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"abstract": "The large screening of exons 18 to 21 of the epidermal growth factor receptor (EGFR) gene may lead to the discovery of rare, atypical molecular alterations for which the sensitivity to tyrosine kinase inhibitors (TKIs) remains uncertain. We are reporting a rare exon 18 EGFR mutation (p.E709_710 > D) that confers sensitivity to second-generation EGFR TKI (afatinib), lasting for 1 year. Tumor progression biopsy showed small cell lung cancer transformation, associated with a SMAD4 mutation. KEY POINTS: A rare exon 18 epidermal growth factor receptor mutation with sensitivity to afatinib is reported.Small cell transformation was observed at tumor progression.Acquisition of a SMAD4 mutation was observed at tumor progression.",
"affiliations": "Department of Pathology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium nicky.d.haene@erasme.ulb.ac.be.;Department of Pathology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium.;Department of Pathology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium.;Department of Pneumology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium.;Department of Pathology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium.;Department of Intensive Care and Oncological Emergencies & Thoracic Oncology, Institut Jules Bordet, Brussels, Belgium.",
"authors": "D'Haene|Nicky|N|0000-0001-8100-377X;Le Mercier|Marie|M|;Salmon|Isabelle|I|;Mekinda|Zita|Z|;Remmelink|Myriam|M|;Berghmans|Thierry|T|",
"chemical_list": "D066246:ErbB Receptors",
"country": "United States",
"delete": false,
"doi": "10.1634/theoncologist.2018-0016",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-7159",
"issue": "24(1)",
"journal": "The oncologist",
"keywords": null,
"medline_ta": "Oncologist",
"mesh_terms": "D000077192:Adenocarcinoma of Lung; D066246:ErbB Receptors; D005260:Female; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D009154:Mutation",
"nlm_unique_id": "9607837",
"other_id": null,
"pages": "9-13",
"pmc": null,
"pmid": "30413663",
"pubdate": "2019-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "9214508;26206867;23470965;26366557;16613914;28498782;26046389;24718890;21430269;26862733",
"title": "SMAD4 Mutation in Small Cell Transformation of Epidermal Growth Factor Receptor Mutated Lung Adenocarcinoma.",
"title_normalized": "smad4 mutation in small cell transformation of epidermal growth factor receptor mutated lung adenocarcinoma"
} | [
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"companynumb": "BE-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2018-BI-056823",
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"activesubstance": {
"activesubstancename": "AFATINIB"
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"abstract": "A distal interphalangeal (DIP) joint involvement in the adult-onset Still's disease (AOSD) has been described in some publications but is rarely reported to be severe. We report severe DIP joints damages in a young patient with AOSD.\n\n\n\nA 22 years old patient presented to our department complaining of inflammatory joints pain associated with prolonged fever and cutaneous rash. Physical examination identified polyarthritis and hepatosplenomegaly but no lymphadenopathies. After an extensive screening for neoplastic, infectious or hematologic diseases, the patient was finally diagnosed with AOSD. Treatment based on corticosteroids was then initiated with a good response on systemic signs. However, the patient continued to have recurrent arthritis affecting wrists and proximal interphalangeal joints. A Few years later, he developed a severe and disabling DIP arthritis with signs of joint destruction on conventional radiographs and MRI. Despite the initiation of methotrexate with optimal dosage, the patient continued to have polyarticular flares. The combination of methotrexate and sulfasalazine was responsible for drug-induced hepatotoxicity and this treatment was stopped. Anti-TNFα treatment was then indicated as general signs improved but severe joints damage persisted. Unfortunately, and due to healthcare system considerations, the patient was not able to benefit from TNFα inhibitors, and remained on methotrexate treatment only.\n\n\n\nThe distal destructive arthritis during AOSD is rare and controversial. Our patient had a severe form with resistance to conventional therapies.",
"affiliations": "Farhat Hached Hospital, University of Medicine of Sousse Rheumatology, Sousse, Tunisia.;Farhat Hached Hospital, University of Medicine of Sousse Rheumatology, Sousse, Tunisia.;Farhat Hached Hospital, University of Medicine of Sousse Rheumatology, Sousse, Tunisia.;Farhat Hached Hospital, University of Medicine of Sousse Rheumatology, Sousse, Tunisia.;Farhat Hached Hospital, University of Medicine of Sousse Rheumatology, Sousse, Tunisia.;Farhat Hached Hospital, University of Medicine of Sousse Rheumatology, Sousse, Tunisia.;Farhat Hached Hospital, University of Medicine of Sousse Rheumatology, Sousse, Tunisia.",
"authors": "Belghali|Safaa|S|;El Amri|Nejla|N|;Baccouche|Khadija|K|;Laataoui|Sadok|S|;Bouzaoueche|Monia|M|;Zeglaoui|Hela|H|;Bouajina|Elyes|E|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D018501:Antirheumatic Agents; D012460:Sulfasalazine; D008727:Methotrexate",
"country": "United Arab Emirates",
"delete": false,
"doi": "10.2174/1573397113666170728124845",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1573-3971",
"issue": "14(3)",
"journal": "Current rheumatology reviews",
"keywords": "AOSD; Still`s disease; adult-onset; distal destructive arthritis; finger joint; hematologic diseases.",
"medline_ta": "Curr Rheumatol Rev",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D018501:Antirheumatic Agents; D001168:Arthritis; D005384:Finger Joint; D006801:Humans; D008297:Male; D008727:Methotrexate; D016706:Still's Disease, Adult-Onset; D012460:Sulfasalazine; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101261938",
"other_id": null,
"pages": "284-288",
"pmc": null,
"pmid": "28758587",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Atypical form of Adult-onset Still's Disease with Distal Interphalangeal Joints Involvement.",
"title_normalized": "atypical form of adult onset still s disease with distal interphalangeal joints involvement"
} | [
{
"companynumb": "TN-MYLANLABS-2018M1088070",
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"occurcountry": "TN",
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"activesubstance": {
"activesubstancename": "SULFASALAZINE"
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... |
{
"abstract": "Prolonged exposure to immunosuppressive medication is a known risk factor for the development of post-transplant malignancies. De novo angiosarcoma in the post-transplant population is extremely rare. We present an 81-year-old female who developed an angiosarcoma at the site of a functioning renal allograft and review contemporary treatment strategies for this devastating disease. The report underscores the importance of periodic surveillance for the development of malignancy in the immunosuppressed population.",
"affiliations": "Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pa., USA.",
"authors": "Ferroni|Matthew C|MC|;Ristau|Benjamin T|BT|;Jackman|Stephen V|SV|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000354413",
"fulltext": null,
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"issn_linking": "0042-1138",
"issue": "95(3)",
"journal": "Urologia internationalis",
"keywords": null,
"medline_ta": "Urol Int",
"mesh_terms": "D000369:Aged, 80 and over; D017809:Fatal Outcome; D005260:Female; D006394:Hemangiosarcoma; D006801:Humans; D007676:Kidney Failure, Chronic; D007680:Kidney Neoplasms; D016030:Kidney Transplantation; D011183:Postoperative Complications",
"nlm_unique_id": "0417373",
"other_id": null,
"pages": "367-9",
"pmc": null,
"pmid": "24662683",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "De novo Angiosarcoma of a Renal Allograft.",
"title_normalized": "de novo angiosarcoma of a renal allograft"
} | [
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"companynumb": "US-SA-2015SA196112",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "ALEMTUZUMAB"
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{
"abstract": "Gingival hyperplasia is a rare finding in clinical practice. Nevertheless, when it occurs, it is a finding of great value as it can lead to definite clinical diagnosis. The present case is a 19-year-old male who was referred for further management of stage 5 chronic kidney disease. On evaluation, he was found to have gingival hyperplasia. He was evaluated for reversible causes of kidney disease, and since none were found, renal replacement therapy was advised. He had been taking amlodipine for blood pressure control. As this was presumed to be the cause of gingival hyperplasia, it was stopped and replaced by a combination of beta-blocker and prazosin. At six-month follow-up, he had complete resolution of gingival hyperplasia. Amlodipine as a cause of gingival hyperplasia is a rare occurrence. However, it is crucial to keep in mind such a possible side effect of this commonly prescribed antihypertensive drug.",
"affiliations": "Department of Medicine, Christian Medical College, Vellore, India.;Department of Medicine, Christian Medical College, Vellore, India.;Department of Medicine, Christian Medical College, Vellore, India.;Department of Medicine, Christian Medical College, Vellore, India.",
"authors": "John|Kevin|K|https://orcid.org/0000-0003-3382-0294;Mishra|Ajay Kumar|AK|;Gunasekaran|Karthik|K|;Iyyadurai|Ramya|R|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2020/7801546",
"fulltext": "\n==== Front\nCase Rep Nephrol\nCase Rep Nephrol\nCRIN\nCase Reports in Nephrology\n2090-6641 2090-665X Hindawi \n\n10.1155/2020/7801546\nCase Report\nAmlodipine-Induced Gingival Hyperplasia in a Young Male with Stage 5 Chronic Kidney Disease\nhttps://orcid.org/0000-0003-3382-0294John Kevin kevinjohn619@gmail.com Mishra Ajay Kumar Gunasekaran Karthik Iyyadurai Ramya Department of Medicine, Christian Medical College, Vellore, India\nAcademic Editor: Ze'ev Korzets\n\n\n2020 \n12 2 2020 \n2020 78015466 11 2019 23 1 2020 Copyright © 2020 Kevin John et al.2020This 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.Gingival hyperplasia is a rare finding in clinical practice. Nevertheless, when it occurs, it is a finding of great value as it can lead to definite clinical diagnosis. The present case is a 19-year-old male who was referred for further management of stage 5 chronic kidney disease. On evaluation, he was found to have gingival hyperplasia. He was evaluated for reversible causes of kidney disease, and since none were found, renal replacement therapy was advised. He had been taking amlodipine for blood pressure control. As this was presumed to be the cause of gingival hyperplasia, it was stopped and replaced by a combination of beta-blocker and prazosin. At six-month follow-up, he had complete resolution of gingival hyperplasia. Amlodipine as a cause of gingival hyperplasia is a rare occurrence. However, it is crucial to keep in mind such a possible side effect of this commonly prescribed antihypertensive drug.\n==== Body\n1. Introduction\nGingival hyperplasia is a physical finding that is rarely encountered in clinical practice. However, once it is confirmed, it is an important sign as it can give a clue for the correct diagnosis of a patient. Over the years, various causes of gingival hyperplasia have been reported in the literature. The common causes of gingival hyperplasia are drugs, non-Hodgkin's lymphoma, acute monocytic leukemia, granulomatous diseases, and chronic periodontal infections [1]. This list can be further narrowed down with a focused history and physical examination. If a precise aetiology is established, it is often possible to avoid a biopsy, and treatment can be instituted by merely avoiding the etiological agent. In this context, it would be useful to know all the causes of gingival hyperplasia, both familiar and obscure. Here, we describe the rare case of a patient who presented with amlodipine-induced gingival hyperplasia in the background of stage 5 chronic kidney disease.\n\n2. Case Presentation\nA 19-year-old boy presented with nocturnal cough and bilateral lower limb swelling of 3 months duration. There were no complaints of frothy urine, decreased urine output, or hematuria. He was evaluated for these complaints at his hometown and diagnosed with hypertension and stage 5 chronic kidney disease. He did not have any addictions, allergies, or significant family history for kidney disease. He was started on 10 mg of amlodipine and referred to our hospital for further evaluation and management. After starting amlodipine, the patient noticed painless, gradually progressive, and irregular swelling of his gums with few episodes of bleeding while brushing his teeth. When he presented to us, he had been taking amlodipine for three months in total.\n\nOn presentation to the outpatient department, he had a blood pressure of 180/100 mmHg in both upper limbs. His heart rate was 84 beats/min, respiratory rate was 18 breaths/min, and arterial oxygen saturation on room air was 98%. He was afebrile. He was noted to have pitting pedal oedema of both lower limbs up to the midcalf. On intraoral examination massive, painless, gingival enlargement involving both the arches, encroaching buccal, palatal, and lingual vestibular spaces was found (Figure 1). The gingiva was pale pink, firm in consistency and not tender on palpation. There were no other positive findings on examination of the other systems.\n\nHe was evaluated for treatable causes of chronic kidney disease. Causes of gingival hyperplasia that were considered included chronic periodontitis, drugs (calcium channel blockers such as amlodipine and nifedipine; cyclosporine and anticonvulsants such as phenytoin), acute monocytic leukemia, and non-Hodgkin's lymphoma.\n\nThe patient's initial blood investigations showed anaemia (Table 1). His creatinine was elevated, and an ultrasound scan showed bilateral shrunken kidneys with grade 3 renal parenchymal changes. The total duration of his kidney disease was not known. Kidney biopsy could not be performed given the small size and poor cortico-medullary differentiation. Hence, a complete evaluation of the cause of his kidney disease could not be conducted.\n\nHis blood leukocyte counts were normal, and this ruled out any blood dyscrasias. His blood picture did not show any blasts. He did not have lymphadenopathy. A diagnosis of stage 5 chronic kidney disease of unknown aetiology and secondary hypertension was made. A provisional diagnosis of amlodipine-induced gingival hyperplasia was made. Due to a clear temporal association, it was decided to assess response to the withdrawal of amlodipine before proceeding with further evaluation.\n\nThe patient was advised to take a low-salt renal diet. Amlodipine was stopped, and he was given a combination of atenolol and prazosin for blood pressure control. He was also started on febuxostat, torsemide, calcium and vitamin D supplements, phosphate binders, iron supplements, and erythropoietin. The need for renal replacement therapy was explained, and he was scheduled for the creation of an A-V(arteriovenous) fistula. The option of a renal transplant was also explained to him.\n\nOn follow-up after six months, the patient had complete resolution of gingival hyperplasia. A WHO-UMC causality assessment was performed, and the case fell into the “probable/likely” category. Proving “certain” causality would have required rechallenging the drug which would have been unethical. Therefore, it was considered to be sufficient evidence to attribute the cause of gingival hyperplasia to amlodipine. Chronic kidney disease was managed medically, and he was planned for an AV fistula creation for initiation of maintenance hemodialysis.\n\n3. Discussion\nAmlodipine is a dihydropyridine calcium channel blocker that is commonly prescribed as an antihypertensive drug. The common side effects of amlodipine include headache, dizziness, and palpitations. Gingival hyperplasia is a rare side effect of this drug. The prevalence of gingival hyperplasia caused by amlodipine had been estimated by Jorgensen in 1997 as 3.3% for patients in the United States of America, while a study conducted in India in 2014 by Tejnaniet al. arrived at a similar number of 3.4% [2, 3]. This suggests that the prevalence of amlodipine induced gingival hyperplasia is similar across populations of different race and geography, and has remained stable over time. Other causes of gingival hyperplasia are drugs (other calcium channel blockers such as nifedipine; cyclosporine and anticonvulsants such as phenytoin), non-Hodgkin's lymphoma, acute monocytic leukemia, granulomatous diseases (sarcoidosis and Crohn's diseases), granulomatosis with polyangiitis, chronic periodontal infections, pyogenic granuloma, benign neoplasms such as fibroma or papilloma, malignant neoplasms such as carcinoma or malignant melanoma, syndromic causes (Rutherford syndrome, Cross syndrome, Ramon syndrome, and Laband syndrome), pregnancy, and idiopathic gingival hyperplasia [4].\n\nIt was known that calcium channel blockers such as nifedipine could cause gingival hyperplasia. When amlodipine was introduced into the market, there were similar reports of gingival hyperplasia with this drug also. This was first reported in 1993 by Ellis et al. [5]. Since then, there have been various reports of similar cases. It is seen to be three times more common in males than in females [6]. There is a reported case of amlodipine causing hyperplasia of the hard palate as well [7].\n\nThe exact mechanism of amlodipine-induced gingival hyperplasia is not known. Various mechanisms have been postulated. These include defective collagenase activity due to reduced folic acid uptake, increase in adrenocorticotrophic hormone (ACTH) due to block in aldosterone synthesis, increase in keratinocyte growth factor, inflammation due to the concentration of drug in the crevices and bacterial plaques, as well as upregulation of transforming growth factor-beta [8–10]. Other factors such as dental hygiene, nutritional deficiencies, comorbidities such as renal failure (as seen with our patient) and male sex may also contribute to the gingival hyperplasia [6]. This could also be a biased observation as a large proportion of patients with chronic kidney disease are on amlodipine therapy as an antihypertensive.\n\nSubstituting the drug amlodipine with another antihypertensive remains the basis of management. In our patient, gingival hyperplasia had resolved entirely within six months of stopping the drug. Regression within three months of stopping the drug has also been reported [11]. This suggests that amlodipine-induced gingival hyperplasia is reversible with cessation of the drug alone. However, some advocate surgical management for a better aesthetic outcome. Gingivectomy or periodontal flap surgery can be performed. Maintenance of good oral hygiene and regular brushing of teeth are also of paramount importance. In summary, amlodipine is a potentially reversible cause of gingival hyperplasia, and this needs to be considered while evaluating patients who present with gingival overgrowth.\n\nAcknowledgments\nThe authors would like to thank Prof. Varghese John for reviewing the manuscript.\n\nEthical Approval\nThe work meets ethical guidelines and adheres to local legal requirements.\n\nConsent\nInformed signed consent was obtained from the patient.\n\nConflicts of Interest\nThe author declares that there are no conflicts of interest regarding the publication of this article.\n\nFigure 1 Photograph showing amlodipine-induced gingival hyperplasia.\n\nTable 1 Lab investigations.\n\nInvestigations\tResult (normal range)\t\nHaemoglobin (g/L)\t90 (140–175)\t\nTotal count (×109/L)\t6 (4.5–11.0)\t\nPlatelet count (×109/L)\t154 (150–350)\t\nHIV, HBV, HCV serology\tNegative\t\nSerum creatinine (μmol/L)\t666.5 (62–106)\t\nErythrocyte sedimentation rate (ESR) (mm/hour)\t22 (0–20)\t\nSerum sodium (mmol/L)\t138 (135–145)\t\nSerum potassium (mmol/L)\t5.2 (3.5–5)\t\nSerum bicarbonate (mmol/L)\t16 (22–29)\t\nSerum uric acid (mg/dL)\t5.8 (4–7)\t\nSerum calcium (mg/dL)\t7.81 (8.3–10.4)\t\nSerum phosphorous (mg/dL)\t5 (2.5–4.6)\t\nSerum parathyroid hormone (pg/ml)\t1305.3 (8–74)\t\nc-ANCA(antineutrophilic cytoplasmic antibodies)\tNegative\t\np-ANCA(antineutrophilic cytoplasmic antibodies)\tNegative\t\nThyroid stimulating hormone (TSH) (µIU/ml)\t2.6\t\nSerum total complement\tNormal\t\n24-hour urine protein (g)\t3.3 (50–150 mg)\n==== Refs\n1 Holmstrup P. Plemons J. Meyle J. Non-plaque-induced gingival diseases Journal of Periodontology 2018 89 S20 S28 S45 10.1111/jcpe.12938 2-s2.0-85048830528 29926945 \n2 Jorgensen M. G. Prevalence of amlodipine-related gingival hyperplasia Journal of Periodontology 1997 68 7 676 678 10.1902/jop.1997.68.7.676 2-s2.0-0030752409 9249639 \n3 Tejnani A. Mani A. Sodhi N. Incidence of amlodipine-induced gingival overgrowth in the rural population of Loni Journal of Indian Society of Periodontology 2014 18 2 p. 226 10.4103/0972-124x.131332 2-s2.0-84899735834 \n4 Cekmez F. Pirgon O. Tanju I. A. Idiopathic gingival hyperplasia International Journal of Biomedical Science: IJBS 2009 5 5 198 200 23675137 \n5 Ellis J. Seymour R. Thomason J. M. Monkman S. Idle J. Gingival sequestration of amlodipine and amlodipine-induced gingival overgrowth The Lancet 1993 341 8852 1102 1103 10.1016/0140-6736(93)92470-e 2-s2.0-0027501986 \n6 Tavassoli S. Yamalik N. Çağlayan F. Çağlayan G. Eratalay K. The clinical effects of nifedipine on periodontal status Journal of Periodontology 1998 69 2 108 112 10.1902/jop.1998.69.2.108 2-s2.0-0031935781 9526908 \n7 Wang X. Liu Q. Dong G. Wang Q. Reversible hard palate hyperplasia associated with amlodipine use: case report International Journal of Clinical Pharmacology and Therapeutics 2016 54 9 712 715 10.5414/cp202541 2-s2.0-84984680213 27251408 \n8 Nyska A. Shemesh M. Tal H. Dayan D. Gingival hyperplasia induced by calcium channel blockers: mode of action Medical Hypotheses 1994 43 2 115 118 10.1016/0306-9877(94)90061-2 2-s2.0-0028141631 7990738 \n9 Das S. J. Olsen I. Keratinocyte growth factor is upregulated by the hyperplasia-inducing drug nifedipine Cytokine 2000 12 10 1566 1569 10.1006/cyto.2000.0756 2-s2.0-0033786335 11023675 \n10 Border W. A. Noble N. A. Transforming growth factor beta in tissue fibrosis The New England Journal of Medicine 1994 331 331 1286 1292 10.1056/NEJM199411103311907 2-s2.0-0028109801 7935686 \n11 Aldemir N. M. Begenik H. Emre H. Erdur F. M. Soyoral Y. Amlodipine-induced gingival hyperplasia in chronic renal failure: a case report African Health Sciences 2012 12 12 576 578 10.4314/ahs.v12i4.30 2-s2.0-84873259014 23516009\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-665X",
"issue": "2020()",
"journal": "Case reports in nephrology",
"keywords": null,
"medline_ta": "Case Rep Nephrol",
"mesh_terms": null,
"nlm_unique_id": "101598418",
"other_id": null,
"pages": "7801546",
"pmc": null,
"pmid": "32099704",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "9526908;7935686;23516009;11023675;27251408;9249639;7990738;24872633;8097007;23675137;29926945",
"title": "Amlodipine-Induced Gingival Hyperplasia in a Young Male with Stage 5 Chronic Kidney Disease.",
"title_normalized": "amlodipine induced gingival hyperplasia in a young male with stage 5 chronic kidney disease"
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"activesubstancename": "AMLODIPINE BESYLATE"
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"abstract": "A 47-year-old man with poorly controlled diabetes mellitus (glycosylated hemoglobin 12%) presented to the ED with a 1-week history of fevers, productive cough, and dyspnea. The patient was febrile and hypoxemic on presentation; laboratory testing was remarkable for hyperglycemia and ketoacidosis. The initial chest CT scan showed right lower lobe consolidation and ground-glass opacities (Fig 1A). He was admitted to the ICU and administered IV antibiotics (cefepime and vancomycin) for the treatment of community-acquired bacterial pneumonia.",
"affiliations": "Department of Pulmonary, Critical Care and Sleep Medicine, University of Texas Medical Branch, Galveston, TX. Electronic address: kmnada@utmb.edu.;Department of Pulmonary, Critical Care and Sleep Medicine, University of Texas Medical Branch, Galveston, TX.;Department of Pulmonary, Critical Care and Sleep Medicine, University of Texas Medical Branch, Galveston, TX.",
"authors": "Nada|Khaled M|KM|;Nishi|Shawn|S|;Duarte|Alexander|A|",
"chemical_list": null,
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"delete": false,
"doi": "10.1016/j.chest.2021.01.025",
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"issn_linking": "0012-3692",
"issue": "159(5)",
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"medline_ta": "Chest",
"mesh_terms": "D018893:Bronchoalveolar Lavage; D001999:Bronchoscopy; D003920:Diabetes Mellitus; D003937:Diagnosis, Differential; D017809:Fatal Outcome; D006801:Humans; D008172:Lung Diseases, Fungal; D008297:Male; D008875:Middle Aged; D009091:Mucormycosis; D011014:Pneumonia; D014057:Tomography, X-Ray Computed",
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"publication_types": "D002363:Case Reports; D016428:Journal Article; D059040:Video-Audio Media",
"references": null,
"title": "Pneumonia and Poorly Controlled Diabetes.",
"title_normalized": "pneumonia and poorly controlled diabetes"
} | [
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"companynumb": "US-PFIZER INC-202101419874",
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"activesubstancename": "CEFEPIME HYDROCHLORIDE"
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"abstract": "A man in his late 50s with a history of membranoproliferative glomerulonephritis presented with fever and mild dyspnoea. He was HIV-negative and had been on corticosteroids as immunosuppression for 6 months prior to tapering them off 1 week before presentation. He was not taking prophylaxis for Pneumocystis jirovecii pneumonia. After unsuccessful treatment for community-acquired pneumonia, his condition worsened and he required intubation and mechanical ventilation. Full respiratory workup including bronchoscopy revealed P jirovecii as a source for the patient's infection. He was treated successfully with a 21-day course of trimethoprim-sulfamethoxazole and eventually weaned off the ventilator. He has had no complications to date. In our review of this case and the existing literature, we believe that proper utilisation of prophylaxis for pneumocystis pneumonia may have prevented our patient's transfer to intensive care unit. In our article, we discuss this issue and explore current evidence for prophylaxis.",
"affiliations": "Department of Internal Medicine, The Reading Hospital and Medical Center, West Reading, Pennsylvania, USA. mjplakke@gmail.com",
"authors": "Plakke|Michael J|MJ|;Jalota|Leena|L|;Lloyd|Benjamin J|BJ|",
"chemical_list": "D000890:Anti-Infective Agents; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
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"title": "Pneumocystis pneumonia in a non-HIV patient on chronic corticosteroid therapy: a question of prophylaxis.",
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"abstract": "Talaromyces marneffei infection is a systemic mycosis, caused by a dimorphic fungus, an opportunistic pathogen formerly known as Penicillium marneffei. This disease is endemic to Southeast Asia and common in human immunodeficiency virus (HIV) infected patients with low CD4 counts. Here we present a very rarely reported case of Talaromyces marneffei infection in an apparent non-immunosuppressed patient presenting decades later in a non-endemic setting (United States).\n\n\n\nOur patient was a 75-year-old Caucasian Navy veteran, who served in Vietnam as a part of the Swift Boat service in 1966. He presented to his primary care provider with uncontrolled nonproductive cough and abnormal chest computerized tomography. Bronchoscopy specimens showed Talaromyces. He was empirically treated with itraconazole and then switched to voriconazole after confirmation of diagnosis but he later deteriorated was changed to liposomal amphotericin B and isavuconazole. Patient did well for the next 90 days on isavuconazole until the therapy was stopped. Soon after stopping the medication (isavuconazole) his symptoms recurred and ultimately patient expired.\n\n\n\nTalaromycosis generally presents as pulmonary infection with manifestations similar with other endemic fungi. It is often seen HIV patients with travel to South east Asia. Very rarely this infection is seen and reported in non-immunosuppressed and in non-endemic areas. To date there are 4 well-documented cases among non-HIV, non-endemic population.\n\n\n\nTalaromyces can cause infection in non-HIV and non-endemic population and could be an underrecognized cause of pulmonary infections among veterans with even a remote history of exposure to the organism during deployment.",
"affiliations": "Universidad Nacional Autonoma de Honduras, Facultad de Ciencias Medicas, Hospital Escuela Universitario, Boulevard Suyapa, Tegucigalpa, Honduras.;Department of Infectious Disease, Citizens Medical Center, 2701 Hospital Dr, Victoria, TX: 77901, United States.;Department of Medicine, Citizens Medical Center, 2701 Hospital Dr, Victoria, TX: 77901, United States.;Department of Medicine, Citizens Medical Center, 2701 Hospital Dr, Victoria, TX: 77901, United States.;Department of Medicine, Scott & White Medical Center, 2401 South 31st Street, Temple, TX: 76508, United States.;Nabriva Therapeutics Plc, 1000 Continental Drive, Suite 600, King of Prussia, PA 19406.;Department of Microbiology, Scott & White Medical Center, 2401 South 31st Street, Temple, TX: 76508, United States.;Department of Medicine, Scott & White Medical Center, 2401 South 31st Street, Temple, TX: 76508, United States.;Department of Medicine, Central Texas Veterans Health Care System, 1901 South Veterans Drive, Temple, TX: 76504, United States.",
"authors": "Castro-Lainez|Miriams Teresita|MT|;Sierra-Hoffman|Miguel|M|;LLompart-Zeno|Juan|J|;Adams|Robin|R|;Howell|Alan|A|;Hoffman-Roberts|Holly|H|;Fader|Robert|R|;Arroliga|Alejandro C|AC|;Jinadatha|Chetan|C|",
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"fulltext": "\n==== Front\nIDCasesIDCasesIDCases2214-2509Elsevier S2214-2509(18)30031-310.1016/j.idcr.2018.02.013ArticleTalaromyces marneffei infection in a non-HIV non-endemic population Castro-Lainez Miriams Teresita aSierra-Hoffman Miguel bLLompart-Zeno Juan cAdams Robin cHowell Alan dHoffman-Roberts Holly eFader Robert fArroliga Alejandro C. dJinadatha Chetan Chetan.Jinadatha@va.govgh⁎a Universidad Nacional Autonoma de Honduras, Facultad de Ciencias Medicas, Hospital Escuela Universitario, Boulevard Suyapa, Tegucigalpa, Hondurasb Department of Infectious Disease, Citizens Medical Center, 2701 Hospital Dr, Victoria, TX: 77901, United Statesc Department of Medicine, Citizens Medical Center, 2701 Hospital Dr, Victoria, TX: 77901, United Statesd Department of Medicine, Scott & White Medical Center, 2401 South 31st Street, Temple, TX: 76508, United Statese Nabriva Therapeutics Plc, 1000 Continental Drive, Suite 600, King of Prussia, PA 19406f Department of Microbiology, Scott & White Medical Center, 2401 South 31st Street, Temple, TX: 76508, United Statesg Department of Medicine, Central Texas Veterans Health Care System, 1901 South Veterans Drive, Temple, TX: 76504, United Statesh Department of Medicine, College of Medicine, Texas A&M University, 8447 Bryan Rd, Bryan, TX: 77807, United States⁎ Corresponding author at: Department of Medicine, Central Texas Veterans Health Care System, 1901 South Veterans Drive, Temple, TX, 76504, United States. Chetan.Jinadatha@va.gov03 3 2018 2018 03 3 2018 12 21 24 16 2 2018 28 2 2018 28 2 2018 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Introduction\nTalaromyces marneffei infection is a systemic mycosis, caused by a dimorphic fungus, an opportunistic pathogen formerly known as Penicillium marneffei. This disease is endemic to Southeast Asia and common in human immunodeficiency virus (HIV) infected patients with low CD4 counts. Here we present a very rarely reported case of Talaromyces marneffei infection in an apparent non-immunosuppressed patient presenting decades later in a non-endemic setting (United States).\n\nPresentation of case\nOur patient was a 75-year-old Caucasian Navy veteran, who served in Vietnam as a part of the Swift Boat service in 1966. He presented to his primary care provider with uncontrolled nonproductive cough and abnormal chest computerized tomography. Bronchoscopy specimens showed Talaromyces. He was empirically treated with itraconazole and then switched to voriconazole after confirmation of diagnosis but he later deteriorated was changed to liposomal amphotericin B and isavuconazole. Patient did well for the next 90 days on isavuconazole until the therapy was stopped. Soon after stopping the medication (isavuconazole) his symptoms recurred and ultimately patient expired.\n\nDiscussion\nTalaromycosis generally presents as pulmonary infection with manifestations similar with other endemic fungi. It is often seen HIV patients with travel to South east Asia. Very rarely this infection is seen and reported in non-immunosuppressed and in non-endemic areas. To date there are 4 well-documented cases among non-HIV, non-endemic population.\n\nConclusion\nTalaromyces can cause infection in non-HIV and non-endemic population and could be an underrecognized cause of pulmonary infections among veterans with even a remote history of exposure to the organism during deployment.\n\nKeywords\nTalaromyces marneffeiNon-HIVNon-endemic population\n==== Body\nIntroduction\nTalaromyces (Penicillium) marneffei is a dimorphic fungus and the only member in its genus known to be pathogenic to humans. It can cause both localized as well as overwhelming disseminated infection. T. marneffei is endemic to Southeast Asia [[1], [2]]. It is an important opportunistic infection in HIV-infected patients who live in or have traveled to endemic regions and is considered an acquired immunodeficiency syndrome (AIDS) defining illness. Recently, there have been several case reports of T. marneffei infection in HIV-negative patients who are otherwise not immunosuppresssed [2]. We report a case of a HIV negative Vietnam war veteran with advanced chronic obstructive pulmonary diseases (COPD) who presented with pulmonary T. marneffei lung infection which reactivated 40 years after a one year tour in Vietnam.\n\nCase\nOur patient was a 75-year-old Caucasian man, a Navy veteran, who served in Vietnam in the Swift Boat service in 1966. He had a history of bullous emphysema and presented to his primary care provider with uncontrollable nonproductive cough, for which he was prescribed oral levofloxacin and steroids with no improvement. He was then referred to pulmonary medicine because of an abnormal chest computerized tomography (CT), which showed a cavitary left lower lobe (LLL) infiltrate and several lung nodules (Fig. 1).Fig. 1 a & b: Computerized tomography of the patient’s lung showing the pulmonary lesion.\n\nFig. 1\n\nBronchoscopy with bronchoalveolar lavage (BAL) yielded no specific etiology and he was treated symptomatically. After transient improvement, there was recurrence of productive cough, night sweats, malaise, and new hemoptysis. A second chest CT showed increase in the size of the LLL cavitary infiltrate, a new small necrotizing lesion in the left lung, and a new small left pleural effusion. Repeat bronchoscopy with transbronchial biopsy and BAL as well as thoracentesis was performed, revealing a sterile exudate and nondiagnostic findings on transbronchial biopsy and BAL. The patient was empirically started on itraconazole suspension on suspicion of an indolent fungal infection even though serologies for Histoplasma, Cryptococcus, and Coccidiomycosis were negative. Therapy had to be stopped due to gastrointestinal (GI) side effects. The patient was then changed to voriconazole but his symptoms continued unabated.\n\nAt this point, the patient was referred to Infectious Disease. Initial evaluation revealed a man with a severe cough, hemoptysis, and purulent sputum. Sputum samples were obtained for culture. Voriconazole was continued but only for short time because of side effects. The initial BAL grew a mold. Because he remained ill, the patient was started on liposomal amphotericin B (LAMB) and isavuconazole. The other bronchoscopy samples grew the same mold, which was identified as Talaromyces (Penicillium) marneffei. He was given 28 days of LAMB and isavuconazole with an excellent response and was discharged home on daily isavuconazole. On follow-up, he did very well and the antifungal was stopped at day 90. However, soon thereafter productive cough and malaise recurred. He was then readmitted and both isavuconazole and LAMB were resumed. His symptoms slowly worsened and isavuconazole was changed to voriconazole, but he continued to worsen. New lesions developed in his left lung as did a right lung cavitary opacity. Micafungin was added empirically and despite triple therapy, the patient progressed clinically and radiographically, and eventually succumbed to his infection. An extensive workup for an immunosuppressive state was nondiagnostic; HIV testing was repeatedly negative, including HIV viral load.\n\nDiscussion\nT. marneffei infection is an important systemic mycosis in HIV infected individuals who reside in or have traveled to Southeast Asia. It was described in many regions of Thailand, Vietnam, northeastern India, Southern China, Hong Kong, Taiwan, Laos, Malaysia, Myanmar, and Cambodia [2]. The prevalence of T. marneffei infection in non-HIV, non-endemic population is very low, only 4 cases were identified in the literature [[3], [4], [5], [6]].\n\nThe first reported case of T. marneffei infection was laboratory acquired in France in 1959 and the first case due to natural exposure was reported in 1973, in a patient who had Hodgkin’s disease and lived in North America and who had traveled to Southeast Asia [1]. However, it was not until the late 1980s, with the arrival of the HIV epidemic in Asia, that the incidence of T. marneffei infection increased in the endemic population and among visitors traveling to Southeast Asia [7]. Hence, T. marneffei infection is considered an AIDS defining opportunistic infection.\n\nWith the use of potent antiretroviral therapy, the incidence of HIV-associated T. marneffei infection decreased considerably [2]. At the same time, the incidence increased in HIV-negative patients with other immunocompromising conditions who traveled to Southeast Asia. This change in epidemiology poses a diagnostic challenge. As a result, there may be delays initiating therapy which may result in disease progression and poor outcomes [[7], [8]]. Often, the only clue a physician may have to make the appropriate diagnosis is a history of travel to an endemic area.\n\nThe pathogenesis of T. marneffei infection is unclear. The main mode of acquisition is inhalation of conidia from the environment. Phagocytic cells are the primary host defense against the fungus, resulting in granulomatous and suppurative reactions in immunocompetent patients and necrotizing reactions in those who are immunocompromised [1]. Disseminated disease via the reticuloendothelial system is common in immunosuppressed individuals, in whom the severity of disease depends on the degree of immunosuppression. Five cases have been reported to date among non-HIV non-endemic patients, including the case described here [[3], [5], [6], [9]]. (Tables 1 & 2). Many of the HIV-negative non-endemic patients had immunocompromising conditions as well as disseminated disease at the time of diagnosis. Yet, only one of the patients reported died of T. marneffei infection. The fatality rate among patients with T. marneffei infection is low but this is based upon knowledge derived from only 5 cases. Since the prognosis of T. marneffei infection is less favorable if diagnosed late, clinician education about this condition should be encouraged to improve early diagnosis and treatment.Table 1 Talaromyces marneffei Infection in non-HIV, non-Endemic Infected Adult Patients.\n\nTable 1\tSex/Age\tResidence\tTravel to Asia\tComorbidities\tSymptoms\tChest X-ray/Computerized Tomography (CT)/other\tDiagnostic Procedure of T. Marneffei\tTreatment\tOutcome\tReference\t\n1\tMale/45\tAustralia\tLaos, Vietnam (recent travel; not specified how long ago before initial symptoms\tNone\tFever, lymphadenopathy, night sweats, cough, left sided pleuritic chest pain (4-month history)\tCT: pulmonary infiltrates and mediastinal lymphadenopathy\tFiberoptic bronchoscopy; histopathological analysis and culture\tFirst, he was treated empirically with TMP sulfamethoxazole.\tResolution\tJoosten SA [9]\t\nAfter diagnosis: inpatient with iv amphotericin B, discharge with Itraconazole\t\n2\tMale/79\tFrance\tThailand 1979 and China in 2002 for 15 days\tChronic obstructive pulmonary disease (has received inhaled corticosteroid for several years)\tHemoptysis (2009)\t2009: CT: left apical opacity, BAL: negative 2012: Thickening of the walls of the left cavity, BAL\t2012: BAL: culture on Sabouraud dextrose agar with chloramphenicol\t2009: for suspected Aspergilloma: voriconazole October 2009-October 2010. 2012: amphotericin B for 10 days followed by itraconazole for 3 months\tResolution\tDe Monte A [5]\t\n3\tMale/67\tAustralia\tVietnam: 10-day vacation in December 2008\tReceived a cadaveric renal transplant for ESRF secondary to systemic vasculitis in 2004 (maintenance immunosuppression consisted of tacrolimus, mycophenolate mofetil, and prednisolone.)\tTwo weeks after his return from vacation, his serum creatinine increased (124 to 190) and renal biopsy showed recurrent vasculitis.\tChest x-ray: no evidence of fungal disease\tBlood and peritoneal fluid cultures after 3 days of incubation grew TM.\tBefore definite diagnosis, the patient was started on IV piperacillin and tazobactam.\tResolution\tJ. Hart [6]\t\nSix weeks later: he presented with a 3-week history of abdominal pain and diarrhea, with 2 days acute severe lower abdominal pain which progressed to septic shock\tLaparotomy: perforated sigmoid colon diverticulum and intraperitoneal pus.\tHistopathological analysis of resected colon revealed CMV colitis but no fungal elements were seen on periodic acid-Schiff or Grocott’s methenamine staining\tAfter a diagnosis of TM: IV liposomal amphotericin B for two weeks followed by itraconazole as induction therapy for 3 months. After induction, prophylaxis of itra 300 mg daily was continued.\t\n4\tFemale/41\tAustralia\t2010: prior lung transplantation: Malaysia, Singapore, Thailand\t2011: Underwent uncomplicated bilateral sequential lung transplantation for cystic fibrosis (maintenance immunosuppression consisted of tacrolimus, mycophenolate mofetil, and prednisolone.)\tTen months after trip to Vietnam: several weeks’ history of wheezing, reduce exercise tolerance, headache, fever, weight loss, anemia, leukopenia\t• Chest x-ray: mild peri-bronchial thickening in the retrocardiac area\n\n\tBAL, blood cultures, and lymph node samples\tTreated empirically with IV piperacillin-tazobactam and IV voriconazole for 12 days, discharge on oral voriconazole for 12 months\tResolution\tA. Stathakis [3]\t\n18 months post-transplant: Vietnam for 2 weeks\t• Chest CT: bulky mediastinal and left hilar lymphadenopathy with narrowing of her left lingular and left lower lobe airways, peri bronchial infiltrate, lingual consolidation, atelectasis and a focal cavitating nodule in the posterior segment of her left upper lobe\n\n\t\n5\tMale/75\tUSA\tVietnam War: 1966\tBullous Emphysema\tProductive cough, night sweats, malaise, hemoptysis\t• Chest CT: bilateral lung nodules and cavitary lesions, necrotizing lesion on left lung and pleural effusion\n\n\tBAL, sputum cultures\tTreated with Liposomal amphotericin B plus isavuconazole for 28 days; discharged on oral isavuconazole for 90 day.\tDeath\tCase report\t\n• Bronchoscopy and Thoracentesis: negative\n\n\tAt relapse: LAMB and Isavuconazole were reinitiated, later exchange isavuconazole to voriconazole and added micafungin\t\n• Biopsy: negative\n\n\t\t\nTable 2 Non-HIV Patients with T. marneffei infection clinical symptoms*.\n\nTable 2Symptom\tP (%)\t\nHemoptysis\t4\t\nNeutropenia\t12\t\nAbdominal pain\t15\t\nDiarrhea\t15\t\nArthritis\t16\t\nSplenomegaly\t19\t\nHepatomegaly\t23\t\nDyspnea\t33\t\nWeight loss\t34\t\nFungemia\t43\t\nAnemia\t47\t\nMalaise\t48\t\nCough\t50\t\nLymphadenopathy\t50\t\nCutaneous or subcutaneous lesions\t53\t\nThrombocytosis\t55\t\nFever\t89\t\n\n\nIt is very important to remember that T. marneffei is a primary pulmonary pathogen which may well use macrophages to proliferate and later cause acute pulmonary, disseminated and/or reactivation disease. The laboratory diagnosis is performed by identifying the fungus by microscopy and culture from a variety of specimens including blood, skin, bone marrow, lymph nodes, respiratory sources, liver biopsies, cerebrospinal fluid, urine, stool, kidney, pericardium, intestine or gastric specimens. A definitive diagnosis of T. marneffei infection by fungal culture has been reported with 100%, 90% and 76% sensitivity from bone marrow, skin biopsy and blood, respectively [1]. T. marneffei can be found on direct examination of a peripheral blood smear in patients with disseminated disease. Histopathological sections stained with hematoxylin and eosin, Grocott methenamine silver or periodic acid Schiff stain will demonstrate T. marneffei in biopsy specimens. In tissue, the yeast forms can be found with clearly defined central septae, characteristic of T. marneffei.\n\nT. marneffei is generally susceptible to miconazole, itraconazole, ketoconazole and flucytosine, whereas amphotericin B has only intermediate fungicidal activity for this pathogen [1]. Current infectious disease guidelines recommend liposomal amphotericin B for 2 weeks, followed by oral itraconazole for ten weeks, followed by secondary prophylaxis [4]. This regimen has resulted in a 97.3% cure rate in a non-randomized study [10]. In our review, 3 patients who were treated initially with IV amphotericin B and later discharged on itraconazole had complete resolution. Our patient succumbed to this invasive fungal infection despite 6 months of intensive antifungal therapy. Initial therapy consisting of 30 days of amphotericin B plus isavuconazole achieved an excellent response. Unfortunately, the infection recurred 3 months later. Voriconazole plus amphotericin B trial was started then, and ultimately, triple therapy with micafungin, voriconazole and amphotericin B was administered with no positive outcome. Although we believe isavuconazole in combination with LAMB had clinical success, time proved that we did not accomplish microbiological eradication since in his recurrence 4 months later this combination was not able to contain the invasive and progressive fungal respiratory infection, nor did any combination that we implemented thereafter. We believe the patient may have had an underlying immunosuppressive disorder that was neither HIV, hypogammaglobinemia or any other obvious hematological disorder which remained undefined even after a reasonable extensive investigation.\n\nAlthough there are only a handful of T. marneffei cases described in the literature among non-HIV, non-endemic patients, this should not keep health care providers from considering the diagnosis in the appropriate clinical context. Early diagnosis and appropriate treatment should result in clinical success and microbiological eradication, but delays in a timely diagnosis may result in a fatal outcome. Penicillium spp often grow from bronchoscopic samples and are typically disregarded as contaminants, but sub-speciation should be pursued in the appropriate clinical setting so as not to miss this potentially lethal pathogen.\n\nWe speculate that our patient is not the first Vietnam veteran who has developed late reactivation of this fungus, which we suspect remains all too frequently undiagnosed. We hope this case report will raise awareness of the potential for late reactivation of this dimorphic fungus in our Vietnam veteran population and promote its inclusion in the differential diagnosis of atypical lung infections in these patients.\n\nConflict of interest\nAll authors have no conflicts of interests to declare.\n\nFunding\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nContributors\nAll authors have reviewed and participated in the manuscript preparation.\n\nCompeting interests\nNone.\n\nAcknowledgements:\nThis work was supported by Baylor Scott & White Memorial Hospital and the Central Texas Veterans Health Care System, Temple, Texas USA. The views expressed in the article are those of the authors and do not represent the views or position of Department of Veterans Affairs.\n==== Refs\nReferences\n1 Vanittanakom N. Cooper C.R. Jr. Fisher M.C. Sirisanthana T. Penicillium marneffei infection and recent advances in the epidemiology and molecular biology aspects Clin Microbiol Rev 19 1 2006 95 110 16418525 \n2 Chan J.F. Lau S.K. Yuen K.Y. Woo P.C. Talaromyces (Penicillium) marneffei infection in non-HIV-infected patients Emerg Microbes Infect 5 2016 e19 26956447 \n3 Stathakis A. Lim K.P. Boan P. Lavender M. Wrobel J. Musk M. Penicillium marneffei infection in a lung transplant recipient Transpl Infect Dis 17 3 2015 429 434 25809145 \n4 Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf. Accessed March 7, 2018. T10-15.\n5 De Monte A. Risso K. Normand A.C. Chronic pulmonary penicilliosis due to Penicilliom marneffei: late presentation in a French traveler J Travel Med 21 4 2014 292 294 24816045 \n6 Hart J. Dyer J.R. Clark B.M. McLellan D.G. Perera S. Ferrari P. Travel-related disseminated Penicillium marneffei infection in a renal transplant patient Transpl Infect Dis 14 4 2012 434 439 22188555 \n7 Wong S.S. Siau H. Tuen K.Y. Penicilliosis marneffei—west meets east J Med Microbiol 48 11 1999 973 975 10535639 \n8 Kawila R. Chaiwarith R. Supparatpinyo K. Clinical and laboratory characteristics of penicilliosis marneffei among patients with and without HIV infection in Northern Thailand: a retrospective study BMC Infect Dis 13 2013 464 24094273 \n9 Joosten S.A. Hannan L. Heroit G. Boerner E. Irving L. Penicillium marneffei presenting as an obstructing endobronchial lesion in an immunocompetent host Eur Respir J 39 6 2012 1540 1543 22654011 \n10 Sirisanthana T. Supparatpinyo K. Epidemiology and management of penicilliosss in human immunodeficiency virus-infected patients Int J Infect Dis 3 1 1998 45 53\n\n",
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"title": "Talaromyces marneffei infection in a non-HIV non-endemic population.",
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"abstract": "Renal failure developed after a prolonged course of vancomycin therapy in 2 patients who were receiving tenofovir disoproxil fumarate as part of an antiretroviral regimen. Tenofovir has been implicated in the development of Fanconi syndrome and renal insufficiency because of its effects on the proximal renal tubule. Vancomycin nephrotoxicity is infrequent but may result from coadministration with a nephrotoxic agent. Clinicians should be aware that tenofovir may raise the risk of renal failure during prolonged administration of vancomycin.",
"affiliations": "Columbia University College of Physicians and Surgeons, Center for Comprehensive Care, St. Luke's Roosevelt Hospital, New York, USA.",
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"abstract": "Infantile hemangiomas (IHs) are common vascular tumors. In most cases, a benign course with favorable outcome can be anticipated. IH typically present as cutaneous lesions either with a localized or diffuse segmental distribution. Segmental hemangiomas in the face may be associated with brain and cardiac anomalies (PHACES syndrome), whereas airway involvement has been reported to be associated with hemangiomas in the \"beard\" area. Multiple cutaneous hemangiomas may be associated with visceral hemangiomas (commonly in the liver). In this report, we present a new association where deep paravertebral hemangiomatous lesions were observed to be associated with cutaneous back hemangiomas in two consecutive cases.",
"affiliations": "Department of Pediatric Surgery, Faculty of Medicine, Ain Shams University, Cairo, Egypt.;Department of Radiodiagnosis, Faculty of Medicine, Ain Shams University, Cairo, Egypt.;Department of Pediatrics, Faculty of Medicine, Ain Shams University, Cairo, Egypt.;Department of Pediatrics, Faculty of Medicine, Ain Shams University, Cairo, Egypt.",
"authors": "AbouZeid|Amr AbdelHamid|AA|0000-0003-2681-6086;Mohammad|Shaimaa Abdelsattar|SA|;Aly|Heba Gomaa|HG|;Ragab|Iman Ahmed|IA|",
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"fulltext": "\n==== Front\nEuropean J Pediatr Surg Rep\nEuropean J Pediatr Surg Rep\n10.1055/s-00024358\nEuropean Journal of Pediatric Surgery Reports\n2194-7619\n2194-7627\nGeorg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany\n\n10.1055/s-0040-1721408\n200538cr\nCase Report\nPosterior Mediastinal and Cutaneous Back Hemangiomas in Infants: A New Association\nhttp://orcid.org/0000-0003-2681-6086\nAbouZeid Amr AbdelHamid 1\nMohammad Shaimaa Abdelsattar 2\nAly Heba Gomaa 3\nRagab Iman Ahmed 3\n1 Department of Pediatric Surgery, Faculty of Medicine, Ain Shams University, Cairo, Egypt\n2 Department of Radiodiagnosis, Faculty of Medicine, Ain Shams University, Cairo, Egypt\n3 Department of Pediatrics, Faculty of Medicine, Ain Shams University, Cairo, Egypt\nAddress for correspondence Amr Abdelhamid AbouZeid, MD Department of Pediatric Surgery, Faculty of Medicine, Ain Shams UniversityLotefy El-Sayed street, 9 Ain-Shams University buildings, Abbassia, Cairo 11657Egyptamrabdelhamid@hotmail.com\n1 2021\n12 5 2021\n9 1 e37e40\n16 5 2020\n25 9 2020\nThe Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ )\n2021\nThe Author(s).\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.\nInfantile hemangiomas (IHs) are common vascular tumors. In most cases, a benign course with favorable outcome can be anticipated. IH typically present as cutaneous lesions either with a localized or diffuse segmental distribution. Segmental hemangiomas in the face may be associated with brain and cardiac anomalies (PHACES syndrome), whereas airway involvement has been reported to be associated with hemangiomas in the “beard” area. Multiple cutaneous hemangiomas may be associated with visceral hemangiomas (commonly in the liver).\n\nIn this report, we present a new association where deep paravertebral hemangiomatous lesions were observed to be associated with cutaneous back hemangiomas in two consecutive cases.\n\nKeywords\n\nhemangioma\nmagnetic resonance imaging\nparavertebral\nvascular tumors\nFunding None.\n==== Body\nIntroduction\n\nInfantile hemangiomas (IHs) are common benign vascular tumors. 1 IHs are characterized by a natural history where most tumors would go into spontaneous involution by the age of 7 years. 1 2 Generally, an excellent prognosis can be anticipated with few reported complications. 3 Exceptionally, very large tumors may cause hemodynamic instability in infancy. Lesions in specific locations are more prone to cause complications: periorbital hemangiomas may obstruct the field of vision, and subglottic lesions can obstruct the airway. 4 5 Expectant treatment is the rule for the management of uncomplicated IHs. When indicated, systemic corticosteroids and more recently propranolol have been successfully used to induce/accelerate tumor regression. 2\n\nIHs typically present as cutaneous lesions either with a localized or diffuse segmental distribution. 2 Segmental hemangiomas in the face may be associated with brain and cardiac anomalies (PHACES syndrome), whereas airway involvement has been reported to be associated with hemangiomas in the “beard” area. 2 5 Multiple cutaneous hemangiomas may be associated with visceral hemangiomas (commonly in the liver). 2\n\nIn this report, we present a new association where deep paravertebral hemangiomatous lesions were observed to associate cutaneous back hemangiomas in two cases.\n\nCase 1\n\nA boy was born with a flat back hemangioma. Rapid increase in the size of the cutaneous lesion (proliferative phase) was noticed by the parents at the age of 1 month. The parents revealed a history of oral propranolol treatment that started at the age of 3 months and discontinued later at the age of one and a half years. At the age of 2 years, the patient was referred to our vascular anomaly clinic with a previously performed magnetic resonance imaging (MRI) study at the age of 3 months ( Fig. 1a–c ). Besides the cutaneous lesion, the MRI study demonstrated the presence of large posterior mediastinal and upper abdominal retroperitoneal soft tissue masses. The mediastinal mass was seen bilateral symmetrical pre- and paravertebral in location, compressing the adjacent posterior aspects of both lung lobes and encasing adjacent parts of the aorta ( Fig. 2a ). The retroperitoneal component was seen in continuity with the mediastinal mass in the suprarenal region partially encasing the upper pole of both kidneys ( Fig. 2c, d ). The deep paravertebral lesions (mediastinal and retroperitoneal) showed typical MRI features of IH: intermediate signal on T1 and bright T2 and STIR signal with characteristic intralesional flow voids ( Fig. 1 a,b ). No evidence of intraspinal or transforaminal extension, hilar or mediastinal lymphadenopathy, or pleural or pericardial sac collection could be detected. Apart from mild microcytic anemia, the hematological parameters of the case were normal. A follow-up CT scan was ordered upon referral (age of 2 years) that showed partial regression of the deep paravertebral lesions ( Fig. 2d–f ); however, atrophy of the right kidney was noted (confirmed by the absence of activity on renal isotopic scan). Upon referral, oral propranolol was represcribed to the patient (2 mg/kg/day in three divided doses) and continued till the age of 3 years. The cutaneous lesion showed progressive regression with propranolol ( Fig. 1c, f ). Similarly, the deep lesions showed marked regression on follow-up imaging ( Fig. 1d, e ; Fig. 2h–i ). Regarding the atrophy of the right kidney, the patient was directed to follow-up at the pediatric nephrology clinic.\n\nFig. 1 First case of a boy with cutaneous back and posterior mediastinal hemangiomas. ( a,b ) magnetic resonance imaging ([MRI] coronal and sagittal) performed at the age of 3 months (before treatment) demonstrating the presence of large intrathoracic posterior mediastinal (paravertebral) hemangioma (bright T2 signal with characteristic intralesional flow voids). White arrows are pointing to cutaneous back hemangioma in ( a ) and ( b ). ( c ) The appearance of back hemangioma at the time of referral (2 years old). ( d–f ) Follow-up at the age of 3 years demonstrating marked regression of the mediastinal lesions on MRI ( d,e ), as well as regression of the cutaneous back hemangioma after propranolol treatment.\n\nFig. 2 First case of a boy with cutaneous back and posterior mediastinal hemangiomas. ( a–c ) Magnetic resonance imaging (MRI) study performed at the age of 3 months before treatment. The mediastinal mass was seen in ( a ) as bilateral symmetrical mass, pre- and paravertebral in location, compressing the adjacent posterior aspects of both lung lobes and encasing adjacent parts of the aorta. The retroperitoneal component was seen in ( b ) and ( c ) in the suprarenal region partially encasing the upper pole of both kidneys. ( d–f ) Computed tomography (CT) study performed at presentation to our clinic (age of 2 years). Note the regression of the paravertebral masses; however, there was atrophy of the right kidney ( black arrow in f ), whereas it was present in the first study at the age of 3 months ( white arrow in c ). ( g–i ) MRI study performed at follow-up after treatment (at the age of 3 years) demonstrating marked regression of the deep hemangiomatous lesions (posterior mediastinal and retroperitoneal). Note atrophy of the right kidney ( black arrow ).\n\nCase 2\n\nA 6-month-old girl presented with respiratory distress and a diffuse back hemangioma ( Fig. 3a ) that was small at birth. Chest X-ray showed tracheal deviation to the right. To avoid the need for general anesthesia, a CT scan rather than MRI was ordered showing a large posterior mediastinal mass extending from the retropharyngeal space to the level of T11, with intense contrast enhancement in the arterial phase. The mass was seen encasing the aortic arch and descending aorta with intraspinal extension and causing tracheal deviation ( Fig. 3b, c ). No sizable mediastinal or hilar adenopathy could be detected. A similar lesion with intense contrast enhancement was seen in the left hepatic lobe ( Fig. 3c ). Hematological investigations showed no abnormality. Systemic corticosteroids were prescribed for the respiratory distress, and a CT-guided biopsy was taken from the posterior mediastinal mass that confirmed the diagnosis of hemangioma. Oral propranolol was added with gradual tapering of corticosteroids, yet the patient had recurrent attacks of bronchitis and pneumonia with bronchospasm necessitating pediatric ICU admission. Interruption of propranolol and resumption of systemic corticosteroids (prednisolone 2 mg/kg/day) was therefore applied for a period of 6 months. The patient had delayed gross motor milestones; neurological examination showed mild hypotonia with normal deep tendon reflexes mostly attributed to prolonged steroid courses. Corticosteroid treatment was discontinued again, and the patient returned to oral propranolol after stabilization of her chest condition. Almost complete regression of the cutaneous lesion was observed. A follow-up CT showed regression of the hepatic lesion ( Fig. 3g ) and mild-to-moderate regression of the deep paraspinal lesion ( Fig. 3e, f ).\n\nFig. 3 Second case of a girl with cutaneous back and posterior mediastinal hemangiomas. ( a ) The appearance of the back hemangioma. ( b–d ) CT with intravenous contrast demonstrating the hemangiomatous lesions in the subcutaneous ( white arrow ), posterior mediastinal, and liver. The mass is seen in ( b ) with intraspinal extension and causing tracheal deviation ( black arrow ), while is seen encasing the aortic descending aorta in ( c ). A similar lesion with intense contrast enhancement was seen in the left hepatic lobe in ( d ). ( e–g ) Follow-up CT demonstrating mild regression in the upper mediastinal lesion in ( e ) with less compression on the airway, which is still displaced to the right ( black arrow ), whereas mild-to-moderate regression of the lesion is seen in ( f ) and ( g ).\n\nDiscussion\n\nReviewing the literature, one can still find confusing terminology in reports on mediastinal hemangiomas when authors described venous malformations using the old terminology of cavernous haemangiomas. 6 7 Truong et al reported on the successful use of propranolol in the treatment of a life-threatening subglottic and mediastinal IH in a female infant with no evidence of cutaneous lesions. 8 In this report, we describe in two consecutive patients a new association between diffuse cutaneous back hemangioma and the presence of deep paravertebral hemangiomatous lesions, which, to the best of our knowledge, has not been reported before.\n\nThe paravertebral hemangioma caused mediastinal compression in one of our cases who suffered from breathing difficulties at the age of 6 months. Propranolol was discontinued for bronchial obstruction, and systemic corticosteroids were used instead. Maybe a combination of both drugs would have achieved a synergistic effect. 9 More invasive treatment modalities can be used, such as intralesional steroid/bleomycin injection; also, sirolimus may be tried for refractory cases. 10 In the first case, the paravertebral lesions were at a lower level and thus did not cause mediastinal compression. However, we have some evidence that the retroperitoneal component of the lesion might have obstructed the right renal vessels during the proliferative phase of the tumor resulting in atrophy of the right kidney.\n\nOne of the two cases was also associated with a hepatic focal lesion displaying characteristic radiological features of hemangioma. Although a similar pathological diagnosis of IH might be suspected, focal hemangiomas of the liver are more commonly congenital (negative for Glut-1). 11\n\nThis new association may prove to be important from two aspects. First, a diagnostic confusion may arise from the presence of the posterior mediastinal (paravertebral) mass. 12 Knowing about the presence of such association besides the typical imaging features of hemangioma can unmask this confusion 13 ; otherwise, invasive diagnostic biopsy will be needed. The other aspect is related to the morbidity associated with such paravertebral hemangiomatous lesions. The rapid proliferation of hemangioma in this critical location encasing the aorta and its main branches may result in significant morbidity. Another potential morbidity is related to intraspinal extension and posterior mediastinal compression manifestations (mediastinal syndrome). Taking in consideration the potential comorbidities of IH in this location, we strongly recommend early establishment of maximum treatment upon diagnosis of such cases with closer follow-up.\n\nNew Insights and the Importance for the Pediatric Surgeon\n\nWe present a new association where deep paravertebral hemangiomatous lesions were observed to be associated with cutaneous back hemangiomas in two cases. This association may prove to be important from two aspects: differential diagnosis of the posterior mediastinal (paravertebral) hemangioma, and another aspect related to the morbidity associated with such location.\n\nConflict of Interest None declared.\n==== Refs\nReferences\n\n1 Gokani V J Sivakumar B Kangesu L Vascular anomalies Surgery 2018 36 314 323\n2 Strub G Sidbury R Bauman N Vascular tumors: infantile hemangioma Cham, Switzerland Springer Nature 2018 37 46\n3 Greene A K Liu A S Mulliken J B Chalache K Fishman S J Vascular anomalies in 5,621 patients: guidelines for referral J Pediatr Surg 2011 46 09 1784 1789 21929990\n4 Herlihy E Hochman M Periocular vascular tumors: infantile hemangioma Cham, Switzerland Springer Nature 2018 105 111\n5 Elluru R G Vascular tumors of the airway Cham, Switzerland Springer Nature 2018 131 137\n6 Li J L Liu H J Cui Y H Mediastinal hemangiomas: spectrum of CT and MRI findings - retrospective case series study and systematic review of the literature Eur J Radiol 2020 126 108905 32145596\n7 Förster C Ostertag H Macchiarini P Infiltrative mediastinal hemangioma Eur J Cardiothorac Surg 2002 21 03 541 11888777\n8 Truong M T Chang K W Berk D R Heerema-McKenney A Bruckner A L Propranolol for the treatment of a life-threatening subglottic and mediastinal infantile hemangioma J Pediatr 2010 156 02 335 338 20105647\n9 Aly M MD Hamza A F Abdel Kader H M Saafan H A Ghazy M S Ragab I A Therapeutic superiority of combined propranolol with short steroids course over propranolol monotherapy in infantile hemangioma Eur J Pediatr 2015 174 11 1503 1509 25982338\n10 Adams D M Practical genetic and biologic therapeutic considerations in vascular anomalies Tech Vasc Interv Radiol 2019 22 04 100629 31864536\n11 Gnarra M Behr G Kitajewski A History of the infantile hepatic hemangioma: From imaging to generating a differential diagnosis World J Clin Pediatr 2016 5 03 273 280 27610342\n12 Petteruti F De Luca G Luciano A Schiavone V Zorzi T Bucciero A Capillary hemangioma mimicking a dumbbell-shaped mediastinal neurinoma Ann Thorac Surg 2011 91 06 1993 21620005\n13 Mohammad S A AbouZeid A A Fawzi A M Magnetic resonance imaging of head and neck vascular anomalies: pearls and pitfalls Ann Pediatr Surg 2017 13 116 124\n\n",
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"title": "Posterior Mediastinal and Cutaneous Back Hemangiomas in Infants: A New Association.",
"title_normalized": "posterior mediastinal and cutaneous back hemangiomas in infants a new association"
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"abstract": "Hypocomplementemic urticarial vasculitis syndrome (HUVS) is a rare disease due to small vessel inflammation and characterized by chronic urticarial vasculitis and arthritis. Multi-organ manifestations may include glomerulonephritis, ocular inflammation (uveitis, episcleritis), and recurrent abdominal pain. To the best of our knowledge, just other nine cases of HUVS with cardiac valvular involvement have been reported in the literature.\nA 32-year-old woman presented to the emergency department because of a cerebral haemorrhage. She suffered from a severe HUVS form with cardiac valvular involvement. In the previous years, she underwent cardiac surgery twice for aortic and mitral valves immune-mediated degeneration. The neurologic event was secondary to Listeria monocytogenes aortic endocarditis, complicated by a cerebral embolism and periaortic abscess.\nPatients with HUVS rarely present valvular heart disease. The latter is mostly secondary to an inflammatory process. Valve degeneration and immunosuppressive therapy increase the risk of infective endocarditis, with dramatic consequences for the prognosis of these patients. Valvular involvement is a sporadic but potentially fatal complication of HUVS, which should be taken in mind in the multidisciplinary evaluation of these patients.",
"affiliations": "Division of Cardiovascular and Perioperative Medicine, Cardiothoracovascular Department, Clinical and Experimental Medicine, Azienda Ospedaliero-Universitaria Careggi, University of Florence, Largo Brambilla 3, 50134 Florence, Italy.;Division of General Cardiology, Cardiothoracovascular Department, Clinical and Experimental Medicine, Azienda Ospedaliero-Universitaria Careggi, University of Florence, Largo Brambilla 3, 50134 Florence, Italy.;Division of Cardiac Surgery, Cardiothoracovascular Department, Clinical and Experimental Medicine, Azienda Ospedaliero-Universitaria Careggi, University of Florence, Largo Brambilla 3, 50134 Florence, Italy.",
"authors": "Scheggi|Valentina|V|https://orcid.org/0000-0001-8182-7074;Marchionni|Niccolò|N|https://orcid.org/0000-0002-8101-4695;Stefàno|Pier Luigi|PL|",
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"fulltext": "\n==== Front\nEur Heart J Case Rep\nEur Heart J Case Rep\nehjcr\nEuropean Heart Journal: Case Reports\n2514-2119\nOxford University Press\n\n10.1093/ehjcr/ytab341\nytab341\nCase Report\nAcademicSubjects/MED00200\nHeart valve disease in hypocomplementemic urticarial vasculitis syndrome: from immune-mediated degeneration to embolic complications of infective endocarditis—a case report\nhttps://orcid.org/0000-0001-8182-7074\nScheggi Valentina 1\nhttps://orcid.org/0000-0002-8101-4695\nMarchionni Niccolò 2\nStefàno Pier Luigi 3\n1 Division of Cardiovascular and Perioperative Medicine, Cardiothoracovascular Department, Clinical and Experimental Medicine, Azienda Ospedaliero-Universitaria Careggi, University of Florence, Largo Brambilla 3, 50134 Florence, Italy\n2 Division of General Cardiology, Cardiothoracovascular Department, Clinical and Experimental Medicine, Azienda Ospedaliero-Universitaria Careggi, University of Florence, Largo Brambilla 3, 50134 Florence, Italy\n3 Division of Cardiac Surgery, Cardiothoracovascular Department, Clinical and Experimental Medicine, Azienda Ospedaliero-Universitaria Careggi, University of Florence, Largo Brambilla 3, 50134 Florence, Italy\nVelagapudi Poonam Handling Editor\nIdris Amr Editor\nNarang Akhil Editor\nPastore Maria Concetta Editor\nTardo Daniel Editor\nRanganathan Deepti Editor\nCorresponding author. Tel: +39 3472706993, Fax: +39 557946316, Email scheggiv@aou-careggi.toscana.it; valentina.scheggi@gmail.com\n9 2021\n18 8 2021\n18 8 2021\n5 9 ytab34118 2 2021\n22 4 2021\n05 8 2021\n14 9 2021\n© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com\n\nAbstract\n\nBackground\n\nHypocomplementemic urticarial vasculitis syndrome (HUVS) is a rare disease due to small vessel inflammation and characterized by chronic urticarial vasculitis and arthritis. Multi-organ manifestations may include glomerulonephritis, ocular inflammation (uveitis, episcleritis), and recurrent abdominal pain. To the best of our knowledge, just other nine cases of HUVS with cardiac valvular involvement have been reported in the literature.\n\nCase summary\n\nA 32-year-old woman presented to the emergency department because of a cerebral haemorrhage. She suffered from a severe HUVS form with cardiac valvular involvement. In the previous years, she underwent cardiac surgery twice for aortic and mitral valves immune-mediated degeneration. The neurologic event was secondary to Listeria monocytogenes aortic endocarditis, complicated by a cerebral embolism and periaortic abscess.\n\nDiscussion\n\nPatients with HUVS rarely present valvular heart disease. The latter is mostly secondary to an inflammatory process. Valve degeneration and immunosuppressive therapy increase the risk of infective endocarditis, with dramatic consequences for the prognosis of these patients. Valvular involvement is a sporadic but potentially fatal complication of HUVS, which should be taken in mind in the multidisciplinary evaluation of these patients.\n\nHypocomplementemic urticarial vasculitis syndrome\nValvular disease\nListeria monocytogenes endocarditis\nCase report\n==== Body\npmcLearning points\n\nSevere valvular heart disease may complicate hypocomplementemic urticarial vasculitis syndrome, secondary to an inflammatory immune complex-mediated process. Prolonged immunosuppressive therapy increases the risk of infective endocarditis from rare agents, such as Listeria monocytogenes.\n\nTransthoracic echocardiography has a low sensitivity (50%) for infective endocarditis on prosthetic valves. In patients with possible infective endocarditis, transoesophageal echocardiography should be performed to exclude the diagnosis.\n\nAfter an intracranial haemorrhage, surgery should generally be postponed for at least 1 month, but this exposes the patient to the risk of endocarditis complications. Some authors recommend serial magnetic resonance imaging to assess the degree of intra-cerebral bleeding to help to guide the surgical timing.\n\nIntroduction\n\nHypocomplementemic urticarial vasculitis syndrome (HUVS) is a rare disease of small vessels characterized by chronic urticarial vasculitis, arthralgia, arthritis, and activation of the classical complement pathway. To the best of our knowledge, just other nine cases1–7 of HUVS with cardiac valvular involvement have been reported in the literature. Unlike previous cases, ours shows an early and severe cardiovascular damage, absence of anti-C1q antibodies, and was not associated with deforming arthritis.\n\nTimeline\n\nTimeline\tDescription\t\n10 years\tDiagnosis of hypocomplementemic urticarial vasculitis syndrome\t\n2 years\tMultiple inflammatory valve damage treated with aortic valve repair, surgical mitral, and tricuspid annuloplasty\t\n1 year\tRelapse of valvular insufficiency treated with aortic and mitral valve replacement with bioprosthesis\t\n2 months\tLeft pyelonephritis from Listeria monocytogenes treated with meropenem and gentamicin for 10 days\t\n1 month\tRemittent fever\t\nDay 0\tAdmission to the emergency department after sudden onset of right hemiplegia, global aphasia, and reduced consciousness (Glasgow Coma Scale 9) Brain computed tomography (CT): cerebral haemorrhage\n\nBrain CT angiography: pseudoaneurysmatic mycotic dilatation\n\nTransoesophageal echocardiogram: aortic valve endocarditis (abscess extending around the prosthesis and the aortic root)\n\nAngiography: 7 mm large mycotic pseudoaneurysm in the M3 tract of left medium cerebral artery, treated with embolization\n\nEmpiric antibiotic therapy\n\n\t\nDay 1\tNeurosurgical haemorrhage evacuation\t\nDay 2\tListeria monocytogenes isolation from blood culture. Treatment with ampicillin and gentamicin\t\nMonth 4\tCoronary embolism and death\t\n\nCase presentation\n\nA 32-year-old woman was brought to the emergency department because of the sudden onset of right hemiplegia, global aphasia, and reduced consciousness (Glasgow Coma Scale 9). At admission, her vital signs were normal, artery pressure was 130/60 mmHg, heart rate 65 b.p.m., she had no hypoxia with normal peripheral oxygen saturation, and her body temperature was 36.8°C. The physical examination revealed a quiet holosystolic flow heart murmur grade 2 over the right second intercostal space, without radiation. Laboratory data showed microcytic anaemia due to a known thalassaemia trait; haemoglobin was 9.5 g/dL, mean corpuscular volume was 75.9 fL; white blood count, renal function, hepatic and cardiac enzymes, C reactive protein, and procalcitonin were normal.\n\nShe suffered from a severe HUVS form with cardiac valvular involvement. Hypocomplementemic urticarial vasculitis syndrome was diagnosed 10 years before, based on recurrent urticarial episodes with hypocomplementemia, associated with arthralgia, and a skin biopsy highlighting a leukocytoclastic vasculitis. After the diagnosis, the patient was treated with azathioprine and subsequently with mycophenolate, followed by steroids per os. Prolonged and high dosage steroid and immunosuppressive treatments exposed her to several systemic infections.\n\nDuring these years, she had already undergone cardiac surgery twice for a chronic aseptic inflammatory process involving aortic and mitral valves. Indeed, she had been subjected 2 years before admission, at the age of 30 years, to cardiac surgery with aortic valve repair and mitral and tricuspid annuloplasty for severe aortic, mitral, and tricuspid regurgitation; 1 year before, at the age of 31 years, she underwent aortic and mitral valve replacement with biological prostheses for the relapse of aortic and mitral regurgitation. Regular cardiologic follow-up showed normal left ventricular and prosthetic function. Two months before admission, she reported left pyelonephritis from Listeria monocytogenes, treated with meropenem 3 g/day and gentamicin 2 mg/kg/day for 10 days. On this occasion, transthoracic echocardiography was unremarkable. During the month before admission, she complained of remittent fever without other symptoms.\n\nAfter admission, the patient underwent several instrumental examinations. A brain computed tomography (CT) without contrast medium showed a left frontoparietal haemorrhage 60 mm × 40 mm large, with perilesional oedema and midline shift of 13 mm (Figure 1). A CT angiography evidenced a lobulated vascular dilatation, which suggested a mycotic aneurysm, considering the history of remittent fever. A transthoracic echocardiogram revealed a paravalvular aortic thickening. A transoesophageal echocardiogram showed an echo lucent space with thickening at the aortic root consistent with an abscess extending around the aortic prosthesis, reaching the first part of the ascending aorta, with signs of internal colliquation, and a maximum thickness of 16 mm (Figure 2 and Video 1). A CT angiography of the aorta confirmed the diagnosis, showing a collection of fluid density around the aortic root (Figure 3).\n\nFigure 1 Brain computed tomography without contrast medium showing a left frontoparietal haemorrhage 60 mm × 40 mm large, with perilesional oedema, and midline shift of 13 mm.\n\nFigure 2 Transoesophageal echocardiography showing an echo lucent space with thickening at the aortic root consistent with an abscess extending around the aortic prosthesis (A, short axis), reaching the first part of the ascending aorta (B, 129°).\n\nFigure 3 Computed tomography angiography showing a collection around the aortic root consistent with a periaortic abscess.\n\nRight hemiplegia and global aphasia were caused by septic embolism to the left medium cerebral artery complicated by cerebral haemorrhage. Angiography confirmed a 7 mm sizable mycotic pseudoaneurysm in the M3 tract of the left medium cerebral artery (Figure 4). After a multidisciplinary consult, endovascular treatment was chosen. A super-selective catheterization of the aneurysm allowed the injection of Glubran inside it, a cyanoacrylate-based synthetic glue, obtaining a complete angiographic obliteration. The day after, the patient underwent neurosurgical evacuation of the haemorrhage. Listeria monocytogenes was isolated from blood cultures; it was the agent responsible for aortic infective endocarditis, probably secondary to prolonged immunosuppressive therapy.\n\nFigure 4 Cerebral selective left carotid angiography showing a lobulated, saccular, 7 mm aneurysm in the M3 tract of the left medium cerebral artery.\n\nThe patient responded to antibiotic treatment with ampicillin 12 g/day, levofloxacin 1000 mg/day, and linezolid 1200 mg/day, and a subsequent transoesophageal ultrasound exam showed a reduction of the abscess engagement after 54 days of therapy. At admission, she was taking deltacortene 12.5 mg/day as a maintenance dose. We continued this therapy after the diagnosis of endocarditis to prevent a vasculitis flare-up. During antibiotic therapy, she was afebrile. A progressive neurological improvement occurred during hospitalization. The patient was directed towards a rehabilitation plan, with the purpose to evaluate elective aortic prosthesis replacement after the improvement of general conditions.\n\nFurther cardiac surgery would have been necessary, but the operative risk was judged too high. The patient died a few months later for an endocarditis relapse, causing a coronary embolism.\n\nIts clinical complexity makes this case a rarity in rarity, in a disease context that is not yet fully understood.\n\nDiscussion\n\nA diagnosis of HUV requires two major criteria and at least two minor criteria. The major criteria are recurrent urticaria for over 6 months and hypocomplementemia. The minor criteria include leukocytoclastic vasculitis on biopsy, joint pain or arthritis, glomerulonephritis, ocular inflammation (uveitis, episcleritis), recurrent abdominal pain, or anti-C1q antibodies.1\n\nThe association between HUVS and cardiac valvular disease has rarely been described in the literature, and most cases, in combination with Jaccoud’s arthropathy.1–7 The presence of valvular involvement is an adverse prognostic factor.\n\nThe anatomopathological evaluation of her native valves showed the typical valve involvement of this disease, with fibrinoid deposits and granulocyte infiltrates.\n\nOther reports have described acute necrotizing endocarditis and fibrin deposition on the surface of valve leaflets, with signs of chronic inflammation, comprising lymphocytes and histiocytes, fibrocalcific degenerative changes, and positive staining for IgG, IgA, IgM, and light-chain determinant-bearing proteins at the valve surface.4\n\nUnlike most cases with valvular involvement, our patient was negative for anti-C1q antibodies, did not have Jaccoud’s hands deformity, and exhibited a highly severe cardiac disease, needing two surgical interventions. Most previous cases1–7 were treated with high-dose steroid therapy and immunosuppressive therapy with either azathioprine, cyclophosphamide, or mycophenolate mofetil, but no other case was complicated by infective endocarditis.\n\nListeria monocytogenes endocarditis ultimately aggravated the patient's condition. This complication is also a rare condition associated with a high mortality rate. Listeria monocytogenes is an aerobic, gram-positive coccobacillus. It is a transient colonizer of the human gastrointestinal tract; infection does not occur unless host factors promoting invasive disease are present, such as immunosuppression. The primary infection from Listeria monocytogenes was pyelonephritis, with subsequent localization on the aortic valve. Endocarditis is observed in ∼8% of adults infected with Listeria monocytogenes and occurs on native and prosthetic valves. The echocardiography performed at the time of the urinary infection was unremarkable. Still, transthoracic echocardiography has a low sensitivity (50%) for infective endocarditis on prosthetic valves,8 and this might have delayed the diagnosis. Penicillin and ampicillin (as monotherapy) are the drugs most frequently used to treat this microbiological agent.9,10 Given the paravalvular extension of the infection, a further surgical intervention would have been the therapy of choice, but the patient’s clinical conditions did not allow this strategy. While cardiac surgery is not contraindicated after an ischaemic embolic stroke complicating infective endocarditis, in cases with intracranial haemorrhage, surgery should generally be postponed for at least 1 month.8 Some authors11 recommend serial magnetic resonance imaging to assess the reduction in the degree of intra-cerebral bleeding to help to guide the surgical timing.\n\nConclusions\n\nThe multidisciplinary evaluation of patients with HUVS should consider valvular heart disease. The latter is probably an immune complex- and cellular-mediated inflammation. Valve degeneration and immunosuppressive therapy increase the risk of infective endocarditis, with dramatic consequences for the prognosis of these patients.\n\nLead author biography\n\nValentina Scheggi graduated in Medicine from Florence University in July 2001 and specialized in Internal Medicine in October 2006. She got the certification from SIECVI in echocardiography in 2006 and in echo stress in 2010. She worked as emergency physician at the emergency department of the Florence University Hospital from 2008 to 2012, when she began to work in the cardiologic and peri-operative Internal Medicine department of the same hospital, where she still works. During the last 5 years this department increased the collaboration with the cardiosurgical one, allowing her to gain a great experience in the clinical management and echocardiographic evaluation of surgical patients.\n\nSupplementary material\n\nSupplementary material is available at European Heart Journal - Case Reports online.\n\nSlide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.\n\nConsent: The patient reported in this case is deceased. Despite the best efforts of the authors, they have been unable to contact the patient’s next-of-kin to obtain consent for publication. Every effort has been made to anonymize the case. This situation has been discussed with the editors.\n\nConflict of interest: None to declared.\n\nFunding: None declared.\n\nSupplementary Material\n\nytab341_Supplementary_Data Click here for additional data file.\n\nAcknowledgements\n\nThe authors are grateful to ‘Fondazione A.R. Card Onlus’ for its unconditional support.\n==== Refs\nReferences\n\n1 AmanoH, FuruhataN, TamuraN, TokanoY, TakasakiY. Hypocomplementemic urticarial vasculitis with Jaccoud's arthropathy and valvular heart disease: case report and review of the literature. Lupus 2008;17 :837–841.18755866\n2 ParkC, ChoiSW, KimM, ParkJ, LeeJS, ChungHC. Membranoproliferative glomerulonephritis presenting as arthropathy and cardiac valvulopathy in hypocomplementemic urticarial vasculitis: a case report. J Med Case Rep 2014;8 :352.25339233\n3 ChenHJ, BlochKJ. Hypocomplementemic urticarial vasculitis, Jaccoud's arthropathy, valvular heart disease, and reversible tracheal stenosis: a surfeit of syndromes. J Rheumatol 2001;28 :383–386.11246684\n4 HouserSL, AskenasePW, PalazzoE, BlochKJ. Valvular heart disease in patients with hypocomplementemic urticarial vasculitis syndrome associated with Jaccoud's arthropathy. Cardiovasc Pathol 2002;11 :210–216.12140126\n5 HauserB, McRorieE, McKayN, BrennT, AmftN. A case of hypocomplementaemic urticarial vasculitis with cardiac valve involvement successfully treated with cyclophosphamide and high-dose glucocorticoids. Int J Rheum Dis 2017;20 :1850–1852.24702778\n6 PalazzoE, BourgeoisP, MeyerO, De BandtM, KazatchkineM, KahnMF. Hypocomplementemic urticarial vasculitis syndrome, Jaccoud's syndrome, valvulopathy: a new syndromic combination. J Rheumatol 1993;20 :1236–1240.8371228\n7 HongL, WackersF, DewarM, KashgarianM, AskenasePW. Atypical fatal hypocomplementemic urticarial vasculitis with involvement of native and homograft aortic valves in an African American man. J Allergy Clin Immunol 2000;106 :1196–1198.11112906\n8 HabibG, LancellottiP, AntunesMJ, BongiorniMG, CasaltaJP, Del ZottiF et al ; ESC Scientific Document Group. 2015 ESC Guidelines for the management of infective endocarditis: the Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC). Endorsed by: European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM). Eur Heart J 2015;36 :3075–3128.26320109\n9 SummaC, WalkerSAN. Endocarditis due to listeria monocytogenes in an academic teaching hospital: case report. Can J Hosp Pharm 2010;63 :312–314.22478994\n10 ValckxW, LutgensSPM, Haerkens-ArendsHE, BarneveldPC, BeutlerJJ, HoogeveenEK. Listeria endocarditis: a diagnostic challenge. J Investig Med High Impact Case Rep 2017;5 :2324709617698995.\n11 BhattacharyyaS, OoA. Timing of surgery after secondary embolic events in infective endocarditis. Ann Cardiothorac Surg 2019;8 :688–690.31832363\n\n",
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"keywords": "Case report; Hypocomplementemic urticarial vasculitis syndrome; Listeria monocytogenes endocarditis; Valvular disease",
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"title": "Heart valve disease in hypocomplementemic urticarial vasculitis syndrome: from immune-mediated degeneration to embolic complications of infective endocarditis-a case report.",
"title_normalized": "heart valve disease in hypocomplementemic urticarial vasculitis syndrome from immune mediated degeneration to embolic complications of infective endocarditis a case report"
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"abstract": "Patients undergone kidney transplantation present higher risk of Urothelial Carcinoma (UC) development and represent a subgroup of special interest. To date, vinflunine is the only drug approved in Europe for the treatment of advanced UC after failure of platinum-based chemotherapy. However, to our knowledge, no data on the concomitant administration of vinflunine and immunosuppressive agents are available.\n\n\n\nThe patient, a 45 years old Caucasian male, presented poorly differentiated UC of the bladder recurred after initial cystectomy with abdominal lymphadenopathies evidenced by FDG-PET/CT. Previously, at the age of 22, he had post-glomerulonephritis renal failure and underwent kidney transplantation from deceased donor. Since then, he has been in treatment with immunosuppressive therapy. At the time of UC recurrence, he was on treatment with cyclosporine. After progression to platinum-based chemotherapy, he received second-line therapy with vinflunine resulting in a complete metabolic response after two cycles. However, despite several dose reductions, the patient experienced severe hematologic toxicity. The pharmacological interaction between vinflunine and cyclosporine, both metabolized by CYP 3A4, may explain the excellent result and the concomitant severe toxicity.\n\n\n\nVinflunine is active on UC developed in kidney transplanted patients. However, special attention should be paid to concomitant administration with immunosuppressive agents that could result in increased toxicity.",
"affiliations": "Medical Oncology Unit, University Hospital of Parma, Via Gramsci 14, 43126, Parma, Italy.;Medical Oncology Unit, University Hospital of Parma, Via Gramsci 14, 43126, Parma, Italy.;Nuclear Medicine Unit, University Hospital of Parma, Via Gramsci 14, 43126, Parma, Italy.;Medical Oncology Unit, University Hospital of Parma, Via Gramsci 14, 43126, Parma, Italy. sebabuti@libero.it.",
"authors": "Bordi|Paola|P|;Tiseo|Marcello|M|;Baldari|Giorgio|G|;Buti|Sebastiano|S|",
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"fulltext": "\n==== Front\nBMC CancerBMC CancerBMC Cancer1471-2407BioMed Central London 266610.1186/s12885-016-2666-6Case ReportMetabolic complete response with vinflunine as second-line therapy in a kidney-transplanted patient with advanced urothelial carcinoma: a case report Bordi Paola pbordi@ao.pr.it 1Tiseo Marcello mtiseo@ao.pr.it 1Baldari Giorgio gbaldari@ao.pr.it 2Buti Sebastiano +39 0521/702894sebabuti@libero.it 11 Medical Oncology Unit, University Hospital of Parma, Via Gramsci 14, 43126 Parma, Italy 2 Nuclear Medicine Unit, University Hospital of Parma, Via Gramsci 14, 43126 Parma, Italy 12 8 2016 12 8 2016 2016 16 62627 1 2016 2 8 2016 © The Author(s). 2016\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\nPatients undergone kidney transplantation present higher risk of Urothelial Carcinoma (UC) development and represent a subgroup of special interest. To date, vinflunine is the only drug approved in Europe for the treatment of advanced UC after failure of platinum-based chemotherapy. However, to our knowledge, no data on the concomitant administration of vinflunine and immunosuppressive agents are available.\n\nCase presentation\nThe patient, a 45 years old Caucasian male, presented poorly differentiated UC of the bladder recurred after initial cystectomy with abdominal lymphadenopathies evidenced by FDG-PET/CT. Previously, at the age of 22, he had post-glomerulonephritis renal failure and underwent kidney transplantation from deceased donor. Since then, he has been in treatment with immunosuppressive therapy. At the time of UC recurrence, he was on treatment with cyclosporine. After progression to platinum-based chemotherapy, he received second-line therapy with vinflunine resulting in a complete metabolic response after two cycles. However, despite several dose reductions, the patient experienced severe hematologic toxicity. The pharmacological interaction between vinflunine and cyclosporine, both metabolized by CYP 3A4, may explain the excellent result and the concomitant severe toxicity.\n\nConclusions\nVinflunine is active on UC developed in kidney transplanted patients. However, special attention should be paid to concomitant administration with immunosuppressive agents that could result in increased toxicity.\n\nKeywords\nKidney transplantationVinflunineUrothelial cancerImmunosuppressive therapyPharmacological interactionissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nIn the USA, bladder cancer ranks 4th and 11th for cancer incidence in males and females, respectively. Whereas urothelial carcinoma (UC) accounts for 90 % of all bladder cancers, superficial UC, defined as non-muscle invasive cancer, represents 60 % of cases and requires local therapy with TURB (Trans-Urethral Resection of Bladder) and subsequent intravesical instillations [1, 2]. UC presents localized muscle invasion or distant metastases in 30 and 10 % of remaining cases, respectively. The management of muscle invasive disease includes neoadjuvant or adjuvant chemotherapy associated with cystectomy [2]. Despite surgery, 5-years survival varies between 36 and 48 %. In fact, peri-operative chemotherapy produce a benefit of approximately 5–7 % and a consistent part of patients develops recurrence of disease. The treatment of patients with recurrent or metastatic disease is currently represented by chemotherapy. As first-line therapy, Cisplatin and Gemcitabine (CG) demonstrated a similar efficacy of MVAC (Metotrexate, Vinblastine, Doxorubicin, Cisplatin) schedule with a more favourable toxicity profile [3]. Therefore, CG is the preferred option in first-line setting. However, considering that UC mainly develops in elderly patient (with a median age at diagnosis of approximately 70 years), the event of treating a patient un-fit for cisplatin is not unusual [4]. Un-fit patients are defined by the presence of at least one of the following: Eastern Cooperative Oncology Group Performance Status (ECOG PS) = 2, clearance of creatinine < 60 mL/min, grade ≥ 2 hearing loss or peripheral neuropathy [according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE)], heart failure (New York Heart Association functional classification class III). In these cases, carboplatin instead of cisplatin may be an option [5].\n\nSo far, vinflunine (VFL) is the only drug approved after failure of platinum-based treatment in Europe. It has been registered on the basis of a phase III trial that compared VFL versus best supportive care in second line setting, demonstrating a benefit of 2.6 months in median overall survival (OS) [6]. Principal VFL-related side effects include: constipation, anemia, neutropenia, vomiting and stomatitis. However, VFL has been proved to be acceptable also for elderly patients if dose reduction and granulocyte-colony stimulating factors (G-CSF) prophylaxis are observed [7]. With this evidence, the activity of a VFL based doublet as first-line therapy has been successfully explored in a phase II trial conducted in patients un-fit for cisplatin and a phase III trial comparing VFL-gemcitabine versus carboplatin-gemcitabine in the same setting is ongoing [8]. Even if preliminary data of check-point inhibition are encouraging also in UC patients, results from ongoing randomized trials will not be available before a couple of years [9, 10]. In conclusion, chemotherapy still play a crucial role in UC management and VFL is expected to be one of the protagonists in the next years scenario.\n\nSmoking habit is the most important risk factor associated with the development of UC in west countries. Another well known risk factor is the exposition to aromatic amines and aniline derivatives [11]. Recently, a higher incidence of UC has been documented in a large series of patients who received renal transplantation [12]. Authors evidenced that patients diagnosed with bladder UC after renal transplantation were younger and presented more aggressive and advanced disease. The immune suppression required after transplantation is considered to support UC carcinogenesis process. Therefore, post-transplantation patients represent a particular subgroup of UC patients requiring special attention due to their comorbidity and concomitant immunosuppressive medications.\n\nHere, we present a case report of a young kidney-transplanted patient who presented complete metabolic response after two cycles of second-line VFL chemotherapy. To our knowledge, this is the first report attesting the use of VFL in a patient under immunosuppressive therapy for kidney transplantation.\n\nCase presentation\nAt the time of diagnosis, the patient, a Caucasian male, was 45-years-old. His past medical history included hypertension, hyperuricemia, previous asymptomatic myocardial infarction and anti-HCV positivity. In 1988 post-glomerulonephritis renal failure occurred and he was treated with dialysis for 13 months. Subsequently, in 1989 the patient underwent kidney transplantation from deceased donor and since then immunosuppressive therapy was introduced. The oncological history started in February 2013, when a routinary abdominal ultra sound (US) exam, performed in another institution, evidenced a bladder wall thickening. Subsequent cystoscopy was performed showing suspect eteroplastic lesion. TURB revealed poorly differentiated transitional cell bladder carcinoma. In May 2013 TURB was repeated showing poorly differentiated carcinoma with neuroendocrine features. In June 2013, the patient had partial cystectomy plus lymphoadenectomy. The histology confirmed high grade UC with lymphatic invasion (stage pT2N0); immunohistochemistry resulted strongly positive for Ki-67 (100 %), negative for cromogranin-A, neuron-specific enolase, somatostatin receptor 2 antibody and synaptophysin. During follow-up, the patient underwent regular cystoscopies and in January 2014 the biopsy of a suspected mucosal area showed residual poorly differentiated carcinoma with focal CD56 stain. Therefore, in March 2014, radical cystectomy was completed with final histological report of poorly differentiated carcinoma with neuroendocrine features (pT1N0). During follow-up, a 18-F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) performed in July 2014 showed the appearance of pathological uptake localized to confluent right iliac and retroaortic lymph nodes.\n\nThe patient came in our institution for the first time in August 2014 to discuss the initiation of first line chemotherapy. At that time, he was in therapy with cyclosporine 125 mg/die as immunosuppressive treatment. Therefore we considered to start chemotherapy with dose reduction as precaution. He started gemcitabine 1000 mg/m2 (day 1,8) on 27th August 2014 and carboplatin AUC 3 (day 1) was added from the second cycle. During the treatment, the patient developed subsequent adverse events (AEs according to NCI-CTCAE version 4): anemia grade (G) 2, thrombocytopenia G1, neutropenia G3, ALT increased G2 and nausea G1. These AEs entailed dose delay and further dose reduction. A FDG-PET/CT was planned after 3 cycles and showed partial response. He completed 6 cycles of treatment but subsequent PET/CT, performed on February 2015, demonstrated progressive disease due to numeric increase of captating bilateral common iliac and paraortic adenopathies (Figs. 1a and 2a). On 27th February 2015 the patient started second line treatment with VFL 280 mg/m2. After the first cycle the patient presented oral mucositis G1, loss of appetite and nausea G1 and prolonged G4 neutropenia that required precautionary hospital admission and administration of G-CSF and antibiotic prophylaxis. Considering the severe haematological toxicity, the second cycle was prescribed with further dose reduction (220 mg/m2) and G-CSF prophylaxis. Despite this, after the second cycle, neutropenia G4 and thrombocytopenia G4 occurred. In April 2015, FDG-PET/CT after two cycles documented complete metabolic response with disappearance of adenopathic pathological uptake (Figs. 1b and 2b). Chemotherapy proceeded with further dose reduction to 200 mg/m2 plus G-CSF prophylaxis and treatment was well tolerated with the exception of G2 temporary transaminases increase. In July 2015, before the 6th cycle, patient presented gastroenteritis and diarrhea (seven stools/die for three consecutive days) with consequent acute renal failure (creatinine 5.5 mg/dL, clearance 23 ml/min). He was admitted to hospital and adequate hydration and supportive care was administered. After resolution of renal failure, which was considered not related to VFL, patient received the 6th and last cycle. After treatment completion, FDG-PET/CT was repeated showing pathological captation of inter aortic-caval and right common iliac nodes. A multidisciplinary team decided for stereotactic radiotherapy on pathological nodes that the patient received in November 2015. A new FDG-PET/CT was planned for the end of January 2016, 2 months after the completion of radiotherapy, and revealed a partial metabolic response to radiotherapy. Then the patient was followed with close clinical and radiological controls.Fig. 1 Para-aortic lymphodenopaties before therapy with vinflunine (VFL) (a) and after treatment (b)\n\nFig. 2 Bilateral common iliac lymphadenopathies before VFL therapy (a) and after treatment (b)\n\n\n\nConclusions\nHere we report the case of a young kidney transplanted patient affected by advanced UC of the bladder and treated with second-line chemotherapy with VFL. To our knowledge, nothing has been previously reported regarding VFL therapy in patients with organ transplantation and immunosuppressive therapy. However, in patients undergone kidney transplantation evidence for an increased risk of aggressive UC development has recently been provided. Thus, the event of treating transplanted patient could be not so rare and sharing our experience could be relevant for other clinicians.\n\nAccordingly to what reported by Yan and colleagues, the clinical behaviour of UC in our patient was highly aggressive [12]. This is consistent with the histo-pathological characteristics of the tumour such as neuroendocrine features, CD56 stain and extremely high proliferation index (Ki67 100 %). These factors were implicated in the two relapses occurred in our patient history that required radical cystectomy and the initiation of systemic chemotherapy later, when disease relapsed in advanced stage.\n\nOur patient did not present any of the known principal negative prognostic factors for second line chemotherapy [13]. In fact, when chemotherapy was initiated for systemic recurrence Hb was higher than 10 g/dL, PS was 1, visceral and bone metastases were absent. As previously described, the patient experienced a significant response to VFL therapy considering the FDG-PET/CT after two cycles showed complete metabolic response. This was achieved despite the aggressiveness of histo-pathological features mentioned above and we argue that the absence of negative predictive factors could have play a role in reaching this result.\n\nNevertheless, treatment-related toxicity was the counterpart of the brilliant result in disease remission. In fact, during treatment patient presented serious side effects related to VFL that determined several dose reductions and required hospital admission and prophylaxis with antibiotic for severe neutropenia. Moreover, the patient also had an admission due to acute renal failure consequent to severe diarrhea complicating an episode of gastroenteritis. Although this event is not likely to be related to VFL therapy, it emphasizes the frailty of patients with kidney transplantation. Before starting therapy, we investigate the potential pharmacologic interaction between immunosuppressive therapy and VFL. During treatment with VFL, the patient was on therapy with cyclosporine as immunosuppressive agent. Both VFL and cyclosporine are prevalently metabolized by cytochrome CYP3A4 [14] (http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000983/WC500039604.pdf). Therefore, we hypothesize that during the concomitant administration, VFL and cyclosporine competed for the same cytochrome with a consequent reduction in their metabolism. For this reason, and considering the patient as frail, we decided to start therapy with 280 instead of 320 mg/m2. However, despite the initial dose reduction, our patient presented several serious AEs, suggesting us that drug interaction was more strong than expected. Our observation is limited by the fact that plasmatic levels of cyclosporine and of VFL have not been determined during treatment and therefore definitive conclusions can not be drawn. However, our hypothesis deserves to be evaluated in future patients.\n\nIn conclusion, patients with kidney transplantation present a higher risk of developing UC of the bladder. In this event, UC is highly aggressive and almost always spread with distant metastasis thus requiring a systemic chemotherapy treatment. Despite the young age, transplanted patients should be considered frail because of their past medical history and concomitant medications. VFL is the only chemotherapy registered after progression to platinum-based chemotherapy in UC. In this particular subset of patients, VFL is active and can be used in clinical practice. However, more attention should be paid to VFL dosage due to the high risk of toxicity probably related to pharmacological interaction between VFL and immunosuppressive concomitant therapy.\n\nAbbreviations\nAEAdverse Events\n\nALTAlanine aminotransferase\n\nAUCArea Under Curve\n\nCD56Cluster of Differentiation 56\n\nCGCisplatin and Gemcitabine\n\nCYP3A4Cytochrome P450 3A4\n\nECOG PSEastern Cooperative Oncology Group Performance Status\n\nFDG-PET/CT18-F-Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography\n\nGGrade\n\nG-CSFGranulocyte-Colony Stimulating Factor\n\nHbHaemoglobin\n\nHCVHepatitis C Virus\n\nMVACMetotrexate, Vinblastine, Doxorubicin, Cisplatin\n\nNCI-CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events\n\nTURBTrans-Urethral Resection of Bladder\n\nUCUrothelial Carcinoma\n\nUSUltra Sound\n\nVFLVinflunine\n\nAcknowledgements\nNo acknowledgements.\n\nFunding\nNo source of funding to declare.\n\nAuthors’ contributions\nPB was involved in data collection and drafted the manuscript. SB conceived the case report, participated in coordination, helped to draft the manuscript and was involved in final critical revision. MT and GB have been involved in drafting the manuscript and revising it critically for important intellectual content. All authors read and approved the final 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. A copy of the written consent is available for review by the Editor of this journal.\n\nEthics approval and consent to participate\nNot applicable.\n==== Refs\nReferences\n1. Siegel RL Miller KD Jemal A Cancer statistics, 2015 CA Cancer J Clin 2015 65 5 29 10.3322/caac.21254 25559415 \n2. Bellmunt J Orsola A Leow JJ Bladder cancer: ESMO practice guidelines for diagnosis, treatment and follow-up Ann Oncol 2014 25 Suppl 3 iii40 8 10.1093/annonc/mdu223 25096609 \n3. Van der Maase H Hansen SW Roberts JT Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin and cisplatin in advanced or metastatic bladder cancer: results of a large randomized, multinational, multicenter phase III study J Clin Oncol 2000 17 3068 77 \n4. Galsky MD Hahn NM Rosenberg J Treatment of patient with metastatic urothelial cancer “unfit” for cisplatin-based chemotherapy J Clin Oncol 2011 29 2432 8 10.1200/JCO.2011.34.8433 21555688 \n5. De Santis M Bellmunt J Mead G Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy : EORTC study 30986 J Clin Oncol 2012 30 191 9 10.1200/JCO.2011.37.3571 22162575 \n6. Bellmunt J Théodore C Demkov T Phase III trial of vinflunine plus best supportive care compared with best supportive care alone after platinum-containing regimen in patients with advanced transitional cell carcinoma of the urothelial tract J Clin Oncol 2009 27 4454 61 10.1200/JCO.2008.20.5534 19687335 \n7. Tourani JM Mourey L Servent V Influence of age on the pharmacokinetics of i.v. vinflunine: results of phase I trial in elderly cancer patients J Geriatric Oncol 2012 3 41 8 10.1016/j.jgo.2011.11.008 \n8. De Santis M Wiechno PJ Lucas C Mature survival (OS) data of a randomised international phase II trial (Jasint1) : vinflunine (VFL) –gemcitabine (GEM) vs. VFL-CBDCA in CDDP-unfit patients (PTS) with advanced urothelial carcinoma (UC) Ann Oncol 2014 25 suppl 4 iv280 304 \n9. Powles T Eder JP Fine GD MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer Nature 2014 515 558 62 10.1038/nature13904 25428503 \n10. Plimack ER Gupta S Bellmunt J A phase 1B study of pembrolizumab (PEMBRO; MK-3475) in patients (PTS) with advanced urothelial tract cancer Ann Oncol 2014 25 Suppl 5 v1 41 \n11. Malats N Real FX Epidemiology of bladder cancer Hematol Oncol Clin North Am 2015 29 177 89 10.1016/j.hoc.2014.10.001 25836927 \n12. Yan L Chen P Chen EZ Risk of bladder cancer in renal transplant recipients: a meta-analysis Br J Cancer 2014 110 1871 7 10.1038/bjc.2014.44 24496458 \n13. Buti S Ciccarese C Zanoni D Prognostic and predictive factors in patients treated with chemotherapy for advanced urothelial cancer: where do we stand? Future Oncol 2015 11 107 19 10.2217/fon.14.172 25572786 \n14. Kronbach T Fischer V Meyer UA Cyclosporine metabolism in human liver: identification of a cytochrome P-450III gene family as the major cyclosporine-metabolizing enzyme explains interactions of cyclosporine with other drugs Clin Pharmacol Ther 1988 43 630 5 10.1038/clpt.1988.87 3378384\n\n",
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"keywords": "Immunosuppressive therapy; Kidney transplantation; Pharmacological interaction; Urothelial cancer; Vinflunine",
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"mesh_terms": "D004347:Drug Interactions; D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms; D019459:Urothelium; D014747:Vinblastine",
"nlm_unique_id": "100967800",
"other_id": null,
"pages": "626",
"pmc": null,
"pmid": "27519420",
"pubdate": "2016-08-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25836927;22162575;21555688;25096609;25572786;25559415;24496458;25428503;11001674;19687335;3378384",
"title": "Metabolic complete response with vinflunine as second-line therapy in a kidney-transplanted patient with advanced urothelial carcinoma: a case report.",
"title_normalized": "metabolic complete response with vinflunine as second line therapy in a kidney transplanted patient with advanced urothelial carcinoma a case report"
