article dict | reports listlengths 1 3.97k |
|---|---|
{
"abstract": "BACKGROUND\nAmong patients in the United States with psoriasis (PsO), limited data exist on the incidence and prevalence of psoriatic arthritis (PsA) based on disease severity.\n\n\nOBJECTIVE\nTo assess the incidence, prevalence, and predictors of PsA among patients with PsO stratified by PsO severity using treatment type.\n\n\nMETHODS\nIncidence of PsA per 100 PsO patient-years (PY) and prevalence were assessed using the Optum electronic health records database. Incidence was assessed from PsO diagnosis and 1 year after PsO diagnosis overall and stratified by mutually exclusive treatment classes as a severity surrogate.\n\n\nRESULTS\nThe overall incidence of PsA was 2.9 (95% CI, 2.9-3.0) events per 100 PY. The incidence (95% CI) by severity surrogate was 2.1 (2.1-2.1), 9.9 (9.5-10.4), and 17.6 (16.9-18.3) events per 100 PY for patients with mild, moderate, and severe PsO as determined by receiving nonsystemics, nonbiologic systemic therapy, and biologics, respectively. When excluding patients diagnosed with PsA 1 year after PsO diagnosis, overall incidence was lower (1.7 [95% CI, 1.6-1.7] events per 100 PY), with similar trends for treatment-severity surrogates.\n\n\nCONCLUSIONS\nResults may not be generalizable to a wider population.\n\n\nCONCLUSIONS\nThe risk of developing PsA increased with disease severity and was highest in patients with the most severe PsO.",
"affiliations": "Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address: jfmerola@bwh.harvard.edu.;Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.;Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.;Novartis Pharma AG, Basel, Switzerland.;KMK Consulting, Inc, New York, New York.;KMK Consulting, Inc, New York, New York.;The University of Texas at Austin, Austin, Texas; Baylor Scott and White Health, Temple, Texas.;Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.;Keck School of Medicine, University of Southern California, Los Angeles, California.",
"authors": "Merola|Joseph F|JF|;Tian|Haijun|H|;Patil|Dhaval|D|;Richardson|Craig|C|;Scott|Amie|A|;Chen|Yen-Hua|YH|;Kim|Nina|N|;Hur|Peter|P|;Armstrong|April W|AW|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.jaad.2021.09.019",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0190-9622",
"issue": null,
"journal": "Journal of the American Academy of Dermatology",
"keywords": "incidence; prevalence; psoriasis; psoriatic arthritis",
"medline_ta": "J Am Acad Dermatol",
"mesh_terms": null,
"nlm_unique_id": "7907132",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34547358",
"pubdate": "2021-09-20",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Incidence and prevalence of psoriatic arthritis in patients with psoriasis stratified by psoriasis disease severity: Retrospective analysis of an electronic health records database in the United States.",
"title_normalized": "incidence and prevalence of psoriatic arthritis in patients with psoriasis stratified by psoriasis disease severity retrospective analysis of an electronic health records database in the united states"
} | [
{
"companynumb": "US-AMGEN-USASP2022061272",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "APREMILAST"
},
"drugadditional": "3",
... |
{
"abstract": "A 60-year-old African American man with end stage renal disease on hemodialysis (HD) for the past 2.5 years developed severe hyperparathyroidism. Other past medical history included atrial fibrillation, type II diabetes mellitus, hypertension, gout, pericardial effusion needing pericardial window, deep vein thrombosis, mitral insufficiency, and cardiomyopathy with implantable cardioversion device placement. His parathyroid hormone (PTH) level peaked at 4,191 pg/mL despite being on cinacalcet, sevelamer, and paricalcitol. He underwent a subtotal parathyroidectomy in January 2015, after which his PTH levels dropped to 184 pg/mL. Approximately 4 weeks later he developed extensive, painful necrotic skin lesions in both his lower extremities and buttocks, suggestive of calciphylaxis which was confirmed by tissue biopsy. The patient was treated with elaborate wound care, wound debridements, increased dialysis dose, and IV sodium thiosulfate (STS) during hemodialysis. Besides STS, he was treated with narcotics, gabapentin, topical lidocaine on intact skin, and oral steroids for pain control. Even though his lesions improved initially, he deteriorated due to recurrent sepsis, respiratory failure, and prolonged hospitalization which culminated in stopping dialysis before he passed away. Calciphylaxis, or calcific uremic arteriolopathy, is a life-threatening complication of end stage renal disease. Treatment of this condition is multidisciplinary which includes elaborate wound care, increasing dialysis dose, and discontinuing vitamin D supplements and calcium containing phosphate binders. Even though STS has been recommended off-label, several studies have shown promising results with resolution of lesions. Thus, sodium thiosulfate has become the mainstay of treatment. Parathyroidectomy is a recommended modality of treatment in those with high PTH levels. Our case was unique in that calciphylaxis developed after subtotal parathyroidectomy. We believe that this is due to a decreased PTH level and decreasing bone turnover which resulted in more circulating calcium facilitating vascular and soft tissue calcification. The exact mechanism of developing calciphylaxis after parathyroidectomy is unknown. Even though parathyroidectomy is an effective treatment for calciphylaxis, clinicians should be aware that it can rarely present after parathyroidectomy.",
"affiliations": "Methodist Dallas Medical Center and Dallas Nephrology Associates, Dallas, Texas, USA.;Methodist Dallas Medical Center and Dallas Nephrology Associates, Dallas, Texas, USA.",
"authors": "Karmegam|Sathish|S|;Shetty|Anupkumar|A|",
"chemical_list": null,
"country": "Canada",
"delete": false,
"doi": "10.1111/hdi.12599",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1492-7535",
"issue": "21 Suppl 2()",
"journal": "Hemodialysis international. International Symposium on Home Hemodialysis",
"keywords": "Calciphylaxis; calcific uremic arteriolopathy; parathyroidectomy",
"medline_ta": "Hemodial Int",
"mesh_terms": "D002115:Calciphylaxis; D006801:Humans; D006961:Hyperparathyroidism; D007676:Kidney Failure, Chronic; D008297:Male; D008875:Middle Aged; D016105:Parathyroidectomy; D006435:Renal Dialysis",
"nlm_unique_id": "101093910",
"other_id": null,
"pages": "S62-S66",
"pmc": null,
"pmid": "29064176",
"pubdate": "2017-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Calciphylaxis after parathyroidectomy.",
"title_normalized": "calciphylaxis after parathyroidectomy"
} | [
{
"companynumb": "US-TEVA-2017-US-829936",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CALCIUM CARBONATE"
},
"drugadditional": "3",
... |
{
"abstract": "Status epilepticus (SE) represents a neurological emergency that leads to considerable morbidity and mortality. Following failure of first-line therapy, usually with benzodiazepines, there is no clear evidence to guide treatment of refractory SE, although a wide variety of approaches has been described anecdotally.\n\n\n\nThe aim of this study was to assess the clinical response to corticosteroids in adults with refractory and super-refractory SE, describing, to the best of our knowledge, the first adult SE cohort treated with corticosteroids.\n\n\n\nWe retrospectively analysed our adult SE registry (2006-2017), identifying 15 out of 987 episodes (1.5%) in which corticosteroids were prescribed de novo as adjuvant therapy to a variety of antiepileptic drug regimens. We analysed incident episodes and defined clinical response as SE ceasing within 1 week of administration, without any other medical intervention.\n\n\n\nOut of 987 SE episodes, 15 (1.5%) were treated with de novo corticosteroids, corresponding to 12 patients, with increasing prevalence as the SE became refractory (10/411; 2.4% of episodes) and super-refractory (5/108; 4.6% of episodes). One patient (a woman with Rasmussen encephalitis) presented with four SE episodes over a period of 3 years, so only her index SE episode was included in subsequent analyses. The episodes treated were predominantly of inflammatory origin (6/12), such as autoimmune or Rasmussen encephalitis. In five out of 12 (42%) of the considered incident episodes, SE resolved following corticosteroids (all within 3 days). The outcome was better in this responders group (for 2/5 episodes, patients did not have a new handicap at discharge, versus 0/7 in non-responders). In patients with inflammatory and acute symptomatic causes, global prognosis was better than in those with progressive or neurodegenerative aetiologies (6/8 vs. 4/4 had a new handicap at discharge or died).\n\n\n\nOur observations seem to support the use of corticosteroids, especially for acute SE of putative inflammatory origin; these compounds, however, were prescribed infrequently.",
"affiliations": "Department of Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne, Clinic of Neurology, Rue du Bugnon 41, 1011, Lausanne, Switzerland. vasiliki.pantazou@chuv.ch.;Department of Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne, Clinic of Neurology, Rue du Bugnon 41, 1011, Lausanne, Switzerland.;Department of Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne, Clinic of Neurology, Rue du Bugnon 41, 1011, Lausanne, Switzerland.",
"authors": "Pantazou|Vasiliki|V|0000-0003-2632-5236;Novy|Jan|J|;Rossetti|Andrea O|AO|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D000927:Anticonvulsants",
"country": "New Zealand",
"delete": false,
"doi": "10.1007/s40263-018-0600-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1172-7047",
"issue": "33(2)",
"journal": "CNS drugs",
"keywords": null,
"medline_ta": "CNS Drugs",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000927:Anticonvulsants; D017024:Chemotherapy, Adjuvant; D015331:Cohort Studies; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D013226:Status Epilepticus; D016896:Treatment Outcome",
"nlm_unique_id": "9431220",
"other_id": null,
"pages": "187-192",
"pmc": null,
"pmid": "30627972",
"pubdate": "2019-02",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": "21464890;26312647;20446219;21967364;26900382;19817823;18769858;9738086;23917849;24014519;27080243;24001085;21914716;26092915;25976064",
"title": "Intravenous Corticosteroids as an Adjunctive Treatment for Refractory and Super-Refractory Status Epilepticus: An Observational Cohort Study.",
"title_normalized": "intravenous corticosteroids as an adjunctive treatment for refractory and super refractory status epilepticus an observational cohort study"
} | [
{
"companynumb": "PHHY2019CH054367",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLONAZEPAM"
},
"drugadditional": "3",
"druga... |
{
"abstract": "Although the putative therapeutic options for patients with systemic lupus erythematosus (SLE) are steadily increasing, refractory disease is indeed a major challenge to many clinicians and patients. The proteasome inhibitor bortezomib - approved for the treatment of multiple myeloma since the beginning of this century - was recently reported successful in twelve cases of refractory SLE by German colleagues. Herein, we describe two Swedish SLE cases with refractory renal and pulmonary manifestations that were rescued by bortezomib as induction of remission followed by monthly doses of belimumab. The patients were carefully monitored with regard to disease activity and renal function. Anti-dsDNA and anti-C1q antibodies, complement proteins and lymphocyte subsets were analysed in consecutive samples. In December 2016, the patients had been in clinical remission post bortezomib administration for a period of 28 and 22 months, respectively. Potential benefits of using belimumab as maintenance therapy to prevent regeneration of autoreactive B cell clones are discussed.",
"affiliations": "1 Rheumatology/AIR, Department of Clinical and Experimental Medicine, Linköping University, Sweden.;2 Clinical Immunology & Transfusion Medicine, Department of Clinical and Experimental Medicine, Linköping University, Sweden.;1 Rheumatology/AIR, Department of Clinical and Experimental Medicine, Linköping University, Sweden.",
"authors": "Sjöwall|C|C|;Hjorth|M|M|;Eriksson|P|P|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D007166:Immunosuppressive Agents; D061988:Proteasome Inhibitors; D000069286:Bortezomib; C511911:belimumab",
"country": "England",
"delete": false,
"doi": "10.1177/0961203317691371",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0961-2033",
"issue": "26(12)",
"journal": "Lupus",
"keywords": "Anti-DNA antibodies; renal lupus; systemic lupus erythematosus",
"medline_ta": "Lupus",
"mesh_terms": "D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D000069286:Bortezomib; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D008180:Lupus Erythematosus, Systemic; D008875:Middle Aged; D061988:Proteasome Inhibitors; D013548:Sweden; D016896:Treatment Outcome",
"nlm_unique_id": "9204265",
"other_id": null,
"pages": "1333-1338",
"pmc": null,
"pmid": "28162031",
"pubdate": "2017-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful treatment of refractory systemic lupus erythematosus using proteasome inhibitor bortezomib followed by belimumab: description of two cases.",
"title_normalized": "successful treatment of refractory systemic lupus erythematosus using proteasome inhibitor bortezomib followed by belimumab description of two cases"
} | [
{
"companynumb": "SE-CONCORDIA PHARMACEUTICALS INC.-GSH201709-005587",
"fulfillexpeditecriteria": "1",
"occurcountry": "SE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE"
},
... |
{
"abstract": "OBJECTIVE\nStroke with tandem occlusion within the anterior circulation presents a lower probability of recanalization and good clinical outcome after intravenous (IV) thrombolysis than stroke with single occlusion. The present study describes the impact of endovascular procedures (EPs) compared with IV thrombolysis alone on recanalization and clinical outcome.\n\n\nMETHODS\nThirty patients with symptom onset less than 4.5 hours and tandem occlusion within the anterior circulation were analyzed retrospectively. Recanalization was assessed per Thrombolysis In Cerebral Infarction (TICI) classification on computed tomography, magnetic resonance imaging, or digital subtraction angiography within 24 hours. Infarct size was detected on follow-up imaging as a dichotomized variable, ie, more than one third of the territory of the middle cerebral artery. Clinical outcomes were major neurologic improvement, independent outcome (90-d modified Rankin Scale [mRS] score), symptomatic intracerebral hemorrhage (sICH; per European Cooperative Acute Stroke Study criteria), and death within 7 days.\n\n\nRESULTS\nPatients treated with EPs (n = 14) were significantly younger and had a history of arterial hypertension more frequently than patients treated with IV thrombolysis alone (n = 16). Recanalization (ie, TICI score 2b/3; EP, 64%; IV, 19%; P = .01), major neurologic improvement (EP, 64%; IV, 19%; P = .01), and independent outcome (mRS score ≤ 2; EP, 54% IV, 13%; P = .02) occurred more often in the EP group, whereas infarct sizes greater than one third of the MCA territory (EP, 43%; IV, 81%; P = .03) were observed less often. Rates of sICH (P = .12) and death within 7 days (P = .74) did not differ significantly.\n\n\nCONCLUSIONS\nHigher recanalization rate, smaller infarct volume, and better clinical outcome in the EP group should encourage researchers to include this subgroup of patients in prospective randomized trials comparing IV thrombolysis versus EP in stroke.",
"affiliations": "Department of Neurology, Charité-Universitätsmedizin, Berlin, Germany. Electronic address: serdar.tuetuencue@charite.de.;Department of Neurology, Charité-Universitätsmedizin, Berlin, Germany; Center of Stroke Research, Berlin, Germany.;Department of Radiology, Charité-Universitätsmedizin, Berlin, Germany.;Center of Stroke Research, Berlin, Germany.;Department of Neurology, Charité-Universitätsmedizin, Berlin, Germany.;Department of Neurology, Charité-Universitätsmedizin, Berlin, Germany; Center of Stroke Research, Berlin, Germany.",
"authors": "Tütüncü|Serdar|S|;Scheitz|Jan F|JF|;Bohner|Georg|G|;Fiebach|Jochen B|JB|;Endres|Matthias|M|;Nolte|Christian H|CH|",
"chemical_list": "D005343:Fibrinolytic Agents",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1051-0443",
"issue": "25(8)",
"journal": "Journal of vascular and interventional radiology : JVIR",
"keywords": null,
"medline_ta": "J Vasc Interv Radiol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D015901:Angiography, Digital Subtraction; D002533:Cerebral Angiography; D004185:Disability Evaluation; D057510:Endovascular Procedures; D005260:Female; D005343:Fibrinolytic Agents; D006801:Humans; D020243:Infarction, Anterior Cerebral Artery; D007262:Infusions, Intravenous; D018810:Magnetic Resonance Angiography; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D020127:Recovery of Function; D012189:Retrospective Studies; D012307:Risk Factors; D015912:Thrombolytic Therapy; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "9203369",
"other_id": null,
"pages": "1165-70",
"pmc": null,
"pmid": "24755087",
"pubdate": "2014-08",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Endovascular procedures versus intravenous thrombolysis in stroke with tandem occlusion of the anterior circulation.",
"title_normalized": "endovascular procedures versus intravenous thrombolysis in stroke with tandem occlusion of the anterior circulation"
} | [
{
"companynumb": "DE-ROCHE-1435251",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ALTEPLASE"
},
"drugadditional": null,
"drug... |
{
"abstract": "Anti-N-methyl-D-aspartate receptor encephalitis is an autoimmune syndrome that presents with personality changes, autonomic dysfunction, and neurologic deterioration. Most patients with this syndrome progress from psychosis to seizure to catatonia, often associated with abnormal movements, autonomic instability, and hypoventilation. First-line treatment constitutes resection of the associated neoplasm, corticosteroids, intravenous immunoglobulin, and plasma exchange. Second-line treatment includes rituximab and cyclophosphamide. A case of confirmed anti-N-methyl-D-aspartate receptor encephalitis is presented that illustrates the diagnostic and treatment challenges associated with this syndrome and underscores the nursing implications of medical management during immunosuppression. This case study recommends surface cooling and a pharmaceutical regimen for management of autonomic storming, which is a hallmark of this disorder.",
"affiliations": null,
"authors": "Halbert|Roger Kelsey|RK|",
"chemical_list": "D000927:Anticonvulsants; D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D000077287:Levetiracetam; D000069283:Rituximab; D003520:Cyclophosphamide; D010889:Piracetam",
"country": "United States",
"delete": false,
"doi": "10.1097/JNN.0000000000000232",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0888-0395",
"issue": "48(5)",
"journal": "The Journal of neuroscience nursing : journal of the American Association of Neuroscience Nurses",
"keywords": null,
"medline_ta": "J Neurosci Nurs",
"mesh_terms": "D000328:Adult; D060426:Anti-N-Methyl-D-Aspartate Receptor Encephalitis; D000927:Anticonvulsants; D003520:Cyclophosphamide; D017809:Fatal Outcome; D005260:Female; D006261:Headache; D006801:Humans; D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D000077287:Levetiracetam; D010051:Ovarian Neoplasms; D010889:Piracetam; D000069283:Rituximab; D012640:Seizures",
"nlm_unique_id": "8603596",
"other_id": null,
"pages": "270-3",
"pmc": null,
"pmid": "27579962",
"pubdate": "2016-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Anti-N-Methyl-D-Aspartate Receptor Encephalitis: A Case Study.",
"title_normalized": "anti n methyl d aspartate receptor encephalitis a case study"
} | [
{
"companynumb": "US-ROCHE-1970405",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MIDAZOLAM HYDROCHLORIDE"
},
"drugadditional": null,
... |
{
"abstract": "Isoniazid preventative therapy is widely used for latent tuberculosis infection. Isoniazid is highly effective but has many adverse effects, including neuropsychiatric. We describe the case of an 80-year-old woman with mania. She had received isoniazid preventative therapy during steroid treatment for rheumatoid arthritis and organising pneumonia for the previous 5 months. Her mania resolved after discontinuation of isoniazid. Adverse effects of isoniazid should be considered even if a long time has elapsed since the start of administration. Physicians other than infectious disease and respiratory specialists also must be aware of the adverse effects of isoniazid preventative therapy.",
"affiliations": "Emergency Medicine and General Internal Medicine, Rakuwakai Marutamachi Hospital, Kyoto, Japan.;Department of Nephrology, Kyoto Okamoto Memorial Hospital, Kuze-gun, Japan.;Emergency Medicine and General Internal Medicine, Rakuwakai Marutamachi Hospital, Kyoto, Japan maruta-GIM_ER-ueda@live.jp.",
"authors": "Nagano|Hiroyuki|H|;Miura|Tomoaki|T|;Ueda|Takeshi|T|",
"chemical_list": "D000995:Antitubercular Agents; D007538:Isoniazid",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-231919",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(11)",
"journal": "BMJ case reports",
"keywords": "TB and other respiratory infections; unwanted effects/adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000369:Aged, 80 and over; D000995:Antitubercular Agents; D001172:Arthritis, Rheumatoid; D001714:Bipolar Disorder; D005260:Female; D006801:Humans; D007538:Isoniazid; D055985:Latent Tuberculosis; D011014:Pneumonia",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31678927",
"pubdate": "2019-11-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11862134;10913407;26017823;22424158;11122994;20658798;26209712;26888997;21494681;27470028;25364275;21772661;16503745;6329054;26545940;26405286;19407047;16517138;11915035;4154500;30067931",
"title": "Mania induced by isoniazid preventive therapy during steroid treatment for rheumatoid arthritis and organising pneumonia.",
"title_normalized": "mania induced by isoniazid preventive therapy during steroid treatment for rheumatoid arthritis and organising pneumonia"
} | [
{
"companynumb": "JP-CMP PHARMA-2019CMP00034",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ESOMEPRAZOLE MAGNESIUM"
},
"drugadditional"... |
{
"abstract": "Minocycline is a semisynthetic broad-spectrum tetracycline used for its bacteriostatic and anti-inflammatory properties in the treatment of moderate to severe acne vulgaris. Minocycline-induced hyperpigmentation (MIH) is a well-recognized phenomenon documented to involve a wide array of anatomic locations including the skin and nails, the sclera and conjunctiva, the oral cavity, and the skeleton and cartilage, as well as within viscera and body fluids. Oral involvement typically includes the hard tissues (eg, alveolar bone, roots, crowns of teeth). We present a case of MIH of the labial, gingival, and lingual oral mucosa after only 2 weeks of treatment. Our case is unique because of the short course of minocycline treatment.",
"affiliations": null,
"authors": "Filitis|Dan C|DC|;Graber|Emmy M|EM|",
"chemical_list": "D000900:Anti-Bacterial Agents; D008911:Minocycline",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0011-4162",
"issue": "92(1)",
"journal": "Cutis",
"keywords": null,
"medline_ta": "Cutis",
"mesh_terms": "D000900:Anti-Bacterial Agents; D005260:Female; D006801:Humans; D017495:Hyperpigmentation; D008911:Minocycline; D009061:Mouth Mucosa; D013997:Time Factors; D055815:Young Adult",
"nlm_unique_id": "0006440",
"other_id": null,
"pages": "46-8",
"pmc": null,
"pmid": "23961526",
"pubdate": "2013-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Minocycline-induced hyperpigmentation involving the oral mucosa after short-term minocycline use.",
"title_normalized": "minocycline induced hyperpigmentation involving the oral mucosa after short term minocycline use"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/14/0041143",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MINOCYCLINE HYDROCHLORIDE"
},
"drugaddit... |
{
"abstract": "We report the case of a 59-year-old patient who accidentally underwent live vaccination against yellow fever during continuous treatment with the TNF-α-antibody (AB) infliximab for ulcerative colitis. The clinical course showed fever of short duration and elevation of liver enzymes without further clinical complications. Yellow fever viremia was not detectable and protective antibodies were developed. A primary vaccination against yellow fever under infliximab has not been reported in the literature before, although vaccination is an important topic in IBD. Live vaccinations, like Stamaril(®) against yellow fever, are contraindicated during TNF-α-AB treatment. Treatment regimens containing TNF-α-AB are of growing importance, not only in gastroenterology, but also in rheumatology and dermatology. We discuss this topic by presenting our case and reviewing the current literature.",
"affiliations": "Department of Internal Medicine IV, Department of Gastroenterology, Hepatology and Infectious Disease, Jena University Hospital, Jena, Germany.;Center for Infectious Diseases and Infection Control, Jena University Hospital, Jena, Germany.;Health Office, City of Erfurt, Erfurt, Germany.;Department of Internal Medicine IV, Department of Gastroenterology, Hepatology and Infectious Disease, Jena University Hospital, Jena, Germany.;Center for Infectious Diseases and Infection Control, Jena University Hospital, Jena, Germany.;Department of Internal Medicine IV, Department of Gastroenterology, Hepatology and Infectious Disease, Jena University Hospital, Jena, Germany.",
"authors": "Rüddel|J|J|;Schleenvoigt|B T|BT|;Schüler|E|E|;Schmidt|C|C|;Pletz|M W|MW|;Stallmach|A|A|",
"chemical_list": "D005765:Gastrointestinal Agents; D022341:Yellow Fever Vaccine; D000069285:Infliximab",
"country": "Germany",
"delete": false,
"doi": "10.1055/s-0042-109871",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0044-2771",
"issue": "54(9)",
"journal": "Zeitschrift fur Gastroenterologie",
"keywords": null,
"medline_ta": "Z Gastroenterol",
"mesh_terms": "D003093:Colitis, Ulcerative; D000075202:Contraindications; D003937:Diagnosis, Differential; D005765:Gastrointestinal Agents; D006801:Humans; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D015004:Yellow Fever; D022341:Yellow Fever Vaccine",
"nlm_unique_id": "0033370",
"other_id": null,
"pages": "1081-4",
"pmc": null,
"pmid": "27612222",
"pubdate": "2016-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Yellow fever vaccination during treatment with infliximab in a patient with ulcerative colitis: A case report.",
"title_normalized": "yellow fever vaccination during treatment with infliximab in a patient with ulcerative colitis a case report"
} | [
{
"companynumb": "DE-CELLTRION HEALTHCARE HUNGARY KFT-2016DE009874",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugad... |
{
"abstract": "We present a 63-year-old man with a medical history of hepatocellular carcinoma who underwent orthotopic liver transplant 10 years prior on long-term immunosuppressive therapy. The patient presented to the clinic with diarrhea, and the workup revealed mantle cell lymphoma. Mantle cell lymphoma is an extremely rare finding in transplanted livers. It is essential to include mantle cell lymphoma, along with a broad differential, during the workup of diarrhea in post-transplant patients.",
"affiliations": "Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL.;Anesthesiology and Perioperative Medicine, Oregon Health Science University Hospital, Portland, OR.;Division of Gastroenterology and Hepatology, Henry Ford Hospital, Detroit, MI.;Division of Pathology, Henry Ford Hospital, Detroit, MI.;Division of Pathology, Henry Ford Hospital, Detroit, MI.;Division of Gastroenterology and Hepatology, Henry Ford Hospital, Detroit, MI.;Division of Gastroenterology and Hepatology, Henry Ford Hospital, Detroit, MI.",
"authors": "Ahmed|Abdelwahab|A|;Naji|Abdullah|A|;Zhang|Jinyu|J|;Raoufi|Mohammad|M|;Alhamar|Mohamed|M|;Salgia|Reena|R|;Mullins|Keith|K|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.14309/crj.0000000000000635",
