour invasion and metastatic activity in certain types of neoplasia, including gastric and colon cancer [10, 11]. In contrast, overexpressed RAGE in lung cancer cells suppresses tumour growth and the acquisition of cancer stem cell features in vitro [12]. sRAGE traps circulating ligands that are overexpressed in lung cancer and thus acts as an inhibitor of RAGE-mediated cell signalling [13]. We were not able to monitor the clinical time course of serum sRAGE level as a surrogate marker in this case. There is speculation that downregulation of both RAGE and sRAGE may be a critical step in the formation of lung tumours [8, 9, 14]. Several genetic single nucleotide polymorphism (SNP) studies identified that the SNPs in the RAGE associated with increased NSCLC risk and a lower chemotherapy response rate and poor prognosis [9, 15, 16]. In addition, increasing concentrations of SAA corresponded to poor response to tyrosine kinase inhibitors and correlated with poor clinical outcome [2, 17]. In the present patient, the onset of lung cancer appeared to match mostly with that of systemic AL amyloidosis with increasing SFLC, regarded as the precursor form of amyloid protein [18]. This case was not AA amyloidosis but systemic AL amyloidosis; thus, SAA levels were within normal limits.\n\nThe relationship between cancer and amyloidosis is still unknown, as well as the relevance of amyloidosis as a paraneoplastic syndrome induced by lung cancers. However, 10 of 12 case reports, including the present case, showed the diagnosed period of lung cancer to be the same as or prior to that of amyloidosis (Table 1) [19–29]. These clinical time courses suggest the prior onset of lung cancer may contribute to the deposition of amyloid through paraneoplastic mechanisms. In the present case, the deterioration of cardiac amyloidosis directly led to death, as a poorer prognostic factor than early lung cancer itself. Generally, RAGE levels are downregulated in lung cancer patients. However, our case showed strong expression of RAGE that was surrounded by lung tissue with amyloid deposition, even though the patient had early-stage lung cancer (Fig. 2b, f).Table 1 Clinicopathological features of lung cancer patients with amyloidosis\n\nAuthor, year\tAge(y)/sex\tCancer type and stage\tAmyloid organ involvement\tType\tPrior diagnosisa\n\tTreatment for lung cancer\tCause of death\t\nvan Bronswijk et al. 1982 [19]\t71/M\tSCLC, Advanced\tK\tAA\tLung cancer\tRadiotherapy\tPulmonary infection\t\nMeyrier et al. 1985 [20]\t59/M\tSCC, TbN1Mx\tA, K, SP\tAA\tLung cancer\tCCRT\tRenal failure due to amyloidosis\t\nFocan et al. 1985 [21]\t70/M\tSCC, Early\tBM, Digestive tract\tN/A\tUnknown\tNone\tPulmonary infection\t\nRichmond et al. 1990 [22]\t72/M\tSCC, Early\tMultiple organs\tAA\tSame\tNone\tPeritonitis and Renal failure due to amyloidosis\t\nBenharroch et al. 1992 [23]\t51/F\tAC, N/A\tF\tAL\tUnknown\tNone\tRenal failure due to systemic sclerosis\t\nPartidge et al. 2000 [24]\t69/M\tNSCLC, Stage IV\tMediastinal LN\tN/A\tSame\tNone\tNSCLC\t\nGarthwhite et al. 2003 [25]\t64/M\tSCC, N/A\tK, L\tAA\tSame\tRadiotherapy\tN/A\t\nBarcelo et al. 2003 [26]\t33/M\tSCC, Stage IIIB\tC, K\tAA\tLung cancer\tChemotherapy\tPulmonary infection\t\nPaydas et al. 2005 [27]\t50/M\tAC, Stage IIIB\tK\tAA\tLung cancer\tCCRT\tN/A\t\nMiyazaki et al. 2011 [28]\t60/M\tAC, Stage IA\tK, L, ST\tAL\tSame\tSurgery\tN/A\t\nGueutin et al. 2013 [29]\t56/M\tAC, Stage IIIB\tK\tAA\tLung cancer\tChemotherapy\tN/A\t\nOur case 2016\t71/F\tAC, Stage IA\tD, H, K, L, ST\tAL\tSame\tNone\tHeart failure due to amyloidosis\t\n\nA adrenal gland, AA amyloid A amyloidosis, AC adenocarcinoma, AL amyloid light-chain amyloidosis, BM bone marrow, C colon, CCRT concurrent chemoradiotherapy, D duodenum, F female, H heart, K kidney, L lung, LN lymph node, M male, N/A not available, NSCLC non-small cell lung carcinoma, SCC squamous cell carcinoma, SCLC small-cell lung cancer, SP spleen, ST stomach, y years\n\n\na ‘Same’ refers to a diagnosis given at the same time as amyloidosis\n\n\n\n\nThus, the RAGE positivity of lung cancer cells in this case suggests an interaction between amyloid-containing tissues and RAGE-expressing cancer cells, which may progress both lung cancer and amyloidosis. Further study is warranted to investigate this association.\n\nConclusion\nWe describe a rare case of amyloid receptor-positive lung adenocarcinoma with systemic AL amyloidosis. Clinicians should be aware that RAGE-positive lung cancer may be a complication of underlying amyloidosis that could impact more severely on the prognosis of the patient than the cancer itself.\n\nAbbreviations\nALAmyloid light-chain\n\nNSCLCNon-small cell lung cancer\n\nRAGEReceptor for advanced glycation end-products\n\nSAASerum amyloid A\n\nSFLCSerum free light chain\n\nSNPSingle nucleotide polymorphism\n\nsRAGEsoluble receptor for advanced glycation end-products\n\nAcknowledgements\nNot applicable.\n\nFunding\nThe authors declare no funding for this study.\n\nAvailability of data and materials\nAll data generated or analysed during this study are included in this published article.\n\nAuthors’ contributions\nSO, IN, and TS collected the clinical data and drafted the manuscript. TS and KT revised the manuscript. SO, YK, JI, and YN carried out the clinical management of the patient. TU carried out the pathological diagnosis. KS and TU carried out immunohistochemical staining. All authors have read and approved the manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.\n\nEthics approval and consent to participate\nThe study was approved by the Ethics Committee of Juntendo University School of Medicine and the methods were carried out in accordance with the approved guidelines.\n==== Refs\nReferences\n1. Kimball KG Amyloidosis in association with neoplastic disease. Report of an unusual case and clinicopathological experience at Memorial Center for Cancer and Allied Diseases during eleven years (1948–1958) Ann Intern Med 1961 55 958 74 10.7326/0003-4819-55-6-958 14455992 \n2. Sung HJ Ahn JM Yoon YH Rhim TY Park CS Park JY Identification and validation of SAA as a potential lung cancer biomarker and its involvement in metastatic pathogenesis of lung cancer J Proteome Res 2011 10 3 1383 95 10.1021/pr101154j 21141971 \n3. Logsdon CD Fuentes MK Huang EH Arumugam T RAGE and RAGE ligands in cancer Curr Mol Med 2007 7 8 777 89 10.2174/156652407783220697 18331236 \n4. Katsuoka F Kawakami Y Arai T Imuta H Fujiwara M Kanma H Type II alveolar epithelial cells in lung express receptor for advanced glycation end products (RAGE) gene Biochem Biophys Res Commun 1997 238 2 512 6 10.1006/bbrc.1997.7263 9299542 \n5. Fehrenbach H Kasper M Tschernig T Shearman MS Schuh D Müller M Receptor for advanced glycation endproducts (RAGE) exhibits highly differential cellular and subcellular localisation in rat and human lung Cell Mol Biol (Noisy-le-grand) 1998 44 7 1147 57 9846897 \n6. Buckley ST Ehrhardt CJ The receptor for advanced glycation end products (RAGE) and the lung J Biomed Biotechnol 2010 20145712 \n7. Sparvero LJ Asafu-Adjei D Kang R Tang D Amin N Im J RAGE (Receptor for Advanced Glycation Endproducts), RAGE ligands, and their role in cancer and inflammation J Transl Med 2009 7 17 10.1186/1479-5876-7-17 19292913 \n8. Bartling B Hofmann HS Weigle B Silber RE Simm A Down-regulation of the receptor for advanced glycation end-products (RAGE) supports non-small cell lung carcinoma Carcinogenesis 2005 26 2 293 301 10.1093/carcin/bgh333 15539404 \n9. Wang H Li Y Yu W Ma L Ji X Xiao W Expression of the receptor for advanced glycation end-products and frequency of polymorphism in lung cancer Oncol Lett 2015 7 10 51 60 \n10. Kuniyasu H Oue N Wakikawa A Shigeishi H Matsutani N Kuraoka K Expression of receptors for advanced glycation end-products (RAGE) is closely associated with the invasive and metastatic activity of gastric cancer J Pathol 2002 196 2 163 70 10.1002/path.1031 11793367 \n11. Fuentes MK Nigavekar SS Arumugam T Logsdon CD Schmidt AM Park JC RAGE activation by S100P in colon cancer stimulates growth, migration, and cell signaling pathways Dis Colon Rectum 2007 50 8 1230 40 10.1007/s10350-006-0850-5 17587138 \n12. Bartling B Demling N Silber RE Simm A Proliferative stimulus of lung fibroblasts on lung cancer cells is impaired by the receptor for advanced glycation end-products Am J Respir Cell Mol Biol 2006 34 1 83 91 10.1165/rcmb.2005-0194OC 16166741 \n13. Herold K Moser B Chen Y Zeng S Yan SF Ramasamy R Receptor for advanced glycation end products (RAGE) in a dash to the rescue: inflammatory signals gone awry in the primal response to stress J Leukoc Biol 2007 82 2 204 12 10.1189/jlb.1206751 17513693 \n14. Jing R Cui M Wang J Wang H Receptor for advanced glycation end products (RAGE) soluble form (sRAGE): a new biomarker for lung cancer Neoplasma 2010 57 1 55 61 10.4149/neo_2010_01_055 19895173 \n15. Xia W Xu Y Mao Q Dong G Shi R Wang J Association of RAGE polymorphisms and cancer risk: a meta-analysis of 27 studies Med Oncol 2015 32 2 442 10.1007/s12032-014-0442-5 25603950 \n16. Wang X Cui E Zeng H Hua F Wang B Mao W RAGE genetic polymorphisms are associated with risk, chemotherapy response and prognosis in patients with advanced NSCLC PLoS One 2012 7 10 10.1371/journal.pone.0043734 23071492 \n17. Garrisi VM Bongarzone I Mangia A Cremona M Bortoli MD Vaghi E Characterization of a serum protein pattern from NSCLC patients treated with Gefitinib Clin Biochem 2011 44 10–11 936 40 10.1016/j.clinbiochem.2011.04.013 21539823 \n18. Comenzo RL Managing systemic light-chain amyloidosis J Natl Compr Canc Netw 2007 5 2 179 87 17335687 \n19. van Bronswijk H Henzen-Logmans SC Alberts C Balk AG Bronchial carcinoma with secondary amyloidosis as a cause of nephrotic syndrome Ned Tijdschr Geneeskd 1982 126 7 285 8 7063053 \n20. Meyrier A Makdassi R Breau JL Amouroux J Mougenot B AA amylosis and the nephrotic syndrome complicating a pulmonary epidermoid carcinoma Nephrologie 1985 6 4 191 2 4088420 \n21. Focan C Swale JL Borlee-Hermans G Claessens JJ Systemic sclerosis, aplastic anemia and amyloidosis associated with lung carcinoma Acta Clin Belg 1985 40 3 204 5 10.1080/22953337.1985.11719080 4024847 \n22. Richmond I Hasleton PS Samadian S Systemic amyloid associated with carcinoma of the bronchus Thorax 1990 45 2 156 7 10.1136/thx.45.2.156 2315877 \n23. Benharroch D Sukenik S Sacks M Bronchioloalveolar carcinoma and generalized amyloidosis complicating progressive systemic sclerosis Hum Pathol 1992 23 7 839 41 10.1016/0046-8177(92)90357-9 1319392 \n24. Partridge A McMenamin M Sugarbaker D Nonmalignant diagnoses in patients. Case 2. Lung cancer with mediastinal lymphadenopathy due to amyloidosis J Clin Oncol 2000 18 13 2636 7 10893298 \n25. Garthwaite EA Sellars L Bhandari S Carcinoma of the bronchus presenting as renal failure secondary to amyloidosis Nephrol Dial Transplant 2003 18 5 1031 10.1093/ndt/gfg063 12686690 \n26. Barceló JR Muñoz A Mañé JM Rubio I Pérez-Hoyos T Viteri A Amyloidosis and lung cancer Clin Lung Cancer 2003 4 4 249 51 10.3816/CLC.2003.n.006 14624716 \n27. Paydas S Soydas B Paydas S Balal M Erdogan S Tuncer I Different glomerulopathies accompanying non-small-cell lung cancer Mt Sinai J Med 2005 72 4 279 81 16021324 \n28. Miyazaki D Yazaki M Ishii W Matsuda M Hoshii Y Nara K A rare lung nodule consisting of adenocarcinoma and amyloid deposition in a patient with primary systemic AL amyloidosis Intern Med 2011 50 3 243 6 10.2169/internalmedicine.50.4094 21297328 \n29. Gueutin V Langlois AL Shehwaro N Elharraqui R Rouvier P Izzedine H Nephrotic syndrome associated with lung cancer: a rare case of malignancy associated with AA amyloidosis Case Rep Nephrol 2013 24558629\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2407",
"issue": "17(1)",
"journal": "BMC cancer",
"keywords": "Amyloidosis; Case report; Lung adenocarcinoma; RAGE",
"medline_ta": "BMC Cancer",
"mesh_terms": "D000230:Adenocarcinoma; D000077192:Adenocarcinoma of Lung; D000368:Aged; D000686:Amyloidosis; D005260:Female; D006801:Humans; D000075363:Immunoglobulin Light-chain Amyloidosis; D008175:Lung Neoplasms; D000067759:Receptor for Advanced Glycation End Products",
"nlm_unique_id": "100967800",
"other_id": null,
"pages": "22",
"pmc": null,
"pmid": "28056871",
"pubdate": "2017-01-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "25603950;11793367;4024847;17587138;21297328;20145712;24558629;14455992;19895173;10893298;19292913;16021324;21141971;16166741;14624716;2315877;9299542;15539404;7063053;12686690;1319392;4088420;17513693;26170976;23071492;18331236;9846897;21539823;17335687",
"title": "Lung adenocarcinoma expressing receptor for advanced glycation end-products with primary systemic AL amyloidosis: a case report and literature review.",
"title_normalized": "lung adenocarcinoma expressing receptor for advanced glycation end products with primary systemic al amyloidosis a case report and literature review"
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"abstract": "Commonly used chemotherapeutic agents, specifically cytarabine and daunorubicin, can cause effusive-constrictive pericarditis. We describe a case of transient effusive-constrictive pericarditis in a patient with acute myelogenous leukemia. This is the first case report of a patient with transient effusive-constrictive pericarditis due to chemotherapy.",
"affiliations": "Department of Medicine, University of Wisconsin Medical School, Madison 53792-3248, USA.",
"authors": "Woods|T|T|;Vidarsson|B|B|;Mosher|D|D|;Stein|J H|JH|",
"chemical_list": "D000903:Antibiotics, Antineoplastic; D000964:Antimetabolites, Antineoplastic; D003561:Cytarabine; D003630:Daunorubicin",
"country": "United States",
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"doi": "10.1002/clc.4960220414",
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"issue": "22(4)",
"journal": "Clinical cardiology",
"keywords": null,
"medline_ta": "Clin Cardiol",
"mesh_terms": "D000903:Antibiotics, Antineoplastic; D000964:Antimetabolites, Antineoplastic; D000971:Antineoplastic Combined Chemotherapy Protocols; D003561:Cytarabine; D003630:Daunorubicin; D004452:Echocardiography; D005500:Follow-Up Studies; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D010490:Pericardial Effusion; D010494:Pericarditis, Constrictive; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "7903272",
"other_id": null,
"pages": "316-8",
"pmc": null,
"pmid": "10198745",
"pubdate": "1999-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Transient effusive-constrictive pericarditis due to chemotherapy.",
"title_normalized": "transient effusive constrictive pericarditis due to chemotherapy"
} | [
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"companynumb": "US-PFIZER INC-2020200713",
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"abstract": "BACKGROUND\nThere aren't many reported skin changes associated with teriflunomide use in patients with multiple sclerosis (MS) mm Only one life-threatening gross skin change has been reported so far; a patient with toxic epidermal necrolysis. There are also a few case reports about cutaneous adverse effects of teriflunomide, such as eczema, rash and palmar pustular psoriasis.\n\n\nMETHODS\nWe herein report the first case of bullous drug reaction in a patient receiving teriflunomide treatment.\n\n\nRESULTS\nA 55-year-old women with relapsing multiple sclerosis (RMS) was diagnosed teriflunomide induced bullous pemphigoid as it was detected in the first three months following the initiation of therapy. It is fully recovered after withdrawal of teriflunomide, in combination with systemic steroid treatment.\n\n\nCONCLUSIONS\nWe report the first case of bullous drug reaction associated with teriflunomide. Multiple drugs have been implicated in the pathogenesis of the disease so far. It is important to point out some immunosuppressants may trigger autoimmune diseases like bullous pemphigoid.\n\n\nCONCLUSIONS\nConsidering recently reported skin reactions associated with teriflunomide, neurologists and patients should be careful on potential warning symptoms and signs of cutaneous drug reactions of this drug.",
"affiliations": "Hacettepe University, Department of Neurology, Hacettepe, 06230, Ankara, Turkey. Electronic address: dorukarslan@hacettepe.edu.tr.;Gazi University, Department of Dermatology, Turkey.;Gazi University, Department of Pathology, Turkey.;Hacettepe University, Department of Neurology, Hacettepe, 06230, Ankara, Turkey.",
"authors": "Arslan|Doruk|D|;Aksakal|Ahmet Burhan|AB|;Erdem|Özlem|Ö|;Tuncer|Meryem Aslı|MA|",
"chemical_list": "D003437:Crotonates; D006885:Hydroxybutyrates; D009570:Nitriles; D004364:Pharmaceutical Preparations; D014052:Toluidines; C527525:teriflunomide",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.msard.2020.102157",
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"issn_linking": "2211-0348",
"issue": "43()",
"journal": "Multiple sclerosis and related disorders",
"keywords": "Cutaneous adverse effect; Drug-induced bullous pemphigoid; Multiple sclerosis; Teriflunomide",
"medline_ta": "Mult Scler Relat Disord",
"mesh_terms": "D003437:Crotonates; D005260:Female; D006801:Humans; D006885:Hydroxybutyrates; D008875:Middle Aged; D009103:Multiple Sclerosis; D020529:Multiple Sclerosis, Relapsing-Remitting; D009570:Nitriles; D010391:Pemphigoid, Bullous; D004364:Pharmaceutical Preparations; D014052:Toluidines",
"nlm_unique_id": "101580247",
"other_id": null,
"pages": "102157",
"pmc": null,
"pmid": "32446168",
"pubdate": "2020-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of drug-induced bullous pemphigoid associated with teriflunomide: A patient with relapsing multiple sclerosis.",
"title_normalized": "a case of drug induced bullous pemphigoid associated with teriflunomide a patient with relapsing multiple sclerosis"
} | [
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"companynumb": "NVSC2020TR166435",
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"actiondrug": "1",
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"activesubstancename": "TERIFLUNOMIDE"
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"drugadditional": "1",
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"abstract": "Ramucirumab(RAM)plus nab-paclitaxel(nab-PTX)therapy is a regimen that is recommended for the second round of chemotherapy in recurrent, progressive gastric cancer. We report the first case of a thoracic aortic dissection developed during RAM plus nab-PTX therapy. A 59-year-old male who had undergone a proximal gastrectomy for esophagogastric junction cancer had a recurrence of cancer 6 years later(metastasis to the para-aortic lymph node and left adrenal gland, local recurrence, and multiple bone metastases). He was treated with RAM plus nab-PTX therapy for second-line chemotherapy. On day 9 of the third cycle, he experienced sudden, severe neck pain and visited the outpatient emergency department. Computed tomography detected a Stanford type-A thoracic aortic dissection. However, the patient suffered from a myocardial infarction before the operation, and died. This is the first report of an aortic dissection associated with RAM. Clinicians must be aware of this complication.",
"affiliations": "Dept. of Surgery, Iwate Medical University.",
"authors": "Nikai|Haruka|H|;Akiyama|Yuji|Y|;Fujisawa|Ryosuke|R|;Endo|Fumitaka|F|;Baba|Shigeaki|S|;Koeda|Keisuke|K|;Sasaki|Akira|A|",
"chemical_list": "C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D061067:Antibodies, Monoclonal, Humanized; C543333:ramucirumab; D017239:Paclitaxel",
"country": "Japan",
"delete": false,
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"issn_linking": "0385-0684",
"issue": "47(6)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000418:Albumins; D000784:Aneurysm, Dissecting; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D005743:Gastrectomy; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D017239:Paclitaxel; D013274:Stomach Neoplasms",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "981-983",
"pmc": null,
"pmid": "32541179",
"pubdate": "2020-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Thoracic Aortic Dissection Case during Treatment with Ramucirumab plus Nab-Paclitaxel.",
"title_normalized": "a thoracic aortic dissection case during treatment with ramucirumab plus nab paclitaxel"
} | [
{
"companynumb": "JP-CELGENEUS-JPN-20200707242",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
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"activesubstancename": "RAMUCIRUMAB"
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... |
{
"abstract": "Several antibiotics, proton pump inhibitors, and nonsteroidal anti-inflammatory drugs can cause acute interstitial nephritis. This is not dose-dependent, and recurrence can occur with a second exposure of the same drug. Stopping the culprit is critical for successful management.",
"affiliations": "Department of Hospital Medicine Ascension Columbia St. Mary's Hospital Milwaukee Wisconsin USA.;Department of Hospital Medicine Mount Carmel East Hospital Columbus Ohio USA.;Department of Internal Medicine University of Illinois at Peoria Peoria Illinois USA.;Department of Hospital Medicine Catholic Health Initiatives St Vincent Infirmary Little Rock Arkansas USA.",
"authors": "Samal|Subhankar|S|https://orcid.org/0000-0002-5634-5484;Singhania|Namrata|N|https://orcid.org/0000-0003-3211-040X;Bansal|Saurabh|S|https://orcid.org/0000-0001-8192-4835;Singhania|Girish|G|https://orcid.org/0000-0002-8128-4222",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.3059",
"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904 John Wiley and Sons Inc. Hoboken \n\n10.1002/ccr3.3059\nCCR33059\nClinical Image\nClinical Images\nAcute interstitial nephritis with only three doses of pantoprazole\nSAMAL et al.Samal Subhankar https://orcid.org/0000-0002-5634-5484\n1\nssamal009@gmail.com Singhania Namrata https://orcid.org/0000-0003-3211-040X\n2\n Bansal Saurabh https://orcid.org/0000-0001-8192-4835\n3\n Singhania Girish https://orcid.org/0000-0002-8128-4222\n4\n \n1 \nDepartment of Hospital Medicine\nAscension Columbia St. Mary's Hospital\nMilwaukee\nWisconsin\nUSA\n\n\n2 \nDepartment of Hospital Medicine\nMount Carmel East Hospital\nColumbus\nOhio\nUSA\n\n\n3 \nDepartment of Internal Medicine\nUniversity of Illinois at Peoria\nPeoria\nIllinois\nUSA\n\n\n4 \nDepartment of Hospital Medicine\nCatholic Health Initiatives St Vincent Infirmary\nLittle Rock\nArkansas\nUSA\n\n* Correspondence\n\nSubhankar Samal, Department of Hospital Medicine, Ascension Columbia St. Mary's Hospital, 2301, N. Lake Drive, Milwaukee, WI 53211.\n\nEmail: ssamal009@gmail.com\n\n24 6 2020 \n10 2020 \n8 10 10.1002/ccr3.v8.102084 2085\n18 1 2020 19 5 2020 29 5 2020 © 2020 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nSeveral antibiotics, proton pump inhibitors, and nonsteroidal anti‐inflammatory drugs can cause acute interstitial nephritis. This is not dose‐dependent, and recurrence can occur with a second exposure of the same drug. Stopping the culprit is critical for successful management.\n\nSeveral antibiotics, proton pump inhibitors, and nonsteroidal anti‐inflammatory drugs can cause acute interstitial nephritis. This is not dose‐dependent, and recurrence can occur with a second exposure of the same drug. Stopping the culprit is critical for successful management.\n\n\nacute interstitial nephritisacute kidney injuryproton pump inhibitors source-schema-version-number2.0cover-dateOctober 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.2 mode:remove_FC converted:16.10.2020\n\n\nSamal \nS \n, \nSinghania \nN \n, \nBansal \nS \n, \nSinghania \nG \n. Acute interstitial nephritis with only three doses of pantoprazole\n. Clin Case Rep . 2020 ;8 :2084 –2085\n. 10.1002/ccr3.3059\n==== Body\nAcute interstitial nephritis is a common complication seen with use of proton pump inhibitors. This is the case of a young male who had severe acute interstitial nephritis with only three doses of pantoprazole.\n\nA 21‐year‐old male presented to the emergency department for an elevated serum creatinine (Scr) level. He denied the use of any medications other than pantoprazole for the previous 3 days. The clinical examination was unremarkable. The diagnostic work‐up revealed blood urea nitrogen at 82 mg/dL (normal range [NR] 7‐20 mg/dL), Scr 15 mg/dL (baseline 0.6 mg/dL; NR 0.7‐1.2 mg/dL), normal creatine kinase level and no eosinophilia. Urinalysis showed non‐nephrotic proteinuria. Toxicology, HIV, hepatitis serologies, complement factors C3 and C4, and protein electrophoresis were unremarkable. Autoimmune workup including ANA, antistreptococcal, anti‐GBM, and ANCA antibodies was negative. Renal ultrasound was normal, and a renal biopsy was performed. There was a diffuse expansion of the interstitium with an accumulation of lymphocytes, plasma cells, and eosinophils with accompanying tubular inflammation consistent with acute interstitial nephritis (AIN) likely secondary to pantoprazole. (Figure 1) Immunofluorescence was negative for immune complex deposition. Pantoprazole was discontinued, and glucocorticoids (500 mg/d for 3 days, followed by 1 mg/kg/d) and hemodialysis were initiated. He recovered completely. Drugs like antibiotics, proton pump inhibitors, and nonsteroidal anti‐inflammatory drugs can cause AIN.\n1\n This is not dose dependent, and recurrence can occur. Stopping the agent and early steroid use in selected cases confers better prognosis.\n2\n\n\n\nFIGURE 1 Renal biopsy showing diffuse expansion of the interstitium with lymphocytes, plasma cells, and eosinophils with accompanying tubular inflammation suggestive of interstitial nephritis\n\nCONFLICT OF INTEREST\nNone declared.\n\nAUTHOR CONTRIBUTIONS\nSS and NS: have contributed equally to the manuscript. They wrote the manuscript and reviewed the literature. SB and GS: have reviewed the manuscript.\n\nACKNOWLEDGMENTS\nConsent statement: Published with written consent of the patient.\n==== Refs\nREFERENCES\n1 \n\nPerazella \nMA \n, \nMarkowitz \nGS \n. Drug‐induced acute interstitial nephritis\n. Nat Rev Nephrol . 2010 ;6 (8 ):461 ‐470\n.20517290 \n2 \n\nFernandez‐Juarez \nG \n, \nPerez \nJV \n, \nCaravaca‐Fontán \nF \n, et al. Duration of treatment with corticosteroids and recovery of kidney function in acute interstitial nephritis\n. Clin J Am Soc Nephrol . 2018 ;13 (12 ):1851 ‐1858\n.30397027\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2050-0904",
"issue": "8(10)",
"journal": "Clinical case reports",
"keywords": "acute interstitial nephritis; acute kidney injury; proton pump inhibitors",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "2084-2085",
"pmc": null,
"pmid": "33088562",
"pubdate": "2020-10",
"publication_types": "D016428:Journal Article",
"references": "20517290;30397027",
"title": "Acute interstitial nephritis with only three doses of pantoprazole.",
"title_normalized": "acute interstitial nephritis with only three doses of pantoprazole"
} | [
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"companynumb": "US-DRREDDYS-USA/USA/20/0125235",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PANTOPRAZOLE SODIUM"
},
"drugadditional"... |
{
"abstract": "Psoriatic plaque erosion is a rare toxic side effect of low-dose methotrexate (LDMTX) that has been reported during the treatment of psoriasis and described as a herald for impending pancytopenia. Fatalities from this have rarely been reported. Even rarer is methotrexate (MTX)-induced erosions of clinically normal skin in patients without a history of psoriasis. We report 3 rare presentations of MTX-induced cutaneous erosions, 2 fatalities occurring with MTX-induced psoriatic plaque erosions, and the sixth reported case of MTX-induced erosions with no prior history of psoriasis. Each were elderly patients on proton pump inhibitors with a history of chronic non-steroidal anti-inflammatory drug (NSAID) use. They all presented with acute onset of erosions after a recent change in their MTX dose. Pancytopenia followed in each case. Physicians' awareness of the sequelae in MTX-induced cutaneous erosions is imperative so MTX can be discontinued and treatment instituted to prevent fatal bone marrow suppression.",
"affiliations": "The University of Arkansas for Medical Sciences.",
"authors": "Shiver|Mallory B|MB|;Hall|Lauren A|LA|;Conner|Kelly B|KB|;Brown|Grace E|GE|;Cheung|Wang L|WL|;Wirges|Marla L|ML|",
"chemical_list": "D018501:Antirheumatic Agents; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1087-2108",
"issue": "20(7)",
"journal": "Dermatology online journal",
"keywords": null,
"medline_ta": "Dermatol Online J",
"mesh_terms": "D000368:Aged; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D001706:Biopsy; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D010198:Pancytopenia; D012867:Skin; D012883:Skin Ulcer",
"nlm_unique_id": "9610776",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "25046458",
"pubdate": "2014-07-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cutaneous erosions: a herald for impending pancytopenia in methotrexate toxicity.",
"title_normalized": "cutaneous erosions a herald for impending pancytopenia in methotrexate toxicity"
} | [
{
"companynumb": "PHHY2014US130154",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional": null,
"drug... |
{
"abstract": "OBJECTIVE\nTo determine the long-term effects of in utero progesterone exposure in twin children.\n\n\nMETHODS\nThis study evaluated the health and developmental outcomes of all surviving children born to mothers who participated in a double-blind, placebo-controlled trial of progesterone given for the prevention of preterm birth in twin pregnancies (STOPPIT, ISRCTN35782581). Follow-up was performed via record linkage and two parent-completed validated questionnaires, the Child Development Inventory and the Health Utilities Index.\n\n\nRESULTS\nRecord linkage was successfully performed on at least one record in 759/781 (97%) children eligible for follow-up. There were no differences between progesterone-exposed and placebo-exposed twins with respect to incidence of death, congenital anomalies and hospitalisation, nor on routine national child health assessments. Questionnaire responses were received for 324/738 (44%) children. The mean age at questionnaire follow-up was 55.5 months. Delay in at least one developmental domain on the Child Development Inventory was observed in 107/324 (33%) children, with no evidence of difference between progesterone-exposed and placebo-exposed twins. There was no evidence of difference between the progesterone and placebo groups in global health status assessed using the Health Utilities Index: 89% of children were rated as having 'excellent' health and a further 8% as having 'very good' health.\n\n\nCONCLUSIONS\nIn this cohort of twin children there was no evidence of a detrimental or beneficial impact on health and developmental outcomes at three to six years of age due to in utero exposure to progesterone.",
"affiliations": "Monash University, Melbourne, Australia.;Information Services Division, NHS National Services Scotland, Edinburgh, United Kingdom.;Information Services Division, NHS National Services Scotland, Edinburgh, United Kingdom.;Department of Neonatal Medicine, Institute for Women's Health, University College London, London, United Kingdom.;Centre for Healthcare Randomised Trials (CHaRT), Health Services Research Unit, University of Aberdeen, Aberdeen, United Kingdom.;Centre for Healthcare Randomised Trials (CHaRT), Health Services Research Unit, University of Aberdeen, Aberdeen, United Kingdom.;Centre for Healthcare Randomised Trials (CHaRT), Health Services Research Unit, University of Aberdeen, Aberdeen, United Kingdom.;Robertson Centre for Biostatistics, University of Glasgow, Glasgow, United Kingdom.;Tommy's Centre for Maternal and Fetal Health, University of Edinburgh MRC Centre for Reproductive Health, The Queen's Medical Research Institute, Edinburgh, United Kingdom.",
"authors": "McNamara|Helen Christine|HC|;Wood|Rachael|R|;Chalmers|James|J|;Marlow|Neil|N|;Norrie|John|J|;MacLennan|Graeme|G|;McPherson|Gladys|G|;Boachie|Charles|C|;Norman|Jane Elizabeth|JE|",
"chemical_list": "D010919:Placebos; D011374:Progesterone",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0122341",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 2588128910.1371/journal.pone.0122341PONE-D-14-57241Research ArticleSTOPPIT Baby Follow-Up Study: The Effect of Prophylactic Progesterone in Twin Pregnancy on Childhood Outcome STOPPIT Baby Follow-Up StudyMcNamara Helen Christine \n1\n*Wood Rachael \n2\nChalmers James \n2\nMarlow Neil \n3\nNorrie John \n4\nMacLennan Graeme \n4\nMcPherson Gladys \n4\nBoachie Charles \n5\nNorman Jane Elizabeth \n6\n\n1 \nMonash University, Melbourne, Australia\n\n2 \nInformation Services Division, NHS National Services Scotland, Edinburgh, United Kingdom\n\n3 \nDepartment of Neonatal Medicine, Institute for Women's Health, University College London, London, United Kingdom\n\n4 \nCentre for Healthcare Randomised Trials (CHaRT), Health Services Research Unit, University of Aberdeen, Aberdeen, United Kingdom\n\n5 \nRobertson Centre for Biostatistics, University of Glasgow, Glasgow, United Kingdom\n\n6 \nTommy’s Centre for Maternal and Fetal Health, University of Edinburgh MRC Centre for Reproductive Health, The Queen’s Medical Research Institute, Edinburgh, United Kingdom\nSun Kang Academic Editor\nShanghai Jiaotong University School of Medicine, CHINA\nCompeting Interests: The authors have declared that no competing interests exist.\n\nConceived and designed the experiments: JEN RW JC NM JN G. McPherson G. MacLennan. Analyzed the data: G. MacLennan CB HCM. Wrote the paper: HCM. Coordinated the record linkage: JC RW. Proposed the design of the follow-up study: JEN. Made comments and contributed to subsequent drafts of the manuscript: CB JEN RW JC NM JN G. McPherson G. MacLennan.\n\n* E-mail: helenmcnamara1@gmail.com16 4 2015 2015 10 4 e012234121 12 2014 15 2 2015 © 2015 McNamara et al2015McNamara et alThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.Objectives\nTo determine the long-term effects of in utero progesterone exposure in twin children.\n\nMethods\nThis study evaluated the health and developmental outcomes of all surviving children born to mothers who participated in a double-blind, placebo-controlled trial of progesterone given for the prevention of preterm birth in twin pregnancies (STOPPIT, ISRCTN35782581). Follow-up was performed via record linkage and two parent-completed validated questionnaires, the Child Development Inventory and the Health Utilities Index.\n\nResults\nRecord linkage was successfully performed on at least one record in 759/781 (97%) children eligible for follow-up. There were no differences between progesterone-exposed and placebo-exposed twins with respect to incidence of death, congenital anomalies and hospitalisation, nor on routine national child health assessments. Questionnaire responses were received for 324/738 (44%) children. The mean age at questionnaire follow-up was 55.5 months. Delay in at least one developmental domain on the Child Development Inventory was observed in 107/324 (33%) children, with no evidence of difference between progesterone-exposed and placebo-exposed twins. There was no evidence of difference between the progesterone and placebo groups in global health status assessed using the Health Utilities Index: 89% of children were rated as having ‘excellent’ health and a further 8% as having ‘very good’ health.\n\nConclusions\nIn this cohort of twin children there was no evidence of a detrimental or beneficial impact on health and developmental outcomes at three to six years of age due to in utero exposure to progesterone.\n\nThis study was funded by the Chief Scientist Office, Scotland (grant number CZH/2/575) and the charity, Tommy’s. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data AvailabilityThe STOPPIT Baby Follow-up Study uses two linked datasets, the STOPPIT clinical trial data and routine NHS data collected by Information Services Division (ISD), NHS Scotland. The governance and ethics approvals for this project around anonymity for the participants do not permit us to deposit the linked dataset on a publicly available website. Individuals wishing to access the STOPPIT clinical trial data should contact Professor Jane E Norman jane.norman@ed.ac.uk or Professor John Norrie john.norrie@abdn.ac.uk for access. General information on how to access data held by ISD for research purposes is available from ISD’s research coordination team – see http://www.isdscotland.org/Products-and-Services/eDRIS. Please contact Rachael Wood rachaelwood@nhs.net for queries about the specific ISD data used in this study.Data Availability\nThe STOPPIT Baby Follow-up Study uses two linked datasets, the STOPPIT clinical trial data and routine NHS data collected by Information Services Division (ISD), NHS Scotland. The governance and ethics approvals for this project around anonymity for the participants do not permit us to deposit the linked dataset on a publicly available website. Individuals wishing to access the STOPPIT clinical trial data should contact Professor Jane E Norman jane.norman@ed.ac.uk or Professor John Norrie john.norrie@abdn.ac.uk for access. General information on how to access data held by ISD for research purposes is available from ISD’s research coordination team – see http://www.isdscotland.org/Products-and-Services/eDRIS. Please contact Rachael Wood rachaelwood@nhs.net for queries about the specific ISD data used in this study.\n==== Body\nIntroduction\nPreterm birth, defined as birth prior to 37 weeks’ estimated gestation, is a leading cause of perinatal mortality and short-term and long-term morbidity. Twin pregnancies contribute disproportionately to preterm birth.