} | [
{
"companynumb": "IT-TEVA-708761ISR",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
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{
"actiondrug": "1",
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"activesubstancename": "VINFLUNINE"
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{
"abstract": "Posterior reversible encephalopathy syndrome (PRES) is a rare syndrome that presents with neurological manifestations, often associated with arterial hypertension. Magnetic resonance imaging (MRI) shows bilateral white matter oedema in the posterior vascular territories. Immunosuppression, (pre) eclampsia and autoimmune diseases can be implicated. A 27-year-old woman, with mixed connective tissue disease under azathioprine, was admitted in the emergency room in status epilepticus and with severe hypertension. The MRI showed bilateral oedema in a pattern compatible with PRES. There was clinical improvement after azathioprine suspension. PRES is typically reversible with prompt recognition of the syndrome and its trigger. The association with azathioprine is rare.\nPosterior reversible encephalopathy syndrome should be considered in patients with sudden onset of headache, altered consciousness and seizures.Recognition of this entity and identification of the trigger are essential for reversal of the clinical picture.Autoimmune diseases and some immunosuppressive drugs have been identified as causative, but reports of an association with azathioprine are very rare.",
"affiliations": "Serviço Medicina III, Hospital Prof. Doutor Fernando Fonseca, Lisbon, Portugal.;Serviço Medicina III, Hospital Prof. Doutor Fernando Fonseca, Lisbon, Portugal.",
"authors": "Vilas-Boas|Sara|S|;Corte-Real|Ana|A|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.12890/2019_001032",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2284-2594",
"issue": "6(1)",
"journal": "European journal of case reports in internal medicine",
"keywords": "Posterior reversible encephalopathy syndrome; azathioprine; seizures",
"medline_ta": "Eur J Case Rep Intern Med",
"mesh_terms": null,
"nlm_unique_id": "101648453",
"other_id": null,
"pages": "001032",
"pmc": null,
"pmid": "30756078",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": "16881437;18268188;18356474;23212858;23690247;27272329",
"title": "Posterior Reversible Encephalopathy Syndrome and Azathioprine.",
"title_normalized": "posterior reversible encephalopathy syndrome and azathioprine"
} | [
{
"companynumb": "PT-SEBELA IRELAND LIMITED-2019SEB00113",
"fulfillexpeditecriteria": "1",
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"drug": [
{
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"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
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{
"abstract": "High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) has a well-established role in the treatment of patients with multiple myeloma. Melphalan 200 mg/m2 (Mel200) is the most commonly used preparative regimen. Several studies have provided evidence for potential synergism and safety when combining bortezomib (Btz) or busulfan (Bu) with melphalan (Mel).\n\n\n\nWe conducted a prospective phase II study to investigate the safety and efficacy of conditioning with pharmacokinetics (PK)-directed intravenous (IV) Bu with Btz and Mel. Bu dosing was adjusted to target a total area under the curve (AUC) of 20,000 μM × min. Patients received Btz (1 mg/m2 × 4 doses) and Mel (140 mg/m2).\n\n\n\nA total of 19 subjects were enrolled. Their median age was 55 years, and the median follow-up period was 23.7 months. PK testing resulted in 86% of patients achieving an estimated total AUC of 20,000 ± 2500 μM × min. The overall response rate (ORR) at day +100 after ASCT was 100% in the evaluable patients, with 11% of patients achieving a complete response. The 2-year progression-free survival rate was 57.9% (95% confidence interval [CI], 38%-89%), and the 2-year overall survival rate was 88.5% (95% CI, 76%-100%). The most common grade 3 and 4 toxicities were febrile neutropenia, dysphagia/odynophagia, and oral mucositis. No case of hepatic sinusoidal obstruction syndrome developed. One treatment-related mortality occurred before day +100.\n\n\n\nA preparative regimen of PK-directed IV Bu with Btz and Mel led to an ORR of 100% with acceptable toxicity and should be considered for direct comparison with the Mel200 regimen in future trials.",
"affiliations": "Fox Chase Cancer Center, Philadelphia, PA; Montefiore Medical Center, Albert Einstein Cancer Center, Bronx, NY. Electronic address: Stefan.Barta@fccc.edu.;Fox Chase Cancer Center, Philadelphia, PA; Montefiore Medical Center, Albert Einstein Cancer Center, Bronx, NY.;NYU Clinical Cancer Institute, New York, NY; Westchester Medical Center, New York Medical College, Valhalla, NY.;Montefiore Medical Center, Albert Einstein Cancer Center, Bronx, NY; Memorial Sloan Kettering Cancer Center, New York, NY.;Montefiore Medical Center, Albert Einstein Cancer Center, Bronx, NY.;Montefiore Medical Center, Albert Einstein Cancer Center, Bronx, NY.;Mount Sinai Beth Israel Hospital, New York, NY.;Montefiore Medical Center, Albert Einstein Cancer Center, Bronx, NY.;NYU Clinical Cancer Institute, New York, NY.;Montefiore Medical Center, Albert Einstein Cancer Center, Bronx, NY.;Montefiore Medical Center, Albert Einstein Cancer Center, Bronx, NY.;Montefiore Medical Center, Albert Einstein Cancer Center, Bronx, NY.;Montefiore Medical Center, Albert Einstein Cancer Center, Bronx, NY.;Montefiore Medical Center, Albert Einstein Cancer Center, Bronx, NY.",
"authors": "Barta|Stefan K|SK|;Jain|Rishi|R|;Mazumder|Amithaba|A|;Carter|Jason|J|;Almanzar|Lawrence|L|;Browne|Roy|R|;Shahnaz|Samira|S|;Elkind|Richard|R|;Kaminetzky|David|D|;Battini|Ramakrishna|R|;Derman|Olga|O|;Kornblum|Noah|N|;Verma|Amit|A|;Braunschweig|Ira|I|",
"chemical_list": "D000069286:Bortezomib; D002066:Busulfan; D008558:Melphalan",
"country": "United States",
"delete": false,
"doi": "10.1016/j.clml.2017.06.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2152-2669",
"issue": "17(10)",
"journal": "Clinical lymphoma, myeloma & leukemia",
"keywords": "Autologous stem cell transplant; High-dose chemotherapy; Personalized medicine; Proteasome inhibition; Targeted therapy",
"medline_ta": "Clin Lymphoma Myeloma Leuk",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069286:Bortezomib; D002066:Busulfan; D060830:Consolidation Chemotherapy; D005260:Female; D006085:Graft Survival; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D053208:Kaplan-Meier Estimate; D060046:Maintenance Chemotherapy; D008297:Male; D008558:Melphalan; D008875:Middle Aged; D009101:Multiple Myeloma; D019233:Retreatment; D016019:Survival Analysis; D019172:Transplantation Conditioning; D014182:Transplantation, Autologous; D016896:Treatment Outcome",
"nlm_unique_id": "101525386",
"other_id": null,
"pages": "650-657",
"pmc": null,
"pmid": "28684379",
"pubdate": "2017-10",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Pharmacokinetics-directed Intravenous Busulfan Combined With High-dose Melphalan and Bortezomib as a Conditioning Regimen for Patients With Multiple Myeloma.",
"title_normalized": "pharmacokinetics directed intravenous busulfan combined with high dose melphalan and bortezomib as a conditioning regimen for patients with multiple myeloma"
} | [
{
"companynumb": "US-MYLANLABS-2017M1071419",
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"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BUSULFAN"
},
"drugadditional": null,
... |
{
"abstract": "Sorafenib is a multi-kinase inhibitor and a vascular endothelial growth factor (VEGF) inhibitor approved to treat patients with advanced hepatocellular carcinoma, renal cell carcinoma and differentiated thyroid carcinoma. Its most common side effects are asthenia/fatigue, skin toxicity, diarrhea and arterial hypertension. Reported respiratory adverse reactions include dyspnea, cough, pleural effusion and hoarseness. The aim of this report is to describe for the first time the occurrence of pneumatocele in two patients treated with Sorafenib. Patients had no respiratory symptoms and alternative diagnoses were ruled out. Primary tumors were different (liver metastases from a pancreatic neuroendocrine tumor and hepatocellular carcinoma) but both patients had been treated with yttrium 90 radioembolization 9 and 17 months before starting on Sorafenib, respectively. No complications occurred and Sorafenib withdrawal was followed by radiologic improvement.",
"affiliations": "Liver Unit, Department of Internal Medicine, Clínica Universidad de Navarra-IDISNA, Pamplona, Navarra, Spain.;Liver Unit, Department of Internal Medicine, Clínica Universidad de Navarra-IDISNA, Pamplona, Navarra, Spain.;Liver Unit, Department of Internal Medicine, Clínica Universidad de Navarra-IDISNA, Pamplona, Navarra, Spain.;Liver Unit, Department of Internal Medicine, Clínica Universidad de Navarra-IDISNA and CIBEREHD, Pamplona, Navarra, Spain.;Department of Respiratory Diseases, Clínica Universidad de Navarra-IDISNA, Pamplona, Navarra, Spain.;Vascular and Interventional Radiology Unit, Clínica Universidad de Navarra-IDISNA, Pamplona, Navarra, Spain.;Liver Unit, Department of Internal Medicine, Clínica Universidad de Navarra-IDISNA and CIBEREHD, Pamplona, Navarra, Spain.",
"authors": "Sangro|Paloma|P|;Bilbao|Idoia|I|;Fernández-Ros|Nerea|N|;Iñarrairaegui|Mercedes|M|;Zulueta|Javier|J|;Bilbao|J I|JI|;Sangro|Bruno|B|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.18632/oncotarget.23599",
"fulltext": "\n==== Front\nOncotargetOncotargetOncotargetImpactJOncotarget1949-2553Impact Journals LLC 294641012359910.18632/oncotarget.23599Case ReportPneumatocele during sorafenib therapy: first report of an unusual complication Sangro Paloma 1Bilbao Idoia 1Fernández-Ros Nerea 1Iñarrairaegui Mercedes 2Zulueta Javier 3Bilbao JI 4Sangro Bruno 21 Liver Unit, Department of Internal Medicine, Clínica Universidad de Navarra-IDISNA, Pamplona, Navarra, Spain2 Liver Unit, Department of Internal Medicine, Clínica Universidad de Navarra-IDISNA and CIBEREHD, Pamplona, Navarra, Spain3 Department of Respiratory Diseases, Clínica Universidad de Navarra-IDISNA, Pamplona, Navarra, Spain4 Vascular and Interventional Radiology Unit, Clínica Universidad de Navarra-IDISNA, Pamplona, Navarra, SpainCorrespondence to:Bruno Sangro,bsangro@unav.es19 1 2018 22 12 2017 9 5 6652 6656 18 8 2017 27 11 2017 Copyright: © 2018 Sangro et al.2018This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Sorafenib is a multi-kinase inhibitor and a vascular endothelial growth factor (VEGF) inhibitor approved to treat patients with advanced hepatocellular carcinoma, renal cell carcinoma and differentiated thyroid carcinoma. Its most common side effects are asthenia/fatigue, skin toxicity, diarrhea and arterial hypertension. Reported respiratory adverse reactions include dyspnea, cough, pleural effusion and hoarseness. The aim of this report is to describe for the first time the occurrence of pneumatocele in two patients treated with Sorafenib. Patients had no respiratory symptoms and alternative diagnoses were ruled out. Primary tumors were different (liver metastases from a pancreatic neuroendocrine tumor and hepatocellular carcinoma) but both patients had been treated with yttrium 90 radioembolization 9 and 17 months before starting on Sorafenib, respectively. No complications occurred and Sorafenib withdrawal was followed by radiologic improvement.\n\niung toxicitySTAT3antiangiogenicsradioembolizationhepatocellular carcinoma\n==== Body\nINTRODUCTION\nPneumatocele is a thin-walled lung cavity filled with air usually seen as a complication of acute pneumonia [1], even though it could also arise from other noninfectious etiologies [2]. The precise pathophysiological mechanism of pneumatocele formation remains unclear although there are different advanced theories. Some suggest that the mechanism would be a combination of parenchymal necrosis and check-valve bronchiolar obstruction [3], whereas others believe in local collections of air in the interstitial tissue [4]. We present for the first time two cases of patients who developed pneumatocele while they were receiving the multikinase inhibitor Sorafenib.\n\nCASE PRESENTATION\nCase 1\nA 36-year-old woman had an invasive pancreatic neuroendocrine tumor removed by means of body and distal pancreatectomy, splenectomy, partial gastrectomy, and transversal colectomy. One-year later, multiple liver metastases were detected in both lobes. At that moment, she had chronic malnutrition despite adequate pancreatic enzyme supplementation and a Trousseau syndrome was also diagnosed. Chronic malnutrition was attributed to a combination of pancreatic insufficiency and a potential hormone-related paraneoplastic syndrome. Systemic chemotherapy with 5-fluorouracil and streptozotocin followed by transarterial bland embolization were performed, and an objective durable remission was achieved. Seven years later, liver progression was detected, restricted mostly to the right lobe. Her performance status was ECOG 1 but she had a BMI of 13.7 kg/m2 due to worsened chronic malnutrition. A left pleural effusion was also observed but no malignant cells were detected on fluid cytology. A right-lobe transarterial radioembolization (TARE) was uneventfully performed. The lung shunt fraction in the macroaggregated albumin scan performed during the TARE workup was 6.4%. The response to TARE was short lived and 9 months later liver disease progressed. The multidisciplinary team recommendation was to start Sorafenib as a special indication under informed consent instead of Sunitinib due to her profound asthenia. The dose used was progressively increased from 400 mg to 600 mg daily with good tolerability and no side effects. Two months later a thoracic CT showed a small pleural effusion in left side and ground glass in left lower lobe. Four months after initiating Sorafenib an abdominal and thoracic CT showed a lung cavity in the left upper lobe (Figure 1). The patient had no respiratory symptoms.\n\nFigure 1 Pneumatocele in the upper left lobe (55 × 38 × 44 mm) (Case 1)\nA bronchoscopy was performed with no macroscopic findings. No malignant cells were observed on cytology of a bronchioalveolar lavage (BAL) and microbiologic cultures were negative. Sorafenib was discontinued after 4 months of treatment. Repeated CT scans performed one and three month after discontinuing Sorafenib showed a reduction in the size of the pneumatocele (Figure 2). Sorafenib was not reintroduced and the patient died 4 years after the pneumatocele was diagnosed due to tumor progression.\n\nFigure 2 Lung cavity improvement after discontinuing Sorafenib treatment (27 × 28 × 42 mm) (Case 1)\nCase 2\nA 62-year-old man was incidentally diagnosed of a hepatocellular carcinoma in the advanced stage due to branch portal vein invasion, as well as alcohol-related cirrhosis (Child Pugh A5). His medical history included a diagnosis of severe chronic obstruction pulmonary disease (COPD), arterial hypertension and peripheral arteriopathy. As part of a lung cancer screening program, he had a chest CT-scan performed a year before receiving Sorafenib which showed mild paraseptal emphysema in upper and lower lobes with no bullae. Selective TARE was followed by an objective prolonged tumor response. One year after TARE, a total body CT showed no signs of extrahepatic disease. Five months later, he reported abdominal pain and a liver MRI revealed liver progression. Sorafenib was started at 800 mg daily but later reduced to 400 mg daily due to intense asthenia and weight loss. The patient had usually two COPD exacerbations per year. Exacerbations were more frequent after the start of Sorafenib and he required antibiotics and systemic corticosteroids. One year after Sorafenib was initiated, he developed cough and progressive dyspnea and a chest CT scan showed a pneumatocele (Figure 3). Sorafenib was discontinued and amoxicillin-clavulanic acid was prescribed with symptom relief. Weeks later, an Aspergillus fumigatus was isolated in a sputum culture and oral voriconazol was introduced despite the good response to antibiotics. A new CT one month after discontinuation of Sorafenib showed a slight reduction in the size of the pneumatocele. Sorafenib was reintroduced at the same reduced dose.\n\nFigure 3 Lung cavity at diagnosis in the right upper lobe (120 × 60 × 60 mm) (Case 2)\nThree months after restarting Sorafenib treatment, he again had asthenia, cough and purulent sputum. A chest X-ray showed an enlarged pneumatocele (Figure 4). Empiric antibiotic therapy with clindamicyn and voriconazol was prescribed. Aspergillus fumigatus was again isolated in the sputum but not in the BAL culture. Symptoms improved although the size of the cavity remained stable. Sorafenib was permanently discontinued after 14 months, recessed and the patient died one month later because of tumor progression.\n\nFigure 4 Pneumatocele enlargement detected in chest X-ray (black arrow) (Case 2)\nDISCUSSION\nPneumatocele is an air-filled cyst that develops within the lung parenchyma usually related to a respiratory infection but it could also develop in another context such as trauma or mechanical ventilation [1]. It is asymptomatic in most cases, and does not require surgical or percutaneous intervention [5]. Complications may occur including tension pneumatocele [6], pneumothorax and superinfection. These two cases share a medical history of uneventful treatment with TARE followed months later by treatment with Sorafenib. TARE may rarely produce radiation pneumonitis, with a diffuse alveolar pattern and fibrosis [7] but cavitation has not been described. On the other hand, respiratory complications are uncommon during Sorafenib therapy but include pneumonia [8] and interstitial pneumonitis [9]. To our knowledge, this is the first time that pneumatocele is reported in Sorafenib-treated patients. Although a potential role of COPD and bacterial and fungal superinfection may not be ruled out in the second patient, the similarity to the first case and the enlargement of the cavity when Sorafenib was resumed in the second case speak against such possibility.\n\nAlthough unraveling the pathogenesis of pneumatocele in these two cases is beyond our prospects, we hypothesize that it might be related to the ability of Sorafenib to interfere in the human signal transducer and activator of transcription (STAT-3) pathway. STAT-3 plays a significant role in regulation of genes involved in tumor cell proliferation, survival and invasion [10]. Sorafenib decreases STAT-3 phosphorylation at both tyrosine and serine residues, regardless of Janus Kinase 2 (JAK 2) and phosphatase shatterproof 2 (SHP2) activity [11]. STAT-3 dephosphorylation induced by Sorafenib has been described in in vitro studies of human medulloblastomas [12] and esophageal adenocarcinomas, [13] and in vivo study of cholangiocarcinomas [14].\n\nOn the other hand, STAT-3 is expressed in numerous cells related to development of postnatal lung. In vitro studies have demonstrated a relationship between STAT-3 and surfactant protein B expression [15]. In the absence of STAT-3, mice exposed to 95% oxygen develop alterations in lung structure, permeability and surfactant, as well as lung mechanics [16]. A connection between STAT-3 and pneumatocele was described in 2007 when a STAT-3 mutation causing STAT-3 deficiency was linked to the hyper-immunoglobulin E syndrome [17], which is characterized by eosinophilia, increased IgE levels and an inadequate destructive inflammatory response in the skin and lung leading to pustular and eczematoid rashes, pneumatocele and bronchiectasis [18]. Therefore, we hypothesize that inhibition of STAT-3 by Sorafenib may lead to pneumatocele formation. An alternative explanation could be based on the antiangiogenic activity of Sorafenib acting on the lung vasculature subclinically damaged by radiation delivered by TARE, but this is even more speculative. Importantly, none of our patients smoked cannabis.\n\nIn summary, pneumatocele may be a rare pulmonary complication of Sorafenib treatment in patients previously treated by TARE. Treatment discontinuation should be considered in the context of tumor response, additional side effects and therapeutic alternatives.\n\nCONFLICTS OF INTEREST\n\nNone.\n==== Refs\nREFERENCES\n1 Al-Saleh S Grasemann H Cox P Necrotizing pneumonia complicated by early and late pneumatoceles Can Respir J 2008 15 129 32 18437254 \n2 Schimpl G Schneider U Traumatic pneumatoceles in an infant: case report and review of the literature Eur J Pediatr Surg 1996 6 104 6 8740134 \n3 Quigley MJ Fraser RS Pulmonary pneumatocele: pathology and pathogenesis AJR Am J Roentgenol 1988 150 1275 7 3259364 \n4 Boisset GF Subpleural emphysema complicating staphylococcal and other pneumonia J Pediatr 1972 81 259 266 4537790 \n5 Zuhdi MK Spear RM Worthen HM Peterson BM Percutaneous catheter drainage of tension pneumatocele, secondarily infected pneumatocele, and lung abscess in children Crit Care Med 1996 24 330 3 8605809 \n6 Shen HN Lu FL Wu HD Yu CJ Yang PC Management of tension pneumatocele with high-frequency oscillatory ventilation Chest 2002 121 284 6 11796465 \n7 Wright CL Werner JD Tran JM Gates VL Rikabi AA Shah MH Salem R Radiation Pneumonitis Following Yttrium-90 Radioembolization: Case Report and Literature Review J Vasc Interv Radiol 2012 23 669 74 22525023 \n8 Horiuchi-Yamamoto Y Gemma A Taniguchi H Inoue Y Sakai F Johkoh T Fujimoto K Kudoh S Drug-induced lung injury associated with sorafenib: analysis of all-patient post-marketing surveillance in Japan Int J Clin Oncol 2013 18 743 9 22752255 \n9 Myung HJ Jeong SH Kim JW Kim HS Jang JH Yoon HI Kim JS Sorafenib-induced Interstitial pneumonitis in a patient with Hepatocellular carcinoma: A case report Gut and Liver 2010 543 546 21253306 \n10 Yu H Pardoll D Jove R STATs in cancer inflammation and immunity: a leading role for STAT3 Nat Rev Cancer 2009 9 798 809 19851315 \n11 Gu FM Sorafenib inhibits growth and metastasis of hepatocellular carcinoma by blocking STAT3 World J Gastroenterol 2011 17 3922 22025881 \n12 Delgado JS Mustafi R Yee J Cerda S Chumsangsri A Dougherty U Lichtenstein L Fichera A Bissonnette M Sorafenib triggers antiproliferative and pro-apoptotic signals in human esophageal adenocarcinoma cells Dig Dis Sci 2008 53 3055 3064 18512153 \n13 Yang F Van Meter TE Buettner R Hedvat M Liang W Kowolik CM Mepani N Mirosevich J Nam S Chen MY Tye G Kirschbaum M Jove R Sorafenib inhibits signal transducer and activator of transcription 3 signaling associated with growth arrest and apoptosis of medulloblastomas Mol Cancer Ther 2008 7 3519 3526 19001435 \n14 Blechacz BRA Smoot RL Bronk SF Werneburg NW Sirica AE Gores GJ Sorafenib inhibits signal transducer and activator of transcription-3 signaling in cholangiocarcinoma cells by activating the phosphatase shatterproof 2 Hepatology 2009 50 1861 70 19821497 \n15 Yan C Naltner A Martin M Naltner M Fangman JM Gurel O Transcriptional stimulation of the surfactant protein B gene by STAT3 in respiratory epithelial cells J Biol Chem 2002 277 10967 72 11788590 \n16 Hokuto I Ikegami M Yoshida M Takeda K Akira S Perl AKT Hull WM Wert SE Whitsett JA STAT-3 is required for pulmonary homeostasis during hyperoxia J Clin Invest 2004 113 28 37 14702106 \n17 Holland SM DeLeo FR Elloumi HZ Hsu AP Uzel G Brodsky N Freeman AF Demidowich A Davis J Turner ML Anderson VL Darnell DN Welch PA STAT3 Mutations in the Hyper-IgE Syndrome N Engl J Med 2007 357 1608 19 17881745 \n18 Freeman AF The Hyper IgE Syndromes Immunol Allergy Clin North Am 2009 28 1 14\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1949-2553",
"issue": "9(5)",
"journal": "Oncotarget",
"keywords": "STAT3; antiangiogenics; hepatocellular carcinoma; iung toxicity; radioembolization",
"medline_ta": "Oncotarget",
"mesh_terms": null,
"nlm_unique_id": "101532965",
"other_id": null,
"pages": "6652-6656",
"pmc": null,
"pmid": "29464101",
"pubdate": "2018-01-19",
"publication_types": "D016428:Journal Article",
"references": "22525023;11788590;19821497;14702106;19851315;22752255;18512153;22025881;3259364;8605809;11796465;18437254;19001435;17881745;4537790;8740134;21253306",
"title": "Pneumatocele during sorafenib therapy: first report of an unusual complication.",
"title_normalized": "pneumatocele during sorafenib therapy first report of an unusual complication"
} | [
{
"companynumb": "ES-BAYER-2018-021103",
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"actiondrug": "1",
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"activesubstancename": "SORAFENIB"
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{
"abstract": "The introduction of tyrosine kinase inhibitors (TKIs) in the treatment of chronic myeloid leukemia (CML) has significantly increased survival rate and quality of life for patients with CML. Despite the high efficacy of imatinib, not all patients benefit from this treatment. Resistance to imatinib can develop from a number of mechanisms. One of the main reasons for treatment failure is a mutation in the BCR-ABL gene, which leads to therapy resistance and clonal evolution. Clearly, new treatment approaches are required for patients who are resistant to imatinib. However, mutated clones are usually susceptible to second-generation TKIs, such as nilotinib and dasatinib. The choice of the therapy depends on the type of mutation. A large trial program showed that dasatinib is effective in patients previously exposed to imatinib. However, for a minority of patients who experience treatment failure with TKI or progress to advanced-phase disease, allogeneic stem cell transplantation (allo-SCT) remains the therapeutic option. In spite of the high curative potential of allo-SCT, its high relapse rate still requires a feasible strategy of posttransplant treatment and prophylaxis. We report a case of a CML patient with primary resistance to first-line TKI therapy. The patient developed an undifferentiated blast crisis. Before dasatinib therapy, the patient was found to have an F317L mutation. He was successfully treated with dasatinib followed by allo-SCT. In the posttransplant period, preemptive dasatinib treatment was used to prevent disease relapse.",
"affiliations": "R.M. Gorbacheva Memorial Institute for Pediatric Oncology, Hematology and Transplantation, I.P. Pavlov First Saint-Petersburg State Medical University, St Petersburg, Russia.;R.M. Gorbacheva Memorial Institute for Pediatric Oncology, Hematology and Transplantation, I.P. Pavlov First Saint-Petersburg State Medical University, St Petersburg, Russia.;R.M. Gorbacheva Memorial Institute for Pediatric Oncology, Hematology and Transplantation, I.P. Pavlov First Saint-Petersburg State Medical University, St Petersburg, Russia.;R.M. Gorbacheva Memorial Institute for Pediatric Oncology, Hematology and Transplantation, I.P. Pavlov First Saint-Petersburg State Medical University, St Petersburg, Russia.;R.M. Gorbacheva Memorial Institute for Pediatric Oncology, Hematology and Transplantation, I.P. Pavlov First Saint-Petersburg State Medical University, St Petersburg, Russia.",
"authors": "Morozova|E V|EV|;Vlasova|Y Y|YY|;Pryanishnikova|M V|MV|;Lepik|K V|KV|;Afanasyev|B V|BV|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.4137/BMI.S22438",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1177-2719",
"issue": "10(Suppl 3)",
"journal": "Biomarker insights",
"keywords": "BCR-ABL mutations; CML; F317L mutation; TKI; allo-SCT; dasatinib",
"medline_ta": "Biomark Insights",
"mesh_terms": null,
"nlm_unique_id": "101288638",
"other_id": null,
"pages": "43-7",
"pmc": null,
"pmid": "26673003",
"pubdate": "2015",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "25581405;24225967;17189410;25929768;24456693;10216068;20008852;25046218;19811824;24385789;14744784;25025064;19779040;19652056;17114651;19589924;17448964;23803709;17976612;25797175;4126434;11423618;9625174;19878872;21562040;16709930;19744571;17151364;18818391;23250623;23890944;12637609;16855631;19517462;22210874;17662883",
"title": "Efficacy of Dasatinib in a CML Patient in Blast Crisis with F317L Mutation: A Case Report and Literature Review.",
"title_normalized": "efficacy of dasatinib in a cml patient in blast crisis with f317l mutation a case report and literature review"
} | [
{
"companynumb": "RU-SUN PHARMACEUTICAL INDUSTRIES LTD-2016RR-110623",
"fulfillexpeditecriteria": "1",
"occurcountry": "RU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IMATINIB"
},
"drugad... |
{
"abstract": "Passive transfer of antibodies secondary to intravenous immunoglobulin infusion is a rare but important side effect that can lead to the wrong diagnosis and therapeutic decisions. It has never been reported in a newborn. A male newborn, vaccinated against hepatitis B and diagnosed with dilated cardiomyopathy, presented positive hepatitis B core antibodies at 12 days of life. Exclusion of hepatitis B infection was mandatory as it would be a contraindication to heart transplant. Passive transfer of antibodies was confirmed at 44 days of age, after seroreversion of hepatitis B core antibodies. Passive transfer of antibodies after intravenous immunoglobulin infusion can lead to a misleading diagnosis if not recognized. In our patient it could have been especially harmful had it prevented heart transplant. Screening for hepatitis B should be performed at least 1 month after intravenous immunoglobulin infusion.",
"affiliations": "Serviço de Cardiologia Pediátrica. Hospital de Santa Cruz. Centro Hospitalar Lisboa Ocidental. Carnaxide. Portugal.;Serviço de Cardiologia Pediátrica. Hospital de Santa Cruz. Centro Hospitalar Lisboa Ocidental. Carnaxide. Portugal.;Serviço de Patologia Clínica. Hospital de São Francisco Xavier. Centro Hospitalar Lisboa Ocidental. Lisboa. Portugal.",
"authors": "Rato|João|J|;Alves|Daniela|D|;Rodrigues|Luís|L|",
"chemical_list": "D006510:Hepatitis B Antibodies; D016756:Immunoglobulins, Intravenous; D014761:Viral Hepatitis Vaccines",
"country": "Portugal",
"delete": false,
"doi": "10.20344/amp.9792",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0870-399X",
"issue": "32(12)",
"journal": "Acta medica portuguesa",
"keywords": "Cardiomyopathy, Dilated; Hepatitis B Antibodies; Immunoglobulins, Intravenous/adverse effects; Infant, Newborn",
"medline_ta": "Acta Med Port",
"mesh_terms": "D002311:Cardiomyopathy, Dilated; D016027:Heart Transplantation; D006509:Hepatitis B; D006510:Hepatitis B Antibodies; D006801:Humans; D007116:Immunization, Passive; D016756:Immunoglobulins, Intravenous; D007231:Infant, Newborn; D008297:Male; D000069078:Seroconversion; D014761:Viral Hepatitis Vaccines",
"nlm_unique_id": "7906803",
"other_id": null,
"pages": "782-784",
"pmc": null,
"pmid": "31851888",
"pubdate": "2019-12-02",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Passive Transfer of Hepatitis B Antibodies through Intravenous Immunoglobulin in a Neonate.",
"title_normalized": "passive transfer of hepatitis b antibodies through intravenous immunoglobulin in a neonate"
} | [
{
"companynumb": "PT-OCTA-GAM25519PT",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HUMAN IMMUNOGLOBULIN G"
},
"drugadditional": "3",
... |
{
"abstract": "Talimogene laherparepvec (T-VEC) is a novel intralesional oncolytic genetically modified herpes simplex virus type 1 vector for the treatment of unresectable cutaneous, subcutaneous, and nodal melanoma. Although immunological therapies such as T-VEC offer therapeutic promise, they carry a risk of immune-related adverse events (irAEs), the full spectrum of which is incompletely understood. We report a 63-year-old previously healthy man with cutaneous melanoma of the right ankle and progressive right lower extremity in-transit metastases despite systemic therapy with immunomodulatory and molecularly targeted treatments. T-VEC treatment resulted in a complete pathologic response on scouting biopsies. Biopsy of the right lateral calf showed lobular and septal panniculitis with lymphoplasmacytic infiltrate and lipophages. Gomori methenamine silver (GMS) stain and acid-fast bacilli (AFB) stains were negative, and no polarizable foreign material was noted. T-VEC was discontinued due to complete pathologic response and, in part, concern for development of irAEs including this panniculitis and an early concomitant autoimmune colitis. This case highlights a previously unreported irAE with this novel treatment for advanced cases of melanoma.",
"affiliations": "Department of Pathology, University of Washington, Seattle, WA.;Department of Pathology, University of Washington, Seattle, WA.;Department of Pathology, University of Washington, Seattle, WA.;Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA.;Division of Dermatology, Department of Medicine, University of Washington School of Medicine, University of Washington, Seattle, WA.",
"authors": "Long|Thomas H|TH|http://orcid.org/0000-0001-6693-594X;Shinohara|Michi M|MM|http://orcid.org/0000-0003-1388-5330;Argenyi|Zsolt B|ZB|;Thompson|John A|JA|;Gardner|Jennifer M|JM|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "United States",
"delete": false,
"doi": "10.1111/cup.13332",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0303-6987",
"issue": "45(11)",
"journal": "Journal of cutaneous pathology",
"keywords": "immunotherapy; melanoma; oncolytic virus; panniculitis; talimogene laherparepvec",
"medline_ta": "J Cutan Pathol",
"mesh_terms": "D000970:Antineoplastic Agents; D018259:Herpesvirus 1, Human; D006801:Humans; D008297:Male; D008545:Melanoma; D008875:Middle Aged; D050130:Oncolytic Virotherapy; D015434:Panniculitis; D012878:Skin Neoplasms",
"nlm_unique_id": "0425124",
"other_id": null,
"pages": "864-868",
"pmc": null,
"pmid": "30054925",
"pubdate": "2018-11",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Panniculitis in a patient with pathologic complete response to talimogene laherparepvec treatment for recurrent, in-transit melanoma.",
"title_normalized": "panniculitis in a patient with pathologic complete response to talimogene laherparepvec treatment for recurrent in transit melanoma"
} | [
{
"companynumb": "US-009507513-1911USA002048",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nTo report a case of hyperacute Streptococcus mitis endophthalmitis after intravitreal ranibizumab resulting in occlusive vasculitis.\n\n\nMETHODS\nRetrospective case report with ultra-wide-field color fundoscopic and fluorescein angiographic imaging.\n\n\nRESULTS\nAn 83-year-old woman received an intravitreal injection of ranibizumab to her right eye and was evaluated the next day (less than 24 hours from the injection) because of acute loss of vision. Her vision had decreased from 20/50 to hand motions in the right eye at the time of reevaluation. Wide-field fundus photography demonstrated pallid optic nerve head edema, generalized vascular attenuation, diffuse vascular sheathing, and scattered large postequatorial intraretinal hemorrhages. Ultra-wide-field fluorescein angiography revealed a severely delayed AV transit time associated with extensive areas of retinal nonperfusion and late retinal vascular leakage consistent with occlusive vasculitis. She underwent immediate pars plana vitrectomy with extensive irrigation of the vitreous cavity and intravitreal injection of antibiotics. In light of a worsening clinical course, she was taken for repeat vitrectomy 1 week later with panretinal endolaser photocoagulation, instillation of silicone oil, and sub-Tenon triamcinolone acetonide. At postoperative month 1, she maintained 20/200 vision with improved retinal perfusion on fluorescein angiography.\n\n\nCONCLUSIONS\nWe describe a hyperacute case of S. mitis endophthalmitis after intravitreal injection with ranibizumab, associated with severe occlusive vasculitis on ultra-wide-field fluorescein angiography. Aggressive early surgical intervention may be associated with better outcomes than previously reported.",
"affiliations": "*St John Providence Health System, Joseph H. Wyatt Ophthalmology Residency, Patrick Murray Eye Center, Detroit, Michigan; and †Associated Retinal consultants, William Beaumont Hospital, Royal Oak, Michigan.",
"authors": "Baxter|Kevin R|KR|;Robinson|Joshua E|JE|;Ruby|Alan J|AJ|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D000069579:Ranibizumab",
"country": "United States",
"delete": false,
"doi": "10.1097/ICB.0000000000000138",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1935-1089",
"issue": "9(3)",
"journal": "Retinal cases & brief reports",
"keywords": null,
"medline_ta": "Retin Cases Brief Rep",
"mesh_terms": "D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors; D009877:Endophthalmitis; D005260:Female; D006801:Humans; D058449:Intravitreal Injections; D000069579:Ranibizumab; D012166:Retinal Hemorrhage; D031300:Retinal Vasculitis; D012189:Retrospective Studies; D013290:Streptococcal Infections; D034361:Streptococcus mitis",
"nlm_unique_id": "101298744",
"other_id": null,
"pages": "201-4",
"pmc": null,
"pmid": "25764316",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Occlusive vasculitis due to hyperacute Streptococcus mitis endophthalmitis after intravitreal ranibizumab.",
"title_normalized": "occlusive vasculitis due to hyperacute streptococcus mitis endophthalmitis after intravitreal ranibizumab"
} | [
{
"companynumb": "US-ROCHE-1599355",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RANIBIZUMAB"
},
"drugadditional": null,
"dru... |
{
"abstract": "Patients with nontoxic lithium levels can still develop hand tremors, downbeat nystagmus, and an unsteady gait.",
"affiliations": "Renown Institute for Neuroscience, Renown Health, Department of Neurology University of Nevada Reno Nevada.",
"authors": "Peng|Yen-Yi|YY|https://orcid.org/0000-0002-5829-6217",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.1981",
"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.1981CCR31981Clinical VideoClinical VideosReversible hand tremors, downbeat nystagmus, and an unsteady gait with nontoxic lithium level PENGPeng Yen‐Yi https://orcid.org/0000-0002-5829-6217ypeng@renown.org \n1\n\n1 \nRenown Institute for Neuroscience, Renown Health, Department of Neurology\nUniversity of Nevada\nReno\nNevada\n* Correspondence\n\nYen‐Yi Peng, Renown Institute for Neuroscience, Renown Health; Department of Neurology, University of Nevada, Reno, NV.\n\nEmail: ypeng@renown.org\n24 1 2019 3 2019 7 3 10.1002/ccr3.2019.7.issue-3599 600 07 10 2018 13 11 2018 06 12 2018 © 2019 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-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Key Clinical Message\nPatients with nontoxic lithium levels can still develop hand tremors, downbeat nystagmus, and an unsteady gait.\n\ndownbeat nystagmuslithiumtremorunsteady gait source-schema-version-number2.0component-idccr31981cover-dateMarch 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.6.1 mode:remove_FC converted:08.03.2019\n\n\nPeng \nY‐Y \n. Reversible hand tremors, downbeat nystagmus, and an unsteady gait with nontoxic lithium level . Clin Case Rep . 2019 ;7 :599 –600 . 10.1002/ccr3.1981\n==== Body\nFour years of hand tremors, 2 years of jumpy eyes, and 6 months of unsteady gait with frequent falls caused the 60‐year‐old woman to be on forced medical leave. In the past 3 years, primidone, propranolol, sinemet, and amantadine have been tried without significant improvement. The patient has been taking lithium for more than 20 years. The lithium level was normal: 0.9 mmol/L (normal range: 0.6‐1.2 mmol/L). The MRI of brain was not remarkable (Figure 1). On examination, the patient had downbeat nystagmus, tremors, and an unsteady gait. Lithium medication was stopped, and symptoms improved within one month1, 2 (Video S1).\n\nFigure 1 The MRI of the brain is unremarkable\n\nCONFLICTS OF INTEREST\nThe author declares no conflicts of interest.\n\nAUTHOR CONTRIBUTION\nYYP: was the neurologist for this patient.\n\nSupporting information\n \n\nClick here for additional data file.\n==== Refs\nREFERENCES\n1 \n\nJorgensen \nJS \n, \nLandschoff Lassen \nL \n, \nWegener \nM \n. Lithium‐induced downbeat nystagmus and horizontal gaze palsy . Open Ophthalmol J . 2016 ;10 :126 ‐128 .27347248 \n2 \n\nHalmagyi \nGM \n, \nLessell \nI \n, \nCurthoys \nIS \n, \nLessell \nS \n, \nHoyt \nWF \n. Lithium‐induced downbeat nystagmus . Am J Ophthalmol . 1989 ;107 (6 ):664 ‐670 .2499196\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2050-0904",
"issue": "7(3)",
"journal": "Clinical case reports",
"keywords": "downbeat nystagmus; lithium; tremor; unsteady gait",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "599-600",
"pmc": null,
"pmid": "30899510",
"pubdate": "2019-03",
"publication_types": "D016428:Journal Article",
"references": "2499196;27347248",
"title": "Reversible hand tremors, downbeat nystagmus, and an unsteady gait with nontoxic lithium level.",
"title_normalized": "reversible hand tremors downbeat nystagmus and an unsteady gait with nontoxic lithium level"
} | [
{
"companynumb": "US-009507513-1903USA009151",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PROPRANOLOL HYDROCHLORIDE"
},
"drugaddition... |
{
"abstract": "Invasive fungal sinusitis can lead to dramatic complications in immunocompromised patients and requires prompt diagnosis. Here we report three cases with ophthalmological complications secondary to invasive fungal sinusitis in immunocompromised patients. From an ophthalmological point of view, these cases illustrate different clinical presentations, evolutions, complications, treatments, prognoses, and highlight different pathophysiological mechanisms. Diagnoses were delayed in all cases. In none of the cases did patients recover better vision than counting fingers at 24 months follow up, and two patients died. This case series highlights key points useful for quickly recognising this highly morbid infection in immunocompromised patients.",
"affiliations": "Ophthalmology Department, Cliniques Universitaires Saint-Luc, Woluwé-Saint-Lambert, Belgium.;Neuroradiology Department, Cliniques Universitaires Saint-Luc, Woluwé-Saint-Lambert, Belgium.;ENT Department, Cliniques Universitaires Saint-Luc, Woluwé-Saint-Lambert, Belgium.;Anatomopathology Department, Cliniques Universitaires Saint-Luc, Woluwé-Saint-Lambert, Belgium.;Ophthalmology Department, Cliniques Universitaires Saint-Luc, Woluwé-Saint-Lambert, Belgium.",
"authors": "Coutel|Maëlle|M|https://orcid.org/0000-0002-5603-1696;Duprez|Thierry|T|;Huart|Caroline|C|;Wacheul|Emilie|E|;Boschi|Antonella|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/01658107.2020.1779315",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0165-8107",
"issue": "45(3)",
"journal": "Neuro-ophthalmology (Aeolus Press)",
"keywords": "Fungal sinusitis; ct scan; immunocompromised patients; magnetic resonance imaging; optic neuropathy; orbital apex syndrome",
"medline_ta": "Neuroophthalmology",
"mesh_terms": null,
"nlm_unique_id": "8408966",
"other_id": null,
"pages": "193-204",
"pmc": null,
"pmid": "34194126",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "17987470;27481947;26830404;13032555;29750016;14601848;23973515;30045315;11957017;11514221;7776048;28011902;8879787;8770260;9366697;11170942;15090423;26616482;9564455;26112869;26137308;10392237;24279587;8890440;30042790;10941354;8290288;25593888;11337328;23279383;19434293;30567122",
"title": "Invasive Fungal Sinusitis with Ophthalmological Complications: Case Series and Review of the Literature.",
"title_normalized": "invasive fungal sinusitis with ophthalmological complications case series and review of the literature"
} | [
{
"companynumb": "BE-ROCHE-2699880",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "3",
... |
{
"abstract": "Here, we report a case of severe immune thrombocytopenia that occurred after orthotopic liver transplant. On day 16 after transplant, the patient was readmitted to our hospital with a platelet count of 0 cells/mL, with the count remaining at a low level of 1000 to 10 000 cells/mL for 46 days. A diagnosis was made, after exclusion of other causes, of thrombocytopenia. Platelet blood transfusion and high-dose prednisone (1mg/kg/d) combined with intravenous immunoglobulin (0.5g/kg/d) were administered with no improvement. After additional treatments, which included altered use of immunosuppressive agents, changing adefovir to lamivudine and continuous steroid therapy, the patient was discharged with a platelet count of 55 000 cells/mL. Both liver and renal functions generally stayed well during hospitalization. The patient was discharged uneventfully and achieved remission during 10-month follow-up after discharge.",
"affiliations": "From the Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China.",
"authors": "Gao|Wei|W|;Song|Jiu-Lin|JL|;Yang|Jian|J|;Yang|Jia-Yin|JY|;Yan|Lu-Nan|LN|",
"chemical_list": "D000998:Antiviral Agents; D016756:Immunoglobulins, Intravenous; D007166:Immunosuppressive Agents; D011241:Prednisone",
"country": "Turkey",
"delete": false,
"doi": "10.6002/ect.2015.0219",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1304-0855",
"issue": "16(1)",
"journal": "Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation",
"keywords": null,
"medline_ta": "Exp Clin Transplant",
"mesh_terms": "D000328:Adult; D000998:Antiviral Agents; D057915:Drug Substitution; D004359:Drug Therapy, Combination; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007166:Immunosuppressive Agents; D016031:Liver Transplantation; D008297:Male; D017713:Platelet Transfusion; D011241:Prednisone; D016553:Purpura, Thrombocytopenic, Idiopathic; D012074:Remission Induction; D012720:Severity of Illness Index; D016896:Treatment Outcome",
"nlm_unique_id": "101207333",
"other_id": null,
"pages": "103-106",
"pmc": null,
"pmid": "27001430",
"pubdate": "2018-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful Treatment of Severe Immune Thrombocytopenia After Orthotopic Liver Transplant.",
"title_normalized": "successful treatment of severe immune thrombocytopenia after orthotopic liver transplant"
} | [
{
"companynumb": "IT-CIPLA LTD.-2016IT18478",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "OMEPRAZOLE"
},
"drugadditional": "1",
... |
{
"abstract": "In 1998 a 57-year-old man having skin leisons of 6 months duration reported to Central Leprosy Teaching and Research Institute (CLTRI), Chengalpattu. It was diagnosed as a case of borderline lepromatous leprosy with a type 2 lepra reaction, was treated with multi bacillary-multi drug therapy (MBMDT) for a period of 12 months and the patient was released from treatment (RFT) in September 1999. For reactions the patient was treated with prednisolone for more than 10 months. After 14 years in April 2013 the same patient presented to CLTRI with complaints of weakness of both hands with loss of sensation for 4 months, so making a diagnosis suggestive of MB relapse with neuritis the patient was started with MB-MDT for period of 12 months with initial prednisolone 25 mg OD dose then increased to 40 mg for painful swollen leg and to follow the neuritis associated pain and swelling. Increased dose is not beneficial and the patient was investigated for other pathology. Doppler ultra-sound revealed a left ileofemoral deep vein thrombosis (DVT) in that patient with levels. Prednisolone was withdrawn and the patient was started with anticoagulant heparin followed by warfarin. During this period rifampicin was also withdrawn. After patient was in good condition he was put on MB-MDT regimen. Till the 6th pulse the patient continues to show improvement in functions without steroids and any tenderness, he is taking multivitamins; regular physiotherapy. This DVT appears to be due to prednisolone and such causative relationship though rare should be kept in mind when patient on long term treatment with steroids/and or immobilized or on prolonged bed rest report with such symptomatology.",
"affiliations": null,
"authors": "Thangaraju|P|P|;Giri|V C|VC|;Aravindan|U|U|;Sajitha|V|V|;Showkath Ali|M K|MK|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D000925:Anticoagulants; D014859:Warfarin; D006493:Heparin; D011239:Prednisolone",
"country": "India",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0254-9395",
"issue": "87(3)",
"journal": "Indian journal of leprosy",
"keywords": null,
"medline_ta": "Indian J Lepr",
"mesh_terms": "D000893:Anti-Inflammatory Agents; D000925:Anticoagulants; D006493:Heparin; D006801:Humans; D056006:Leprosy, Multibacillary; D008297:Male; D008875:Middle Aged; D011239:Prednisolone; D020246:Venous Thrombosis; D014859:Warfarin",
"nlm_unique_id": "8409173",
"other_id": null,
"pages": "165-8",
"pmc": null,
"pmid": "26999989",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Ileofemoral Deep Vein Thrombosis (DVT) in Steroid Treated Lepra Type 2 Reaction Patient.",
"title_normalized": "ileofemoral deep vein thrombosis dvt in steroid treated lepra type 2 reaction patient"
} | [
{
"companynumb": "IN-BAUSCH-BL-2016-001192",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CLOFAZIMINE"
},
"drugadditional": null,
... |
{
"abstract": "Acute gastric dilatation is a rare cause of gas within the hepatic portal vein, but one that is important to recognise as prompt decompression via a nasogastric tube is usually successful in resolving the situation. We report the rare case of a 68-year-old man with spontaneous acute gastric dilatation 50 minutes after a dobutamine stress echo that resulted in pneumoporta. The patient had a Nissen's fundoplication 18 months previously; patients with previous antireflux surgery or who have a degree of gastric outlet obstruction may be at increased risk of this unusual condition. Conservative management, with placement of a nasogastric tube was successful in resolving his symptoms.",
"affiliations": "Musgrove Park Hospital , Taunton , UK.;Musgrove Park Hospital , Taunton , UK.",
"authors": "Williamson|Jml|J|;Mahon|D|D|",
"chemical_list": "D058665:Adrenergic beta-1 Receptor Agonists; D004280:Dobutamine",
"country": "England",
"delete": false,
"doi": "10.1308/rcsann.2016.0204",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0035-8843",
"issue": "98(8)",
"journal": "Annals of the Royal College of Surgeons of England",
"keywords": "Acute gastric distension; Antireflux surgery; Gastric volvulous; Nissen’s fundoplication; Pneumoporta; Portal vein gas",
"medline_ta": "Ann R Coll Surg Engl",
"mesh_terms": "D058665:Adrenergic beta-1 Receptor Agonists; D000368:Aged; D004280:Dobutamine; D025401:Echocardiography, Stress; D004618:Embolism, Air; D018662:Fundoplication; D013271:Gastric Dilatation; D006801:Humans; D008297:Male; D011169:Portal Vein",
"nlm_unique_id": "7506860",
"other_id": null,
"pages": "e157-e159",
"pmc": null,
"pmid": "27388544",
"pubdate": "2016-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25276288;20066568;23819076;116516;23267868;17429565;9183605;19653334;18729313;19528392;19495499;3492104",
"title": "Dobutamine stress echocardiography resulting in acute gastric dilatation and pneumoporta.",
"title_normalized": "dobutamine stress echocardiography resulting in acute gastric dilatation and pneumoporta"
} | [
{
"companynumb": "GB-PFIZER INC-2017040270",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOBUTAMINE HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "Immune checkpoint inhibitors (ICIs) are associated with a range of organ-specific toxicities known as immune-related adverse events (irAEs). Immune-mediated ototoxicity from ICIs is poorly described. Herein, we describe the clinical presentation, diagnostic evaluation and management of six ICI-treated patients who developed immune-mediated ototoxicity, identified by a multidisciplinary immune-related toxicity team. This is the largest case series to date and identifies bilateral high-frequency hearing loss and tinnitus as the most common reported symptoms and can be associated with abnormal speech reception thresholds and word recognition ability on audiogram in select patients. We propose multidisciplinary evaluation of patients with suspected otologic irAEs including referral to otolaryngology, audiometry evaluation±magnetic resonance imaging for evaluation of suspected immune-mediated ototoxicity.",
"affiliations": "Department of Oncology, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA srosner3@jhmi.edu.;Otolaryngology, Johns Hopkins Hospital, Baltimore, Maryland, USA.;Otolaryngology, Johns Hopkins Hospital, Baltimore, Maryland, USA.;Radiology and Radiological Science, Johns Hopkins Hospital, Baltimore, Maryland, USA.;Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.;Oncology, Johns Hopkins University, Baltimore, Maryland, USA.;Oncology, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA.",
"authors": "Rosner|Samuel|S|0000-0003-4768-3921;Agrawal|Yuri|Y|;Sun|Daniel Q|DQ|;Aygun|Nafi|N|;Schollenberger|Megan D|MD|;Lipson|Evan|E|0000-0003-2976-0911;Naidoo|Jarushka|J|0000-0002-3470-8686",
"chemical_list": "D000082082:Immune Checkpoint Inhibitors",
"country": "England",
"delete": false,
"doi": "10.1136/jitc-2020-001675",
"fulltext": "\n==== Front\nJ Immunother Cancer\nJ Immunother Cancer\njitc\njitc\nJournal for Immunotherapy of Cancer\n2051-1426 BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR \n\njitc-2020-001675\n10.1136/jitc-2020-001675\nCase Report\n1506\n2518 1619\nImmune-mediated ototoxicity associated with immune checkpoint inhibitors in patients with melanoma\nhttp://orcid.org/0000-0003-4768-3921Rosner Samuel 1 Agrawal Yuri 2 Sun Daniel Q 2 Aygun Nafi 3 Schollenberger Megan D 4 http://orcid.org/0000-0003-2976-0911Lipson Evan 5 http://orcid.org/0000-0002-3470-8686Naidoo Jarushka 678 1 Department of Oncology, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA\n2 Otolaryngology, Johns Hopkins Hospital, Baltimore, Maryland, USA\n3 Radiology and Radiological Science, Johns Hopkins Hospital, Baltimore, Maryland, USA\n4 Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA\n5 Oncology, Johns Hopkins University, Baltimore, Maryland, USA\n6 Oncology, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA\n7 The Bloomberg~Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland, USA\n8 Beaumont Hospital Dublin, The Royal College of Surgeons Dublin, Dublin, Ireland\nCorrespondence to Dr Samuel Rosner; srosner3@jhmi.edu\n2020 \n16 12 2020 \n8 2 e00167522 11 2020 © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.2020http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.Immune checkpoint inhibitors (ICIs) are associated with a range of organ-specific toxicities known as immune-related adverse events (irAEs). Immune-mediated ototoxicity from ICIs is poorly described. Herein, we describe the clinical presentation, diagnostic evaluation and management of six ICI-treated patients who developed immune-mediated ototoxicity, identified by a multidisciplinary immune-related toxicity team. This is the largest case series to date and identifies bilateral high-frequency hearing loss and tinnitus as the most common reported symptoms and can be associated with abnormal speech reception thresholds and word recognition ability on audiogram in select patients. We propose multidisciplinary evaluation of patients with suspected otologic irAEs including referral to otolaryngology, audiometry evaluation±magnetic resonance imaging for evaluation of suspected immune-mediated ototoxicity.\n\nimmunotherapycase reportsmelanomaspecial-featureunlocked\n==== Body\nIntroduction\nImmune checkpoint inhibitors (ICIs) that block receptors, such as cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and programmed death-1 (PD-1), have led to improvements in survival for patients with metastatic disease.1–3 However, these agents are also associated with wide-ranging toxicities, termed immune-related adverse events (irAEs), which can involve various organ systems.4 Common organ-specific toxicities include pneumonitis, colitis, dermatitis, arthritis and endocrinopathies.5 Otologic irAEs have not been widely described.\n\nLittle is known about the incidence, natural history, diagnosis and management of potential ICI-mediated ototoxicity. Based on a small number of published case reports, a spectrum of clinical phenotypes of ICI-mediated ototoxicity may exist and include isolated hearing loss, tinnitus,6 7 combined hearing loss with vestibular symptoms,8 combined visual and hearing loss9 or as a complex syndrome known has Vogt-Koyanagi-Harada (VKH) leading to ocular, dermatologic and neurologic involvement.10–12\n\nHerein, we describe the diagnostic evaluation, management and outcomes of six patients who developed immune-mediated ototoxicity, without accompanying non-otologic findings as part of a multi-organ syndrome, after receiving ICIs for metastatic melanoma.\n\nCase descriptions\nCase 1\nA 40-year-old man presented with metastatic melanoma involving the liver, spleen and bones. No intracranial metastases were seen on brain MRI. He received first-line ipilimumab (anti-CTLA-4; 3 mg/kg) and nivolumab (anti-PD-1; 1 mg/kg). Two weeks post-ICI start, the patient developed grade 3 immune-mediated dermatitis by Common Terminology Criteria for Adverse Events (CTCAE) V.5.0,13 and grade 2 anterior uveitis requiring administration of low-dose oral prednisone (table 1). At a timepoint 3 weeks post-ICI start, while still taking prednisone for prior irAEs, he developed tinnitus and aural fullness, with bilateral moderately severe high-frequency sensorineural hearing loss (SNHL) on audiometric examination (figure 1A). Bilateral speech reception thresholds (30 dbl) were obtained and demonstrated reduced word recognition ability (right: 88%; left: 92%). Tympanometry revealed normal middle ear pressure bilaterally. Oral prednisone was increased to a dose of 60 mg daily, resulting in subjective hearing improvement within 2 weeks of this increase. Based on multiple irAEs and likely ICI-ototoxicity, ICI was discontinued after a single dose of each drug. The patient experienced a partial response to therapy per Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1,14 ongoing at 3.5 months.\n\nTable 1 Patient characteristics: summary table of demographic data, relevant treatment and toxicity history, presenting symptoms, diagnostic course and treatment offered for ototoxicity\n\n\tPatient 1\tPatient 2\tPatient 3\tPatient 4\tPatient 5\tPatient 6\t\nAge (years)\t40\t61\t41\t52\t62\t55\t\nSex\tM\tF\tM\tM\tM\tF\t\nRace\tW\tAA\tW\tW\tW\tW\t\nPrior systemic therapy\tNone\tNone\tIL-2, Carboplatin/Paclitaxel\tInterferon\tNone\tNone\t\nPrior brain radiotherapy (Y/N)\tN\tY\tN\tN\tN\tY\t\nImmunotherapy agent(s)\tIpilimumab+Nivolumab\tIpilimumab+Nivolumab\tNivolumab\tRecombinant IL-21 +Nivolumab\tNivolumab\tPembrolizumab\t\nIntracranial metastasis (Y/N)\tN\tY\tN\tY\tN\tY\t\nOther irAEs\tAnterior uveitis, dermatitis\tHypophysitis\tNone\tDermatitis, arthritis\tNone\tThyroiditis, pancreatitis\t\nOther irAE treatments\tUveitis: prednisolone eye drops, cyclopentolate eye drops\nInflammatory arthritis: topical triamcinolone, oral prednisone\tPrednisone, levothyroxine\tN/A\tInflammatory arthritis: celecoxib\nDermatitis: benadryl\tN/A\tThyroiditis: levothyroxine\nPancreatitis: prednisone, infliximab\t\nBest response to ICI\n(RECIST v1.1)\tPartial response\tPartial response\tPartial response\tPartial response\tComplete response\tProgressive disease\t\nLaterality of hearing symptoms\tBilateral\tBilateral\tUnilateral\tBilateral\tBilateral\tBilateral\t\nTime to ototoxicity symptoms from immunotherapy start (weeks)\t3\t16\t2\t16\t10\t164\t\nNumber of ICI doses received prior to ototoxicity\t1\t2\t1\t9\t5\t12\t\nTotal number of doses of ICI received\t1\t4\t48\t26\t32\t12\t\nDiagnostic evaluation and treatment for hearing loss\t\nAudiogram (Y/N)\tY\tY\tY\tY\tY\tY\t\nMRI brain with contrast (Y/N)\tN\tY\tN\tY\tY\tY\t\nDegree of SNHL\tModerate-severe\tModerate-severe\tModerate-severe to profound\tMild-moderate\tNone\tMild\t\nSymmetric vs asymmetric audiometry findings\tSymmetric\tAsymmetric\tAsymmetric\tAsymmetric\tSymmetric\tAsymmetric\t\nReduction in speech reception thresholds (Y/N)\tY\tY\tY\tN\tN\tN\t\nReduction in word recognition ability (Y/N)\tY\tN\tY\tN\tN\tY\t\nOtotoxicity treatment\tPrednisone\tHearing aids\tNone\tHearing aids\tHearing aids (pt declined)\tNone\t\nSubjective change in hearing loss\tImproved\tStable\tStable\tStable\tStable\tStable\t\nAA, African American; anti-PD-1, anti-programmed death-1; F, female; ICI, immune checkpoint inhibitor; IL, interleukin; irAE, immune-related adverse event; M, male; pt, patient; RECIST, response evaluation criteria in solid tumors; SNHL, sensorineural hearing loss; W, white.\n\nFigure 1 Post-treatment audiograms depicting hearing loss among three patients treated with ICIs for metastatic melanoma. The vertical (y) axis depicts hearing loss measured in decibels in hearing level (dB HL). Zero dB HL represents the softest sound level a person with normal hearing would be expected to hear at a given frequency. The horizontal (x) axis depicts sound frequency measured in hertz (Hz). Blue line, left ear; red line, right ear. Sensorineural hearing loss is distinguished from conductive hearing loss when there is no difference between the air conduction and the bone conduction thresholds, indicating that the hearing loss is in the cochlea, as is the case for all three patients. The upper left panel (patient 1; 3 weeks into ICI) illustrates a mild sloping to moderately severe sensorineural hearing loss bilaterally. The upper right panel (patient 2; 4 months into ICI) reveals a moderate to moderately severe sensorineural hearing loss bilaterally, L>R. The bottom panels (patient 4) represent evaluations at 4 months (left panel; normal hearing through 1500 Hz bilaterally, sloping to a mild sensorineural loss in the right ear and a moderate 6000 Hz sensorineural notch in the left ear) and 13 months (right panel; normal hearing through 4000 Hz sloping to a mild hearing loss in the right ear and normal hearing limits through 1500 Hz, then sloping to a moderate sensorineural hearing loss in the left ear), ultimately revealing stable objective findings at these two separate time points. ICI, immune checkpoint inhibitor.\n\nCase 2\nA 61-year-old woman with melanoma of the urethra metastatic to brain was treated with first-line ipilimumab (3 mg/kg) plus nivolumab (1 mg/kg) and stereotactic radiosurgery to a 4 mm brain metastasis at the anterior putamen. At 3.5 weeks post-ICI start, after receiving two doses of combination ICI, she developed grade 2 hypophysitis treated with prednisone (table 1). Over the next 3 months, the patient reported progressive hearing loss, tinnitus and dizziness. Brain MRI demonstrated stability of the intracranial metastasis. An audiogram revealed moderate-severe bilateral SNHL (figure 1B), with reduced speech recognition threshold in the left ear, but preserved word recognition ability (right: 96%, threshold 35 dbl; left: 100%, threshold 50 dbl). Tympanometry results were not available. Because her hearing loss did not improve with previously administered corticosteroids, for treatment of hypophysitis, the patient’s SNHL was treated with bilateral hearing aids. She experienced a partial response to ICI lasting 22 months, after which her disease progressed.\n\nCase 3\nA 41-year-old man presented with melanoma metastatic to liver and lymph nodes. No intracranial metastases were seen on brain MRI. His disease progressed after treatment with high-dose interleukin-2 (IL-2) followed by carboplatin plus paclitaxel combination chemotherapy. He then received nivolumab (3 mg/kg). At 2 weeks post-ICI start, the patient experienced tinnitus and left-sided hearing loss. Audiometry revealed mild-moderate SNHL through 4000 Hz in the right ear and mild to profound SNHL in the left ear. Speech discrimination ability was normal in the right and poor in the left ear. Over the next 5 months, the patient continued to receive ICI but noted increasing subjective hearing decline, while tinnitus was unchanged. Repeat audiometric evaluation completed at 7 months revealed mild SNHL from 2000 to 4000 Hz in the right ear and moderate-severe to profound SNHL, from 2000 to 8000 Hz, in the left hear. Word discrimination was 100% in the right and 60% in the left ear. Tympanometry revealed normal middle ear pressure bilaterally. The patient’s symptoms stabilized without intervention. He experienced a partial response to nivolumab lasting 31 months, after which his disease progressed.\n\nCase 4\nA 52-year-old man with metastatic melanoma received first-line recombinant interleukin-21 plus nivolumab (3 mg/kg). At 4 weeks, he developed grade 1 immune-mediated dermatitis and grade 1 inflammatory arthritis (table 1). At 4 months post-ICI start, the patient reported new bilateral tinnitus. Audiometry showed mild SNHL in the right ear and moderate SNHL in the left (figure 1C). Speech reception threshold was obtained down to 10 dB HL bilaterally and speech recognition was 100% bilaterally. An MRI brain revealed a new 2 cm cerebellar mass that was treated with a single fraction of SRS, without reported changes in tinnitus symptoms. Based on the location of the intracranial lesion, it was thought an unlikely cause for his tinnitus. A repeat audiogram 7 months later demonstrated unchanged bilateral high-frequency mild to moderate SNHL (figure 1D), and the patient’s hearing loss was managed with hearing aids including tinnitus maskers.\n\nCase 5\nA 62-year-old man with metastatic melanoma involving the groin and scrotum received first-line therapy with nivolumab (3 mg/kg). At 2 months post-ICI start, he developed tinnitus without subjective hearing loss. MRI brain at this time showed no evidence of intracranial metastases. ENT evaluation with audiometry revealed normal hearing sensitivity bilaterally on standard 8000 Hz audiogram. Speech recognition thresholds showed excellent word discrimination bilaterally. Ultra-high frequency audiometry to evaluate for more subtle abnormalities was not employed. The patient declined hearing aid placement. He continued to receive nivolumab without subjective worsening in symptoms and experienced a complete response of his metastatic melanoma, ongoing at 10 years.\n\nCase 6\nA 55-year-old woman presented with metastatic melanoma and underwent surgical resection and SRS for brain metastases followed by first-line pembrolizumab (2 mg/kg). She experienced regression of metastatic lesions in the body but progression of brain metastases was treated with whole-brain radiotherapy (WBRT) and concomitant temozolomide, at which time pembrolizumab was held during the duration of WBRT and subsequently restarted. Her clinical course was complicated by grade 2 immune-mediated thyroiditis and grade 3 pancreatitis (table 1). At approximately 3 years post-ICI start, the patient reported new bilateral ear “fullness” and decreased hearing. Brain MRI was negative for leptomeningeal disease. Audiometry showed mild left-sided SNHL (sensorineural notch at 4000 Hz), 88% word recognition scoring with the right ear, 100% word recognition score with the left ear and normal tympanometry bilaterally. The patient declined symptomatic management for suspected ICI-toxicity with hearing aids. She remains without evidence of tumor progression at ~4 years post-ICI start.\n\nDiscussion\nHerein, we describe the largest series of patients with clinical and functional evidence of ICI-mediated ototoxicity. In each case, evidence supporting an immune-mediated phenomenon related to ICI included one or more of the following factors: (1) the temporal relationship between administration of ICI and development of symptoms, (2) symptom improvement after administration of corticosteroids and (3) absence of another causative factor (eg, a brain metastasis with apposite behavior and location).\n\nWe observed several important clinical features of ICI-mediated ototoxicity in this series. In terms of time to onset, patients tended to develop ICI-mediated ototoxicity early in their treatment course (within ~4 months of initiating ICI), consistent with other irAEs.5 Clinically, ICI-mediated ototoxicity manifested most commonly as bilateral tinnitus with or without high-frequency hearing loss and speech and/or word recognition deficits. Functionally, we observed that severity of ICI-mediated ototoxicity on audiogram varied widely, spanning a range of patients who exhibited objective reductions in word recognition scoring or varying degrees of SNHL to those with no abnormality on audiology. Importantly, we also identified that ICI-mediated ototoxicity could develop as a single irAE or in concert with other irAEs.\n\nWhile we observed that optimal treatment in all six cases of ICI-mediated ototoxicity was unclear, in one case, symptomatic improvement was seen after administration of corticosteroids, while others were treated with hearing aids or simply observed. In cases 4, 5 and 6, steroids were not employed, as symptoms were insidious and mild without overt impairment of functional ability. Instead, symptomatic management with hearing aids was offered, with only patient in case 4 accepting this therapy with clinical improvement.\n\nInterestingly, five of the six patients observed objective responses to ICI therapy. The association between irAEs and ICI efficacy is controversial and may depend on the site of toxicity. Retrospective studies suggest that site-specific toxicities may have a correlation with ICI efficacy. Dermatologic toxicities after PD-1 inhibitor use for metastatic melanoma have been associated with favorable response rates,15 whereas pneumonitis secondary to ICI in NSCLC corresponds with poor survival.16 For this reason, exact conclusions regarding irAE and toxicity are hard to draw and further research regarding the association of rarer irAEs, such as ototoxicity, and clinical response to ICI is needed.\n\nThree of our six patients had presence of intracranial metastases, with two receiving some form of intracranial radiation. Evidence showing SNHL as a potential toxicity to radiotherapy have been reported. SNHL after stereotactic radiosurgery may occur in up to 1/3 of cases where the inner ear is within radiation field.17 For our patient in case 2, the left anterior putamen was treated with cyberknife therapy, without inclusion of inner ear structures in the prescribed radiation field. Ototoxicity from WBRT, which was used in case 6, is a rare toxicity with some variability based on dosing of radiation and the use of radiosensitizing agents.18 Nonetheless, preceding radiotherapy prior to onset of ototoxicity is a confounding variable. While, based on our series, ototoxicity can arise in absence of prior radiotherapy, the potential interaction between intracranial radiation and ICI warrants further study.\n\nTo date, there have been a small number of reports of patients with isolated hearing loss after receiving ICI for cancer therapy.6–8 In two reports of patients treated for melanoma, symptoms of bilateral high-frequency SNHL, corroborated by audiometry, developed within 6 weeks of initiating ICI,6 7 showing a similar acute time course to the majority of patients in our series. In a separate four-patient case series, ICIs caused a cochleovestibular toxicity in which patients had dizziness and ataxia with or without accompanying hearing loss.8 Thus, those who develop ototoxicities from ICIs may exhibit a broad spectrum of symptoms based on current reports, including ours. Last, several reports have documented ototoxicity as part of a spectrum disorder known as VKH in patients with melanoma or non-small cell lung cancer treated with ICIs, where the diagnosis largely hinged on pathognomonic fundoscopic findings.10–12 Thus, it is important to distinguish between isolated hearing changes and hearing changes as part of a collective syndrome in those with suspected ICI-mediated toxicity, and to institute appropriate management. We did not specifically evaluate ototoxicity in non-melanoma patients. However, within our institution, to our knowledge, we have not identified a non-melanoma patient treated with ICI who developed isolated ototoxicity. That being said, as noted in case series by Lemasson et al, two of their four patients with ICI-mediated ototoxicity were being treated for NSCLC,8 suggesting that this toxicity is not restricted to melanoma.\n\nThe mechanisms underlying the development of ICI-mediated ototoxicity are currently unknown. Preclinical rat models of ICI-mediated ototoxicity demonstrated significant differences in auditory brainstem responses (ABR) in those treated with ICIs vs controls, as well as pathologic evidence of a reduction in the outer hair cells and flattening of the organ of Corti in those treated with ICI.19 Interestingly, ototoxicity has also been reported from adoptive cell therapy for melanoma.20 The proposed mechanism of this toxicity involves auto-antigenicity against melanocyte specific antigens such as MART-1 present in the inner ear, uvea and epithelium of the skin.21\n\nMost cases of otologic toxicity in cancer care are associated with cisplatin-based chemotherapy.22 Similar to our observed cases of ICI-mediated ototoxicity in this series, patients who develop cisplatin-induced ototoxicity present with slowly progressive SNHL. Learning from this phenomenon, these changes may be missed on standard audiograms and warrant consideration for ultrahigh frequency audiometry in consultation with an otolaryngologist, in selected cases where high-frequency hearing loss is suspected but not detected on standard clinical audiogram.23 We know that chemotherapy-induced ototoxicity is dose-dependent, due to direct damage of cochlear hair cells from reactive oxygen species,24 and is usually permanent.25 However, the relationship between ICI dose and ototoxicity as well as long-term outcomes are unknown.\n\nThis series has several limitations. As a single-institution retrospective report, we recognize that identification of cases may be subject to both selection and recall bias and may not represent the experience of other centers. A lack of baseline audiograms for each patient created challenges for distinguishing between age-related hearing loss and treatment specific changes on post-ICI audiometry. Additionally, it may have been helpful to have brain imaging at the time otologic symptom development in all cases to definitively rule out intracranial cancer progression.\n\nIn summary, we report the largest case series of patients with metastatic melanoma who developed ototoxicity in association with ICI therapy. Our report and others serve to highlight bilateral SNHL and tinnitus as the most prominent clinical features of this irAE. Based on our findings, treating oncologists should consider asking patients about hearing loss, tinnitus and/or ear fullness during ICI therapy. Among patients who develop hearing loss or tinnitus, brain MRI and subspecialist otolaryngology evaluation is warranted, including high-frequency audiometry with speech reception thresholds, word recognition ability and tympanometry to assess for middle ear disease. Both brain MRI and audiology are key in making this diagnosis, helping to rule out intracranial metastatic disease and quantify the severity of dysfunction.\n\nIn selected patients, with severe and functionally limiting symptoms, administration of corticosteroids may provide symptom improvement. Otherwise, hearing aid placement may be recommended. The decision of whether to hold or permanently discontinue ICI is difficult and requires further multidisciplinary discussion before providing exact guidance. Such a decision would involve weighing the severity of ototoxicity, clinical benefit they are receiving from ICI and the potential reversibility of their toxicity. Based on a small case series, it is hard to assess the utility and cost-effectiveness of obtaining baseline audiograms for all patients prior to initiating ICI but is certainly a topic worth studying, to help capture a more precise incidence and characterization of this toxicity. Larger, collaborative multidisciplinary studies conducted by oncologists, otolaryngologists and audiologists are needed to estimate the incidence of this phenomenon and explore optimal approaches for diagnosis and management.\n\nTwitter: @DrJNaidoo\n\nEL and JN contributed equally.\n\nContributors: EL: Bloomberg∼Kimmel Institute for Cancer Immunotherapy, the Barney Family Foundation, Moving for Melanoma of Delaware, The Laverna Hahn Charitable Trust and the National Cancer Institute P30 CA006973. JN: Bloomberg∼Kimmel Institute for Cancer Immunotherapy.\n\nFunding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.\n\nCompeting interests: EL: Institutional research grant funding from Bristol-Myers Squibb, Merck, and Regeneron. Consultant for Array BioPharma, Bristol-Myers Squibb, EMD Serono, MacroGenics, Novartis, Merck, Regeneron, Sanofi Genzyme. JN: Research Grant: Bristol-Myers Squibb, Merck, AstraZeneca; Consultant: Bristol-Myers Squibb, AstraZeneca, Roche/Genentech; Honoraria: Bristol-Myers Squibb, Merck, AstraZeneca.\n\nPatient consent for publication: Obtained.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n1 Larkin J , Chiarion-Sileni V , Gonzalez R , et al \nFive-Year survival with combined nivolumab and ipilimumab in advanced melanoma\n. N Engl J Med \n2019 ;381 :1535 –46\n. 10.1056/NEJMoa1910836 31562797 \n2 Hellmann MD , Paz-Ares L , Bernabe Caro R , et al \nNivolumab plus ipilimumab in advanced non-small-cell lung cancer\n. N Engl J Med \n2019 ;381 :2020 –31\n. 10.1056/NEJMoa1910231 31562796 \n3 Motzer RJ , Tannir NM , McDermott DF , et al \nNivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma\n. 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JAMA Oncol \n2019 ;5 :906 –8\n. 10.1001/jamaoncol.2019.0046 30998826 \n16 Suresh K , Psoter KJ , Voong KR , et al \nImpact of checkpoint inhibitor pneumonitis on survival in NSCLC patients receiving immune checkpoint immunotherapy\n. J Thorac Oncol \n2019 ;14 :494 –502\n. 10.1016/j.jtho.2018.11.016 30503891 \n17 Jereczek-Fossa BA , Zarowski A , Milani F , et al \nRadiotherapy-Induced ear toxicity\n. Cancer Treat Rev \n2003 ;29 :417 –30\n. 10.1016/S0305-7372(03)00066-5 12972360 \n18 Tsao MN , Xu W , Wong RK , et al \nWhole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases\n. Cochrane Database Syst Rev \n2018 ;1 :CD003869 . 10.1002/14651858.CD003869.pub4 29365347 \n19 Kuzucu İhsan , Baklacı D , Guler İsmail , et al \nInvestigation of the ototoxic effect of pembrolizumab using a rat model\n. Cureus \n2019 ;11 :e6057. 10.7759/cureus.6057 31827988 \n20 Seaman BJ , Guardiani EA , Brewer CC , et al \nAudiovestibular dysfunction associated with adoptive cell immunotherapy for melanoma\n. Otolaryngol Head Neck Surg \n2012 ;147 :744 –9\n. 10.1177/0194599812448356 22597578 \n21 Plonka PM , Passeron T , Brenner M , et al \nWhat are melanocytes really doing all day long?\n\nExp Dermatol \n2009 ;18 :799 –819\n. 10.1111/j.1600-0625.2009.00912.x 19659579 \n22 Nagy JL , Adelstein DJ , Newman CW , et al \nCisplatin ototoxicity: the importance of baseline audiometry\n. Am J Clin Oncol \n1999 ;22 :305 –8\n. 10.1097/00000421-199906000-00020 10362343 \n23 Singh Chauhan R , Saxena RK , Varshey S \nThe role of ultrahigh-frequency audiometry in the early detection of systemic drug-induced hearing loss\n. Ear Nose Throat J \n2011 ;90 :218 –22\n. 10.1177/014556131109000506 21563089 \n24 Rybak LP , Whitworth CA , Mukherjea D , et al \nMechanisms of cisplatin-induced ototoxicity and prevention\n. Hear Res \n2007 ;226 :157 –67\n. 10.1016/j.heares.2006.09.015 17113254 \n25 Frisina RD , Wheeler HE , Fossa SD , et al \nComprehensive audiometric analysis of hearing impairment and tinnitus after cisplatin-based chemotherapy in survivors of adult-onset cancer\n. J Clin Oncol \n2016 ;34 :2712 –20\n. 10.1200/JCO.2016.66.8822 27354478\n\n",
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"issue": "8(2)",
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"keywords": "case reports; immunotherapy; melanoma",
"medline_ta": "J Immunother Cancer",
"mesh_terms": "D000328:Adult; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D007167:Immunotherapy; D008297:Male; D008545:Melanoma; D008875:Middle Aged; D000081015:Ototoxicity",
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"title": "Immune-mediated ototoxicity associated with immune checkpoint inhibitors in patients with melanoma.",
"title_normalized": "immune mediated ototoxicity associated with immune checkpoint inhibitors in patients with melanoma"
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"abstract": "Minimizing IS to reduce side effects without compromising long-term renal transplant survival is the goal of all IS protocols. We conducted a retrospective study of pediatric renal transplants performed August 1988 to July 2008 and treated with two-drug maintenance therapy by one of three protocols: prednisone/cyclosporine without induction (SB) or with daclizumab induction (SBI), or tacrolimus/mycophenolate with daclizumab induction (SF). Kaplan-Meier survival curves were used to determine graft and patient survival at one, three, five, and 10 yr. Associations between graft survival and patient/transplant characteristics were determined using log-rank test and CPH model adjusting for treatment group. About 208 patients were included in the analysis (96 SB, 97 SBI, 15 SF; 148 DD, 60 LD, 37 pre-emptive). Overall graft and patient survival at one, three, five, and 10 yr were similar to the previously published results of pediatric renal transplants in similar years treated predominantly with three-drug maintenance therapy (https://web.emmes.com/study/ped/annlrept/2010). Only biopsy-proven TG was significantly associated with worse graft survival (HR 11.5, 95% CI: 3.4, 38.7). Malignancy rate was low (2.4%) with little PTLD (0.5%). Few opportunistic or other infections occurred (<5% patients). Minimizing IS to a two-drug maintenance regimen had no adverse effect on long-term transplant outcome and had low malignancy and infection rates.",
"affiliations": "Renal Section, Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA.;Dan L. Duncan Institute for Clinical and Translational Research, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA.;Renal Section, Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA.;Renal Section, Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA.",
"authors": "Michael|Mini|M|;Minard|Charles G|CG|;Kale|Arundhati S|AS|;Brewer|Eileen D|ED|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D000077561:Daclizumab; D009173:Mycophenolic Acid; D011241:Prednisone; D016559:Tacrolimus",
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"mesh_terms": "D000293:Adolescent; D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D001706:Biopsy; D002648:Child; D016572:Cyclosporine; D000077561:Daclizumab; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006085:Graft Survival; D006801:Humans; D007074:Immunoglobulin G; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D053208:Kaplan-Meier Estimate; D016030:Kidney Transplantation; D008297:Male; D015999:Multivariate Analysis; D009173:Mycophenolic Acid; D011241:Prednisone; D016016:Proportional Hazards Models; D051437:Renal Insufficiency; D012189:Retrospective Studies; D016559:Tacrolimus; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult",
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"title": "Outcomes of two-drug maintenance immunosuppression for pediatric renal transplantation: 10-yr follow-up in a single center.",
"title_normalized": "outcomes of two drug maintenance immunosuppression for pediatric renal transplantation 10 yr follow up in a single center"
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"abstract": "Psoriasis and vitiligo are 2 multifactorial immune-mediated diseases, partially sharing pathogenetic underpinnings. Their coexistence in the same patient, although uncommon, is documented in the literature. Further, several cases of vitiligo induced by biological drugs in psoriatic patients are reported. However, improvements in psoriasis and pre-existing vitiligo after the introduction of biological therapy are also described. To date, anti-TNF-alpha is the most cited group of biological drugs that induce new-onset vitiligo or progression of pre-existence vitiligo in psoriatic patients. Even anti-IL-12/23 class would seem to induce vitiligo (as in our case) or even worse it. Anti-IL-17 drugs induce a progression of pre-existing vitiligo while, to date, no cases are reported in literature considering anti-IL-23 class.",
"affiliations": "Section of Dermatology, DISSAL, University of Genoa, Ospedale-Policlinico San Martino, IRCCS, Genova, Italy.;Section of Dermatology, DISSAL, University of Genoa, Ospedale-Policlinico San Martino, IRCCS, Genova, Italy.;Section of Dermatology, DISSAL, University of Genoa, Ospedale-Policlinico San Martino, IRCCS, Genova, Italy.;Section of Dermatology, DISSAL, University of Genoa, Ospedale-Policlinico San Martino, IRCCS, Genova, Italy.",
"authors": "Burlando|Martina|M|;Muracchioli|Andrea|A|;Cozzani|Emanuele|E|;Parodi|Aurora|A|",
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"fulltext": "\n==== Front\nCase Rep Dermatol\nCase Rep Dermatol\nCDE\nCase Reports in Dermatology\n1662-6567\nS. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com\n\n10.1159/000514198\ncde-0013-0372\nCase and Review\nPsoriasis, Vitiligo, and Biologic Therapy: Case Report and Narrative Review\nBurlando Martina *\nMuracchioli Andrea\nCozzani Emanuele\nParodi Aurora\nSection of Dermatology, DISSAL, University of Genoa, Ospedale-Policlinico San Martino, IRCCS, Genova, Italy\n*Martina Burlando, martinaburlando@hotmail.com\nMay-Aug 2021\n16 7 2021\n16 7 2021\n13 2 372378\n5 12 2020\n3 1 2021\n2021\nCopyright © 2021 by S. Karger AG, Basel\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This 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.\nPsoriasis and vitiligo are 2 multifactorial immune-mediated diseases, partially sharing pathogenetic underpinnings. Their coexistence in the same patient, although uncommon, is documented in the literature. Further, several cases of vitiligo induced by biological drugs in psoriatic patients are reported. However, improvements in psoriasis and pre-existing vitiligo after the introduction of biological therapy are also described. To date, anti-TNF-alpha is the most cited group of biological drugs that induce new-onset vitiligo or progression of pre-existence vitiligo in psoriatic patients. Even anti-IL-12/23 class would seem to induce vitiligo (as in our case) or even worse it. Anti-IL-17 drugs induce a progression of pre-existing vitiligo while, to date, no cases are reported in literature considering anti-IL-23 class.\n\nKeywords\n\nPsoriasis\nVitiligo\nBiologic therapy\nNarrative review\n==== Body\nIntroduction\n\nSeveral cases of vitiligo induced by biological drugs in psoriatic patients are reported in the literature. However, improvements of pre-existing vitiligo after the introduction of biological therapy are also described. This relationship is not still clear. Based on the case of a young Italian male suffering from psoriasis, who developed a progression of a pre-existence vitiligo after treatment with ustekinumab, we explore the association between psoriasis, vitiligo, and biological therapy. We evaluated all the cases and studies reported in the literature, elaborating a narrative review to define, to date, which biological drugs are more involved in the progression/onset of vitiligo in the psoriatic patient.\n\nCase Report\n\nA 32-year-old male outpatient came for a visit in April 2008 in our Dermatology department for the worsening of his psoriasis. He has suffered from plaque psoriasis, localized at the genitalia, elbows, and scalp, since the age of 11. The patient was treated with various topical therapies without success and followed up regularly. In November 2012, vitiligo patches appeared in the subaxillary area and subsequently on the perioral area (shown in Fig. 1). The thyroid function was investigated and was normal; furthermore, celiac disease was excluded. Therapy with methotrexate (10 mg/week IM) followed by folic acid 24 h later was started in February 2016. After 24 months, it was suspended for intolerance and inefficacy. In April 2018, his clinical state worsened. The Psoriasis Area and Severity Index (PASI) was 15, while the hypopigmented patches were stable. Having appropriate screening exams, he started biologic therapy with ustekinumab (Stelara®) 90 mg SC (followed by injection after 4 weeks and every 12 weeks for maintenance). His psoriasis improved after 8 weeks (from PASI 15 to PASI 5) but a vitiligo patch appeared on the penis shaft (shown in Fig. 2a, b), close to the resolved psoriasis patches. After 6 months, the penis vitiligo patch increased (shown in Fig. 3) in size while the subaxillary patches remained unchanged. At the last control, performed 12 months later the hypopigmented lesions had stabilized.\n\nMethodology of the Literature Search\n\nLiterature searches in the PubMed database were conducted using the following search terms: “psoriasis” and “vitiligo” and ‘biologic therapy or “anti TNF-Alpha” or “anti IL-12/23” or “anti IL-17” or “anti IL-23” or “infliximab” or “adalimumab” or “etanercept” or “certolizumab pegol” or “ustekinumab” or “secukinumab,” or “ixekizumab” or “brodalumab” or “guselkumab.” The inclusion criterion was the English language. Articles not focused on psoriasis (i.e., biologic treatment not used to treat specifically psoriasis) were excluded.\n\nResults\n\nThe search yielded 10 publications, described as follows, and summarized in Table 1.\n\nVitiligo and Anti-TNF-Alpha Class\n\nSix articles reported vitiligo associated with TNF-alpha inhibitors in psoriatic patients. Adalimumab is the most represented drug and reported in 4 articles. Except for one paper by Campanati et al. [2] wherein vitiligo and psoriasis improved after 24 months of treatment with etanercept, all publications described new-onset vitiligo or a progression of a pre-existence vitiligo. Lu et al. [1] described a case of nonsegmental vitiligo that appeared following infliximab infusion. The disease has been regressing for 1 year after drug interruption. Palazzo [3] described the case of a patient who suffered from vitiligo in correspondence of the psoriatic lesions after the treatment with adalimumab which resolved in 1 year switching to secukinumab. Tirado-Sánchez and Bonifaz [4] reported a case of new-onset vitiligo and bullous pemphigoid disease associated with adalimumab treatment for psoriasis. Smith and Heffernan [5] reported a case of new-onset vitiligo (nonsegmental type) that appeared in correspondence of resolute psoriatic plaques after adalimumab therapy. The lesions remained stable during biological therapy.\n\nFor certolizumab pegol, 2 cases of de novo vitiligo are reported. The disease for which the patient used the drug is not indicated [8]. According to a cohort study [10], adalimumab and infliximab seem to be the anti-TNF-alpha inhibitors with the highest risk to develop vitiligo. Overall, in the literature, the use of anti TNF-alpha drugs in repigmentation is considered ineffective [11]. Until now, no case of golimumab-induced vitiligo has been reported.\n\nVitiligo and Anti-IL-12/23 Class\n\nData from the literature are limited and reported in only 3 papers. In fact, a case of vitiligo improvement was reported in a psoriatic patient treated with ustekinumab [7]. Instead, Mery-Bossard et al. [6] and Anthony et al. [8] reported, respectively, in 2 different studies, 18 total cases of ustekinumab-induced vitiligo and one case of drug-induced worsening vitiligo. In both papers, the patient's disease is not specified.\n\nVitiligo and Anti-IL-17 Class\n\nSpeeckaert et al. [9] reported a study on 8 patients in which secukinumab were used to treat a nonsegmental form of vitiligo. A progression of the disease was observed in 7 patients, without any sign of repigmentation. Furthermore, the authors concluded that the use of anti-IL-17 was not likely to affect the pathogenetic mechanism of vitiligo, considering that IL-17 and Th17 lymphocytes do not participate in the cytotoxic destruction of melanocytes. Instead, the authors suggested that drugs acting on the differentiation imbalance of Th17 to Th17.1/Th1 lymphocytes would be more promising. No cases are reported for brodalumab and ixekizumab.\n\nVitiligo and Anti-IL-23 Class\n\nSo far, there are no published reports of vitiligo induced/worse by the anti-IL-23 class.\n\nDiscussion\n\nPsoriasis is an immune-mediated and multifactorial chronic inflammatory skin disease, with an estimated prevalence ranging from 0.51 to 11.43% in adults [12]. Data about the prevalence of vitiligo vary from 0.06 to 2.28% in the general population [12]. The prevalence of the association between these 2 diseases is not clear: it is considered a rare event, but probably, it is underestimated [12]. In fact, observational studies are very scarce, and data are inconsistent. In clinical practice, 2 conditions usually show this association: first, psoriasis and vitiligo are present at the same time in the same patient (the so-called immune patient); second, the appearance of vitiligo is the side effect of the drugs used to treat psoriasis. In the first case, psoriasis has a strong tendency to associate with other autoimmune/immune-mediated diseases. Data suggest that a patient during the lifetime has a 25% chance of developing vitiligo [13]. Similarly, psoriasis was found to be the second most associated comorbidity in patients with vitiligo [14]. These 2 disorders present a similar pathogenetic background: psoriasis and vitiligo are cell-mediated Th-1 diseases with increased TNF-alpha and interferon γ levels [15]. Also, both share the activation of the Th17 pathway [12]. So far, it is unknown which of the 2 concurrent pathologies appears first. They can appear in the same areas or can be localized in different sites. As reported in the study [14], in almost 47% of patients with both diseases the lesions were separated, as in our case, while 34% of patient's psoriasis plaques covered the vitiligo patches [15].\n\nRegarding vitiligo as a side effect, the literature is focused on the biological therapies and few cases are reported. Two scenarios are described: (1) vitiligo appears for the first time as a consequence of the onset of biological therapy (i.e., new-onset vitiligo) or (2) there is a pre-existence vitiligo that improves or worsens as a consequence of the biological treatment. This difference has an important prognostic value: in fact, the new-onset vitiligo shows a better outcome when the biological therapy is maintained [6]. Instead, regarding a pre-existence vitiligo, the use of some biological drugs can aggravate it, inducing a progression [6], as happened to our patient.\n\nConclusion\n\nThe relationship among psoriasis, vitiligo, and biological drugs is still unclear. Although data are limited, this narrative review of the literature seems to show the detrimental impact of anti-TNF-alpha treatment on vitiligo. The pathogenetic mechanisms by which this class can induce or improve vitiligo are unknown. It is difficult to understand how a molecule that blocks high levels of TNF-alpha can trigger the mechanisms underlying this phenomenon. It has been proposed that the long-term use of anti TNF-alpha could create a cytokines-imbalance favoring a certain type of cytokines background that would provoke vitiligo [10].\n\nHowever, it should be considered that this class of drug has been on market for the longest than other classes of biologics, and this could also explain these results. Anti-IL-12/23 drugs could be considered a trigger of vitiligo too. Except for one case reported [7], ustekinumab seems to induce vitiligo (as well as in our case) or even to worse it when it is pre-existing.\n\nThe use of anti-IL-17 seems to produce bad outcomes in pre-existing vitiligo. Conversely, the data about anti-IL-23 are scarce, possibly because this drug has been marketed only recently.\n\nThus, this review highlights the paucity of data on the link between psoriasis and vitiligo underlining the gaps of knowledge on this topic. Further studies aimed at highlighting the pathogenetic mechanisms underlying the 2 diseases are strongly needed.\n\nStatement of Ethics\n\nAll the procedures adopted in the present study were in respect to the ethical standards in the World Medical Association Declaration of Helsinki. The subject gave his written informed consent to publish the present case (including publication of images).\n\nConflict of Interest Statement\n\nThe authors have no conflicts of interest to declare.\n\nFunding Sources\n\nNo funding was received.\n\nAuthor Contributions\n\nMartina Burlando concept the design of the work, draft the work, and revising it critically. Andrea Muracchioli drafts the work and contributes to the conception and the design of the work, to the acquisition and the interpretation of data. Emanuele Cozzani and Aurora Parodi have provided general support, critical review, and approval of the article.\n\nFig. 1 Patches of vitiligo under the left axillary area appeared in November 2012. These lesions have remained unchanged until today.\n\nFig. 2 a Psoriasis plaques (yellow arrows) in the resolution phase, located on the foreskin and the right-side area of the penis shaft. b At the base of the penis shaft (blue arrow) can be observed a large patch of vitiligo and 2 hypopigmented small maculae. These lesions appeared after 8 weeks of ustekinumab injections.\n\nFig. 3 Increase in size of the vitiligo patch after 6 months. The lesion occupies a large part of the dorsal surface of the penis shaft.\n\nTable 1 The main results of the works (by author) analyzed are summarized in the table by the class of biological drug, the clinical aspect of vitiligo reported, pre-existing or new-onset form, and outcome\n\nAuthors\tBiological drug\tVitiligo form\tType vitiligo: new-onset vitiligo/pre-existing vitiligo\tOutcome\t\nAnti TNF-α\t\t\t\t\t\n Lu et al. [1]\tInfliximab\tNonsegmental vitiligo\tNew-onset vitiligo\tRegression of the disease after drug interruption\t\n Campanati et al. [2]\tEtanercept\tNonsegmental vitiligo\tPre-existing vitiligo\tImprovement of both psoriasis/vitiligo\t\n Palazzo [3]\tAdalimumab\tNonsegmental vitiligo\tNew-onset vitiligo\tImprovement of vitiligo after the suspension of the drug and introduction of secukinumab\t\n Tirado-Sánchez and Bonifaz [4]\tAdalimumab\tNonsegmental vitiligo\tNew-onset vitiligo\tProgression of the disease (including BP) after the reintroduction of the drug\t\n Smith and Heffernan [5]\tAdalimumab\tNonsegmental vitiligo\tNew-onset vitiligo\tVitiligo patches appeared in correspondence with previously psoriatic lesions. The disease remained stable\t\n Mery-Bossard et al. [6]\tCertolizumab pegol\tNot defined\tNew-onset vitiligo\tNot reported\t\nAnti-IL-12/23\t\t\t\t\t\n Amir et al. [7]\tUstekinumab\tNot reported\tPre-existing vitiligo\tImprovement of the disease\t\n Mery-Bossard et al. [6]\tUstekinumab\tLocalized\tPre-existing vitiligo\tStable/improvement of the disease\t\n Mery-Bossard et al. [6]\tUstekinumab\tLocalized\tThree cases of new-onset vitiligo\tNot reported\t\n Anthony et al. [8]\tUstekinumab\tNot reported\tFifteen cases of new-onset vitiligo\tNot reported\t\nAnti-IL-17\t\t\t\t\t\n Speeckaert et al. [9]\tSecukinumab\tNonsegmental vitiligo\tEight cases of pre-existing vitiligo\tWorsening of the disease\t\n Palazzo [3]\tSecukinumab\tNonsegmental vitiligo\tNew-onset vitiligo\tResolved\n==== Refs\nReferences\n\n1 Lu X Gao Y Ding Y Vitiligo in a patient receiving infliximab for chronic plaque psoriasis Dermatol Ther 2019 5 32 (3) e12917 30994249\n2 Campanati A Giuliodori K Ganzetti G Liberati G Offidani AM A patient with psoriasis and vitiligo treated with etanercept Am J Clin Dermatol 2010 11 (Suppl 1) 46 8 20586509\n3 Palazzo G Resolution of post-adalimumab vitiligo with secukinumab in a patient with psoriasis vulgaris Oxf Med Case Rep 2020 1 2020 (1) omz134\n4 Tirado-Sánchez A Bonifaz A Simultaneous bullous pemphigoid and vitiligo associated with adalimumab therapy in a patient with psoriasis vulgaris Indian Dermatol Online J 2020 Mar-Apr 11 (2) 229 31 32477986\n5 Smith DI Heffernan MP Vitiligo after the resolution of psoriatic plaques during treatment with adalimumab J Am Acad Dermatol 2008 2 58 (2 Suppl) S50 2 18191709\n6 Méry-Bossard L Bagny K Chaby G Khemis A Maccari F Marotte H New-onset vitiligo and progression of pre-existing vitiligo during treatment with biological agents in chronic inflammatory diseases J Eur Acad Dermatol Venereol 2017 1 31 (1) 181 6 27291924\n7 Elkady A Bonomo L Amir Y Vekaria AS Guttman-Yassky E Effective use of ustekinumab in a patient with concomitant psoriasis, vitiligo, and alopecia areata JAAD Case Rep 2017 11 3 (6) 477 9 28971137\n8 Anthony N Bourneau-Martin D Ghamrawi S Lagarce L Babin M Briet M Drug-induced vitiligo: a case/non-case study in Vigibase®, the WHO pharmacovigilance database Fundam Clin Pharmacol 2020 12 34 (6) 736 42 32246859\n9 Speeckaert R Mylle S van Geel N IL-17A is not a treatment target in progressive vitiligo Pigment Cell Melanoma Res 2019 11 32 (6) 842 7 31063266\n10 Bae JM Kim M Lee HH Kim KJ Shin H Ju HJ Increased risk of vitiligo following anti-tumor necrosis factor therapy: a 10-year population-based cohort study J Invest Dermatol 2018 4 138 (4) 768 74 29175284\n11 Alghamdi KM Khurrum H Taieb A Ezzedine K Treatment of generalized vitiligo with anti-TNF-α agents J Drugs Dermatol 2012 4 11 (4) 534 9 22453596\n12 Yen H Chi CC Association between psoriasis and vitiligo: a systematic review and meta-analysis Am J Clin Dermatol 2019 2 20 (1) 31 40 30317450\n13 Masood S Sajid S Jafferani A Tabassum S Ansar S Multiple autoimmune syndromes associated with psoriasis: a rare clinical presentation Oman Med J 2014 3 29 (2) 130 1 24715941\n14 Sheth VM Guo Y Qureshi AA Comorbidities associated with vitiligo: a ten-year retrospective study Dermatology 2013 227 (4) 311 5 24107643\n15 Sandhu K Kaur I Kumar B Psoriasis and vitiligo J Am Acad Dermatol 2004 7 51 (1) 149 50 15243545\n\n",
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"title": "Psoriasis, Vitiligo, and Biologic Therapy: Case Report and Narrative Review.",
"title_normalized": "psoriasis vitiligo and biologic therapy case report and narrative review"
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... |
{
"abstract": "Intravenous zolendronic acid is an established anti-resorptive treatment for post-menopausal osteoporosis and is usually well tolerated. Common side effects, including the classical 'acute phase response', are consented for prior to treatment. However, rare but serious adverse reactions to zolendronic acid have been described. We report the case of an older patient with osteoporosis and osteoarthritis who presented within 12 hours of her first zolendronic acid infusion with evidence of a severe acute polyarthritis affecting her peripheral appendicular skeleton, in joints affected by pre-existing osteoarthritis. Despite the prevalence of osteoarthritis, this is the most severe case of polyarthritis following intravenous zolendronic acid to date and only the second reported case. We remind prescribing physicians treating patients with intravenous bisphosphonates, to bear in mind possible rare serious adverse reactions as well as common benign side effects. We postulate age-associated frailty may reduce tolerability to even milder acute phase reactions.",
"affiliations": "Consultant Geriatrician, Department of Medicine for the Elderly, Great Western Hospitals NHS Foundation Trust, Swindon, Wiltshire, UK.;Foundation Year 2 Trainee, Department of Medicine, Yeovil District Hospital, NHS Foundation, Yeovil, Somerset, UK.;Consultant Senior Lecturer and Orthogeriatrician, University of Bristol Musculoskeletal Unit, Avon Orthopaedic Centre, Southmead Hospital, Bristol & Royal United Hospital, Bath, UK.;Consultant Rheumatologist and Medical Director Royal National Hospital for Rheumatic Diseases, Bath & Senior Honorary Lecturer at the University of Bath, Bath, UK.",
"authors": "White|Sarah Louise|SL|;Jacob|Alyssa|A|;Gregson|Celia|C|;Bhalla|Ashok|A|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.11138/ccmbm/2015.12.1.069",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1724-8914",
"issue": "12(1)",
"journal": "Clinical cases in mineral and bone metabolism : the official journal of the Italian Society of Osteoporosis, Mineral Metabolism, and Skeletal Diseases",
"keywords": "acute phase reaction; osteoporosis; polyarthritis; zolendronic acid",
"medline_ta": "Clin Cases Miner Bone Metab",
"mesh_terms": null,
"nlm_unique_id": "101250935",
"other_id": null,
"pages": "69-74",
"pmc": null,
"pmid": "26136802",
"pubdate": "2015",
"publication_types": "D002363:Case Reports",
"references": "18057668;15606619;17032148;12947959;15095748;17476007;17491196;18203307;21305270;21887097;21986094;16645968;18095793;15956222;19118304;15248201;16755241;15258605;19936866;18488162;21701624;22366634;17516617;11920413;21047568;15710802;16314620;15550592;9556058;20554708;21508139;15965285;19040323;22753670;21116816;17627083;23986744;15028823;16332258;12963702;14573746;22105344;16547070;17308956;17878149;23115481",
"title": "Severe polyarthritis secondary to zolendronic acid: a case report and literature review.",
"title_normalized": "severe polyarthritis secondary to zolendronic acid a case report and literature review"
} | [
{
"companynumb": "GB-CIPLA LTD.-2016GB02568",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GLICLAZIDE"
},
"drugadditional": null,
... |
{
"abstract": "Background The onset of early and/or late seizures in brain injured patients is associated with worse outcome. So far, phenytoin is the most commonly used antiepileptic drug to prevent seizures in this group of patients. Objective In the current metaanalysis, we aimed to compare the efficacy and safety of phenytoin versus levetiracetam for seizure prophylaxis in brain injured patients. Methods A systematic search was conducted in PubMed and Cochrane Library Database by 2 investigators. Four randomized controlled trials (RCTs) were included (295 patients). Data were extracted and the quality of each RCT was assessed. Results Levetiracetam was found to be more effective than phenytoin in seizure prophylaxis (OR = 0.23; CI 95% [0.09-0.56]; Q test p value = 0.18 and I2 = 38%). A trend toward less serious side effects was also found in patients treated with levetiracetam (OR = 0.27; CI 95% [0.07-1.07]; Q test p value = 0.72 and I2 = 0%). Conclusion Levetiracetam is more effective and safer than phenytoin for seizure prophylaxis in brain injured patients.",
"affiliations": "King Hamad University Hospital, Muharraq, Bahrain. anischaari2004@yahoo.fr.;King Hamad University Hospital, Muharraq, Bahrain.;King Hamad University Hospital, Muharraq, Bahrain.;King Hamad University Hospital, Muharraq, Bahrain.;King Hamad University Hospital, Muharraq, Bahrain.",
"authors": "Chaari|Anis|A|http://orcid.org/0000-0003-4034-0176;Mohamed|Alaa Sayed|AS|;Abdelhakim|Karim|K|;Kauts|Vipin|V|;Casey|William Francis|WF|",
"chemical_list": "D000927:Anticonvulsants; D000077287:Levetiracetam; D010672:Phenytoin; D010889:Piracetam",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s11096-017-0507-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "39(5)",
"journal": "International journal of clinical pharmacy",
"keywords": "Efficacy; Levetiracetam; Phenytoin, Prophylaxis; Seizure; Side effects",
"medline_ta": "Int J Clin Pharm",
"mesh_terms": "D000927:Anticonvulsants; D001930:Brain Injuries; D006801:Humans; D000077287:Levetiracetam; D010672:Phenytoin; D010889:Piracetam; D056990:Post-Exposure Prophylaxis; D016032:Randomized Controlled Trials as Topic; D012640:Seizures",
"nlm_unique_id": "101554912",
"other_id": null,
"pages": "998-1003",
"pmc": null,
"pmid": "28780739",
"pubdate": "2017-10",
"publication_types": "D016428:Journal Article; D017418:Meta-Analysis; D016454:Review; D000078182:Systematic Review",
"references": "12915082;17511552;19169651;10386527;15662039;22642837;11441269;17431204;8520077;22738092;16833033;25208668;27416857;25511789;6358722;12958120;23986742;26746902;15159471;24489133;2115976;24277723;19898966;19797183;17228257;18162875;11564121;25437330;8721797;24761136;26454641;15335297;10722121;20067501;11580764;7496762;25738821",
"title": "Levetiracetam versus phenytoin for seizure prophylaxis in brain injured patients: a systematic review and meta-analysis.",
"title_normalized": "levetiracetam versus phenytoin for seizure prophylaxis in brain injured patients a systematic review and meta analysis"
} | [
{
"companynumb": "US-CIPLA LTD.-2017US15679",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nAntibodies to myelin oligodendrocyte glycoprotein (MOG) are detectable in inflammatory demyelinating CNS diseases, and MOG antibody-associated diseases seem to have a better prognosis despite occasionally severe presentations.\n\n\nMETHODS\nWe report the case of a 71-year-old patient with acute visual and gait disturbance that dramatically worsened to bilateral amaurosis, tetraplegia, and respiratory insufficiency within a few days.\n\n\nRESULTS\nMRI showed multiple progressive cerebral and spinal lesions with diffusion restriction (including both optic nerves) and marginal contrast enhancement. Routine blood and CSF measures including oligoclonal bands were normal. At disease onset, MOG immunoglobulin G was detected (serum titer 1:1,280, corresponding CSF titer was 1:20) and remained positive in patient serum. Aquaporin-4 antibodies were absent at disease onset but seroconverted to positive at week 9. In addition, CSF glial fibrillary acid protein and myelin basic protein levels were very high at onset but decreased during disease course. After 4 months, the patient died despite immunomodulatory treatment. Postmortem neuropathologic examination revealed an acute multiple sclerosis (MS) defined by multiple demyelinating lesions with a pronounced destructive component and loss of astrocytes. Lesion pattern of optic chiasm met MS pattern II characterized by antibody and complement-mediated demyelination.\n\n\nCONCLUSIONS\nThe case with the clinical presentation of an acute demyelinating encephalomyelitis with predominant optic and spinal involvement, absent oligoclonal bands, a histopathology of acute MS pattern II and development of aquaporin-4 antibodies extends the spectrum of MOG antibody-associated encephalomyelitis. Although, MOG antibodies are suspected to indicate a favorable prognosis, fulminant disease courses are possible and warrant an aggressive immunotherapy.",