"fulltext": "\n==== Front\nACG Case Rep J\nACG Case Rep J\nACGCRJ\nACGCRJ\nAC9\nACG Case Reports Journal\n2326-3253\nWolters Kluwer Maryland, MD\n\nACGCR-20-0915\n10.14309/crj.0000000000000635\n00018\nCase Report\nEndoscopy\nMantle Cell Lymphoma Presenting as Diarrhea in a Liver Transplant Recipient\nAhmed Abdelwahab MD 1\nNaji Abdullah DO 2abdullah.naji@westernu.edu\n\nZhang Jinyu MD 3jzhang6@hfhs.org\n\nRaoufi Mohammad MD 4Mraoufi1@hfhs.org\n\nAlhamar Mohamed MD 4MAlhama1@hfhs.org\n\nSalgia Reena MD 3RSALGIA1@hfhs.org\n\nMullins Keith MD 3KMULLIN4@hfhs.org\n\n1 Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL\n2 Anesthesiology and Perioperative Medicine, Oregon Health Science University Hospital, Portland, OR\n3 Division of Gastroenterology and Hepatology, Henry Ford Hospital, Detroit, MI\n4 Division of Pathology, Henry Ford Hospital, Detroit, MI\nCorrespondence: Abdelwahab Ahmed, BSc (abdul.ahmed343@gmail.com).\n7 2021\n21 7 2021\n8 7 e0063522 7 2020\n30 3 2021\n© 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.\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.\n\nABSTRACT\n\nWe present a 63-year-old man with a medical history of hepatocellular carcinoma who underwent orthotopic liver transplant 10 years prior on long-term immunosuppressive therapy. The patient presented to the clinic with diarrhea, and the workup revealed mantle cell lymphoma. Mantle cell lymphoma is an extremely rare finding in transplanted livers. It is essential to include mantle cell lymphoma, along with a broad differential, during the workup of diarrhea in post-transplant patients.\n\nOPEN-ACCESSTRUE\n==== Body\nINTRODUCTION\n\nSolid organ transplants are life-saving surgeries that involve a complex interplay between the doctor, patient, and donor. Diarrhea frequently occurs after solid organ transplants.1 One retrospective study has shown that diarrhea is the most common gastrointestinal complication in liver transplant recipients, with infections and post-transplant medications being the leading causes.1,2 Rare causes of diarrhea in liver transplant recipients include lymphoproliferative diseases, such as mantle cell lymphoma (MCL).3 MCL is a subtype of non-Hodgkin lymphoma (NHL), which develops because of abnormalities involving B cells.4 MCL tends to occur in patients in their 60s, is predominant in men at a ratio of 2:1, and presents with B symptoms, such as fever and fatigue.5 Because of the long-term use of immunosuppressive medications to prevent rejection, the risk of NHL in solid organ transplant recipients increases by 6 times relative to the general population.6,7 However, in contrast to various subtypes of NHLs, the incidence of MCL in solid organ transplant recipients does not significantly increase.6 Hence, we present a rare case describing a 63-year-old man who received a liver transplant and was found to have diffuse MCL after presenting with chronic diarrhea.\n\nCASE REPORT\n\nA 63-year-old orthotopic liver transplant patient with a medical history of hepatitis C cirrhosis complicated by pretransplant hepatocellular carcinoma presented to the clinic with chronic nonbloody diarrhea. His pretransplantation surgical history included a right hepatic lobe segmentectomy and distal pancreatectomy for an isolated islet cell tumor. Two years after this surgery, radiologic evaluation revealed evidence of growing cancer in the liver. Initial therapy for his hepatocellular carcinoma was chemoembolization. The patient subsequently received a liver transplantation in 2010 with thymoglobulin induction. Both the donor and the recipient had negative serologic testing for hepatitis C virus, Epstein-Barr virus, and cytomegalovirus.\n\nThree months before initial presentation with diarrhea, abdominal magnetic resonance imaging was completed for chronic mild elevations in liver function tests and revealed stable prominent mesenteric lymph nodes, the largest being 11 mm, of unclear etiology. His presenting symptoms included more than 6 loose stools a day, bloating, cramping more than 8 months, and weight loss of 15 pounds. On presentation, the patient's aspartate aminotransferase level was 37 IU/L, and his alanine transaminase level was 75 IU/L. The patient reported no other B symptoms. There were no concerning findings on abdominal examination. At the time of presentation, his immunosuppressive regimen consisted of mycophenolate mofetil 500 mg twice daily, cyclosporine 100 mg twice daily, and ursodiol 300 mg twice daily. The patient endorsed taking only half of the prescribed dosage because of a miscommunication. No stool studies were performed because the patient's chronic diarrhea was thought to be due to causes other than infection. However, bulking agents were prescribed, which improved the patient's diarrhea, and endoscopic evaluation was scheduled for 1 month later.\n\nEndoscopic evaluation revealed duodenal inflammation and mild continuous erythema in the rectosigmoid colon up to 30 cm from the anal verge (Figure 1). Biopsies of the duodenum, right colon, and left colon were performed. Histologic sections of colonic mucosa revealed prominent infiltrate of small atypical lymphocytes with round to irregular nuclei, mature chromatin, and scant to moderate clear cytoplasm (Figure 2). There was no evidence of intraepithelial lymphocytes and villous atrophy to suggest celiac disease. Immunostaining of the biopsies was negative for cytomegalovirus.\n\nFigure 1. Image of the sigmoid colon revealing the areas of erythematous mucous.\n\nFigure 2. Colonic mucosa with a prominent infiltrate of small atypical lymphocytes that have round to irregular nuclei, mature chromatin, and scant to moderate clear cytoplasm (hematoxylin and eosin stain, 10× magnification).\n\nThe biopsy results were indicative of lymphoma, which prompted a bone marrow biopsy. Pathology revealed that 10% of the marrow was mantle cell; fluorescence in situ hybridization revealed an 11;14 chromosomal translocation. The patient was diagnosed with stage IV MCL with diffuse gastrointestinal involvement; all biopsies from the endoscopic evaluation were retrospectively examined and tested positive for MCL. Treatment was then tailored to the patient's new diagnosis and included ibrutinib (140 mg daily) to target MCL and an antirejection regimen of cyclosporine (150 mg twice daily) and prednisone (60 mg daily). The patient's most recent bone marrow biopsy revealed residual disease, and the current plan is to have the hematology team follow the patient clinically.\n\nDISCUSSION\n\nPatients who develop post-transplant MCL may present with B symptoms, such as diarrhea, gastrointestinal bleeding, and hypoalbuminemia.8 Although our patient was within the typical age range for developing MCL, his presentation of diarrhea 10 years after transplantation in the absence of many classic B symptoms made the diagnosis of MCL clinically challenging. The typical differential diagnosis for post-transplant diarrheal disease is an opportunistic infection from pathogens, such as Clostridium difficile and cytomegalovirus, graft-vs-host disease, mycophenolate-induced injury, and microscopic colitis.9 Therefore, MCL within the context of diarrheal disease post-transplantation has a high likelihood of being overlooked within the initial differential diagnosis.\n\nOn the suspicion of post-transplant lymphoproliferative disease, upper and lower endoscopies with biopsies are advised because they can highlight noninfectious causes, including MCL.10 Infection with Epstein-Barr virus also substantially increases the suspicion of lymphoid malignancies,9 and notably, neither our patient nor his transplant donor was positive for this pathogen. The molecular hallmark of MCL is an 11;14 chromosomal translocation,11 which was observed in our patient; thus, genetic testing can be informative. Hence, many lines of inquiry can assist in the diagnosis of post-transplant MCL.\n\nTreatment strategies for MCL in liver transplant recipients involve adjusting immunosuppressive medications and initiating chemotherapy. Reduction of immunosuppressive therapy may be considered; however, because MCL is not a typical manifestation of post-transplant lymphoproliferative disease, this treatment modality should be approached with caution because targeted approaches are available.12 A study of 111 patients with MCL showed that those taking ibrutinib had an overall response rate of 68% and a complete response rate of 21%.13 Although ibrutinib has shown promising results in patients with MCL, incidents of severe hepatotoxic reactions have occurred.14 Thus far, our patient has not had any drug-induced liver injury from ibrutinib therapy.\n\nIn conclusion, we have reported a rare case of diarrhea secondary to MCL in a 63-year-old male orthotopic liver transplant recipient in the setting of long-term immunosuppressive medication. Our patient's case has added to the limited but growing knowledge of MCL in liver transplant recipients who present with diarrhea.\n\nDISCLOSURES\n\nAuthor contributions: A. Ahmed and A. Naji wrote the article. J. Zhang, R. Salgia, and K. Mullins edited the article. M. Raoufi and M. Alhamar provided the images. K. Mullins is the article guarantor.\n\nAcknowledgment: We would like to acknowledge Karla Passalacqua, PhD, at Henry Ford Hospital for editorial assistance.\n\nFinancial disclosure: None to report.\n\nInformed consent was obtained for this case report.\n==== Refs\nREFERENCES\n\n1. Cox GJ Matsui SM Lo RS . Etiology and outcome of diarrhea after marrow transplantation: A prospective study. Gastroenterology. 1994;107 :1398–407.7926504\n2. Wong NA Bathgate AJ Bellamy CO . Colorectal disease in liver allograft recipients—A clinicopathological study with follow‐up. Eur J Gastroenterol Hepatol. 2002;14 :231–6.11953686\n3. Jain A Nalesnik M Reyes J . Posttransplant lymphoproliferative disorders in liver transplantation: A 20‐year experience. Ann Surg. 2002;236 :429–36.12368671\n4. Gerard‐Marchant R Hamlin I Lennert K . Classification of non‐Hodgkin's lymphomas [letter]. Lancet. 1974;2 :405–8.\n5. Tiemann M Schrader C Klapper W . Histopathology, cell proliferation indices and clinical outcome in 304 patients with mantle cell lymphoma (MCL): A clinicopathological study from the European MCL Network. Br J Haematol. 2005;131 :29–38.16173960\n6. Clarke CA Morton LM Lynch C . Risk of lymphoma subtypes after solid organ transplantation in the United States. Br J Cancer. 2013;109 (1 ):280–8.23756857\n7. Engels EA Pfeiffer RM Fraumeni JF Jr . Spectrum of cancer risk among US solid organ transplant recipients. JAMA. 2011;306 (17 ):1891–901.22045767\n8. Younes BS Ament ME McDiarmid SV Martin MG Vargas JH . The involvement of the gastrointestinal tract in posttransplant lymphoproliferative disease in pediatric liver transplantation. J Pediatr Gastroenterol Nutr. 1999;28 :380–5.10204501\n9. Ginsburg PM Thuluvath PJ . Diarrhea in liver transplant recipients: Etiology and management. Liver Transpl. 2005;11 (8 ):881–90.16035068\n10. Kocoshis SA . Endoscopic diagnosis of lymphoproliferative disease after solid organ transplantation. J Pediatr Gastroenterol Nutr. 1999;28 :375–6.10204499\n11. Vose JM . Mantle cell lymphoma: 2017 update on diagnosis, risk-stratification, and clinical management. Am J Hematol. 2017;92 (8 ):806–13.28699667\n12. Al-Mansour Z Nelson BP Evens AM . Post-transplant lymphoproliferative disease (PTLD): Risk factors, diagnosis, and current treatment strategies. Curr Hematol Malig Rep. 2013;8 (3 ):173–83.23737188\n13. Wang L Rule S Martin P . Targeting BTK with Ibrutinib in relapsed or refractory mantle cell lymphoma. N Engl J Med. 2014;369 :507–16.\n14. Tafesh ZH Coleman M Fulmer C Nagler J . Severe hepatotoxicity due to ibrutinib with a review of published cases. Case Rep Gastroenterol. 2019;13 (2 ):357–36.31607836\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2326-3253",
"issue": "8(7)",
"journal": "ACG case reports journal",
"keywords": null,
"medline_ta": "ACG Case Rep J",
"mesh_terms": null,
"nlm_unique_id": "101638398",
"other_id": null,
"pages": "e00635",
"pmc": null,
"pmid": "34307713",
"pubdate": "2021-07",
"publication_types": "D002363:Case Reports",
"references": "23737188;23782157;16035068;10204501;10204499;12368671;7926504;28699667;16173960;31607836;22045767;23756857;11953686",
"title": "Mantle Cell Lymphoma Presenting as Diarrhea in a Liver Transplant Recipient.",
"title_normalized": "mantle cell lymphoma presenting as diarrhea in a liver transplant recipient"
} | [
{
"companynumb": "US-ALLERGAN-2218710US",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "URSODIOL"
},
"drugadditional": "3",
"dr... |
{
"abstract": "Distal renal tubular acidosis is a rare genetic disease, characterised by deficit in renal tubular transport. Clinical features are metabolic acidosis with hypercloraemia and hypokalemia, and inability in urine acidification. Hypercalciuria may also be present, often treated with the use of a diuretic therapy with thiazides.\n\n\n\nWe present a severe disease onset in a neonate with consanguineous parents, both autosomal-recessive for an ATP6VOA4 gene mutation, and a nevertheless severe episode of metabolic alkalosis, occurred in the same patient after few months, during the diuretic therapy.\n\n\n\nBiochemical results lead us to hypothesize a susceptibility to the treatment that need further investigations.",
"affiliations": "University of Modena and Reggio Emilia. laura.lucaccioni@unimore.it.",
"authors": "Lucaccioni|Laura|L|;Coccolini|Elena|E|;Dozza|Alessandra|A|;Cantatore|Sante Lucio|SL|;Berardi|Alberto|A|;Predieri|Barbara|B|;Iughetti|Lorenzo|L|",
"chemical_list": "D004232:Diuretics; C501005:MT-ATP6 protein, human; D049971:Thiazides; D025261:Mitochondrial Proton-Translocating ATPases",
"country": "Italy",
"delete": false,
"doi": "10.23750/abm.v90i2.6886",
"fulltext": "\n==== Front\nActa BiomedActa BiomedActa Bio Medica : Atenei Parmensis0392-42032531-6745Mattioli 1885 Italy 31125018ACTA-90-34810.23750/abm.v90i2.6886Case ReportSevere metabolic alkalosis due to diuretic treatment in a patient with distal renal tubular acidosis: a rare association Laura Lucaccioni 1Elena Coccolini 2Alessandra Dozza 3Sante Lucio Cantatore 3Alberto Berardi 1Barbara Predieri 3Lorenzo Iughetti 231 Neonatal Intensive Care Unit, Department of Clinical and Surgical Sciences of the Mother, Children and Adult, University of Modena and Reggio Emilia, Modena, Italy2 Pediatric Unit, Department Post-graduate School of Pediatrics, University of Modena and Reggio Emilia, Modena, Italy3 Department of Medical and Surgical Sciences for Mothers, Children and Adults, University of Modena and Reggio Emilia, Modena, ItalyCorrespondence: Professor Lorenzo Iughetti, Departments for Medical and Surgical Sciences of Mothers, Children and Adults, University of Modena & Reggio Emilia, Paediatric Unit, Modena, Italy Tel: +39-594225382; Fax: +39-594223895 E-mail: lorenzo.iughetti@unimore.it2019 09 12 2019 90 2 348 352 09 11 2017 20 7 2018 Copyright: © 2019 ACTA BIO MEDICA SOCIETY OF MEDICINE AND NATURAL SCIENCES OF PARMA2019This work is licensed under a Creative Commons Attribution 4.0 International LicenseIntroduction:\nDistal renal tubular acidosis is a rare genetic disease, characterised by deficit in renal tubular transport. Clinical features are metabolic acidosis with hypercloraemia and hypokalemia, and inability in urine acidification. Hypercalciuria may also be present, often treated with the use of a diuretic therapy with thiazides.\n\nCase Presentation:\nWe present a severe disease onset in a neonate with consanguineous parents, both autosomal-recessive for an ATP6VOA4 gene mutation, and a nevertheless severe episode of metabolic alkalosis, occurred in the same patient after few months, during the diuretic therapy.\n\nConclusion:\nBiochemical results lead us to hypothesize a susceptibility to the treatment that need further investigations. (www.actabiomedica.it)\n\ndistal renal tubular acidosismetabolic alkalosishydrochlorothiazide\n==== Body\nIntroduction\nDistal renal tubular acidosis (dRTA), called “Classic distal” or “Type 1”, is a rare genetic disease grouping in the renal tubular acidosis (RTA) syndromes. These diseases are characterized by different tubular transport defects that lead to the inability to secrete hydrogen ions (H+) with development of metabolic acidosis (1). In children, dRTA is most of the times observed as primary entity often in families with autosomal-dominant (AD) or autosomal-recessive (AR) pattern of inheritance (2). Type 1 presents an inefficient H+ secretion, with inadequate hydrogen ion gradient between the blood and tubule fluid (3, 4). This leads to low plasma HCO3- levels, metabolic acidosis, electrolytes alterations, as hypercloraemia and hypokalemia, and inability in urine acidification. Hypercalciuria may also be present as result of calcium phosphate mobilization from bones to compensate systemic acidosis, and hypocitraturia, as consequence of increased citrate excretion to buffer systemic acidosis. High urine pH, high calcium (Ca++) and low citrate urine levels promote nephrocalcinosis, often associated with nephrolithiasis. Chronic renal failure could develop as long-term effect. Clinical manifestations may also be failure to growth, anorexia, vomiting, dehydration and hypotonia (1, 2).\n\nRTA main treatment consists in continuous administration of the appropriate amount of alkali in the form of either bicarbonate or citrate (1, 5, 6). This leads to correct metabolic acidosis and electrolytes alterations, improves growth and prevents renal and bone diseases (2).\n\nThiazide diuretics (TDs) have also been used to treat renal hypercalciuria, reducing the risk of nephrolithiasis. In particular, the most used is the hydrochlorothiazide (HCT) (7, 8).\n\nThe appropriate dosage and duration of treatment is controversial (9) since literature documents several cases of pseudo-Bartter’s syndrome (10-12).\n\nWe present an early diagnosis of dRTA characterized by the homozygotic mutation of the ATP6VOA4 gene, showing two severe electrolytes dysfunctional episodes: the first at the disease onset and the second during the TDs treatment, leading to speculate a possible susceptibility to the diuretic treatment.\n\nCase presentation\nXY, 29-days-old, was admitted to the Emergency Department for severe weight loss and critical dehydration (estimated loss of 520 gr in 15 days). Medical history was uneventful except for parental consanguinity (first-degree cousins).\n\nPhysical examination showed impairment of general conditions, dry skin, cold extremities, refill time of 5”. Biochemical evaluation revealed critic metabolic acidosis with hypernatremia, hyperchloraemia and ipokaliemia, hyperammoniemia and acute renal insufficiency (Table 1).\n\nTable 1. Gas analysis, plasmatic electrolytes concentration and renal function at first evaluation with severe metabolic acidosis (first row) and gas analysis and plasmatic electrolytes concentration at second evaluation with severe metabolic alkalosis (during treatment with hydrochlorothiazide – second row)\n\n\tPH\tpCO2 (mmHg)\tpO2 (mmHg)\tBE (mmol/L)\tHC03- (mmol/L)\tNa++ (mEq/L)\tK+ (mEq/L)\tCa++ (mEq/L)\tCl- (mEq/L)\tUrea (mg/dl)\tCreatinine (mg/dl)\tAmmonium (mmol/1)\t\nFirst episode\t7,01\t24,2\t43,3\t-23,6\t6,0\t157\t2,44\t7,40\t109\t231\t1,54\t103\t\nSecond episode\t7,61\t72,9\t29,8\t-43,3\t71,9\t130\t1,49\t--\t54\t--\t--\t--\t\nUrine analysis showed an alkaline pH (6.5) with presence of leucocytes, proteins and blood. The anion gap was normal.\n\nHe was rehydrated with intravenous fluids to support the circle and electrolyte replacement (K+ and HCO−3) to correct the severe electrolyte imbalance. He was rapidly transferred to Neonatal Intensive Care Unit (NICU) because of his critical conditions. Suspecting a sepsis, microbiologic samples were collected (cerebrospinal fluid, blood, urine) and empirical antibiotics therapy was started (ampicillin and gentamicin). Cultures resulted negative. Cerebral ultrasound was normal whereas the abdominal scan showed bilateral medullary nephrocalcinosis. Despite the infusive treatment with K+ and HCO−3, XY continued to show a trend to maintain hypokaliemic metabolic acidosis and hypercalciuria: this led to the dTRA hypothesis.\n\nXY was transferred to the Pediatric Unit four days later, presenting improved clinical conditions and plasma electrolyte concentrations. Continuous vital parameters monitoring, fluids balance, blood gas analysis and electrolytes status were performed. Infusive treatment was adjusted until oral administration of NaHCO3 and Potassium Citrate (Kcit) was achieved.\n\nThe detection of a homozygotic mutation in ATP6VOA4 gene located on cr. 7q33-34 confirmed the suspect of dTRA. Parents and brother are heterozygotic carriers of the same mutation.\n\nAt the discharge, the oral therapy with NaHCO3 and Kcit was integrated with administration of HCT (about 2 mg/kg twice a day) to reduce kidney stones formation.\n\nOne a month later, the patient was admitted again to the emergency department presenting vomiting, decreased urine output and poor appetite. He presented lost of weight and dehydrated appearance (dry skin and furred tongue).\n\nBlood analysis revealed a severe hypocloraemic and hypokaliemic alkalosis (Table 1) and electrocardiogram showed a prolongation in QT interval (QTc >0, 50 sec). He was immediately rehydrated with intravenous fluids and electrolyte replacement, and the diuretic treatment was stopped, with good resolution. A month later the treatment with HCT was started again during a recovery at the hospital: periodic blood analysis revealed the same trend to hypocloraemic and hypokaliemic severe alkalosis, leading the doctors to stop the diuretic treatment.\n\nNo other episodes were referred and XY is still periodically evaluated by paediatric nephrologists: he now presents regular weight and height growth, no neurological deafness and no hearing loss; full blood count, renal and liver function, acid-base blood status and urines are normal; last abdominal ultrasound was unchanged. Current oral therapy of the child involves NaHCO3 four times/day and Kcit.\n\nDiscussion\nClinical and biochemical features of dTRA onset can be easily confused with neonatal sepsis.\n\nXY presented poor general conditions, with very severe hypokalemia, hypernatremia and metabolic acidosis. However, sepsis was excluded by negative microbiologic cultures, not improving with antibiotic therapy and persistent metabolic acidosis resistant to bicarbonate treatment.\n\nThe alkaline urinary pH associated to normal values of the anion gap could lead to dRTA diagnosis. In particular, in case of hyperchloraemic metabolic acidosis with normal anion gap, the presence of urine PH >5.5 and normal or low plasmatic K levels are strongly suggestive of dRTA. Moreover, the presence of nephrocalcinosis found during the first abdominal ultrasound is another sign strongly indicative of dRTA (1, 2).\n\nOur hypothesis was confirmed by genetic investigations: in particular mutations of the ATP6V0A4 gene configuring the AR dTRA variant without sensorineural deafness (1, 4).\n\nA family history of consanguinity (Figure 1) is the hallmark of patients with AR dTRA (2):they are more severely affected and require aggressive administration of intravenous fluids and NaHCO3 and Kcit replacement.\n\nFigure 1. Family tree. In green: newborns dead after a few days of life for unknown reasons. In light blue: a 16 years old boy dead for neoplasm. In dark blue: a brother with thyroglossal duct cyst. The remnants deaths in the family were in adulthood, for unknown reasons\n\nOn the second admission, XY presented a severe hypocloraemic (Cl 54 mEq/L) and hypokaliemic (K 1,49 mEq/L) alkalosis, with life-threatening value of pH (7,61), HCO3- (71,9 mmol/L) and BE (43,3 mmol/L). The hypokaliemia caused an important prolongation in QT interval (QTc >0, 50 sec), justifying an aggressive therapeutic approach.\n\nTDs therapy, stopped after this episode, is normally used for renal hypercalciuria treatment even in children, decreasing the risk of nephrolithiasis. In fact, TDs reduce NaCl reabsorption and renal excretion of Ca++, favouring diuresis with an anti-hypertensive effect; it also increases K+, HCO3-, Mg++ and phosphates excretion (13).\n\nIt is controversial what dosage is appropriate and how long the treatment should be performed. It is reported that low-dose TDs (0,5-0,75 mg/kg/day) in children with idiopathic renal hypercalciuria are safe and effective in long-term control of hypercalciuria (9), however sometimes it is required to increase dosages to 1-2 mg/kg/day in children and 2-4 mg/kg/day in neonates/infants to obtain a long-lasting correction (14).\n\nOur patient received HCT at the dosage of about 2 mg/kg twice a day, because of his age and the presence of bilateral medullary kidney stones, to prevent kidney functional impairment. In literature there are few cases of pseudo-Bartter’s syndrome described from surreptitious diuretic (10-12). It is a condition characterized by hypokaliemia, hypochloremia, metabolic alkalosis and hyperreninemia with normal blood pressure and positive TDs urine excretion.\n\nIt is indeed likely that our patient developed a pseudo-Bartter episode (with severe alkalosis) although his strong predisposition to acidosis. Excluding parental difficulties on treatment administration (both HCT and bicarbonate) and errors in galenic preparation of HCT consigned to the family, and seen the biochemical trend during HCT treatment checked during a recovery, we can speculate a particular susceptibility of our dRTA patient to the thiazidic treatment that may need further investigations for understanding the pathophysiological pathway.\n\nDuring the first year of life XY was evaluated every three months adjusting the treatment dosage. He did not develop hearing loss and he always maintained HCO3- level in the normality range (23-24 mmol/L). Unmodified nephrocalcinosis still persists also considering that XY may not benefit of the diuretic treatment.\n\nConclusion\nTo the best of our knowledge this is the first case of distal tubular acidosis type 1 developing a severe metabolic alkalosis due to thiazidic diuretic treatment, although appropriate regular dose administration. It is possible that our patient presents an increased susceptibility to hydrochlorothiazide that may need further investigation.\n\nConflict of interest:\nEach author declares that he or she has no commercial associations (e.g. consultancies, stock ownership, equity interest, patent/licensing arrangement etc.) that might pose a conflict of interest in connection with the submitted article\n==== Refs\nReferences\n1 Rodriguez Soriano J Renal tubular acidosis: the clinical entity J Am Soc Nephrol 2002 13 8 2160 2170 12138150 \n2 Caldas A Broyewr M Dechaux M Kleinknecht C Primary distal tubular acidosis in childhood: Clinical study and long-term follow-up of 28 patients J Pediatr 1992 121 2 233 241 1640289 \n3 Batlle D Ghanekar H Jain S Mitra A Hereditary distal renal tubular acidosis: new understandings Annu Rev Med 2001 52 471 484 11160790 \n4 Fry AC Karet FE Inherited renal acidoses Physiology (Bethesda) 2007 22 202 211 17557941 \n5 Domrongkitchaiporn S Khositseth S Stitchantrakul W Tapaneya-olarn W Radinahamed P Dosage of potassium citrate in the correction of urinary abnormalities in pediatric distal renal tubular acidosis patients Am J Kidney Dis 2002 39 2 383 391 11840381 \n6 Tapaneya-Olarn W Khositseth S Tapaneya-Olarn C The optimal dose of potassium citrate in the treatment of children with distal renal tubular acidosis J Med Assoc Thai 2002 85 Suppl 4 S1143 1149 12549788 \n7 Lamberg BA Kuhlback B Effect of chlorothiazide and hydrochlorothiazide on the excretion of calcium in urine Scand J Clin Lab Invest 1959 11 351 357 14413581 \n8 Voskaki I al Qadreh A Mengreli C Sbyrakis S Effect of hydrochlorothiazide on renal hypercalciuria Child Nephrol Urol 1992 12 1 6 9 1606587 \n9 Choi JN Lee JS Shin JI Low-dose thiazide diuretics in children with idiopathic renal hypercalciuria Acta Paediatr 2011 100 8 e71 74 21284722 \n10 Colussi G Rombolà G Airaghi C De Ferrari ME Minetti L Pseudo-Bartter’s syndrome from surreptitious diuretic intake: differential diagnosis with true Bartter’s syndrome Nephrol Dial Transplant 1992 7 9 896 901 1328936 \n11 Unuma K Tojo A Harada K Autopsy report on pseudo-Bartter syndrome with renal calcification induced by diuretics and diet pills BMJ Case Rep 2009 2009 \n12 Olveira Fuster G Mancha Doblas I Vázquez San Miguel F Esteva de Antonio I C-Soriaguer Escofet F Surreptitious intake of diuretics as the cause of pseudo-Bartter’s syndrome: apropos of a case and differential diagnosis An Med Interna 1996 13 10 496 499 9019198 \n13 Wile D Diuretics: a review Ann Clin Biochem 2012 49 Pt 5 419 431 22783025 \n14 Naseri M Sadeghi R Role of high-dose hydrochlorothiazide in idiopathic hypercalciuric urolithiasis of childhood Iran J Kidney Dis 2011 5 3 162 168 21525575\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0392-4203",
"issue": "90(2)",
"journal": "Acta bio-medica : Atenei Parmensis",
"keywords": null,
"medline_ta": "Acta Biomed",
"mesh_terms": "D000141:Acidosis, Renal Tubular; D000471:Alkalosis; D001774:Blood Chemical Analysis; D003241:Consanguinity; D004232:Diuretics; D004636:Emergency Service, Hospital; D005500:Follow-Up Studies; D006061:Gonadal Dysgenesis, 46,XY; D006801:Humans; D007231:Infant, Newborn; D025261:Mitochondrial Proton-Translocating ATPases; D009154:Mutation; D035583:Rare Diseases; D012720:Severity of Illness Index; D049971:Thiazides; D016482:Urinalysis; D015431:Weight Loss",
"nlm_unique_id": "101295064",
"other_id": null,
"pages": "348-352",
"pmc": null,
"pmid": "31125018",
"pubdate": "2019-05-23",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22783025;21284722;21525575;1606587;14413581;9019198;12549788;1640289;11840381;17557941;11160790;12138150;21686346;1328936",
"title": "Severe metabolic alkalosis due to diuretic treatment in a patient with distal renal tubular acidosis: a rare association.",
"title_normalized": "severe metabolic alkalosis due to diuretic treatment in a patient with distal renal tubular acidosis a rare association"
} | [
{
"companynumb": "IT-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-213799",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROCHLOROTHIAZIDE"
},
... |
{
"abstract": "Intrapartum hypoxia was thought to contribute to the incidence of cerebral palsy, seizures and mental retardation. Electronic fetal monitoring was expected to prevent or reduce this incidence. Electronic fetal monitoring has a high false positive rate and fetal blood sampling, which is an invasive procedure, only allows an intermittent assessment. Efforts are being made to improve fetal heart rate analysis and clinical management. Fetal pulse oximetry, fetal electrocardiogram waveform analysis and the intermittent measurement of lactate levels by fetal blood sampling may become established as an adjunct to electronic fetal monitoring.",
"affiliations": "Department of Obstetrics and Gynaecology, Derby City Hospital, Derby, UK.",
"authors": "Jibodu|O A|OA|;Arulkumaran|S|S|",
"chemical_list": "D007773:Lactates",
"country": "England",
"delete": false,
"doi": "10.1097/00001703-200004000-00011",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1040-872X",
"issue": "12(2)",
"journal": "Current opinion in obstetrics & gynecology",
"keywords": null,
"medline_ta": "Curr Opin Obstet Gynecol",
"mesh_terms": "D015148:Cardiotocography; D004562:Electrocardiography; D005260:Female; D005312:Fetal Blood; D005323:Fetal Monitoring; D006801:Humans; D007773:Lactates; D010092:Oximetry; D011247:Pregnancy",
"nlm_unique_id": "9007264",
"other_id": null,
"pages": "123-7",
"pmc": null,
"pmid": "10813574",
"pubdate": "2000-04",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Intrapartum fetal surveillance.",
"title_normalized": "intrapartum fetal surveillance"
} | [
{
"companynumb": "GB-PFIZER INC-2018010786",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DINOPROSTONE"
},
"drugadditional": null,
... |
{