\n\nProgesterone, administered either as intramuscular 17 α-hydroxyprogesterone caproate or vaginal progesterone, has been demonstrated to reduce the rate of preterm birth in women with high-risk singleton pregnancies [1–7]. In contrast, we and others have shown that neither progesterone nor 17 α-hydroxyprogesterone caproate prevents preterm birth in multiple pregnancies [8–13]. Use of progesterone for prevention of preterm birth in women with a previous preterm birth and/or with a short cervix is becoming widespread [14]. In 2011, the USA Food and Drug Administration approved use of 17 α-hydroxyprogesterone caproate for the prevention of preterm birth in women at risk because of previous spontaneous preterm birth [15].\n\nPrevious studies have demonstrated that agents given to pregnant women with the aim of improving pregnancy outcomes can have unexpected effects on children which may not be apparent at birth but harmful long-term [16]. Hence, long-term follow-up data on children exposed to progesterone are needed.\n\nThere is emerging but limited evidence on the long-term effects of in utero exposure to progesterone when given for the prevention of preterm birth. Follow-up of 274 singleton children, born to mothers participating in a randomised placebo-controlled trial of 17 α-hydroxyprogesterone caproate in high-risk singleton pregnancies, demonstrated no difference in health status, physical examination, or mean score on the Ages and Stages Questionnaire at four years of age despite prolongation of pregnancy [17]. Follow-up of 991 children born to mothers with twin pregnancies enrolled in the PREDICT randomised control trial comparing progesterone with placebo revealed no difference in mean score on the Ages and Stages Questionnaire at six months and at 18 months of age. Progesterone had no effect on duration of pregnancy in the PREDICT trial [12].\n\nThe aim of our study was to determine the potential adverse and/or beneficial effects of prophylactic in utero progesterone on health and developmental outcomes of children at three to six years of age. We evaluated a cohort of twin pregnancies in which progesterone had no effect on short-term (obstetric and neonatal) outcomes, thus allowing any direct effects of progesterone to be determined.\n\nMethods\nThis study evaluated outcomes of twin children born to mothers who participated in the STOPPIT trial, a randomised, double-blind, placebo-controlled trial of progesterone given for the prevention of preterm birth to women with twin pregnancy.\n\nBriefly, the STOPPIT trial (registered clinical trial, ISRCTN35782581), conducted at nine National Health Service (NHS) hospitals across the United Kingdom, randomised women to receive either progesterone gel or placebo gel daily from 24 weeks’ gestation for an average period of ten weeks. In the original trial, outcome assessment was limited to obstetric and neonatal outcomes. These results have previously been reported: there were no differences in the primary outcome of intrauterine death or preterm delivery prior to 34 weeks and 0 days of gestation, nor any differences in neonatal outcomes between the progesterone and placebo groups [10]. All participating women were informed of the possibility of follow-up of their children and were given the opportunity to withdraw consent for future contact from the research team if they wished.\n\nWe aimed to include all children born to mothers resident in Scotland who had been recruited to the STOPPIT trial, and for whom routine health data could therefore be accessed through Information Services Division, NHS Scotland. Given that such routine health data were available for twins resident in Scotland, mothers who were resident in England at the time of the trial, and all those who emigrated out of a Scottish Health Board after the birth of their babies were not eligible for follow-up. Mothers who were lost to follow-up, and those for whom there were insufficient data for tracing were excluded from follow-up. Mothers who withdrew consent for questionnaire follow-up and those who had experienced the death of one or more twins were also excluded.\n\nThe personal identifiers of mothers of eligible children were used to identify mothers’ records on the Community Health Index (CHI) database and thus obtain their up to date contact details to enable questionnaire distribution. The CHI database contains a record of all patients registered with a General Practitioner in Scotland.\n\nThe personal identifiers of mothers were also used to identify the CHI numbers of children via linkage to statutory birth registration records. CHI numbers of children are documented on all routine health records in Scotland, and hence record linkage enabled follow-up of twins’ outcomes through examination of routine health data. In addition, statutory death registration records were searched using children’s personal identifiers to identify any additional deaths of twins for whom the CHI numbers were unknown.\n\nRecords for twins with known CHI numbers were identified on the national child health programme information systems Health Visitor First Visit, Six to Eight Week Check, Primary-1 Screening, Neonatal Hearing Screening and Preschool Vision Screening records. Subsequent to April 2005, child health programme records included a Health Plan Indicator assigned to indicate a child’s level of need for ongoing support to achieve good health and developmental outcomes.\n\nTwin records were also identified on the hospital outpatient attendance (Scottish Morbidity Record 00—SMR00) and inpatient and day case discharge (SMR01) datasets. For all twins with hospital attendances, primary diagnoses at time of discharge (coded via World Health Organisation International Classification of Disease, 10th edition (ICD-10)[18]) were examined. Those with outpatient or inpatient entries with diagnoses ICD-10 codes Q00-Q99 (Chapter XVII: Congenital malformations, deformations and chromosomal abnormalities) were defined as having a congenital abnormality.\n\nTwins in the progesterone and placebo groups were heterogeneous with respect to age, sex, and gestational age at birth. Accordingly, measures of height, weight and head circumference were converted into z-scores (standard deviations) using freely available LMS software [19] and UK 1990 growth reference data [20].\n\nWe selected two validated parent-completed questionnaires, the Health Utilities Index (HUI) [21] and the Child Development Inventory (CDI) [22] from available paediatric developmental assessment tools, purchasing licenses for the use and exact reproduction of each questionnaire. Mothers were invited by letter to participate in questionnaire follow-up. All letters were accompanied by a demographic data questionnaire, an information sheet and a written consent form. Where telephone numbers of mothers were available, a courtesy call was made to ensure questionnaires had been received. Questionnaires were mailed out in 2011 and again in 2012. In the unusual event that a mother replied twice, data from the most recent questionnaire were used. Mothers completed and returned all questionnaires and investigators calculated aggregate scores prior to any unmasking. Thereafter, treatment allocation was revealed to four mothers at their request.\n\nWe compared baseline demographic characteristics including maternal age at randomisation, household index of multiple deprivation (quintile), gestation and chorionicity, and the age of the children at the time of questionnaire completion in the responding and non-responding groups.\n\nWe summarised all baseline characteristics and outcomes using means (standard deviation), medians (25th and 75th centiles) or frequencies and percentages where relevant. Outcomes were analysed using generalised linear models (linear or logistic regression) where appropriate, adjusting for the clustering at the level of the mother. For other outcomes, Fisher’s exact test or a comparison of medians was used. Where possible, all effect sizes have 95% percent confidence intervals. All analyses were conducted using SAS version 9.2 (SAS Institute, Cary, North Carolina). There was no imputation of missing data and all analyses were as randomised.\n\nEthics approval was granted by the South East Scotland Research Committee 02 (reference number 10/S1102/70).\n\nAll women recruited to the original STOPPIT trial had been informed of the possibility of direct and record-based follow-up of their babies prior to providing written informed consent for participation. At the conclusion of the trial, women were reminded of the intention to complete a follow-up study in a newsletter and were given the opportunity to withdraw consent for further contact from the research team.\n\nAt the time of the follow-up study, Community Health Index Advisory Group (CHIAG) and Privacy Advisory Committee (PAC) approvals were obtained in order to update contact details of mothers of children eligible for follow-up, identify CHI numbers of eligible children, and perform anonymised record linkage of children’s CHI numbers to national child health records so that health data could be obtained. Parents were contacted and gave additional written informed consent for the completion of questionnaires.\n\nResults\nOf the 500 women in the original STOPPIT trial, 68 were excluded from attempted record linkage as they lived in England (and would therefore not have relevant health records in Scotland), leaving 432 for whom record linkage was attempted. A further six women were lost to follow-up at the end of the original trial and ten could not be identified on the CHI database. Therefore, 416 women were potentially eligible to be sent a questionnaire and had current contact details available. Linkage to the children’s CHI numbers was performed in March 2013. CHI numbers of one child (in seven women) and both children (in 22 women) could not be identified, leaving 781 children whose CHI numbers were submitted for linkage to national child health records at ISD (386 in the progesterone group and 395 in the placebo group). Record linkage was successfully performed on at least one record in 759/781 (97%) children. The numbers of children for whom records were linked in each group are shown in Fig 1.\n\n10.1371/journal.pone.0122341.g001Fig 1 Flow of twins through record linkage at ISD.\nStillbirth, neonatal or paediatric death was identified in 26 twins in the study cohort: 15 twins in the progesterone group and 11 twins in the placebo group. Two deaths were identified as having occurred since the findings of the original STOPPIT trial were reported. Deaths, congenital malformations, and health service utilisation were similar in the progesterone and control groups.\n\nThe rate of congenital malformations, identified using data pertaining to primary diagnoses in children with hospital attendances, was 4% in both the progesterone and placebo groups (Table 1).\n\n10.1371/journal.pone.0122341.t001Table 1 Health service use and rate of congenital malformations identified in hospital.\n\tProgesterone\tPlacebo\t\t\n\tn/N children (%)\tn/N children (%)\tEffect size (95% CI), p-value\t\n\nHospital outpatient attendance record (SMR-00)\n\t\t\t\t\n Number of children with any attendance\t246/386 (64)\t260/395 (66)\t0.91 (0.64–1.28), 0.58\t\n Median number of visits per child*\n\t0 [0, 1]\t0 [0, 1]\t\np = 0.65\t\n\nGeneral hospital inpatient record (SMR-01)\n\t\t\t\t\n Number of children with any admission\t159/386 (41)\t165/395 (42)\t0.97 (0.71–1.33), 0.87\t\n Median cumulative length of stay per admission (days)*\n\t39 [10, 62]\t31 [10, 59]\tp = 0.26**\n\t\n\nCongenital malformations (SMR-01)\n\t\t\t\t\n Number of children with any congenital malformation\t17/386 (4)\t17/395 (4)\t1.04 (0.49–1.21), 0.92\t\n*Data presented as median [IQR]\n\n**Two-sided p value from Wilcoxon Rank Sum test\n\nHealth service utilisation, including outpatient hospital attendances and inpatient hospitalisations, was similar for twins in the progesterone and placebo groups. For those who were hospitalised, the median (interquartile range) cumulative length of stay was 39 (10, 62) days in the progesterone group and 31 (10, 59) days in the placebo group (p = 0.26).\n\nChild Health Surveillance Programme data revealed no differences in terms of developmental screening between twins in the progesterone and placebo groups (Table 2). There were no differences in the incidence of developmental concern raised by the parent at the Health Visitor First Visit nor in developmental assessment at the Six to Eight Week Check. Height and weight data collected at the Primary-1 Screening demonstrated no evidence that progesterone exposure in utero had an important effect on growth in childhood. Both progesterone and placebo exposed children were near to but less than the 50th centile for weight and height. Although height centile was marginally significantly lower in the progesterone group compared with the placebo group, there were no differences in mean height. Hence, the clinical relevance of the height centile difference is likely to be limited.\n\n10.1371/journal.pone.0122341.t002Table 2 Child Health Surveillance Programme.\n\t\nProgesterone\n\t\nPlacebo\n\t\t\n\nHealth Visitor First Visit (0–10 days of life)\t\nn/N children (%)\n\t\nn/N children (%)\n\t\nEffect size (95% CI), p-value\n\t\n\n Parental concern*\n\t\t\t\t\n Number of children with any concern identified\t53/307 (17)\t77/311 (25)\t0.65 (0.40–1.07), 0.09\t\n\nHealth Plan Indicator\n\t\t\t\t\n Core\t183/307 (60)\t191/311 (61)\t0.043\n†\n\n\t\n Additional\t21/307 (7)\t26/311 (8)\t\t\n Intensive\t23/307 (7)\t8/311 (3)\t\t\n PH4P\n#\n or unknown\t80/307 (26)\t86/311 (28)\t\t\n\n6–8 Week Check (6–8 weeks of life)\t\t\t\t\n\n Developmental assessment**\n\t\t\t\t\n Number of children with any domains identified as doubtful/uncertain or abnormal\t8/310 (3)\t15/320 (5)\t0.55 (0.21–1.46), 0.23\t\n\n Health Plan Indicator\n\t\t\t\t\n Core\t182/310 (59)\t176/320 (55)\t0.47\n†\n\n\t\n Additional\t48/310 (15)\t55/320 (17)\t\t\n Intensive\t10/310 (3)\t6/320 (2)\t\t\n PH4P\n#\n or unknown\t70/310 (23)\t83/320 (26)\t\t\n\nPrimary 1 Screening (4.5–5.5 years)\t\nMean (SD), n\n\t\nMean (SD), n\n\t\nMean difference [95% CI], p-value\n\t\n\n Measurement and growth\n\t\t\t\t\n Height (cm)\t111 (5), 165\t112 (5), 189\t-0.6 [-2.1, 0.8], 0.41\t\n Weight (kg)\t19.4 (3.2), 165\t19.7 (2.8), 189\t0.2 [-1.0, 1.4], 0.74\t\n BMI\t15.6 (2), 165\t15.6 (1.5), 189\t0.2 [-0.3, 0.4], 0.64\t\n Height centile\t42.1 (28), 165\t48.5 (28.8), 189\t-6.4 [-12.3, -0.4], 0.04\t\n Weight centile\t43.5 (29.7), 165\t48.6 (29.2), 189\t-5.2 [-11.3, 1.0], 0.10\t\n\n Health Plan Indicator\n\t\t\t\t\n Core\t236/371 (64)\t264/388 (68)\t0.43\n†\n\n\t\n Additional\t50/371 (13)\t39/388 (10)\t\t\n Intensive\t3/371 (1)\t2/388 (1)\t\t\n PH4P\n#\n or unknown\t82/371 (22)\t83/388 (21)\t\t\n* The health visitor records parental concerns relating to the child’s feeding, illness, crying, appearance, weight and sleep.\n\n** The health visitor assesses the following developmental domains: gross motor; hearing and communication; and vision and social awareness. Development is assessed to be normal; abnormal; doubtful/uncertain; or not assessed/incomplete.\n\n\n#PH4P (Pre-Hall 4 Programme): The Health for All Children screening and surveillance programme was introduced in Scotland from April 2005. The PH4P utilises the Health Plan Indicator. Children assessed prior to the introduction of the PH4P at local health care providers were not classified using this system\n\n\n† P-value for chi-square test of association.\n\nThere were no differences in the outcomes of sensory screening between the progesterone and placebo groups (Table 3).\n\n10.1371/journal.pone.0122341.t003Table 3 Sensory Screening.\n\tProgesterone\tPlacebo\t\t\n\tn/N children (%)\tn/N children (%)\tEffect size (95% CI), p-value\t\n\nNeonatal hearing screening *\n\t\t\t\t\n Either ear fail\t41/302 (14)\t31/301 (10)\t1.38 (0.81–2.35), 0.23\t\n\nPreschool vision screening **\n\t\t\t\t\n Either eye fail\t70/250 (28)\t71/263 (27)\t1.04 (0.67–1.64), 0.85\t\n*Screeners record the outcome of the first screen of each ear as pass, fail/refer, or not done/incomplete.\n\n**Preschool vision screening includes an assessment of visual acuity and ocular movement. The outcome of screening for each eye is recorded as pass, refer or ongoing follow-up (both indicating failing screening), or recall (indicating screening could not be satisfactorily completed).\n\nThe flow of participants through the questionnaire arm of the study is shown in Fig 2. After relevant exclusions, 369 families were sent a questionnaire. A positive response was received from 167 mothers. Data for the primary outcome (CDI and HUI scores) were obtained from 162 mothers (44% of those mailed questionnaires).\n\n10.1371/journal.pone.0122341.g002Fig 2 Flow of participants through questionnaire arm of study.\nThe mean age of children at the time of questionnaire response was 55.5 months. S1 Table (see Supporting Information) shows the characteristics of the responders in comparison with the non-responders and those who were not sent a questionnaire. Responders tended to be older, had less social deprivation, had taken more study medication (progesterone and placebo), and their children were born at a higher gestational age. Within the group of responders, there were no differences in demographic characteristics when those allocated to progesterone were compared to those allocated to placebo. Additionally, within those who responded, there were no differences in demographic characteristics evaluated in those whose mothers were originally in the progesterone group compared with those whose mothers were originally in the placebo group.\n\n\nTable 4 shows the proportion of children classified as having borderline or delayed development on the CDI. No significant difference in risk of abnormal development was seen between children who received progesterone and those who received placebo.\n\n10.1371/journal.pone.0122341.t004Table 4 Child Development Inventory score categorisation.\n\t\nProgesterone\n\t\nPlacebo\n\t\t\n\tn/N children (%)\tn/N children (%)\tOR (95% CI), p-value\t\n\nBorderline development\n\t18/140 (13)\t39/184 (21)\t0.55 (0.26–1.19), 0.13\t\n(25 to <30% below age range)\t\t\t\t\n\nDelayed development\n\t42/140 (30)\t65/184 (35)\t0.87 (0.46–1.63), 0.66\t\n(≥30% below age range)\t\t\t\t\n\nBorderline/delayed development\n\t60/140 (43)\t104/184 (57)\t0.67 (0.35–1.28), 0.23\t\n(≥25% below age range)\t\t\t\t\nThe CDI is normed so that a child who performs at the level of a child that is ≥30% younger than their chronological age is classed as having delayed development. This equates to a developmental performance ≥2.0 standard deviations below the mean. Around 2% of children would be expected to be in this category. A child that performs at a level of a child 25 to <30% younger is between 1.5 and <3.0 SD below the mean for developmental performance and is classed as having borderline development. Around a further 3% of children would be expected to be in this category. An odds ratio less than one indicates a beneficial effect of progesterone.\n\n\nTable 5 shows global health status in the progesterone and placebo groups. There were no differences in the global health rating or the individual multi-attribute health status (HUI Mark II and HUI Mark III) for children in the progesterone group compared with those in the placebo group.\n\n10.1371/journal.pone.0122341.t005Table 5 Health Utilities Index multi-attribute health status and global health rating.\n\t\nProgesterone\n\t\nPlacebo\n\t\t\n\tMean (SD), n\n\tMean (SD), n\n\tMean difference\t\n\t\t\t[95% CI], p-value\t\n\nMulti-attribute health status\n\t\t\t\t\n HUI Mark II\t0.96 (0.10), 147\t0.96 (0.09), 184\t0.00 [-0.03, 0.02], 0.70\t\n HUI Mark III\t0.96 (0.12), 147\t0.97 (0.07), 184\t-0.01 [-0.03, 0.02], 0.57\t\n\t\nn/N children (%)\n\t\nn/N children (%)\n\t\np-value\n\t\n\nGlobal health rating\n\t\t\t\t\n Excellent\t129/147 (88)\t166/184 (90)\t0.51\t\n Very good\t14/147 (10)\t14/184 (8)\t\t\n Good\t4/147 (3)\t4/184 (2)\t\t\nThe Health Utilities Index includes two complementary systems of classification of multi-attribute health status in children. HUI Mark II measures health status as a function of seven attributes: sensation, ambulation, self-care, cognition, emotion, pain and fertility. The HUI Mark III assesses eight attributes: vision, hearing, speech, ambulation, dexterity, cognition, emotion and pain. Parental responses to questionnaire items are combined and ascribed a multi-attribute utility score between 0.00 and 1.00 (where 1.00 describes perfect health), calculated using standard formulas for the HUI Mark II and for the HUI Mark III. Additionally, parents give a global rating of child health on a 5-point Likert-type scale (excellent, very good, good, fair, poor).\n\nThe proportion of children in each group with a health utilities index of more than one (indicating some level of impairment) in each developmental domain is shown in S2 Table. Again, there were no differences in the individual components of the HUI score between the groups.\n\nDiscussion\nThe results of this follow-up evaluation of children exposed in utero to progesterone for the prevention of preterm birth in women with twin pregnancies suggest that progesterone has no direct effect on child health and developmental outcomes. These findings complement the findings of the original STOPPIT trial in which progesterone was found to have no significant effect on the composite outcome of death or delivery before 34 weeks’ gestation [10].\n\nThe use of a cohort of women with twin pregnancies, in which progesterone had no effect on gestational length, allows the direct effect of progesterone to be determined independent of any effect of progesterone on preterm birth. Hence, our study provides no significant evidence that in utero progesterone exposure directly enhances the health of exposed children. This is perhaps surprising; progesterone has been shown to have anti-inflammatory and neuroprotective properties in models of adult acquired brain injury, and a direct beneficial effect on neurodevelopment is plausible [23]. In our study, the parent reported health status of twin children was excellent or very good for 98% of children, despite 33% of children having evidence of some developmental delay. The developmental delay likely relates to prematurity, with 28% of children having been born before 35 weeks’ gestation.\n\nThe results of this follow-up study additionally provide reassurance that progesterone does not cause harm to children exposed in utero. No difference was found in the overall rate of congenital anomalies in the progesterone and placebo groups. In the absence of an anomaly register, detection of congenital anomalies was limited to diagnoses made in children who presented to hospital. Nevertheless, anomalies that cause hospital admission and early death are likely to have been well recorded and linked.\n\nPrevious studies have suggested that progesterone exposure in early pregnancy might increase the risk of hypospadias in males [24]. In the STOPPIT trial, progesterone therapy was initiated after 24 weeks’ gestation. Thus, administration occurred after the completion of the embryological development of the male genitalia at 14 weeks. Current evidence indicates there is no increase in the risk of hypospadias in males exposed to progesterone after 16 weeks [25]. The results of our follow-up study support this hypothesis.\n\nOther studies have raised concerns regarding behavioural outcomes in children exposed in utero to progesterone [26]. We reported no significant differences between the progesterone and placebo groups with respect to social development (reported on the CDI), emotion and cognition (reported on the HUI).\n\nThis follow-up did not include a formal evaluation of intelligence and school performance. Future linkage to educational records could demonstrate whether the apparently high incidence of some developmental delay has any adverse effects on educational attainment.\n\nOur study extends the duration of follow-up of a twin cohort exposed to progesterone in utero to a mean age of 55.5 months. To date, limited evidence has been published regarding the long-term (post neonatal) effects of exposure in utero to vaginal progesterone in twins. Only one published study has evaluated the effects of vaginal progesterone. The previously published study had a larger sample size (n = 991), but the duration of postnatal follow-up was 18 months [12]. The duration of follow-up in our study is comparable with that in a study of intrauterine exposure to an alternative formulation of progesterone, 17 α-hydroxyprogesterone caproate [17]. This latter study of 274 singleton children, born to mothers participating in a randomised placebo-controlled trial of 17 α-hydroxyprogesterone caproate in high-risk singleton pregnancies, demonstrated no difference in child health measures despite prolongation of pregnancy (Table 6).\n\n10.1371/journal.pone.0122341.t006Table 6 Studies examining the long-term effects of prophylactic progesterone exposure in utero on childhood outcomes.\nAuthor, year\tStudy population\tProgesterone\tGestational age given\tDelivery <34 weeks\tFollow-up rate\tFollow-up age\tCongenital anomalies\tAssessment tool 1 Progesterone vs. placebo\tAssessment tool 2 Progesterone vs. placebo\t\n\nNorthen et al 2007 USA\tSingletons (prior PTB)\tIntramuscular 17 α-OHPC 250 mg/week\t16–20 weeks to 36 weeks\tRR 0.67 (0.48–0.93)\n#\n\n\t80%\tMean 48 months\tGenital / reproductive (2.1% vs. 1.2%; p = 1.0)\tASQ score below cut-off on at least one area (27.5% vs. 28%; p = 0.92)\tPAI mean score (Boys: 66.5 vs. 67.3; p = 0.3. Girls: 32 vs. 33; p = 0.5)\t\n\nRode et al 2011 Austria/Denmark (PREDICT)\tTwins\tVaginal natural progesterone 200 mg/day\t20–24 weeks to 34 weeks\tOR 0.80 (0.5–1.2)\t79.2% and 74.8%*\n\t6 months, 18 months\tCongenital / chromosomal (3.8% vs. 4.0%; OR 1.0, 0.5–1.7)\tASQ mean score at 6 months of age (215 vs. 218; p = 0.45)\tASQ mean score at 18 months of age (193 vs. 194; p = 0.89)\t\n\nMcNamara et al 2015 United Kingdom (STOPPIT)\tTwins\tVaginal natural progesterone 90 mg/day\t24 to 34 weeks\tOR 1.36 (0.89–2.09)\t97% and 44%**\n\tMean 55 months\tCongenital (4.0% vs. 4.0%; p = 0.92)\tCDI score below cut-off on at least one area (30% vs. 35%; p = 0.66)\tHUI global health rating‘Excellent’ (88% vs. 90%; p = 0.51)\t\nPTB = preterm birth. 17 α -OHPC = 17 α -hydroxyprogesterone caproate. RR = relative risk (95% confidence interval). OR = odds ratio (95% confidence interval).\n\nASQ = Ages and Stages Questionnaire. PAI = Preschool Activities Inventory. CDI = Child Development Inventory. HUI = Health Utilities Index.\n\n\n#Delivery <35 weeks’ gestation.\n\n*In the PREDICT study, follow-up was achieved for 79.2% of twins at 6 months of age and 74.8% of twins at 18 months of age.\n\n**In our study, follow-up was achieved for 97% of twins via record linkage of at least one health record and 44% of twins via parental questionnaire.\n\nGiven that the accuracy and reliability of paediatric developmental assessment is improved over time, the longer-term follow-up in our study is important. The relative neuroplasticity of the immature brain limits the capacity to ascertain a child’s neurodevelopmental status and prognosis until the age of at least two years [27]. Moreover, subtle delays are more easily identified as children become social and are exposed to environments where they are directly compared to peers [28]. This is particularly relevant where parent report is used as the method of assessment.\n\nThe rigour of our findings is enhanced by the use of record linkage, which avoids the selection bias inherent in questionnaire-based studies. Our ability to trace records on 97% of eligible children using record linkage demonstrates that in the Scottish population, record linkage is an economical and effective strategy for follow-up of children of women recruited to clinical trials in pregnancy. We believe that it is unlikely that lack of linkage to the 3% of missing children would have altered the overall findings.\n\nQuestionnaire data supported data from the record linkage and provided more detail on specific individual outcomes. However, the success rate of questionnaire follow-up was lower, with only 44% of eligible parents responding. Nevertheless, the questionnaire data supported the findings of our record linkage study (where the percentage of women and children followed up was excellent); exposure in utero to progesterone after 20 weeks’ gestation had no adverse effects.\n\nThe power of our follow-up study was dictated by the original sample of the STOPPIT trial. Additionally, the effective sample size of the follow-up study was reduced by the non-independence of data collected for each twin. Clustering was accounted for with multi-level modelling in our statistical analysis. If the impact of clustering is ignored, our study had 80% power to detect an absolute increase of 10% in hospital admissions, and 95% power to detect an absolute increase of 13% in hospital admissions in the progesterone group compared with the placebo group.\n\nConclusions\nIn conclusion, we have found that exposure in utero to progesterone, given in twin pregnancies for the prevention of preterm birth, has no significant impact on child health and developmental outcomes at three to six years. We demonstrate that, in the absence of an effect on gestational length, progesterone has no beneficial or adverse effects on childhood development. The limitations of our study are acknowledged and the strengths asserted.\n\nIn women with high-risk singleton pregnancies because of short cervix or preterm delivery, progesterone administration (vaginal progesterone or intramuscular 17 α-hydroxyprogesterone caproate respectively) has been shown to reduce the rate of preterm birth. An ongoing randomised trial (OPPTIMUM, ISRCTN14568373) will determine whether vaginal progesterone administration to women at risk because of either a previous preterm birth or a short cervix is associated with long-term gains in terms of child health and development.\n\nSupporting Information\nS1 Table Demographic characteristics of responders and non-responders and those not sent a follow-up questionnaire.\n(DOCX)\n\nClick here for additional data file.\n\n S2 Table Health Utilities Index individual domains.\n(DOCX)\n\nClick here for additional data file.\n\n We would like to thank Andrew Duffy who performed record linkage with assistance from Diane Thom, Judith Tait and Lynne Jarvis, Information Services Division, Scotland, and Lorraine Adamson (administrator) who sent out questionnaires and derived summary values from returned questionnaires. We are grateful to the original collaborators in the STOPPIT trial and especially to all the parents and children who participated in this follow-up study.\n==== Refs\nReferences\n1 \nda Fonseca EB , Bittar RE , Carvalho MH , Zugaib M (2003 ) Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: a randomized placebo-controlled double-blind study . Am J Obstet Gynecol \n188 : 419 –424 .\n12592250 \n2 \nMeis PJ , Klebanoff M , Thom E , Dombrowski MP , Sibai B , et al (2003 ) Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate . N Engl J Med \n348 : 2379 –2385 .\n12802023 \n3 \nFonseca EB , Celik E , Parra M , Singh M , Nicolaides KH , et al (2007 ) Progesterone and the risk of preterm birth among women with a short cervix . N Engl J Med \n357 : 462 –469 .\n17671254 \n4 \nHassan SS , Romero R , Vidyadhari D , Fusey S , Baxter JK , et al (2011 ) Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial . Ultrasound Obstet Gynecol \n38 : 18 –31 . 10.1002/uog.9017 \n21472815 \n5 Dodd JM, Flenady V, Cincotta R, Crowther CA (2006) Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth. Cochrane Database of Systematic Reviews Issue 1. Art. No.: CD004947. 10.1002/14651858.CD004947.pub2 \n\n6 \nDodd JM , Flenady VJ , Cincotta R , Crowther CA (2008 ) Progesterone for the prevention of preterm birth: a systematic review . Obstet Gynecol \n112 : 127 –134 . 10.1097/AOG.0b013e31817d0262 \n18591318 \n7 \nRomero R , Nicolaides K , Conde-Agudelo A , Tabor A , O'Brien JM , et al (2012 ) Vaginal progesterone in women with an asymptomatic sonographic short cervix in the midtrimester decreases preterm delivery and neonatal morbidity: a systematic review and metaanalysis of individual patient data . Am J Obstet Gynecol \n206 : 124.e1 –124.e19 . 10.1016/j.ajog.2011.12.003 \n22284156 \n8 \nRouse DJ , Caritis SN , Peaceman AM , Sciscione A , Thom EA , et al (2007 ) A trial of 17 alpha-hydroxyprogesterone caproate to prevent prematurity in twins . N Engl J Med \n357 : 454 –461 .\n17671253 \n9 \nCombs CA , Garite T , Maurel K , Das A , Porto M , et al (2011 ) 17-hydroxyprogesterone caproate for twin pregnancy: a double-blind, randomized clinical trial . Am J Obstet Gynecol \n204 : 221.e1 –221.e8 . 10.1016/j.ajog.2010.12.042 \n21376161 \n10 \nNorman JE , Mackenzie F , Owen P , Mactier H , Hanretty K , et al (2009 ) Progesterone for the prevention of preterm birth in twin pregnancy (STOPPIT): a randomised, double-blind, placebo-controlled study and meta-analysis . Lancet \n373 : 2034 –2040 . 10.1016/S0140-6736(09)60947-8 \n19523680 \n11 \nWood S , Ross S , Tang S , Miller L , Sauve R , et al (2012 ) Vaginal progesterone to prevent preterm birth in multiple pregnancy: a randomized controlled trial . J Perinat Med \n40 : 593 –599 .23093256 \n12 \nRode L , Klein K , Nicolaides KH , Krampl-Bettelheim E , Tabor A , et al (2011 ) Prevention of preterm delivery in twin gestations (PREDICT): a multicenter, randomized, placebo-controlled trial on the effect of vaginal micronized progesterone . Ultrasound Obstet Gynecol \n38 : 272 –280 . 10.1002/uog.9093 \n21739497 \n13 \nSerra V , Perales A , Meseguer J , Parrilla JJ , Lara C , et al (2013 ) Increased doses of vaginal progesterone for the prevention of preterm birth in twin pregnancies: a randomised controlled double-blind multicentre trial . BJOG \n120 : 50 –57 . 10.1111/j.1471-0528.2012.03448.x \n22882759 \n14 \nNess A , Dias T , Damus K , Burd I , Berghella V (2006 ) Impact of the recent randomized trials on the use of progesterone to prevent preterm birth: a 2005 follow-up survey . Am J Obstet Gynecol \n195 : 1174 –1179 .\n17000251 \n15 \nU.S. Food and Drug Administration (2011 ) FDA approves drug to reduce risk of preterm birth in at-risk pregnant women\nU.S. Food and Drug Administration .\n16 \nKenyon S , Pike K , Jones DR , Brocklehurst P , Marlow N , et al (2008 ) Childhood outcomes after prescription of antibiotics to pregnant women with preterm rupture of the membranes: 7-year follow-up of the ORACLE I trial . Lancet \n372 : 1310 –1318 . 10.1016/S0140-6736(08)61202-7 \n18804274 \n17 \nNorthen AT , Norman GS , Anderson K , Moseley L , Divito M , et al (2007 ) Follow-up of children exposed in utero to 17 alpha-hydroxyprogesterone caproate compared with placebo . Obstet Gynecol \n110 : 865 –872 .\n17906021 \n18 \nWorld Health Organisation (2009 ) International statistical classification of diseases and health related problems, 10th revision (ICD-10)\n2008 ed. \nGeneva : World Health Organisation .\n19 iGrow (2011) LMS growth, a Microsoft Excel add-in to access growth references based on the LMS method. Version 2.74. (Accessed at http://www.healthforallchildren.co.uk).\n20 \nFreeman JV , Cole TJ , Chinn S , Jones PR , White EM , et al (1995 ) Cross sectional stature and weight reference curves for the UK, 1990 . Arch Dis Child \n73 : 17 –24 .\n7639543 \n21 \nFurlong WJ , Feeny DH , Torrance GW , Barr RD (2001 ) The Health Utilities Index (HUI) system for assessing health-related quality of life in clinical studies . Ann Med \n33 : 375 –384 .\n11491197 \n22 \nIreton H (2005 ) Child Development Inventory manual\nMinneapolis, Minnesota : Child Development Review, Behaviour Science Systems Inc .\n23 \nXiao G , Wei J , Yan W , Wang W , Lu Z (2008 ) Improved outcomes from the administration of progesterone for patients with acute severe traumatic brain injury: a randomized controlled trial . Crit Care \n12 : R61 \n10.1186/cc6887 \n18447940 \n24 \nCarmichael SL , Shaw GM , Laurent C , Croughan MS , Olney RS , et al (2005 ) Maternal progestin intake and risk of hypospadias . Arch Pediatr Adolesc Med \n159 : 957 –962 .\n16203941 \n25 \nHemminki E , Gissler M , Toukomaa H (1999 ) Exposure to female hormone drugs during pregnancy: effect on malformations and cancer . Br J Cancer \n80 : 1092 –1097 .\n10362122 \n26 \nNicol MB , Hirst JJ , Walker D (1999 ) Effects of pregnanolone on behavioural parameters and the responses to GABA(A) receptor antagonists in the late gestation fetal sheep . Neuropharmacology \n38 : 49 –63 .\n10193898 \n27 \nClaas MJ , de Vries LS , Bruinse HW , van Haastert IC , Uniken Venema MM , et al (2011 ) Neurodevelopmental outcome over time of preterm born children ≤750g at birth . Early Hum Dev \n87 : 183 –191 . 10.1016/j.earlhumdev.2010.12.002 \n21220192 \n28 \nDall'oglio AM , Rossiello B , Coletti MF , Bultrini M , De Marchis C , et al (2010 ) Do healthy preterm children need neuropsychological follow-up? Preschool outcomes compared with term peers . Dev Med Child Neurol \n52 : 955 –961 . 10.1111/j.1469-8749.2010.03730.x \n20722666\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1932-6203",
"issue": "10(4)",
"journal": "PloS one",
"keywords": null,
"medline_ta": "PLoS One",
"mesh_terms": "D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D010919:Placebos; D011247:Pregnancy; D011256:Pregnancy Outcome; D011374:Progesterone",
"nlm_unique_id": "101285081",
"other_id": null,
"pages": "e0122341",
"pmc": null,
"pmid": "25881289",
"pubdate": "2015",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D018486:Twin Study",
"references": "10193898;7639543;16203941;16437505;17000251;17671253;17671254;17906021;18447940;18591318;18804274;19523680;20722666;21220192;21376161;21472815;21739497;22284156;22882759;23093256;11491197;12592250;12802023;10362122",
"title": "STOPPIT Baby Follow-up Study: the effect of prophylactic progesterone in twin pregnancy on childhood outcome.",
"title_normalized": "stoppit baby follow up study the effect of prophylactic progesterone in twin pregnancy on childhood outcome"