"affiliations": "Clinical Department of Neurology (F.D.P., M.R., R.B., K.S., E.S., T.B.) and Department of Neuroradiology (P.R.), Medical University of Innsbruck; Institute of Neurology (R.H.) and Center for Brain Research (H.L.), Medical University of Vienna, Austria; and Departments of Neurology and Multiple Sclerosis Therapeutics (D.S., K.F.), Tohoku University Graduate School of Medicine, Sendai, Japan.;Clinical Department of Neurology (F.D.P., M.R., R.B., K.S., E.S., T.B.) and Department of Neuroradiology (P.R.), Medical University of Innsbruck; Institute of Neurology (R.H.) and Center for Brain Research (H.L.), Medical University of Vienna, Austria; and Departments of Neurology and Multiple Sclerosis Therapeutics (D.S., K.F.), Tohoku University Graduate School of Medicine, Sendai, Japan.;Clinical Department of Neurology (F.D.P., M.R., R.B., K.S., E.S., T.B.) and Department of Neuroradiology (P.R.), Medical University of Innsbruck; Institute of Neurology (R.H.) and Center for Brain Research (H.L.), Medical University of Vienna, Austria; and Departments of Neurology and Multiple Sclerosis Therapeutics (D.S., K.F.), Tohoku University Graduate School of Medicine, Sendai, Japan.;Clinical Department of Neurology (F.D.P., M.R., R.B., K.S., E.S., T.B.) and Department of Neuroradiology (P.R.), Medical University of Innsbruck; Institute of Neurology (R.H.) and Center for Brain Research (H.L.), Medical University of Vienna, Austria; and Departments of Neurology and Multiple Sclerosis Therapeutics (D.S., K.F.), Tohoku University Graduate School of Medicine, Sendai, Japan.;Clinical Department of Neurology (F.D.P., M.R., R.B., K.S., E.S., T.B.) and Department of Neuroradiology (P.R.), Medical University of Innsbruck; Institute of Neurology (R.H.) and Center for Brain Research (H.L.), Medical University of Vienna, Austria; and Departments of Neurology and Multiple Sclerosis Therapeutics (D.S., K.F.), Tohoku University Graduate School of Medicine, Sendai, Japan.;Clinical Department of Neurology (F.D.P., M.R., R.B., K.S., E.S., T.B.) and Department of Neuroradiology (P.R.), Medical University of Innsbruck; Institute of Neurology (R.H.) and Center for Brain Research (H.L.), Medical University of Vienna, Austria; and Departments of Neurology and Multiple Sclerosis Therapeutics (D.S., K.F.), Tohoku University Graduate School of Medicine, Sendai, Japan.;Clinical Department of Neurology (F.D.P., M.R., R.B., K.S., E.S., T.B.) and Department of Neuroradiology (P.R.), Medical University of Innsbruck; Institute of Neurology (R.H.) and Center for Brain Research (H.L.), Medical University of Vienna, Austria; and Departments of Neurology and Multiple Sclerosis Therapeutics (D.S., K.F.), Tohoku University Graduate School of Medicine, Sendai, Japan.;Clinical Department of Neurology (F.D.P., M.R., R.B., K.S., E.S., T.B.) and Department of Neuroradiology (P.R.), Medical University of Innsbruck; Institute of Neurology (R.H.) and Center for Brain Research (H.L.), Medical University of Vienna, Austria; and Departments of Neurology and Multiple Sclerosis Therapeutics (D.S., K.F.), Tohoku University Graduate School of Medicine, Sendai, Japan.;Clinical Department of Neurology (F.D.P., M.R., R.B., K.S., E.S., T.B.) and Department of Neuroradiology (P.R.), Medical University of Innsbruck; Institute of Neurology (R.H.) and Center for Brain Research (H.L.), Medical University of Vienna, Austria; and Departments of Neurology and Multiple Sclerosis Therapeutics (D.S., K.F.), Tohoku University Graduate School of Medicine, Sendai, Japan.;Clinical Department of Neurology (F.D.P., M.R., R.B., K.S., E.S., T.B.) and Department of Neuroradiology (P.R.), Medical University of Innsbruck; Institute of Neurology (R.H.) and Center for Brain Research (H.L.), Medical University of Vienna, Austria; and Departments of Neurology and Multiple Sclerosis Therapeutics (D.S., K.F.), Tohoku University Graduate School of Medicine, Sendai, Japan.;Clinical Department of Neurology (F.D.P., M.R., R.B., K.S., E.S., T.B.) and Department of Neuroradiology (P.R.), Medical University of Innsbruck; Institute of Neurology (R.H.) and Center for Brain Research (H.L.), Medical University of Vienna, Austria; and Departments of Neurology and Multiple Sclerosis Therapeutics (D.S., K.F.), Tohoku University Graduate School of Medicine, Sendai, Japan.",
"authors": "Di Pauli|Franziska|F|;Höftberger|Romana|R|;Reindl|Markus|M|;Beer|Ronny|R|;Rhomberg|Paul|P|;Schanda|Kathrin|K|;Sato|Douglas|D|;Fujihara|Kazuo|K|;Lassmann|Hans|H|;Schmutzhard|Erich|E|;Berger|Thomas|T|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1212/NXI.0000000000000175",
"fulltext": "\n==== Front\nNeurol Neuroimmunol NeuroinflammNeurol Neuroimmunol NeuroinflammnnnNEURIMMINFLNeurology® Neuroimmunology & Neuroinflammation2332-7812Lippincott Williams & Wilkins Hagerstown, MD NEURIMMINFL201500725210.1212/NXI.000000000000017540414244132ArticleFulminant demyelinating encephalomyelitis Insights from antibody studies and neuropathologyDi Pauli Franziska MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nBiogen idec, funding for travel to conference and speaker honoraria Genzyme, funding for travel to conference and speaker honoraria\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nHöftberger Romana MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nReindl Markus PhDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nPLOS ONE, academic editor, 2012-Current Medicinal Chemistry, editorial board, 2006-2012 Autoimmune Diseases, 2012-2013\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nThe University Hospital and Medical University of Innsbruck (Austria, Markus Reindl) receive payments for antibody assays (NMDAR, AQP4 and other autoantibodies) and for AQP4 antibody validation experiments organized by Euroimmun.\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\n(1) This study was supported by a research grant from the Austrian Federal Ministery of Science and Economy (grant BIG WIG MS).\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nBeer Ronny MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\n(1) Austrian Science Fund, KLI 375-B00, Principal Investigator, 2014-2016.\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nRhomberg Paul MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nSchanda Kathrin MScScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nSato Douglas MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nSpeaker honoraria from Novartis\n\n\n\nEditorial Boards:\nAssociate editor of Arquivos de Neuropsiquiatria (2013-present)\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\n(1) Ministry of Education, Culture, Sports, Science & Technology (MEXT) in Japan, Japanese Government Scholarship Program, 4 years (2010 - 2014)\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\n(1) Grant-in-aid for scientific research from the Japan Society for the Promotion of Science (KAKENHI 15K19472) (2) Research support from CAPES/Brasil (88881.068012/2014)\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nFujihara Kazuo MDScientific Advisory Boards:\nServes on scientific advisory boards for Bayer Schering Pharma, Biogen Idec, Mitsubishi Tanabe Pharma Corporation, Novartis Pharma, Chugai Pharmaceutical, Ono Pharmaceutical, Nihon Pharmaceutical, Merck Serono, Alexion Pharmaceuticals, Medimmune and Medical Review.\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nhas received funding for travel and speaker honoraria from Bayer Schering Pharma, Biogen Idec, Eisai Inc., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma, Astellas Pharma Inc., Takeda Pharmaceutical Company Limited, Asahi Kasei Medical Co., Daiichi Sankyo, and Nihon Pharmaceutical.\n\n\n\nEditorial Boards:\nServe as an editorial board member of Clinical and Experimental Neuroimmunology (2009-present) and a advisory board member of Sri Lanka journal of Neurology.\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nhas received research support from Bayer Schering Pharma, Biogen Idec Japan, Asahi Kasei Medical, The Chemo-Sero-Therapeutic Research Institute, Teva Pharmaceutical, Mitsubishi Tanabe Pharma, Teijin Pharma, Chugai Pharmaceutical,Ono Pharmaceutical, Nihon Pharmaceutical, and Genzyme Japan.\n\n\n\nResearch Support, Government Entities:\nfunded as the investigator (2010?present) by the Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Technology of Japan and as the secondary investigator by the Grants-in-Aid for Scientific Research from the Ministry of Health, Welfare and Labor of Japan (2010?present).\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nLassmann Hans MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nI have received speaker and travel honoraria for several scientific meetings from Biogen Idec, Novartis and Teva.\n\n\n\nEditorial Boards:\nI am member of the Editorial Board of several Journals in the fields of Neurology and Neuroscience.\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nI have served as a consultant for Biogen Idec and AMGEN.\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nAustrian Science Fund, Projects P19854, P 24245;principal investigator; 2007-2012 European Union FP7 Project Neuroprmise Pl 018637 2007-2011; Subproject; E-Rare Project EDEN; 2011-2014; subproject This funding is not directly related to the respective article\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nSchmutzhard Erich MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nUCB and ZOLL Medical: speaker honoraria\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nBerger Thomas MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nFrom the Clinical Department of Neurology (F.D.P., M.R., R.B., K.S., E.S., T.B.) and Department of Neuroradiology (P.R.), Medical University of Innsbruck; Institute of Neurology (R.H.) and Center for Brain Research (H.L.), Medical University of Vienna, Austria; and Departments of Neurology and Multiple Sclerosis Therapeutics (D.S., K.F.), Tohoku University Graduate School of Medicine, Sendai, Japan.Correspondence to Dr. Berger: thomas.berger@i-med.ac.atFunding information and disclosures are provided at the end of the article. Go to Neurology.org/nn for full disclosure forms. The Article Processing Charge was paid by authors.\n\n04 11 2015 12 2015 04 11 2015 2 6 e17528 7 2015 18 9 2015 © 2015 American Academy of Neurology2015American Academy of NeurologyThis is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially.Objectives:\nAntibodies to myelin oligodendrocyte glycoprotein (MOG) are detectable in inflammatory demyelinating CNS diseases, and MOG antibody–associated diseases seem to have a better prognosis despite occasionally severe presentations.\n\nMethods:\nWe report the case of a 71-year-old patient with acute visual and gait disturbance that dramatically worsened to bilateral amaurosis, tetraplegia, and respiratory insufficiency within a few days.\n\nResults:\nMRI showed multiple progressive cerebral and spinal lesions with diffusion restriction (including both optic nerves) and marginal contrast enhancement. Routine blood and CSF measures including oligoclonal bands were normal. At disease onset, MOG immunoglobulin G was detected (serum titer 1:1,280, corresponding CSF titer was 1:20) and remained positive in patient serum. Aquaporin-4 antibodies were absent at disease onset but seroconverted to positive at week 9. In addition, CSF glial fibrillary acid protein and myelin basic protein levels were very high at onset but decreased during disease course. After 4 months, the patient died despite immunomodulatory treatment. Postmortem neuropathologic examination revealed an acute multiple sclerosis (MS) defined by multiple demyelinating lesions with a pronounced destructive component and loss of astrocytes. Lesion pattern of optic chiasm met MS pattern II characterized by antibody and complement-mediated demyelination.\n\nConclusion:\nThe case with the clinical presentation of an acute demyelinating encephalomyelitis with predominant optic and spinal involvement, absent oligoclonal bands, a histopathology of acute MS pattern II and development of aquaporin-4 antibodies extends the spectrum of MOG antibody–associated encephalomyelitis. Although, MOG antibodies are suspected to indicate a favorable prognosis, fulminant disease courses are possible and warrant an aggressive immunotherapy.\n\nOPEN-ACCESSTRUE\n==== Body\nAcute inflammatory demyelinating syndromes of the CNS comprise heterogeneous diseases such as multiple sclerosis (MS), neuromyelitis optica (NMO), and acute disseminated encephalomyelitis (ADEM) with different pathogenesis, severity, prognosis, disease course, and treatment options.1 Diagnosis, based on clinical examination, neuroimaging, as well as CSF examination2 might be challenging, and reliable biomarkers are—except for NMO3—still missing. Although biopsy is only rarely performed to exclude other treatable differential diagnoses, neuropathologic characteristics of different MS patterns, ADEM, and NMO are well known4 and facilitate the diagnosis of different demyelinating CNS diseases.5 However, since the initial clinical assessment does not always correlate with the final diagnosis, less invasive markers are necessary to identify different diseases or disease patterns.\n\nIn addition to antibodies to aquaporin-4 (AQP4) in NMO, myelin oligodendrocyte glycoprotein (MOG), a cell surface protein of myelin sheaths and oligodendrocytes in the CNS, is an important and extensively studied target structure of immunoreactivity in CNS demyelinating diseases.6 Measured by cell-based assay, MOG antibodies are predominately found in children with CNS demyelinating diseases.7–11 However, MOG antibodies have also been described in adults with ADEM, in anti-AQP4 antibody–negative NMO cases,12,13 and in patients with anti-NMDA receptor encephalitis with demyelination.14\n\nHerein, we report the postmortem neuropathologic examination of a patient with an acute demyelinating fatal CNS disease and antibodies against MOG.\n\nCASE REPORT\nClinical course.\nA 71-year-old male patient with a current history of bronchial asthma and arterial hypertension complained of acute bilateral vision and gait disturbance in August 2013. Initial assessment, performed at an external hospital, included cerebral MRI and lumbar puncture. CSF analysis including oligoclonal bands was normal. Cerebral and spinal MRI showed multiple supra- and infratentorial lesions with marked diffusion restriction, only slight hyperintensity on T2-weighted images (figures 1A, 2, A and D), and intramedullary lesions (figure 2B). Lesions marginally enhanced contrast (figure 2C). After admission, the patient's condition worsened dramatically to bilateral amaurosis within 2 days and tetraplegia within 5 days.\n\nFigure 1 Cerebral MRI during the disease course\nCerebral MRI with multiple cerebral supratentorial lesions during the disease course: periventricular lesions with diffusion restriction, only slight hyperintensity on T2-weighted images (A). Progressive diffusion restriction and now clearly hyperintense lesions on T2-weighted images 2 weeks after disease onset (B) and 4 weeks after disease onset (C). ADC = apparent diffusion coefficient.\n\nFigure 2 Cerebral and spinal MRI\n(A) Restricted diffusion of both optic nerves (arrows) on diffusion-weighted and apparent diffusion coefficient imaging. (B) Intramedullary lesions. (C) Marginal contrast enhancement at disease onset (arrows). (D) Brainstem lesions (arrows).\n\nSubsequently, the patient was referred to our neurologic intensive care unit for further diagnostics and treatment. Within 1 day, the patient's condition deteriorated again, and acute respiratory insufficiency necessitated mechanical ventilation.\n\nThe cerebral and spinal MRI showed progressive multiple cerebral supra- and infratentorial and spinal lesions. The lesions were now clearly hyperintense on T2-weighted images and were predominantly localized periventricular, in the brainstem and intramedullary. The MRI also demonstrated a restricted diffusion of both optic nerves (figure 2A). There was no evidence of any vascular pathology. Incidental findings were a frontotemporal meningioma and vertebrostenosis due to degenerative changes of spinal column (figure 2, B and C).\n\nA second CSF sample taken 1 week after disease onset now revealed inflammation with pleocytosis composed of lymphocytes and neutrophilic granulocytes, and increased permeability of the blood–brain barrier. Oligoclonal bands were absent. Routine laboratory findings including cell count of peripheral blood and inflammatory measures were normal. Further detailed laboratory investigations such as serologic analyses for potential infectious agents (including culture and PCR in blood and CSF) and several autoantibodies (such as anti-ganglioside and onconeural antibodies, thyroid antibodies, PR3 and MPO antineutrophil cytoplasmic antibodies, antiphospholipid antibodies) were negative. However, immunoglobulin G (IgG) MOG antibodies were positive in serum with a titer of 1:1,280 (IgG1 only with a titer of 1:640) and in CSF (titer 1:20), whereas AQP4 antibodies were absent at disease onset (figure 3). MOG and AQP4 antibodies were measured using a recombinant live cell-based immunofluorescence assay and an optimized tissue-based immunohistochemistry antibody assay as described before.12,13\n\nFigure 3 Antibody titers during the disease course\nTemporal dynamic of MOG and AQP4 antibodies and time points of MRI and CSF sampling. AQP4 = aquaporin-4; MOG = myelin oligodendrocyte glycoprotein.\n\nAn empiric antimicrobial combination therapy was initiated because of the differential diagnostic suspicion of an infectious cause. However, no treatment response was observed, and another cerebral MRI showed progressive findings 2 weeks after disease onset (figure 1B). Simultaneously, an immunomodulatory therapy with corticosteroids and IV immunoglobulins was started. Because the patient did not respond to the immune treatment as evidenced by repeated neuroimaging, a brain biopsy was performed. Corticosteroids were discontinued 3 weeks before biopsy. Histopathology showed small fragments of an actively demyelinating lesion with inflammatory infiltrates consisting of macrophages and CD3- and CD8-positive T cells (figure 4, A–C). There was no evidence of CD20-positive B cells (data not shown). One vessel in the periplaque white matter revealed perivascular complement deposition (figure 4D).\n\nFigure 4 Neuropathology of MOG and AQP4 antibody–associated demyelinating lesions in the brain\nThe biopsy specimen revealed a small actively demyelinating lesion (A, arrow in the magnified section indicates macrophages containing LFB-positive myelin degradation products) and inflammatory infiltrates composed of CD68-positive macrophages (B), and CD8-positive T cells (C). One vessel showed perivascular deposits of activated complement complex C9neo (D, arrows). The autopsy tissue showed confluent demyelinating lesions in the brain that were immunohistochemically characterized by loss of MBP (E, rectangle enlarged in H) but contained large preoligodendrocytes that strongly labeled for CNPase (F, rectangle enlarged in I) while MOG was almost negative (G, rectangle enlarged in J; lesion borders highlighted with dotted lines). The inflammatory infiltrates mainly contained CD3-positive (K) and CD8-positive (L) T cells and perivascular CD79a-positive B cells (M). The lesion in the optic chiasm showed perivascular deposits of activated complement complex C9neo (N, arrows) and was characterized by a destructive tissue injury with loss of astrocytes in the anti-AQP4 (O), AQP1 (P), and GFAP staining (Q). One plaque in the medulla oblongata showed a selective loss of AQP4 (R; lesion border highlighted with dotted lines) while AQP1 (S) and GFAP (T) were still preserved. The astrocytes in this lesion showed clasmatodendrosis with beading or loss of processes resulting in rounded astrocytes (T, magnified sections). Magnification: E–G: ×40; A and O–T: ×100; B–D: 200×; H–N and magnified section in T: 400×; magnified section in A: 600×. AQP = aquaporin; CNPase = 2',3'-cyclic-nucleotide 3'-phosphodiesterase; GFAP = glial fibrillary acid protein; LFB = Luxol fast blue; MBP = myelin basic protein; MOG = myelin oligodendrocyte glycoprotein.\n\nThe diagnostic findings suggested an acute demyelinating encephalomyelitis with predominantly optic and spinal involvement associated with MOG antibodies.\n\nIn the following 3 months of continuous hospitalization, repeated MRI, CSF, and laboratory analyses were performed. All MRI controls (from September to December 2013) showed a stable lesion load without any contrast enhancement (MRI 4 weeks after disease onset, figure 1C). CSF cell counts continuously decreased to normal ranges in December 2013. Serial serum MOG antibody testing was conducted at weeks 1, 4, 6, 8, 9, and 14 after disease onset. At 4 weeks, serum MOG antibody titer had decreased to 1:640 and at 14 weeks to 1:80 (figure 3). CSF MOG antibodies (available at disease onset and at weeks 1, 4, 9, and 14) were detectable at onset with a titer of 1:20, at week 1 (1:20), and week 4 (1:4) and were negative at weeks 9 and 14. Subclass analyses of IgG 1–4 revealed that the antibodies belonged to the IgG1 subgroup. Furthermore, only at disease onset, IgM MOG antibodies were present at a titer of 1:160. Serum AQP4 antibodies were absent at disease onset but seroconverted to low-titer positive at week 9 (titer 1:40; IgG1 subclass only; figure 3) by cell-based immunofluorescence assay and were negative using tissue immunohistochemistry. CSF AQP4 antibodies were negative at all time points. The patient was negative for AQP1 antibodies at all time points.\n\nCSF glial fibrillary acid protein (GFAP) and myelin basic protein (MBP) levels were retrospectively analyzed by Sato and colleagues at disease onset, week 4, and week 9 as described before.15 Initial levels of GFAP and MBP were very high at 152,492 and 3,709 ng/mL, respectively; CSF GFAP levels decreased in week 4 to 709 ng/mL, whereas CSF MBP levels firstly increased to 7,224 ng/mL. In week 9, both CSF GFAP and MBP levels clearly declined to 12 and 291 ng/mL, respectively.\n\nApart from stable or even improved laboratory and imaging findings, the clinical condition of the patient with amaurosis and tetraplegia was unchanged and required continuous mechanical ventilation. Because of the prolonged clinical course without any functional improvements, treatment was switched to comfort therapy according to the patient's living will. The patient died at the end of December, 2013, and an autopsy was performed.\n\nNeuropathology.\nPostmortem examination of the brain revealed multiple demyelinating lesions in optic chiasm, cerebrum, and brainstem. The cerebrum showed multiple confluent chronic inactive demyelinated plaques with well-demarcated lesion borders (figure 4, E–G) and relatively better preserved axons (data not shown). The plaques were characterized by an absence of myelin in the Luxol fast blue, anti-PLP (data not shown), and anti-MBP staining (figure 4H) but contained abundant large preoligodendrocytes that strongly labeled for CNPase (figure 4I) while MOG was almost negative (figure 4J). Cortical plaques were not visible. The inflammatory infiltrates mainly contained CD3- and CD8-positive T cells (figure 4, K and L), and perivascular CD20- and CD79a-positive B cells (figure 4M). The optic chiasm showed demyelination with residual lesion activity with perivascular complement deposition (figure 4N) and was characterized by destructive tissue injury with tissue rarefaction and severe loss of astrocytes in the anti-AQP4, AQP1, and GFAP staining (figure 4, O–Q). One plaque in the medulla oblongata was characterized by selective loss of AQP4 (figure 4R) while AQP1 and GFAP were still preserved (figure 4, S–T). The astrocytes in this lesion showed clasmatodendrosis with beading or loss of cellular processes resulting in rounded astrocytes (figure 4T, magnified sections). Activated complement deposition was not found in these areas.\n\nDISCUSSION\nWe report the case of an acute fatal CNS demyelinating disease with MOG antibodies and postmortem neuropathologic examination. The case shared clinical, imaging, and laboratory features of different demyelinating diseases. Clinically, the patient had an acute inflammatory demyelinating disease with predominant involvement of optic nerves and spinal cord. The older age of the patient is unusual. However, several cases with acute CNS demyelinating diseases in this age group were described before.16,17 Cerebral and spinal MRI showed lesions of both optic nerves and a longitudinally extensive transverse myelitis compatible with the diagnosis of NMO. However, since there were additional multiple brain lesions with gadolinium enhancement and a negative AQP4 antibody status at disease onset, the 2013 criteria as well as the new, recently published diagnostic criteria of NMO were not met.18,19 Other potential differential diagnoses of our case were ADEM and MS. In children, diagnostic criteria for ADEM require a demyelinating polyfocal CNS event accompanied by encephalopathy and typical MRI alterations,20 whereas widely accepted ADEM diagnostic criteria in adults are lacking.21 In our case, the presence of periventricular T1 hypointense lesions, which are useful to distinguish ADEM from MS,22,23 argued against diagnosis of ADEM.\n\nFulminant clinical course, imaging findings, and absence of oligoclonal bands are also not typical for MS and current diagnostic criteria of a relapsing remitting or primary progressive MS were not met.2\n\nHowever, neuropathology revealed features of acute MS characterized by destructive lesions with typical hallmarks of pattern II demyelination24: well-demarcated demyelinating lesions were characterized by T cell–mediated inflammation, absence of myelin, preserved axons, and complement deposits. Similar to our case, the clinical presentation may lead to the misdiagnosis of ADEM, as it has been shown that 9% of patients with a clinical diagnosis of ADEM had in contrast to ADEM with typical perivenous demyelination, confluent demyelination in histopathology and revealed clinically definite MS in the follow-up.25\n\nIn our case, inflammatory infiltrates were composed of CD68-positive macrophages and CD3- and CD8-positive T cells in accordance with pattern II demyelination.24 In contrast to pattern I, the presence of immunoglobulins and complement is a typical finding and indicates the important role of the humoral immune response. The diagnosis of the case presented here was complicated by the fact that both early MOG and late AQP4 antibodies were detected. MOG antibodies were recently shown to be present in a subgroup of AQP4 antibody–negative NMO cases.12,26 In addition, they have been found in different CNS demyelinating diseases such as ADEM,7,11,27,28 optic neuritis, transverse myelitis, recurrent optic neuritis,29,30 and a subgroup of anti-NMDA receptor encephalitis with signs of demyelination.14 In MOG antibody–positive ADEM cases, NMO typical sites of demyelination (such as longitudinally extensive transverse myelitis/recurrent optic neuritis) seem to be involved more often than in MOG antibody–negative cases.31,32 The disease course of this patient was fulminant without any signs of improvement and finally fatal. In other studies, MOG antibodies were associated with a more favorable disease outcome,13,26,33 although patients with antibodies occasionally have severe acute presentations.9 Because of the possible differential diagnosis of an infectious disease, start of immunomodulatory treatment was delayed and no treatment escalation was induced. These factors in combination with the older age of the patient may have been relevant for the poor outcome.\n\nMOG antibody–positive patients with demyelinating diseases in whom histopathologic results of a biopsy were available are rare,34,35 and in accordance with our case, pathology showed MS findings of pattern II. Furthermore, in the present case and another case,34 antibodies mainly belong to the IgG1 subclass with the capability to bind complement. Since MOG was identified as a potential target of antibodies in MS and experimental autoimmune encephalomyelitis,36 a MOG-specific immunoreactivity in the group of MOG antibody–associated encephalomyelitis seems likely. Although bystander activation cannot be completely excluded, the high immunoreactivity at disease onset and histopathologic evidence of an antibody-mediated disease mechanism supports the hypothesis of a primary involvement of MOG antibodies in disease pathogenesis.\n\nBesides MOG antibodies, our patient also developed AQP4 antibodies and lesions with complement activation and AQP4 loss, indicating AQP4-mediated NMO pathology.37 Coexistence of AQP4 and MOG antibodies is very rare; only single cases are described in literature.12,13,33,38 The temporal dynamics of antibodies to AQP4 (first detectable after 9 weeks) and MOG (high titer at disease onset) might indicate that the immune response to AQP4 developed secondary to the release of a new antigen(s). However, severe loss of astrocytes in optic chiasm and selective loss of AQP4 in one brainstem lesion suggests, in addition to the loss of myelin per se, a pathogenic relevant immunoreaction against astrocytes, although typical pathologic findings of NMO were missing. Furthermore, the initial elevation of GFAP as well as MBP levels, markers for astrocyte and myelin damage, respectively, supports a coexisting injury of myelin and astrocytes early at disease onset. A possible explanation for the high GFAP levels at disease onset instead of negative AQP4 antibodies is that AQP4 antibodies were bound to sites of inflammation and not detectable in serum, as described in a patient with very large and fulminant NMO lesions in whom serum AQP4 antibody titers decreased and accumulated in the corresponding CNS lesion.39 Finally, it is also possible that 2 different pathogenic processes associated with MOG and AQP4 antibodies overlapped in a single patient as has been demonstrated in a subgroup of patients with anti-NMDA receptor encephalitis and demyelinating syndromes with MOG or AQP4 antibodies14 or the co-occurrence of antibodies to MOG and the glycine receptor α1 subunit in patients with isolated optic neuritis.40\n\nIn different clinical presentations, MOG antibodies are detectable and MOG antibody–associated diseases seem to be related to an MS pattern II pathology. These findings elucidate the upcoming spectrum of MOG antibody–associated diseases and importantly contribute to the understanding of their pathogenic mechanism.\n\nAUTHOR CONTRIBUTIONS\nCase analysis: F.D.P., R.B., E.S., T.B. Neuropathology: R.H., H.L. Antibody analysis: M.R., K.S. MRI: P.R. GFAP and MBP measurements: D.S., K.F. Wrote the manuscript: F.D.P., M.R.\n\nSTUDY FUNDING\nThis study was supported by a research grant from the Austrian Federal Ministry of Science and Economy (grant BIG WIG MS).\n\nDISCLOSURE\nF. Di Pauli received travel funding and/or speaker honoraria from Biogen Idec and Genzyme. R. Höftberger reports no disclosures. M. Reindl is an academic editor for PLOS ONE, is on the editorial board for Current Medicinal Chemistry and Autoimmune Diseases, and received research support from the Austrian Federal Ministry of Science and Economy. The University Hospital and Medical University of Innsbruck receive payments for antibody assays (NMDA receptor, AQP4, and other autoantibodies) and for AQP4 antibody validation experiments organized by Euroimmun. R. Beer received research support from Austrian Science Fund. P. Rhomberg and K. Schanda report no disclosures. D. Sato received speaker honoraria from Novartis, is an associate editor for Arquivos de Neuropsiquiatria, and received research support from the Ministry of Education, Culture, Sports, Science & Technology in Japan, Japanese Government Scholarship Program, Japan Society for the Promotion of Science, and CAPES/Brasil. K. Fujihara is on the scientific advisory board for Bayer Schering Pharma, Biogen Idec, Mitsubishi Tanabe Pharma Corporation, Novartis, Chugai Pharmaceutical, Ono Pharmaceutical, Nihon Pharmaceutical, Merck Serono, Alexion Pharmaceuticals, MedImmune, and Medical Review, received travel funding and speaker honoraria from Bayer Schering Pharma, Biogen Idec, Eisai Inc., Mitsubishi Tanabe Pharma Corporation, Novartis, Astellas Pharma Inc., Takeda Pharmaceutical Company Limited, Asahi Kasei Medical Co., Daiichi Sankyo, and Nihon Pharmaceutical, is on the editorial board for Clinical and Experimental Neuroimmunology, is on the advisory board for Sri Lanka Journal of Neurology, received research support from Bayer Schering Pharma, Biogen Idec Japan, Asahi Kasei Medical, The Chemo-Sero-Therapeutic Research Institute, Teva Pharmaceutical, Mitsubishi Tanabe Pharma, Teijin Pharma, Chugai Pharmaceutical, Ono Pharmaceutical, Nihon Pharmaceutical, Genzyme Japan, Ministry of Education, Science and Technology of Japan, and the Ministry of Health, Welfare and Labor of Japan. H. Lassmann has received speaker honoraria and travel funding from Biogen Idec, Novartis, and Teva, is on the editorial board for several journals in the fields of neurology and neuroscience, has consulted for Biogen Idec and AMGEN, and received research support from the Austrian Science Fund and the European Union. E. Schmutzhard received speaker honoraria from UCB and ZOLL Medical. T. Berger reports no disclosures. Go to Neurology.org/nn for full disclosure forms.\n\nGLOSSARY\nADEMacute disseminated encephalomyelitis\n\nAQP4aquaporin-4\n\nGFAPglial fibrillary acid protein\n\nIgimmunoglobulin\n\nMBPmyelin basic protein\n\nMOGmyelin oligodendrocyte glycoprotein\n\nMSmultiple sclerosis\n\nNMOneuromyelitis optica\n==== Refs\nREFERENCES\n1. Karussis D \nThe diagnosis of multiple sclerosis and the various related demyelinating syndromes: a critical review . J Autoimmun \n2014 ;48–49 :134 –142 .\n2. 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Hoftberger R Sepulveda M Armangue T \nAntibodies to MOG and AQP4 in adults with neuromyelitis optica and suspected limited forms of the disease . Mult Scler \n2015 ;21 :866 –874 .25344373 \n14. Titulaer MJ Hoftberger R Iizuka T \nOverlapping demyelinating syndromes and anti-N-methyl-D-aspartate receptor encephalitis . Ann Neurol \n2014 ;75 :411 –428 .24700511 \n15. Takano R Misu T Takahashi T Sato S Fujihara K Itoyama Y \nAstrocytic damage is far more severe than demyelination in NMO: a clinical CSF biomarker study . Neurology \n2010 ;75 :208 –216 .20644148 \n16. Krumbholz M Hofstadt-van Oy U Angstwurm K \nVery late-onset neuromyelitis optica spectrum disorder beyond the age of 75 . J Neurol \n2015 ;262 :1379 –1384 .25957640 \n17. Collongues N Marignier R Jacob A \nCharacterization of neuromyelitis optica and neuromyelitis optica spectrum disorder patients with a late onset . Mult Scler \n2013 ;20 :1086 –1094 .24323817 \n18. Wingerchuk DM Lennon VA Pittock SJ Lucchinetti CF Weinshenker BG \nRevised diagnostic criteria for neuromyelitis optica . Neurology \n2006 ;66 :1485 –1489 .16717206 \n19. Wingerchuk DM Banwell B Bennett JL \nInternational consensus diagnostic criteria for neuromyelitis optica spectrum disorders . Neurology \n2015 ;85 :177 –189 .26092914 \n20. Krupp LB Tardieu M Amato MP \nInternational Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions . Mult Scler \n2013 ;19 :1261 –1267 .23572237 \n21. Koelman DL Mateen FJ \nAcute disseminated encephalomyelitis: current controversies in diagnosis and outcome . J Neurol \n2015 ;262 :2013 –2024 .25761377 \n22. Callen DJ Shroff MM Branson HM \nMRI in the diagnosis of pediatric multiple sclerosis . Neurology \n2009 ;72 :961 –967 .19038852 \n23. Verhey LH Branson HM Shroff MM \nMRI parameters for prediction of multiple sclerosis diagnosis in children with acute CNS demyelination: a prospective national cohort study . Lancet Neurol \n2011 ;10 :1065 –1073 .22067635 \n24. Lucchinetti C Bruck W Parisi J Scheithauer B Rodriguez M Lassmann H \nHeterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination . Ann Neurol \n2000 ;47 :707 –717 .10852536 \n25. Young NP Weinshenker BG Parisi JE \nPerivenous demyelination: association with clinically defined acute disseminated encephalomyelitis and comparison with pathologically confirmed multiple sclerosis . Brain \n2010 ;133 :333 –348 .20129932 \n26. Kitley J Woodhall M Waters P \nMyelin-oligodendrocyte glycoprotein antibodies in adults with a neuromyelitis optica phenotype . Neurology \n2012 ;79 :1273 –1277 .22914827 \n27. Reindl M Rostasy K \nMOG antibody-associated diseases . Neurol Neuroimmunol Neuroinflamm \n2015 ;2 :e60 .25635258 \n28. Brilot F Dale RC Selter RC \nAntibodies to native myelin oligodendrocyte glycoprotein in children with inflammatory demyelinating central nervous system disease . Ann Neurol \n2009 ;66 :833 –842 .20033986 \n29. Waters P Woodhall M O'Connor KC \nMOG cell-based assay detects non-MS patients with inflammatory neurologic disease . Neurol Neuroimmunol Neuroinflamm \n2015 ;2 :e89 .25821844 \n30. Rostasy K Mader S Schanda K \nAnti-myelin oligodendrocyte glycoprotein antibodies in pediatric patients with optic neuritis . Arch Neurol \n2012 ;69 :752 –756 .22371853 \n31. Baumann M Sahin K Lechner C \nClinical and neuroradiological differences of paediatric acute disseminating encephalomyelitis with and without antibodies to the myelin oligodendrocyte glycoprotein . J Neurol Neurosurg Psychiatry \n2015 ;86 :265 –272 .25121570 \n32. Huppke P Rostasy K Karenfort M \nAcute disseminated encephalomyelitis followed by recurrent or monophasic optic neuritis in pediatric patients . Mult Scler \n2013 ;19 :941 –946 .23128668 \n33. Kitley J Waters P Woodhall M \nNeuromyelitis optica spectrum disorders with aquaporin-4 and myelin-oligodendrocyte glycoprotein antibodies: a comparative study . JAMA Neurol \n2014 ;71 :276 –283 .24425068 \n34. Spadaro M Gerdes LA Mayer MC \nHistopathology and clinical course of MOG-antibody-associated encephalomyelitis . Ann Clin Transl Neurol \n2015 ;2 :295 –301 .25815356 \n35. Konig FB Wildemann B Nessler S \nPersistence of immunopathological and radiological traits in multiple sclerosis . Arch Neurol \n2008 ;65 :1527 –1532 .19001173 \n36. Genain CP Cannella B Hauser SL Raine CS \nIdentification of autoantibodies associated with myelin damage in multiple sclerosis . Nat Med \n1999 ;5 :170 –175 .9930864 \n37. Misu T Hoftberger R Fujihara K \nPresence of six different lesion types suggests diverse mechanisms of tissue injury in neuromyelitis optica . Acta Neuropathol \n2013 ;125 :815 –827 .23579868 \n38. Kezuka T Usui Y Yamakawa N \nRelationship between NMO-antibody and anti-MOG antibody in optic neuritis . J Neuroophthalmol \n2012 ;32 :107 –110 .22157536 \n39. Aboulenein-Djamshidian F Hoftberger R Waters P \nReduction in serum aquaporin-4 antibody titers during development of a tumor-like brain lesion in a patient with neuromyelitis optica: a serum antibody-consuming effect? \nJ Neuropathol Exp Neurol \n2015 ;74 :194 –197 .25668569 \n40. Martinez-Hernandez E Sepulveda M Rostasy K \nAntibodies to aquaporin 4, myelin-oligodendrocyte glycoprotein, and the glycine receptor alpha1 subunit in patients with isolated optic neuritis . JAMA Neurol \n2015 ;72 :187 –193 .25506781\n\n",
"fulltext_license": "CC BY-NC-ND",
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"title": "Fulminant demyelinating encephalomyelitis: Insights from antibody studies and neuropathology.",
"title_normalized": "fulminant demyelinating encephalomyelitis insights from antibody studies and neuropathology"
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"abstract": "Nafcillin-induced acute liver injury is a rare and potentially fatal complication that has been known since the 1960s but inadequately studied. At this time, the only proven treatment is early discontinuation of the drug. Because of the high prevalence of nafcillin class antibiotic use in the United States, it is important for clinicians to have a high clinical suspicion for this diagnosis. We present a case of liver failure attributable to nafcillin use in a 68-year-old male with a history methicillin-sensitive Staphylococcus and L3/L4 osteomyelitis. After starting long-term antibiotic therapy, he presented with painless jaundice which necessitated discontinuation of the drug. At the time of presentation, the patient's lab work exhibited a bilirubin/direct bilirubin of 9.4/8.2 mg/dL, alkaline phosphatase of 311 IU/L, and aspartate transaminase/alanine transaminase of 109/127 IU/L. The patient was switched to i.v. vancomycin given the concern for drug-induced liver injury. Imaging did not show obstruction of the hepatobiliary or pancreaticobiliary trees. Serology was unremarkable for viral etiology, autoimmune processes, Wilson disease, and hemochromatosis. A liver biopsy showed findings consistent with drug-induced liver injury. The patient's liver function tests peaked at day 7 of admission and trended towards normal levels with cessation of nafcillin therapy. The patient was discharged with a diagnosis of nafcillin-induced acute liver injury. Our case highlights the importance of early recognition of the diagnosis and careful monitoring of liver function when nafcillin is employed in the clinical setting.",
"affiliations": "Department of Medicine, Stony Brook University Hospital, Stony Brook, New York, USA.;Department of Medicine, Stony Brook University Hospital, Stony Brook, New York, USA.;Department of Medicine, Stony Brook University Hospital, Stony Brook, New York, USA.;Department of Medicine, Stony Brook University Hospital, Stony Brook, New York, USA.;Department of Medicine, Stony Brook University Hospital, Stony Brook, New York, USA.",
"authors": "Rao|Qin|Q|;Schuster|Isaiah|I|;Seoud|Talal|T|;Zarrabi|Kevin|K|;Goolsarran|Nirvani|N|",
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"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 10.1159/000480071crg-0011-0564Single CaseA Patient with Nafcillin-Associated Drug-Induced Liver Failure Rao Qin *Schuster Isaiah Seoud Talal Zarrabi Kevin Goolsarran Nirvani Department of Medicine, Stony Brook University Hospital, Stony Brook, New York, USA*Qin Rao, MD, Stony Brook University Hospital, 100 Nicolls Rd, Stony Brook, NY (USA), E-Mail qin.rao@stonybrookmedicine.eduSep-Dec 2017 26 9 2017 26 9 2017 11 3 564 568 23 5 2017 1 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.Nafcillin-induced acute liver injury is a rare and potentially fatal complication that has been known since the 1960s but inadequately studied. At this time, the only proven treatment is early discontinuation of the drug. Because of the high prevalence of nafcillin class antibiotic use in the United States, it is important for clinicians to have a high clinical suspicion for this diagnosis. We present a case of liver failure attributable to nafcillin use in a 68-year-old male with a history methicillin-sensitive Staphylococcus and L3/L4 osteomyelitis. After starting long-term antibiotic therapy, he presented with painless jaundice which necessitated discontinuation of the drug. At the time of presentation, the patient's lab work exhibited a bilirubin/direct bilirubin of 9.4/8.2 mg/dL, alkaline phosphatase of 311 IU/L, and aspartate transaminase/alanine transaminase of 109/127 IU/L. The patient was switched to i.v. vancomycin given the concern for drug-induced liver injury. Imaging did not show obstruction of the hepatobiliary or pancreaticobiliary trees. Serology was unremarkable for viral etiology, autoimmune processes, Wilson disease, and hemochromatosis. A liver biopsy showed findings consistent with drug-induced liver injury. The patient's liver function tests peaked at day 7 of admission and trended towards normal levels with cessation of nafcillin therapy. The patient was discharged with a diagnosis of nafcillin-induced acute liver injury. Our case highlights the importance of early recognition of the diagnosis and careful monitoring of liver function when nafcillin is employed in the clinical setting.\n\nKeywords\nNafcillinLiverJaundiceDrug-induced liver injury\n==== Body\nIntroduction\nCholestatic hepatitis is a rare complication of nafcillin and its class equivalent narrow-spectrum beta-lactam antibiotics [1]. A review of the literature reveals that the first case of oxacillin-induced hepatitis was reported in 1965. Since then, there have been only a few case reports and 2 cohort studies on the subject. The first cohort study by Viehman et al. [2] followed 224 patients at a single institution who were receiving antibiotics for more than 1 month. Within this population, 3% of oxacillin users and 4% of nafcillin users developed acute hepatic toxicity, without a significant difference in rates between the 2 groups [2]. The second cohort study followed 222 children on antibiotics for 4 years and revealed an acute hepatitis rate of 22% for oxacillin and 0% for nafcillin [1].\n\nIt remains unclear if there is a mortality rate associated with nafcillin drug-induced hepatitis. However, both acute drug-induced liver injury (DILI) and its progressive disease, drug-induced liver injury-acute liver failure (DILI-ALF) carry a high morbidity and mortality rate. These disease processes can lead to encephalopathy, hypercoagulability, and acute spontaneous bacterial peritonitis; require ICU level of care, and the need for liver transplantation [3].\n\nTreatment options for DILI/DILI-ALF are limited and the most efficacious approach is withdrawal of the offending agent. Thus, early recognition of the signs of beta-lactam-induced acute hepatic toxicity is imperative to limit the risk of organ failure. Below, we report a recent case of nafcillin-induced hepatotoxicity and provide further insight into this rare complication.\n\nCase Report\nWe report a case of a 68-year-old Caucasian man (90 kg, 177.8 cm, BMI 28.47) with a past medical history of hypertension and diabetes mellitus, who presented with new-onset painless jaundice. The patient had recently been hospitalized for treatment of L3/L4 osteomyelitis secondary to methicillin-sensitive Staphylococcus aureus bacteremia. He was treated with intravenous nafcillin, 2 g every 4 h, as an inpatient and was continuing treatment as an outpatient. The patient had been on antibiotic therapy for 4 weeks at the time of presentation. The patient reported that his skin had turned yellow, his urine had grown darker, and his stools had turned grey over a course of 5 days. He also suffered a 20-lb weight loss over a 3-week period prior to presentation. The patient denied abdominal pain, fever/chills, nausea, vomiting, diarrhea, and sick contacts. The patient further denied any use of alcohol, illicit drugs, herbal supplements, or any new medications except nafcillin.\n\nOn presentation, the patient was afebrile and hemodynamically stable. Physical exam revealed intact mentation, scleral and sublingual icterus, trace asterixis, jaundiced skin tone, normal bowel sounds, no abdominal tenderness, and no hepatomegaly. Lab work revealed total bilirubin/direct bilirubin 9.4/8.2 mg/dL; alkaline phosphatase of 311 IU/L; aspartate transaminase/alanine transaminase 109/127 IU/L; INR 1.6; ammonia level 17 μmol/L; and acetaminophen level <5 μg/mL. The Model for End-Stage Liver Disease (MELD) score was 22, with 19.6% estimated 3-month mortality. Eosinophils were elevated to 20.7% of blood leukocytes.\n\nCT scan of the abdomen and pelvis at the time of initiation of nafcillin therapy on the previous admission revealed a normal-sized liver, an unremarkable gallbladder, no biliary ductal dilation, and no pancreatic lesions. On this admission, a right upper quadrant ultrasound did not identify stones, sludge, or biliary pathology. Further imaging study with an MRCP showed an unremarkable pancreatobiliary tree, no focal lesions in the liver, and no intrahepatic/extrahepatic biliary dilatation.\n\nHepatic workup included viral hepatitis serology (genotype A, B, and C), anti-mitochondrial antibody, anti-smooth muscle antibody, total immunoglobulin levels, anti-LK microsomal antibodies, iron studies, and ceruloplasmin levels. All serology and titers were unremarkable (online suppl. Table 1, see www.karger.com/doi/10.1159/000480071). Lactulose was started as a preventive measure against encephalopathy and empiric intravenous N-acetylcysteine was administered. Nafcillin was discontinued on admission and the patient was transitioned to intravenous vancomycin for further treatment of the osteomyelitis given the concern for DILI-ALF.\n\nThe patient underwent a percutaneous liver biopsy. Pathology revealed findings consistent with cholestatic hepatitis. Liver enzymes trended upwards and peaked at AST/ALT 313/190 IU/L on day 7 of admission (Fig. 1). Total/direct bilirubin peaked at 13.1/11.6 mg/dL on day 4 of admission (Fig. 2). A diagnosis of nafcillin-induced acute liver injury was made. The patient was discharged 10 days after admission with outpatient gastroenterology follow up for further evaluation. Transaminases, bilirubin levels, and the INR decreased to baseline levels with complete resolution of the jaundice at the time of follow up 2 weeks after discharge. The MELD score improved to 17, with 6.0% estimated 3-month mortality.\n\nDiscussion\nNafcillin, a semi-synthetic penicillin, is frequently used in the management of disease states caused by gram-positive species. Since the 1960s, the penicillin class of antibiotics has become associated with a number of hepatic and renal toxicities which in many patients may contribute to a high degree of morbidity and mortality [4, 5]. The hepatotoxicity is frequently associated with underlying cholestasis that in some cases may present with jaundice and on laboratory evaluation with a significant transaminitis and/or hyperbilirubinemia [6]. At this time, no data have demonstrated a sensitive marker for predicting the onset of this form of injury in the setting of antibiotic use.\n\nThis case highlights the importance of early recognition of nafcillin-induced acute liver injury. As demonstrated in this patient, complete withdrawal of nafcillin resulted in complete recovery of liver function and the drug effects were proven reversible and we add to the growing body of literature supporting the finding of DILI. The current opinion is that nafcillin is generally well tolerated, with the most common side effects being mild to moderate gastrointestinal and hematological toxicities. For this reason, treatment discontinuation due to toxicity is a rare occurrence.\n\nA thorough workup of the patient's liver failure was conducted and no underlying etiology was identified to explain the liver failure. The patient had no prior hepatic or renal disease to explain possible decreased clearance of the drug. Moreover, there were no hepatotoxic drugs administered at or around the time of the observed liver failure. Due to the acute nature of the patient's presentation, the cholestatic pattern of the liver injury, and eosinophilia, there was high suspicion for DILI. Pathology further confirmed our diagnosis. Following discontinuation of the medication, the patient's symptomatology dramatically improved and his liver function normalized. Due to the severity of the morbidity/mortality associated with DILI, we believe that patients with long-term treatment with nafcillin and its class equivalent narrow-spectrum beta-lactam antibiotics will benefit from serial liver function testing throughout therapy.\n\nIn conclusion, we highlight the importance of recognizing drug-induced liver failure secondary to prolonged use of nafcillin. The patient presented with painless jaundice and lab work revealed a marked transaminitis and hyperbilirubinemia. This case highlights the importance of monitoring liver function in patients undergoing nafcillin therapy. If hepatic injury is observed, prompt discontinuation of the therapy should be considered.\n\nStatement of Ethics\nThe authors have no ethical conflicts to disclose.\n\nDisclosure Statement\nThe authors declare that there is no conflict of interest regarding the publication of this paper.\n\nSupplementary Material\nSupplementary data\n\nClick here for additional data file.\n\n Fig. 1 Transaminase levels. Variation in AST, ALT, and ALP levels following initiation of nafcillin treatment. The solid arrow indicates initiation of antibiotic therapy (day 1) and the dashed line indicates withdrawal of treatment (day 24). AST, aspartate transaminase; ALT, alanine transaminase; ALP, alkaline phosphatase.\n\nFig. 2 Bilirubin levels. Variations in total and direct bilirubin levels following initiation of nafcillin treatment. The solid arrow indicates initiation of antibiotic therapy (day 1) and the dashed line indicates withdrawal of therapy (day 24).\n==== Refs\nReferences\n1 Maraqa NF Higher occurrence of hepatotoxicity and rash in patients treated with oxacillin, compared with those treated with nafcillin and other commonly used antimicrobials Clin Infect Dis 2002 34 50 54 11731945 \n2 Viehman JA Adverse events lead to drug discontinuation more commonly among patients who receive nafcillin than among those who receive oxacillin Antimicrob Agents Chemother 2016 60 3090 3095 26976858 \n3 Lee WM Drug-induced acute liver failure Clin Liver Dis 2013 17 575 586 viii. 24099019 \n4 Pas AT Quinn EL Cholestatic hepatitis following the administration of sodium oxacillin JAMA 1965 191 674 675 14242432 \n5 Lestico MR Vick KE Hetsko CM Hepatic and renal dysfunction following nafcillin administration Ann Pharmacother 1992 26 985 990 1504413 \n6 Alam MB Kadoura A Sathaiah M A fatal case of nafcillin-induced hepatotoxicity: a case report and the literature review Case Rep Med 2012 2012 953714 22844299\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-0631",
"issue": "11(3)",
"journal": "Case reports in gastroenterology",
"keywords": "Drug-induced liver injury; Jaundice; Liver; Nafcillin",
"medline_ta": "Case Rep Gastroenterol",
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"nlm_unique_id": "101474819",
"other_id": null,
"pages": "564-568",
"pmc": null,
"pmid": "29033779",
"pubdate": "2017",
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"references": "11731945;1504413;22844299;24099019;14242432;26976858",
"title": "A Patient with Nafcillin-Associated Drug-Induced Liver Failure.",
"title_normalized": "a patient with nafcillin associated drug induced liver failure"
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"activesubstancename": "NAFCILLIN\\NAFCILLIN SODIUM"
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"abstract": "OBJECTIVE\nUltrasound-guided thrombin injection has become standard treatment for extremity pseudoaneurysms. Our specific aims were to determine the procedural success rate, the procedural complication rate, and the factors associated with pseudoaneurysm recurrence.\n\n\nMETHODS\nA total of 262 consecutive cases of ultrasound-guided thrombin repair of pseudoaneurysms were identified between January 1, 2006, and March 20, 2016. The procedural and follow-up ultrasound studies were reviewed. Outcomes of interest included procedural success (defined as complete thrombosis at the time of injection and on a follow-up examination), incomplete pseudoaneurysm thrombosis, and postprocedural recurrence. Postprocedural pseudoaneurysm recurrences were compared to procedural successes with regard to patient demographics, pseudoaneurysm characteristics, amount of thrombin injected, and periprocedural laboratory values.\n\n\nRESULTS\nProcedural success occurred in 85.7% of cases. Complications occurred in 3.0% of cases. The mean patient age ± SD was 72.3 ± 11.3 years. The median amount of thrombin injected was 500 U (interquartile range, 400 U). The median follow-up time was 1 day (interquartile range, 0 days). A pseudoaneurysm size of 2 cm or larger and thrombocytopenia were significant independent predictors of pseudoaneurysm recurrence (P = .003 and .03, respectively). The odds ratios for pseudoaneurysm recurrence were 2.29 for pseudoaneurysm size of 2 cm or larger (P = .03) and 1.04 for thrombocytopenia (P = .04).\n\n\nCONCLUSIONS\nThrombin injection of pseudoaneurysms is an off-label procedure with few complications and a high success rate. Follow-up imaging is recommended in all pseudoaneurysms that are 2 cm or larger and in patients with thrombocytopenia.",
"affiliations": "Department of Radiology, Northwell Health System, Hofstra Northwell School of Medicine, Manhasset, New York, USA.;Department of Radiology, Northwell Health System, Hofstra Northwell School of Medicine, Manhasset, New York, USA.",
"authors": "Esterson|Yonah B|YB|;Pellerito|John S|JS|",
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"keywords": "interventional-intraoperative ultrasound; pseudoaneurysm; pseudoaneurysm recurrence; thrombin; ultrasound-guided treatment",
"medline_ta": "J Ultrasound Med",
"mesh_terms": "D000368:Aged; D017541:Aneurysm, False; D005260:Female; D005500:Follow-Up Studies; D006490:Hemostatics; D006801:Humans; D008297:Male; D012008:Recurrence; D012189:Retrospective Studies; D013917:Thrombin; D016896:Treatment Outcome; D018084:Ultrasonography, Interventional",
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"title": "Recurrence of Thrombin-Injected Pseudoaneurysms Under Ultrasound Guidance: A 10-Year Retrospective Analysis.",
"title_normalized": "recurrence of thrombin injected pseudoaneurysms under ultrasound guidance a 10 year retrospective analysis"
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"abstract": "Dexamethasone is widely used in current practice for the prevention of postoperative nausea and vomiting. Although its use in the perioperative setting has been associated with several side effects (eg, hyperglycemia and suppression of adrenal cortisol production), their clinical significance remains questionable. We present the case of a healthy 27-year-old woman who developed acute adrenal insufficiency after receiving intraoperative dexamethasone for postoperative nausea and vomiting prophylaxis during a laparoscopic left oophorectomy.",
"affiliations": "From the Department of Anesthesiology, Mount Sinai Medical Center, Miami Beach, Florida.;University of Arizona College of Medicine-Phoenix, Phoenix, Arizona.;Miami Beach Anesthesiology Associates, Inc, Department of Anesthesiology, Mount Sinai Medical Center, Miami Beach, Florida.",
"authors": "Bacigalupo Landa|Andres|A|;Viswanath|Omar|O|;D'Mello|Jayanand|J|",
"chemical_list": "D000932:Antiemetics; D003907:Dexamethasone; D006854:Hydrocortisone",
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"mesh_terms": "D000309:Adrenal Insufficiency; D000328:Adult; D000932:Antiemetics; D003907:Dexamethasone; D019468:Disease Management; D005260:Female; D006801:Humans; D006854:Hydrocortisone; D007430:Intraoperative Care; D010052:Ovariectomy; D020250:Postoperative Nausea and Vomiting",
"nlm_unique_id": "101714112",
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"pubdate": "2019-06-15",
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"references": null,
"title": "Acute Adrenal Insufficiency After an Antiemetic Dose of Dexamethasone: A Case Report.",
"title_normalized": "acute adrenal insufficiency after an antiemetic dose of dexamethasone a case report"
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... |
{
"abstract": "OBJECTIVE\nThe aim of the present study was to investigate the dissemination of carbapenem-resistant Klebsiella pneumoniae (CRKP) isolates in integrated intensive care units (IICUs) and emergency ICUs (EICUs) for controlling the spread of CRKP in different ICUs of the hospital.\n\n\nMETHODS\nFrom January 2016 to April 2017, a total of 46 non-duplicate CRKP isolates were consecutively isolated from a tertiary hospital. The production of carbapenemases was determined by the modified carbapenem inactivation method (mCIM) test. The resistance and virulence-associated genes were detected by PCR and DNA sequencing. A hypermucoviscosity phenotype was identified by the string test. Bacterial clonal relatedness of the CRKP isolates tested was determined by multi-locus sequence typing (MLST) and PFGE.\n\n\nRESULTS\nAll CRKP isolates showed multiple drug resistance. All CRKP isolates harboured blaKPC-2-encoding carbapenemase and at least one of the other β-lactamase genes tested, with positive rates of 89.1 % (41/46) for blaCTX-M-65. qnrS was found among 76.1 % (35/46) of the CRKP isolates. A hypermucoviscosity phenotype was found in only two (4.3 %, 2/46) CRKP isolates. The virulence-associated genes with positive rates of more than 90 % among the 46 isolates tested included wabG (100 %, 46/46), ycf (100 %, 46/46), ureA (95.6 %, 44/46) and fim H (95.6 %, 44/46). MLST results showed that 46 CRKP isolates belonged to ST11 (95.6 %, 44/46) and ST86 (4.4 %, 2/46). PFGE patterns showed four clusters.\n\n\nCONCLUSIONS\nThe CRKP ST11 clone with co-production of CTX-M-65 and KPC-2 disseminated in ICUs of this tertiary teaching hospital in central China. The emergence of CRKP with a hypermucoviscosity phenotype in ICUs should be of particular concern.",
"affiliations": "1 Department of Laboratory Medicine, the Second Affiliated Hospital of Nanchang University, Nanchang Jiangxi Provincial Key Laboratory of Medicine, Nanchang 330006, PR China.;1 Department of Laboratory Medicine, the Second Affiliated Hospital of Nanchang University, Nanchang Jiangxi Provincial Key Laboratory of Medicine, Nanchang 330006, PR China.;1 Department of Laboratory Medicine, the Second Affiliated Hospital of Nanchang University, Nanchang Jiangxi Provincial Key Laboratory of Medicine, Nanchang 330006, PR China.;1 Department of Laboratory Medicine, the Second Affiliated Hospital of Nanchang University, Nanchang Jiangxi Provincial Key Laboratory of Medicine, Nanchang 330006, PR China.;1 Department of Laboratory Medicine, the Second Affiliated Hospital of Nanchang University, Nanchang Jiangxi Provincial Key Laboratory of Medicine, Nanchang 330006, PR China.;1 Department of Laboratory Medicine, the Second Affiliated Hospital of Nanchang University, Nanchang Jiangxi Provincial Key Laboratory of Medicine, Nanchang 330006, PR China.;1 Department of Laboratory Medicine, the Second Affiliated Hospital of Nanchang University, Nanchang Jiangxi Provincial Key Laboratory of Medicine, Nanchang 330006, PR China.;1 Department of Laboratory Medicine, the Second Affiliated Hospital of Nanchang University, Nanchang Jiangxi Provincial Key Laboratory of Medicine, Nanchang 330006, PR China.;1 Department of Laboratory Medicine, the Second Affiliated Hospital of Nanchang University, Nanchang Jiangxi Provincial Key Laboratory of Medicine, Nanchang 330006, PR China.;1 Department of Laboratory Medicine, the Second Affiliated Hospital of Nanchang University, Nanchang Jiangxi Provincial Key Laboratory of Medicine, Nanchang 330006, PR China.;2 Department of Clinical Laboratory, Shanghai Pulmonary Hospital, Tongji University, School of Medicine, Shanghai 200443, PR China.",
"authors": "Yu|Feng|F|;Hu|Longhua|L|;Zhong|Qiaoshi|Q|;Hang|Yaping|Y|;Liu|Yanling|Y|;Hu|Xiaoyan|X|;Ding|Hui|H|;Chen|Yanhui|Y|;Xu|Xiuhua|X|;Fang|Xueyao|X|;Yu|Fangyou|F|",
"chemical_list": "D001426:Bacterial Proteins; D015780:Carbapenems; D001618:beta-Lactamases; C063912:carbapenemase",
"country": "England",
"delete": false,
"doi": "10.1099/jmm.0.000981",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-2615",
"issue": "68(6)",
"journal": "Journal of medical microbiology",
"keywords": "Dissemination; KPC-2; Klebsiella pneumoniae; ST11; carbapenem resistance",
"medline_ta": "J Med Microbiol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001426:Bacterial Proteins; D015373:Bacterial Typing Techniques; D000073182:Carbapenem-Resistant Enterobacteriaceae; D015780:Carbapenems; D002681:China; D004632:Emergency Medical Services; D005260:Female; D006801:Humans; D007362:Intensive Care Units; D007710:Klebsiella Infections; D007711:Klebsiella pneumoniae; D008297:Male; D008875:Middle Aged; D058885:Multilocus Sequence Typing; D062606:Tertiary Care Centers; D055815:Young Adult; D001618:beta-Lactamases",
"nlm_unique_id": "0224131",
"other_id": null,
"pages": "882-889",
"pmc": null,
"pmid": "31050634",
"pubdate": "2019-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Dissemination of Klebsiella pneumoniae ST11 isolates with carbapenem resistance in integrated and emergency intensive care units in a Chinese tertiary hospital.",
"title_normalized": "dissemination of klebsiella pneumoniae st11 isolates with carbapenem resistance in integrated and emergency intensive care units in a chinese tertiary hospital"
} | [
{
"companynumb": "CN-BAYER-2019-162003",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
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"actiondrug": "6",
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"activesubstancename": "MOXIFLOXACIN"
},
"drugadditional": null,
... |
{
"abstract": "Dopamine supersensitivity psychosis (DSP) is a type of acute exacerbation of recurrent psychosis caused by long-term treatment with antipsychotics in schizophrenic patients. Although DSP is exceedingly troublesome for clinicians, effective treatment has not yet been established. Based on clinical research and our animal study, we hypothesize that aripiprazole, an atypical antipsychotic, may reduce the exacerbation of recurrent psychotic episodes. We report the case of a 46-year-old female who suffered from schizophrenia with DSP. In this case, sustained treatment with a high dose of aripiprazole gradually reduced the severity of her recurrent psychotic episodes. In conclusion, sustained treatment with aripiprazole may reduce the exacerbation of recurrent psychotic episodes in schizophrenic patients with DSP, and may be an effective treatment of DSP.",
"affiliations": "Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan.;Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan.;Division of Medical Treatment and Rehabilitation, Chiba University Center for Forensic Mental Health, Chiba, Japan.;Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.;Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan.",
"authors": "Tadokoro|Shigenori|S|;Nonomura|Naho|N|;Kanahara|Nobuhisa|N|;Hashimoto|Kenji|K|;Iyo|Masaomi|M|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.9758/cpn.2017.15.1.79",
"fulltext": "\n==== Front\nClin Psychopharmacol NeurosciClin Psychopharmacol NeurosciClinical Psychopharmacology and Neuroscience1738-10882093-4327Korean College of Neuropsychopharmacology 2813811810.9758/cpn.2017.15.1.79cpn-15-079Case ReportReduction of Severity of Recurrent Psychotic Episode by Sustained Treatment with Aripiprazole in a Schizophrenic Patient with Dopamine Supersensitivity: A Case Report Tadokoro Shigenori 12Nonomura Naho 13Kanahara Nobuhisa 4Hashimoto Kenji 5Iyo Masaomi 11 Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, \nJapan2 Health Administration Center, Muroran Institute of Technology, Hokkaido, \nJapan3 Department of Biomedical Ethics, Graduate School of Medicine, University of Tokyo, Tokyo, \nJapan4 Division of Medical Treatment and Rehabilitation, Chiba University Center for Forensic Mental Health, Chiba, \nJapan5 Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, \nJapanAddress for correspondence: Shigenori Tadokoro, MD, PhD, Health Administration Center, Muroran Institute of Technology, 27-1, Mizumoto-cho, Muroran, Hokkaido 050-8585, Japan, Tel: +81-143-46-5851, Fax: +81-143-46-5850, E-mail: tadokoroshigenori@gmail.com2 2017 28 2 2017 15 1 79 81 24 2 2016 21 5 2016 23 5 2016 Copyright © 2017, Korean College of Neuropsychopharmacology2017This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Dopamine supersensitivity psychosis (DSP) is a type of acute exacerbation of recurrent psychosis caused by long-term treatment with antipsychotics in schizophrenic patients. Although DSP is exceedingly troublesome for clinicians, effective treatment has not yet been established. Based on clinical research and our animal study, we hypothesize that aripiprazole, an atypical anti-psychotic, may reduce the exacerbation of recurrent psychotic episodes. We report the case of a 46-year-old female who suffered from schizophrenia with DSP. In this case, sustained treatment with a high dose of aripiprazole gradually reduced the severity of her recurrent psychotic episodes. In conclusion, sustained treatment with aripiprazole may reduce the exacerbation of recurrent psychotic episodes in schizophrenic patients with DSP, and may be an effective treatment of DSP.\n\nAntipsychotic agentsDisease exacerbationReceptorsdopamine D2RecurrenceSchizophrenia\n==== Body\nINTRODUCTION\nDopamine supersensitivity psychosis (DSP) is a type of acute exacerbation of recurrent psychosis in schizophrenic patients with excessive sensitivity to dopamine, caused by long-term treatment with antipsychotics.1) Furthermore, it has been estimated that more than half the cases of treatment-resistant schizophrenia might be related to DSP.2) Because DSP is associated with tolerance development for antipsychotics and/or vulnerability to minor stress,1) it is exceedingly troublesome for clinicians. Nevertheless, no effective treatment has yet been established for DSP.\n\nOn the other hand, some clinical studies on the treatment of patients with schizophrenia have suggested that aripiprazole, one of the atypical antipsychotics, might lower the risk of relapse and prevent the exacerbation of psychotic symptoms more efficiently than other antipsychotics.3,4) Furthermore, in a previous study where we used an animal model of DSP, results suggested that aripiprazole may have not only preventive but also therapeutic effects on DSP through the reduction of excessive sensitivity to dopamine.5) Based on these findings, we hypothesize that aripiprazole may reduce the exacerbation of recurrent psychotic episodes in schizophrenic patients with DSP. Here we report a case study supporting our hypothesis. Incidentally, informed consent was obtained from the patient for publication of this case report.\n\nCASE\nThe patient is a 46-year-old married Japanese woman with a long history of schizophrenia. Her psychotic symptoms, which include delusions of persecution and thought broadcasting, first appeared at age 35 years. At the time, she underwent ambulatory treatment with 4-mg risperidone, and as a result did not experience another psychotic episode for about 10 years. Nevertheless, one year ago, her first recurrence of a psychotic episode was triggered by a trifling family problem, and her psychotic symptoms increased in severity to the point that she required hospitalization. On this occasion, an additional dose of risperidone and doses of other antipsychotics barely cured her symptoms, and she was discharged from the hospital after two months. Three months later, however, her psychotic symptoms relapsed without any apparent trigger, and this time, neither the maximum dose of risperidone nor other antipsychotics were able to control her psychotic episodes. Therefore, she was admitted to Chiba University Hospital for specialized treatment.\n\nAfter admission, she was mainly treated with a high dose (24 mg or more) of aripiprazole, together with a variable dose of olanzapine (5–10 mg) or quetiapine (200–700 mg) for a short period of time. Over approximately two months, similar episodes of acute exacerbation of psychotic symptoms were repeated and continued for about a week each time. She was violently excited, refused medication, and demanded to be discharged. As a result, she was forced to live in an isolated room. Three months after the start of sustained treatment with the high dose of aripiprazole, however, the duration of exacerbation episodes became shorter, while the severity of her psychotic symptoms were gradually alleviated. Six months after the start of the treatment, episodes of exacerbation ended within half a day, and her psychotic symptoms became insignificant. She was able to move to an open room (4-bed ward). Finally, ten months after the start of treatment, she was discharged from our hospital without any significant psychotic episodes.\n\nIn order to quantify the severity of acute exacerbation episodes, we used the Excited Component of the Positive and Negative Syndrome Scale (PANSS-EC).6) We defined the Acute Exacerbation Severity (AES) score as the PANSS-EC score multiplied by the duration of the episode in 0.5-day units, and examined the AES score of each episode. We recorded the AES scores of the patient during the 305 days of hospital treatment (Fig. 1), and detected 11 episodes of acute exacerbation. As can be seen from the figure, the AES score of each episode decreased along with the time course of sustained treatment with aripiprazole.\n\nDISCUSSION\nWe think that this patient suffered from DSP caused by long-term treatment with risperidone. Therefore, she had repeated similar episodes of acute exacerbation without any apparent trigger, owing to her excessive dopamine sensitivity. We consider that sustained treatment with a high dose of aripiprazole gradually reduced the severity of her recurrent psychotic episodes through the reduction of this excessive sensitivity to dopamine. It is known that chronic treatment with D2 dopamine receptor antagonists, such as haloperidol, up-regulates the density of D2 receptors, and leads to DSP.7) Based on the results of our animal study and our theoretical findings, we think that aripiprazole can down-regulate the density of D2 receptors and ameliorate DSP, as a result of its partial-agonistic effects on the D2 receptors.8) Therefore, we believe that sustained treatment with a high dose of aripiprazole might have down-regulated the density of the patient’s D2 receptors, and as a result, reduced the exacerbation of her recurrent psychotic episodes.\n\nBecause aripiprazole yields excessive dopaminergic neurotransmission in patients with DSP due to increased D2 receptor density, a transient worsening of psychosis can appear following the switch to aripirazole.5,9) In fact, the results of a clinical survey suggested that patients with DSP were more likely to experience psychotic worsening following the switch to aripiprazole, especially when the patients had undergone relatively slow titration, i.e., a low initial dose with a gradual increase of aripiprazole.10) However, our patient had undergone a quick titration of aripiprazole. We therefore suspect that the excessive dopaminergic neurotransmission can gradually down-regulate the density of a patient’s D2 receptors due to compensatory systems induced over the time course of treatment, without causing any transient worsening of psychosis.\n\nIn this case, sustained treatment with aripiprazole may have reduced the exacerbation of recurrent psychotic episodes in a schizophrenic patient with DSP. It might be an effective treatment of DSP. However, well-designed, randomized, double blind, placebo-controlled studies using a large sample would be needed to confirm this.\n\nAcknowledgments\nFunding for this study was provided by Department of Psychiatry, Graduate School of Medicine, Chiba University.\n\nFig. 1 This figure shows the relationship between Acute Exacerbation Severity (AES) scores of 11 recurrent psychotic episodes and the duration of sustained treatment with aripiprazole. AES scores were defined as the Excited Component of the Positive and Negative Syndrome Scale scores multiplied by the episode duration in 0.5-day units. As may be seen, the AES score of each episode decreased along with the time course of sustained treatment with aripiprazole.\n==== Refs\nREFERENCES\n1 Chouinard G Severe cases of neuroleptic-induced super-sensitivity psychosis. Diagnostic criteria for the disorder and its treatment Schizophr Res 1991 5 21 33 10.1016/0920-9964(91)90050-2 1677263 \n2 Chouinard G Chouinard VA Atypical antipsychotics: CATIE study, drug-induced movement disorder and resulting iatrogenic psychiatric-like symptoms, supersensitivity rebound psychosis and withdrawal discontinuation syndromes Psychother Psychosom 2008 77 69 77 10.1159/000112883 18230939 \n3 Gorwood P1 Meeting everyday challenges: antipsychotic therapy in the real world Eur Neuropsychopharmacol 2006 16 Suppl 3 S156 S162 10.1016/j.euroneuro.2006.06.002 16872807 \n4 Croxtall JD Aripiprazole: a review of its use in the management of schizophrenia in adults CNS Drugs 2012 26 155 183 10.2165/11208400-000000000-00000 22296317 \n5 Tadokoro S Okamura N Sekine Y Kanahara N Hashimoto K Iyo M Chronic treatment with aripiprazole prevents development of dopamine supersensitivity and potentially supersensitivity psychosis Schizophr Bull 2012 38 1012 1020 10.1093/schbul/sbr006 21402722 \n6 Montoya A Valladares A Lizán L San L Escobar R Paz S Validation of the Excited Component of the Positive and Negative Syndrome Scale (PANSS-EC) in a naturalistic sample of 278 patients with acute psychosis and agitation in a psychiatric emergency room Health Qual Life Outcomes 2011 9 18 10.1186/1477-7525-9-18 21447155 \n7 Samaha AN Seeman P Stewart J Rajabi H Kapur S “Breakthrough” dopamine supersensitivity during ongoing antipsychotic treatment leads to treatment failure over time J Neurosci 2007 27 2979 2986 10.1523/JNEUROSCI.5416-06.2007 17360921 \n8 Iyo M Tadokoro S Kanahara N Hashimoto T Niitsu T Watanabe H Optimal extent of dopamine D2 receptor occupancy by antipsychotics for treatment of dopamine supersensitivity psychosis and late-onset psychosis J Clin Psychopharmacol 2013 33 398 404 10.1097/JCP.0b013e31828ea95c 23609386 \n9 Di Lorenzo R Amoretti A Forghieri M Fiorini F Genedani S Rigatelli M Aripiprazole: effectiveness and safety under naturalistic conditions Exp Clin Psychopharmacol 2007 15 569 575 10.1037/1064-1297.15.6.569 18179310 \n10 Takase M Kanahara N Oda Y Kimura H Watanabe H Iyo M Dopamine supersensitivity psychosis and dopamine partial agonist: a retrospective survey of failure of switching to aripiprazole in schizophrenia J Psychopharmacol 2015 29 383 389 10.1177/0269881115570083 25735995\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1738-1088",
"issue": "15(1)",
"journal": "Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology",
"keywords": "Antipsychotic agents; Disease exacerbation; Receptors, dopamine D2; Recurrence; Schizophrenia",
"medline_ta": "Clin Psychopharmacol Neurosci",
"mesh_terms": null,
"nlm_unique_id": "101207332",
"other_id": null,
"pages": "79-81",
"pmc": null,
"pmid": "28138118",
"pubdate": "2017-02-28",
"publication_types": "D002363:Case Reports",
"references": "25735995;23609386;21447155;18179310;1677263;22296317;21402722;16872807;18230939;17360921",
"title": "Reduction of Severity of Recurrent Psychotic Episode by Sustained Treatment with Aripiprazole in a Schizophrenic Patient with Dopamine Supersensitivity: A Case Report.",
"title_normalized": "reduction of severity of recurrent psychotic episode by sustained treatment with aripiprazole in a schizophrenic patient with dopamine supersensitivity a case report"
} | [
{
"companynumb": "JP-MYLANLABS-2017M1026116",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"drugadditional": "3",
... |
{
"abstract": "Acquired thrombotic thrombocytopenic purpura (aTTP) is a life-threatening systemic thrombotic microangiopathy characterized by the presence of anti-ADAMTS13 antibodies (inhibitor). Here we report the case of a patient with refractory aTTP successfully treated with cyclosporine. A 69-year-old man presenting with hematuria and petechiae was referred to our hospital; he was disoriented and febrile. Laboratory results revealed Coombs-negative hemolytic anemia, thrombocytopenia, and renal failure. Undetectable ADAMTS13 activity and presence of anti-ADAMTS13 antibodies (inhibitor) confirmed the diagnosis of aTTP. Despite performing plasma exchange and administering prednisolone and rituximab (375 mg/m2), we were unable to restore his platelet counts to the normal level. Therefore, he was treated with cyclophosphamide (500 mg/bodyweight), vincristine (1.4 mg/m2), bortezomib (1.3 mg/m2), and cyclosporine (2.5 mg/kg). After the cyclosporine therapy, his platelet counts gradually normalized. Continuous cyclosporine maintenance therapy led to complete disappearance of the inhibitor. Therapeutic strategies for refractory aTTP have not yet been established. Further investigations are warranted to establish a therapeutic strategy for refractory aTTP.",
"affiliations": "Department of Hematology and Oncology, Mie University Hospital.;Department of Hematology and Oncology, Mie University Hospital.;Department of Hematology and Oncology, Mie University Hospital.;Department of Hematology and Oncology, Mie University Hospital.;Department of Hematology and Oncology, Mie University Hospital.;Department of Hematology and Oncology, Mie University Hospital.",
"authors": "Nato|Yuma|Y|;Nagaharu|Keiki|K|;Okano|Motohiko|M|;Suzuki|Kei|K|;Matsumoto|Takeshi|T|;Tawara|Isao|I|",
"chemical_list": "D000069283:Rituximab; D016572:Cyclosporine; D000071120:ADAMTS13 Protein",
"country": "Japan",
"delete": false,
"doi": "10.11406/rinketsu.62.176",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0485-1439",
"issue": "62(3)",
"journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology",
"keywords": "Acquired thrombotic thrombocytopenic purpura; Bortezomib; Cyclosporine; Vincristine",
"medline_ta": "Rinsho Ketsueki",
"mesh_terms": "D000071120:ADAMTS13 Protein; D000368:Aged; D016572:Cyclosporine; D006801:Humans; D008297:Male; D010951:Plasma Exchange; D010956:Plasmapheresis; D011697:Purpura, Thrombotic Thrombocytopenic; D000069283:Rituximab",
"nlm_unique_id": "2984782R",
"other_id": null,
"pages": "176-179",
"pmc": null,
"pmid": "33828010",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful treatment with cyclosporine in a patient with rituximab-refractory thrombocytopenic purpura.",
"title_normalized": "successful treatment with cyclosporine in a patient with rituximab refractory thrombocytopenic purpura"
} | [
{
"companynumb": "JP-MYLANLABS-2021M1034883",
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"patient": {
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{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo estimate the effect of dose-dense chemotherapy during pregnancy on maternal and neonatal outcomes.\n\n\nMETHODS\nThis is a retrospective cohort study in which women were identified from the international Cancer and Pregnancy Registry at Cooper Medical School at Rowan University in Camden, New Jersey. A chart analysis was completed and Fisher's exact test and independent t test were used in comparing patient outcomes.\n\n\nRESULTS\nTen women received dose-dense chemotherapy, received every 2 weeks, and 99 women received conventional chemotherapy, received with at least 3-week intervals, for breast cancer during pregnancy. Birth weight, gestational age at delivery, rate of growth restriction, congenital anomalies, and incidence of maternal and neonatal neutropenia were not statistically different between the two groups.\n\n\nCONCLUSIONS\nIn the small cohort of women in our registry, dose-dense chemotherapy does not appear to increase the risk of fetal or maternal complications.",
"affiliations": "Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, Cooper University Hospital, Camden, New Jersey 08103, USA. Cardonick-Elyce@CooperHealth.edu",
"authors": "Cardonick|Elyce|E|;Gilmandyar|Dzhamala|D|;Somer|Robert A|RA|",
"chemical_list": "D000970:Antineoplastic Agents; D004317:Doxorubicin; D003520:Cyclophosphamide",
"country": "United States",
"delete": false,
"doi": "http://10.1097/AOG.0b013e31826c32d9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0029-7844",
"issue": "120(6)",
"journal": "Obstetrics and gynecology",
"keywords": null,
"medline_ta": "Obstet Gynecol",
"mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D001724:Birth Weight; D001943:Breast Neoplasms; D003520:Cyclophosphamide; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin; D005260:Female; D005865:Gestational Age; D006801:Humans; D015994:Incidence; D008505:Medical Staff, Hospital; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic; D011256:Pregnancy Outcome; D011297:Prenatal Exposure Delayed Effects; D015995:Prevalence; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "0401101",
"other_id": null,
"pages": "1267-72",
"pmc": null,
"pmid": "23168749",
"pubdate": "2012-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Maternal and neonatal outcomes of dose-dense chemotherapy for breast cancer in pregnancy.",
"title_normalized": "maternal and neonatal outcomes of dose dense chemotherapy for breast cancer in pregnancy"
} | [
{
"companynumb": "US-JNJFOC-20121207930",
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DACTINOMYCIN"
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"drugadditional": null,
... |
{
"abstract": "High-dose cytarabine (ara-c) may overcome cytarabine resistance in leukemic blasts. It has been used as a successful salvage and in postremission therapy but not as initial induction treatment. Patients aged 15 to 60 years, presenting with newly diagnosed acute myeloid leukemia (AML) were randomized to receive either high-dose cytarabine, 3 g/m2 12 hourly on days 1, 3, 5, and 7 for 8 doses, daunorubicin 50 mg/m2 days 1 to 3, etoposide 75 mg/m2 days 1 to 7, (HIDAC-3-7) or standard dose cytarabine 100 mg/m2 continuous intravenous infusion for 7 days with daunorubicin and etoposide at the same dose and schedule as above (7-3-7). Patients could receive a second or third induction course if complete remission (CR) was not achieved. All patients received the same postinduction consolidation therapy (5-2-5) for 2 courses. Eligible patients had no prior chemotherapy or myelodysplastic disease. Patients have been followed for a median of 4.5 years. Of 301 patients treated, complete response (CR) was achieved in 71% with HIDAC-3-7 and 74% with 7-3-7. For patients in CR, the estimated median remission duration was 45 months with HIDAC-3-7 and 12 months with 7-3-7 (P = .0005 univariate analysis, P = .0004 multivariate analysis). The estimated percentage of patients relapse free 5 years after achieving a CR was 49% on HIDAC-3-7 and 24% on 7-3-7. Patients in CR tended to survive longer with HIDAC-3-7 but there were no overall survival differences between the two arms. HIDAC-3-7 was associated with significantly more toxicity in induction with more leukopenia, thrombocytopenia, nausea, and vomiting and eye toxicity (all P < .001) but a similar incidence of severe central nervous system and cerebellar toxicity compared to 7-3-7. The consolidation treatment was the same in both arms but caused significantly more leukopenia and thrombocytopenia in patients previously treated with HIDAC-3-7 induction (P < .0001). We conclude that a dose-effect exists for cytarabine in AML and that HIDAC-3-7 prolongs remission duration and disease-free survival and is tolerable when used as initial induction therapy in patients with de novo AML.",
"affiliations": "Australian Leukemia Study Group, Peter MacCallum Cancer Institute, Melbourne, Australia.",
"authors": "Bishop|J F|JF|;Matthews|J P|JP|;Young|G A|GA|;Szer|J|J|;Gillett|A|A|;Joshua|D|D|;Bradstock|K|K|;Enno|A|A|;Wolf|M M|MM|;Fox|R|R|;Cobcroft|R|R|;Herrmann|R|R|;Van Der Weyden|M|M|;Lowenthal|R M|RM|;Page|F|F|;Garson|O M|OM|;Juneja|S|S|",
"chemical_list": "D003561:Cytarabine; D005047:Etoposide; D003630:Daunorubicin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0006-4971",
"issue": "87(5)",
"journal": "Blood",
"keywords": null,
"medline_ta": "Blood",
"mesh_terms": "D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D016026:Bone Marrow Transplantation; D002493:Central Nervous System Diseases; D003131:Combined Modality Therapy; D003561:Cytarabine; D003630:Daunorubicin; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005047:Etoposide; D005128:Eye Diseases; D005260:Female; D005767:Gastrointestinal Diseases; D006801:Humans; D007951:Leukemia, Myeloid; D015993:Life Tables; D008297:Male; D008875:Middle Aged; D012074:Remission Induction; D016019:Survival Analysis; D016896:Treatment Outcome",
"nlm_unique_id": "7603509",
"other_id": null,
"pages": "1710-7",
"pmc": null,
"pmid": "8634416",
"pubdate": "1996-03-01",
"publication_types": "D016430:Clinical Trial; D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A randomized study of high-dose cytarabine in induction in acute myeloid leukemia.",
"title_normalized": "a randomized study of high dose cytarabine in induction in acute myeloid leukemia"
} | [
{
"companynumb": "AU-PFIZER INC-2021256942",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DAUNORUBICIN HYDROCHLORIDE"
},
"drugadditional... |
{
"abstract": "OBJECTIVE\nThis study aimed to: document the extent of the reduction of serum prolactin (PRL) levels induced by aripiprazole (ARI) treatment in children and adolescents, compare this effect by age group, and shed light on this phenomenon.\n\n\nMETHODS\nPRL serum levels in unmedicated subjects were compared to those in subjects treated with aripiprazole to calculate the rate of subnormal PRL levels during aripiprazole treatment. Next, a literature search was performed to better understand the effects of dopaminergic drugs on PRL levels by age group.\n\n\nRESULTS\nSixty percent of those treated with aripiprazole exhibited subnormal PRL serum levels versus 8% of unmedicated subjects. The rate of PRL subnormality in response to aripiprazole was half as frequent in adolescents and was minimal in adults. The drug-induced reduction of PRL serum levels became more prominent with increasing doses of aripiprazole and with an increased treatment duration.\n\n\nCONCLUSIONS\nWith the increasing use of aripiprazole in the United States population, it is important that future research be conducted to explore the potential sequelae of subnormal PRL serum levels in children and adolescents.",
"affiliations": "Departments of Psychiatry and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. dsafer@jhmi.edu",
"authors": "Safer|Daniel J|DJ|;Calarge|Chadi A|CA|;Safer|Alan M|AM|",
"chemical_list": "D014150:Antipsychotic Agents; D010879:Piperazines; D015363:Quinolones; D000068180:Aripiprazole; D011388:Prolactin",
"country": "United States",
"delete": false,
"doi": "10.1089/cap.2012.0062",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1044-5463",
"issue": "23(4)",
"journal": "Journal of child and adolescent psychopharmacology",
"keywords": null,
"medline_ta": "J Child Adolesc Psychopharmacol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000367:Age Factors; D014150:Antipsychotic Agents; D000068180:Aripiprazole; D002648:Child; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010879:Piperazines; D011388:Prolactin; D015363:Quinolones",
"nlm_unique_id": "9105358",
"other_id": null,
"pages": "282-9",
"pmc": null,
"pmid": "23647135",
"pubdate": "2013-05",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D016454:Review",
"references": "19102734;23087;22582593;3972716;16135860;17728426;20416024;3505371;14747427;16401666;11109502;17123740;1426359;21532364;19339912;18581041;21813076;21823912;11249538;7580171;22549762;22336227;12650682;21720228;21206777;8595709;7104766;18759644;12521235;12188977;19906348;19948625;15910215;16467250;16768639;19706318;18719199;10630453;18765484;4575856;4422004;22213771;11015620;9166213;20520299;19877981;7554710;7033847;3098774;16321731;12860772;2619414;12874491;12153826;409726;8399785;16675366;21265942;22648307;20035580;17760883;2407314;21413838;22152402;20814333;21318565;19797985;19906340;19210705;21993869;22472310;19519261;5061775;19702495;15650492;22724627;15456328;11264615;17805214;16696834;2715755",
"title": "Prolactin serum concentrations during aripiprazole treatment in youth.",
"title_normalized": "prolactin serum concentrations during aripiprazole treatment in youth"
} | [
{
"companynumb": "US-OTSUKA-2020_011534",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nAn increasing number of pediatric patients suffer from thrombotic events necessitating anticoagulation therapy including heparins. Some such patients develop heparin-induced thrombocytopenia (HIT) and thus require alternative anticoagulation. As such, studies evaluating the safety, efficacy, and dosing of alternative anticoagulants are required.\n\n\nMETHODS\nIn this multicenter, single arm, open-label study, 18 patients ≤ 16 years old received argatroban for either a suspicion of or being at risk for HIT, or other conditions requiring nonheparin anticoagulation. Endpoints included thrombosis, thromboembolic complications, and bleeding.\n\n\nRESULTS\nPatients (ages, 1.6 weeks to 16 years) received argatroban usually for continuous anticoagulation (n = 13) or cardiac catheterization (n = 4). One catheterization patient received a 250 µg/kg bolus only; 17 patients received argatroban continuous infusion (median (range)) 1.1 (0.3-12) µg/kg/min (of whom four received a bolus) for 3.0 (0.1-13.8) days. In patients without bolus dosing, typically argatroban 1 µg/kg/min was initiated, with therapeutic activated partial thromboplastin times (aPTTs) (1.5-3× baseline) achieved within 7 hr. Within 30 days, thrombosis occurred in five patients (two during therapy). No one required amputation or died due to thrombosis during therapy. Two patients had major bleeding. Pharmacometric analyses demonstrated the optimal initial argatroban dose to be 0.75 µg/kg/min (if normal hepatic function), with dose reduction necessary in hepatic impairment.\n\n\nCONCLUSIONS\nIn pediatric patients requiring nonheparin anticoagulation, argatroban rapidly provides adequate levels of anticoagulation and is generally well tolerated. For continuous anticoagulation, argatroban 0.75 µg/kg/min (0.2 µg/kg/min in hepatic impairment), adjusted to achieve therapeutic aPTTs, is recommended.",
"affiliations": "Division of Hematology/Oncology, Children's Hospital Los Angeles, Los Angeles, California, USA. gyoung@chla.usc.edu",
"authors": "Young|G|G|;Boshkov|L K|LK|;Sullivan|J E|JE|;Raffini|L J|LJ|;Cox|D S|DS|;Boyle|D A|DA|;Kallender|H|H|;Tarka|E A|EA|;Soffer|J|J|;Hursting|M J|MJ|",
"chemical_list": "D000925:Anticoagulants; D010875:Pipecolic Acids; D010975:Platelet Aggregation Inhibitors; D013449:Sulfonamides; D006493:Heparin; D001120:Arginine; C031942:argatroban",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.22852",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "56(7)",
"journal": "Pediatric blood & cancer",
"keywords": null,
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000925:Anticoagulants; D001120:Arginine; D002648:Child; D002675:Child, Preschool; D005260:Female; D006470:Hemorrhage; D006493:Heparin; D006801:Humans; D007223:Infant; D008111:Liver Function Tests; D008297:Male; D010875:Pipecolic Acids; D010975:Platelet Aggregation Inhibitors; D011446:Prospective Studies; D013449:Sulfonamides; D015996:Survival Rate; D013921:Thrombocytopenia; D013927:Thrombosis; D014018:Tissue Distribution; D016896:Treatment Outcome",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "1103-9",
"pmc": null,
"pmid": "21488155",
"pubdate": "2011-07-01",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Argatroban therapy in pediatric patients requiring nonheparin anticoagulation: an open-label, safety, efficacy, and pharmacokinetic study.",
"title_normalized": "argatroban therapy in pediatric patients requiring nonheparin anticoagulation an open label safety efficacy and pharmacokinetic study"
} | [
{
"companynumb": "US-PFIZER INC-2016216284",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ARGATROBAN"
},
"drugadditional": null,
... |
{
"abstract": "Extramedullary multiple myeloma (EMM) is an aggressive sub-entity of multiple myeloma (MM). Despite an excellent improvement in survival for most patients with MM over recent decades, the overall survival (OS) of patients with EMM was usually not longer than 3 years. Standard treatment for patients with EMM has not been established, and their management is particularly challenging. We presented a heavily pretreated young patient with relapsed EMM and refractoriness to a proteasome inhibitor (PI; bortezomib), a next-generation PI (ixazomib), immunomodulatory drugs (IMiDs; lenalidomide), autologous hematopoietic stem cell transplantation (ASCT), and monoclonal antibody (directed against CD38: daratumumab) and indicated that myeloablative haploidentical hematopoietic stem cell transplantation (haploidentical-HSCT) as a salvage treatment of relapse after a chimeric antigen receptor (CAR)-T cell therapy that targeted B-cell maturation antigen (BCMA) (NCT04650724) is feasible. Taken together of the contemporary literature, the promising results on the effect of anti-BCMA CAR-T cell therapy and allogeneic HSCT might present a proof-of-principle for patients with EMM, and therefore, patients with the disease need to be included in future studies.",
"affiliations": "Department of Hematology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.;Department of Hematology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.;Department of Hematology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.;Department of Hematology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.;Hangzhou Integrative Medicine Hospital, Hangzhou, China.;PersonGen BioTherapeutics (Suzhou) Co., Ltd., Suzhou, China.;PersonGen BioTherapeutics (Suzhou) Co., Ltd., Suzhou, China.;Department of Hematology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.",
"authors": "Qian|Ying|Y|;Qian|Zijun|Z|;Zhao|Xiujie|X|;Pan|Wenjue|W|;Wei|Xinzheng|X|;Meng|Huimin|H|;Yang|Lin|L|;Xiao|Haowen|H|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fmed.2021.649824",
"fulltext": "\n==== Front\nFront Med (Lausanne)\nFront Med (Lausanne)\nFront. Med.\nFrontiers in Medicine\n2296-858X\nFrontiers Media S.A.\n\n10.3389/fmed.2021.649824\nMedicine\nCase Report\nSuccessful Treatment of Relapsed/Refractory Extramedullary Multiple Myeloma With Anti-BCMA CAR-T Cell Therapy Followed by Haploidentical Hematopoietic Stem Cell Transplantation: A Case Report and a Review of the Contemporary Literature\nQian Ying 1†\nQian Zijun 1†\n\nZhao Xiujie 1\nPan Wenjue 1\nWei Xinzheng 2\nMeng Huimin 34\nYang Lin 34\nXiao Haowen 15*\n\n1Department of Hematology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China\n2Hangzhou Integrative Medicine Hospital, Hangzhou, China\n3PersonGen BioTherapeutics (Suzhou) Co., Ltd., Suzhou, China\n4State Key Laboratory of Radiation Medicine and Protection, Collaborative Innovation Center of Hematology, CyrusTang Medical Institute, Soochow University, Suzhou, China\n5Institute of Hematology, Zhejiang University, Hangzhou, China\nEdited by: Jacalyn Rosenblatt, Beth Israel Deaconess Medical Center and Harvard Medical School, United States\n\nReviewed by: Siddhartha Ganguly, University of Kansas Hospital, United States; Omar Nadeem, Dana–Farber Cancer Institute, United States\n\n*Correspondence: Haowen Xiao haowenxiaoxiao@zju.edu.cn\nThis article was submitted to Gene and Cell Therapy, a section of the journal Frontiers in Medicine\n\n†These authors have contributed equally to this work\n\n07 5 2021\n2021\n8 64982405 1 2021\n22 3 2021\nCopyright © 2021 Qian, Qian, Zhao, Pan, Wei, Meng, Yang and Xiao.\n2021\nQian, Qian, Zhao, Pan, Wei, Meng, Yang and Xiao\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nExtramedullary multiple myeloma (EMM) is an aggressive sub-entity of multiple myeloma (MM). Despite an excellent improvement in survival for most patients with MM over recent decades, the overall survival (OS) of patients with EMM was usually not longer than 3 years. Standard treatment for patients with EMM has not been established, and their management is particularly challenging. We presented a heavily pretreated young patient with relapsed EMM and refractoriness to a proteasome inhibitor (PI; bortezomib), a next-generation PI (ixazomib), immunomodulatory drugs (IMiDs; lenalidomide), autologous hematopoietic stem cell transplantation (ASCT), and monoclonal antibody (directed against CD38: daratumumab) and indicated that myeloablative haploidentical hematopoietic stem cell transplantation (haploidentical-HSCT) as a salvage treatment of relapse after a chimeric antigen receptor (CAR)-T cell therapy that targeted B-cell maturation antigen (BCMA) (NCT04650724) is feasible. Taken together of the contemporary literature, the promising results on the effect of anti-BCMA CAR-T cell therapy and allogeneic HSCT might present a proof-of-principle for patients with EMM, and therefore, patients with the disease need to be included in future studies.\n\nextramedullary multiple myeloma\nchimeric antigen receptor T-cell\nrefractory\nhaploidentical allogeneic hematopoietic stem cell transplantation\nmultiple myeloma\n==== Body\nIntroduction\n\nExtramedullary multiple myeloma (EMM) is an aggressive sub-entity of multiple myeloma (MM). Importantly, the definition of EMM should refer to purely extramedullary disease and so explicitly exclude “solitary extramedullary plasmacytoma” and “bone-related plasmacytomas arising from the neighboring bone marrow” (1, 2). EMM is found in 6–8% of newly diagnosed MM (NDMM) patients, and the prevalence of EMM increases during the disease course with 10–30% of patients (3). Despite an excellent improvement in survival for most patients with MM over recent decades, the outcomes are generally dismal when EMM develops. The overall survival (OS) of patients with EMM in various informative studies was usually not longer than 3 years (2), especially for patients refractory to standard therapies or relapse after autologous hematopoietic stem cell transplantation (ASCT) with a median OS of <1 year (4). Standard treatment for EMM has not been established. Although, most patients with MM respond to modern first-line therapy, current therapies have not sufficiently improved patient outcomes with EMM. Several studies suggested that regimens containing bortezomib and/or immunomodulatory drugs (IMiDs) improved outcomes; however, the gains in progression-free survival (PFS) and OS were less pronounced than those in the case of classic MM (5, 6). Furthermore, most studies consistently showed an inferior outcome of patients with EMM despite the use of ASCT. Even regarding the efficacy of daratumumab, a CD38-targeting antibody, either alone or in combination, the overall response rate was only 16.7% in EMM (7), with a median PFS and OS of 2.3 and 6.6 months, respectively (8). Therefore, innovative strategies are critically needed. This study presented a heavily pretreated patient with relapsed EMM and refractoriness to a proteasome inhibitor (PI; bortezomib), a next-generation PI (ixazomib), IMiDs (lenalidomide), ASCT, and monoclonal antibody (directed against CD38: daratumumab) and indicated that myeloablative haploidentical hematopoietic stem cell transplantation (haploidentical-HSCT) as a salvage treatment of relapse after a chimeric antigen receptor (CAR)-T cell therapy that targeted B-cell maturation antigen (BCMA) is feasible. The study was approved by the Ethics Committee of Sir Run Run Shaw Hospital at Zhejiang University School of Medicine. The study was registered as NCT04650724 at ClinicalTrials.gov. Written informed consent was obtained from the patient for the publication of any potentially identifiable images or data included in this article.\n\nCase Presentation\n\nA 46-year-old female patient was referred to the hospital in August 2018 with a 3-week history of recurrent chest pain. Chest computed tomography (CT) scanning showed a right subpleural extraosseous soft mass (7.6 × 2.06 cm2). Subsequent imaging on whole-spine magnetic resonance imaging and X-ray skeletal survey showed multiple bone destruction of the ribs, vertebrae, and pelvis. Laboratory investigations revealed anemia with a hemoglobin level of 86 g/L, hypercalcemia (3.53 mmol/L), and renal dysfunction (serum creatinine 139 μmol/L). The serum IgG level was 38.8 g/L [normal range (NR) < 15.6 g/L], the IgA level was 12.9 g/L (NR <4.53 g/L), and the serum protein electrophoresis showed a paraprotein of 31 g/L. Further serum immunofixation electrophoresis confirmed double clones of IgA and IgG lambda (λ). The amount of serum λ light chain was 2,780 mg/dl (NR <723 mg/dl). A bone marrow aspirate and biopsy demonstrated λ-restricted clonal plasma cell infiltration (43.6%) with a CD138+, CD38+, CD19−, and CD56+ phenotype. The albumin level was 26.2 g/L, the beta-2-microglobulin level was 6.0 mg/L, and the lactate dehydrogenase level was within normal limits. Fluorescence in situ hybridization confirmed cytogenetics features, including IgH-FGFR3/t (4, 9) translocation, gain of 1q21, and del 13q14. She agreed with the biopsy of the right subpleural extraosseous soft mass. The pathological diagnosis suggested an EMM infiltration, whose genotype was CD38+, CD138+, Kappa−, Lambda+, CD20−, CD3−, Syn−, CgA−, CK-pan−, BCL-2−, PD-1−, and Ki-67 (80%) (Figure 1A). The patient was diagnosed with double clones of IgA/IgG lambda (λ) –MM with EMM (Durie–Salmon stage IIIA, ISS stage III).\n\nFigure 1 Summary of laboratory findings and clinical course. (A) Hematoxylin and eosin staining (original magnification, ×400) and immunohistochemical staining for CD138 (original magnification, ×100), Lambda (original magnification, ×100), and CD38 (original magnification, ×100), BCL-2 (original magnification, ×100) and PD-1 (original magnification, ×100) of the biopsy of the right subpleural extraosseous soft mass. (B) The patient presented with fever with the highest temperature at 39°C 14 days post-CAR-T cells infusion, and her serum ferritin level gradually rose to reach a peak level. The trends of serum interleukin (IL)-6, IL-10, and interferon γ (IFN-γ) concentrations and the expansion trend of CAR-T cells are also shown during the course of CAR-T therapy. (C) Multiple abnormal masses in the right lung disappeared and could not be detected by CT scanning 1 month post-CAR-T cell therapy. (D) The trends of the serum IgA, IgG, and monoclonal protein concentrations (M spike) throughout the treatment.\n\nFollowing 2 cycles of induction chemotherapy with weekly cyclophosphamide, bortezomib, and dexamethasone (CyBorD), the M-band and the right subpleural soft mass could not be detected. After 4 cycles of CyBorD, a CT scan indicated no evidence of abnormal mass in the right lung. No monoclonal band was detected, and the free light chain ratio returned to normal (0.409, upper limit of normal 1.56). She achieved a stringent complete response (sCR) according to the International Myeloma Working Group (IMWG) response criteria. In view of good response, peripheral blood stem cells (PBSCs) were harvested with high dose cyclophosphamide. PBSC harvesting yielded 2.2 × 106/kg CD34-positive stem cells in total.\n\nUnfortunately, when the patient planned to proceed to subsequent ASCT, the right subpleural soft mass recurred with a size of 6.21 × 1.24 cm2. The bone marrow examination revealed no clonal plasma cells. The serum and urine protein electrophoresis showed that the amounts of free light chains were within normal limits. The biopsy of the recurred soft mass was performed again, and the pathological genotype was the same as the de novo mass. The positron emission tomography-CT (PET-CT) scan indicated pleural thickening with abnormal fluorodeoxyglucose uptake. The patient was switched to second-line treatment with VRD (bortezomib, lenalidomide, and dexamethasone) and IRD (ixazomib, lenalidomide, and dexamethasone). She failed to achieve control with the right subpleural extraosseous soft mass enlarged to 9.53 × 2.33 cm2. The patient was treated with three cycles of intensive chemotherapy with the (V) DT-PACE regimen (bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide) because carfilzomib, pomalidomide, and daratumumab were not available at that time in China. Consequently, the soft mass reduced in size and then disappeared and hence could not be detected by CT scanning. In September 2019, ASCT was performed after conditioning with melphalan (140 mg/m2) and bortezomib (1 mg/m2 four times). Thereafter, the right subpleural soft mass could no longer be detected. The patient received maintenance therapy with lenalidomide and bortezomib after transplantation.\n\nHowever, in December 2019, 3 months after ASCT, the size of the subpleural soft mass increased again. Although, the serum monoclonal protein concentration (M-band) reached 3.32 g/L, no clonal plasma cells were detected on bone marrow examination. She received a weekly regimen with daratumumab, bortezomib, and dexamethasone. This combination therapy, however, failed to achieve any response. The patient developed multiple abnormal masses in the right lung with the M-band increased to 6.16 g/L. The patient developed numbness and pain in the right upper limb and limited movement of the right finger due to nerve compression caused by the rapid progression of lung mass. Considering her poor prognosis, the patient was enrolled in a BCMA-targeted CAR-T trial in our center (NCT04650724). The patient's bone marrow sample obtained at diagnosis showed strong positive BCMA expression (95.85%) on the clonal plasma cells, as detected by flow cytometry. On March 9, 2020, the patient was infused with autologous CAR-T cells targeting BCMA at a dose of 1.0 × 106/kg after conditioning chemotherapy of fludarabine and cyclophosphamide. The patient presented with fever 11 days after infusion of CAR-T cells, and the peak of temperature was 39°C on day 14 and lasted for a total of 16 days. Her serum ferritin level and serum interleukin (IL)-6, IL-10, and interferon γ (IFN-γ) concentrations also gradually rose to reach a peak level during CAR-T cell expansion to peak (Figure 1B). Grade 1 cytokine release syndrome (CRS) was considered according to the guidelines of the CARTOX Working Group (10). Under supportive care without use of tocilizumab or glucocorticoid, the patient's body temperature and the inflammatory cytokines returned into NRs within 14 days. The patient also achieved recovery from cytopenia. Four weeks post-CAR-T cell therapy, repeated CT showed no evidence of a subpleural soft mass, and flow cytometry showed minimal residual disease (MRD) negativity in the bone marrow. The M-band was not detected, and immunofixation electrophoresis was negative. The trends of the size of the subpleural soft mass before and after CAR-T cell therapy detected by CT are shown in Figure 1C.\n\nThe disease-free state lasted for 3 months after the infusion of CAR-T cells, and the right subpleural soft mass recurred again with a size of 3.8 × 3.6 cm2. In June 2020, the patient underwent HLA-haploidentical HSCT from her son with a myeloablative conditioning regimen consisting of cytarabine [4 g/(m2 · d) IV on days −10 to −9], Bu [3.2 mg/(m2 · d) IV on days −8 to −6], Cy [1.8 g/(m2 · d) IV on days −3 to −2], and rabbit anti-thymocyte globulin (Genzyme, MA, USA) (7.5 mg/kg total dose). The HLA-haploidentical HSCT was tolerated well with grade 1 mucositis and an episode of fever during the neutropenic phase, managed at the ward level with antimicrobials and supportive care. Another adverse event during the treatment was grade 1 nausea. Complete hematological response and sCR were achieved by day 30 after HSCT. At the moment of writing, the patient was in good clinical condition and had a good performance status. She is currently in a state of sCR with complete donor chimerism. The trends of the serum IgA, IgG, and monoclonal protein concentrations (M spike) throughout the treatment are shown in Figure 1D.\n\nDiscussion\n\nAdvancements in treatment, including the introduction of IMiDs, PIs, and monoclonal antibodies, have prolonged the survival of patients with MM. However, nearly all patients, even those who achieve a complete response, inevitably relapse or become refractory to therapy. A multicenter IMWG study showed that patients with refractory relapsed MM (RRMM), who received at least three prior lines of therapy, were refractory to both an IMiD (lenalidomide or pomalidomide) and a PI (bortezomib or carfilzomib), and were exposed to an alkylating agent, had a median OS of 13 months (11). Daratumumab is a CD38-targeting monoclonal antibody (CD38 MoAB) with remarkable activity in RRMM. Daratumumab monotherapy in heavily pretreated patients with RRMM had an overall response rate of 31% with a median OS of 20.1 months (7). However, patients with MM refractory to CD38 MoAB had a dismal prognosis with a median OS of only 8.6 months (12). Hence, it is clear that new therapeutic approaches need to be developed to further prolong disease control beyond what is afforded by the currently available drugs. The introduction of CAR-modified T cells has revolutionized immunotherapy and cancer treatment as a whole. To date, anti-BCMA CAR-T cells have shown remarkable results in published clinical trials. Data from 18 published phase I/II clinical trials encompassing nearly 300 patients with MM treated with anti-BCMA CAR-T cells showed that the overall response rate was about 64–100% with acceptable rates of grades 3–4 CRS and neurotoxicity (13). Moreover, the efficacy of CAR-T cell therapy was not significantly influenced by previous treatment exposure. In a phase I study involving 33 patients with RRMM, in which 79% of patients were exposed to bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab, the objective response rate of anti-BCMA CAR-T cell therapy was 85%, including 15 patients (45%) with a complete response (14).\n\nHowever, the outcomes remain particularly poor when patients with MM develop EMM. The currently available standard therapies have not sufficiently improved the outcomes for patients with EMM. To the best of our knowledge, there are no prospective clinical trials that have been specifically dedicated to EMM patients. Therefore, it is difficult to recommend a specific treatment strategy over another. CAR-T cell therapy, tandem ASCT, and novel antibodies have recently shown promising results in a limited number of patients with EMM. Herein, the clinical data of these agents are summarized in Table 1.\n\nTable 1 Outcomes of patients with EMM after treatment with CAR-T cell therapy, novel agents, and stem cell transplant.