"abstract": "We reviewed the medical history of 26 women with differentiated thyroid cancer who became pregnant after receiving therapeutic doses of radioactive iodine (131I) in order to document the possibility of a greater risk for disorders in these pregnancies. There were a total of 39 pregnancies, 6 of which occurred during the first year after therapy. In 3 cases the following anomalies were encountered: a male suffering Trisomy 18 (Edward's syndrome), a female with constitutional aplastic anemia, and a male with a congenital hip dysplasia. Of the 33 pregnancies that occurred after the first year post-therapy, there were 2 spontaneous abortions and a male effected by ureteral stenosis. Based on these data, although it cannot be confirmed that these congenital disorders are due to the 131I therapy, we recommend that pregnancy be avoided for the first year after therapy.",
"affiliations": "Servicio de Endocrinología y Nutrición, Hospial Universitario Virgen del Rocío, Sevilla, Spain.",
"authors": "Ayala|C|C|;Navarro|E|E|;Rodríguez|J R|JR|;Silva|H|H|;Venegas|E|E|;Astorga|R|R|",
"chemical_list": "D007457:Iodine Radioisotopes",
"country": "United States",
"delete": false,
"doi": "10.1089/thy.1998.8.1009",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1050-7256",
"issue": "8(11)",
"journal": "Thyroid : official journal of the American Thyroid Association",
"keywords": null,
"medline_ta": "Thyroid",
"mesh_terms": "D000022:Abortion, Spontaneous; D000328:Adult; D000741:Anemia, Aplastic; D002887:Chromosomes, Human, Pair 18; D003251:Constriction, Pathologic; D005260:Female; D005306:Fertilization; D006618:Hip Dislocation, Congenital; D006801:Humans; D007457:Iodine Radioisotopes; D008297:Male; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic; D011832:Radiation Injuries; D012189:Retrospective Studies; D013964:Thyroid Neoplasms; D014314:Trisomy; D014515:Ureteral Diseases",
"nlm_unique_id": "9104317",
"other_id": null,
"pages": "1009-11",
"pmc": null,
"pmid": "9848714",
"pubdate": "1998-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Conception after iodine-131 therapy for differentiated thyroid cancer.",
"title_normalized": "conception after iodine 131 therapy for differentiated thyroid cancer"
} | [
{
"companynumb": "ES-CURIUM-2022000325",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SODIUM IODIDE I-131"
},
"drugadditional": "4",
... |
{
"abstract": "The aim of induction therapy in the management of kidney transplant is to reduce the incidence of acute rejection and delayed graft function after kidney transplant. The agent for induction therapy differs depending on the recipient risks. The regimen can be either polyclonal (rabbit antithymocyte globulin [rATG]) or monoclonal antibody (basiliximab). Basiliximab is commonly used in patients with low immunologic risk. However, to date we know that the use of rATG on T cell depletion is dose dependent and more potent antirejection therapy. Therefore, we would like to look at 1-year graft function of very low-dose rATG in low immunologic risk recipients. All low immunologic risk patients who received low-dose rATG (0.5 mg/kg of body weight daily) during transplant (day 0) and on days 1 and 2 were recruited. Their renal function, HLA donor-specific antibodies, lymphocyte counts, protocol biopsy results, and cytomegalovirus (CMV) polymerase chain reaction were monitored as per clinical practice. All 10 patients had immediate graft function. Low-dose rATG caused lymphocyte counts to deplete immediately on day 0, and the effect lasted about 1 month post-transplant. All the patients had stable graft function without any significance episode of rejection. Only one patient had de novo HLA-DQ antibody. It is good to know that without prophylaxis antiviral in CMV+ donor to CMV+ recipient, the incidence of CMV viremia is considerably low in our cohort. Very low-dose rATG is an effective induction immunosuppression in low immunologic risk patients with acceptable infection risk.",
"affiliations": "Division of Nephrology, Department of Medicine, University Malaya Medical Centre, Kuala Lumpur, Malaysia. Electronic address: mai_jalal@yahoo.com.;Division of Nephrology, Department of Medicine, University Malaya Medical Centre, Kuala Lumpur, Malaysia.;Division of Nephrology, Department of Medicine, University Malaya Medical Centre, Kuala Lumpur, Malaysia.;Division of Nephrology, Department of Medicine, University Malaya Medical Centre, Kuala Lumpur, Malaysia.;Division of Nephrology, Department of Medicine, University Malaya Medical Centre, Kuala Lumpur, Malaysia.;Division of Nephrology, Department of Medicine, University Malaya Medical Centre, Kuala Lumpur, Malaysia.",
"authors": "Jalalonmuhali|Maisarah|M|;Ng|Kok Peng|KP|;Ong|Chun Seong|CS|;Lee|Yee Wan|YW|;Wan Md Adnan|Wan Ahmad Hafiz|WAH|;Lim|Soo Kun|SK|",
"chemical_list": "D000961:Antilymphocyte Serum; D007166:Immunosuppressive Agents; D000077552:Basiliximab",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2020.02.139",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "52(6)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000328:Adult; D000961:Antilymphocyte Serum; D000077552:Basiliximab; D001706:Biopsy; D015331:Cohort Studies; D005260:Female; D006084:Graft Rejection; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D007239:Infections; D007668:Kidney; D016030:Kidney Transplantation; D019520:Living Donors; D008212:Lymphocyte Depletion; D008214:Lymphocytes; D008297:Male; D008875:Middle Aged; D062606:Tertiary Care Centers; D019737:Transplants; D016896:Treatment Outcome",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "1709-1714",
"pmc": null,
"pmid": "32448669",
"pubdate": "2020",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article",
"references": null,
"title": "Low Immunologic Risk Living Related Renal Transplant Using Very Low-Dose Antithymocyte Globulin as Induction Therapy: A Single Tertiary Hospital Experience.",
"title_normalized": "low immunologic risk living related renal transplant using very low dose antithymocyte globulin as induction therapy a single tertiary hospital experience"
} | [
{
"companynumb": "MY-TEVA-2020-MY-1824863",
"fulfillexpeditecriteria": "1",
"occurcountry": "MY",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "Hepatic VOD is a potentially fatal complication during stem cell transplantation and is rarely seen in the non-transplant setting. We report the case of a five-year-old boy who presented with visual complaints during delayed intensification phase of treatment for ALL. He was found to have bilateral retinal hemorrhages associated with profound thrombocytopenia due to chemotherapy. VOD was diagnosed based on EBMT criteria and was managed with supportive care. Despite resolution of VOD, his vision progressively deteriorated and resulted in blindness. This case highlights the significance of close monitoring of ALL patients in delayed intensification when they are at risk for developing VOD, the importance of refractory thrombocytopenia as a diagnostic feature and the potential for VOD to manifest with intraocular bleeding.",
"affiliations": "Pediatric Hematology, Oncology and Bone Marrow Transplantation, Nationwide Children's Hospital, Columbus, OH, USA.;Pediatric Hematology, Oncology and Bone Marrow Transplantation, Nationwide Children's Hospital, Columbus, OH, USA.;Pediatric Hematology, Oncology and Bone Marrow Transplantation, Nationwide Children's Hospital, Columbus, OH, USA.;Department of Ophthalmology, Ohio State University, Columbus, OH, USA.;Pediatric Hematology, Oncology and Bone Marrow Transplantation, Nationwide Children's Hospital, Columbus, OH, USA.",
"authors": "Bhunia|Nabanita|N|0000-0001-6068-5783;Yeager|Nicholas D|ND|;Colace|Susan I|SI|;Buzzaco|Dominic|D|;Bajwa|Rajinder P S|RPS|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D013866:Thioguanine",
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.13638",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "24(1)",
"journal": "Pediatric transplantation",
"keywords": "leukemia; retinal hemorrhage; thioguanine; veno occlusive disease",
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D000964:Antimetabolites, Antineoplastic; D001766:Blindness; D002675:Child, Preschool; D006504:Hepatic Veno-Occlusive Disease; D006801:Humans; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D012166:Retinal Hemorrhage; D013866:Thioguanine; D013921:Thrombocytopenia",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "e13638",
"pmc": null,
"pmid": "31840375",
"pubdate": "2020-02",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Ocular hemorrhage secondary to thioguanine-associated veno-occlusive disease in a child with acute lymphoblastic leukemia in delayed intensification.",
"title_normalized": "ocular hemorrhage secondary to thioguanine associated veno occlusive disease in a child with acute lymphoblastic leukemia in delayed intensification"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-237681",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"dr... |
{
"abstract": "To evaluate and compare benefits and harms of three biological treatments with different modes of action versus active conventional treatment in patients with early rheumatoid arthritis.\n\n\n\nInvestigator initiated, randomised, open label, blinded assessor, multiarm, phase IV study.\n\n\n\nTwenty nine rheumatology departments in Sweden, Denmark, Norway, Finland, the Netherlands, and Iceland between 2012 and 2018.\n\n\n\nPatients aged 18 years and older with treatment naive rheumatoid arthritis, symptom duration less than 24 months, moderate to severe disease activity, and rheumatoid factor or anti-citrullinated protein antibody positivity, or increased C reactive protein.\n\n\n\nRandomised 1:1:1:1, stratified by country, sex, and anti-citrullinated protein antibody status. All participants started methotrexate combined with (a) active conventional treatment (either prednisolone tapered to 5 mg/day, or sulfasalazine combined with hydroxychloroquine and intra-articular corticosteroids), (b) certolizumab pegol, (c) abatacept, or (d) tocilizumab.\n\n\n\nThe primary outcome was adjusted clinical disease activity index remission (CDAI≤2.8) at 24 weeks with active conventional treatment as the reference. Key secondary outcomes and analyses included CDAI remission at 12 weeks and over time, other remission criteria, a non-inferiority analysis, and harms.\n\n\n\n812 patients underwent randomisation. The mean age was 54.3 years (standard deviation 14.7) and 68.8% were women. Baseline disease activity score of 28 joints was 5.0 (standard deviation 1.1). Adjusted 24 week CDAI remission rates were 42.7% (95% confidence interval 36.1% to 49.3%) for active conventional treatment, 46.5% (39.9% to 53.1%) for certolizumab pegol, 52.0% (45.5% to 58.6%) for abatacept, and 42.1% (35.3% to 48.8%) for tocilizumab. Corresponding absolute differences were 3.9% (95% confidence interval -5.5% to 13.2%) for certolizumab pegol, 9.4% (0.1% to 18.7%) for abatacept, and -0.6% (-10.1% to 8.9%) for tocilizumab. Key secondary outcomes showed no major differences among the four treatments. Differences in CDAI remission rates for active conventional treatment versus certolizumab pegol and tocilizumab, but not abatacept, remained within the prespecified non-inferiority margin of 15% (per protocol population). The total number of serious adverse events was 13 (percentage of patients who experienced at least one event 5.6%) for active conventional treatment, 20 (8.4%) for certolizumab pegol, 10 (4.9%) for abatacept, and 10 (4.9%) for tocilizumab. Eleven patients treated with abatacept stopped treatment early compared with 20-23 patients in the other arms.\n\n\n\nAll four treatments achieved high remission rates. Higher CDAI remission rate was observed for abatacept versus active conventional treatment, but not for certolizumab pegol or tocilizumab versus active conventional treatment. Other remission rates were similar across treatments. Non-inferiority analysis indicated that active conventional treatment was non-inferior to certolizumab pegol and tocilizumab, but not to abatacept. The results highlight the efficacy and safety of active conventional treatment based on methotrexate combined with corticosteroids, with nominally better results for abatacept, in treatment naive early rheumatoid arthritis.\n\n\n\nEudraCT2011-004720-35, NCT01491815.",
"affiliations": "Copenhagen Center for Arthritis Research (COPECARE) and DANBIO, Center for Rheumatology and Spine Diseases, Rigshospitalet, Glostrup, Denmark merete.hetland@dadlnet.dk.;Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway.;Rheumatology Clinic, Sahlgrenska University Hospital, Gothenburg, Sweden.;Division of Rheumatology, Helsinki University Hospital, Helsinki, Finland.;Amsterdam Rheumatology and Immunology Center, Reade, Netherlands.;Landspitali University Hospital, Reykjavik, Iceland.;Department of Medicine, Rheumatology Unit, Center for Molecular Medicine (CMM), Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.;Danish Hospital for Rheumatic Diseases, University Hospital of Southern Denmark, Sønderborg, Denmark.;Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway.;Landspitali University Hospital, Reykjavik, Iceland.;Copenhagen Center for Arthritis Research (COPECARE) and DANBIO, Center for Rheumatology and Spine Diseases, Rigshospitalet, Glostrup, Denmark.;Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway.;Department of Epidemiology and Biostatistics, Amsterdam University Medical Centres, Amsterdam, Netherlands.;Department of Medicine, Rheumatology Unit, Center for Molecular Medicine (CMM), Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.;Copenhagen Center for Arthritis Research (COPECARE) and DANBIO, Center for Rheumatology and Spine Diseases, Rigshospitalet, Glostrup, Denmark.;Copenhagen Center for Arthritis Research (COPECARE) and DANBIO, Center for Rheumatology and Spine Diseases, Rigshospitalet, Glostrup, Denmark.;Department of Medicine, Rheumatology Unit, Center for Molecular Medicine (CMM), Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.;Rheumatology Clinic, Sahlgrenska University Hospital, Gothenburg, Sweden.;Copenhagen Center for Arthritis Research (COPECARE) and DANBIO, Center for Rheumatology and Spine Diseases, Rigshospitalet, Glostrup, Denmark.;Section of Rheumatology, Department of Clinical Sciences Lund, Skåne University Hospital, Lund and Malmö, Sweden.;Department of Medicine, Rheumatology Unit, Center for Molecular Medicine (CMM), Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.;Division of Rheumatology, Helsinki University Hospital, Helsinki, Finland.;Department of Rheumatology, Silkeborg University Clinic, Silkeborg, Denmark.;Department of Rheumatology, Skåne University Hospital, Malmö, Sweden.;Department of Medical Sciences, Uppsala University, Uppsala, Sweden.;Danish Hospital for Rheumatic Diseases, University Hospital of Southern Denmark, Sønderborg, Denmark.;Amsterdam Rheumatology and Immunology Center, Reade, Netherlands.;Department of Medicine and University of Eastern Finland, Jyväskylä Central Hospital, Jyväskylä, Finland.;Department of Rheumatology, Falu Hospital, Falun, Sweden.;Department of Rheumatology, Ålesund Hospital, Ålesund, Norway.;Department of Rheumatology, Haukeland University Hospital, Bergen, Norway.;Rheumatology Research Unit, Odense University Hospital, Southern University of Denmark, Denmark.;Department of Rheumatology, Örebro University Hospital, Örebro, Sweden.;Rheumatology Clinic, Västmanlands Hospital Västerås, Sweden.;Department of Rheumatology, Linköping University Hospital, Sweden.;Academic Specialist Center, Stockholm, Sweden.;Department of Rheumatology, Aalborg University Hospital, Aalborg, Denmark.;Section of Rheumatology, Department of Medicine, Svendborg Hospital OUH, Denmark.;Department of Rheumatology, St Olav's Hospital, University Hospital of Trondheim, Trondheim, Norway.;Department of Rheumatology, Aarhus University Hospital, Denmark.;Department of Rheumatology, University Hospital of North Norway, Tromsø, Norway.;Department of Research Support for Clinical Trials, Oslo University Hospital, Norway.;Department of Rheumatology and Amsterdam Rheumatology Center, Amsterdam University Medical Centers, Amsterdam, Netherlands.",
"authors": "Hetland|Merete Lund|ML|0000-0003-4229-6818;Haavardsholm|Espen A|EA|;Rudin|Anna|A|;Nordström|Dan|D|;Nurmohamed|Michael|M|;Gudbjornsson|Bjorn|B|;Lampa|Jon|J|;Hørslev-Petersen|Kim|K|;Uhlig|Till|T|;Grondal|Gerdur|G|;Østergaard|Mikkel|M|;Heiberg|Marte S|MS|;Twisk|Jos|J|;Lend|Kristina|K|;Krabbe|Simon|S|;Hyldstrup|Lise Hejl|LH|;Lindqvist|Joakim|J|;Hultgård Ekwall|Anna-Karin|AK|;Grøn|Kathrine Lederballe|KL|;Kapetanovic|Meliha|M|;Faustini|Francesca|F|;Tuompo|Riitta|R|;Lorenzen|Tove|T|;Cagnotto|Giovanni|G|;Baecklund|Eva|E|;Hendricks|Oliver|O|;Vedder|Daisy|D|;Sokka-Isler|Tuulikki|T|;Husmark|Tomas|T|;Ljoså|Maud-Kristine Aga|MA|;Brodin|Eli|E|;Ellingsen|Torkell|T|;Söderbergh|Annika|A|;Rizk|Milad|M|;Olsson|Åsa Reckner|ÅR|;Larsson|Per|P|;Uhrenholt|Line|L|;Just|Søren Andreas|SA|;Stevens|David John|DJ|;Laurberg|Trine Bay|TB|;Bakland|Gunnstein|G|;Olsen|Inge C|IC|;van Vollenhoven|Ronald|R|;|||",
"chemical_list": "D000075422:Anti-Citrullinated Protein Antibodies; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D001688:Biological Products; D005938:Glucocorticoids; D012460:Sulfasalazine; D006886:Hydroxychloroquine; D000069594:Abatacept; D002097:C-Reactive Protein; D012217:Rheumatoid Factor; D011239:Prednisolone; C502936:tocilizumab; D000068582:Certolizumab Pegol; D008727:Methotrexate",
"country": "England",
"delete": false,
"doi": "10.1136/bmj.m4328",
"fulltext": "\n==== Front\nBMJ\nBMJ\nBMJ-UK\nbmj\nThe BMJ\n0959-8138 1756-1833 BMJ Publishing Group Ltd. \n\nhetm060182\n10.1136/bmj.m4328\nResearch\nActive conventional treatment and three different biological treatments in early rheumatoid arthritis: phase IV investigator initiated, randomised, observer blinded clinical trial\nhttp://orcid.org/0000-0003-4229-6818Hetland Merete Lund professor1 2 Haavardsholm Espen A professor3 Rudin Anna senior lecturer4 5 Nordström Dan professor6 7 Nurmohamed Michael professor8 9 Gudbjornsson Bjorn professor10 11 Lampa Jon professor12 Hørslev-Petersen Kim professor13 14 Uhlig Till professor3 15 Grondal Gerdur professor10 11 Østergaard Mikkel professor1 2 Heiberg Marte S senior consultant3 Twisk Jos statistician16 Lend Kristina research assistant12 Krabbe Simon doctoral student1 2 Hyldstrup Lise Hejl research nurse1 2 Lindqvist Joakim doctoral student12 Hultgård Ekwall Anna-Karin associate professor4 5 Grøn Kathrine Lederballe registrar1 Kapetanovic Meliha senior consultant17 Faustini Francesca doctoral student12 Tuompo Riitta senior consultant6 7 Lorenzen Tove senior consultant18 Cagnotto Giovanni doctoral student19 20 Baecklund Eva professor21 Hendricks Oliver professor13 Vedder Daisy doctoral student8 Sokka-Isler Tuulikki professor22 Husmark Tomas senior consultant23 Ljoså Maud-Kristine Aga senior consultant24 Brodin Eli senior consultant25 Ellingsen Torkell professor26 Söderbergh Annika senior consultant27 Rizk Milad senior consultant28 Olsson Åsa Reckner senior consultant29 Larsson Per associate professor30 Uhrenholt Line doctoral student31 Just Søren Andreas senior consultant32 Stevens David John senior consultant33 Laurberg Trine Bay senior consultant34 Bakland Gunnstein senior consultant35 Olsen Inge C statistician36 van Vollenhoven Ronald professor9 12 on behalf of the NORD-STAR study group\n1 Copenhagen Center for Arthritis Research (COPECARE) and DANBIO, Center for Rheumatology and Spine Diseases, Rigshospitalet, Glostrup, Denmark \n\n2 Department of Clinical Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark\n\n3 Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway\n\n4 Rheumatology Clinic, Sahlgrenska University Hospital, Gothenburg, Sweden\n\n5 Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy of University of Gothenburg, Gothenburg, Sweden\n\n6 Division of Rheumatology, Helsinki University Hospital, Helsinki, Finland\n\n7 University of Helsinki, Helsinki, Finland\n\n8 Amsterdam Rheumatology and Immunology Center, Reade, Netherlands\n\n9 Department of Rheumatology and Amsterdam Rheumatology Center, Amsterdam University Medical Centers, Amsterdam, Netherlands\n\n10 Landspitali University Hospital, Reykjavik, Iceland\n\n11 Faculty of Medicine, University of Iceland, Reykjavik, Iceland\n\n12 Department of Medicine, Rheumatology Unit, Center for Molecular Medicine (CMM), Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden\n\n13 Danish Hospital for Rheumatic Diseases, University Hospital of Southern Denmark, Sønderborg, Denmark\n\n14 Department of Regional Health Research, University of Southern Denmark, Odense, Denmark\n\n15 University of Oslo, Oslo, Norway\n\n16 Department of Epidemiology and Biostatistics, Amsterdam University Medical Centres, Amsterdam, Netherlands\n\n17 Section of Rheumatology, Department of Clinical Sciences Lund, Skåne University Hospital, Lund and Malmö, Sweden\n\n18 Department of Rheumatology, Silkeborg University Clinic, Silkeborg, Denmark\n\n19 Department of Rheumatology, Skåne University Hospital, Malmö, Sweden\n\n20 Rheumatology, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden\n\n21 Department of Medical Sciences, Uppsala University, Uppsala, Sweden\n\n22 Department of Medicine and University of Eastern Finland, Jyväskylä Central Hospital, Jyväskylä, Finland\n\n23 Department of Rheumatology, Falu Hospital, Falun, Sweden\n\n24 Department of Rheumatology, Ålesund Hospital, Ålesund, Norway\n\n25 Department of Rheumatology, Haukeland University Hospital, Bergen, Norway\n\n26 Rheumatology Research Unit, Odense University Hospital, Southern University of Denmark, Denmark\n\n27 Department of Rheumatology, Örebro University Hospital, Örebro, Sweden\n\n28 Rheumatology Clinic, Västmanlands Hospital Västerås, Sweden\n\n29 Department of Rheumatology, Linköping University Hospital, Sweden\n\n30 Academic Specialist Center, Stockholm, Sweden\n\n31 Department of Rheumatology, Aalborg University Hospital, Aalborg, Denmark\n\n32 Section of Rheumatology, Department of Medicine, Svendborg Hospital OUH, Denmark\n\n33 Department of Rheumatology, St Olav’s Hospital, University Hospital of Trondheim, Trondheim, Norway\n\n34 Department of Rheumatology, Aarhus University Hospital, Denmark\n\n35 Department of Rheumatology, University Hospital of North Norway, Tromsø, Norway\n\n36 Department of Research Support for Clinical Trials, Oslo University Hospital, Norway\nNORD-STAR study group Bengtsson Anders Gülfe Anders Aga Anna-Birgitte Blanken Annelies Schlemmer Annette Kononoff Aulikki Turesson Carl Dackhammar Christina Gentline Cidem Glinatsi Daniel Lindqvist Elisabet Hauge Ellen-Margrethe Hermansson Elsa Grenholm Emma af Klint Erik Rødevand Erik Markros Fredrik Rezaei Hamed Lindegaard Hanne Merete Relas Heikki Valleala Heikki Qirjazo Ilia Jensen Hansen Inger Marie Rutanen Jarno Pedersen Jens Kristian Rathmann Jens Back Johan Wallman Johan Carlestam Johanna Einarsson Jon Lysholm Jörgen Öberg Kajsa Almehed Katarina Mykkänen Kati Karlberg Lena Hemberg Malin Stilling-Vinther Maria K Leirisalo-Repo Marjatta Hameed Mohaned Vivar Nancy Kaipiainen-Seppänen Oili Olsson Peter Linge Petrus Lindell Pia Jensen Pia Neuer Parmanne Pinja Østgård René Dieperink Sabine Christiansen Sara Nysom Exarchou Sofia Saleh Thiab Olofsson Tor Bruun Trude Rantalaiho Vappu Borgas Ylva Correspondence to M L Hetland Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Rigshospitalet, Valdemar Hansens Vej 17, DK-2600 Glostrup, Denmark, merete.hetland@dadlnet.dk\n2020 \n2 12 2020 \n371 m432819 8 2020 © Author(s) (or their employer(s)) 2019. Re-use permitted under CC\nBY-NC. No commercial re-use. See rights and permissions. Published by\nBMJ.2020BMJhttp://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 and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.Abstract\nObjective\nTo evaluate and compare benefits and harms of three biological treatments with different modes of action versus active conventional treatment in patients with early rheumatoid arthritis.\n\nDesign\nInvestigator initiated, randomised, open label, blinded assessor, multiarm, phase IV study.\n\nSetting\nTwenty nine rheumatology departments in Sweden, Denmark, Norway, Finland, the Netherlands, and Iceland between 2012 and 2018.\n\nParticipants\nPatients aged 18 years and older with treatment naive rheumatoid arthritis, symptom duration less than 24 months, moderate to severe disease activity, and rheumatoid factor or anti-citrullinated protein antibody positivity, or increased C reactive protein.\n\nInterventions\nRandomised 1:1:1:1, stratified by country, sex, and anti-citrullinated protein antibody status. All participants started methotrexate combined with (a) active conventional treatment (either prednisolone tapered to 5 mg/day, or sulfasalazine combined with hydroxychloroquine and intra-articular corticosteroids), (b) certolizumab pegol, (c) abatacept, or (d) tocilizumab.\n\nMain outcome measures\nThe primary outcome was adjusted clinical disease activity index remission (CDAI≤2.8) at 24 weeks with active conventional treatment as the reference. Key secondary outcomes and analyses included CDAI remission at 12 weeks and over time, other remission criteria, a non-inferiority analysis, and harms.\n\nResults\n812 patients underwent randomisation. The mean age was 54.3 years (standard deviation 14.7) and 68.8% were women. Baseline disease activity score of 28 joints was 5.0 (standard deviation 1.1). Adjusted 24 week CDAI remission rates were 42.7% (95% confidence interval 36.1% to 49.3%) for active conventional treatment, 46.5% (39.9% to 53.1%) for certolizumab pegol, 52.0% (45.5% to 58.6%) for abatacept, and 42.1% (35.3% to 48.8%) for tocilizumab. Corresponding absolute differences were 3.9% (95% confidence interval −5.5% to 13.2%) for certolizumab pegol, 9.4% (0.1% to 18.7%) for abatacept, and −0.6% (−10.1% to 8.9%) for tocilizumab. Key secondary outcomes showed no major differences among the four treatments. Differences in CDAI remission rates for active conventional treatment versus certolizumab pegol and tocilizumab, but not abatacept, remained within the prespecified non-inferiority margin of 15% (per protocol population). The total number of serious adverse events was 13 (percentage of patients who experienced at least one event 5.6%) for active conventional treatment, 20 (8.4%) for certolizumab pegol, 10 (4.9%) for abatacept, and 10 (4.9%) for tocilizumab. Eleven patients treated with abatacept stopped treatment early compared with 20-23 patients in the other arms.\n\nConclusions\nAll four treatments achieved high remission rates. Higher CDAI remission rate was observed for abatacept versus active conventional treatment, but not for certolizumab pegol or tocilizumab versus active conventional treatment. Other remission rates were similar across treatments. Non-inferiority analysis indicated that active conventional treatment was non-inferior to certolizumab pegol and tocilizumab, but not to abatacept. The results highlight the efficacy and safety of active conventional treatment based on methotrexate combined with corticosteroids, with nominally better results for abatacept, in treatment naive early rheumatoid arthritis.\n\nTrial registration\nEudraCT2011-004720-35, NCT01491815.\n==== Body\nIntroduction\nRheumatoid arthritis is a chronic inflammatory joint disease associated with joint destruction, pain, functional impairment, and increased comorbidity and mortality.1\n2 Early and active treatment is associated with improved outcome.3 The optimal first line treatment for patients with early rheumatoid arthritis has been debated, especially whether it should include a biological disease modifying drug.4 Currently, treatment recommendations in Europe and the United States advocate early treatment with conventional slow acting synthetic disease modifying drugs, with methotrexate as the anchor drug.4\n5 The addition of short term low to moderate dose corticosteroids to methotrexate (termed active conventional treatment) might optimise results.4\n6\n7\n8 Biological disease modifying antirheumatic drugs with different modes of action have been marketed. The most frequently used treatments prescribed early in the disease course are tumour necrosis factor α inhibition, T cell costimulation blocker, and interleukin 6 inhibition. Previous trials have shown superior outcomes in treatment naïve patients who have received biological drugs in combination with methotrexate compared with methotrexate and placebo.9\n10\n11\n12\n13 Several biological drugs are available whose benefits and harms need to be compared with one another in treatment naïve patients. Studies are needed to determine whether one or more biologicals might be more beneficial or safer, or better tailored to different subgroups of patients with rheumatoid arthritis. Therefore, a consortium of Scandinavian and Dutch academic investigators planned and conducted a randomised trial examining the comparative benefits and safety of biological drugs with different modes of action versus active conventional treatment in treatment naïve patients with rheumatoid arthritis.\n\nIn the first part of the NOrdic Rheumatic Diseases Strategy Trials And Registries (NORD-STAR) study our objective was to assess and compare the efficacy and safety after 24 weeks of active conventional treatment (either methotrexate combined with oral corticosteroids or methotrexate combined with intra-articular corticosteroids and other conventional synthetic disease modifying antirheumatic drugs) versus three biological treatments: a tumour necrosis factor inhibitor (certolizumab pegol), a T cell costimulation blocker (abatacept), and an interleukin 6 inhibitor (tocilizumab), all given in combination with methotrexate. Our hypothesis was that a higher clinical disease activity index (CDAI) remission rate would be observed for one or several of the biologicals compared with active conventional treatment.