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"abstract": "We retrospectively investigated the prognostic factor of lenalidomide plus low-dose dexamethasone (Rd) in Japanese patients with refractory or relapsed multiple myeloma (RRMM) registered in the Kansai Myeloma Forum from January 2006 to December 2013. A total of 140 patients were analyzed. The median age was 66 years. The overall response rate was 68.6 %, including 33.1 % with a better than very good partial response. At 13.0 months median follow-up, the median overall survival (OS) and progression-free survival (PFS) were 34.2 and 17.0 months, respectively. In univariate analyses, patients with one or two prior therapies had significantly longer OS (41.2 vs. 21.5 months; P = 0.002) and PFS (29.0 vs. 13.0 months; P = 0.006) than patients treated with three or more prior therapies. Prior use of thalidomide was associated with significantly shorter PFS (19.0 vs. 16.0 months; P = 0.045). The prior use of bortezomib or high-dose therapy with stem cell transplantation, and the International Staging System had no impact on long-term outcome. Multivariate analysis showed that only the number of prior therapies was a significant predictor of both OS and PFS. Our findings suggest that greater benefit may occur when Rd therapy is used at the first or second relapse in RRMM.",
"affiliations": "Division of Hematology and Oncology, Graduate School of Medicine, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan, t-koba@koto.kpu-m.ac.jp.",
"authors": "Kobayashi|Tsutomu|T|;Kuroda|Junya|J|;Fuchida|Shin-ichi|S|;Kaneko|Hitomi|H|;Yagi|Hideo|H|;Shibayama|Hirohiko|H|;Tanaka|Hirokazu|H|;Kosugi|Satoru|S|;Uoshima|Nobuhiko|N|;Kobayashi|Masayuki|M|;Adachi|Yoko|Y|;Ohta|Kensuke|K|;Ishii|Kazuyoshi|K|;Uchiyama|Hitoji|H|;Matsuda|Mitsuhiro|M|;Nakatani|Eiji|E|;Tsudo|Mitsuru|M|;Shimazaki|Chihiro|C|;Takaori-Kondo|Akifumi|A|;Nomura|Shosaku|S|;Matsumura|Itaru|I|;Taniwaki|Masafumi|M|;Kanakura|Yuzuru|Y|;|||",
"chemical_list": "D013792:Thalidomide; D003907:Dexamethasone; D000077269:Lenalidomide",
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"issue": "101(1)",
"journal": "International journal of hematology",
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"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D003907:Dexamethasone; D005260:Female; D006801:Humans; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D009367:Neoplasm Staging; D011379:Prognosis; D012008:Recurrence; D012189:Retrospective Studies; D016019:Survival Analysis; D013792:Thalidomide; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "9111627",
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"references": "24035714;23032723;15809451;19626046;18332230;21860026;11049970;18245666;22966948;20559759;24580032;19853510;11521808;10564685;18032763;20460639;18492953;21841166;16855634;19302559;20072152;18032762;24584872;17975015",
"title": "Impact of early use of lenalidomide and low-dose dexamethasone on clinical outcomes in patients with relapsed/refractory multiple myeloma.",
"title_normalized": "impact of early use of lenalidomide and low dose dexamethasone on clinical outcomes in patients with relapsed refractory multiple myeloma"
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"abstract": "BACKGROUND\nEpidermal growth factor receptor (EGFR) 20 exon insertion is the second most common EGFR aberrations in non-small cell lung cancer (NSCLC). Despite some novel EGFR inhibitors, clinically obtainable management for this subset of patients remains an unmet need. there are no previous reports of upfront combination therapy with immunotherapy and chemotherapy for lung adenocarcinoma with brain metastasis harboring EGFR 20 insertion.\nA 56-year-old man who sought care for dry cough was diagnosed with lung adenocarcinoma with brain metastases indicating a poor prognosis.\n\n\nMETHODS\nNext-generation sequencing of lung biopsied tissue revealed an EGFR exon 20 in-frame insertion (P772_H773insYNP+H773Y).\n\n\nMETHODS\nThe patient started treatment of pemetrexed and carboplatin plus programmed cell death-1 inhibitor sintilimab in November 2019.\n\n\nRESULTS\nThe patient achieved partial responses both intra- and extra-cranially. After 6 cycles of treatment, the patient accepted sintilimab plus pemetrexed every 3 weeks as maintenance therapy, which was well-tolerated without any toxicity and is still ongoing after 18 months since initiation of 1st-line treatment.\n\n\nCONCLUSIONS\nThis is the first case report of the clinical benefit of upfront immune checkpoint inhibitors (ICIs) plus chemotherapy for a brain metastatic NSCLC patient harboring EGFR exon 20 insertion mutation. Further study is needed to validate the predictor involved in responders to ICIs-based therapy with EGFR mutations.",
"affiliations": "Department of Thoracic Surgery, Xuanwu Hospital, Cancer Center of National Clinical Research Center for Geriatric Diseases, Diagnostic and Treatment Center of Lung Cancer, Capital Medical University, Beijing, China.;Beijing United Family Healthcare Hospital, Beijing, China.;Department of Thoracic Surgery, Xuanwu Hospital, Cancer Center of National Clinical Research Center for Geriatric Diseases, Diagnostic and Treatment Center of Lung Cancer, Capital Medical University, Beijing, China.;Department of Thoracic Surgery, Xuanwu Hospital, Cancer Center of National Clinical Research Center for Geriatric Diseases, Diagnostic and Treatment Center of Lung Cancer, Capital Medical University, Beijing, China.",
"authors": "Nong|Jingying|J|0000-0002-0682-2190;Gu|Yanfei|Y|;Yao|Shuyang|S|;Zhang|Yi|Y|",
"chemical_list": "C512478:EGFR protein, human; D066246:ErbB Receptors",
"country": "United States",
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"doi": "10.1097/MD.0000000000026650",
"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974\n1536-5964\nLippincott Williams & Wilkins Hagerstown, MD\n\nMD-D-21-02638\n10.1097/MD.0000000000026650\n26650\n5700\nResearch Article\nClinical Case Report\nDurable response to immunotherapy plus chemotherapy in a patient with untreated, brain-metastatic, EGFR exon 20 insertion mutation lung adenocarcinoma\nA case report\nhttp://orcid.org/0000-0002-0682-2190\nNong Jingying MD, PhD a\nGu Yanfei MD, PhD b\nYao Shuyang MD a\nZhang Yi MD a∗\nSaranathan. Maya\na Department of Thoracic Surgery, Xuanwu Hospital, Cancer Center of National Clinical Research Center for Geriatric Diseases, Diagnostic and Treatment Center of Lung Cancer, Capital Medical University, Beijing, China.\nb Beijing United Family Healthcare Hospital, Beijing, China.\n∗ Correspondence: Yi Zhang, Department of Thoracic Surgery, Xuanwu Hospital, Cancer Center of National Clinical Research Center for Geriatric Diseases, Diagnostic and Treatment Center of Lung Cancer, Capital Medical University, Beijing, China (e-mail: steven9130@sina.com).\n23 7 2021\n23 7 2021\n100 29 e2665021 4 2021\n4 6 2021\n28 6 2021\nCopyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0\n\nAbstract\n\nRational:\n\nEpidermal growth factor receptor (EGFR) 20 exon insertion is the second most common EGFR aberrations in non-small cell lung cancer (NSCLC). Despite some novel EGFR inhibitors, clinically obtainable management for this subset of patients remains an unmet need. there are no previous reports of upfront combination therapy with immunotherapy and chemotherapy for lung adenocarcinoma with brain metastasis harboring EGFR 20 insertion.\n\nPatient concerns:\n\nA 56-year-old man who sought care for dry cough was diagnosed with lung adenocarcinoma with brain metastases indicating a poor prognosis.\n\nDiagnosis:\n\nNext-generation sequencing of lung biopsied tissue revealed an EGFR exon 20 in-frame insertion (P772_H773insYNP+H773Y).\n\nInterventions:\n\nThe patient started treatment of pemetrexed and carboplatin plus programmed cell death-1 inhibitor sintilimab in November 2019.\n\nOutcomes:\n\nThe patient achieved partial responses both intra- and extra-cranially. After 6 cycles of treatment, the patient accepted sintilimab plus pemetrexed every 3 weeks as maintenance therapy, which was well-tolerated without any toxicity and is still ongoing after 18 months since initiation of 1st-line treatment.\n\nLessons:\n\nThis is the first case report of the clinical benefit of upfront immune checkpoint inhibitors (ICIs) plus chemotherapy for a brain metastatic NSCLC patient harboring EGFR exon 20 insertion mutation. Further study is needed to validate the predictor involved in responders to ICIs-based therapy with EGFR mutations.\n\nKeywords\n\nEGFR rare mutations\nimmune checkpoint inhibitors\nlung cancer\nOPEN-ACCESSTRUE\n==== Body\n1 Introduction\n\nProgrammed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) immune checkpoint inhibitors (ICIs), alone or in combination with chemotherapy, have revolutionized the standard treatment for non-small-cell lung cancer (NSCLC), bringing unprecedented durable clinical benefit to late-stage patients. Despite this, a portion of patients displays only modest responses or remains unresponsive.[1,2] Increasing evidence indicates epidermal growth factor receptor (EGFR) mutation to be a negative predictive factor for immunotherapy, with most data explored in classic EGFR mutations 19del and L858R,[3,4] while data in patients harboring EGFR exon 20 insertion mutation are lacking. High-throughput sequencing such as next-generation sequencing could provide more information for treatment selection.\n\nHere we describe a rare case of an advanced-stage lung adenocarcinoma patient with brain metastases (BM) harboring EGFR exon 20 insertion mutation who responded to 1st-line PD-1 inhibitor sintilimab plus chemotherapy (pemetrexed and carboplatin), with a continuous partial response both cranial and extra-cranial and progress free survival beyond 18 months.\n\n2 Case presentation\n\nThis case was approved by the Ethics Committee, and written informed consent was obtained from the patient for the publication of this case report and accompanying images. Figure 1 shows the timeline of a 56-year-old man who sought care for dry cough that had been progressively worsening over 4 weeks, he was neurologically asymptomatic and had tobacco use of 1 pack × 20 years. A computed tomographic scan revealed a large mass in the left lower lobe of the lung. Magnetic resonance imaging (MRI) of the head revealed numerous tumor lesions, with mass effect and local edema. A core biopsy specimen of the left lower lobe mass showed lung adenocarcinoma that was positive for cytokeratin 7 (CK7), negative for cytokeratin 20 (CK20), and positive for thyroid transcription factor 1 on immunoperoxidase staining. The PD-L1 (SP263) testing showed high expression with a tumor proportion score of 90% (Fig. 2A). The patient was a stage IV lung adenocarcinoma according to TNM staging 8th edition.\n\nFigure 1 Timeline of clinical response. Shown is the timeline of cranial and extra-cranial clinical response of the NSCLC patient with EGFR 20 exon insertion mutant to 1st-line PD-1 inhibitor plus chemotherapy. The evolution of the disease was demonstrated by brain MRI and chest CT at various time points. NGS analyses were performed at the time of diagnosis (October 2019). Sintilimab plus chemotherapy (pemetrexed+carboplatin) were initially provided for 6 cycles, followed by Sintilimab plus pemetrexed as maintenance therapy.\n\nFigure 2 Histopathologic analyses and Molecular detection by NGS at diagnosis. (A) Histopathologic analyses at diagnosis. (upper left) CT imaging shows the biopsy site (arrowhead) at the left lower lobe mass of the lung. (lower left) Low-power magnification (original magnification, 10×) shows lung biopsy widely infiltrated by adenocarcinomatous architecture. (upper right) High-power magnification (original magnification, 40×) shows neoplastic cells with abundant pale eosinophilic cytoplasm and atypical round to oval nuclei. (lower right) 90% of these neoplastic cells express PD-L1. (B) Molecular alterations of lung biopsy by NGS at diagnosis.\n\nMolecular testing on the biopsied tissue via next-generation sequencing (NGS) revealed an EGFR exon 20 in-frame insertion (P772_H773insYNP+H773Y), Microsatellite stability, and high tumor mutational burden (TMB) 10.5 Mut/Mb. Also, alterations in immune-related genes were revealed including CTNNB1 (Catenin β1) S37F, and ARID2 (AT-rich interactive domain-containing protein 2) E1056X, with some variants of unknown significance (Fig. 2B).\n\nThe patient started treatment of chemotherapy (pemetrexed 500 mg/m2 and carboplatin AUC = 5) plus PD-1 inhibitor sintilimab 200 mg per 3 weeks in November 2019. After 4 cycles of treatment, the patient achieved a partial response per Response Evaluation Criteria In Solid Tumors, Version 1.1. He was in a good performance status without experience of any treatment-related adverse event except for grade II neutropenia. After 6 cycles of treatment, the patient then accepted sintilimab 200 mg plus pemetrexed 500 mg/m2 every 3 weeks as maintenance therapy, which was well-tolerated without any toxicity.\n\nFollow-up imaging, by brain MRI, chest, abdominal, pelvic CT, and bone-scan at various time points showed a continuous decrease of both the lung and brain lesions, with no new sites of disease (Fig. 1). By the last follow-up in May 2021, the patient had achieved a PFS of 18 months. The treatment with pemetrexed plus PD-1 inhibitor is still ongoing since initiation of 1st-line treatment without evidence of progressive disease or any toxicity.\n\n3 Discussion\n\nEGFR mutations are detected in 20% to 50% of lung adenocarcinoma patients, EGFR exon 20 insertions are the next most common EGFR mutations in NSCLC after classical mutations, accounting for 4% to 10% of all observed EGFR aberration.[5,6] Most EGFR exon 20 insertion mutations predict resistance to clinically achievable levels of tyrosine kinase inhibitors (TKIs) in advanced NSCLC, although there are rare exceptions. Some novel EGFR inhibitors have shown encouraging antitumor activity for EGFR exon 20 insertions,[7] but commercially obtainable effective targeted drugs remain an unmet need in clinical management. Therefore, platinum-based chemotherapy is considered standard treatment for these patients.\n\nThis patient harbored EGFR exon 20 in-frame insertion (P772_H773insYNP+H773Y). exon 20 H773Y was previously detected combined with exon 20 insertions.[6,8] Preclinical research indicated that the complex mutations of exon 20 insertion combined with H773Y resist 1st-generation EGFR-TKIs,[8] while clinical evidence for the effect of 2nd or 3rd generation EGFR-TKIs are lacking.\n\nAlthough ICIs have revolutionized the systemic treatment of patients of NSCLC with EGFRwild-type (WT), the activity and clinical impact in the subgroup of EGFR mutation-positive tumors have been lower than in the EGFRWT population in large 2nd- and 3rd-line phase III trials and 1st-line trials evaluating the efficacy of ICIs often excluded EGFR-mutation-positive patients. Anecdotal evidence suggests that some EGFR mutation-positive patients benefit from PD-1/PD-L1 inhibitors.[9]EGFR exon 20 mutations demonstrated a higher response rate and longer survival compared to classic EGFR mutations.[10] A case report demonstrated that a heavily pre-treated patient of NSCLC with EGFR exon 20 insertion mutation responded to ICIs-based therapy.[11] But the effect of upfront ICIs in lung cancer patients harboring EGFR exon 20 insertion mutation is lacking. This patient had high PD-L1 expression. PD-L1 is a positive predictive biomarker of ICIs, which has been prospectively validated and approved by the Food and Drug Administration, and was also positively associated with outcomes for ICIs in EGFR mutant NSCLC.[4]\n\nConsidering this patient was neurologically asymptomatic, with rare EGFR mutations, high PD-L1 expression, and High TMB,[12] therefore, 1st-line immunotherapy plus chemotherapy was applied. A durable response was achieved with impressive control in both extra-cranial and cranial tumor lesions.\n\nBrain metastases, associated with poor clinical outcomes, are diagnosed in approximately 20% of NSCLC patients.[13] For asymptomatic BM, upfront systemic chemotherapy could be an option. However, traditional chemotherapy drugs have a limited role in BM management, owing to the presence of efflux pumps,[14,15] and lacking penetration of the blood-brain barrier. Here is the rational basis for ICIs-based treatment in patients with BM: first, antitumor T cells are activated and home to the brain from extra-cranial sites. Second, tumor neo-vessels are leaky to facilitate ICIs penetrating to stimulate tumor-associated T cells. Prospective trials evaluating ICIs efficacy in previously untreated BM are scarce. It was supported by a few studies of anti-PD-1 mono-therapy that ICIs can induce intra-cranial response.[16–18] Series of retrospective studies provided evidence that intracranial and extra-cranial efficacy of ICIs are comparable.[16,19]\n\nSome questions have yet to be resolved regarding how to identify the patients most likely to benefit from ICIs-based therapy, and how to weigh the probability of immunotherapy benefit when concomitant potential positive and negative factors both exist. For this patient, concomitant alterations in immune-related genes were revealed including CTNNB1 S37F and ARID2 E1056X. CTNNB1 S37F is a gain-of-function mutation that could lead to aberrant activation of the WNT/β-catenin signaling, which is enriched in non-T cell inflamed tumors[20,21] and has been linked to lack of benefit of immunotherapy in NSCLC.[22] Whereas, ARID2 E1056X is a loss-of-function mutation. ARID2, encoding a PBAF complex subunit, acts as an immunomodulator. ARID2 mutation is a potential biomarker positively indicating ICIs effectiveness in melanoma patients.[23–25] Considering that biomarkers are often complex and non-binary, and we only see part of the picture since the potential heterogeneity has not been evaluated, therefore, it is overly simplistic to seek predictive power from a single biomarker. An interconnected network of multiple factors would be the eventual biomarker to form a more complete puzzle.\n\n4 Conclusion\n\nIn conclusion, our case demonstrated that upfront chemotherapy plus PD-1 inhibitor might be an option for some NSCLC patients of BM harboring EGFR exon 20 insertion and high PD-L1 expression/high TMB. Additional insights into gene aberrations provide more information. Further study is needed to validate the predictor involved in responders to ICIs-based therapy with EGFR mutations.\n\nAuthor contributions\n\nConceptualization: Jingying Nong, Yi Zhang.\n\nData curation: Jingying Nong, Shuyang Yao.\n\nResources: Yanfei Gu, Shuyang Yao.\n\nSupervision: Yi Zhang.\n\nWriting – original draft: Jingying Nong.\n\nWriting – review & editing: Jingying Nong, Yanfei Gu, Yi Zhang.\n\nAbbreviations: ARID2 = AT-rich interactive domain-containing protein 2, BM = brain metastases, CK = cytokeratin, CTNNB1= Catenin β1, EGFR = epidermal growth factor receptor, ICIs = immune checkpoint inhibitors, MRI = magnetic resonance imaging, NSCLC = non-small-cell lung cancer, PD-1 = Programmed cell death-1, PD-L1 = programmed cell death-ligand 1, TKIs = tyrosine kinase inhibitors, TMB = tumor mutational burden.\n\nHow to cite this article: Nong J, Gu Y, Yao S, Zhang Y. Durable response to immunotherapy plus chemotherapy in a patient with untreated, brain-metastatic, EGFR exon 20 insertion mutation lung adenocarcinoma: a case report. Medicine. 2021;100:29(e26650).\n\nThe authors have no conflicts of interest to disclose.\n\nThe datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.\n==== Refs\nReferences\n\n[1] Brahmer J Reckamp KL Baas P . Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015;373 :123–35. doi: 10.1056/NEJMoa1504627.26028407\n[2] Herbst RS Baas P Kim DW . Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 2016;387 :1540–50. doi: 10.1016/S0140-6736(15)01281-7.26712084\n[3] Takada K Toyokawa G Tagawa T . PD-L1 expression according to the EGFR status in primary lung adenocarcinoma. Lung Cancer 2018;116 :01–6.\n[4] Mazieres J Drilon A Lusque A . Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry. Ann Oncol 2019;30 :1321–8. doi: 10.1093/annonc/mdz167.31125062\n[5] Arcila ME Nafa K Chaft JE . EGFR exon 20 insertion mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and clinicopathologic characteristics. Mol Cancer Ther 2013;12 :220–9.23371856\n[6] Ikemura S Yasuda H Matsumoto S . Molecular dynamics simulation-guided drug sensitivity prediction for lung cancer with rare EGFR mutations. Proc Natl Acad Sci U S A 2019;116 :10025–30. doi: 10.1073/pnas.1819430116.31043566\n[7] Remon J Hendriks LEL Cardona AF . Anti-tumour treatment EGFR exon 20 insertions in advanced non-small cell lung cancer: a new history begins. Cancer Treat Rev 2020;90 :102105 doi: 10.1016/j.ctrv.2020.102105.32979839\n[8] Chi-Hsien C Gow C-H Chong-Jen Y . Clinical response of gefitinib on malignant pleural effusions in patients with non-small cell lung cancer. J Cancer Mol 2008;4 :23–8.\n[9] Gettinger S Horn L Jackman D . Five-year follow-up of nivolumab in previously treated advanced non-small-cell lung cancer: results from the CA209-003 study. J Clin Oncol 2018;36 :1675–84.29570421\n[10] Negrao MV Reuben A Robichaux JP . Association of EGFR and HER-2 exon 20 mutations with distinct patterns of response to immune checkpoint blockade in non-small cell lung cancer. J Clin Oncol 2018;36 : 15_suppl : 9052–19052.\n[11] Huang X Yang Y Wang P . A heavily pre-treated adenocarcinoma patient with EGFR exon 20 insertion mutation responded to pembrolizumab plus nab-paclitaxel/bevacizumab: a case report. Ann Palliat Med 2020;9 :03–3.\n[12] Carbone DP Reck M Paz-Ares L . First-line nivolumab in stage IV or recurrent non-small-cell lung cancer. N Engl J Med 2017;376 :2415–26. doi: 10.1056/NEJMoa1613493.28636851\n[13] Barnholtz-Sloan JS . Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System. J Clin Oncol 2004;22 :2865–72.15254054\n[14] Eichler AF Chung E Kodack DP Loeffler JS Fukumura D Jain RK . The biology of brain metastases-translation to new therapies. Nat Rev Clin Oncol 2011;8 :344–56.21487419\n[15] Fortin D . The blood-brain barrier: its influence in the treatment of brain tumors metastases. Curr Cancer Drug Targets 2012;12 :247–59.22229251\n[16] Dudnik E Yust-Katz S Nechushtan H . Intracranial response to nivolumab in NSCLC patients with untreated or progressing CNS metastases. Lung Cancer 2016;98 : 4 Suppl : 114–7.27393516\n[17] Crinò L Bronte G Bidoli P . Nivolumab and brain metastases in patients with advanced non-squamous non-small cell lung cancer. Lung Cancer 2019;129 :35–40.30797489\n[18] Goldman JW Crino L Vokes EE . Nivolumab (nivo) in patients (pts) with advanced (adv) NSCLC and central nervous system (CNS) metastases (mets). J Clin Oncol 2016;34 : 15_suppl : 9038–19038.\n[19] Watanabe H Kubo T Ninomiya T . The effect of nivolumab treatment for central nervous system metastases in non-small cell lung cancer. J Clin Oncol 2017;35 : 15_suppl : e20601–120601.\n[20] Spranger S Bao R Gajewski TF . Melanoma-intrinsic beta-catenin signalling prevents anti-tumour immunity. Nature 2015;523 :231–5. doi: 10.1038/nature14404.25970248\n[21] Luke JJ Bao R Sweis RF . WNT/beta-catenin pathway activation correlates with immune exclusion across human cancers. Clin Cancer Res 2019;25 :3074–83. doi: 10.1158/1078-0432.CCR-18-1942.30635339\n[22] Montana FJR Iranzo P Pedrola A . WNT pathway mutations (APC/CTNNB1) and immune checkpoint inhibitors (ICI) response in metastatic non-small cell lung cancer (NSCLC) patients. Ann Oncol 2019;30 : Supplement_5 : v799 doi:10.1093/annonc/mdz269.007.\n[23] Deng P Aya K Peng J . A major chromatin regulator determines resistance of tumor cells to T cell–mediated killing. Science 2018;359 :770–5.29301958\n[24] Miao D Margolis CA Gao W . Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma. Science 2018;359 :801–6.29301960\n[25] Fukumoto T Lin J Fatkhutdinov N . ARID2 deficiency correlates with the response to immune checkpoint blockade in melanoma. J Invest Dermatol 2020;141 :1564–72.e4. doi: 10.1016/j.jid.2020.11.026.33333124\n\n",
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"title": "Durable response to immunotherapy plus chemotherapy in a patient with untreated, brain-metastatic, EGFR exon 20 insertion mutation lung adenocarcinoma: A case report.",
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"affiliations": "Department of Obstetrics and Gynaecology, Royal Oldham Hospital, Manchester, United Kingdom.;Department of Infectious Disease, Monsall Unit, North Manchester General Hospital, Manchester, United Kingdom.;Department of Obstetrics and Gynaecology, Royal Oldham Hospital, Manchester, United Kingdom.;Department of Infectious Disease, Monsall Unit, North Manchester General Hospital, Manchester, United Kingdom.",
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"title": "Disseminated herpes simplex infection during pregnancy, rare but important to recognise.",
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"abstract": "Capsular contracture is fundamentally an immunological/inflammatory response to the implant, treating it as a foreign body in need of exclusion from the immune system. The capsule surrounding the implant is populated by a rich variety of immunologically active cells such as macrophages, T lymphocytes, and myofibroblasts. Vaccination in general and the COVID-19 vaccine in particular result in specific and nonspecific activation of the immune system, including those immune cells in proximity to the implant. This phenomenon has been previously demonstrated in delayed inflammatory reactions to previously implanted hyaluronic acid fillers following COVID-19 vaccination. This report is what is believed to be the first case of the rapid development of severe ipsilateral capsular contracture in the immediate aftermath of the second dose of the BNT162b2 (Pfizer) vaccine.",
"affiliations": null,
"authors": "Restifo|Richard J|RJ|",
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"doi": "10.1093/asjof/ojab021",
"fulltext": "\n==== Front\nAesthet Surg J Open Forum\nAesthet Surg J Open Forum\nasjopenforum\nAesthetic Surgery Journal. Open Forum\n2631-4797\nOxford University Press US\n\n10.1093/asjof/ojab021\nojab021\nBreast Surgery\nCase Report\nAcademicSubjects/MED00987\nA Case Report of Capsular Contracture Immediately Following COVID-19 Vaccination\nRestifo Richard J MD\nCorresponding Author: Dr Richard J. Restifo, 620 Racebrook Road, Orange, CT 06477, USA. Email address: rrestifo@msn.com; Twitter: @DrRestifo\nDr. Restifo is a plastic surgeon in private practice in Orange, CT, USA\n\n9 2021\n22 5 2021\n22 5 2021\n3 3 ojab02118 5 2021\n17 5 2021\n26 7 2021\n© 2021 The Aesthetic Society.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.\n\nAbstract\n\nCapsular contracture is fundamentally an immunological/inflammatory response to the implant, treating it as a foreign body in need of exclusion from the immune system. The capsule surrounding the implant is populated by a rich variety of immunologically active cells such as macrophages, T lymphocytes, and myofibroblasts. Vaccination in general and the COVID-19 vaccine in particular result in specific and nonspecific activation of the immune system, including those immune cells in proximity to the implant. This phenomenon has been previously demonstrated in delayed inflammatory reactions to previously implanted hyaluronic acid fillers following COVID-19 vaccination. This report is what is believed to be the first case of the rapid development of severe ipsilateral capsular contracture in the immediate aftermath of the second dose of the BNT162b2 (Pfizer) vaccine.\n==== Body\nCapsular contracture is a multifactorial process with immunologic and inflammatory components. The end result of this process is a fibrotic foreign body reaction surrounding the implant, which is the body’s attempt to isolate the implant from the immune system. The cellular composition of the capsule includes macrophages, lymphocytes, fibroblasts, and contractile myofibroblasts.1 The capsule/implant contact zone demonstrates a multilayered accumulation of immunologically active cells, including activated CD4+ T cells.2 These cells in and around the capsule can produce a variety of profibrotic cytokines, including transforming growth factor-beta 1 (TGFβ1) and several interleukins.3 The reasons why the inflammatory/immunologic process abates in most patients, but in other patients continues long after the initial surgical insult, are incompletely understood and are what drives most capsular contracture research. Certain factors, such as hematoma, seroma, or subclinical infection/biofilms, are considered to be triggers to the continued immunologic/inflammatory response that leads to contracture.4,5 Strategies to prevent or treat capsular contracture target these processes and include meticulous surgical technique, steroids, leukotriene inhibitors, antibiotic-coated mesh as well as a variety of other anti-inflammatory modalities.6-8\n\nThe COVID-19 pandemic has drastically altered many facets of everyday life, to say nothing of the public health hazard that has resulted in over 3 million deaths worldwide at the time of this writing. Fortunately, several effective vaccines have made it to the market and the rate of vaccination is accelerating in many countries. An effective vaccine should elicit both an antibody response and a T-cell–mediated response,9 and the BNT162b2 (Pfizer, New York, NY) vaccine has been shown to cause a rise in antigen-specific neutralizing antibodies as well as in CD8+ and CD4+ T cells,10 which presumably underlie its 95% efficacy in terms of preventing primary COVID-19 infection. This stimulation of an immune response by the vaccine is not without collateral effects, which fortunately have been largely limited to mild local (pain, swelling), regional (lymphadenopathy), and systemic (headache, fevers, chills, and myalgias) reactions. There has also been a handful of delayed inflammatory reactions to previously implanted hyaluronic acid fillers, which although requiring treatment were not life-threatening. Most of these were following the mRNA-1273 (Moderna, Cambridge, MA) vaccine, but there has been one reported case where a patient experienced infraorbital swelling at the site of a tear trough injection (two and a half years previously) following the second dose of the Pfizer vaccine.11\n\nThis manuscript presents a case in which a patient with silicone implants placed approximately 6 months previously developed a sudden and severe capsular contracture of one breast following the second Pfizer vaccine dose. To the author’s knowledge, this is the first report of this type.\n\nCASE REPORT\n\nA completely healthy gravida 3, para 3 woman was seen in consultation for postpartum mammary involution and ptosis (Figure 1). Subsequently, she underwent augmentation/periareolar mastopexy with a subpectoral 440 cc smooth-walled implant. Preoperative intravenous cefazolin (1 g) was given. The implant pocket was irrigated with triple antibiotic solution (1 g cefazolin, 50,000 U of bacitracin, 80 mg gentamicin) as well as with povidone-iodine solution. Poly-4-hydroxybutyrate (GalaFLEX, Galatea Surgical, Inc, Lexington, MA) mesh reinforcement was used inside the implant pocket; this product is routinely used by the author for augmentation/mastopexies to support both the parenchyma and the implant position. Tegaderm nipple shields, routinely used by the author for augmentations, were not used in this case due to the need to transpose the nipple-areolar complex. The implant was placed with an insertion funnel through a separate inframammary incision. Postoperatively she did well, and at 6 weeks, postoperative photographs demonstrate good implant position (Figure 2), and at 10 weeks, postop was noted to have good implant position with soft and movable implants (Baker I) bilaterally.\n\nFigure 1. A 34-year-old healthy woman presented for augmentation/mastopexy. Preoperative AP view.\n\nFigure 2. Six weeks’ postoperative AP view. Implants are soft and moveable (Baker I).\n\nFive months postoperatively she had the first dose of the Pfizer vaccine and 21 days later had the second dose; both injections were placed in the left shoulder. Six days after the second dose, she noted an enlarged lymph node in her left axilla (Figure 3). Thirteen days after the second dose, she reported that her left breast was firm, swollen, and “tight” (Video, available online at www.asjopenforum.com). Soon after this, she was started on montelukast. The situation progressed until 20 days after the second dose, she was examined and seen to have a painful, distorted Baker IV capsular contracture (Figure 4). Because of the severity of her symptoms, she underwent early revisional surgery with capsulectomy and implant exchange. Intraoperatively she was found to have an intact implant and a dense fibrotic capsule containing 37 cc of a thin reddish-brown fluid but no hematoma or organized blood clot.\n\nFigure 3. Six and one-half months’ postoperative AP view/6 days after the second dose of Pfizer vaccine. Enlarged left axillary lymph node.\n\nFigure 4. Seven months’ postoperative AP view/20 days after the second dose of Pfizer vaccine. Left breast is hard and painful (Baker IV).\n\nDISCUSSION\n\nAlthough capsular contracture is typically thought of as a process that takes place over weeks to months,12 there is experimental evidence that provides a mechanism for capsular contracture evolving over only a few days, as seems to have occurred in this case. For example, tissue cultures obtained from the contracted capsules of women with silicone implants demonstrated the ability to induce a rapid upregulation of the genes for TGFβ1, interleukin 8 as well as other inflammatory and profibrotic cytokines in vitro, which in turn, were thought to be responsible for the stimulation of contracture of fibroblast-populated collagen lattices over a 48- to 120-hour period.13 Another study also using tissue media derived from the capsules of women with implants showed enhanced T-cell proliferation and increased cytokine levels as compared to peripheral blood.3 These studies further support the concept of an immunologically mediated and rapid process for capsular contracture; the cellular composition of the capsule and the surrounding tissue seems poised to respond to an immunological stimulus.\n\nIt is possible that the timing of the capsular contracture vis-à-vis the vaccine was a mere coincidence. The contracture occurred during the typical time frame for contracture (most are within the first year14), and it occurred following an operation (augmentation/mastopexy) that has a high contracture rate.15 In fact, the presence of a clearly hemorrhagic collection within the capsule raises an alternative hypothesis, that a small delayed hematoma was the cause of the contracture. There are just over 30 case reports in the literature of hematomas occurring at least 6 months following cosmetic breast augmentation.16 Many of these had instigating events, such as trauma or physical strain or a recent iatrogenic coagulopathy, and many occurred in cases with aggressively textured implants, where the separation of the implant from the adherent capsule was thought to be the reason for the bleeding. This patient had none of these possible factors in her history. She denied trauma, was not engaged in implant displacement exercises or any kind of weightlifting, and her coagulation tests and platelet counts were normal. In delayed hematomas without a discernible etiology, the so-called called spontaneous cases, several authors suggest a variety of nonspecific inflammatory conditions as possible causes.17-19 Along these lines, the inflammatory response seen in a delayed hypersensitivity reaction (as in the aforementioned post-vaccine reactions to hyaluronic acid fillers) can induce angiogenesis and increased vascular permeability within days in animal models.20 Furthermore, the complex inflammatory and angiogenesis cascades share some of the same mediators, for example, TGFβ1 and interleukin 820-22 and can be activated in concert.23 Therefore, the finding of a small amount of a bloody fluid in the capsule does not preclude an inflammatory, vaccine-induced mechanism for capsular contracture. Additionally, with the tight temporal sequence of events—the second dose of the vaccine, then lymph node enlargement, then a discernible tightening that rapidly progressed to a Baker IV contracture—it seems hard to completely exculpate the vaccination as a possible cause, by one mechanism or another.\n\nIt is also possible that the placement of the poly-4-hydroxybutyrate mesh in direct opposition to the implant contributed to the contracture, although the limited evidence that is available seems to suggest, if anything, that poly-4-hydroxybutyrate is more preventative than causative when it comes to capsular contracture.24 The ipsilaterality of the contracture to the vaccine site is also interesting; one might suspect that a systemic response to a vaccine would demonstrate no such side preference, although in this case there was an ipsilateral regional reaction with the enlarged lymph node.\n\nIt would be premature to propose any protocol based upon a single case report. The preemptive use of zafirlukast has been suggested, for augmented patients getting the vaccine who experience any tightening, on at least 1 plastic surgical practice website and this makes sense from a mechanistic point of view. However, as a blanket recommendation for all augmented patients getting the vaccine, this would seem to treat many patients unnecessarily with a drug that is not entirely benign. Furthermore, even though zafirlukast acts upon a somewhat distal part of the immunological/inflammatory cascade (suppression of myofibroblasts), any interference with the body’s immune response immediately after the vaccine might seem to be unwise and counterproductive to the entire point of the vaccine. Certainly at this point patients with implants should not avoid COVID-19 vaccination, consistent with The Aesthetic Society president’s recommendation that patients with previous hyaluronic acid fillers be vaccinated without hesitation.\n\nCONCLUSIONS\n\nThis report details the case of a woman who developed severe capsular contracture that may have been precipitated by COVID-19 vaccination. As the pace of vaccination accelerates, more capsular contracture cases may appear which may necessitate the formulation of specific treatment guidelines.\n\nDisclosures\n\nThe author declared no potential conflicts of interest with respect to the research, authorship, and publication of this article.\n\nFunding\n\nThe author received no financial support for the research, authorship, and publication of this article.\n==== Refs\nREFERENCES\n\n1. Headon H, Kasem A, Mokbel K. Capsular contracture after breast augmentation: an update for clinical practice. Arch Plast Surg. 2015;42 (5 ):532-543.26430623\n2. Wolfram D, Dolores W, Rainer C, et al. Cellular and molecular composition of fibrous capsules formed around silicone breast implants with special focus on local immune reactions. J Autoimmun. 2004;23 (1 ):81-91.15236756\n3. Wolfram D, Rabensteiner E, Grundtman C, et al. T regulatory cells and TH17 cells in peri-silicone implant capsular fibrosis. Plast Reconstr Surg. 2012;129 (2 ):327e-337e.\n4. Ajdic D, Zoghbi Y, Gerth D, Panthaki ZJ, Thaller S. The relationship of bacterial biofilms and capsular contracture in breast implants. Aesthet Surg J. 2016;36 (3 ):297-309.26843099\n5. Steiert AE, Boyce M, Sorg H. Capsular contracture by silicone breast implants: possible causes, biocompatibility, and prophylactic strategies. Med Devices (Auckl). 2013;6 :211-218.24324348\n6. Adams WP Jr, Rios JL, Smith SJ. Enhancing patient outcomes in aesthetic and reconstructive breast surgery using triple antibiotic breast irrigation: six-year prospective clinical study. Plast Reconstr Surg. 2006;117 (1 ):30-36.16404244\n7. Costagliola M, Atiyeh BS, Rampillon F. An innovative procedure for the treatment of primary and recurrent capsular contracture (CC) following breast augmentation. Aesthet Surg J. 2013;33 (7 ):1008-1017.24008234\n8. Wang Y, Tian J, Liu J. Suppressive effect of leukotriene antagonists on capsular contracture in patients who underwent breast surgery with prosthesis: a meta-analysis. Plast Reconstr Surg. 2020;145 (4 ):901-911.32221199\n9. Jeyanathan M, Afkhami S, Smaill F, Miller M, Lichty B, Xing Z. Immunological considerations for Covid-19 vaccine strategies. Nat Rev Immunol. 2020;20 (10 ):615-632.32887954\n10. Polack FP, Thomas SJ, Kitchin N, et al. ; C4591001 Clinical Trial Group. Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine. N Engl J Med. 2020;383 (27 ): 2603-2615.33301246\n11. Munavalli G, Guthridge R, Knutson-Larson S, Brodsky A, Matthew E, Landau M. Covid-19/SARS-CoV-2 virus spike protein-related delayed inflammatory reaction to hyaluronic acid dermal fillers: a challenging clinical conundrum in diagnosis and treatment. Arch Derm Res. 2021:1-15. [Epub ahead of print].32519001\n12. Jacombs A, Allan J, Hu H, et al. Prevention of biofilm-induced capsular contracture with antibiotic-impregnated mesh in a porcine model. Aesthet Surg J. 2012;32 (7 ):886-891.22942116\n13. Kyle DJT, Bayat A. Enhanced contraction of a normal breast-derived fibroblast-populated three-dimensional collagen lattice via contracted capsule fibroblast-derived paracrine factors: functional significance in capsular contracture formation. Plast Reconstr Surg. 2015;135 (5 ):1413-1429.25919257\n14. Araco A, Caruso R, Araco F, Overton J, Gravante G. Capsular contractures: a systematic review. Plast Reconstr Surg. 2009;124 (6 ):1808-1819.19952637\n15. Calobrace MB, Herdt DR, Cothron KJ. Simultaneous augmentation/mastopexy: a retrospective 5-year review of 332 consecutive cases. Plast Reconstr Surg. 2013;131 (1 ):145-156.22965238\n16. Grippaudo FR, Renzi L, Costantino B, Longo B, Santanelli F. Late unilateral hematoma after breast reconstruction with implants: case report and literature review. Aesthet Surg J. 2013;33 (6 ):830-834.23864111\n17. Daw JL, Lewis VL, Smith JW. Chronic expanding hematoma within a periprosthetic breast capsule. Plast Reconstr Surg. 1996;97 (7 ):1469-1472.8643734\n18. Iorwerth A, Cochrane R, Webster DJ. Chronic haematoma as a late complication of cosmetic breast augmentation. Breast. 2000;9 (3 ):158-160.14731841\n19. Rasko Y, Saint-Cyr M, Peng Y, Rao R. Spontaneous hematoma of the breast 30 years after augmentation. Plast Reconstr Surg. 2010;126 (1 ):41e-42e.20220555\n20. Lange-Asschenfeldt B, Weninger W, Velasco P, et al. Increased and prolonged inflammation and angiogenesis in delayed-type hypersensitivity reactions elicited in the skin of thrombospondin-2–deficient mice. Blood. 2002;99 (2 ):538-545.11781236\n21. Kang S, Sutthiwanjampa C, Heo C, Kim W, Lee S, Park H. Current approaches including novel nano/microtechniques to reduce silicone implant-induced contracture with adverse immune responses. Int J Mol Sci. 2018;19 (4 ):1171.\n22. Pepper M, Belin D, Montesano R, Orci L, Vassalli J. Transforming growth factor-beta 1 modulates basic fibroblast growth factor-induced proteolytic and angiogenic properties of endothelial cells in vitro. J Cell Biol. 1990;111 (2 ):743-755.1696269\n23. Roberts A, Sporn M, Assoian R, et al. Transforming growth factor type β: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc Nat Acad Sci USA. 1986;83 (12 ):4167-4171.2424019\n24. Nair NM, Mills DC. Poly-4-hydroxybutyrate (P4HB) scaffold internal support: preliminary experience with direct implant opposition during complex breast revisions. Aesthet Surg J. 2019;39 (11 ):1203-1213.30321265\n\n",