\n\nNumber of MM patients (period covered)\tIncidence of EMM, n (%)\tPrior therapy\tTreatment plan\tORR, OS, or PFS\tReference\t\nCAR-T cell therapy\t\n17 (April to November 2017)\t5 (29.4%)\tBortezomib and lenalidomide for all patients including one patient also receiving carfilzomib, ixazomib, pomalidomide, and ASCT\tAnti-BCMA CAR-T (LCAR-B38M)\tORR: 90%\tXu et al. (15)\t\n33 (January 2016 to April 2018)\t9 (27%)\tBortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab\tAnti-BCMA CAR-T (bb2121)\tORR: 89%\tRaje et al. (14)\t\n25 (November 2015 to December 2017)\t7 (28%)\tBortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, and ASCT\tAnti-BCMA CAR-T\tORR: 57%\tCohen et al. (16)\t\nNovel agents\t\n196 (June 2018 to January 2019)\t40 (20.4%)\tBortezomib, carfilzomib, lenalidomide, pomalidomide, and anti-CD38 monoclonal antibodies (daratumumab, isatuximab)\tBelantamab mafodotin (GSK2857916) (an immunoconjugate targeting BCMA), with 2.5 or 3.4 mg/kg\tORR: 9.1% in 2.5 mg/kg cohort, 5.6% in 3.4 mg/kg cohort\tLonial et al. (17)\t\n157 (December 2016 to October 2019)\t55 (35%)\tAnti-CD38 monoclonal antibodies (daratumumab or others), pomalidomide, proteasome inhibitor, and alkylator therapy\tMelflufen 40 mg intravenously on day 1 of each 28-day cycle plus once weekly oral dexamethasone at a dose of 40 mg (20 mg in patients older than 75 years)\tThe ORR was 29% in the all-treated population, with 26% in the triple-class-refractory population. In the all-treated population, the median duration of response was 5.5 months, median PFS was 4.2 months, and median OS was 11.6 months at a median follow-up of 14 months. Of patients in the extramedullary subgroup, 13 patients achieved a PR or better as the best response.\tRichardson et al. (18)\t\nASCT or allo-HSCT\t\n226 (January 2010 to November 2017)\t176 patients (77.9%) with EMM and 50 patients with bone-related plasmacytomas\tBortezomib, carfilzomib, thalidomide, lenalidomide, and pomalidomide\t100 patients (44.2%) receiving ASCT\tThe median PFS was 49 vs. 28.1 months in patients undergoing ASCT compared with those who did not (P < 0.001).\tBeksac et al. (19)\t\n3,744 adult patients with NDMM (2005–2014)\t139 (3.7%)\tNot reported\tUp-front single ASCT (n = 124), tandem ASCT (n = 15)\tPatients with EMM involvement showed no significant difference in both 3-year PFS and OS after tandem vs. single transplantation: 56.2 (95% CI: 27.2–85.3) vs. 48.3% (95% CI: 36.6–60.1; P = 0.98) and 52.0 (95% CI: 20.0–84.0) vs. 64.9% (95% CI: 54.2–75.7; P = 0.39).\tGagelmann et al. (20)\t\n488 adult patients with NDMM and extramedullary involvement (2003–2015)\t488 (100%)\t355 patients (73%) receiving bortezomib-based induction therapy and 133 patients (27%) receiving non-bortezomib-based induction therapy before first transplant\tSingle ASCT (n = 373), tandem ASCT (n = 84), or auto–allo HSCT (n = 31)\tTandem ASCT was significantly associated with better OS (P = 0.02) and PFS (P = 0.03) than single ASCT, whereas auto–allo HSCT did not show the survival advantage compared with single ASCT or tandem ASCT\tGagelmann et al. (21)\t\n\nData regarding the efficacy of newer classes of drugs, such as carfilzomib, daratumumab, and so on, either alone or in combination, in EMM are limited. Published data suggested that the presence of EMM resulted in a strong trend toward a shorter duration of response than that of classic MM despite treatment with novel drugs (8, 9). In a study to analyze the efficacy of pomalidomide and dexamethasone in 21 patients from 9 hospitals of Catalonia (Spain), with relapsed or refractory MM with paraskeletal plasmacytomas or EMM, there were no responses observed among patients with EMM (22). Recently, an open-label, two-arm, phase 2 study at 58 MM specialty centers in 8 countries was done to investigate the safety and activity of belantamab mafodotin (GSK2857916), an immunoconjugate targeting BCMA, in 196 adult patients with relapsed or refractory MM with disease progression after three or more lines of therapy and who were refractory to IMiDs and PIs and refractory or intolerant (or both) to an anti-CD38 monoclonal antibody. Forty of 196 patients have EMM and achieved an overall response of 9.1% when receiving 2.5 mg/kg of GSK2857916 and 5.6% when receiving 3.4 mg/kg. However, the overall response rates were 31% and 34% in patients without EMM, respectively (17). Richardson recently reported the results of the phase II HORIZON trial with melphalan flufenamide (melflufen) in RRMM, which is a first-in-class peptide–drug conjugate that targets aminopeptidases and rapidly and selectively releases alkylating agents into tumor cells. Of 157 patients with RRMM refractory to pomalidomide and/or an anti-CD38 monoclonal antibody enrolled and treated, 55 (35%) had EMM. Of patients in the extramedullary subgroup, 13 patients achieved a partial remission (PR) or better as the best response to melflufen plus dexamethasone (18).\n\nEmerging cellular therapies, including CAR-T cell therapy, also hold promise to improve the prognosis of EMM. However, data reporting the efficacy of CAR-T cell therapy in EMM are scarce. In clinical trials of anti-BCMA CAR-T cell therapy with available data on patients with extramedullary disease or not, the response rates of 57–90% were observed among patients who had EMM at baseline (14–16) (Table 1). Further, prospective studies of CAR-T cell therapy should be designed for MM patients with EMM.\n\nFew studies suggested that ASCT could overcome the poor prognostic impact of EMM. In a retrospective multi-institutional study from Europe, 100 patients with EMM underwent ASCT, of which 51.5% had primary EMM. Patients undergoing ASCT achieved a superior PFS than those who did not undergo ASCT (median PFS: 49 vs. 28.1 months, P < 0.001) (19). However, most studies consistently showed an inferior outcome despite the use of ASCT (2). With respect to efficacy of tandem ASCT, a study from the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplantation (EBMT) including 3,744 adult MM patients who received up-front single (n = 3,391) or tandem ASCT (n = 353) between 2005 and 2014 with available data on extramedullary involvement at diagnosis, data showed that first-line treatment with tandem ASCT compared with single transplantation resulted in similar survival in patients with extramedullary disease at diagnosis (P = 0.13) (20). Thereafter, the EBMT further conducted a study to analyze data from 488 adult MM patients with EMM, who underwent single ASCT (n = 373), tandem ASCT (n = 84), or autologous–allogeneic transplant (n = 31) between 2003 and 2015. In multivariate analysis, tandem ASCT significantly improved OS and PFS vs. single ASCT and may overcome the poor prognosis of high-risk cytogenetics. However, autologous–allogeneic transplant did not significantly differ in outcomes but appeared to improve OS, but results were limited because of the small population (21) (Table 1).\n\nAllogeneic hematopoietic cell transplantation (allo-HCT) is one of the most promising ways of restoring the immune system's ability to recognize and destroy MM cells and is currently the only potentially curative approach for patients with MM. However, the cumulative incidence of relapse after allo-HCT was significantly lower; this therapeutic modality was severely hampered by the high treatment-related morbidity and mortality (23, 24). Allo-HSCT might benefit carefully selected patients with a median OS of 39.2 months; the non-relapse mortality (NRM) was relatively low with a cumulative incidence of 12.4% after 10 years (25). Few studies explored the efficacy of HLA-haploidentical HSCT in MM. A multicenter investigation from China compared the main outcomes of haploidentical HSCT in patients with MM with the outcomes of HLA-matched sibling HSCT. The data showed no statistically significant differences in relapse, NRM, PFS, and OS between the two groups (26). A report from the EBMT/Center for International Blood and Marrow Transplant Research (CIBMTR) suggested that haploidentical HSCT was feasible for patients with multiply relapsed or high-risk MM, with an encouraging 2-year OS of 48% and an NRM of 21% at 1 year, supporting further investigation of haploidentical HSCT in suitable candidates with MM (27).\n\nAlthough, in some patients, CAR-T cell therapy can induce sustained remission and replace allo-HSCT. CAR-T cells combined with HSCT may be a more effective strategy to decrease the risk of relapse. Clinical trials are now needed to address the relative roles of CAR-T cells and HSCT in the context of transplantation-eligible patients. Anti-CD19 CAR-T therapy as consolidation therapy after high-dose melphalan and autologous HSCT has been used to a patient with refractory MM at the University of Pennsylvania, which led to a CR with no evidence of progression and no measurable serum or urine monoclonal protein at 12 months after treatment (28). As one way to prevent relapse, CAR-T cells can induce remissions as a bridge to allo-HSCT in B-cell malignancies (29). Our patient relapsed after anti-BCMA CAR-T cell therapy and was rescued by a haploidentical HSCT. The follow-up after haploidentical HSCT to our case is short and needs longer follow-up to confirm the efficiency of haploidentical HSCT to maintain remission. Transplantation-related mortality, such as graft-versus-host disease (GVHD), should also be paid attention to. We can only conclude that myeloablative haploidentical HSCT as a salvage treatment of relapse after anti-BCMA CAR-T cell therapy is feasible. Although anti-BCMA CAR-T cell therapy provides very high rate of response in RRMM, most of the studies still show PFS less than a year. Maintenance regimens post-CAR-T cell therapy, such as subsequently planned allo-HSCT or subsequent multiple CAR-T cell infusions over time, or maintenance treatment with PIs and/or IMiDs should be considered as some of the future directions.\n\nIn conclusion, the present case study highlighted the poor outcome for patients with relapsed refractory EMM. The findings indicated that these patients needed more specific and less toxic ways of exploiting the myeloma-targeting capabilities of the immune system. In the future, subgroup analyses of large prospective trials focusing on EMM should be conducted to address this issue.\n\nData Availability Statement\n\nThe datasets presented in this article are not readily available. Requests to access the datasets should be directed to haowenxiaoxiao@zju.edu.cn.\n\nEthics Statement\n\nThe studies involving human participants were reviewed and approved by the study was approved by the Ethics Committee of Sir Run Run Shaw Hospital at Zhejiang University School of Medicine. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\n\nHX, YQ, and LY designed the research study. HX, ZQ, and XZ analyzed the data and wrote the paper. HM and LY provided the CAR-T cells and performed the related experiments. YQ, XZ, WP, and HX treated and managed the patient. All authors contributed to the article and approved the submitted version.\n\nConflict of Interest\n\nHM and LY were employed by the company PersonGen BioTherapeutics (Suzhou) Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nSupplementary Material\n\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fmed.2021.649824/full#supplementary-material\n\nClick here for additional data file.\n\nFunding. This work was supported by the National Natural Science Foundation of China (no. 81870136).\n==== Refs\nReferences\n\n1. Weinstock M Ghobrial IM . Extramedullary multiple myeloma. Leuk Lymphoma. (2013) 54 :1135–41. 10.3109/10428194.2012.740562 23210572\n2. Bhutani M Foureau DM Atrash S Voorhees PM Usmani SZ . Extramedullary multiple myeloma. Leukemia. (2020) 34 :1–20. 10.1038/s41375-019-0660-0 31776467\n3. Touzeau C Moreau P . How i treat extramedullary myeloma. Blood. (2016) 127 :971–6. 10.1182/blood-2015-07-635383 26679866\n4. Pour L Sevcikova S Greslikova H Kupska R Majkova P Zahradova L . Soft-tissue extramedullary multiple myeloma prognosis is significantly worse in comparison to bone-related extramedullary relapse. Haematologica. (2014) 99 :360–4. 10.3324/haematol.2013.094409 24038024\n5. Mangiacavalli S Pompa A Ferretti V Klersy C Cocito F Varettoni M . The possible role of burden of therapy on the risk of myeloma extramedullary spread. Ann Hematol. (2017) 96 :73–80. 10.1007/s00277-016-2847-z 27766391\n6. Kumar L Gogi R Patel AK Mookerjee A Sahoo RK Malik PS . Multiple myeloma with extramedullary disease: impact of autologous stem cell transplantation on outcome. Bone Marrow Transplant. (2017) 52 :1473–5. 10.1038/bmt.2017.165 28805789\n7. Usmani SZ Weiss BM Plesner T Bahlis NJ Belch A Lonial S . Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma. Blood. (2016) 128 :37–44. 10.1182/blood-2016-03-705210 27216216\n8. Pick M Vainstein V Goldschmidt N Lavie D Libster D Gural A . Daratumumab resistance is frequent in advanced-stage multiple myeloma patients irrespective of CD38 expression and is related to dismal prognosis. Eur J Haematol. (2018) 100 :494–501. 10.1111/ejh.13046 29453884\n9. Muchtar E Gatt ME Rouvio O Ganzel C Chubar E. C. Suriu . Efficacy and safety of salvage therapy using Carfilzomib for relapsed or refractory multiple myeloma patients: a multicentre retrospective observational study. Br J Haematol. (2016) 172 :89–96. 10.1111/bjh.13799 26567759\n10. Neelapu SS Tummala S Kebriaei P Wierda W Gutierrez C Locke FL . Chimeric antigen receptor T-cell therapy - assessment and management of toxicities. Nat Rev Clin Oncol. (2018) 15 :47–62. 10.1038/nrclinonc.2017.148 28925994\n11. Kumar SK Dimopoulos MA Kastritis E Terpos E Nahi H Goldschmidt H . Natural history of relapsed myeloma, refractory to immunomodulatory drugs and proteasome inhibitors: a multicenter IMWG study. Leukemia. (2017) 31 :2443–8. 10.1038/leu.2017.138 28620163\n12. Gandhi UH Cornell RF Lakshman A Gahvari ZJ McGehee E Jagosky MH . Outcomes of patients with multiple myeloma refractory to CD38-targeted monoclonal antibody therapy. Leukemia. (2019) 33 :2266–75. 10.1038/s41375-019-0435-7 30858549\n13. Susanibar Adaniya SP Cohen AD Garfall AL . Chimeric antigen receptor T cell immunotherapy for multiple myeloma: a review of current data and potential clinical applications. Am J Hematol. (2019) 94 :S28–33. 10.1002/ajh.25428 30730071\n14. Raje N Berdeja J Lin Y Siegel D Jagannath S Madduri D . Anti-BCMA CAR T-Cell Therapy bb2121 in relapsed or refractory multiple myeloma. N Engl J Med. (2019) 380 :1726–37. 10.1056/NEJMoa1817226 31042825\n15. Xu J Chen LJ Yang SS Sun Y Wu W Liu YF . Exploratory trial of a biepitopic CAR T-targeting B cell maturation antigen in relapsed/refractory multiple myeloma. Proc Natl Acad Sci U S A. (2019) 116 :9543–51. 10.1073/pnas.1819745116 30988175\n16. Cohen D Garfall AL Stadtmauer EA Melenhorst JJ Lacey SF Lancaster E . B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma. J Clin Invest. (2019) 129 :2210–21. 10.1172/JCI126397 30896447\n17. Lonial S Lee HC Badros A Trudel S Nooka AK Chari A . Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study. Lancet Oncol. (2020) 21 :207–21. 10.1016/S1470-2045(19)30788-0 31859245\n18. Richardson PG Oriol A Larocca A Blade J Cavo MP Rodriguez-Otero . Melflufen and dexamethasone in heavily pretreated relapsed and refractory multiple myeloma. J Clin Oncol. (2021) 39 :757–67. 10.1200/JCO.20.02259 33296242\n19. Beksac M Seval GC Kanellias N Coriu D Rosinol L Ozet G . A real world multicenter retrospective study on extramedullary disease from Balkan Myeloma Study Group and Barcelona University: analysis of parameters that improve outcome. Haematologica. (2020) 105 :201–8. 10.3324/haematol.2019.219295 31278209\n20. Gagelmann N Eikema DJ Iacobelli S Koster L Nahi H Stoppa AM . Impact of extramedullary disease in patients with newly diagnosed multiple myeloma undergoing autologous stem cell transplantation: a study from the Chronic Malignancies Working Party of the EBMT. Haematologica. (2018) 103 :890–7. 10.3324/haematol.2017.178434 29419433\n21. Gagelmann N Eikema DJ Koster L Caillot D Pioltelli P Lleonart JB . Tandem autologous stem cell transplantation improves outcomes in newly diagnosed multiple myeloma with extramedullary disease and high-risk cytogenetics: a study from the Chronic Malignancies Working Party of the European Society for blood and marrow transplantation. Biol Blood Marrow Transplant. (2019) 25 :2134–42. 10.1016/j.bbmt.2019.07.004 31288095\n22. Jimenez-Segura R Granell M Gironella M Abella E Garcia-Guinon A Oriol A . Pomalidomide-dexamethasone for treatment of soft-tissue plasmacytomas in patients with relapsed/refractory multiple myeloma. Eur J Haematol. (2019) 102 :389–94. 10.1111/ejh.13217 30719772\n23. Lokhorst H Einsele H Vesole D Bruno B San Miguel J Perez-Simon JA . International Myeloma Working Group consensus statement regarding the current status of allogeneic stem-cell transplantation for multiple myeloma. J Clin Oncol. (2010) 28 :4521–30. 10.1200/JCO.2010.29.7929 20697091\n24. Vekemans MC Michaux L Van Den Neste E Ferrant A . Long-term survival after allogeneic stem cell transplantation for advanced stage multiple myeloma. Br J Haematol. (2014) 166 :616–8. 10.1111/bjh.12881 24697308\n25. Greil C Engelhardt M Ihorst G Schoeller K Bertz H Marks R . Allogeneic transplantation of multiple myeloma patients may allow long-term survival in carefully selected patients with acceptable toxicity and preserved quality of life. Haematologica. (2019) 104 :370–9. 10.3324/haematol.2018.200881 30237266\n26. Chen Y Fu WJ Xu LP Ren HY Lai YR Liu DH . Comparison of outcomes after human leukocyte antigen-matched and haploidentical hematopoietic stem-cell transplantation for multiple myeloma. Chin Med J. (2019) 132 :1765–72. 10.1097/CM9.0000000000000341 31306219\n27. Sahebi F Garderet L Kanate AS Eikema DJ Knelange NS Alvelo OFD . Outcomes of haploidentical transplantation in patients with relapsed multiple myeloma: An EBMT/CIBMTR Report. Biol Blood Marrow Transplant. (2019) 25 :335–42. 10.1016/j.bbmt.2018.09.018 30243581\n28. Garfall L Maus MV Hwang WT Lacey SF Mahnke YD Melenhorst JJ . Chimeric antigen receptor T cells against CD19 for multiple myeloma. N Engl J Med. (2015) 373 :1040–7. 10.1056/NEJMoa1504542 26352815\n29. Kenderian SS Porter DL Gill S . Chimeric antigen receptor T cells and hematopoietic cell transplantation: how not to put the CART before the horse. Biol Blood Marrow Transplant. (2017) 23 :235–46. 10.1016/j.bbmt.2016.09.002 27638367\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2296-858X",
"issue": "8()",
"journal": "Frontiers in medicine",
"keywords": "chimeric antigen receptor T-cell; extramedullary multiple myeloma; haploidentical allogeneic hematopoietic stem cell transplantation; multiple myeloma; refractory",
"medline_ta": "Front Med (Lausanne)",
"mesh_terms": null,
"nlm_unique_id": "101648047",
"other_id": null,
"pages": "649824",
"pmc": null,
"pmid": "34026784",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "31306219;30243581;29419433;24697308;26567759;28805789;26679866;20697091;24038024;30896447;26352815;31042825;30719772;28925994;27638367;31776467;31288095;30237266;23210572;27216216;31278209;30858549;30730071;29453884;30988175;31859245;28620163;33296242;27766391",
"title": "Successful Treatment of Relapsed/Refractory Extramedullary Multiple Myeloma With Anti-BCMA CAR-T Cell Therapy Followed by Haploidentical Hematopoietic Stem Cell Transplantation: A Case Report and a Review of the Contemporary Literature.",
"title_normalized": "successful treatment of relapsed refractory extramedullary multiple myeloma with anti bcma car t cell therapy followed by haploidentical hematopoietic stem cell transplantation a case report and a review of the contemporary literature"
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"companynumb": "CN-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-320425",
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"abstract": "OBJECTIVE\nThe extent to which adverse cognitive effects (ACEs) to a specific antiepileptic drug (AED) affect the chance of developing ACEs to other AEDs (i.e., cross-sensitivity) is unknown. We investigated the rates of cross-sensitivity of ACEs among AEDs and examined the association between clinical characteristics and occurrence of having ACEs to multiple AEDs in adults with epilepsy.\n\n\nMETHODS\nThe rates of cross-sensitivity of intolerable ACEs (IACEs; i.e., ACEs leading to dosage reduction or discontinuation) and the non-AED predictors of IACEs were investigated in 2269 patients who had taken at least two AEDs at a single center. We accounted for AED load and looked for specific cross-sensitivities between AEDs as well as cross-sensitivity based on the AED mechanism of action.\n\n\nRESULTS\nAmong the 2269 patients, the highest rates of IACEs were seen with TPM (26.3%), ZNS (9.8%), PHT (8.8%), and VPA (8.5%). Intolerable ACEs to two or more AEDs occurred in 100 patients (4.4%). History of psychiatric condition(s) and absence seizure type were independent predictors of IACEs to two or more AEDs. High rates of cross-sensitivity of IACEs were seen between phenytoin (PHT) and lamotrigine (LTG), valproate (VPA) and phenytoin, and valproate and zonisamide (ZNS). For example, of patients who had IACEs to VPA and were also prescribed ZNS, 46.2% had IACEs to ZNS (abbreviated as VPA→ZNS: 46.2%); of patients who had IACEs to ZNS and were also prescribed VPA, 37.5% had IACEs to VPA (abbreviated as ZNS→VPA: 37.5%). Other results are as follows: LTG→PHT: 28.6%, PHT→LTG: 20.0%, PHT→VPA: 42.9%, and VPA→PHT: 27.3%. No specific cross-sensitivities were found among AEDs sharing a similar mechanism of action.\n\n\nCONCLUSIONS\nThe probability of ACE intolerability to an AED can increase if a patient developed ACE intolerability to another AED. The cross-sensitivity rates for ACE intolerability between LTG and PHT, PHT and VPA, and VPA and ZNS were found to be particularly high. The cross-sensitivity rates provided here may be clinically useful for predicting ACE intolerability in patients taking certain AEDs and for AED selection in individual patients.",
"affiliations": "Department of Neurology, Yale University, New Haven, CT, USA. Electronic address: baibing.chen@yale.edu.;Department of Neurology, Yale University, New Haven, CT, USA.;Department of Neurology, Yale University, New Haven, CT, USA.;Department of Neurology, Yale University, New Haven, CT, USA.;Department of Neurology, Columbia University, New York, NY, USA.;Department of Neurology, Columbia University, New York, NY, USA.;Department of Neurology, Columbia University, New York, NY, USA.;Department of Neurology, Columbia University, New York, NY, USA.;Department of Neurology, Columbia University, New York, NY, USA.",
"authors": "Chen|Baibing|B|;Detyniecki|Kamil|K|;Hirsch|Lawrence J|LJ|;Moeller|Jeremy|J|;Javed|Asif|A|;Kato|Kenneth|K|;Legge|Alexander|A|;Buchsbaum|Richard|R|;Choi|Hyunmi|H|",
"chemical_list": "D000927:Anticonvulsants",
"country": "United States",
"delete": false,
"doi": null,
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"issn_linking": "1525-5050",
"issue": "46()",
"journal": "Epilepsy & behavior : E&B",
"keywords": "Adverse effects; Antiepileptic drug; Cognitive; Cross-sensitivity",
"medline_ta": "Epilepsy Behav",
"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D003072:Cognition Disorders; D004827:Epilepsy; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "100892858",
"other_id": null,
"pages": "151-7",
"pmc": null,
"pmid": "25935515",
"pubdate": "2015-05",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Cross-sensitivity of patient-perceived adverse cognitive effects with antiepileptic drug use.",
"title_normalized": "cross sensitivity of patient perceived adverse cognitive effects with antiepileptic drug use"
} | [
{
"companynumb": "US-JNJFOC-20150803692",
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"occurcountry": "US",
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"activesubstance": {
"activesubstancename": "TOPIRAMATE"
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{
"abstract": "Use of nonsteroidal anti-inflammatory drugs (NSAIDs) during pregnancy may increase risk for neural tube defects (NTDs), including spina bifida. Folic acid intake can prevent NTDs, but it is not known whether it modifies any risks associated with NSAID use.\n\n\n\nTo assess the impact of periconceptional NSAID use on the risk of spina bifida overall and stratified by folic acid intake.\n\n\n\nWe analyzed 1998-2015 data from the Slone Epidemiology Center Birth Defects Study, a multi-site, case-control study. Mothers were interviewed to identify sociodemographic factors, behaviors, and exposures during pregnancy. Periconceptional NSAID use was defined as use of aspirin, ibuprofen, naproxen, or COX2 inhibitors within the month before or after the last menstrual period. Logistic regression models were used to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for NSAID use, adjusted for study center and race/ethnicity stratified by average daily folic acid intake above (\"high FA\") or below (\"low FA\") 400 mcg/day.\n\n\n\nWe compared mothers of 267 infants with spina bifida to mothers of 6,233 nonmalformed controls. Among control mothers, 20% used NSAIDS periconceptionally (16% ibuprofen, 4% aspirin, 3% naproxen, and <1% COX-2 inhibitors). For any NSAID use, the aORs among low FA and high FA women were 1.70 (95% CI [1.13, 2.57]) and 1.09 (95% CI [0.69, 1.71]), respectively.\n\n\n\nWe observed a small increase in the risk for spina bifida among infants born to women who used NSAIDs periconceptionally, but this risk was limited to those who had inadequate folic acid intake.",
"affiliations": "Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts, USA.;Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts, USA.;Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts, USA.;National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.;Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts, USA.",
"authors": "Esposito|Daina B|DB|0000-0003-2894-0523;Parker|Samantha E|SE|;Mitchell|Allen A|AA|;Tinker|Sarah C|SC|0000-0002-7610-6288;Werler|Martha M|MM|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D004364:Pharmaceutical Preparations; D005492:Folic Acid",
"country": "United States",
"delete": false,
"doi": "10.1002/bdr2.1944",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "113(17)",
"journal": "Birth defects research",
"keywords": "folic acid; neural tube defects; nonsteroidal anti-inflammatory drugs; pregnancy; spina bifida",
"medline_ta": "Birth Defects Res",
"mesh_terms": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D016022:Case-Control Studies; D005260:Female; D005492:Folic Acid; D006801:Humans; D007223:Infant; D004364:Pharmaceutical Preparations; D011247:Pregnancy; D016135:Spinal Dysraphism",
"nlm_unique_id": "101701004",
"other_id": null,
"pages": "1257-1266",
"pmc": null,
"pmid": "34346174",
"pubdate": "2021-10-15",
"publication_types": "D016428:Journal Article; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": null,
"title": "Periconceptional nonsteroidal anti-inflammatory drug use, folic acid intake, and the risk of spina bifida.",
"title_normalized": "periconceptional nonsteroidal anti inflammatory drug use folic acid intake and the risk of spina bifida"
} | [
{
"companynumb": "US-JNJFOC-20170919189",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null,
... |
{
"abstract": "International guidelines suggest hepatitis C virus (HCV) eradication by direct-acting antivirals (DAAs) after first-line immunochemotherapy (I-CT) in patients with HCV-positive diffuse large B-cell lymphoma (DLBCL), although limited experiences substantiate this recommendation. Moreover, only a few data concerning concurrent administration of DAAs with I-CT have been reported.\n\n\n\nWe analyzed hematological and virological outcome and survival of 47 consecutive patients with HCV-positive DLBCL treated at 23 Italian and French centers with DAAs either concurrently (concurrent cohort [ConC]: n = 9) or subsequently (sequential cohort [SeqC]: n = 38) to first-line I-CT (mainly rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone [R-CHOP]-like).\n\n\n\nMedian age was 61 years, 89% of patients had stage III/IV, and 25% presented evidence of cirrhosis. Genotype was 1 in 56% and 2 in 34% of cases. Overall, 46 of 47 patients obtained complete response to I-CT. All patients received appropriate DAAs according to genotype, mainly sofosbuvir-based regimens (n = 45). Overall, 45 patients (96%) achieved sustained virological response, 8 of 9 in ConC and 37 of 38 in SeqC. DAAs were well tolerated, with only 11 patients experiencing grade 1-2 adverse events. Twenty-three patients experienced hepatic toxicity (grade 3-4 in seven) following I-CT in SeqC, compared to only one patient in ConC. At a median follow-up of 2.8 years, two patients died (2-year overall survival, 97.4%) and three progressed (2-year progression-free survival, 93.1%).\n\n\n\nExcellent outcome of this cohort of HCV-positive DLBCL suggests benefit of HCV eradication by DAAs either after or during I-CT. Moreover, concurrent DAAs and R-CHOP administration appeared feasible, effective, and ideally preferable to deferred administration of DAAs for the prevention of hepatic toxicity.\n\n\n\nHepatitis C virus (HCV)-associated diffuse large B-cell lymphomas (DLBCLs) represent a great therapeutic challenge, especially in terms of hepatic toxicity during immune-chemotherapy (I-CT) and long-term hepatic complications. The advent of highly effective and toxicity-free direct-acting antivirals (DAAs) created an exciting opportunity to easily eradicate HCV shortly after or in concomitance with first-line immunochemotherapy (usually R-CHOP). This retrospective international study reports the real-life use of the combination of these two therapeutic modalities either in the concurrent or sequential approach (DAAs after I-CT) in 47 patients. The favorable reported results on long-term outcome seem to support the eradication of HCV with DAAs in all patients with HCV-positive DLBCL. Moreover, the results from the concurrent approach were effective and safe and displayed an advantage in preventing hepatic toxicity during I-CT.",
"affiliations": "Hematology, University Hospital Ospedale di Circolo e Fondazione Macchi-ASST Sette Laghi, University of Insubria, Varese, Italy michele.merli@asst-settelaghi.it.;Department of Molecular Medicine, University of Pavia, Pavia, Italy.;Department of Internal Medicine and Digestive Diseases, University Hospital Toulouse, UMR 152 PharmaDev, IRD Toulouse 3 University, France.;Cell Therapy and Hematology, Ospedale San Bortolo, Vicenza, Italy.;Unit of Hematology-Oncology, Centre Hospitalier de Versailles, Le Chesnay; Université Versailles Saint Quentin en Yvelines; INSERM U1018, Centre pour la Recherche en Epidemiologie et Sante des Populations (CESP), Equipe Generations et Sante, Gustave Roussy, Villejuif, France.;Hematology, Azienda Ospedaliera Careggi, Florence, Italy.;Cellular Biotechnologies and Hematology, Sapienza University of Rome, Rome, Italy.;Hematology Unit, Azienda Unità Sanitaria Locale-IRCCS Reggio Emilia, Italy.;Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.;Translational Medicine, University of Piemonte Orientale UPO, Novara, Italy.;Medicine-Hematology, University of Padova, Padova, Italy.;Hepatology, Centre Hospitalier Universitaire de Limoges, U-1248 INSERM, Université de Limoges, Limoges, France.;Haematology Unit, Azienda AUSL, Piacenza, Italy.;Department of Clinical and Experimental Oncology, Veneto Institute of Oncology, IOV IRCCS, Padova, Italy.;Oncology and Hematology, AOU \"Luigi Vanvitelli\", Naples, Italy.;Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.;Hematology and Oncology, Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan, Italy.;Onco-Hematology, Hematology Unit, AO of Cosenza, Cosenza, Italy.;Hematology, Azienda Ospedaliera Senese, University of Siena, Siena, Italy.;Infectious Diseases, University of Catania, Catania, Italy.;Hepatology, Ospedale San Giuseppe IRCCS Multimedica, University of Milan, Milan, Italy.;Department of Molecular Medicine, University of Pavia, Pavia, Italy.;Infectious and Tropical Diseases, University Hospital Ospedale di Circolo e Fondazione Macchi - ASST Sette Laghi, University of Insubria, Varese, Italy.;Division of Hematology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.;Division of Hematology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.;Cell Therapy and Hematology, Ospedale San Bortolo, Vicenza, Italy.;Hematology Department, Centre Hospitalier de Versailles, Versailles, France.;Infectious and Tropical Diseases, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy.;Hematology, University Hospital Ospedale di Circolo e Fondazione Macchi-ASST Sette Laghi, University of Insubria, Varese, Italy.;Department of Molecular Medicine, University of Pavia, Pavia, Italy.",
"authors": "Merli|Michele|M|0000-0002-0905-5927;Frigeni|Marco|M|;Alric|Laurent|L|;Visco|Carlo|C|;Besson|Caroline|C|;Mannelli|Lara|L|;Di Rocco|Alice|A|;Ferrari|Angela|A|;Farina|Lucia|L|;Pirisi|Mario|M|;Piazza|Francesco|F|;Loustaud-Ratti|Véronique|V|;Arcari|Annalisa|A|;Marino|Dario|D|;Sica|Antonello|A|;Goldaniga|Maria|M|;Rusconi|Chiara|C|;Gentile|Massimo|M|;Cencini|Emanuele|E|;Benanti|Francesco|F|;Rumi|Maria Grazia|MG|;Ferretti|Virginia Valeria|VV|;Grossi|Paolo|P|;Gotti|Manuel|M|;Sciarra|Roberta|R|;Tisi|Maria Chiara|MC|;Cano|Isabel|I|;Zuccaro|Valentina|V|;Passamonti|Francesco|F|;Arcaini|Luca|L|",
"chemical_list": "D000998:Antiviral Agents; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.1634/theoncologist.2018-0331",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-7159",
"issue": "24(8)",
"journal": "The oncologist",
"keywords": "Diffuse large B‐cell lymphoma; Direct‐acting antivirals; Hepatitis C virus; R‐CHOP",
"medline_ta": "Oncologist",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D000998:Antiviral Agents; D003520:Cyclophosphamide; D018572:Disease-Free Survival; D004317:Doxorubicin; D005260:Female; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006801:Humans; D015994:Incidence; D007558:Italy; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008875:Middle Aged; D011241:Prednisone; D012189:Retrospective Studies; D000069283:Rituximab; D014750:Vincristine",
"nlm_unique_id": "9607837",
"other_id": null,
"pages": "e720-e729",
"pmc": null,
"pmid": "30552159",
"pubdate": "2019-08",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": "12714514;14504078;16418500;17087949;18387498;18678434;19132749;19957347;20823454;23542089;24270404;24795199;24799461;25113753;25417909;26104059;26712592;26850490;26980727;27501007;27605512;27667367;27730654;28140702;28378929;28683174;28714143;28939993;28949959;29045541;29047108",
"title": "Direct-Acting Antivirals in Hepatitis C Virus-Associated Diffuse Large B-cell Lymphomas.",
"title_normalized": "direct acting antivirals in hepatitis c virus associated diffuse large b cell lymphomas"
} | [
{
"companynumb": "IT-BAUSCH-BL-2019-026347",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nTo investigate retrospectively the effects of bone metastases and bisphosphonates in sunitinib-treated metastatic renal cell carcinoma patients.\n\n\nMETHODS\nPatients in Groups (Gp) 1 and 2, but not Gp3, had bone metastases. Gp2 received bisphosphonates following standard practice.\n\n\nRESULTS\nGp2 had less favorable prognosis than Gp1. Gp3 had fewer metastases and the best prognosis. More serious adverse events occurred in Gp2 versus Gp1. The difference in overall survival between Gp1 and Gp2 was not significant after adjusting for covariates. Significantly shorter overall survival in Gp1 versus Gp3 persisted after adjusting for covariates.\n\n\nCONCLUSIONS\nBone metastases may have a negative prognostic impact in metastatic renal cell carcinoma. Bisphosphonates may have delayed early disease progression for prognostically worse sunitinib/bisphosphonate-treated patients.",
"affiliations": "Centre of Oncology, Medical School Split, University Hospital Split, Split, Spinciceva 1, 21000 Split, Croatia.;Royal Marsden Hospital, Fulham Road, London, SW3 6JJ, UK.;Pfizer, Boulevard de la Plaine 17, 1050 Elsene/Ixelles (Brussels), Belgium.;Department of Oncology, Central Clinical Hospital, Military Institute of Medicine, Szaserόw 128, 00-909 Warsaw, Poland.;Biotherapy Department, N. N. Blokhin Russian Cancer Research Centre, 24 Kashirskoe Shosse, Moscow 115478, Russia.;University Hospitals Leuven, Leuven Cancer Institute, Herestraat 49, 3000 Leuven, Belgium.;Department of Oncotherapy, University of Szeged, Korányi fasor 12, 6720, Szeged, Hungary.;Department of Medical Oncology, National Cancer Institute, Vlárska 7, 833 91 Bratislava, Slovakia.;Pfizer, 10646 Science Center Drive, La Jolla, San Diego, CA 92121, USA.;Pfizer, 235 East 42nd Street, New York, NY 10017, USA.;Department of Oncology, Assaf Harofeh Medical Center Zerifin, Beer Yacov, Tel Aviv 70300, Israel.",
"authors": "Vrdoljak|Eduard|E|;Gore|Martin|M|;Leyman|Sophie|S|;Szczylik|Cezary|C|;Kharkevich|Galina|G|;Schöffski|Patrick|P|;Torday|Laszlo|L|;Mardiak|Josef|J|;Zhang|Ke|K|;Sajben|Peter|P|;Sella|Avishay|A|",
"chemical_list": "D000970:Antineoplastic Agents; D050071:Bone Density Conservation Agents; D007211:Indoles; D011758:Pyrroles; D000077210:Sunitinib",
"country": "England",
"delete": false,
"doi": "10.2217/fon.15.140",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1479-6694",
"issue": "11(20)",
"journal": "Future oncology (London, England)",
"keywords": "VEGF; angiogenesis inhibitor; metastasis; pamidronate; renal cell carcinoma; sunitinib; zoledronic acid",
"medline_ta": "Future Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D050071:Bone Density Conservation Agents; D001859:Bone Neoplasms; D002292:Carcinoma, Renal Cell; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007211:Indoles; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms; D008297:Male; D008875:Middle Aged; D011758:Pyrroles; D000077210:Sunitinib; D055815:Young Adult",
"nlm_unique_id": "101256629",
"other_id": null,
"pages": "2831-40",
"pmc": null,
"pmid": "26118456",
"pubdate": "2015",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Bisphosphonates in patients with renal cell carcinoma and bone metastases: a sunitinib global expanded-access trial subanalysis.",
"title_normalized": "bisphosphonates in patients with renal cell carcinoma and bone metastases a sunitinib global expanded access trial subanalysis"
} | [
{
"companynumb": "HR-ROCHE-1735025",
"fulfillexpeditecriteria": "1",
"occurcountry": "HR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBANDRONIC ACID"
},
"drugadditional": "3",
"... |
{
"abstract": "Refractory cardiogenic and vasoplegic shock after congenital heart surgery is a threatening condition leading to high morbidity and mortality. Control of hemodynamic and inflammatory response is fundamental in medical strategy. We report the case of a newborn with cardiogenic and vasoplegic shock secondary to cardiopulmonary bypass for atrioseptostomy and prostaglandin treatment in the context of hypoplastic left heart syndrome, successfully treated with a combination of mechanical circulatory support and cytokine hemoadsorption column (CytoSorb®). Vasopressor support was weaned during the time of treatment without multiple organ failure occurrence. The use of CytoSorb® cartridge inserted in an extra-corporeal circuit even in a newborn is easy and feasible, as long as some precautions are considered. Routine monitoring of drugs levels is mandatory during the use of the cartridge and immediately after.",
"affiliations": "1 Paediatric Intensive Care Unit, Department of Paediatrics, Lausanne University Hospital (CHUV), Lausanne, Switzerland.;1 Paediatric Intensive Care Unit, Department of Paediatrics, Lausanne University Hospital (CHUV), Lausanne, Switzerland.;1 Paediatric Intensive Care Unit, Department of Paediatrics, Lausanne University Hospital (CHUV), Lausanne, Switzerland.;1 Paediatric Intensive Care Unit, Department of Paediatrics, Lausanne University Hospital (CHUV), Lausanne, Switzerland.;1 Paediatric Intensive Care Unit, Department of Paediatrics, Lausanne University Hospital (CHUV), Lausanne, Switzerland.;1 Paediatric Intensive Care Unit, Department of Paediatrics, Lausanne University Hospital (CHUV), Lausanne, Switzerland.;2 Adult Intensive Care Unit, Lausanne University Hospital (CHUV), Lausanne, Switzerland.;1 Paediatric Intensive Care Unit, Department of Paediatrics, Lausanne University Hospital (CHUV), Lausanne, Switzerland.;3 Paediatric Cardiology Unit, Department of Paediatrics, Lausanne University Hospital (CHUV), Lausanne, Switzerland.",
"authors": "Perez|Marie-Hélène|MH|;Maitre|Guillaume|G|;Longchamp|David|D|;Amiet|Vivianne|V|;Natterer|Julia|J|;Ferry|Thomas|T|;Schneider|Antoine|A|;Plaza Wuthrich|Sonia|S|;Di Bernardo|Stefano|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/0391398819837539",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0391-3988",
"issue": "42(9)",
"journal": "The International journal of artificial organs",
"keywords": "CytoSorb; cardiogenic shock; mechanical cardiac support; vasoplegic shock",
"medline_ta": "Int J Artif Organs",
"mesh_terms": "D002315:Cardiopulmonary Bypass; D015199:Extracorporeal Membrane Oxygenation; D006330:Heart Defects, Congenital; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D011183:Postoperative Complications; D012770:Shock, Cardiogenic; D016060:Sorption Detoxification",
"nlm_unique_id": "7802649",
"other_id": null,
"pages": "521-524",
"pmc": null,
"pmid": "30968739",
"pubdate": "2019-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "CytoSorb® hemoadsorption and mechanical circulatory support in a newborn with refractory shock after congenital heart surgery.",
"title_normalized": "cytosorb hemoadsorption and mechanical circulatory support in a newborn with refractory shock after congenital heart surgery"
} | [
{
"companynumb": "CH-TEVA-2019-CH-1128735",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MILRINONE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nThis study aims to evaluate the efficacy and safety of crizotinib for advanced ALK-positive non-small cell lung cancer (NSCLC) patients.\n\n\nMETHODS\nTwenty-eight patients with advanced ALK-positive NSCLC were given orally crizotinib 250 mg b. i.d., and were followed up to evaluate the therapeutic efficacy and safety.\n\n\nRESULTS\nAmong the 28 patients, the objective response rate (ORR) was 71.4% (20/28) and disease control rate (DCR) was 92.9% (26/28). Three patients achieved complete response. Seventeen patients had partial response. The most common drug-related adverse events were mild flickering vision and gastrointestinal reaction. Eleven patients experienced flickering vision. Nine patients had nausea and vomiting. Eight patients had diarrhea. They were all reversible and of grade I or II. Only one patient had grade III myelosuppression. Among the 28 patients, 16 cases were disease-free and 12 cases had progressive disease, with a progression-free survival of 8.2 months.\n\n\nCONCLUSIONS\nCrizotinib is effective and tolerable in the treatment of advanced ALK-positive NSLCC. However, its long-term treatment efficacy requires to be further studied.",
"affiliations": "Department of Thoracic Medical Oncology, Zhejiang Cancer Hospital, Hangzhou 310022, China.;Department of Thoracic Medical Oncology, Zhejiang Cancer Hospital, Hangzhou 310022, China.;Department of Thoracic Medical Oncology, Zhejiang Cancer Hospital, Hangzhou 310022, China.;Department of Thoracic Medical Oncology, Zhejiang Cancer Hospital, Hangzhou 310022, China.;Department of Thoracic Medical Oncology, Zhejiang Cancer Hospital, Hangzhou 310022, China.;Department of Thoracic Medical Oncology, Zhejiang Cancer Hospital, Hangzhou 310022, China.;Department of Thoracic Medical Oncology, Zhejiang Cancer Hospital, Hangzhou 310022, China.;Department of Thoracic Medical Oncology, Zhejiang Cancer Hospital, Hangzhou 310022, China; Email: zyp@medmail.com.cn.",
"authors": "Wang|Wenxian|W|;Song|Zhengbo|Z|;Yu|Xinmin|X|;Lou|Guangyuan|G|;Gu|Cuiping|C|;Shi|Xun|X|;Zhao|Jun|J|;Zhang|Yiping|Y|",
"chemical_list": "D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; D020794:Receptor Protein-Tyrosine Kinases",
"country": "China",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0253-3766",
"issue": "37(10)",
"journal": "Zhonghua zhong liu za zhi [Chinese journal of oncology]",
"keywords": null,
"medline_ta": "Zhonghua Zhong Liu Za Zhi",
"mesh_terms": "D000970:Antineoplastic Agents; D002289:Carcinoma, Non-Small-Cell Lung; D000077547:Crizotinib; D003967:Diarrhea; D018572:Disease-Free Survival; D006801:Humans; D008175:Lung Neoplasms; D009325:Nausea; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D020794:Receptor Protein-Tyrosine Kinases; D014839:Vomiting",
"nlm_unique_id": "7910681",
"other_id": null,
"pages": "784-7",
"pmc": null,
"pmid": "26813601",
"pubdate": "2015-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Efficacy of crizotinib for 28 cases of advanced ALK-positive non-small cell lung cancer.",
"title_normalized": "efficacy of crizotinib for 28 cases of advanced alk positive non small cell lung cancer"
} | [
{
"companynumb": "CN-PFIZER INC-2016064983",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CRIZOTINIB"
},
"drugadditional": null,
... |
{
"abstract": "Little is known about the incidence of severe critical events in children undergoing general anaesthesia in Europe. We aimed to identify the incidence, nature, and outcome of severe critical events in children undergoing anaesthesia, and the associated potential risk factors.\n\n\n\nThe APRICOT study was a prospective observational multicentre cohort study of children from birth to 15 years of age undergoing elective or urgent anaesthesia for diagnostic or surgical procedures. Children were eligible for inclusion during a 2-week period determined prospectively by each centre. There were 261 participating centres across 33 European countries. The primary endpoint was the occurence of perioperative severe critical events requiring immediate intervention. A severe critical event was defined as the occurrence of respiratory, cardiac, allergic, or neurological complications requiring immediate intervention and that led (or could have led) to major disability or death. This study is registered with ClinicalTrials.gov, number NCT01878760.\n\n\n\nBetween April 1, 2014, and Jan 31, 2015, 31 127 anaesthetic procedures in 30 874 children with a mean age of 6·35 years (SD 4·50) were included. The incidence of perioperative severe critical events was 5·2% (95% CI 5·0-5·5) with an incidence of respiratory critical events of 3·1% (2·9-3·3). Cardiovascular instability occurred in 1·9% (1·7-2·1), with an immediate poor outcome in 5·4% (3·7-7·5) of these cases. The all-cause 30-day in-hospital mortality rate was 10 in 10 000. This was independent of type of anaesthesia. Age (relative risk 0·88, 95% CI 0·86-0·90; p<0·0001), medical history, and physical condition (1·60, 1·40-1·82; p<0·0001) were the major risk factors for a serious critical event. Multivariate analysis revealed evidence for the beneficial effect of years of experience of the most senior anaesthesia team member (0·99, 0·981-0·997; p<0·0048 for respiratory critical events, and 0·98, 0·97-0·99; p=0·0039 for cardiovascular critical events), rather than the type of health institution or providers.\n\n\n\nThis study highlights a relatively high rate of severe critical events during the anaesthesia management of children for surgical or diagnostic procedures in Europe, and a large variability in the practice of paediatric anaesthesia. These findings are substantial enough to warrant attention from national, regional, and specialist societies to target education of anaesthesiologists and their teams and implement strategies for quality improvement in paediatric anaesthesia.\n\n\n\nEuropean Society of Anaesthesiology.",
"affiliations": "Department of Anaesthesia, Pharmacology and Intensive Care, University Hospitals of Geneva, Geneva, Switzerland; University of Geneva, Geneva, Switzerland. Electronic address: walid.habre@hcuge.ch.;Department of Anaesthesia, Istituto Giannina Gaslini, Genova, Italy.;Bolyai Institute, University of Szeged, Szeged, Hungary.;Department of Anaesthesia and Intensive Care, Cnopf'sche Kinderklinik/Klinik Hallerwiese, Nürnberg, Germany.;Department of Anaesthesia and Intensive Care, Odense University Hospital, Odense, Denmark; Department of Clinical Research, The University of Southern Denmark, Odense, Denmark.;Department of Anaesthesia, Luzerner Kantonsspital, Luzern, Switzerland.;Research Department, European Society of Anaesthesiology, Brussels, Belgium.;Department of Anaesthesia, Royal Hospital For Children, Glasgow, UK; University of Glasgow, Glasgow, UK.;Department of Anaesthesiology, Maastricht University Medical Centre, Maastricht, Netherlands.;Department of Anaesthesiology and Intensive Care, Wroclaw Medical University, Wroclaw, Poland.;Department of Medical Physics and Informatics, University of Szeged, Szeged, Hungary.;Département d'Anesthésie-Réanimation pédiatrique, Hôpital Jeanne de Flandre, CHRU de Lille, Lille, France.",
"authors": "Habre|Walid|W|;Disma|Nicola|N|;Virag|Katalin|K|;Becke|Karin|K|;Hansen|Tom G|TG|;Jöhr|Martin|M|;Leva|Brigitte|B|;Morton|Neil S|NS|;Vermeulen|Petronella M|PM|;Zielinska|Marzena|M|;Boda|Krisztina|K|;Veyckemans|Francis|F|;|||",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/S2213-2600(17)30116-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2213-2600",
"issue": "5(5)",
"journal": "The Lancet. Respiratory medicine",
"keywords": null,
"medline_ta": "Lancet Respir Med",
"mesh_terms": "D000293:Adolescent; D000367:Age Factors; D000768:Anesthesia, General; D002318:Cardiovascular Diseases; D002648:Child; D002675:Child, Preschool; D002983:Clinical Competence; D004342:Drug Hypersensitivity; D005060:Europe; D005260:Female; D006304:Health Status; D006761:Hospitals; D006801:Humans; D015994:Incidence; D007223:Infant; D007231:Infant, Newborn; D007431:Intraoperative Complications; D008297:Male; D009422:Nervous System Diseases; D011183:Postoperative Complications; D011446:Prospective Studies; D012140:Respiratory Tract Diseases",
"nlm_unique_id": "101605555",
"other_id": null,
"pages": "412-425",
"pmc": null,
"pmid": "28363725",
"pubdate": "2017-05",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Incidence of severe critical events in paediatric anaesthesia (APRICOT): a prospective multicentre observational study in 261 hospitals in Europe.",
"title_normalized": "incidence of severe critical events in paediatric anaesthesia apricot a prospective multicentre observational study in 261 hospitals in europe"
} | [
{
"companynumb": "CH-MYLANLABS-2018M1019468",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ERYTHROMYCIN"
},
"drugadditional": "3",
... |
{
"abstract": "Cutaneous leukocytoclastic vasculitis (LCV) can occur as skin-limited disease or as part a systemic vasculitis. Appropriate workup includes the evaluation of antineutrophil cytoplasmic antibodies (ANCAs), with a positive titer raising concern for the associated primary vasculitides including microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), or eosinophilic granulomatosis with polyangiitis (EGPA). In the absence of systemic findings, however, a drug etiology must also be considered. Tumor necrosis factor (TNF) inhibitors, propylthiouracil, levamisole-adulterated cocaine, hydralazine, and minocycline have been previously documented to induce ANCA-positive vasculitis (APV), which may present with conspicuously high ANCA titers. Herein we report trimethoprim-sulfamethoxazole as another culprit in drug-induced APV. Our case reinforces the need to consider drug etiology for APV and cautions against interpreting positive ANCAs as equivalent to evidence of systemic disease.",
"affiliations": "Department of Dermatology, University of Illinois College of Medicine at Peoria, Peoria, Illinois. stephanie.frisch@imail.org.",
"authors": "Woodring|Therese|T|;Abraham|Ronnie|R|;Frisch|Stephanie|S|",
"chemical_list": "D000900:Anti-Bacterial Agents; D019268:Antibodies, Antineutrophil Cytoplasmic; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1087-2108",
"issue": "23(8)",
"journal": "Dermatology online journal",
"keywords": null,
"medline_ta": "Dermatol Online J",
"mesh_terms": "D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; D019268:Antibodies, Antineutrophil Cytoplasmic; D005260:Female; D006801:Humans; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"nlm_unique_id": "9610776",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29469750",
"pubdate": "2017-08-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of probable trimethoprim-sulfamethoxazole induced circulating antineutrophil cytoplasmic antibody-positive small vessel vasculitis.",
"title_normalized": "a case of probable trimethoprim sulfamethoxazole induced circulating antineutrophil cytoplasmic antibody positive small vessel vasculitis"
} | [
{
"companynumb": "US-TEVA-817623USA",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM"
},
"drugadditional": ... |
{
"abstract": "Recently, mycophenolate mofetil (MMF) has been introduced in the immunosuppressive strategy after kidney transplantation. Recently, the existence of a MMF associated embriopathy has been hypothesized, namely, multiple craniofacial malformations. Only 1 report has described chorioretinal coloboma. We report a case of woman who used MMF throughout pregnancy after kidney transplantation. Her newborn developed coloboma of the right eye associated with an ocular cyst without any other malformation. The other drugs used by our patient are not considered teratogenic. Therefore, it seems reasonable to conclude a causal relationship between MMF and the malformation observed in this newborn.",
"affiliations": "Department of Gynecology and Obstetrics, University Sapienza of Rome, Rome, Italy. marialuisa.framarino@gmail.com",
"authors": "Dei Malatesta|M Framarino|MF|;Rocca|B|B|;Gentile|T|T|;Hadjistilianou|T|T|;Borri|M|M|;de Francesco|S|S|;Pisani|F|F|;Famulari|A|A|",
"chemical_list": "D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2009.03.088",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "41(4)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D003103:Coloboma; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D007231:Infant, Newborn; D016030:Kidney Transplantation; D008279:Magnetic Resonance Imaging; D009173:Mycophenolic Acid; D011247:Pregnancy",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "1407-9",
"pmc": null,
"pmid": "19460573",
"pubdate": "2009-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of coloboma in a newborn to a woman taking mycophenolate mofetil in pregnancy after kidney transplantation.",
"title_normalized": "a case of coloboma in a newborn to a woman taking mycophenolate mofetil in pregnancy after kidney transplantation"
} | [
{
"companynumb": "GXKR2009IT07032",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": null,
... |
{
"abstract": "A 31-year-old patient of post-surgical recurrent buccal carcinoma (post-chemo and radiotherapy) on multimodal analgesia with methadone, paracetamol and gabapentin presented to pain clinic with occasional bleeding from tumor area and incidental hypercalcemia. The hypercalcemia was attributed to adrenal insufficiency due to methadone, with no other obvious reasons identified for hypercalcemia or adrenal insufficiency. The patient was managed with the change of opioid, regular aseptic wound dressings and management of hypercalcemia with hydration, calcitonin and steroid therapy. Hypercalcemia in a cancer patient can have multiple other causes like hypercalcemia of malignancy and primary or secondary parathyroid carcinoma. A strong clinical suspicion and appropriate battery of tests may be required to arrive at the diagnosis. Prompt management, including identification and management of the primary pathology along with aggressive hydration with hormonal therapy, may prove to be life-saving.",
"affiliations": "Department of Onco-Anesthesia and Palliative Medicine, All India Institute of Medical Sciences, New Delhi, India.;Department of Onco-Anesthesia and Palliative Medicine, All India Institute of Medical Sciences, New Delhi, India.;Department of Onco-Anesthesia and Palliative Medicine, National Cancer Institute (AIIMS), Jhajjar, Haryana, India.;Department of Onco-Anesthesia and Palliative Medicine, National Cancer Institute (AIIMS), Jhajjar, Haryana, India.;Department of Onco-Anesthesia and Palliative Medicine, All India Institute of Medical Sciences, New Delhi, India.",
"authors": "Sharma|Ankit|A|;Subhash|Mahajan Jitendra|MJ|;Pandit|Anuja|A|0000-0002-4609-903X;Bhan|Swati|S|;Bhatnagar|Sushma|S|",
"chemical_list": "D008691:Methadone",
"country": "England",
"delete": false,
"doi": "10.1017/S1478951520001133",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1478-9515",
"issue": "18(6)",
"journal": "Palliative & supportive care",
"keywords": "Adrenal insufficiency; Analgesics; Hypercalcemia; Methadone; Opioid",
"medline_ta": "Palliat Support Care",
"mesh_terms": "D000309:Adrenal Insufficiency; D000328:Adult; D006801:Humans; D006934:Hypercalcemia; D008297:Male; D008691:Methadone; D009062:Mouth Neoplasms; D059408:Pain Management",
"nlm_unique_id": "101232529",
"other_id": null,
"pages": "751-753",
"pmc": null,
"pmid": "33118914",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hypercalcemia due to methadone-induced adrenal insufficiency in a case of oral cancer.",
"title_normalized": "hypercalcemia due to methadone induced adrenal insufficiency in a case of oral cancer"
} | [
{
"companynumb": "GB-EPIC PHARMA LLC-2020EPC00360",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": nu... |
{
"abstract": "We report a case of Fusarium endophthalmitis following refractive lens exchange (RLE) for the correction of high myopia that was initially diagnosed as lens-induced uveitis. Endophthalmitis is a rare but often devastating complication of intraocular lens surgery. In contrast to cataract surgery, in which the potential increase in visual acuity clearly outweighs the potential risks involved in the procedure, RLE has all the potential risks of conventional cataract surgery and the indication for surgery, \"no more glasses or contact lenses,\" is not that straightforward.",
"affiliations": "Department of Ophthalmology, the Ludwig Boltzmann Institut for Retinology and Biomicroscopic Laser Surgery, Rudolf Foundation Clinic, Vienna, Austria. tina.aggermann@wienkav.at",
"authors": "Aggermann|Tina|T|;Haas|Paulina|P|;Krepler|Katharina|K|;Binder|Susanne|S|;Hochwarter|Anelia|A|",
"chemical_list": "D000935:Antifungal Agents; D011743:Pyrimidines; D014230:Triazoles; D065819:Voriconazole",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jcrs.2009.04.026",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0886-3350",
"issue": "35(8)",
"journal": "Journal of cataract and refractive surgery",
"keywords": null,
"medline_ta": "J Cataract Refract Surg",
"mesh_terms": "D000867:Anterior Chamber; D000935:Antifungal Agents; D009877:Endophthalmitis; D015821:Eye Infections, Fungal; D005260:Female; D005670:Fusarium; D006801:Humans; D019654:Lens Implantation, Intraocular; D008875:Middle Aged; D009181:Mycoses; D047728:Myopia, Degenerative; D011743:Pyrimidines; D012086:Reoperation; D014230:Triazoles; D014792:Visual Acuity; D065819:Voriconazole",
"nlm_unique_id": "8604171",
"other_id": null,
"pages": "1468-70",
"pmc": null,
"pmid": "19631137",
"pubdate": "2009-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fusarium endophthalmitis following refractive lens exchange for correction of high myopia.",
"title_normalized": "fusarium endophthalmitis following refractive lens exchange for correction of high myopia"
} | [
{
"companynumb": "ALCN2009AT002958",
"fulfillexpeditecriteria": "1",
"occurcountry": "AT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "KANAMYCIN SULFATE"
},
"drugadditional": "1",
... |
{
"abstract": "Kaposi's sarcoma is associated with immunosuppressant treatment administered to patients with organ transplant and other immune related disorders. Several case reports have reported association of Kaposi's sarcoma and steroids. Almost all patients in those case reports had localised disease to skin and they responded to tapering doses or discontinuation of steroids. Here we present a case of an elderly asthmatic man who was using self-medication with systemic and inhaled steroids for about two decades. He presented with widespread skin lesions and anemia. Upper gastrointestinal endoscopy revealed multiple gastric lesions. Skin and gastric lesion biopsies established the diagnosis of disseminated Kaposi's sarcoma. Work-up for HIV, HTLV-1 and HHV-8 was negative. He had low lymphocytes and CD4 counts. He also had steroid-induced hypoadrenalism. Patient was treated with systemic chemotherapy due to visceral metastases to which he responded well and is in stable remission.",
"affiliations": "Department of Medicine, Sultan Qaboos University Hospital, Muscat, Sultanate of Oman.;Department of Medicine, Sultan Qaboos University Hospital, Muscat, Sultanate of Oman.;Department of Pathology, Sultan Qaboos University Hospital, Muscat, Sultanate of Oman.;Department of Pathology, Sultan Qaboos University Hospital, Muscat, Sultanate of Oman.",
"authors": "Kumar|Shiyam|S|;Burney|Ikram A|IA|;Saparamadu|P A M|PAM|;Silva|Chandu de|C|",
"chemical_list": "D007166:Immunosuppressive Agents; D013256:Steroids",
"country": "Pakistan",
"delete": false,
"doi": "226",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1022-386X",
"issue": "26(11)",
"journal": "Journal of the College of Physicians and Surgeons--Pakistan : JCPSP",
"keywords": null,
"medline_ta": "J Coll Physicians Surg Pak",
"mesh_terms": "D000368:Aged; D001249:Asthma; D006801:Humans; D016867:Immunocompromised Host; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D008297:Male; D012514:Sarcoma, Kaposi; D013256:Steroids",
"nlm_unique_id": "9606447",
"other_id": null,
"pages": "135-136",
"pmc": null,
"pmid": "28666508",
"pubdate": "2016-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Disseminated Kaposi's Sarcoma in an Immunosuppressed Patient after Long-Term Inhaled and Systemic Steroid Therapy.",
"title_normalized": "disseminated kaposi s sarcoma in an immunosuppressed patient after long term inhaled and systemic steroid therapy"
} | [
{
"companynumb": "OM-MYLANLABS-2017M1059570",
"fulfillexpeditecriteria": "1",
"occurcountry": "OM",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BETAMETHASONE"
},
"drugadditional": "1",
... |
{
"abstract": "The programmed cell death protein 1 inhibitor pembrolizumab, an immune checkpoint inhibitor, has subsequently been approved for the treatment of a wide variety of malignant tumors. Compared with conventional chemotherapy, immunotherapy is associated with a unique set of immune reactions, known collectively as immune-related adverse events. Although often mild, dermatologic toxicity can occasionally be high grade and potentially life-threatening. Here we describe a rare case of bullous pemphigoid (BP) associated with pembrolizumab. A 79-year-old male patient presented with scattered erythema, papules, blisters, and pruritus after pembrolizumab treatment. Then, the rash gradually aggravated and spread to the whole body. The extensive edematous erythema, blisters, bullae, and blood blisters were loose and easy to rupture, forming an erosive surface and with pruritus and obvious pain. The hemidesmosomal protein BP180 (type XVII collagen) was detectable in the serum, and the histological examination diagnosis was bullous pemphigoid. After 10 days of glucocorticoid (methylprednisolone, iv, 80 mg/day) treatment, new blister formation ceased. We need to increase the awareness on and facilitate the earlier identification of the cutaneous adverse effects of BP with immunotherapy so that treat can begin early in order to limit the duration and severity of toxicity.",
"affiliations": "Department of Pulmonary and Critical Care Medicine, Air Force Medical Center, Beijing, China.;Department of Pulmonary and Critical Care Medicine, Air Force Medical Center, Beijing, China.;Department of Pulmonary and Critical Care Medicine, Air Force Medical Center, Beijing, China.;Department of Pulmonary and Critical Care Medicine, Air Force Medical Center, Beijing, China.;Department of Dermatology, Air Force Medical Center, Beijing, China.",
"authors": "Zhang|Xiaoyan|X|;Sui|Dongjiang|D|;Wang|Dong|D|;Zhang|Lina|L|;Wang|Ruiyan|R|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fimmu.2021.731774",
"fulltext": "\n==== Front\nFront Immunol\nFront Immunol\nFront. Immunol.\nFrontiers in Immunology\n1664-3224\nFrontiers Media S.A.\n\n10.3389/fimmu.2021.731774\nImmunology\nCase Report\nCase Report: A Rare Case of Pembrolizumab-Induced Bullous Pemphigoid\nZhang Xiaoyan 1 *\n\nSui Dongjiang 1\nWang Dong 1\nZhang Lina 1\nWang Ruiyan 2\n1Department of Pulmonary and Critical Care Medicine, Air Force Medical Center, Beijing, China\n2Department of Dermatology, Air Force Medical Center, Beijing, China\nEdited by: Hubing Shi, Sichuan University, China\n\nReviewed by: Alessandro Pileri, Università di Bologna, Italy; Dario Didona, University Hospital Giessen and Marburg, Germany; Ana Maria Abreu-Velez, Georgia Dermatopathology Associates, United States\n\n*Correspondence: Xiaoyan Zhang, zhangxyrespirology@163.com\nThis article was submitted to Cancer Immunity and Immunotherapy, a section of the journal Frontiers in Immunology\n\n14 9 2021\n2021\n12 73177428 6 2021\n23 8 2021\nCopyright © 2021 Zhang, Sui, Wang, Zhang and Wang\n2021\nZhang, Sui, Wang, Zhang and Wang\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nThe programmed cell death protein 1 inhibitor pembrolizumab, an immune checkpoint inhibitor, has subsequently been approved for the treatment of a wide variety of malignant tumors. Compared with conventional chemotherapy, immunotherapy is associated with a unique set of immune reactions, known collectively as immune-related adverse events. Although often mild, dermatologic toxicity can occasionally be high grade and potentially life-threatening. Here we describe a rare case of bullous pemphigoid (BP) associated with pembrolizumab. A 79-year-old male patient presented with scattered erythema, papules, blisters, and pruritus after pembrolizumab treatment. Then, the rash gradually aggravated and spread to the whole body. The extensive edematous erythema, blisters, bullae, and blood blisters were loose and easy to rupture, forming an erosive surface and with pruritus and obvious pain. The hemidesmosomal protein BP180 (type XVII collagen) was detectable in the serum, and the histological examination diagnosis was bullous pemphigoid. After 10 days of glucocorticoid (methylprednisolone, iv, 80 mg/day) treatment, new blister formation ceased. We need to increase the awareness on and facilitate the earlier identification of the cutaneous adverse effects of BP with immunotherapy so that treat can begin early in order to limit the duration and severity of toxicity.\n\nbullous pemphigoid\npembrolizumab\nprogrammed cell death protein 1\nimmunotherapy\nglucocorticoid\n==== Body\npmcIntroduction\n\nPembrolizumab is a humanized monoclonal antibody IgG4 programmed cell death protein 1 (PD-1) antagonist. As a new drug of immune checkpoint inhibitor, pembrolizumab has shown great promising prospects in clinical antitumor immunotherapy and has rapidly become the first-line therapy for a variety of advanced malignancies. It has been recommended in antitumor guidelines of many countries and opened a new era of tumor immunotherapy (1). While immune checkpoint inhibitors can enhance the immune system and cause cells to attack tumor cells, they can also cause cells to attack normal cells in the body, causing a series of inflammatory diseases mimicking autoimmune diseases, some of which may be serious. These major adverse effects are termed “immune-related adverse events” (irAEs) and present with organ-specific tissue inflammation (2–4). Here we report a case of bullous pemphigoid (BP) associated with pembrolizumab, emerging with a potentially serious dermatologic toxicity, and we will use this case to highlight the diagnosis and management of cutaneous irAEs associated with checkpoint inhibitors.\n\nCase Report\n\nIn May 2019, a 79-year-old male patient underwent resection of the left kidney and ureter for invasive high-grade papillary urothelial carcinoma. The tumor size was 1.2 × 1 × 0.2 cm, and the tumor TNM scale was T1N0M1. In January 2020, multiple round nodules of different sizes can be seen in both lungs by CT and PET-CT, with a smooth boundary. The largest one is located in the left lower lung, about 2.2 × 1.8 cm. From February to September 2020, he had received 10 cycles of pembrolizumab therapy (100 mg, iv, q21d) because of lung metastatic carcinoma. From April 2020, erythema and pimples accompanied by pruritus appeared successively on the trunks and limbs of the patient. After symptomatic treatment, the rash subsided and appeared repeatedly. From November 2020, the rash aggravated gradually; macroscopically, the lesions appeared as strained blisters filled with serous fluid and blood on erythematous skin, spreading throughout the body. The blood bullae were big, loose, and easy to break, forming the erosive surface (Figures 1A, B), and accompanied by itchy and obvious pain. According to the descriptions of select cutaneous immune-related adverse events as defined by the CTCAE, version 5.0 (Common Terminology Criteria for Adverse Events), given the blisters of the patient covering >30% of body surface area which limit his self-care/activities of daily living, his disease grade was classified as grade 3.\n\nFigure 1 (A, B) Skin lesions on admission.\n\nHistopathological findings showed epidermal hyperplasia and edema, subepidermal blister formation, numerous eosinophils in the blister, and obvious eosinophil infiltration around the superficial dermis vessels (Figures 2A, B). Immunofluorescence was positive for IgG (Figure 3) and C3 (Figure 4). The hemidesmosomal protein BP180 (type XVII collagen) was detectable in the serum, with 137.32 U/ml titer by enzyme-linked immunosorbent assay (ELISA) method. BP230 detection was normal. Taken together, the clinical presentation and laboratory findings were consistent with the diagnosis of BP. According to Naranjo’s adverse drug reaction assessment with a score of 8 (Table 1), BP probably caused by pembrolizumab was considered.\n\nFigure 2 Skin pathology: (A) H&E, ×200; (B) H&E, ×400.\n\nFigure 3 IgG immunoglobulin deposits along the dermo-epidermal junction.\n\nFigure 4 C3 deposits along the dermo-epidermal junction.\n\nTable 1 Naranjo’s assessment scale in the evaluation of adverse drug reaction (ADR).\n\nRelated issues\tResults\tScore\t\n1. Is there any previous conclusive report on this ADR?\tNo\t0\t\n2. Does the ADR occur after the use of suspicious drugs?\tYes\t2\t\n3. Does the ADR get remission after drug withdrawal or anti-drug application?\tYes\t1\t\n4. Is the ADR repeated after the use of the suspected drug again?\tYes\t1\t\n5. Is there any other reason that can cause the ADR alone?\tNo\t2\t\n6. Does the ADR recur after placebo?\tUnknown\t0\t\n7. Does the drug reach a toxic concentration in the blood or other body fluids?\tUnknown\t0\t\n8. Does the ADR aggravate with the increase of dose or alleviate with the decrease of dose?\tYes\t1\t\n9. Has the patient ever been exposed to the same or similar drugs and had similar reactions?\tNo\t0\t\n10. Is there any objective evidence to confirm the reaction?\tNo\t1\t\nTotal score\t\tr\t\nNaranjo’s score: ≥ 9 points, definite; 5 – 8 points, probable, 1 – 4 points, possible; ≤ 0 points, doubtful.\n\nOur differential diagnosis included paraneoplastic pemphigus (PNP). Direct immunofluorescence did not show a deposition of immunoglobulins at the cell surface of keratinocytes. By employing PET-CT, multiple hypermetabolic metastases in the lungs were detected on January 10, 2020, while the PET-CT image taken on November 19, 2020 showed that the original lesions were not clearly displayed. This suggested that immunotherapy was effective in the early stage, and the tumor achieved clinical complete remission (CR) after the treatment. No typical malignant hypermetabolic lesions were found in the rest of the body, so PNP can be excluded. BP can be caused by some drugs, including furosemide and anti-DPP4 inhibitors. This patient was not prescribed with these drugs.\n\nAfter 3 days of glucocorticoid treatment (methylprednisolone, iv, 80 mg/day, 1.25 mg/kg/day), the cutaneous lesions improved. In some parts, the blister fluid was absorbed and the skin surface shrunk, the erosive surface began to scab and heal, and the color of erythema became pale. After 10 days, all the blisters disappeared, and new bullae formation ceased. All the superficial erosions were scabby and most of the scabs fell off, leaving dark red pigmentation spots (Figures 5A, B). After 2 weeks of glucocorticoid treatment, the methylprednisolone dose was changed to oral administration and gradually tapered. At 1 month later, BP180 detection was normal with 8.49 U/ml titer.\n\nFigure 5 (A, B) Skin lesions on the 8th day after glucocorticoid treatment.\n\nIn February 2021, when methylprednisolone has been used as treatment for 4 months and was reduced to 24 mg/day, several blood blisters fused together with a size of about 20 × 7cm, which appeared in the skin of the left hip joint of the patient. BP180 was redetected, suggesting BP recurrence. The dose of methylprednisolone was increased to 44 mg for treatment. The blood blisters were broken and formed a big ulcer with yellow green pyoderma, and regular debridement and treatment with topical ointment, such as human epidermal growth factor gel, halometasone cream, and silver ion dressing, were continued for several months. So far (in July 2021), the skin lesions were not healed (Figure 6), the dose of methylprednisolone was reduced to 25 mg/day, and the monitored BP180 was in the normal range. In March 2021, the patient began to have a cough and low fever, and the lung CT showed invasive pulmonary fungal infection; he received antifungal treatment. During the antifungal treatment, for three times the lung CT showed that there was no lung carcinoma, and the carcinoma was still in CR.\n\nFigure 6 Bullous pemphigoid reappearance after steroid tapering and continuous therapy for 5 months; skin of left hip joint.\n\nDiscussion\n\nAs a new anti-tumor drug, pembrolizumab is an IgG4 antibody which antagonizes the PD-1 receptor. It has been approved for the treatment of a wide variety of malignant tumors, including melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, classical Hodgkin’s lymphoma, urothelial carcinoma, gastric cancer, and cervical cancer. However, immune checkpoint inhibitors may abnormally enhance the normal immune response and cause T cells to attack the tumor cells in the body, causing a series of toxic reactions similar to autoimmune diseases (5, 6). Although the immune-related toxicity of pembrolizumab events are rare, serious adverse events, such as BP, can occur if it involves multiple systems and has a wide range of influence. It has been reported that the rash caused by the PD-1 inhibitor is often seen as pruritus or atypical macular papules in the early stage, and mucosal involvement is rare (7–9). The incidence of high-grade cutaneous toxicity with PD-1 inhibitors is low (approximately 1–2%) (10). Direct immunofluorescence showed the linear deposition of IgG and C3 at the dermo-epidermal junction. ELISA is the most commonly used antibody to detect the dermal component BP 180 (11), and in our case, BP 180 antibody was detected. The immune checkpoint inhibitors may determine the depletion of regulatory T cells (TREGs) that, in turn, leads to the proliferation of antigen-specific B cells and can facilitate the humoral response at the germinal center lever of lymphatic follicles. All these caused the production of the BP180 antibody (12). Sometimes the antibody to BP230 can be detected. Although this is the same pathomechanism believed to cause conventional BP, it is still unclear how anti-PD-1/PD-L1 immunotherapy facilitates this reaction (9).\n\nDifferently from other BP induced by traditional drugs, BP related to anti- PD-1/PDL1 may continue for several months after drug withdrawal. The incubation period of BP induced by PD-1 inhibitors is longer. Bullous lesions usually appear within the first 20–32 weeks of treatment; the mean time is 39 weeks, with some cases taking even more than 80 weeks. This may be related to the sustained immune activation (12, 13). BP is of high-grade dermatologic toxicity and potentially life-threatening if not be treated early. The delayed effect of the PD-1 inhibitor induced BP and may be the lasting effect of the drug itself, or the pathomechanism of the PD-1 inhibitor induced BP, which involves the key node in the pathogenesis of BP. Once triggered, it will form a positive feedback cycle and can no longer stop by itself. In our case, the onset of BP induced by PD-1 inhibitors is about 28 weeks.\n\nPembrolizumab has changed the treatment of malignant tumor, but more and more patients have immune-related adverse events. BP is of high-grade cutaneous toxicity to patients and potentially life-threatening. Although the continued use of anti-PD-1 drugs may aggravate BP, discontinuation does not lead to complete remission. These patients may still need intermittent or continuous treatment of BP. According to the severity of BP, glucocorticoid can be used locally or systematically. The systemic application of glucocorticoids can improve the prognosis of pemphigoid and reduce the mortality to 25–45%. After combining with other adjuvant therapy, the mortality was less than 10%. The cause of death of pemphigoid is very complex. Most scholars believed that respiratory tract infection and hormone adverse effects are the main cause. Some people think that the prognosis of pemphigoid is related to systemic failure and coronary heart disease. A few patients died of complications of long-term systemic use of high-dose corticosteroids and immunosuppressants, and infection was the most common cause of death (3).\n\nConclusion\n\nWith the use of pembrolizumab, clinicians should have increased awareness and facilitate the earlier identification of this rare but potentially serious cutaneous irAEs. Because cutaneous irAEs may occur late and even occur after pembrolizumab therapy has been completed, clinicians should keep in mind and evaluate carefully the new cutaneous adverse effects. Early treatment of BP is important to limit the duration and severity of toxicity. It is important to prevent and/or reduce interruptions in potentially life-saving cancer therapy.\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.\n\nEthics Statement\n\nWritten informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\n\nXZ and DS contributed to data collection, data analysis, data interpretation, and manuscript preparation. DW and LZ contributed to data analysis and data interpretation. RW contributed to data collection. XZ contributed to data review and interpretation. All authors contributed to the article and approved the submitted version.\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nPublisher’s Note\n\nAll claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.\n\nAcknowledgments\n\nWe would like to give sincere thanks to the patient and his family for understanding and supporting the publication of the case.\n==== Refs\nReferences\n\n1 Yoest JM . Clinical Features, Predictive Correlates, and Pathophysiology of Immune-Related Adverse Events in Immune Checkpoint Inhibitor Treatments in Cancer: A Short Review. Immunotarg Ther (2017) 6 :73–82. doi: 10.2147/ITT.S126227\n2 Okane GM Labbe C Doherty MK Young K Albaba H Leighl NB . Monitoring and Management of Immune-Related Adverse Events Associated With Programmed Cell Death Protein-1 Axis Inhibitors in Lung Cancer. Oncologist (2017) 22 (1 ):70–80. doi: 10.1634/theoncologist.2016-0164 27534573\n3 De Velasco G Je Y Bosse D Awad MM Ott PA Moreira RB . Comprehensive Meta-Analysis of Key Immune-Related Adverse Events From CTLA-4 and PD-1/PDL1 Inhibitors in Cancer Patients. Cancer Immunol Res (2017) 5 (4 ):312–8. doi: 10.1158/2326-6066.CIR-16-0237\n4 Chen TW Razak AR Bendard PL Siu LL Hansen AR . A Systematic Review of Immune-Related Adverse Event Reporting in Clinical Trials of Immune Checkpoint Inhibitors. Ann Oncol (2015) 26 (9 ):1824–9. doi: 10.1093/annonc/mdv182\n5 Kennedy LB . A Review of Cancer Immunotherapy Toxicity. CA Cancer J Clin (2020) 70 (2 ):86–104. doi: 10.3322/caac.21596 31944278\n6 Champlat S Lambotte O Barreau E Belkhir R Berdelou A Carbonnel F . Management of Immune Checkpoint Blockade Dysimmune Toxicities: A Collaborative Position Paper. Ann Oncol (2016) 27 (4 ):559–74. doi: 10.1093/annonc/mdv623\n7 Honigman AD Lai F Elakis J Prall O Goh M McCormack C . Pembrolizumab-Induced Sarcoid Granulomatous Panniculitis and Bullous Pemphigoid in a Single Patient. Clin Case Rep (2019) 7 (4 ):773–5. doi: 10.1002/ccr3.2090\n8 Morris LM Lewis HA Cornelius LA Chen DY Rosman IS . Neutrophil-Predominant Bullous Pemphigoid Induced by Checkpoint Inhibitors: A Case Series. J Cutan Pathol (2020) 47 (8 ):742–6. doi: 10.1111/cup.13687\n9 Naidoo J Schindler K Querfeld C Busam K Cunningham J Page DB . Autoimmune Bullous Skin Disorders With Immune Checkpoint Inhibitors Targeting PD-1 and PD-L1. Cancer Immunol Res (2016) 4 (5 ):383–9. doi: 10.1158/2326-6066.CIR-15-0123\n10 Belum VR Benhuri B Postow MA Hellmann MD Lesokhin AM Segal NH . Characterisation and Management of Dermatologic Adverse Events to Agents Targeting the PD-1 Receptor. Eur J Cancer (2016) 60 :12–25. doi: 10.1016/j.ejca.2016.02.010 27043866\n11 Sadik CD Langan EA Gratz V Zillikens D Terheyden P . Checkpoint Inhibition may Trigger the Rare Variant of Anti-LAD-1 IgG-Positive, Anti-BP180 NC16A IgG-Negative Bullous Pemphigoid. Front Immunol (2019) 10 :1934. doi: 10.3389/fimmu.2019.01934 31474998\n12 Cosimati A Rossi L Didona D Forcella C Didona B . Bullous Pemphigoid in Elderly Woman Affected by Non-Small Cell Lung Cancer Treated With Pembrolizumab: A Case Report and Review of Literature. J Oncol Pharm Pract (2021) 27 (3 ):727–33. doi: 10.1177/1078155220946370\n13 Lopez AT Khanna T Antonov N Audrey-Bayan C Geskin L . A Review of Bullous Pemphigoid Associated With PD-1 and PD-L1 Inhibitors. Int J Dermatol (2018) 57 (6 ):664–9. doi: 10.1111/ijd.13984\n\n",
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"abstract": "Bowen's disease (BD) is a form of squamous cell carcinoma in situ often associated with human papillomavirus. Co-infection with human immunodeficiency virus (HIV) is associated with a greater risk of malignancy. We describe a case of BD in a 52-year-old unmarried HIV-positive male who presented with extensive skin lesions of 1-year duration. Histopathology was suggestive of BD. He had been tried with topical imiquimod cream and cryo-therapy for 6 months. We observed no response for these above therapies. He was started on with anti-retroviral therapy (ART) as his CD4 count was 253 cells/mm3. The entire cutaneous lesions completely disappeared within 6 months of ART, which was an interesting incidence.",
"affiliations": "Department of Skin and STD, V.M.K.V. Medical College and Hospitals, Salem, Tamil Nadu, India.;Department of Skin and STD, V.M.K.V. Medical College and Hospitals, Salem, Tamil Nadu, India.;Department of Skin and STD, V.M.K.V. Medical College and Hospitals, Salem, Tamil Nadu, India.;Department of Skin and STD, V.M.K.V. Medical College and Hospitals, Salem, Tamil Nadu, India.",
"authors": "Gopalan|Kannan|K|;Vellaisamy|Seethalakshmi Ganga|SG|;Manickam|Navakumar|N|;Ahamed|Razil|R|",
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"fulltext": "\n==== Front\nIndian J Sex Transm Dis AIDSIndian J Sex Transm Dis AIDSIJSTDIndian Journal of Sexually Transmitted Diseases and AIDS2589-05572589-0565Medknow Publications & Media Pvt Ltd India 27890959IJSTD-37-20110.4103/2589-0557.192123Case ReportAnti-retroviral therapy's miracle in the treatment of Bowen's disease in a human immunodeficiency virus-positive patient: A rare case report Gopalan Kannan Vellaisamy Seethalakshmi Ganga Manickam Navakumar Ahamed Razil Department of Skin and STD, V.M.K.V. Medical College and Hospitals, Salem, Tamil Nadu, IndiaAddress for correspondence: Dr. Kannan Gopalan, No. 80, Nedunchalai Nagar, Salem - 636 005, Tamil Nadu, India. E-mail: drkannang@yahoo.comJul-Dec 2016 37 2 201 204 Copyright: © 2016 Indian Journal of Sexually Transmitted Diseases and AIDS2016This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Bowen's disease (BD) is a form of squamous cell carcinoma in situ often associated with human papillomavirus. Co-infection with human immunodeficiency virus (HIV) is associated with a greater risk of malignancy. We describe a case of BD in a 52-year-old unmarried HIV-positive male who presented with extensive skin lesions of 1-year duration. Histopathology was suggestive of BD. He had been tried with topical imiquimod cream and cryo-therapy for 6 months. We observed no response for these above therapies. He was started on with anti-retroviral therapy (ART) as his CD4 count was 253 cells/mm3. The entire cutaneous lesions completely disappeared within 6 months of ART, which was an interesting incidence.\n\nKey words\nAnti-retroviral therapyBowen's diseasehuman Immunodeficiency virus\n==== Body\nINTRODUCTION\nBowen's disease (BD) is a rare, persistent, progressive intra-epidermal carcinoma, which may be potentially malignant, with up to 8% of the cases progressing to squamous cell carcinoma (SCC).[1] The various treatment modalities include physical destruction using electrocautery, cryotherapy, curettage, laser therapy or surgical excision, intralesional interferon alpha or bleomycin, and noninvasive methods such as photodynamic therapy and topical 5-fluorouracil.[1] Here, we report a case of multiple BD in an immunosuppressed seropositive adult patient which completely resolved with anti-retroviral therapy (ART) which is a very rare event.\n\nCASE REPORT\nA 52-year-old unmarried male, human immunodeficiency virus (HIV)-positive since 2006 presented in August 2014 with slowly progressive asymptomatic skin lesions all over the body of 1-year duration. He gave a history of Siddha treatment for his immunodeficient state during the year 2007-2008 for 1 year. However he was unable to tell the details of his treatment. Systemic examination was normal and vitals were stable.\n\nDermatological examination showed multiple, discrete, reddish-brown-colored, 1-1.5cms papular and nodular lesions with crusting on the chest, back, and both thighs [Figures 1 and 2]. Except for palpable inguinal nodes on both sides, examination of external genitalia was normal. Mucosae were normal and there was no other clinical evident sign suggestive of chronic arsenic ingestion.\n\nFigure 1 Reddish-brown-papular and nodular lesions in the chest wall\n\nFigure 2 Reddish-brown-papular and nodular lesions over thigh\n\nAll his hematological and biochemical investigations were within normal limits. His chest X-ray and ultrasound examination of the abdomen were normal. A skin biopsy was done from the right thigh lesion, and histopathological examination (HPE) showed hyperkeratosis, parakeratosis, and dyskeratosis with marked acanthosis [Figure 3]. Epidermis showed atypical cells and moderate to severe dysplasia with intact basement membrane [Figure 4]. From the above HPE findings, a diagnosis of BD was made. As his CD4 count was 380 cells/mm3, ART was not started. He was treated initially with topical 5% imiqumod cream for 3 months. As there was no response, he was treated with cryotherapy for the next 3 months. However, we observed only failure to these therapies. At this juncture, he was started on ART (Zidovudine, Lamivudine, and Nevirapine) since his CD4 count was 253 cells/mm3 at that time. Skin lesions completely disappeared within 6 months of ART [Figure 5]. It was a miraculous response to ART. The patient is being followed up till date. His CD4 count as on December 2015 was 390 cells/mm3.\n\nFigure 3 Hyperkeratosis, marked acanthosis with intact basement membrane. (H and E, ×40)\n\nFigure 4 Atypical dyskeratotic cells with hyperchromatic nucleus and intact basement membrane. (H and E, ×100)\n\nFigure 5 Clearance of the lesions after treatment\n\nDISCUSSION\nBD is a form of SCC in situ originally described in 1912 by Bowen, a Boston dermatologist.[2] BD may occur at any age in adults but more common in individuals older than 60 years of age with a slight preponderance in women.[3] It is commonly located on the lower limbs, head, and neck. However, BD is also seen in subungual or periungual, palmar, genital, and perianal areas. Usually, BD is a solitary lesion, but in 10–20%, it occurs at multiple sites.[4]\n\nSeveral etiological factors of BD have been reported, such as irradiation (ultraviolet irradiation, radiotherapy, and photochemotherapy), carcinogens (e.g., arsenic), immunosuppression (e.g., after organ transplantation, AIDS), viral (strong association of perianal and genital lesions with human papilloma-virus, especially [HPV] 16; 47% of acral and 24% of nonacral extragenital BD contain HPV genome), and some others such as chronic injury, or dermatoses.[56]\n\nMultiple lesions of BD are mostly seen in individuals exposed to arsenic. Arsenic exposure toxicity due to several medications has been reported in the past.[78] Our case had no occupational exposure suggestive of arsenic toxicity in the past. It is possible that long-term Siddha medication could be the reason in our patient. However, this could not be confirmed due to the lack of availability of Siddha medication which he had ingested in the past. The estimation of blood arsenic level was futile because it tends to normalize within a short span of 6 months after nil arsenic exposure.[9] It is known that gradual improvement occurs in signs of chronic arsenicism over a period of 18 months if no further exposure to arsenic occurs.[9] However, diffuse pigmentation may remain in such patients.[9] Clinically arsenical BD can be differentiated from nonarsenical BD by its multiple and recrudescent lesions, occurring mainly on sun-protected areas of skin. However, we are not able to confirm that arsenic could be the reason for multiple BD in our case.\n\nClinically, a typical BD presents as discrete, slowly enlarging, well-demarcated erythematous thin plaque, with well-demarcated, irregular borders, and overlying crusts. The clinical variants of BD include erythematous type, hyperkeratotic type, pigmented type, intertriginous type, and subungual or periungual type. Clinically, it should be differentiated from actinic keratosis, irritated seborrheic keratosis, lichen planus, psoriasis, amelanotic melanoma, superficial basal cell carcinoma, viral warts, and SCC.\n\nHPE is important for absolute diagnosis which shows full-thickness involvement of the epidermis, and sometimes, the pilosebaceous epithelium, by atypical keratinocytes. This is associated with disorderly maturation of the epidermis, mitoses at different levels, multinucleate keratinocytes, and dyskeratotic cells. Throughout the epidermis, the cells lie in complete disorder, resulting in a “windblown appearance”. Usually, there is a loss of the granular layer, with overlying parakeratosis and, sometimes, hyperkeratosis with intact basement membrane. In some cases, the proliferating cells may be surrounded by relatively normal epidermal cells to give a characteristic “Borst-Jadassohn” appearance.[10]\n\nThe histological variants of BD includes psoriasiform type, atrophic type, verrucous-hyperkeratotic type, papillated variant, irregular variant, pigmented type, and pagetoid type. Histopathologically, BD must be differentiated from bowenoid actinic keratosis, Paget's disease, pagetoid melanoma in situ, and bowenoid papulosis. No histologic difference exists between bowenoid actinic keratosis and BD. They may differ merely in size, with the bowenoid actinic keratosis usually being smaller than BD. Pagetoid variant of BD is sometimes difficult to distinguish from Paget's disease and from in situ superficial spreading melanoma.[11] However, in Paget's disease, there will not be any dyskeratotic cells like BD. Melanoma cells are positive for S100 proteins, whereas Paget cells usually demonstrate carcinoembryonic antigen.[11]\n\nThere is a wide range of therapeutic options available for the treatment of BD including cryotherapy, curettage, cautery, photo-dynamic therapy, laser destruction, excision, 5-fluorouracil cream, imiquimod cream, and radiotherapy.[6] Early diagnosis carries a better prognosis. The patients should be followed up till life.\n\nCONCLUSION\nWe are presenting this case for its rare occurrence. To the best of our knowledge, this happens to be the first case of BD in an HIV-positive individual which cleared miraculously with ART.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Patel KB Bowen's disease treated with imiquimod and cryotherapy Indian J Dermatol 2012 57 239 41 22707785 \n2 Bowen JT Precancerous dermatoses. A study of two cases of chronic atypical epithelial proliferation J Cutan Dis 1912 30 241 \n3 Kossard S Rosen R Cutaneous Bowen's disease. An analysis of 1001 cases according to age, sex, and site J Am Acad Dermatol 1992 27 406 10 1401276 \n4 Thestrup-Pedersen K Ravnborg L Reymann F Morbus Bowen. A description of the disease in 617 patients Acta Derm Venereol 1988 68 236 9 2455417 \n5 Clavel CE Huu VP Durlach AP Birembaut PL Bernard PM Derancourt CG Mucosal oncogenic human papillomaviruses and extragenital Bowen disease Cancer 1999 86 282 7 10421264 \n6 Cox NH Eedy DJ Morton CA Therapy Guidelines and Audit Subcommittee, British Association of Dermatologists. Guidelines for management of Bowen's disease: 2006 update Br J Dermatol 2007 156 11 21 17199561 \n7 Chakraborti D Mukherjee SC Saha KC Chowdhury UK Rahman MM Sengupta MK Arsenic toxicity from homeopathic treatment J Toxicol Clin Toxicol 2003 41 963 7 14705842 \n8 Khandpur S Malhotra AK Bhatia V Gupta S Sharma VK Mishra R Chronic arsenic toxicity from Ayurvedic medicines Int J Dermatol 2008 47 618 21 18477160 \n9 Yamaoka H Ikoma N Kato M Akasaka E Tamiya S Matsuyama T Multiple Bowen's disease in a patient with a history of possible arsenic exposure: A case report Tokai J Exp Clin Med 2011 36 53 7 21769774 \n10 Quinn AG Perkins W Burns DA Breathnach SM Cox NH Griffiths CE Non melanoma skin cancer and other epidermal skin tumors Rook's Textbook of Dermatology 2010 Vol. 52 8th ed Singapore Wiley-Blackwell 32 4 \n11 Weedon D Weedon's Skin Pathology 2010 3rd ed London, UK Churchill Livingstone 679 80\n\n",
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"abstract": "Acute generalized exanthematous pustulosis (AGEP) is a rare inflammatory dermatosis characterized by multiple nonfollicular pustules that occur on erythematous skin. Despite its similarity to pustular psoriasis and association with fever and leukocytosis, AGEP typically heals quickly. Etiologically, drugs and viruses have been suspected in most cases. Here, we present a case of AGEP, in a woman, that developed 1 day after starting bupropion for smoking cessation, as a rare side effect of the treatment.",
"affiliations": "Department of Dermatology, Faculty of Medicine, Dumlupinar University, 43100 Kutahya, Turkey.;Department of Pathology, Faculty of Medicine, Dumlupinar University, 43100 Kutahya, Turkey.;Department of Dermatology, Faculty of Medicine, Dumlupinar University, 43100 Kutahya, Turkey.;Department of Dermatology, Faculty of Medicine, Dumlupinar University, 43100 Kutahya, Turkey.;Department of Dermatology, Faculty of Medicine, Dumlupinar University, 43100 Kutahya, Turkey.",
"authors": "Tak|Hasan|H|;Koçak|Cengiz|C|;Sarıcı|Gülben|G|;Dizen Namdar|Nazlı|N|;Kıdır|Mehtap|M|",
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"fulltext": "\n==== Front\nCase Rep Dermatol MedCase Rep Dermatol MedCRIDMCase Reports in Dermatological Medicine2090-64632090-6471Hindawi Publishing Corporation 10.1155/2015/421765Case ReportAn Uncommon Side Effect of Bupropion: A Case of Acute Generalized Exanthematous Pustulosis Tak Hasan \n1\n\n*\nKoçak Cengiz \n2\nSarıcı Gülben \n1\nDizen Namdar Nazlı \n1\nKıdır Mehtap \n1\n1Department of Dermatology, Faculty of Medicine, Dumlupinar University, 43100 Kutahya, Turkey2Department of Pathology, Faculty of Medicine, Dumlupinar University, 43100 Kutahya, Turkey*Hasan Tak: htak70@yahoo.comAcademic Editor: Akimichi Morita\n\n2015 24 11 2015 2015 4217654 10 2015 5 11 2015 11 11 2015 Copyright © 2015 Hasan Tak et al.2015This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Acute generalized exanthematous pustulosis (AGEP) is a rare inflammatory dermatosis characterized by multiple nonfollicular pustules that occur on erythematous skin. Despite its similarity to pustular psoriasis and association with fever and leukocytosis, AGEP typically heals quickly. Etiologically, drugs and viruses have been suspected in most cases. Here, we present a case of AGEP, in a woman, that developed 1 day after starting bupropion for smoking cessation, as a rare side effect of the treatment.\n==== Body\n1. Introduction\nAcute generalized exanthematous pustulosis (AGEP) is a rare inflammatory eruption characterized by the sudden development of multiple small sterile pustules on erythematous skin. It is accompanied by fever and leukocytosis. The disease has typical histopathological findings and recovers spontaneously within 15 days [1]. Mucosal membrane involvement occurs in about 20% of the cases and the majority of patients have mild oral lesions [2].\n\nEtiologically, antibiotics, mostly aminopenicillins and macrolides, play a role in more than 90% of the cases [2].\n\nThe differential diagnosis of AGEP includes generalized pustular psoriasis, subcorneal pustular dermatosis, pemphigus foliaceus, toxic epidermal necrolysis, drug reaction with eosinophilia, systemic symptoms syndrome, and other follicular eruptions such as acneiform and bacterial folliculitis [1, 2].\n\nBupropion is a dopamine reuptake inhibitor that is used as an antidepressant and for smoking cessation. There are 28 reports of dermatological side effects from bupropion, including angioedema, erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, urticaria, and serum disease [3].\n\nHere, we report a case of AGEP that developed as a rare side effect of bupropion.\n\n2. Case Report\nA 30-year-old woman visited our outpatient clinic with acute eruptions that appeared 4 days earlier on her face and trunk and then spread to her extremities. She took a bupropion tablet for smoking cessation 1 day before beginning of the eruptions and had a fever for the past 4 days. There was no history of psoriasis, previous drug allergy, or use of another drug with bupropion. She denied the use of any over-the-counter medications, supplements, or herbal remedies. She had not used a new soap, shampoo, or laundry soap before the skin reaction appeared.\n\nDermatological examination revealed numerous pustules on her face, trunk, and legs. The erythematous areas tended to fuse and were not characterized by follicular localization (Figure 1). There were no lesions on the oral mucosa and the examination of other systems was unremarkable. Her axillary temperature was 38.2°C.\n\nThe laboratory results showed leukocytosis (12.90 × 109/L, 88.8% neutrophils) and an increased C-reactive protein level. There was no eosinophilia. Her liver enzymes, serum protein, albumin, and electrolytes were normal.\n\nTo confirm the diagnosis of AGEP and to rule out generalized pustular psoriasis, a 4 mm punch biopsy was taken from the skin. The histopathology showed neutrophilic pustular lesions (red arrow) together with epidermal spongiosis, minimal irregular acanthosis (black arrow) in the epidermis, and neutrophilic and eosinophilic infiltration (blue arrow) around dermal vessels (Figures 2 and 3).\n\nThe diagnosis of AGEP was made histopathologically, combined with the clinical findings (a fever for 4 days and an eruption that spreads from the face and trunk to the extremities) and a history of the absence of psoriasis or other drug use. The patient discontinued the bupropion treatment after the fever and eruption appeared. Intravenous methylprednisolone (40 mg/day) was administered for 4 days. In addition, topical corticosteroid and oral analgesic and antihistaminic were used. Within 4 days of the treatment, there were no new pustules and the healing was complete within 10 days with exfoliation.\n\n3. Discussion\nIn 1980, Beylot et al. first described AGEP as a different entity from a drug eruption, characterized by sterile pustules on erythematous skin and usually confused with generalized pustular psoriasis [4]. Then, in 1991, Roujeau et al. outlined the characteristic features of AGEP in 63 cases [5]. These characteristic features were nonfollicular sterile pustules (5 mm) that were intraepidermal or subcorneal on histopathology (together with one or more additional findings like dermal edema, vasculitis, perivascular eosinophilia, or focal keratinocyte necrosis), disappearance of the eruptions within 15 days after drug cessation, presence of fever over 38°C, and neutrophilia over 7 × 109/L.\n\nThere are several theories on the pathogenesis of AGEP. Britschgi et al. suggested a T-cell mediated mechanism, as evidenced by positive findings on patch tests and lymphocyte transformation tests [6]. Moreau et al. proposed that AGEP is a delayed-type hypersensitivity reaction [7]. Another possible mechanism is the production of antigen-antibody complexes induced by an infection or drug that activates the complement system, which in turn leads to neutrophil chemotaxis [8].\n\nIn recent years, a new concept called pharmacological interaction has been developed to explain drug-induced hypersensitivity reactions. This concept implies direct, reversible interactions of the drug with T-cell receptors and is classified as a T-cell mediated reaction. Previous drug exposure is not necessary [9].\n\nIn our patient, since the reaction occurred within a single day of taking the first bupropion tablet, we believe that the pathogenesis of AGEP involves a pharmacological interaction or an unknown mechanism.\n\nThe EuroSCAR group has developed a validated scale for determining causation of AGEP by a medication [2]. This scale suggests that our case was definitely caused by bupropion, while the Naranjo algorithm [10] suggests that it was probably caused by bupropion. These results were similar to those of Ray and Wall [11].\n\nAlthough viral infections [5, 12] or hypersensitivity to mercury [13] has been reported in the etiology, Sidoroff et al. suggested that drugs are more likely to trigger AGEP, and they found no relationship between infection and the development of AGEP [14].\n\nA high proportion of AGEP cases have been attributed to aminopenicillins or macrolides but, interestingly, not to sulfonamides, which have a higher potential for causing other cutaneous drug reactions. Some cases have been attributed to antimycotic drugs. Moreover, several nonantibiotics, especially calcium channel blockers, carbamazepine, and paracetamol, have been reported as the culprit agents in numerous cases [2].\n\nTo the best of our knowledge, 129 different drugs have been implicated in the etiology of AGEP [3]. Recently, tigecycline and labetalol and psychotropic drugs such as amoxapine, sertraline, and bupropion were added to this list [3, 15, 16]. When we searched the literature for an association between bupropion and AGEP, ours was the second reported case [11].\n\nThe differential diagnosis of AGEP includes generalized pustular psoriasis. Although the pustules in the two diseases cannot be distinguished clinically, histopathological examination shows widespread edema in the dermis, vasculitis, perivascular eosinophilic infiltration, and focal keratinocyte necrosis in AGEP, while the presence of regular acanthosis in the epidermis supports pustular psoriasis [17, 18]. In our case, the minimal irregular acanthosis, widespread dermal edema, and perivascular lymphocytic and eosinophilic infiltration were thought to favor a diagnosis of AGEP.\n\nThe treatment of AGEP involves stopping the causative drug and supportive treatment for the symptoms and local lesions. Systemic corticosteroids are not required in most cases [2].\n\nAcute generalized exanthematous pustulosis should be included in the differential diagnosis of a patient with a sudden-onset widespread pustular eruption. In such patients, a history of psoriasis and drug use should also be investigated. We also need to consider bupropion as the cause of these cutaneous side effects.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFigure 1 Revealed pustules on erythematous areas that tended to unite and did not display a follicular localization on the abdomen.\n\nFigure 2 A photomicrograph of the biopsy showing neutrophilic pustular lesion together with epidermal spongiosis (thin arrow), minimal irregular acanthosis in epidermis (thick arrow), and neutrophilic and eosinophilic infiltration around dermal vessels (dashed arrow) (H&E ×200).\n\nFigure 3 A photomicrograph of the biopsy showing neutrophilic pustular lesion together with epidermal spongiosis (thin arrow), minimal irregular acanthosis in epidermis (thick arrow), and neutrophilic and eosinophilic infiltration around dermal vessels (dashed arrow) (H&E ×400).\n==== Refs\n1 Freedberg I. M. Eisen A. Z. Wolf K. Fitzpatrick's Dermatology in General Medicine 2003 6th New York, NY, USA McGraw-Hill \n2 Sidoroff A. Halevy S. Bavinck J. N. B. Vaillant L. Roujeau J.-C. Acute generalized exanthematous pustulosis (AGEP)—a clinical reaction pattern Journal of Cutaneous Pathology 2001 28 3 113 119 10.1034/j.1600-0560.2001.028003113.x 2-s2.0-0035147013 11168761 \n3 Litt J. Z. Drug Eruptions& Reactions Manual 2013 19th New York, NY, USA Taylor & Francis \n4 Beylot C. Bioulac P. Doutre M. S. Acute generalized exanthematic pustuloses Annales de Dermatologie et de Vénéréologie 1980 107 37 48 6989310 \n5 Roujeau J.-C. Bioulac-Sage P. Bourseau C. Acute generalized exanthematous pustulosis: analysis of 63 cases Archives of Dermatology 1991 127 9 1333 1338 10.1001/archderm.127.9.1333 2-s2.0-0026010193 1832534 \n6 Britschgi M. Steiner U. C. Schmid S. T-cell involvement in drug-induced acute generalized exanthematous pustulosis The Journal of Clinical Investigation 2001 107 11 1433 1441 10.1172/jci12118 2-s2.0-0034986623 11390425 \n7 Moreau A. Dompmartin A. Castel B. Remond B. Leroy D. Drug-induced acute generalized exanthematous pustulosis with positive patch tests International Journal of Dermatology 1995 34 4 263 266 10.1111/j.1365-4362.1995.tb01593.x 2-s2.0-0028916614 7790142 \n8 Beylot C. Doutre M.-S. Beylot-Barry M. Acute generalized exanthematous pustulosis Seminars in Cutaneous Medicine and Surgery 1996 15 4 244 249 10.1016/S1085-5629(96)80037-X 2-s2.0-0030435648 9069592 \n9 Pichler W. J. Pharmacological interaction of drugs with antigen-specific ımmune receptors: the p-i concept Current Opinion in Allergy & Clinical Immunology 2002 2 4 301 305 10.1097/00130832-200208000-00003 12130944 \n10 Naranjo C. A. Busto U. Sellers E. M. A method for estimating the probability of adverse drug reactions Clinical Pharmacology & Therapeutics 1981 30 2 239 245 10.1038/clpt.1981.154 2-s2.0-0019799332 7249508 \n11 Ray A. K. Wall G. C. Bupropion-induced acute generalized exanthematous pustulosis Pharmacotherapy 2011 31 6, article 621 10.1592/phco.31.6.621 2-s2.0-84914173353 \n12 Rouchouse B. Bonnefoy M. Pallot B. Jacquelin L. Dimoux-Dime G. Claudy A. L. Acute generalized exanthematous pustular dermatitis and viral infection Dermatologica 1986 173 4 180 184 10.1159/000249246 2-s2.0-0022492020 3533666 \n13 Belhadjali H. Mandhouj S. Moussa A. Mercury-induced acute generalized exanthematous pustulosis misdiagnosed as a drug-related case Contact Dermatitis 2008 59 1 52 54 10.1111/j.1600-0536.2007.01306.x 2-s2.0-47249142854 18598307 \n14 Sidoroff A. Dunant A. Viboud C. Risk factors for acute generalized exanthematous pustulosis (AGEP)-results of a multinational case-control study (EuroSCAR) British Journal of Dermatology 2007 157 5 989 996 10.1111/j.1365-2133.2007.08156.x 2-s2.0-35348873346 17854366 \n15 Ozturk S. Ustun C. Pehlivan S. Ucak H. Acute generalized exanthematous pustulosis associated with tigecycline Annals of Dermatology 2014 26 2 246 249 10.5021/ad.2014.26.2.246 2-s2.0-84901775297 24882982 \n16 Gómez Torrijos E. García Rodríguez C. Sánchez Caminero M. P. Castro Jiménez A. García Rodríguez R. Feo-Brito F. First case report of acute generalized exanthematous pustulosis due to labetalol Journal of Investigational Allergology & Clinical Immunology 2015 25 2 148 149 25997315 \n17 Beylot C. Doutre M.-S. Beylot-Barry M. Acute generalized exanthematous pustulosis Seminars in Cutaneous Medicine and Surgery 1996 15 4 244 249 10.1016/s1085-5629(96)80037-x 2-s2.0-0030435648 9069592 \n18 Auer-Grumbach P. Pfaffenthaler E. Soyer H. P. Pustulosis acuta generalisata is a post-streptococcal disease and is distinct from acute generalized exanthematous pustulosis British Journal of Dermatology 1995 133 1 135 139 2-s2.0-0029055479 7669626\n\n",
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"title": "An Uncommon Side Effect of Bupropion: A Case of Acute Generalized Exanthematous Pustulosis.",
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"abstract": "Ictal respiratory changes have been mainly described following generalized tonic-clonic seizures and recently considered to be a biomarker to assess the risk of sudden unexplained death in epilepsy (SUDEP). Nonetheless, modification of respiratory pattern can be related also to focal seizures, especially arising from the temporal lobe. Changes in cardiac function such as tachycardia or bradycardia could be often associated. We report a short case series of four patients with temporal lobe epilepsy admitted to our Epilepsy Monitoring Unit (EMU) presenting with an ictal central apnea as the first clinical manifestation of their seizures. None of these patients was aware of the occurrence of respiratory arrest. Age at onset ranged from 15 to 29 years. One patient had seizures with prolonged central apnea accompanied by a significant decrease in oxygen saturation. Neuroimaging in two patients showed alterations of mesial temporal lobe structures, including the amygdala. Recent neurophysiological studies supported the existence of a cortical network involving the limbic system that modulates downstream brainstem respiratory centers. Monitoring for respiratory changes and oxygen saturation in focal seizures is warranted for their potential value in identifying the epileptogenic zone and for a better understanding of ictal respiratory changes that could potentially define a subgroup of patients with high risk of seizure-related autonomic changes.",
"affiliations": "Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.;Neurology Unit, Ospedale Civile di Baggiovara (OCB) Hospital, Azienda Ospedaliera-Universitaria, Modena, Italy.;Neurology Unit, Ospedale Civile di Baggiovara (OCB) Hospital, Azienda Ospedaliera-Universitaria, Modena, Italy.;Neurology Unit, Ospedale Civile di Baggiovara (OCB) Hospital, Azienda Ospedaliera-Universitaria, Modena, Italy.;Neurology Unit, Ospedale Civile di Baggiovara (OCB) Hospital, Azienda Ospedaliera-Universitaria, Modena, Italy.;Neurology Unit, Ospedale Civile di Baggiovara (OCB) Hospital, Azienda Ospedaliera-Universitaria, Modena, Italy.",
"authors": "Micalizzi|Elisa|E|;Vaudano|Anna Elisabetta|AE|;Giovannini|Giada|G|;Turchi|Giulia|G|;Giunta|Leandra|L|;Meletti|Stefano|S|",
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"doi": "10.3389/fneur.2021.753860",