\n\nMethods\nTrial design and conduct\nThe design of this investigator initiated, multicentre, randomised, open label, blinded assessor trial (ClinicalTrials.gov: NCT01491815) has been published previously.14 The protocol is included in the online supplementary files. The trial has two parts: initial randomisation to one of four different treatment arms aiming to achieve remission (up to 80 weeks’ follow-up); and rerandomisation to two different tapering strategies of patients who reach the remission target. We present the 24 week analyses of the primary clinical outcome and key secondary outcomes. A steering committee of academic investigators designed and oversaw the trial. They also analysed and interpreted the data and contributed to the manuscript. We report our findings in accordance with the CONSORT (Consolidated Standards of Reporting Trials) statements, including the extension for multiarm, parallel group randomised trials.15\n16\n17\n\n\nStudy population\nThe trial population consisted of patients with early rheumatoid arthritis according to the American College of Rheumatology and European League Against Rheumatism (ACR/EULAR) 2010 classification criteria.18 Key inclusion criteria were age 18 years or older, symptom duration less than 24 months, moderate to severe disease activity with disease activity score (DAS28) greater than 3.2 (DAS28 calculated from 28 swollen and tender joint counts, patient global score, and C reactive protein), at least two (of 66) swollen and at least two (of 68) tender joints, and rheumatoid factor or anti-citrullinated protein antibody positivity (ACPA), or C reactive protein at least 10 mg/L. Key exclusion criteria included previous treatment with disease modifying antirheumatic drugs. Table S1 provides details about the inclusion and exclusion criteria.\n\nRandomisation and interventions\nPatients were randomised 1:1:1:1, stratified by country, sex, and ACPA status. Randomisation was done through the trial centre at the Karolinska Institute (see supplementary appendix for details). All patients started methotrexate on day 1 (escalated within four weeks to 25 mg every week) with folic acid supplementation (minimum 5 mg every week) combined with one of the following:\n\nArm 1 (active conventional treatment)—either (a) oral prednisolone (tapered from 20 to 5 mg/day in nine weeks); or (b) enterotablets sulfasalazine (2 g/day) combined with hydroxychloroquine (35 mg/kg every week or 200 mg/day) and mandatory intra-articular triamcinolone hexacetonide injection (or equivalent) in all swollen joints at each visit (maximally four joints and 80 mg every visit and no later than week 20)\n\nArm 2 (certolizumab pegol)—200 mg every other week subcutaneously (loading dose 400 mg at week 0, 2, and 4)\n\nArm 3 (abatacept)—125 mg every week subcutaneously\n\nArm 4 (tocilizumab)—8 mg/kg every four weeks intravenously or 162 mg every week subcutaneously.\n\nIntra-articular corticosteroid injections were allowed on demand up to week 20 in arm 1 and up to week 12 in arms 2-4; for details see protocol and statistical analysis plan in supplementary files.14 Patients received folate, vitamin D, and calcium supplementation according to local or national guidelines.\n\nTrial outcomes and blinding\nThe primary clinical efficacy outcome was adjusted CDAI remission (defined as CDAI≤2.8) at week 24.19 CDAI is calculated as the sum of swollen joint count (0-28), tender joint count (0-28), patient’s global score of disease activity (0-10), and investigator’s global score (0-10). An independent blinded assessor with no other roles in the study conducted the joint counts. Key secondary efficacy outcomes included CDAI remission at week 12 and over time (at week 4, 8, 12, 16, and 24); and other remission criteria at week 12, week 24, and over time: ACR/EULAR Boolean criteria, DAS28 and simplified disease activity index remission, and EULAR good response (see statistical analysis plan in supplementary files).20\n21\n22\n23\n\n\nSafety outcomes were the numbers and percentages of patients with serious and non-serious adverse events for each treatment arm. Predefined adverse events of interest included infections, cardiovascular disease, cataract, venous thromboembolism, demyelinating disease, diabetes mellitus, herpes zoster, malignancy, osteoporosis, tuberculosis, and weight gain. All safety events were MedDRA coded (version 22.0).\n\nStatistical analysis\nThis was a phase IV trial done in a clinical setting, not a confirmatory phase III trial. Therefore, as prespecified in the statistical analysis plan, effect estimates and 95% confidence intervals are reported for the differences between treatment arms at specific time points. Formal hypothesis tests were not performed, and confidence limits were not adjusted for multiplicity (see the statistical framework and statistical analysis plan in supplementary files).\n\nThe a priori sample size calculation indicated that we needed to randomise 724-832 patients to detect an overall difference between the four treatment groups with a power of 85-90%, assuming CDAI remission rates of 12%, 22%, 22%, and 26% in the active conventional treatment, certolizumab pegol, abatacept, and tocilizumab arms, respectively9\n10\n11\n24\n25\n26\n27\n28 (see protocol and statistical framework for details). We expected one or several of the three biological drugs to have higher remission rates than the active conventional treatment. The three comparisons were conducted in parallel, with inference made in each comparison.\n\nThe primary analysis population was the intention-to-treat population, defined as all randomised patients except 17 Finnish patients, for whom allocated treatment (tocilizumab) was not available (see statistical analysis plan in supplementary files). Strictly interpreted, these patients should have remained in the intention-to-treat population with non-responder imputation. Instead, the steering committee decided before data lock to exclude them from the intention-to-treat population to allow a fair analysis of the efficacy of tocilizumab. For transparency, the results of the analyses conducted on the strict intention-to-treat population are presented in the supplementary appendix.\n\nThe primary analysis of the primary and secondary dichotomous outcomes was done using a logistic regression model, adjusted for sex, ACPA status, country, age, body mass index, and DAS28 at baseline, with missing remission status imputed with worst case (non-remission). We present adjusted average marginal differences in remission rates with 95% confidence intervals, estimated by the delta method. Robustness analyses were performed using unadjusted logistic regression and longitudinally using adjusted and unadjusted generalised estimating equations, accounting for within patient correlation. Generalised estimating equations used non-imputed data with an exchangeable correlation structure. Robustness analyses were also performed and included the 17 Finnish patients mentioned above. Continuous secondary outcomes were analysed using generalised linear mixed gamma (C reactive protein and erythrocyte sedimentation rate), negative binomial (joint counts), or normal models (other), all with random intercept adjusted for baseline characteristics and value. Some of the other secondary outcomes are not reported here; we will report them in a separate publication (table S15 gives details).\n\nWe conducted non-inferiority analyses in the per protocol population, which consisted of patients who received study drugs as planned, by predefining a margin of 15% based on previous trials (see statistical analysis plan and statistical framework in supplementary files).29\n30 For safety outcomes, descriptive statistics were applied on the safety population.\n\nPatient and public involvement\nPatients or the public were not involved in the design, or conduct, or reporting of the study, but the patient organisations of the involved countries will be involved in the dissemination plans of our research.\n\nResults\nParticipants\nFrom 3 December 2012 to 11 December 2018, 903 patients were assessed for eligibility at 29 sites (listed in supplementary files). The proportion of screened patients who did not undergo randomisation was 10% (91/903); 812 underwent randomisation (fig S1). The last 24 week visit was conducted on 28 May 2019. Patient characteristics were well balanced (table 1). The mean age was 54.3 years, 68.8% of the patients were women, average symptom duration was 204 days, and mean time since diagnosis was 14 days. Disease activity was moderate to severe, with an average DAS28 of 5.0 and CDAI of 28.0. Rheumatoid factor was positive in 74.7% of patients, while 81.9% were ACPA positive.\n\nTable 1 Personal and clinical characteristics of patients at baseline (intention-to-treat population). Values are means (standard deviations) unless stated otherwise\n\nCharacteristic\tActive conventional treatment (n=200)\tCertolizumab pegol and methotrexate (n=203)\tAbatacept and methotrexate (n=204)\tTocilizumab and methotrexate (n=188)\t\nAge (years)\t54.6 (14.5)\t55.3 (15.3)\t54.7 (14.4)\t52.4 (14.5)\t\nWomen (n (%))\t139 (69.5)\t139 (68.5)\t140 (68.6)\t129 (68.6)\t\nSymptom duration (days)\t195 (167)\t203 (166)\t212 (168)\t208 (155)\t\nTime since diagnosis (days)\t13 (21)\t12 (17)\t16 (34)\t16 (33)\t\nBody mass index*\t26.6 (5.4)\t25.7 (4.9)\t26 (4.9)\t26.8 (5.1)\t\nNon-smoker (n (%))\t80 (40)\t76 (37.4)\t77 (37.7)\t85 (45.2)\t\nFormer smoker (n (%))\t85 (42.5)\t79 (38.9)\t78 (38.2)\t60 (31.9)\t\nCurrent smoker (n (%))\t35 (17.5)\t47 (23.2)\t49 (24)\t43 (22.9)\t\nAnti-citrullinated peptide antibody positive (n (%))\t163 (81.5)\t166 (81.8)\t169 (82.8)\t153 (81.4)\t\nRheumatoid factor positive (n (%))\t151 (75.5)\t149 (73.4)\t159 (77.9)\t135 (71.8)\t\nClinical disease activity index (CDAI)\t28.6 (12.1)\t27.9 (12.4)\t28.6 (11.3)\t26.6 (11.7)\t\nDisease activity score of 28 joints (CRP based)\t5.1 (1.1)\t5.0 (1.1)\t5.1 (1)\t4.9 (1)\t\nTender joint count (68 joints)\t17 (11.4)\t15.3 (10.4)\t16.1 (10.7)\t14.8 (10.2)\t\nSwollen joint count (66 joints)\t11.4 (7.3)\t11.2 (7.6)\t11.1 (7.3)\t9.8 (6.4)\t\nPatient’s global assessment of disease activity (mm)\t56.7 (23.2)\t56.6 (23.7)\t60.4 (23.6)\t57.4 (22.6)\t\nPhysician’s global assessment of disease activity (mm)\t48.8 (19.2)\t49.3 (19.2)\t51.7 (18.7)\t49.7 (18.1)\t\nPatient’s assessment of pain (mm)\t56 (24.2)\t55.7 (24.7)\t59.3 (24.2)\t55.3 (23)\t\nHealth assessment questionnaire (0-3)\t1.1 (0.6)\t1 (0.6)\t1.1 (0.6)\t1.1 (0.5)\t\nCRP=C reactive protein.\n\n* Two patients had missing value for body mass index at baseline. The missing values were imputed with the median. \n\nEfficacy outcomes\n\nTable 2 summarises efficacy outcomes. The adjusted CDAI remission rate at 24 weeks was 42.7% (95% confidence interval 36.1% to 49.3%) for patients in the active conventional treatment group, 46.5% (39.9% to 53.1%) for the certolizumab pegol group, 52.0% (45.5% to 58.6%) for the abatacept group, and 42.1% (35.3% to 48.8%) for the tocilizumab group. With active conventional treatment as the reference, the adjusted difference in CDAI remission rate was 3.9% (95% confidence interval −5.5% to 13.2%) for certolizumab pegol, 9.4% (0.1% to 18.7%) for abatacept, and −0.6% (−10.1% to 8.9%) for tocilizumab. The adjusted CDAI remission rates at 12 weeks were largely similar across treatments; with active conventional treatment as the reference, the remission rates were 4.5%, 2.6%, and 4.6% higher for certolizumab pegol, abatacept, and tocilizumab, respectively. The mean adjusted difference in CDAI remission over time was 6.3% (−0.4% to 12.9%) for certolizumab pegol, 1.5% (−5.0% to 7.9%) for abatacept, and 2.0% (−4.7% to 8.7%) for tocilizumab. Figure 1 shows that for adjusted CDAI remission rates over time no clear separation was found between the four treatment arms. For key secondary outcomes, results were generally similar across the four treatment groups (table 2, figs S3-S6). Table S2 and figs S7-S13 present results for other secondary outcomes.\n\nTable 2 Primary and key secondary outcomes. Values are percentage differences in rates (95% confidence intervals) with active conventional treatment as reference\n\nParameter\tWeek No\tCertolizumab pegol and methotrexate v active conventional treatment\tAbatacept and methotrexate v active conventional treatment\tTocilizumab and methotrexate v active conventional treatment\t\n\nPrimary outcome\n\t\t\t\t\t\nCDAI remission\t24\t3.9 (−5.5 to 13.2)\t9.4 (0.1 to 18.7)\t−0.6 (−10.1 to 8.9)\t\n\nKey secondary outcomes\n\t\t\t\t\t\nCDAI remission\t12\t4.5 (−4.4 to 13.3)\t2.6 (−6.1 to 11.4)\t4.6 (−4.4 to 13.7)\t\nACR/EULAR Boolean remission\t24\t3.6 (−5.7 to 12.9)\t4.6 (−4.6 to 13.9)\t−3.8 (−13.2 to 5.6)\t\nACR/EULAR Boolean remission\t12\t7.1 (−1.3 to 15.6)\t7.2 (−1.2 to 15.7)\t9.2 (0.5 to 18)\t\nDAS28 remission\t24\t2.6 (−6.2 to 11.4)\t4.5 (−4.2 to 13.2)\t−0.7 (−9.8 to 8.4)\t\nDAS28 remission\t12\t5.8 (−3.3 to 14.9)\t2.2 (−6.9 to 11.3)\t14 (4.8 to 23.1)\t\nSDAI remission\t24\t6.4 (−3 to 15.7)\t8.9 (−0.3 to 18.2)\t1.4 (−8.1 to 10.9)\t\nSDAI remission\t12\t6.9 (−2 to 15.7)\t3.6 (−5.2 to 12.3)\t7.5 (−1.5 to 16.6)\t\nEULAR good response\t24\t4.4 (−4.1 to 12.8)\t7.6 (−0.7 to 15.8)\t0.4 (−8.4 to 9.2)\t\nEULAR good response\t12\t7.3 (−1.3 to 16)\t4.9 (−3.8 to 13.6)\t10.4 (1.8 to 19.1)\t\nACR=American College of Rheumatology; CDAI=clinical disease activity index; DAS28=disease activity score of 28 joints (C reactive protein based, four variables); EULAR=European League Against Rheumatism; SDAI=simple disease activity index.\n\nPrimary analyses, intention-to-treat population, logistic regression analysis adjusted for baseline covariates. Marginal estimates averaged over the covariates as observed in the sample.\n\nFig 1 Probability of clinical disease activity index (CDAI) remission over time for each treatment group. Longitudinal analysis on the intention-to-treat population using adjusted generalised estimating equations and accounting for within patient correlation. Average marginal estimates are shown, averaged over the covariates as observed in the sample. Bars indicate 95% confidence intervals\n\nRobustness analyses\nWe conducted prespecified robustness analyses of the primary and key secondary efficacy outcomes. The results were consistent with those of the primary analyses (fig S14 and tables S3-S5).\n\nNon-inferiority analyses\nFor CDAI remission at 24 weeks, differences in remission rates for the active conventional treatment versus certolizumab pegol and tocilizumab, but not abatacept, remained within the predefined non-inferiority margin of 15% (fig 2). Tables S6-S7 show the results of the non-inferiority analyses.\n\nFig 2 Forest plot of risk differences. Estimated differences (95% confidence intervals) in clinical disease activity index (CDAI) remission rates at 24 weeks between active conventional treatment and methotrexate in combination with certolizumab pegol, abatacept, or tocilizumab. Logistic regression analysis, adjusted for sex, anti-citrullinated protein antibody positivity status, country, age, body mass index and baseline disease activity score of 28 joints (C reactive protein based, four variables; marginal estimates averaged over covariates as observed in sample). Dashed line shows non-inferiority margin. Figure based on per protocol dataset\n\nCorticosteroids\nThe use of corticosteroids was mandatory in arm 1, either orally (bridging treatment with tapering, arm 1A, n=137) or as mandatory injections of swollen joints (arm 1B, n=63). In arm 1A, prednisolone was reduced from 20 to 5 mg in nine weeks, then kept stable (5 mg) through week 32, then reduced and stopped at week 36. In arm 1B, from week 0 to week 4 the cumulative dose of triamcinolone hexacetonide corresponded to a median of 50 mg (interquartile range 34-80 mg), increasing to a total of 66 (40-94) mg by week 24. In the certolizumab pegol, abatacept, and tocilizumab arms the cumulative doses from week 0 to week 24 were 20 (0.0-80) mg, 20 (0.0-80) mg, and 0.0 (0.0-40) mg triamcinolone hexacetonide, respectively. The median cumulative dose of triamcinolone hexacetonide corresponded to a daily dose of less than 1 mg prednisolone in arm 1B and less than 0.5 mg in the certolizumab pegol and abatacept arms under the assumption that 40 mg of triamcinolone is equivalent to 50 mg of prednisolone.\n\nSafety outcomes and adherence to treatment\nNo suspected unexpected harms were reported. The percentages of patients who reported at least one adverse event in the groups receiving active conventional treatment, certolizumab pegol, abatacept, and tocilizumab were 86.3%, 82.7%, 79.9%, and 95.1%, respectively (table 3); at least one serious adverse event was reported in 5.6%, 8.4%, 4.9%, and 4.9% of patients, respectively. The number of patients who stopped treatment early was lowest for patients receiving abatacept (11 patients), compared with 20, 23, and 22 patients in the active conventional treatment, certolizumab pegol, and tocilizumab arms, respectively. Figure S1 gives the reasons for stopping treatment early.\n\nTable 3 Adverse events in the safety population at 24 weeks. Values are number of events (number of patients; percentage of patients in that arm who experienced at least one event)\n\nParameter\tActive conventional treatment (n=197)\tCertolizumab pegol and methotrexate (n=202)\tAbatacept and methotrexate (n=204)\tTocilizumab and methotrexate (n=184)\t\n\nSummary of adverse events\n\t\t\t\t\t\nAdverse events\t562 (170; 86.3)\t530 (167; 82.7)\t527 (163; 79.9)\t653 (175; 95.1)\t\nSerious adverse events\t13 (11; 5.6)\t20 (17; 8.4)\t10 (10; 4.9)\t10 (9; 4.9)\t\nDeaths\t—\t1 (1; 0.5)*\t—\t—\t\n\nAdverse events of special interest†\n\t\t\t\t\t\nInfections\t93 (68; 34.5)\t103 (74; 36.6)\t102 (70; 34.3)\t126 (84; 45.7)\t\nCardiovascular disease\t3 (3; 1.5)\t8 (7; 3.5)\t10 (9; 4.4)\t6 (6; 3.3)\t\nCataract\t3 (2; 1)\t—\t3 (2; 1)\t—\t\nDemyelinating disease\t—\t1 (1; 0.5)\t—\t—\t\nDiabetes mellitus\t2 (2; 1)\t—\t—\t—\t\nHerpes zoster\t3 (3; 1.5)\t1 (1; 0.5)\t—\t—\t\nMalignancy\t—\t1 (1; 0.5)\t2 (2; 1)\t3 (3; 1.6)\t\nOsteoporosis\t1 (1; 0.5)\t3 (3; 1.5)\t—\t1 (1; 0.5)\t\nWeight gain\t2 (2; 1)\t—\t1 (1; 0.5)\t1 (1; 0.5)\t\nPatients could have more than one category of events. Adverse events are summarised by the safety population, and by actual treatment (not as randomised). The 17 Finnish patients randomised to arm 4 (tocilizumab) but not receiving it owing to unavailability are not included.\n\n* Sudden death in 78 year old woman. A lump in the breast was discovered at the screening visit, later breast cancer was diagnosed. She stopped treatment early in the trial on study day 42, had mastectomy on study day 47, and died suddenly thereafter on study day 102. The events were assessed as not related to study drug by the investigator.\n\n† No events were coded as venous thromboembolism and tuberculosis. Osteoporosis events were reported shortly after baseline, based on, for example, baseline dual energy x ray absorptiometry scan.\n\nOf the prespecified adverse events of interest, infections were reported in 34.5%, 36.6%, 34.3%, and 45.7% of patients treated with active conventional treatment, certolizumab pegol, abatacept, and tocilizumab, respectively. Harms associated with corticosteroid use (cataract, diabetes mellitus, osteoporosis, and weight gain) were rare (0-1.5% in all arms), and cardiovascular disease was reported in 1.5%, 3.5%, 4.4%, and 3.3% of patients, respectively.\n\nGastrointestinal symptoms were reported in 42.1%, 29.7%, 37.3%, and 29.9% of patients treated with active conventional treatment, certolizumab pegol, abatacept, and tocilizumab, respectively (table S14). Increased liver enzymes were reported in 10.7%, 14.4%, 14.2%, and 30.4%, and increased neutropenia or leukopenia in 1%, 1%, 1.5%, and 12.5% of patients, respectively. For more details on harms, see tables S9-S14.\n\nDiscussion\nStatement of principal findings\nWe found that CDAI remission was achieved in more than 40% of patients with treatment naïve early rheumatoid arthritis who were treated with biological drugs with different modes of action (certolizumab pegol, abatacept, or tocilizumab), which were all given in combination with methotrexate. Patients who received active conventional treatment (methotrexate combined with bridging treatment with corticosteroids, and in some patients also sulfasalazine and hydroxychloroquine) had comparable remission rates. With the active conventional treatment as the reference, abatacept performed 9% better in achieving CDAI remission (primary efficacy outcome). For all key secondary outcomes, including longitudinal analysis and a range of other remission and response criteria, the overall differences between treatments were modest with overlapping confidence intervals. A prespecified non-inferiority analysis of the primary outcome showed that active conventional treatment was non-inferior to certolizumab pegol and tocilizumab, but not to abatacept. Among the prespecified harms of interest, serious adverse event rates were highest in the certolizumab pegol group, whereas infection rates and events of increased hepatic enzymes and neutropenia or leukopenia were higher in the tocilizumab arm. We found no increased risk of adverse events attributable to corticosteroid use in the active conventional treatment arm, whereas gastrointestinal symptoms were most common in this arm.\n\nStrengths and weaknesses of the study\nThis randomised clinical trial examined the comparative benefits and safety of biological drugs with different modes of action versus active conventional treatment in treatment naïve patients with rheumatoid arthritis, and includes three different biological drugs. We consider the generalisability of our findings to be high because 90% of screened patients underwent randomisation, and the baseline characteristics were typical for treatment naïve patients with poor prognosis.\n\nOne limitation is that, although this was a large investigator initiated study in patients with early rheumatoid arthritis, it was not powered to directly compare the biological drugs to each other. Another limitation is the open label design, which could influence the decision to proceed in the trial after randomisation. Only two patients (one in arm 1 and one in arm 4) withdrew informed consent after randomisation. The open label design, although partly offset by the use of blinded joint assessors, could influence certain subjective outcomes; expectation bias would probably have disfavoured the conventional treatment arm in this instance. Longer treatment follow-up is needed for cardiovascular events, corticosteroid related safety outcomes, and structural damage; these will be assessed after 48 weeks.\n\nStrengths and weaknesses in relation to other studies, discussing important differences in results\nOur findings contrast with phase III trials that have consistently shown a minimum of 10-20% lower remission rates in the methotrexate alone arm.11\n12\n13 Inspired by clinical practice (and in contrast to phase III trials), we used corticosteroids as bridging treatment because methotrexate is a slow acting drug. Some trials in treatment naïve patients with early rheumatoid arthritis have studied methotrexate combined with corticosteroids (orally or intra-articularly) as bridging treatment and shown good efficacy. However, these trials were without biological comparators, used biological treatment only as induction treatment, combined the biological comparator with corticosteroids, or used higher doses of corticosteroids and suboptimal doses of methotrexate.6\n7\n31\n32\n33\n\n\nIn the EXXELERATE study of methotrexate, which included insufficient responders with established rheumatoid arthritis, two tumour necrosis factor inhibitors were compared (certolizumab pegol and adalimumab) and no differences in efficacy were found.34 In the ORBIT trial,35 rituximab was non-inferior to tumour necrosis factor inhibitors (adalimumab or etanercept) in patients who were seropositive and had early rheumatoid arthritis, and insufficient response to synthetic disease modifying drugs. In the ATTEST and AMPLE trials, abatacept was compared with infliximab (a tumour necrosis factor inhibitor) and adalimumab, respectively, in patients with inadequate response to methotrexate and the efficacy of abatacept was similar to that of the tumour necrosis factor inhibitor.36\n37 In agreement with our findings, abatacept had fewer discontinuations owing to adverse events than adalimumab.37\n\n\nWhat the study adds in light of relevant systematic reviews and meta-analyses\nA recent systematic review and network meta-analysis of methotrexate naïve patients mainly provided indirect comparisons of biologicals to each other.38 The authors concluded that moderate quality evidence was found that, compared with methotrexate alone, biologicals given in combination with methotrexate were associated with absolute and relative clinically meaningful benefits (15%) in DAS28 remission rates, and no higher risk of serious adverse events existed compared with methotrexate. Other systematic reviews and network meta-analyses looking at the comparative effectiveness of biological drugs have mainly focused on patients with disease that has failed to respond to methotrexate.39\n\n\nMeaning of the study: possible explanations and implications for clinicians and policy makers\nThe primary clinical outcome was CDAI remission at 24 weeks, a more stringent remission criterion than the DAS28 based criterion, which has traditionally been used in many trials. We chose the CDAI because the algorithm does not include acute phase reactants, which are differentially impacted upon by different biological treatments.\n\nNational preferences on the exact implementation of active conventional treatment were reflected in slightly different strategies in Denmark and Finland (triple treatment with methotrexate, sulfasalazine, and hydroxychloroquine combined with intra-articular triamcinolone hexacetonide) versus Sweden, Norway, the Netherlands, and Iceland (methotrexate combined with 20 mg prednisolone initially, tapered to 5 mg after nine weeks and discontinued after nine months). The active conventional treatment strategy with bridging corticosteroid brought promising results until week 24; the clinical results at week 48 will inform us if this is sustainable in the long term.\n\nAbatacept had fewest discontinuations, which contributed to its higher remission rate, because patients who stopped treatment early were imputed as non-responders. This finding emphasises the role of tolerability and harms in the evaluation of drug efficacy.\n\nUnanswered questions and future research\nThe study is ongoing. Follow-up at 48 weeks will show long term efficacy, and structural damage and harms for each of the four treatments. The second part of the trial will assess and compare two alternative de-escalation strategies in patients who have achieved remission. Research projects based on the NORD-STAR biobank will inform us whether one or more of the biological drugs might be better tailored to different subgroups of patients.\n\nConclusion\nHigh remission rates were found in disease modifying antirheumatic drug naïve patients with early rheumatoid arthritis who started treatment with methotrexate in combination with abatacept, certolizumab pegol, tocilizumab, or active conventional treatment. We observed higher CDAI remission rates for abatacept versus active conventional treatment, but not for certolizumab pegol or tocilizumab versus active conventional treatment. Other remission rates were similar across treatments. Non-inferiority analysis indicated that active conventional treatment was non-inferior to certolizumab pegol and tocilizumab, but not to abatacept. Rates of adverse events and early withdrawals were lowest for abatacept. The results highlight the efficacy and safety of active conventional treatment based on methotrexate combined with corticosteroids, with nominally better results for abatacept, in treatment naive early rheumatoid arthritis.\n\nWhat is already known on this topic\nRheumatoid arthritis is associated with joint destruction, pain, functional impairment, and increased comorbidity and mortality\n\nThe optimal first line treatment has been debated, especially whether it should include a biological disease modifying drug\n\nWith multiple biological treatments, whose benefits and harms have not been compared in treatment naïve patients, it is unclear whether one or more biological drugs might be more beneficial or safer in patients with early rheumatoid arthritis\n\nWhat this study adds\nThis trial compared the benefits and safety of three biological drugs with different modes of action, all given in combination with methotrexate, versus active conventional treatment in treatment naïve patients with rheumatoid arthritis\n\nAt 24 weeks, higher clinical disease activity index (CDAI) remission rate was observed for abatacept versus active conventional treatment (9.4%), but not for certolizumab pegol (3.9%) or tocilizumab (−0.6%) versus active conventional treatment\n\nNon-inferiority analysis indicated that active conventional treatment was non-inferior to certolizumab pegol and tocilizumab, but not to abatacept\n\nWe thank the patients, investigators, nurses, joint assessors, and study teams who were involved in the NORD-STAR trial; Eleonore Nilsson, chief study nurse, Niels Steen Krogh, data manager, Monica Rydén Aulin, study coordinator, and Eva Larsson, patient research partner.\n\nNORD-STAR study group: Anders Bengtsson, Anders Gülfe, Anna-Birgitte Aga, Annelies Blanken, Annette Schlemmer, Aulikki Kononoff, Carl Turesson, Christina Dackhammar, Cidem Gentline, Daniel Glinatsi, Elisabet Lindqvist, Ellen-Margrethe Hauge, Elsa Hermansson, Emma Grenholm, Erik af Klint, Erik Rødevand, Fredrik Markros, Hamed Rezaei, Hanne Merete Lindegaard, Heikki Relas, Heikki Valleala, Ilia Qirjazo, Inger Marie Jensen Hansen, Jarno Rutanen, Jens Kristian Pedersen, Jens Rathmann, Johan Back, Johan Wallman, Johanna Carlestam, Jon Einarsson, Jörgen Lysholm, Kajsa Öberg, Katarina Almehed, Kati Mykkänen, Lena Karlberg, Malin Hemberg, Maria K Stilling-Vinther, Marjatta Leirisalo-Repo, Mohaned Hameed, Nancy Vivar, Oili Kaipiainen-Seppänen, Peter Olsson, Petrus Linge, Pia Lindell, Pia Neuer Jensen, Pinja Parmanne, René Østgård, Sabine Dieperink, Sara Nysom Christiansen, Sofia Exarchou, Thiab Saleh, Tor Olofsson, Trude Bruun, Vappu Rantalaiho, Ylva Borgas.