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"title": "A Case Report of Capsular Contracture Immediately Following COVID-19 Vaccination.",
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"abstract": "We report the case of a 32-year-old man with a caecal adenocarcinoma with major lymph node extension and peritoneal carcinomatosis, presenting a BRAF-K601E mutation. A triplet (5FU plus oxaliplatin plus irinotecan) combination with bevacizumab achieved tumor control but the disease progressed immediately after cessation and the patient died 8 months after the diagnosis. A short review of BRAF non-V600E mutations shows that outcome and clinical features depend on the mutation.",
"affiliations": "Department of Medical Oncology, Institut de Cancérologie de l'Ouest, Saint-Herblain, France.;Department of Medical Oncology, Institut de Cancérologie de l'Ouest, Saint-Herblain, France.;Department of Medical Oncology, Institut de Cancérologie de l'Ouest, Saint-Herblain, France.;Department of Biology, Institut de Cancérologie de l'Ouest, Angers, France.;Department of Biology, Institut de Cancérologie de l'Ouest, Angers, France.;Department of Medical Oncology, Institut de Cancérologie de l'Ouest, Saint-Herblain, France.;Department of Medical Oncology, Institut de Cancérologie de l'Ouest, Saint-Herblain, France.",
"authors": "Moisset|Laure|L|;Raimbourg|Judith|J|;Hiret|Sandrine|S|;Dauve|Jonathan|J|;Boisdron-Celle|Michèle|M|;Senellart|Hélène|H|;Raoul|Jean-Luc|JL|",
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"fulltext": "\n==== Front\nCase Rep OncolCase Rep OncolCROCase Reports in Oncology1662-6575S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH-4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000500857cro-0012-0426Case ReportBRAF Non-V600E Mutated Metastatic Colorectal Cancer in a Young Patient: Discussion from a Case Report Moisset Laure aRaimbourg Judith aHiret Sandrine aDauve Jonathan bBoisdron-Celle Michèle bSenellart Hélène aRaoul Jean-Luc a*aDepartment of Medical Oncology, Institut de Cancérologie de l'Ouest, Saint-Herblain, FrancebDepartment of Biology, Institut de Cancérologie de l'Ouest, Angers, France*Prof. Jean-Luc Raoul, Department of Medical Oncology, Institut de Cancérologie de l'Ouest, FR-44805 Saint-Herblain (France), E-Mail jean-luc.raoul@ico.unicancer.frMay-Aug 2019 5 6 2019 5 6 2019 12 2 426 429 2 5 2019 6 5 2019 2019 Copyright © 2019 by S. Karger AG, Basel2019This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.We report the case of a 32-year-old man with a caecal adenocarcinoma with major lymph node extension and peritoneal carcinomatosis, presenting a BRAF-K601E mutation. A triplet (5FU plus oxaliplatin plus irinotecan) combination with bevacizumab achieved tumor control but the disease progressed immediately after cessation and the patient died 8 months after the diagnosis. A short review of BRAF non-V600E mutations shows that outcome and clinical features depend on the mutation.\n\nKeywords\nMetastatic colorectal cancerBRAF mutationPrognosisMolecular characterization\n==== Body\nIntroduction\nMetastatic colorectal cancer (mCRC) is common and 25% of patients present with metastases at diagnosis. Over the last two decades the prognosis of metastatic cases has improved and is more than double that of 20 years ago. This is related to new and efficient systemic therapies and to biomarker-based selection, particularly RAS and BRAF testing [1]. RAS mutational status is predictive of efficacy of anti-EGFR monoclonal antibodies. BRAF mutations [2], found in 8 to 12% of patients with mCRC, are considered as a negative prognostic marker with a median overall survival (mOS) for patients with BRAF-mutant (BRAF-mt) mCRC which is far shorter (less than 12 months) than for patients with BRAF-wild type (BRAF-wt) mCRC (more than 30 months) [1]. This is related to activation of the MEK-ERK pathway stimulating cell proliferation and survival. BRAF mutations are very frequent in melanoma (>50% of the cases) and have led to the development of specific therapies. Many BRAF-mt alleles have been found but the most common is BRAF-mt V600E. The clinical and prognostic significance of BRAF-mt non-V600E mutations is not well known but this is evolving.\n\nCase Presentation\nHere we report the case of a 32-year-old man who died from a BRAF-mt K601E tumor. This patient, with no familial or personal history (apart from obesity, BMI = 37 kg/m2), had a cholecystectomy in March 2018 due to right upper quadrant pain and vomiting with enlarged gallbladder on US exam. Nothing was noted during laparoscopic cholecystectomy but pain persisted. Several weeks later a CT scan revealed multiple enlarged retroperitoneal and mediastinal lymph nodes with a right colon mass and regional adenomegalies. Biopsy of a supraclavicular node revealed a poorly differentiated adenocarcinoma; colonoscopy disclosed a large caecal tumor, tumor markers (CEA and CA 19–9) were normal. In May 2018 the patient underwent surgery (right colectomy) because of a subocclusion. A peritoneal carcinomatosis was found. Pathological exam of the right colectomy revealed a large (11 cm) caecal tumor which histologically corresponded to a poorly differentiated adenocarcinoma invading the serosa with a colloid component of 10%; 34 of the 35 resected lymph nodes were invaded. The tumor was classified pT4aN2b with nodal and peritoneal metastases. The tumor was MMR proficient, with no mutation of RAS, but a BRAF mutation on codon 601 (nucleotide substitution c.1801 A>G; BRAF-mt K601E) was identified; this mutation was considered as activating. Following the usual guidelines, a first-line chemotherapy combining 5FU, folinic acid, irinotecan and oxaliplatin associated with bevacizumab [3] was introduced. After 6 cycles the general status improved and pain disappeared, but CT scan showed only a 10% decrease in tumor size. Therefore, the same regimen was proposed for 6 other cycles. After 9 cycles the patient presented mild neuropathy and oxaliplatin was stopped. A few days later a pulmonary embolism led to withdrawal of bevacizumab. In mid-December, after 12 cycles, the patient reported no pain. He was tired (PS 1), but physical examination was normal. The CT scan images remained stable. It was decided to give him time off from chemotherapy during the 2 last weeks of December but when he came back in early January, pain had recurred and his performance status had worsened to PS 2. Despite medical palliative care, PS worsened and the patient died in mid-February, 8 months after colonic surgery. He never developed liver or lung metastases.\n\nDiscussion\nIn melanoma, BRAF-mt K601E mutations were observed in 1–5% of cases [4] and their prognosis does not seem unusual. The incidence of BRAF-mt non-V600E mutations reported in different series of mCRC patients ranges from 1.6% [5] to 5.4% [6]. A large retrospective cohort (nearly 10,000 mCRC patients) from three US reference laboratories focused on BRAF-mt non-V600E mutations in mCRC [7]. These mutations represented 22% of all BRAF-mt and were observed in 2.2% of all patients. When compared with BRAF-mt V600E, these non-V600E mutations were found in younger patients, more frequently females, with fewer high grade and right-sided tumors and less frequent peritoneal carcinomatosis. These patients with BRAF-mt non-V600E mutations were less likely to have MSI (6% vs. 30%). Surprisingly, their mOS (analyzed in a subgroup) was significantly longer; in this large series, mOS of BRAF wt (n = 249) was 43.0 months, versus 11.4 months for BRAF-mt V600E (n = 99) and 60.7 months for BRAF-mt non-V600E (n = 101)! Among their series of 208 patients with BRAF-mt non-V600E, the codon mutation distribution showed that 93 mutations were on codon 594, 29 on 469, 23 on 466 and 16 on 601 [8]. In melanoma, mutations in codons 594 and 596 were associated with a better prognosis than V600E mutations [9]. A small series of 7 BRAF-mt non-V600E mCRC was reported but their phenotype and prognosis seemed close to that observed in BRAF-mt V600E [10]. Cremolini et al. reported 10 cases of BRAF-mt on codons 594 and 596 and found that their prognosis was better and that these cancers were left-sided [5].\n\nBRAF mutations are currently grouped into 3 classes: activating RAS-independent signaling as monomer (class 1: V600E) or as dimers (class 2: codon 597/601), and RAS-dependent with impaired kinase activity (class 3: codons 594/596) [11]. In this series, class 3 BRAF-mutated mCRC were more frequently left-sided, with no peritoneal deposits and had a better prognosis, close to BRAF-wt mCRC. This aggressive phenotype of BRAF-mt non-V600E was observed in our patient. In the database of our genetic laboratory we found 2 other cases of mCRC BRAF-mt K601E; both cases occurred in elderly women and both had peritoneal carcinomatosis of a right-sided colon cancer and survived less than 8 months.\n\nConclusion\nIn conclusion, this case of a young patient with mCRC harboring a BRAF-mt K601E mutation is of interest. The tumor did not respond to the usual triplet combination plus bevacizumab used in such cases and the patient died within a few months without any liver or lung metastases but only lymph node invasion and peritoneal carcinomatosis. BRAF-mt non-V600E mutations are detected by NGS-based testing and are not so uncommon. Moreover, we have to know that these mutations are diverse and that some are associated with a less aggressive phenotype and a better prognosis; then it is of paramount importance not to consider all these patients as “usual BRAF-mt patients” and to adapt treatment strategy to the molecular characterization.\n\nStatement of Ethics\nThe authors have no ethical conflicts to declare.\n\nDisclosure Statement\nThe authors have no conflicts of interest to declare.\n==== Refs\nReferences\n1 Van Cutsem E Cervantes A Adam R Sobrero A Van Krieken JH Aderka D ESMO consensus guidelines for the management of patients with metastatic colorectal cancer Ann Oncol 2016 8 27 (8) 1386 422 27380959 \n2 Sanz-Garcia E Argiles G Elez E Tabernero J BRAF mutant colorectal cancer: prognosis, treatment, and new perspectives Ann Oncol 2017 11 28 (11) 2648 57 29045527 \n3 Cremolini C Loupakis F Antoniotti C Lupi C Sensi E Lonardi S FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study Lancet Oncol 2015 10 16 (13) 1306 15 26338525 \n4 Marconcini R Galli L Antonuzzo A Bursi S Roncella C Fontanini G Metastatic BRAF K601E-mutated melanoma reaches complete response to MEK inhibitor trametinib administered for over 36 months Exp Hematol Oncol 2017 3 6 (1) 6 28344857 \n5 Cremolini C Di Bartolomeo M Amatu A Antoniotti C Moretto R Berenato R BRAF codons 594 and 596 mutations identify a new molecular subtype of metastatic colorectal cancer at favorable prognosis Ann Oncol 2015 10 26 (10) 2092 7 26153495 \n6 Shimada Y Tajima Y Nagahashi M Ichikawa H Oyanagi H Okuda S Clinical Significance of BRAF Non-V600E Mutations in Colorectal Cancer: A Retrospective Study of Two Institutions J Surg Res 2018 12 232 72 81 30463788 \n7 Jones JC Renfro LA Al-Shamsi HO Schrock AB Rankin A Zhang BY Non-V600 BRAF Mutations Define a Clinically Distinct Molecular Subtype of Metastatic Colorectal Cancer J Clin Oncol 2017 8 35 (23) 2624 30 28486044 \n8 Wan PT Garnett MJ Roe SM Lee S Niculescu-Duvaz D Good VM Cancer Genome Project Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF Cell 2004 3 116 (6) 855 67 15035987 \n9 Wu X Yan J Dai J Ma M Tang H Yu J Mutations in BRAF codons 594 and 596 predict good prognosis in melanoma Oncol Lett 2017 9 14 (3) 3601 5 28927118 \n10 Shinozaki E Yoshino T Yamazaki K Muro K Yamaguchi K Nishina T Clinical significance of BRAF non-V600E mutations on the therapeutic effects of anti-EGFR monoclonal antibody treatment in patients with pretreated metastatic colorectal cancer: the Biomarker Research for anti-EGFR monoclonal Antibodies by Comprehensive Cancer genomics (BREAC) study Br J Cancer 2017 11 117 (10) 1450 8 28972961 \n11 Schirripa M Biason P Lonardi S Pella N Pino MS Urbano F Class 1, 2 and 3 BRAF mutated metastatic colorectal cancer: a detailed clinical, pathological and molecular characterization Clin Cancer Res 2019 4 clincanres.0311.2019\n\n",
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"issue": "12(2)",
"journal": "Case reports in oncology",
"keywords": "BRAF mutation; Metastatic colorectal cancer; Molecular characterization; Prognosis",
"medline_ta": "Case Rep Oncol",
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"title": "BRAF Non-V600E Mutated Metastatic Colorectal Cancer in a Young Patient: Discussion from a Case Report.",
"title_normalized": "braf non v600e mutated metastatic colorectal cancer in a young patient discussion from a case report"
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"abstract": "We report a case of a 49-year-old woman who presented with acutely worsening episodic abdominal pain. Workup was negative but CT of the abdomen showed right upper quadrant omental fat stranding, suggestive of fat necrosis or infarct. Treatment for the patient was largely supportive with pain management and fluid resuscitation.",
"affiliations": "Family Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.;Family Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.;Family Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.;Family Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.",
"authors": "McMillen|Brock|B|;Hekman|Daniel Paul|DP|;Nguyen|Michelle Thuy Tien|MTT|;Grewal|Dennis|D|",
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"keywords": "emergency medicine; gastroenterology; general practice / family medicine",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D015746:Abdominal Pain; D005218:Fat Necrosis; D005260:Female; D006801:Humans; D007238:Infarction; D008875:Middle Aged; D009852:Omentum; D010532:Peritoneal Diseases",
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"pubdate": "2019-03-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Idiopathic omental infarction: managed conservatively.",
"title_normalized": "idiopathic omental infarction managed conservatively"
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"abstract": "Revesz syndrome (RS) is an extremely rare variant of dyskeratosis congenita (DKC) with only anecdotal reports in the literature.\n\n\n\nTo further characterize the typical features and natural course of the disease, we screened the English literature and summarized the clinical and epidemiological features of previously published RS cases. In addition, we herein describe the first recorded patient in central Europe.\n\n\n\nThe literature review included 18 children. Clinical features are summarized, indicating a low prevalence of the classical DKC triad. All patients experienced early bone marrow failure, in most cases within the second year of life (median age 1.5 years; 95% CI 1.4-1.6). Retinopathy occurred typically between 6 and 18 months of age (median age 1.1 years; 95% CI 0.7-1.5). The incidence of seizures was low and was present in an estimated 20% of patients. The onset of seizures was exclusively during early childhood. The Kaplan-Meier estimate of survival was dismal (median survival 6.5 years; 95% CI 3.6-9.4), and none of the patients survived beyond the age of 12 years. Stem cell transplantation (SCT) was performed in eight children, and after a median of 22 months from SCT four of these patients were alive at the last follow up visit.\n\n\n\nRS is a severe variant of DKC with early bone marrow failure and retinopathy in all patients. Survival is dismal, but stem cell transplantation may be performed successfully and might improve prognosis in the future.",
"affiliations": "Department of Pediatrics, University Medical Center Mannheim, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany. michael.karremann@umm.de.;Department of Neuroradiology, University Medical Center Mannheim, Mannheim, Germany.;Department of Ophthalmology, University Medical Center Mannheim, Mannheim, Germany.;Department of Hematology and Oncology, University Hospital of RWTH Aachen, Aachen, Germany.;Department of Hematology and Oncology, University Hospital of RWTH Aachen, Aachen, Germany.;SYNLAB Center for Human Genetics Mannheim, Mannheim, Germany.;Department of Pediatrics, Pediatric Stem Cell Transplantation, University Hospital Frankfurt, Frankfurt, Germany.;Department of Pediatrics, University Medical Center Mannheim, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.",
"authors": "Karremann|Michael|M|0000-0002-9961-4752;Neumaier-Probst|Eva|E|;Schlichtenbrede|Frank|F|;Beier|Fabian|F|;Brümmendorf|Tim H|TH|;Cremer|Friedrich W|FW|;Bader|Peter|P|;Dürken|Matthias|M|",
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"fulltext": "\n==== Front\nOrphanet J Rare Dis\nOrphanet J Rare Dis\nOrphanet Journal of Rare Diseases\n1750-1172 BioMed Central London \n\n1553\n10.1186/s13023-020-01553-y\nReview\nRevesz syndrome revisited\nhttp://orcid.org/0000-0002-9961-4752Karremann Michael michael.karremann@umm.de 1 Neumaier-Probst Eva 2 Schlichtenbrede Frank 3 Beier Fabian 4 Brümmendorf Tim H. 4 Cremer Friedrich W. 5 Bader Peter 6 Dürken Matthias 1 1 grid.411778.c0000 0001 2162 1728Department of Pediatrics, University Medical Center Mannheim, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany \n2 grid.411778.c0000 0001 2162 1728Department of Neuroradiology, University Medical Center Mannheim, Mannheim, Germany \n3 grid.411778.c0000 0001 2162 1728Department of Ophthalmology, University Medical Center Mannheim, Mannheim, Germany \n4 grid.412301.50000 0000 8653 1507Department of Hematology and Oncology, University Hospital of RWTH Aachen, Aachen, Germany \n5 SYNLAB Center for Human Genetics Mannheim, Mannheim, Germany \n6 grid.411088.40000 0004 0578 8220Department of Pediatrics, Pediatric Stem Cell Transplantation, University Hospital Frankfurt, Frankfurt, Germany \n23 10 2020 \n23 10 2020 \n2020 \n15 29925 5 2020 22 9 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\nRevesz syndrome (RS) is an extremely rare variant of dyskeratosis congenita (DKC) with only anecdotal reports in the literature.\n\nMethods\nTo further characterize the typical features and natural course of the disease, we screened the English literature and summarized the clinical and epidemiological features of previously published RS cases. In addition, we herein describe the first recorded patient in central Europe.\n\nResults\nThe literature review included 18 children. Clinical features are summarized, indicating a low prevalence of the classical DKC triad. All patients experienced early bone marrow failure, in most cases within the second year of life (median age 1.5 years; 95% CI 1.4–1.6). Retinopathy occurred typically between 6 and 18 months of age (median age 1.1 years; 95% CI 0.7–1.5). The incidence of seizures was low and was present in an estimated 20% of patients. The onset of seizures was exclusively during early childhood. The Kaplan–Meier estimate of survival was dismal (median survival 6.5 years; 95% CI 3.6–9.4), and none of the patients survived beyond the age of 12 years. Stem cell transplantation (SCT) was performed in eight children, and after a median of 22 months from SCT four of these patients were alive at the last follow up visit.\n\nConclusion\nRS is a severe variant of DKC with early bone marrow failure and retinopathy in all patients. Survival is dismal, but stem cell transplantation may be performed successfully and might improve prognosis in the future.\n\nKeywords\nBone marrow failureCerebellar hypoplasiaExudative retinopathyGrowth retardationPancytopeniaRevesz syndromeShelterinTelomereTINF2Projekt DEALOpen Access funding enabled and organized by Projekt DEAL.\n\nissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nDyskeratosis congenita (DKC) is a multisystem disorder classically defined by a triad of clinical symptoms including oral leukoplakia, hyperpigmented reticular skin lesions, and nail dystrophy, but the clinical features are highly variable [1, 2]. Individuals are prone to develop bone marrow failure, malignancies, immunodeficiency, and pulmonary complications. Less common features include dental and eye abnormalities, esophageal stenosis, urethral stenosis, avascular necrosis of the femur and/or humerus, osteopenia, enteropathy, and liver disease [3]. Within this wide spectrum of clinical phenotypes, some rare entities represent distinct variants of DKC, namely Høyeraal-Hreidarsson syndrome (HHS, OMIM #305000) and Revesz syndrome (RS; OMIM #268130) [4]. Cerebroretinal microangiopathy with calcifications and cysts (CRMCC; formerly Coats plus syndrome, OMIM #612199) is another disorder of telomere maintenance, with distinct overlap to RS in clinical presentation [5].\n\nHøyeraal-Hreidarsson syndrome is a severe variant of DKC [6]. Patients typically harbor intrauterine growth retardation, microcephaly, and cerebellar hypoplasia. The further course of disease is characterized by developmental delay, and early, progressive bone marrow failure, with the latter leading to death during childhood [7, 8]. First described in 1988 by Tolmie et al. [9, 10], extensive intracranial calcifications, leukodystrophy, and bilateral exudative retinopathy characterize CRMCC. Other features, including bone marrow failure during adolescence and early adulthood, increased risk of intestinal bleeding and bony lesions have been described [11–14], and may help to clinically discriminate CRMCC from RS [15]. The latter entity was first described in 1992 [16], and is characterized by early bone marrow failure and bilateral exudative retinopathy. It features skin, hair, and nail abnormalities, intracerebral calcifications, cerebellar hypoplasia, and ataxia. In addition, children may be born small for gestational age and exhibit developmental delay. Death usually occurs during early childhood [17–20].\n\nAll variants of DKC share dysfunctional telomere maintenance, resulting in a reduced protection from cellular senescence and accelerated exhaustion of (in particular) high turnover tissues, genetic instability, and increased frequency of secondary malignancy. To date, a minimum of 11 genes of the DKC complex have been shown to harbor mutations accounting for the different subtypes of DKC. However, the association of genotype and phenotype is highly variable. While patients with classical DKC harbor mutations in ACD, CTC1, DKC1, NHP2, NOP10, PARN, RTEL1, TERC, TERT, TINF2, and WRAP53 [4], several of these mutations may also underlay the more severe HHS [6, 21]. In contrast, CRMCC and RS are linked to mutations in distinct genes, namely the CST telomere replication complex component 1 (CTC1), and in the TRF1-interacting nuclear factor-2 (TINF2), respectively [22, 23].\n\nIn RS, mutations in TINF2 at chromosome 14q11.2 result in dysfunctional TIN2 protein leading to impaired telomere protection by the shelterin complex [24]. Patients harbor extremely short telomeres, even compared to patients with classical DKC [3, 20]. Mutations in additional genes reported in DKC patients affecting the telomerase complex have not been associated with RS. Nevertheless, the same mutations in TINF2 may be found in classical DKC patients presenting clinically without the distinct RS phenotype, hence, the genotype alone is not able to define RS [20, 25, 26]. Discriminating RS from other variants solely by clinical criteria may also be challenging. Furthermore, the clinical features vary significantly in individual patients, and overlap of RS with other DKC variants [27, 28] or alternate disease entities, such as Fanconi anemia or others, is common [29–32]. In addition, accelerated telomere shortening can also be observed in non-hereditary clonal and non-clonal disorders affecting individual (mostly the hematopoietic) stem cell compartments [33].\n\nTo the best of our knowledge, no more than 17 patients with RS, together with sufficient clinical data, have been published in the English literature to date [3, 16–20, 23, 34–42]. Reviewing these cases and reporting the first patient in central Europe, the present work aimed to further characterize this rare entity.\n\nPatients and methods\nMutational and telomere length analysis\nThe average length of telomere repeats in peripheral blood lymphocytes and granulocytes of the patient (at the age of 15 months), as well as her parents and siblings, was determined by flow-FISH as previously described [43]. Molecular analysis included screening for genetic alterations within exon six of the TINF2 gene.\n\nLiterature search\nTo identify previously published patients with RS, an electronic PubMed search of the English literature was performed using the terms “bone marrow failure”, “aplastic anemia”, and “pancytopenia”, each in combination with “retinopathy”. In addition, PubMed was searched for “Revesz syndrome”, and “TINF2”. Further case reports were included, if referred to in the relevant literature. In case of insufficient clinical information within the publications, the respective corresponding authors were contacted and requested to provide missing data. Individuals who provided further information are mentioned in the acknowledgement section.\n\nStatistical analyses\nStatistical analysis was performed using IBM SPSS Statistics® version 25 (IBM, Armonk, NY, USA). Survival, as well as the time-dependent cumulative risk to develop bone marrow failure, retinopathy, and seizures, was estimated by Kaplan–Meier analysis. Patients were censored in case of death, and at the age of the last reported visit. All patients were defined regarding gender (male/female), and potential features of RS (present/absent/unknown). A chi2-test was applied to compare the sex of patients to an equal gender distribution. Due to the small number of patients, the retrospective character of the study, and a potential bias since the underlying case reports might not be representative, the prevalence of these features was discussed cautiously. Statistical numbers are intended to be “hypotheses generating”. Details are given in Table 1.Table 1 Summary of clinical findings and outcome in 18 patients with RS\n\n\tRatio ± or m/f (number of patients with information)\tDuprey and Steger [35]\tRevesz et al. [16]\tKajtar and Mehes [36]\tRiyaz et al. [39]\tScheinfeld et al. [23]\tNegron et al. [38]\tSavage and Bertuch [3]\tSasa et al. [20]\tAsai et al. [34]\tMcElnea et al. [37]\tTamura et al. [40]#\tGupta et al. [17]\tGupta et al. [17]\tMoussa et al. [18]\tTomcikova et al. [41] #\tWatanabe et al. [42]\tSakwit et al. [19]\tThis report\t\nPatient number\t\t1\t2\t3\t4\t5\t6\t7\t8\t9\t10\t11\t12\t13\t14\t15\t16\t17\t18\t\nGender (m/f)\t11/7 (18)\tf\tm\tf\tf\tm\tm\tm\tm\tm\tm\tm\tf\tf\tm\tm\tf\tm\tf\t\nMedical history\t\nPreterm\t4/12 (16)\t–\t–\t–\t–\t–\t–\t?\t–\t–\t+ \t–\t+ \t+ \t?\t–\t?\t?\t+ \t\nSmall for gestational age\t9/6 (15)\t+ \t+ \t+ \t+ \t–\t+ \t?\t–\t+ \t–\t+ \t–\t–\t?\t+ \t+ \t?\t–\t\nFailure to thrive\t6/4 (10)\t+ \t–\t–\t+ \t–\t–\t?\t+ \t?\t?\t?\t?\t?\t?\t?\t+ \t+ \t+ \t\nNeurologic findings\t\nMicrocephaly\t6/5 (11)\t+ \t–\t+ \t+ \t–\t–\t?\t+ \t?\t?\t–\t?\t?\t?\t–\t+ \t?\t+ \t\nCerebellar hypoplasia\t13/4 (17)\t–\t+ \t+ \t?\t+ \t–\t+ \t+ \t–\t+ \t+ \t+ \t+ \t+ \t–\t+ \t+ \t+ \t\nCerebral calcifications\t11/2 (13)\t+ \t+ \t–\t?\t+ \t+ \t?\t?\t+ \t?\t–\t+ \t+ \t+ \t+ \t?\t+ \t+ \t\nAtaxia\t4/5 (9)\t–\t+ \t–\t?\t–\t–\t?\t+ \t?\t?\t+ \t?\t?\t?\t–\t?\t?\t+ \t\nSeizures\t3/14 (17)\t+ \t–\t–\t–\t–\t–\t?\t–\t–\t–\t–\t–\t–\t–\t–\t–\t+ \t+ \t\nNeurodevelopmental delay\t12/5 (17)\t+ \t+ \t–\t+ \t+ \t–\t+ \t+ \t–\t+ \t+ \t–\t–\t+ \t+ \t?\t+ \t+ \t\nOphthalmologic findings\t\nExudative retinopathy\t18/0 (18)\t+ \t+ \t+ \t+ \t+ \t+ \t+ \t+ \t+ \t+ \t+ \t+ \t+ \t+ \t+ \t+ \t+ \t+ \t\nGlaucoma\t3/11 (14)\t–\t–\t+ \t–\t–\t+ \t?\t–\t–\t–\t?\t–\t–\t–\t+ \t?\t–\t?\t\nBone marrow failure\t18/0 (18)\t+ \t+ \t+ \t+ \t+ \t+ \t+ \t+ \t+ \t+ \t+ \t+ \t+ \t+ \t+ \t+ \t+ \t+ \t\nDermatologic findings\t\nIrregular nails\t13/2 (15)\t+ \t–\t+ \t+ \t+ \t–\t+ \t+ \t+ \t+ \t+ \t?\t?\t+ \t+ \t?\t+ \t+ \t\nSkin findings\t6/5 (11)\t+ \t+ \t–\t+ \t–\t–\t+ \t?\t–\t?\t+ \t?\t?\t?\t+ \t?\t?\t–\t\nLeukoplakia\t6/8 (14)\t–\t–\t+ \t+ \t–\t–\t+ \t+ \t–\t–\t–\t?\t?\t?\t–\t?\t+ \t+ \t\nFine, sparse hair\t4/4 (8)\t–\t+ \t+ \t+ \t–\t?\t?\t?\t?\t?\t–\t?\t?\t?\t–\t?\t?\t+ \t\nTherapy and outcome\t\nStem cell transplantation\t8/12 (18)\tNo\tNo\tYes\tNo\tNo\tNo\tYes\tYes\tYes\tNo\tYes\tNo\tNo\tYes\tNo\tYes\tNo\tYes\t\nLast follow up (age/years)\t–\t4\t1.6\t3.5\t6\t5\t12\t6.8\t2.0\t3.5\t1.2\t6.5\t1.5\t1.5\t3.3\t7\t3.4\t2.7\t4.2\t\nAlive\t10/6 (18)\tYes\tNo\tYes\tNo\tYes\tNo\tNo\tNo\tYes\tYes\tNo\tYes\tYes\tYes\tYes\tYes\tNo\tNo\t\nGenetic TINF2 alteration\t12/0 (12)\t?\t?\t?\t?\t?\t?\tp.R282H\tp.K280RfsX36\tp.R282H\tp.R282H\tp.R282H\tp.T284P\tp.T284P\tp.R282H\tp.P289S\tp.R282H\tp.T284Nfsx6\tp.R282H\t\n+ prevalent, – absent, ? not determined, # additional information was provided by personal communication\n\n\n\nResults\nCase report\nThe female infant was delivered preterm after 33 gestational weeks (birth weight 1360 g, P10) as the 4th child of non-consanguineous parents with Caucasian descent. Apart from a mild oligohydramnios and suspected growth retardation, pregnancy was uneventful. Delivery and postnatal course were without complication and, in particular, no respiratory support was required.\n\nAt the age of 2½ months, the girl experienced her first partial seizure following vaccination. MRI imaging revealed cerebellar hypoplasia and periventricular white matter changes, at this time attributed to prenatal hypoxemia (Fig. 1). Due to recurrent seizures, an anticonvulsive treatment with levetiracetam and topiramate was initiated. Pancytopenia was first seen at the age of 9 months, during an episode of bronchitis (leukocytes 2600/µL, hemoglobin 8.7 g/dL, thrombocytes 15,000/µL). Over the next few months, the blood count continued to worsen to very severe neutropenia (absolute neutrophil count < 200/µL), resulting in platelet transfusions twice weekly and erythrocyte transfusions every other week. Diagnostic workup showed bone marrow aplasia without signs of myelodysplasia or cytogenetic abnormalities. Metabolic diseases and infections, as well as Fanconi anemia and paroxysmal nocturnal hemoglobinuria, were ruled out as the underlying pathology for the observed bone marrow failure.Fig. 1 Initial MRI at the age of 2.5 months performed after the first partial seizure. Sagittal T1-weighted MRI image demonstrates cerebellar hypoplasia with an emphasis on the vermis and tonsils (arrow) and consecutive enlargement of the cerebrospinal fluid (CSF) spaces. The corpus callosum has a normal shape and size (thick arrow) (a). Transversal T1-weighted MRI image shows normal myelination within the internal capsule concealing the punctuate high signal (b) corresponding to the low signal areas in the T2-weighted (c) and T2*-weighted images within the thalami (d). These areas of signal abnormality correspond to calcifications. Also note the abnormal signal intensity in the frontal lobes (b, c) corresponding to leukencephalopathic areas also seen in the follow ups. At this point there was no administration of gadolinium contrast material\n\n\n\nSoon after birth, an exudative retinopathy had been diagnosed and treated with repeated intraocular Bevacizumab injections. Furthermore, the patient exhibited a mild psychomotor developmental delay and a failure to thrive, e. g. body weight of 5 kg (< P3), length of 62 cm (< P3), and head circumference of 40 cm (< P3) at the age of 10 months. In contrast to her siblings, she had fine, sparse hair, but normal skin and nails (nail dystrophy developed by the age of 4 years). A second MRI of the brain at the age of 1 year confirmed cerebellar hypoplasia, but also revealed multiple demyelinating areas, both in the periventricular and subcortical white matter, in part with calcifications (Fig. 2 and Additional file 1: Figure 1). In addition, a distinct hypoplasia of the corpus callosum developed, most likely due to increasing leukoencephalopathy (Additional file 2: Figure 2).Fig. 2 Axial T2-weighted images demonstrate progression of symmetric white matter lesions periventricular, within the thalamus, in the internal capsule, and the basal ganglia at the age of 1 year (a), 2 years (b), and 3.8 years (c). The corresponding axial susceptibility-weighted images (SWI) demonstrated progressive foci with susceptibility artefacts distributed symmetrically within the basal ganglia, the thalami, and on the border between gray and white matter (d, e), corresponding to calcifications. At the age of 2 years the patient suffered from a hemorrhage at the level of the left temporal horn with intraventricular breakthrough, shown as an area of high intensity (arrow) on the T1-weighted image (f), and hydrocephalic congestion (b, f), resulting in the need for ventricular-peritoneal shunt insertion. The artefact on the right side is due to the implanted shunt (c)\n\n\n\nThe diagnosis of RS was finally suspected based on of the clinical signs and MRI findings. This was confirmed by telomere length analysis, which revealed extremely short telomeres of 2.47 kilobases (kb) in peripheral blood lymphocytes and 2.48 kb in peripheral blood granulocytes, both substantially below the first percentile of healthy controls. Both parents and three siblings exhibited telomere lengths within the normal range (Fig. 3). Mutation analysis detected a genetic alteration in exon six of TINF2 with a previously published base change c.845G > A, leading to the amino acid change Arg282His.Fig. 3 Telomere length analysis of the patient (red), her siblings (yellow), and parents (blue) demonstrates the shortening in the patient’s a lymphocytes and b granulocytes, substantially below the first percentile of age. In contrast, the results of her parents and siblings were within normal limits. c Pedigree. Circle indicates female, square indicates male gender\n\n\n\nThe child underwent allogeneic bone marrow transplantation (SCT) from a healthy HLA-identical sibling at the age of 17 months. The conditioning regimen included fludarabine (30 mg/m2 day − 7 to − 3), cyclophosphamide (30 mg/kg day − 6 to − 3), and anti-thymocyte globulin (20 mg/kg day − 4 to − 2). Apart from an invasive aspergillosis of the lungs and a mild acute graft-versus-host disease, no serious complications occurred. Hematological engraftment was achieved after day + 11, and day + 55 for granulocytes and thrombocytes, respectively. The girl exhibited an early T-cell expansion with > 500 CD3 + cells/mL at day + 60. A reactivation of Adenovirus detected by PCR at day + 70 resolved spontaneously. Aspergillus infection was treated with intravenous liposomal amphotericin B and caspofungin, followed by an oral treatment with voriconcazole until 10 months from SCT, resulting in residual lesions in both upper pulmonary lobes. Further mild and non-persisting complications within the first year from SCT included Epstein-Barr virus reactivation (treated by one single infusion of rituximab), and persisting mild thrombocytopenia, most likely attributed to anticonvulsive treatment.