"fulltext": "\n==== Front\nFront Neurol\nFront Neurol\nFront. Neurol.\nFrontiers in Neurology\n1664-2295\nFrontiers Media S.A.\n\n10.3389/fneur.2021.753860\nNeurology\nCase Report\nCase Report: Ictal Central Apnea as First and Overlooked Symptom in Temporal Lobe Seizures\nMicalizzi Elisa 1\n\nVaudano Anna Elisabetta 2\n\nGiovannini Giada 2 3 4\n\nTurchi Giulia 2\n\nGiunta Leandra 2\n\nMeletti Stefano 2 3 *\n\n1Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy\n2Neurology Unit, Ospedale Civile di Baggiovara (OCB) Hospital, Azienda Ospedaliera-Universitaria, Modena, Italy\n3Department of Biomedical, Metabolic and Neural Science, University of Modena and Reggio Emilia, Modena, Italy\n4PhD Program in Clinical and Experimental Medicine, University of Modena and Reggio Emilia, Modena, Italy\nEdited by: Fernando Cendes, State University of Campinas, Brazil\n\nReviewed by: Andreas V. Alexopoulos, Cleveland Clinic, United States; Vaclav Kremen, Mayo Clinic, United States\n\n*Correspondence: Stefano Meletti stefano.meletti@unimore.it\nThis article was submitted to Epilepsy, a section of the journal Frontiers in Neurology\n\n04 11 2021\n2021\n12 75386005 8 2021\n05 10 2021\nCopyright © 2021 Micalizzi, Vaudano, Giovannini, Turchi, Giunta and Meletti.\n2021\nMicalizzi, Vaudano, Giovannini, Turchi, Giunta and Meletti\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nIctal respiratory changes have been mainly described following generalized tonic-clonic seizures and recently considered to be a biomarker to assess the risk of sudden unexplained death in epilepsy (SUDEP). Nonetheless, modification of respiratory pattern can be related also to focal seizures, especially arising from the temporal lobe. Changes in cardiac function such as tachycardia or bradycardia could be often associated. We report a short case series of four patients with temporal lobe epilepsy admitted to our Epilepsy Monitoring Unit (EMU) presenting with an ictal central apnea as the first clinical manifestation of their seizures. None of these patients was aware of the occurrence of respiratory arrest. Age at onset ranged from 15 to 29 years. One patient had seizures with prolonged central apnea accompanied by a significant decrease in oxygen saturation. Neuroimaging in two patients showed alterations of mesial temporal lobe structures, including the amygdala. Recent neurophysiological studies supported the existence of a cortical network involving the limbic system that modulates downstream brainstem respiratory centers. Monitoring for respiratory changes and oxygen saturation in focal seizures is warranted for their potential value in identifying the epileptogenic zone and for a better understanding of ictal respiratory changes that could potentially define a subgroup of patients with high risk of seizure-related autonomic changes.\n\namygdala\ntemporal lobe epilepsy\nseizures\nSUDEP\nictal apnea\n==== Body\npmcIntroduction\n\nPeri-ictal autonomic changes might occur in epileptic seizures and are a potential biomarker for the risk of sudden unexplained death in epilepsy (SUDEP), which is the most common direct cause of death in patients with epilepsy (1). Both cardiac and respiratory dysfunction have been implicated as possible precipitating causes in SUDEP (2). Respiratory changes during epileptic seizures have been described in the literature (3, 4). Peri ictal respiratory changes are commonly related to bilateral tonic-clonic seizures (4) but can also be observed in focal seizures originating from the mesial structures of the temporal lobe. Desaturations and ictal central apnea (ICA) occurred most frequently in seizures arising from the temporal lobe (1, 2), and the longer the duration of the seizure, the higher the degree of desaturation. We report four cases of ICA as the first ictal clinical manifestation of seizures originating from the temporal lobe recorded in our epilepsy monitoring unit by means of a 10-20 EEG system integrated with EKG, SpO2, and thoracoabdominal bands for respiratory inductance plethysmography. According to published criteria, we considered as apnea a respiratory arrest of 5 or more seconds on the pneumographic channel; a desaturation was defined as a drop of SpO2 value below 95% (mild 90–94%, moderate 75–89%, severe <75%) (1, 5).\n\nCases Description\n\nCase 1\n\nThe patient is a right-handed 31-year-old female with no relevant past medical history and no family history of epilepsy. At the age of 25, she presented with two possible motor episodes during sleep and was started on antiseizure medication (ASM) with lamotrigine at a low dosage (50 mg/day). Around that time, she referred the occurrence of stereotyped subjective brief episodes characterized by forced thought, intense déjà-vu, anxious feeling associated with an ascending epigastric sensation. She would always be able to recall the events that tended to recur in brief clusters during the menstrual period. After 4 years of treatment, considering the persistence of these subjective episodes and the negative findings on interictal awake/sleep EEG recordings, as well as on 1.5 tesla brain MRI, lamotrigine was stopped in the hypothesis of non-epileptic seizures. A year later, she was admitted to our epilepsy monitoring unit where she underwent a long-term video-EEG monitoring (LTM) during wake and sleep. Routine laboratory findings as well as physical and neurological examinations were normal. A 3T brain MRI showed a slight hyperintensity of the anteromedial structures of the left temporal lobe. FDG-PET imaging was unremarkable. The interictal EEG showed sharp waves on left temporal region only during NREM and REM sleep. During LTM, we recorded three electroclinical seizures, two of them arising from sleep and one during wakefulness, characterized by ICA for around 17 s before any other clinical manifestation (Figure 1). In addition, the patient had impairment of awareness with disruption of contact, face pallor, and late oroalimentary automatisms. In each of the three recorded seizures, the respiratory disruption lasted for the entire ictal phase accompanied by drop of oxygen saturation (from 95% to a minimum of 75%) and mean delay between desaturation and clear EEG changes was of 22 s (Table 1). On the EEG, a left temporal ictal onset was observed. The patient was not aware of the apnea and did not present any respiratory distress. Lamotrigine was started again (50 mg/day) with complete control of seizures at a 5-month follow-up.\n\nFigure 1 (A) A 2-min view of the EEG pattern with polygraphy of a left temporal lobe seizure characterized by rhythmic theta and delta activity on left fronto-temporal regions in patient 1. This long-lasting apnea induces a severe oxygen desaturation (SpO2 75%). (B) A more detailed view of the onset of apnea preceding EEG changes and EMG movement-related artifacts by 20 s. (A,B) Red arrows highlight the onset of the apnea. Note the ictal marked increase in heart rate. Red channel: ECG; blue channel: thoracoabdominal respirogram.\n\nTable 1 Summary of apnea related findings in the described patients.\n\nPatient\tMean apnea duration (seconds)\tLatency of apnea to first EEG changes (seconds)\tMax desaturation\tAwareness of apnea\tAwareness impairment\tHeart rate changes\tOther ictal manifestations\t\n1\t71.7\t22\t75%\tNo\tYes\tTachycardia\tPsychomotor arrest, staring, oroalimentary automatisms\t\n2\t9.8\t7.4\tNo desaturation\tNo\tYes\tTachycardia\tPsychomotor arrest, staring, oromandibular automatisms, contralateral hand dystonia\t\n3\t16\t1\t89%\tNo\tNot known\tTachycardia\tPsychomotor arrest\t\n4\t19.5\t9.5\t92%\tNo\tYes\tTachycardia\tPsychomotor arrest, late oromandibular automatisms\t\n\nCase 2\n\nThe patient is a left-handed 31-year-old male with a past medical history of puberal growth delay treated with GH hormone and negative family history for epilepsy. Since the age of 23, he manifested episodes characterized by sudden appearance of intrusive thoughts and epigastric discomfort followed by staring, unresponsiveness, and oroalimentary automatisms, occurring monthly in short clusters. Hence, in the hypothesis of epileptic seizures, lacosamide was started (up to 200 mg/day) with little or no benefit. In 2018, brain MRI showed a T2 FLAIR cortico-subcortical hyperintensity and T1 hypointensity of the right mesial temporal lobe (amygdala and uncus) without contrast enhancement (Figure 2A), interpreted as possible dysplasia or low-grade neuroglial lesion, that remained unvaried on subsequent follow-up. FDG-PET imaging showed right temporal lobe hypometabolism, especially of the temporal pole and of mesial structures (Figure 2A). The EEGs performed since the beginning of seizures were characterized by interictal slow abnormalities, spikes, and sharp waves over both left and right temporal derivations, occurring independently. In 2020, neuropsychological tests highlighted deficits of visuo-spatial memory and executive functions. He was admitted to our epilepsy monitoring unit in March 2021. Routine laboratory findings and physical and neurological examinations were unremarkable. He tested negative for anti-CNS antibodies on both serum and CSF. The interictal EEG confirmed spikes and sharp waves on left and right anterior temporal channels during wakefulness and sleep. A total of nine electroclinical seizures were recorded (2/9 during NREM sleep, 7/9 during wakefulness) arising from right anterior temporal channels. In 5/9 artifact-free seizures, ICA, lasting from 7 to 15 s, was recorded, as the first ictal clinical sign, followed by disruption of contact, staring, dystonic posturing of the left hand, oroalimentary automatisms, and eventually nose wiping with the right hand. He was unaware of the occurrence of these seizures and of the apnea. In this patient, no reduction of SpO2 was noticed. A time between 3 and 13 s from ICA onset elapsed before any observable EEG change, longer for the seizures occurring during NREM sleep. Tachycardia was present in all recorded seizures despite of the occurrence of respiratory arrest. He underwent right anterior temporal lobectomy with pathology showing aspecific gliosis. No seizures were reported at a 7-month follow-up.\n\nFigure 2 (A) Coronal FLAIR MRI of patient 2 (left) showing a hyperintense right amygdala with red arrow pointing to an area of increased signal intensity (red arrow). On the right, the FDG-PET image of the same patient showing right temporal hypometabolism involving the temporal pole and mesial regions. (B) Coronal FLAIR MRI of patient 4 (on the left) showing a temporo-mesial lesion that on T1 imaging (on the right) present a clear gadolinium enhancement suggesting a tumoral origin.\n\nCase 3\n\nA woman of 25 years, right-handed, reported the occurrence of two episodes of loss of consciousness with motor features during sleep at the age of 15. A first brain MRI was normal. Relying on clinical features, epilepsy was suspected and levetiracetam was started (up to 1,500 mg/day) with consistent efficacy. At the age of 16, during wakefulness, she manifested rare episodes characterized by impairment of awareness, staring, language disturbances, and hypersalivation followed by spontaneous recovery after 1 or 2 min. Right after, she was able to speak properly but not to recall the event. Then, lamotrigine was started (up to 300 mg/day) in association with levetiracetam with slight reduction in frequency of these episodes. After 4 years of seizure freedom, brief but frequent stereotyped episodes with the same features as described above recurred. Lacosamide was added in polytherapy (200 mg/day) without seizures' remission. A second brain MRI (3T) and the FDG-PET were unremarkable. The EEGs performed during the years showed frequent interictal spikes and slow waves over the left temporal lobe derivations. General and neurological examinations were normal. She was admitted to our monitoring unit where we recorded one seizure arising from the left temporal lobe characterized by ICA lasting 23 s, preceding by one second the EEG ictal onset with subsequent moderate desaturation to SpO2 89% and psychomotor arrest (Table 1). The patient was unaware for the occurrence of ictal modification of breathing and showed no respiratory distress.\n\nCase 4\n\nThis patient is a 31-year-old male, left-handed, with no relevant past medical history except for the recurrence of stereotyped episodes characterized by brief déjà-vu sensations along with a mild headache in the last 2 years. He was admitted to our monitoring unit after a bilateral tonic-clonic seizure. Neurological and general examinations were unremarkable. Laboratory findings were normal. The 1.5 T MRI showed a right mesial temporal cortico-subcortical lesion (amygdala, temporal uncus, hippocampal head, and part of the hippocampal body) with gadolinium enhancement (Figure 2B). He underwent video-EEG LTM that showed rare spikes and sharp waves over the fronto-temporal regions during NREM sleep. We recorded four seizures arising from the right temporal regions during wakefulness, with occurrence of central apnea (lasting from 15 to 40 s) preceding the first EEG changes by 6–27 s (Figure 3). A mild ictal desaturation (SpO2 nadir 92%) was noted in all seizures. Clinically, the patient did not warn and manifested psychomotor and respiratory arrest, late oroalimentary, and some motor automatisms; when asked, he reported a mental picture which he could not recall but that seemed to be familiar to him. Ictal increase of heart rate was always observed. He was unaware of the occurrence of the apnea and did not report dyspnea. Lacosamide was started (until 200 mg/day); subsequently, the patient was addressed to surgery to perform an anterior temporal lobectomy. Pathology revealed a ganglioglioma, a grade I neuronal-glial tumor according to the 2016 CNS WHO classification. The patient appeared seizure-free at a 12-month follow-up.\n\nFigure 3 (A) A 120-s view of a right temporal lobe seizure of patient 4. The apnea was the first ictal sign. The ictal EEG is characterized by a slow rhythmic theta activity on right temporal regions. (B) Apnea started 15 s before first EEG changes. (A,B) Red arrows point at the beginning of apnea on thoraco-abdominal polygraphic channel. Note the ictal marked increase in heart rate. Red channel: ECG; blue channel: respirogram.\n\nDiscussion\n\nHere, we reported four patients with TLE whose seizures were characterized by an ictal central apnea of variable duration that preceded, or was concomitant, with the scalp-EEG recorded seizures (see Table 1). The first description of a respiratory disruption in a patient experiencing focal seizure belongs to Jackson (6). A systematic review and meta-analysis of 21 studies (4) found an incidence of ictal hypoxemia around one third of seizures, with higher estimates found for adult patients presenting with tonic-clonic seizures. Severe peri-ictal desaturation (below 75% of SpO2) were associated to higher risk of SUDEP, considering that respiratory dysfunctions are correlated with increased risk of fatal cardiac rhythm abnormalities (7, 8). While data on peri-postictal apnea in tonic-clonic seizures are well-known, little attention has been paid until recent years toward ictal apnea in focal non-motor/non convulsive seizures. Here, we described four very similar cases in whom ICA was the first ictal symptoms in seizures involving temporo-limbic networks.\n\nData suggesting a functional connection between the amygdala and neural networks in the brainstem that control the involuntary respiratory drive derive from studies conducted on animals, such as cats (9), rabbits (10), and primates (11). As regards this functional connection between amygdala and brainstem in humans, the only data available come from clinical evidence, especially from invasive neurophysiological and neurosurgical studies. In 1952, Kaada and Jasper reported that intraoperative stimulation of different targets in the temporolimbic cortex-provoked apnea in their subjects (12). In 1954, Penfield and Jasper demonstrated that intraoperative stimulation of the cingulate cortex, rolandic cortex, and uncal regions could also generate brief apneic responses (13). Afterwards, in 1972, Bonvallet and Bobo noted that intraoperative stimulation of the amygdala was associated with apnea and bradycardia (9). Dlouhy et al. (14) documented with intracranial electrodes in one patient that apnea conditioning desaturation could be elicited by seizure spread to basolateral and lateral amygdala (left side) and in three patients upon direct stimulation of these nuclei (both left and right). As it occurred in our patients, none of them was aware of ictal respiratory modification nor appeared distressed. They observed a reduction in heart rate, differently from our four patients who presented tachycardia. They also assessed that unilateral amygdala stimulation is sufficient to cause apnea. More recently, Lacuey et al. (15) reported an incidence of ICA of 68.7% in their patients with mesial temporal lobe seizures, suggesting that this can be a common feature of temporal lobe epilepsy (TLE). They also noted that ICA is often the first clinical sign and sometimes the only clinical manifestation in medial TLE, suggesting its relevance in the anatomo-electro-clinical localization of the seizure onset zone. In another study, Lacuey et al. (15) investigated nineteen consecutive adult patients undergoing stereotactic EEG recordings and elicited a central apnea in 13/19 patients by electrical stimulation of the amygdala, hippocampus head and body, anterior parahippocampal gyrus, and antero-mesial fusiform gyrus. Therefore, they concluded that might exist a limbic and paralimbic network involved in the respiratory regulation of brainstem respiratory centers. Notably, amygdala stimulation might induce functional deafferentation of brainstem structures impairing involuntary breathing controlled by brainstem connections.\n\nThe apnea agnosia observed in our patients could be the reason why ICA in focal seizures is often unrecognized by clinicians. Different physiopathological mechanisms underlying this phenomenon have been proposed (14): (i) amygdala stimulation is thought to inhibit forebrain structures (insula or cingulate cortex) that are implicated in the conscious perception of dyspnea (16); (ii) amygdala stimulation can inhibit CO2/pH-sensitive serotoninergic neurons in the midbrain that mediate CO2-evoked arousal (17, 18); (iii) the absence of apnea awareness could be related to the effect of ictal activity on midbrain structures implicated in maintaining arousal/vigilance levels.\n\nRegardless of the pathophysiologic mechanisms underlying ICA, the lack of awareness of apnea could lead to increased risk of SUDEP, especially while sleeping in prone position when self-defense response to respiratory distress could be fundamental (14). ICA is usually a self-limited event but, in some cases, can be prolonged and might be responsible of unobserved death in patients with epilepsy (1). Of course, at present, no data can link ICA to an increased risk of SUDEP; however, ICA could define a subgroup of patients with high-risk of seizure-related autonomic changes that warrant to be studied in more detail. Another interesting finding in our small case series is that apnea precede the scalp-EEG ictal changes by many seconds (up to 20 s in patient 1), suggesting that seizure activity can remain very localized for such a time before spreading to other brain regions, as reported in studies that combined scalp and intracranial EEG (15, 19). Hence, in the absence of an adequate polygraphic monitoring, seizures might go unrecognized, especially if the apnea is the only clinical manifestation. For this reason, we advocate recordings of respiratory changes and oxygen saturation in long-term monitoring of epilepsy patients, that in our view should become a “standard of care” in the context of the epilepsy monitoring unit.\n\nLimitations of our findings may be due to the limited number of our patients and the lack of recordings of intracranial EEG activity that could give more precise information about the symptomatogenic zone of the seizure network. However, we would suggest monitoring of respiratory parameters, such as SpO2 and respiratory inductance plethysmography, also in a diagnostic and pre-surgical work up in patients with focal epilepsy. Data obtained from this type of monitoring could be useful to better localize the epileptogenic zone and to assess potential seizure-related biomarkers of increased SUDEP risk.\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.\n\nEthics Statement\n\nThe studies involving human participants were reviewed and approved by Comitato Etico Area Vasta Emilia Nord. The patients/participants provided their written informed consent to participate in this study.\n\nAuthor Contributions\n\nAll authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.\n\nFunding\n\nThis work was supported by Dipartimento di eccellenza 2018-2022, MIUR, Italy, to the Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia; Ricerca Finalizzata, project code NET-2013-02355313, Ministry of Health to the Azienda Ospedaliera-Universitaria di Modena Centro hub chirurgia epilessia (DGR 1172/18).\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nPublisher's Note\n\nAll claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.\n==== Refs\nReferences\n\n1. Vilella L Lacuey N Hampson JP Rani MRS Loparo K Sainju RK . Incidence, recurrence, and risk factors for peri-ictal central apnea and sudden unexpected death in epilepsy. Front Neurol. (2019) 10 :166. 10.3389/fneur.2019.00166 30890997\n2. Bateman LM Li CS Seyal M . Ictal hypoxemia in localization-related epilepsy: analysis of incidence, severity and risk factors. Brain. (2008) 131 :3239–45. 10.1093/brain/awn277 18952672\n3. Blum AS . Respiratory physiology of seizures. J Clin Neurophysiol. (2009) 26 :309–15. 10.1097/WNP.0b013e3181b7f14d 20168130\n4. Bruno E Maira G Biondi A Richardson MP on behalf of the RADAR-CNS Consortium. Ictal hypoxemia: a systematic review and meta-analysis. Seizure Eur J Epilepsy. (2018) 63 :7–13. 10.1016/j.seizure.2018.10.011 30391664\n5. Lacuey N Zonjy B Hampson JP Sandhya Rani MR Zaremba A Sainju RK . The incidence and significance of peri-ictal apnea in epileptic seizures. Epilepsia. (2018) 59 :573–82. 10.1111/epi.14006 29336036\n6. Jackson JH . On Asphyxia in slight epileptic paroxysms: On the symptomatology of slight epileptic fits supposed to depend on discharge-lesions of the uncinate gyrus. Lancet. (1899) 1 :79–8.\n7. Kiely DG Cargill RI Grove A Struthers AD Lipworth BJ . Abnormal myocardial repolarization in response to hypoxaemia and fenoterol. Thorax. (1995) 50 :1062–6. 10.1136/thx.50.10.1062 7491554\n8. Roche F Reynaud C Pichot V Duverney D . Effect of acute hypoxia on QT rate dependence and corrected QT interval in healthy subjects. Am J Cardiol. (2003) 91 :916–9. 10.1016/S0002-9149(03)00040-7 12667592\n9. Bonvallet M Bobo EG . Changes in phrenic activity and heart rate elicited by localized stimulation of amygdala and adjacent structures. Electroencephalog Clin Neurophysiol. (1972) 32 :1–16. 10.1016/0013-4694(72)90223-4 4109912\n10. Applegate CD Kapp BS Underwood MD McNall CL . Autonomic and somatosensory effects of amygdala central N. stimulaton in awake rabbits. Physiol Nehav. (1983) 31 :353–60. 10.1016/0031-9384(83)90201-9 6635005\n11. Reis DJ McHugh PR . Hypoxia as a cause of bradycardia during amygdala stimulation in monkey. Am J Physiol. (1968) 214 :601–10. 10.1152/ajplegacy.1968.214.3.601 4966348\n12. Kaada BR Jasper H . Respiratory responses to stimulation of temporal pole, insula, and hippocampal and limbic gyri in man. AMA Arch Neurol Psychiatry. (1952) 68 :609–19. 10.1001/archneurpsyc.1952.02320230035004 12984874\n13. Penfield W Jasper H . Epilepsy and the Functional Anatomy of the Human Brain. Boston: Little, Brown and Company (1954). p. 830–1.\n14. Dlouhy BJ Gehlbach BK Kreple CJ Kawasaki H Oya H Buzza C . Breathing inhibited when seizures spread to the amygdala and upon amygdala stimulation. J Neurosci. (2015) 35 :10281–9. 10.1523/JNEUROSCI.0888-15.2015 26180203\n15. Lacuey N Hampson JP Harper RM Miller JP Lhatoo D . Limbic and paralimbic structures driving ictal central apnea. Neurology. (2019) 92 :e655–69. 10.1212/WNL.0000000000006920 30635481\n16. Buchanan GF Richerson GB . Role of chemoreceptors in mediating dyspnea. Respir Physiol Neurobiol. (2009) 167 :9–19. 10.1016/j.resp.2008.12.002 19118647\n17. Buchanan GF Richerson GB . Central serotonin neurons are required for arousal to CO2. Proc Natl Acad Sci USA. (2010) 107 :16354–9. 10.1073/pnas.1004587107 20805497\n18. Severson CA Wang W Pieribone VA Dohle CI Richerson GB . Midbrain serotonergic neurons are central pH chemoreceptors. Nat Neurosci. (2003) 6 :1139–1140. 10.1038/nn1130 14517544\n19. Lacuey N Hupp NJ Hampson J Lhatoo SD . Ictal Central Apnea (ICA) may be a useful semiological sign in invasive epilepsy surgery evaluations. Epilepsy Res. (2019) 156 :106164. 10.1016/j.eplepsyres.2019.106164 31330483\n\n",
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"issn_linking": "1664-2295",
"issue": "12()",
"journal": "Frontiers in neurology",
"keywords": "SUDEP; amygdala; ictal apnea; seizures; temporal lobe epilepsy",
"medline_ta": "Front Neurol",
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"pubdate": "2021",
"publication_types": "D002363:Case Reports",
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"title": "Case Report: Ictal Central Apnea as First and Overlooked Symptom in Temporal Lobe Seizures.",
"title_normalized": "case report ictal central apnea as first and overlooked symptom in temporal lobe seizures"
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"abstract": "Objective: To explore the efficacy and safety of ibrutinib treatment for relapsed/refractory (R/R) primary autoimmune hemolytic anemia (AIHA) . Methods: Two cases of primary AIHA with relapse events were refractory to glucocorticoid, anti-CD20 monoclonal antibody, immunosuppressive drugs, and splenectomy (case 1 only) . Ibrutinib treatment was administered at an initial dose of 280 mg/d (420 mg/d for case 1 from the 3rd to 8th week) . Results: Both patients achieved transfusion independence and HGB>20 g/L above baseline after 2 weeks (partial response) . For case 1, HGB concentration restored to 113 g/L but with incomplete hemolysis recovery after 10 weeks; HGB reached the level of 118 g/L, also with incomplete hemolysis recovery, after 6 weeks in case 2. They all acquired complete response with incomplete hemolysis recovery (CRi) . The responses sustained 14 weeks and 10 weeks after follow-up at 16 weeks and 12 weeks, respectively. During the treatment, hematologic and nonhematologic toxicity is mild and acceptable. Conclusion: Ibrutinib alone is effective for the 2 R/R primary AIHA cases. We need further clinical trial to identify its efficacy and safety.",
"affiliations": "State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Scienes and Peking Union Medical College, Tianjin 300020, China.;State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Scienes and Peking Union Medical College, Tianjin 300020, China.;State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Scienes and Peking Union Medical College, Tianjin 300020, China.",
"authors": "Fang|L W|LW|;Pan|H|H|;Shi|J|J|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D000069283:Rituximab; D000225:Adenine",
"country": "China",
"delete": false,
"doi": "10.3760/cma.j.issn.0253-2727.2020.05.009",
"fulltext": "\n==== Front\nZhonghua Xue Ye Xue Za Zhi\nZhonghua Xue Ye Xue Za Zhi\nCJH\nChinese Journal of Hematology\n0253-2727 2707-9740 Editorial office of Chinese Journal of Hematology No. 288, Nanjing road, Heping district, Tianjin \n\n32536139\ncjh-41-05-412\n10.3760/cma.j.issn.0253-2727.2020.05.009\n论著\n伊布替尼治疗复发/难治原发性自身免疫性溶血性贫血二例——探索性研究\nIbrutinib treatment for 2 cases of relapsed/refractory autoimmune hemolytic anemia:a pilot study 方 力维 Fang Liwei 潘 虹 Pan Hong 施 均 Shi Jun 中国医学科学院、北京协和医学院血液病医院（中国医学科学院血液学研究所），实验血液学国家重点实验室，国家血液系统疾病临床医学研究中心，天津 300020State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Scienes and Peking Union Medical College, Tianjin 300020, China\n刘 爽 通信作者：施均(Shi Jun)，Email：shijun@ihcams.ac.cn\n5 2020 \n41 5 412 416\n10 3 2020 2020年版权归中华医学会所有Copyright © 2020 by Chinese Medical Association2020This work is licensed under a Creative Commons Attribution 3.0 License (CC-BY-NC). The Copyright own by Publisher. Without authorization, shall not reprint, except this publication article, shall not use this publication format design. Unless otherwise stated, all articles published in this journal do not represent the views of the Chinese Medical Association or the editorial board of this journal.目的\n探索伊布替尼治疗复发/难治原发性自身免疫性溶血性贫血（AIHA）的疗效及安全性。\n\n方法\n2例原发性AIHA患者多次复发，1例有脾切除史，经糖皮质激素、利妥昔单抗及多种免疫抑制药物治疗无效，诊断为复发/难治原发性AIHA。给予伊布替尼起始剂量280 mg/d（例1第3～8周加量到420 mg/d）治疗，观察疗效及安全性。\n\n结果\n例1治疗2周后脱离输血，HGB增长>20 g/L，获得部分疗效；10周后HGB 113 g/L伴有代偿性溶血实验室改变，获得完全缓解伴代偿性溶血状态（CRi）。例2治疗2周后脱离输血，HGB增长>20 g/L，获得部分疗效；6周后HGB 118 g/L伴有代偿性溶血实验室改变，获得CRi。2例患者分别随访16周和12周，已维持疗效14周和10周，未复发。伊布替尼治疗期间2例患者血液学不良反应轻，非血液学不良反应轻微。\n\n结论\n伊布替尼单药治疗复发/难治原发性AIHA有初步疗效，尚需规范的临床研究试验进一步验证其疗效及安全性。\n\nObjective\nTo explore the efficacy and safety of ibrutinib treatment for relapsed/refractory（R/R）primary autoimmune hemolytic anemia（AIHA）.\n\nMethods\nTwo cases of primary AIHA with relapse events were refractory to glucocorticoid, anti-CD20 monoclonal antibody, immunosuppressive drugs, and splenectomy（case 1 only）. Ibrutinib treatment was administered at an initial dose of 280 mg/d（420 mg/d for case 1 from the 3rd to 8th week）.\n\nResults\nBoth patients achieved transfusion independence and HGB>20 g/L above baseline after 2 weeks（partial response）. For case 1, HGB concentration restored to 113 g/L but with incomplete hemolysis recovery after 10 weeks;HGB reached the level of 118 g/L, also with incomplete hemolysis recovery, after 6 weeks in case 2. They all acquired complete response with incomplete hemolysis recovery（CRi）. The responses sustained 14 weeks and 10 weeks after follow-up at 16 weeks and 12 weeks, respectively. During the treatment, hematologic and nonhematologic toxicity is mild and acceptable.\n\nConclusion\nIbrutinib alone is effective for the 2 R/R primary AIHA cases. We need further clinical trial to identify its efficacy and safety.\n\n自身免疫性溶血性贫血复发/难治伊布替尼Autoimmune hemolytic anemiaRelapsed/refractoryIbrutinib基金项目：国家自然科学基金（81670120）；中国医学科学院医学与健康科技创新工程项目（2017-I2M-3-018）；天津市科学技术委员会重大疾病防治科技重大专项（18ZXDBSY00070）Fund program:National Natural Science Foundation of China（81670120）; CAMS Initiative Fund for Medical Sciences（2017-I2M-3-018）; Tianjin Municipal Science and Technology Commission Major Project（18ZXDBSY00070）\n==== Body\n自身免疫性溶血性贫血（AIHA）是一类自身抗体介导的溶血性疾病，B淋巴细胞在自身抗体产生中发挥了重要作用[1]–[3]。糖皮质激素一线治疗有效率高达80%，约三分之一的患者可以获得长期无治疗缓解，而糖皮质激素治疗无效、治疗依赖或多次复发患者二线治疗应优先选择利妥昔单抗[4]–[6]。目前国际诊疗共识将脾切除术及其他免疫抑制剂如硫唑嘌呤、环孢素A、霉酚酸酯作为三线治疗，治疗失败者可尝试应用环磷酰胺、抗CD52单克隆抗体或蛋白酶体抑制剂等药物治疗[4]–[5]。但目前复发/难治AIHA尚无有效治疗方案，患者生存质量差，病死率为5%～10%[7]–[10]。如何提高该类患者的临床疗效，改善生存质量，减少治疗药物相关并发症是亟待解决的临床难题。\n\n利妥昔单抗治疗AIHA重要机制是清除B淋巴细胞，减少自身抗体产生[7],[10]。而B细胞信号通路关键分子Bruton酪氨酸激酶（BTK）抑制剂伊布替尼有效治疗惰性小B细胞淋巴瘤的主要分子机制是靶向抑制B淋巴细胞活化、增殖及功能[11]–[13]。利妥昔单抗已经成功用于治疗AIHA，提示我们能靶向抑制B淋巴细胞的伊布替尼是否也具有良好的治疗疗效，这是我们开展这项研究的科学假设。已有文献报道伊布替尼成功治疗继发于惰性小B细胞淋巴瘤AIHA[14]–[17]，但BTK抑制剂治疗原发性AIHA患者国际国内尚未有报道。我们受此启发，经我院伦理委员会批准（NI2020001-EC-1），收治了2例原发性、复发/难治AIHA患者，给予伊布替尼探索性治疗，2周时获得疗效并已持续缓解10～14周，现报道如下。\n\n病例资料\n例1，女性，17岁，“诊断AIHA 8年余，4个月前溶血再次发作，激素治疗无效”于2019年8月21日入我院。4岁时诊断“原发免疫性血小板减少症（ITP）”并行脾切除术。9岁时外院确诊AIHA，糖皮质激素治疗有效，HGB正常并可停药，但溶血每年发作1次。2018年始联合服用霉酚酸酯治疗至本次入院。入院HGB 42 g/L，网织红细胞（Ret）比例16.11%、绝对值177.2×109/L；直接Coombs试验IgG+C3阳性，冷凝集素试验阳性（效价1∶128，积分46）；骨髓检查流式细胞免疫分型、免疫组化未见淋巴瘤证据；IgH、Igκ、TCR βγδ重排均阴性，游离轻链比值正常，单克隆免疫球蛋白电泳阴性；EB病毒、巨细胞病毒、微小病毒B19、乙型肝炎病毒均阴性；风湿免疫全套抗体阴性。予利妥昔单抗100 mg每周1次，连续4周治疗并逐渐减停甲泼尼龙。利妥昔单抗治疗后第9周时溶血急性加重，HGB 19 g/L，Ret低于检测下限，中性粒细胞及血小板正常，诊断为复发/难治原发性AIHA（温冷双抗体型）。给予紧急分次输血5.5 U，甲泼尼龙40 mg/d联合丙种球蛋白急救治疗3 d。征得患者与家属知情同意并签署知情同意书后，于10月30日开始口服伊布替尼单药治疗。治疗前血常规：WBC 7.03×109/L，PLT 666×109/L，HGB 47 g/L，Ret绝对值84.5×109/L，淋巴细胞绝对值2.41×109/L；生化：总胆红素199.1 µmol/L，LDH 680 U/L；结合珠蛋白<0.125 g/L，IgG 14.6 g/L，补体C3 0.40 g/L，补体C4 0.02 g/L；直接Coombs试验IgG+C3阳性（IgG效价1∶256，C3效价1∶512），冷凝集试验阳性（效价1∶1 024）；CD4+/CD8+淋巴细胞比值1.33，CD19+淋巴细胞比例为5.8%。伊布替尼单药治疗起始剂量为280 mg/d（口服）。治疗第2周HGB升至75 g/L，淋巴细胞绝对值4.55×109/L。治疗第3周加量为420 mg/d。治疗第5周EPO水平（30.93 IU/L）及血清铁饱和度（14%）降低，给予EPO 10 000 U隔日1次皮下注射联合口服多糖铁复合物（150 mg，每日2次）治疗，2周后停用。伊布替尼治疗第9周减量为280 mg/d。目前随访16周，患者持续达完全缓解伴代偿性溶血状态（CRi）标准［HGB≥110 g/L（女性）或HGB≥120 g/L（男性），溶血相关实验室指标改善］。治疗期间未发生3～4级不良反应，1～2级不良反应包括粒细胞减少、淋巴细胞增多及高尿酸血症，均缓解。\n\n例2，女，7岁，“乏力、浓茶色尿7个月”于2019年10月22日入我院。2019年3月起病，4月当地医院查HGB 40 g/L，Ret比例60%，WBC、PLT正常，直接Coombs阳性，诊断AIHA。首次治疗给予甲泼尼龙500 mg/d联合丙种球蛋白12 g/d冲击治疗3 d，后甲泼尼龙40 mg/d维持治疗有效，甲泼尼龙减量至16 mg/d后溶血复发。2019年9月予大剂量甲泼尼龙（1 000 mg/d）冲击治疗3 d，联合利妥昔单抗100 mg每周1次×4周，10月再次给予丙种球蛋白15 g/d连续3 d治疗，无效后来我院。入院HGB 66 g/L，Ret比例32.72%、绝对值589×109/L；直接Coombs试验IgG阳性，冷凝集素试验阳性（效价1∶64，积分40）。淋巴瘤、病毒感染均排除，风湿免疫抗体除抗Ro52（±）、抗线粒体M2（±）外均阴性。诊断为复发/难治原发性AIHA（温冷双抗体型）。给予环磷酰胺10 mg/kg每周1次联合环孢素A 100 mg/d，持续4周无效。征得患者与家属知情同意并签署知情同意书后，于12月2日开始口服伊布替尼单药治疗。治疗前血常规：WBC 3.08×109/L，PLT 248×109/L，HGB 65 g/L，Ret绝对值738.9×109/L，淋巴细胞绝对值1.00×109/L；生化：总胆红素51.0 µmol/L，LDH 255 U/L；结合珠蛋白<0.125 g/L，IgG 6.04 g/L，补体C3 0.73 g/L，补体C4 0.25 g/L；直接Coombs试验IgG阳性（效价1∶128），冷凝集试验阳性（效价1∶64）；CD4+/CD8+淋巴细胞比值1.81，CD19+淋巴细胞比例为0。予伊布替尼280 mg/d口服治疗，在基线时最后一次输注红细胞2 U，HGB达65 g/L 2周后稳定在90 g/L，4周时达95 g/L，因此判定在2周时获得部分缓解（PR）（HGB≥100 g/L或较基线值增长≥20 g/L，且脱离输血）；第6周HGB达到118 g/L，并维持疗效至末次随访（第12周），达到CRi标准。不良反应包括3～4级白细胞减少、粒细胞减少，1～2级恶心、高尿酸血症、低钾血症。\n\n随访期间2例患者HGB变化见图1。2例患者均在治疗第2周脱离输血依赖、HGB增长超过基线值20 g/L，达到PR。例1在第10周HGB达到113 g/L，并维持疗效至末次随访第16周，符合CRi标准；例2在第6周HGB达到118 g/L，并维持疗效至末次随访第12周，达到CRi标准。截至末次随访，2例患者均维持有效反应分别达14和12周，其中CRi疗效均维持6周。溶血实验室指标改善状况如图2所示，例2 Ret绝对值基线水平较高，治疗后呈持续下降，但即使HGB完全恢复正常，网织红细胞仍然有代偿性增高（图2A）。治疗后总胆红素水平呈明显下降（例2）和稳定下降（例1），但尚未到正常水平（图2B）。与Ret和总胆红素不同，治疗后乳酸脱氢酶水平迅速降到正常水平（图2C），与这2例患者主要是血管外溶血为主有关。监测患者免疫功能状况评估显示（表1），免疫球蛋白、补体C3、C4含量没有降低，外周血CD19+B淋巴细胞比例，CD4+、CD8+T细胞比例均无异常变化。文献报道，伊布替尼治疗慢性淋巴细胞白血病会有短暂的、一过性淋巴细胞增多[12]–[13]，我们在例1中的确看到治疗第2周开始淋巴细胞数增高，第4周达高峰，8周以后开始下降，16周恢复到基线值。2例患者伊布替尼治疗中ANC未发生持续性下降。\n\n图1 2例复发/难治原发性自身免疫性溶血性贫血患者伊布替尼治疗后HGB改善情况\nPR：部分缓解；CRi：完全缓解伴代偿性溶血状态\n\n图2 2例复发/难治原发性自身免疫性溶血性贫血患者伊布替尼治疗后溶血实验室指标改善情况\n表1 2例复发/难治原发性AIHA患者伊布替尼治疗不同时间免疫功能指标变化\n指标\t例1\t例2\t\n基线\t2周\t4周\t8周\t12周\t16周\t基线\t4周\t9周\t\nIgG（g/L）\t14.6\t12.7\t12.3\t14.1\t-\t-\t6.04\t6.49\t5.99\t\nC3（g/L）\t0.4\t0.47\t0.47\t0.53\t-\t-\t0.73\t0.71\t0.66\t\nC4（g/L）\t0.02\t0.02\t0.03\t0.05\t-\t-\t0.25\t0.20\t0.22\t\nCD19+ B淋巴细胞比例（%）\t5.8\t6.0\t4.1\t4.6\t-\t-\t0.0\t0.3\t0.1\t\nCD4+ T淋巴细胞比例（%）\t42.4\t44.6\t41.4\t42.2\t-\t-\t56.5\t50.4\t46.0\t\nCD8+ T淋巴细胞比例（%）\t32.0\t39.0\t32.1\t28.0\t-\t-\t31.2\t25.9\t36.4\t\n淋巴细胞绝对值（×109/L）\t2.41\t4.55\t7.41\t5.42\t4.88\t3.20\t1.00\t0.82\t1.00\t\n中性粒细胞绝对值（×109/L）\t3.86\t1.41\t3.01\t3.38\t2.97\t2.65\t1.50\t1.48\t3.48\t\n注：AIHA：自身免疫性溶血性贫血；-：未检测\n\n讨论\n复发/难治AIHA尚无国际国内统一诊断标准，我们综合文献[2]-[5],[18]拟定复发/难治AIHA诊断标准：①糖皮质激素1.0～2.0 mg/kg治疗3周无效者；②糖皮质激素治疗依赖者（每日维持量≥15 mg泼尼松）；③2种或2种以上治疗措施（糖皮质激素、利妥昔单抗、脾切除术）无效或复发者；④2种或2种以上免疫抑制药物联合治疗HGB仍然<110 g/L者；⑤需要3种或3种以上免疫抑制药物联合治疗方能维持HGB>110 g/L者。\n\n鉴于糖皮质激素3周内高达80%以上的有效率，糖皮质激素治疗依赖者极容易反复溶血发作，长期使用不良反应大，多篇文献将糖皮质激素治疗无效或治疗依赖者归于复发/难治[4],[7],[18]。因为考虑到糖皮质激素长期使用的严重不良反应，多数临床诊治共识不建议长期应用糖皮质激素，认为糖皮质激素治疗3周无效、治疗依赖、治疗后首次复发时即应该启动二线治疗措施[2]–[5],[20]。早期文献[2],[5],[21]将利妥昔单抗及脾切除作为二线治疗，但是2019年国际专家共识[1],[4]已将利妥昔单抗作为唯一二线治疗药物，也可以针对性选择重度溶血贫血患者、合并症较多的老年患者作为一线选择用药，与糖皮质激素联合。脾切除术与其他免疫抑制剂如硫唑嘌呤、环孢素A、吗替麦考酚酯作为三线治疗。2个随机对照临床研究也证实了利妥昔单抗联合糖皮质激素虽然不提高3～6个月总有效率，但是可以明显提高完全缓解率及1～3年无复发生存率（70%～80%），而单用糖皮质激素1年无复发生存率仅50%[22]–[23]。文献报道复发/难治AIHA发生的危险因素可能与发病时贫血严重程度，非温抗体型AIHA（温冷双抗体型或冷抗体型），伴有血小板减少，利妥昔单抗延迟使用有关[24]。复发/难治AIHA患者接受目前的三四线治疗药物疗效不能很好维持，且不良反应较大[25]–[26]，寻找新的高效且不良反应较低的治疗药物将为AIHA整个治疗路径带来新的治疗前景，患者群体有较大的获益。\n\n分子靶向治疗血液肿瘤的优势在于良好的疗效和耐受性，针对惰性小B淋巴瘤的BTK抑制剂已经作为初诊老年患者及复发/难治患者的有效药物[11]–[13]。文献[14]–[17]报道5例继发于慢性淋巴细胞白血病、套细胞淋巴瘤的AIHA患者经伊布替尼治疗后溶血获得缓解。本研究结果显示减低剂量伊布替尼治疗短期内即可明显控制溶血，脱离输血依赖，获得了有效反应，第6、10周血常规指标正常，溶血指标持续改善，疗效维持至治疗第12、16周均未复发。既往报道的5例中4例为伊布替尼联合糖皮质激素治疗，药物剂量为420～560 mg/d，而我们报道的2例无原发疾病，单用伊布替尼治疗，减低剂量也可以获得满意疗效，可能与无原发淋巴瘤病因有关。我们报道的2例和之前报道的5例在起效时间上比较一致，一般在8周内获得完全缓解（表2）。安全性评价数据显示安全性良好，对机体免疫功能没有抑制作用。\n\n表2 伊布替尼治疗7例复发/难治AIHA患者临床资料汇总\n病例来源\t性别\t年龄（岁）\t原发病\tHGB（g/L）\t治疗方案\t疗效\t起效时间（周）\t\n基线\t治疗有效\t\nManda等[14]\t男\t70\tCLL伴17p−\t76\t115\t伊布替尼420 mg/d联合糖皮质激素\tCR\t3\t\nSt Bernard等[15]\t男\t70\tCLL伴13q−\t85\t120\t伊布替尼420 mg/d联合糖皮质激素\tCR\t16\t\nSt Bernard等[15]\t女\t70\tCLL伴13q−\t60\t125\t伊布替尼420 mg/d单药\tCR\t8\t\nCavazzini等[16]\t男\t62\tCLL伴17p−\t63\t105\t伊布替尼420 mg/d联合糖皮质激素\tPR\t5\t\nBarot等[17]\t女\t75\tMCL\t92\t110\t伊布替尼560 mg/d联合糖皮质激素\tCR\t7\t\n例1\t女\t17\t−\t47\t113\t伊布替尼280 mg/d单药（第3～8周加量为420 mg/d）\tPR/CRi\t2/10\t\n例2\t女\t7\t−\t65（输血后）\t118\t伊布替尼280 mg/d单药\tPR/CRi\t2/6\t\n注：AIHA：自身免疫性溶血性贫血；CLL：慢性淋巴细胞白血病；MCL：套细胞淋巴瘤；−：不适用；CR：完全缓解；PR：部分缓解；CRi：完全缓解伴代偿性溶血状态\n\n综合以上数据，我们认为BTK抑制剂有望成为复发/难治原发性AIHA新的二线治疗药物选择。本报道尚属于探索性研究，仍然需要在规范的临床试验中使用BTK抑制剂治疗复发/难治AIHA进一步验证其疗效及安全性。\n==== Refs\nReferences\n1 Brodsky RA Warm Autoimmune Hemolytic Anemia[J] N Engl J Med 2019 381 7 647 654 10.1056/NEJMcp1900554 31412178 \n2 Hill A Hill QA Autoimmune hemolytic anemia[J] Hematology Am Soc Hematol Educ Program 2018 2018 1 382 389 10.1182/asheducation-2018.1.382 30504336 \n3 Barcellini W Fattizzo B Zaninoni A Current and emerging treatment options for autoimmune hemolytic anemia[J] Expert Rev Clin Immunol 2018 14 10 857 872 10.1080/1744666X.2018.1521722 30204521 \n4 Jäger U Barcellini W Broome CM Diagnosis and treatment of autoimmune hemolytic anemia in adults: Recommendations from the First International Consensus Meeting[J] Blood Rev 2019 100648 10.1016/j.blre.2019.100648 31839434 \n5 Hill QA Stamps R Massey E The diagnosis and management of primary autoimmune haemolytic anaemia[J] Br J Haematol 2017 176 3 395 411 10.1111/bjh.14478 28005293 \n6 Lechner K Jäger U How I treat autoimmune hemolytic anemias in adults[J] Blood 2010 116 11 1831 1838 10.1182/blood-2010-03-259325 20548093 \n7 Reynaud Q Durieu I Dutertre M Efficacy and safety of rituximab in auto-immune hemolytic anemia: A meta-analysis of 21 studies[J] Autoimmun Rev 2015 14 4 304 313 10.1016/j.autrev.2014.11.014 25497766 \n8 Barcellini W Fattizzo B Zaninoni A Clinical heterogeneity and predictors of outcome in primary autoimmune hemolytic anemia: a GIMEMA study of 308 patients[J] Blood 2014 124 19 2930 2936 10.1182/blood-2014-06-583021 25232059 \n9 Roumier M Loustau V Guillaud C Characteristics and outcome of warm autoimmune hemolytic anemia in adults: New insights based on a single-center experience with 60 patients[J] Am J Hematol 2014 89 9 E150 155 10.1002/ajh.23767 24847759 \n10 Dierickx D Kentos A Delannoy A The role of rituximab in adults with warm antibody autoimmune hemolytic anemia[J] Blood 2015 125 21 3223 3229 10.1182/blood-2015-01-588392 25827833 \n11 Byrd JC Furman RR Coutre SE Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia[J] N Engl J Med 2013 369 1 32 42 10.1056/NEJMoa1215637 23782158 \n12 Huang X Qiu L Jin J Ibrutinib versus rituximab in relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma: a randomized, open-label phase 3 study[J] Cancer Med 2018 7 4 1043 1055 10.1002/cam4.1337 29533000 \n13 Shanafelt TD Wang XV Kay NE Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia[J] N Engl J Med 2019 381 5 432 443 10.1056/NEJMoa1817073 31365801 \n14 Manda S Dunbar N Marx-Wood CR Ibrutinib is an effective treatment of autoimmune haemolytic anaemia in chronic lymphocytic leukaemia[J] Br J Haematol 2015 170 5 734 736 10.1111/bjh.13328 25716177 \n15 St Bernard R Hsia CC Safe utilization of ibrutinib with or without steroids in chronic lymphocytic leukemia patients with autoimmune hemolytic anemia[J] Ann Hematol 2015 94 12 2077 2079 10.1007/s00277-015-2487-8 26334319 \n16 Cavazzini F Lista E Quaglia FM Response to ibrutinib of refractory life-threatening autoimmune hemolytic anemia occurring in a relapsed chronic lymphocytic leukemia patient with 17p deletion[J] Leuk Lymphoma 2016 57 11 2685 2688 10.3109/10428194.2016.1154955 26999572 \n17 Barot SV Lee SS Patel BJ Ibrutinib is Effective in Refractory Type II Cryoglobulinemia[J] Clin Lymphoma Myeloma Leuk 2019 19 12 e629 629e632 10.1016/j.clml.2019.07.442 31585822 \n18 范 斯斌 王 志军 毛 强 复发/难治自身免疫性溶血性贫血患者脾切除术疗效分析[J] 中华血液学杂志 2019 40 2 132 136 10.3760/cma.j.issn.0253-2727.2019.02.007 \n19 中华医学会血液学分会红细胞疾病(贫血)学组 自身免疫性溶血性贫血诊断与治疗中国专家共识(2017年版)[J] 中华血液学杂志 2017 38 4 265 267 10.3760/cma.j.issn.0253-2727.2017.04.001 \n20 Sys J Provan D Schauwvlieghe A The role of splenectomy in autoimmune hematological disorders: Outdated or still worth considering?[J] Blood Rev 2017 31 3 159 172 10.1016/j.blre.2017.01.001 28077241 \n21 Zanella A Barcellini W Treatment of autoimmune hemolytic anemias[J] Haematologica 2014 99 10 1547 1554 10.3324/haematol.2014.114561 25271314 \n22 Birgens H Frederiksen H Hasselbalch HC A phase III randomized trial comparing glucocorticoid monotherapy versus glucocorticoid and rituximab in patients with autoimmune haemolytic anaemia[J] Br J Haematol 2013 163 3 393 399 10.1111/bjh.12541 23981017 \n23 Michel M Terriou L Roudot-Thoraval F A randomized and double-blind controlled trial evaluating the safety and efficacy of rituximab for warm auto-immune hemolytic anemia in adults (the RAIHA study)[J] Am J Hematol 2017 92 1 23 27 10.1002/ajh.24570 27696475 \n24 Barcellini W Zaninoni A Fattizzo B Predictors of refractoriness to therapy and healthcare resource utilization in 378 patients with primary autoimmune hemolytic anemia from eight Italian reference centers[J] Am J Hematol 2018 93 9 E243 243E246 10.1002/ajh.25212 29981267 \n25 Piatek CI Bocian H Algaze S A Retrospective Study of the Combination of Rituximab, Cyclophosphamide and Dexamethasone for the Treatment of Relapsed/Refractory Warm Antibody Autoimmune Hemolytic Anemia[J] Acta Haematol 2019 1 6 10.1159/000501538 \n26 Ratnasingam S Walker PA Tran H Bortezomib-based antibody depletion for refractory autoimmune hematological diseases[J] Blood Adv 2016 1 1 31 35 10.1182/bloodadvances.2016001412 29296693\n\n",
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"journal": "Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi",
"keywords": "Autoimmune hemolytic anemia; Ibrutinib; Relapsed/refractory",
"medline_ta": "Zhonghua Xue Ye Xue Za Zhi",
"mesh_terms": "D000225:Adenine; D000744:Anemia, Hemolytic, Autoimmune; D058846:Antibodies, Monoclonal, Murine-Derived; D006801:Humans; D010865:Pilot Projects; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; D000069283:Rituximab",
"nlm_unique_id": "8212398",
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"pages": "412-416",
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"pmid": "32536139",
"pubdate": "2020-05-14",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Ibrutinib treatment for 2 cases of relapsed/refractory autoimmune hemolytic anemia: a pilot study.",
"title_normalized": "ibrutinib treatment for 2 cases of relapsed refractory autoimmune hemolytic anemia a pilot study"
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"abstract": "OBJECTIVE\nAlthough three-weekly high-dose (100mg/m(2)) cisplatin (three cycles) chemoradiotherapy has been considered a standard regimen for patients with advanced head and neck squamous cell carcinomas (HNSCC), this protocol is associated with significant acute and late toxicities. Therefore, weekly cisplatin at a dose of 40mg/m(2) has been used at our institution since 2006. This retrospective study was aimed at assessing the oncologic efficacy of weekly cisplatin chemoradiotherapy for the control of nodal metastasis.\n\n\nMETHODS\nWe analyzed 28 patients with node-positive HNSCC treated with weekly cisplatin and concurrent radiotherapy. Computed tomography was performed 4-8 weeks after the completion of chemoradiotherapy to evaluate nodal response. If residual neck disease was apparent or suspected, we performed early salvage neck dissection (ND). In cases with a complete response (CR), we took a \"wait and see\" approach. When no viable tumor cells were observed in the surgical specimens obtained by ND, nodal metastasis was defined as controlled by weekly cisplatin chemoradiotherapy alone.\n\n\nRESULTS\nNodal metastasis was evaluated as having a CR in 20 patients (71%). Eight patients (29%) underwent early salvage ND. Recurrent primary tumors were observed in the other four patients (14%). Salvage primary resection and associated ND were performed for these four patients. In 7 of 12 patients undergoing ND, no viable tumor cells were observed. In 23of 28 patients, neck diseases were controlled by chemoradiotherapy alone (not including salvage by ND). In 27 of 28 patients, neck diseases were controlled by the overall treatment (including salvage by ND). The rate of nodal control by chemoradiotherapy alone and by the overall treatment was found to be 82.0% and 96.3%, respectively, using the Kaplan-Meier method. The three-year overall and disease free survival rates were 86.8% and 80.8%, respectively.\n\n\nCONCLUSIONS\nConcomitant weekly cisplatin at a dose of 40mg/m(2) chemoradiotherapy showed a good control rate of not only primary lesions but also neck diseases.",
"affiliations": "Department of Otolaryngology- Head & Neck Surgery, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-ku, Sapporo 060-8638, Japan. t-sakashita@med.hokudai.ac.jp",
"authors": "Sakashita|Tomohiro|T|;Homma|Akihiro|A|;Oridate|Nobuhiko|N|;Suzuki|Seigo|S|;Hatakeyama|Hiromitsu|H|;Kano|Satoshi|S|;Mizumachi|Takatsugu|T|;Onimaru|Rikiya|R|;Tsuchiya|Kazuhiko|K|;Yasuda|Koichi|K|;Shirato|Hiroki|H|;Fukuda|Satoshi|S|",
"chemical_list": "D000970:Antineoplastic Agents; D002945:Cisplatin",
"country": "Netherlands",
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"issn_linking": "0385-8146",
"issue": "40(2)",
"journal": "Auris, nasus, larynx",
"keywords": null,
"medline_ta": "Auris Nasus Larynx",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D002294:Carcinoma, Squamous Cell; D059248:Chemoradiotherapy; D002945:Cisplatin; D018572:Disease-Free Survival; D005260:Female; D006258:Head and Neck Neoplasms; D006801:Humans; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009333:Neck; D037981:Neck Dissection; D012189:Retrospective Studies; D016879:Salvage Therapy; D000077195:Squamous Cell Carcinoma of Head and Neck; D016896:Treatment Outcome",
"nlm_unique_id": "7708170",
"other_id": null,
"pages": "211-5",
"pmc": null,
"pmid": "22867524",
"pubdate": "2013-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Regional control after concomitant chemoradiotherapy without planned neck dissection in node-positive head and neck squamous cell carcinomas.",
"title_normalized": "regional control after concomitant chemoradiotherapy without planned neck dissection in node positive head and neck squamous cell carcinomas"
} | [
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"companynumb": "JP-MYLANLABS-2015M1001310",
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"abstract": "Follicular dendritic cell sarcoma (FDCS) is a very rare malignant tumor derived from follicular dendritic cells. Radical resection is the standard therapy for patients with local disease, but an optimal chemotherapy regimen has not been determined for unresectable disease. We report our experience of an FDCS patient with multiorgan involvement. In the present case, disease was only located in the pancreas initially and radical resection was performed. Multiple metastasis developed after the treatment and several factors that indicated a poor prognosis were observed. The present case had a very poor prognostic disease but survived for a long time with a good performance status because of the multiple chemotherapy regimens, which follow therapeutic strategies for malignant lymphoma and soft tissue sarcoma. As far as we know, this is the first study reporting the indication of bendamustine for FDCS patients.",
"affiliations": "Division of Breast and Medical Oncology, National Cancer Center Hospital East, Chiba, Japan.;Division of Psychosomatic medicine, Kinki University Hospital, Osaka, Japan.;Division of Breast and Medical Oncology, National Cancer Center Hospital East, Chiba, Japan.;Division of Pathology, National Cancer Center Hospital East, Chiba, Japan.;Division of Breast and Medical Oncology, National Cancer Center Hospital East, Chiba, Japan.",
"authors": "Sasaki|Masaoki|M|;Izumi|Hiroaki|H|;Yokoyama|Takaaki|T|;Kojima|Motohiro|M|;Hosono|Ako|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/hon.2364",
"fulltext": "\n==== Front\nHematol OncolHematol Oncol10.1002/(ISSN)1099-1069HONHematological Oncology0278-02321099-1069John Wiley and Sons Inc. Hoboken 10.1002/hon.2364HON2364HON-16-0065.R2Case ReportCase ReportsFollicular dendritic cell sarcoma treated with a variety of chemotherapy FDCS treated with a variety of chemotherapySASAKI et al.Sasaki Masaoki massasak@east.ncc.go.jp \n1\nIzumi Hiroaki \n3\nYokoyama Takaaki \n1\nKojima Motohiro \n2\nHosono Ako \n1\n\n1 \nDivision of Breast and Medical Oncology\nNational Cancer Center Hospital East\nChiba\nJapan\n\n2 \nDivision of Pathology\nNational Cancer Center Hospital East\nChiba\nJapan\n\n3 \nDivision of Psychosomatic medicine\nKinki University Hospital\nOsaka\nJapan\n* \nCorrespondence\n\nMasaoki Sasaki, Breast and Medical Oncology, National Cancer Center Hospital East, 6‐5‐1, Kashiwanoha, Kashiwa‐shi, Chiba, Japan.\n\nEmail: massasak@east.ncc.go.jp\n13 10 2016 12 2017 35 4 10.1002/hon.v35.4905 908 24 3 2016 26 8 2016 08 9 2016 © 2016 The Authors. Hematological Oncology published by John Wiley & Sons LtdThis is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Abstract\nFollicular dendritic cell sarcoma (FDCS) is a very rare malignant tumor derived from follicular dendritic cells. Radical resection is the standard therapy for patients with local disease, but an optimal chemotherapy regimen has not been determined for unresectable disease. We report our experience of an FDCS patient with multiorgan involvement. In the present case, disease was only located in the pancreas initially and radical resection was performed. Multiple metastasis developed after the treatment and several factors that indicated a poor prognosis were observed. The present case had a very poor prognostic disease but survived for a long time with a good performance status because of the multiple chemotherapy regimens, which follow therapeutic strategies for malignant lymphoma and soft tissue sarcoma. As far as we know, this is the first study reporting the indication of bendamustine for FDCS patients.\n\nbendamustinechemotherapyfollicular dendritic cell sarcoma source-schema-version-number2.0component-idhon2364cover-dateDecember 2017details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.2.8 mode:remove_FC converted:11.01.2018\n\n\nSasaki \nM \n, \nIzumi \nH \n, \nYokoyama \nT \n, \nKojima \nM \n, \nHosono \nA \n. Follicular dendritic cell sarcoma treated with a variety of chemotherapy . Hematological Oncology . 2017 ;35 :905 –908 . https://doi.org/10.1002/hon.2364\n27734516\n==== Body\n1 INTRODUCTION\nDendritic cells are immune cells involved in antigen presentation and endocytosis and are classified as T‐cell–associated dendritic cells and B‐cell–associated dendritic cells. Follicular dendritic cells are B‐cell–associated dendritic cells present in lymph follicles. Follicular dendritic cells are mesenchymal in origin, and although they play a role in the maintenance of the lymph follicle environment and the activation of B cells in lymph follicles, they have no antigen presenting or endocytosis functions unlike other dendritic cells.\n\nFollicular dendritic cell sarcoma (FDCS) is a very rare malignant tumor derived from follicular dendritic cells. It is not always easy to make the distinction because of histological similarities with non‐Hodgkin lymphoma, sarcoma, melanoma, undifferentiated carcinomas, and other dendritic and histiocytic cell disease. The diagnosis is based on morphology and immunohistochemical assay. Morphology is characterized by spindled to ovoid cells forming fascicles, whorls, diffuse sheets, or nodules. Lymphoplasmacytic infiltration is frequently present in tumor tissue. Tumor cells typically express markers of follicular dendritic cell differentiation, including CD21, CD23, and CD35. Clusterin, fascin, and podoplanin are additional markers that are uniformly positive.1, 2, 3, 4 Radical resection is the standard therapy for patients with local disease, and adjuvant radiotherapy did not have a significant influence on survival outcomes.1, 5 Chemotherapy is indicated for patients with unresectable disease or multiorgan involvement.1, 6 An optimal chemotherapy regimen has not been determined for this rare disease and cytotoxic agents for malignant lymphoma or soft tissue sarcoma are commonly used to treat FDCS patients.4, 7, 8 Therefore, the accumulation of case reports is important to clarify the pathophysiology of FDCS and establish an optimal treatment strategy. We report our experience of an FDCS patient with multiorgan involvement whose disease was controlled by multiple chemotherapy regimens and who maintained a good performance status over a long period.\n\n2 CASE REPORT\n2.1 Clinical course\nA 42‐year‐old Japanese woman initially complained of chest discomfort. The patient was initially diagnosed with a solid pseudopapillary neoplasm (SPN) localized to the pancreas and received distal pancreatectomy, splenectomy, and fundectomy. Five months later, an abdominal computerized tomography scan identified multiple liver metastasis, lymph node metastasis, and peritoneum dissemination. The metastatic tumor showed rapid growth and she was admitted to our hospital.\n\nAlthough the final pathology report was not settled at the time of first‐line chemotherapy, we implemented chemotherapy for SPN with SG regimen (S‐1, 80 mg/body, on days 1–14 and Gemcitabine, 1000 mg/m2, on days 1 and 8 of the 21‐day cycle) based on the pathology evaluation from the pathologist who diagnosed first owing to rapid tumor growth, but disease progression was evidently observed after 1 cycle. Combination therapy was selected as first‐line chemotherapy because of its high response rate in patients with pancreas cancer.9 At the same time, an accurate pathologic diagnosis was made from tumor specimens and she was diagnosed with FDCS. Histological analysis of the patient tumor biopsy demonstrated a tumor mass with a diffuse growth of spindle cells, multinucleated cells, intranuclear inclusions, and Hodgikinoid plasma cells (Figure 1).\n\nFigure 1 Hematoxylin and eosin staining and immunochemical features of the tumor\n\nImmunohistochemical analysis revealed that the tumor cells were positive for CD21, CD23, CD68 (weak), vimentin, clusterin, and fascin and were negative for CD1a, HMB‐45, desmin, smooth muscle actin, and S100.\n\nAfter 6 cycles of doxorubicin (DXR) (60 mg/m2, on day 1 of the 21‐day cycle), a standard cytotoxic agent of soft tissue sarcoma,10, 11 a good partial response was observed, and careful observation without chemotherapy was continued for 3 months (Figure 2). Ifosfamide (IFM) administered at 1.8 mg/m2 on days 1–3 of the 21‐day cycle was selected as a third‐line chemotherapeutic agent because it is a standard cytotoxic agent for the treatment of soft tissue sarcoma,11, 12 and CHOP (cyclophosphamide, vincristine, doxorubicin, prednisolone), which is a standard regimen for malignant lymphoma,13, 14 was selected as a fourth‐line chemotherapy treatment. However, despite this treatment, disease rapidly progressed. ESHAP (etoposide, methylprednisolone, cisplatin, cytarabine), which is a standard salvage regimen for malignant lymphoma,15 was selected as a fifth‐line chemotherapy treatment. Shrinkage of the abdominal mass was observed after 1 cycle of ESHAP. Because of the high‐grade adverse effects (nausea, vomiting, and fatigue) associated with ESHAP, the patient required an 80% reduction in chemotherapy doses from the third cycle of ESHAP onward. At the end of 4 cycles of ESHAP, renal dysfunction due to cisplatin was observed and ESHAP was not continued. We selected a weekly dose of paclitaxel (PTX) (80 mg/m2) as a sixth‐line chemotherapy treatment because PTX is metabolized by the liver and taxane is effective for soft tissue sarcoma therapy. Weekly administered PTX controlled the disease progression, and the patient maintained a good performance status for 4 months. At the next onset of disease progression, we selected bendamustine (120 mg/m2, on days 1 and 2 of the 21‐day cycle), which is effective for the treatment of malignant lymphomas,16 as a seventh‐line therapy. After administration of bendamustine, the laboratory data were improved rapidly. However, a second course could not be initiated at day 22 because of the development of adverse effects caused by bendamustine such as diarrhea and loss of appetite. Although we attempted to recover the beneficial performance status of the treatment using intravenously administered saline to counter the dehydration caused by excessive diarrhea, disease progression continued, and we decided that a continuation of the chemotherapy was impossible.\n\nFigure 2 CT images of abdomen. A, Before DXR. B, After DXR\n\n2.2 Laboratory data\nCT scans were performed before progression, and we finally decided treatment change. However, in this case, changes in alkaline phosphatase (ALP) and C‐reactive protein (CRP) looked associated with CT image, and we also used ALP and CRP as a possible surrogate marker to infer effectiveness of treatment. The relationship between disease control and laboratory data is shown in Figure 3. During effective chemotherapy treatment with DXR, ESHAP, or PTX, CRP and ALP values were decreased or were maintained at the same level, and during disease progression, these values were increased significantly. After the first administration of bendamustine, CRP and ALP levels were significantly and rapidly decreased. However, adverse events related to bendamustine were prolonged, and we could not start a second cycle of chemotherapy on day 22 of the first cycle. On day 35 of the first cycle, ALP, lactate dehydrogenase, and CRP were significantly increased and disease progression was observed.\n\nFigure 3 Relationship between changes in laboratory data (CRP and ALP) and tumor responses to chemotherapy\n\n3 DISCUSSION\nIn a pooled analysis of FDCS patients by Saygin et al,1 68% of FDCS patients had extranodal disease, and a common extranodal site, including the liver, lung, tonsil, spleen, or soft tissue, was involved. FDCS of the pancreas as reported in the present case is very rare. In this analysis, they reported that early disease accounted for 85% of all FDCS cases. Because radical resection is indicated for most of FDCS patients, there have been few reports of advanced disease, which is indicated for chemotherapy. In another case report, CHOP, which is the standard chemotherapy for malignant lymphoma and salvage therapy for refractory cases after the treatment of malignant lymphomas and soft tissue sarcomas, was indicated for unresectable patients.6 Other studies reported that chemotherapy for malignant lymphoma or soft tissue sarcoma was commonly selected, but optimal palliative chemotherapy regimens are controversial and data on the use of palliative chemotherapy are limited for refractory FDCS.\n\nTo our knowledge, the control of disease in an FDCS patient using many different chemotherapy regimens to maintain a good performance status has not been reported previously. Saygin et al reported prognostic variables of FDCS patients from a pooled univariate analysis of all published data and indicated that age (young age ≤ 40 years), absence of lymphoplasmacytic infiltration, large tumor size (>6 cm), and mitotic counts (≥5/10 high‐power field) were significant indicators of a poor prognosis. In multivariate analysis, lymphoplasmacytic infiltration and tumor size were associated with a poor prognosis. Furthermore, the median survival for local disease was 168 months, and the 2‐year survival rate was 82.8% for local disease. However, the 2‐year survival rate was 42.8% for metastatic disease.1 In the present case, disease was only located in the pancreas initially, and radical resection was performed, but disease‐free survival was only 6 months. In the current case study, multiple metastasis developed after the treatment, and several factors that indicated a poor prognosis were observed that were in accordance with a previous study by Saygin et al. The current case study had a very poor prognostic disease but survived for a long time with a good performance status because of the multiple chemotherapy treatments administered.\n\nThe characteristics of the clinical course of the present case were as follows: (i) although it was a very aggressive tumor and performance status was low before DXR, the tumor shrunk rapidly and the patient's performance status recovered immediately after the indication of DXR; (ii) the response to DXR was very good, and the reason for changing to another regimen was not due to progressive disease; nevertheless, IFM and CHOP (containing DXR) was not effective in treating the disease; (iii) although the use of the third‐ and the fourth‐line chemotherapy, normally used to treat soft tissue sarcoma and malignant lymphoma, was not effective, the fifth‐line chemotherapy (ESHAP) and sixth‐line PTX were effective and performance status recovered.\n\nAs far as we know, this is the first study reporting the indication of bendamustine for FDCS patients. Bendamustine is very effective for low‐grade B‐cell lymphoma and is a current standard chemotherapy for low‐grade B‐cell lymphoma.16 In addition, clinical trials evaluating the use of bendamustine in diffuse large B‐cell lymphoma, an intermediate grade lymphoma, are under way. The result of a phase II clinical trial to evaluate the effectiveness of bendamustine in previously treated diffuse large B‐cell lymphoma reported that the overall response rate was 62.7%, the complete response rate was 37.3%, and the progression‐free survival was 6.7 months.17 Bendamustine is expected to become a key drug for the treatment of intermediate grade lymphoma. The result of a phase II clinical trial to evaluate the effectiveness of bendamustine in previously treated soft tissue sarcoma reported that the partial response rate was 3%, the stable disease rate was 31%, and the 3‐month progression‐free survival rate was 35.3% and 6‐month progression‐free survival rate was 23.5%.18 Bendamustine was selected for the seventh‐line chemotherapy treatment because it has antitumor effects and low cross‐resistance with other alkylators, thus making it suitable for the treatment of alkylator‐refractory patients. After the administration of bendamustine, ALP and CRP levels were decreased dramatically. This clinical course was observed when DXR or ESHAP was administrated and changes in ALP and CRP levels were associated with disease control. Although it was impossible to continue bendamustine treatment because of bendamustine‐induced adverse effects and subsequent reduced physical strength of the patient, a rapid decrease of ALP and CRP was observed regardless of the many other chemotherapy regimens administered previously. As for present case, bendamustine could not continue after 1 cycle, and we did not demonstrate good outcome with bendamustine. However, there may be room for examination in the adequacy of bendamustine as treatment option for FDCS.\n\nCONFLICT OF INTEREST\nThere is no conflict of interest.\n\nETHICS STATEMENT\nThis is a retrospective case report of FDCS. Any identifying information of patient has not been revealed. Additional examinations were not performed for this study.\n\nACKNOWLEDGEMENT\nThere is no source of support.\n==== Refs\nREFERENCES\n1 \n\nSaygin \nC \n, \nUzunaslan \nD \n, \nOzguroglu \nM \n, et al. Dendritic cell sarcoma: a pooled analysis including 462 cases with presentation of our case series . Crit Rev Oncol Hematol . 2013 ;88 (2 ):253 –271 .23755890 \n2 \n\nDalia \nS \n, \nShao \nH \n, \nSagatys \nE \n, et al. Dendritic cell and histiocytic neoplasms: biology, diagnosis, and treatment . Cancer Control . 2014 ;21 (4 ):290 –300 .25310210 \n3 \n\nDalia \nS \n, \nJaglal \nM \n, \nChervenick \nP \n, et al. Clinicopathologic characteristics and outcomes of histiocytic and dendritic cell neoplasms: the moffitt cancer center experience over the last twenty five years . Cancers . 2014 ;6 (4 ):2275 –2295 .25405526 \n4 \n\nCaces \nDB \n, \nDaniel \nS \n, \nParedes‐Tejada \nJM \n, et al. Spontaneous regression of follicular dendritic cell sarcoma . J Clin Oncol . 2012 ;30 (3 ):e24 –e26 .22162586 \n5 \n\nPerkins \nSM \n, \nShinohara \nET \n. Interdigitating and follicular dendritic cell sarcomas: a SEER analysis . Am J Clin Oncol . 2013 ;36 (4 ):395 –398 .22772431 \n6 \n\nSoriano \nAO \n, \nThompson \nMA \n, \nAdmirand \nJH \n, et al. Follicular dendritic cell sarcoma: a report of 14 cases and a review of the literature . Am J Hematol . 2007 ;82 (8 ):725 –728 .17373675 \n7 \n\nShinagare \nAB \n, \nRamaiya \nNH \n, \nJagannathan \nJP \n, et al. Primary follicular dendritic cell sarcoma of liver treated with cyclophosphamide, doxorubicin, vincristine, and prednisone regimen and surgery . J Clin Oncol . 2011 ;29 (35 ):e849 –e851 .22042944 \n8 \n\nChoi \nBS \n, \nBaek \nJH \n, \nShin \nYM \n, et al. Follicular dendritic cell sarcoma: a case report and review of the literature . Cancer Res Treat . 2010 ;42 (2 ):121 –124 .20622968 \n9 \n\nUeno \nH \n, \nIoka \nT \n, \nIkeda \nM \n, et al. Randomized phase III study of gemcitabine plus S‐1, S‐1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study . J Clin Oncol . 2013 ;31 (13 ):1640 –1648 .23547081 \n10 \n\nSantoro \nA \n, \nTursz \nT \n, \nMouridsen \nH \n, et al. Doxorubicin versus CYVADIC versus doxorubicin plus ifosfamide in first‐line treatment of advanced soft tissue sarcomas: a randomized study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group . J Clin Oncol . 1995 ;13 (7 ):1537 –1545 .7602342 \n11 \n\nJudson \nI \n, \nVerweij \nJ \n, \nGelderblom \nH \n, et al. Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first‐line treatment of advanced or metastatic soft‐tissue sarcoma: a randomised controlled phase 3 trial . Lancet Oncol . 2014 ;15 (4 ):415 –423 .24618336 \n12 \n\nvan Oosterom \nAT \n, \nMouridsen \nHT \n, \nNielsen \nOS \n, et al. Results of randomised studies of the EORTC Soft Tissue and Bone Sarcoma Group (STBSG) with two different ifosfamide regimens in first‐ and second‐line chemotherapy in advanced soft tissue sarcoma patients . European J Cancer . 2002 ;38 (18 ):2397 –2406 .12460784 \n13 \n\nFisher \nRI \n, \nGaynor \nER \n, \nDahlberg \nS \n, et al. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non‐Hodgkin's lymphoma . N Engl J Med . 1993 ;328 (14 ):1002 –1006 .7680764 \n14 \n\nCoiffier \nB \n, \nLepage \nE \n, \nBriere \nJ \n, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large‐B‐cell lymphoma . N Engl J Med . 2002 ;346 (4 ):235 –242 .11807147 \n15 \n\nVelasquez \nWS \n, \nMcLaughlin \nP \n, \nTucker \nS \n, et al. ESHAP—an effective chemotherapy regimen in refractory and relapsing lymphoma: a 4‐year follow‐up study . J Clin Oncol . 1994 ;12 (6 ):1169 –1176 .8201379 \n16 \n\nRummel \nMJ \n, \nNiederle \nN \n, \nMaschmeyer \nG \n, et al. Bendamustine plus rituximab versus CHOP plus rituximab as first‐line treatment for patients with indolent and mantle‐cell lymphomas: an open‐label, multicentre, randomised, phase 3 non‐inferiority trial . Lancet . 2013 ;381 (9873 ):1203 –1210 .23433739 \n17 \n\nVacirca \nJL \n, \nAcs \nPI \n, \nTabbara \nIA \n, et al. Bendamustine combined with rituximab for patients with relapsed or refractory diffuse large B cell lymphoma . Ann Hematol . 2014 ;93 (3 ):403 –409 .23955074 \n18 \n\nHartmann \nJT \n, \nMayer \nF \n, \nSchleicher \nJ \n, et al. Bendamustine hydrochloride in patients with refractory soft tissue sarcoma: a noncomparative multicenter phase 2 study of the German sarcoma group (AIO‐001) . Cancer . 2007 ;110 (4 ):861 –866 .17599772\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0278-0232",
"issue": "35(4)",
"journal": "Hematological oncology",
"keywords": "bendamustine; chemotherapy; follicular dendritic cell sarcoma",
"medline_ta": "Hematol Oncol",
"mesh_terms": "D000328:Adult; D054740:Dendritic Cell Sarcoma, Follicular; D005260:Female; D006801:Humans; D011379:Prognosis",
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"pages": "905-908",
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"pmid": "27734516",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports",
"references": "17599772;23755890;8201379;7602342;12460784;20622968;23955074;23547081;7680764;25310210;22162586;22042944;22772431;11807147;25405526;17373675;23433739;27734516;24618336",
"title": "Follicular dendritic cell sarcoma treated with a variety of chemotherapy.",
"title_normalized": "follicular dendritic cell sarcoma treated with a variety of chemotherapy"
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"abstract": "We describe three cases of acute exacerbation of interstitial lung diseases (ILDs) in which patients were treated with pulsed-doses of corticosteroids followed by nintedanib and maintenance doses of corticosteroids. All cases responded well to pulsed-dose corticosteroids. However, in conventional practice, corticosteroids can complicate adverse events, including opportunistic infections, diabetes, and osteoporosis. One of the cases reported here involved dermatomyositis-associated ILD with anti-EJ antibodies. Considering possible side effects of corticosteroids and the frequent recurrence of ILDs associated with anti-EJ antibodies, we decided to use nintedanib as a sequential treatment for acute exacerbation of ILDs. Nintedanib has just been approved for treatment of progressive fibrosing ILD, but to date, few reports of acute exacerbation of ILDs treated with nintedanib have been published. This case series may contribute to a more thorough discussion regarding the use and timing of nintedanib in treating acute exacerbation of ILDs.",
"affiliations": "Department of Respiratory Medicine, Hamanomachi Hospital, Fukuoka, 810-8539, Japan.;Department of Respiratory Medicine, Hamanomachi Hospital, Fukuoka, 810-8539, Japan.;Department of Pharmacy, Hamanomachi Hospital, Fukuoka, 810-8539, Japan.;Department of Respiratory Medicine, Hamanomachi Hospital, Fukuoka, 810-8539, Japan.;Department of Respiratory Medicine, Hamanomachi Hospital, Fukuoka, 810-8539, Japan.;Department of Respiratory Medicine, Hamanomachi Hospital, Fukuoka, 810-8539, Japan.;Department of Respiratory Medicine, Hamanomachi Hospital, Fukuoka, 810-8539, Japan.",
"authors": "Nakashima|Kazuki|K|;Yanagihara|Toyoshi|T|;Ishida|Sae|S|;Ogo|Naruhiko|N|;Egashira|Ayaka|A|;Asoh|Tatsuma|T|;Maeyama|Takashige|T|",
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"doi": "10.1016/j.rmcr.2021.101385",
"fulltext": "\n==== Front\nRespir Med Case Rep\nRespir Med Case Rep\nRespiratory Medicine Case Reports\n2213-0071\nElsevier\n\nS2213-0071(21)00047-2\n10.1016/j.rmcr.2021.101385\n101385\nCase Report\nThree cases of sequential treatment with nintedanib following pulsed-dose corticosteroids for acute exacerbation of interstitial lung diseases\nNakashima Kazuki a\nYanagihara Toyoshi yanagiha@kokyu.med.kyushu-u.ac.jp\na∗\nIshida Sae b\nOgo Naruhiko a\nEgashira Ayaka a\nAsoh Tatsuma a\nMaeyama Takashige a\na Department of Respiratory Medicine, Hamanomachi Hospital, Fukuoka, 810-8539, Japan\nb Department of Pharmacy, Hamanomachi Hospital, Fukuoka, 810-8539, Japan\n∗ Corresponding author. yanagiha@kokyu.med.kyushu-u.ac.jp\n09 3 2021\n2021\n09 3 2021\n33 10138512 2 2021\n26 2 2021\n4 3 2021\n© 2021 The Author(s)\n2021\nThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nWe describe three cases of acute exacerbation of interstitial lung diseases (ILDs) in which patients were treated with pulsed-doses of corticosteroids followed by nintedanib and maintenance doses of corticosteroids. All cases responded well to pulsed-dose corticosteroids. However, in conventional practice, corticosteroids can complicate adverse events, including opportunistic infections, diabetes, and osteoporosis. One of the cases reported here involved dermatomyositis-associated ILD with anti-EJ antibodies. Considering possible side effects of corticosteroids and the frequent recurrence of ILDs associated with anti-EJ antibodies, we decided to use nintedanib as a sequential treatment for acute exacerbation of ILDs. Nintedanib has just been approved for treatment of progressive fibrosing ILD, but to date, few reports of acute exacerbation of ILDs treated with nintedanib have been published. This case series may contribute to a more thorough discussion regarding the use and timing of nintedanib in treating acute exacerbation of ILDs.\n\nKeywords\n\nNintedanib\nAcute exacerbation\nInterstitial lung disease\nProgressive fibrosing interstitial lung disease\n==== Body\n1 Introduction\n\nInterstitial lung diseases (ILDs) are a heterogeneous group of diseases characterized by variable degrees of inflammation and fibrosis of the lung. In some cases, ILDs show a chronic course with progressive scarring of lung tissue. During the clinical course of ILDs, acute exacerbation (AE) can occur at any time and is associated with significant morbidity and mortality [1]. Initially, AE-ILD was described in idiopathic pulmonary fibrosis (IPF), the most severe form of progressive fibrosing interstitial lung disease of unknown etiology. The international working group for AE-IPF has revised the definition and diagnostic criteria for AE-IPF [2]: (a) Previous or concurrent diagnosis of IPF (b) Acute worsening or development of dyspnea, typically of <1 month duration (c) CT with new, bilateral ground-glass opacities (GGOs) and/or consolidation superimposed on a background pattern consistent with the usual interstitial pneumonia pattern (d) Deterioration not fully explained by cardiac failure or fluid overload. Similarly, AE-ILD manifests radiographically as emerging diffuse, bilateral, GGOs superimposed on a background of chronic fibrotic changes consistent with fibrosing ILDs on high-resolution CT imaging [2,3]. Because of the disease behavior, clinical trials for AE-ILDs are challenging, and there is little clinical evidence on which to base a treatment strategy for them [4].\n\nHere, we describe three cases of AE-ILDs that were treated with pulsed doses of corticosteroids followed by nintedanib and a maintenance dose of corticosteroids. We discuss the rationale for this treatment with limitations and propose a new therapeutic strategy for AE-ILDs.\n\n2 Case presentations\n\n2.1 Case #1\n\nAn 88-year-old Japanese woman was admitted to Hamanomachi Hospital due to a worsening dry cough and progressive exertional dyspnea that arose within the previous 1 month. She was a non-smoker and had no family history of lung disease. There was no suspicion of pulmonary infection, connective tissue disease, or occupational exposure relevant to interstitial lung disease. She was diagnosed as having an ILD based on the usual interstitial pneumonia (UIP) pattern in chest CT findings for 13 years (Fig. 1C). Since then, she had been followed up without specific therapy for the ILD and had remained stable until 1 month prior.Fig. 1 Radiographic images of case #1. Chest X-ray images of the patient (A) before and (B) at the diagnosis of acute exacerbation of interstitial lung disease. Chest CT images of the patient (C) before and (D) at the diagnosis of acute exacerbation of interstitial lung disease.\n\nFig. 1\n\nOn admission day 1, she was initially diagnosed with exacerbation of chronic heart failure due to an upper airway infection. She was treated with furosemide and levofloxacin in addition to oxygen therapy. Even though the diuresis was sufficient, her oxygen saturation (SpO2) deteriorated. On day 3, a chest X‐ray revealed worsened bilateral infiltrative shadows (Fig. 1B), and a repeat chest CT showed new bilateral GGOs with traction bronchiectasis superimposed on the background UIP pattern (Fig. 2D), indicating AE-ILD. She was referred to the Department of Respiratory Medicine on the same day. Physical data at the time of referral were as follows: height, 145.5 cm; weight, 46.5 kg; and body surface area, 1.36 m2. She had a temperature of 36.5 °C, blood pressure of 120/66 mmHg, a heart rate of 72 beats per minute, oxygen saturation of 92% under non-invasive positive pressure ventilation (NPPV) with oxygen fraction (FiO2) of 0.5. Physical examination revealed bilateral late inspiratory crackles in her back. A PCR test for SARS-CoV-2 was negative. Increased levels of C‐reactive protein (CRP) (25.50 mg/dL), serum lactate dehydrogenase (LDH) (593 U/mL), and serum Krebs von den Lungen‐6 (KL‐6) (1121 U/mL; normal, <500 U/mL) were noted. Following admission, we ordered an additional serological examination to evaluate the etiology of ILDs: Anti-neutrophil cytoplasmic antibody (ANCA), antinuclear antibody (ANA), anti-citrullinated protein antibodies (ACPA), anti-Ro, anti-Scl-70, and anti-aminoacyl tRNA synthetase (ARS) antibodies were all negative. The rheumatoid factor (RF) level was 17 U/dL, which was not significant. Based on her CT findings and serological results, the patient was diagnosed as having IPF.Fig. 2 Radiographic images of case #2. Chest X-ray images of the patient (A) before and (B) at the diagnosis of acute exacerbation of interstitial lung disease. Chest CT images of the patient (C) before and (D) at the diagnosis of acute exacerbation of interstitial lung disease.\n\nFig. 2\n\nPulsed-dose methylprednisolone (mPSL) was initiated from day 3 (Fig. 4). She responded well to the treatment. Her respiratory condition improved gradually. Levels of CRP and LDH peaked, and her chest X-ray showed improvement of bilateral infiltrative shadows. On day 7, the prednisolone (PSL) dose was reduced to a maintenance dose of 50 mg per day. On day 8, she no longer required oxygen at rest; however, long-term oxygen therapy with 2 L/min on exercise was initiated due to remaining exertional dyspnea and desaturation with SpO2 under 90% on exercise. On day 11, the PSL dose was tapered to 30 mg per day, and 100 mg/day of nintedanib was initiated as a sequential treatment. The PSL dosage was further tapered to 12.5 mg/day. She was discharged on day 44, continuing with nintedanib and a PSL maintenance dose without significant side effects. She has not suffered a relapse in the one month since her discharge.\n\n2.2 Case #2\n\nA 55-year-old Japanese man was admitted to Hamanomachi Hospital due to progressive exertional dyspnea within 1 week. He had smoked 2 packs of cigarettes per day for 33 years and quit smoking last year. He had been treated for dermatomyositis and associated ILD for 6 years with maintenance-dose PSL and azathioprine. He had once suffered AE-ILD half a year before and was treated with pulsed-dose mPSL followed by nintedanib in combination with a PSL maintenance dose. However, nintedanib administration had been discontinued after 1 week because of an asymptomatic pulmonary embolism on a repeated chest CT. Three months of anticoagulation therapy were performed and pulmonary thrombi disappeared. On his last visit, one month before admission, he was in stable condition with 22.5 mg/day of PSL and 100 mg/day of azathioprine. There was no suspicion of pulmonary infection, new medications, or occupational exposure relevant to interstitial lung disease.\n\nAdmission data were: height, 153.7 cm; weight, 58.4 kg; and body surface area, 1.56 m2. He had a temperature of 35.5 °C, blood pressure of 119/69 mmHg, a heart rate of 64 beats per minute, oxygen saturation of 99% under a non-rebreather reservoir bag oxygen mask 5L per minute. Physical examination revealed late inspiratory crackles in his right back. A chest X‐ray (Fig. 2B) showed infiltrative shadows in the right lower lung fields. An HRCT scan revealed new GGOs in the right lung fields superimposed on a background of lung fibrosis (Fig. 2D). Increased levels of LDH and KL‐6 were noted (610 U/mL, 841 U/mL, respectively). A PCR test for SARS-CoV-2 was negative.\n\nHe was diagnosed with AE-ILD due to infection, and pulsed-dose mPSL and revofloxacin were initiated on admission day 1 (Fig. 4). Intravenous immunoglobulin (IVIG) was added from day 2 to day 6. He responded well to the treatments. His respiratory condition improved gradually from day 2. Levels of CRP and LDH peaked, and his chest X-ray showed improvement of infiltrative shadows. On day 6, the PSL dose was reduced to a maintenance dose of 60 mg per day. On day 7, he no longer required oxygen. On day 12, the PSL dose was tapered to 40 mg per day. Additional serological examination was positive for anti-EJ antibodies. Considering the side effects of corticosteroids and the possibility of further recurrence of AE-ILD, 200 mg/day of nintedanib were initiated on day 13 as a sequential treatment. The PSL dose was tapered to 30 mg/day and he was discharged on day 20. On an outpatient basis, the PSL dose was further tapered to 20 mg/day with continuing nintedanib. Treatment with azathioprine had been continued through the course. He has not relapsed in the three months since his discharge.\n\n2.3 Case #3\n\nAn 85-year-old Japanese man was admitted to Hamanomachi Hospital due to progressive exertional dyspnea that morning. He suffered a runny nose and dry cough 3 days before admission. He had smoked 2 packs of cigarettes per day for 45 years, but had quit 20 years earlier. He had a history of tuberculosis in his 30s. There were no new medications, and no connective tissue disease or occupational exposure relevant to ILD. He had been suspected of having an ILD and chronic obstructive pulmonary disease (COPD) based on clinical findings and a UIP pattern in a chest CT (Fig. 3C). He was followed up without specific therapy for his ILD and remained in stable condition until his previous visit, 1 month before admission.Fig. 3 Radiographic images of case #3. Chest X-ray images of the patient (A) before and (B) at the diagnosis of acute exacerbation of interstitial lung disease. Chest CT images of the patient (C) before and (D) at the diagnosis of acute exacerbation of interstitial lung disease.\n\nFig. 3\n\nFig. 4 Clinical courses of cases 1 and 2. mPSL: methylprednisolone, PSL: prednisolone, IVIG: intravenous immunoglobulin, LVFX: levofloxacin, CRP: C-reactive protein, LDH: lactate dehydrogenase, RM: reservoir mask, NHF: nasal high flow, FiO2: fraction of inspiratory oxygen.\n\nFig. 4\n\nAdmission data were: height, 163.5 cm; weight, 50.9 kg; body surface area, 1.54 m2. He had a temperature of 37.4 °C, blood pressure of 124/64 mmHg, a heart rate of 92 beats per minute, oxygen saturation of 98% under nasal O2 1L per min.\n\nPhysical examination revealed bilateral late inspiratory crackles in his back. A chest X‐ray (Fig. 3B) showed bilateral infiltrative shadows in the lower lung fields, which were worse than 1 month earlier (Fig. 3A). HRCT imaging revealed new, bilateral, multifocal GGOs superimposed on a background of emphysema and lung fibrosis (Fig. 3D). A PCR test for SARS-CoV-2 was negative. Increased CRP (11.22 mg/dL), LDH (245 U/mL), and KL‐6 (783 U/mL) were noted. He was diagnosed with AE-ILD due to infection. Upon admission, we ordered an additional serological examination to evaluate the etiology of ILDs: ANCA, ANA, ACPA, anti-Ro, anti-Scl-70, and anti-ARS antibodies were all negative, and the level of RF was 35.9 U/dL, which were not significant findings. Based on CT findings and serological results, his ILD was diagnosed as IPF. Pulsed-dose mPSL (1000 mg) was initiated on admission day 1. He responded well to the treatment. His respiratory condition improved gradually. Levels of CRP and LDH peaked, and chest X-rays showed improvement of bilateral infiltrative shadows. On day 4, the PSL dose was reduced to a maintenance dose of 60 mg per day. On day 5, he no longer required oxygen at rest. On day 12, 100 mg/day of nintedanib were initiated. On day 18, the nintedanib dose was increased to 200 mg/day. The PSL dose was tapered to 7.5 mg/day and he was discharged on day 23. On an outpatient basis, the PSL dose was tapered off while continuing nintedanib. He has not relapsed and remains without significant side effects two month after discharge.\n\n3 Discussion\n\nWe presented two cases of AE of IPF and one case of dermatomyositis-associated ILD that were treated with pulsed doses of corticosteroids followed by nintedanib and corticosteroid tapering. Corticosteroids are generally prescribed in AE-ILDs, including AE of IPF, based on historical evidence of beneficial results [2,5]. Long-term corticosteroid treatment, however, can induce several adverse side effects, such as immunocompromised infection. Indeed, patient case #3 had a history of tuberculosis and there was a serious concern that long-term corticosteroid treatment might cause tuberculosis relapse. Moreover, corticosteroids with immunosuppresive treatment are no longer recommended for stable IPF [6]. From these points of view, it might be less desirable to maintain corticosteroids long after remission of AE of IPF. On the other hand, relapse of AE of IPF is a major concern during rapid tapering of corticosteroids. Nintedanib is expected to slow progression of IPF as measured by forced vital capacity (FVC) beyond 4 years and might reduce the risk of AE-ILD [[7], [8], [9]]. Additionally, nintedanib may have therapeutic effects on AE-ILD by attenuating neutrophilic inflammation, normalizing alveolar permeability, and inhibiting profibrotic signals [10,11]. Thus, sequential treatment with nintedanib following pulsed-dose corticosteroids for AE of IPF is a reasonable strategy to reduce the risk of relapse during corticosteroid tapering.\n\nOur patient in case #2 had anti-EJ antibodies and had suffered a relapse of AE-ILD in the previous half a year. A high recurrence rate was reported in patients with dermatomyositis-associated ILDs having anti-EJ antibodies [12]. This suggests that an additional strategy may be required for standard therapy. Recently, we reported successful treatment with nintedanib and intensive immunosuppressive therapy for rapidly progressive ILD presenting anti-ARS antibodies [13]. In addition, a retrospective study in inflammatory myopathy-related ILDs showed that patients with nintedanib treatment had better prognoses and a lower incidence of rapidly progressive ILD [14]. These studies may support the additional use of nintedanib for the acute phase of dermatomyositis-associated ILDs, especially having anti-EJ antibodies. We thus believe that nintedanib may be able to prevent disease relapses when administered in combination with corticosteroids and immunosuppressive agents.\n\nHowever, side effects occasionally become problematic when using nintedanib. The most serious involve hepatotoxicity and diverse gastrointestinal events, which could necessitate early termination of the therapy [15]. Small physique, Asian heritage, and advanced age are reported risk factors for these side effects [[16], [17], [18], [19], [20]]. In these three cases, we initiated nintedanib with low doses (100–200 mg/day) due to small patient physiques (all cases), Asian heritage (all cases), and advanced age (cases #1 and #3). This low-dosage strategy may avoid early termination due to side effects and appears to allow early tapering of corticosteroids. This strategy is supported by Ogura et al. [21], who recommended a low initial dose of nintedanib to prevent early termination. Therapeutic efficacy at a dose of 200 mg/day is based on two results. One is a retrospective study performed in Japan [21] and the other is an analysis of the INPULSIS-ON trial [22], both of which revealed no significant differences in FVC decline between patients treated with 200 mg/day and those receiving 300 mg/day. However, we could not measure the actual blood concentration of nintedanib in these patients with 100 mg/day or 200 mg/day.\n\nPirfenidone, another anti-fibrotic agent approved for treatment of IPF, can be an alternative option for AE of IPF. A retrospective study conducted by Furuya et al. revealed that three-month survival was better in patients treated with pirfenidone than in the control group for AE of IPF [23]. However, since the etiology of ILDs in patient #1 and #3 on admission were unknown and because nintedanib can be used for any type of ILDs that show progression and fibrosis, we chose nintedanib in these cases.\n\nAs a limitation, the observational periods may be too short to confirm that nintedanib therapy contributed to suppress the relapse of AE-ILDs. The most important point of the case series is, however, to contribute to a more thorough discussion regarding the use and timing of nintedanib in treating acute exacerbation of ILDs. We thus prioritized publishing the case series with the current observational periods rather than waiting for longer periods.\n\nTo summarize the main points, a low starting dose of nintedanib for AE-ILDs may enable early tapering of corticosteroids while simultaneously avoiding side effects of nintedanib, especially for patients of small physique, Asian ancestry, and advanced age, thus reducing side effects of steroids as well. We hope that this case report will contribute to a thorough discussion of the use and timing of nintedanib for AE-ILDs and that a standardized method of nintedanib use for AE-ILD will be established.\n\nPatient consent for publication\n\nWritten, informed consent was obtained from all patients.\n\nDeclaration of competing interest\n\nThe authors declare that they have no conflicts of interest relative to this publication.\n==== Refs\nReferences\n\n1 Kim D.S. Park J.H. Park B.K. Lee J.S. Nicholson A.G. Colby T. Acute exacerbation of idiopathic pulmonary fibrosis: frequency and clinical features Eur. Respir. J. 27 2006 143 150 10.1183/09031936.06.00114004 16387947\n2 Collard H.R. Ryerson C.J. Corte T.J. Jenkins G. Kondoh Y. Lederer D.J. Lee J.S. Maher T.M. Wells A.U. Antoniou K.M. Behr J. Brown K.K. Cottin V. Flaherty K.R. Fukuoka J. Hansell D.M. Johkoh T. Kaminski N. Kim D.S. Kolb M. Lynch D.A. Myers J.L. Raghu G. Richeldi L. Taniguchi H. Martinez F.J. Acute exacerbation of idiopathic pulmonary fibrosis an international working group report Am. J. Respir. Crit. Care Med. 194 2016 265 275 10.1164/rccm.201604-0801CI 27299520\n3 Suda T. Kaida Y. Nakamura Y. Enomoto N. Fujisawa T. Imokawa S. Hashizume H. Naito T. Hashimoto D. Takehara Y. Inui N. Nakamura H. Colby T.V. Chida K. Acute exacerbation of interstitial pneumonia associated with collagen vascular diseases Respir. Med. 103 2009 846 853 10.1016/j.rmed.2008.12.019 19181509\n4 Kolb M. Bondue B. Pesci A. Miyazaki Y. Song J.W. Bhatt N.Y. Huggins J.T. Oldham J.M. Padilla M.L. Roman J. Shapera S. Acute exacerbations of progressive-fibrosing interstitial lung diseases Eur. Respir. Rev. 27 2018 180071 10.1183/16000617.0071-2018 30578331\n5 Raghu G. Collard H.R. Egan J.J. Martinez F.J. Behr J. Brown K.K. Colby T.V. Cordier J.F. Flaherty K.R. Lasky J.A. Lynch D.A. Ryu J.H. Swigris J.J. Wells A.U. Ancochea J. Bouros D. Carvalho C. Costabel U. Ebina M. Hansell D.M. Johkoh T. Kim D.S. King T.E. Kondoh Y. Myers J. Müller N.L. Nicholson A.G. Richeldi L. Selman M. Dudden R.F. Griss B.S. Protzko S.L. Schünemann H.J. An Official ATS/ERS/JRS/ALAT Statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management Am. J. Respir. Crit. Care Med. 183 2011 788 824 10.1164/rccm.2009-040GL 21471066\n6 Raghu G. Rochwerg B. Zhang Y. Garcia C.A.C. Azuma A. Behr J. Brozek J.L. Collard H.R. Cunningham W. Homma S. Johkoh T. Martinez F.J. Myers J. Protzko S.L. Richeldi L. Rind D. Selman M. Theodore A. Wells A.U. Hoogsteden H. Schünemann H.J. ATSErs J.R.S. An official ATS/ERS/JRS/ALAT clinical practice guideline: treatment of idiopathic pulmonary fibrosis: an update of the 2011 clinical practice guideline Am. J. Respir. Crit. Care Med. 192 2015 e3 e19 10.1164/rccm.201506-1063ST 26177183\n7 Richeldi L. du Bois R.M. Raghu G. Azuma A. Brown K.K. Costabel U. Cottin V. Flaherty K.R. Hansell D.M. Inoue Y. Kim D.S. Kolb M. Nicholson A.G. Noble P.W. Selman M. Taniguchi H. Brun M. Le Maulf F. Girard M. Stowasser S. Schlenker-Herceg R. Disse B. Collard H.R. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis N. Engl. J. Med. 370 2014 2071 2082 10.1056/nejmoa1402584 24836310\n8 Richeldi L. Cottin V. du Bois R.M. Selman M. Kimura T. Bailes Z. Schlenker-Herceg R. Stowasser S. Brown K.K. Nintedanib in patients with idiopathic pulmonary fibrosis: combined evidence from the TOMORROW and INPULSIS® trials Respir. Med. 113 2016 74 79 10.1016/j.rmed.2016.02.001 26915984\n9 Crestani B. Huggins J.T. Kaye M. Costabel U. Glaspole I. Ogura T. Song J.W. Stansen W. Quaresma M. Stowasser S. Kreuter M. Long-term safety and tolerability of nintedanib in patients with idiopathic pulmonary fibrosis: results from the open-label extension study, INPULSIS-ON Lancet Respir. Med. 7 2019 60 68 10.1016/S2213-2600(18)30339-4 30224318\n10 Ito Y. Tazaki G. Kondo Y. Takahashi G. Sakamaki F. Therapeutic effect of nintedanib on acute exacerbation of interstitial lung diseases Respir. Med. Case Reports. 26 2019 317 320 10.1016/j.rmcr.2019.02.021\n11 Tomioka H. Takada H. Treatment with nintedanib for acute exacerbation of idiopathic pulmonary fibrosis Respirol. Case Reports. 5 2017 5 7 10.1002/rcr2.215\n12 Liu Y. Liu X. Xie M. Chen Z. He J. Wang Z. Dai J. Cai H. Clinical characteristics of patients with anti-EJ antisynthetase syndrome associated interstitial lung disease and literature review Respir. Med. 165 2020 105920 10.1016/j.rmed.2020.105920 32174452\n13 Yanagihara T. Suzuki K. Egashira A. Ogo N. Asoh T. Nara T. Takatsuki K. Yoshizawa S. Chong S.G. Hamada N. Maeyama T. Nintedanib and intensive immunosuppressive therapy to treat rapidly progressive interstitial lung disease presenting anti-ARS antibodies Respir. Med. Case Reports 31 2020 101272 10.1016/j.rmcr.2020.101272\n14 Liang J. Cao H. Yang Y. Ke Y. Yu Y. Sun C. Yue L. Lin J. Efficacy and tolerability of nintedanib in idiopathic-inflammatory-myopathy-related interstitial lung disease: a pilot study Front. Med. 8 2021 1 14 10.3389/fmed.2021.626953\n15 Uchida Y. Ikeda S. Sekine A. Katano T. Tabata E. Oda T. Okuda R. Kitamura H. Baba T. Komatsu S. Ogura T. Tolerability and safety of nintedanib in elderly patients with idiopathic pulmonary fibrosis Respir. Investig. 59 2021 99 105 10.1016/j.resinv.2020.08.003\n16 Ikeda S. Sekine A. Baba T. Yamanaka Y. Sadoyama S. Yamakawa H. Oda T. Okuda R. Kitamura H. Okudela K. Iwasawa T. Ohashi K. Takemura T. Ogura T. Low body surface area predicts hepatotoxicity of nintedanib in patients with idiopathic pulmonary fibrosis Sci. Rep. 7 2017 1 7 10.1038/s41598-017-11321-x 28127051\n17 Kato M. Sasaki S. Nakamura T. Kurokawa K. Yamada T. Ochi Y. Ihara H. Takahashi F. Takahashi K. Gastrointestinal adverse effects of nintedanib and the associated risk factors in patients with idiopathic pulmonary fibrosis Sci. Rep. 9 2019 1 9 10.1038/s41598-019-48593-4 30626917\n18 Toi Y. Kimura Y. Domeki Y. Kawana S. Aiba T. Ono H. Aso M. Tsurumi K. Suzuki K. Shimizu H. Sugisaka J. Saito R. Terayama K. Kawashima Y. Nakamura A. Yamanda S. Honda Y. Sugawara S. Association of low body surface area with dose reduction and/or discontinuation of nintedanib in patients with idiopathic pulmonary fibrosis: a pilot study Sarcoidosis Vasc. Diffuse Lung Dis. 36 2019 74 78 10.36141/svdld.v36i1.7383 32476938\n19 Ochi Y. Kato M. Sasaki S. Nakamura T. Yamada T. Ihara H. Takahashi F. Takahashi K. Nintedanib treatment for elderly patients with idiopathic pulmonary fibrosis Am. J. Respir. Crit. Care Med. 2019 American Thoracic Society A4775–A4775, h ttps://doi.org/doi:10.1164/ajrccm-conference.2019.199.1_MeetingAbstracts.A4775\n20 Drug Information for Nintedanib n.d. https://www.pmda.go.jp/drugs/2015/P20150619001/index.html\n21 Ikeda S. Sekine A. Baba T. Katano T. Tabata E. Shintani R. Yamakawa H. Niwa T. Oda T. Okuda R. Kitamura H. Ogura T. Low starting-dosage of nintedanib for the reduction of early termination Respir. Investig. 57 2019 282 285 10.1016/j.resinv.2018.12.010\n22 Crestani Bruno Long-term safety and tolerability of nintedanib in patients with idiopathic pulmonary fibrosis: results from the open-label extension study, INPULSIS-ON The Lancet Respiratory Medicine 7 1 2019 60 68 10.1016/S2213-2600(18)30339-4 30224318\n23 Furuya K. Sakamoto S. Shimizu H. Sekiya M. Kinoshita A. Isshiki T. Sugino K. Matsumoto K. Homma S. Pirfenidone for acute exacerbation of idiopathic pulmonary fibrosisA retrospective study Respir. Med. 126 2017 93 99 10.1016/j.rmed.2017.03.026 28427556\n\n",
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"title": "Three cases of sequential treatment with nintedanib following pulsed-dose corticosteroids for acute exacerbation of interstitial lung diseases.",
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"abstract": "In patients with immunosuppressive disorders, S. stercoralis infection may develop into a hyperinfection syndrome which, on rare occasions, may be a life-threatening condition. Therapy of S. stercoralis infection with thiabendazole has been limited, due to its numerous side effects, and has been replaced by albendazole and ivermectin. The present case report describes a case of Strongyloides Hyperinfection Syndrome (SHS) in a patient with Hansen's disease and lack of response to first-line anthelmintic treatment. A 38 year-old man was diagnosed as having borderline lepromatous leprosy. He developed Erythema Nodosum Leprosum and was treated with thalidomide and prednisone. In May 2010 he was diagnosed with S. stercoralis infection and was treated with albendazole. One year later, the stool examination showed continued presence of S. stercoralis larvae. He was treated with ivermectin (6 mg) in a double dose (given 1 month apart) which resulted in larvae excretion clearance. The absence of infection was confirmed three times during a 1 year followup period by stool examination and non-detection of anti-S. stercoralis IgG levels.",
"affiliations": null,
"authors": "De Souza|Joelma Nascimento|JN|;Machado|Paulo Roberto Lima|PR|;Teixeira|Márcia Cristina Aquino|MC|;Soares|Neci Matos|NM|",
"chemical_list": "D000871:Anthelmintics",
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"mesh_terms": "D000328:Adult; D000818:Animals; D000871:Anthelmintics; D006801:Humans; D007918:Leprosy; D008297:Male; D017171:Strongyloides stercoralis; D013322:Strongyloidiasis",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Recurrence of strongyloides stercoralis infection in a patient with Hansen's disease: a case report.",
"title_normalized": "recurrence of strongyloides stercoralis infection in a patient with hansen s disease a case report"
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"companynumb": "BR-SUN PHARMACEUTICAL INDUSTRIES LTD-2015R1-95217",
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"abstract": "Primary prophylaxis with granulocyte colony-stimulating factor can effectively prevent febrile neutropenia (FN) during breast cancer treatment. The aims of this study were to evaluate the incidence of FN and the ANC profile in patients undergoing chemotherapy and pegfilgrastim primary prophylaxis.\nPatients receiving 6 cycles of adjuvant docetaxel, doxorubicin, and cyclophosphamide (TAC) chemotherapy were included in this study. Pegfilgrastim was administered with analgesics 24 hours after treatment. Laboratory tests were performed on day 0 (before chemotherapy) and ANC was measured daily starting day 5 until it were restored to 1,000/mm3. Bone pain was checked via the numeral rating scale (NRS).\nA total of 61 patients and 366 cycles were evaluated. Mean age was 49.2 ± 7.1 years. FN was seen in 5 patients (16.4%) and 12 cycles (3.3%) with pegfilgrastim. Grades 3 and 4 neutropenia was seen in 91.5% of cycles with FN. The ANC nadir was most commonly seen at day 7 and the mean ANC nadir depth was 265.7/m3. Age was negatively correlated with nadir depth (r = -0.137, P = 0.009). Severe pain higher than NRS 7 occurred in less than 20% of patients after the administration of pegfilgrastim.\nIncidence of FN was low during the chemotherapy by primary prophylaxis with pegfilgrastim. The ANC nadir was seen on day 7 after chemotherapy. Bone pain with pegfilgrastim was well tolerated during TAC chemotherapy.",
"affiliations": "Department of Surgery, Soonchunhyang University Seoul Hospital, Seoul, Korea.;Department of Surgery, Soonchunhyang University Cheonan Hospital, Cheonan, Korea.;Department of Surgery, Soonchunhyang University Bucheon Hospital, Bucheon, Korea.;Department of Surgery, Soonchunhyang University Cheonan Hospital, Cheonan, Korea.;Department of Surgery, Soonchunhyang University Bucheon Hospital, Bucheon, Korea.;Department of Surgery, Soonchunhyang University Cheonan Hospital, Cheonan, Korea.;Department of Surgery, Soonchunhyang University Seoul Hospital, Seoul, Korea.;Department of Surgery, Soonchunhyang University Bucheon Hospital, Bucheon, Korea.",
"authors": "Lee|Jihyoun|J|;Lee|Jong Eun|JE|;Kim|Zisun|Z|;Han|Sun Wook|SW|;Hur|Sung Mo|SM|;Kim|Sung Yong|SY|;Lee|Min Hyuk|MH|;Lim|Cheol Wan|CW|https://orcid.org/0000-0001-9490-4964",
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"doi": "10.4174/astr.2018.94.5.223",
"fulltext": "\n==== Front\nAnn Surg Treat ResAnn Surg Treat ResASTRAnnals of Surgical Treatment and Research2288-65752288-6796The Korean Surgical Society 10.4174/astr.2018.94.5.223Original ArticlePegfilgrastim for primary prophylaxis of febrile neutropenia in breast cancer patients undergoing TAC chemotherapy Lee Jihyoun 1Lee Jong Eun 2Kim Zisun 3Han Sun Wook 2Hur Sung Mo 3Kim Sung Yong 2Lee Min Hyuk 1https://orcid.org/0000-0001-9490-4964Lim Cheol Wan 31 Department of Surgery, Soonchunhyang University Seoul Hospital, Seoul, Korea.2 Department of Surgery, Soonchunhyang University Cheonan Hospital, Cheonan, Korea.3 Department of Surgery, Soonchunhyang University Bucheon Hospital, Bucheon, Korea.Corresponding Author: Cheol Wan Lim. Department of Surgery, Soonchunhyang University Bucheon Hospital, 170 Jomaru-ro, Wonmi-gu, Bucheon 14584, Korea. Tel: +82-32-621-6647, Fax: +82-32-621-6950, cwlim@schmc.ac.kr5 2018 30 4 2018 94 5 223 228 27 11 2017 18 1 2018 13 2 2018 Copyright © 2018, the Korean Surgical Society2018The Korean Surgical SocietyAnnals of Surgical Treatment and Research is an Open Access Journal. All articles are distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Purpose\nPrimary prophylaxis with granulocyte colony-stimulating factor can effectively prevent febrile neutropenia (FN) during breast cancer treatment. The aims of this study were to evaluate the incidence of FN and the ANC profile in patients undergoing chemotherapy and pegfilgrastim primary prophylaxis.\n\nMethods\nPatients receiving 6 cycles of adjuvant docetaxel, doxorubicin, and cyclophosphamide (TAC) chemotherapy were included in this study. Pegfilgrastim was administered with analgesics 24 hours after treatment. Laboratory tests were performed on day 0 (before chemotherapy) and ANC was measured daily starting day 5 until it were restored to 1,000/mm3. Bone pain was checked via the numeral rating scale (NRS).\n\nResults\nA total of 61 patients and 366 cycles were evaluated. Mean age was 49.2 ± 7.1 years. FN was seen in 5 patients (16.4%) and 12 cycles (3.3%) with pegfilgrastim. Grades 3 and 4 neutropenia was seen in 91.5% of cycles with FN. The ANC nadir was most commonly seen at day 7 and the mean ANC nadir depth was 265.7/m3. Age was negatively correlated with nadir depth (r = −0.137, P = 0.009). Severe pain higher than NRS 7 occurred in less than 20% of patients after the administration of pegfilgrastim.\n\nConclusion\nIncidence of FN was low during the chemotherapy by primary prophylaxis with pegfilgrastim. The ANC nadir was seen on day 7 after chemotherapy. Bone pain with pegfilgrastim was well tolerated during TAC chemotherapy.\n\nBreast neoplasmsAdjuvant chemotherapyFebrile neutropeniaGranulocyte colony-stimulating factorKyowa Hakko Kirin KoreaSoonchunhyang Universityhttp://dx.doi.org/10.13039/501100002560\n==== Body\nINTRODUCTION\nFebrile neutropenia (FN) is one of the life-threatening adverse effects of breast cancer treatment. Performance status, nutritional status, advanced stage, prior episode of FN, and dose intensity are factors increasing the risk of FN. Prolonged duration of FN can interrupt chemotherapy treatment or lead to frequent hospitalization, thereby raising the burden of these patients. FN can also reduce relative dose intensity, which can impair the effect of chemotherapeutic treatment [1].\n\nThe use of granulocyte colony-stimulating factor (G-CSF) is helpful in decreasing incidence of FN [2]. Primary prophylaxis involves using G-CSF in the first and subsequent sessions of chemotherapy, whereas secondary prophylaxis involves the administration of G-CSF to patients who have experienced neutropenic complications following a treatment session. Treatment guidelines recommend to use G-CSF as primary prophylaxis during chemotherapy if the risk of FN is more than 20% [345]. Use of G-CSF is not considered to significantly increase the incidence of leukemia during chemotherapy for breast cancer [6].\n\nDocetaxel-containing regimens have been used widely and adding docetaxel showed increased response to chemotherapy. However, these treatments have been associated with increased incidence of FN, 25.2% without G-CSF primary prophylaxis and 5.5% with primary prophylaxis [7]. Pegfilgrastim is a pegylated form of G-CSF that has longer half-life than short-acting G-CSF because of reduced renal clearance; therefore, it can be given once-per-cycle subcutaneously. In a study comparing G-CSF primary prophylaxis with pegfilgrastim (6 mg, once) versus daily administration of short-acting G-CSF (5 µg/kg/day for 5 days), FN incidence and related complications were significantly lower in the pegfilgrastim-treated group [8]. FN-related complications were lower with long-acting G-CSF treatment than with daily administration of short-acting G-CSF [910]. Adding prophylactic antibiotics was the most effective way to prevent FN during docetaxel, adriamycin, and cyclophosphamide (TAC) chemotherapy [8]. Although mild to moderate bone pain is frequently reported during G-CSF treatment [11], it can be managed by analgesics.\n\nAdjuvant TAC chemotherapy is accompanied by high incidence of FN [12]. Primary prophylaxis with pegfilgrastim during adjuvant TAC and other high risk treatments is now covered by the Korean National Health Insurance System. In this study, we investigated the effect of G-CSF primary prophylaxis on ANC levels, FN incidence, toxicity of chemotherapy, and quality of life in breast cancer patients receiving TAC chemotherapy.\n\nMETHODS\nStudy design and subjects\nFemale breast cancer patients who received adjuvant TAC chemotherapy were enrolled in this study. Doxorubicin (50 mg/m2), cyclophosphamide (500 mg/m2), and docetaxel (75 mg/m2) were given intravenously (day 1) every 21 days for 6 cycles. Pegfilgrastim (Neulasta, pegfilgrastim 6 mg), a pegylated G-CSF was administered subcutaneously between 24 hours to 48 hours after administration of chemotherapy (day 2). A nonsteroidal anti-inflammatory drug (naproxen, 500 mg, twice daily) was given for 5 days since day 2 immediately following pegfilgrastim treatment. Prophylactic antibiotics (ciprofloxacin, 500 mg, twice daily) and nystatin or chlorohexidine gargle were given in case of grade 4 neutropenia (ANC < 500/mm3), in accordance with Common Terminology Criteria for Adverse Events version 4.0 grading. Patient age at diagnosis, histology of breast cancer, stage, type of primary surgery, and menopausal status were recorded. Laboratory tests including complete blood test (CBC), liver enzyme, and creatinine levels were checked the day before chemotherapy. CBC was checked daily starting at day 5 until the ANC restored up to 1,000/mm3. For the ANC profile, we defined the lowest ANC level as ANC nadir, and if the nadir was not seen at day 7, we recorded the nadir day as −2 days, −1 day, or +1 day. FN was defined depending on whether the patient's temperature was >38.3℃ or remained ≥38.0℃ for over 1 hour with grade 4 neutropenia.\n\nSeverity of bone pain was determined by completion of a self-reporting questionnaire based on numeral rating scale (NRS) from days 1 to 5 in every cycle. Quality of life using the Functional Assessment of Cancer Therapy Questionnaire for Breast (FACT-B) questionnaire was evaluated at four time points: baseline, after 2nd cycle, after 6th cycle, and 4 months after the completion of chemotherapy. FACT-B total score is calculated by summation of physical well-being score, social/family well-being score, emotional well-being score, functional well-being score, and breast cancer subscale score. Scores of each subscale were assessed with reversal of negative items and considered missing items. This study was approved by Institutional Review Board of Soonchunhyang University Seoul Hospital (IRB No. 2017-11-011). Informed consent was obtained from all patients.\n\nStatistical analysis\nThe correlation between body surface area (BSA), body weight, and age and ANC profiles from days 5 to 10 was assessed using Pearson correlation analysis (<0.5, weak correlation; 0.50–0.80, moderate correlation; 0.80–0.99, strong correlation). Statistical analyses were performed using IBM SPSS Statistics ver. 21.0 (IBM Co., Armonk, NY, USA).\n\nRESULTS\nBaseline characteristics\nA total of 65 patients were enrolled. Data from 61 subjects and 366 cycles of chemotherapy were included in evaluation, with 4 patients excluded due to withdrawal of consent. The electronic medical records were reviewed. The mean age of patients was 49.2 ± 7.1 years. Mean weight was 59.7±1.0 kg and BSA was 1.6 ± 0.1m2. Most of the patients were more than T2 (71.1%). More than half of the patients (55.7%) were N1. The types of primary surgeries included breast conserving surgery (41.0%), mastectomy (36.1%), and skin sparing or nipple sparing mastectomy (23.0%). The clinical characteristics of the breast cancer patients are summarized in Table 1.\n\nIncidence of neutropenia, febrile neutropenia, and related events\nAll patients experienced grade 4 neutropenia during at least one cycle. A few patients completed some sessions without experiencing severe (grade 3 or 4) neutropenia (31 cycles, 8.5%). Mean duration of severe neutropenia was 2.4 ± 1.6 days. Grade 4 neutropenia was seen in 83.3% of the cycles and mean duration was 1.8 ± 1.2 days. FN occurred in 16.4% of patients and 3.3% of all cycles throughout six sessions of chemotherapy. FN was most frequent in the first cycle (41.7%) followed by 5th cycle (33.3%). Mean duration of FN was 2.1 ± 1.4 days. All patients completed scheduled treatment without treatment interruption. One patient treated with reduced chemotherapeutic dose into 80% because of febrile neutropenia. Neutropenic infection was seen in five patients, which were anogenital herpes, pneumonia, urinary tract infection, and chemoport infection. Severe anemia was seen in 3.0% out of all cycles, with 8 cycles (2.2%) requiring blood transfusion. Except 1 patient who had significantly elevated AST and ALT, most patients did not present with severe hepatotoxicity and nephrotoxicity (Table 2).\n\nANC profile and factors associated with nadir depth\nThe ANC profile is seen in Fig. 1. ANC decreased at day 6, and reached its lowest point at day 7. The mean ANC at day 7 was 375.3/m3 (0–4,860/m3) and the mean depth of ANC nadir was 265.7/m3 (0–4,760/m3). ANC nadir was seen at day 7 in most of the cycles (243 out of 366 cycles, 66.4%). Nadir at day 6 (−1 day) was seen in 29.2% of all cycles and nadir at day 8 (+1 day) was seen in 2.5%. The proportion of patients experiencing ANC nadir at −1 day increased as sessions continued (6.6% in cycle 1 and 39.3% in cycle 6). There was a negative correlation between ANC nadir and age, as determined by Pearson correlation analysis (r = −0.137, P = 0.009). There was no correlation between BSA or body weight with ANC nadir depth (r = 0.052, P = 0.328 and r = 0.042, P = 0.429, respectively). The duration and nadir depth showed moderate correlation (r = −0.586, P < 0.001). Age was also related to duration of neutropenia (r = −0.137, P = 0.009), and there were no relationships between duration and BSA or body weight.\n\nPatterns of bone pain and quality of life\nSevere bone pain (>NRS 7) presented was shown at day 1 (chemotherapy) was 0.3 % of the patients and increased at day 2 (pegfilgrastim). Pain reached its highest level on day 5 (18.2%, Fig. 2). Quality of life measured by FACT-B decreased at midcycle, after chemotherapy, and four months after chemotherapy (Table 3). Physical well-being score decreased at midcycle (19.3 ± 7.5 vs. 16.8 ± 7.0), and did not recover to baseline levels until four months after chemotherapy (15.5 ± 8.7).\n\nDISCUSSION\nIn this study, TAC chemotherapy with administration of long-acting G-CSF pegfilgrastim was useful towards completing the planned treatment without significant complications. Except for one individual, most of the patients received planned dose intensity. No life-threatening neutropenic infection occurred during the TAC chemotherapy.\n\nThe incidence of FN in this study was markedly lower compared to the incidence in Korean patients without pegfilgrastim-based primary prophylaxis (16.4% vs. 63.4%, respectively) [13]. We found the duration of grades 3 and 4 neutropenia lower (2.1 ± 1.4 days) than the previous report [14] (4.16 days) in Korean women. This was consistent with a previous report of TAC regimen, showing 17% of FN and 2% of grade 3/4 thrombocytopenia in TAC chemotherapy [15]. In a Japanese report, the incidence of neutropenia during TAC chemotherapy was 96.6%, and the incidence of FN was 3.4% of total cycles when using pegfilgrastim (6 mg), consistent with our study [16].\n\nThe musculoskeletal pain accompanying G-CSF administration is known to be related to bone marrow expansion, interaction with the nervous system, immune system modulation, or G-CSF's effect on bone metabolism [11]. However, pain is manageable with nonnarcotic analgesics [17]. Muscle pain and joint pain related to G-CSF (either short-acting or long-acting) presented most severely at days 3 to 6 in a previous report [18]. Our result showed more than 20% of patients had severe bone pain during days 6 to 8 (Fig. 2), suggesting that the pain could be related to the lowest ANC levels rather than pegfilgrastim injection.\n\nIn this study, we found significant correlation of old age with nadir depth and duration of neutropenia. Age is one of the characteristics of The Multinational Association for Supportive Care in Cancer (MASCC) risk index score [19] which is used in conjunction with other risk factors to predict low-risk FN patients [202122]. There has been a tendency to do dose capping to BSA 2 during chemotherapy in obese patients or applying ideal weight in overweight patients because of the concern of FN [23], bring about the lower incidence of FN. Since we did not modify dose intensity in obese or overweight patients, we did not find the correlation between body weight and duration of neutropenia or depth of ANC nadir. ANC nadir was found at day 7 in most of the cycles, consistent with previous reports [242526]. However, we found the proportion of ANC nadir on day 6 gradually increased as the sessions proceeded. Therefore, intensive patient education regarding adequate personal hygiene and food preparation should be required for the prevention of neutropenic infection.\n\nNo significant difference in 10-year disease free survival and overall survival was found when comparing concurrent and sequential administration of docetaxel (TAC 6 cycles every 3 weeks versus AC 4 cycles followed by docetaxel 4 cycles, respectively). The toxicity profile, however, is different in both arms, showing more incidence of myalgia and sensory neuropathy in AC-T arm [15]. From the results of Korean patients, TAC was associated with higher incidence of FN without primary prophylaxis, but showed similar quality of life compared to AC-T treatment [13]. In Korea, AC-T chemotherapy is only reimbursed during docetaxel sessions as secondary prophylaxis. Therefore, 6 cycles of TAC can provide shorter duration of treatment and could improve the quality of life during TAC with primary prophylaxis than without. If the patients are considered low risk from the MASCC risk index score, therapeutic strategies in an outpatient setting can be possible.\n\nThis study had some limitations. First, although it was a prospective study, we could not directly compare the effect of primary prophylaxis and secondary prophylaxis, the drug efficacy, and the side effects because it was conducted as a single arm observational study. Second, the sample size was relatively small so that the patient group of FN was limited when comparing the severity of bone pain and quality of life. Finally, we found that the FACT-B total score and all other items decreased during the treatment and did not recover to baseline 4 months after chemotherapy. However, several patient records at the 4-month time point were missing, so we could not make substantial conclusions regarding the recovery of quality of life.\n\nIn conclusion, the use of primary prophylaxis through long-acting G-CSF was associated with decreased incidence of FN in adjuvant TAC chemotherapy in breast cancer. Age was an important factor related to the duration of neutropenia and depth of ANC nadir. ANC nadir was mostly seen in days 6 and 7 of chemotherapy. Therefore, adequate supportive care and education for patient might be important during this period.\n\nACKNOWLEDGEMENTS\nThis study was supported by Kyowa Hakko Kirin Korea and also funded by the Soonchunhyang University Research Fund. This study was performed with the proper licensing agreement of Korean version of FACT-B.\n\nThis study has been presented at Fall scientific meeting of the Korean Society of Surgical Oncology, 2017.\n\nCONFLICTS OF INTEREST: No potential conflict of interest relevant to this article was reported.\n\nFig. 1 ANC profiles after chemotherapy. (A) ANC shows lowest value at day 7 after chemotherapy. Panel B shows nadir depth of all cycles regardless of time after chemotherapy.\nFig. 2 Severe bone pain related to pegfilgrastim administration. Day 1 represents the day of chemotherapy. Severe pain more than numeral rating scale (NRS) 7 was shown less than 20% during days 3 to 5 after pegfilgrastim administration (day 2).\nTable 1 Baseline characteristics at diagnosis in patients with breast cancer (n = 61)\nValues are presented as mean ± standard deviation or number (%).\n\nBSA, body surface area; ER, estrogen receptor; PgR, progesterone receptor; BCS, breast conserving surgery; SSM, skin sparing mastectomy; NSM, nipple sparing mastectomy.\n\nTable 2 Incidence of febrile neutropenia and chemotherapy-related events during treatment\nValues are presented as number (%).\n\na)Grades 3 and 4 toxicity assessed from Common Terminology Criteria for Adverse Events (CTCAE) ver. 4.0 grading.\n\nTable 3 Quality of life scores in each time of treatment\nSD, standard deviation.\n\na)Functional Assessment of Cancer Therapy-Breast (FACT-B). b)FACT-B total score is calculated by summation of physical well-being score, social/family well-being score, emotional well-being score, functional well-being score, and breast cancer subscale score.\n==== Refs\n1 Chirivella I Bermejo B Insa A Perez-Fidalgo A Magro A Rosello S Optimal delivery of anthracycline-based chemotherapy in the adjuvant setting improves outcome of breast cancer patients Breast Cancer Res Treat 2009 114 479 484 18463977 \n2 Clark OA Lyman GH Castro AA Clark LG Djulbegovic B Colony-stimulating factors for chemotherapy-induced febrile neutropenia: a meta-analysis of randomized controlled trials J Clin Oncol 2005 23 4198 4214 15961767 \n3 Aapro MS Bohlius J Cameron DA Dal Lago L Donnelly JP Kearney N 2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours Eur J Cancer 2011 47 8 32 21095116 \n4 Crawford J Caserta C Roila F ESMO Guidelines Working Group Hematopoietic growth factors: ESMO Clinical Practice Guidelines for the applications Ann Oncol 2010 21 Suppl 5 v248 v251 20555091 \n5 National Comprehensive Cancer Network NCCN clinical practice guidelines in oncology (NCCN Guidelines) [Internet] Fort Wathington (PA) National Comprehensive Cancer Network 2018 cited 2018 Apr 16 Available from: http://www.nccn.org/professionals/physician_gls/f_ guidelines.asp \n6 Aapro M Crawford J Kamioner D Prophylaxis of chemotherapy-induced febrile neutropenia with granulocyte colonystimulating factors: where are we now? Support Care Cancer 2010 18 529 541 20191292 \n7 Martin M Segui MA Anton A Ruiz A Ramos M Adrover E Adjuvant docetaxel for high-risk, node-negative breast cancer N Engl J Med 2010 363 2200 2210 21121833 \n8 von Minckwitz G Kummel S du Bois A Eiermann W Eidtmann H Gerber B Pegfilgrastim +/– ciprofloxacin for primary prophylaxis with TAC (docetaxel/doxorubicin/cyclophosphamide) chemotherapy for breast cancer. Results from the GEPARTRIO study Ann Oncol 2008 19 292 298 17846019 \n9 Mitchell S Li X Woods M Garcia J Hebard-Massey K Barron R Comparative effectiveness of granulocyte colony-stimulating factors to prevent febrile neutropenia and related complications in cancer patients in clinical practice: A systematic review J Oncol Pharm Pract 2016 22 702 716 26769697 \n10 Almenar D Mayans J Juan O Bueno JM Lopez JI Frau A Pegfilgrastim and daily granulocyte colony-stimulating factor: patterns of use and neutropenia-related outcomes in cancer patients in Spain--results of the LEARN Study Eur J Cancer Care (Engl) 2009 18 280 286 19076208 \n11 Lambertini M Del Mastro L Bellodi A Pronzato P The five “Ws” for bone pain due to the administration of granulocyte-colony stimulating factors (G-CSFs) Crit Rev Oncol Hematol 2014 89 112 128 24041627 \n12 Cortes de Miguel S Calleja-Hernandez MA Menjon-Beltran S Vallejo-Rodriguez I Granulocyte colony-stimulating factors as prophylaxis against febrile neutropenia Support Care Cancer 2015 23 547 559 25284722 \n13 Lee J Ahn MH Jang YH Lee EJ Park JH Rho J Toxicity and quality of life of Korean breast cancer patients treated with docetaxel-containing chemotherapy without primary G-CSF prophylaxis Breast Cancer 2014 21 670 676 23371824 \n14 Woo HD Kim HS Lee JH Kim HM Han SW Kim SY Toxicity and tolerability study of adjuvant TAC regimen chemotherapy in Korean patients with breast cancer J Breast Cancer 2011 14 Suppl 1 S44 S49 \n15 Mackey JR Pienkowski T Crown J Sadeghi S Martin M Chan A Long-term outcomes after adjuvant treatment of sequential versus combination docetaxel with doxorubicin and cyclophosphamide in node-positive breast cancer: BCIRG-005 randomized trial Ann Oncol 2016 27 1041 1047 26940688 \n16 Masuda N Tokuda Y Nakamura S Shimazaki R Ito Y Tamura K Dose response of pegfilgrastim in Japanese breast cancer patients receiving six cycles of docetaxel, doxorubicin, and cyclophosphamide therapy: a randomized controlled trial Support Care Cancer 2015 23 2891 2898 25733000 \n17 Kirshner JJ Heckler CE Janelsins MC Dakhil SR Hopkins JO Coles C Prevention of pegfilgrastim-induced bone pain: a phase III double-blind placebo-controlled randomized clinical trial of the university of rochester cancer center clinical community oncology program research base J Clin Oncol 2012 30 1974 1979 22508813 \n18 Leung M Florendo J Kano J Marr-Del Monte T Higgins B Myers R A modified filgrastim regimen does not reduce pain burden compared to pegfilgrastim in women receiving chemotherapy for non-metastatic breast cancer Support Care Cancer 2015 23 1669 1677 25421443 \n19 Klastersky J Paesmans M Rubenstein EB Boyer M Elting L Feld R The Multinational Association for Supportive Care in Cancer risk index: a multinational scoring system for identifying low-risk febrile neutropenic cancer patients J Clin Oncol 2000 18 3038 3051 10944139 \n20 Lyman GH Kuderer NM Crawford J Wolff DA Culakova E Poniewierski MS Predicting individual risk of neutropenic complications in patients receiving cancer chemotherapy Cancer 2011 117 1917 1927 21509769 \n21 Ahn S Lee YS Lee JL Lim KS Yoon SC A new prognostic model for chemotherapy-induced febrile neutropenia Int J Clin Oncol 2016 21 46 52 26049405 \n22 Bozcuk H Yıldız M Artac M Kocer M Kaya C Ulukal E A prospectively validated nomogram for predicting the risk of chemotherapy-induced febrile neutropenia: a multicenter study Support Care Cancer 2015 23 1759 1767 25433439 \n23 Lote H Sharp A Redana S Papadimitraki E Capelan M Ring A Febrile neutropenia rates according to body mass index and dose capping in women receiving chemotherapy for early breast cancer Clin Oncol (R Coll Radiol) 2016 28 597 603 26936608 \n24 Lee KH Kim JY Lee MH Han HS Lim JH Park KU A randomized, multicenter, phase II/III study to determine the optimal dose and to evaluate the efficacy and safety of pegteograstim (GCPGC) on chemotherapy-induced neutropenia compared to pegfilgrastim in breast cancer patients: KCSG PC10-09 Support Care Cancer 2016 24 1709 1717 26423618 \n25 Green MD Koelbl H Baselga J Galid A Guillem V Gascon P A randomized double-blind multicenter phase III study of fixed-dose single-administration pegfilgrastim versus daily filgrastim in patients receiving myelosuppressive chemotherapy Ann Oncol 2003 14 29 35 12488289 \n26 Holmes FA O'Shaughnessy JA Vukelja S Jones SE Shogan J Savin M Blinded, randomized, multicenter study to evaluate single administration pegfilgrastim once per cycle versus daily filgrastim as an adjunct to chemotherapy in patients with high-risk stage II or stage III/IV breast cancer J Clin Oncol 2002 20 727 731 11821454\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2288-6575",