\n\nWeb extra Extra material supplied by authors\n\nWeb appendix: Supplementary appendix\n\n Web appendix: Original protocol\n\n Web appendix: Final protocol\n\n Web appendix: Statistical analysis plan\n\n Web appendix: Protocol amendments\n\n Web appendix: Study sites\n\n Contributors: MLH, EAH, DN, BG, KHP, TU, GG, MØ, RvV designed the study and wrote the protocol. RvV, DN, MSH, EAH, Niels Steen Krogh, DG, SK, MLH developed the CRFs. MLH, EAH, AR, DN, MN, BG, JL, KHP, TU, GG, MØ, MSH, SK, JL, AKHE, KLG, MK, FF, RT, TL, GC, EBa, OH, DV, TSI, TH, MKAL, EBr, TE, AS, MR, ÅRO, PL, LU, SAJ, DJS, TBL, GB, RvV contributed to the data collection and data cleaning. SK and Niels Steen Krogh did data management. JT and ICO conducted the statistical analyses. ICO and SK made the figures. MLH wrote the manuscript with input from all authors. All authors had access to the raw dataset and vouch for the veracity of the results. All authors read and approved the final version of the manuscript including the decision to submit the paper. MLH and RvV are guarantors of the overall content, accept full responsibility for the work and the conduct of the study, had access to the data, and controlled the decision to publish. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.\n\nFunding: Funding was obtained through public sources: Academy of Finland (grant No 258536), Finska Läkaresällskapet, grant from the South-Eastern Health Region, Norway, HUCH Institutional grant, Finland (grant No 1159005), Icelandic Society for Rheumatology, interregional grant from all health regions in Norway, NordForsk (grant No 70945), Regionernes Medicinpulje, Denmark (grant No 14/217), Stockholm County Council, Sweden (grant No 20100490), Swedish Medical Research Council (grant No C0634901, D0342301, 2015-00891_5), Swedish Rheumatism Association, The Research Fund of University Hospital, Reykjavik, Iceland (A2015017). UCB supported the work in the context of an investigator initiated study where UCB provided certolizumab pegol at no cost. UCB had no role in study design, collection, analysis, and interpretation of data, in the writing of the report, or in the decision to submit for publication. Bristol-Myers Squibb (BMS) provided abatacept at no cost. In addition, the Karolinska Institute received several unrestricted grants from BMS; these were subsequently transferred to the principal investigators of Denmark, Finland, and the Netherlands to help defray various trial related costs at the local level. BMS had no role in study design, collection, analysis, and interpretation of data, in the writing of the report, or in the decision to submit for publication. The final manuscript was provided for courtesy review to UCB and BMS in line with Good Publication Practice (GPP3). We confirm the independence of researchers from funders and that all authors, external and internal, had full access to all of the data (including statistical reports and tables) in the study and can take responsibility of the integrity of the data and the accuracy of the data analysis.\n\nCompeting interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: support from Academy of Finland, Finska Läkaresällskapet, South-Eastern Health Region (Norway), HUCH (Finland), Icelandic Society for Rheumatology, all health regions in Norway, NordForsk, Regionernes Medicinpulje (Denmark), Stockholm County Council (Sweden), Swedish Medical Research Council, Swedish Rheumatism Association, The Research Fund of University Hospital (Reykjavik, Iceland) for the submitted work; MLH reports grants from Nordforsk, from Danske Regioner during the conduct of the study; grants from Bristol-Myers Squibb, grants from AbbVie, grants from Roche, grants from Novartis, grants and personal fees from Merck, grants and personal fees from Biogen, grants and personal fees from Pfizer, personal fees from Eli Lilly, personal fees from Orion Pharma, personal fees from CellTrion, personal fees from Samsung Bioepsi, personal fees from Janssen Biologics BV, personal fees from MSD, outside the submitted work; she chairs the steering committee of the Danish Rheumatology Quality Registry (DANBIO), which receives public funding from the hospital owners and funding from pharamaceutical companies; EAH reports grants from NORDFORSK, grants from the Norwegian Regional Health Authorities, grants from the South-Eastern Norway Regional Health Authority, during the conduct of the study; personal fees from Pfizer, personal fees from AbbVie, personal fees from Celgene, personal fees from Novartis, personal fees from Janssen, personal fees from Gilead, personal fees from Eli-Lilly, personal fees from UCB, outside the submitted work; AR reports grants from the Swedish Research Council, financial support from AstraZeneca, outside the submitted work; DN reports grants from UCB, grants from BMS, during the conduct of the study; grants from AbbVie, grants from Celgene, grants from MSD, grants from Novartis, grants from Pfizer outside the submitted work; MN reports grants from BMS, during the conduct of the study; grants from Abbvie, grants from BMS, personal fees from Celltrion, grants from MSD, grants from Pfizer, personal fees from Eli Lilly, grants from Amgen, outside the submitted work; BG reports personal fees from Novartis, outside the submitted work; TU reports a grant from NORDFORSK during the conduct of the study; personal fees from Grünenthal, personal fees from Lilly, personal fees from Novartis, personal fees from Pfizer, outside the submitted work; MØ reports grants, personal fees and non-financial support from AbbVie, grants, personal fees and non-financial support from BMS, personal fees from Boehringer-Ingelheim, personal fees from Eli Lilly, personal fees and non-financial support from Janssen, grants, personal fees and non-financial support from Merck, personal fees and non-financial support from Pfizer, personal fees and non-financial support from Roche, grants, personal fees and non-financial support from UCB, grants and personal fees from Celgene, personal fees from Sanofi, personal fees from Regeneron, grants, personal fees and non-financial support from Novartis, personal fees from Orion, personal fees from Hospira, outside the submitted work; MSH reports grants from the South-Eastern Norway Regional Health Authority, during the conduct of the study; personal fees from Lilly, outside the submitted work; SK reports receiving grants from AbbVie, MSD and Novartis outside the submitted work; AKHE reports receiving personal fees from AbbVie, personal fees from Pfizer, outside the submitted work; KLG reports grants from BMS, outside the submitted work; RT reports grants from Finnish Rheumatology Research Fund, during the conduct of the study; OH reports non-financial support from Pfizer, personal fees from Abbvie, personal fees from Novartis, during the conduct of the study; TSI reports non-financial support from DiaGraphIT, personal fees from Abbvie, personal fees from BMS, personal fees from Celgene, personal fees from Medac, personal fees from Merck, personal fees from Novartis, personal fees from Orion Pharma, personal fees from Pfizer, personal fees from Roche, personal fees from Sandoz, personal fees from UCB, personal fees from Bohringer Ingelheim, outside the submitted work; LU reports personal fees from Abbvie, Eli Lilly and Novartis (speaker fees), outside the submitted work; DJS reports grants from KLINBEFORSK, during the conduct of the study; TBL reports personal fees from UCB, outside the submitted work; GB reports personal fees from BMS, outside the submitted work; ABA reports personal fees from Abbvie, personal fees from Eli Lilly, personal fees from Novartis, personal fees from Pfizer, outside the submitted work; AB reports grants from BMS, during the conduct of the study; CT reports grants and personal fees from Bristol Myers-Squibb, personal fees from Roche, personal fees from Abbvie, personal fees from Pfizer, outside the submitted work; HR reports personal fees from MSD, personal fees from Roche, personal fees from Abbvie, personal fees from Celgene, outside the submitted work; JR reports grants from BMS, during the conduct of the study; JW reports fees from Celgene, fees from Eli Lilly, fees from Novartis, outside the submitted work; KM reports personal fees from Abbvie, personal fees from Celgene, personal fees from Medac, personal fees from BMS, outside the submitted work; OKS reports grants from the Research Committee of the Kuopio University Hospital Catchment Area for the State Research Funding, during the conduct of the study; non-financial support from Pfizer, non-financial support from Novartis, non-financial support from MSD, personal fees from Boeringer Ingelheim, outside the submitted work; PP reports personal fees from Novartis Finland Oy, outside the submitted work; RØ reports personal fees from Bristol-Meyer Squibb, personal fees and non-financial support from AbbVie, personal fees from Gilead, personal fees from Janssen, personal fees from Eli-Lilly, personal fees from Novartis, outside the submitted work; SNC reports personal fees from Bristol Myers Squibb, personal fees from General Electric, outside the submitted work; SE reports personal fees from Novartis, outside the submitted work; TO reports personal fees from Eli Lilly, consultancy fee from Merck Sharp and Dohme, outside the submitted work; reports grants from BMS, during the conduct of the study; grants from Roche, grants from Mylan, other from Abbvie, outside the submitted work; VR reports grants from BMS, during the conduct of the study; grants from Roche, grants from Mylan, other from Abbvie, outside the submitted work; RvV reports grants from BMS, during the conduct of the study; grants from BMS, GSK, Lilly, UCB, grants from Pfizer, Roche, personal fees from AbbVie, AstraZeneca, Biogen, Biotest, Celgene, Galapagos, Gilead, Janssen, Pfizer, Servier, UCB, outside the submitted work; no other relationships or activities that could appear to have influenced the submitted work.\n\nEthical approval: The study was approved by national medical agencies, institutional review boards and independent ethics committees in participating countries and was conducted in accordance with national regulations and the International Conference on Harmonization Good Clinical Practice requirements, based on the Declaration of Helsinki. Names of the ethics committees and ID# were: Regionala etikprövningsnämnden i Stockholm, ID: 2011/2069-31/4 (Sweden); Den Videnskabsetiske Komite for Region Hovedstaden, ID: H-2-2013-153 (Denmark); Regional committees for medical and health research ethics, ID: 2014/2191/REC South East (Norway); Ethics Committee of Internal Medicine at the Helsinki University Hospital (HUS), ID: 240/13/03/01/2012 (Finland); Medisch Ethische Toetsingscommissie voor het Slotervaartziekenhuis en Reade, ID: NL60775.048.17 (The Netherlands); The National Bioethics Committee (NBC) Iceland; ID: 13-085 (Iceland). All the patients provided written informed consent before any study-related procedures.\n\nData sharing: The authors commit to making the relevant anonymised patient level data available on reasonable request.\n\nThe lead author (MLH) affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as originally planned have been explained.\n\nDissemination to participants and related patient and public communities: The patient organisations of the involved countries will be involved in the dissemination plans of this research. We plan to disseminate the results to study participants and to patient organisations as well as to the public through the media after publication.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\n1 \nSmolen JS Aletaha D McInnes IB \nRheumatoid arthritis\n. Lancet \n2016 ;388 :2023 -38\n\n10.1016/S0140-6736(16)30173-8 .27156434 \n2 \nKlareskog L Catrina AI Paget S \nRheumatoid arthritis\n. Lancet \n2009 ;373 :659 -72\n\n10.1016/S0140-6736(09)60008-8 .19157532 \n3 \nEmery P Salmon M \nEarly rheumatoid arthritis: time to aim for remission?\n\nAnn Rheum Dis \n1995 ;54 :944 -7\n\n10.1136/ard.54.12.944 .8546524 \n4 \nSmolen JS Landewé RBM Bijlsma JWJ \nEULAR recommendations for the management of rheumatoid arthritis with synthetic and biological modifying antirheumatic drugs: 2019 update\n. Ann Rheum Dis \n2020 ;79 :685 -699\n\n10.1136/annrheumdis-2019-216655 .31969328 \n5 Singh JA, Saag KG, Bridges SL, et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Care Res (Hoboken). 2016. http://onlinelibrary.wiley.com/doi/\n\n6 \nHetland ML Stengaard-Pedersen K Junker P \nCombination treatment with methotrexate, cyclosporine, and intraarticular betamethasone compared with methotrexate and intraarticular betamethasone in early active rheumatoid arthritis: an investigator-initiated, multicenter, randomized, double-blind, par\n. Arthritis Rheum \n2006 ;54 :1401 -9\n\n10.1002/art.21796 .16645967 \n7 \nGoekoop-Ruiterman YPM de Vries-Bouwstra JK Allaart CF \nClinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis the BeSt Study: a randomized controlled trial\n. Arthritis Rheum \n2005 ;52 :3381 -90\n.16258899 \n8 \nWassenberg S Rau R Steinfeld P Zeidler H \nVery low-dose prednisolone in early rheumatoid arthritis retards radiographic progression over two years: a multicenter, double-blind, placebo-controlled trial\n. Arthritis Rheum \n2005 ;52 :3371 -80\n\n10.1002/art.21421 .16255011 \n9 \nSt Clair EW Van der Heijde DMFM Smolen JS \nCombination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial\n. Arthritis Rheum \n2004 ;50 :3432 -43\n\n10.1002/art.20568 .15529377 \n10 \nBreedveld FC Weisman MH Kavanaugh AF \nThe PREMIER study: a multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previo\n. Arthritis Rheum \n2006 ;54 :26 -37\n\n10.1002/art.21519 .16385520 \n11 \nWesthovens R Robles M Ximenes AC \nClinical efficacy and safety of abatacept in methotrexate-naive patients with early rheumatoid arthritis and poor prognostic factors\n. Ann Rheum Dis \n2009 ;68 :1870 -7\n\n10.1136/ard.2008.101121 .19124524 \n12 \nBijlsma JWJ Welsing PMJ Woodworth TG \nEarly rheumatoid arthritis treated with tocilizumab, methotrexate, or their combination (U-Act-Early): a multicentre, randomised, double-blind, double-dummy, strategy trial\n. Lancet \n2016 ;388 :343 -55\n\n10.1016/S0140-6736(16)30363-4 .27287832 \n13 \nEmery P Bingham CO Burmester GR \nCertolizumab pegol in combination with dose-optimised methotrexate in DMARD-naïve patients with early, active rheumatoid arthritis with poor prognostic factors: 1-year results from C-EARLY, a randomised, double-blind, placebo-controlled phase III study\n. Ann Rheum Dis \n2017 ;76 :96 -104\n\n10.1136/annrheumdis-2015-209057 .27165179 \n14 \nGlinatsi D Heiberg MS Rudin A \nHead-to-head comparison of aggressive conventional therapy and three biological treatments and comparison of two de-escalation strategies in patients who respond to treatment: study protocol for a multicenter, randomized, open-label, blinded-assessor, pha\n. Trials \n2017 ;18 :161 \n10.1186/s13063-017-1891-x .28376912 \n15 Schulz KF, Altman DG, Moher D. coNSorT 2010 Statement: updated guidelines for reporting parallel group randomised trials. BMJ. 2010. www.consort-statement.org\n\n16 \nJuszczak E Altman DG Hopewell S Schulz K \nReporting of multi-arm parallel-group randomized trials: extension of the CONSORT 2010 statement\n. JAMA \n2019 ;321 :1610 -20\n\n10.1001/jama.2019.3087 .31012939 \n17 \nMoher D Hopewell S Schulz KF \nCONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials\n. BMJ \n2010 ;340 :c869 \n10.1136/bmj.c869 .20332511 \n18 \nAletaha D Neogi T Silman AJ \n2010 Rheumatoid arthritis classification criteria: An American College of Rheumatology/European League Against Rheumatism collaborative initiative\n. Arthritis Rheum \n2010 ;62 :2569 -81\n\n10.1002/art.27584 .20872595 \n19 \nAletaha D Martinez-Avila J Kvien TK Smolen JS \nDefinition of treatment response in rheumatoid arthritis based on the simplified and the clinical disease activity index\n. Ann Rheum Dis \n2012 ;71 :1190 -6\n\n10.1136/annrheumdis-2012-201491 .22454398 \n20 \nFelson DT Smolen JS Wells G \nAmerican College of Rheumatology/European League Against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials\n. Arthritis Rheum \n2011 ;63 :573 -86\n\n10.1002/art.30129 .21294106 \n21 \nFransen J Creemers MCW Van Riel PLCM \nRemission in rheumatoid arthritis : agreement of the disease activity score (DAS28) with the ARA preliminary remission criteria\n. Rheumatology (Oxford) \n2004 ;43 :1252 -5\n\n10.1093/rheumatology/keh297 .15238643 \n22 \nAletaha D Ward MM Machold KP Nell VPK Stamm T Smolen JS \nRemission and active disease in rheumatoid arthritis defining criteria for disease activity states\n. Arthritis Rheum \n2005 ;52 :2625 -36\n\n10.1002/art.21235 .16142705 \n23 \nvan Gestel AM Haagsma CJ Van Riel PLCM \nValidation of rheumatoid arthritis improvement criteria that include simplified joint counts\n. Arthritis Rheum \n1998 ;41 :1845 -50\n\n10.1002/1529-0131(199810)41:10<1845::AID-ART17>3.0.CO;2-K .9778226 \n24 \nvan Vollenhoven RF Ernestam S Geborek P \nAddition of infliximab compared with addition of sulfasalazine and hydroxychloroquine to methotrexate in patients with early rheumatoid arthritis (Swefot trial): 1-year results of a randomised trial\n. Lancet \n2009 ;374 :459 -66\n\n10.1016/S0140-6736(09)60944-2 .19665644 \n25 \nEmery P Breedveld FC Hall S \nComparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis (COMET): a randomised, double-blind, parallel treatment trial\n. Lancet \n2008 ;372 :375 -82\n\n10.1016/S0140-6736(08)61000-4 .18635256 \n26 \nMoreland LW O’Dell JR Paulus HE Curtis JR Bathon JM St Clair EW \nA randomized comparative effectiveness study of oral triple therapy versus etanercept plus methotrexate in early aggressive rheumatoid arthritis: the treatment of early aggressive rheumatoid arthritis trial\n. Arthritis Rheum \n2012 ;64 :2824 -35\n\n10.1002/art.34498 .22508468 \n27 \nSokka T Hetland ML Makinen H \nRemission and rheumatoid arthritis data on patients receiving usual care in twenty-four countries\n. Arthritis Rheum \n2008 ;58 :2642 -51\n\n10.1002/art.23794 .18759292 \n28 \nEmery P Keystone E Tony HP \nIL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals : results from a 24-week multicentre randomised placebo-controlled trial\n. Ann Rheum Dis \n2008 ;67 :1516 -23\n\n10.1136/ard.2008.092932 .18625622 \n29 \nYoo DH Hrycaj P Miranda P \nA randomised, double-blind, parallel-group study to demonstrate equivalence in efficacy and safety of CT-P13 compared with innovator infliximab when coadministered with methotrexate in patients with active rheumatoid arthritis: the PLANETRA study\n. Ann Rheum Dis \n2013 ;72 :1613 -20\n\n10.1136/annrheumdis-2012-203090 .23687260 \n30 \nJørgensen KK Olsen IC Goll GL \nSwitching from originator infliximab to biosimilar CT-P13 compared with maintained treatment with originator infliximab (NOR-SWITCH): a 52-week, randomised, double-blind, non-inferiority trial\n. Lancet \n2017 ;389 :2304 -16\n\n10.1016/S0140-6736(17)30068-5 .28502609 \n31 \nHørslev-Petersen K Hetland ML Junker P \nAdalimumab added to a treat-to-target strategy with methotrexate and intra-articular triamcinolone in early rheumatoid arthritis increased remission rates, function and quality of life. The OPERA Study: an investigator-initiated, randomised, double-blind\n. Ann Rheum Dis \n2014 ;73 :654 -61\n\n10.1136/annrheumdis-2012-202735 .23434570 \n32 \nde Jong PH Hazes JM Han HK \nRandomised comparison of initial triple DMARD therapy with methotrexate monotherapy in combination with low-dose glucocorticoid bridging therapy; 1-year data of the tREACH trial\n. Ann Rheum Dis \n2014 ;73 :1331 -9\n\n10.1136/annrheumdis-2013-204788 .24788619 \n33 \nVerschueren P De Cock D Corluy L \nMethotrexate in combination with other DMARDs is not superior to methotrexate alone for remission induction with moderate-to-high-dose glucocorticoid bridging in early rheumatoid arthritis after 16 weeks of treatment: the CareRA trial\n. Ann Rheum Dis \n2015 ;74 :27 -34\n\n10.1136/annrheumdis-2014-205489 .25359382 \n34 \nSmolen JS Burmester G Combe B \nHead-to-head comparison of certolizumab pegol versus adalimumab in rheumatoid arthritis: 2-year effi cacy and safety results from the randomised EXXELERATE study\n. Lancet \n2016 ;388 :2763 -74\n\n10.1016/S0140-6736(16)31651-8 .27863807 \n35 \nPorter D Van Melckebeke J Dale J \nTumour necrosis factor inhibition versus rituximab for patients with rheumatoid arthritis who require biological treatment (ORBIT): an open-label, randomised controlled, non-inferiority, trial\n. Lancet \n2016 ;388 :239 -47\n. 10.1016/S0140-6736(16)00380-9 .27197690 \n36 \nSchiff M Keiserman M Codding C \nEfficacy and safety of abatacept or infliximab vs placebo in ATTEST : a phase III, multi-centre, randomised, double-blind, placebo-controlled study in patients with rheumatoid arthritis and an inadequate response to methotrexate\n. Ann Rheum Dis \n2008 ;67 :1096 -103\n\n10.1136/ard.2007.080002 .18055472 \n37 \nSchiff M Weinblatt ME Valente R \nHead-to-head comparison of subcutaneous abatacept versus adalimumab for rheumatoid arthritis: two-year efficacy and safety findings from AMPLE trial\n. Ann Rheum Dis \n2014 ;73 :86 -94\n\n10.1136/annrheumdis-2013-203843 .23962455 \n38 \nSingh JA Hossain A Mudano A Tanjong Ghogomu E Suarez-almazor M Buchbinder R \nBiologics or tofacitinib for people with rheumatoid arthritis naive to methotrexate: a systematic review and network meta-analysis (Review)\n. Cochrane Database Syst Rev \n2017 ;5 .\n39 \nJanke K Biester K Krause D \nComparative effectiveness of biological medicines in rheumatoid arthritis: Systematic review and network meta-analysis including aggregate results from reanalysed individual patient data\n. BMJ \n2020 ;370 :1 -11\n.\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0959-8138",
"issue": "371()",
"journal": "BMJ (Clinical research ed.)",
"keywords": null,
"medline_ta": "BMJ",
"mesh_terms": "D000069594:Abatacept; D000328:Adult; D000368:Aged; D000075422:Anti-Citrullinated Protein Antibodies; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D001688:Biological Products; D002097:C-Reactive Protein; D000068582:Certolizumab Pegol; D003718:Denmark; D004359:Drug Therapy, Combination; D061345:Early Medical Intervention; D005260:Female; D005387:Finland; D005938:Glucocorticoids; D006801:Humans; D006886:Hydroxychloroquine; D007270:Injections, Intra-Articular; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D009426:Netherlands; D009664:Norway; D011239:Prednisolone; D012217:Rheumatoid Factor; D012720:Severity of Illness Index; D016037:Single-Blind Method; D012460:Sulfasalazine; D013548:Sweden; D016896:Treatment Outcome",
"nlm_unique_id": "8900488",
"other_id": null,
"pages": "m4328",
"pmc": null,
"pmid": "33268527",
"pubdate": "2020-12-02",
"publication_types": "D017429:Clinical Trial, Phase IV; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "18055472;25359382;28376912;24788619;23434570;18625622;22454398;20332511;18759292;22508468;16142705;28481462;16645967;23687260;20872595;27165179;31012939;19665644;27863807;21294106;18635256;19124524;27156434;27287832;9778226;28502609;15529377;8546524;19157532;16385520;32636183;27197690;16258899;23962455;31969328;16255011;15238643",
"title": "Active conventional treatment and three different biological treatments in early rheumatoid arthritis: phase IV investigator initiated, randomised, observer blinded clinical trial.",
"title_normalized": "active conventional treatment and three different biological treatments in early rheumatoid arthritis phase iv investigator initiated randomised observer blinded clinical trial"
} | [
{
"companynumb": "DK-UCBSA-2020053495",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CERTOLIZUMAB PEGOL"
},
"drugadditional": "3",
... |
{
"abstract": "A 41-year-old woman presented to her primary doctor with nausea, back pain and lower extremity oedema. Initial labs showed elevated serum creatinine and white blood cell count (WBC), which her doctor attributed to ibuprofen use and a recent upper respiratory infection. Five days later, she presented to the eye clinic with eye pain, redness and blurred vision. She was diagnosed with iritis, conjunctivitis and keratitis. The inflammatory eye disease with decreased renal function prompted the ophthalmologist to initiate systemic autoimmune and infectious disease work-up. Before laboratory testing was complete, she developed severe haemoptysis. Diagnosis of granulomatosis with polyangiitis (GPA) was confirmed using blood testing, radiological imaging and kidney biopsy. She received plasmapheresis, then cyclophosphamide and prednisone with good effect. This case highlights the need to consider GPA in the differential when patients present with inflammatory eye disease with decreased renal function and the need for multispecialty collaboration including ophthalmologists in the diagnosis of GPA.",
"affiliations": "Department of Ophthalmology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York, USA.;Department of Head and Neck Surgery, Section of Ophthalmology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Department of Ophthalmology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York, USA.;Department of Ophthalmology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York, USA.",
"authors": "Blumberg|Max J|MJ|;Tung|Cynthia I|CI|;May|Lindsay A|LA|;Patel|Sangita P|SP|http://orcid.org/0000-0001-6969-490X",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2016-218030",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "Acute renal failure; Ophthalmology; Vasculitis",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D003937:Diagnosis, Differential; D005260:Female; D014890:Granulomatosis with Polyangiitis; D006469:Hemoptysis; D006801:Humans",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28487300",
"pubdate": "2017-05-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11738428;12045940;16333191;17602941;19752730;20638092;23252657;27060746;27195187;28225490;6336643;7564726",
"title": "Granulomatosis with polyangiitis: seeing the diagnosis.",
"title_normalized": "granulomatosis with polyangiitis seeing the diagnosis"
} | [
{
"companynumb": "US-BION-006324",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional": "3",
"drugadmi... |
{
"abstract": "Management of complex regional pain syndrome (CRPS) can be challenging. Various pharmacological approaches have produced mixed results. Buprenorphine activates mu-opioid receptors and antagonizes kappa and delta receptors, acts at N-methyl-d-aspartate (NMDA) receptor, and is an orphan-related ligand-1 receptor agonist. It is available in transdermal patches that last for up to 7 days. This report describes two patients with refractory CRPS who were treated with transdermal buprenorphine. The patients experienced approximately 50% reduction in pain intensity scores. Application site rash that occurred was managed with topical steroid spray used before applying the patch.",
"affiliations": null,
"authors": "Onofrio|Sarah|S|;Vartan|Christine M|CM|;Nazario|Mitchell|M|;DiScala|Sandra|S|;Cuevas-Trisan|Ramon|R|;Melendez-Benabe|John|J|",
"chemical_list": "D000701:Analgesics, Opioid; D002047:Buprenorphine",
"country": "England",
"delete": false,
"doi": "10.3109/15360288.2016.1173756",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1536-0288",
"issue": "30(2)",
"journal": "Journal of pain & palliative care pharmacotherapy",
"keywords": "Butrans; buprenorphine; buprenorphine transdermal system; causalgia; complex regional pain syndrome; regional sympathetic dystrophy",
"medline_ta": "J Pain Palliat Care Pharmacother",
"mesh_terms": "D000368:Aged; D000701:Analgesics, Opioid; D002047:Buprenorphine; D020918:Complex Regional Pain Syndromes; D006801:Humans; D008297:Male; D010147:Pain Measurement; D057968:Transdermal Patch; D016896:Treatment Outcome",
"nlm_unique_id": "101125608",
"other_id": null,
"pages": "124-7",
"pmc": null,
"pmid": "27172230",
"pubdate": "2016-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "The Use of Transdermal Buprenorphine in Complex Regional Pain Syndrome: A Report of Two Cases.",
"title_normalized": "the use of transdermal buprenorphine in complex regional pain syndrome a report of two cases"
} | [
{
"companynumb": "US-MUNDIPHARMA DS AND PHARMACOVIGILANCE-GBR-2016-0039149",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRAMADOL"
},
"... |
{
"abstract": "BACKGROUND\nFirst manifestation of Cushing's syndrome during pregnancy is rare. The diagnosis of both Cushing's and primary aldosteronism within a pregnancy has not been previously documented. Diagnosis is especially challenging due to the normal physiological changes that occur during pregnancy. Consequently, many tests that are normally used for diagnosis are not reliable. Tumor based etiologies can be surgically removed. Etiologies that are not tumor based are challenging to treat during pregnancy.\n\n\nMETHODS\nA 25 year old G1P0 was admitted in the 22 5/7 week of pregnancy with elevated blood pressure (200/100 mm Hg), acne, moon facies, abdominal striae and hirsutism. With five antihypertensive medications her blood pressure remained 190/100 mm Hg. The patient was admitted to the ICU for intravenous medications and monitoring. She was diagnosed with Cushing's syndrome and primary aldosteronism. In spite of therapy with spironolactone and metyrapone she developed preeclampsia and was delivered in the 26 0/7 week of pregnancy. At her follow up visit eight weeks postpartum she had blood pressure within normal limits, no clinical signs or symptoms, and all medications had been discontinued.\n\n\nCONCLUSIONS\nEarly diagnosis of pregnancy induced Cushing's syndrome and primary aldosteronism requires an interdisciplinary approach. Late detection has been associated with increased perinatal morbidity and mortality including but not limited to placental abruption and intrauterine demise. Collaboration is essential in the optimization of maternal and fetal outcomes.",
"affiliations": "Department of Obstetrics and Gynecology, University of Ulm (Universitätsklinikum Ulm), Ulm, Germany.;Department of Obstetrics and Gynecology, University of Ulm (Universitätsklinikum Ulm), Ulm, Germany.;Department of Obstetrics and Gynecology, University of Ulm (Universitätsklinikum Ulm), Ulm, Germany.;Department of Obstetrics and Gynecology, Munich Klinik Harlaching (München Klinik Harlaching), Munich, Germany. Katrina.Kraft@muenchen-klinik.de.",