\n\nDuring the second year after SCT, the girl experienced progressive abdominal pain crises resulting predominantly in malnutrition and further failure to thrive. The cause of these could not be clarified, but graft versus host disease of the gut was ruled out. In addition, a spontaneous intraventricular hemorrhage occurred at the age of 2 years, finally resulting in hydrocephalus and a need for ventricular-peritoneal shunting (Fig. 2f). At this time, blood count and hemostaseologic parameters were within normal limits. Therefore, we propose that this bleeding event was most likely due to an increased intracerebral pressure during extensive crying, and perhaps fostered by an increased fragility of the intracerebral vessels.\n\nDuring the girl’s 3rd and 4th year of life, psychomotor delay remained despite extensive training. Visual acuity worsened, resulting in a nearly complete loss of vision at the age of 3 years (corresponding retinal detachment shown in Additional file 3: Figure 3). Also, somatic development was seriously delayed. At the age of 4 years, the patient experienced severe aspiration pneumonia, and finally passed away due to refractory lung failure.\n\nLiterature search\nIn addition to the patient reported in this work, a literature search revealed 22 cases of RS. Five patients were excluded, since only very limited clinical data were available. Additional information concerning missing clinical data within the references was provided by the respective authors of the case reports on request for patient #11 and #15. Patient #1, with features of RS published in 1988, was included, even though this was published prior to the characterization and definition of Revesz. Thus, 17 patients from the literature were eligible for evaluation.\n\nPatients characteristics\nIn total, this study reviewed 18 cases of RS (Table 1); seven females and 11 males, resulting in a male predominance of 1.6:1 (not significant). Of note, stigmata belonging to the classical clinical DKC triad of oral leukoplakia, hyperpigmented skin findings, and nail dystrophy were prevalent in only 43% (n = 6/14), 55% (n = 6/11), and 87% (n = 13/15) of patients with information, respectively. In contrast to classical DKC, all cases of RS represented de novo mutations with unaffected parents, reflecting the severe course and early death in this disease.\n\nThe very severe prognosis of RS could be substantiated in the present work. Kaplan–Meier analysis estimated a median survival of only 6.5 years (95% CI 3.6–9.4), and no patient beyond the age of 12 years was identified in the literature (Fig. 4). Patients died from BMF in most cases, but refractory lung failure was another cause of death in some cases. Bone marrow failure occurred in all patients between birth and the age of 6 years, in most cases within the second year of life (median age 1.5 years; 95% CI 1.4–1.6, Fig. 5a). BMF lead to stem cell transplantation in eight patients, four of whom were still alive at the end of follow up 1 month (#3), 20 months (#9), and 2 years (#14 and #16) from SCT. Details on the conditioning regimen were specified in four patients; all underwent a reduced conditioning regimen, including fludarabine (100–180 mg/m2), cyclophosphamide (100–120 mg/kg), and anti-thymocyte globulin. Patients with this regimen tolerated SCT well without severe early transplantation-related toxicity. All patients developed retinopathy, most likely between the ages of 6 and 18 months (median age 1.1 years; 95% CI 0.7–1.5; Fig. 5b). Despite treatment, retinopathy led to a severe loss of visual acuity in most patients. Glaucoma occurred in three cases. Frequent features of RS include neurological and neuroanatomical abnormalities. In the present cohort, cerebellar hypoplasia (76%, n = 13/17) and intracranial calcifications (85%, n = 11/13) were common features, whereas microcephalia and ataxia were reported less often (Table 1). Only three patients (unknown in one) experienced seizures, that developed exclusively during early childhood, resulting in a cumulative incidence rate of 20% (SD 10.7; Fig. 5c). Our study substantiated neurodevelopmental delay and/or mental retardation to be a frequent feature of RS, and this was present in 71% of patients (n = 12/17), frequently emerging during infancy. However, learning deficits were often mild, and absent in others, indicating that neurocognitive impairment is not an obligatory feature of the syndrome. Of note, intracranial hemorrhage was detected in three patients during the course of the disease and might represent a yet underrecognized cerebrovascular vulnerability. Patients with RS are born small for gestational age and/or preterm, resulting in a mean birth weight of 1950 g ± 410 (SD), and one out of three patients failed to thrive (Table 1).Fig. 4 Kaplan–Meier estimate of survival in 18 patients with Revesz syndrome. Median survival was 6.5 years (95% CI 3.6–9.4)\n\nFig. 5 Estimated cumulative incidence of various features of RS: a All patients developed bone marrow failure (BMF) by the age of 6 years. Time of diagnosis was available in 16 patients, with BMF occurring most frequently in the second year of life (median age 1.5 years; 95% CI 1.4–1.6). b Accordingly, retinopathy was present in all cases (time of diagnosis was available in 15 patients). Most children developed retinopathy between the ages of 6 and 18 months of life (median age 1.1 years; 95% CI 0.7–1.5). c Only three patients (unknown in two) experienced seizures. These developed exclusively during early childhood, resulting in an estimated cumulative incidence rate of 20% (SD 10.7)\n\n\n\nGenetic mutational analysis was available in 66% of patients (n = 12) and was performed in all patients that were published since 2010. All of these harbored a TINF2 mutation and the underlying alterations were restricted to exon six. The most frequent mutation was c.845G > A, a missense mutation resulting in an amino acid substitution of Alanine to Histidine at position 282 of the TIN2 protein. Further mutations included two heterozygous deletions resulting in a frameshift and premature stop codon leading to truncated TIN2 proteins (c.839delA, p.K280RfsX36, patient #9; and c.851-855 del CAGTC; p.T284Nfsx, patient #17) and alternate missense mutations at position 284 (c.850A > C; p.T284P; patients #12, 13) and 289 (c.865C > T, p.P289S, patient #15) of the TIN2 protein. Hence, all mutations were located between amino acid 280 and 289.\n\nTelomere analysis was available in seven patients. All presented with very short lengths, reported as “below the first percentile for their age” (patients #10, #12, #13, #20), reported in absolute numbers of 2.3–2.8 kb (#8) and 2.5 kb (#20) and/or given as relative shortening of − 5.7 SD (#16).\n\nDiscussion\nRevesz syndrome is an extremely rare disorder, and to date, patients have only been published anecdotally. Therefore, the present work aimed at further characterization of this rare entity by summarizing the clinical findings of 17 previously published cases of RS [3, 16–20, 23, 34–42], and presenting the one further case reported in this work. The latter represents the first published patient from central Europe.\n\nMedical history and clinical signs\nIn the present cohort, we found a slight and non-significant male predominance. This is far less pronounced compared to DKC, with its often X-linked inheritance [2]. Given the autosomal background in RS, we would agree with Gupta and coworkers who state an equal gender distribution in RS [17]. In all, our findings argue against previous presumptions of a considerable male predominance of 3:1 [18].\n\nLooking into the patients’ medical history, growth retardation, either prevalent at birth or a failure to thrive was prevalent in most cases. Four children were delivered preterm, and of note, those did not present small for gestational age. Unfortunately, information on further somatic development was available for only one of these children, and this girl experienced severe failure to thrive soon after birth, indicating that growth retardation starts during late pregnancy or postnatally. However, some children regained underweight. Hence, growth retardation is common, but not a general trait in patients with RS.\n\nNail dystrophy was the most frequent feature of the clinical DKC triad. In line with findings in classical DKC, typical skin pigmentation and oral leukoplakia were even less frequent [44], resulting in the complete clinical triad in only two cases, in contrast to 35% in DKC [44]; hence, the clinical signs of the DKC triad seem less common in patients with RS [45]. This might be confusing, since the prevalence of these correlate with a more severe course of the disease and early onset BMF in classical DKC [4, 44]. However, the seemingly low incidence in RS is in line with previous assumptions [26] and might well be due to the young age at diagnosis and early death of these patients, since the DKC triad may develop with age and sometimes following BMF [4, 45] between the ages of five and 13 years [2, 46]. Accordingly, in patients #11 and #18 of our cohort, nail dystrophy was absent when the diagnosis of RS was made but developed during course of disease. Furthermore, this review might underestimate the prevalence, since findings may be subtle and not all case reports commented on these signs. We would therefore suggest careful screening for signs of the DKC triad in patients with suspected RS, not only at time of initial diagnosis but also at older ages. However, diagnosis of RS is based on additional features and a lack of DKC signs, especially in young children, should not preclude from providing a diagnosis [4].\n\nAs in DKC, patients with RS may be prone to developing secondary malignancies [47]. Most likely due to the short survival time, none of the patients from the present report experienced such complications. However, once survival might improve, patients should be monitored accordingly.\n\nBone marrow failure\nTINF2 mutations have been linked to severe BMF [48]. Accordingly, BMF, occurring at an even younger age than previously suspected, is a general trait of RS [18]. Reflecting the most severe course of disease, BMF was most likely to develop within the second year of life and, in all cases, developed by the age of 6 years (Fig. 5a).\n\nStem cell transplantation (SCT) was performed in eight patients from the present cohort, and four of these were still alive at the last documented visit. Hence, SCT should be offered to patients, if required clinically, potentially resulting in improved survival in the future. Various conditioning regimens, stem cell sources, and donors have been published [3, 18, 20, 34, 36, 40, 42]. The authors point out a relevant treatment-related toxicity due to the underlying telomere disorder (particularly affecting the lung), and the approach should take into account experiences in DKC patients. In this regard, Ostronoff suggested a reduced intensity conditioning (RIC) regimen including fludarabine, cyclophosphamide, and anti-thymocyte globulin in DKC patients [49]. Within the present cohort, four of the eight cases, including our patient, underwent this regimen with only limited acute SCT-associated toxicity [34, 40, 42]. Hence, we suggest applying this conditioning regimen in patients with RS, but still SCT in RS remains a high-risk transplantation and should, therefore, be carried out by experienced centers only.\n\nPulmonary disease\nLung complications contribute to treatment-related mortality, especially following SCT in adult DKC patients [46, 48, 50]. Accordingly, two deaths in this series occurred due to terminal lung failure 2 years [this report] and 4.5 years [40] after the date of the successful SCT. Conditioning regimens with potential pulmonary toxicity should, therefore, be avoided to prevent worsening of occult lung disease [42, 51]. Given that pulmonary interstitial fibrosis is independently attributed to TINF2-mutations [49, 52, 53], lung disease due to insufficient telomere maintenance may be regarded as an obligatory late sequela in patients with RS also without SCT [52]. Accordingly, in DKC, sporadic lung disease may develop within the second and third decade, but with a median of 4.7 years following SCT [53]. Only one of the 10 cases without SCT in the present review experienced lung failure (at the age of 12 years), most likely due to the short survival time of the others [38]. Therefore, this complication should not preclude one from performing SCT, but patients should be educated and monitored accordingly. Potentially, early and aggressive interventions in case of respiratory symptoms might further improve survival (especially following SCT) in the future.\n\nRetinopathy\nIn the present study, exudative retinopathy occurred during infancy and early childhood, most likely between the ages of 6 and 18 months (Fig. 5b). Some children were born preterm, but the medical history was unlikely to determine an association between retinopathy and prematurity. Hence, RS should be considered in case of Coats-like retinopathy in infants without a typical history. Therapy included photocoagulation [17, 18, 20, 23, 34, 37, 41], repeated bevacizumab injections [17, 34], retinocryopexia [35, 36], and surgical approaches, including vitrectomy [17, 34, 37, 41] and enucleation, in cases of complete loss of visual acuity with or without painful glaucoma [16, 36, 41]. To date, laser photocoagulation is the preferred mode of therapy, and bevacizumab injections are an alternative [50]. However, in RS-associated retinopathy, most patients will develop a severe loss of visual acuity despite treatment.\n\nExudative retinopathy is a defining trait of RS [4]. However, there is a huge overlap to alternate entities that may harbor other features of RS, including BMF, failure to thrive, mental retardation, and the cerebral abnormalities. These include patients with DKC and potentially mutations other than TINF2, in whom retinopathy may occur occasionally [28, 51, 54, 55]. These patients may be discriminated from RS by the less severe course of disease and/or the absence of a TINF2 mutation. In addition, in cases of a familial history of DKC, the diagnosis of RS should be questioned. HHS may be associated with retinopathy [27], mimicking the severe course of RS. However, a familial history of DKC and mutations outside TINF2 may exclude RS and classify these patients as HHS. Moreover, a relevant overlap is found with CRMCC. This disease, formerly called Coats plus syndrome, resembles RS regarding bilateral exudative retinopathy, intracranial calcifications, mucocutaneous abnormalities, and bone marrow failure. It can be discriminated by molecular analysis, since CRMCC is restricted to CTC1 mutations. Clinically, it differs from RS by the prevalence of bony lesions and intestinal bleeding [11–14]. Since SCT is dispensable due to the late onset and often mild course of BMF, discriminating CRMCC from RS is of upmost importance [15]. Further disorders include Fanconi anemia [31, 32, 56] and rare entities, including mutations in DNAJC21 and ERCC6L2 [29, 30].\n\nConversely, patients with features of RS including early onset of BMF and TINF2-mutations but lacking exudative retinopathy are published in the literature. These cases differ from RS not only in terms of the ophthalmologic findings, but they also usually exhibit a less progressive course and longer survival. These patients should not be classified as RS [3], but represent variants of autosomal dominant DKC [57–59]. Therefore, accurate clinical evaluation, including verification or exclusion of retinopathy, is essential to classify the disease properly and thereby enabling clear decisions on best possible treatment of the patient.\n\nCentral nervous system (CNS) manifestation\nCerebral calcifications is a central trait of RS [4, 46], reported in all but two patients with clinical information. Hence, even if calcifications may be seen in other entities, including CRMCC, HS, and DKC, this feature in combination with retinopathy, early onset of BMF, and the molecular evaluation of TINF2 is a valuable predictor of RS. Therefore, diagnosis of RS in the absence of cerebral calcifications should be based on other strong criteria. Microcephaly and cerebellar hypoplasia were less common. The latter is usually attributed to HHS [21]. However, cerebral abnormalities are common in TBD and seem to widely overlap between the various DKC variants, with none being specific for a distinct entity [60]. In this regard, we describe the first patient with RS and a hypoplastic corpus callosum. Of note, given that the first MRI soon after birth revealed normal findings, we would hypothesize that the hypoplasia may be attributed to leukoencephalopathy, and the rarity of this trait in RS may be due to the short life expectancy in most patients. In this regard, involution of the corpus callosum may be a general feature in TBI, as it has been described in various patients with HHS [61]. Rarely, gliotic lesions may occur [23].\n\nOf note, three patients of the present cohort experienced intracranial hemorrhages resulting in relevant morbidity [19, 38]. These bleeds might have been associated with cerebrovascular fragility rather than with low platelets or a plasmatic bleeding predisposition, since cerebral bleeding has been reported in other patients with TINF2 mutations [58], and bleeding from telangiectasias including gastrointestinal hemorrhages is a common trait of other telomere biology disorders [50]. Negron and coworkers hypothesized that reabsorption and healing of such cerebral (micro)bleedings might result in calcifications and, hence, be a pathophysiological trigger of this frequent feature in RS [38].\n\nScheinfeld has summarized neuroradiologic findings in RS [23]. Herein, we provide further paradigmatic NMR imaging findings.\n\nNeurodevelopmental delay is common in RS, but symptoms may be mild, with “satisfying” neurocognitive development [36], or absent in some patients. In fact, one of the patients was a “good student with above-average intelligence and a skillful violin player” [38]. However, early and repeated neurodevelopmental assessment is indispensable in patients with RS and adequate treatment is essential in cases of pathological delay. Despite the numerous cerebral abnormalities, only few patients experienced seizures, and these developed exclusively during early childhood (Fig. 5c). Hence, in line with other telomere biology disorders [46], epilepsy may occur occasionally, but is not a typical feature of RS.\n\nGenetic background and telomere biology\nRS is a telomere biology disorder (TBD) within the DKC spectrum resulting in impaired telomere maintenance [62]. The principles of TBD have been summarized by Barbaro, who focused on the various clinical entities [46], whereas Smith has extensively reviewed the biochemical background of telomere maintenance [24].\n\nIn contrast to DKC, RS is restricted to mutations in one single gene, namely TINF2 on chromosome 14q12 [46]. Five different mutations have been published to date, all affecting exon six, similar to all TINF2 mutations described in DKC. The most common germline alteration is c.845G > A, a missense mutation with substitution of guanine to adenine, leading to an amino acid substitution from arginine to histidine at position 282 of the TIN2 protein. Further mutations have been found sporadically that are summarized in Table 1 [17, 19, 34, 41]. Dysfunctional TIN2 results in an impaired protection of telomere ends by the shelterin complex and patients harbor extremely short telomeres. Hence, premature shortening of telomere repeats leads to premature cell senescence [62]. Regarding the variant molecular interactions of the mutant TIN2 protein with its natural ligands, the readers are referred to the respective literature [63–65]. It is still under debate whether the extent of telomere shortening is generally associated with the severity of symptoms [66, 67]. Undoubtedly, extremely short telomeres in RS, even compared to other TBD, correlate with a more severe course as well as the early onset of this disorder.\n\nIt is noteworthy that not all alterations in TINF2 are pathogenic, hence polymorphisms of the gene exist [66]. Conversely, most patients with TINF2 mutations develop TBDs other than the classical phenotype of RS, including not only 11 to 24% of DKC patients [3, 20, 46], but also HHS, idiopathic pulmonary fibrosis, and aplastic anemia [20, 21, 48, 68, 69]. Even the most frequent TINF2 mutation, p.R282H, is not specific for RS and it is yet unclear which additional mechanisms lead to its full phenotype. Recently, TIN2 was identified as a modifier of telomerase activity via interaction with TPP1/POT1, representing an alternate mechanism of telomere pathology in TINF2 mutations [70], and failure to restore telomere length during early pregnancy was hypothesized to contribute to very short telomeres in severe variants [67]. In addition, varying gene expression within different tissues may be related to clinical phenotypes [17], but there is still much effort required to elucidate the pathogenic biological mechanisms. Therefore, at the present time, clinical features, a mutation within exon six of TINF2, and very short telomeres, e.g. below the first percentile of age, are needed to make an accurate diagnosis.\n\nConclusion\nWe present a comprehensive review on Revesz syndrome by studying previously published patients, in addition to an individual case report first presented here. In summary, RS is characterized by an early onset of exudative retinopathy and bone marrow failure, as well as a very poor survival. Features of the DKC triad, cerebral calcifications, growth retardation, and neurodevelopmental delay are part of the disease in most but not all cases. In addition, we report the first patient from central Europe, who in contrast to all previously published cases, developed hypoplasia of the corpus callosum during early childhood. Since TINF2 mutations are not restricted to RS, clear definition of clinical features is essential for an adequate diagnosis, but symptoms overlap with other entities. Therefore, clinical registries and further genetic studies are needed to elucidate the molecular background of this rare disorder as well as support the exploration of novel therapeutic strategies aiming at improved telomere maintenance [71].\n\nSupplementary information\n\nAdditional file 1: Figure 1. Axial T1-weighted images at the age of one year (a, b) and 3.8 years (c, d) before (a, c) and after (b, d) administration of gadolinium contrast material. Primary high signal intensity was observed within the symmetrical calcified areas in the thalamus and occipital lobe, with foci of pathological enhancement in the front right (arrow) (b), and later reinforced enhancement of the primary high intensity areas (d). There was also, not shown, symmetrical enhancement within the partially calcified nucleus ruber.\n\n Additional file 2: Figure 2. Sagittal T2-weighted images demonstrate a reduction in the size of the corpus callosum over time (arrows) due to increasing leukoencephalopathy at one (a) and 3.8 years (b) of age.\n\n Additional file 3: Figure 3. Axial T2-weighted MRI images demonstrate initial normal bulbi at age 2.5 months (a), an abnormal right globe with hemorrhage and detachment at age 2.2 years (b), and an abnormal left globe with V-shaped detachment at age 3.8 years (c).\n\n \n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nSupplementary information\nSupplementary information accompanies this paper at 10.1186/s13023-020-01553-y.\n\nAcknowledgements\nWe greatly acknowledge Shinichi Tamura and Dana Tomcikova for providing additional clinical information on patients #11 and #15, respectively.\n\nAuthors’ contributions\nM.K. was responsible for study concept, literature review, and wrote the manuscript. E.N.P. provided neuroradiological imaging and F.B. performed telomere length analysis and provided Fig. 3. F.S., T.B., F.C., P.B., and M.D. critically reviewed the manuscript for important intellectual content. All authors have read and approved the final version of the manuscript.\n\nFunding\nOpen Access funding enabled and organized by Projekt DEAL. The authors declare no specific grant was awarded for this research from any funding agency.\n\nAvailability of data and materials\nThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\nThe present study has been approved by the Institutional Review Board II, Medical Faculty Mannheim, Heidelberg University (2020-832R).\n\nConsent for publication\nThe patient described in this manuscript finally died in 2014. Since then, her parents have not visited our hospital again, and we have failed to contact them recently to ask for their consent to the present publication. No identifiable photos of the child have been added to the manuscript, and due to the huge catchment area of our hospital, including a population of approximately two million citizens, identification of the family by the clinical description seems largely excluded. We, however, hope that the case description as well as the representative neuroradiological imaging and the impressive figure concerning telomer shortening may remain in the present review.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Niewisch MR Savage SA An update on the biology and management of dyskeratosis congenita and related telomere biology disorders Expert Rev Hematol 2019 12 12 1037 1052 10.1080/17474086.2019.1662720 31478401 \n2. Garofola C, Gross GP. Dyskeratosis congenita. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020.\n3. 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Anderson BH Kasher PR Mayer J Szynkiewicz M Jenkinson EM Bhaskar SS Urquhart JE Daly SB Dickerson JE O'Sullivan J Leibundgut EO Muter J Abdel-Salem GM Babul-Hirji R Baxter P Berger A Bonafe L Brunstom-Hernandez JE Buckard JA Chitayat D Chong WK Cordelli DM Ferreira P Fluss J Forrest EH Franzoni E Garone C Hammans SR Houge G Hughes I Jacquemont S Jeannet PY Jefferson RJ Kumar R Kutschke G Lundberg S Lourenco CM Mehta R Naidu S Nischal KK Nunes L Ounap K Philippart M Prabhakar P Risen SR Schiffmann R Soh C Stephenson JB Stewart H Stone J Tolmie JL van der Knaap MS Vieira JP Vilain CN Wakeling EL Wermenbol V Whitney A Lovell SC Meyer S Livingston JH Baerlocher GM Black GC Rice GI Crow YJ Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus Nat Genet 2012 44 3 338 342 10.1038/ng.1084 22267198 \n23. Scheinfeld MH Lui YW Kolb EA Engel HM Gomes WA Weidenheim KM Bello JA The neuroradiological findings in a case of Revesz syndrome Pediatr Radiol 2007 37 11 1166 1170 10.1007/s00247-007-0592-0 17874088 \n24. Smith EM Pendlebury DF Nandakumar J Structural biology of telomeres and telomerase Cell Mol Life Sci 2019 77 61 79 10.1007/s00018-019-03369-x 31728577 \n25. Monoi A Sugawa M Kato M Seki M Yoshida K Shiraishi Y Sakaguchi H Ogawa S Takita J Atypical dyskeratosis congenita diagnosed using whole-exome sequencing Pediatr Int 2017 59 8 933 935 10.1111/ped.13314 28643950 \n26. Walne AJ Vulliamy T Beswick R Kirwan M Dokal I TINF2 mutations result in very short telomeres: analysis of a large cohort of patients with dyskeratosis congenita and related bone marrow failure syndromes Blood 2008 112 9 3594 3600 10.1182/blood-2008-05-153445 18669893 \n27. Allingham MJ Bilateral proliferative retinopathy associated with Hoyeraal-Hreidarsson syndrome, a severe form of dyskeratosis congenita Ophthalmic Surg Lasers Imaging Retina 2016 47 4 366 368 10.3928/23258160-20160324-11 27065378 \n28. Sharma A Myers K Ye Z D'Orazio J Dyskeratosis congenita caused by a novel TERT point mutation in siblings with pancytopenia and exudative retinopathy Pediatr Blood Cancer 2014 61 12 2302 2304 10.1002/pbc.25161 25067791 \n29. D'Amours G Lopes F Gauthier J Saillour V Nassif C Wynn R Alos N Leblanc T Capri Y Nizard S Lemyre E Michaud JL Pelletier VA Pastore YD Soucy JF Refining the phenotype associated with biallelic DNAJC21 mutations Clin Genet 2018 94 2 252 258 10.1111/cge.13370 29700810 \n30. Shabanova I Cohen E Cada M Vincent A Cohn RD Dror Y ERCC6L2-associated inherited bone marrow failure syndrome Mol Genet Genomic Med 2018 6 3 463 468 10.1002/mgg3.388 29633571 \n31. Denny M Haug SJ Cunningham ET Jr Jumper JM Fanconi anemia presenting as bilateral diffuse retinal occlusive vasculopathy Retin Cases Brief Rep 2016 10 2 171 174 10.1097/ICB.0000000000000219 26579591 \n32. Martin-Sanz R Pena D Lopez-Miguel A Coco-Martin MB Gonzalez-Garcia H Alvarez-Guisasola FJ Pastor JC Coats disease in a patient with Fanconi anemia: a case report Eur J Ophthalmol 2015 25 2 182 183 10.5301/ejo.5000517 25264118 \n33. Brummendorf TH Balabanov S Telomere length dynamics in normal hematopoiesis and in disease states characterized by increased stem cell turnover Leukemia 2006 20 10 1706 1716 10.1038/sj.leu.2404339 16888616 \n34. Asai D Osone S Imamura T Sakaguchi H Nishio N Kuroda H Kojima S Hosoi H Allo-SCT in a patient with CRMCC with aplastic anemia using a reduced intensity conditioning regimen Bone Marrow Transplant 2012 47 8 1126 1127 10.1038/bmt.2011.221 22080964 \n35. Duprey PA Steger JW An unusual case of dyskeratosis congenita with intracranial calcifications J Am Acad Dermatol 1988 19 4 760 762 10.1016/S0190-9622(88)80357-8 3183098 \n36. Kajtar P Mehes K Bilateral coats retinopathy associated with aplastic anaemia and mild dyskeratotic signs Am J Med Genet 1994 49 4 374 377 10.1002/ajmg.1320490404 8160728 \n37. McElnea EM van der Spek N Smith O Fitzsimon S Patel CK O'Marcaigh A Revesz syndrome masquerading as bilateral cicatricial retinopathy of prematurity J AAPOS 2013 17 6 634 636 10.1016/j.jaapos.2013.07.016 24321428 \n38. Negron D Colon-Castillo L Morales-Melecio I Correa-Rivas M Association of extensive brain calcifications, myelofibrosis, and retinopathy in a 12-year-old child Pediatr Dev Pathol 2008 11 2 148 151 10.2350/06-03-0061.1 17990901 \n39. Riyaz A Riyaz N Jayakrishnan MP Mohamed Shiras PT Ajith Kumar VT Ajith BS Revesz syndrome Indian J Pediatr 2007 74 9 862 863 10.1007/s12098-007-0155-2 17901676 \n40. Tamura S Imamura T Urata T Kobayashi M Gen M Tomii T Do J Osone S Ishida H Hosoi H Kuroda H Allogeneic hematopoietic cell transplantation for dyskeratosis congenita: a report of 3 cases J Pediatr Hematol Oncol 2017 39 7 e394 e398 10.1097/MPH.0000000000000844 28538506 \n41. Tomcikova D Gerinec A Busanyova B Gresikova M Biskup S Hortnagel K Why is it necessary to examine retina when the patient suffers from aplastic anemia? Bratisl Lek Listy 2018 119 5 275 277 29749240 \n42. Watanabe K Arakawa Y Kambe T Oguma E Kishimoto H Koh K Unrelated allogeneic hematopoietic stem cell transplantation in a patient with Revesz syndrome, a severe variant of dyskeratosis congenita Pediatr Blood Cancer 2019 66 1 e27476 10.1002/pbc.27476 30259646 \n43. Ferreira MSV Kirschner M Halfmeyer I Estrada N Xicoy B Isfort S Vieri M Zamora L Abels A Bouillon AS Begemann M Schemionek M Maurer A Koschmieder S Wilop S Panse J Brummendorf TH Beier F Comparison of flow-FISH and MM-qPCR telomere length assessment techniques for the screening of telomeropathies Ann N Y Acad Sci 2020 1466 1 93 103 10.1111/nyas.14248 31647584 \n44. Ward SC Savage SA Giri N Alter BP Rosenberg PS Pichard DC Cowen EW Beyond the triad: inheritance, mucocutaneous phenotype, and mortality in a cohort of patients with dyskeratosis congenita J Am Acad Dermatol 2018 78 4 804 806 10.1016/j.jaad.2017.10.017 29042228 \n45. Dokal I Dyskeratosis congenita Hematol Am Soc Hematol Educ Program 2011 2011 480 486 10.1182/asheducation-2011.1.480 \n46. Barbaro PM Ziegler DS Reddel RR The wide-ranging clinical implications of the short telomere syndromes Intern Med J 2016 46 4 393 403 10.1111/imj.12868 26247919 \n47. Walsh MF Chang VY Kohlmann WK Scott HS Cunniff C Bourdeaut F Molenaar JJ Porter CC Sandlund JT Plon SE Wang LL Savage SA Recommendations for childhood cancer screening and surveillance in DNA repair disorders Clin Cancer Res 2017 23 11 e23 e31 10.1158/1078-0432.CCR-17-0465 28572264 \n48. Du HY Mason PJ Bessler M Wilson DB TINF2 mutations in children with severe aplastic anemia Pediatr Blood Cancer 2009 52 5 687 10.1002/pbc.21903 19090550 \n49. Ostronoff F Ostronoff M Calixto R Florencio R Domingues MC Souto Maior AP Sucupira A Tagliari C Fludarabine, cyclophosphamide, and antithymocyte globulin for a patient with dyskeratosis congenita and severe bone marrow failure Biol Blood Marrow Transplant 2007 13 3 366 368 10.1016/j.bbmt.2006.11.015 17317590 \n50. Higgs C Crow YJ Adams DM Chang E Hayes D Jr Herbig U Huang JN Himes R Jajoo K Johnson FB Reynolds SD Yonekawa Y Armanios M Boulad F DiNardo CD Dufour C Goldman FD Khan S Kratz C Myers KC Raghu G Alter BP Aubert G Bhala S Cowen EW Dror Y El-Youssef M Friedman B Giri N Helms Guba L Khincha PP Lin TF Longhurst H McReynolds LJ Nelson A Olson T Pariser A Perona R Sasa G Schratz K Simonetto DA Townsley D Walsh M Stevens K Agarwal S Bertuch AA Savage SA Understanding the evolving phenotype of vascular complications in telomere biology disorders Angiogenesis 2019 22 1 95 102 10.1007/s10456-018-9640-7 30168024 \n51. Mason JO 3rd Yunker JJ Nixon PA Vail RS Tsilou E Giri N Alter BP Proliferative retinopathy as a complication of dyskeratosis congenita Retin Cases Brief Rep 2009 3 3 259 262 10.1097/01.ICB.0000315662.87050.bf 25389579 \n52. Arish N Petukhov D Wallach-Dayan SB The role of telomerase and telomeres in interstitial lung diseases: from molecules to clinical implications Int J Mol Sci 2019 20 12 2996 10.3390/ijms20122996 6627617 \n53. Giri N, Ravichandran S, Wang Y, Gadalla SM, Alter BP, Fontana J, Savage SA. Prognostic significance of pulmonary function tests in dyskeratosis congenita, a telomere biology disorder. ERJ Open Res 2019;5(4).\n54. Teixeira LF Shields CL Marr B Horgan N Shields JA Bilateral retinal vasculopathy in a patient with dyskeratosis congenita Arch Ophthalmol 2008 126 1 134 135 10.1001/archophthalmol.2007.4 18195234 \n55. Tsilou ET Giri N Weinstein S Mueller C Savage SA Alter BP Ocular and orbital manifestations of the inherited bone marrow failure syndromes: Fanconi anemia and dyskeratosis congenita Ophthalmology 2010 117 3 615 622 10.1016/j.ophtha.2009.08.023 20022637 \n56. Chai SM Mathur R Ong SG Retinal vasculopathy in Fanconi anemia Ophthalmic Surg Lasers Imaging 2009 40 5 498 500 10.3928/15428877-20090901-11 19772276 \n57. Abdollahi M Gao MM Munoz DG Distinct pattern of neostriatal calcifications in dyskeratosis congenita: a case report and literature review Clin Neuropathol 2018 37 6 277 282 10.5414/NP301088 30106361 \n58. Sarper N Zengin E Kilic SC A child with severe form of dyskeratosis congenita and TINF2 mutation of shelterin complex Pediatr Blood Cancer 2010 55 6 1185 1186 10.1002/pbc.22624 20979174 \n59. Tsangaris E Adams SL Yoon G Chitayat D Lansdorp P Dokal I Dror Y Ataxia and pancytopenia caused by a mutation in TINF2 Hum Genet 2008 124 5 507 513 10.1007/s00439-008-0576-7 18979121 \n60. Bhala S Best AF Giri N Alter BP Pao M Gropman A Baker EH Savage SA CNS manifestations in patients with telomere biology disorders Neurol Genet 2019 5 6 370 10.1212/NXG.0000000000000370 31872047 \n61. Akaboshi S Yoshimura M Hara T Kageyama H Nishikwa K Kawakami T Ieshima A Takeshita K A case of Hoyeraal-Hreidarsson syndrome: delayed myelination and hypoplasia of corpus callosum are other important signs Neuropediatrics 2000 31 3 141 144 10.1055/s-2000-7531 10963101 \n62. Savage SA. Beginning at the ends: telomeres and human disease. F1000Res 2018;7:524.\n63. Amir M Khan P Queen A Dohare R Alajmi MF Hussain A Islam A Ahmad F Hassan I Structural features of nucleoprotein CST/shelterin complex involved in the telomere maintenance and its association with disease mutations Cells 2020 9 2 359 10.3390/cells9020359 7072152 \n64. Hu C Rai R Huang C Broton C Long J Xu Y Xue J Lei M Chang S Chen Y Structural and functional analyses of the mammalian TIN2-TPP1-TRF2 telomeric complex Cell Res 2017 27 12 1485 1502 10.1038/cr.2017.144 29160297 \n65. Nelson ND Dodson LM Escudero L Sukumar AT Williams CL Mihalek I Baldan A Baird DM Bertuch AA The C-Terminal extension unique to the long isoform of the shelterin component TIN2 enhances its interaction with TRF2 in a phosphorylation- and dyskeratosis congenita cluster-dependent fashion Mol Cell Biol 2018 38 12 e00025-18 10.1128/MCB.00025-18 29581185 \n66. Vulliamy T Beswick R Kirwan MJ Hossain U Walne AJ Dokal I Telomere length measurement can distinguish pathogenic from non-pathogenic variants in the shelterin component, TIN2 Clin Genet 2012 81 1 76 81 10.1111/j.1399-0004.2010.01605.x 21199492 \n67. Alter BP Rosenberg PS Giri N Baerlocher GM Lansdorp PM Savage SA Telomere length is associated with disease severity and declines with age in dyskeratosis congenita Haematologica 2012 97 3 353 359 10.3324/haematol.2011.055269 22058220 \n68. Keel SB Scott A Sanchez-Bonilla M Ho PA Gulsuner S Pritchard CC Abkowitz JL King MC Walsh T Shimamura A Genetic features of myelodysplastic syndrome and aplastic anemia in pediatric and young adult patients Haematologica 2016 101 11 1343 1350 10.3324/haematol.2016.149476 27418648 \n69. Hoffman TW van der Vis JJ van Oosterhout MF van Es HW van Kessel DA Grutters JC van Moorsel CH TINF2 gene mutation in a patient with pulmonary fibrosis Case Rep Pulmonol 2016 2016 1310862 27088026 \n70. Pike AM Strong MA Ouyang JPT Greider CW TIN2 functions with TPP1/POT1 to stimulate telomerase processivity Mol Cell Biol 2019 39 21 e00593-18 10.1128/MCB.00593-18 31383750 \n71. Townsley DM Dumitriu B Liu D Biancotto A Weinstein B Chen C Hardy N Mihalek AD Lingala S Kim YJ Yao J Jones E Gochuico BR Heller T Wu CO Calado RT Scheinberg P Young NS Danazol treatment for telomere diseases N Engl J Med 2016 374 20 1922 1931 10.1056/NEJMoa1515319 27192671\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1750-1172",