"issue": "94(5)",
"journal": "Annals of surgical treatment and research",
"keywords": "Adjuvant chemotherapy; Breast neoplasms; Febrile neutropenia; Granulocyte colony-stimulating factor",
"medline_ta": "Ann Surg Treat Res",
"mesh_terms": null,
"nlm_unique_id": "101622895",
"other_id": null,
"pages": "223-228",
"pmc": null,
"pmid": "29732352",
"pubdate": "2018-05",
"publication_types": "D016428:Journal Article",
"references": "22508813;26936608;26940688;11821454;20555091;17846019;10944139;26423618;25421443;21121833;15961767;19076208;23371824;25284722;26769697;25733000;21509769;20191292;24041627;25433439;12488289;18463977;21095116;26049405",
"title": "Pegfilgrastim for primary prophylaxis of febrile neutropenia in breast cancer patients undergoing TAC chemotherapy.",
"title_normalized": "pegfilgrastim for primary prophylaxis of febrile neutropenia in breast cancer patients undergoing tac chemotherapy"
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"abstract": "BACKGROUND Liver transplantation is considered to be the best available treatment option for patients with liver failure. In Kazakhstan, the liver transplantation program was established a decade ago. In this study, we analyzed a low-volume transplant center experience of liver transplantation in Kazakhstan. MATERIAL AND METHODS Clinical data of the 64 consecutive liver transplantations from deceased and living donors between 2010 and 2020 were retrieved from electronic records. All data were retrospectively analyzed. RESULTS A total of 64 liver transplantations, 11 from deceased donors and 53 from living donors, were carried out in our center between 2010 and 2020. The mean age of the recipient was 44 years, 53% were female, and 47% were male. Hepatitis B+hepatitis D infection was the most common cause of end-stage liver disease (21 cases; 32.8%). The overall patient survival rates for 1, 3, and 5 years were 75%, 69.5%, and 59.6%, respectively, for recipients of a liver transplant from a living donor and 54.5%, 45.5%, and 39% for recipients of a liver transplant from a deceased donor. CONCLUSIONS Our clinical outcomes had a high rate of biliary and vascular complications that led to a low survival rate of the recipients. Starting the transplant program in Kazakhstan faced various challenges. In the early period, most transplantations were performed in collaboration with or under the guidance of transplant teams from Russia, Turkey, and South Korea. Improving surgical techniques and protocols of pre- and posttransplantation management could reduce the complications after transplantation.",
"affiliations": "Department of Hepatology, Gastroenterology, and Organ Transplantation, LLP National Research Oncology Center, Nur-Sultan, Kazakhstan.;Department of Hepatology, Gastroenterology, and Organ Transplantation, LLP National Research Oncology Center, Nur-Sultan, Kazakhstan.;Department of Hepatology, Gastroenterology, and Organ Transplantation, LLP National Research Oncology Center, Nur-Sultan, Kazakhstan.;Department of Hepatology, Gastroenterology, and Organ Transplantation, LLP National Research Oncology Center, Nur-Sultan, Kazakhstan.;Department of Hepatology, Gastroenterology, and Organ Transplantation, LLP National Research Oncology Center, Nur-Sultan, Kazakhstan.;Department of Hepatology, Gastroenterology, and Organ Transplantation, LLP National Research Oncology Center, Nur-Sultan, Kazakhstan.;Department of Hepatology, Gastroenterology, and Organ Transplantation, LLP National Research Oncology Center, Nur-Sultan, Kazakhstan.",
"authors": "Saparbay|Jamilya|J|;Spatayev|Janat|J|;Sharmenov|Abylaikhan|A|;Aytbayev|Shokan|S|;Uristenova|Aizhan|A|;Mukazhanov|Adilbek|A|;Zhexembayev|Asan|A|",
"chemical_list": null,
"country": "United States",
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"doi": "10.12659/AOT.931786",
"fulltext": "\n==== Front\nAnn Transplant\nAnn Transplant\nAnnals of Transplantation\nAnnals of Transplantation\n1425-9524\n2329-0358\nInternational Scientific Literature, Inc.\n\n34226437\n10.12659/AOT.931786\n931786\nOriginal Paper\nLiver Transplantation: A 10-Year Low-Volume Transplant Center Experience in Kazakhstan\nSaparbay Jamilya ABCDEF\nSpatayev Janat ADEF\nSharmenov Abylaikhan AB\nAytbayev Shokan BCD\nUristenova Aizhan B\nMukazhanov Adilbek BCDE\nZhexembayev Asan ADE\nDepartment of Hepatology, Gastroenterology, and Organ Transplantation, LLP National Research Oncology Center, Nur-Sultan, Kazakhstan\nCorresponding Author: Jamilya Saparbay, e-mail: dzhamilyasaparbay@gmail.com\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\n2021\n06 7 2021\n18 6 2021\n26 e931786-1e931786-6\n24 2 2020\n17 5 2021\n© Ann Transplant, 2021\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)\nBackground\n\nLiver transplantation is considered to be the best available treatment option for patients with liver failure. In Kazakhstan, the liver transplantation program was established a decade ago. In this study, we analyzed a low-volume transplant center experience of liver transplantation in Kazakhstan.\n\nMaterial/Methods\n\nClinical data of the 64 consecutive liver transplantations from deceased and living donors between 2010 and 2020 were retrieved from electronic records. All data were retrospectively analyzed.\n\nResults\n\nA total of 64 liver transplantations, 11 from deceased donors and 53 from living donors, were carried out in our center between 2010 and 2020. The mean age of the recipient was 44 years, 53% were female, and 47% were male. Hepatitis B+hepatitis D infection was the most common cause of end-stage liver disease (21 cases; 32.8%). The overall patient survival rates for 1, 3, and 5 years were 75%, 69.5%, and 59.6%, respectively, for recipients of a liver transplant from a living donor and 54.5%, 45.5%, and 39% for recipients of a liver transplant from a deceased donor.\n\nConclusions\n\nOur clinical outcomes had a high rate of biliary and vascular complications that led to a low survival rate of the recipients. Starting the transplant program in Kazakhstan faced various challenges. In the early period, most transplantations were performed in collaboration with or under the guidance of transplant teams from Russia, Turkey, and South Korea. Improving surgical techniques and protocols of pre- and posttransplantation management could reduce the complications after transplantation.\n\nEnd Stage Liver Disease\nLiver Transplantation\nLiving Donors\n==== Body\nBackground\n\nLiver transplantation is the only treatment option for patients with end-stage liver disease (ESLD) [1]. According to the Republican Center for the Coordination of Transplantation of the Ministry of Health of the Republic of Kazakhstan, 127 adults and 8 children are currently registered on the waiting list for liver transplantation [2]. The first successful deceased donor liver transplantation (DDLT) in Kazakhstan was performed in 1996. However, due to the lack of trained transplant surgeons and immunologists, and especially the absence of deceased donor organs, the first case was the only case for almost 10 years. Asian countries have the lowest rate of liver transplantation from deceased donors. By 2010, the rate of deceased organ donation was 0.05–6.0 per million on a population basis, while in the United States it was 33.9 per million [3]. Currently, the organ transplantation program in Kazakhstan is in its early stages. Similar to other Eastern countries, developing transplant services has met a variety of obstacles. An absence of education regarding the importance of organ donation and transplantation is common, alongside a lack of governmental support and poorly developed health care system, and these factors create a barrier for deceased organ donation development [4–6]. Thus, a notable discrepancy exists between the availability of organs and the patients awaiting liver transplantation in Kazakhstan. Living donation is the most attractive option in solving the organ shortage problem [7]. In Kazakhstan, the first successful liver transplantation from a living donor was performed in 2011 in collaboration with a transplant team from Belarus [8]. Since 2013, liver transplantation numbers have been steadily increasing in transplant centers of Kazakhstan (Figure 1). In Kazakhstan, live donor liver transplantation (LDLT) accounted for 80% of the total liver transplantation cases in 2019. Here, we present a 10-year single-center experience of liver transplantation in a low-volume transplant center in Kazakhstan.\n\nMaterial and Methods\n\nThis retrospective study was conducted in compliance with the principles of the Declaration of Helsinki. The Local Ethics Committee of National Research (permit number #7) approved this study.\n\nA total of 64 liver transplantations were performed in our center between January 2011, when the transplant program started in Kazakhstan, and October 2020. Of these transplantations, 11 were from deceased donors and 53 were from living donors. All data concerning recipients and donors were retrieved from electronic data, and we reviewed the course of the recipients. The follow-up period was more than 1 year in all cases. All recipients who received liver transplantation from a deceased or living donor were listed in the National Waiting List of the Republic of Kazakhstan.\n\nAlmost all grafts from living donors were right lobe hepatectomy, except 1 left hepatectomy. In all right hepatectomy cases, the middle hepatic vein was left in the donor remnant liver. Remnant liver volume, evaluated by computed tomography, was more than 35%, and graft-to-recipient body weight ratio >0.8 was acceptable in our center. An interposition synthetic graft was used for venous drainage of segments 5 and 8. Biliary reconstruction was completed either with duct-to-duct anastomoses or with hepaticojejunostomy.\n\nBasiliximab (anti-interleukin-2 receptor antagonist) was used for induction therapy. For mainstay therapy, a calcineurin inhibitor-based immunosuppressive regimen was used in our center. Three-component therapy involved tacrolimus, steroid, and mycophenolate mofetil.\n\nOral nucleoside analogs were used in recipients with hepatitis B virus (HBV)-associated ESLD prior to liver transplantation and continued after liver transplantation as prophylaxis against recurrence.\n\nThe demographic and medical data of participants were analyzed retrospectively. Information on the age of recipients and donors, sex of recipients and donors, donor type, the causes of liver cirrhosis, hospital stay length, postsurgical complications, cold ischemic time, operation time, and bleeding volume is presented in Tables 1–3. The overall survival was defined as the time between the diagnosis date and death or the last follow-up visit. The difference between groups was considered significant if the P-value was <0.05. STATA 14.0 software was used to perform the statistical analyses.\n\nResults\n\nAmong 64 liver transplantations, 11 liver grafts were from deceased donors and 53 were from living donors (50 donors were relatives of the recipient, 3 were unrelated donors). There was 1 LDLT from an ABO-incompatible donor. The major causes of liver cirrhosis were hepatitis B and D in 21 cases (32.8%), hepatitis B in 9 (14%), primary biliary cirrhosis in 9 (14%), autoimmune hepatitis in 7 (10.9%), hepatitis C in 4 cases (6.3%), nonalcoholic steatohepatitis in 3 cases (4.7%), and hepatitis B, C, and D in 1 case (1.5%). In 2 cases, hepatocellular carcinoma was an indication for liver transplantation. Cryptogenic cirrhosis (6.3%) and Chanarin-Dorfman syndrome (1.6%) were rare indications for liver transplantation.\n\nThe mean age of transplant recipients was 44 years (range 15–63), with a slight majority of female recipients (53%) compared with male recipients (47%). The mean hospital stay was 40±25 days (range 11–196). Demographic and clinical characteristics of the liver recipients are shown in Table 1.\n\nThe mean age of liver donors was 31.5 years (range 19–54); 45 (70.35%) donors were men, and 19 (29.7%) were women. All living donors survived the procedure. Among living related donors, the donor was a parent of the recipient in 12 cases (22.6%), offspring in 17 cases (32.0%), and sibling in 21 cases (39.6%); the 3 unrelated living donors (5.67%) were the spouse of the recipient. No major complications were experienced in living donors. Demographic and clinical characteristics of the liver donors are shown in Table 2.\n\nThe mean cold ischemic time was 234.2±153 min, ranging from 330 to 830 min. The mean operation time was 555±114 min. The mean bleeding volume was 1835±1226 mL, ranging from 600 to 8000 mL (Table 3).\n\nMost of the recipients experienced biliary complications (n=21, 32.8%). Among these 21 cases, anastomotic biliary stricture occurred in 8 (38%), bile leakage in 9 (42.8%), nonanastomotic biliary stricture in 1 (4.8%), and cholangitis in 3 (14.4%). Bile leakage was treated conservatively in 3 cases (33.3%) and reoperation was performed in 5 cases (55.5%) to remove the biloma or reanastomosis. Anastomotic biliary stricture needed reoperation with Roux-en-Y hepaticojejunostomy. When high bilirubinemia persisted even after reanastomosis in recipients, percutaneous transhepatic draining of the bile ducts was performed. Portal vein thrombosis occurred in 7 recipients and hepatic artery thrombosis in 4 cases, all after LDLT.\n\nAcute rejection was observed in 7 patients (10.9%) after liver transplantation, with 1 case (9%) occurring after DDLT and 6 cases (11.3%) after LDLT. There was a significant association between donor type (living/deceased) and rejection rate (P=0.004) (Table 3). All patients with acute rejection were treated with steroid therapy. We did not observe any steroid-resistant rejection.\n\nThe overall patient survival rates for 1, 3, and 5 years were 75%, 69.5%, and 59.6%, respectively, for liver transplant recipient from a living donor and 54.5%, 45.5%, and 39% for a liver recipient from a deceased donor (Figure 2).\n\nDiscussion\n\nThe National Research Oncology Center is one of the few transplant centers in Kazakhstan, the largest country of central Asia. In this study, we analyzed the outcome of 64 liver transplantations performed in our center since 2010. Clinico-demographic characteristics of donors, recipients, and outcomes were described in this paper. Our data showed that the main cause of ESLD among our patients was HBV, which accords with a systematic review indicating that Kazakhstan has the highest prevalence of HBV in central Asia [9]. Among a total of 64 liver transplantations, 53 recipients received a liver graft from living donors. Worldwide, LDLT has developed significantly, with the highest distribution in Asian countries [10]. The main disadvantage of the living donation is the donor hepatectomy, which can lead to various complications [11]. We made a strict selection of so-called ideal donors; the volume of remnant liver varied from 35% to 40%, liver steatosis was less than 10%, and the mean age was 32.5 years. In our study, living donors did not experience any major complications.\n\nThe liver transplant procedure itself is technically complicated, and partial liver transplantation is an even more challenging procedure. Numerous perioperative complications occurred in our case series. Biliary and vascular complications are the major cause of morbidity and mortality after liver transplantation. The most common complication in our study involved biliary complications. The incidence of biliary complications in liver recipients varies from 10% to 15% in DDLT and from 15% to 30% in LDLT [12]. The rate of biliary complications in our study was 32.8%. Most of the cases of biliary stenosis were treated with reoperation and hepaticojejunostomy or transhepatic draining. Hepaticojejunostomy often led to chronic cholangitis and biliary cirrhosis of the liver graft.\n\nOur data revealed that DDLT patients had fewer episodes of acute rejection (9% vs 11.3%), which is not similar to other transplant centers’ data. We suggest that a higher rate of acute rejection in LDLT recipients might be due to a higher rate of hepatic artery thrombosis after LDLT.\n\nDespite the high rate of acute rejection in LDLT patients, overall survival was significantly higher in LDLT recipients than in DDLT recipients (P<0.05).\n\nThis study is limited due to the small-size cohort and its retrospective character. A longer observation period, a higher number of liver transplantation cases, and improved donor and recipient selection are necessary for further work.\n\nConclusions\n\nFor developing countries, starting a liver transplant program is challenging due to many factors, such as insufficient financial support and lack of opportunity to train surgeons and other specialists. These factors are essential for the complicated procedure of liver transplantation and efficient follow-up. Improving surgical technique, preventing biliary and vascular complications, and overcoming the organ shortage problems remain to be achieved.\n\nIn conclusion, in Kazakhstan, similar to other developing countries, establishment of transplantation programs is essential for health care system improvement.\n\nAcknowledgments\n\nWe would like to thank the transplant team of the National Research Oncology center for their great work throughout 10 years.\n\nFigure 1 Total transplantation cases and proportion of living/deceased donor liver transplantation (LDLT/DDLT) in all transplant centers of Kazakhstan from 2012 to 2019.\n\nFigure 2 Overall patient survival rate after living/deceased liver transplantation.\n\nTable 1 Demographics and clinical characteristics of liver recipients.\n\nVariable\tMean (SD)\tMedian (range)\tN (%)\t\nAge\t44 (11)\t46.5 (15–63)\t64\t\nGender (Male/Female)\t\t\t30 (47)–34 (53)\t\nCause of ESLD\t\n PBC\t\t\t9 (14)\t\n HCV\t\t\t4 (6.35)\t\n HBV\t\t\t9 (14)\t\n AIH\t\t\t7 (10.9)\t\n HCC\t\t\t2 (3.17)\t\n HBV+HDV\t\t\t21 (32.8)\t\n HBV+HDV+HCV\t\t\t1 (1.6)\t\nCryptogenic cirrhosis\t\t\t4 (6.3)\t\n NASH\t\t\t3 (4.7)\t\n Others\t\t\t4 (6.3)\t\nMELD (points)\t16 (6)\t15 (6–34)\t64\t\nChild-Pugh classification\t\t\t\t\n A\t\t\t5\t\n B\t\t\t31\t\n C\t\t\t28\t\nBilirubin (μmol/l)\t135.01 (141.6)\t136.8 (14.4–434)\t64\t\nCreatinine (μmol/l)\t62.69 (22.8)\t63.4 (30–143.75)\t64\t\nBMI – body mass index; ESLD – end-stage liver disease; PBC – primary biliary cirrhosis; HCV – hepatitis C virus; HBV – hepatitis B virus; AIH – autoimmune hepatitis; HCC – hepatocellular carcinoma; NASH – non-alcoholic steatohepatitis; MELD – model of end-stage liver disease.\n\nTable 2 Demographics and clinical characteristics of liver donors.\n\nVariable\tMean (SD)\tMedian (range)\tN (%)\t\nAge\t32.5 (9.26)\t36.5 (22–54)\t64\t\nGender (Male/Female)\t\t\t45 (70.35)/19 (29.7)\t\nLiving/Cadaveric\t\t\t53 (82.8)/11 (17.2)\t\nLiving related\t\t\t\t\nParent\t\t\t12 (22.6)\t\nOffspring\t\t\t17 (32.0)\t\nSibling\t\t\t21 (39.6)\t\nLiving unrelated\t\t\t\t\nSpouse\t\t\t3 (5.67)\t\nBilirubin (μmol/l)\t15.14 (10.7)\t(3.61–31.1)\t64\t\nCreatinine (μmol/l)\t59.6 (13.9)\t(47–81)\t64\t\n\nTable 3 Postoperative complications and surgical data.\n\nVariable\tMean (SD)\tMedian (range)\tN (%)\t\nOperation time (minute)\t555 (114)\t545 (330–830)\t64\t\nCIT (minute)\t234.3 (153.4)\t171.5 (60–630)\t\t\nBleeding volume (ml)\t1835.7 (1226.5)\t1500 (600–8000)\t\t\nPostoperative complication\t\t\t\t\nBleeding\t\t\t18 (28.57%)\t\nBiliary complications\t\t\t21 (32.8%)\t\nBile leakage\t\t\t9 (42.8%)\t\nBiliary stricture (anastomotic)\t\t\t8 (38%)\t\nBiliary stricture (non-anastomotic)\t\t\t1 (4.8%)\t\nCholangitis\t\t\t3 (14.4%)\t\nPVT\t\t\t7 (10.93%)\t\nInfection\t\t\t18 (28.57%)\t\nHAT\t\t\t3 (4.68%)\t\nCIT – cold ischemic time; HAT – hepatic artery thrombosis; PVT – portal vein thrombosis.\n\nConflict of Interest\n\nNone.\n\nDeclaration of Figures Authenticity\n\nAll figures submitted have been created by the authors, who confirm that the images are original with no duplication and have not been previously published in whole or in part.\n\nSource of support: Departmental sources\n==== Refs\nReferences\n\n1 Murray KR Carithers RL Jr AASLD practice guidelines: Evaluation of the patient for liver transplantation Hepatology 2005 41 1407 32 15880505\n2 Republican Center for Coordination of Transplantation (RCCT), Healthcare Ministry of Kazakhstan Statistics Waiting List Accessed September 4, 2020 https://transplant.kz/ru/[in Russian]\n3 Chen CL Kabiling CS Concejero AM Why does living donor liver transplantation flourish in Asia? Nat Rev Gastroenterol Hepatol 2013 10 12 746 51 24100300\n4 Altinors N Haberal M Brain death and transplant in Islamic countries Exp Clin Transplant 2016 14 Suppl 3 48 52 27805511\n5 Shaheen FAM Souqiyyeh MZ How to improve organ donation in the MESOT countries Ann Transplant 2004 9 1 19 21\n6 Shaheen FAM Souqiyyeh MZ Current obstacles to organ transplant in Middle Eastern countries Exp Clin Transplant 2015 13 Suppl 1 1 3\n7 Abouna GM Organ shortage crisis: Problems and possible solutions Transplant Proc 2008 40 1 34 38 18261540\n8 Sultanaliev T Zhexembayev A Mukazhanov A Liver transplant outcomes in a newly started program Exp Clin Transplant 2015 13 Suppl 3 120 22 26640930\n9 Davlidova S Haley-Johnson Z Nyhan K Prevalence of HIV, HCV and HBV in Central Asia and the Caucasus: A systematic review Int J Infect Dis 2021 104 510 25 33385583\n10 Rela M Reddy MS Living donor liver transplant (LDLT) is the way forward in Asia Hepatol Int 2017 11 2 148 51 28097531\n11 Sun Z Yu Z Yu S Post-operative complications in living liver donors: A single-center experience in China PLoS One 2015 10 8 e0135557 26270475\n12 Daniel K Said A Early biliary complications after liver transplantation Clin Liver Dis (Hoboken) 2017 10 3 63 67 30992762\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1425-9524",
"issue": "26()",
"journal": "Annals of transplantation",
"keywords": null,
"medline_ta": "Ann Transplant",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D006528:Carcinoma, Hepatocellular; D058625:End Stage Liver Disease; D005260:Female; D006509:Hepatitis B; D003699:Hepatitis D; D006801:Humans; D007623:Kazakhstan; D008113:Liver Neoplasms; D016031:Liver Transplantation; D019520:Living Donors; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9802544",
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"pages": "e931786",
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"pmid": "34226437",
"pubdate": "2021-07-06",
"publication_types": "D016428:Journal Article",
"references": "30992762;27805511;28097531;26270475;33385583;25894118;15478882;26640930;15880505;24100300;18261540",
"title": "Liver Transplantation: A 10-Year Low-Volume Transplant Center Experience in Kazakhstan.",
"title_normalized": "liver transplantation a 10 year low volume transplant center experience in kazakhstan"
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"abstract": "This article describes the first reported case of dramatic lymphocytosis flare after initiation of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy for an indolent lymphoma. The study patient exhibited a marginal zone lymphoma with mild nodal involvement but packed infiltration of the bone marrow. After initiation of RCHOP therapy, lymphocyte count increased from 329 to 707 × 10⁹/L at day 7. Patient exhibited grade III infusion-related side effect during rituximab therapy. Lymphocyte flare was not accompanied with other clinical manifestation such as lymph node enlargement. Because patient's bone marrow aspirate showed a packed infiltration, it was hypothesized that lymphocytosis flare was a link to lymphocyte release from bone marrow and lymphocyte demargination. This report highlights the necessity to be vigilant after initiation of RCHOP therapy for lymphoma when pathologist notified a pack infiltration of the bone marrow.",
"affiliations": "1Service d'Hématologie and 2Service d'Hématologie et de Biologie Vasculaire, Centre Hospitalier Universitaire La Conception, Marseille, France; and 3Technologies Avancées pour la Génomique et la Clinique (TAGC)/Unité INSERM U928, Marseille, France.",
"authors": "Farnault|Laure|L|;Mercier|Cedric|C|;Berda-Haddad|Yael|Y|;Sebahoun|Gerard|G|;Costello|Regis|R|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.1097/01.mjt.0000434041.54749.3d",
"fulltext": null,
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"issn_linking": "1075-2765",
"issue": "23(1)",
"journal": "American journal of therapeutics",
"keywords": null,
"medline_ta": "Am J Ther",
"mesh_terms": "D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D004317:Doxorubicin; D006801:Humans; D008218:Lymphocytosis; D008223:Lymphoma; D008297:Male; D011241:Prednisone; D000069283:Rituximab; D014750:Vincristine",
"nlm_unique_id": "9441347",
"other_id": null,
"pages": "e295-7",
"pmc": null,
"pmid": "24675549",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Is R-CHOP Therapy a Lymphoma Growth Factor?",
"title_normalized": "is r chop therapy a lymphoma growth factor"
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"abstract": "Some severe asthmatic patients experience frequent bacterial respiratory tract infections, which contribute significantly to their disease burden, and often are attributed to their use of systemic corticosteroids and comorbid bronchiectasis. We report a case of a 58-year-old woman who had prednisone-dependent asthma and exacerbations with intense mixed eosinophilic and neutrophilic bronchitis. Autosomal dominant hyper-IgE syndrome, which is a primary immunodeficiency characterized by elevated IgE, eosinophilia, and recurrent infections, caused by a novel pathogenic mutation in STAT3 was identified as the cause of her airway disease. We believe that this is the first report of the demonstration of an IL-5 driven eosinophilia that is associated with a STAT3 mutation that was treated successfully with an anti-IL5 biological.",
"affiliations": "Firestone Institute for Respiratory Health, St Joseph's Healthcare Hamilton, McMaster University, Hamilton, ON, Canada; Division of Clinical Immunology and Allergy, McMaster University, Hamilton, ON, Canada.;Firestone Institute for Respiratory Health, St Joseph's Healthcare Hamilton, McMaster University, Hamilton, ON, Canada; Division of Respirology, McMaster University, Hamilton, ON, Canada.;Firestone Institute for Respiratory Health, St Joseph's Healthcare Hamilton, McMaster University, Hamilton, ON, Canada; Division of Respirology, McMaster University, Hamilton, ON, Canada.;Division of Molecular Medicine, McMaster Immunology Research Centre, Department of Medicine, McMaster University, Hamilton, ON, Canada.;Division of Clinical Immunology and Allergy, McMaster University, Hamilton, ON, Canada.;Firestone Institute for Respiratory Health, St Joseph's Healthcare Hamilton, McMaster University, Hamilton, ON, Canada; Division of Respirology, McMaster University, Hamilton, ON, Canada. Electronic address: parames@mcmaster.ca.",
"authors": "Adatia|Adil|A|;Allen|Christopher J|CJ|;Wald|Joshua|J|;Richards|Carl D|CD|;Waserman|Susan|S|;Nair|Parameswaran|P|",
"chemical_list": "D018927:Anti-Asthmatic Agents; D061067:Antibodies, Monoclonal, Humanized; D005938:Glucocorticoids; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C571386:benralizumab; D004247:DNA; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.1016/j.chest.2020.11.042",
"fulltext": null,
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"issn_linking": "0012-3692",
"issue": "159(4)",
"journal": "Chest",
"keywords": "STAT3; asthma; benralizumab; eosinophilia; hyper-IgE syndrome",
"medline_ta": "Chest",
"mesh_terms": "D018927:Anti-Asthmatic Agents; D061067:Antibodies, Monoclonal, Humanized; D001249:Asthma; D004247:DNA; D004252:DNA Mutational Analysis; D018450:Disease Progression; D004359:Drug Therapy, Combination; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D000073658:Loss of Function Mutation; D008875:Middle Aged; D011241:Prednisone; D011657:Pulmonary Eosinophilia; D050796:STAT3 Transcription Factor",
"nlm_unique_id": "0231335",
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"pages": "e181-e184",
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"pmid": "34022014",
"pubdate": "2021-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Benralizumab for Prednisone-Dependent Eosinophilic Asthma Associated With Novel STAT3 Loss of Function Mutation.",
"title_normalized": "benralizumab for prednisone dependent eosinophilic asthma associated with novel stat3 loss of function mutation"
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"activesubstancename": "BENRALIZUMAB"
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"abstract": "Four patients, from three families, with alkaptonuria receiving 4-hydroxyphenylpyruvate dioxygenase-inhibiting nitisinone therapy, which lowers homogentisic acid and increases tyrosine, developed vitiligo. Three of the four patients were receiving nitisinone 2 mg daily, while the fourth was on 10 mg daily. All four patients were either receiving or had received transiently proton-pump inhibitors as therapy for dyspepsia. The ages of the patients were 35, 42, 40, and 67 years, respectively. Three patients were men and one was a woman. All four patients were either taking a proton-pump inhibitor or had been taking one at some point. Three of the four were of South Asian and one of Caucasian background. The three patients with South Asian background also had either a personal or family history of autoimmune disease. Distressing vitiligo, initially in an acrofacial distribution, developed unexpectedly in these four patients, before then progressing to involve other parts of the body. Potential factors in the appearance of vitiligo in this setting, including nitisinone and other drug therapy, are explored and responses to the appearance of vitiligo are discussed.",
"affiliations": "Department of Clinical Biochemistry and Metabolic Medicine Royal Liverpool University Hospital Liverpool UK.;Department of Clinical Biochemistry and Metabolic Medicine Royal Liverpool University Hospital Liverpool UK.;Department of Clinical Biochemistry and Metabolic Medicine Royal Liverpool University Hospital Liverpool UK.;Department of Clinical Biochemistry and Metabolic Medicine Royal Liverpool University Hospital Liverpool UK.;Department of Clinical Biochemistry and Metabolic Medicine Royal Liverpool University Hospital Liverpool UK.;Department of Dermatology Royal Liverpool University Hospital Liverpool UK.",
"authors": "Ranganath|Lakshminarayan|L|https://orcid.org/0000-0002-4205-2269;Khedr|Milad|M|;Evans|Leanne A|LA|;Bygott|Helen|H|;Luangrath|Emily|E|;West|Elizabeth|E|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/jmd2.12225",
"fulltext": "\n==== Front\nJIMD Rep\nJIMD Rep\n10.1002/(ISSN)2192-8312\nJMD2\nJIMD Reports\n2192-8304\n2192-8312\nJohn Wiley & Sons, Inc. Hoboken, USA\n\n10.1002/jmd2.12225\nJMD212225\nCase Report\nCase Reports\nVitiligo, alkaptonuria, and nitisinone—A report of three families and review of the literature\nRanganath et al.\nRanganath Lakshminarayan https://orcid.org/0000-0002-4205-2269\n1 lrang@liv.ac.uk\n\nKhedr Milad 1\nEvans Leanne A. 1\nBygott Helen 1\nLuangrath Emily 1\nWest Elizabeth 2\n1 Department of Clinical Biochemistry and Metabolic Medicine Royal Liverpool University Hospital Liverpool UK\n2 Department of Dermatology Royal Liverpool University Hospital Liverpool UK\n* Correspondence\nLakshminarayan Ranganath, Department of Clinical Biochemistry and Metabolic Medicine, Royal Liverpool University Hospital, Prescot Street, Liverpool L7 8XP, UK.\nEmail: lrang@liv.ac.uk\n\n14 6 2021\n9 2021\n61 1 10.1002/jmd2.v61.1 2533\n04 5 2021\n07 4 2021\n07 5 2021\n© 2021 The Authors. JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.\n\nAbstract\n\nFour patients, from three families, with alkaptonuria receiving 4‐hydroxyphenylpyruvate dioxygenase‐inhibiting nitisinone therapy, which lowers homogentisic acid and increases tyrosine, developed vitiligo. Three of the four patients were receiving nitisinone 2 mg daily, while the fourth was on 10 mg daily. All four patients were either receiving or had received transiently proton‐pump inhibitors as therapy for dyspepsia. The ages of the patients were 35, 42, 40, and 67 years, respectively. Three patients were men and one was a woman. All four patients were either taking a proton‐pump inhibitor or had been taking one at some point. Three of the four were of South Asian and one of Caucasian background. The three patients with South Asian background also had either a personal or family history of autoimmune disease. Distressing vitiligo, initially in an acrofacial distribution, developed unexpectedly in these four patients, before then progressing to involve other parts of the body. Potential factors in the appearance of vitiligo in this setting, including nitisinone and other drug therapy, are explored and responses to the appearance of vitiligo are discussed.\n\nalkaptonuria\nhomogentisic acid\nnitisinone\nproton‐pump inhibitors\ntyrosine\nvitiligo\nNHS England Highly Specialized Services source-schema-version-number2.0\ncover-dateSeptember 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.6 mode:remove_FC converted:02.09.2021\nRanganathL, KhedrM, EvansLA, BygottH, LuangrathE, WestE. Vitiligo, alkaptonuria, and nitisinone—A report of three families and review of the literature. JIMD Reports. 2021;61 (1 ):25–33. 10.1002/jmd2.12225\n\nCommunicating Editor: Jörn Oliver Sass\n\nFunding information NHS England Highly Specialized Services\n==== Body\npmc1 INTRODUCTION\n\nAlkaptonuria (AKU) (OMIM#203500) is an inherited disorder present from birth, with a frequency of around 1 in 250 000 people in most parts of the world, where consanguinity is not common.1, 2, 3 AKU is characterized by increased accumulation of homogentisic acid (HGA) due to deficient homogentisate 1,2 dioxygenase activity (EC:1.13.11.5).4 Accumulating HGA undergoes oxidation to a melanin‐like pigment via a benzoquinone acetate intermediary in a process known as ochronosis, in which the brown‐black pigment deposits in joint and spine cartilage, tendons, and ligaments.5, 6 The resulting ochronotic tissue is stiff and brittle and is the precursor for the damaging clinical features of the disease.7\n\nMultiple organs and tissues are affected in AKU, a severe, progressive, multisystem disease with a delayed onset of symptomatic disease. The involvement of eyes, ears, laryngo‐tracheal‐bronchial tree, articular and fibrocartilage of joints and spine, urinary system, as well as the heart and vasculature has been well described.8 The clinical features in AKU, namely kidney and prostate stones, aortic stenosis, bone fractures, tendon/ligament/muscle ruptures, kyphosis, scoliosis, spinal surgery, and joint replacements, reflect the damage to the predisposed tissues.9\n\nUntil recently, there has been a lack of HGA‐lowering disease‐modifying therapy.10 Nitisinone inhibits p‐hydroxyphenyl‐pyruvate dioxygenase enzyme and has been used as treatment for hereditary tyrosinemia type 1 since 1991.11 In 1998, it was hypothesized that nitisinone could decrease HGA, and was trialed in the National Institutes of Health, USA, with an inconclusive outcome.12 Since 2012, 60 patients have received nitisinone 2 mg daily and followed up for at least 12 months in the United Kingdom National Alkaptonuria Centre (NAC); overall, 88 patients have visited the center at least once. Data on 28 patients, not on nitisinone, have been assessed as part of this article. Nitisinone has been used off‐license under approval from NHS England Highly Specialized Services NAC, subject to annual review of safety and efficacy. As part of the safety and efficacy review, we report four cases of vitiligo, from three families, in patients attending the Royal Liverpool University Hospital which hosts the NAC, after commencing nitisinone therapy. No cases of vitiligo were seen in those not on nitisinone. These cases are described and possible genesis of these lesions are discussed. Ochronosis of the skin and nails in untreated AKU and itchy rash following nitisinone treatment in AKU has been previously described.13, 14, 15\n\nThe data on cases 1 to 3, presented below, collected from the NAC was approved by the Institutional Audit Committee (Audit No: ACO3836). Case 4 with AKU participated in the Suitability of Nitisinone in Alkaptonuria 2 (SONIA 2) study (EC Liverpool [NRES Committee North‐West ‐ Liverpool Central] Reference number: 13/NW/0567). Medline search was carried out using search words such as vitiligo, alkaptonuria, nitisinone, and hereditary tyrosinemia type 1.\n\n2 CASE REPORTS\n\n2.1 Case 1\n\nA 35‐year‐old man of South Asian background presented with recently diagnosed established alkaptonuria characterized by lumbar spondylosis, arthropathy in both feet, left shoulder, mild stable aortic valve stenosis, and mitral valve calcification and regurgitation at the baseline visit (Tables 1 and 2, Figure 1). Out of five brothers and a sister, three brothers (including this patient) and a sister were diagnosed with Alkaptonuria. He mentioned no pigmentary skin changes on questioning at baseline. Physical examination revealed a man of 1.82 m and a weight of 87 kg with a body mass index of 26.5 kg/m2. Blood pressure was 125/80. There was no pigmentation of the skin or the nails of the hands or feet. At baseline, he had been taking paracetamol 500 mg and ibuprofen 300 mg when needed. He was commenced on nitisinone 2 mg alternate days for 3 months and then the dose was increased to 2 mg daily. At review 13 months after baseline, he was found to be vitamin D deficient, and was taking lansoprazole 15 mg, lidocaine 5% patches, liquid oral morphine 30 mg, and nitisinone 2 mg. Two years after the baseline visit, he was found to have compensated primary hypothyroidism but had discontinued lansoprazole. Four years after the baseline visit, he was diagnosed with vitiligo and itching affecting his face, hands, and lower abdomen and was using topical steroid creams. He was also taking thyroxine 100 mg daily by this time. His vitiligo had progressed much more by 6 years since the first visit, involving dorsal and palm aspects of his hands, dorsal aspects of his feet, trunk, knees, and popliteal fossa in addition to his face and lower abdomen.\n\nTABLE 1 Characteristics of vitiligo in four patients with nitisinone‐treated alkaptonuria\n\n\tCase 1\tCase 2\tCase 3\tCase 4\t\nEthnic background\tSouth Asian\tSouth Asian\tSouth Asian\tCaucasian\t\nAge at baseline (y)\t35\t42\t40\t67\t\nSex\tMale\tMale\tFemale\tMale\t\nDose of nitisinone\t2 mg\t2 mg\t2 mg\t10 mg\t\nAreas affected by vitiligo\tFace\tYes\tYes\tYes\tNo\t\nHands\tHands\tYes\tYes\tYes\t\nFeet\tYes\tNo\tNo\tYes\t\nTrunk\tYes\tYes\tYes\tNo\t\nOther\tKnees\tGenital, scalp\t—\t—\t\nOnset of vitiligo after nitisinone (mo.)\t51\t48\t36\t3\t\nHyperpigmentation preceding vitiligo\tNo\tYes (at 12 mo.)\tYes\tNo\t\nWhether vitiligo accompanied by itching\tYes\tYes\tYes\tNo\t\nHow was itching treated\tTopical steroids\tTopical steroids\tAntihistamine\tNone\t\nKnown autoimmune disorder\tHypothyroidism\tNo\tHypothyroidism (age 18 y)\tNo\t\nFamily history autoimmune disorder\tSister with SLE\tYes, as with case 1\tNo\tNone\t\nType of vitiligo\tNonsegmental\tNonsegmental\tNonsegmental\tNonsegmental\t\nProgression of vitiligo\tYes\tYes\tYes\tYes\t\nFamily history of vitiligo\tYes\tYes\tNo\tNo\t\nHistory of proton‐pump inhibitors therapy\tTransient use of Lansoprazole\tOmeprazole\tOmeprazole\tOmeprazole\t\nTiming of proton‐pump inhibitors\tDiscontinued after brief use\tVitiligo more than 1 y of PPI\tPrior to baseline visit\tVitiligo 6 wk post‐PPI\t\nAbbreviation: PPI, proton‐pump inhibitor therapy; SLE, systemic lupus erythematosus.\n\nTABLE 2 Baselinec laboratory data in four cases of vitiligo in nitisinone‐treated alkaptonuria\n\nMeasurement\tNormal ranges\tCase 1\tCase 2\tCase 3\tCase 4\t\nSex\t\tMale\tMale\tFemale\tMale\t\nSerum urea (mmol/L)\t2.5‐7.8\t3.1\t4.6\t4.2\t5.8\t\nSerum creatinine (μmol/L)\t50‐130\t79\t72\t62\t82\t\nAdjusted serum calcium (mmol/L)\t2.2‐2.6\t2.37\t2.32\t2.29\t2.5\t\nTotal bilirubin (μmol/L)\t<21\t14\t14\t7\t11\t\nGamma glutamyl transferase (U/L)\t<35 F; <50 M\t15\t19\t36\t79\t\nAlkaline phosphatase (U/L)\t30‐130\t62\t73\t66\t79\t\nAlanine transaminase (U/L)\t<35 F; <50 M\t21\t21\t28\t22\t\nPlasma glucose (mmol/L)\t3.5‐6.0\t5.1\t5.4\t4.6\t4.7\t\nFreeT4 (pmol/L)\t10‐22\t15.6\t19.6\t22.4\t—\t\nTSH (mU/L)\t0.3‐6.0\t10.3\t2.5\t0.7\t—\t\nHemoglobin (g/L)\t118‐148 F; 130‐160 M\t137\t134\t125\t165\t\nWhite cell count (× 109/L)\t3.5‐11\t5.7\t12.0\t4.4\t9.3\t\nPlatelets (× 109/L)\t150‐400\t292\t356\t272\t221\t\nSerum homogentisic acid (μmol/L)a\t<3.1\t19.0\t22.9\t34.1\t52.4\t\nSerum homogentisic acid (μmol/L)b\t<3.1\t6.3\t7.3\t4.5\t0.4\t\nSerum tyrosine (μmol/L)a\t26‐96\t56\t44\t33\t80\t\nSerum tyrosine (μmol/L)b\t26‐96\t503\t692\t997\t1394\t\nIncrease in tyrosine post‐nitisinone (× baseline)\t\t9.0\t15.7\t30.2\t17.4\t\nSerum nitisinone (μmol/L)a\t<0.2\t<0.2\t<0.2\t<0.2\t<0.2\t\nSerum nitisinone (μmol/L)b\t<0.2\t0.6\t0.9\t0.8\t4.1\t\n24‐h urine homogentisic acid (μmol/d)a\tNA\t17 870\t24 611\t23 682\t42 847\t\n24‐h urine homogentisic acid (μmol/d)b\tNA\t1737\t2350\t886\t92\t\nAbbreviation: NA, not available; TSH, thyroid stimulating hormone.\n\na Pre‐nitisinone.\n\nb Post‐nitisinone.\n\nc Baseline unless otherwise stated.\n\nFIGURE 1 Photographs in case 1 showing (A) normal face pigmentation pre‐nitisinone in 2014, (B) earlier facial vitiligo in 2017 and (C) more extensive vitiligo in 2020, (D) shows hand and trunk vitiligo in 2020, (E) shows vitiligo on extensor surface of elbow in 2020, and (F) shows bilateral popliteal fossa vitiligo in 2020\n\n2.2 Case 2\n\nA 42‐year‐old man of South Asian background recently diagnosed with AKU was referred for further management at first visit (Tables 1 and 2, Figure 2). He has bilateral ear and eye ochronosis, nail ochronosis, previously passed renal stones at age 27 years, dyspepsia, angina, generalized spondylosis affecting, cervical, thoracic and lumber spine, with generalized joint pains. He is one of the siblings mentioned in case 1. He was 1.67 m and weighing 70 kg, with a blood pressure of 116/74 mm Hg. His medications consisted of buprenorphine patches, co‐codamol, vitamin C, vitamin D, cetirizine, and beclomethasone cream. He was commenced on nitisinone 2 mg alternate days for 3 months and then the dose was increased to 2 mg daily. At the 2‐year visit, an increase in skin pigmentation was noticed in the dorsal aspects of the thumb and middle finger of the right hand. At the 3‐year visit, he mentioned increased discoloration of the skin in the genital region. At his 4‐year visit, he was diagnosed with vitiligo affecting his scalp, periorbital regions, and groin. His sister with AKU also had systemic lupus erythematosus and has not developed vitiligo so far despite also being on nitisinone 2 mg for 5 years. Five years after the baseline visit, the vitiligo had extended to involve his trunk. He was on the following mediations at this time namely, nitisinone 2 mg, buprenorphine patches (5 mg patch), co‐codamol (codeine 50 mg, paracetamol 500 mg), vitamin C (1 g), vitamin D (800 units), cetirizine 10 mg, cream containing betamethasone and clotrimazole, omeprazole 20 mg, pregabalin 75 mg, testosterone 2% gel, clenil modulite 200 mcg inhaler twice a day. At the 6‐year visit, vitiligo had extended to all over his body including the covered areas, forehead, armpits, around his groin and his left hand. Topical steroid cream made no difference.\n\nFIGURE 2 Photographs in case 2 showing vitiligo in forehead and scalp in (A) 2017, (B) 2018, and (C) 2019\n\n2.3 Case 3\n\nA 40‐year‐old woman of South Asian background, with AKU diagnosed at age 33 years, was referred for further management of AKU (Tables 1 and 2, Figure 3A‐D). She was born of a consanguineous union, and had a brother and six sisters, with a sister also suffering with AKU. She had ear and eye ochronosis, spondylosis (cervical, thoracic, and lumbar), and arthropathy (knees, shoulders). She has noticed change in the skin color especially around the eye and brown spots in the hands 3 years before the baseline visit. Her height and weight were 1.61 m and 75.6 kg, respectively, with a blood pressure of 110/77 mm Hg. Other health conditions included primary hypothyroidism requiring thyroxine therapy since age 18 years, and hypercholesterolemia managed by diet. Her medications at time of referral included tramadol 50 mg, meloxicam 7.5 mg, paracetamol 500 mg, thyroxine 100 μg, omeprazole, and calcichew D3 Forte (calcium 500 mg/vitamin D3 400 units). She was commenced on nitisinone 2 mg alternate days for 3 months and then the dose was increased to 2 mg daily. A year after the first visit, she noticed hyperpigmentary changes on her right forearm and both hands. At the 3‐year visit, she noticed depigmented macules were seen on her hands and anterior chest wall and a diagnosis of vitiligo was made. Vitiligo progressed further with pruritus. At her 5‐year visit, vitiligo also extended to her face with continued itching.\n\nFIGURE 3 Photographs in case 3 shows vitiligo in 2018 on (A) trunk, (B) right hand, (C) left hand, and (D) front of chest wall. Photograph (E) shows vitiligo on hands in case 4\n\n2.4 Case 4\n\nA 67‐year‐old Caucasian man was seen in the Royal Liverpool University Hospital with documented AKU (Figure 3E, Tables 1 and 2). He had a brother and sister with AKU, and neither had vitiligo nor received nitisinone. He had advanced AKU features including bilateral ear and eye ochronosis, prostate stones, osteoporosis, mild aortic stenosis, ischemic heart disease, arthropathy (of left shoulder, left wrist, and both knees), as well as spondylosis (cervical, lumber, sacroiliac). His skin at baseline visit was normal. He was taking piroxicam 100 mg and potassium citrate at baseline. He started nitisinone 10 mg daily at his baseline visit. He had a successful coronary bypass surgery, 2 months after his baseline visit, following which he started taking omeprazole 40 mg, bisoprolol 2.5 mg, aspirin 80 mg, and rosuvastatin 10 mg, which he was on when he was seen at his three‐monthly visit after baseline. During his visit 3 months after baseline, he had vitiligo on his hands and feet, which persisted and progressed until discharge four from baseline. There was no personal or family history of autoimmune disorders. At discharge, he was receiving ibuprofen 400 mg, vitamin D 25000 units monthly, calcium carbonate 1.25 g, alendronate 70 mg, in addition to bisoprolol, aspirin, rosuvastatin, potassium citrate, and omeprazole, as drug therapy.\n\n3 DISCUSSION\n\nEighty‐eight patients had attended NAC at least once; of these 28 had either not received nitisinone or not had a follow‐up visit on nitisinone. In these 88 patients, 29 were on proton‐pump inhibitor therapy (PPI), with 15 on lansoprazole and 14 on omeprazole. Vitiligo has not previously been described in AKU after nitisinone, even though there is a single case report of vitiligo in a 15‐year‐old boy with autoimmune diathesis and AKU.16 Four cases of vitiligo, three men and one woman, three with South Asian and one with Caucasian background, appearing at varying duration after beginning nitisinone treatment. None of the four patients had vitiligo at baseline pre‐nitisinone. These four cases all arose in adult patients over the age of 35 years, with the vitiligo showing a nonsegmental distribution with a predominant acro‐facial distribution. The prevalence of vitiligo has been reported around 1%.17 The prevalence of vitiligo in AKU patients treated with nitisinone attending the hospital from which this report appears is 5% (4 out of 80 nitisinone treated patients). This may suggest that nitisinone‐treated AKU patients may be at higher risk of developing vitiligo.\n\nHowever, all four patients were also on PPI, at some point, now associated with development of vitiligo by poorly understood mechanisms. Case 1 was transiently on lansoprazole and only developed vitiligo 3 years later. Case 2 developed vitiligo more than a year after starting omeprazole. Case 3 was already on omeprazole at baseline and developed vitiligo 3 years after her baseline visit to the NAC. Case 4 developed vitiligo within weeks of starting omeprazole therapy. There is data describing omeprazole and its congeners inhibit melanogenesis in cells and human skin. It has been suggested that PPI could inhibit metallation of newly synthesized tyrosinase via ATP7A. The ATP7A protein regulates cellular copper homeostasis within cells thereby controlling the supply of copper to copper‐dependent enzymes, as well as the export of excess copper from the cytoplasm.18 The effect of PPIs appears to rapidly cause vitiligo, and only case 4 appears to fit the time‐line of starting omeprazole and appearance of vitiligo. Case 4 is also different from the other three cases in that the patient was Caucasian with no personal or family history of autoimmune diathesis. Since not everyone administered PPIs develop vitiligo, there is a suggestion that additional factor(s), currently unclarified, is(are) needed for the induction of vitiligo by PPI.19\n\nThree of the patients had either autoimmune disease themselves or had a family history of autoimmune disease; vitiligo is an autoimmune destruction of melanocytes in the skin leading to depigmented macules. The two patients with personal autoimmune hypothyroidism had the most extensive vitiligo after starting nitisinone. Two of the four cases reported increased skin pigmentation before vitiligo appeared; following nitisinone serum and tissue tyrosine increase markedly, between 8.98 and 30.2 times baseline, making available more substrate for melanin synthesis. A previous NIH study has shown that nitisinone improved albinism due to increased melanin synthesis following the increase in tyrosine, demonstrating that increase in tyrosine circulating concentrations results in increased flux down the melanin pathway.20 Nitisinone‐induced transient hyperthyroidism occurred in a case with hypothyroidism on thyroxine replacement supporting the idea that increased tyrosine can drive pathways involving tyrosine (unpublished observations). Tyrosine administration has been shown to increase melanin formation.21, 22\n\nEpidermal reactive oxygen species accumulation has been considered the main culprit in the pathogenesis of vitiligo, the most notable of which is hydrogen peroxide (H2O2). The concentration of H2O2 may reach a mmol/L.23 At this concentration, H2O2 leads to changes in the mitochondria and, consequently, apoptosis and death of the melanocytes.24 It has been shown that tyrosine upon entering the melaninogenic pathways, in which tyrosinases participate, produces certain electrically unstable by‐products, which have the potential to damage other cellular substrates resulting in death of the melanocytes.25\n\nThree of the four cases also reported itching when the vitiligo appeared and continued over time. The exact mechanism of itching in vitiligo is not well understood. A recent review estimated the prevalence of itching in vitiligo at 20.2%.26 Nitisinone has been used in the treatment of children with HT‐1 since 1991 and the manufacturer's prescribing information does not list vitiligo as a side effect although it lists itching, urticaria, and maculopapular rash, all at a prevalence of 1%.14\n\nThe mechanism underlying vitiligo in this case report is unknown. We speculate on the mechanism to explain the onset of vitiligo after nitisinone in these four AKU patients (Figure 4), as follows. In AKU, HGA is increased, as can be seen in all four patients at baseline, before commencement of nitisinone. HGA is a reducing agent and can mop up oxidant products including hydrogen peroxide; analytical interference due to this reducing property of HGA, in an enzymatic assay of creatinine has been previously described, and supports this role for HGA in AKU.27 Decrease in HGA after nitisinone could decrease this protection against oxidant stress, increasing the vulnerability to vitiligo. Additionally, following administration of nitisinone, the inhibition of 4‐hydroxyphenylpyruvate dioxygenase results in a marked increase in serum and tissue tyrosine.28 Since the usual metabolism of tyrosine through HGA is interrupted, increased flux along alternate pathways results. One of these alternate pathways is the melanin synthesis pathway, leading to stimulation of melanin formation, with hyperpigmentation, noted in two of the four patients, supports this idea. Increased oxidant reactions during stimulation of melanin formation lead to production of oxidants including hydrogen peroxide, which has been linked with melanocyte damage and cell death.23, 24, 25 We also propose that the decrease of HGA and the increase in tyrosine after administration of nitisinone in AKU patients accelerate underlying autoimmune diathesis, predisposing to the melanocyte death and appearance of vitiligo. Support for this hypothesis comes from the fact that three of the four patients had autoimmune disease or a family predisposition to autoimmune disease. The decrease in HGA and the increase in tyrosine can be readily appreciated from Table 1. It is possible that UV radiation from sunlight could participate in the vitiligo process as all four patients experienced vitiligo in the hands and face, exposed to sunlight, before spreading further. The greater frequency of vitiligo in patients with South Asian background in this report, three of four patients, who have an increased activity of the melanin pathway, compared with Caucasians, is consistent with our hypothesis. It has been shown that more pigmented skin can produce more melanin when stimulated such as by UV radiation of sunlight, with response in South Asians four times greater than in white Caucasians.29, 30 The quickest appearance of vitiligo following nitisinone administration was in case 4 who received the larger dose of nitisinone, and also with the greatest increase in serum tyrosine. The final observation that only one of the four patients in this report was a woman, generally more prone to autoimmune disease, could be due to the beneficial effect of estrogen in directing the tyrosine pathway toward 4‐hydroxyphenylpyruvate through stimulation of rate‐limiting tyrosine aminotransferase.31\n\nFIGURE 4 Tyrosine at normal concentrations is converted to melanin via parallel pathways of L‐DOPA and dopamine, mediated by tyrosinase, in the melanocyte. The action of tyrosinase results in reactive oxygen species (ROS) generation. ROS has been implicated in the death of melanocytes in the setting of autoimmune vitiligo. Homogentisic acid (HGA) as a reducing agent can protect against reactive oxygen species, which can be lost after nitisinone therapy, due to decrease in HGA. Further, tyrosine concentrations increase more than 10‐fold following nitisinone therapy, thus potentially increasing ROS generation by increasing flux in the melanin pathway, thereby further increasing the risk of melanocyte death. Cu, copper; DDC, dopamine decarboxylase; Fe, iron; H2O2, hydrogen peroxide; O2, superoxide; OH, hydroxyl radical; SOD, superoxide dismutase; TH, tyrosine hydroxylase; TY, tyrosinase; Zn, zinc\n\nFinally, nitisinone was continued in these four patients because of the lack of certainty about causation. Further, it is the only treatment option for the progressive severe morbidity, which would result if nitisinone was withdrawn in these cases without any other HGA‐lowering disease‐modifying therapy on the horizon. Vitiligo is generally considered irreversible; it is a dilemma whether to stop nitisinone knowing that vitiligo will probably not reverse, but with the certainty that AKU disease will progress. It is important that patients be counseled about this risk when it appears, and involved in the decision to continue or stop nitisinone. It is also worthwhile bearing in mind that other medications, such as PPI, could not only independently cause vitiligo but could possibly enhance or add to the risk of vitiligo due to nitisinone and/or autoimmune diathesis; alternatives to PPIs in the context of nitisinone in AKU especially in the setting of autoimmune disease predisposition should be considered. Further investigations are needed addressing the risk of vitiligo in nitisinone therapy in those with a personal or family history of autoimmune diseases. We are learning more about nitisinone therapy in adult AKU and we should be vigilant in recognizing new health issues in these situations going forwards, with nitisinone therapy now approved for the treatment of adult AKU by the European Medicines Agency.32 Learning points\n\nVitiligo may be more prevalent in AKU after nitisinone therapy.\n\nAKU patients with pigmented skin may be more at risk of vitiligo after nitisinone.\n\nItching may be an accompanying factor.\n\nPersonal or family history of autoimmune disease may increase risk of vitiligo in AKU post‐nitisinone.\n\nUse of other vitiligo‐causing medications should be reviewed to minimize vitiligo after nitisinone.\n\nCONFLICT OF INTEREST\n\nThe authors declare no potential conflict of interest.\n\nAUTHOR CONTRIBUTIONS\n\nLakshminarayan Ranganath assessed the patients, recognized the adverse event as being related to nitisinone, and wrote the manuscript. Milad Khedr assessed the patients, and edited the manuscript. Leanne A. Evans was involved in compiling the data and edited the manuscript. Helen Bygott suggested the omeprazole link to vitiligo, and edited the manuscript. Emily Luangrath helped compile the data and edit the manuscript. Elizabeth West helped assess the patients and edited the manuscript.\n\nETHICS STATEMENT\n\nThe data collected from the NAC for patients 1 to 3 were approved by the Institutional Audit Committee (Audit No: ACO3836). Patient 4 with alkaptonuria participated in the Suitability of Nitisinone in Alkaptonuria 2 (SONIA 2) study (EC Liverpool [NRES Committee North‐West ‐ Liverpool Central] Reference number: 13/NW/0567).\n\nINFORMED CONSENT\n\nAll procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all patients for being included in the study. Further clarification has been provided in the previous page.\n\nACKNOWLEDGMENTS\n\nThis work was supported by funding granted in April 2012 by the NHS England Highly Specialized Services in establishing the UK National Alkaptonuria Centre in the Royal Liverpool University Hospital. The funding source was not involved in the study design, collection, analysis and interpretation of data, the writing of the manuscript, or in the decision to submit the manuscript for publication. The authors confirm independence from the funders; the content of the article has not been influenced by the funders.\n\nDATA AVAILABILITY STATEMENT\n\nThe authors agree to honor any reasonable request by other researchers for materials, methods, or data necessary to verify the conclusion of the article.\n==== Refs\nREFERENCES\n\n1 AscherDB, SpigaO, SekelskaM, et al. Homogentisate 1,2‐dioxygenase (HGD) gene variants, their analysis and genotype–phenotype correlations in the largest cohort of patients with AKU. 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Clin Biochem. 2014;47 :640‐647.24373924\n28 KhedrM, CooperM, HughesAT, et al. Nitisinone causes acquired tyrosinosis in alkaptonuria. J Inherit Metab Dis. 2020;43 :1014‐1023.32083330\n29 RawlingsAV. Ethnic skin types: are there differences in skin structure and function. Int J Cosmet Sci. 2006;28 :79‐93.18492142\n30 TadokoroT, KobayashiN, ZmudzkaBZ, et al. UV induced DNA damage and melanin content in human skin differing in racial/ethnic origin. FASEB J. 2003;10 :1177‐1179.\n31 RoseDP, CrampDG. Reduction of plasma tyrosine by oral contraceptives and oestrogens: a possible consequence of tyrosine aminotransferase induction. Clin Chim Acta. 1970;29 :49‐53.5500691\n32 First Treatment for Rare Metabolic Disorder Alkaptonuria. https://www.ema.europa.eu/en/news/first-treatment-rare-metabolic-disorder-alkaptonuria. Accessed May 24, 2021.\n\n",
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"keywords": "alkaptonuria; homogentisic acid; nitisinone; proton‐pump inhibitors; tyrosine; vitiligo",
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"title": "Vitiligo, alkaptonuria, and nitisinone-A report of three families and review of the literature.",
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"abstract": "Immune checkpoint inhibitors (ICIs) are now widely used to many malignant diseases, but some patients suffer from immune-related adverse events during or after ICI treatments. The monoclonal antibody infliximab is usually chosen as a salvage treatment to combat corticosteroid-resistant adverse events, but infliximab is not recommended as a response to hepatitis because of the potential risk of liver failure. An alternative treatment option has not been established. We treated a head and neck cancer patient (a 50-year-old Japanese male) who suffered from corticosteroid-resistant hepatitis during treatment with nivolumab, an anti-PD-1 ICI, and that was recovered by mycophenolate mofetil salvage therapy.",
"affiliations": "Department of Medical Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan.;Department of Medical Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan.;Department of Medical Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan.;Department of Medical Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan.;Department of Medical Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan.;Department of Head and Neck Surgery, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan.;Department of Medical Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan.",
"authors": "Nakano|Kenji|K|0000-0002-3721-004X;Nishizawa|Masatoshi|M|;Fukuda|Naoki|N|;Urasaki|Tetsuya|T|;Wang|Xiaofei|X|;Mitani|Hiroki|H|;Takahashi|Shunji|S|",
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"doi": "10.1093/omcr/omaa027",
"fulltext": "\n==== Front\nOxf Med Case Reports\nOxf Med Case Reports\nomcr\nOxford Medical Case Reports\n2053-8855 Oxford University Press \n\n32477577\n10.1093/omcr/omaa027\nomaa027\nCase Report\nMycophenolate mofetil as a successful treatment of corticosteroid-resistant immune checkpoint inhibitor-induced hepatitis\nhttp://orcid.org/0000-0002-3721-004XNakano Kenji 1 Nishizawa Masatoshi 1 Fukuda Naoki 1 Urasaki Tetsuya 1 Wang Xiaofei 1 Mitani Hiroki 2 Takahashi Shunji 1 1 \nDepartment of Medical Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan\n2 \nDepartment of Head and Neck Surgery, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan\nCorrespondence address. Department of Medical Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Ariake, Tokyo 135-8550, Japan. Tel: +81-3-3520-0111; Fax: +81-3-3520-0141; E-mail: kenji.nakano@jfcr.or.jp\nApr-May 2020 \n23 5 2020 \n23 5 2020 \n2020 4-5 omaa02718 2 2020 7 3 2020 8 4 2020 © The Author(s) 2020. Published by Oxford University Press.2020This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nImmune checkpoint inhibitors (ICIs) are now widely used to many malignant diseases, but some patients suffer from immune-related adverse events during or after ICI treatments. The monoclonal antibody infliximab is usually chosen as a salvage treatment to combat corticosteroid-resistant adverse events, but infliximab is not recommended as a response to hepatitis because of the potential risk of liver failure. An alternative treatment option has not been established. We treated a head and neck cancer patient (a 50-year-old Japanese male) who suffered from corticosteroid-resistant hepatitis during treatment with nivolumab, an anti-PD-1 ICI, and that was recovered by mycophenolate mofetil salvage therapy.\n\nimmune-related adverse eventhead and neck cancernivolumabmycophenolate\n==== Body\nINTRODUCTION\nImmune checkpoint inhibitors (ICIs) have become the standard treatment options for many malignant diseases [1]. As treatments for head and neck cancer, the anti-programmed death-1 (PD-1) antibodies nivolumab and pembrolizumab provided prolonged overall survival in clinical trials [2, 3].\n\nThe safety profiles of ICIs differ from those of other antitumor drugs, and the adverse events that occur specifically in ICI treatments are categorized as immune-related adverse events (irAEs) [4]. Systemic corticosteroids are usually considered for treating irAEs, but an appropriate alternative option to corticosteroid-resistant liver toxicity has not been established [5].\n\nHere we report the clinical sequence of a head and neck cancer patient who suffered from severe irAEs including liver toxicity during nivolumab treatment. The liver toxicity was resistant to corticosteroid, and the subsequent addition of mycophenolate mofetil (MMF) to the corticosteroid succeeded in improving the patient’s liver function.\n\nCASE PRESENTATION\nThe patient was a 50-year-old Japanese male diagnosed with laryngeal cancer. The clinical stage was IVB (cT4N2cM0), and he underwent curative surgery, i.e. a total pharyngolaryngectomy and bilateral neck dissection. After the surgery, a CT scan revealed liver and pancreatic lesions which had been not observed before surgery, and the liver biopsy revealed squamous cell carcinoma that corresponded to the carcinoma of the larynx. The patient had a history of hepatitis B, and HB antigen was still positive (HBV-DNA was negative); entecavir prophylaxis was therefore started, and the combination of cetuximab, 5-fluorouracil, and cetuximab were administered with a partial response. After 9 months, recurrences in multiple lymph nodes were observed, and nivolumab 3 mg/kg every 2 weeks was started. The patient’s disease was stable while receiving nivolumab with no signs of disease progression. At the 13th cycle of nivolumab, the patient complained of fatigue, and his lab data showed that the levels of both cortisol and adrenocorticotropic hormone (ACTH) were low. Oral prednisolone (PSL) 5 mg/day was thus prescribed. The PSL prescription improved the patient’s fatigue, and the 14th cycle of nivolumab was administered with PSL continuation.\n\nHowever, 2 weeks later the patient came to the hospital with complaints of diarrhea, systemic skin rash and fever, and he was hospitalized immediately. At admission, the patient’s performance status was ECOG 2, fatigue and diarrhea were grade 2, and systemic and severe grade 3 rashes were seen; bullous dermatitis in mucosa was not observed. Lab tests revealed that the patient’s cortisol and ACTH levels were still low and that hepatic transaminases were increased (AST 363 U/L and ALT 246 U/L); such increases had been not shown by the lab tests 2 weeks earlier. CT and abdominal echography did not show the progression of liver metastases or biliary obstruction.\n\nSoon after the patient’s hospitalization, high-dose methylprednisolone (mPSL) 500 mg/day was intravenously administered, and his skin lesions and diarrhea immediately recovered. However, his hepatic transaminase levels had exacerbated during the mPSL therapy, and total bilirubin (T-Bil) and alkaline phosphatase (ALP) were also increased. Thus, after 3 days of mPSL pulse therapy, we added MMF 2000 mg/day to the intravenous PSL continuation, and a liver biopsy was planned. The biopsy on the sixth day of hospitalization revealed lymphocyte infiltration to Glisson’s capsule and piecemeal necrosis, which were consistent with hepatitis due to nivolumab treatment. On day 31 of hospitalization, the patient’s liver function test results had recovered to grade 0, and we began to gradually reduce the MMF and PSL. The patient was discharged with oral MMF 1500 mg/day and PSL 30 mg/day on day 68 of hospitalization. These drugs’ dosages were gradually reduced in the outpatient setting; the MMF was terminated on the 25th day from the discharge and the PSL was continued at 10 mg/day after that. The treatment sequence following nivolumab treatment is provided in Fig. 1.\n\nFigure 1 The treatment sequence of the patient, a 51-year-old male. The changes in the patient’s liver function test data following nivolumab treatment are also shown. ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; MMF, mycophenolate mofetil; PSL, prednisolone; T-Bil, total bilirubin.\n\nThe radiographic evaluation after the patient’s discharge showed tumor progression in multiple lymph node metastases, and palliative radiotherapy was performed; ICIs or other systemic chemotherapies were not administered, concerning about the recurrence of irAEs. The patient finally died of the laryngeal cancer progression at 16.3 months after the nivolumab induction, 9.7 months after the hospitalization due to irAEs.\n\nDISCUSSION\nDuring and after ICI treatments, irAEs can occur in organs all over the body, and the prevalence and severity of irAEs are different in injured organs [4], and the reported incidence of liver injury induced by ICIs is 3.5% [6].\n\nIn our present patient, multiple irAEs of skin lesions, endocrine abnormality and diarrhea were observed simultaneously. Most of these irAEs were rapidly improved by high-dose corticosteroid therapy, and only the patient’s liver dysfunction worsened despite the corticosteroid therapy.\n\nMMF is a purine antagonist that inhibits the proliferation of lymphocytes and considered to be effective against autoimmune hepatitis that is resistant to corticosteroids [7]. Thus, MMF is considered to have the potential to be a treatment option for corticosteroid-resistant immune-related hepatitis induced by an ICI and shown as an option to corticosteroid-resistant hepatitis in the clinical guideline [5]. There are case reports of the successful treatment of hepatotoxicity due to ICI treatment by the addition of MMF to corticosteroid therapy [8, 9].\n\nAn additional concern in our patient’s case was that he was an HBV carrier and under a continued entecavir regimen. In our patient’s case, an HBV-DNA assay was conducted at the occurrence and multiple times during the treatment of the irAEs, but the HBV-DNA status was never positive regardless of the patient’s liver function disorders.\n\nIt cannot be denied that hepatitis B could be a risk factor for the liver injury that is induced by ICIs, but our patient’s hepatitis was not the reactivation of HBV. A small randomized trial of HBV carriers with idiopathic nephrotic syndrome indicated that MMF treatment did not cause HBV reactivation compared to corticosteroid [10].\n\nWe have reported a case of severe irAEs (particularly immune-related hepatitis that was resistant to corticosteroids) which was successfully treated with MMF. The provision of our patient’s treatment sequence herein may contribute to the optimal treatment of other patients with ICI-induced hepatitis that is resistant to corticosteroids and requires other salvage therapies, e.g. MMF.\n\nDISCLOSURE STATEMENT\nThe authors have no conflicts of interests to declare.\n\nACKNOWLEDGEMENTS\nWe thank all the staff members of the Departments of Medical Oncology and Head and Neck Surgery at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research for diagnosing and treating the patient.\n\nFUNDING\nNone.\n\nETHICAL APPROVAL\nNo specific ethical approval was required.\n\nCONSENT\nWritten informed consent was obtained from the patient for submission of this manuscript.\n\nGUARANTOR\nK.N. is the guarantor of this article.\n==== Refs\nREFERENCES\n1. \nRibas A , Wolchok JD \nCancer immunotherapy using checkpoint blockade\n. Science 2018 ;359 :1350 –5\n. doi: 10.1126/science.aar4060 .29567705 \n2. \nFerris RL , Blumenschein G Jr, Fayette J , Guigay J , Colevas AD , Licitra L et al. \nNivolumab for recurrent squamous-cell carcinoma of the head and neck\n. N Engl J Med 2016 ;375 :1856 –67\n. doi: 10.1056/NEJMoa1602252 .27718784 \n3. \nBurtness B , Harrington KJ , Greil R , Soulières D , Tahara M , de Castro G Jret al. \nKEYNOTE-048 investigators. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study\n. Lancet 2019 ;394 :1915 –28\n. doi: 10.1016/S0140-6736(19)32591-7 .31679945 \n4. \nBaxi S , Yang A , Gennareli RL , Khan N , Wang Z , Boyce L et al. \nImmune-related adverse events for anti-PD1- and anti-PD-L1 drugs: systematic review and meta-analysis\n. BMJ 2018 ;360 :k793 . doi: 10.1136/bmj.k793 .29540345 \n5. \nBrahmer JR , Lacchetti C , Schneider BJ , Atkins MB , Brassil KJ , Caterino JM et al. \nNational Comprehensive Cancer Network. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline\n. J Clin Oncol 2018 ;36 :1714 –68\n. doi: 10.1200/JCO.2017.77.6385 .29442540 \n6. \nDe Martin E , Michot JM , Papouin B , Champiat S , Mateus C , Lambotte O et al. \nCharacterization of liver injury induced by cancer immunotherapy using immune checkpoint inhibitors\n. J Hepatol 2018 ;68 :1181 –90\n. doi: 10.1016/j.jhep.2018.01.033 .29427729 \n7. \nHeneghan MA , McFarlane IG \nCurrent and novel immunosuppressive therapy for autoimmune hepatitis\n. Hepatology 2002 ;35 :7 –13\n. doi: 10.1053/jhep.2002.30991 .11786954 \n8. \nTanaka R , Fujisawa Y , Sae I , Maruyama H , Ito S , Hasegawa N et al. \nSevere hepatitis arising from ipilimumab administration, following melanoma treatment with nivolumab\n. Jpn J Clin Oncol 2017 ;47 :175 –8\n. doi: 10.1093/jjco/hyw167 .28173241 \n9. \nDoherty GJ , Duckworth AM , Davies SE , Mells GF , Brais R , Harden SV et al. \nSevere steroid-resistant anti-PD1 T-cell checkpoint inhibitor-induced hepatotoxicity driven by biliary injury\n. ESMO Open 2017 ;2 :e000268 . doi: 10.1136/esmoopen-2017-000268 .29081991 \n10. \nLi X , Tian J , Wu J , He Q , Han F , Li Q et al. \nA comparison of a standard-dose prednisone regimen and mycophenolate mofetil combined with a lower prednisone dose in Chinese adults with idiopathic syndrome who were carriers of hepatitis B surface antigen: a prospective cohort study\n. Clin Ther 2009 ;31 :741 –50\n. doi: 10.1016/j.clinthera.2009.04.011 .19446147\n\n",
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"issue": "2020(4)",
"journal": "Oxford medical case reports",
"keywords": "head and neck cancer; immune-related adverse event; mycophenolate; nivolumab",
"medline_ta": "Oxf Med Case Reports",
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"pubdate": "2020-04",
"publication_types": "D016428:Journal Article",
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"title": "Mycophenolate mofetil as a successful treatment of corticosteroid-resistant immune checkpoint inhibitor-induced hepatitis.",
"title_normalized": "mycophenolate mofetil as a successful treatment of corticosteroid resistant immune checkpoint inhibitor induced hepatitis"
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"abstract": "B cells may be involved in the pathophysiology of multiple sclerosis (MS). Inebilizumab (formerly MEDI-551) binds to and depletes CD19+ B cells.\n\n\n\nTo assess safety, tolerability, pharmacokinetics, pharmacodynamics and immunogenicity of inebilizumab in adults with relapsing MS.\n\n\n\nThis phase 1 trial randomised 28 patients 3:1 (21, inebilizumab; 7, placebo) to inebilizumab (2 intravenous (IV) doses, days 1 and 15: 30, 100 or 600 mg; or single subcutaneous (SC) dose on day 1: 60 or 300 mg) or matching placebo, with follow-up until at least week 24 or return of CD19+ B-cell count to ⩾80 cells/µL.\n\n\n\nComplete B-cell depletion was observed across all doses. Infusion/injection (grade 1/2) reactions occurred in 6/15 patients receiving inebilizumab IV, 2/5 placebo IV and 1/6 inebilizumab SC. Serious adverse events occurred in three patients receiving inebilizumab: pyrexia, mixed-drug intoxication (unrelated to inebilizumab; resulted in death) and urinary tract infection. Mean number of cumulative new gadolinium-enhancing lesions over 24 weeks was 0.1 with inebilizumab versus 1.3 with placebo; mean numbers of new/newly enlarging T2 lesions were 0.4 and 2.4, respectively.\n\n\n\nInebilizumab had an acceptable safety profile in relapsing MS patients and showed a trend in reductions in new/newly enlarging and gadolinium-enhancing lesions.",
"affiliations": "Department of Neurology, University of California, Davis, CA, USA/VA Northern California Health Care System, Sacramento, CA, USA; Multiple Sclerosis Center, Barrow Neurological Institute, Phoenix, AZ, USA.;Neuro-Care, Katowice, Poland.;KMK-Clinical Sp. z o.o., NZOZ Rawa-Med, Katowice, Poland.;Osrodek Badan Klinicznych Indywidualnej Specjalistycznej Praktyki Lekarskiej, Szczecin, Poland.;MedImmune, Mountain View, CA, USA.;MedImmune, Gaithersburg, MD, USA/Alexion Pharmaceuticals, Lexington, MA, USA.;MedImmune, Gaithersburg, MD, USA.;MedImmune, Gaithersburg, MD, USA.;MedImmune, Cambridge, UK.;MedImmune, Gaithersburg, MD, USA.;MedImmune, Gaithersburg, MD, USA.",
"authors": "Agius|Mark A|MA|;Klodowska-Duda|Gabriela|G|;Maciejowski|Maciej|M|;Potemkowski|Andrzej|A|;Li|Jing|J|;Patra|Kaushik|K|;Wesley|Jacob|J|;Madani|Soraya|S|;Barron|Gerard|G|;Katz|Eliezer|E|;Flor|Armando|A|",
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"fulltext": "\n==== Front\nMult SclerMult. SclerMSJspmsjMultiple Sclerosis (Houndmills, Basingstoke, England)1352-45851477-0970SAGE Publications Sage UK: London, England 10.1177/135245851774064110.1177_1352458517740641Original Research PapersSafety and tolerability of inebilizumab (MEDI-551), an anti-CD19 monoclonal antibody, in patients with relapsing forms of multiple sclerosis: Results from a phase 1 randomised, placebo-controlled, escalating intravenous and subcutaneous dose study Agius Mark A Department of Neurology, University of California, Davis, CA, USA/VA Northern California Health Care System, Sacramento, CA, USA; Multiple Sclerosis Center, Barrow Neurological Institute, Phoenix, AZ, USAKlodowska-Duda Gabriela Neuro-Care, Katowice, PolandMaciejowski Maciej KMK-Clinical Sp. z o.o., NZOZ Rawa-Med, Katowice, PolandPotemkowski Andrzej Osrodek Badan Klinicznych Indywidualnej Specjalistycznej Praktyki Lekarskiej, Szczecin, PolandLi Jing MedImmune, Mountain View, CA, USAPatra Kaushik MedImmune, Gaithersburg, MD, USA/Alexion Pharmaceuticals, Lexington, MA, USAWesley Jacob MedImmune, Gaithersburg, MD, USAMadani Soraya MedImmune, Gaithersburg, MD, USABarron Gerard MedImmune, Cambridge, UKKatz Eliezer MedImmune, Gaithersburg, MD, USAFlor Armando MedImmune, Gaithersburg, MD, USAMultiple Sclerosis Center, Barrow Neurological Institute, 240 West Thomas Road, Suite #400, Fourth Floor, Phoenix, AZ 85013, USA. mark.agius@dignityhealth.org16 11 2017 2 2019 25 2 235 245 2 6 2017 15 9 2017 19 9 2017 © The Author(s), 20172017SAGE PublicationsThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Background:\nB cells may be involved in the pathophysiology of multiple sclerosis (MS). Inebilizumab (formerly MEDI-551) binds to and depletes CD19+ B cells.\n\nObjectives:\nTo assess safety, tolerability, pharmacokinetics, pharmacodynamics and immunogenicity of inebilizumab in adults with relapsing MS.\n\nMethods:\nThis phase 1 trial randomised 28 patients 3:1 (21, inebilizumab; 7, placebo) to inebilizumab (2 intravenous (IV) doses, days 1 and 15: 30, 100 or 600 mg; or single subcutaneous (SC) dose on day 1: 60 or 300 mg) or matching placebo, with follow-up until at least week 24 or return of CD19+ B-cell count to ⩾80 cells/µL.\n\nResults:\nComplete B-cell depletion was observed across all doses. Infusion/injection (grade 1/2) reactions occurred in 6/15 patients receiving inebilizumab IV, 2/5 placebo IV and 1/6 inebilizumab SC. Serious adverse events occurred in three patients receiving inebilizumab: pyrexia, mixed-drug intoxication (unrelated to inebilizumab; resulted in death) and urinary tract infection. Mean number of cumulative new gadolinium-enhancing lesions over 24 weeks was 0.1 with inebilizumab versus 1.3 with placebo; mean numbers of new/newly enlarging T2 lesions were 0.4 and 2.4, respectively.\n\nConclusion:\nInebilizumab had an acceptable safety profile in relapsing MS patients and showed a trend in reductions in new/newly enlarging and gadolinium-enhancing lesions.\n\nB cellsintravenous administrationpharmacodynamicspharmacokineticssubcutaneous administration\n==== Body\nIntroduction\nMultiple sclerosis (MS) is a chronic, immune-mediated disease of the central nervous system (CNS) with focal, multifocal and diffuse inflammation characterised by demyelination and gliosis as a result of immune cell infiltration across the blood–brain barrier. The neurologic signs and symptoms of the disease are highly variable and dependent upon the location of lesions in the CNS. Disability accumulates over time and may include cognitive deficits and motor impairments.\n\nAlthough MS is considered to be a disorder involving primarily T cells, an increasing body of evidence now supports a role of B cells in the pathogenesis of MS through antibody-dependent and antibody-independent mechanisms.1–3 Patients suffering from severe relapses who fail to respond to treatment with high-dose corticosteroids benefit from plasmapheresis,4 thus suggesting a role of the humoral response in the disease. Regulatory B cells secreting interleukin (IL)-10, an immunoregulatory cytokine that downregulates the immune response and controls inflammation, are found in lower numbers in the peripheral blood of MS patients than in healthy controls.5 A higher clinical progression rate has been found in patients with relapsing and secondary progressive MS who possess high B-cell and low monocyte numbers in the cerebrospinal fluid (CSF).6 In addition to antibody production, B cells also play a key role in antigen presentation in experimental autoimmune encephalomyelitis (EAE) models. CNS-resident B cells also have been shown to induce cytokine production and activation of infiltrating T cells.3\n\nB-cell depletion therapy with anti-CD20 monoclonal antibodies, such as rituximab and ocrelizumab, has shown clinical benefit in patients with relapsing-remitting MS.7,8 During B-cell development, CD20 is expressed on pro-B cells through memory B cells. CD19 is expressed at an earlier stage in B-cell development, appearing on early pro-B cells, and persists through maturation to plasmablasts and some plasma cells (PCs).9,10 The clinical implications of this differential expression of CD19 are not known. Preclinical data suggest that the elimination of CD19+ plasmablasts and some PCs could provide a greater clinical effect in B-cell–driven autoimmune diseases.11 Patients with MS were shown to have greater numbers of CD19+ B cells in the blood than healthy controls.12 Short-lived plasmablasts expressing CD19 have been suggested to be a primary effector B-cell population involved in ongoing active inflammation in patients with MS.3,13 Therefore, there is a scientific rationale for depleting CD19+ B cells in patients with relapsing forms of MS.\n\nInebilizumab (formerly MEDI-551; MedImmune, Gaithersburg, MD, USA), a humanised, afucosylated IgG1κ monoclonal antibody, binds to and depletes CD19+ B cells.14 Afucosylation of inebilizumab results in an approximately 10-fold increased affinity for the activating Fcγ receptor IIIA and significantly enhances antibody-dependent cellular cytotoxicity of effector cells. In a mouse EAE model, administration of inebilizumab reduced the incidence and severity of disease and prevented the development of EAE when given prior to induction.15 This phase 1 dose escalation study was designed to determine the safety and tolerability profile of ascending intravenous (IV) and subcutaneous (SC) doses of inebilizumab in patients with relapsing forms of MS.\n\nMethods\nThis was a multicentre, randomised, blinded, placebo-controlled, dose escalation, phase 1 study (clinicaltrials.gov identifier: NCT01585766). The primary end point was safety and tolerability of ascending IV and SC doses of inebilizumab. Secondary end points included evaluations of pharmacokinetics, pharmacodynamics and immunogenicity. Exploratory objectives included evaluation of the effect of inebilizumab on magnetic resonance imaging (MRI) outcomes, including the number of new gadolinium (Gd)-enhancing lesions and the number of new or newly enlarging T2 lesions, relapse, Expanded Disability Status Scale (EDSS) scores and tetanus titres. An independent data monitoring and safety committee was established to review safety data on an ongoing basis and to provide guidance on trial continuation, modification or termination.\n\nPatients\nEligible patients were aged 18–65 years with confirmed relapsing forms of MS defined by the McDonald 2010 criteria,16 with at least one relapse (Appendix 1) in the last 3 years, EDSS score ⩽6.5, normal baseline CD19 B-cell count (>80 cells/μL) and no more than 20 Gd-enhancing lesions on MRI. Key exclusion criteria were abnormal liver function tests and low immunoglobulin, neutrophil, platelet, haemoglobin or total lymphocyte counts. In addition, patients who had received at any time total lymphoid irradiation, cladribine, mitoxantrone, cyclophosphamide or T-cell vaccination were excluded, as were patients who had received monthly treatment with a corticosteroid as disease modification for relapsing MS or who had received an IV or high-dose oral corticosteroid for an MS exacerbation within 30 days prior to the study.\n\nThe following washout periods were required for prior medications: 1 month for interferon beta and glatiramer acetate; 3 months for fingolimod, dimethyl fumarate, intravenous immunoglobulin therapy and plasmapheresis; 6 months for cyclosporine, azathioprine, methotrexate, mycophenolate and teriflunomide; 1 year for patients who received natalizumab for more than 3 months; and 1 year for monoclonal antibodies.\n\nDesign and treatment\nFollowing a screening period of up to 28 days, patients were randomised as follows. The investigator or designee entered eligible subjects’ names and relevant information into an interactive voice-response system (IVRS). The IVRS then assigned subjects in a 3:1 ratio in six cohorts to receive inebilizumab 30, 100 or 600 mg IV on days 1 and 15, or inebilizumab 60 or 300 mg SC on day 1, or matching placebo (Figure 1). Study site personnel and patients were blinded to treatment; the study sponsor’s staff members were not blinded. Patients who received IV inebilizumab were premedicated with IV methylprednisolone 100 mg or equivalent, oral acetaminophen 500–650 mg or equivalent, and oral diphenhydramine 25–50 mg or equivalent 30–60 minutes prior to infusion to reduce risk of possible infusion reactions. The study comprised three study periods: screening (day −28 to day −1), treatment/follow-up (day 1 to day 169) and long-term follow-up for B-cell recovery (day 170 to 18 months or longer).\n\nFigure 1. Study design. The number of patients in each group included those who received inebilizumab and those who received placebo. The SC cohorts received inebilizumab or placebo on day 1 only; the IV cohorts received inebilizumab or placebo at days 1 and 15. Long-term follow-up occurred for patients with reduced B-cell counts at week 24.\n\nIV: intravenous; LTFU: long-term follow-up; SC: subcutaneous.\n\nStudy outcomes and procedures\nSafety and tolerability were assessed by evaluation of adverse events (AEs) and serious AEs (SAEs) for each dose and for the route of administration, as well as by laboratory evaluations and physical examinations. Blood was collected before dosing for pharmacokinetic analysis at weeks 0, 1, 2, 4, 8, 12, 16, 20 and 24; in the IV cohorts, blood was also collected after dosing for pharmacokinetic analysis at weeks 0 and 2. Blood was collected for B-cell count, B-cell subsets and immunoglobulins (including total immunoglobulin, immunoglobulin G (IgG), IgM, IgA and IgE) at weeks 0, 2, 4, 8, 12, 16, 20 and 24, and during long-term follow-up. Blood was collected for analysis of anti-inebilizumab antibodies at weeks 0, 4, 12 and 24 and every 3 months thereafter during long-term follow-up.\n\nPatients were followed until their CD20 B-cell counts returned to the lower limit of normal (80 cells/µL) or baseline; patients who did not meet these criteria at 24 weeks entered long-term follow-up for B-cell repletion. Because the presence of inebilizumab in samples interferes with CD19-based detection of B cells by flow cytometry, both CD19+ and CD20+ B cells were measured in this study.\n\nThe effect of inebilizumab on reductions in the number of PCs was evaluated using the PC gene signature method, a robust, sensitive and accurate measure of PCs in clinical samples.17 The relative change in PC numbers was evaluated by whole-genome microarray analysis of blood samples obtained at various time points following treatment.\n\nCranial MRI with and without Gd contrast was performed at screening and at weeks 4, 8, 12, 16, 20 and 24 for cohort 1 only (30 mg IV) and at weeks 12, 16, 20 and 24 for cohorts 2 through 5. All scans were sent to a central MRI laboratory where a blinded read was performed for the interpretation used for analysis. The EDSS scores were assessed at weeks 0, 12 and 24 and at relapse.\n\nStatistical analysis\nSample sizes were based on clinical judgement but not on statistical criteria as done in a typical phase 1 study. The analysis of the study results was based on the safety population, which included all patients who received any amount of investigational product. A non-compartmental pharmacokinetic analysis was performed. The proportion of patients free of new inflammatory activity (i.e. no Gd-enhancing lesions and no new or newly enlarging T2 lesions) and the proportion of patients who were relapse free were calculated. Safety, pharmacokinetic, pharmacodynamic and clinical activity data were summarised descriptively.\n\nEthical considerations\nThe study was conducted in accordance with the principles of the Declaration of Helsinki, the International Conference on Harmonisation guidelines on good clinical practice, any applicable laws and requirements, and any conditions required by local regulatory authorities and/or institutional review boards. All patients provided written informed consent.\n\nResults\nPatients\nA total of 28 patients were randomised into the following treatment groups: inebilizumab 30 mg IV (n = 6), inebilizumab 60 mg SC (n = 3), inebilizumab 100 mg IV (n = 3), inebilizumab 300 mg SC (n = 3), inebilizumab 600 mg IV (n = 6), and placebo IV or SC (n = 7). In all, 27 patients, 20 in the inebilizumab groups overall and 7 in the placebo group, completed the protocol-defined treatment period (day 169/week 24) (Figure 2); one patient in the inebilizumab 30-mg IV group died during the study. Of the 27 patients who completed week 24, 1 patient (14.3%) in the IV or SC placebo group and 20 patients (95.2%) in the inebilizumab groups (5 patients in the 30-mg IV group; 3 each in the 60-mg SC, 100-mg IV and 300 mg-SC groups; and 6 in the 600-mg IV groups) entered long-term follow-up for B-cell recovery monitoring. Patient demographics and baseline disease characteristics are summarised in Table 1. Briefly, most patients were female and White (68% and 82%, respectively). The median baseline EDSS score was 4.0 (range, 0–6.5), the mean number of Gd-enhancing lesions at baseline was 0.9 (range, 0–4), and the mean absolute CD19+ B-cell count was 215.5 cells/μL (range, 83.5–693.0). Patients in the inebilizumab group had a higher number of Gd-enhancing lesions, a greater volume of T2 lesions and a higher EDSS score at baseline than the placebo group (Table 1).\n\nFigure 2. Patient disposition. In all, 28 patients were randomised, 27 patients completed through end of treatment (day 169/week 24) and 24 patients completed the study.\n\naSubject did not complete the study owing to investigator decision.\n\nIV: intravenous; SC: subcutaneous.\n\nTable 1. Patient demographics and baseline characteristics.\n\nParameter\tPlacebo (n = 7)\tTotal inebilizumab (n = 21)\tTotal (N = 28)\t\nAge, median (range), years\t42 (21–62)\t44 (28–65)\t44 (21–65)\t\nFemale, n (%)\t6 (86)\t13 (62)\t19 (68)\t\nMale, n (%)\t1 (14)\t8 (38)\t9 (32)\t\nRace, n (%)\t\n White\t5 (71)\t18 (86)\t23 (82)\t\n Black\t2 (29)\t1 (5)\t3 (11)\t\n Other/multiple\t0\t2 (9)\t2 (7)\t\nAge at MS symptom onset, median (range), years\t26 (14–50)\t30 (21–60)\t30 (14–60)\t\nAge at MS diagnosis, median (range), years\t33 (17–59)\t33 (22–63)\t33 (17–63)\t\nEDSS score, median (range)\t3.0 (1.5–5.0)\t4.0 (0–6.5)\t4.0 (0–6.5)\t\nNumber of Gd+ lesions, mean (SD)\t0.4 (1.13)\t1.1 (1.30)\t0.9 (1.27)\t\nVolume of T2 brain lesions, median (range), cm3\t6.46 (1.54–26.56)\t14.44 (1.25–55.92)\t12.31 (1.25–55.92)\t\nCD19+ cell absolute count, median (range), cells/µL\t146.5 (83.5–281.0)\t216.5 (101.0–693.0)\t215.5 (83.5–693.0)\t\nPrior disease-modifying therapies\t\n Antineoplastic agentsa\t0\t1 (6)\t1 (5)\t\n Antipsoriaticsb\t0\t1 (6)\t1 (5)\t\n Corticosteroids (systemic use)c\t1 (33)\t3 (19)\t4 (21)\t\n Immunoglobulins\t0\t1 (6)\t1 (5)\t\n Immunostimulantsd\t3 (100)\t13 (81)\t16 (84)\t\n Immunosuppressantse\t0\t5 (31)\t5 (26.3%)\t\nEDSS: Expanded Disability Status Scale; Gd+: gadolinium-enhancing; MS: multiple sclerosis; SD: standard deviation.\n\na Chlormethine hydrochloride.\n\nb Fumaric acid.\n\nc Methylprednisolone, prednisone.\n\nd Albumin (human + glucose + interferon beta), glatiramer acetate, interferon, interferon beta and interferon beta-1a.\n\ne Azathioprine, ciclosporin, fingolimod, natalizumab.\n\nSafety, tolerability and immunogenicity\nMost treatment-related AEs observed in the inebilizumab treatment groups up to week 24 were single events. The most frequently seen AEs in the inebilizumab group included nasopharyngitis (24%), upper respiratory tract infection (19%), urinary tract infection (14%), urinary tract inflammation (14%), pyrexia (14%) and increased blood pressure (14%). Treatment-related AEs observed in at least 10% of all patients are summarised in Table 2. Infusion-related reactions were observed in 6/15 (40%) patients receiving IV inebilizumab and 2/5 (40%) receiving IV placebo; injection-related reactions were observed in 1/6 (17%) patients receiving SC inebilizumab and no patients receiving SC placebo. Most injection and infusion reactions were grade 1 (4 patients in the inebilizumab groups and 1 in the placebo group) or grade 2 (2 patients in the inebilizumab groups and 1 in the placebo group) in severity; one grade 2 injection-related reaction was observed in the inebilizumab 300-mg SC group.\n\nTable 2. Treatment-related adverse events in ⩾10% of patients at 24 weeks.\n\nParameter\tPlacebo (n = 7)\tTotal inebilizumab (n = 21)\t\nTotal number of events\t4\t37\t\nNumber of patients reporting events, n (%)\t3 (43)\t13 (62)\t\nEvent, number of patients (%)\t\n Pyrexia\t0\t2 (10)\t\n Nasopharyngitis\t0\t2 (10)\t\n Oral herpes\t0\t2 (10)\t\n Increased blood pressure\t0\t2 (10)\t\nInfections were observed in two patients (29%) receiving placebo, four (80%) receiving inebilizumab 30 mg IV, one (33%) receiving inebilizumab 60 mg SC, three (75%) receiving inebilizumab 100 mg IV, three (100%) receiving inebilizumab 300 mg SC and two (33%) receiving inebilizumab 600 mg IV and did not appear to be related to the inebilizumab dose. Most infections were grade 1 or grade 2 in severity; only one patient receiving inebilizumab 600 mg IV had a grade 3 urinary tract infection that was not related to study drug. No AEs resulted in discontinuation of treatment. Three SAEs occurred in three patients in the inebilizumab group, including pyrexia (n = 1), urinary tract infection (n = 1) and accidental mixed-drug intoxication (n = 1; resulted in death), and one SAE occurred in one patient in the placebo group (MS relapse). The death occurred 133 days after the last dose of inebilizumab (30 mg IV) and was assessed by the investigator to be due to an accidental mixed-drug intoxication that was not related to inebilizumab (see Appendix 2).\n\nA decrease was seen in total immunoglobulin levels in inebilizumab-treated patients. The mean percentage decrease from baseline in total immunoglobulin at week 24 was −10.5% for inebilizumab-treated patients and −0.1% for the placebo group. A reduction was observed in all immunoglobulin subtypes (IgA, IgE, IgG, IgM) and was greatest for the IgM subtype. At the 18-month follow-up, the mean decrease in total immunoglobulin was −15.0% in the inebilizumab group. The total immunoglobulin levels did not fall below the normal range in any study patient. No change was seen in tetanus titres between baseline and week 24 in either the inebilizumab or the placebo group. Anti-inebilizumab antibodies were not detected in any patients receiving inebilizumab or placebo.\n\nPharmacokinetics and pharmacodynamics\nInebilizumab pharmacokinetic parameters are summarised in Table 3. The terminal elimination phases were parallel in all dose groups. A dose-proportional increase in maximum observed concentration and in area under the concentration–time curve was observed for all dose levels (Figure 3). The mean systemic clearance appeared to be independent of dose levels for both IV and SC cohorts. The median half-life of inebilizumab was 16 days (range, 11–25 days), and the calculated bioavailability using non-compartmental analysis was 58% and 46% following a single 60-mg and 300-mg SC dose, respectively. A rapid decline in CD20 B-cell counts was observed for all inebilizumab IV and the inebilizumab 300-mg SC dose groups, whereas a slower decline was observed with the 60-mg SC dose group (Figure 4). Overall, higher inebilizumab doses caused longer duration of B-cell depletion. The median time for B-cell return to lower limit of normal (80 cells/µL) or baseline after a sign of recovery was similar across dose cohorts (range, 196–277 days). Circulating PCs as measured by the PC gene signature in whole blood also were reduced following inebilizumab administration across all doses (Figure 5).\n\nTable 3. Pharmacokinetic parameters for inebilizumab.\n\nInebilizumab dose, mg\tRoute\t\nn\n\tCmax, µg/mL\tAUC0-last, µg d/mL\tAUC0-inf, µg d/mL\tCL or CL/F, mL/d\tT½, day\tF, %\t\n30\tIV\t5\t17.9 (13.2)\t436a\t440a\t139a\t17.7a\tNA\t\n100\tIV\t4b\t43.1 (11.4)\t1140 (278)\t1150 (286)\t181 (44.5)\t17.7 (6.3)\tNA\t\n600\tIV\t6\t248.0 (66.8)\t6850 (1340)\t6950 (1430)\t180 (41.5)\t18.7 (2.0)\tNA\t\n60\tSC\t3\t6.7 (2.9)\t197 (92.6)\t201 (91.5)\t351 (177)\t12.3 (1.7)\t58\t\n300\tSC\t3\t24.7 (9.4)\t788 (455)\t794 (453)\t457 (214)\t15.1 (4.3)\t46\t\nAUC0-inf: area under the concentration–time curve extrapolated to infinity after dosing; AUC0-last: area under the concentration–time curve from 0 to the last quantifiable concentration; CL: systemic clearance; CL/F: apparent clearance after extravascular administration; Cmax: maximum observed concentration; F: bioavailability; IV: intravenous; NA: not applicable; SC: subcutaneous; T½: terminal elimination half-life.\n\na Standard deviation was not calculated with two patients in the 30-mg cohort. Two patients who received only one dose and one patient with insufficient data to calculate parameters were excluded.\n\nb Parameters were calculated from three patients by excluding one patient who received lower dose.\n\nFigure 3. Mean inebilizumab concentrations versus time. Data below the lower limit of quantification (LLOQ) (0.1 µg/mL; as shown by dashed line) are plotted at half of the LLOQ, for illustrative purposes only. Error bars represent standard deviation of the mean. Arrows indicate dosing events (IV on days 1 and 15; SC on day 1).\n\nIV: intravenous; LLOQ: lower limit of quantification; SC: subcutaneous.\n\nFigure 4. Median CD20 B-cell counts over time following inebilizumab administration. Data after week 24 reflect only patients who had not achieved B-cell repletion. Data used to calculate median value were collected from ⩾2 patients. *One subject in the 60-mg SC cohort and two subjects in the 600-mg IV cohort did not fully reach repletion to the lower limit of normal during the long-term follow-up period and received other standard-of-care MS therapies.\n\nIV: intravenous; SC: subcutaneous.\n\nFigure 5. Effect of inebilizumab on plasma cell signature in whole blood. Mean values are plotted. Signature scores were calculated by determining the median fold change of the panel of genes at each time point for each subject within a dose cohort. Results were reported as fold change in PC signature compared with the value at baseline (pretreatment) with the baseline value set to 1. Values <1 represent depletion of the PC signature, and values >1 represent an increase in the PC signature compared with pretreatment levels.\n\nPC: plasma cells; WB: Western blot.\n\nMRI outcomes by week 24\nThe mean number of cumulative new Gd-enhancing lesions was 0.1 (standard deviation (SD) = 0.30) in the inebilizumab group versus 1.3 (SD = 1.38) in the placebo group (Figure 6). The mean number of new or newly enlarging T2 lesions was 0.4 (SD = 0.94) in the inebilizumab group versus 2.4 (SD = 3.26) in the placebo group. The proportion of patients free of new inflammatory activity (i.e. no new Gd-enhancing lesions and no new or newly enlarging T2 lesions) was 75% in the inebilizumab group versus 43% in the placebo group.\n\nFigure 6. Magnetic resonance imaging outcomes by week 24.\n\nGd+: gadolinium-enhancing.\n\nRelapses and EDSS scores\nOne patient who received placebo experienced a protocol-defined MS relapse. No protocol-defined relapses were seen in the inebilizumab group. The median EDSS score did not change in either treatment group.\n\nDiscussion\nThe role of B cells in the pathogenesis of MS has been increasingly appreciated lately.7,8,18 Experimental evidence suggests that CD19+ B-cell levels in the blood are elevated in patients with MS12 and that CD19+ plasmablasts are associated with ongoing inflammation in MS.13 Studies with anti-CD20 antibodies have demonstrated that B-cell depletion may be an important therapeutic approach to MS.7,8,18 In this study, inebilizumab, a novel anti-CD19 antibody, exhibited durable pharmacodynamic effects in which circulating B cells (as measured by immunocytochemistry/flow cytometry) and PCs (as measured by the PC gene signature) were rapidly depleted.14 Inebilizumab is the first anti-CD19 monoclonal antibody to be tested in MS patients, and one could hypothesise that it may be more efficacious than anti-CD20 antibodies such as rituximab, ocrelizumab and ofatumumab due to its targeting of a larger spectrum of B cells. However, at this time, it is unknown whether targeting CD19+ B cells will translate into any difference in clinical efficacy relative to targeting CD20+ B cells.\n\nThe phase 1 study reported here was conducted in patients with relapsing forms of MS to assess the safety of inebilizumab and to analyse its pharmacokinetic and pharmacodynamic profile. In this phase 1 study (n = 28), inebilizumab appeared to have an acceptable safety and tolerability profile during the period tested.\n\nThe median half-life of inebilizumab was 16 days, which is shorter than expected for an IgG antibody (≈21 days);19 the shorter half-life of inebilizumab is probably due to afucosylation, although the small number of patients and a high mannose level (8.4%) on the inebilizumab antibody may also be contributing factors. Rapid B-cell depletion was observed at all inebilizumab doses except the 60-mg SC dose. B-cell depletion, duration of depletion remaining ⩾90% from baseline, and time to start of recovery were dose dependent, with most dose groups maintaining 90% depletion throughout the 24-week follow-up period. Patients who received inebilizumab SC had slower depletion of the PC signature than patients who received inebilizumab IV; however, no dose-dependent relationship was observed in the extent of depletion of the PC signature.\n\nThe inebilizumab-treated patients developed notably fewer new Gd-enhancing and new or newly enlarging T2 MRI lesions. This finding is consistent with what has been observed with other B-cell depleters evaluated in relapsing forms of MS.7 It is notable that, at baseline, patients in the inebilizumab group had a higher number of Gd-enhancing lesions (1.1 vs 0.4), a greater volume of T2 lesions (14.44 vs 6.46 cm3) and a higher EDSS score (4.0 vs 3.0) than the placebo group. However, owing to the small sample size, no conclusions can be reached from this study regarding the drug’s effect on relapse rate, MRI outcomes and EDSS scores. No changes were seen in EDSS score at week 24, probably owing to the short duration of the study and small sample sizes. Larger studies would be needed to evaluate the effect of inebilizumab on clinical outcomes in relapsing MS, such as the relapse rate and the proportion of patients who experience disability progression.\n\nThe authors thank John Ratchford, MD, for his involvement in the analysis and interpretation of the data and for his critical review of the manuscript; Wenliang Yao, PhD, for his assistance with the biostatistical analysis; Martin Schwickart for his involvement in the peripheral blood analyses; Sarah Sweeny for project management of the study; and Katie Streicher, PhD, for plasma cell gene signature data; all with MedImmune.\n\nDeclaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: The University of California at Davis received funding, with M.A.A. as principal investigator, for the conduct of this study. M.A.A. has also served as a consultant for Novartis, Roche, Sanofi and Serono and has received research funding from Biogen, Celgene, Novartis, Roche and Sanofi. G.K.-D. has received research funding for the conduct of this study and has had travel, accommodation and/or investigator meeting expenses paid by MedImmune. M.M. has received lecture fees from Biogen, Novartis and Merck. A.P. received research funding for the conduct of this study and has served as a consultant and on an advisory board for MedImmune. J.L., K.P., J.W., S.M., G.B., E.K. and A.F. are employees of MedImmune and may own stock and/or stock options in AstraZeneca. M.A.A., G.K.-D., M.M. and A.P. received no honoraria or other form of financial support related to the development of this manuscript.\n\nFunding: The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: This study was sponsored by MedImmune, the global biologics R&D arm of AstraZeneca. Medical writing and editorial support were provided by Amy Zannikos, PharmD, of Peloton Advantage, LLC (Parsippany, NJ) and were funded by MedImmune.\n\nAppendix 1\nRelapse criteria\nThree types of clinical relapses were defined in the study: protocol-defined clinical relapse, non–protocol-defined clinical relapse and suspected clinical relapse. A protocol-defined clinical relapse required that the patient be seen within 7 days of onset, verified by the treating investigator and independently observed as a change in Expanded Disability Status Scale (EDSS) by the examining investigator. A new symptom or worsening of an old symptom attributable to multiple sclerosis (MS) must have been present, accompanied by a change in the neurologic examination (defined as ⩾0.5 increase in the EDSS over the last scheduled or unscheduled visit, a 2-point change in one functional system, or a 1-point change in two functional systems, except for bladder and cognitive changes), lasting at least 24 hours in the absence of fever and preceded by stability or improvement for at least 30 days. A non–protocol-defined clinical relapse was similar to a protocol-defined clinical relapse, except that the patient was not seen within the 7-day window. A suspected clinical relapse was a relapse that failed to meet the above criteria but that may have been a relapse; that is, all circumstances point to a relapse, but upon examination by the investigator, no residual or change in the EDSS was noted.\n\nAppendix 2\nAccidental mixed-drug intoxication fatal event\nThe subject who suffered the fatal accidental mixed-drug intoxication had a medical history that included relapsing-remitting MS, anxiety, depression, prior suicide attempts via overdose with prescription medication, necrotising pneumonitis, seizure, avascular necrosis of the hips with two left-hip replacements, pulmonary embolism, mild asthma, hyperlipidaemia, hysterectomy, osteoarthritis, factor 5 Leiden deficiency, gastroesophageal reflux disease, migraine headache, urinary tract infections and seasonal allergies. The subject received two doses of inebilizumab (30 mg inebilizumab IV), on day 1 and day 15. On day 56, the subject had an accidental opioid overdose that lasted 7 days. A second and fatal accidental drug intoxication event occurred on day 134. The autopsy attributed the cause of death to mixed-drug intoxication resulting in accidental fatal overdose. Blood levels for morphine and cyclobenzaprine were somewhat elevated. It appeared that the subject had taken these medications in excess of the prescription instructions; however, the blood levels and remaining pill counts did not suggest deliberate overdose. The death was assessed as not related to investigational product by the investigator.\n==== Refs\nReferences\n1 \nBaranzini SE Jeong MC Butunoi C et al \nB cell repertoire diversity and clonal expansion in multiple sclerosis brain lesions . J Immunol \n1999 ; 163 : 5133 –5144 .10528220 \n2 \nDuddy M Niino M Adatia F et al \nDistinct effector cytokine profiles of memory and naive human B cell subsets and implication in multiple sclerosis . J Immunol \n2007 ; 178 : 6092 –6099 .17475834 \n3 \nProbstel AK Sanderson NS Derfuss T. \nB cells and autoantibodies in multiple sclerosis . Int J Mol Sci \n2015 ; 16 : 16576 –16592 .26197319 \n4 \nFaissner S Nikolayczik J Chan A et al \nPlasmapheresis and immunoadsorption in patients with steroid refractory multiple sclerosis relapses . J Neurol \n2016 ; 263 : 1092 –1098 .27039388 \n5 \nKnippenberg S Peelen E Smolders J et al \nReduction in IL-10 producing B cells (Breg) in multiple sclerosis is accompanied by a reduced naive/memory Breg ratio during a relapse but not in remission . J Neuroimmunol \n2011 ; 239 : 80 –86 .21940055 \n6 \nCepok S Jacobsen M Schock S et al \nPatterns of cerebrospinal fluid pathology correlate with disease progression in multiple sclerosis . Brain \n2001 ; 124 : 2169 –2176 .11673319 \n7 \nHauser SL Waubant E Arnold DL et al \nB-cell depletion with rituximab in relapsing-remitting multiple sclerosis . N Engl J Med \n2008 ; 358 : 676 –688 .18272891 \n8 \nKappos L Li D Calabresi PA et al \nOcrelizumab in relapsing-remitting multiple sclerosis: A phase 2, randomised, placebo-controlled, multicentre trial . Lancet \n2011 ; 378 : 1779 –1787 .22047971 \n9 \nLeBien TW Tedder TF. \nB lymphocytes: How they develop and function . Blood \n2008 ; 112 : 1570 –1580 .18725575 \n10 \nOtero DC Anzelon AN Rickert RC \nCD19 function in early and late B cell development: I. Maintenance of follicular and marginal zone B cells requires CD19-dependent survival signals . J Immunol \n2003 ; 170 : 73 –83 .12496385 \n11 \nChen D Gallagher S Monson NL et al \nInebilizumab, a B cell-depleting anti-CD19 antibody for the treatment of autoimmune neurological diseases: Insights from preclinical studies . J Clin Med \n2016 ; 5 : E107 .27886126 \n12 \nHabib J Deng J Lava N et al \nBlood B cell and regulatory subset content in multiple sclerosis patients . J Mult Scler \n2015 ; 2 : 139 .\n13 \nCepok S Rosche B Grummel V et al \nShort-lived plasma blasts are the main B cell effector subset during the course of multiple sclerosis . Brain \n2005 ; 128 : 1667 –1676 .15800022 \n14 \nHerbst R Wang Y Gallagher S et al \nB-cell depletion in vitro and in vivo with an afucosylated anti-CD19 antibody . J Pharmacol Exp Ther \n2010 ; 335 : 213 –222 .20605905 \n15 \nChen D Blazek M Ireland S et al \nSingle dose of glycoengineered anti-CD19 antibody (MEDI551) disrupts experimental autoimmune encephalomyelitis by inhibiting pathogenic adaptive immune responses in the bone marrow and spinal cord while preserving peripheral regulatory mechanisms . J Immunol \n2014 ; 193 : 4823 –4832 .25281717 \n16 \nPolman CH Reingold SC Banwell B et al \nDiagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria . Ann Neurol \n2011 ; 69 : 292 –302 .21387374 \n17 \nStreicher K Morehouse CA Groves CJ et al \nThe plasma cell signature in autoimmune disease . Arthritis Rheumatol \n2014 ; 66 : 173 –184 .24431284 \n18 \nSorensen PS Lisby S Grove R et al \nSafety and efficacy of ofatumumab in relapsing-remitting multiple sclerosis: A phase 2 study . Neurology \n2014 ; 82 : 573 –581 .24453078 \n19 \nLeveque D Wisniewski S Jehl F. \nPharmacokinetics of therapeutic monoclonal antibodies used in oncology . Anticancer Res \n2005 ; 25 : 2327 –2343 .16080460\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1352-4585",