"authors": "Kersten|Maria|M|;Hancke|Katharina|K|;Janni|Wolfgang|W|;Kraft|Katrina|K|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s12884-020-03117-1",
"fulltext": "\n==== Front\nBMC Pregnancy Childbirth\nBMC Pregnancy Childbirth\nBMC Pregnancy and Childbirth\n1471-2393 BioMed Central London \n\n3117\n10.1186/s12884-020-03117-1\nCase Report\nPregnancy induced Cushing’s syndrome and primary aldosteronism: a case report\nKersten Maria 1 Hancke Katharina 1 Janni Wolfgang 1 Kraft Katrina Katrina.Kraft@muenchen-klinik.deemtpkat@yahoo.com 2 1 grid.6582.90000 0004 1936 9748Department of Obstetrics and Gynecology, University of Ulm (Universitätsklinikum Ulm), Ulm, Germany \n2 grid.507576.60000 0000 8636 2811Department of Obstetrics and Gynecology, Munich Klinik Harlaching (München Klinik Harlaching), Munich, Germany \n25 7 2020 \n25 7 2020 \n2020 \n20 42113 7 2019 16 7 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nFirst manifestation of Cushing’s syndrome during pregnancy is rare. The diagnosis of both Cushing’s and primary aldosteronism within a pregnancy has not been previously documented. Diagnosis is especially challenging due to the normal physiological changes that occur during pregnancy. Consequently, many tests that are normally used for diagnosis are not reliable. Tumor based etiologies can be surgically removed. Etiologies that are not tumor based are challenging to treat during pregnancy.\n\nCase presentation\nA 25 year old G1P0 was admitted in the 22 5/7 week of pregnancy with elevated blood pressure (200/100 mm Hg), acne, moon facies, abdominal striae and hirsutism. With five antihypertensive medications her blood pressure remained 190/100 mm Hg. The patient was admitted to the ICU for intravenous medications and monitoring. She was diagnosed with Cushing’s syndrome and primary aldosteronism. In spite of therapy with spironolactone and metyrapone she developed preeclampsia and was delivered in the 26 0/7 week of pregnancy. At her follow up visit eight weeks postpartum she had blood pressure within normal limits, no clinical signs or symptoms, and all medications had been discontinued.\n\nConclusions\nEarly diagnosis of pregnancy induced Cushing’s syndrome and primary aldosteronism requires an interdisciplinary approach. Late detection has been associated with increased perinatal morbidity and mortality including but not limited to placental abruption and intrauterine demise. Collaboration is essential in the optimization of maternal and fetal outcomes.\n\nKeywords\nCushing’s syndromePrimary aldosteronismPregnancyMetyraponePreeclampsiaSpironolactoneissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nFirst manifestation of Cushing’s syndrome (CS) and primary aldosteronism (PA) during pregnancy is rare. The most frequent etiologies have been attributed to adenomas, adrenal hyperplasia, or tumors. A small number of cases have been classified as pregnancy induced.\n\nDue to the small number of documented cases of pregnancy induced CS there is not a lot known about the pathophysiology. Case reports of tumor free patients with adrenocorticotropic hormone (ACTH) -independent pregnancy induced CS have been published. It is hypothesized that some adrenocortical cells have estrogen receptors. These receptors are stimulated in pregnancy (as a result of elevated estrogen levels) resulting in an increase in cortisol production [1].\n\nDiagnosis of CS and PA is challenging due to the normal physiological changes that occur in pregnancy. Many of the available diagnostic tests can be inconclusive. Brue et al. described the difficulty of diagnosing CS during pregnancy. The overlapping symptoms that occur as a result of hypercortisolism and the normal symptoms of pregnancy, including hirsutism, fatigue and weight gain can lead to a delay in diagnosis [2]. Signs and symptoms of CS such as hypokalemia may result from hyperemesis. Hypertension and hyperglycemia can be complications of pregnancy without underlying pathology.\n\nIncrease in plasma cortisol begins in the first trimester and continues to increase throughout the entire pregnancy. There are elevations in corticosteroid-binding globulin (CBG) and increases in CRH and ACTH produced by the placenta (beginning at week 7 and increasing until the end of pregnancy). The increased total levels of cortisol can make the interpretation of tests, such as the dexamethasone suppression test, extremely difficult. Urinary free cortisol (UFC) increases during the second trimester. Diagnostic tests with UFC are only reliable in the first trimester of pregnancy. CS that is diagnosed during pregnancy has been associated with more complications than CS diagnosed outside of pregnancy. Additional complications include growth retardation, preeclampsia, premature delivery, and intrauterine fetal demise [2]. PA symptoms include hypertension and hypokalemia. The incidence of preeclampsia in patients with PA is not higher than that of the general population [3].\n\nWe present a case of a patient with pregnancy induced CS and PA.\n\nCase presentation\nA 25 year old G1P0 was transferred to our center in the 225/7 week of pregnancy. The patient was admitted with blood pressure 200/100 mm Hg and presented with acne, moon facies, purple abdominal striae and hirsutism that she first noticed five weeks before admission (Figs. 1 and 2). She denied headache, abdominal pain, edema, visual disturbances, or rapid weight gain. Reflexes were normal. Sonography on admission showed singleton pregnancy with growth at the 68th percentile, fetal and maternal Doppler within normal limits. The patient denied family history of pregnancy-induced illnesses including CS, hypertension in pregnancy, or a history of preeclampsia.\nFig. 1 Typical signs of Cushing's syndrome including facial acne, moon facies, and abdominal striae\n\nFig. 2 Typical signs of Cushing's syndrome including facial acne, moon facies, and abdominal striae\n\n\n\nWe initiated therapy with methyldopa and began additional medications including hydralazine 25 milligrams (mg) three times daily (TID), metoprolol 95 mg two times daily (BID), nifedipine (retard) 20 mg BID, hydrochlorothiazide (HCTZ) 12.5 mg BID. The methyldopa was maximized at 2000 mg daily. In spite of the five antihypertensive medications her blood pressure remained elevated at190/100 mm Hg. The patient was transferred to our intensive care unit where the oral medications were supplemented with intravenous urapidil (alpha 1 adrenoreceptor antagonist and 5-HT1A receptor agonist). Hydralazine was given intravenously.\n\nPheochromocytoma was ruled out (free metanephrine 18.5 nanogram/Liter (ng/L (normal 7.9–88.7)), free normetanephrine < 2.8 ng/l (normal 20.1–135.4)). A negative renal artery Doppler allowed us to rule out stenosis. Magnetic resonance imaging (MRI) to rule out adrenal adenoma was inconclusive. Micronodules in the left adrenal gland (the largest 4 millimeter) were found so that unilateral adrenal hyperplasia could not be completely ruled out. After consultation with our urology department, surgical intervention was not warranted.\n\nMRI of the neck and thorax were negative for tumors. In 241/7 weeks we saw an increase in aspartate aminotransferase (AST) to 74 U/l and in alanine aminotransferase (ALT) to 102 U/l (normal < 50 U/l and < 45 U/l respectively) with a decrease in thrombocytes to 89 Giga/l (normal 150–450 Giga/l) and a decreasing haptoglobin to 0.41 g/l (normal 0.3–2 g/l).\n\nThe patient began rapidly gaining weight (13 kg within 13 days).\n\nDue to the complex clinical presentation we consulted with our endocrinology department and performed additional diagnostic tests. Plasma cortisol levels were found to be elevated at 50.3 mcg/dl, (normal 2.47–19.5 mcg/dl), urinary free cortisol (UFC) was elevated at 974 µg/day (mcg/d, normal 50–190 mcg/d), ACTH was low at 3.6 pg/ml (normal 7.2–63.3), and the aldosterone-to-renin ratio (ARR) was elevated at 100.1 (normal 0.5–37.8). A summary of the hormonal results can be found in Table 1.\nTable 1 Hormonal findings in chronological order\n\n\t23 0/7 weeks\t24 4/7 weeks\t25 3/7 weeks\t25 5/7 weeks\t1 month after delivery\t2 months after delivery\t4 months after delivery\t\nPlasma cortisol (normal 2.47–19.5 mcg/dl)\t50.3\t\t36.4\t25.5\t15.4\t4.65\t\t\nUrinary free cortisol (normal 50–190 mcg/d)\t\t974\t\t\t\t\t88.5\t\nACTH (normal 7.2–63.3 pg/ml)\t3.6\t\t\t\t14.4\t23.7\t\t\nAldosterone-to-renin ratio (normal 0.5–37.8)\t100.1\t\t\t\t\t65.7\t23.6\t\n\n\nA dexamethasone suppression test was performed and resulted in a cortisol of 39 mcg/dl (no suppression) and ACTH < 1.5 pg/ml. The patient was diagnosed with CS and PA and started on spironolactone 100 mg BID and metyrapone 2.5 g daily at 250/7 weeks.\n\nA risk of undervirilization has been described in male rat infants exposed to high doses of sprinolactone. To date undervirilization not been observed in humans [3]. The sex of the fetus (female) was determined and confirmed on multiple occasions prior to beginning the spironolactone therapy. Following consultation with our endocrinology and embryotoxicology departments and after reviewing the literature, we began therapy with spironolactone 100 mg twice daily.\n\nHypomagnesemia was treated intravenously after oral substitution attempts failed. After three days of therapy the intravenous urapidil and hydralazine could be discontinued.\n\nThe fetus was monitored for growth and fetal Doppler and cardiotocography were regularly performed.\n\nIn 260/7 weeks an abnormal fetal Doppler with near zero flow in the ductus venosus, zero flow in the umbilical artery and low flow in the middle cerebral artery (MCA) was diagnosed. The patient was delivered by cesarean section on the same day. Antenatal corticosteroids were not given due to the elevated maternal cortisol blood levels.\n\nWe delivered a female newborn with birthweight 595 g (13th percentile), Apgar 4/7/10, umbilical artery pH 7.20, Base Excess − 4.7. The newborn was admitted to the neonatal intensive care ward and received surfactant postnatally. Hypoglycemia and hyponatremia were successfully treated. Our neonatologists were concerned about the high levels of maternal cortisol that were potentially transferred to the fetus in utero. The newborn had a significant risk for postnatal adrenal cortex insufficiency (due to potential in utero suppression) with subsequent hypocortisolism. A prophylactic hydrocortisone therapy was initiated to decrease the risk of a subsequent life threatening Addisonian crisis. Stress of delivery alone can lead to elevated cortisol levels in newborns after delivery. Neonatal cortisol levels remained elevated on the second day of life. The hydrocortisone therapy could be reduced and eventually discontinued on day 8 of life.\n\nThere were no further complications, no evidence of bronchopulmonary dysplasia, intraventricular hemorrhage or necrotizing enterocolitis. The newborn was discharged without long term medications or complications.\n\nThe patient was discharged with metyrapone 2.5 g daily, spironolactone 100 mg BID, methyldopa 2000 mg daily, hydralazine 25 mg TID, metoprolol 95 mg BID, HCTZ 12.5 mg BID and nifedipine 5 mg BID. Within 2 months all medications could be discontinued, the blood pressure was within normal limits (110/70 mm Hg) and within 4 months all laboratory values were within normal limits (Table 1).\n\nDiscussion and conclusions\nCS and PA are rare diseases in pregnancy. Roughly 200 cases of CS and less than 50 cases of PA in pregnancy have been published [3, 4]. Published cases of simultaneous CS and PA in pregnancy could not be found.\n\nPregnancy induced CS is very rare. Kaperlik-Zaluska et al. described a patient who had signs and symptoms of CS in three pregnancies. The patient was reported to have hirsutism, acne, striae, and lab abnormalities consistent with CS. The first two pregnancies ended prematurely after placental abruption in the 24th and 25th weeks of pregnancy. The third pregnancy was monitored very closely and a therapy with metyrapone was started in the 6th week of pregnancy. At 28 weeks she developed hypertension, at 32 weeks she was delivered per emergency cesarean due to placental abruption [1]. Examinations performed after delivery and during follow up visits showed no evidence of CS, lab values were within normal limits, the clinical signs and symptoms diminished.\n\nClose et al. described a case of CS due to bilateral adrenal hyperplasia found at 23 weeks of pregnancy. The patient was treated with metyrapone until 34 weeks and was delivered via cesarean section due to decline in fetal growth. Four weeks after delivery adrenal function was within normal limits [5].\n\nAndreescu et al. reported cases of CS within pregnancy in which the increase in human chorionic gonadotropin hormone (hCG) was associated with hypercortisolism. Aberrant luteinizing hormone (LH) receptors were found within adrenal adenomas after adrenalectomy. These adenomas were responsive to luteinizing hormone releasing hormone (LHRH) and hCG, leading the authors to conclude that high levels of hCG resulted in high levels of cortisol with the associated signs and symptoms of CS [6]. The patients with aberrant receptors continued to have symptoms and abnormal lab values after delivery. After adrenalectomy the symptoms decreased and the lab values normalized. Pregnancy induced cases of CS are summarized in Table 2.\nTable 2 Summary of pregnancy induced CS cases\n\nCase\tPresentation\tTherapy and Imaging\tOutcome\t\nKasperlik-Zaluska 2000 [1]\tHypertension (190/110 mmHg), muscular atrophy, purple striae, hirsutism, hypokalemia at 16 weeks\tNone described\tCesarean section 24th week due placental abruption, postpartum lab values normal after 4 weeks\t\nKasperlik-Zaluska 2000 [1]\tSimilar features with elevated UFC at 16 weeks\tNone described\tCesarean section 25th week due to placental abruption, postpartum lab values normal after 3 months\t\nKasperlik-Zaluska 2000 [1]\tElevated UFC at 5 weeks, no symptoms\tMetyrapone 0.75 g daily until 17 weeks, then increased to 1 gram due to increasing cortisol\tCesarean section at 32nd week due to placental abruption, normalization of lab values beginning at 2 weeks postpartum\t\nClose 1993 [5]\tElevated cortisol, UFC and CS at 23 weeks\tBilateral adrenal hyperplasia in CT, Metyrapone\tCesarean section at 34 weeks by growth retardation, normal lab values at 4 weeks postpartum\t\nAndreescu 2017 [6]\tPurple striae, bruising, hypertension (165/90 mmHg), mild hypokalemia, proteinuria at 32 weeks, elevated UFC\tEnalapril 40 mg daily Labetalol 600 mg daily\n\nCT: 3.8 cm Adenoma, LH receptor positive (immunohistochemical examination)\n\n\tInduction of Labor at 35 weeks, Adrenalectomy and hydrocortisone replacement 4 months postpartum\t\nAndreescu 2017 [6]\tHypertension (140/86 mmHg), purple striae, hirsutism, diabetes mellitus\tLabetalol 400 mg daily\n\nMRI: 3.3 cm Adenoma, LH receptor positive (immunohistochemical examination)\n\n\tSpontaneous labor and vaginal delivery 38 weeks, Adrenalectomy and hydrocortisone around 4 months postpartum\t\nAndreescu 2017 [6]\tGestational diabetes, depression, hirsutism, bruising\tParoxetine 20 mg daily\n\nCT: 3.4 cm Adenoma (no immunohistochemical examination performed)\n\n\tSpontaneous labor and vaginal delivery at 38 weeks, Adrenalectomy and hydrocortisone 6 months postpartum\t\n\n\nMicronodules were detected in our MRI but were not interpreted by our radiology department as adenomas. Unilateral adrenal hyperplasia could not be completely ruled out. It is possible that our patient had aberrant receptors without the presence of adenomas. In order to completely rule out the presence of aberrant receptors additional diagnostic tests would have to be performed postpartum including an in vivo acute hormone stimulation test [6]. Gene expression tests are definitive for the diagnosis, but require sampling of adrenal tissue.\n\nThe commonest causes of PA are aldosterone-producing adenoma and idiopathic adrenal bilateral hyperplasia. Symptoms are less severe than in CS and are often limited to hypertension. A retrospective study found no increased incidence of preeclampsia in patients with PA than that of the general population [3].\n\nThe diagnosis of CS in pregnancy is especially challenging due to the normal hormonal changes that occur. There is an increase in plasma cortisol, salivary cortisol and UFC in the first trimester. The levels increase continually throughout the pregnancy, resulting in plasma cortisol levels that are two to three times higher by the third trimester. These high levels make the dexamethasone suppression test difficult to interpret [2]. Brue et al. described the difficulty of diagnosing CS during pregnancy due to the overlapping of symptoms that occur as a result of hypercortisolism and the normal symptoms of pregnancy. The symptoms include hirsutism, fatigue and weight gain [2]. Hypokalemia may result from hyperemesis, and hypertension and hyperglycemia can be complications of pregnancy without underlying pathology. There are elevations in corticosteroid-binding globulin (CBG) and increases in CRH and ACTH produced by the placenta (beginning at week 7 and increasing until the end of pregnancy). The increased levels of cortisol make interpretation of the dexamethasone suppression test difficult. Urinary free cortisol (UFC) increases during the second trimester. Tests utilizing UFC are therefore considered to reliable only in the first trimester of pregnancy. With regard to salivary cortisol levels, Ambroziak et al. could not detect differences in the salivary cortisol levels during pregnancy. They recommended the utilization of normal adult levels for pregnant women despite reporting higher salivary levels in some pregnant patients with hypercortisolism [7]. In spite of these confounding results, salivary cortisol levels may still be helpful for diagnosis of hypercortisolism in the first two trimesters of pregnancy [2].\n\nThe renin-aldosterone axis changes during pregnancy. The increase in estrogen and placental renin combined with increased progesterone results in increased aldosterone and deoxycorticosterone. Despite these changes there are few signs and symptoms that are considered as “classic” indicators of hypercortisolism and include muscle weakness, weight gain, purple striae, and bruising [2]. Pregnant patients presenting with both hypokalemia and hypertension should be screened for PA. Diagnosis of PA in pregnancy is made in patients presenting with suppressed renin (normally elevated in pregnancy) and an elevated aldosterone-to-renin ratio (ARR). False negative results are possible. MRI and ultrasound are useful imaging modalities. Confirmatory tests such as saline infusion tests and captopril tests are contraindicated in pregnancy [3].\n\nTreatment of CS and PA is challenging. While surgical management has often been described as superior to medical therapy, the evidence is limited to case reports. If surgery must be performed, the recommended time frame is during the second trimester [2].\n\nKetoconazole is widely used for treatment of CS in non-pregnant women but is contraindicated in pregnancy. There are isolated case reports of women who became pregnant while being treated with ketoconazole. In all cases the therapy was discontinued as soon as the pregnancy was confirmed.\n\nThere are reports of patients undergoing surgery in the second trimester and being treated postoperatively with metyrapone or hydrocortisone [8]. Metyrapone is a medication that has been used both successfully and unsuccessfully in the treatment of CS in pregnant patients. Classified as an inhibitor of glucocorticoid synthesis, the medication inhibits 11-beta-hydroxylase, thereby blocking the production of cortisol. This blockade results in increased ACTH, 11-deoxycortisol, and deoxycorticosterone. The increase in deoxycorticosterone has been known to worsen hypertension and has been therefore associated with an increased risk of preeclampsia [2]. Lim et al. performed a literature search in Pubmed and Medline and found a total of 12 patients with CS in pregnancies that were subsequently treated with metyrapone. An estimated 20% of these women developed pre-eclampsia. Two neonatal deaths and one stillborn delivery were reported [9]. Metyrapone passes through the placenta. Its effects on fetal adrenal steroid synthesis are not well documented.\n\nIn PA mineralcorticoid receptor antagonists are the treatment of choice. Some animal studies have reported an association between spironolactone and genital anomalies in males. These results could not be reproduced in human studies. Rose et al. published a study in which rats were given 400 milligrams daily. The undervirilization could not be confirmed [10]. An extensive analysis of the data was performed by Liszewski and Boull in April 2019. The authors examined the literature and found that feminization was reported in 6 of 9 animal studies. Five of the studies exposed the animals to doses of more than 200 mg daily. Five human cases where spironolactone was given during pregnancy were summarized; normal genitals at birth were reported in all cases [11].\n\nA therapy with eplerenone would have been an alternative to spironolactone. Eplerenone is a medication that has been on the market for less than 20 years and carries an FDA Pregnancy Category B classification, making it preferential to medications with category C. There are not enough studies in pregnant women to make conclusions about its efficacy in comparison to spironolactone in the treatment of primary aldosteronism.\n\nBrue described a fetal upregulation of 11-beta-hydroxysteroid dehydrogenase-type 2 in fetuses exposed to high maternal cortisol levels. In spite of this protective measure, pregnancies with CS have been documented to have increased incidences of prematurity (43%), growth retardation (21%), and intrauterine fetal demise (5%). Outcomes were significantly worse for mothers who were diagnosed during pregnancy [2].\n\nThe diagnosis of CS and PA in pregnancy is challenging. For patients without obvious tumor etiologies the treatment is limited to medications and can be difficult. The use of metyrapone has been widely documented. Its use is associated with the development of preeclampsia and its effects on the fetus and fetal steroid synthesis remain unclear. In PA mineralcorticoid receptor antagonists are the treatment of choice.\n\nCombined CS and PA in a pregnancy are rare and extremely difficult to treat. Due to the substantial risk of delivery complications including premature delivery, placental abruption, and preeclampsia, patients should be referred to a perinatal center. Early diagnosis combined with an interdisciplinary approach is essential in the optimization of maternal and fetal outcomes.\n\nAbbreviations\nCSCushing's syndrome\n\nPAPrimary aldosteronism\n\nACTHAdrenocorticotropic hormone\n\nCBGCorticosteroid-binding globulin\n\nCRHCorticotropin-releasing hormone\n\nTIDThree times daily\n\nBIDTwo times daily\n\nMRIMagnetic resonance imaging\n\nASTAspartate Aminotransferase\n\nALTAlanine Aminotransferase\n\nU/lUnits per liter\n\ng/lGram per Liter\n\nmcg/dlMicrogram per deciliter\n\nmcg/dMicrogram per day\n\npg/mlPicogram per milliliter\n\nARRAldosterone-to-renin ratio\n\nMCAMiddle cerebral artery\n\nHCTZHydrochlorothiazide\n\nhCGHuman chorionic gonadotropin hormone\n\nLHLuteinizing hormone\n\nLHRHLuteinizing hormone-releasing hormone\n\nUFCUrinary free cortisol\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nThe authors would like to thank Dr. Martin Wagner and the Department of Endocrinology as well as the departments of Neonatology, Urology, and Radiology at the University of Ulm (Universitätsklinikum Ulm) for their support and consultation in this case.\n\nAuthors’ contributions\nM.K. was responsible for project development, data collection and manuscript writing. K.H. was responsible for manuscript writing and editing. W.J. was responsible for manuscript editing and writing. K.K. was responsible for project development, data collection and manuscript writing. All authors read and approved the final manuscript.\n\nFunding\nNo funding was received for this case report. There are no financial conflicts of interests.\n\nAvailability of data and materials\nNot applicable.\n\nEthics approval and consent to participate\nThe patient described in this case report provided informed consent. Identifying data (birthdate and name) has been removed. An ethics board review was not required. All procedures performed involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Kasperlik-Zaluska AA Szczupacka I Leszczynska-Bystrzanowska J Drus-Przybyszewska G Pregnancy-dependent Cushing’s syndrome in three pregnancies BJOG 2000 107 810 2 10.1111/j.1471-0528.2000.tb13348.x 10847243 \n2. Brue T Amodru V Castinetti F Management of Endocrine Disease: Management of Cushing’s syndrome during pregnancy: solved and unsolved questions Eur J Endocrinol 2018 178 R259 66 10.1530/EJE-17-1058 29523633 \n3. Riester A, Reincke M. Progress in primary aldosteronism: mineralocorticoid receptor antagonists and management of primary aldosteronism in pregnancy. Eur J Endocrinol. 2015;172:R23–30.\n4. Caimari F Valassi E Garbayo P Steffensen C Santos A Corocy R Webb SM Cushing’s syndrome and pregnancy outcomes: a systematic review of published cases Endocrine 2017 55 555 63 10.1007/s12020-016-1117-0 27704478 \n5. Close CF Mann MC Watts JF Taylor KG ACTH-independent Cushing’s syndrome in pregnancy with spontaneous resolution after delivery: control of the hypercortisolism with metyrapone Clin Endocrinol (Oxf) 1993 39 375 9 10.1111/j.1365-2265.1993.tb02380.x 8222300 \n6. Andreescu CE Alwani RA Hofland J Looijenga LHJ De Herder WW Hofland LJ Feelders RA Adrenal Cushing’s syndrome during pregnancy Eur J Endocrinol 2017 177: K13 20 10.1530/EJE-17-0263 28819015 \n7. Ambroziak U Kondracka A Bartoszewicz Z Krasnodebska-Kiljanska M Bednarczuk T The morning and late-night salivary cortisol ranges for healthy women may be used in pregnancy Clin Endocrinol 2015 83 774 8 10.1111/cen.12853 \n8. Blanco C Maqueda E Rubio JA Rodriguez A Cushing’s syndrome during pregnancy secondary to adrenal adenoma: metyrapone treatment and laparoscopic adrenalectomy J Endocrinol Invest 2006 29 164 7 10.1007/BF03344091 16610244 \n9. Lim WH Torpy DJ Jeffries WS The medical management of Cushing’s syndrome during pregnancy Eur J Obstet Gynecol Reprod Biol 2013 168 1 6 10.1016/j.ejogrb.2012.12.015 23305861 \n10. Rose LI, Regestein Q, Reckler JM. Lack of effect of spironolactone on male genital development. Invest Urol. 1975 Sep;13(2):95–6.\n11. Liszewski W, Boull C. Lack of evidence for feminization of males exposed to spironolactone in utero: A systematic review. J Am Acad Dermatol. 2019 Apr;80(4):1147–8. doi:10.1016/j.jaad.2018.10.023. Epub 2018 Oct 21.\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2393",
"issue": "20(1)",
"journal": "BMC pregnancy and childbirth",
"keywords": "Cushing’s syndrome; Metyrapone; Preeclampsia; Pregnancy; Primary aldosteronism; Spironolactone",
"medline_ta": "BMC Pregnancy Childbirth",
"mesh_terms": "D000328:Adult; D003480:Cushing Syndrome; D005260:Female; D006801:Humans; D006929:Hyperaldosteronism; D011247:Pregnancy; D011248:Pregnancy Complications",
"nlm_unique_id": "100967799",
"other_id": null,
"pages": "421",
"pmc": null,
"pmid": "32711486",
"pubdate": "2020-07-25",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "8222300;30352280;26173372;25163723;29523633;16610244;27704478;23305861;1184344;10847243;28819015",
"title": "Pregnancy induced Cushing's syndrome and primary aldosteronism: a case report.",
"title_normalized": "pregnancy induced cushing s syndrome and primary aldosteronism a case report"
} | [
{
"companynumb": "DE-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-264979",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HYDRALAZINE HYDROCHLORIDE"
},
... |
{
"abstract": "Endo-ventricular thrombosis represents a possible clinical complication of stress(takotsubo)-cardiomyopathy (SC). Depressed ventricular systolic ventricular function, localized left ventricular (LV) dyskinesis, but also an increased pro-thrombotic state induced by catecholamine surge may facilitate the occurrence of endovascular thrombosis in SC. SC, however, may also present as right ventricular (RV) dysfunction or even as biventricular ballooning. Ventricular thrombosis may therefore theoretically occur in either ventricles or both. We report the case of an 88-year old woman, with vascular dementia and depression, admitted for abdominal pain, diarrhea, and rectal bleeding. Unexpectedly, electrocardiogram showed induced QT-prolongation with diffuse negative T-waves, while echocardiogram severe LV dysfunction (ejection fraction 35%), but also RV dysfunction and biventricular thrombosis. The diagnosis was therefore biventricular SC complicated by biventricular thrombosis; LV recovered after 10 days. When SC presents with a biventricular involvement, a careful assessment of either ventricular cavities should be therefore recommended to exclude the presence of (bi)ventricular thrombosis. It remains unresolved whether biventricular SC may represent a condition at higher risk of ventricular thrombosis.",
"affiliations": "Cardiology Departement, Ospedale San Paolo, Bari, Italy.;Cardiology Departement, Ospedale San Paolo, Bari, Italy.;Cardiology Departement, Ospedale San Paolo, Bari, Italy.;Cardiology Departement, Ospedale San Paolo, Bari, Italy.;Cardiology Departement, Ospedale San Paolo, Bari, Italy.;Cardiology Departement, Ospedale San Paolo, Bari, Italy.;Cardiology Departement, Ospedale San Paolo, Bari, Italy.;Department of Medical and&Surgical Sciences, University of Foggia, Foggia, Italy.;Department of Medical and&Surgical Sciences, University of Foggia, Foggia, Italy. natale.brunetti@unifg.it.;Cardiology Departement, Ospedale San Paolo, Bari, Italy.",
"authors": "De Gennaro|Luisa|L|;Ruggiero|Massimo|M|;Musci|Sergio|S|;Tota|Francesco|F|;De Laura|Domenica|D|;Resta|Manuela|M|;Locuratolo|Nicola|N|;Santoro|Francesco|F|;Brunetti|Natale Daniele|ND|http://orcid.org/0000-0001-9610-7408;Caldarola|Pasquale|P|",