"issue": "15(1)",
"journal": "Orphanet journal of rare diseases",
"keywords": "Bone marrow failure; Cerebellar hypoplasia; Exudative retinopathy; Growth retardation; Pancytopenia; Revesz syndrome; Shelterin; TINF2; Telomere",
"medline_ta": "Orphanet J Rare Dis",
"mesh_terms": "D001851:Bone Diseases, Metabolic; D001853:Bone Marrow; D002648:Child; D002675:Child, Preschool; D019871:Dyskeratosis Congenita; D005060:Europe; D006801:Humans; D007223:Infant; D012160:Retina",
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"pages": "299",
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"pmid": "33097095",
"pubdate": "2020-10-23",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": "17874088;28095086;31647584;24321428;22080964;30259646;18076099;31383750;9007502;25389579;30478948;10222456;31728577;21199492;27418648;29581185;18669893;20022637;19090550;29633571;18979121;27065378;31872047;25067791;29749240;29770205;20979174;25940403;22160078;26247919;29523622;26579591;28866069;21523908;19772276;21477109;29160297;30168024;28643950;10963101;28538506;31248154;18195234;23453664;29081935;22267198;22058220;11992766;22387016;31754622;29700810;17901676;25264118;27088026;32033110;3183098;17317590;3402627;1404302;21189492;30106361;31478401;8160728;28572264;17990901;29042228;22705805;16888616;27192671",
"title": "Revesz syndrome revisited.",
"title_normalized": "revesz syndrome revisited"
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"abstract": "Coccidioidal meningitis typically presents with symptoms that may include headache, altered mental status including personality changes, fever, nausea, vomiting, gait abnormalities, and focal neurological deficits. This is a case of coccidioidal meningitis that initially presented as 4 consecutive crescendo cerebrovascular transient ischemic attacks with focal neurological deficits that resolved within minutes. Imaging showed a left basilar coccidioma. Follow-up at 4 months showed treatment response to conservative therapy of fluconazole 1000 mg with a dexamethasone taper. Crescendo cerebrovascular transient ischemic attacks are a unique initial presentation of coccidioidal meningitis.",
"affiliations": "Kern Medical-UCLA, Bakersfield, CA, USA.;Kern Medical-UCLA, Bakersfield, CA, USA.;Kern Medical-UCLA, Bakersfield, CA, USA.;Kern Medical-UCLA, Bakersfield, CA, USA.",
"authors": "D'Assumpcao|Carlos|C|https://orcid.org/0000-0001-9967-9612;Heidari|Arash|A|;Sabetian|Katayoun|K|;Johnson|Royce H|RH|",
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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 10.1177/232470961881317810.1177_2324709618813178Case ReportCrescendo Transient Ischemic Attacks Due to Basilar Coccidioidal Meningitis With Coccidioma https://orcid.org/0000-0001-9967-9612D’Assumpcao Carlos MD12Heidari Arash MD13Sabetian Katayoun MD1Johnson Royce H. MD131 Kern Medical—UCLA, Bakersfield, CA, USA2 Ross University, Miramar, FL, USA3 Valley Fever Institute, Bakersfield, CA, USACarlos D’Assumpcao, MD, Kern Medical—UCLA, 1700 Mount Vernon Avenue, Bakersfield, CA 93306, USA. Email: cdassumpcao@gmail.com19 11 2018 Jan-Dec 2018 6 23247096188131781 8 2018 2 10 2018 7 10 2018 © 2018 American Federation for Medical Research2018American Federation for Medical ResearchThis article is distributed under the terms of the Creative Commons Attribution 4.0 License (http://www.creativecommons.org/licenses/by/4.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Coccidioidal meningitis typically presents with symptoms that may include headache, altered mental status including personality changes, fever, nausea, vomiting, gait abnormalities, and focal neurological deficits. This is a case of coccidioidal meningitis that initially presented as 4 consecutive crescendo cerebrovascular transient ischemic attacks with focal neurological deficits that resolved within minutes. Imaging showed a left basilar coccidioma. Follow-up at 4 months showed treatment response to conservative therapy of fluconazole 1000 mg with a dexamethasone taper. Crescendo cerebrovascular transient ischemic attacks are a unique initial presentation of coccidioidal meningitis.\n\ncoccidioidomycosiscoccidioidal meningitiscrescendo transient ischemic attackcover-dateJanuary-December 2018\n==== Body\nIntroduction\nCoccidioides is found as 2 species, immitis and posadasii, that are clinically indistinguishable. Coccidioidomycosis is most commonly an asymptomatic infection. When symptomatic, it is commonly a pneumonia often mistaken for community-acquired pneumonia.1 However, in the few the disease can disseminate anywhere in the body. Meningitis is the most feared form of disseminated coccidioidomycosis. The most common presenting symptom is headache. Other symptoms include altered mental status, with or without fever, personality changes, nausea, vomiting, meningismus, gait abnormalities, and focal neurological deficits.2 Presented here is a case of coccidioidal meningitis that initially presented as multiple consecutive crescendo cerebrovascular transient ischemic attacks (TIAs).\n\nCase\nA 64-year-old Hispanic male with diagnosis of pulmonary coccidioidomycosis 2 years prior at another institution and placed on therapy with 400 mg fluconazole daily for 1½ years. Initial serum coccidioidal immunodiffusion of IgM (immunoglobulin) and IgG were weakly reactive with complement fixation titers of 1:4. Symptoms resolved, and his physician decreased fluconazole to 200 mg daily for 4 months. He did well for 1 month until he developed left-sided headaches. After 2 weeks, he had 2 episodes of left arm and leg weakness without ability to walk and lower right facial palsy over a period of 10 minutes.\n\nIn the emergency department, while having his vitals taken, the patient had another episode of lower right facial palsy and left-sided weakness that resolved in 5 minutes. Computed tomography scan of brain without contrast as well as computed tomography angiogram of head and neck were completed and were unremarkable. Three hours later, the patient had another episode of right facial droop and left-sided weakness, followed by new-onset slurring of speech, resolving in 5 minutes. Magnetic resonance imaging of the brain showed no infarcts or intracranial hemorrhage, but it did show increased peripontine enhancement with several nodular enhancements in the basilar area suspicious for coccidioma (Figure 1). Lumbar puncture demonstrated opening pressure of 140 mm H2O, white blood cells 240 (34% lymphocytes, 39% monocytes, 18% neutrophils, 4% eosinophils, and 5% basophils), elevated protein 127 mg/dL (normal = 14-45 mg/dL), glucose 38 mg/dL (normal = 40-75 mg/dL), and coccidioidal compliment fixation titer of 1:4 diagnostic of coccidioidal meningitis. Serum coccidioidal immunodiffusion IgM and IgG were reactive with a compliment fixation titer of 1:16 (Table 1). He had a total of 4 cerebrovascular TIAs that were increasing in intensity and symptomology. He was placed on fluconazole 1000 mg daily1 and a dexamethasone 20 mg daily for 7 days then tapered by 4 mg every 4 days.3 He was discharged to be followed in clinic.\n\nFigure 1. T1-weighted magnetic resonance image with gadopentetate dimeglumine contrast showing several nodular enhancements in the left peripontine area suspicious for coccidioma (arrows) in patient with multiple consecutive crescendo cerebrovascular transient ischemic attacks.\n\nTable 1. Laboratory Results Summary. Serum serology at 2-month postdischarge were from a hospital visit for skin and soft tissue infection of left ankle unrelated to coccidioidomycosis.\n\nLaboratory Test\t2 Years Prior\tPresenting Studies\t2-Month Hospital Visit\t4-Month Follow-up\tNormal Range\t\nCSF WBC\t\t240 cells/cm2\t\t50 cells/cm2\t<5 cells/cm2\t\nCSF protein\t\t127 mg/dL\t\t66 mg/dL\t15-45 mg/dL\t\nCSF glucose\t\t38 mg/dL\t\t43 mg/dL\t40-75 mg/dL\t\nCSF CF\t\t1:4\t\t<1:1\t<1:1\t\nSerum IgM\tWeakly reactive\tVery weakly reactive\tNot reactive\tNot reactive\tNot reactive\t\nSerum IgG\tWeakly reactive\tReactive\tReactive\tReactive\tNot reactive\t\nSerum CF\t1:4\t1:16\t1:4\t1:8\t<1:1\t\nAbbreviations: CSF, cerebrospinal fluid; WBC, white blood cell; CF, compliment immunofixation titer; IgM/IgG, immunoglobulin immunodiffusion serology.\n\nHe had been and continues to be compliant with fluconazole therapy. At 2-month hospital visit for skin and soft tissue infection of left ankle unrelated to coccidioidomycosis, serum coccidioidal fixation titers were improved to 1:4. At 4-month follow-up, the patient had been asymptomatic. Lumbar puncture in office demonstrated white blood cell count of 50 (81% lymphocytes, 16% monocytes, 1% neutrophils, 1% eosinophils, and 1% basophils), protein 66 mg/dL (normal = 15-45 mg/dL), glucose 43 (normal = 40-75 mg/dL), and coccidioidal fixation titer of less than 1:1. However, serum coccidioidal fixation titers were 1:8 (Table 1).\n\nDiscussion\nTo our knowledge, this is the first reported case of multiple consecutive cerebrovascular TIAs that were increasing in intensity and symptomology with each attack as the presenting manifestation of coccidioidal meningitis.4 Presenting characteristics are recurrent episodes of sudden discrete neurological symptoms that completely resolve within 24 hours that repeat with increasing duration, frequency, and severity indicative of critical narrowing of the involved artery.5 This patient had 3 coccidiomas in the basilar meninges (Figure 1). Four episodes of transient neurological deficits were documented. The coccidioidal meningitis with associated transient vasculitis was treated conservatively with fluconazole 1000 mg1 and a dexamethasone taper.3 Cerebrospinal fluid studies at 4 months showed treatment response. However, repeat serum serology at 2 and 4 months demonstrated persistent coccidioidomycosis (Table 1). Whenever logistically feasible, follow-up sooner than 4 months for CSF studies is ideal. There were no early indications of risk to dissemination at time of pulmonary coccidioidomycosis diagnosis. Physicians in areas endemic for coccidioidomycosis should be aware that cerebrovascular TIAs can be the initial presentation of coccidioidal meningitis.\n\nAuthors’ Note: This case report was presented as a poster at the 61st Annual Meeting of the Coccidioidomycosis Study Group in collaboration with the 7th International Coccidioidomycosis Symposium at Stanford University, California, on August 2017, as well as at the American Federation for Medical Research Western Medical Research Conference in Carmel, California, on January 2018. Views expressed in this article are our own and not the official position of the institutions listed.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nEthics Approval: Ethical approval to report this case was obtained from the Kern Medical Center Institutional Review Board (Study #17048).\n\nInformed Consent: Informed consent for patient information to be published in this article was not obtained because patient or legal representative was not available in time for publication. The information in the investigator’s written request for “Waiver of Consent” coupled with the written research proposal disclosing the data use plan were reviewed by Kern Medical Center Institutional Review Board to determine that under the conditions of study approval, there should be minimal or less risk for exposure of patient identity. Kern Medical Center Institutional Review Board approved the request for the Waiver of Consent as part of its ethics approval of the study.\n\nORCID iD: Carlos D’Assumpcao \nhttps://orcid.org/0000-0001-9967-9612\n==== Refs\nReferences\n1 \nGalgiani JN Ampel NM Blair JE et al \n2016 Infectious Diseases Society of America (IDSA) clinical practice guideline for the treatment of coccidioidomycosis . Clin Infect Dis . 2016 ;63 :e112 -e146 .27470238 \n2 \nJohnson RH Einstein HE. \nCoccidioidal meningitis . Clin Infect Dis . 2006 ;42 :103 -107 .16323099 \n3 \nThompson GR 3rdBlair JE Wang S et al \nAdjunctive corticosteroid therapy in the treatment of coccidioidal meningitis . Clin Infect Dis . 2017 ;65 :338 -341 .28419259 \n4 \nWilliams PL Johnson R Pappagianis D et al \nVasculitic and encephalitic complications associated with Coccidioides immitis infection of the central nervous system in humans: report of 10 cases and review . Clin Infect Dis . 1992 ;14 :673 -682 .1562659 \n5 \nSpengos K Panas M Tsivgoulis G Vemmos K Sfagos K Vassilopoulos D. \nCrescendo transient ischemic attacks due to middle cerebral artery stenosis . Cerebrovasc Dis . 2004 ;17 :266 -268 .14981349\n\n",
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"journal": "Journal of investigative medicine high impact case reports",
"keywords": "coccidioidal meningitis; coccidioidomycosis; crescendo transient ischemic attack",
"medline_ta": "J Investig Med High Impact Case Rep",
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"abstract": "Methotrexate (MTX) is an established immunomodulating agent used in low doses (LDMTX) to treat several autoimmune diseases. Ulcerative stomatitis (US) may be observed as a long-term LDMTX adverse effect showing a wide histopathologic spectrum. A 73-year old female presented with painful oral ulcers of 5 days duration. The patient had been under treatment for rheumatoid arthritis with LDMTX, while one week before presentation she was prescribed ciprofloxacin for a urinary infection. Histopathologic examination of a lingual ulcer revealed a polymorphous lymphohistiocytic proliferation with scattered binucleated atypical lymphocytes. Immunohistochemically, most cells were of T-cell lineage while the EBER test was negative and a diagnosis of MTX-induced reactive ulceration was rendered. MTX cessation resulted in complete resolution of the ulcers with no recurrences reported so far. The clinical and histopathologic features of MTX-induced oral ulcers are not always diagnostic and a detailed history and an extensive clinicopathologic investigation may be needed to exclude a lymphoproliferative disorder. Key words:Atypical oral ulcers, ciprofloxacin, lymphoproliferative disorders, methotrexate.",
"affiliations": "DDS, MSc, MSc in Oral Medicine and Pathology, Department of Oral Medicine and Oral Pathology, School of Dentistry, National and Kapodistrian University of Athens, Athens, Greece.;DDS, PhD, Assistant Professor, Department of Oral Medicine and Oral Pathology, School of Dentistry, National and Kapodistrian University of Athens, Athens, Greece.;DDS, MSc, PhD, Assistant Professor, Department of Oral Medicine and Oral Pathology, School of Dentistry, National and Kapodistrian University of Athens, Athens, Greece.;MD, PhD, Consultant Hematopathologist, 1st Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.;DDS, MSc, PhD, Professor, Department of Oral Medicine and Oral Pathology, School of Dentistry, National and Kapodistrian University of Athens, Athens, Greece.",
"authors": "Katsoulas|Nikolaos|N|;Chrysomali|Evanthia|E|;Piperi|Evangelia|E|;Levidou|Georgia|G|;Sklavounou-Andrikopoulou|Alexandra|A|",
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"fulltext": "\n==== Front\nJ Clin Exp DentJ Clin Exp DentMedicina Oral S.L.Journal of Clinical and Experimental Dentistry1989-5488Medicina Oral S.L. 5290910.4317/jced.52909Case ReportOral Medicine and PathologyAtypical methotrexate ulcerative stomatitis with features of lymphoproliferative like disorder: Report of a rare ciprofloxacin-induced case and review of the literature Katsoulas Nikolaos 1Chrysomali Evanthia 2Piperi Evangelia 3Levidou Georgia 4Sklavounou-Andrikopoulou Alexandra 51 DDS, MSc, MSc in Oral Medicine and Pathology, Department of Oral Medicine and Oral Pathology, School of Dentistry, National and Kapodistrian University of Athens, Athens, Greece2 DDS, PhD, Assistant Professor, Department of Oral Medicine and Oral Pathology, School of Dentistry, National and Kapodistrian University of Athens, Athens, Greece3 DDS, MSc, PhD, Assistant Professor, Department of Oral Medicine and Oral Pathology, School of Dentistry, National and Kapodistrian University of Athens, Athens, Greece4 MD, PhD, Consultant Hematopathologist, 1st Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece5 DDS, MSc, PhD, Professor, Department of Oral Medicine and Oral Pathology, School of Dentistry, National and Kapodistrian University of Athens, Athens, Greece Department of Oral Medicine and Oral Pathology\nSchool of Dentistry, National and Kapodistrian University of Athens\n2 Thivon Str, 11527\nAthens, Greece\n, E-mail: echryso@dent.uoa.gr\nConflict of interest statement:The authors declare that they have no conflict of interest.\n\n1 12 2016 12 2016 8 5 e629 e633 28 2 2016 17 12 2015 Copyright: © 2016 Medicina Oral S.L.2016This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Methotrexate (MTX) is an established immunomodulating agent used in low doses (LDMTX) to treat several autoimmune diseases. Ulcerative stomatitis (US) may be observed as a long-term LDMTX adverse effect showing a wide histopathologic spectrum. A 73-year old female presented with painful oral ulcers of 5 days duration. The patient had been under treatment for rheumatoid arthritis with LDMTX, while one week before presentation she was prescribed ciprofloxacin for a urinary infection. Histopathologic examination of a lingual ulcer revealed a polymorphous lymphohistiocytic proliferation with scattered binucleated atypical lymphocytes. Immunohistochemically, most cells were of T-cell lineage while the EBER test was negative and a diagnosis of MTX-induced reactive ulceration was rendered. MTX cessation resulted in complete resolution of the ulcers with no recurrences reported so far. The clinical and histopathologic features of MTX-induced oral ulcers are not always diagnostic and a detailed history and an extensive clinicopathologic investigation may be needed to exclude a lymphoproliferative disorder.\n\n\n\n Key words:Atypical oral ulcers, ciprofloxacin, lymphoproliferative disorders, methotrexate.\n==== Body\nIntroduction\nMethotrexate (MTX), a well-known antimetabolite, functions as a folic acid antagonist and is widely used in high doses as a chemotherapeutic agent for the treatment of lymphomas, leukemias and some solid tumors (1). MTX is a well-established immuno-modulating drug that is administered in low doses (low-dose MTX-LDMTX), with concurrent folate supplementation for the treatment of chronic autoimmune and immune-mediated diseases such as rheumatoid arthritis, systemic lupus erythematosus and psoriasis (1,2).\n\nLDMTX administration may be accompanied by a variety of adverse reactions. MTX toxicity is generally dose-dependent and rapidly dividing tissues, such as the bone marrow and the gastrointestinal tract are most commonly affected. Oral ulcerative stomatitis may be seen in about 14% of patients demonstrating a wide histopathologic spectrum that ranges from non-specific ulceration to lichenoid reactions to EBV (+/-) lymphoproliferative disorders (LPDs) (2,3).\n\nA rare case of MTX-associated ulcerations is presented in a patient under long-term LDMTX that histopathologically exhibited atypical features mimicking a lymphoproliferative disorder.\n\nCase Report\nA 73-year-old, non-smoker Caucasian female presented in the Department of Oral Medicine and Pathology complaining of pain-ful oral lesions of 5-day duration. The lesions had been developed after initiation of a per os ciprofloxacin course (500 mg 1x3) on 5th therapy day for an acute urinary tract Escherichia coli infection diagnosed 10 days ago. Two days before the patient’s visit in our clinic, the urologist recommended ciprofloxacin replacement by metronidazole and cefaclor. According to the patient, similar lesions had appeared in the past after ciprofloxacin intake, though she was not sure regarding the MTX intake at that particular time.\n\nThe patient had a known rheumatoid arthritis (RA) history diagnosed 15 years ago. Medication for the RA management consisted of a low-dose methotrexate therapy (2.5mg 1x1/week) supplemented with folic acid (5mg 1x1/week), prednisone 5mg 1x1/day, in addition to a 5-courses of rituximab IV (Mabthera inj.sol 500mg/50ml 1/week x2) administration; the last rituximab IV injection was given 10 months before the lesions presentation. Alendronic acid (5600iu/tab 1x1/weekly) and daily calcium supplementation were taken for osteoporosis management.\n\nThe oral examination revealed multiple ulcerative lesions of variable size and irregular shape, located on the dorsal and lateral borders of the tongue, the lower lip, the alveolar maxillary and mandibular mucosa, which were covered by a grey-whitish thick pseudo-membrane (Fig. 1), and showed a slightly vegetative ulcer base. There was no evidence of other mucocutaneous lesions or cervical lymphadenopathy. LDMTX-associated oral ulcers, drug-induced oral reaction, drug-induced erythema multiforme and a possible atypical viral or bacterial infection were considered in the differential diagnosis, taking into account the iatrogenic immunosuppression history, the abrupt onset of lesions, and the possible drug reaction (previous report of ciprofloxacin-induced oral lesions).\n\nFigure 1 Atypical ulcers with irregular borders and yellow fibrinopurulent pseudomembrane on the dorsal surface of the tongue and the lower lip mucosa.\n\n\n\nTissue swabs from the ulcers were examined for viral, microbial and fungal infection, while a complete laboratory investigation was ordered. PCR tests for HSV, CMV and EBV were negative. A superimposed yeast infection by geotrichum candidum was detected, and interpreted to the long-standing iatrogenic immunosuppression. Complete blood test results were normal, including the folic acid levels. Elevated ESR and CRP levels and significant hypogammaglobulinemia (350 mg/dl, normal range: 700-1600 mg/dl) were noted. A lingual ulcer incisional biopsy was performed under local anesthesia.\n\nHistopathologic examination revealed extensive ulceration of the covering stratified squamous epithelium extended deeply into subjacent striated muscle and adipose tissue that showed degeneration. The ulcer base was widely infiltrated by a dense polymorphous inflammatory cell population consisting of lymphocytes, histiocytes of variable size, along with neutrophils and scarce eosinophils (Fig. 2a). Among the inflammatory infiltration few scattered large binucleated lymphoid cells with noticeable atypical features were observed similar to Reed-Sternberg cells (Fig. 2b). Both the polymorphous inflammatory cells and the Re-ed-Sternberg-like cells exhibited positive immunostaining for T-cell markers CD2, CD3, CD4, CD8 and CD15 and negative for B-cell and NK-cell markers (CD20, CD30, Pax-5, CD56, TIA-1 and granzyme) (Figs. 2c-d). LMP-1 immunostaining and EBER test proved to be negative excluding the EBV presence. The above findings were suggestive of an EBV (-) lymphocytic infiltrate of T-cell phenotype. Based upon the patient’s medical history, the complete laboratory investigation, the clinical and histopathologic findings, a diagnosis of MTX-related non-specific ulcerative stomatitis was rendered, possibly induced by the recent ciprofloxacin administration.\n\nFigure 2 a) Diffuse mixed inflammatory infiltrate of the lamina propria by lymphocytes of varying size, histiocytes, neutrophils, and scarce eosinophils. b) Scattered irregularly-shaped binucleated atypical lymphocytes (Reed-Sternberg-like cells, asterisks) among the dense cellular infiltrate (H&E X250). Immunohistochemical evaluation revealed, among other markers, positivity for CD2 c) and CD4 d), (immunohistochemical stain X400).\n\n\n\nWith the rheumatologist’s consent, MTX intake was ceased and 3 weeks later the oral ulcers had healed completely (Fig. 3). Two months after MTX withdrawal, the drug was restarted, with no evidence of recurrence of the oral lesions noted so far.\n\nFigure 3 Resolution of the lingual and labial ulcers 3 weeks after MTX cessation.\n\n\n\nThe patient had provided written informed consent for publication of this case report and any accompanying images in a scientific journal, after the authors explained the possible benefits to dental science.\n\nDiscussion\nLDMTX adverse reactions may be present in 30-80% of the patients, while up to 30% discontinue the treatment as a consequence (2). Common side effects include myelosuppresion, nausea, diarrhea, abdominal pain, weight loss, and hepatotoxicity. The oral lesions seem to be dose-dependent, and a possible early sign of drug toxicity. Stomatitis has been referred in approximately 14%, and treatment discontinue in 3% of the patients, thus oral clinicians may be encountered with a MTX-induced lesion more often than previously thought (3). The risk of MTX-induced ulcers appears to be increased in patients with pre-existing folate deficiency. Elevated drug levels in the saliva acting topically are considered to promote the oral lesions development. Measurement of the excreted MTX concentration in the saliva has been proposed useful in predicting oral ulceration (3,4).\n\nThe LDMTX-associated oral ulcers may be apparent within the first few weeks, whereas in long-term toxicity the lesions can occur even years later in the disease course (2). MTX metabolism may be affected by age, compromised hepatic or renal function, whereas several contraindicated drugs may influence pharmacokinetics (1). Among them, quinolones and specifically ciprofloxacin may promote a reduced renal tubular MTX clearance resulting in MTX plasma levels elevation (5). In the current case, the ulcerative lesions appeared after a 5-day course of ciprofloxacin administration suggesting an acute MTX toxicity, despite the patient was under LDMTX treatment.\n\nLDMTX-associated stomatitis may mimic various oral inflammatory conditions, infections or vesiculobullous diseases (3,6). In our case, the differential diagnosis included the ciprofloxacin-induced oral minor erythema multiforme (EM) due to patient’s history of similar oral lesions in the past, as well as herpes-associated EM, due to immunosuppresion. The possibility of oral EM seemed more unlikely based on the clinical features of the lesions, the lack of the EM characteristic hemorrhagic crusts on the lips vermillion border, and the gingival involvement that usually is not seen in EM.\n\nThe etiology of multiple, deep painful ulcers covered by thick necrotic pseudomembrane in medically immunocompromised patients may be associated with HSV, CMV or bacterial infection. Among the affected oral sites, dorsal tongue, hard palate, and/or gingiva have been referred as frequent locations (7). A possible infection was also considered in the differential diagnosis, but the microbiologic tests proved to be negative, additionally to the fact that the patient was already under a course of broad-spectrum antibiotics.\n\nThe interval between initiation of MTX therapy and MTX-induced LPDs varies, with most patients diagnosed after 3-5 years of continuous treatment (8). Several tissues and/or internal organs can be affected, including liver, kidneys, gastrointestinal mucosa, lung, spleen and skin. Besides the MTX-treatment associated neoplastic potential, the risk for hematopoietic malignancies, most often lymphoma, is 2-20-fold increased in patients with RA (3). Among them, MTX administration has been especially linked to the development of EBV-related LPDs (9).\n\nThe histopathologic diagnosis of LDMTX oral ulcers may be challenging, since the lesions comprise a wide spectrum of features (3,9). Twelve cases of oral LPDs in patients under LDMTX have been published in the English literature ( Table 1). Despite the well-established incidence of these lesions, to the best of our knowledge, this is the first case that was characterized by the finding of atypical Reed-Sternberg-like cells sharing features similar to a lymphoproliferative disorder, causing diagnostic dilemma. Atypical EBV negative cells simulating a lymphoma has not been referred in the previously published cases, though Kalantzis et al. described atypical cells in the ulcer base, but further specific analysis was not provided (3).\n\nTable 1 Reported cases of oral LDMTX-LPDs in the English-language literature.\n\n\nTreatment of MTX-induced oral lesions consists of drug cessation or dose reduction, supplemented sometimes with folate administration, topical palliative therapies or conservative surgical excision. The gradual MTX polyglutamates clearance may result in healing of the ulcers within 2-3 weeks. A close follow-up course is of paramount importance, since recurrence of the lesions has been referred after a few months of drug removal in nearly 50% of patients (3,4,15).\n\nIn conclusion, a careful medical and pharmacologic history, along with a recent full blood test investigation is mandatory in patients under MTX intake. Clinicians should be aware of the possible side effects of LDMTX in the oral mucosa, as well as the drug pharmacokinetics, to avoid prescription of a contraindicated drug that may interfere with MTX metabolism.\n==== Refs\n1 Said S Jeffes EW Weinstein GD Methotrexate Clin Dermatol 1997 15 781 97 9313976 \n2 Troeltzsch M von Blohn G Kriegelstein S Woodlock T Gassling V Berndt R Oral mucositis in patients receiving low-dose methotrexate therapy for rheumatoid arthritis: report of 2 cases and literature review Oral Surg Oral Med Oral Pathol Oral Radiol 2013 115 28 33 23601229 \n3 Kalantzis A Marshman Z Falconer DT Morgan PR Odell EW Oral effects of low-dose methotrexate treatment Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005 100 52 62 15953917 \n4 Hashimoto K Nagao T Saito T Kinoshita H Methotrexate-associated lymphoproliferative disorders of the tongue developing in patients with rheumatoid arthritis: a report of 2 cases and a review Oral Surg Oral Med Oral Pathol Oral Radiol 2015 119 e1 5 24927637 \n5 Dalle JH Auvrignon A Vassal G Leverger G Interaction between methotrexate and ciprofloxacin J Pediatr Hematol Oncol 2002 24 321 2 11972105 \n6 Horie N Kawano R Kaneko T Shimoyama T Methotrexate-related lymphoproliferative disorder arising in the gingiva of a patient with rheumatoid arthritis Aust Dent J 2015 60 408 11 25302816 \n7 Mainville GN Marsh WL Allen CM Oral ulceration associated with concurrent herpes simplex virus, cytomegalovirus, and Epstein-Barr virus infection in an immunocompromised patient Oral Surg Oral Med Oral Pathol Oral Radiol 2015 119 e306 14 25544404 \n8 Kudoh M Harada H Matsumoto K Sato Y Omura K Ishii Y Methotrexate-associated lymphoproliferative disorder arising in the retromolar triangle and lung of a patient with rheumatoid arthritis Oral Surg Oral Med Oral Pathol Oral Radiol 2014 118 e105 10 24811204 \n9 Dojcinov SD Venkataraman G Raffeld M Pittaluga S Jaffe ES EBV positive mucocutaneous ulcer-a study of 26 cases associated with various sources of immunosuppression Am J Surg Pathol 2010 34 405 17 20154586 \n10 Ishida M Hodohara K Yoshii M Okuno H Horinouchi A Nakanishi R Methotrexate-related Epstein-Barr virus-associated lymphoproliferative disorder occurring in the gingiva of a patient with rheumatoid arthritis Int J Clin Exp Pathol 2013 6 2237 41 24133604 \n11 Kikuchi K Miyazaki Y Tanaka A Shigematu H Kojima M Sakashita H Methotrexate-related Epstein-Barr Virus (EBV)-associated lymphoproliferative disorder-so called \"Hodgkin-like lesion\"- of the oral cavity in a patient with rheumatoid arthritis Head Neck Pathol 2010 4 305 11 20676828 \n12 Uneda S Sonoki T Nakamura Y Matsuoka H Nakakuma H Rapid vanishing of tumors by withdrawal of methotrexate in Epstein-Barr virus-related B cell lymphoproliferative disorder Intern Med 2008 47 1445 6 18670155 \n13 Tanaka A Shigematsu H Kojima M Sakashita H Kusama K Methotrexate-associated lymphoproliferative disorder arising in a patient with adult Still's disease J Oral Maxillofac Surg 2008 66 1492 5 18571037 \n14 Pastor-Nieto MA Kilmurray LG López-Chumillas A O'Valle F Garcia-Del Moral R Puig AM Methotrexate-associated lymphoproliferative disorder presenting as oral ulcers in a patient with rheumatoid arthritis Actas Dermosifiliogr 2009 100 142 6 19445880 \n15 Naidu A Kessler HP Pavelka MA Epstein-Barr virus-positive oral ulceration simulating Hodgkin lymphoma in a patient treated with methotrexate: case report and review of the literature J Oral Maxillofac Surg 2014 72 724 9 24246254\n\n",
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"title": "Atypical methotrexate ulcerative stomatitis with features of lymphoproliferative like disorder: Report of a rare ciprofloxacin-induced case and review of the literature.",
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"abstract": "Malignant bowel obstruction (MBO) frequently defines the trajectory of end-stage ovarian cancer and results in severe physical and psychological distress in patients and their caregivers. Venting gastrostomy (VG) is an alternative to both prolonged medical therapy with nasogastric intubation and intestinal bypass/diversion for refractory MBO. Limited published data from large academic research centers support use of VG in patients with advanced ovarian cancer and MBO. In this case series, we describe supportive care outcomes in ovarian cancer patients with MBO receiving the effects of VG in a community setting. Six cases of advanced ovarian cancer involving MBO were evaluated for VG from July 2009 through February 2012. Five of six patients were managed with VG. Our experience suggests that VG may be beneficial in controlling nausea and vomiting in ovarian cancer patients with MBO and that VG placement with concurrent evacuation of large-volume ascites was associated with minimal complications. Future prospective studies to evaluate the benefits of VG are warranted.",
"affiliations": "1 St. Mary's Medical Center , Huntington, West Virginia.;2 Department of Palliative Care and Rehabilitation Medicine, UT MD Anderson Cancer Center , Houston, Texas.",
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"abstract": "Methotrexate is a frequently prescribed drug and is considered to be safe at a low dosage. However, serious complications may occur during treatment. In this article we describe a 78-year-old male who used low-dose methotrexate for psoriatic arthritis. He died of multi-organ failure caused by sepsis and methotrexate intoxication as a result of deteriorating renal function. The second patient was a 56-year-old male who used low-dose methotrexate for rheumatoid arthritis. This patient developed pancytopenia and methotrexate pneumonitis during treatment with methotrexate. We recommend the frequent monitoring of blood count and renal and liver function tests to detect early deterioration. Furthermore, doctors should be aware of conditions and factors predisposing to methotrexate intoxication, such as impaired kidney function and co-medication. If methotrexate intoxication is suspected, intravenous folinic acid should be administered immediately.",
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"abstract": "Calcineurin-inhibitor induced pain syndrome (CIPS) also called the \"symmetrical bone syndrome\" is a condition describing reversible lower extremity pain in patients after organ transplantation who are receiving calcineurin inhibitors, especially tacrolimus. We present a case of CIPS after orthotopic heart transplant complicated with concurrent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We emphasize the presentation; diagnostic evaluation, and findings. We then discuss the proposed pathophysiologic mechanisms of CIPS and conclude with discussion of management strategies. Additionally, we present a table to guide clinicians in assessing posttransplant bone pain syndromes. To our knowledge, this is the first article to describe a case of CIPS with concurrent SARS-CoV-2 infection.",