"issue": "25(2)",
"journal": "Multiple sclerosis (Houndmills, Basingstoke, England)",
"keywords": "B cells; intravenous administration; pharmacodynamics; pharmacokinetics; subcutaneous administration",
"medline_ta": "Mult Scler",
"mesh_terms": "D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting",
"nlm_unique_id": "9509185",
"other_id": null,
"pages": "235-245",
"pmc": null,
"pmid": "29143550",
"pubdate": "2019-02",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "11673319;10528220;15800022;27039388;20605905;17475834;26137596;27886126;26197319;24453078;12496385;16080460;18725575;22047971;24431284;25281717;21940055;18272891;21387374",
"title": "Safety and tolerability of inebilizumab (MEDI-551), an anti-CD19 monoclonal antibody, in patients with relapsing forms of multiple sclerosis: Results from a phase 1 randomised, placebo-controlled, escalating intravenous and subcutaneous dose study.",
"title_normalized": "safety and tolerability of inebilizumab medi 551 an anti cd19 monoclonal antibody in patients with relapsing forms of multiple sclerosis results from a phase 1 randomised placebo controlled escalating intravenous and subcutaneous dose study"
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"companynumb": "US-PFIZER INC-2019084752",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MORPHINE SULFATE"
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{
"abstract": "BACKGROUND\nThe immunologic syndrome induced by severe acute coronavirus disease 2019 (COVID-19) is yet not fully understood. Typical patterns of clinical and laboratory features match secondary hemophagocytic lymphohistiocytosis (sHLH). However, the optimal approach to COVID-19 patients testing positive for sHLH is still unclear.\nThree patients with COVID-19 are reviewed. All showed hyperinflammation and cytokine storm, necessitating intensive care treatment including mechanical ventilation.\n\n\nMETHODS\nSecondary hemophagocytic lymphohistiocytosis due to severe COVID-19; diagnosed via HScore.\n\n\nMETHODS\nA treatment regimen of methylprednisolone, pentaglobin, and anakinra was developed and administered.\n\n\nRESULTS\nOne patient survived the ICU stay. Two other patients, in whom sHLH was diagnosed too late, deceased.\n\n\nCONCLUSIONS\nA routine screening of COVID-19 patients for secondary HLH by using the HScore is feasible; especially those patients deteriorating clinically with no sufficient response to shock management might be at particular high risk. A stepwise therapeutic approach comprising corticosteroids, immunoglobulins and anakinra, accompanied by immunoadsorption, may dampen cytokine storm effects, and potentially reduce mortality.",
"affiliations": "Department of Emergency Medicine, Medical University of Vienna.;Department of Pulmonology, Clinic Penzing, Vienna Healthcare Group.;Division of Clinical Virology, Department of Laboratory Medicine, Medical University of Vienna.;Division of Clinical Virology, Department of Laboratory Medicine, Medical University of Vienna.;Department of Pulmonology, Clinic Penzing, Vienna Healthcare Group.;Department of Emergency Medicine, Medical University of Vienna.;Department of Internal Medicine I, Medical University of Vienna, Austria.;Department of Emergency Medicine, Medical University of Vienna.",
"authors": "Schnaubelt|Sebastian|S|0000-0003-0057-8200;Tihanyi|Daniel|D|;Strassl|Robert|R|;Schmidt|Ralf|R|;Anders|Sonja|S|;Laggner|Anton N|AN|;Agis|Hermine|H|;Domanovits|Hans|H|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D007070:Immunoglobulin A; D007075:Immunoglobulin M; D016756:Immunoglobulins, Intravenous; D007166:Immunosuppressive Agents; D053590:Interleukin 1 Receptor Antagonist Protein; C060166:pentaglobulin; D008775:Methylprednisolone",
"country": "United States",
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"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974\n1536-5964\nLippincott Williams & Wilkins Hagerstown, MD\n\n33761694\nMD-D-20-12636\n10.1097/MD.0000000000025170\n25170\n3\n3900\nResearch Article\nClinical Case Report\nHemophagocytic lymphohistiocytosis in COVID-19\nCase reports of a stepwise approach\nhttp://orcid.org/0000-0003-0057-8200\nSchnaubelt Sebastian MD a ∗\nTihanyi Daniel MD b\nStrassl Robert MD c\nSchmidt Ralf MD c\nAnders Sonja MD b\nLaggner Anton N. MD a\nAgis Hermine MD d\nDomanovits Hans MD a\nSaranathan. Maya\na Department of Emergency Medicine, Medical University of Vienna\nb Department of Pulmonology, Clinic Penzing, Vienna Healthcare Group\nc Division of Clinical Virology, Department of Laboratory Medicine, Medical University of Vienna\nd Department of Internal Medicine I, Medical University of Vienna, Austria.\n∗ Correspondence: Sebastian Schnaubelt, Department of Emergency Medicine, Medical University of Vienna, Waehringer Guertel 18-20, Vienna 1090, Austria (e-mail: sebastian.schnaubelt@meduniwien.ac.at).\n26 3 2021\n26 3 2021\n26 3 2021\n100 12 e2517022 12 2020\n15 2 2021\n25 2 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\nThis article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections.\n\nAbstract\n\nRationale:\n\nThe immunologic syndrome induced by severe acute coronavirus disease 2019 (COVID-19) is yet not fully understood. Typical patterns of clinical and laboratory features match secondary hemophagocytic lymphohistiocytosis (sHLH). However, the optimal approach to COVID-19 patients testing positive for sHLH is still unclear.\n\nPatient concerns:\n\nThree patients with COVID-19 are reviewed. All showed hyperinflammation and cytokine storm, necessitating intensive care treatment including mechanical ventilation.\n\nDiagnosis:\n\nSecondary hemophagocytic lymphohistiocytosis due to severe COVID-19; diagnosed via HScore.\n\nInterventions:\n\nA treatment regimen of methylprednisolone, pentaglobin, and anakinra was developed and administered.\n\nOutcomes:\n\nOne patient survived the ICU stay. Two other patients, in whom sHLH was diagnosed too late, deceased.\n\nLessons:\n\nA routine screening of COVID-19 patients for secondary HLH by using the HScore is feasible; especially those patients deteriorating clinically with no sufficient response to shock management might be at particular high risk. A stepwise therapeutic approach comprising corticosteroids, immunoglobulins and anakinra, accompanied by immunoadsorption, may dampen cytokine storm effects, and potentially reduce mortality.\n\nKeywords\n\ncoronavirus disease 2019\nhemophagocytic lymphohistiocytosis\nmacrophage activation syndrome\nOPEN-ACCESSTRUE\n==== Body\npmc Key Points\n\nSecondary hemophagocytic lymphohistiocytosis may be highly prevalent in critically-ill COVID-19 patients not responding to shock management.\n\nA stepwise treatment regimen of corticosteroids, immunoglobulins, anakinra, and immunoadsorption may dampen cytokine storm effects, and potentially reduce mortality.\n\n1 Introduction\n\nA sepsis-like clinical picture has repeatedly been reported in coronavirus disease 2019 (COVID-19), creating a yet not fully understood syndrome. Hyperinflammation, cytokine storm, and secondary hemophagocytic lymphohistiocytosis (sHLH) are discussed as aggravating factors.[1,2] Both sHLH mortality rates in non-COVID-19 patients (around 40%) and in critically-ill COVID-19 patients (around 65%) are high, and viral infections are known as sHLH triggers.[1,2] Immunosuppression has been suggested as a treatment option,[3,4] and first reports are promising.[1] In this context, more data on clinical management of sHLH triggered by COVID-19 are urgently expected\n\n2 Methods\n\n2.1 Patients\n\nWe reviewed COVID-19 patients admitted to an intensive care unit in Vienna, Austria between April and May 2020, who were diagnosed with sHLH. Patients’ clinical-, imaging-, and laboratory data (see Supplements and the supplemental figure) were assessed.\n\n2.2 SARS-CoV-2 diagnosis\n\nTesting for the presence of severe acute respiratory syndrome coronavirus 2 RNA in pharyngeal or tracheal respiratory specimens was performed by Real-Time qPCR. Positive results (Ct value >35) were confirmed by repeated testing.\n\n2.3 sHLH diagnosis\n\nsHLH was diagnosed using the HScore:[5] Nine variables are assessed: core temperature, hepato- and/or splenomegaly, number of cytopenias, levels of TG, fibrinogen, ferritin and ASAT, history of immunosuppression, and (if feasible) presence of bone marrow haemophagocytosis. A positive result yields a 93% sensitivity and 86% specificity for HLH.\n\n2.4 Immunosuppressive therapy\n\nImmunosuppressive treatment for sHLH was conducted in a stepwise approach:\n\n1. 1 g of methylprednisolone intravenously once daily for 3 days,\n\n2. 1 g/kg of Pentaglobin (50 mg/ml human plasma protein containing ≥95% of immunoglobulin [6 mg IgM, 6 mg IgA, 38 mg IgG], Biotest Corp., Dreieich, Germany) via continuous infusion over 48 hours,\n\n3. 200 mg of anakinra subcutaneously twice daily until clinical improvement. Anakinra was used as an off-label salvage treatment.\n\n2.5 Patient consent and ethical review\n\nAll data have been anonymized. Informed consent for publication of anonymized data from the patient or their relatives have been obtained. Ethical review was not necessary for case reports following local respective guidelines.\n\n2.6 Patient 1\n\nA 51-year old male (BMI 26.2) with a fever for 6 days was hospitalized due to respiratory failure and tested positive for SARS-CoV-2. Showing acute respiratory distress syndrome (ARDS), he was intubated and mechanically ventilated. Acute kidney injury (AKI) necessitated continuous renal replacement therapy (CRRT), upgraded with an immunoadsorption filter (day 5 of hospitalization) against cytokine storm. Despite noradrenaline support, the hemodynamic profile deteriorated. Dobutamine was added due to heart failure with reduced ejection fraction and impaired left ventricular function. While levosimendan, argipressin, and landiolol led to a transient clinical improvement, hemodynamics further worsened. On the 21st day of hospitalization, sHLH was diagnosed (Table 1), and immunosuppressive therapy was started with methylprednisolone for 72 hours, followed by Pentaglobin (see Methods). After 26 days of ICU treatment, hemodynamics further deteriorated, and he deceased due to multi organ failure.\n\nTable 1 Patients’ initial sHLH diagnosis details including Hscore (5) points and the subsequent course of sHLH from the day of diagnosis onwards, monitored through the Hscore.\n\n\tPatient 1\tPatient 2\tPatient 3\t\nInitial diagnosis\tParameter\tValue\tHscore points\tParameter\tValue\tHscore points\tParameter\tValue\tHscore points\t\n\ttemperature (°C)\t38.2\t33\ttemperature (°C)\t37.0\t0\ttemperature (°C)\t39\t33\t\n\torganomegaly\tliver & spleen\t38\torganomegaly\tliver\t23\torganomegaly\tliver\t23\t\n\tnumber of cytopenias\t2\t24\tnumber of cytopenias\t2\t24\tnumber of cytopenias\t2\t24\t\n\ttriglycerides (mmol/L)\t10.5\t64\ttriglycerides (mmol/L)\t6.08\t64\ttriglycerides (mmol/L)\t4.9\t64\t\n\tfibrinogen (g/L)\t4.97\t0\tfibrinogen (g/L)\t9.95\t0\tfibrinogen (g/L)\t7.03\t0\t\n\thaemophagocytosis in bone marrow aspirate\tn.a.\t0\thaemophagocytosis in bone marrow aspirate\tn.a.\t0\thaemophagocytosis in bone marrow aspirate\tn.a.\t0\t\n\tferritin (μg/L)\t9858\t50\tferritin (μg/L)\t7377\t50\tferritin (μg/L)\t3558\t35\t\n\tserum ASAT (IU/L)\t108\t19\tserum ASAT (IU/L)\t173\t19\tserum ASAT (IU/L)\t82\t19\t\n\tknown immunosuppression\tno\t0\tknown immunosuppression\tno\t0\tknown immunosuppression\tno\t0\t\ncourse of sHLH\tday of hospitalization\tHscore points\tpositive for sHLH\tday of hospitalization\tHscore points\tpositive for sHLH\tday of hospitalization\tHscore points\tpositive for sHLH\t\n\t21 (= day of sHLH diagnosis) to 23\t228\tyes\t19 (= day of sHLH diagnosis)\t180\tyes\t16 (= day of sHLH diagnosis)\t198\tyes\t\n\t24\t195\tyes\t20\t156\tno\t17 to 19\t141\tno\t\n\t25\t180\tyes\t21 to 23\t180\tyes\t20 to 22\t165\tno\t\n\t26\t195\tyes\t\t\t\t23 to 25\t141\tno\t\n\t\t\t\t\t\t\t26\t198\tyes\t\n\t\t\t\t\t\t\t27 to 28\t174\tyes\t\n\t\t\t\t\t\t\t29 to 35\t141\tno\t\n°C = degrees Celsius, μg = micrograms, ASAT = aspartate-aminotransferase, g = grams, IU = international units, L = liter, mmol = millimole, sHLH = secondary hemophagocytic lymphohistiocytosis.\n\n2.7 Patient 2\n\nDelirium and dyspnea for 4 days were reported by a 75-year old man (BMI 29.4) before he was hospitalized and tested positive for SARS-CoV-2. ARDS led to intubation, mechanical ventilation, and intermittent prone positioning. CRRT with immunoadsorption due to AKI and cytokine storm were established (3rd day of hospitalization). Deteriorating heart failure with reduced ejection fraction and intermittent noncompensatory tachycardia necessitated a treatment regimen of noradrenaline, dobutamine, agripressin, landiolol, and levosimendan, leading to a sustainable hemodynamic improvement. On the 19th day of hospitalization, sHLH was diagnosed (Table 1). Intravenous methylprednisolone was started, but before escalating the immunosuppressive therapy, fulminant pulmonary embolism occurred, not responding to systemic thrombolysis, and resulting in a fatal outcome on the 23rd day.\n\n2.8 Patient 3\n\nA 74-year old woman (BMI 19.4) was tested positive for SARS-CoV-2. Aggravating dyspnea and delirium – not manageable by noninvasive ventilation – necessitated intubation due to ARDS. Cytokine storm and AKI were present; CRRT with immunoadsorption was initiated on the 18th day. Mild noradrenaline support was necessary to sustain a stabile hemodynamics. sHLH was diagnosed on the 16th day of hospitalization (Table 1). Steps 1 to 3 of the described immunosuppressive regimen were administered (see Methods) without serious adverse events. Markers of cytokine storm and sHLH regressed, and CRRT and hemodynamic support could be stopped. After 35 days of ICU-care and negative tests for SARS-CoV-2, the patient entered a successful weaning process and was still alive at a follow-up on day 85.\n\n3 Discussion\n\n3.1 Complex pathophysiology\n\nAll 3 COVID-19 patients showed cytokine storm, and their clinical course is in line with typical clinical- (fever, hypoxia, delirium) and laboratory (hyperferritinemia, lymphopenia, elevated IL-6, and CRP) features of critically-ill COVID-19 patients in general,[3,6] and those with severe cardiac injury or coagulopathy.[3,7] A surge of inflammatory cytokines, ensuing hyperinflammation and tissue damage, is suspected as the main mechanism for multiorgan failure.[2,3,7] This suggests a considerable percentage of critically-ill COVID-19 patients suffering from sHLH, which – if left undiagnosed – could explain high mortality rates.[3,4] COVID-19 cytokine profiles resemble those in sHLH, strengthening this theory.[8]\n\n3.2 An under-diagnosed syndrome\n\nsHLH is often unrecognized and remains a diagnostic challenge. Several scoring systems have been developed.[2,9] The Hscore postulated by Fardet et al[5] makes a quick evaluation possible. So far, no randomized-controlled trials for sHLH treatment regimens are available, and data remains scarce even in the non-COVID-19 population. Immunomodulation has shown the potency to reduce mortality and was also suggested in COVID-19.[4] Cytokine storm may respond well to immunosuppressive agents such as tocilizumab (IL-6 receptor antibody) or anakinra (IL-1 receptor antagonist). Moreover, reports show a benefit of combining corticosteroids and immunoglobulins in severely-ill COVID-19 patients.[1,3,4,7,10]\n\n3.3 A stepwise treatment-approach\n\nAll our patients showed the full sHLH characteristics.[2,4,5] As discussed before,[2] we applied and suggest a three-step approach to sHLH caused by COVID-19 (see Fig. 1 and Methods): initial immune attenuation through high-dose pulsed methylprednisolone, followed by a bodyweight-adapted dose of immunoglobulins, and lastly anakinra until clinical improvement. This approach bears the benefits of a cheap and easy-to-obtain substance as the initial line of attack, followed by the stronger immunomodulatory agents. In parallel, we recommend immunoadsorption for cytokine storm dampening, especially in CRRT.\n\nFigure 1 Flowchart for the suggested diagnostic and therapeutic approach concerning secondary haemophagocytic lymphohistiocytosis (sHLH) in COVID-19 patients with refractory shock. The Hscore as published by Fardet et al[5] is used. ASAT = aspartate-aminotransferase, CRRT = continuous renal replacement therapy, SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2, TG = triglycerides.\n\nWe believe that sHLH diagnosis came too late to reverse outcomes for patients 1 and 2, whereas our approach led to a favourable outcome in patient 3 - similar as reported by Dimopoulus and colleagues.[1]\n\n3.4 Early diagnosis is key\n\nThe risk of diagnosing sHLH too late must be weighed against the potential side effects of aggressive immunosuppression,[2] such as coagulopathy after immunoglobulin application. However, we believe that routine sHLH-screening of COVID-19 patients and early goal-directed therapy can lead to improved outcomes. sHLH should especially be considered in patients deteriorating fast without sufficient response to shock management. As the magnitude of cytokine levels may not correlate with sHLH severity and since specific markers (e.g. soluble-IL-2-receptor) are often not available, trends in ferritin could be used in treatment response tracking and outcome prognostication.[2,7] Special attention should be paid to a possible rebound after treatment discontinuation.[2] First reports of sHLH treatment in COVID-19 are encouraging,[1] and results of a prospective COVID-19 sHLH cohort are expected for late 2020 (Clinical Trials-ID: NCT04347460). However, further interventional trials are needed to confirm our assumptions.\n\n4 Conclusion\n\nRoutine screening for sHLH in COVID-19 using the HScore appears reasonable; patients without sufficient response to shock management might be at particular risk. A stepwise therapeutic approach comprising corticosteroids, immunoglobulins, and anakinra, accompanied by immunoadsorption, may dampen cytokine storm effects and reduce mortality.\n\nAcknowledgments\n\nWe thank the Viennese nursing and physician staff for their continuous efforts during the ongoing pandemic.\n\nAuthor contributions\n\nConceptualization: Sebastian Schnaubelt.\n\nData curation: Sebastian Schnaubelt, Daniel Tihanyi.\n\nFormal analysis: Sebastian Schnaubelt, Daniel Tihanyi, Robert Strassl, Ralf Schmidt, Hermine Agis.\n\nInvestigation: Sebastian Schnaubelt, Robert Strassl, Sonja Anders, Hermine Agis.\n\nMethodology: Sebastian Schnaubelt, Robert Strassl, Sonja Anders, Hermine Agis.\n\nProject administration: Sebastian Schnaubelt, Sonja Anders, Hans Domanovits.\n\nResources: Sebastian Schnaubelt, Daniel Tihanyi, Robert Strassl, Ralf Schmidt.\n\nSoftware: Sebastian Schnaubelt, Robert Strassl, Ralf Schmidt.\n\nSupervision: Sonja Anders, Anton N Laggner, Hans Domanovits.\n\nValidation: Sebastian Schnaubelt, Daniel Tihanyi, Robert Strassl, Hermine Agis, Hans Domanovits.\n\nVisualization: Sebastian Schnaubelt.\n\nWriting – original draft: Sebastian Schnaubelt.\n\nWriting – review & editing: Sebastian Schnaubelt, Daniel Tihanyi, Robert Strassl, Ralf Schmidt, Sonja Anders, Anton N Laggner, Hermine Agis, Hans Domanovits.\n\nSupplementary Material\n\nSupplemental Digital Content\n\nSupplementary Material\n\nSupplemental Digital Content\n\nAbbreviations: AKI = acute kidney injury, ARDS = acute respiratory distress syndrome, BMI = body mass index, COVID-19 = coronavirus disease 2019, CRRT = continuous renal replacement therapy, HLH = hemophagocytic lymphohistiocytosis, ICU = intensive care unit, sHLH = secondary hemophagocytic lymphohistiocytosis.\n\nHow to cite this article: Schnaubelt S, Tihanyi D, Strassl R, Schmidt R, Anders S, Laggner AN, Agis H, Domanovits H. Hemophagocytic lymphohistiocytosis in COVID-19: case reports of a stepwise approach. Medicine. 2021;100:12(e25170).\n\nEven though all data have been anonymized, the surviving patient gave their consent for publication.\n\nThe authors have no conflicts of interests to disclose.\n\nThe datasets generated during and/or analyzed during the current study are not publicly available, but are available from the corresponding author on reasonable request.\n\nSupplemental digital content is available for this article.\n==== Refs\nReferences\n\n[1] Dimopoulos G Mast Q. de Markou N . Favorable Anakinra responses in severe COVID-19 patients with secondary hemophagocytic lymphohistiocytosis. Cell Host Microbe 2020;doi: 10.1016/j.chom.2020.05.007. PubMed PMID: 32411313.\n[2] Bauchmuller K Manson JJ Tattersall R . Haemophagocytic lymphohistiocytosis in adult critical care. J Intensive Care Soc 2020;21 :256–68.32782466\n[3] Misra DP Agarwal V Gasparyan AY . Rheumatologists’ perspective on coronavirus disease 19 (COVID-19) and potential therapeutic targets. Clin Rheumatol 2020;39 :2055–62.32277367\n[4] Mehta P McAuley DF Brown M . COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 2020;395 :1033–4.32192578\n[5] Fardet L Galicier L Lambotte O . Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome. Arthritis Rheumatol 2014;66 :2613–20.24782338\n[6] Chen N Zhou M Dong X . Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020;395 :507–13.32007143\n[7] McGonagle D Sharif K O’Regan A . The role of cytokines including interleukin-6 in COVID-19 induced pneumonia and macrophage activation syndrome-like disease. Autoimmun Rev 2020;19 :102537.32251717\n[8] Wan S Yi Q Fan S . Characteristics of lymphocyte subsets and cytokines in peripheral blood of 123 hospitalized patients with 2019 novel coronavirus pneumonia (NCP) 2020;doi.org/10.1101/2020.02.10.20021832.\n[9] Eloseily EM Weiser P Crayne CB . Benefit of anakinra in treating pediatric secondary hemophagocytic lymphohistiocytosis. Arthritis Rheumatol 2020;72 :326–34.31513353\n[10] Moore JB June CH . Cytokine release syndrome in severe COVID-19. Science 2020;368 :473–4.32303591\n\n",
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"abstract": "Saksenaea species are a rare cause of mucormycosis, the majority associated with cutaneous and subcutaneous infections resulting from trauma in both immunocompromised and immunocompetent individuals. Unlike other causative agents of mucormycosis, cerebral infections are exceptionally rare. We describe the first case of isolated cerebral infection by Saksenaea in a 4-year-old previously healthy male child who presented with headaches. He had no past medical history other than an episode of febrile seizures. In addition to raising the awareness of an unusual presentation of infection by Saksenaea, this case highlights the importance of pathologic examination for the prompt diagnosis of mucormycosis as well as the specific fungal identification for treatment as Saksenaea spp. may be more susceptible to posaconazole and less susceptible to amphotericin B compared to more common causes of mucormycosis.",
"affiliations": "Department of Pathology, Loma Linda University Medical Center and School of Medicine, Loma Linda, California, USA.;Department of Neurosurgery, Loma Linda University Medical Center and School of Medicine, Loma Linda, California, USA.;Division of Infectious Diseases, Department of Pediatrics, Loma Linda University Medical Center and School of Medicine, Loma Linda, California, USA.;Department of Radiology, Loma Linda University Medical Center and School of Medicine, Loma Linda, California, USA.;Department of Pathology, Loma Linda University Medical Center and School of Medicine, Loma Linda, California, USA.",
"authors": "Magaki|Shino|S|https://orcid.org/0000-0003-0433-5759;Minasian|Tanya|T|;Bork|Jane|J|;Harder|Sheri L|SL|;Deisch|Jeremy K|JK|",
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"title": "Saksenaea infection masquerading as a brain tumor in an immunocompetent child.",
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"abstract": "We report a cystic fibrosis patient infected with influenza 2009H1N1 who had persistent viral shedding and clinical deterioration despite prolonged treatment with oseltamivir and zanamivir. The patient was diagnosed with H275Y neuraminidase inhibitor resistant influenza during treatment, thus was treated for 10 days with DAS181, an investigational host-directed inhaled sialidase fusion protein. Viral clearance occurred after 5 days of therapy and the patient became eligible for lung transplantation. Although the patient succumbed prior to receiving a transplant, this case exemplifies the potential utility of a host-directed approach against influenza which has potential to become resistant to neuraminidase inhibitors.",
"affiliations": "Department of Medicine, Division of Infectious Diseases, University of Pittsburgh, Pittsburgh, PA, USA.",
"authors": "Silveira|Fernanda P|FP|;Abdel-Massih|Rima|R|;Bogdanovich|Tatiana|T|;Pakstis|Diana L|DL|;Routh|Rebecca L|RL|;Moss|Ronald B|RB|",
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"abstract": "In Gaucher disease (GD), enzyme replacement therapy (ERT) results in the alleviation of hematological abnormalities and visceral infiltration as well as improvement in quality of life and life-span. However, several years may be required for skeletal manifestations, which are usually observed in type 1 and 3 GD, to respond to ERT. Infants with type 2 GD rarely present skeletal manifestations because most of these patients die within the first 2 years of life before they develop skeletal involvement. The use of ERT may prolong the lifespan of these patients and influence the natural history of the disease. The present study reports a new natural history of treated GD in which a 2-year and 7-month-old girl with type 2 GD who was receiving ERT developed valproate-induced Fanconi syndrome, pathological fractures, and pyogenic osteomyelitis. In conclusion, skeletal disease may occur in any type of GD, and Fanconi syndrome may lead to severe skeletal complications in patients with GD.",
"affiliations": "Department of Pediatrics, Shiga Medical Center for Children, Moriyama, Shiga 524-0022, Japan. Electronic address: anri520@msn.com.;Department of Pediatrics, Shiga Medical Center for Children, Moriyama, Shiga 524-0022, Japan.;Department of Pediatrics, Shiga Medical Center for Children, Moriyama, Shiga 524-0022, Japan.;Department of Pediatrics, Shiga Medical Center for Children, Moriyama, Shiga 524-0022, Japan.;Department of Pediatrics, Shiga Medical Center for Children, Moriyama, Shiga 524-0022, Japan.;Department of Pediatrics, Shiga Medical Center for Children, Moriyama, Shiga 524-0022, Japan.;Department of Pediatrics, Shiga Medical Center for Children, Moriyama, Shiga 524-0022, Japan.;Department of Pediatrics, Shiga Medical Center for Children, Moriyama, Shiga 524-0022, Japan.",
"authors": "Hayashi|Anri|A|;Kawakita|Rie|R|;Kumada|Tomohiro|T|;Nozaki|Fumihito|F|;Hiejima|Ikuko|I|;Miyajima|Tomoko|T|;Kusunoki|Takashi|T|;Fujii|Tatsuya|T|",
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"keywords": "Fanconi syndrome; Gaucher disease; Pathological fracture; Pyogenic osteomyelitis",
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"mesh_terms": "D000927:Anticonvulsants; D002675:Child, Preschool; D056947:Enzyme Replacement Therapy; D005198:Fanconi Syndrome; D005260:Female; D005269:Femur; D005598:Fractures, Spontaneous; D005776:Gaucher Disease; D006801:Humans; D008279:Magnetic Resonance Imaging; D010019:Osteomyelitis; D014635:Valproic Acid",
"nlm_unique_id": "7909235",
"other_id": null,
"pages": "830-3",
"pmc": null,
"pmid": "24412634",
"pubdate": "2014-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pathological fracture and pyogenic osteomyelitis in a patient with type 2 Gaucher disease.",
"title_normalized": "pathological fracture and pyogenic osteomyelitis in a patient with type 2 gaucher disease"
} | [
{
"companynumb": "JP-FRESENIUS KABI-FK201502961",
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"abstract": "Osteoporotic patients being treated with bisphosphonates present an interesting dilemma when removing hardware such as dynamic hip screws \"DHS\". In this paper, we describe the case of a 66-year-old osteoporotic patient who was placed on long term bisphosphonate therapy after sustaining an intertrochanteric hip fracture which was stabilized with a DHS. She presented with a subtrochantric fracture on the ipsilateral side. She was planned for DHS removal and intramedullary nailing. Removal of the dynamic hip screw proved to be difficult, likely due to possible cold welding of the DHS to the barrel of the side plate and sclerotic bone formation around the hardware secondary to the extended bisphosphonate use. The patient had an intra-operative femoral neck fracture while attempting the DHS removal. We had to convert to an unanticipated total hip replacement. Careful considerations should be taken when removing hardware from patients on long term bisphosphonate treatment.",
"affiliations": "Department of Orthopedic Surgery, McGill University Health Centre, Montreal, Canada.;Department of Experimental Surgery, McGill University Health Centre, Montreal, Canada.;Department of Orthopedic Surgery, King Abdulaziz University, Jeddah, Saudi Arabia.;Division of Orthopaedic Surgery, Jewish General Hospital and McGill University, Canada.;Division of Orthopaedic Surgery, Jewish General Hospital and McGill University, Canada.",
"authors": "Barimani|Bardia|B|;Khan|Kashif|K|;Abduljabbar|Fahad|F|;Volesky|Monica|M|;Antoniou|John|J|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.tcr.2020.100290",
"fulltext": "\n==== Front\nTrauma Case Rep\nTrauma Case Rep\nTrauma Case Reports\n2352-6440 2352-6440 Elsevier \n\nS2352-6440(20)30014-5\n10.1016/j.tcr.2020.100290\n100290\nCase Report\nUnexpected iatrogenic fracture of the femoral neck during subtrochanteric fracture fixation in a patient on bisphosphonate treatment for osteoporosis: Case report\nBarimani Bardia bardia.barimani@mail.mcgill.caa⁎ Khan Kashif kashif.khan2@mail.mcgill.cab Abduljabbar Fahad c Volesky Monica monika.volesky@mcgill.cad Antoniou John d a Department of Orthopedic Surgery, McGill University Health Centre, Montreal, Canada.\nb Department of Experimental Surgery, McGill University Health Centre, Montreal, Canada.\nc Department of Orthopedic Surgery, King Abdulaziz University, Jeddah, Saudi Arabia.\nd Division of Orthopaedic Surgery, Jewish General Hospital and McGill University, Canada.\n⁎ Corresponding author at: Montreal General Hospital, McGill University Health Centre, 1650 Cedar Avenue, T8-200, Montreal, QC H3G 1A4, Canada. bardia.barimani@mail.mcgill.ca\n07 3 2020 \n4 2020 \n07 3 2020 \n26 10029017 2 2020 © 2020 Published by Elsevier Ltd.2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Osteoporotic patients being treated with bisphosphonates present an interesting dilemma when removing hardware such as dynamic hip screws “DHS”. In this paper, we describe the case of a 66-year-old osteoporotic patient who was placed on long term bisphosphonate therapy after sustaining an intertrochanteric hip fracture which was stabilized with a DHS. She presented with a subtrochantric fracture on the ipsilateral side. She was planned for DHS removal and intramedullary nailing. Removal of the dynamic hip screw proved to be difficult, likely due to possible cold welding of the DHS to the barrel of the side plate and sclerotic bone formation around the hardware secondary to the extended bisphosphonate use. The patient had an intra-operative femoral neck fracture while attempting the DHS removal. We had to convert to an unanticipated total hip replacement. Careful considerations should be taken when removing hardware from patients on long term bisphosphonate treatment.\n\nKeywords\nCase reportOrthopedic surgeryBisphosphonateSubtrochanteric fracture\n==== Body\nIntroduction\nSecond hip fractures are common, affecting approximately 10% of those with previous fractures [1]. The risk factors for these subsequent fractures are limited to intrinsic qualities such as age, cognitive impairments and low bone mass [2]. In contrast, there has been interest in the association between long-term bisphosphonate (BP) therapy and risk for subsequent fracture [3]. BP therapy is often commenced in patients with osteoporosis, as they increase bone density and reduce risk of future fractures. However, among other side effects such as osteonecrosis of the jaw, recent evidence from epidemiological studies suggests that BPs may also increase the risk for atypical femoral fractures due to the accumulation of micro damages and alteration in the bone turnover rate [3]. A BP-induced osteopetrosis model has been described previously [4], however to our knowledge, this implication has not yet been studied in adults.\n\nThere is limited literature on the removal of hardware from patients, especially following long term BP use, with possible BP-induced osteopetrosis leading to unforeseen complications. In this case report, we discuss an unusual complication in a 66-year-old osteoporotic female on long term BP (Alendronate) therapy that presented with an atypical subtrochanteric fracture 10 years after sustaining an intertrochanteric fracture treated with a dynamic hip screw (DHS).\n\nCase presentation\nA 66-year old osteoporotic woman presented to the emergency room with right sided hip pain following a mechanical fall. The patient provided informed consent, which followed the McGill University Health Centre guidelines for experimental investigation. The patient was exiting her car when she slipped on the ice and landed on her right side. 10 years prior to her presentation, she sustained a right intertrochanteric femur fracture which was treated with a DHS. Since then, she has been on alendronate for her osteoporosis. On examination, there was clear shortening and external rotation of the right leg, but she was neurovascularly intact. She did not sustain any head trauma or loss of consciousness.\n\nThe patient's x-ray showed a subtrochanteric fracture distal to the DHS plate (Fig. 1). She was booked for removal of the DHS followed by antegrade femoral nailing. During the operation, removal of the DHS failed with the usual technique as the side plate was cold welded to the hip screw. We resorted to using a diamond burr to cut the top of the barrel on the DHS to assist with its removal. This technique also failed and the final method attempted was helicoptering the plate out with the screw as a single unit in a counter-clockwise direction. During that maneuver, we applied excessive torque and subsequently felt a sudden give. The possibility of a fracture was confirmed by fluoroscopy and the x-ray showed an iatrogenic subcapital femoral neck fracture (Fig. 2A, B). Failure to remove the hardware and the unexpected femoral neck fracture in conjunction with the unavailability of an arthroplasty surgeon, the procedure was decided to be aborted as we were not prepared for a complex total hip arthroplasty. The incision was closed in layer and skin traction was applied. The next day and after thorough planning, the DHS was removed using a standard posterior approach with the morselization of the femoral head. The difficulty experienced with the removal of the DHS is evident by its aesthetics following removal. Subsequently a total hip replacement was performed using a long fully porous coated stem prosthesis and periprosthetic cerclage wires were added to bypass the fracture site, with good implant positioning on post op x-ray (Fig. 3).Fig. 1 Anteroposterior x-ray of right hip with periprosthetic subtrochanteric fracture distal to DHS with lateral angulation of bony fragments.\n\nFig. 1Fig. 2 Anteroposterior (A) and lateral (B) intraoperative fluoroscopy images of the right hip showing a subcapital femoral neck fracture.\n\nFig. 2Fig. 3 Anteroposterior x-ray of right hip post-total hip arthroplasty with long stem, fully porous stem and cerclage wiring.\n\nFig. 3\n\nFollowing definitive management of her hip fracture, Alendronic acid treatment was stopped. Instead, the patient was started on vitamin D, calcium, denosumab and teriparatide as for patients who have failed typical osteoporosis therapy with a follow up in 3 months with the patient's family doctor and rheumatologist. The patient was followed up in arthroplasty clinic and was mobilizing well with no difficulties or complications. Her 2-year follow-up x-ray is shown with satisfactory position of the hardware (Fig. 4).Fig. 4 2-year follow up anteroposterior x-ray of right hip post-total hip arthroplasty showing satisfactory position and no radiological evidence of malfunction.\n\nFig. 4\n\nDiscussion\nIn this report, we present an unusual case of a femoral neck fracture during subtrochanteric fracture fixation. The patient presented with symptoms of hip pain after a fall and x-ray imaging concluded a subtrochanteric fracture distal to the DHS plate previously inserted. Multiple attempts to remove the DHS device failed, with the final attempt to remove it, she had an unexpected iatrogenic femoral neck fracture leading to an eventual total hip replacement.\n\nHardware implantation is likely to cause pain post-surgery, and removal seems to be the only option for some of these patients [5]. In patients with long term BP use, the abnormal thickening of the bone makes it especially difficult to remove hardware, as seen with our patient. Hardware removal in these patients has been shown to lead to femoral neck fracture [6], likely due to osteoporosis-induced limb fragility. In our case, we report unique complications that may be associated with hardware removal on a patient being treated with long term BP use. The BP-induced osteopetrosis promoted infusion of the thickened bone around the DHS threads, making removal of the hardware very difficult.\n\nAtypical hip fractures post-BP treatment are becoming more common [3]. BPs are synthetic analogues of inorganic pyrophosphate which reduce osteoclastic bone resorption and thus reduce bone turnover. Although BPs are well known to aid in the rejuvenation of bone in osteoporotic patients, they are also associated with adverse side effects such as osteonecrosis of the jaw, musculoskeletal pain, atrial fibrillation and BP induced osteopetrosis [3,4], which increases the risk of atypical femoral fractures as seen with our case. The increased risk of femoral fractures with this drug may be due to the increased bone thickening found in the lateral cortex of these patients. In a recent case report, histological analysis of this thickened cortex found no tertrate-resistant acid phosphatase-positive osteoclasts, indicative of impaired bone resorption [7]. This may suggest that complete bone remodeling is necessary to protect the bone from atypical breaks. As BPs adhere avidly to bone, it has been found that a large reservoir of the drug accumulates with long term use. ‘Drug holidays’ every 5 years have been proposed by various studies in an attempt to reduce side effects experienced by patients on long term BPs [8].\n\nMultiple reports have been made of subtrochanteric fractures associated with long term BP use [9]. Aside from prodromal pain experienced, fractures associated with prolonged BP use have been reported to have characteristic features consisting of cortical thickening lateral to the subtrochanteric region, transverse in nature, with a medial cortical spike [7]. Kwek et al. reviewed 17 patients who sustained subtrochanteric fractures following long term BP use characteristic in nature as described above, with 9 of these patients (53%) having bilateral stress fractures [9]. Lenart et al. found distinct radiological patterns, which they described as simple oblique (<30°) fractures of the proximal femoral shaft with breaking of the cortex and thickening of the cortex [10]. Furthermore, if CT imaging is available prior to atypical femoral fractures in these patients, the findings are not consistent, but may show cortical thickening. These findings are similar to those seen in stress fractures, with evidence of callus formation and evidence of an attempt at bone repair. The most important imaging modality prior to such fractures occurring is an MRI which will show, similar to stress fractures, characteristic periosteal high signal and normal bone marrow on STIR of the lateral aspect of the femur. Additionally, increased periosteal changes and bone marrow edema with possible cortical thickening can be seen.\n\nConclusions\nThis case explains the difficulties associated with the management of periprosthetic fractures following long term BP therapy. BP induced osteopetrosis makes bone abnormally dense and increases the risk of atypical fractures. The thickening of the bone is also found to engross hardware making its removal extremely difficult as found with our case. The management of such cases require extensive pre-operative planning and anticipation of difficult removal to ensure safe and successful outcomes. Surgeons should not only consider the risk of femoral neck fractures during hardware removal, but also prepare for a different treatment option with patients on BPs.\n\nSource of funding\nNo funding was provided for this work.\n\nDeclaration of competing interest\nAll authors declare that there are no sources of actual or potential conflicts of interest.\n==== Refs\nReferences\n1 Lönnroos E. Kautiainen H. Karppi P. Hartikainen S. Kiviranta I. Sulkava R. Incidence of second hip fractures. A population-based study Osteoporos. Int. 18 2007 1279 1285 17440675 \n2 Egan M. Jaglal S. Byrne K. Wells J. Stolee P. Factors associated with a second hip fracture: a systematic review Clin. Rehabil. 22 2008 272 282 18057086 \n3 Saita Y. Ishijima M. Kaneko K. Atypical femoral fractures and bisphosphonate use: current evidence and clinical implications Ther. Adv. Chronic Dis. 6 2015 185 193 26137208 \n4 Whyte M.P. McAlister W.H. Novack D.V. Clements K.L. Schoenecker P.L. Wenkert D. Bisphosphonate-induced osteopetrosis: novel bone modeling defects, metaphyseal osteopenia, and osteosclerosis fractures after drug exposure ceases J. Bone Miner. Res. 23 2008 1698 1707 doi 10.1359/jbmr.080511 18505375 \n5 Gardenbroek T.J. Segers M.J. Simmermacher R.K. Hammacher E.R. The proximal femur nail antirotation: an identifiable improvement in the treatment of unstable pertrochanteric fractures? J. Trauma 71 2011 169 174 21818023 \n6 a Shaer J. Hileman B.M. Newcomer J.E. Hanes M.C. Femoral neck fracture following hardware removal Orthopedics 35 2012 e83 e87 22229620 \n7 Kajino Y. Kabata T. Watanabe K. Tsuchiya H. Histological finding of atypical subtrochanteric fracture after long-term alendronate therapy J. Orthop. Sci. 17 2012 313 318 21604044 \n8 Watts N.B. Diab D.L. Long-term use of bisphosphonates in osteoporosis J. Clin. Endocrinol. Metab. 95 2010 1555 1565 20173017 \n9 Kwek E.B.K. Goh S.K. Koh J.S.B. Png M.A. Howe T.S. An emerging pattern of subtrochanteric stress fractures: a long-term complication of alendronate therapy? Injury 39 2008 224 231 18222447 \n10 Lenart B.A. Lorich D.G. Lane J.M. Atypical fractures of the femoral diaphysis in postmenopausal women taking alendronate N. Engl. J. Med. 358 2008 1304 1306 18354114\n\n",
"fulltext_license": "CC BY-NC-ND",
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"issue": "26()",
"journal": "Trauma case reports",
"keywords": "Bisphosphonate; Case report; Orthopedic surgery; Subtrochanteric fracture",
"medline_ta": "Trauma Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101711730",
"other_id": null,
"pages": "100290",
"pmc": null,
"pmid": "32181318",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports",
"references": "18354114;20173017;18505375;21604044;18057086;22229620;21818023;18222447;17440675;26137208",
"title": "Unexpected iatrogenic fracture of the femoral neck during subtrochanteric fracture fixation in a patient on bisphosphonate treatment for osteoporosis: Case report.",
"title_normalized": "unexpected iatrogenic fracture of the femoral neck during subtrochanteric fracture fixation in a patient on bisphosphonate treatment for osteoporosis case report"
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"companynumb": "CA-TEVA-2020-CA-1222401",
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"occurcountry": "CA",
"patient": {
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ALENDRONIC ACID"
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"abstract": "Vardenafil is a potent phosphodiesterase-5 (PDE-5) inhibitor used in the treatment of erectile dysfunction. Several cases of stroke related to the use of PDE-5 inhibitors have been reported. Here, we describe the case of a 51-year-old man with headache and right ophthalmoplegia subsequent to vardenafil consumption. Computed tomography and magnetic resonance imaging showed a suprasellar mass with hemorrhage suggesting pituitary apoplexy. He underwent transsphenoidal resection of the pituitary mass. Histopathology confirmed the diagnosis of a necrotic pituitary adenoma with hemorrhage. This report suggests a possible association between pituitary apoplexy and vardenafil use. In patients with preexisting pituitary adenoma, vardenafil may enhance the risk of pituitary apoplexy. Although headache is the most commonly reported side effect of vardenafil, pituitary apoplexy should be considered in the differential diagnosis of a patient with headache and ophthalmoplegia subsequent to vardenafil intake.",
"affiliations": "Department of Neurosurgery, Kagawa Rosai Hospital, Marugame, Kagawa, Japan. uneda-oka@umin.ac.jp.;Department of Neurosurgery, Kagawa Rosai Hospital, Marugame, Kagawa, Japan.;Department of Neurosurgery, Kagawa Rosai Hospital, Marugame, Kagawa, Japan.;Department of Neurosurgery, Kagawa Rosai Hospital, Marugame, Kagawa, Japan.;Department of Neurological Surgery, Dentistry, and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.",
"authors": "Uneda|Atsuhito|A|0000-0001-9709-6034;Hirashita|Koji|K|;Yunoki|Masatoshi|M|;Yoshino|Kimihiro|K|;Date|Isao|I|",
"chemical_list": "D058986:Phosphodiesterase 5 Inhibitors; D014665:Vasodilator Agents; D000069058:Vardenafil Dihydrochloride",
"country": "Austria",
"delete": false,
"doi": "10.1007/s00701-018-3763-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0001-6268",
"issue": "161(1)",
"journal": "Acta neurochirurgica",
"keywords": "Phosphodiesterase-5 inhibitor; Pituitary adenoma; Pituitary apoplexy; Stroke; Vardenafil",
"medline_ta": "Acta Neurochir (Wien)",
"mesh_terms": "D000236:Adenoma; D006801:Humans; D008297:Male; D008875:Middle Aged; D058986:Phosphodiesterase 5 Inhibitors; D010899:Pituitary Apoplexy; D010911:Pituitary Neoplasms; D000069058:Vardenafil Dihydrochloride; D014665:Vasodilator Agents",
"nlm_unique_id": "0151000",
"other_id": null,
"pages": "129-131",
"pmc": null,
"pmid": "30542775",
"pubdate": "2019-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pituitary adenoma apoplexy associated with vardenafil intake.",
"title_normalized": "pituitary adenoma apoplexy associated with vardenafil intake"
} | [
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"companynumb": "JP-BAYER-2019-001897",
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{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VARDENAFIL HYDROCHLORIDE TRIHYDRATE"
},
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{
"abstract": "The purpose of the study was to evaluate the results of high-dose-rate plesiobrachytherapy for local relapse after mastectomy and radiotherapy in terms of both local control and survival.\n\n\n\nWe reviewed retrospectively 43 patients who experienced a chest wall relapse of breast cancer after local excision (22 patients) or not (21 patients). Patients were treated with an individually designed mold with four to six fractions of 3-6 Gy high-dose-rate brachytherapy, two fractions per week. Mean total dose was 24 Gy.\n\n\n\nAfter surgical resection, the 3- and 5-year local control rates were 80% and 73%, respectively. For nonresectable patients, the overall response rate was 86%, and the 3-year infield local control and chest wall local control were 51% and 26%, respectively. The 5-year survival rate was 50.5% for the whole population, 62% after surgery, and 45.4% for irresectable patients. Acute Grade 2 or 3 toxicity occurred in 43% of the patients, resolving in a few days. Two patients had a local necrosis lasting 3 to 7 months. Late toxicity was observed in 5 patients.\n\n\n\nHigh-dose-rate plesiobrachytherapy is a simple outpatient technique to treat chest wall local relapse of breast cancer. As a reirradiation technique, its tolerance is acceptable. This technique may obtain long-term local control after incomplete surgery; in case of nonresectable disease, a high response rate was observed, which might improve the quality of life of these patients.",
"affiliations": "Department of Radiation Oncology, Hôpital Saint-Louis, Paris, France.;Department of Radiation Oncology, Hôpital Saint-Louis, Paris, France. Electronic address: christophe.hennequin2@aphp.fr.;Department of Radiation Oncology, Hôpital Saint-Louis, Paris, France; Breast Disease Centre, Hôpital Saint-Louis, Paris, France.;Department of Radiation Oncology, Hôpital Saint-Louis, Paris, France.;Department of Radiation Oncology, Hôpital Saint-Louis, Paris, France.;Department of Radiation Oncology, Hôpital Saint-Louis, Paris, France.;Breast Disease Centre, Hôpital Saint-Louis, Paris, France.;Department of Radiation Oncology, Hôpital Saint-Louis, Paris, France.",
"authors": "Besson|Nadia|N|;Hennequin|Christophe|C|;Guillerm|Sophie|S|;Fumagalli|Ingrid|I|;Martin|Valentine|V|;Michaud|Sophie|S|;Texeira|Luis|L|;Quero|Laurent|L|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.brachy.2017.10.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1538-4721",
"issue": "17(2)",
"journal": "Brachytherapy",
"keywords": "Brachytherapy; Breast cancer; Mastectomy",
"medline_ta": "Brachytherapy",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001918:Brachytherapy; D001943:Breast Neoplasms; D005260:Female; D006801:Humans; D008408:Mastectomy; D008875:Middle Aged; D009336:Necrosis; D011788:Quality of Life; D011855:Radiodermatitis; D011879:Radiotherapy Dosage; D018714:Radiotherapy, Adjuvant; D012008:Recurrence; D012189:Retrospective Studies; D015996:Survival Rate; D013899:Thoracic Neoplasms; D035441:Thoracic Wall",
"nlm_unique_id": "101137600",
"other_id": null,
"pages": "425-431",
"pmc": null,
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"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Plesiobrachytherapy for chest wall recurrences of breast cancer after mastectomy and radiotherapy for breast cancer.",
"title_normalized": "plesiobrachytherapy for chest wall recurrences of breast cancer after mastectomy and radiotherapy for breast cancer"
} | [
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"companynumb": "FR-PFIZER INC-2018105226",
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"activesubstancename": "PACLITAXEL"
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{
"abstract": "Voice disorder is occasionally associated with systemic autoimmune diseases. Bamboo nodes of the vocal fold have a characteristic bamboo-shaped appearance and strongly indicate the presence of an underlying autoimmune disorder. Both mechanical and immunologic mechanisms are assumed to be involved in the pathogenesis of vocal disorder. We present a 27-year-old woman with hoarseness, sore throat, and a unilateral bamboo node of the vocal fold. Serum anti-SS-A and -SS-B antibodies were positive, but she had no systemic signs or symptoms suggestive of Sjögren's syndrome. Oral systemic glucocorticoid treatment was not effective, but surgical resection improved her hoarseness. Histopathologic findings of the resected vocal node revealed fibrosis with hyaline degeneration. Thereafter, she had no recurrence of hoarseness for 2 years. Bamboo nodes of the vocal fold may occur without definitive autoimmune diseases, although immunologic abnormalities such as autoantibody-positivity may occur.",
"affiliations": "Division of Rheumatology and Clinical Immunology, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi 329-0498, Japan; Third Department of Internal Medicine, University of Yamanashi, 1110 Shimokato, Chuo-shi, Yamanashi 409-3898, Japan. Electronic address: shanai@yamanashi.ac.jp.;Division of Rheumatology and Clinical Immunology, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi 329-0498, Japan.;Division of Rheumatology and Clinical Immunology, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi 329-0498, Japan.;Division of Rheumatology and Clinical Immunology, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi 329-0498, Japan.;Division of Rheumatology and Clinical Immunology, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi 329-0498, Japan.;Division of Rheumatology and Clinical Immunology, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi 329-0498, Japan.;Tokyo Voice Center, International University of Health and Welfare, 8-10-16 Akasaka, Minato-ku, Tokyo 107-0052, Japan.;Division of Rheumatology and Clinical Immunology, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi 329-0498, Japan.",
"authors": "Hanai|Shunichiro|S|;Sato|Takeo|T|;Akiyama|Yoichiro|Y|;Nagatani|Katsuya|K|;Nagashima|Takao|T|;Iwamoto|Masahiro|M|;Kanazawa|Takeharu|T|;Minota|Seiji|S|",
"chemical_list": "D000974:Antibodies, Antinuclear; C035356:SS-A antibodies; C035357:SS-B antibodies",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.anl.2019.07.003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-8146",
"issue": "47(4)",
"journal": "Auris, nasus, larynx",
"keywords": "Autoimmunity; Connective tissue disease; Dysphonia; Immune complex; Vocal cord lesion",
"medline_ta": "Auris Nasus Larynx",
"mesh_terms": "D000328:Adult; D000974:Antibodies, Antinuclear; D003240:Connective Tissue Diseases; D005260:Female; D006685:Hoarseness; D006801:Humans; D007818:Laryngeal Diseases; D007828:Laryngoscopy; D010612:Pharyngitis; D014827:Vocal Cords; D014832:Voice Disorders",
"nlm_unique_id": "7708170",
"other_id": null,
"pages": "706-710",
"pmc": null,
"pmid": "31337521",
"pubdate": "2020-08",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Unilateral bamboo node of the vocal fold associated with anti-SS-A and anti-SS-B antibody.",
"title_normalized": "unilateral bamboo node of the vocal fold associated with anti ss a and anti ss b antibody"
} | [
{
"companynumb": "JP-MYLANLABS-2020M1091731",
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"activesubstancename": "PREDNISOLONE"
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... |
{
"abstract": "OBJECTIVE\nOchroconis gallopava is a darkly pigmented septated fungus that rarely infects humans, almost universally immunocompromised individuals. Only one previous case has been reported of O. gallopava endophthalmitis, in which the patient progressed to a visual acuity of no light perception. The authors currently describe the first successfully treated case of O. gallopava endophthalmitis.\n\n\nMETHODS\nA 65-year-old Hispanic woman on chronic immunosuppression after a right lung transplant was admitted to the hospital for O. gallopava respiratory tract infection and was found to have bilateral endogenous endophthalmitis. Examination revealed multiple, cream-colored, chorioretinal lesions in the fundus, including one near the temporal macula in the left eye. There was no diffuse vitritis. Visual acuity was 20/30 in both eyes at presentation but dropped to 20/400 in the right eye and counting fingers at 3 feet in the left eye over the hospital course despite receiving an intravitreal injection of voriconazole in the left eye and concurrent IV amphotericin B, posaconazole, and micafungin. The patient was then treated with multiple simultaneous intravitreal amphotericin B and voriconazole injections bilaterally, as well as IV posaconazole, which was switched to IV voriconazole for improved intraocular penetration.\n\n\nRESULTS\nThe chorioretinal lesions were noted to regress with treatment. Concomitantly, the patient's respiratory status improved, and she was discharged with a visual acuity of 20/40 in the right eye and 20/60 in the left eye. The patient completed a 1-year course of oral voriconazole as an outpatient without signs of recurrent activity. Seventeen months after the initial presentation, the patient had 20/40 vision bilaterally with a residual, white, fibrotic scar at the temporal macula in the left eye.\n\n\nCONCLUSIONS\nThis report describes the first successful treatment regimen against O. gallopava endophthalmitis using a combination of intravitreal amphotericin B and voriconazole injections, as well as IV posaconazole and voriconazole, which resulted in an excellent visual outcome.",
"affiliations": "Department of Ophthalmology, Keck School of Medicine of the University of Southern California, USC Roski Eye Institute, Los Angeles, California.",
"authors": "Kim|Esther L|EL|;Patel|Sachi R|SR|;George|Meena S|MS|;Ameri|Hossein|H|",
"chemical_list": "D000935:Antifungal Agents; D000666:Amphotericin B; D065819:Voriconazole",
"country": "United States",
"delete": false,
"doi": "10.1097/ICB.0000000000000505",
"fulltext": null,
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"issn_linking": "1935-1089",
"issue": "12(4)",
"journal": "Retinal cases & brief reports",
"keywords": null,
"medline_ta": "Retin Cases Brief Rep",
"mesh_terms": "D000368:Aged; D000666:Amphotericin B; D000935:Antifungal Agents; D009877:Endophthalmitis; D015821:Eye Infections, Fungal; D005260:Female; D006801:Humans; D058449:Intravitreal Injections; D016896:Treatment Outcome; D065819:Voriconazole",
"nlm_unique_id": "101298744",
"other_id": null,
"pages": "310-313",
"pmc": null,
"pmid": "28002285",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "OCHROCONIS GALLOPAVA ENDOPHTHALMITIS SUCCESSFULLY TREATED WITH INTRAVITREAL VORICONAZOLE AND AMPHOTERICIN B.",
"title_normalized": "ochroconis gallopava endophthalmitis successfully treated with intravitreal voriconazole and amphotericin b"
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"abstract": "Cefiderocol is a new siderophore cephalosporin with activity against carbapenem-resistant gram-negative bacteria. Data on its clinical efficacy are limited to complicated urinary tract infections. We present a series of 3 patients successfully treated with cefiderocol for complicated health care-associated infections and review published case reports.",
"affiliations": "Division of Infectious Diseases & Hospital Epidemiology, University Hospital Basel and University of Basel, Basel, Switzerland.;Division of Internal Medicine, University Hospital Basel, Basel, Switzerland.;Division of Infectious Diseases & Hospital Epidemiology, University Hospital Basel and University of Basel, Basel, Switzerland.;Division of Internal Medicine, University Hospital Basel, Basel, Switzerland.;Division of Infectious Diseases & Hospital Epidemiology, University Hospital Basel and University of Basel, Basel, Switzerland.;Division of Clinical Bacteriology and Mycology, University Hospital Basel, Basel, Switzerland.;Division of Clinical Bacteriology and Mycology, University Hospital Basel, Basel, Switzerland.;Division of Infectious Diseases & Hospital Epidemiology, University Hospital Basel and University of Basel, Basel, Switzerland.;Division of Infectious Diseases & Hospital Epidemiology, University Hospital Basel and University of Basel, Basel, Switzerland.;Division of Infectious Diseases & Hospital Epidemiology, University Hospital Basel and University of Basel, Basel, Switzerland.;Division of Infectious Diseases & Hospital Epidemiology, University Hospital Basel and University of Basel, Basel, Switzerland.;Division of Infectious Diseases & Hospital Epidemiology, University Hospital Basel and University of Basel, Basel, Switzerland.",
"authors": "Zingg|Sandra|S|;Nicoletti|G Jacopo|GJ|;Kuster|Sabine|S|;Junker|Milena|M|;Widmer|Andreas|A|;Egli|Adrian|A|;Hinic|Vladimira|V|;Sendi|Parham|P|;Battegay|Manuel|M|;Bättig|Veronika|V|;Khanna|Nina|N|0000-0002-2642-419X;Tschudin-Sutter|Sarah|S|0000-0003-4875-5368",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1093/ofid/ofaa185",
"fulltext": "\n==== Front\nOpen Forum Infect Dis\nOpen Forum Infect Dis\nofid\nOpen Forum Infectious Diseases\n2328-8957 Oxford University Press US \n\n10.1093/ofid/ofaa185\nofaa185\nBrief Report\nAcademicSubjects/MED00290\nCefiderocol for Extensively Drug-Resistant Gram-Negative Bacterial Infections: Real-world Experience From a Case Series and Review of the Literature\nZingg Sandra 1 Nicoletti G Jacopo 2 Kuster Sabine 1 Junker Milena 2 Widmer Andreas 1 Egli Adrian 34 Hinic Vladimira 3 Sendi Parham 15 Battegay Manuel 1 Bättig Veronika 1 http://orcid.org/0000-0002-2642-419XKhanna Nina 1 http://orcid.org/0000-0003-4875-5368Tschudin-Sutter Sarah 16 1 \nDivision of Infectious Diseases & Hospital Epidemiology, University Hospital Basel and University of Basel, Basel, Switzerland\n2 \nDivision of Internal Medicine, University Hospital Basel, Basel, Switzerland\n3 \nDivision of Clinical Bacteriology and Mycology, University Hospital Basel, Basel, Switzerland\n4 \nApplied Microbiology Research, Department of Biomedicine, University of Basel, Basel, Switzerland\n5 \nDepartment of Orthopaedics and Traumatology, University Hospital Basel, University of Basel, Basel, Switzerland\n6 \nDepartment of Clinical Research, University Hospital Basel, Basel, Switzerland\nCorrespondence: Sarah Tschudin-Sutter, MD, MSc, Division of Infectious Diseases and Hospital Epidemiology, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland (sarah.tschudin@usb.ch).Equal contribution\n\n\n6 2020 \n21 5 2020 \n21 5 2020 \n7 6 ofaa18511 2 2020 12 5 2020 18 5 2020 10 6 2020 © The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.2020This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nCefiderocol is a new siderophore cephalosporin with activity against carbapenem-resistant gram-negative bacteria. Data on its clinical efficacy are limited to complicated urinary tract infections. We present a series of 3 patients successfully treated with cefiderocol for complicated health care–associated infections and review published case reports.\n\ncarbapenemasecase seriescefiderocoldrug-resistant gram-negativesreviewUniversity Hospital Basel and the University of Basel\n==== Body\nCefiderocol is a new siderophore cephalosporin with activity against carbapenem-resistant gram-negative bacteria, including Enterobacterales [1] and nonfermenters [2]. Its novel bacterial cell wall penetration mechanism overcomes all classes of carbapenemases [3], porin channel mutations, and efflux pump overexpression [4]. Data on the clinical efficacy of cefiderocol are limited mainly to complicated urinary tract infections [5]. Based on the results of a phase II trial [5], cefiderocol was granted US Food & Drug Administration (FDA) approval for the treatment of adult patients with complicated urinary tract infections (UTIs) caused by susceptible gram-negative bacteria with limited or no alternative treatment options in November 2019 (https://www.fda.gov/news-events/press-announcements/fda-approves-new-antibacterial-drug-treat-complicated-urinary-tract-infections-part-ongoing-effort). Clinical data on the efficacy of cefiderocol for treatment of multidrug-resistant bacterial infections involving other body sites are lacking. We present a series of 3 consecutive patients treated with cefiderocol for complicated health care–associated infections and review published clinical case reports.\n\nThe University Hospital of Basel is a tertiary care center with ~670 beds, admitting around 35 000 adult patients annually. It serves as a referral center for patients requiring specialized medical care in the northwestern part of Switzerland. We applied to Shionogi’s cefiderocol compassionate use program for 3 patients hospitalized at our institution between 12/2018 and 12/2019. Susceptibility testing for cefiderocol was performed with disk diffusion testing according to the company’s instructions. The susceptibility patterns of all other agents were reported according to the 2018 European Committee on Antimicrobial Susceptibility Testing (EUCAST) recommendations, or the 2018 Clinical and Laboratory Standards Institute (CLSI) Performance Standards for Antimicrobial Susceptibility Testing if EUCAST recommendations were not available. Susceptibility testing for cefiderocol was interpreted according to the company’s instructions. Results, as well as cefiderocol inhibition zone diameters, are presented in Table 1. Carbapenemase-encoding genes were confirmed through molecular diagnostics (Easyplex SuperBug CPE Assay, Amplex BioSystems, Giessen, Germany).\n\nTable 1. Susceptibility Patterns of Treated Gram-Negative Bacteria\n\n\tCefepim\tCeftazidim\tAztreonam\tCeftazidim/ Avibactam\tMeropenem\tImipenem\tCiprofloxacin\tTobramycin\tAmikacin\tColistin\tTige cyclin\tFosfo mycin\tCefiderocol Inhibition Zone Diameter (Interpretation)\t\nCase 1\t\t\t\t\t\t\t\t\t\t\t\t\t\t\n\nP. aeruginosa (VIM)\tR\tR\tR\tR\tR\tR\tR\tR\tR\tS\t-\tS \t24 mm (S)\t\n\nA. baumannii (OXA-23)\tR\tR\t-\tR\tR\tR\tR\tR\tR\tS\tS\tS\t23 mm (S)\t\n\nE. cloacae (KPC)\tI\tR\tR\tS\tR\tI\tR\tS\tR\tS\tS\tR\t14 mm (R)\t\nCase 2\t\t\t\t\t\t\t\t\t\t\t\t\t\t\n\nA. baumannii (OXA-40, NDM)\tR\tR\tR\tR\tR\tR\tR\tR\tR\tS\tR\tR\t18 mm (S)\t\nCase 3\t\t\t\t\t\t\t\t\t\t\t\t\t\t\n\nA. baumannii (OXA-23, OXA-58)\tR\tR\tR\tR\tR\tR\tR\tR\tI\tS\tR\tR\t20 mm (S)\t\nAbbreviations: I, intermediate; KPC, Klebsiella- pneumoniae-Carbapenemase; NDM, New-Delhi-Metallobetalactamase; OXA: oxacillinases; R, resistant; S, susceptible; VIM, Verona-Integron-Metallobetalactamase.\n\nTo identify clinical reports of cefiderocol treatment beyond the setting of clinical trials, we searched Embase and Medline for all reports published up to January 7, 2020, using the search terms “cefiderocol” or “S-649266.”\n\nAll patients included in this report are part of an ongoing cohort study on patients with carbapenemase-producing bacteria at our institution (ClinicalTrials.gov Identifier: NCT04098133), which has been approved by the local ethics committee (Ethikkommission Nordwest-und Zentralschweiz, Project-ID 2019-01548). The main characteristics of the 3 cases treated at our institution, as well as the cases identified by the literature search, are summarized in Table 2 and Supplementary Table 1. The standard dose of cefiderocol (2 g 3 times daily) was initiated in all 3 patients with normal baseline creatinine levels.\n\nTable 2. Characteristics of the 3 Cases Treated at our Institution, as Well as the Cases Identified by the Literature Search\n\nCase\tAge, y\tSex\tExposition\tDiagnosis\tPathogen(s) and Carbapenemases \tDays on Cefiderocol\tConcomitant Antibiotic Therapya\tAdverse Events\tOutcome\t\nCase 1\t29\tM\tColumbia\tAcute osteomyelitis\t\nA. baumannii (OXA-23) E. cloacae (KPC) P. aeruginosa (VIM)\t14\tCeftazidim/ avibactam, colistin\tNone\tCured\t\nCase 2\t64\tM\tSerbia\tPostoperative implant-associated surgical site infection\t\nA. baumannii (OXA-40, NDM)\t54\tCeftazidim/ avibactam (6d), colistin (14d)\tNone\tCured\t\nCase 3\t62\tM\tThailand\tPleural empyema\t\nA. baumannii (OXA-23, OXA-58)\t42\tColistin\tNone\tCured\t\nStevens et al. [6]\t46\tM\tUSA\tTertiary peritonitis\t\nP. aeruginosa (no carbapenemase detected)\t28\tNone\tNone reported\tCured\t\nContreras et al. [7]\t68\tM\tUSA\tPostoperative intra-abdominal infection\t\nK. pneumoniae (2 strains; OXA-232, NDM- 1, CTX-M-15)\t13\tPolymixin B, ceftazidim/ avibactam\tNone reported\tDiedb\t\nEdgeworth et al. [8]\t78\tF\tKuwait\tNative valve endocarditis\t\nP. aeruginosa (no carbapenemase detected)\t23\tColistin, meropenem (7d)\tNeutropenia\tCured\t\nTrecarichi et al. [9]\tAdult\tM\tItaly\tVentilator-associated pneumonia\t\nA. baumannii (no carbapenemase reported), K. pneumoniae\t14\tNone\tNone reported\tCured\t\nAlamarat et al. [10]\t15\tM\tNigeria\tChronic implant- associated osteomyelitis\t\nP. aeruginosa (NDM-1)\t95\tAztreonam (13d)\tNeutropenia\tCured\t\nAbbreviations: CTX-M-15, Cefotaximase Munich β-lactamase; d, days; F, female; KPC, Klebsiella-pneumoniae-Carbapenemase; M, male; NDM, New-Delhi-Metallobetalactamase; OXA, oxacillinases; VIM, Verona-Integron-Metallobetalactamase; y, years.\n\n\naOnly compounds with activity against gram-negative bacteria are reported. When combination therapy was not continued during the entire course of cefiderocol treatment, the number of days of combination treatment is reported in brackets.\n\n\nbDeath attributed to polymicrobial infections with vancomycin-resistant enterococci, Candida glabrata, and Clostridoides difficile.\n\nCase 1\nA 29-year-old male patient was transferred to our hospital after being hospitalized in Colombia due to a polytrauma after a motorcycle accident. He underwent surgery with external fixation of a third-degree open fracture of the tibia. At the time of repatriation, an early postoperative implant-associated polymicrobial wound infection with carbapenemase-producing Pseudomonas aeruginosa (VIM), Acinetobacter baumannii (OXA-23), and Enterobacter cloacae (KPC) was diagnosed. He underwent multiple surgeries with removal of the external fixation and osteosynthesis of the tibia. Histopathology confirmed acute osteomyelitis. Cefiderocol was started after removal of all foreign implants and was continued for 2 weeks. In addition, ceftazidime-avibactam and colistin were administered and continued for 4 weeks. No significant adverse events were recorded during treatment. A minimal drop in neutrophil count (nadir 1.13 ×109/L) was seen at the end of the therapy with cefiderocol, normalizing at a consecutive control. After an antibiotic-free interval of 2 weeks, bone biopsies showed no evidence for persistent infection. The patient underwent definite surgery with implantation of an internal fixation device after receiving preoperative antibiotic prophylaxis with single-dose colistin, ceftazidime-avibactam, and cefiderocol. By the time of hospital discharge, there was no clinical sign of recurrent infection, and blood chemistry results showed a normal C-reactive protein (CRP) level (<10 mg/L). After 8 months of follow-up, there were no clinical or radiological signs of recurrent infection at the surgical site.\n\nCase 2\nA 64-year-old male patient was transferred from a hospital in Serbia, where he was admitted with polytrauma after falling off a ladder. He underwent transpedicular stabilization Th11–L3 and external fixation of the femur. Later, internal fixation of a trans/subtrochanteric femoral fracture and osteosynthesis of a medial malleolus ankle fracture and of a periprosthetic fracture of the tibia were performed. At the time of repatriation, he was found to have an early postoperative implant-associated infection of the spine with A. baumannii (NDM, OXA-40). Cefiderocol in combination with colistin was started after surgical revision with removal of the osteosynthesis from the spine. On the 12th day of treatment, the patient developed acute renal injury (AKIN I; creatinine-increase from 70 µmol/L [0.8 mg/dL] at baseline to 140 µmol/L [1.6 mg/dL]). Colistin was stopped, and cefiderocol doses were adapted to a glomerular filtration rate of 44 mL/min (1.5 g 3 times daily). Within 1 week, renal function fully recovered. Cefiderocol was continued at a standard dose to complete 6 weeks of treatment for acute vertebral osteomyelitis. No further significant adverse events were recorded. After completion, the patient underwent osteosynthesis of the spine, and cefiderocol was discontinued on the 12th postoperative day as intraoperative biopsies remained negative. During treatment, a second episode of reversible acute kidney failure occurred, most likely associated with re-exposure to colistin, which was administered for preoperative prophylaxis. After 13 weeks of follow-up, no signs of recurrent infection at the spinal site were noted, the CRP value was normal, and radiological control revealed spinal stabilization without any signs of loosening.\n\nCase 3\nA 62-year-old male patient was repatriated from a hospital in Bangkok, Thailand, where he initially was admitted following blunt thoracic trauma with injury of the lung parenchyma, hemothorax, and serial rib fractures after a fall. He received repeated surgery and required invasive ventilation. His course was further complicated by hospital-acquired pneumonia with Klebsiella pneumoniae, XDR A. baumannii, and the development of multiple pressure ulcers. At admission to our institution, the patient was found to have left-sided pleural empyema with XDR A. baumannii (OXA-23, OXA-58) and Corynebacterium striatum. He underwent multiple surgical revisions of the pleural cavity, with consecutive detection of Candida albicans, Enterococcus faecalis, and Corynebacterium tuberculostearicum, among others. Treatment with cefiderocol in combination with colistin was initiated and complemented with daptomycin and fluconazole. After 14 days of treatment, the patient developed acute renal injury (AKIN II, creatinine increase from 40 µmol/L [0.45 mg/dL] at baseline to 122 µmol/L [1.38 mg/dL]). Colistin was discontinued, and cefiderocol doses were adjusted to a glomerular filtration rate of 58 mL/min (1.5 g 3 times daily). Renal function fully recovered within 4 days. Cefiderocol was discontinued after 14 days. After surgery for the pressure ulcer on the back, the patient was found to have histopathologically confirmed acute osteomyelitis of the processus spinosus (Th12) with detection of XDR A. baumannii. At the same time, the patient developed fever attributed to a urinary tract infection with XDR A. baumannii. A second course of cefiderocol was initiated and continued for a total duration of 6 weeks. Clinical improvement was documented (resolution of fever, normalization of CRP and leukozyte count). After 6 weeks of follow-up, no radiological signs of recurrent infection of the pleural cavity, the spinal site, or the urinary tract occurred.\n\nReview of Published Case Reports\nFive case reports were identified (Table 2): Stevens et al. [6] reported the successful treatment of a 46-year-old polymorbid patient with a polymicrobial intra-abdominal abscess after colon perforation and detection of an XDR P. aeruginosa, susceptible only to amikacin and colistin. Cefiderocol monotherapy was administered for 28 days with resolution of the abscess. Contreras et al. [7] presented a 68-year-old patient with a bloodstream infection caused by NDM-1 and OXA-48 K. pneumoniae, only susceptible to colistin and tigecycline, and vancomycin-resistant E. faecium, originating from a postoperative abscess/hematoma complicating a kidney transplant from a deceased donor. Clinical response was noted with polymyxin B, ceftazidime-avibactam, and cefiderocol. The patient died due to complicating infections with vancomycin-resistant enterococci, Candida glabrata, and Clostridoides difficile. Edgeworth et al. [8] reported a 78-year-old woman from Kuwait with hospital-acquired native aortic valve endocarditis with XDR P. aeruginosa following complications of hydronephrosis. She recovered while undergoing treatment with cefiderocol, colistin, and valve replacement. Trecarichi et al. [9] describe the case of an adult patient with glucose-6-phosphate dehydrogenase deficiency and Aarskog-Scott syndrome who was successfully treated with cefiderocol plus linezolid for hospital-acquired pneumonia with XDR A. baumannii and KPC K. pneumoniae. Finally, a first report of successful prolonged cefiderocol treatment for implant-associated chronic osteomyelitis with NDM-1 P. aeruginosa and ESBL Klebsiella pneumoniae in a 15-year-old boy was recently published by Alamarat et al. [10].\n\nDiscussion\nWe present a single-center series of 3 consecutive patients treated within the cefiderocol compassionate use program for complicated health care–associated infections (without detected bloodstream infections) with MDR gram-negative organisms. After a median follow-up time of 13 weeks (range, 6–32 weeks), treatment response without recurrence was documented for all patients.\n\nAll 3 patients received cefiderocol in combination with colistin, possibly favorably influencing the patients’ outcomes, as observed with other compounds in gram-negative infections [11]. Two patients developed acute kidney injury, which resolved after discontinuation of colistin but required dose adjustment of cefiderocol. Colistin-induced acute kidney injury is frequent, reported in ~30% of colistin-treated patients [12]. Whether combination therapy with cefiderocol represents an additional risk factor is unclear and warrants special attention. No further safety issues attributable to cefiderocol were recorded in any of the 3 cases, even after prolonged treatment of up to 54 days.\n\nIn line with our results, all case reports identified by the literature search reported cure of gram-negative infection with cefiderocol treatment. Although the results of further clinical trials investigating the efficacy of cefiderocol for treatment of severe infections with carbapenem-resistant gram-negative bacteria (NCT02714595), nosocomial pneumonia (NCT03032380), and bloodstream infections (NCT03869437) are pending, these results suggest that cefiderocol may constitute a promising treatment option for infections caused by extensively drug-resistant gram-negative bacteria, including complicated health care– and implant-associated infections.\n\nSupplementary Data\nSupplementary materials are available at Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.\n\nofaa185_suppl_Supplementary_Table Click here for additional data file.\n\n Acknowledgments\nWe thank Shionogi Limited London UK for the provision of cefiderocol.\n\n\nFinancial support. This study was funded in part by the University Hospital Basel and the University of Basel.\n\n\nPotential conflicts of interest. All authors declare no conflicts of interest relevant to this article. All authors: no reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.\n==== Refs\nReferences\n1. \nKohira N , West J , Ito A , et al. \nIn vitro antimicrobial activity of a siderophore cephalosporin, S-649266, against Enterobacteriaceae clinical isolates, including carbapenem-resistant strains\n. Antimicrob Agents Chemother 2016 ; 60 :729 –34\n.26574013 \n2. \nIto A , Kohira N , Bouchillon SK , et al. \nIn vitro antimicrobial activity of S-649266, a catechol-substituted siderophore cephalosporin, when tested against non-fermenting gram-negative bacteria\n. J Antimicrob Chemother 2016 ; 71 :670 –7\n.26645269 \n3. \nIto-Horiyama T , Ishii Y , Ito A , et al. \nStability of novel siderophore cephalosporin S-649266 against clinically relevant carbapenemases\n. Antimicrob Agents Chemother 2016 ; 60 :4384 –6\n.27139465 \n4. \nYamano Y \nIn vitro activity of cefiderocol against a broad range of clinically important gram-negative bacteria\n. Clin Infect Dis 2019 ; 69 :544 –51\n.\n5. \nPortsmouth S , van Veenhuyzen D , Echols R , et al. \nCefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infections caused by gram-negative uropathogens: a phase 2, randomised, double-blind, non-inferiority trial\n. Lancet Infect Dis 2018 ; 18 :1319 –28\n.30509675 \n6. \nStevens RW , Clancy M \nCompassionate use of cefiderocol in the treatment of an intraabdominal infection due to multidrug-resistant pseudomonas aeruginosa: a case report\n. Pharmacotherapy 2019 ; 39 :1113 –8\n.31550054 \n7. \nContreras DA , Fitzwater SP , Nanayakkara DD , et al. \nCo-infections of two strains of NDM-1 and OXA-232 co-producing Klebsiella pneumoniae in a kidney transplant patient\n. Antimicrob Agents Chemother 2020 ; 64:e00948-19. \n8. \nEdgeworth JD , Merante D , Patel S , et al. \nCompassionate use of cefiderocol as adjunctive treatment of native aortic valve endocarditis due to extremely drug-resistant Pseudomonas aeruginosa\n. Clin Infect Dis 2019 ; 68 :1932 –4\n.30418554 \n9. \nTrecarichi EM , Quirino A , Scaglione V , et al ; IMAGES Group \nSuccessful treatment with cefiderocol for compassionate use in a critically ill patient with XDR Acinetobacter baumannii and KPC-producing Klebsiella pneumoniae: a case report\n. J Antimicrob Chemother 2019 ; 74 :3399 –401\n.31369095 \n10. \nAlamarat ZI , Babic J , Tran TT , et al. \nLong term compassionate use of cefiderocol to treat chronic osteomyelitis caused by XDR-Pseudomonas aeruginosa and ESBL-producing Klebsiella pneumoniae in a pediatric patient\n. Antimicrob Agents Chemother 2020 ; 64:e01872-19 .\n11. \nSchmid A , Wolfensberger A , Nemeth J , et al. \nMonotherapy versus combination therapy for multidrug-resistant gram-negative infections: systematic review and meta-analysis\n. Sci Rep 2019 ; 9 :15290 .31664064 \n12. \nNation RL , Rigatto MHP , Falci DR , Zavascki AP \nPolymyxin acute kidney injury: dosing and other strategies to reduce toxicity\n. Antibiotics (Basel) 2019 ; 8:24 .\n\n",
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"keywords": "carbapenemase; case series; cefiderocol; drug-resistant gram-negatives; review",
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"pubdate": "2020-06",
"publication_types": "D016428:Journal Article",
"references": "27139465;30418554;30875778;31871075;31724049;31664064;31369095;26574013;31527031;31550054;30509675;26645269",
"title": "Cefiderocol for Extensively Drug-Resistant Gram-Negative Bacterial Infections: Real-world Experience From a Case Series and Review of the Literature.",
"title_normalized": "cefiderocol for extensively drug resistant gram negative bacterial infections real world experience from a case series and review of the literature"
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"... |
{
"abstract": "Pentobarbital and propofol are used for the treatment of refractory status epilepticus or elevated intracranial pressure, typically with continuous EEG monitoring. We report a series of patients who developed generalized periodic discharges related to anesthetic withdrawal (GRAWs), different from previous seizure activity. At times, this pattern was misinterpreted as recurrent seizure activity, leading to reinstitution of drug-induced coma, but resolved spontaneously without additional treatment.We identified five patients who developed GRAWs during pentobarbital or propofol withdrawal. Two patients received pentobarbital for increased intracranial pressure. One patient received pentobarbital and propofol for encephalopathy accompanied by a rhythmic EEG pattern erroneously thought to be ictal. Two patients received pentobarbital for refractory partial status epilepticus. In all cases, anesthetic agents were withdrawn after 24 to 48 hours of burst suppression on EEG. We analyzed the course of GRAWs on EEG and the associated clinical outcomes.All five patients developed GRAWs, consisting of periodic 1 to 4 Hz generalized periodic discharge, not previously seen on EEG. In all cases, the pattern eventually resolved spontaneously, over 12 to 120 hours. However, in three cases, the pattern was initially thought to represent ictal activity, and drug-induced coma was reinitiated. The pattern recurred during repeated anesthetic withdrawal, was then recognized as nonictal, and then resolved without further treatment. In all cases but one, the patients exhibited improvement to near-baseline mentation.Generalized periodic discharges related to anesthetic withdrawal may occur de novo after pentobarbital or propofol withdrawal. They should resolve spontaneously without treatment and without recurrence of clinical seizure activity. However, GRAWs are not likely to represent status epilepticus and should not prompt resumption of drug-induced coma, unless there is reappearance of original electrographic seizure activity.",
"affiliations": "*Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee, U.S.A.; †Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, U.S.A.; and ‡Department of Neurology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, U.S.A.",
"authors": "Bhatt|Amar B|AB|;Popescu|Alexandra|A|;Waterhouse|Elizabeth J|EJ|;Abou-Khalil|Bassel W|BW|",
"chemical_list": "D000777:Anesthetics",
"country": "United States",
"delete": false,
"doi": "10.1097/WNP.0000000000000051",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-0258",
"issue": "31(3)",
"journal": "Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society",
"keywords": null,
"medline_ta": "J Clin Neurophysiol",
"mesh_terms": "D000777:Anesthetics; D002648:Child; D004569:Electroencephalography; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D013226:Status Epilepticus; D013375:Substance Withdrawal Syndrome",
"nlm_unique_id": "8506708",
"other_id": null,
"pages": "194-8",
"pmc": null,
"pmid": "24887600",
"pubdate": "2014-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "11571331;15805807;17511550;1961405;10082092;8710130;10368075;22528274;18329995;8814099;9129572;15592005;2187023;2303022",
"title": "De novo generalized periodic discharges related to anesthetic withdrawal resolve spontaneously.",
"title_normalized": "de novo generalized periodic discharges related to anesthetic withdrawal resolve spontaneously"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/14/0042223",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ALPRAZOLAM"
},
"drugadditional": null,
... |
{
"abstract": "Clozapine is an atypical antipsychotic known to cause multiple hematologic abnormalities, most seriously agranulocytosis, but also notably eosinophilia. It is considered as an allergic reaction with a spontaneous remission, however, sometimes, it may predict subsequent major inflammatory complications. The aim of this study was to investigate the relationship between clozapine usage and drug-induced pneumonia based on characteristic respiratory symptoms and radiological findings, retrospectively in 69 Japanese treatment-resistant schizophrenia patients. Comparisons of the 26 weeks consecutive levels: white blood cell count with neutrophil and eosinophil, relative to their baseline levels were performed within total subjects and two groups divided by the findings of pneumonia. The crude odds ratios with 95% confidence intervals for developing pneumonia and potential confounders were calculated. The levels of eosinophils significantly increased at 1 month in each group. The introduction season between October and January and higher eosinophil level at first month were correlated with the risk of pneumonia, which occurred independent of clozapine dosage and term and relapsed in subjects when developed within initial 1 month. Clozapine-induced eosinophilic pneumonia was considered transient and reversible, however, the risks and benefits must be considered and close monitoring should be done to avoid life-threatening conditions during clozapine treatment.",
"affiliations": "Department of Psychiatric Internal Medicine, Kosekai-Kusatsu Hospital, Hiroshima.;Department of Psychiatric Internal Medicine, Sunlight Brain Research Center, Yamaguchi, Japan.",
"authors": "Nakamura|Masaru|M|;Nagamine|Takahiko|T|",
"chemical_list": "D014150:Antipsychotic Agents; D003024:Clozapine",
"country": "England",
"delete": false,
"doi": "10.1097/YIC.0000000000000311",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0268-1315",
"issue": "35(5)",
"journal": "International clinical psychopharmacology",
"keywords": null,
"medline_ta": "Int Clin Psychopharmacol",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D003024:Clozapine; D004351:Drug Resistance; D004906:Erythrocyte Count; D005260:Female; D006801:Humans; D007958:Leukocyte Count; D008297:Male; D011657:Pulmonary Eosinophilia; D012189:Retrospective Studies; D055815:Young Adult",
"nlm_unique_id": "8609061",
"other_id": null,
"pages": "285-291",
"pmc": null,
"pmid": "32282447",
"pubdate": "2020-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Eosinophilic pneumonia during treatment with clozapine: reports from a retrospective case series.",
"title_normalized": "eosinophilic pneumonia during treatment with clozapine reports from a retrospective case series"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-269237",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLOZAPINE"
},
"druga... |
{
"abstract": "Effective management of immune-related adverse events in patients receiving immunotherapy for cancer is problematic. In this report, we present the case of a 58-year-old man with advanced clear cell renal cell carcinoma who responded well to a combination of ipilimumab and nivolumab. However, after two courses of treatment, he developed fulminant hepatitis and died. An autopsy confirmed that the primary lesion in the left kidney was more than 99% necrotic with only six small residual tumor lesions. These lesions were infiltrated by large numbers of CD8-positive/TIA-1-positive lymphocytes. However, a metastatic lesion in the right kidney harbored few lymphocytes. Furthermore, the tumor cells in the metastatic lesion and one of the residual lesions showed decreased expression of HLA class I molecules, which are a prerequisite for cytotoxic T-lymphocyte-mediated immunotherapy in tumor cells. In this patient, more than 80% of hepatocytes were destroyed and the parenchyma was infiltrated with CD8-positive/TIA-1-positive lymphocytes. The patient had polyuria, which was attributed to neurohypophysitis caused by the infiltration of CD8-positive/TIA-1-positive lymphocytes. We believe that this is an instructive case for immuno-oncologists.",
"affiliations": "Department of Pathology, School of Medicine, Sapporo Medical University, Sapporo, Japan.;Department of Surgical Pathology, Sapporo Medical University Hospital, Sapporo, Japan.;Department of Pathology, School of Medicine, Sapporo Medical University, Sapporo, Japan.;Department of Urology, School of Medicine, Sapporo Medical University, Sapporo, Japan.;Department of Urology, School of Medicine, Sapporo Medical University, Sapporo, Japan.;Department of Urology, School of Medicine, Sapporo Medical University, Sapporo, Japan.;Department of Urology, School of Medicine, Sapporo Medical University, Sapporo, Japan.;Department of Urology, School of Medicine, Sapporo Medical University, Sapporo, Japan.;Department of Surgical Pathology, Sapporo Medical University Hospital, Sapporo, Japan.;Sapporo Clinical Laboratory Inc., Sapporo, Japan.;Department of Pathology, School of Medicine, Sapporo Medical University, Sapporo, Japan.;Department of Pathology, School of Medicine, Sapporo Medical University, Sapporo, Japan.;Department of Pathology, School of Medicine, Sapporo Medical University, Sapporo, Japan.;Department of Pathology, School of Medicine, Sapporo Medical University, Sapporo, Japan.;Department of Surgical Pathology, Sapporo Medical University Hospital, Sapporo, Japan.;Department of Urology, School of Medicine, Sapporo Medical University, Sapporo, Japan.;Department of Pathology, School of Medicine, Sapporo Medical University, Sapporo, Japan.",
"authors": "Kubo|Terufumi|T|https://orcid.org/0000-0001-9274-2551;Sugawara|Taro|T|;Shinkawa|Tomoyo|T|;Kurisu|Tomoyo|T|;Kouzen|Nodoka|N|;Tanaka|Toshiaki|T|;Fukuta|Fumimasa|F|;Yamasaki|Kouji|K|;Sugita|Shintaro|S|;Matsuo|Kazuhiko|K|;Morita|Rena|R|;Hirohashi|Yoshihiko|Y|;Tsukahara|Tomohide|T|;Kanaseki|Takayuki|T|;Hasegawa|Tadashi|T|;Masumori|Naoya|N|;Torigoe|Toshihiko|T|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/25785826.2020.1788229",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2578-5826",
"issue": "44(2)",
"journal": "Immunological medicine",
"keywords": "Fulminant hepatitis; autopsy; immune checkpoint inhibitor; immune-related adverse events",
"medline_ta": "Immunol Med",
"mesh_terms": null,
"nlm_unique_id": "101736847",
"other_id": null,
"pages": "136-141",
"pmc": null,
"pmid": "32634346",
"pubdate": "2021-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Fatal fulminant hepatitis induced by combined ipilimumab and nivolumab therapy despite favorable histologic response and confirmed by autopsy in a patient with clear cell renal cell carcinoma.",
"title_normalized": "fatal fulminant hepatitis induced by combined ipilimumab and nivolumab therapy despite favorable histologic response and confirmed by autopsy in a patient with clear cell renal cell carcinoma"
} | [
{
"companynumb": "JP-BRISTOL-MYERS SQUIBB COMPANY-BMS-2019-097328",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METOCLOPRAMIDE"
},
"dru... |
{
"abstract": "Classic homocystinuria is due to deficiency of cystathionine beta-synthase (CBS), a pyridoxine-dependent enzyme that, depending on the molecular variants, may be co-factor responsive. Elevated methionine is often used as the primary analyte to detect CBS deficiency (CBSD) on newborn screening (NBS), but is limited by increased detection of other biochemical disorders with less clear clinical significance such as methionine aminotransferase (MAT) I/III heterozygotes. Our state has implemented a two-tier NBS algorithm for CBSD that successfully reduced the number of MATI/III heterozygotes, yet effectively detected a mild, co-factor responsive form of CBSD. After initial diagnosis, newborns with CBSD often undergo a pyridoxine challenge with high-dose pyridoxine to determine responsiveness. Here we describe our NBS-identified patient with a mild form of pyridoxine responsive CBSD who developed respiratory failure and rhabdomyolysis consistent with pyridoxine toxicity during a pyridoxine challenge. This case highlights the need for weight-based dosing and duration recommendations for pyridoxine challenge in neonates.",
"affiliations": "Division of Pediatric Genetics, Metabolism, and Genomic Medicine, Department of Pediatrics, University of Michigan Health System, Ann Arbor, Michigan, USA.;Division of Pediatric Genetics, Metabolism, and Genomic Medicine, Department of Pediatrics, University of Michigan Health System, Ann Arbor, Michigan, USA.;Division of Genetic, Genomic, and Metabolic Disorders, Children's Hospital of Michigan, Detroit, Michigan, USA.;Metabolic Newborn Screening Laboratory, Bureau of Laboratories, Michigan Department of Health and Human Services, Lansing, Michigan, USA.;Division of Genetic, Genomic, and Metabolic Disorders, Children's Hospital of Michigan, Detroit, Michigan, USA.;Division of Pediatric Genetics, Metabolism, and Genomic Medicine, Department of Pediatrics, University of Michigan Health System, Ann Arbor, Michigan, USA.",
"authors": "Ames|Elizabeth G|EG|https://orcid.org/0000-0002-0428-1909;Scott|Anthony J|AJ|;Pappas|Kara B|KB|;Moloney|Shawn M|SM|;Conway|Robert L|RL|;Ahmad|Ayesha|A|",
"chemical_list": "D014803:Vitamin B Complex; D003541:Cystathionine beta-Synthase; D011736:Pyridoxine",
"country": "United States",
"delete": false,
"doi": "10.1002/ajmg.a.61815",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1552-4825",
"issue": "182(11)",
"journal": "American journal of medical genetics. Part A",
"keywords": "homocystinuria; hypermethioninemia; pyridoxine responsive",
"medline_ta": "Am J Med Genet A",
"mesh_terms": "D003541:Cystathionine beta-Synthase; D004305:Dose-Response Relationship, Drug; D005260:Female; D006712:Homocystinuria; D006801:Humans; D007231:Infant, Newborn; D015997:Neonatal Screening; D011379:Prognosis; D011736:Pyridoxine; D012131:Respiratory Insufficiency; D012206:Rhabdomyolysis; D014803:Vitamin B Complex",
"nlm_unique_id": "101235741",
"other_id": null,
"pages": "2704-2708",
"pmc": null,
"pmid": "32820583",
"pubdate": "2020-11",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "A cautionary tale of pyridoxine toxicity in cystathionine beta-synthase deficiency detected by two-tier newborn screening highlights the need for clear pyridoxine dosing guidelines.",
"title_normalized": "a cautionary tale of pyridoxine toxicity in cystathionine beta synthase deficiency detected by two tier newborn screening highlights the need for clear pyridoxine dosing guidelines"
} | [
{
"companynumb": "US-FRESENIUS KABI-FK202100454",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PYRIDOXINE"
},
"drugadditional": "1",
... |
{
"abstract": "OBJECTIVE\nHypothalamic-pituitary (HP) neurosarcoidosis (NS) accounts for 0.5 % cases of sarcoidosis and 1 % of HP masses. Correlative data on endocrine and neurological outcomes is lacking.\n\n\nMETHODS\nRetrospective case series and literature review of presentation, treatment and outcome of HP NS.\n\n\nRESULTS\nOur series includes 4 men, ages 34-59, followed for a median of 7.3 years (range 1.5-17). All had optic neuropathy, multiple pituitary hormone abnormalities (PHAs) and other organ involvement by sarcoidosis (lung, sino-nasal, brain/spine and facial nerve). Two patients had central diabetes insipidus and one impaired thirst with polydipsia. After treatment with high-dose glucocorticoids, optic neuropathy improved in one case and stabilized in the others. After treatment, HP lesions improved radiologically, but PHAs persisted in all cases. Review of four published series on HP NS in addition to ours yielded 46 patients, age 37 ± 11.8 years, 65 % male. PHAs consisted of anterior hypopituitarism (LH/FSH 88.8 %, TSH 67.4 %, GH 50.0 %, ACTH 48.8 %), hyperprolactinemia (48.8 %) and diabetes insipidus (65.2 %). PHAs were the first sign of disease in 54.3 % patients. Vision problems occurred in 28.3 % patients, but optic neuropathy was not well documented in previous series. Most patients (93.5 %) received high-dose glucocorticoids followed by taper; 50 % also received other immunomodulators, including methotrexate, mycophenolate mofetil, cyclosporine, azathioprine, infliximab and hydrochloroquine. Only 13 % patients showed improvement in PHAs. All-cause mortality was 8.7 %.\n\n\nCONCLUSIONS\nHP NS is a serious disease requiring multidisciplinary treatment and lifelong follow-up. Prospective multicentric studies are needed to determine a more standardized approach to HP NS and outline predictors of disease outcome.",
"affiliations": "Specialty Care, Atlanta Veterans Affairs Medical Center, Decatur, GA, USA.;Department of Neurology, Emory University, Atlanta, GA, USA.;Division of Endocrinology, Department of Medicine, Emory University, 1365 B Clifton Rd., NE, B6209, Atlanta, GA, 30322, USA. aioachi@emory.edu.",
"authors": "Anthony|Jeremy|J|;Esper|Gregory J|GJ|;Ioachimescu|Adriana|A|",
"chemical_list": "D005938:Glucocorticoids; D007155:Immunologic Factors",
"country": "United States",
"delete": false,
"doi": "10.1007/s11102-015-0678-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1386-341X",
"issue": "19(1)",
"journal": "Pituitary",
"keywords": "Hypopituitarism; Hypothalamic; Neurosarcoidosis; Pituitary; Vision loss",
"medline_ta": "Pituitary",
"mesh_terms": "D000328:Adult; D005938:Glucocorticoids; D006801:Humans; D007018:Hypopituitarism; D007031:Hypothalamus; D007155:Immunologic Factors; D008297:Male; D008875:Middle Aged; D010900:Pituitary Diseases; D010902:Pituitary Gland; D012189:Retrospective Studies; D012507:Sarcoidosis; D014786:Vision Disorders",
"nlm_unique_id": "9814578",
"other_id": null,
"pages": "19-29",
"pmc": null,
"pmid": "26267304",
"pubdate": "2016-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "21602453;7421913;19585359;22753675;19205596;18226738;10430755;9228380;18432542;15575248;11437156;10209662;15634713;12108526;18226739;10754478;19202508;20736834;12897340;15805561;9789890;17873755;15207796;3896208;22595777;17171131",
"title": "Hypothalamic-pituitary sarcoidosis with vision loss and hypopituitarism: case series and literature review.",
"title_normalized": "hypothalamic pituitary sarcoidosis with vision loss and hypopituitarism case series and literature review"
} | [
{
"companynumb": "US-PFIZER INC-2017001192",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "1",
... |
{
"abstract": "Takotsubo cardiomyopathy (TC) is an acute cardiac dysfunction, clinically similar to myocardial ischemia. The physiopathology of the syndrome seems to be related to excessive sympathetic activity that is triggered by physical or emotional stress factors. We report the case of an 83-year-old woman with advanced Alzheimer disease who had recently used nortriptyline and sertraline and was admitted with chest pain. An electrocardiogram showed ST-elevation, and markers of myocardial necrosis were slightly increased. However, coronariography did not demonstrate stenotic lesions. Transthoracic echocardiography and ventriculography identified decreased ventricular function, apical akinesia, and compensatory hyperkinesia of other segments that were compatible with TC. The patient evolved with cardiogenic shock and died. Alzheimer patients may be more susceptible to develop TC, both because of the disease itself and because of the multiple medications they are exposed to that increase catecholamine levels. In this case, antidepressant drugs were considered to be a potential factor that enhanced the susceptibility.",
"affiliations": "Hospital Universitário Cassiano Antônio de Moraes (HUCAM), Universidade Federal do Espírito Santo (UFES).;Hospital Universitário Cassiano Antônio de Moraes (HUCAM), Universidade Federal do Espírito Santo (UFES).;Hospital Universitário Cassiano Antônio de Moraes (HUCAM), Universidade Federal do Espírito Santo (UFES).;Hospital Universitário Cassiano Antônio de Moraes (HUCAM), Universidade Federal do Espírito Santo (UFES).;Hospital Universitário Cassiano Antônio de Moraes (HUCAM), Universidade Federal do Espírito Santo (UFES).;Hospital Universitário Cassiano Antônio de Moraes (HUCAM), Universidade Federal do Espírito Santo (UFES).",
"authors": "Moulin Mares|Stephanie R A|SRA|;Groner|Jaqueline S|JS|;de Oliveira|Melissa P|MP|;Lírio|Ludmilla V|LV|;Coutinho|Paulo C|PC|;Luchi|Weverton M|WM|",
"chemical_list": "D000928:Antidepressive Agents; D000929:Antidepressive Agents, Tricyclic; D009661:Nortriptyline; D020280:Sertraline",
"country": "United States",
"delete": false,
"doi": "10.1097/WAD.0000000000000395",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0893-0341",
"issue": "34(4)",
"journal": "Alzheimer disease and associated disorders",