"chemical_list": "D002395:Catecholamines",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s11239-017-1510-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0929-5305",
"issue": "44(2)",
"journal": "Journal of thrombosis and thrombolysis",
"keywords": "Biventricular dyskinesis; Biventricular thrombosis; Stress cardiomyopathy",
"medline_ta": "J Thromb Thrombolysis",
"mesh_terms": "D000369:Aged, 80 and over; D002395:Catecholamines; D005260:Female; D006352:Heart Ventricles; D006801:Humans; D054549:Takotsubo Cardiomyopathy; D013927:Thrombosis; D018497:Ventricular Dysfunction, Right",
"nlm_unique_id": "9502018",
"other_id": null,
"pages": "234-237",
"pmc": null,
"pmid": "28577159",
"pubdate": "2017-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23628296;28079765;23151669;23001102;25618766;26880830;24202848;23608401;24820744;19411722;18718684;22000424;27538839;27390957;26072914;26332547;19193453;23954602;18692258;19438699;27003690;18998198;17125856;22205847;17674380;25304075;23765730;22494862;18607250",
"title": "Biventricular thrombosis in biventricular stress(takotsubo)-cardiomyopathy.",
"title_normalized": "biventricular thrombosis in biventricular stress takotsubo cardiomyopathy"
} | [
{
"companynumb": "IT-MYLANLABS-2017M1058734",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ALPRAZOLAM"
},
"drugadditional": null,
... |
{
"abstract": "Alopecia has been observed with many anticoagulants although the mechanism is unclear. A 20 year old female with recurrent DVTs developed alopecia with multiple anticoagulants, including heparin derivatives and the new oral anticoagulants. This resolved with discontinuation of the agents. The patient was ultimately able to be anticoagulated with fondaparinux long term without any alopecia. This case addresses the key clinical question of management and recognition of anticoagulant induced alopecia. This side effect can result from almost any of the available agents and is quickly reversible, underlining the importance of tailoring treatment to the individual and their experiences.",
"affiliations": "University of Michigan Medical School, Department of Pediatrics and Communicable Diseases, Division of Pediatric Hematology and Oncology, 8200 MSRB III, 1150 W. Medical Center Drive, Ann Arbor, MI 48109, (ph) 734-615-8232.;University of Michigan Medical School, Department of Pediatrics and Communicable Diseases, Division of Pediatric Hematology and Oncology, 8200 MSRB III, 1150 W. Medical Center Drive, Ann Arbor, MI 48109, (ph) 734-615-8232, @clot1.",
"authors": "Weyand|Angela C|AC|;Shavit|Jordan A|JA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/rth2.12001",
"fulltext": "\n==== Front\nRes Pract Thromb HaemostRes Pract Thromb Haemost10.1002/(ISSN)2475-0379RTH2Research and Practice in Thrombosis and Haemostasis2475-0379John Wiley and Sons Inc. Hoboken 2905739110.1002/rth2.12001RTH212001Case ReportCase ReportAgent specific effects of anticoagulant induced alopecia Weyand Angela C. MDacweyand@med.umich.edu \n1\nShavit Jordan A. MD, PhDjshavit@umich.edu \n1\n\n1 \nDepartment of Pediatrics and Communicable Diseases\nDivision of Pediatric Hematology and Oncology\nUniversity of Michigan Medical School\nAnn Arbor\nMI\nUSA\n* Correspondence\n\nAngela C. Weyand; Jordan A. Shavit, Department of Pediatrics and Communicable Diseases, Division of Pediatric Hematology and Oncology, University of Michigan Medical School, Ann Arbor, MI, USA.\n\nEmails: acweyand@med.umich.edu; jshavit@umich.edu\nhttps://twitter.com/acweyand; https://twitter.com/Clot1\n30 5 2017 7 2017 1 1 10.1002/rth2.2017.1.issue-190 92 01 3 2017 30 3 2017 © 2017 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals, Inc on behalf of International Society on Thrombosis and Haemostasis.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.Abstract\nAlopecia has been observed with many anticoagulants although the mechanism is unclear. A 20 year old female with recurrent DVTs developed alopecia with multiple anticoagulants, including heparin derivatives and the new oral anticoagulants. This resolved with discontinuation of the agents. The patient was ultimately able to be anticoagulated with fondaparinux long term without any alopecia. This case addresses the Key Clinical Question of management and recognition of anticoagulant induced alopecia. This side effect can result from almost any of the available agents and is quickly reversible, underlining the importance of tailoring treatment to the individual and their experiences.\n\nadverse effectsalopeciaanticoagulantsfondaparinuxthrombosisNational Hemophilia Foundation Shire Clinical FellowshipNIHR01‐HL124232 source-schema-version-number2.0component-idrth212001cover-dateJuly 2017details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.4 mode:remove_FC converted:25.07.2018\n\n\nWeyand \nAC \n, \nShavit \nJA \n. Agent specific effects of anticoagulant induced alopecia . Res Pract Thromb Haemost . 2017 ;1 :90 –92 . 10.1002/rth2.12001 \n29057391 \n\n\n\nFunding information\n\n\nGrant support: National Hemophilia Foundation Shire Clinical Fellowship, NIH (R01‐HL124232)\n==== Body\nEssentials\n\nAnticoagulant medications have been known to cause alopecia.\n\nThe reported patient experienced significant alopecia with most anticoagulants.\n\nAlopecia was quickly reversible.\n\nMultiple therapeutic trials may be required to identify a tolerable anticoagulant regimen.\n\n\n\n\n\n\n\n1 CASE REPORT\nA 20 year old female with type 2 spinal muscular atrophy, wheelchair dependence, and chronic respiratory failure requiring tracheotomy and ventilator support presented with one day of left lower extremity swelling following prolonged car travel. A duplex venous ultrasound revealed an extensive deep vein thrombosis (DVT) extending from the external iliac to the common peroneal vein. She was started on anticoagulation with enoxaparin (1 mg/kg/dose with anti‐Xa activity monitoring to achieve a therapeutic range). One month after initiation of anticoagulation she was seen in the emergency room for worsening symptoms. A repeat ultrasound revealed maturation of her known thrombi but a right lower extremity examination discovered an asymptomatic DVT of the right common femoral vein. Due to a second event while on anticoagulation and her ongoing immobility, the decision was made to continue her on indefinite anticoagulation. Given the potential risk of osteopenia with long term exposure to heparins, and patient preference to avoid laboratory monitoring and injections, she was switched to rivaroxaban (15 mg daily). After initiation of anticoagulation with enoxaparin, the patient had noted mild hair loss. Immediately following the transition to rivaroxaban, she reported a significant increase in diffuse hair loss, and approximately 50% of her total scalp hair‐bearing area became hairless within a month of starting the medication. Hair loss was reported to be spontaneous as well as secondary to manipulations, such as brushing. This resulted in significant thinning and multiple bald spots averaging 2 cm in diameter. Due to patient distress regarding the new onset alopecia, she was transitioned to fondaparinux (2.5 mg daily with anti‐Xa monitoring). Following this change, she immediately noted less hair loss and over time had complete hair regrowth. Due to preference for an oral anticoagulant, a trial of apixaban (2.5 mg twice daily) was attempted which again resulted in rapid hair loss, resolving upon transition to fondaparinux. Fondaparinux was then replaced with the direct thrombin inhibitor dabigatran (initially 75 mg twice daily, then increased to 150 mg twice daily in order to achieve detectable anti‐IIa activity). She tolerated this medication for approximately 10 months before noting a decrease in lower extremity hair growth, followed by return of major spontaneous hair loss from her scalp. At that time her anti‐IIa activity was detectable and slightly lower than the previous determination, and her kidney function was unchanged. Given this, she was transitioned back to fondaparinux, which she continues to tolerate without any signs of hair loss (clinical course illustrated in Figure 1).\n\nFigure 1 Time course of patient's symptoms and medication usage\n\n2 DISCUSSION\nThe hair growth cycle is comprised of three stages. The first stage is growth or anagen phase, during which hair grows continuously due to vigorous mitotic activity in the matrix. This typically lasts months to years and the duration of this phase determines the length. This stage is followed by a catagen phase during which the hair matrix cells undergo apoptosis. Growth ceases, there is shortening of the follicle, and mature hair moves upwards toward the scalp where it enters the telogen or rest phase.1 This final stage lasts approximately 3 months and during this period the hair rests in anticipation of shedding by mechanical forces or replacement by newly growing follicles. Between 85% and 90% of hair at any given time is in the anagen phase with 9‐14% in the telogen phase and 1% in the catagen phase. There is significant variability between individuals with regards to the proportion of hair in and length of each phase.2\n\n\nDrug‐induced hair loss occurs by two different mechanisms, both of which affect the anagen phase. Anagen effluvium involves abrupt cessation of hair growth through antimitotic activities and is seen with cytotoxic agents such as chemotherapy. Typically, alopecia onset is rapid and anagen hairs fall out within days to weeks of exposure.1 Alternatively, telogen effluvium results from premature shifting of anagen hair into the catagen phase followed by the telogen phase. The effects are usually seen a few months following a trigger and can be secondary to childbirth, malnutrition, fever, surgery, hemorrhage, as well as pharmaceuticals.3\n\n\nAlopecia during anticoagulation has been described, with heparins and vitamin K antagonists (VKAs) being the most common offenders. Reported incidences range from 30% to 40% with VKAs and 54‐66% with unfractionated heparin4, 5 although these numbers seem quite high compared to our center's adult and pediatric clinical experience. Another report describes diffuse alopecia, principally involving the scalp, in 40% of patients on warfarin.6 It does not appear that age, duration or dosage are risk factors6 and diffuse, but reversible alopecia usually begins a few weeks after initiation.6, 7, 8 Warfarin does not affect the intermediate (catagen) phase but instead forces follicles to enter the shedding (telogen) phase too early. Based on the timing and presentation of the hair loss reported, it has been proposed that telogen effluvium is the likely process by which alopecia occurs.9 Loss has been described with the use of rivaroxaban. Findings from the Dresden New Oral Anticoagulant (NOAC) registry report an incidence of 4.4 per 100 patient years,10 with onset between 22 and 183 days following initiation of treatment in the 12 patients reported. Five cases associated with rivaroxaban and one associated with dabigatran were found within the French Pharmacovigilance Database.11\n\n\nOur patient also experienced hair loss following the initiation of rivaroxaban although the symptom occurred rapidly after initiation, more suggestive of anagen effluvium. Heparin is known to possess some antimitotic activity12 which may support this hypothesis. Other mechanisms may also be involved as heparin has been shown to increase dermal‐epidermal cohesion in rats13 as well as to have inhibitory effects on hair growth.14 On the adverse drug reaction probability scale developed by Naranjo et al15 this case scores an 8, making causality highly probable. Further support for causation exists in that hair regrowth occurred with the switch to fondaparinux and loss recurred after the switch to apixaban. Most of the offenders in this report exert their anticoagulant effect through anti‐Xa activity, although it is surprising that fondaparinux did not cause hair loss given the common mechanism. One difference is that fondaparinux acts through antithrombin III (although enoxaparin does as well), while rivaroxaban and apixaban bind directly to factor Xa. We therefore selected dabigatran, a direct thrombin inhibitor which resulted in hair regrowth and no signs of alopecia for approximately 10 months. Review of reports of anticoagulant‐induced hair loss through VigiAccess demonstrates that all agents can cause multiple symptoms of hair pathology, with alopecia being the most predominant for each one (Table 1, VigiAccess is an online tool which allows users to access Vigibase, the World Health Organization database of suspected adverse reaction reports, which includes more than ten million cases from over 120 countries, from 1968 to the present16). To date there are 234 reports of dabigatran associated alopecia, as well as 4 reports of madarosis (loss of eyelashes or eyebrows),16 so perhaps it is not surprising that this ultimately caused alopecia as well in our patient, despite a long lag time. Interestingly, enoxaparin and fondaparinux had the fewest reports, although this could reflect frequency of usage.16 Fondaparinux is a very small heparin derivative (a simple pentasaccharide). The common side effects of larger heparins, such as heparin‐induced thrombocytopenia and osteopenia are reduced with decreased molecular weight,17, 18, 19 which also might partially explain the differential effects in our patient.\n\nTable 1 VigiAccess data on hair loss with anticoagulants\n\nAnticoagulant\tAlopecia\tMadarosis\tOther\t\nEnoxaparin\t47\t2\t7\t\nWarfarin\t721\t6\t249\t\nRivaroxaban\t615\t2\t60\t\nFondaparinux\t8\t1\t0\t\nDabigatran\t232\t4\t24\t\nApixaban\t149\t0\t12\t\nData obtained from Vigiaccess.org (referenced March 201716) include reports from 1968 to the present.\n\nMadarosis is loss of eyelashes or eyebrows. Other symptoms include abnormal hair growth, abnormal hair patterns, hair color changes, abnormal hair texture, trichorrhexis (weak points along hair shaft predisposing to breakage).\n\nJohn Wiley & Sons, LtdIn summary, we have found that anticoagulant‐induced alopecia occurs with multiple agents, although the mechanisms remain unclear. We initially hypothesized that this could have been dose‐related as levels were monitored while on enoxaparin, fondaparinux, and dabigatran, but not on apixaban and rivaroxaban. However, eventual alopecia following dabigatran suggests that this is not the complete explanation. Additionally, this case demonstrates that the effects are quickly reversible and we were able to find a regimen that served our patient's needs, while avoiding the concerning side effect. Further study is required to determine whether this effect is dose‐related, or linked to patient specific factors.\n\nAUTHOR CONTRIBUTION\nA. C. Weyand reviewed medical records, reviewed the literature and drafted the manuscript. J. A. Shavit initiated case write‐up and performed extensive draft editing and revisions.\n\nACKNOWLEDGMENTS\nThe authors would like to thank Allison Ferguson for figure creation.\n==== Refs\nREFERENCES\n1 \n\nKligman \nAM \n. Pathologic dynamics of human hair loss. I. Telogen effuvium . Arch Dermatol. \n1961 ;83 :175 –98 .13756813 \n2 \n\nIoannides \nG \n. Alopecia: a pathologist's view . Int J Dermatol. \n1982 ;21 :316 –28 .6749712 \n3 \n\nPillans \nPI \n, \nWoods \nDJ \n. Drug‐associated alopecia . Int J Dermatol. \n1995 ;34 :149 –58 .7751086 \n4 \n\nTudhope \nGR \n, \nCohen \nH \n, \nMeikle \nRW \n. Alopecia following treatment with dextran sulphate and other anticoagulant drugs . BMJ. \n1958 ;1 :1034 –7 .13536411 \n5 \n\nFischer \nR \n, \nBircher \nJ \n, \nReich \nT \n. [Falling of hair after anticoagulant therapy] . Schweizerische Medizinische Wochenschrift. \n1953 ;83 :509 –11 .13076091 \n6 \n\nUmlas \nJ \n, \nHarken \nDE \n. Warfarin‐induced alopecia . Cutis. \n1988 ;42 :63 –4 .3203535 \n7 \n\nThiedke \nCC \n. Alopecia in women . Am Fam Physician. \n2003 ;67 :1007 –14 .12643360 \n8 \n\nMotel \nPJ \n. Captopril and alopecia: a case report and review of known cutaneous reactions in captopril use . J Am Acad Dermatol. \n1990 ;23 :124 –5 .2142169 \n9 \n\nWatras \nMM \n, \nPatel \nJP \n, \nArya \nR \n. Traditional anticoagulants and hair loss: a role for direct oral anticoagulants? a review of the literature . Drugs ‐ Real World Outcomes. \n2016 ;3 :1 –6 .\n10 \n\nGelbricht \nV \n, \nKoehler \nC \n, \nWerth \nS \n, et al. Hair loss is a potential side effect of novel oral anticoagulants‐findings from the dresden noac registry . Blood . 2012 ;120 :1173 .\n11 \n\nChretien \nB \n, \nBesnard \nA \n, \nSassier \nM \n, et al. Rivaroxaban‐induced hair loss . Eur J Clin Pharmacol. \n2015 ;71 :1413 –4 .26300206 \n12 \n\nRegelson \nW \n. The antimitotic activity of polyanions (antitumor, antiviral, and antibacterial action of heparin, heparinoids, anionic dyes, and synthetic polymers) . Advances in Chemotherapy. \n1968 ;3 :303 –70 .4968881 \n13 \n\nHumbert \nP \n, \nRenaud \nA \n, \nMillet \nJ \n, et al. Evaluation of the effect of heparin and tetracycline on the cohesion of the dermal‐epidermal junction . Acta Dermato‐Venereologica. \n1989 ;69 :434 –6 .2572113 \n14 \n\nPaus \nR \n. Hair growth inhibition by heparin in mice: a model system for studying the modulation of epithelial cell growth by glycosaminoglycans? \nBr J Dermatol. \n1991 ;124 :415 –22 .2039716 \n15 \n\nNaranjo \nCA \n, \nBusto \nU \n, \nSellers \nEM \n, et al. A method for estimating the probability of adverse drug reactions . Clin Pharmacol Ther. \n1981 ;30 :239 –45 .7249508 \n16 \nVigibase \n, the World Health Organization database of suspected adverse reaction reports . [cited 2017 March 13]. Available from http://Vigiaccess.org\n\n17 \n\nOsip \nSL \n, \nButcher \nM \n, \nYoung \nE \n, \nYang \nL \n, \nShaughnessy \nSG \n. Differential effects of heparin and low molecular weight heparin on osteoblastogenesis and adipogenesis in vitro . Thromb Haemost. \n2004 ;92 :803 –10 .15467912 \n18 \n\nRajgopal \nR \n, \nBear \nM \n, \nButcher \nMK \n, \nShaughnessy \nSG \n. The effects of heparin and low molecular weight heparins on bone . Thromb Res. \n2008 ;122 :293 –8 .17716711 \n19 \n\nKelton \nJG \n, \nArnold \nDM \n, \nBates \nSM \n. Nonheparin anticoagulants for heparin‐induced thrombocytopenia . The New England Journal of Medicine. \n2013 ;368 :737 –44 .23425166\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2475-0379",
"issue": "1(1)",
"journal": "Research and practice in thrombosis and haemostasis",
"keywords": "Adverse Effects; Alopecia; Anticoagulants; Fondaparinux; Thrombosis",
"medline_ta": "Res Pract Thromb Haemost",
"mesh_terms": null,
"nlm_unique_id": "101703775",
"other_id": null,
"pages": "90-92",
"pmc": null,
"pmid": "29057391",
"pubdate": "2017-07",
"publication_types": "D002363:Case Reports",
"references": "26300206;13756813;12643360;27747798;2572113;29057391;2142169;13076091;4968881;3203535;13536411;6749712;23425166;7249508;17716711;15467912;7751086;2039716",
"title": "Agent specific effects of anticoagulant induced alopecia.",
"title_normalized": "agent specific effects of anticoagulant induced alopecia"
} | [
{
"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2018-BI-048070",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
... |
{
"abstract": "This study evaluated the impact of antibacterial prophylaxis with levofloxacin in relapsed/refractory acute myeloid leukemia (AML) patients.\n\n\n\nThis was a retrospective, single-center, cohort study. Adult patients with relapsed/refractory AML admitted for reinduction chemotherapy between November 1, 2006 and June 15, 2015 were screened for inclusion. A protocol initiating levofloxacin prophylaxis was implemented on December 1, 2013. Patients receiving hypomethylating agents (decitabine/azacitidine) were not administered antibacterial prophylaxis and thus not included in this analysis. Patients receiving broad spectrum antibiotics on day 1 of reinduction chemotherapy or receiving another antibacterial agent for prophylaxis were also excluded. Ninety-seven patients were included in the control group (no prophylaxis), while 48 patients received levofloxacin prophylaxis. Patients in the prophylaxis group received levofloxacin 500 mg once daily on day 1 of chemotherapy and continued until neutrophil recovery (or hospital discharge or death).\n\n\n\nThere was a reduction in the rate of bacteremia in the prophylaxis group (37.5 %) compared to the control group (53.6 %, p = 0.0789), largely due to a reduction in gram-negative bacteremia (2.1 vs. 21.6 % respectively, p = 0.001). No difference was found between prophylaxis and the control groups in the incidence of neutropenic fever, incidence of multidrug resistance, length of hospital or ICU stay, or mortality.\n\n\n\nLevofloxacin prophylaxis reduced the rate of infections overall in adult patients with relapsed/refractory AML, without increasing rates of multidrug-resistant organisms.",
"affiliations": "Department of Pharmacy Services and College of Pharmacy, University of Michigan Health System, 1111 E. Catherine St., Rm 330, Ann Arbor, MI, 48109, USA.;Department of Pharmacy Services and College of Pharmacy, University of Michigan Health System, 1111 E. Catherine St., Rm 330, Ann Arbor, MI, 48109, USA.;Department of Pharmacy Services and College of Pharmacy, University of Michigan Health System, 1111 E. Catherine St., Rm 330, Ann Arbor, MI, 48109, USA.;Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.;Department of Pharmacy Services and College of Pharmacy, University of Michigan Health System, 1111 E. Catherine St., Rm 330, Ann Arbor, MI, 48109, USA. ajperis@med.umich.edu.",
"authors": "Ganti|Beejal R|BR|;Marini|Bernard L|BL|;Nagel|Jerod|J|;Bixby|Dale|D|;Perissinotti|Anthony J|AJ|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00520-016-3436-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0941-4355",
"issue": "25(2)",
"journal": "Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer",
"keywords": "Acute myeloid leukemia; Antibacterial prophylaxis; Bacteremia; Febrile neutropenia",
"medline_ta": "Support Care Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D019072:Antibiotic Prophylaxis; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D012189:Retrospective Studies; D055815:Young Adult",
"nlm_unique_id": "9302957",
"other_id": null,
"pages": "541-547",
"pmc": null,
"pmid": "27738797",
"pubdate": "2017-02",
"publication_types": "D016428:Journal Article",
"references": "16206099;18929686;25165543;22052225;25298044;16575919;17448922;16148284;24210467;24750350;25734080;15714332;17077101;16148283;21205990;12015693;23319691;16331335;25576429;18089873",
"title": "Impact of antibacterial prophylaxis during reinduction chemotherapy for relapse/refractory acute myeloid leukemia.",
"title_normalized": "impact of antibacterial prophylaxis during reinduction chemotherapy for relapse refractory acute myeloid leukemia"
} | [
{
"companynumb": "US-JNJFOC-20170104049",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYTARABINE"
},
"drugadditional": "3",
"... |
{
"abstract": "Due to paucity of evidence to guide management of allogeneic haematopoietic stem cell transplantation (allo-HSCT) patients with respiratory syncytial virus (RSV) infections national and international guidelines make disparate recommendations.\n\n\n\nThe outcomes of allo-HSCT recipients with RSV infection between 2015 and 2017 were assessed using the following treatment stratification; upper respiratory tract infections (URTI) being actively monitored and lower respiratory tract infections (LRTI) treated with short courses of oral ribavirin combined with intravenous immunoglobulin (IVIG, 2 g/kg).\n\n\n\nDuring the study period 49 RSV episodes were diagnosed (47% URTI and 53% LRTI). All patients with URTI recovered without pharmacological intervention. Progression from URTI to LRTI occurred in 15%. Treatment with oral ribavirin given until significant symptomatic improvement (median 7 days [3-12]) and IVIG for LRTI was generally well tolerated. RSV-attributable mortality was low (2%).\n\n\n\nIn this cohort study, we demonstrate that active monitoring of allo-HSCT patients with RSV in the absence of LRTI was only associated with progression to LRTI in 15% of our patients and therefore appears to be a safe approach. Short course oral ribavirin in combination with IVIG was effective and well-tolerated for LRTI making it a practical alternative to aerosolised ribavirin. This approach was beneficial in reducing hospitalisation, saving nursing times and by using oral as opposed to nebulised ribavirin.",
"affiliations": "Department of Clinical Haematology, Cancer and Haematology Centre, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Old Road, Headington, Oxford OX3 7LE, UK; NHS Blood and Transplant, John Radcliffe Hospital, Oxford, UK. Electronic address: katalin.balassa@ouh.nhs.uk.;Department of Clinical Haematology, Cancer and Haematology Centre, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Old Road, Headington, Oxford OX3 7LE, UK.;Department of Clinical Haematology, Cancer and Haematology Centre, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Old Road, Headington, Oxford OX3 7LE, UK.;Department of Clinical Haematology, Cancer and Haematology Centre, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Old Road, Headington, Oxford OX3 7LE, UK.;Department of Clinical Haematology, Cancer and Haematology Centre, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Old Road, Headington, Oxford OX3 7LE, UK.;Department of Clinical Haematology, Cancer and Haematology Centre, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Old Road, Headington, Oxford OX3 7LE, UK.;Department of Microbiology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.;Department of Clinical Immunology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.;Department of Radiology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.;Department of Clinical Haematology, Cancer and Haematology Centre, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Old Road, Headington, Oxford OX3 7LE, UK.;Department of Clinical Haematology, Cancer and Haematology Centre, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Old Road, Headington, Oxford OX3 7LE, UK.;Department of Clinical Haematology, Cancer and Haematology Centre, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Old Road, Headington, Oxford OX3 7LE, UK; NHS Blood and Transplant, John Radcliffe Hospital, Oxford, UK.;Department of Clinical Haematology, Cancer and Haematology Centre, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Old Road, Headington, Oxford OX3 7LE, UK; Anthony Nolan Research Institute, Royal Free Hospital, London, UK.;Department of Clinical Haematology, Cancer and Haematology Centre, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Old Road, Headington, Oxford OX3 7LE, UK; NHS Blood and Transplant, John Radcliffe Hospital, Oxford, UK.;Department of Clinical Haematology, Cancer and Haematology Centre, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Old Road, Headington, Oxford OX3 7LE, UK.",
"authors": "Balassa|Katalin|K|;Salisbury|Richard|R|;Watson|Edmund|E|;Lubowiecki|Marcin|M|;Tseu|Bing|B|;Maouche|Nadjoua|N|;Jeffery|Katie|K|;Misbah|Siraj A|SA|;Benamore|Rachel|R|;Rowley|Lara|L|;Barton|Daja|D|;Pawson|Rachel|R|;Danby|Robert|R|;Rocha|Vanderson|V|;Peniket|Andy|A|",
"chemical_list": "D000998:Antiviral Agents; D016756:Immunoglobulins, Intravenous; D012254:Ribavirin",
"country": "England",
"delete": false,
"doi": "10.1016/j.jinf.2019.04.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0163-4453",
"issue": "78(6)",
"journal": "The Journal of infection",
"keywords": "Allogeneic stem cell transplantation; Intravenous immunoglobulin (IVIG); Oral ribavirin; Respiratory syncytial virus (RSV) infection",
"medline_ta": "J Infect",
"mesh_terms": "D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000998:Antiviral Agents; D015331:Cohort Studies; D019468:Disease Management; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016756:Immunoglobulins, Intravenous; D008875:Middle Aged; D017410:Practice Guidelines as Topic; D018357:Respiratory Syncytial Virus Infections; D012141:Respiratory Tract Infections; D012254:Ribavirin; D012307:Risk Factors; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "7908424",
"other_id": null,
"pages": "461-467",
"pmc": null,
"pmid": "30965067",
"pubdate": "2019-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Treatment stratification of respiratory syncytial virus infection in allogeneic stem cell transplantation.",
"title_normalized": "treatment stratification of respiratory syncytial virus infection in allogeneic stem cell transplantation"
} | [
{
"companynumb": "GB-ROCHE-2319251",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RIBAVIRIN"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "Campylobacter species are known to cause enteritis. However, over the past 40-50 years, there have been reports of varying presentations, such as cellulitis, spondylodiscitis and bacteraemia. Of the Campylobacter species, Campylobacter jejuni is the most common culprit for causing bacteraemia, however, Campylobacter coli bacteraemia is becoming more prevalent. Here, we discuss an unusual case of C. coli bacteraemia in a patient with decompensated liver cirrhosis.",
"affiliations": "Internal Medicine, University of Missouri Kansas City, Kansas City, Missouri, USA.;Internal Medicine, CMH Lahore Medical College and Institute of Dentistry, Lahore, Pakistan.;Internal Medicine, Naples Community Hospital Healthcare System, Naples, Florida, USA yousuf.zafar.iqbal@gmail.com.",
"authors": "Pisipati|Sindhura|S|;Zafar|Adnan|A|;Zafar|Yousaf|Y|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000942:Antigens, Bacterial; D004573:Electrolytes",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-236634",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "13(12)",
"journal": "BMJ case reports",
"keywords": "infection (gastroenterology); infections",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000900:Anti-Bacterial Agents; D000942:Antigens, Bacterial; D016470:Bacteremia; D002169:Campylobacter Infections; D017000:Campylobacter coli; D003092:Colitis; D004359:Drug Therapy, Combination; D004573:Electrolytes; D005243:Feces; D005440:Fluid Therapy; D006801:Humans; D008103:Liver Cirrhosis; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33370970",