"affiliations": "Section of Advanced Heart Failure and Transplant Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana. Electronic address: oilonze@iu.edu.;Section of Advanced Heart Failure and Transplant Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.;Section of Advanced Heart Failure and Transplant Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.;Section of Advanced Heart Failure and Transplant Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.;Section of Advanced Heart Failure and Transplant Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.;Section of Advanced Heart Failure and Transplant Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.",
"authors": "Ilonze|Onyedika J|OJ|;Giovannini|Marina|M|;Jones|Mark A|MA|;Rao|Roopa|R|;Ballut|Kareem|K|;Guglin|Maya|M|",
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"abstract": "Objective: To evaluate the efficacy and safety of low-dose mycophenolate mofetil (MMF, 1,000 mg/day) treatment of neuromyelitis optica spectrum disorders (NMOSDs). Methods: This study was a multicenter, open, prospective, follow-up clinical trial. The data include retrospective clinical data from the pretreatment phase and prospective data from the post-treatment phase. From September 2014 to February 2017, NMOSD patients seropositive for aquaporin 4-IgG (AQP4-IgG) were treated with low-dose MMF. Results: Ninety NMOSD patients were treated with MMF for a median duration of 18 months (range 6-40 months). The median annual recurrence rate (ARR) decreased from 1.02 before treatment to 0 (P < 0.0001) after treatment, and the Expanded Disability Status Scale (EDSS) score decreased from 4 to 3 (P < 0.0001). The EDSS score was significantly lower (P = 0.038) after the first 90 days of treatment. The serum AQP4-IgG titer decreased in 50 cases (63%). The median Simple McGill pain score (SF-MPQ) was reduced in 65 patients (88%) with myelitis from 17 (range 0-35) to 11 (range 0-34) after treatment (P < 0.0001). The median Hauser walking index (Hauser Walk Rating Scale) was reduced from 2 (range 1-9) before treatment to 1 (range 0-7) after treatment (P < 0.0001). Adverse events were documented in 43% of the patients, and eight patients discontinued MMF due to intolerable adverse events. Fourteen (16%) of the total patients discontinued MMF after our last follow-up for various reasons and switched to azathioprine or rituximab. Conclusion: Low-dose MMF reduced clinical relapse and disability in NMOSD patients in South China. However, some patients still suffered from adverse events at this dosage.\n\n\n\nwww.ClinicalTrials.gov, identifier : NCT02809079.",
"affiliations": "Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.;Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.;Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.;Department of Neuro-Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.;Department of Neurology, Guangdong 999 Brain Hospital, Guangzhou, China.;Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.;Department of Neurology, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.;Department of Neurology, Nanfang Hospital, Guangzhou, China.;Department of Neurology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.;School of Mathematics, Sun Yat-sen University, Guangzhou, China.;Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.;Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.;Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.",
"authors": "Huang|Qiao|Q|;Wang|Jingqi|J|;Zhou|Yifan|Y|;Yang|Hui|H|;Wang|Zhanhang|Z|;Yan|Zhenwen|Z|;Long|Youming|Y|;Yin|Jia|J|;Feng|Huiyu|H|;Li|Caixia|C|;Lu|Zhengqi|Z|;Hu|Xueqiang|X|;Qiu|Wei|W|",
"chemical_list": "C496030:AQP4 protein, human; D051401:Aquaporin 4; D001323:Autoantibodies; D000069283:Rituximab; D009173:Mycophenolic Acid; D001379:Azathioprine",
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fimmu.2018.02066",
"fulltext": "\n==== Front\nFront ImmunolFront ImmunolFront. Immunol.Frontiers in Immunology1664-3224Frontiers Media S.A. 10.3389/fimmu.2018.02066ImmunologyClinical TrialLow-Dose Mycophenolate Mofetil for Treatment of Neuromyelitis Optica Spectrum Disorders: A Prospective Multicenter Study in South China Huang Qiao 12†Wang Jingqi 1†Zhou Yifan 1†Yang Hui 3Wang Zhanhang 4Yan Zhenwen 5Long Youming 6Yin Jia 7Feng Huiyu 8Li Caixia 9Lu Zhengqi 1Hu Xueqiang 1Qiu Wei 1*1Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China2Department of Neurology, Zhaoqing No. 2 People's Hospital, Zhaoqing, China3Department of Neuro-Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China4Department of Neurology, Guangdong 999 Brain Hospital, Guangzhou, China5Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China6Department of Neurology, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China7Department of Neurology, Nanfang Hospital, Guangzhou, China8Department of Neurology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China9School of Mathematics, Sun Yat-sen University, Guangzhou, ChinaEdited by: Fabienne Brilot, University of Sydney, Australia\n\nReviewed by: Romain Marignier, Hospices Civils de Lyon, France; Sudarshini Ramanathan, University of Sydney, Australia; Michael Levy, Johns Hopkins University, United States\n\n*Correspondence: Wei Qiu qiuwei120@vip.163.comThis article was submitted to Multiple Sclerosis and Neuroimmunology, a section of the journal Frontiers in Immunology\n\n†These authors have contributed equally to this work and share first authorship\n\n11 9 2018 2018 9 206606 6 2018 21 8 2018 Copyright © 2018 Huang, Wang, Zhou, Yang, Wang, Yan, Long, Yin, Feng, Li, Lu, Hu and Qiu.2018Huang, Wang, Zhou, Yang, Wang, Yan, Long, Yin, Feng, Li, Lu, Hu and QiuThis 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.Objective: To evaluate the efficacy and safety of low-dose mycophenolate mofetil (MMF, 1,000 mg/day) treatment of neuromyelitis optica spectrum disorders (NMOSDs).\n\nMethods: This study was a multicenter, open, prospective, follow-up clinical trial. The data include retrospective clinical data from the pretreatment phase and prospective data from the post-treatment phase. From September 2014 to February 2017, NMOSD patients seropositive for aquaporin 4-IgG (AQP4-IgG) were treated with low-dose MMF.\n\nResults: Ninety NMOSD patients were treated with MMF for a median duration of 18 months (range 6–40 months). The median annual recurrence rate (ARR) decreased from 1.02 before treatment to 0 (P < 0.0001) after treatment, and the Expanded Disability Status Scale (EDSS) score decreased from 4 to 3 (P < 0.0001). The EDSS score was significantly lower (P = 0.038) after the first 90 days of treatment. The serum AQP4-IgG titer decreased in 50 cases (63%). The median Simple McGill pain score (SF-MPQ) was reduced in 65 patients (88%) with myelitis from 17 (range 0–35) to 11 (range 0–34) after treatment (P < 0.0001). The median Hauser walking index (Hauser Walk Rating Scale) was reduced from 2 (range 1–9) before treatment to 1 (range 0–7) after treatment (P < 0.0001). Adverse events were documented in 43% of the patients, and eight patients discontinued MMF due to intolerable adverse events. Fourteen (16%) of the total patients discontinued MMF after our last follow-up for various reasons and switched to azathioprine or rituximab.\n\nConclusion: Low-dose MMF reduced clinical relapse and disability in NMOSD patients in South China. However, some patients still suffered from adverse events at this dosage.\n\nClinical Trial Registration: www.ClinicalTrials.gov, identifier : NCT02809079.\n\nneuromyelitis optica spectrum disordersmycophenolate mofetiltherapya prospective studySouth China\n==== Body\nIntroduction\nNeuromyelitis optica spectrum disorders (NMOSDs) are different from multiple sclerosis and represent a type of B cell-mediated astrocytopathic glial disease (1, 2). NMOSDs mainly affect the optic nerve, spinal cord, and area postrema of the medulla oblongata. NMOSDs have overall high recurrence disability rates. The recurrence rate of NMOSDs is increased in patients with specific biomarkers, such as aquaporin 4-IgG (AQP4-IgG), and the degree of disability increases with the cumulative effects of relapse (3). Therefore, clinicians urgently need to find effective and safe immunomodulatory drugs to treat this condition.\n\nTo date, no treatment for NMOSDs has been granted regulatory approval. Because the disease is rare, most relevant clinical studies include small samples and have a retrospective design, and no controlled clinical studies have been reported. Azathioprine (AZA), mycophenolate mofetil (MMF) and rituximab (RTX) are the most widely used agents to treat NMOSDs (4). Our recent study showed that MMF had the same efficacy but fewer adverse events than AZA (5). RTX is more effective than MMF or AZA in preventing relapses and stabilizing disability (6–11). However, the need for regular redosing and monitoring, the cost, and the availability of RTX limit its broad usage in a sizable proportion of NMOSD patients.\n\nMMF has been used in organ transplantation recipients (12) and rheumatoid disease patients (13, 14). Recently, MMF has been gradually introduced as a treatment for neuroimmunological diseases with some success (15–17). Multiple studies have shown that MMF is effective as a treatment for NMOSDs (18–20), and its effect may be better than that of AZA and other traditional immunosuppressive agents (6, 21). The efficiency of MMF is not affected by previous use of other immunosuppressant (6–8, 21, 22). A few studies have reported that MMF is associated with significant adverse events, such as diarrhea, liver enzyme abnormalities, infection, bone marrow suppression, and the occurrence of progressive multifocal cerebral white encephalopathy (6–8, 18, 19, 21, 23).\n\nThe dose of MMF used across different institutes for clinical treatment varies, with the dose used in organ transplantations ranging from 250 mg/day to 3,000 mg/day (24, 25). Similarly, in the past, NMOSD patients have received MMF doses of 750–3,000 mg/day, but the safety of the medication has not been fully defined. Therefore, we conducted a multicenter clinical trial to evaluate the efficacy and safety of low-dose MMF for the treatment of NMOSD patients seropositive for AQP4-IgG in South China.\n\nMaterials and methods\nStudy design\nThis study is a multicenter, open, prospective, follow-up, and self-controlled study (ClinicalTrials.gov ID: NCT02809079). The data include retrospective clinical data from the pretreatment phase and prospective data from the post treatment phase. This study was approved by the medical ethics committee of the Third Affiliated Hospital of Sun Yat-sen University (Approval No. the Third Affiliated Hospital of Sun Yat-sen University (2014)2-15 and the Third Affiliated Hospital of Sun Yat-sen University (2015)2-147 No. 1). Eleven patients were enrolled between September 2014 and February 2015 according to the 2006 NMO diagnostic criteria after ethical approval was granted in 2014. Then, the approval was updated following publication of new diagnostic criteria in 2015. The initial 11 patients were reappraised, and all patients conformed to the new criteria. All patients voluntarily provided informed consent.\n\nSubjects (Figure 1)\nInclusion criteria: (1) conformed to the 2006 NMO diagnostic criteria (26) or 2015 NMOSD diagnostic criteria (4); (2) seropositive for AQP4-IgG; (3) aged 18 years old or older; (4) more than 2 relapses within the 2 years prior to MMF treatment or more than 1 attack in the 1 year prior to treatment; and (5) all other immunosuppressive agents were suspended except for glucocorticoids for more than 3 months.\n\nFigure 1 Flow chart of the inclusion and exclusion processes.\n\nExclusion criteria: (1) transaminase levels beyond the upper limit of normal values; (2) routine blood tests: white blood cell count (WBC) < 4 × 109/L, hemoglobin (HGB) < 110 g/L, and platelet count (PLT) < 100 × 109/L; (3) complications, such as serious circulatory system or other diseases or malignant tumors, immune deficiency, or infection; (4) pregnancy or lactation in women or a recent planned pregnancy for males or females; and (5) a malacetil or glucocorticoid allergy.\n\nAQP4-IgG was tested in the Department of Neurology, the Third Affiliated Hospital of Sun Yat-sen University, using a cell-based assay with HEK293T cells transfected with human AQP4-M23 genes.\n\nTherapeutic regimen\nAll patients were treated with MMF plus oral prednisone or methylprednisolone. The total treatment duration for the glucocorticoid was 18 months. The MMF dosage was 500 mg/day for the first 2 weeks and was adjusted to 1,000 mg/day after 2 weeks. Patients who had a relapse were administered intravenous methylprednisolone (500–1,000 mg/day) for 3–5 days, followed by oral prednisone at 30 mg/day (or methylprednisolone at 24 mg/day) for 8 weeks. The prednisone or methylprednisolone dosage was decreased by 5 mg or 4 mg, respectively, every 3 weeks until it reached 10 or 8 mg, respectively, and then was administered every other day.\n\nWe prospectively collected clinical features (e.g., disease onset time, relapse time, and recurrences) and evaluated disability, magnetic resonance imaging (MRI) results, immunosuppressant use, the course of drug use, and relevant adverse events.\n\nEfficacy assessments\nThe average annual recurrence rate (ARR) before and after MMF treatment was the primary clinically effective outcome. Clinical recurrence was defined as a new symptom of a functional nervous system defect that lasted more than 24 h, an increase in the Expanded Disability Status Scale (EDSS) score of by more than 0.5 points, or MRI results confirming the existence of new lesions.\n\nThe degree of disability before and after MMF treatment was the secondary clinically effective outcome and was defined using functional evaluations [i.e., EDSS, SF-MPQ, and the Hauser walking index (Hauser Walk Rating Scale) scores] and structural evaluations (i.e., the longitudinal focus of a spinal T2 sequence on MRI).\n\nSafety assessments\nIn this trial, the rate of MMF-relevant adverse events was used as a safety evaluation index. MMF-relevant adverse events were defined as the occurrence of adverse events in line with the characteristics of MMF metabolism. Symptoms must show a clear sequence and improve after suspending MMF. Drug-relevant adverse events, their occurrence times, and the implemented treatment plans were recorded.\n\nStatistical analysis\nData were analyzed using the R-Studio open source software R-Studio 3.1. The figures were constructed using GraphPad Prism, version 5 (GraphPad Software, La Jolla, CA). A paired Wilcoxon rank sum test was used to compare changes in the titers before and after MMF treatment. A Kaplan-Meier curve was used to compare the incidence of adverse events before and after MMF (95% confidence interval), and the rates were compared using the log-rank test. A meta-analysis was conducted with the R package “metafor” to combine 7 MMF treatment studies of NMOSD patients. The heterogeneity test was performed to detect dispersion across effect sizes, and then the fixed (or random) effects model under no heterogeneity (or under heterogeneity) was constructed to obtain the combined effect. P < 0.05 was considered significant.\n\nResults\nClinical features (Table 1)\nFrom September 2014 to February 2017, 91 patients with serum AQP4-IgG-positive NMOSDs were enrolled for MMF treatment. Among these cases, 1 discontinued MMF on the fourteenth day due to an accidental pregnancy and experienced a relapse during the second month after delivery. The remaining 90 patients were included in the statistical analysis. Seventy patients were treated only with glucocorticoid prior to MMF treatment. The median therapeutic course was 17 months (range 1–32 months). The other 20 patients received AZA combined with glucocorticoid therapy for a median of 14 months (range 6–66 months) before receiving MMF treatment. These patients had experienced a relapse or adverse events and had stopped AZA more than 3 months prior to beginning MMF treatment. At the last follow-up, 14 cases (15.6%) had switched from MMF to AZA or RTX.\n\nTable 1 Clinical characteristics of the 90 NMOSD patients.\n\nClinical characteristic\tValue\t\nTotal patients\t90\t\nFemale to male ratio\t14:1\t\nAge of onset (y)\t36 (10–65)\t\nDisease duration before MMF (mo)\t52 (1–271)\t\n ARR pre-MMF\t1.02 (0.0–19.21)\t\n ARR post-MMF\t0 (0–2.44)\t\n EDSS pre-MMF\t4.0 (0.0–8.5)\t\n EDSS post-MMF\t3.0 (0.0–8.0)\t\nOther autoantibodies, n (%)\t34 (37.8)\t\nOther autoimmune diseases, n (%)\t4 (4.3)\t\nAdverse event, n (%)\t39 (43)\t\nPatients who received AZA before MMF\t20\t\n ARR pre-MMF\t0.92 (0.09–1.90)\t\n ARR post-MMF\t0 (0–2.00)\t\n EDSS pre-MMF\t4.0 (3.0–7.5)\t\n EDSS post-MMF\t3.0 (1.0–5.0)\t\nPatients who were immunosuppressant naive\t70\t\n ARR pre-MMF\t1.02 (0–19.21)\t\n ARR post-MMF\t0 (0–2.44)\t\n EDSS pre-MMF\t4.0 (0.0–8.5)\t\n EDSS post-MMF\t3.0 (0.0–8.0)\t\nARR, annual recurrence rate; EDSS, Expanded Disability Status Scale score. Data are presented as the frequency (%) or median with range.\n\nEfficacy assessments\nRelapsing\nNinety patients with NMOSDs were treated with MMF at a dose of 1,000 mg/day. For the ARR analysis, we excluded patients with an MMF treatment duration of less than 6 months. The median duration of treatment for the remaining 86 patients was 18 months (range 6–40 months). The median ARR decreased from 1.02 before treatment to 0 after treatment (P < 0.0001); a total of 90% of the patients had a reduction in their ARRs, and 73% patients experienced no clinical recurrence (Figure 2). The mean duration of follow-up after introduction of MMF was 13.5 months, although three cases were followed up for < 1 year. Furthermore, some other studies did not exclude patients with a disease duration of < 12 months (19).\n\nFigure 2 Clinical episodes before and after MMF treatment. For the ARR analysis, we excluded patients with an MMF treatment duration of less than 6 months. The median duration of treatment for the 86 patients was 18 months (range 6–40 months), and the median ARR decreased from 1.02 before treatment to 0 after treatment (P < 0.0001). A total of 90% of the patients had a reduction in the ARR, and 73% of the patients had no clinical recurrence.\n\nIn this study, a subgroup analysis was performed based on whether or not the patient was previously treated with AZA. For the 67 patients who were initially treated with MMF plus glucocorticoid, the median ARR decreased from 1.02 to 0 (P < 0.0001), and the ARR decreased in 90% of the patients. Nineteen patients were previously treated with AZA combined with corticosteroids before switching to MMF with corticosteroids. The median ARR in these patients decreased from 1 to 0 (P < 0.0001), and the ARR decreased in 91% of these patients. The Cox model was used to correct for sex and age after the Kaplan-Meier survival analysis (Supplementary Figure 2) and showed that the two groups had a significantly lower risk of relapse after treatment with MMF combined with a glucocorticoid (HR = 0.308, 95% CI: 0.209–0.455; P < 0.001). However, no significant difference was observed between the two groups (P = 0.762).\n\nDisability\nOf the 90 patients treated with MMF combined with a glucocorticoid, the EDSS score decreased from 4 before treatment to 3 after treatment (P < 0.001), and the EDSS score decreased or stabilized in 90% of the enrolled patients. The EDSS score began to decrease after 90 days of MMF treatment, and a significant difference was observed between the groups (P = 0.0038). The median Simple McGill pain score (SF-MPQ) was reduced in 65 patients (88%) with myelitis from 17 (range 0–35) to 11 (range 0–34) after treatment (P < 0.0001). The median Hauser walking index (Hauser Walk Rating Scale) was reduced from 2 (range 1–9) before treatment to 1 (range 0–7) after treatment (P < 0.0001).\n\nSerum AQP4-IgG titers\nAll patients were serum AQP4-IgG-positive. The serum AQP4-IgG titers were measured in 79 patients before and after MMF treatment. The median AQP4-IgG titer was 100 (range 10–320) at the beginning of MMF treatment and dropped to 32 (0–100) at the end of the follow-up period (p < 0.001). The titer decreased in 63% of the patients, and 14% (11/79) of the patients had negative antibody results after treatment. Eight patients who were negative for AQP4-IgG antibodies experienced no clinical recurrence after a median follow-up of 16 months (range 13–26 months) (Supplementary Figure 1).\n\nSpinal cord MRI\nThe spinal cord MRI results were compared among 44 patients before and after MMF treatment. The median length of the observed lesion segments was 6 (range 0–17) at the beginning of MMF treatment and dropped to 2.5 (range 0–15) at the end of treatment. In total, 75% of the patients showed a decrease in spinal cord lesions; the lesions were completely absorbed in 32% (14/44) of these patients (Supplementary Figure 1).\n\nSafety assessments (Table 2)\nDuring the study, 43% (39/90) of the patients experienced MMF-related adverse events, which were concentrated during the period from 14 to 360 days after initiation of MMF treatment. These events included digestive system symptoms (24%, 22/90), infections (23%, 21/90), blood system abnormalities (11%, 10/90), and other adverse effects (hair loss 2%, 2/90; rectal cancer, 1%, 1/90; and renal insufficiency, 1%, 1/90). After correction in the Cox model, the Kaplan-Meier survival (Figure 3) analysis showed that the rate of adverse events associated with MMF combined with glucocorticoid treatment decreased significantly (HR = 0.434, 95% CI: 0.202–0.933; P = 0.003).\n\nTable 2 Adverse events after MMF treatment in 90 NMOSD patients.\n\n\tPatients with adverse events, n (%)\tPatients discontinuing MMF because of AE, n (%)\t\nTotal, n (%)\t39 (43)\t8 (9)\t\nGastrointestinal AE, n (%)\t22 (24)\t2 (2)\t\n Diarrhea\t2 (2)\t1 (1)\t\n Deranged liver enzymes\t18 (20)\t1 (1)\t\n Hyperbilirubinemia\t2 (2)\t0 (0)\t\nInfections, n (%)\t21 (23)\t3 (3)\t\n Respiratory infection\t11 (12)\t2 (2)\t\n Urinary tract infection\t5 (6)\t0 (0)\t\n Varicella-zoster virus infection\t5 (6)\t1 (1)\t\nHematological AE, n (%)\t10 (11)\t0 (0)\t\n Anemia\t6 (7)\t0 (0)\t\n Leucopenia\t4 (4)\t0 (0)\t\nOthers, n (%)\t4 (4)\t3 (3)\t\n Rectal cancer\t1(1)\t1 (1)\t\n Renal insufficiency\t1(1)\t1 (1)\t\n Hair loss\t2 (2)\t1 (1)\t\nAE, adverse event. Data are presented as the frequency (%).\n\nFigure 3 Kaplan-Meier survival analysis pertaining to the probabilities of adverse events pre-MMF and post-MMF in 90 patients. All patients were prescribed MMF at time 0. The incidence of adverse events decreased significantly after MMF administration compared to that before MMF treatment (HR = 0.434, 95% CI: 0.202–0.933; P = 0.003).\n\nIn total, 9% (8/90) of the patients terminated MMF treatment, and one patient was converted to AZA treatment. In particular, 2 of the 3 cases of severe pneumonia needed ventilator support. Additionally, 1 patient had “hemorrhagic varicella” in the third month of MMF treatment at a dosage of 1,000 mg/d and died of acute respiratory distress syndrome 4 days later. One patient was treated with MMF for 6 months, had a serum carcinogenic embryonic antigen (CEA) level of 20.90 μg/L, and received an electron colonoscopy indicating a rectal tumor; the pathology of the mass indicated a differentiated adenocarcinoma. MMF was discontinued in this patient, who was subsequently treated with chemotherapy.\n\nMeta-analysis (Supplementary Figure 2)\nA meta-analysis was performed for 7 studies that evaluated MMF treatments in NMOSD patients, including the present study. The median decline in the ARR rate was 0.88, and the rate of stability or decline in the EDSS score was 0.91. In this study, the ARR decreased in 90% of the NMOSD patients, and no clinical recurrence occurred in 73% of the patients. In 90% of the patients, the EDSS score was stable or decreased, and no significant difference was observed between these results and those reported in previous studies.\n\nDiscussion\nIn this study, the rationale for the use of a lower MMF dose (1,000 mg/day) includes the following. (1) According to our domestic consensus on NMOSD treatment, the recommended MMF dosage is 1.0–1.5 g per day in China (27). (2) Our previous studies have shown that a daily dosage of 20 mg/kg is effective (17). (3) Several studies have reported a higher possibility of adverse events associated with higher MMF doses. A dose-finding study by Squifflet et al. (28) found that a daily dose of 1.0 g was associated with a lower rate of gastrointestinal and hematologic adverse events. Mourad et al. (24) also demonstrated that a 2.0 g dose per day was associated with higher risk of side effects. (4) Finally, economic cost and treatment compliance were taken into consideration for NMOSDs, because the duration of the therapy might be long.\n\nThe results of this study demonstrated that a low MMF dose could also effectively reduce the recurrence of NMOSDs and disability. Therefore, we suggest that low-dose MMF can be used in clinical practice, especially in patients in South China with a high relapse risk, high serum AQP4-IgG titers and long segment myelitis, but patients must be closely monitored for adverse reactions. After 90 days of MMF treatment, a significant difference was found in the EDSS scores. Moreover, in this study, the ARRs and EDSS scores were significantly lower in the 20 (22.2%) patients who converted to MMF following AZA treatment, indicating that MMF could be used as a substitute for AZA in patients who did not respond well to AZA. This result is in agreement with the report by Elsone et al. (29), which showed that 46% of NMOSD patients suffered from intolerance or ineffective treatment after AZA treatment. In this study, 27% of the patients still suffered recurrences, which were concentrated within 90–450 days of treatment initiation. Of these patients, 6 cases were changed treatments indicating that some patients experienced poor MMF effects. These unsatisfactory effects may be related to factors such as sex (30, 31), autoantibody production (32), and high serum AQP4-IgG titers (33–35).\n\nAlthough a lower MMF dose combined with glucocorticoid therapy was used in this study, the adverse events rate (43%) was higher than the rates reported in previous studies. These events, including altered transaminase levels and opportunistic infections, caused 9% of the patients to terminate MMF treatment, which was similar to the proportion observed in another study in which MMF was combined with small-dose glucocorticoids (36, 37). In the meta-analysis (Supplementary Figure 3), the median adverse event rate was 0.29. In this study, the MMF dose was small, but the adverse event rate was higher than the rates reported in previous studies (at an MMF dose of 1,500–3,000 mg/day). We propose that these discrepancies might be related to the following factors: (1) differences in research and study designs, because this study was designed for prospective follow-up and therefore was more likely to record adverse events, and (2) differences in the patient population. For example, a great deal of interindividual variation exists in drug enterohepatic circulation pathways, and the pharmacokinetics of MMF are unstable (38, 39).\n\nWe acknowledge that this study has some weaknesses. First, this study did not include a randomized, double blind, cohort design. Additionally, the study lacked a control group. However, the median NMOSD disease duration prior to inclusion was 52 months, and the ARR calculation was based on a long observation period. Therefore, the significant reduction in the relapse rate in our study was most likely evidence of a therapeutic effect and not secondary to recruitment of outlier NMOSD patients with a short history and high relapse rate and subsequent regression to the mean. Another limitation is the short follow-up duration post-MMF therapy, which may underestimate the ARRs of referred patients. Second, no MMF dose stratification study was conducted, and the combination of MMF and glucocorticoid therapy might have affected evaluations of the effects of MMF. Oral steroids may also be beneficial for disease remission. In this study, 70 patients took oral steroids before initiation of MMF treatment. Those patients showed a reduction in the ARR and EDSS score after taking MMF. Third, the myelitis lesion length does not reflect disease severity or recovery and is only taken as a secondary endpoint in the present study. Finally, because we used a standard MMF dosage (1,000 mg per day), we did not monitor the lymphocyte counts. However, in clinical practice, using a target absolute lymphocyte count (e.g., 1,000–1,500 cells/μL) to titrate the dosage is suggested to reduce the adverse event rate of MMS.\n\nIn conclusion, low-dose MMF reduced clinical relapse and disability in NMOSD patients in South China. However, some patients still suffered from adverse events at this dosage.\n\nAuthor contributions\nAll authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.\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\nWe acknowledge Prof. Allan G. Kermode from University of Western Australia and Prof. Ying Fu from Shaanxi Normal University for their help with the trial design and data analysis. This research was funded by the Zhongshan University Clinical Medicine Research 5010 program (2016017).\n\nSupplementary material\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2018.02066/full#supplementary-material\n\nClick here for additional data file.\n==== Refs\nReferences\n1. Lucchinetti CF Guo Y Popescu BF Fujihara K Itoyama Y Misu T . The pathology of an autoimmune astrocytopathy: lessons learned from neuromyelitis optica . Brain Pathol. (2014 ) 24 :83 –97 . 10.1111/bpa.12099 24345222 \n2. Weinshenker BG Wingerchuk DM . Neuromyelitis spectrum disorders . Mayo Clin Proc. (2017 ) 92 :663 –79 . 10.1016/j.mayocp.2016.12.014 28385199 \n3. Lennon VA Wingerchuk DM Kryzer TJ Pittock SJ Lucchinetti CF Fujihara K . 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(2017 ) 23 :1377 –84 . 10.1177/1352458516678474 27885065 \n23. Kleiter I Gold R . Present and future therapies in neuromyelitis optica spectrum disorders . Neurotherapeutics (2016 ) 13 :70 –83 . 10.1007/s13311-015-0400-8 26597098 \n24. Mourad M Malaise J Chaib Eddour D De Meyer M Konig J Schepers R . Correlation of mycophenolic acid pharmacokinetic parameters with side effects in kidney transplant patients treated with mycophenolate mofetil . Clin Chem. (2001 ) 47 :88 –94 . 11148182 \n25. Chen Y Chu SH Wei TY Yen TH Chiang YJ Wu CT . Does mycophenolate mofetil increase the incidence of infections in stable renal transplant recipients initially treated with a two-drug regimen? \nTransplant Proc. (2004 ) 36 :2122 –3 . 10.1016/j.transproceed.2004.08.015 15518769 \n26. Wingerchuk DM Lennon VA Pittock SJ Lucchinetti CF Weinshenker BG . Revised diagnostic criteria for neuromyelitis optica . Neurology (2006 ) 66 :1485 –9 . 10.1212/01.wnl.0000216139.44259.74 16717206 \n27. 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Kim SM Waters P Woodhall M Kim YJ Kim JA Cheon SY . Gender effect on neuromyelitis optica spectrum disorder with aquaporin4-immunoglobulin G . Multiple Scler. (2017 ) 23 :1104 –11 . 10.1177/1352458516674366 27760862 \n32. Kimbrough DJ Mealy MA Simpson A Levy M . Predictors of recurrence following an initial episode of transverse myelitis . Neurol Neuroimmunol Neuroinflamm. (2014 ) 1 :e4 . 10.1212/NXI.0000000000000004 25340060 \n33. Takahashi T Fujihara K Nakashima I Misu T Miyazawa I Nakamura M . Anti-aquaporin-4 antibody is involved in the pathogenesis of NMO: a study on antibody titre . Brain (2007 ) 130 :1235 –43 . 10.1093/brain/awm062 17449477 \n34. Jarius S Franciotta D Paul F Ruprecht K Bergamaschi R Rommer PS . Cerebrospinal fluid antibodies to aquaporin-4 in neuromyelitis optica and related disorders: frequency, origin, and diagnostic relevance . J Neuroinflamm. (2010 ) 7 :52 . 10.1186/1742-2094-7-52 20825655 \n35. Yoshimura S Isobe N Matsushita T Yonekawa T Masaki K Sato S . Distinct genetic and infectious profiles in Japanese neuromyelitis optica patients according to anti-aquaporin 4 antibody status . J Neurol Neurosurg Psychiatry (2013 ) 84 :29 –34 . 10.1136/jnnp-2012-302925 23038741 \n36. Beissert S Mimouni D Kanwar AJ Solomons N Kalia V Anhalt GJ . Treating pemphigus vulgaris with prednisone and mycophenolate mofetil: a multicenter, randomized, placebo-controlled trial . J invest Dermatol. (2010 ) 130 :2041 –8 . 10.1038/jid.2010.91 20410913 \n37. Hou JH Le WB Chen N Wang WM Liu ZS Liu D . Mycophenolate mofetil combined with prednisone versus full-dose prednisone in IgA nephropathy with active proliferative lesions: a randomized controlled trial . Am J Kidney Dis. (2017 ) 69 :788 –95 . 10.1053/j.ajkd.2016.11.027 28215945 \n38. van Hest RM Hesselink DA Vulto AG Mathot RA van Gelder T \nIndividualization of mycophenolate mofetil dose in renal transplant recipients . Expert Opin Pharmacother. (2006 ) 7 :361 –76 . 10.1517/14656566.7.4.361 16503809 \n39. 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"fulltext_license": "CC BY",
"issn_linking": "1664-3224",
"issue": "9()",
"journal": "Frontiers in immunology",
"keywords": "South China; a prospective study; mycophenolate mofetil; neuromyelitis optica spectrum disorders; therapy",
"medline_ta": "Front Immunol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D051401:Aquaporin 4; D001323:Autoantibodies; D001379:Azathioprine; D002648:Child; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D009471:Neuromyelitis Optica; D011446:Prospective Studies; D000069283:Rituximab",
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"pages": "2066",
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"pmid": "30258442",
"pubdate": "2018",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
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"title": "Low-Dose Mycophenolate Mofetil for Treatment of Neuromyelitis Optica Spectrum Disorders: A Prospective Multicenter Study in South China.",
"title_normalized": "low dose mycophenolate mofetil for treatment of neuromyelitis optica spectrum disorders a prospective multicenter study in south china"
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"abstract": "BACKGROUND\nStatus epilepticus requires immediate treatment because treatment delay can cause permanent neurologic complications. Dexmedetomidine may be an option for the treatment of status epilepticus although its effect remains unclear with conflicting reports.\n\n\nMETHODS\nA 64-year-old woman with epilepsy with complex partial seizures underwent total knee arthroplasty. After emergence from general anesthesia, she developed status epilepticus and was transferred to the intensive care unit. Following initial treatment using benzodiazepines, phenytoin, and levetiracetam, dexmedetomidine (0.37 μg/kg loading in 10 min followed by 0.6 μg/kg/h) was administered and seizures terminated in 20 min. Color density spectral array using Root® with SedLine® (Masimo, Irvine, CA, USA) showed an increase in power in high frequency band of the electroencephalogram during the seizure attacks.\n\n\nCONCLUSIONS\nWe described a case of status epilepticus which was treated with dexmedetomidine and monitored using color density spectral array.",
"affiliations": "Surgical Operation Department, Fukushima Medical University Hospital, 1 Hikarigaoka, Fukushima, 960-1295, Japan. obashin99@gmail.com.;Department of Anesthesiology, Fukushima Medical University Hospital, 1 Hikarigaoka, Fukushima, 960-1295, Japan.;Department of Anesthesiology, Fukushima Medical University Hospital, 1 Hikarigaoka, Fukushima, 960-1295, Japan.;Department of Anesthesiology, Fukushima Medical University Hospital, 1 Hikarigaoka, Fukushima, 960-1295, Japan.;Department of Anesthesiology, Fukushima Medical University Hospital, 1 Hikarigaoka, Fukushima, 960-1295, Japan.;Department of Anesthesiology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, 960-1295, Japan.",
"authors": "Obara|Shinju|S|http://orcid.org/0000-0001-8619-2864;Kakinouchi|Koh|K|;Honda|Jun|J|;Noji|Yoshie|Y|;Hanayama|Chie|C|;Murakawa|Masahiro|M|",
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"doi": "10.1186/s40981-019-0234-1",