"keywords": null,
"medline_ta": "Alzheimer Dis Assoc Disord",
"mesh_terms": "D000369:Aged, 80 and over; D000544:Alzheimer Disease; D000928:Antidepressive Agents; D000929:Antidepressive Agents, Tricyclic; D002637:Chest Pain; D004452:Echocardiography; D004562:Electrocardiography; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D009661:Nortriptyline; D020280:Sertraline; D054549:Takotsubo Cardiomyopathy",
"nlm_unique_id": "8704771",
"other_id": null,
"pages": "360-361",
"pmc": null,
"pmid": "32520737",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Takotsubo Cardiomyopathy in an Alzheimer Disease Patient: The Potential Contribution of Antidepressant Agents.",
"title_normalized": "takotsubo cardiomyopathy in an alzheimer disease patient the potential contribution of antidepressant agents"
} | [
{
"companynumb": "BR-PFIZER INC-2020236011",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CLONAZEPAM"
},
"drugadditional": null,
... |
{
"abstract": "We present a case of a 75-year-old woman treated with an ACE inhibitor, who presented with angio-oedema of the tongue and had difficulty speaking. No symptoms of anaphylaxis or urticaria were present. The patient was treated intravenously with antihistamine and glucocorticoid in combination with adrenaline inhalations. After 6 h in the hospital the swelling progressed, and the patient was admitted to the intensive care unit and treated with one injection of icatibant-a bradykinin receptor antagonist. The patient reported subjective relief after 20-30 min and the swelling resolved within 2 h. Although the angio-oedema was potentially life threatening, the patient avoided intubation and mechanical ventilation. ACE inhibitor-induced angio-oedema is most likely caused by an accumulation of bradykinin and substance P. Consequently, a bradykinin receptor antagonist is the rational treatment of choice instead of antiallergic medications, which have no proven efficacy in this condition.",
"affiliations": "Department of Anaesthesiology and Intensive Care, Roskilde University Hospital, Roskilde, Denmark.;Dermatology and Allergy Center, University Hospital of Odense, Odense, Denmark.;Department of Otorhinolaryngology Head and Neck Surgery, Koege Hospital, Koege, Denmark.",
"authors": "Ostenfeld|Sarah|S|;Bygum|Anette|A|;Rasmussen|Eva Rye|ER|",
"chemical_list": "D000806:Angiotensin-Converting Enzyme Inhibitors; D065168:Bradykinin Receptor Antagonists; C065679:icatibant; D001920:Bradykinin",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2015()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D000799:Angioedema; D000806:Angiotensin-Converting Enzyme Inhibitors; D001920:Bradykinin; D065168:Bradykinin Receptor Antagonists; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D014059:Tongue",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "26498671",
"pubdate": "2015-10-23",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16043683;25629740;23178416;17620062;18413488;22100478;18450117;20084844;18757085;24096073;16957427;23160589;16451161;22677247;21250556;25145895;20447725",
"title": "Life-threatening ACE inhibitor-induced angio-oedema successfully treated with icatibant: a bradykinin receptor antagonist.",
"title_normalized": "life threatening ace inhibitor induced angio oedema successfully treated with icatibant a bradykinin receptor antagonist"
} | [
{
"companynumb": "DK-LUPIN PHARMACEUTICALS INC.-2016-00383",
"fulfillexpeditecriteria": "2",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LISINOPRIL"
},
"drugadditional... |
{
"abstract": "We have reported previously that after 1-year follow up, gonadotropin-releasing hormone agonist (GnRHa) did not prevent chemotherapy-induced premature ovarian failure (POF) in patients with lymphoma, but may provide protection of the ovarian reserve. Here, we report the final analysis of the cohort after 5 years of follow up.\n\n\n\nA total of 129 patients with lymphoma were randomly assigned to receive either triptorelin plus norethisterone (GnRHa group) or norethisterone alone (control group) during chemotherapy. Ovarian function and fertility were reported after 2, 3, 4, and 5 to 7 years of follow up. The primary end point was POF, defined as at least one follicle-stimulating hormone value of > 40 IU/L after 2 years of follow up.\n\n\n\nSixty-seven patients 26.21 ± 0.64 years of age had available data after a median follow-up time of 5.33 years in the GnRHa group and 5.58 years in the control group (P = .452). Multivariate logistic regression analysis showed a significantly increased risk of POF in patients according to age (P = .047), the conditioning regimen for hematopoietic stem cell transplant (P = .002), and the cumulative dose of cyclophosphamide > 5 g/m(2) (P = .019), but not to the coadministration of GnRHa during chemotherapy (odds ratio, 0.702; P = .651). The ovarian reserve, evaluated using anti-Müllerian hormone and follicle-stimulating hormone levels, was similar in both groups. Fifty-three percent and 43% achieved pregnancy in the GnRHa and control groups, respectively (P = .467).\n\n\n\nTo the best of our knowledge, this is the first long-term analysis confirming that GnRHa is not efficient in preventing chemotherapy-induced POF in young patients with lymphoma and did not influence future pregnancy rate. These results reopen the debate about the drug's benefit in that it should not be recommended as standard for fertility preservation in patients with lymphoma.",
"affiliations": "Isabelle Demeestere, Julie Dechene, Yvon Englert, and Viviane De Maertelaer, Université Libre de Bruxelles; Alain Kentos and Yvon Englert, Erasme Hospital; Eric Van Den Neste, Cliniques Universitaires UCL Saint-Luc; Dominique Bron, J. Bordet Institute, Brussels; Pierre Zachee, Algemeen Ziekenhuis Stuivenberg, Antwerpen, Belgium; Pauline Brice, St Louis Hospital, APHP; Jehan Dupuis, Hôpital Henri Mondor, Paris; Olivier Casasnovas, CHU de Dijon, Dijon, France; and Fedro A. Peccatori, Istituto Europeo di Oncologia, Milano, Italy. idemeest@ulb.ac.be.;Isabelle Demeestere, Julie Dechene, Yvon Englert, and Viviane De Maertelaer, Université Libre de Bruxelles; Alain Kentos and Yvon Englert, Erasme Hospital; Eric Van Den Neste, Cliniques Universitaires UCL Saint-Luc; Dominique Bron, J. Bordet Institute, Brussels; Pierre Zachee, Algemeen Ziekenhuis Stuivenberg, Antwerpen, Belgium; Pauline Brice, St Louis Hospital, APHP; Jehan Dupuis, Hôpital Henri Mondor, Paris; Olivier Casasnovas, CHU de Dijon, Dijon, France; and Fedro A. Peccatori, Istituto Europeo di Oncologia, Milano, Italy.;Isabelle Demeestere, Julie Dechene, Yvon Englert, and Viviane De Maertelaer, Université Libre de Bruxelles; Alain Kentos and Yvon Englert, Erasme Hospital; Eric Van Den Neste, Cliniques Universitaires UCL Saint-Luc; Dominique Bron, J. Bordet Institute, Brussels; Pierre Zachee, Algemeen Ziekenhuis Stuivenberg, Antwerpen, Belgium; Pauline Brice, St Louis Hospital, APHP; Jehan Dupuis, Hôpital Henri Mondor, Paris; Olivier Casasnovas, CHU de Dijon, Dijon, France; and Fedro A. Peccatori, Istituto Europeo di Oncologia, Milano, Italy.;Isabelle Demeestere, Julie Dechene, Yvon Englert, and Viviane De Maertelaer, Université Libre de Bruxelles; Alain Kentos and Yvon Englert, Erasme Hospital; Eric Van Den Neste, Cliniques Universitaires UCL Saint-Luc; Dominique Bron, J. Bordet Institute, Brussels; Pierre Zachee, Algemeen Ziekenhuis Stuivenberg, Antwerpen, Belgium; Pauline Brice, St Louis Hospital, APHP; Jehan Dupuis, Hôpital Henri Mondor, Paris; Olivier Casasnovas, CHU de Dijon, Dijon, France; and Fedro A. Peccatori, Istituto Europeo di Oncologia, Milano, Italy.;Isabelle Demeestere, Julie Dechene, Yvon Englert, and Viviane De Maertelaer, Université Libre de Bruxelles; Alain Kentos and Yvon Englert, Erasme Hospital; Eric Van Den Neste, Cliniques Universitaires UCL Saint-Luc; Dominique Bron, J. Bordet Institute, Brussels; Pierre Zachee, Algemeen Ziekenhuis Stuivenberg, Antwerpen, Belgium; Pauline Brice, St Louis Hospital, APHP; Jehan Dupuis, Hôpital Henri Mondor, Paris; Olivier Casasnovas, CHU de Dijon, Dijon, France; and Fedro A. Peccatori, Istituto Europeo di Oncologia, Milano, Italy.;Isabelle Demeestere, Julie Dechene, Yvon Englert, and Viviane De Maertelaer, Université Libre de Bruxelles; Alain Kentos and Yvon Englert, Erasme Hospital; Eric Van Den Neste, Cliniques Universitaires UCL Saint-Luc; Dominique Bron, J. Bordet Institute, Brussels; Pierre Zachee, Algemeen Ziekenhuis Stuivenberg, Antwerpen, Belgium; Pauline Brice, St Louis Hospital, APHP; Jehan Dupuis, Hôpital Henri Mondor, Paris; Olivier Casasnovas, CHU de Dijon, Dijon, France; and Fedro A. Peccatori, Istituto Europeo di Oncologia, Milano, Italy.;Isabelle Demeestere, Julie Dechene, Yvon Englert, and Viviane De Maertelaer, Université Libre de Bruxelles; Alain Kentos and Yvon Englert, Erasme Hospital; Eric Van Den Neste, Cliniques Universitaires UCL Saint-Luc; Dominique Bron, J. Bordet Institute, Brussels; Pierre Zachee, Algemeen Ziekenhuis Stuivenberg, Antwerpen, Belgium; Pauline Brice, St Louis Hospital, APHP; Jehan Dupuis, Hôpital Henri Mondor, Paris; Olivier Casasnovas, CHU de Dijon, Dijon, France; and Fedro A. Peccatori, Istituto Europeo di Oncologia, Milano, Italy.;Isabelle Demeestere, Julie Dechene, Yvon Englert, and Viviane De Maertelaer, Université Libre de Bruxelles; Alain Kentos and Yvon Englert, Erasme Hospital; Eric Van Den Neste, Cliniques Universitaires UCL Saint-Luc; Dominique Bron, J. Bordet Institute, Brussels; Pierre Zachee, Algemeen Ziekenhuis Stuivenberg, Antwerpen, Belgium; Pauline Brice, St Louis Hospital, APHP; Jehan Dupuis, Hôpital Henri Mondor, Paris; Olivier Casasnovas, CHU de Dijon, Dijon, France; and Fedro A. Peccatori, Istituto Europeo di Oncologia, Milano, Italy.;Isabelle Demeestere, Julie Dechene, Yvon Englert, and Viviane De Maertelaer, Université Libre de Bruxelles; Alain Kentos and Yvon Englert, Erasme Hospital; Eric Van Den Neste, Cliniques Universitaires UCL Saint-Luc; Dominique Bron, J. Bordet Institute, Brussels; Pierre Zachee, Algemeen Ziekenhuis Stuivenberg, Antwerpen, Belgium; Pauline Brice, St Louis Hospital, APHP; Jehan Dupuis, Hôpital Henri Mondor, Paris; Olivier Casasnovas, CHU de Dijon, Dijon, France; and Fedro A. Peccatori, Istituto Europeo di Oncologia, Milano, Italy.;Isabelle Demeestere, Julie Dechene, Yvon Englert, and Viviane De Maertelaer, Université Libre de Bruxelles; Alain Kentos and Yvon Englert, Erasme Hospital; Eric Van Den Neste, Cliniques Universitaires UCL Saint-Luc; Dominique Bron, J. Bordet Institute, Brussels; Pierre Zachee, Algemeen Ziekenhuis Stuivenberg, Antwerpen, Belgium; Pauline Brice, St Louis Hospital, APHP; Jehan Dupuis, Hôpital Henri Mondor, Paris; Olivier Casasnovas, CHU de Dijon, Dijon, France; and Fedro A. Peccatori, Istituto Europeo di Oncologia, Milano, Italy.;Isabelle Demeestere, Julie Dechene, Yvon Englert, and Viviane De Maertelaer, Université Libre de Bruxelles; Alain Kentos and Yvon Englert, Erasme Hospital; Eric Van Den Neste, Cliniques Universitaires UCL Saint-Luc; Dominique Bron, J. Bordet Institute, Brussels; Pierre Zachee, Algemeen Ziekenhuis Stuivenberg, Antwerpen, Belgium; Pauline Brice, St Louis Hospital, APHP; Jehan Dupuis, Hôpital Henri Mondor, Paris; Olivier Casasnovas, CHU de Dijon, Dijon, France; and Fedro A. Peccatori, Istituto Europeo di Oncologia, Milano, Italy.;Isabelle Demeestere, Julie Dechene, Yvon Englert, and Viviane De Maertelaer, Université Libre de Bruxelles; Alain Kentos and Yvon Englert, Erasme Hospital; Eric Van Den Neste, Cliniques Universitaires UCL Saint-Luc; Dominique Bron, J. Bordet Institute, Brussels; Pierre Zachee, Algemeen Ziekenhuis Stuivenberg, Antwerpen, Belgium; Pauline Brice, St Louis Hospital, APHP; Jehan Dupuis, Hôpital Henri Mondor, Paris; Olivier Casasnovas, CHU de Dijon, Dijon, France; and Fedro A. Peccatori, Istituto Europeo di Oncologia, Milano, Italy.",
"authors": "Demeestere|Isabelle|I|;Brice|Pauline|P|;Peccatori|Fedro A|FA|;Kentos|Alain|A|;Dupuis|Jehan|J|;Zachee|Pierre|P|;Casasnovas|Olivier|O|;Van Den Neste|Eric|E|;Dechene|Julie|J|;De Maertelaer|Viviane|V|;Bron|Dominique|D|;Englert|Yvon|Y|",
"chemical_list": "D017329:Triptorelin Pamoate; D007987:Gonadotropin-Releasing Hormone; D009640:Norethindrone",
"country": "United States",
"delete": false,
"doi": "10.1200/JCO.2015.65.8864",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0732-183X",
"issue": "34(22)",
"journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology",
"keywords": null,
"medline_ta": "J Clin Oncol",
"mesh_terms": "D000328:Adult; D005260:Female; D005298:Fertility; D059247:Fertility Preservation; D007987:Gonadotropin-Releasing Hormone; D006801:Humans; D008223:Lymphoma; D008875:Middle Aged; D009640:Norethindrone; D010053:Ovary; D016649:Primary Ovarian Insufficiency; D011446:Prospective Studies; D017329:Triptorelin Pamoate",
"nlm_unique_id": "8309333",
"other_id": null,
"pages": "2568-74",
"pmc": null,
"pmid": "27217453",
"pubdate": "2016-08-01",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "No Evidence for the Benefit of Gonadotropin-Releasing Hormone Agonist in Preserving Ovarian Function and Fertility in Lymphoma Survivors Treated With Chemotherapy: Final Long-Term Report of a Prospective Randomized Trial.",
"title_normalized": "no evidence for the benefit of gonadotropin releasing hormone agonist in preserving ovarian function and fertility in lymphoma survivors treated with chemotherapy final long term report of a prospective randomized trial"
} | [
{
"companynumb": "BE-JNJFOC-20160814481",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PROCARBAZINE"
},
"drugadditional": "3",
... |
{
"abstract": "Current guidelines conflict on the management of older adults who have blunt head trauma taking anticoagulant and antiplatelet medications. This is partially due to the limited data comparing patients who are taking these medications with those who are not.\n\n\n\nTo investigate the incidence of delayed traumatic intracranial hemorrhage in older adults with head trauma, including those taking anticoagulant and antiplatelet medications.\n\n\n\nThis prospective observational cohort study included patients 55 years and older who had blunt head trauma and were transported via emergency medical services between August 1, 2015, and September 30, 2016. The setting was a multicenter study conducted at 11 hospitals in northern California. Patients were excluded if they had traumatic intracranial hemorrhage on the initial cranial computed tomographic scan, did not have a cranial computed tomographic scan performed at the initial emergency department visit, refused consent for a follow-up telephone call, or did not have reliable means of follow-up.\n\n\n\nThe primary outcome of this study was the incidence of delayed traumatic intracranial hemorrhage within 14 days of injury.\n\n\n\nAmong 859 patients enrolled in the study, the median age was 75 years (interquartile range, 64-85 years), and 389 (45.3%) were male. A total of 343 patients (39.9%) were taking an anticoagulant or antiplatelet medication. Three patients (0.3%; 95% CI, 0.1%-1.0%) had a delayed traumatic intracranial hemorrhage. Of the 3 patients, 1 of 75 patients (1.3%; 95% CI, 0.0%-7.2%) who were taking warfarin sodium alone and 2 of 516 patients (0.4%; 95% CI, 0.1%-1.4%) who were not taking any anticoagulant or antiplatelet medication had a delayed traumatic intracranial hemorrhage. Thirty-nine patients (4.5%; 95% CI, 3.2%-6.2%) were lost to follow-up.\n\n\n\nOverall, the incidence of delayed intracranial hemorrhage in older adults who have blunt head trauma is low, including patients taking an anticoagulant or antiplatelet medication. These findings suggest that routine observation and serial cranial computed tomography may not be necessary in these patients.",
"affiliations": "Department of Emergency Medicine, University of California, Davis, School of Medicine, Sacramento.;Department of Emergency Medicine, University of California, Davis, School of Medicine, Sacramento.;Centers for Disease Control and Prevention, Atlanta, Georgia.;Department of Emergency Medicine, University of California, Davis, School of Medicine, Sacramento.;Department of Emergency Medicine, University of California, Davis, School of Medicine, Sacramento.",
"authors": "Chenoweth|James A|JA|;Gaona|Samuel D|SD|;Faul|Mark|M|;Holmes|James F|JF|;Nishijima|Daniel K|DK|;|||",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1001/jamasurg.2017.6159",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2168-6254",
"issue": "153(6)",
"journal": "JAMA surgery",
"keywords": null,
"medline_ta": "JAMA Surg",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D002140:California; D005260:Female; D005500:Follow-Up Studies; D016489:Head Injuries, Closed; D006801:Humans; D015994:Incidence; D020300:Intracranial Hemorrhages; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D014057:Tomography, X-Ray Computed; D014193:Trauma Centers",
"nlm_unique_id": "101589553",
"other_id": null,
"pages": "570-575",
"pmc": null,
"pmid": "29450470",
"pubdate": "2018-06-01",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study; D052061:Research Support, N.I.H., Extramural; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": "20928982;23114492;19509609;24458049;26218702;22182870;11985628;17161086;26144101;24859719;16832256;18698666;22626015;21839444;19027497;20016390;22244878;26282266",
"title": "Incidence of Delayed Intracranial Hemorrhage in Older Patients After Blunt Head Trauma.",
"title_normalized": "incidence of delayed intracranial hemorrhage in older patients after blunt head trauma"
} | [
{
"companynumb": "US-TEVA-2018-US-937943",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "WARFARIN SODIUM"
},
"drugadditional": "3",
... |
{
"abstract": "Postural tachycardia syndrome (POTS) is a form of autonomic dysfunction characterized by symptoms of orthostatic intolerance, often accompanied by sudomotor dysfunction and gastrointestinal dysmotility. Recently, evidence has accumulated that in a subset of patients, the pathogenesis of dysautonomia may be immune-mediated. The aim of the current report was to evaluate the use of intravenous immunoglobulin (IVIG) treatment in patients with progressive and/or refractory immune-mediated POTS.\n\n\n\nWe retroactively assessed the effect and tolerance of monthly administered IVIG in six patients using autonomic function testing, standardized symptom questionnaires, and patients' symptom diaries both before and 6 months into IVIG treatment. Objective outcome measures included heart rate increase after 10 min of head-up tilt as well as duration and anhidrotic area in a thermoregulatory sweat test. Subjective outcome measures were patient reports and symptom ratings from the symptom questionnaire.\n\n\n\nAll patients responded to immunomodulatory treatment, regardless of disease duration. After 6 months of IVIG, symptom severity was reduced by nearly 40%. Autonomic function testing showed improved cardiovascular functioning by 50% and a reduction of anhidrotic areas by one third. Overall, tolerance of IVIG treatment was poor, but could be improved by a reduction in infusion rate, premedication with steroids, and additional intravenous hydration.\n\n\n\nUsing subjective but also standardized objective measures, the case series describes promising effects of IVIG treatment in POTS patients with immune-mediated dysautonomia. By reducing the infusion rate, pretreatment with steroids, and intravenous hydration, tolerance could be improved, and no patient had to discontinue the treatment.",
"affiliations": "Department of Neurosurgery, Inselspital, Bern University Hospital, Bern, Switzerland.;Department of Neurology, Inselspital, Bern University Hospital, Bern, Switzerland.;Department of Neurology, Inselspital, Bern University Hospital, Bern, Switzerland.;Department of Neurology, Inselspital, Bern University Hospital, Bern, Switzerland.;Department of Neurosurgery, Inselspital, Bern University Hospital, Bern, Switzerland.",
"authors": "Rodriguez|Belén|B|0000-0003-2426-0045;Hoepner|Robert|R|;Salmen|Anke|A|0000-0002-4751-299X;Kamber|Nicole|N|;Z'Graggen|Werner J|WJ|0000-0002-5684-4419",
"chemical_list": "D016756:Immunoglobulins, Intravenous",
"country": "England",
"delete": false,
"doi": "10.1111/ene.14711",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1351-5101",
"issue": "28(5)",
"journal": "European journal of neurology",
"keywords": "alpha-1 adrenergic receptor; autoantibodies; autoimmune; disturbance of sweating; gastroparesis; muscarinic cholinergic receptors; orthostatic intolerance",
"medline_ta": "Eur J Neurol",
"mesh_terms": "D006339:Heart Rate; D006801:Humans; D016756:Immunoglobulins, Intravenous; D054972:Postural Orthostatic Tachycardia Syndrome; D054969:Primary Dysautonomias",
"nlm_unique_id": "9506311",
"other_id": null,
"pages": "1692-1697",
"pmc": null,
"pmid": "33382525",
"pubdate": "2021-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Immunomodulatory treatment in postural tachycardia syndrome: A case series.",
"title_normalized": "immunomodulatory treatment in postural tachycardia syndrome a case series"
} | [
{
"companynumb": "CH-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-312267",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METOPROLOL"
},
"drug... |
{
"abstract": "Neutrophil/lymphocyte (NLR) and platelet/lymphocyte (PLR) ratios might represent a yet unrecognized risk factor for venous thromboembolism (VTE) in cancer out-patients receiving chemotherapy. Accordingly, this study was aimed at analyzing the significance of these novel markers in the risk prediction of a first VTE episode in a population representative of a general practice cohort. To this purpose, a mono-institutional cohort study was conducted to retrospectively analyze NLR and PLR in 810 consecutive cancer out-patients with primary or relapsing solid cancer at the start of a new chemotherapy regimen. Over a median follow-up of 9.2 months, VTE occurred in 6.7% of patients. Incidental VTE was diagnosed at time of restaging in 47% of cases. Median pre-chemotherapy NLR (p = 0.015) and PLR (p = 0.040) were significantly higher in patients with intermediate risk class who developed symptomatic VTE with a twofold increased VTE risk for both inflammation-based markers (NLR: p = 0.022; PLR: p = 0.037) and a worst 1-year VTE-free survival for patients with high NLR or PLR. However, only PLR (HR = 2.4, p = 0.027) confirmed to be an independent predictor of future VTE in patients in the intermediate risk class in multivariate analysis, together with ECOG performance status (HR = 3.4, p = 0.0002) and bevacizumab use (HR = 4.7, p = 0.012). We may, thus, conclude that PLR, but to a lesser extent NLR, could represent useful clinical predictors of VTE, especially in selected categories of patients such as those in the intermediate risk class in whom the assessment of PLR could allow a better risk stratification of VTE without additional costs to the national health systems.",
"affiliations": "Biomarker Discovery and Advanced Biotechnology (BioDAT) Laboratory, IRCCS San Raffaele Pisana, Research Center, Rome, Italy.",
"authors": "Ferroni|Patrizia|P|;Riondino|Silvia|S|;Formica|Vincenzo|V|;Cereda|Vittore|V|;Tosetto|Livia|L|;La Farina|Francesca|F|;Valente|Maria Giovanna|MG|;Vergati|Matteo|M|;Guadagni|Fiorella|F|;Roselli|Mario|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/ijc.29076",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0020-7136",
"issue": "136(5)",
"journal": "International journal of cancer",
"keywords": "chemotherapy; inflammation; neutrophils; platelets; venous thromboembolism",
"medline_ta": "Int J Cancer",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000553:Ambulatory Care; D001792:Blood Platelets; D015331:Cohort Studies; D003131:Combined Modality Therapy; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008214:Lymphocytes; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009369:Neoplasms; D009504:Neutrophils; D011379:Prognosis; D012307:Risk Factors; D054556:Venous Thromboembolism; D055815:Young Adult",
"nlm_unique_id": "0042124",
"other_id": null,
"pages": "1234-40",
"pmc": null,
"pmid": "25042739",
"pubdate": "2015-03-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Venous thromboembolism risk prediction in ambulatory cancer patients: clinical significance of neutrophil/lymphocyte ratio and platelet/lymphocyte ratio.",
"title_normalized": "venous thromboembolism risk prediction in ambulatory cancer patients clinical significance of neutrophil lymphocyte ratio and platelet lymphocyte ratio"
} | [
{
"companynumb": "IT-ROCHE-1163015",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"drugadditional": null,
"druga... |
{
"abstract": "BACKGROUND\nThyroid crisis is a life-threatening condition in thyrotoxic patients. Although differentiated thyroid cancer is one of the causes of hyperthyroidism, reports on thyroid crisis caused by thyroid cancer are quite limited. Here, we describe a case of thyroid crisis caused by metastatic thyroid cancer.\n\n\nMETHODS\nA 91-year-old woman was admitted to our hospital because of loss of appetite. Two years prior to this hospitalization, she presented with subclinical thyrotoxicosis and was diagnosed with histologically unidentified thyroid cancer with multiple metastases, and she refused aggressive medical interventions. On admission, she exhibited extreme thyrotoxicosis, and the presence of fever, severe tachycardia, impaired consciousness, and heart failure revealed the presence of thyroid crisis. All thyroid autoantibodies were negative. Multidisciplinary conservative treatment was initiated; however, she died on the fifth day after admission. Autopsy revealed the presence of primary anaplastic thyroid carcinoma and multiple metastatic foci arising from follicular thyroid carcinoma. Both primary and metastatic follicular thyroid carcinoma likely induced thyrotoxicosis, which could have been exacerbated by anaplastic thyroid carcinoma.\n\n\nCONCLUSIONS\nEven though the trigger of thyroid crisis in this patient is not clear, the aggravated progression of her clinical course suggests that careful monitoring of thyroid hormones and appropriate intervention are essential for patients with thyroid cancer.",
"affiliations": "Department of Internal Medicine 1, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo, Shimane, 693-8501, Japan.;Department of Internal Medicine 1, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo, Shimane, 693-8501, Japan. mnotsu25@med.shimane-u.ac.jp.;Department of Internal Medicine 1, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo, Shimane, 693-8501, Japan.;Department of Internal Medicine 1, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo, Shimane, 693-8501, Japan.;Department of Internal Medicine 1, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo, Shimane, 693-8501, Japan.;Department of Internal Medicine 1, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo, Shimane, 693-8501, Japan.;Department of Pathology, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo, Shimane, 693-8501, Japan.;Department of Pathology, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo, Shimane, 693-8501, Japan.;Department of Internal Medicine 1, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo, Shimane, 693-8501, Japan.",
"authors": "Takedani|Kai|K|;Notsu|Masakazu|M|http://orcid.org/0000-0002-8326-8154;Adachi|Naoko|N|;Tanaka|Sayuri|S|;Yamamoto|Masahiro|M|;Yamauchi|Mika|M|;Yamauchi|Naotake|N|;Maruyama|Riruke|R|;Kanasaki|Keizo|K|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s12902-021-00875-7",
"fulltext": "\n==== Front\nBMC Endocr Disord\nBMC Endocr Disord\nBMC Endocrine Disorders\n1472-6823\nBioMed Central London\n\n875\n10.1186/s12902-021-00875-7\nCase Report\nThyroid crisis caused by metastatic thyroid cancer: an autopsy case report\nTakedani Kai 1\nhttp://orcid.org/0000-0002-8326-8154\nNotsu Masakazu mnotsu25@med.shimane-u.ac.jp\n\n1\nAdachi Naoko 1\nTanaka Sayuri 1\nYamamoto Masahiro 1\nYamauchi Mika 1\nYamauchi Naotake 23\nMaruyama Riruke 2\nKanasaki Keizo 1\n1 grid.411621.1 0000 0000 8661 1590 Department of Internal Medicine 1, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo, Shimane 693-8501 Japan\n2 grid.411621.1 0000 0000 8661 1590 Department of Pathology, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo, Shimane 693-8501 Japan\n3 grid.267346.2 0000 0001 2171 836X Department of Pathology, Faculty of Medicine, University of Toyama, 2630 Sugitani, Toyama, Toyama 930-0194 Japan\n24 10 2021\n24 10 2021\n2021\n21 21330 3 2021\n15 10 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nThyroid crisis is a life-threatening condition in thyrotoxic patients. Although differentiated thyroid cancer is one of the causes of hyperthyroidism, reports on thyroid crisis caused by thyroid cancer are quite limited. Here, we describe a case of thyroid crisis caused by metastatic thyroid cancer.\n\nCase presentation\n\nA 91-year-old woman was admitted to our hospital because of loss of appetite. Two years prior to this hospitalization, she presented with subclinical thyrotoxicosis and was diagnosed with histologically unidentified thyroid cancer with multiple metastases, and she refused aggressive medical interventions. On admission, she exhibited extreme thyrotoxicosis, and the presence of fever, severe tachycardia, impaired consciousness, and heart failure revealed the presence of thyroid crisis. All thyroid autoantibodies were negative. Multidisciplinary conservative treatment was initiated; however, she died on the fifth day after admission. Autopsy revealed the presence of primary anaplastic thyroid carcinoma and multiple metastatic foci arising from follicular thyroid carcinoma. Both primary and metastatic follicular thyroid carcinoma likely induced thyrotoxicosis, which could have been exacerbated by anaplastic thyroid carcinoma.\n\nConclusions\n\nEven though the trigger of thyroid crisis in this patient is not clear, the aggravated progression of her clinical course suggests that careful monitoring of thyroid hormones and appropriate intervention are essential for patients with thyroid cancer.\n\nKeywords\n\nThyroid crisis\nFollicular thyroid carcinoma\nAnaplastic thyroid carcinoma\nMetastasis\nissue-copyright-statement© The Author(s) 2021\n==== Body\npmcBackground\n\nThyroid crisis is a life-threatening condition requiring emergency treatment in thyrotoxic patients [1, 2]. Patients with thyroid crisis exhibit multiple organ failure induced by the disruption of haemodynamics due to excess thyroid hormone and have a mortality rate higher than 10% in Japan [1]. Graves’ disease is the most common cause of both hyperthyroidism and thyroid crisis [1, 3]. Often, individuals with thyroid crisis have triggers for the onset of thyroid crisis. Although differentiated thyroid cancer is one of the causes of hyperthyroidism, [4] reports on thyroid crisis caused by thyroid cancer are quite limited.\n\nHere, we present a case of uncontrollable thyroid crisis caused by thyroid cancer with multiple metastases.\n\nCase presentation\n\nA 91-year-old woman was admitted to Shimane University Hospital because of loss of appetite. Two years prior to this hospitalization, at the age of 89, computed tomography (CT) scans incidentally revealed a 55 mm tumour in the right lobe of the thyroid gland, mediastinal lymphadenopathy, and multiple pulmonary nodules. Fine-needle aspiration cytology demonstrated nuclear grooves in the tumour, which formed small follicular structures, but intranuclear cytoplasmic inclusion was not observed. Cytology could not specify the type of thyroid cancer. Due to her age, she did not wish to receive aggressive management to treat the histologically unidentified thyroid cancer with multiple metastases. Her thyroid-stimulating hormone (TSH) was under the detection limit, and she had subclinical thyrotoxicosis (free thyroxine (FT4) 1.0 ng/dL) with high thyroglobulin (Tg) levels (Fig. 1). She did not have any symptoms. We discussed the risks and benefits associated with anti-thyroid treatment with her and her family, and they chose no specific treatment for her thyrotoxicosis. Until 2 months prior to hospitalization, her condition was unremarkable. Two weeks before admission, however, she demonstrated overt thyrotoxicosis (free triiodothyronine (FT3) 9.2 pg/mL, FT4 2.4 ng/dL, and FT3/FT4 ratio 3.8) without overt symptoms. She was prescribed potassium iodide (KI) (50 mg); however, her general status worsened to include loss of appetite. She was hospitalized to improve her general status and to treat thyrotoxicosis. Fig. 1 Clinical course. When the patient was diagnosed with a thyroid tumour, her TSH was under the detection limit, and her thyroid hormone levels were normal; she had subclinical thyrotoxicosis. Her thyroid hormones worsened gradually until 2 weeks before admission; however, thyrotoxicosis rapidly deteriorated in the last 2 weeks. She also had a high Tg level at the first visit, which peaked 2 months before admission and then decreased\n\nSix months after the thyroid tumour was diagnosed, she experienced a pathological left hip fracture due to bone metastasis. She also had a history of cerebral infarction treated with an antiplatelet drug. Her activities of daily living were generally suitable before the emergency admission.\n\nHer height was 143 cm, her body weight was 29.3 kg, and her body mass index was 14.3 kg/m2. The Glasgow coma scale score was E4V4M6. Her blood pressure was 167/100 mmHg, pulse rate was 160/min, body temperature was 38.4 °C, oxygen saturation (SpO2) was 97% (room air), and respiratory rate was 26/min. Her anterior neck was markedly swollen without overt pain. The other physical findings were unremarkable except for mild pitting oedema of the bilateral lower extremities.\n\nThe laboratory findings on admission are shown in Table 1. She had extreme thyrotoxicosis above the sensitivity limits (TSH < 0.003 μU/mL, FT3 > 25 pg/mL, FT4 > 8 ng/dL). The presence of fever, severe tachycardia, impaired consciousness, and heart failure suggested thyroid crisis. TSH receptor antibody and Hashimoto thyroiditis-related antibodies were all negative, suggesting that her thyrotoxicosis was caused by thyroid cancer or destructive thyroiditis. A CT scan identified an enlarged thyroid tumour and metastases (Fig. 2). Ultrasound revealed diffuse enlargement of the right lobe of the thyroid gland with increased blood flow (Fig. 3). An electrocardiogram showed severe sinus tachycardia without atrial fibrillation. Echocardiography revealed diffuse asynergy, suggesting takotsubo cardiomyopathy, likely due to the aberrant sympatho-adrenergic activation induced by thyrotoxicosis. The ejection fraction was 22%. The presence of infection was excluded by physical examination, CT images acquired at the time of hospitalization and only minor elevation of an inflammatory marker. Human chorionic gonadotropin (HCG)-induced hyperthyroidism was also excluded. Table 1 Baseline laboratory data\n\nParameter\tObserved\tReference range\t\nVenous blood gas analyses\t\n pH\t7.28\t7.35–7.45\t\n pCO2, mmHg\t34\t35–48\t\n HCO3−, mEq/L\t15\t21–28\t\n lactic acid, mg/dL\t22\t4.5–13.5\t\nUrinalysis\t\n pH\t6.0\t4.5–7.5\t\n blood\t±\t–\t\n protein\t2+\t–\t\n ketone\t2+\t–\t\n I/Cr, μg/gCr\t27,120\t200–1000\t\nComplete blood count\t\n WBC,/μL\t12,730\t3300–8600\t\n Neutro, %\t87\t40–75\t\n Hb, g/dL\t9.9\t11.6–14.8\t\n Plt,/μL\t12.0 × 104\t15.8–34.8 × 104\t\nSerum characteristics\t\n Alb, g/dL\t3.4\t4.1–5.1\t\n T-Bil, mg/dL\t0.7\t0.4–1.5\t\n AST, IU/L\t26\t13–30\t\n ALT, IU/L\t28\t7–23\t\n LDH, IU/L\t193\t124–222\t\n ALP, IU/L\t152\t106–322\t\n CK, IU/L\t93\t41–153\t\n CK-MB, ng/mL\t10.6\t< 3.7\t\n TNI, ng/mL\t1.09\t< 0.04\t\n T-chol, mg/dL\t95\t142–248\t\n HbA1c, %\t5.3\t4.9–6.0\t\n BUN, mg/dL\t28\t8–20\t\n Cr, mg/dL\t0.54\t0.46–0.79\t\n Na, mEq/L\t142\t138–145\t\n K, mEq/L\t4.1\t3.6–4.8\t\n Cl, mEq/L\t110\t101–108\t\n cCa, mg/dL\t8.9\t8.8–10.1\t\n CRP, mg/dL\t2.4\t< 0.03\t\n PCT, ng/mL\t0.06\t< 0.50\t\n BNP, pg/mL\t2796\t< 20\t\n FT3, pg/mL\t> 25\t2.1–3.8\t\n FT4, ng/dL\t> 8.0\t0.8–1.5\t\n TSH, μU/mL\t< 0.003\t0.50–3.00\t\n TRAb, IU/L\t< 0.9\t< 2.0\t\n TSAb, %\t114\t< 120\t\n Tg-Ab, IU/mL\t< 5.0\t< 5.0\t\n TPO-Ab, IU/mL\t< 3.0\t< 3.0\t\n Tg, ng/mL\t6510\t< 33.7\t\n HCG, mIU/mL\t< 1.0\t< 2.7\t\nI iodide, Cr creatinine, WBC white blood cell, Neutro neutrophils, Hb haemoglobin, Plt platelet, Alb albumin, T-Bil, total bilirubin, AST aspartate transaminase, ALT alanine aminotransferase, LDH lactate dehydrogenase, ALP alkaline phosphatase, CK creatine kinase, TNI troponin i, T-chol total cholesterol, HbA1c haemoglobin A1c, BUN blood urea nitrogen, Na sodium, K potassium, Cl chlorine, cCa corrected calcium, CRP C-reactive protein, PCT procalcitonin, BNP brain natriuretic peptide, FT3 free triiodothyronine, FT4 free thyroxine, TSH thyroid-stimulating hormone, TRAb TSH receptor antibody, TSAb thyroid stimulating antibody, Tg-Ab anti-thyroglobulin antibody, TPO-Ab anti-myeloperoxidase antibody, Tg thyroglobulin, HCG human chorionic gonadotropin\n\nFig. 2 Computed tomography scan. A: The thyroid was markedly swollen with calcification. Tracheal deviation was identified. B: The hilar and mediastinal lymph nodes were swollen. C: Multiple nodules were identified in both lungs. D: A pathological left hip fracture was identified\n\nFig. 3 Thyroid ultrasonography. A Two years before hospitalization. A large tumour was revealed in the right lobe with calcification and slight blood flow. B At the time of hospitalization. Diffuse enlargement of the right lobe with increased blood flow was revealed\n\nDespite treatment with KI, her thyrotoxicosis worsened. Considering possible augmentation of her thyrotoxicosis by the administered iodide, the KI was discontinued. Treatment with intravenous hydrocortisone and oral thiamazole was initiated; however, due to her severe illness, the oral administration of thiamazole was not possible. The maximum dose of landiolol also failed to manage her tachycardia. Her condition deteriorated progressively, and she died on the fifth day of hospitalization.\n\nAfter a discussion with her family, an autopsy was performed.\n\n<Thyroid> 110 g, 7.6 × 6.4 × 3.0 cm\n\nThe thyroid was slightly hard and was weakly adhered to the trachea (Fig. 4). The tumour invaded the sternothyroid muscle, lymph nodes, and veins over the thyroid capsule. The cut surface showed a white solid mass with central haemorrhagic necrosis. The histological images revealed mainly formed nodules with thyroid follicles of various sizes invading the surrounding tissues, but they were mixed with atypical spindle tumour cells proliferating solidly without follicles (Fig. 5). After immunostaining, the spindle tumour cells were positive for cytokeratin AE1/AE3, CAM5.2 and paired box gene 8 (PAX8) and negative for epithelial membrane antigen (EMA), Tg, carcinoembryonic antigen (CEA), thyroid transcription factor-1 (TTF-1), and p53. Based on these findings, she was diagnosed with anaplastic thyroid carcinoma (ATC) arising from follicular thyroid carcinoma (FTC). Fig. 4 Gross image of the thyroid. A The thyroid weighed 110 g and was 7.6 × 6.4 × 3.0 cm in size. The thyroid was slightly hard. B The cut surface of thyroid showed a white solid mass with central haemorrhagic necrosis\n\nFig. 5 Microscopic image of the thyroid. A Nodules with thyroid follicles of various sizes invading the surrounding tissues were mainly observed (hematoxylin and eosin, low magnification). B Atypical spindle tumour cells proliferating solidly without follicles were also observed (hematoxylin and eosin, low magnification). C Enlargement of the image shown in B (hematoxylin and eosin, high magnification). After immunostaining, the spindle tumour cells were positive for cytokeratin AE1/AE3 (D), CAM5.2 (E) and PAX8 (F) (high magnification)\n\n<Other organs>\n\nThe FTC filtrated the trachea. There were well-defined white lesions in both lungs, which were histologically metastases of FTC (Fig. 6). In addition, metastases were also observed in the hilar and superior mediastinal lymph nodes. No anaplastic cancer tissue was found in the metastatic lesions, which all showed findings of FTC. The ascending colon cancer that had been found before her death was moderately differentiated tubular adenocarcinoma invading the subserosal tissue. However, the histological and immunohistochemical features of this tumour were completely different from those of thyroid cancer. No infarction in the cardiac wall or obstruction in the coronary arteries was observed. Fig. 6 Pathological findings of left lung. A There were well-defined white lesions in left lung. B Follicles of various sizes were observed and were considered to be metastases of FTC. No anaplastic cancer tissue was found in the metastatic lesions, which all showed findings of FTC (hematoxylin and eosin, low magnification)\n\nDiscussion and conclusions\n\nWe reported a case of thyroid crisis likely caused by metastatic thyroid cancer. Multidisciplinary conservative treatment was not effective for her illness, and she died on the fifth day of hospitalization. The autopsy revealed the presence of primary ATC arising from FTC and multiple FTC metastases.\n\nThe Japan Thyroid Association has proposed diagnostic criteria for thyroid crisis [2]. The presence of thyrotoxicosis with elevated levels of FT3 or FT4 is a prerequisite for diagnosis. Patients with thyroid crisis have central nervous system manifestations, fever, tachycardia, congestive heart failure, and gastrointestinal/hepatic manifestations. Our patient displayed all of these parameters except for gastrointestinal/hepatic manifestations, so her symptoms were consistent with the diagnosis of thyroid crisis.\n\nIn Japan, the primary cause of thyrotoxicosis among patients with thyroid crisis is Graves’ disease, followed by destructive thyroiditis [1]. The potential trigger of thyroid crisis has been proven in 70% of patients. The most common trigger of thyroid crisis was the irregular use or discontinuation of antithyroid medication, and the second was infection. Other minor triggers are also known, such as diabetic ketoacidosis, severe emotional stress, trauma, surgery, radioiodine therapy, and pregnancy/delivery [1, 2] Among the causes of thyrotoxicosis, Graves’ disease was excluded as she was negative for TSH receptor antibody. She had displayed prolonged thyrotoxicosis for 2 years before hospitalization; her clinical course was not typical for destructive thyroiditis, such as subacute thyroiditis and painless thyroiditis. In addition, the FT3/FT4 ratio is lower in destructive thyroiditis than in Graves’ disease, and several studies have shown that the optimal FT3/FT4 ratio cut-off value is 2.8–3.0 [5, 6]. In the present case, the FT3/FT4 ratio was elevated at the time of the first diagnosis of overt thyrotoxicosis. These findings suggested that the thyrotoxicosis in this case was not due to destructive thyroiditis. Thus, most likely, thyroid cancer induced her thyroid crisis; however, the trigger is not completely clear.\n\nHyperfunctioning thyroid cancer can absorb iodine and synthesize/release thyroid hormone [4]. Activating mutations in TSH receptor genes activate the intracellular cyclic adenosine monophosphate (cAMP) cascade, which is the most considerable cause of hyperthyroidism due to thyroid cancer [7]. Among hyperfunctioning thyroid cancers, FTC has been shown to have a markedly higher prevalence (46.5% for primary and 71.4% for metastatic disease) than other types [4]. The Surveillance, Epidemiology and End Results (SEER) cancer registry (1974–2013) indicates that FTC only accounts for 10.8% of all thyroid cancers [8]. These data indicate that the proportion of FTC among hormone-producing thyroid cancers is high. Additionally, the tumour burden of hyperfunctioning thyroid cancer is remarkably larger (4.25 ± 2.12 cm) [4]. By comparison, the SEER cancer registry programme indicates that 28.6% of thyroid carcinomas are ≤1.0 cm in size, 26.0% are > 1.0 to ≤2.0 cm, 23.0% are > 2.0 to ≤4.0 cm, and 9.6% are > 4.0 cm [8]. Furthermore, in cases of metastatic hyperfunctioning thyroid cancers, tumour metastases are widespread or large [4]. Large primary or metastatic tumours synthesize excessive thyroid hormones, resulting in the onset of hyperthyroidism. In the present case of FTC, the primary tumour was large in size, and the metastases were widespread, consistent with previous reports. The patient had subclinical thyrotoxicosis at the time of the first diagnosis. Hormone production by both/either primary and/or metastatic FTC lesions would cause/later augment her thyrotoxicosis.\n\nThe effect of KI on hyperthyroidism in thyroid cancer patients has not yet been established, although a former report indicated the beneficial effects of inorganic iodine used in combination with antithyroid drugs and glucocorticoids on thyroid cancer-associated hyperthyroidism [9, 10]. KI in combination with antithyroid drugs is generally the gold standard in thyroid crisis cases [1]. However, surprisingly, little is known about whether KI is effective in thyroid cancer patients via the Wolff-Chaikoff effect. The molecular mechanisms of the Wolff-Chaikoff effect have not been established [11, 12]. Most research analysing the direct effects of iodine was performed on hypophysectomized animals given a standard dose of TSH, essentially regulating thyroid activity [13]. Therefore, the effects of KI in patients with diminished levels of either TSH or thyroid-stimulating antibody, such as the presented patient, are absolutely unknown, and we could not even obtain sufficient information from preclinical studies. Taken together, whether KI should be used in thyroid cancer patients with hyperthyroidism needs to be established by further investigations, and we may need to consider the harmful influence of iodine in cancer patients due to thyroid hormone secretion and potential crisis.\n\nTo the best of our knowledge, there have been only five reports about thyroid crisis due to thyroid cancer (Table 2) [9, 10, 14–16]. All were due to differentiated thyroid cancer, including papillary thyroid carcinoma (PTC) (one case), a follicular variant of PTC (three cases) and FTC (two cases, including our case). Metastases were found in five cases, including our case. Most patients had triggers, and three patients had Graves’ disease, which is similar to the general characteristics of patients with thyroid crisis [1]. The mortality rate was also high. Table 2 Reported cases of thyroid crisis due to thyroid cancer\n\nNo.\tAge\tSex\tPathology\tMetastasis\tTrigger\tOutcome\tGraves’ disease\tRemarks\tRefs.\t\n1\t20\tF\tPTC\tno\t1) pregnancy?\n\n2) delivery\n\n\talive\t+\n\npropylthiouracil\n\n\ttwo episodes of thyroid crisis\n\n1) at 25 weeks gestation\n\n2) at 2 weeks post-partum\n\n\t14\t\n2\t71\tF\tFVPTC\tbone, lung\tcontrast-enhanced CT\n\nincisional biopsy\n\n\tdeath\t+\n\nno treatment\n\n\t\t9\t\n3\t68\tM\tFVPTC\tbone\ttotal thyroidectomy\talive\t+\n\nthiamazole\n\n\t\t15\t\n4\t66\tF\tFVPTC\tbone, lung\ttotal thyroidectomy\tdeath\t–\t\t10\t\n5\t54\tM\tFTC\tbone\tburn injury\n\nsurgery\n\n\tdeath\tunknown\tpost total thyroidectomy and treatment with radioactive iodine before 14 months\t16\t\n6\t91\tF\tFTC\n\nATC\n\n\tbone, lung\tunknown\tdeath\t–\tprimary ATC arising from FTC and multiple FTC metastases\tour case\t\nPTC papillary thyroid carcinoma, FVPTC follicular variant of PTC, FTC follicular thyroid carcinoma, ATC anaplastic thyroid carcinoma\n\nThyroid crisis associated with the presence of mixed FTC and ATC has never been reported. ATC proliferates rapidly and has a very poor prognosis [17]. There are several reports of patients with thyrotoxicosis due to ATC [18]. Compared to other subtypes of thyroid cancer, ATC rarely causes thyrotoxicosis or thyroid crisis. ATC may cause thyrotoxicosis through two mechanisms: leakage of thyroid hormone into the bloodstream via the mechanical destruction of thyrocytes, or hyperfunctioning metastatic tumours [19, 20]. In the present case, the patient’s symptoms rapidly deteriorated in the last 2 weeks before admission. During the clinical course, Tg peaked 6 months before admission then decreased, and her urinary iodine excretion was very high on admission. These data suggest that the ATC developed from the transformation of the coexisting FTC. Fozzatti et al. showed that the secretome of cancer-associated fibroblasts activated by ATC cell-derived conditioned media promoted FTC proliferation and invasion [21]. Based on this report, ATC facilitated FTC proliferation and metastases in the present case, promoting thyrotoxicosis severity.\n\nIn summary, we reported a case of thyroid crisis due to metastatic thyroid cancer. The autopsy revealed the presence of ATC arising from FTC and multiple metastases composed of FTC. Her thyrotoxicosis was caused by both/either primary and/or metastatic FTC lesions and perhaps facilitated by ATC. Although the trigger of her thyroid crisis was not identified, the aggravated progression of her clinical course suggests that careful monitoring of thyroid hormones and appropriate intervention are essential for the management of patients with thyroid cancer.\n\nAbbreviations\n\nCT Computed tomography\n\nTSH Thyroid-stimulating hormone\n\nFT4 Free thyroxine\n\nTg Thyroglobulin\n\nFT3 Free triiodothyronine\n\nKI Potassium iodide\n\nHCG Human chorionic gonadotropin\n\nPAX8 Paired box gene 8\n\nEMA Epithelial membrane antigen\n\nCEA Carcinoembryonic antigen\n\nTTF-1 Thyroid transcription factor-1\n\nATC Anaplastic thyroid carcinoma\n\nFTC Follicular thyroid carcinoma\n\ncAMP Cyclic adenosine monophosphate\n\nPTC Papillary thyroid carcinoma\n\nAcknowledgements\n\nNot applicable.\n\nAuthors’ contributions\n\nKT, MN, NA, and ST managed the patient as the attending physicians. M Yamamoto, M Yamauchi, and KK evaluated the medical management strategies. NY and RM performed the autopsy. KT, MN, RM, and KK wrote the paper. All authors read and approved the final manuscript.\n\nFunding\n\nNot applicable.\n\nAvailability of data and materials\n\nThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\n\nDeclarations\n\nEthics approval and consent to participate\n\nNot applicable.\n\nConsent for publication\n\nConsent for publication was obtained from all individual participants included in the study.\n\nCompeting interests\n\nThe authors declare that they have no competing interests in this paper.\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. Akamizu T Thyroid Storm: A Japanese Perspective Thyroid 2018 28 1 32 40 10.1089/thy.2017.0243 28899229\n2. Akamizu T Satoh T Isozaki O Suzuki A Wakino S Iburi T Tsuboi K Monden T Kouki T Otani H Teramukai S Uehara R Nakamura Y Nagai M Mori M Japan Thyroid Association Diagnostic criteria, clinical features, and incidence of thyroid storm based on nationwide surveys Thyroid. 2012 22 7 661 679 10.1089/thy.2011.0334 22690898\n3. De Leo S Lee SY Braverman LE Hyperthyroidism Lancet 2016 388 10047 906 918 10.1016/S0140-6736(16)00278-6 27038492\n4. Liu J Wang Y Da D Zheng M Hyperfunctioning thyroid carcinoma: a systematic review Mol Clin Oncol 2019 11 535 10.3892/mco.2019.1927 31798874\n5. Tura Bahadır Ç Yılmaz M Kılıçkan E Free triiodothyronine to free thyroxine ratio in the differential diagnosis of thyrotoxicosis and hyperthyroidism: a retrospective study Int J Clin Pract 2021 75 5 e14003 10.1111/ijcp.14003 33403716\n6. 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A rare cause of hyperthyroidism: functioning thyroid metastases. Case Reports. 2014, 2014:bcr2014206468.\n11. Markou K Georgopoulos N Kyriazopoulou V Vagenakis AG Iodine-induced hypothyroidism Thyroid. 2001 11 5 501 510 10.1089/105072501300176462 11396709\n12. Leung AM Braverman LE Consequences of excess iodine Nat Rev Endocrinol 2014 10 3 136 142 10.1038/nrendo.2013.251 24342882\n13. Solis-S JC Villalobos P Orozco A Delgado G Quintanar-Stephano A Garcia-Solis P Hernandez-Montiel HL Robles-Osorio L Valverde-R C Inhibition of intrathyroidal dehalogenation by iodide J Endocrinol 2011 208 1 89 96 10.1677/JOE-10-0300 20974636\n14. Tewari K Balderston KD Carpenter SE Major CA Papillary thyroid carcinoma manifesting as thyroid storm of pregnancy: case report Am J Obstet Gynecol 1998 179 3 818 819 10.1016/S0002-9378(98)70091-2 9757998\n15. 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Basaria S Udelsman R Tejedor-Sojo J Westra WH Krasner AS Anaplastic pseudothyroiditis Clin Endocrinol 2002 56 4 553 555 10.1046/j.1365-2265.2002.01495.x\n20. Phillips JS Pledger DR Hilger AW Rapid thyrotoxicosis in anaplastic thyroid carcinoma J Laryngol Otol 2007 121 7 695 697 10.1017/S0022215106005330 17156585\n21. Fozzatti L Alamino VA Park S Giusiano L Volpini X Zhao L Stempin CC Donadio AC Cheng SY Pellizas CG Interplay of fibroblasts with anaplastic tumor cells promotes follicular thyroid cancer progression Sci Rep 2019 9 1 8028 10.1038/s41598-019-44361-6 31142771\n\n",
"fulltext_license": "CC BY",
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"issue": "21(1)",
"journal": "BMC endocrine disorders",
"keywords": "Anaplastic thyroid carcinoma; Follicular thyroid carcinoma; Metastasis; Thyroid crisis",
"medline_ta": "BMC Endocr Disord",
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"nlm_unique_id": "101088676",
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"pages": "213",
"pmc": null,
"pmid": "34689780",
"pubdate": "2021-10-24",
"publication_types": "D016428:Journal Article",
"references": "9286911;20974636;11966749;33403716;28362912;11396709;31142771;28899229;9757998;29319130;31966991;17156585;31798874;24342882;15671779;16284430;29071241;25301427;22690898;27240885;27038492",
"title": "Thyroid crisis caused by metastatic thyroid cancer: an autopsy case report.",
"title_normalized": "thyroid crisis caused by metastatic thyroid cancer an autopsy case report"
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"abstract": "A 20-year-old woman underwent lacrimal gland biopsy for unilateral swelling and was unexpectedly found to have olive-green discoloration of her orbital rim. Postoperative questioning revealed that as a teenager she had been treated for acne with minocycline, a semisynthetic tetracycline antibiotic and a first-line treatment for moderate and severe acne. While hyperpigmentation is a known side effect of minocycline, reports of pigmentation changes of the periorbital bones are relatively rare and could pose a diagnostic dilemma during surgery.",
"affiliations": "Section of Plastic Surgery, Department of Surgery, University of Michigan, Ann Arbor, Michigan.;Department of Ophthalmology, University of Michigan, Ann Arbor, Michigan. Electronic address: cesarb@med.umich.edu.",
"authors": "Ballard|Tiffany N S|TN|;Briceño|César A|CA|",
"chemical_list": "D000900:Anti-Bacterial Agents; D008911:Minocycline",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1091-8531",
"issue": "20(2)",
"journal": "Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus",
"keywords": null,
"medline_ta": "J AAPOS",
"mesh_terms": "D000152:Acne Vulgaris; D000900:Anti-Bacterial Agents; D001706:Biopsy; D005260:Female; D006801:Humans; D007765:Lacrimal Apparatus; D008911:Minocycline; D009916:Orbital Diseases; D010859:Pigmentation Disorders; D014792:Visual Acuity; D055815:Young Adult",
"nlm_unique_id": "9710011",
"other_id": null,
"pages": "182-4",
"pmc": null,
"pmid": "26988772",
"pubdate": "2016-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Minocycline-induced orbital rim discoloration.",
"title_normalized": "minocycline induced orbital rim discoloration"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/16/0080249",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MINOCYCLINE HYDROCHLORIDE"
},
"drugaddit... |
{
"abstract": "Influenza myocarditis is an underappreciated and severe complication of influenza infection, estimated to be present in about 10% of all influenza cases. We present a case of a woman who precipitously died of fulminant influenza myocarditis and then review the historical data, literature and expert recommendations for suspecting and managing influenza myocarditis.",
"affiliations": "Pharmacy, Montefiore Wakefield Campus, Bronx, New York, USA.;Cleveland Clinic, Cleveland, Ohio, USA.;Infectious Diseases, Montefiore Wakefield Campus, Bronx, New York, USA.",
"authors": "Saraiya|Nidhi|N|;Singh|Supriya|S|;Corpuz|Marilou|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-228201",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(7)",
"journal": "BMJ case reports",
"keywords": "cardiovascular medicine; influenza",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007251:Influenza, Human; D008875:Middle Aged; D009205:Myocarditis; D017180:Tachycardia, Ventricular",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31266755",
"pubdate": "2019-07-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25793705;10904853;24046380;24150467;19880690;23304476;18625525;20945722;18617482;27832612",
"title": "Fatal influenza myocarditis with incessant ventricular tachycardia.",
"title_normalized": "fatal influenza myocarditis with incessant ventricular tachycardia"
} | [
{
"companynumb": "US-PFIZER INC-2019315802",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ALBUTEROL SULFATE"
},
"drugadditional": null,... |
{
"abstract": "Polyarteritis nodosa (PAN) is a necrotising systemic vasculitis involving medium-sized and small-sized vessels. PAN limited to a single organ is rare, particularly in the elderly population. Herein, we present a 73-year-old-woman who developed severe abdominal pain. Mesenteric angiography showed multifocal areas of segmental dilation and narrowing of the superior mesenteric, ileocolic and right colonic arteries. Exploratory laparotomy revealed multiple areas of necrosis of the jejunum for which resection was performed. Histopathological exam disclosed mesenteric vasculitis with fibrinoid necrosis of the arterial wall with leucocytic infiltrates and haemorrhages consistent with PAN. She was started on high-dose corticosteroids with an initial good response. However, 6 months later, she developed intestinal pseudo-obstruction for which oral cyclophosphamide was started. After 5 months of cyclophosphamide therapy, she remained stable without further relapses. Our case suggests that PAN should be considered in elderly patients presenting with abdominal pain even in the absence of systemic involvement.",
"affiliations": "Department of Medicine, Division of Rheumatology, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico.;Department of Pathology and Laboratory Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico.;Department of Pathology and Laboratory Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico.;Department of Medicine, Division of Rheumatology, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico luis.vila2@upr.edu.",
"authors": "González-Meléndez|Ariana|A|;Medina-Parrilla|Eduardo J|EJ|;Vélez|Román|R|;Vilá|Luis M|LM|",
"chemical_list": "D003520:Cyclophosphamide",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-241431",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(3)",
"journal": "BMJ case reports",
"keywords": "geriatric medicine; small intestine; vasculitis",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D015746:Abdominal Pain; D000368:Aged; D000792:Angiography; D003520:Cyclophosphamide; D005260:Female; D006801:Humans; D007422:Intestines; D010488:Polyarteritis Nodosa",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33664043",
"pubdate": "2021-03-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Isolated intestinal polyarteritis nodosa in an elderly patient.",
"title_normalized": "isolated intestinal polyarteritis nodosa in an elderly patient"
} | [
{
"companynumb": "PR-TEVA-2021-PR-1907132",
"fulfillexpeditecriteria": "1",
"occurcountry": "PR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DENOSUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "The use of vascular endothelial growth factor inhibitors such as sorafenib is limited by a risk of severe cardiovascular toxicity. A 28-year-old man with acute myeloid leukemia treated with prednisone, tacrolimus, and sorafenib following stem cell transplantation presented with severe bilateral lower extremity claudication. The patient was discharged against medical advice prior to finalizing a cardiovascular evaluation, but returned 1 week later with signs suggestive of septic shock. Laboratory tests revealed troponin I of 12.63 ng/mL, BNP of 1690 pg/mL, and negative infectious workup. Electrocardiogram showed sinus tachycardia and new pathologic Q waves in the anterior leads. Coronary angiography revealed severe multivessel coronary artery disease. Peripheral angiography revealed severely diseased left anterior and posterior tibial arteries, tibioperoneal trunk, and peroneal artery, and subtotal occlusion of the right posterior tibial artery. Multiple coronary and peripheral drug-eluting stents were implanted. An intra-aortic balloon pump was placed. Cardiac magnetic resonance imaging revealed chronic left ventricular infarction with some viability, 17% ejection fraction, and left ventricular mural thrombi. The patient opted for medical management. Persistent symptoms 9 months later led to repeat angiography, showing total occlusion of the second obtuse marginal artery due to in-stent restenosis with proximal stent fracture, and chronic total occlusion of the right internal iliac artery extending to the pudendal branch. Cardiac positron emission tomography/computed tomography viability study demonstrated viable myocardium, deeming revascularization appropriate. Symptom resolution was obtained with no recurrences. Sorafenib-associated vasculopathy may follow a fulminant course. Multimodality cardiovascular imaging is essential for optimal management.",
"affiliations": "Department of Internal Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.;Department of Cardiology, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street, 1451, 77030, Houston, TX, USA.;Department of Cardiology, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street, 1451, 77030, Houston, TX, USA.;Department of Cardiology, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street, 1451, 77030, Houston, TX, USA.;Department of Cardiology, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street, 1451, 77030, Houston, TX, USA.;Department of Cardiology, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street, 1451, 77030, Houston, TX, USA.;Department of Cardiology, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street, 1451, 77030, Houston, TX, USA.;Department of Cardiology, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street, 1451, 77030, Houston, TX, USA.;Department of Internal Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.;Department of Internal Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.;Department of Cardiology, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street, 1451, 77030, Houston, TX, USA. ciliescu@mdanderson.org.",
"authors": "Sudasena|Daryl|D|;Balanescu|Dinu Valentin|DV|;Donisan|Teodora|T|;Hassan|Saamir|S|;Palaskas|Nicolas|N|;Kim|Peter|P|;Karimzad|Kaveh|K|;Lopez-Mattei|Juan|J|;Arain|Salman|S|;Gould|K Lance|KL|;Iliescu|Cezar|C|0000-0002-8817-4579",
"chemical_list": "D000970:Antineoplastic Agents; D002317:Cardiovascular Agents; D047428:Protein Kinase Inhibitors; D000077157:Sorafenib",
"country": "United States",
"delete": false,
"doi": "10.1007/s12012-018-9499-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1530-7905",
"issue": "19(4)",
"journal": "Cardiovascular toxicology",
"keywords": "Cardio-Oncology; Cardiotoxicity; Coronary artery disease; Sorafenib; Tyrosine kinase inhibitors; Vasculopathy",
"medline_ta": "Cardiovasc Toxicol",
"mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D066126:Cardiotoxicity; D002317:Cardiovascular Agents; D003324:Coronary Artery Disease; D023903:Coronary Restenosis; D047548:Defibrillators; D017147:Defibrillators, Implantable; D054855:Drug-Eluting Stents; D004554:Electric Countershock; D057510:Endovascular Procedures; D006801:Humans; D007423:Intra-Aortic Balloon Pumping; D015470:Leukemia, Myeloid, Acute; D008297:Male; D009203:Myocardial Infarction; D058729:Peripheral Arterial Disease; D047428:Protein Kinase Inhibitors; D000077157:Sorafenib; D016896:Treatment Outcome",
"nlm_unique_id": "101135818",
"other_id": null,
"pages": "382-387",
"pmc": null,
"pmid": "30543051",
"pubdate": "2019-08",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Fulminant Vascular and Cardiac Toxicity Associated with Tyrosine Kinase Inhibitor Sorafenib.",
"title_normalized": "fulminant vascular and cardiac toxicity associated with tyrosine kinase inhibitor sorafenib"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/19/0113476",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "IDARUBICIN"
},
"drugadditional": null,
... |
{
"abstract": "HSV-2 is an important cause of the acute retinal necrosis (ARN) syndrome in younger patients. We describe an atypical case of HSV-2 ARN in the context of neonatal exposure and subconjunctival steroid injection. Clinicians should be aware of the association of neonatal or congenital exposure to HSV-2 as a risk factor for this disease because early treatment may improve outcome and/or avoid involvement of both eyes.",
"affiliations": "Department of Ophthalmology, Royal Brisbane & Women's Hospital; ; School of Medicine, University of Queensland, Brisbane;",
"authors": "McGrath|Lindsay|L|;Woods|Marion|M|;Lee|Lawrence|L|;Conrad|Diana|D|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D000998:Antiviral Agents; D005938:Glucocorticoids; D003907:Dexamethasone",
"country": "United States",
"delete": false,
"doi": "10.5693/djo.02.2013.02.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1542-8958",
"issue": "19(2)",
"journal": "Digital journal of ophthalmology : DJO",
"keywords": null,
"medline_ta": "Digit J Ophthalmol",
"mesh_terms": "D000328:Adult; D000893:Anti-Inflammatory Agents; D000998:Antiviral Agents; D003907:Dexamethasone; D015828:Eye Infections, Viral; D005938:Glucocorticoids; D006561:Herpes Simplex; D018258:Herpesvirus 2, Human; D006801:Humans; D008297:Male; D011251:Pregnancy Complications, Infectious; D015882:Retinal Necrosis Syndrome, Acute; D016896:Treatment Outcome; D014775:Virus Activation",
"nlm_unique_id": "9605355",
"other_id": null,
"pages": "28-32",
"pmc": null,
"pmid": "24109247",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "1652896;10209451;19050917;15973328;10704570;10682968;17184841;16764663;8053466;20079537;11320015;9227211;8956648;17504853;11351976;22889540;12488268;8349421;8172275;11508880;11449326;17972224;19624343",
"title": "Acute retinal necrosis (ARN) in the context of neonatal HSV-2 exposure and subconjunctival dexamethasone: case report and literature review.",
"title_normalized": "acute retinal necrosis arn in the context of neonatal hsv 2 exposure and subconjunctival dexamethasone case report and literature review"
} | [
{
"companynumb": "PHHY2015AU064816",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GENTAMICIN"
},
"drugadditional": null,
"drug... |
{
"abstract": "A 29-year-old primigravida woman with a known history of primary aldosteronism due to a right aldosteronoma presented with uncontrolled hypertension at 5 weeks of estimated gestation of a spontaneous pregnancy. Her hypertension was inadequately controlled with pharmacotherapy which lead to the consideration of surgical management for her primary aldosteronism. She underwent curative right unilateral adrenalectomy at 19 weeks of estimated gestational age. The procedure was uncomplicated, and her blood pressure normalized post-operatively. She did, however, have a preterm delivery by cesarean section due to intrauterine growth retardation with good neonatal outcome. She is normotensive to date.\nPrimary aldosteronism is the most common etiology of secondary hypertension with an estimated prevalence of 5-10% in the hypertensive population. It is important to recognize the subtypes of primary aldosteronism given that certain forms can be treated surgically. Hypertension in pregnancy is associated with significantly higher maternal and fetal complications. Data regarding the treatment of primary aldosteronism in pregnancy are limited. Adrenalectomy can be considered during the second trimester of pregnancy if medical therapy fails to adequately control hypertension from primary aldosteronism.",
"affiliations": "Section on Endocrinology and Genetics, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.;Section on Endocrinology and Genetics, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.;Section on Endocrinology and Genetics, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.;Section on Endocrinology and Genetics, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.;Section on Endocrinology and Genetics, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.",
"authors": "Shekhar|Skand|S|;Haykal|Rasha|R|;Kamilaris|Crystal|C|;Stratakis|Constantine A|CA|0000-0002-4058-5520;Hannah-Shmouni|Fady|F|0000-0001-6829-6205",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": null,
"fulltext": "\n==== Front\nEndocrinol Diabetes Metab Case Rep\nEndocrinol Diabetes Metab Case Rep\nEDM\nEndocrinology, Diabetes & Metabolism Case Reports\n2052-0573 Bioscientifica Ltd Bristol \n\n10.1530/EDM-20-0043\nEDM200043\nAdult\nFemale\nBlack - African\nUnited States\nAdrenal\nAdrenal\nAldosterone\nRenin\nHyperaldosteronism\nHypertension\nHypokalaemia\nAdrenocortical Adenoma\nIntrauterine Growth Retardation\nHypertension\nHypokalaemia\nAldosterone (serum)\nRenin plasma activity\nBicarbonate\nPotassium\nMRI\nCT scan\nBlood pressure\nResection of tumour\nLaparoscopic adrenalectomy\nCaesarean section\nLabetalol\nBeta-blockers\nAlpha-blockers\nNifedipine\nHydralazine*\nTerazosin\nHydrochlorothiazide\nLosartan\nPotassium chloride\nVerapamil*\nCardiology\nUnique/Unexpected Symptoms or Presentations of a Disease\nUnique/Unexpected Symptoms or Presentations of a Disease\nCurative resection of an aldosteronoma causing primary aldosteronism in the second trimester of pregnancy\nS Shekhar and othersPA and pregnancyShekhar Skand 1 Haykal Rasha 1 Kamilaris Crystal 1 http://orcid.org/0000-0002-4058-5520Stratakis Constantine A 1 http://orcid.org/0000-0001-6829-6205Hannah-Shmouni Fady 1 1 Section on Endocrinology and Genetics, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA\nCorrespondence should be addressed to F Hannah-Shmouni; Email: fady.hannah-shmouni@nih.gov\n04 8 2020 \n2020 \n2020 20-004321 6 2020 13 7 2020 © 2020 The authors2020The authors This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License..Summary\nA 29-year-old primigravida woman with a known history of primary aldosteronism due to a right aldosteronoma presented with uncontrolled hypertension at 5 weeks of estimated gestation of a spontaneous pregnancy. Her hypertension was inadequately controlled with pharmacotherapy which lead to the consideration of surgical management for her primary aldosteronism. She underwent curative right unilateral adrenalectomy at 19 weeks of estimated gestational age. The procedure was uncomplicated, and her blood pressure normalized post-operatively. She did, however, have a preterm delivery by cesarean section due to intrauterine growth retardation with good neonatal outcome. She is normotensive to date.\n\nLearning points:\nPrimary aldosteronism is the most common etiology of secondary hypertension with an estimated prevalence of 5–10% in the hypertensive population.\n\nIt is important to recognize the subtypes of primary aldosteronism given that certain forms can be treated surgically.\n\nHypertension in pregnancy is associated with significantly higher maternal and fetal complications.\n\nData regarding the treatment of primary aldosteronism in pregnancy are limited.\n\nAdrenalectomy can be considered during the second trimester of pregnancy if medical therapy fails to adequately control hypertension from primary aldosteronism.\n\nPatient Demographics\nAdultFemaleBlack - African United StatesClinical Overview\nAdrenalAdrenalAldosteroneReninHyperaldosteronismHypertensionHypokalaemiaAdrenocortical adenomaIntrauterine growth retardationDiagnosis and Treatment\nHypertensionHypokalaemiaAldosterone (serum)Renin plasma activityBicarbonatePotassiumMRICT scanBlood pressureResection of tumourLaparoscopic adrenalectomyCaesarean sectionLabetalolBeta-blockersAlpha-blockersNifedipineHydralazine*TerazosinHydrochlorothiazideLosartanPotassium chlorideVerapamil*Related Disciplines\nCardiologyPublication Details\nUnique/unexpected symptoms or presentations of a diseaseAugust2020\n==== Body\nBackground\nHypertension in pregnancy is a relatively common occurrence that is consistently associated with poor maternal and fetal outcomes (1). Secondary hypertension caused by endocrine dysfunction is less frequent, estimated to comprise less than 2% of all hypertension in pregnancy (1). Physiological hormonal changes that occur in pregnancy make establishing the diagnosis of endocrine hypertension such as that due to primary aldosteronism (PA) challenging, with less than 100 such cases reported in the literature (2). We report a case of PA in pregnancy due to an aldosterone producing adrenocortical adenoma that was successfully treated with unilateral adrenalectomy in the second trimester after the failure of medical therapy.\n\nCase presentation\nA 29-year-old woman from Ghana with a known history of resistant hypertension and hypokalemia was evaluated at the National Institutes of Health (NIH) Clinical Center under protocol 00-CH-0160 (Study of Adrenal Gland Tumors, NICHD, NIH, ClinicalTrials.gov Identifier: NCT00005927) for PA. She was diagnosed with hypertension at the age of 27 and was initiated on treatment with anti-hypertensive medications; however, she had progressive hypertension and hypokalemia to 3 mmol/L (3.4–5.1 mmol/L). She moved to the United States 11 months prior to her NIH visit and at the time adjustments were made to her anti-hypertensive therapy but secondary causes of hypertension were not evaluated. About 7 months later, she was found to have significantly elevated blood pressure with systolic blood pressure greater than 200 mmHg and diastolic blood pressure greater than 110 mmHg during evaluation by a reproductive endocrinologist for infertility. She was referred to a local emergency department for further care and was admitted to the hospital. Upon discharge from this hospital, she sought an assessment with a new healthcare provider who detected worsening hypertension and hypokalemia and initiated evaluation for PA. That workup led to her initial diagnosis of PA and referral to the NIH.\n\nHer other medical conditions included elevated Lp(a) and infertility due to blocked fallopian tubes. She did not have a history of nicotine, alcohol or other recreational drug use and her family history was significant for late-onset hypertension in both parents and maternal grandparents. Her physical examination was significant for stage 2 hypertension (based on blood pressure readings), but was otherwise unremarkable, without physical signs of hypercortisolemia, including obesity, facial fullness, dorsocervical or supraclavicular fat deposition, facial plethora, acne, hirsutism, alopecia, thin skin, bruising, striae, muscle weakness, or impaired memory. At the time of her initial evaluation at our Clinical Center, her medications included labetalol, nifedipine, hydrochlorothiazide, losartan, and potassium chloride. To facilitate biochemical evaluation for PA per our research protocol, her anti-hypertensive medications were switched to hydralazine, verapamil, and terazosin.\n\nInvestigation\nAt her initial pre-pregnancy visit, she underwent biochemical screening for PA with plasma renin activity and plasma aldosterone concentration, which was diagnostic for PA. As per our research protocol, she had additional testing with saline suppression test, which was also consistent with PA (data not shown). She did not have biochemical evidence of hypercortisolism, with the 1-mg overnight dexamethasone suppression test and serial urinary free cortisol measurements within the normal range, and pheochromocytoma was biochemically excluded (Table 1). A CT of the adrenal glands revealed a low attenuation nodule in her right adrenal gland measuring 1.6 cm × 1.0 cm, with a density of 8 HU pre-contrast consistent with a benign adenoma (Fig. 1A and B). An MRI of the adrenal glands showed a hypoenhancing, isointense T1, hypointense T2 right adrenal nodule measuring 2.2 cm × 1.0 cm with signal loss in out of phase sequence, and a normal left adrenal gland (Fig. 1C). As part of the research protocol, she underwent an uncomplicated adrenal venous sampling which localized her disease to the right adrenal gland (data not shown). Following her adrenal venous sampling, she was discharged on the following anti-hypertensive therapy: verapamil 240 mg twice daily, terazosin 5 mg twice daily, hydralazine 50 mg every 8 h and potassium chloride 40 mEq daily.\nFigure 1 Imaging of the adrenal glands. Non-contrast CT adrenal of the patient: (A) Coronal view. (B) Axial view. (C) MRI of the adrenal glands. Arrow points to the adrenal adenoma.\n\n\nTable 1 Laboratory evaluation of the patient.\n\n08:00 h (fasting) laboratory parameter\tNormal range\tMeasured value\t\nSodium, mmol/L\t136–145\t141\t\nPotassium, mmol/L\t3.4–5.1\t2.6\t\nChloride, mmol/L\t98–107\t98 \t\nBlood urea nitrogen, mg/dL\t6–20\t10\t\nSerum creatinine, mg/dL\t0.51–0.95\t0.60\t\nPlasma glucose, mg/dL\t74–106\t110\t\nBicarbonate, mEq/L\t22–24\t30\t\nPlasma aldosterone concentration, ng/dL\t0–30\t26.2\t\nPlasma renin activity, ng/mL/h\t0.6–4.3\t<0.15\t\nSerum cortisol*, µg/dL\t<1.8\t<1.8\t\n24-h urinary free cortisol, µg/day\t3.5–45\t40.1 \t\n24-h urinary free cortisol, µg/day\t3.5–45\t40.8\t\n24-ho urinary free cortisol, µg/day\t3.5–45\t39.5\t\n24-h urine metanephrines**, µg/day \t<400\t160\t\n24-h urine normetanephrine**, µg/day \t<900\t297 \t\n24-h urine total metanephrine**, µg/day \t<1300\t457 \t\n*After 1 mg overnight dexamethasone suppression test; **when hypertensive.\n\n\n\n\nTreatment\nGiven the patient’s unilateral PA, she was referred for unilateral right adrenalectomy and was counselled regarding contraception prior to surgical treatment. The patient returned 8 weeks later for the planning of the definitive surgical management of her PA, but she was noted to be spontaneously and unintentionally pregnant with an estimated gestational age (EGA) of 5 weeks. Her treatment was switched to hydralazine 50 mg every 8 h and labetalol 200 mg twice daily with initial control of her hypertension. However, 2 weeks later, the patient’s blood pressure was noted to be persistently elevated with blood pressure readings necessitating the addition of nifedipine to her pharmacotherapy and eventual increase in her labetalol dose to 300 mg in the morning and 400 mg in the evening. These medical treatment measures failed to normalize her blood pressure with systolic blood pressure >150 mmHg and diastolic blood pressure >90 mmHg. The patient was counselled about her treatment options and she elected to pursue laparoscopic unilateral right adrenalectomy. The operation was challenging given that the right adrenal gland was densely adherent to the liver and the inferior vena cava and was positioned high in the retroperitoneum. Ultimately, the patient had right adrenalectomy with clear margins.\n\nOutcome and follow-up\nIn the immediate post-operative period, the patient was weaned from labetalol 400 mg twice daily to 150 mg twice daily and her blood pressure and serum potassium gradually improved. At the next post-operative follow-up visit (EGA 23 weeks), when she was off all anti-hypertensive medications, her blood pressure was within the normal range. At EGA of 35 weeks, the patient underwent delivery by cesarean section due to intrauterine growth retardation. She was pre-emptively started on labetalol but remained normotensive and was weaned off this medication by 6 weeks postpartum.\n\nDiscussion\nChronic hypertension affects 1.8% of all pregnancies and fewer than 100 cases of secondary hypertension from PA have been reported to date (1). The diagnosis of PA in pregnancy poses a unique challenge since the placenta upregulates the secretion of renin and angiotensinogen, which in turn leads to a higher secretion of aldosterone and sodium retention (Fig. 2). Further, a systematic review reported that PA occurrence in pregnancy may only be identified postpartum as persistent hypertension (3).\nFigure 2 Physiological changes in the renin–angiotensin–aldosterone system in pregnancy. Courtesy of Skand Shekhar, NICHD, NIH.\n\n\n\n\nPA may behave variably in pregnancy, that is, the degree of PA may improve or worsen in pregnancy. This is because, in some women, the anti-mineralocorticoid activity of progesterone may attenuate the effects of aldosterone; whereas in other women the increased activation of the renin-angiotensin-aldosterone system may cause increased secretion of aldosterone, which may exacerbate the hypokalemia and hypertension. Furthermore, increased expression of LH receptor and the gonadotropin-releasing hormone receptor in aldosteronomas may trigger aldosterone release with worsening clinical features in pregnancy (4, 5).\n\nOf the previously reported cases of PA in pregnancy, the majority delivered before term (1, 6, 7, 8, 9, 10). Other notable adverse associations of PA in pregnancy include intrauterine growth retardation and intrauterine fetal demise (1). Our patient underwent a preterm cesarean section in the setting of intrauterine growth retardation reinforcing the association between PA and pregnancy complications. There is recent evidence of the presence of unique adrenal CTNNB1 pathogenic variants in pregnant women who developed PA (5). Our patient developed PA pre-pregnancy. Genetic and immunohistochemical analyses of her aldosteronoma were not pursued.\n\nWhile non-pregnant reference ranges for plasma aldosterone concentration and plasma renin activity cannot be used in pregnancy due to the aforementioned physiology, the first step in the detection of PA in pregnancy remains the measurement of plasma aldosterone concentration and plasma renin activity or direct renin concentration (11). Alternatively, measurement of 24-h urine sodium and aldosterone (on a liberal sodium diet) can be performed. Malha and colleagues have proposed a cutoff of plasma renin activity of less than 4 ng/mL/h instead of less than 1 ng/mL/h as in non-pregnant patients (12). Notably, in normokalemic patients with a positive initial screening test, confirmatory testing is advisable. It is important to note that our patient’s triad of hypokalemia, elevated plasma aldosterone concentration of greater than 20 ng/dL and suppressed plasma renin activity (or direct renin concentration equivalent) of less than 1 ng/mL/h confirms PA without the need for additional testing. However, our patient was enrolled in a research protocol and, for that reason, additional testing (including saline suppression test and lateralization studies) was performed per protocol. The patient had another notable finding of hypercarbia, which can be seen in PA due to hydrogen excretion from the kidneys. In general, confirmatory testing with saline suppression test or subtype classification with adrenal venous sampling are also not recommended during pregnancy given the risks of iatrogenic volume overload and radiation exposure, respectively. Fortunately, most pregnancies occur in females less than 35–40 years of age, an age cutoff used by the Endocrine Society to forego adrenal venous sampling (11).\n\nMedical management of PA in non-pregnant female patients is achieved by primarily using mineralocorticoid receptor antagonists (MRA) such as spironolactone or eplerenone (13). Given the teratogenic potential of these agents, options for medical management during pregnancy include beta blockers, calcium channel blockers, hydralazine and alpha blockers, which were employed by us in an attempt to control this patient’s blood pressure. Some suggest eplerenone as the MRA of choice if an MRA needs to be used in pregnancy (13, 14). However, if hypertension and hypokalaemia remain suboptimally controlled, then surgical intervention such as unilateral adrenalectomy is indicated.\n\nOur patient had pre-pregnancy confirmation of unilateral PA, which aided in choosing a surgical option. This is generally not available to pregnant patients with PA since confirmatory/localization testing is contraindicated. In some reports, six cases of successful adrenalectomy in PA have been reported, of whom five had preterm delivery, similar to our case (1, 2, 15). One patient who refused surgery in the setting of uncontrolled hypertension and an adrenal lesion had an unfavourable fetal outcome (16). MRI of the abdomen is the radiographic modality of choice to identify the adrenal anatomy and the presence of adrenal tumors before proceeding with surgery. Although most adrenalectomies can be deferred until after delivery, surgeries that must be performed during pregnancy are reserved for the second trimester for the best outcomes (17). Indications for adrenalectomy during pregnancy include patient preference, adrenocortical cancer, or severe or poorly controlled hypertension (as in our case).\n\nIn conclusion, while PA is rare in pregnancy, it is the most common cause of secondary hypertension with unique diagnostic and therapeutic challenges. If not optimally treated, PA is associated with poor maternal and fetal outcomes.\n\nDeclaration of interest\nConstantine Stratakis holds patents on the PRKAR1A, PDE11A, and the GPR101 genes and his laboratory is the recipient of past and ongoing research grant support from Pfizer, Inc.\n\nFunding\nThis work was supported by the research project Z01-HD008920 (Principal Investigator: Constantine A Stratakis) of the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA.\n\nPatient consent\nWritten informed consent has been obtained from the patient for publication of the submitted article and accompanying images.\n\nAuthor contribution statement\nS S drafted the manuscript, obtained images, drafted tables and approved the final version. R H drafted the manuscript, cared directly for the patient and approved the final version. C K drafted the manuscript, conceptualized the draft and approved the final version. C A S and F H S conceptualized the draft, oversaw the writing, cared for the patient and approved the final version.\n==== Refs\nReferences\n1 Affinati AH Auchus RJ \nEndocrine causes of hypertension in pregnancy\n. Gland Surgery \n2020 \n9 \n69 –79\n. (10.21037/gs.2019.12.04 )32206600 \n2 Landau E Amar L \nPrimary aldosteronism and pregnancy\n. Annales d’Endocrinologie \n2016 \n77 \n148 –160\n. (10.1016/j.ando.2016.04.009 )\n3 Kilmartin C Opu T Podymow T Dayan N \nPrimary hyperaldosteronism presenting as persistent postpartum hypertension: illustrative case and systematic review\n. Obstetric Medicine \n2019 \n12 \n190 –195\n. (10.1177/1753495X18772999 )31853260 \n4 Gagnon N Cáceres-Gorriti KY Corbeil G El Ghoyareb N Ludwig N Latour M Lacroix A Bourdeau I \nGenetic characterization of GnRH/LH-responsive primary aldosteronism\n. Journal of Clinical Endocrinology and Metabolism \n2018 \n103 \n2926 –2935\n. (10.1210/jc.2018-00087 )29726953 \n5 Teo AE Garg S Shaikh LH Zhou J Karet Frankl FE Gurnell M Happerfield L Marker A Bienz M Azizan EA , \nPregnancy, primary aldosteronism, and adrenal CTNNB1 mutations\n. New England Journal of Medicine \n2015 \n373 \n1429 –1436\n. (10.1056/NEJMoa1504869 )26397949 \n6 Morton A \nPrimary aldosteronism and pregnancy\n. Pregnancy Hypertension \n2015 \n5 \n259 –262\n. (10.1016/j.preghy.2015.08.003 )26597737 \n7 Okawa T Asano K Hashimoto T Fujimori K Yanagida K Sato A \nDiagnosis and management of primary aldosteronism in pregnancy: case report and review of the literature\n. American Journal of Perinatology \n2002 \n19 \n31 –36\n. (10.1055/s-2002-20170 )11857094 \n8 Eguchi K Hoshide S Nagashima S Maekawa T Sasano H Kario K \nAn adverse pregnancy-associated outcome due to overlooked primary aldosteronism\n. Internal Medicine \n2014 \n53 \n2499 –2504\n. (10.2169/internalmedicine.53.2762 )25366010 \n9 Albiger NM Sartorato P Mariniello B Iacobone M Finco I Fassina A Mantero F \nA case of primary aldosteronism in pregnancy: do LH and GNRH receptors have a potential role in regulating aldosterone secretion?\n\nEuropean Journal of Endocrinology \n2011 \n164 \n405 –412\n. (10.1530/EJE-10-0879 )21330483 \n10 Shigematsu K Yamaguchi N Nakagaki T Sakai H \nA case of unilateral adrenal hyperplasia being difficult to distinguish from aldosterone-producing adenoma\n. Experimental and Clinical Endocrinology and Diabetes \n2009 \n117 \n124 –128\n. (10.1055/s-2008-1078737 )18561092 \n11 Funder JW Carey RM Mantero F Murad MH Reincke M Shibata H Stowasser M Young WF \nThe management of primary aldosteronism: case detection, diagnosis, and treatment: an Endocrine Society clinical practice guideline\n. Journal of Clinical Endocrinology and Metabolism \n2016 \n101 \n1889 –1916\n. (10.1210/jc.2015-4061 )26934393 \n12 Malha L August P \nSecondary hypertension in pregnancy\n. Current Hypertension Reports \n2015 \n17 \n53 (10.1007/s11906-015-0563-z )26068655 \n13 Riester A Reincke M \nProgress in primary aldosteronism: mineralocorticoid receptor antagonists and management of primary aldosteronism in pregnancy\n. European Journal of Endocrinology \n2015 \n172 \nR23 –R30\n. (10.1530/EJE-14-0444 )25163723 \n14 Gunganah K Carpenter R Drake WM \nEplerenone use in primary aldosteronism during pregnancy\n. Clinical Case Reports \n2016 \n4 \n81 –82\n. (10.1002/ccr3.355 )26783442 \n15 Nursal TZ Caliskan K Ertorer E Parlakgumus A Moray G \nLaparoscopic treatment of primary hyperaldosteronism in a pregnant patient\n. Canadian Journal of Surgery \n2009 \n52 \nE188 –E190\n.\n16 Kreze A JrKothaj P Dobakova M Rohon S \nPrimary aldosteronism caused by aldosterone-producing adenoma in pregnancy – complicated by EPH gestosis\n. Wiener Klinische Wochenschrift \n1999 \n111 \n855 –857\n.10586491 \n17 Kamoun M Mnif MF Charfi N Kacem FH Naceur BB Mnif F Dammak M Rekik N Abid M \nAdrenal diseases during pregnancy: pathophysiology, diagnosis and management strategies\n. American Journal of the Medical Sciences \n2014 \n347 \n64 –73\n. (10.1097/MAJ.0b013e31828aaeee )23514671\n\n",
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"keywords": "2020; Adrenal; Adrenocortical adenoma; Adult; Aldosterone; Aldosterone (serum); Alpha-blockers; August; Beta-blockers; Bicarbonate; Black - African ; Blood pressure; CT scan; Caesarean section; Cardiology; Female; Hydralazine*; Hydrochlorothiazide; Hyperaldosteronism; Hypertension; Hypokalaemia; Intrauterine growth retardation; Labetalol; Laparoscopic adrenalectomy; Losartan; MRI; Nifedipine; Potassium; Potassium chloride; Renin; Renin plasma activity; Resection of tumour; Terazosin; Unique/unexpected symptoms or presentations of a disease; United States; Verapamil*",
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"title": "Curative resection of an aldosteronoma causing primary aldosteronism in the second trimester of pregnancy.",
"title_normalized": "curative resection of an aldosteronoma causing primary aldosteronism in the second trimester of pregnancy"
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"abstract": "Calcineurin inhibitors are imperative in the success of a transplanted organ. However, these immunosuppressants can lead to a rare complication known as calcineurin inhibitor-induced pain syndrome, which may not be recognized early and managed appropriately. We present a case of a 35-year-old woman who underwent a combined liver/kidney transplant and developed lower extremity pain while being maintained on tacrolimus. This case illustrates a patient with previously reported characteristic clinical features of calcineurin inhibitor-induced pain syndrome in addition to uncharacteristic neuropathic symptoms and imaging findings. The patient was treated successfully with gabapentin, calcitonin nasal spray, and acupuncture. Early recognition of this syndrome can help improve a patient's quality of life.\n\n\n\nV.",
"affiliations": "Medical College of Wisconsin, Medical College of Wisconsin Affiliated Hospitals (MCWAH), Milwaukee, WI.;Medical College of Wisconsin, Medical College of Wisconsin Affiliated Hospitals (MCWAH), Milwaukee, WI.",
"authors": "Mohideen|Thanzeela Kausar|TK|;Wu|Hong|H|",
"chemical_list": "D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents",
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"mesh_terms": "D000328:Adult; D065095:Calcineurin Inhibitors; D005260:Female; D006084:Graft Rejection; D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D016031:Liver Transplantation; D035002:Lower Extremity; D010149:Pain, Postoperative",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Immunosuppressant Medication-Induced Lower Extremity Pain After Combined Liver and Kidney Transplant: A Case Report.",
"title_normalized": "immunosuppressant medication induced lower extremity pain after combined liver and kidney transplant a case report"
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"abstract": "Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of hematopoietic cell transplantation conditioning or high-dose chemotherapy. The underlying pathogenesis involves toxic injury to hepatocytes and sinusoidal endothelial cells. Presenting symptoms include ascites, weight gain, hepatomegaly, and hyperbilirubinemia. Severe VOD/SOS with multiorgan failure has a mortality rate of >80% if left untreated. Thioguanine, a chemotherapy drug used to treat acute lymphoblastic leukemia, has been shown to cause VOD/SOS. Here, we describe cases of 2 patients who developed very severe VOD/SOS after starting thioguanine for acute lymphoblastic leukemia; both achieved complete remission with defibrotide and experienced no defibrotide-related adverse events.",
"affiliations": "Department of Pediatrics Section of Pediatric Radiology, Institute of Diagnostic and Interventional Radiology, Jena University Hospital, Jena, Germany.",
"authors": "Gruhn|Bernd|B|;Brodt|Grit|G|;Mentzel|Hans-Joachim|HJ|;Ernst|Jana|J|",
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"fulltext": "\n==== Front\nJ Pediatr Hematol Oncol\nJ Pediatr Hematol Oncol\nMPH\nJournal of Pediatric Hematology/Oncology\n1077-4114\n1536-3678\nLippincott Williams & Wilkins\n\n33885036\n10.1097/MPH.0000000000002172\n00073\nOnline Articles: Clinical and Laboratory Observations\nTwo Cases of Veno-occlusive Disease/Sinusoidal Obstruction Syndrome After Thioguanine Treatment for Acute Lymphoblastic Leukemia\nGruhn Bernd MD bernd.gruhn@med.uni-jena.de\n*\nBrodt Grit MD *Grit.Brodt@med.uni-jena.de\n\nMentzel Hans-Joachim MD †Hans-Joachim.Mentzel@med.uni-jena.de\n\nErnst Jana MD *Jana.Ernst@med.uni-jena.de\n\n* Department of Pediatrics\n† Section of Pediatric Radiology, Institute of Diagnostic and Interventional Radiology, Jena University Hospital, Jena, Germany\nReprints: Bernd Gruhn, MD, Head of the Unit for Hematology, Oncology and Stem Cell Transplantation, Department of Pediatrics, Jena University Hospital, Am Klinikum 1, Jena D-07747, Germany (e-mail: bernd.gruhn@med.uni-jena.de).\n3 2022\n21 4 2021\n44 2 e572e575\n17 12 2020\n16 3 2021\nCopyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.\n2022\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/\n\nVeno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of hematopoietic cell transplantation conditioning or high-dose chemotherapy. The underlying pathogenesis involves toxic injury to hepatocytes and sinusoidal endothelial cells. Presenting symptoms include ascites, weight gain, hepatomegaly, and hyperbilirubinemia. Severe VOD/SOS with multiorgan failure has a mortality rate of >80% if left untreated. Thioguanine, a chemotherapy drug used to treat acute lymphoblastic leukemia, has been shown to cause VOD/SOS. Here, we describe cases of 2 patients who developed very severe VOD/SOS after starting thioguanine for acute lymphoblastic leukemia; both achieved complete remission with defibrotide and experienced no defibrotide-related adverse events.\n\nKey Words:\n\npediatric\nacute lymphoblastic leukemia\nveno-occlusive disease/sinusoidal obstruction syndrome\nthioguanine\ndefibrotide\nOPEN-ACCESSTRUE\nSTATUSONLINE-ONLY\n==== Body\npmcVeno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of hematopoietic cell transplantation (HCT) conditioning or high-dose chemotherapy. The underlying pathogenesis of VOD/SOS involves toxic injury to hepatocytes and sinusoidal endothelial cells, causing a release of inflammatory cytokines and chemokines, which create gaps in the endothelial lining. These gaps allow debris, which gradually sloughs off the endothelial lining, to enter the space of Disse. The sinusoidal lining cells eventually embolize downstream, blocking sinusoidal flow and causing sinusoidal narrowing.1–3 VOD/SOS typically presents with clinical symptoms such as ascites, weight gain, hepatomegaly, and hyperbilirubinemia. Notably, the most severe form of VOD/SOS is associated with multiorgan failure and has a reported mortality rate of >80% when treated with supportive care alone.1,3\n\nThioguanine is an antimetabolite chemotherapy drug that is commonly used to treat acute lymphoblastic leukemia (ALL). It has cytotoxic activity against ALL cell lines and leukemic blasts,4 but has been shown to cause VOD/SOS and is acknowledged as a potential cause of chronic VOD/SOS in the National Comprehensive Cancer Network (NCCN) guidelines for pediatric ALL.5 Thioguanine was first associated with VOD/SOS in 1976 in 2 adult male patients with acute leukemia.6 In the Children’s Cancer Group 1952 study (N=2027), 1017 pediatric patients with ALL were randomized to receive thioguanine, of whom 257 (25%) subsequently developed VOD/SOS or disproportionate thrombocytopenia attributed to thioguanine and were switched to 6-mercaptopurine.4 In the United Kingdom Medical Research Council trial ALL97, 95 (13%) of the 748 children randomized to thioguanine developed VOD/SOS, which was assumed to be caused by thioguanine.7 Lastly, in a case report of 99 children with ALL who received either thioguanine or 6-mercaptopurine, 12% of those on thioguanine developed VOD/SOS.8\n\nOver the years, VOD/SOS has been diagnosed using various diagnostic criteria, including Baltimore, modified Seattle, and EBMT criteria, which have been regularly used in the clinic. In contrast to the Baltimore and modified Seattle criteria, the pediatric EBMT criteria recognize anicteric VOD/SOS (bilirubin <2 mg/dL), thus allowing for earlier diagnosis of VOD/SOS by not requiring hyperbilirubinemia for diagnosis, and consider refractory thrombocytopenia as a VOD/SOS diagnosis criterion.9–12\n\nCurrently, defibrotide is the only approved drug for the treatment of severe VOD/SOS;13 a number of studies have demonstrated the safety and efficacy of defibrotide in the VOD/SOS setting.14–16 In a historically controlled, multicenter, open-label, phase 3 study (N=102), patients with hepatic VOD/SOS with multiorgan failure post-HCT were treated with defibrotide. Complete response (CR) was achieved by day 100 post-HCT in 25.5% of defibrotide-treated patients compared with 12.5% of historical controls (P=0.016), and defibrotide was well tolerated with manageable toxicity.14 In an expanded-access program (T-IND), the Kaplan-Meier (KM)–estimated day 100 survival post-HCT for the 1000 patients with VOD/SOS treated with defibrotide was 58.9%;16 among the 82 patients with VOD/SOS following nontransplant-associated chemotherapy, KM-estimated day 70 survival was 74.1%.17 Lastly, in an open-label, international compassionate-use program, 272 patients with VOD/SOS (that primarily developed post-HCT) received defibrotide at the recommended dose of 25 mg/kg/day and had a KM-estimated day 100 survival of 58%.15 These studies demonstrate the utility of defibrotide in treating VOD/SOS post-HCT. Here, we describe cases of 2 patients who did not undergo HCT and developed very severe VOD/SOS after starting thioguanine treatment for ALL but were successfully treated with defibrotide.\n\nCASE STUDY 1\n\nIn 2017, a 7-year-old boy who presented with low thrombocyte count and increasing abdominal pain was admitted for the administration of platelets. He had previously been diagnosed with standard-risk B-cell precursor ALL and was undergoing reinduction (protocol IIB) using the AIEOP-BFM ALL 2009 protocol,18 which consisted of oral thioguanine, intravenous cyclophosphamide, intravenous cytarabine, and intrathecal methotrexate. The patient received a 14-day course of thioguanine, which was his first exposure to thioguanine. However, on the day of admission, he suddenly exhibited slurred speech, reduced left arm strength, and numbness in his left hand. The patient had received his last dose of intrathecal methotrexate 5 days before the presentation of neurologic symptoms. Magnetic resonance imaging did not reveal thromboses, bleeding, or suspicious foci. It is possible that the neurologic symptoms could be attributed to methotrexate leukoencephalopathy. No treatment was given specifically to address neurologic symptoms. Over the course of 3 days, the patient experienced weight gain >5%, ascites, refractory thrombocytopenia, hepatomegaly, and reduced portal vein flow observed through ultrasound (Fig. 1). These findings led to the diagnosis of very severe VOD/SOS, 4 days after the last dose of thioguanine, using the pediatric EBMT severity grading criteria based on persistent refractory thrombocytopenia lasting more than 7 days and liver function tests more than 5× normal.12 Thioguanine was therefore discontinued based on the assumption that it was the causative factor for VOD/SOS. As a result, defibrotide 25 mg/kg/day was initiated, which was considered off-label use for VOD/SOS since the patient had not undergone HCT. The patient received defibrotide for 21 days and achieved CR on day 18. He experienced no defibrotide-related adverse events (AEs). The patient was alive at the time of this report.\n\nFIGURE 1 Ultrasound of reduced portal vein flow in patient 1. Lateral intercostal view of the region of the portal vein (C9-3 MHz, iU22, Philips, Eindhoven). Doppler mode showed reduced flow velocity and undulant curve.\n\nCASE STUDY 2\n\nIn 2019, a 4-year-old girl with standard-risk B-cell precursor ALL and no prior thioguanine exposure was admitted for planned chemotherapy under the AIEOP-BFM ALL 2017 protocol.19 Reinduction (protocol IIB) was initiated, which included oral thioguanine, intravenous cyclophosphamide, intravenous cytarabine, and intrathecal methotrexate. The patient received a 14-day course of thioguanine. On the last week of reinduction, she presented with an increasingly distended abdomen; on examination, she was discovered to have ascites, hepatomegaly, and reversal of portal vein flow observed through ultrasound (Fig. 2). Using the pediatric EBMT diagnostic criteria, these findings suggested a diagnosis of very severe VOD/SOS on the last day of thioguanine administration, because of persistent refractory thrombocytopenia lasting more than 7 days and a bilirubin level >34 µmol/L.12 Thus, defibrotide 25 mg/kg/day was administered for 21 days. The patient showed significant improvement within 10 days and achieved CR on day 17. Similar to patient 1, she experienced no defibrotide-related AEs and was alive at the time of this report.\n\nFIGURE 2 Ultrasound of reversal of portal vein flow in patient 2. Lateral intercostal view of the portal vein (C9-3 MHz, ZS3, Zonare Med Syst., Mountain View). Color Doppler revealed a red signal in the hepatic artery and a blue signal in the portal vein, corresponding to a reversal flow direction in the portal vein. The duplex curve showed negative values according to this finding.\n\nDISCUSSION\n\nPhysicians need to be aware of the potential for VOD/SOS when using thioguanine to treat patients with ALL, with or without HCT. Here, we reviewed 2 cases in which patients who did not undergo HCT developed very severe VOD/SOS after treatment that included thioguanine. The present cases add to previously published reports of VOD/SOS in patients with newly diagnosed ALL who had received short courses of thioguanine.20,21 In the case series of 10 patients reported by McAtee et al,21 patients developed moderate to severe VOD/SOS within 6 to 42 days of initiating thioguanine therapy, with the vast majority demonstrating isolated thrombocytopenia and reversal of flow by ultrasound. Similar to the patients in McAtee et al, the patients described in the present series had refractory thrombocytopenia and ultrasound findings indicative of abnormal portal vein flow.\n\nTreatment for VOD/SOS consists of defibrotide, in addition to intensive supportive care, which can include maintenance of electrolyte balance and measures to relieve symptoms arising from ascites, hypoxia, pleural effusion, and renal dysfunction.3,9 Both patients described here achieved CR after defibrotide treatment, with no defibrotide-related AEs.\n\nThioguanine is a purine analog of guanine that has been specifically associated with VOD/SOS.22 The mechanism behind development of VOD/SOS in patients receiving thioguanine is unclear. Current hypotheses include acute inflammation of the hepatic sinusoidal vasculature and accumulation of hepatotoxic thioguanine metabolites.8,20–22 Toxic exposure of hepatocytes to thioguanine metabolites likely leads to an imbalance between coagulation and fibrinolysis, accumulation of fibrin, and occlusion of the hepatic sinusoid.20,23\n\nRefractory thrombocytopenia was the earliest sign of VOD/SOS in both patients in this case series. Both patients were diagnosed using the pediatric EBMT diagnostic criteria, which acknowledge thrombocytopenia as a criterion for VOD/SOS and, thus, allowed for earlier diagnosis and treatment compared with the Baltimore or modified Seattle criteria, which do not consider refractory thrombocytopenia for diagnosis of VOD/SOS.9 Further, patient 1 did not present with hyperbilirubinemia and did not exhibit weight gain until 3 days after the initial symptom presentation. Elevated bilirubin and weight gain are key criteria for VOD/SOS diagnosis using Baltimore or modified Seattle criteria. In both patients, use of EBMT criteria facilitated prompt diagnosis; later diagnosis may have resulted in delayed treatment and led to different outcomes.\n\nIn this case report, prompt diagnosis and initiation of defibrotide treatment was associated with positive outcomes in both pediatric patients with very severe VOD/SOS. Following the patients’ diagnosis using EBMT criteria, early initiation of the recommended defibrotide treatment for at least 21 days and until full resolution of VOD/SOS23 resulted in a CR and no defibrotide-related AEs. In conclusion, the very severe VOD/SOS, which we believe resulted from thioguanine use, was successfully treated with defibrotide in these patients.\n\nMedical writing and editorial assistance were provided by Nancy Tang, PharmD, of SciFluent Communications, Inc., and were financially supported by Jazz Pharmaceuticals.\n\nThe authors declare no conflict of interest.\n==== Refs\nREFERENCES\n\n1 Coppell JA Richardson PG Soiffer R . Hepatic veno-occlusive disease following stem cell transplantation: incidence, clinical course, and outcome. Biol Blood Marrow Transplant. 2010;16 :157–168.19766729\n2 Carreras E Diaz-Ricart M . The role of the endothelium in the short-term complications of hematopoietic SCT. Bone Marrow Transplant. 2011;46 :1495–1502.21460864\n3 Richardson PG Grupp SA Pagliuca A . Defibrotide for the treatment of hepatic veno-occlusive disease/sinusoidal obstruction syndrome with multiorgan failure. Int J Hematol Oncol. 2017;6 :75–93.30302228\n4 Stork LC Matloub Y Broxson E . Oral 6-mercaptopurine versus oral 6-thioguanine and veno-occlusive disease in children with standard-risk acute lymphoblastic leukemia: report of the Children’s Oncology Group CCG-1952 clinical trial. Blood. 2010;115 :2740–2748.20124218\n5 National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Pediatric Acute Lymphoblastic Leukemia Version 2. 2020.\n6 Griner PF Elbadawi A Packman CH . Veno-occlusive disease of the liver after chemotherapy of acute leukemia. Report of two cases. Ann Intern Med. 1976;85 :578–582.1068643\n7 Lennard L Richards S Cartwright CS . The thiopurine methyltransferase genetic polymorphism is associated with thioguanine-related veno-occlusive disease of the liver in children with acute lymphoblastic leukemia. Clin Pharmacol Ther. 2006;80 :375–383.17015055\n8 Stoneham S Lennard L Coen P . Veno-occlusive disease in patients receiving thiopurines during maintenance therapy for childhood acute lymphoblastic leukaemia. Br J Haematol. 2003;123 :100–102.14510948\n9 Bonifazi F Barbato F Ravaioli F . Diagnosis and treatment of VOD/SOS after allogeneic hematopoietic stem cell transplantation. Front Immunol. 2020;11 :489.32318059\n10 Jones RJ Lee KS Beschorner WE . Venoocclusive disease of the liver following bone marrow transplantation. Transplantation. 1987;44 :778–783.3321587\n11 McDonald GB Hinds MS Fisher LD . Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients. Ann Intern Med. 1993;118 :255–267.8420443\n12 Corbacioglu S Carreras E Ansari M . Diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in pediatric patients: a new classification from the European society for blood and marrow transplantation. Bone Marrow Transplant. 2018;53 :138–145.28759025\n13 DEDefitelio (defibrotide sodium). Summary of product characteristics. Villa Guardia, Italy: Gentium SpA; 2018. Avalable at: https://www.ema.europa.eu/documents/product-information/defitelio-epar-product-information_en.pdf. Accessed March 3, 2021.\n14 Richardson PG Riches ML Kernan NA . Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure. Blood. 2016;127 :1656–1665.26825712\n15 Corbacioglu S Carreras E Mohty M . Defibrotide for the treatment of hepatic veno-occlusive disease: final results from the international compassionate-use program. Biol Blood Marrow Transplant. 2016;22 :1874–1882.27397724\n16 Kernan NA Grupp S Smith AR . Final results from a defibrotide treatment-IND study for patients with hepatic veno-occlusive disease/sinusoidal obstruction syndrome. Br J Haematol. 2018;181 :816–827.29767845\n17 Kernan NA Richardson PG Smith AR . Defibrotide for the treatment of hepatic veno-occlusive disease/sinusoidal obstruction syndrome following nontransplant-associated chemotherapy: final results from a post hoc analysis of data from an expanded-access program. Pediatr Blood Cancer. 2018;65 :e27269.29873895\n18 ClinicalTrials.gov. International collaborative treatment protocol for children and adolescents with acute lymphoblastic leukemia. Available at: https://clinicaltrials.gov/ct2/show/study/NCT01117441. Accessed September 8, 2020.\n19 ClinicalTrials.gov. Treatment protocol for children and adolescents with acute lymphoblastic leukemia—AIEOP-BFM ALL 2017. Available at: https://clinicaltrials.gov/ct2/show/study/NCT03643276. Accessed September 8, 2020.\n20 Pawlik-Gwozdecka D Irga-Jaworska N Tomaszewski M . Sinusoidal obstruction syndrome in a paediatric patient with acute lymphoblastic leukaemia after completion of reinduction therapy according to ALL Intercontinental Berlin-Frankfurt-Münster 2009. Contemp Oncol (Pozn). 2018;22 :266–269.30783392\n21 McAtee CL Schneller N Brackett J . Treatment-related sinusoidal obstruction syndrome in children with de novo acute lymphoblastic leukemia during intensification. Cancer Chemother Pharmacol. 2017;80 :1261–1264.29051993\n22 Oancea I Png CW Das I . A novel mouse model of veno-occlusive disease provides strategies to prevent thioguanine-induced hepatic toxicity. Gut. 2013;62 :594–605.22773547\n23 Mohty M Malard F Abecassis M . Sinusoidal obstruction syndrome/veno-occlusive disease: current situation and perspectives—a position statement from the European Society for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant. 2015;50 :781–789.25798682\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1077-4114",
"issue": null,
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": null,
"nlm_unique_id": "9505928",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33885036",
"pubdate": "2021-04-21",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Two Cases of Veno-occlusive Disease/Sinusoidal Obstruction Syndrome After Thioguanine Treatment for Acute Lymphoblastic Leukemia.",
"title_normalized": "two cases of veno occlusive disease sinusoidal obstruction syndrome after thioguanine treatment for acute lymphoblastic leukemia"
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