"fulltext": "\n==== Front\nJA Clin RepJA Clin RepJA Clinical Reports2363-9024Springer Berlin Heidelberg Berlin/Heidelberg 23410.1186/s40981-019-0234-1Case ReportDexmedetomidine administration in a patient with status epilepticus under color density spectral array monitoring http://orcid.org/0000-0001-8619-2864Obara Shinju +81-24-547-1342obashin99@gmail.com 1Kakinouchi Koh kakinoko@fmu.ac.jp 2Honda Jun j-honda@fmu.ac.jp 2Noji Yoshie noyoshie@fmu.ac.jp 2Hanayama Chie hana8780@fmu.ac.jp 2Murakawa Masahiro murakawa@fmu.ac.jp 31 0000 0004 0449 2946grid.471467.7Surgical Operation Department, Fukushima Medical University Hospital, 1 Hikarigaoka, Fukushima, 960-1295 Japan 2 0000 0004 0449 2946grid.471467.7Department of Anesthesiology, Fukushima Medical University Hospital, 1 Hikarigaoka, Fukushima, 960-1295 Japan 3 0000 0001 1017 9540grid.411582.bDepartment of Anesthesiology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, 960-1295 Japan 27 2 2019 27 2 2019 12 2019 5 1217 1 2019 20 2 2019 © The Author(s) 2019, Corrected publication 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.Background\nStatus epilepticus requires immediate treatment because treatment delay can cause permanent neurologic complications. Dexmedetomidine may be an option for the treatment of status epilepticus although its effect remains unclear with conflicting reports.\n\nCase presentation\nA 64-year-old woman with epilepsy with complex partial seizures underwent total knee arthroplasty. After emergence from general anesthesia, she developed status epilepticus and was transferred to the intensive care unit. Following initial treatment using benzodiazepines, phenytoin, and levetiracetam, dexmedetomidine (0.37 μg/kg loading in 10 min followed by 0.6 μg/kg/h) was administered and seizures terminated in 20 min. Color density spectral array using Root® with SedLine® (Masimo, Irvine, CA, USA) showed an increase in power in high frequency band of the electroencephalogram during the seizure attacks.\n\nConclusion\nWe described a case of status epilepticus which was treated with dexmedetomidine and monitored using color density spectral array.\n\nKeywords\nDexmedetomidineStatus epilepticusAnesthesiaColor density spectral arrayProcessed electroencephalogramissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nStatus epilepticus, considered the most extreme form of seizure, requires immediate treatment, usually with benzodiazepines, because treatment delay can cause permanent neurologic complications [1]. Epilepsy patients may suffer seizures with convulsions at emergence from general anesthesia [2], even if the disease is stabilized before the induction of anesthesia [3]. Dexmedetomidine, a highly selective α-2-adrenoceptor agonist, has sedative and analgesic effects without respiratory depression and is used perioperatively. The effect of dexmedetomidine on seizures remains unclear with conflicting reports although it may be an option for the treatment of status epilepticus. Color density spectral array (CDSA) that is displayed on processed electroencephalogram (EEG) monitors shows the power spectrum over time of the EEG, which may be useful to monitor patients with seizures.\n\nHere, we describe a case of status epilepticus after emergence of general anesthesia in which dexmedetomidine was administered and the effect was observed using CDSA.\n\nCase presentations\nWritten informed consent was obtained from the patient for publication of this case report. A 64-year-old woman (body weight, 72 kg; height, 155 cm) with a history of epilepsy with complex partial seizures developed right knee osteoarthritis and was scheduled for total knee arthroplasty. One year previously, she underwent the same operation on the contralateral side and developed tonic-clonic convulsions after emergence of general anesthesia in the operating room and the ward. She was then treated with repeated diazepam administration; however, her postoperative management became difficult due to repeated respiratory arrests. Her epilepsy control improved subsequently although seizure attacks occurred approximately once a week, according to her medical record. She was under medication of valproate sodium, carbamazepine, and levetiracetam, each of which blood concentrations was in a therapeutic range. Preoperative examinations revealed no other abnormal findings except for an increase in γ-glutamyltransferase (61 U/L) probably due to medication. On the morning of surgery, she took usual anticonvulsants and received no anesthetic premedication. Patient monitoring included continuous electrocardiography, pulse oximetry (SpO2), capnometry, and non-invasive blood pressure. Patient state index was also monitored using Root® with SedLine® (Masimo, Irvine, CA, USA; version 2000). After femoral nerve block with 20 mL of 0.375% ropivacaine, general anesthesia with tracheal intubation was induced with propofol 80 mg, remifentanil 0.19 μg/kg/min, and rocuronium 50 mg, and maintained with sevoflurane 1.3% and remifentanil 0.14–0.23 μg/kg/min. During the anesthesia, SpO2 was maintained at 97% or more and end-tidal CO2 was kept between 36 and 41 mmHg (more than 39 mmHg at most time points during the last hour). Patient state index were between 22 and 27. For postoperative analgesia, acetaminophen 1 g and flurbiprofen axetil 50 mg were intravenously administered. The surgery was completed without incident, and after the recovery of consciousness and spontaneous respiration, patient’s trachea was extubated. Tonic muscular contraction was observed in the upper limbs, body trunk, neck, and face along with respiratory depression. SpO2 decreased from 100 to 88%. Although these symptoms were temporarily relieved by midazolam 3 mg iv, they recurred in a few minutes. Additional midazolam 6 mg and phenytoin 125 mg were administered in the recovery room, but the symptoms did not improve, and the patient was transferred to the intensive care unit (ICU). Levetiracetam 500 mg was administered by intravenous drip. In addition, a total of 15 mg diazepam was administered intermittently during the first hour and the patient often required respiratory assistance with jaw thrust. However, convulsions persisted. CDSA showed a spread of warmer colors (i.e., higher power) in a wide frequency band of the EEG during the convulsions (Fig. 1a) with PSI > 80. She could not rest in bed and complained of knee pain once with dizziness. Dexmedetomidine (0.37 μg/kg loading in 10 min followed by 0.6 μg/kg/h) was administered, and she was sedated in 20 min. During the improvement from the convulsion, CSDA showed a decrease in warmer colors in a wide frequency band and raw EEG showed decreased amplitude (Fig. 1b). After termination of convulsions, in the CDSA, blue tones, which indicate a drop in EEG power, became predominant (Fig. 1c). Dexmedetomidine administration was continued until the next morning while gradually decreasing the dose to 0.2 μg/kg/h (Fig. 1d). No cardiopulmonary suppression or recurrence of convulsions that required intervention was observed. Blood test revealed no electrolyte disturbance. She was unconscious after induction of general anesthesia until the next morning. She had convulsions once on the eighth day after surgery without major problems and was discharged on the 20th day.Fig. 1 Screen captures of color density spectral array (CDSA) in the intensive care unit. The upper and lower portions of left panels represent EEG power spectrum obtained from the left and right forehead, respectively. X-axis represents time. Y-axes represent frequency (Hz). The farther from the center horizontal line the higher the frequency. The right vertical line represents power of EEG (dB) where warmer colors represent higher power. White curves represent spectral edge frequency 95%, which is the frequency below which 95% of the spectral power of an EEG resides. Vertical white bars represent missing data on CDSA due to artifacts. Right panels represent 10-s EEG in the left front polar (fp1) region, corresponding to selected time points (black triangle) in left panels. a CDSA immediately after the patient entered the ICU. A black arrow represents the time of administration of diazepam 5 mg iv. Black horizontal bars represent convulsions. b A black arrow represents the start of dexmedetomidine administration. c Approximately 2 h after the start of dexmedetomidine infusion. Patient state index was about 23. d CDSA next morning. A black arrow represents the spontaneous awakening. PSI increased from 40 to 83 in a minute. Corresponding EEG of d could not be downloaded due to a technical failure. Although d shows an asymmetric CDSA, the cause is unknown. Raw EEG waves were illustrated by EDFbrowser 1.64 (https://www.teuniz.net/edfbrowser/; last accessed on February 11, 2019) using “.edf” files downloaded from Root® system\n\n\n\nDiscussion\nThe Japanese guidelines for epilepsy treatment [4] state that a seizure lasting 5 min or longer is considered as status epilepticus and initial treatment should be started. The first-line treatments for status epilepticus include administration of benzodiazepines (stage I treatment), followed by fosphenytoin, phenytoin, and levetiracetam, among others (stage II treatment). In case of insufficient effect, general anesthesia is performed using propofol, barbiturate, or midazolam (stages III and IV treatments). However, benzodiazepines and barbiturates have a respiratory depression effect, and general anesthesia requires tracheal intubation and mechanical ventilation. Therefore, anticonvulsants that do not cause respiratory depression are preferable. Anticonvulsant property of dexmedetomidine has been reported. In animal studies, dexmedetomidine has increased the seizure threshold [5, 6]. Using an in vitro rat model, Kurosawa et al. demonstrated that the anticonvulsant effect of dexmedetomidine is mediated mainly via α-2-adrenoceptors and imidazoline type 1 and 2 receptors are involved in the effect of dexmedetomidine on the epileptiform activity [7].\n\nOn the other hand, contradictory results about the effects of dexmedetomidine on seizures have been reported. Talke et al. revealed that dexmedetomidine did not have a statistically significant effect on interictal epileptiform activity in patients with refractory seizure disorders [8]. Oda et al. showed that dexmedetomidine did not affect spike activity in patients with temporal lobe epilepsy anesthetized with sevoflurane [9]. Furthermore, a decrease in the seizure threshold by dexmedetomidine in animal studies has been reported [10, 11]. In neonates, dexmedetomidine-induced epileptic seizures were reported [12].\n\nThe inhibition of central noradrenergic transmission facilitates seizure expression [10]. Dexmedetomidine agonistically acts on presynaptic and postsynaptic α-2-adrenoceptors. If dexmedetomidine dominantly acts on the presynaptic α-2- adrenoceptors, proconvulsive actions with a reduction in noradrenaline release due to the negative feedback system can induce seizure. Contrary to the presynaptic effect, preferential binding to postsynaptic α-2- adrenoceptors would enhance noradrenaline-mediated postsynaptic activity [10], and anticonvulsant action could be produced. Thus, effects of dexmedetomidine on epilepsy could be dependent on which synaptic site is dominant. The dominance may be dependent on patients and situations, and a method to clinically control the dominance has not been reported. In the current case, the anticonvulsant action was observed that may be associated with the above-mentioned mechanism, under a clinical dose of dexmedetomidine.\n\nIn the current case, the patient developed seizures after emergence from anesthesia. We decided to manage the patient in the ICU as we expected that initial treatment would not produce sufficient effect according to her past history and that general anesthesia would be required. The seizures stopped after administration of benzodiazepine but recurred within 10 min, and this was repeated. Dexmedetomidine was initially used to reduce her knee pain and the risk associated with body motion, which showed anticonvulsant effect, probably due to interaction with other drugs which had already been administered. Although in a rat model, plasma dexmedetomidine concentration levels at which loss of the righting reflex is induced were associated with a decrease in convulsive seizures caused by local anesthetics [5], pharmacodynamics (i.e., relationship between plasma or effect-site concentration vs clinical effect) of the anticonvulsant effect of dexmedetomidine in humans is still unclear. In terms of sedative effect, according to pharmacokinetic and pharmacodynamic simulations using a recently published model [13], simulated bispectral index decreases from 97 to 80 in the first 10 min and then stabilizes around 75 in the following few hours (i.e., equivalent to “light sedation”), which agrees with the current course of treatment. Assuming that anticonvulsive and sedative effects are produced in similar effect-site concentrations of dexmedetomidine even in humans, we can consider that dexmedetomidine worked as an anticonvulsant to some extent in the current case. The patient was to undergo general anesthesia if dexmedetomidine was not effective; however, as a result, she could avoid tracheal intubation. The loading dose of dexmedetomidine was less than the recommended dose (1 μg/kg in 10 min) to avoid bradycardia because the heart rate was around 50/min.\n\nCDSA shows time on the x-axis, frequency on the y-axis, and the color spectrum ranged from blue (minimum power) to dark red (maximum power) (see figure). Seizure evolution may involve increases in frequency and amplitude in EEG and thus may appear on CDSA images as upward arches on the y-axis (increased frequency) in warmer colors (increased power) [14]. In the current case, CDSA showed high power (i.e., high amplitude in raw EEG as shown in the right panel of Fig. 1a) in the high-frequency range during convulsions. Therefore, after the termination of convulsions by administration of dexmedetomidine in the ICU, we planned to increase the dexmedetomidine dose or to use benzodiazepines as a rescue therapy in case CDSA showed such patterns or convulsions occurred; however, this was not required. Thus, the CDSA obtained using a processed EEG monitor may be useful for perioperative monitoring of epileptic patients, especially of those with non-convulsive status epilepticus of which the difficulty in visual diagnosis can cause delay in treatment. However, CDSA changes should be carefully examined because of possibilities of false-positive results caused by various artifacts including electromyograms and body movements. In addition, for the evaluation of epilepsy treatment under general anesthesia, the disappearance of convulsions and epileptiform discharge on EEG are required [4]. Furthermore, the maintenance of flat EEG [15] or burst suppression on EEG [16] may contribute to better outcomes. For these monitoring, CDSA obtained using processed EEG monitors with a limited number of channels is inadequate, and continuous monitoring with conventional EEG is required.\n\nConclusion\nIn this case report, we presented a case of status epilepticus which was treated with dexmedetomidine and monitored using CDSA. This strategy may be an option for the management of patients with status epilepticus.\n\nAbbreviations\nCDSAColor density spectrum array\n\nEEGElectroencephalogram\n\nPSIPatient state index\n\nThis work was carried out at Fukushima Medical University Hospital, 1 Hikarigaoka, Fukushima, Fukushima, Japan 960-1295\n\nThe original version of this article was revised: Following publication of the original article [1], the authors reported an error in Fig. 1b and Fig. 1c.\n\nChange history\n\n3/23/2019\n\nFollowing publication of the original article [1], the authors reported an error in Fig. 1b and c. A black bar and arrows were added.\n\nAcknowledgements\nThe authors would like to thank the Scientific English Editing Section of Fukushima Medical University for editing a draft of this manuscript.\n\nFunding\nThe authors declare no funding for this report.\n\nAvailability of data and materials\nNot applicable\n\nAuthors’ contributions\nSO treated the patient and wrote the manuscript. KK and JH treated the patient. YN, CH, and MM helped to design the case report. All authors reviewed and approved the final draft.\n\nEthics approval and consent to participate\nIn our institution, IRB approval is not required for a case report.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Trinka E Cock H Hesdorffer D Rossetti AO Scheffer IE Shinnar S Shorvon S Lowenstein DH A definition and classification of status epilepticus--report of the ILAE Task Force on Classification of Status Epilepticus Epilepsia. 2015 56 1515 1523 10.1111/epi.13121 26336950 \n2. Niesen AD Jacob AK Aho LE Botten EJ Nase KE Nelson JM Kopp SL Perioperative seizures in patients with a history of a seizure disorder Anesth Analg 2010 111 729 735 10.1213/ANE.0b013e3181e534a4 20547823 \n3. Kim MJ Lim DG Yeo JS Refractory status epilepticus occurred at the end of sevoflurane anesthesia in patient with epilepsy Korean J Anesthesiol 2013 65 93 94 10.4097/kjae.2013.65.1.93 23904950 \n4. Neurology TJSo. 2018 Guidelines for the treatment of epilepsy. 2018 [updated 2018; cited 2018 November 26]; Available from: https://www.neurology-jp.org/guidelinem/tenkan_2018.html.\n5. Tanaka K Oda Y Funao T Takahashi R Hamaoka N Asada A Dexmedetomidine decreases the convulsive potency of bupivacaine and levobupivacaine in rats: involvement of alpha2-adrenoceptor for controlling convulsions Anesth Analg 2005 100 687 696 10.1213/01.ANE.0000144420.87770.FE 15728053 \n6. Whittington RA Virag L Vulliemoz Y Cooper TB Morishima HO Dexmedetomidine increases the cocaine seizure threshold in rats Anesthesiology. 2002 97 693 700 10.1097/00000542-200209000-00024 12218537 \n7. Kurosawa A Sato Y Sasakawa T Kunisawa T Iwasaki H Dexmedetomidine inhibits epileptiform activity in rat hippocampal slices Int J Clin Exp Med 2017 10 6704 6711 \n8. Talke P Stapelfeldt C Garcia P Dexmedetomidine does not reduce epileptiform discharges in adults with epilepsy J Neurosurg Anesthesiol 2007 19 195 199 10.1097/ANA.0b013e318060d281 17592352 \n9. Oda Y Toriyama S Tanaka K Matsuura T Hamaoka N Morino M Asada A The effect of dexmedetomidine on electrocorticography in patients with temporal lobe epilepsy under sevoflurane anesthesia Anesth Analg 2007 105 1272 1277 10.1213/01.ane.0000281075.77316.98 17959954 \n10. Mirski MA Rossell LA McPherson RW Traystman RJ Dexmedetomidine decreases seizure threshold in a rat model of experimental generalized epilepsy Anesthesiology. 1994 81 1422 1428 10.1097/00000542-199412000-00017 7992911 \n11. Miyazaki Y Adachi T Kurata J Utsumi J Shichino T Segawa H Dexmedetomidine reduces seizure threshold during enflurane anaesthesia in cats Br J Anaesth 1999 82 935 937 10.1093/bja/82.6.935 10562794 \n12. Kubota T Fukasawa T Kitamura E Magota M Kato Y Natsume J Okumura A Epileptic seizures induced by dexmedetomidine in a neonate Brain and Development 2013 35 360 362 10.1016/j.braindev.2012.05.011 22727734 \n13. Colin PJ Hannivoort LN Eleveld DJ Reyntjens K Absalom AR Vereecke HEM Struys M Dexmedetomidine pharmacokinetic-pharmacodynamic modelling in healthy volunteers: 1. Influence of arousal on bispectral index and sedation Br J Anaesth 2017 119 200 210 10.1093/bja/aex085 28854538 \n14. Pensirikul AD Beslow LA Kessler SK Sanchez SM Topjian AA Dlugos DJ Abend NS Density spectral array for seizure identification in critically ill children J Clin Neurophysiol 2013 30 371 375 10.1097/WNP.0b013e31829de01c 23912575 \n15. Krishnamurthy KB Drislane FW Depth of EEG suppression and outcome in barbiturate anesthetic treatment for refractory status epilepticus Epilepsia. 1999 40 759 762 10.1111/j.1528-1157.1999.tb00775.x 10368075 \n16. Shorvon S Baulac M Cross H Trinka E Walker M The drug treatment of status epilepticus in Europe: consensus document from a workshop at the first London Colloquium on Status Epilepticus Epilepsia. 2008 49 1277 1285 10.1111/j.1528-1167.2007.01478.x 18638280\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2363-9024",
"issue": "5(1)",
"journal": "JA clinical reports",
"keywords": "Anesthesia; Color density spectral array; Dexmedetomidine; Processed electroencephalogram; Status epilepticus",
"medline_ta": "JA Clin Rep",
"mesh_terms": null,
"nlm_unique_id": "101682121",
"other_id": null,
"pages": "12",
"pmc": null,
"pmid": "32026959",
"pubdate": "2019-02-27",
"publication_types": "D016428:Journal Article",
"references": "17592352;18638280;15728053;26336950;10562794;7992911;10368075;22727734;23904950;17959954;23912575;20547823;12218537;28854538",
"title": "Dexmedetomidine administration in a patient with status epilepticus under color density spectral array monitoring.",
"title_normalized": "dexmedetomidine administration in a patient with status epilepticus under color density spectral array monitoring"
} | [
{
"companynumb": "JP-ACCORD-173268",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PROPOFOL"
},
"drugadditional": "3",
"drugadm... |
{
"abstract": "A 48-year old woman with metastatic breast cancer and extensive bone marrow infiltration was admitted with extreme lethargy, jaundice and deranged liver function tests. She had been started on anastrozole in May 2013 for bony metastases, detected on a bone scan. A CT scan performed at that time had shown no evidence of metastatic or nodal disease elsewhere. Over the subsequent 2 months, the patient had become progressively jaundiced. Outpatient abdominal ultrasound and CT liver had shown a fatty liver with no focal lesions. She was admitted in August 2013 with bilirubin 567, alkaline phosphatase 385, alanine aminotransferase 98, albumin 25 and international normalised ratio 1.9. The patient ultimately had a liver biopsy, which demonstrated features of drug-induced steatohepatitis, and anastrozole was found to have been the probable cause. This case explores the differentials of jaundice in a patient with cancer and describes a rare cause of drug-induced liver injury.",
"affiliations": "Department of Gastroenterology, Royal Berkshire NHS Trust, Reading, UK.;Department of Gastroenterology, Royal Berkshire NHS Trust, Reading, UK.",
"authors": "Lacey|Rachel|R|;Evans|Alex|A|",
"chemical_list": "D018931:Antineoplastic Agents, Hormonal; D009570:Nitriles; D014230:Triazoles; D000077384:Anastrozole",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2014()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000077384:Anastrozole; D018931:Antineoplastic Agents, Hormonal; D001706:Biopsy; D001943:Breast Neoplasms; D056486:Chemical and Drug Induced Liver Injury; D003937:Diagnosis, Differential; D005234:Fatty Liver; D005260:Female; D006801:Humans; D007565:Jaundice; D008099:Liver; D008111:Liver Function Tests; D008875:Middle Aged; D009570:Nitriles; D014230:Triazoles",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "25540208",
"pubdate": "2014-12-24",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16887480;21175441;21453541;14643022;17033446;17208628;12879993;24935270",
"title": "An unusual cause of jaundice in a patient with breast cancer.",
"title_normalized": "an unusual cause of jaundice in a patient with breast cancer"
} | [
{
"companynumb": "GB-APOTEX-2015AP006421",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ANASTROZOLE"
},
"drugadditional": null,
... |
{
"abstract": "Mutations localized in THAP1 gene, locus 18p11.21 have been reported as causative of primary dystonia type 6 (DYT6). Disease which is characterized mainly by focal dystonia, frequently involving the craniocervical region, however associated also with early-onset generalized dystonia and spasmodic dysphonia. Here we report a novel mutation in the THAP1 gene identified in a Polish family with DYT6 phenotype - the c.15C>G substitution in exon 1 introducing the missense mutation p.Cys5Trp within the N-terminal THAP domain. The mutation was described in two generations, in patients showing a broad spectrum of focal and generalized dystonia symptoms of variable onset. Our results indicate that certain mutations in the THAP1 gene may lead to primary dystonia with remarkable intrafamilial clinical variability.",
"affiliations": "Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland. Electronic address: martajurek@wp.pl.;Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland.;Department of Neurology, Faculty of Heath Science, Medical University of Warsaw, Warsaw, Poland.;Department of Neurology, Faculty of Heath Science, Medical University of Warsaw, Warsaw, Poland.;Department of Neurology, Faculty of Heath Science, Medical University of Warsaw, Warsaw, Poland.;Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland.",
"authors": "Jurek|Marta|M|;Hoffman-Zacharska|Dorota|D|;Koziorowski|Dariusz|D|;Mądry|Jacek|J|;Friedman|Andrzej|A|;Bal|Jerzy|J|",
"chemical_list": "D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C474080:THAP1 protein, human",
"country": "Poland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-3843",
"issue": "48(4)",
"journal": "Neurologia i neurochirurgia polska",
"keywords": "DYT6; Phenotypical variability; Reduced penetrance; THAP1",
"medline_ta": "Neurol Neurochir Pol",
"mesh_terms": "D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; D020821:Dystonic Disorders; D005192:Family Health; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation; D011044:Poland",
"nlm_unique_id": "0101265",
"other_id": null,
"pages": "254-7",
"pmc": null,
"pmid": "25168324",
"pubdate": "2014",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Intrafamilial variability of the primary dystonia DYT6 phenotype caused by p.Cys5Trp mutation in THAP1 gene.",
"title_normalized": "intrafamilial variability of the primary dystonia dyt6 phenotype caused by p cys5trp mutation in thap1 gene"
} | [
{
"companynumb": "PHHY2014PL119371",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BOTULINUM TOXIN TYPE A"
},
"drugadditional": null,
... |
{
"abstract": "Listeria monocytogenes is a gram-positive bacterium that causes listeriosis. Brain abscess is a very uncommon manifestation of listeriosis and has not been reported to be associated with adalimumab (humira), one of the approved medications for treating Crohn's disease. A 45-year-old female with Crohn's disease presented with sudden onset of fever, headache, nausea, vomiting, and altered mental status for 1 day. She was on prednisone and 6-mercaptopurine. She had started taking adalimumab 17 days prior to admission. She had signs of toxicity, confusion, and nuchal rigidity, but showed neither central nervous system deficits nor focal deficits. The laboratory results revealed Gram-positive coccobacillus, positive blood and cerebrospinal fluid culture for Listeria monocytogenes, and a 5 × 5 mm ring-enhancing lesion of brain abscess on MRI. After holding off 6-mercaptopurine and adalimumab, her mental status improved on the next day. Finally, she was discharged on day 7 of hospitalization with ampicillin 2 g intravenously every 4 h for a total of 2 weeks. Two weeks later, the follow-up MRI showed a 2-mm area of residual enhancement in the left temporal lobe at the site of the previous brain abscess. Adalimumab, as a tumor necrosis factor (TNF)-alpha inhibitor, carries a risk of triggering opportunistic infection, such as listeriosis. With an altered mental status or neurological signs in patients receiving TNF-alpha antagonizing agent, physicians should suspect bacterial infection in the central nervous system and promptly initiate treatment for brain abscess if needed.",
"affiliations": "MetroWest Medical Center, Framingham, Massachusetts, USA.;MetroWest Medical Center, Framingham, Massachusetts, USA.;MetroWest Medical Center, Framingham, Massachusetts, USA.;MetroWest Medical Center, Framingham, Massachusetts, USA.",
"authors": "Atsawarungruangkit|Amporn|A|;Dominguez|Fernando|F|;Borda|Gustavo|G|;Mavrogiorgos|Nikolaos|N|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000481165",
"fulltext": "\n==== Front\nCase Rep GastroenterolCase Rep GastroenterolCRGCase Reports in Gastroenterology1662-0631S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH-4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000481165crg-0011-0667Single CaseListeria Monocytogenes Brain Abscess in Crohn's Disease Treated with Adalimumab Atsawarungruangkit Amporn *Dominguez Fernando Borda Gustavo Mavrogiorgos Nikolaos MetroWest Medical Center, Framingham, Massachusetts, USA*Amporn Atsawarungruangkit, MD, Department of Medicine, MetroWest Medical Center, Framingham, MA 01702 (USA), E-Mail a.atsawarungruangkit@mwmc.comSep-Dec 2017 9 11 2017 9 11 2017 11 3 667 671 2 8 2017 29 8 2017 Copyright © 2017 by S. Karger AG, Basel2017This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Listeria monocytogenes is a gram-positive bacterium that causes listeriosis. Brain abscess is a very uncommon manifestation of listeriosis and has not been reported to be associated with adalimumab (humira), one of the approved medications for treating Crohn's disease. A 45-year-old female with Crohn's disease presented with sudden onset of fever, headache, nausea, vomiting, and altered mental status for 1 day. She was on prednisone and 6-mercaptopurine. She had started taking adalimumab 17 days prior to admission. She had signs of toxicity, confusion, and nuchal rigidity, but showed neither central nervous system deficits nor focal deficits. The laboratory results revealed Gram-positive coccobacillus, positive blood and cerebrospinal fluid culture for Listeria monocytogenes, and a 5 × 5 mm ring-enhancing lesion of brain abscess on MRI. After holding off 6-mercaptopurine and adalimumab, her mental status improved on the next day. Finally, she was discharged on day 7 of hospitalization with ampicillin 2 g intravenously every 4 h for a total of 2 weeks. Two weeks later, the follow-up MRI showed a 2-mm area of residual enhancement in the left temporal lobe at the site of the previous brain abscess. Adalimumab, as a tumor necrosis factor (TNF)-alpha inhibitor, carries a risk of triggering opportunistic infection, such as listeriosis. With an altered mental status or neurological signs in patients receiving TNF-alpha antagonizing agent, physicians should suspect bacterial infection in the central nervous system and promptly initiate treatment for brain abscess if needed.\n\nKeywords\nListeria monocytogenesBrain abscessCrohn's diseaseAdalimumab\n==== Body\nIntroduction\nListeria monocytogenes (LM), a gram-positive bacterium, is commonly found in food or water. Patients infected with LM usually have fever, muscle aches, and sometimes nausea or diarrhea. The common manifestations of listeriosis are meningitis, meningoencephalitis, and bacteremia in immunosuppressed patients. However, brain abscess is rarely found in patient with LM infection. On the other hand, adalimumab (humira), a recombinant human IgG1 monoclonal antibody directed against tumor necrosis factor (TNF), is one of the approved treatments for Crohn's disease [1]. There were a few reports about patients who developed brain abscess from LM infection [2, 3]. To the best of our knowledge, there is no reported evidence of LM brain abscesses in patient treated with adalimumab. Herein, we present a patient with Crohn's disease who developed a left temporal lobe abscess within 17 days after adding adalimumab to her standing regimen of prednisone and 6-mercaptopurine.\n\nCase Report\nA 45-year-old female presented with sudden onset of fever, headache, nausea, vomiting, and altered mental status for 1 day. She had a past medical history of Crohn's disease. Additionally, she was on oral prednisone 30 mg daily and oral 6-mercaptopurine 25 mg daily. Seventeen days before admission, she had started taking adalimumab. On physical examination, the patient had a temperature of 39.8°C, blood pressure of 133/94 mm Hg, heart rate of 122 beats/min, respiratory rate of 20 breaths/min, and oxygen saturation of 20% in room air. Apart from that, she had signs of toxicity, confusion, and nuchal rigidity. Due to the patient's discomfort, the tests for Kernig's sign and Brudzinski's sign were not performed.\n\nA neurological examination revealed neither central nervous system (CNS) deficits nor focal deficits. For laboratory data, complete blood count was notable for leukocytosis of 12.7 k/mL with bandemia (band neutrophils 15%), hemoglobin 14.5%, hematocrit 42.5 g/dL, and platelet count 151,000/µL. Her comprehensive metabolic panel was remarkable for hyponatremia (serum sodium 132 mmol/L), hypochloremia (chloride 87 mmol/L), anion gap metabolic acidosis (anion gap 25 mmol/L and carbon dioxide 20 mmol/L), lactic acidosis (lactic acid 2.53 mmol/L), and hyperglycemia (glucose 142 mg/dL). By lumbar puncture we could extract 1.5 mL of turbid cerebrospinal fluid (CSF); CSF analysis showed white blood cell count 2,300 cells/mL (48% segmented neutrophils, 6% lymphocytes, and 43% monocytes), red blood cell count 130 cells/mL, glucose 44 mg/dL, and protein 216 mg/dL. CSF stain revealed Gram-positive coccobacilli, the patient was given vancomycin, ceftriaxone, and ampicillin. At the same time, 6-mercaptopurine and adalimumab were discontinued immediately together with tapering off prednisone. Consequently, the patient's mental status improved on the next day despite persistent headache and fever with a body temperature of 37.8°C. Since both blood and CSF culture were positive for LM, vancomycin and ceftriaxone were hence discontinued; the patient eventually defervesced.\n\nThen, the initial MRI of the brain came back showing a 5 × 5 mm ring-enhancing lesion in the left temporal lobe with surrounding increased T2 and FLAIR signal consistent with brain abscess (Fig. 1). The patient was discharged on day 7 of hospitalization with ampicillin 2 g intravenously every 4 h for a total of 2 weeks. The follow-up MRI at 2 weeks after the initial treatment of ampicillin revealed decreasing signs of a ring-enhancing lesion in the left temporal lobe (Fig. 2). After completing 3 weeks of ampicillin, the patient received an additional week of trimethoprim/sulfamethoxazole 10 mg/kg/day. A repeat MRI of the brain was performed 4 weeks after the initial treatment, showing no evidence of a ring-enhancing lesion in the left temporal lobe (Fig. 3).\n\nDiscussion\nLM is one of the most harmful food-borne pathogens, as the Center for Disease Control estimates that listeriosis causes approximately 1,600 illnesses and 260 deaths per year in the United States [4]. As an intracellular organism, LM can invade tissues normally resistant to infection, such as the CNS, the gravid uterus, or a fetus [5]. Thus, cellular immune response plays an important role for protective immunity against LM; any conditions or medications associated with impaired cellular immunity may prone to LM infection [3].\n\nBrain abscess accounts for approximately 10% of CNS infections by LM [6]. The diagnosis of LM brain abscess may be suspected from the clinical findings. However, there is no clinical method to separate LM brain abscess from other infectious diseases that can lead to fever, constitutional symptoms, headache, and focal neurological deficits. For this reason, a positive blood or CSF culture is required for a definite diagnosis. However, there was a report that patients with LM brain abscess were tested positive for LM based on blood culture in 79% and CSF culture in 23% of all cases [3].\n\nIn this case, the patient had started taking adalimumab, a TNF-alpha inhibitor, as a treatment for Crohn's disease. Consequently, adalimumab suppressed the inflammatory response, which led to listeriosis. In 2011, the risk of developing listeriosis from TNF-alpha inhibitors was added to the drug label according the US Food and Drug Administration [7]. It is also worth noting that most patients who developed these infections were taking concomitant immunosuppressants, such as methotrexate or corticosteroids [7, 8]. A recent review article identified 26 cases of LM infection associated with adalimumab: 36% were CNS infections (i.e., meningitis or encephalitis) and 90% were taking concomitant immunosuppressants (i.e., steroid, methotrexate, or azathioprine) [8]. To the best of our knowledge, there is no reported evidence of LM brain abscess in patients following adalimumab therapy. Yet, right thalamus cerebral toxoplasmosis was reported in a 67-year-old man with rheumatoid arthritis who underwent treatment with adalimumab [9].\n\nUnlike other reported incidences, this patient developed LM brain abscess at the left temporal lobe 17 days after adding adalimumab to a standing regimen of prednisone and 6-mercaptopurine. Although the patient carried a risk for brain abscess from prednisone and 6-mercaptopurine, she had never been reported to have brain abscess before. The addition of adalimumab could have accelerated a serious opportunistic infection such as LM brain abscess. We strongly encourage physicians to maintain a high level of suspicion of listeriosis in patients, who are on a TNF-alpha antagonizing agent, with an altered mental status or neurological signs and promptly initiate treatment for brain abscess if needed.\n\nStatement of Ethics\nThe authors have no ethical conflicts to disclose.\n\nDisclosure Statement\nThere are no financial disclosures for any of the authors.\n\nFig. 1 MRI brain on admission day showing a 5 × 5 mm ring-enhancing lesion in the left temporal lobe.\n\nFig. 2 MRI brain at 2 weeks after treatment showing decreasing signs of a ring-enhancing lesion in the left temporal lobe.\n\nFig. 3 MRI brain at 4 weeks after treatment showing no evidence of a ring-enhancing lesion in the left temporal lobe.\n==== Refs\nReferences\n1 Lichtenstein GR Hanauer SB Sandborn WJ Practice Parameters Committee of American College of Gastroenterology Management of Crohn's disease in adults Am J Gastroenterol. 2009 104 465 483 quiz 464, 484 19174807 \n2 Eckburg PB Montoya JG Vosti KL Brain abscess due to Listeria monocytogenes: five cases and a review of the literature Medicine (Baltimore) 2001 80 223 235 11470983 \n3 Limmahakhun S Chayakulkeeree M Listeria monocytogenes brain abscess: two cases and review of the literature Southeast Asian J Trop Med Public Health 2013 44 468 478 24050079 \n4 Centers for Disease Control and Prevention Listeria (Listeriosis). \nwww.cdc.gov/Listeria/statistics.html (accessed: July 30, 2016).\n5 Gellin BG Broome CV Listeriosis JAMA 1989 261 1313 1320 2492614 \n6 Lorber B Listeriosis Clin Infect Dis 1997 24 1 9 quiz 10–11 8994747 \n7 US Food & Drug Administration FDA Drug Safety Communication Drug labels for the Tumor Necrosis Factor-alpha (TNFα) blockers now include warnings about infection with Legionella and Listeria bacteria. \nwww.fda.gov/Drugs/DrugSafety/ucm270849.htm (accessed: July 30, 2017).\n8 Bodro M Paterson DL Listeriosis in patients receiving biologic therapies Eur J Clin Microbiol Infect Dis 2013 32 1225 1230 23568606 \n9 Nardone R Zuccoli G Brigo F Trinka E Golaszewski S Cerebral toxoplasmosis following adalimumab treatment in rheumatoid arthritis Rheumatology (Oxford) 2014 53 284 24191065\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-0631",
"issue": "11(3)",
"journal": "Case reports in gastroenterology",
"keywords": "Adalimumab; Brain abscess; Crohn's disease; Listeria monocytogenes",
"medline_ta": "Case Rep Gastroenterol",
"mesh_terms": null,
"nlm_unique_id": "101474819",
"other_id": null,
"pages": "667-671",
"pmc": null,
"pmid": "29282389",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "24191065;19174807;8994747;11470983;24050079;2492614;23568606",
"title": "Listeria Monocytogenes Brain Abscess in Crohn's Disease Treated with Adalimumab.",
"title_normalized": "listeria monocytogenes brain abscess in crohn s disease treated with adalimumab"
} | [
{
"companynumb": "US-TEVA-2018-US-864551",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "1",
... |
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