"pubdate": "2020-12-22",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Campylobacter coli bacteraemia: how common is it?",
"title_normalized": "campylobacter coli bacteraemia how common is it"
} | [
{
"companynumb": "US-009507513-2002USA008337",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CILASTATIN SODIUM\\IMIPENEM"
},
"drugadditio... |
{
"abstract": "Inflammation of the pouch after ileal pouch-anal anastomosis (IPAA) can significantly impact quality of life and be difficult to treat. We assessed the effectiveness and safety of vedolizumab in Crohn's disease (CD) of the pouch and chronic antibiotic-dependent or antibiotic-refractory pouchitis.\n\n\n\nThis was a retrospective, multicenter cohort study at 5 academic referral centers in the United States. Adult patients with endoscopic inflammation of the pouch who received vedolizumab were included. The primary outcome was clinical response at any time point. Secondary outcomes included clinical remission, endoscopic response, and remission. Univariate analysis and multivariate analysis were performed for the effect of the following variables on clinical response: fistula, onset of pouchitis less than 1 year after IPAA, younger than 35 years old, gender, previous tumor necrosis factor inhibitor-alpha use, and BMI >30.\n\n\n\nEighty-three patients were treated with vedolizumab for inflammation of the pouch between January 2014 and October 2017. Median follow-up was 1.3 years (interquartile range 0.7-2.1). The proportion of patients that achieved at least a clinical response was 71.1%, with 19.3% achieving clinical remission. Of the 74 patients with a follow-up pouchoscopy, the proportion of patients with endoscopic response and mucosal healing was 54.1% and 17.6%, respectively. Patients who developed pouchitis symptoms less than 1 year after undergoing IPAA were less likely to respond to vedolizumab, even after controlling for other risk factors.\n\n\n\nVedolizumab is safe and effective in the management of CD of the pouch and chronic pouchitis. Further studies are needed to compare vedolizumab with other biologic therapies for pouchitis and CD of the pouch.",
"affiliations": "Division of Gastroenterology and Hepatology, Washington University School of Medicine, St. Louis, Missouri, USA.;Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.;Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.;Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.;Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.;Division of Gastroenterology and Hepatology, Washington University School of Medicine, St. Louis, Missouri, USA.;Division of Gastroenterology and Hepatology, Washington University School of Medicine, St. Louis, Missouri, USA.;Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.;Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.;Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California, USA.;Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.;Division of Gastroenterology and Hepatology, Washington University School of Medicine, St. Louis, Missouri, USA.;Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.;Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.;Division of Gastroenterology and Hepatology, Washington University School of Medicine, St. Louis, Missouri, USA.",
"authors": "Gregory|Martin|M|;Weaver|Kimberly N|KN|;Hoversten|Patrick|P|;Hicks|Stephen Bradley|SB|;Patel|Devin|D|;Ciorba|Matthew A|MA|;Gutierrez|Alexandra M|AM|;Beniwal-Patel|Poonam|P|;Palam|Sowmya|S|;Syal|Gaurav|G|;Herfarth|Hans H|HH|;Christophi|George|G|;Raffals|Laura|L|;Barnes|Edward L|EL|;Deepak|Parakkal|P|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D005765:Gastrointestinal Agents; C543529:vedolizumab",
"country": "England",
"delete": false,
"doi": "10.1093/ibd/izz030",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-0998",
"issue": "25(9)",
"journal": "Inflammatory bowel diseases",
"keywords": "Crohn’s disease; pouchitis; vedolizumab",
"medline_ta": "Inflamm Bowel Dis",
"mesh_terms": "D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D003424:Crohn Disease; D004351:Drug Resistance; D005260:Female; D005500:Follow-Up Studies; D005765:Gastrointestinal Agents; D006801:Humans; D008297:Male; D008875:Middle Aged; D019449:Pouchitis; D016737:Proctocolectomy, Restorative; D011379:Prognosis; D012189:Retrospective Studies; D014481:United States",
"nlm_unique_id": "9508162",
"other_id": null,
"pages": "1569-1576",
"pmc": null,
"pmid": "30810748",
"pubdate": "2019-08-20",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "18929686;27057684;24316949;28097380;23964933;27930413;29266360;17665259;26288002;30151202;23602818;28449273;27296941;28243458;11768572;29660321;28698974;29106505;19183338;14572574;11089581;26681763;17973304;28426474;8170189;12755839;21160308",
"title": "Efficacy of Vedolizumab for Refractory Pouchitis of the Ileo-anal Pouch: Results From a Multicenter US Cohort.",
"title_normalized": "efficacy of vedolizumab for refractory pouchitis of the ileo anal pouch results from a multicenter us cohort"
} | [
{
"companynumb": "US-TAKEDA-2019TUS036768",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "VEDOLIZUMAB"
},
"drugadditional": null,
... |
{
"abstract": "Progressive multifocal leukoencephalopathy rarely occurs in patients with multiple myeloma. Intracranial central nervous system invasion is also an uncommon event in multiple myeloma, occurring in less than 1% of cases. We describe herein an exceptional case of coexisting progressive multifocal leukoencephalopathy and intraparenchymal central nervous system myeloma infiltration. A 73-year-old woman with relapsed multiple myeloma was treated with 15 cycles of lenalidomide and dexamethasone, but therapy had to be stopped because of a hip fracture after a fall. During hospitalization, the patient developed progressive multifocal leukoencephalopathy caused by John Cunningham virus, and a prominent intra-parenchymal CD138-positive infiltrate was detected. VDJ rearrangements of the immunoglobulin heavy chain gene and the mutational profile of plasma cells in bone marrow at the time of diagnosis and in brain biopsy after progression were analyzed by next generation sequencing, showing genetic differences between medullary and extramedullary myeloma cells. The role of long-term treatment with lenalidomide and dexamethasone in the development progressive multifocal leukoencephalopathy or intraparenchymal central nervous system myeloma infiltration remains unknown. However, our results suggest that both events may have arisen as a consequence of treatment-related immunosuppression. Thus, an appropriate clinical approach compatible with the simultaneous treatment of progressive multifocal leukoencephalopathy and multiple myeloma should be developed.",
"affiliations": "1 Department of Hematology, Hospital Universitario 12 de Octubre, Hematological Malignancies Clinical Research Unit H120-CNIO, Madrid, Spain.;1 Department of Hematology, Hospital Universitario 12 de Octubre, Hematological Malignancies Clinical Research Unit H120-CNIO, Madrid, Spain.;2 Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany.;1 Department of Hematology, Hospital Universitario 12 de Octubre, Hematological Malignancies Clinical Research Unit H120-CNIO, Madrid, Spain.;1 Department of Hematology, Hospital Universitario 12 de Octubre, Hematological Malignancies Clinical Research Unit H120-CNIO, Madrid, Spain.;3 Department of Hematology, Mayo Clinic, Phoenix/Scottsdale, USA.;3 Department of Hematology, Mayo Clinic, Phoenix/Scottsdale, USA.;4 Department of Microbiology, Hospital Universitario 12 de Octubre, Madrid, Spain.;5 Department of Radiology, Hospital Universitario 12 de Octubre, Madrid, Spain.;6 Department of Internal Medicine, Complutense University of Madrid, Madrid, Spain.;7 Department of Neurology, Hospital Universitario 12 de Octubre, Madrid, Spain.;8 Department of Pathology (Neuropathology), Hospital Universitario 12 de Octubre - Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain.;8 Department of Pathology (Neuropathology), Hospital Universitario 12 de Octubre - Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain.;1 Department of Hematology, Hospital Universitario 12 de Octubre, Hematological Malignancies Clinical Research Unit H120-CNIO, Madrid, Spain.",
"authors": "Ruiz-Heredia|Yanira|Y|;Sanchez-Vega|Beatriz|B|;Barrio|Santiago|S|;Linares|María|M|;Rapado|Inmaculada|I|;Braggio|Esteban|E|;Stewart|Keith|K|;Folgueira|M Dolores|MD|;Ramos|Ana|A|;Collado|Luis|L|;Ruiz|Juan|J|;Toldos|Oscar|O|;Hernandez-Lain|Aurelio|A|;Martinez-Lopez|Joaquin|J|https://orcid.org/0000-0001-5904-0902",
"chemical_list": "D003907:Dexamethasone; D000077269:Lenalidomide",
"country": "England",
"delete": false,
"doi": "10.1177/1078155218769367",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "25(4)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "John Cunningham virus; Progressive multifocal leukoencephalopathy; central nervous system myeloma infiltration; inmunomodulator side effect",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000368:Aged; D001921:Brain; D003907:Dexamethasone; D005260:Female; D006801:Humans; D007577:JC Virus; D000077269:Lenalidomide; D007968:Leukoencephalopathy, Progressive Multifocal; D008279:Magnetic Resonance Imaging; D009101:Multiple Myeloma; D009361:Neoplasm Invasiveness",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "998-1002",
"pmc": null,
"pmid": "29690814",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Concurrent progressive multifocal leukoencephalopathy and central nervous system infiltration by multiple myeloma: A case report.",
"title_normalized": "concurrent progressive multifocal leukoencephalopathy and central nervous system infiltration by multiple myeloma a case report"
} | [
{
"companynumb": "ES-BAUSCH-BL-2019-013291",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
... |
{
"abstract": "Post-transplant lymphoproliferative disease (PTLD) has the highest incidence following intestinal transplantation (ITx). Our center has seen a recent increase in PTLD. Our aim was to review a single-center PTLD experience with a focus on clinical characteristics and outcomes. We completed a retrospective review of biopsy-proven PTLD cases using a prospectively maintained database of 115 ITx recipients transplanted between 1991 and 2014. Nineteen (17%) ITx recipients developed 25 PTLD cases during a median follow-up time of 6.4 (1.6-14.6) years. The incidence of early PTLD was 6% (n = 7). There was a trend toward increased risk of PTLD in children compared with adults (P = .11) and a significantly increased risk of PTLD in re-ITx compared with primary ITx recipients (P = .03). Most PTLD cases were diagnosed between 2010 and 2014 (n = 14). All early PTLD cases were EBV+ on in situ hybridization. Overall graft and patient survival are 68% and 74%, respectively. Second episodes of PTLD were diagnosed in 43% of surviving pediatric patients. Our program has a low incidence of early PTLD with overall excellent graft and patient survival following diagnosis. However, we have also seen a rising incidence of late PTLD. The cause of the increase is unknown as no major changes in immunosuppression protocols have occurred since 1999.",
"affiliations": "Pediatric Gastroenterology, Hepatology, and Nutrition, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.;Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.;Pediatric Gastroenterology, Hepatology, and Nutrition, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.;Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.;Pediatric Hematology and Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.;Pediatric Hematology and Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.;Pediatric Gastroenterology, Hepatology, and Nutrition, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.;Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.;Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.;Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.;Pediatric Gastroenterology, Hepatology, and Nutrition, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.;Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.",
"authors": "Wozniak|Laura J|LJ|0000-0002-4473-1812;Mauer|Tian L|TL|;Venick|Robert S|RS|;Said|Jonathan W|JW|;Kao|Roy L|RL|0000-0002-1985-8870;Kempert|Pamela|P|;Marcus|Elizabeth A|EA|;Hwang|Vilayphone|V|;Cheng|Elaine Y|EY|;Busuttil|Ronald W|RW|;McDiarmid|Sue V|SV|;Farmer|Douglas G|DG|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/ctr.13313",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-0063",
"issue": "32(8)",
"journal": "Clinical transplantation",
"keywords": "Epstein-Barr virus; intestinal transplantation; post-transplant lymphoproliferative disease",
"medline_ta": "Clin Transplant",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D007422:Intestines; D008232:Lymphoproliferative Disorders; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D011379:Prognosis; D011446:Prospective Studies; D012189:Retrospective Studies; D015996:Survival Rate",
"nlm_unique_id": "8710240",
"other_id": null,
"pages": "e13313",
"pmc": null,
"pmid": "29888807",
"pubdate": "2018-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical characteristics and outcomes of PTLD following intestinal transplantation.",
"title_normalized": "clinical characteristics and outcomes of ptld following intestinal transplantation"
} | [
{
"companynumb": "PHHY2018US046599",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
"druga... |
{
"abstract": "Experience in combined liver-kidney transplantation (CLKT) in children is limited.\n\n\n\nWe conducted a retrospective study of all pediatric CLKTs performed at our medical institution between 1992 and 2013.\n\n\n\nWe identified 18 pediatric patients (9 girls) who had undergone CLKT at our institution during the study period. The median age [range] and body weight [range] of this patient group was 3.6 [1.0-18.6] years and 13 [10-40] kg, respectively; 11 patients weighed <15 kg at the time of CLKT. Indications for CLKT were primary hyperoxaluria (PH1; n = 14), association of hepatic fibrosis and end-stage renal disease (n = 3) and methylmalonic acidemia (n = 1). In the early postoperative period, eight patients required dialysis. Median stay in the pediatric intensive care unit was 10 [6-29] days. One patient died from cardiovascular disease 10 years after CLKT. There were no liver graft losses despite six acute liver rejection episodes, whereas four kidney grafts were lost. At last follow-up (6 [0.5-21] years) for patients with a functioning renal graft, the glomerular filtration rate was 71 [26-146] mL/min/1.73 m(2). In PH1 patients, urine oxalate normalized in six patients within 3 years after CLKT, but three patients still presented with elevated oxaluria at 1, 2 and 3 years after CLKT.\n\n\n\nPediatric CLKT provides encouraging results in the long term, even in the youngest patients.",
"affiliations": "Centre de Référence des Maladies Rénales Rares Néphrogones, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France. remi.duclauxloras@gmail.com.;Centre de Référence des Maladies Rénales Rares Néphrogones, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France.;Information Médicale Evaluation Recherche, Hospices Civils de Lyon, Lyon, France.;Hépatologie Gastro-Entérologie et Nutrition Pédiatrique, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, 59 boulevard Pinel, 69677, Bron cedex, France.;Chirurgie Pédiatrique, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France.;Université Claude-Bernard Lyon 1, Lyon, France.;Chirurgie Pédiatrique, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France.;Université Claude-Bernard Lyon 1, Lyon, France.;Université Claude-Bernard Lyon 1, Lyon, France.;Université Claude-Bernard Lyon 1, Lyon, France.;Université Claude-Bernard Lyon 1, Lyon, France.;Centre de Référence des Maladies Rénales Rares Néphrogones, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France.",
"authors": "Duclaux-Loras|Rémi|R|;Bacchetta|Justine|J|;Berthiller|Julien|J|;Rivet|Christine|C|;Demède|Delphine|D|;Javouhey|Etienne|E|;Dubois|Rémi|R|;Dijoud|Frédérique|F|;Lachaux|Alain|A|;Badet|Lionel|L|;Boillot|Olivier|O|;Cochat|Pierre|P|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00467-016-3324-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0931-041X",
"issue": "31(9)",
"journal": "Pediatric nephrology (Berlin, Germany)",
"keywords": "Boichis syndrome; Child; Combined liver–kidney transplantation; Methylmalonic acidemia; Primary hyperoxaluria type 1",
"medline_ta": "Pediatr Nephrol",
"mesh_terms": "D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D016030:Kidney Transplantation; D008099:Liver; D016031:Liver Transplantation; D008297:Male; D006435:Renal Dialysis; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "8708728",
"other_id": null,
"pages": "1517-29",
"pmc": null,
"pmid": "27060059",
"pubdate": "2016-09",
"publication_types": "D016428:Journal Article",
"references": "20070563;26164477;9627602;10603104;17401587;19847156;17096763;11502971;10469379;21544033;21115623;15961948;22499586;25917555;26341656;4688793;25274400;19741470;7701148;16697565;25039018;22129440;19508969;23644898;23944302;23937869;16861941;26354144;11793078;14657686;26270957;24865477;17692657;23582048",
"title": "Pediatric combined liver-kidney transplantation: a single-center experience of 18 cases.",
"title_normalized": "pediatric combined liver kidney transplantation a single center experience of 18 cases"
} | [
{
"companynumb": "PHHY2016FR125700",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": null,
... |
{
"abstract": "A 35-year-old man was diagnosed to have gastric cancer by endoscopic and histological examinations. Staging laparoscopy detected peritoneal metastasis. Systemic chemotherapy was started, but the patient complained of severe headache. Subsequently, a lumbar puncture demonstrated adenocarcinoma cells in the spinal fluid, suggesting the occurrence of meningeal carcinomatosis (MC) from gastric cancer. MC occurs only rarely in patients with gastric cancer, but the prognosis is invariably poor. However, this patient nevertheless survived for 12 months after receiving intrathecal MTX/Ara-C together with systemic chemotherapy. Therefore, the early detection of meningeal irritation sign and intrathecal chemotherapy might greatly improve the prognosis of gastric cancer patients with MC.",
"affiliations": "Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Japan.",
"authors": "Yamasaki|Takahisa|T|;Fukui|Hirokazu|H|;Sei|Hiroo|H|;Hara|Ken|K|;Eda|Hirotsugu|H|;Kondo|Takashi|T|;Toyoshima|Fumihiko|F|;Kono|Tomoaki|T|;Tozawa|Katsuyuki|K|;Ikehara|Hisatomo|H|;Tomita|Toshihiko|T|;Oshima|Tadayuki|T|;Watari|Jiro|J|;Miwa|Hiroto|H|",
"chemical_list": "D003561:Cytarabine; D008727:Methotrexate",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.55.5129",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0918-2918",
"issue": "55(6)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": null,
"medline_ta": "Intern Med",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D003561:Cytarabine; D017809:Fatal Outcome; D006261:Headache; D006801:Humans; D007278:Injections, Spinal; D008297:Male; D055756:Meningeal Carcinomatosis; D008727:Methotrexate; D011379:Prognosis; D013129:Spinal Puncture; D013274:Stomach Neoplasms",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "609-11",
"pmc": null,
"pmid": "26984076",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Efficacy of Intrathecal MTX/Ara-C Combined with Systemic Chemotherapy in a Gastric Cancer Patient with Meningeal Carcinomatosis.",
"title_normalized": "efficacy of intrathecal mtx ara c combined with systemic chemotherapy in a gastric cancer patient with meningeal carcinomatosis"
} | [
{
"companynumb": "JP-BAUSCH-BL-2016-008408",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,
... |
{
"abstract": "Only limited data concerning hepatitis B (HBV) and C viruses (HCV) coinfection are available. Direct-acting antivirals (DAAs) may be more effective for HCV clearance than interferon (IFN)-based regimens with a risk of HBV reactivation.\nWe retrospectively enrolled 40 HBV/HCV-coinfected patients to evaluate their clinical profile and treatment outcomes.\nChronic dual infection was present in 25/40 (62.5%) patients, acute HCV superinfection in 5/40 (12.5%) patients and acute HBV superinfection in 10/40 (25%). Twenty-five patients (62.5%) were treated: 16/25 (64%) with IFN, 4/25 (16%) with nucleot(s)ide analogs (NUCs) and 5/25 (20%) with DAAs. Of the 16 patients treated with IFN-based therapy, 6 (37.5%) achieved both sustained virological response (SVR) and HBsAg clearance. Of the 4 patients treated with NUCs, one (25%) achieved both SVR and HBsAg clearance. All five patients treated with DAAs (100%) achieved SVR, while one case of HBV reactivation was recorded. Fifteen of the 40 patients (37.5%) did not receive any treatment. Eight of them (53.5%) presented with acute HBV superinfection: spontaneous HCV clearance was recorded in 5/8 (62.5%), while HBsAg clearance occurred in 6/8 (75%). Three of them (20%) presented with acute HCV superinfection; spontaneous HCV clearance was recorded in one of the three (33.5%). The other four patients (26.5%) presented with dual HBV/HCV infection.\nA significant proportion of patients presented with active HBV replication. Treatment with DAAs seems to be efficacious for HCV eradication. However, clinicians should be aware of HBV reactivation. HBV superinfection may lead to both HBsAg and HCV clearance.",
"affiliations": "1st Department of Internal Medicine, 417 Army Share Fund Hospital of Athens (Nikolaos Papadopoulos, Anna Pavlidou), Athens, Greece.;2nd Academic Department of Internal Medicine, Medical School National and Kapodistrian University of Athens, Hippokration Hospital (Maria Papavdi, Dimitris Konstantinou, Hariklia Kranidioti, George Kontos, John Koskinas, Spilios Manolakopoulos, Melanie Deutsch), Athens, Greece.;1st Department of Internal Medicine, 417 Army Share Fund Hospital of Athens (Nikolaos Papadopoulos, Anna Pavlidou), Athens, Greece.;2nd Academic Department of Internal Medicine, Medical School National and Kapodistrian University of Athens, Hippokration Hospital (Maria Papavdi, Dimitris Konstantinou, Hariklia Kranidioti, George Kontos, John Koskinas, Spilios Manolakopoulos, Melanie Deutsch), Athens, Greece.;2nd Academic Department of Internal Medicine, Medical School National and Kapodistrian University of Athens, Hippokration Hospital (Maria Papavdi, Dimitris Konstantinou, Hariklia Kranidioti, George Kontos, John Koskinas, Spilios Manolakopoulos, Melanie Deutsch), Athens, Greece.;2nd Academic Department of Internal Medicine, Medical School National and Kapodistrian University of Athens, Hippokration Hospital (Maria Papavdi, Dimitris Konstantinou, Hariklia Kranidioti, George Kontos, John Koskinas, Spilios Manolakopoulos, Melanie Deutsch), Athens, Greece.;2nd Academic Department of Internal Medicine, Medical School National and Kapodistrian University of Athens, Hippokration Hospital (Maria Papavdi, Dimitris Konstantinou, Hariklia Kranidioti, George Kontos, John Koskinas, Spilios Manolakopoulos, Melanie Deutsch), Athens, Greece.;Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, Laiko General Hospital (George V. Papatheodoridis), Athens, Greece.;2nd Academic Department of Internal Medicine, Medical School National and Kapodistrian University of Athens, Hippokration Hospital (Maria Papavdi, Dimitris Konstantinou, Hariklia Kranidioti, George Kontos, John Koskinas, Spilios Manolakopoulos, Melanie Deutsch), Athens, Greece.;2nd Academic Department of Internal Medicine, Medical School National and Kapodistrian University of Athens, Hippokration Hospital (Maria Papavdi, Dimitris Konstantinou, Hariklia Kranidioti, George Kontos, John Koskinas, Spilios Manolakopoulos, Melanie Deutsch), Athens, Greece.",
"authors": "Papadopoulos|Nikolaos|N|;Papavdi|Maria|M|;Pavlidou|Anna|A|;Konstantinou|Dimitris|D|;Kranidioti|Hariklia|H|;Kontos|George|G|;Koskinas|John|J|;Papatheodoridis|George V|GV|;Manolakopoulos|Spilios|S|;Deutsch|Melanie|M|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": "10.20524/aog.2018.0255",
"fulltext": "\n==== Front\nAnn GastroenterolAnn GastroenterolAnnals of Gastroenterology1108-74711792-7463Hellenic Society of Gastroenterology Greece AnnGastroenterol-31-36510.20524/aog.2018.0255Original ArticleHepatitis B and C coinfection in a real-life setting: viral interactions and treatment issues Papadopoulos Nikolaos aPapavdi Maria bPavlidou Anna aKonstantinou Dimitris bKranidioti Hariklia bKontos George bKoskinas John bPapatheodoridis George V. cManolakopoulos Spilios bDeutsch Melanie ba 1st Department of Internal Medicine, 417 Army Share Fund Hospital of Athens (Nikolaos Papadopoulos, Anna Pavlidou), Athens, Greeceb 2nd Academic Department of Internal Medicine, Medical School National and Kapodistrian University of Athens, Hippokration Hospital (Maria Papavdi, Dimitris Konstantinou, Hariklia Kranidioti, George Kontos, John Koskinas, Spilios Manolakopoulos, Melanie Deutsch), Athens, Greecec Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, Laiko General Hospital (George V. Papatheodoridis), Athens, Greece\nCorrespondence to: Nikolaos Papadopoulos, Monis Petraki 10-12, 11521 Athens, Greece, e-mail: npnck7@yahoo.com, nipapmed@gmail.comMay-Jun 2018 28 3 2018 31 3 365 370 09 10 2017 18 2 2018 Copyright: © Hellenic Society of Gastroenterology2018This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background:\nOnly limited data concerning hepatitis B (HBV) and C viruses (HCV) coinfection are available. Direct-acting antivirals (DAAs) may be more effective for HCV clearance than interferon (IFN)-based regimens with a risk of HBV reactivation.\n\nMethods:\nWe retrospectively enrolled 40 HBV/HCV-coinfected patients to evaluate their clinical profile and treatment outcomes.\n\nResults:\nChronic dual infection was present in 25/40 (62.5%) patients, acute HCV superinfection in 5/40 (12.5%) patients and acute HBV superinfection in 10/40 (25%). Twenty-five patients (62.5%) were treated: 16/25 (64%) with IFN, 4/25 (16%) with nucleot(s)ide analogs (NUCs) and 5/25 (20%) with DAAs. Of the 16 patients treated with IFN-based therapy, 6 (37.5%) achieved both sustained virological response (SVR) and HBsAg clearance. Of the 4 patients treated with NUCs, one (25%) achieved both SVR and HBsAg clearance. All five patients treated with DAAs (100%) achieved SVR, while one case of HBV reactivation was recorded. Fifteen of the 40 patients (37.5%) did not receive any treatment. Eight of them (53.5%) presented with acute HBV superinfection: spontaneous HCV clearance was recorded in 5/8 (62.5%), while HBsAg clearance occurred in 6/8 (75%). Three of them (20%) presented with acute HCV superinfection; spontaneous HCV clearance was recorded in one of the three (33.5%). The other four patients (26.5%) presented with dual HBV/HCV infection.\n\nConclusions:\nA significant proportion of patients presented with active HBV replication. Treatment with DAAs seems to be efficacious for HCV eradication. However, clinicians should be aware of HBV reactivation. HBV superinfection may lead to both HBsAg and HCV clearance.\n\nHepatitis Bhepatitis Cdirect-acting antiviralsinterferon\n==== Body\nIntroduction\nThe exact prevalence of hepatitis B (HBV) and C viruses (HCV) coinfection is actually unknown. It is estimated to be between 0.7% and 16%, a percentage that ranges over a wide interval among several studies in the literature, mainly depending on the geographical region and the study population [1-3]. However, in regions where HBV is endemic the probability of coinfection increases, especially in groups of patients with well-known risk factors for HCV infection, such as persons who inject drugs (PWID) or had blood transfusions before 1990-91.\n\nOn the other hand, HBV/HCV-coinfected patients represent a group with significant heterogeneity regarding clinical features, impact on the severity of liver disease and therapeutic options. While liver disease activity and progression are generally more severe in the presence of double infection, the host’s immune response plays an important role in coordinating each single viral replication and the viral interference, usually leading to a predominance of one of the two viruses [1-2, 4-5]. Thus, several clinical scenarios have been described in the natural course of this dual infection [6]. HCV superinfection is more frequent, while HBV superinfection is rare [7-8]. In addition, acute HBV/HCV coinfection is more prevalent in PWID [9]. Most HBV/HCV-coinfected patients have HCV RNA levels similar to those in patients with HCV mono-infection, but relatively lower levels of serum HBV DNA compared to patients with chronic HBV mono-infection [10].\n\nTreatment may result in complete disruption of the delicate co-existence of HBV/HCV viruses. Thus, the treatment-induced eradication of each virus could lead to reactivation of the other [6].\n\nIn this retrospective study, we aimed to evaluate a series of HBV/HCV-coinfected patients followed in our units, emphasizing their initial clinical profile, treatment efficacy and outcomes.\n\nPatients and methods\nWe reviewed the records of all anti-HCV and HBsAg-positive patients who visited two tertiary liver centers in Athens between 1990 and 2016. Patients who were coinfected with human immunodeficiency virus were excluded. The database included patients’ demographic and epidemiological characteristics, medical history data, clinical and laboratory data, and treatment history. The study was performed according to the World Medical Association Declaration of Helsinki and was approved by the hospital’s ethics committee.\n\nManagement profile and treatment decisions were individualized for each patient according to their compliance and the practice of the treating physicians. Contraindications for interferon (IFN)-based therapies included current uncontrolled depression, psychosis, or epilepsy, uncontrolled autoimmune diseases, pregnancy or unwillingness to use adequate contraception, alcohol use, decompensated cirrhosis, severe heart failure, and chronic obstructive pulmonary disease.\n\nDefinitions\nChronic hepatitis B (CHB) and chronic hepatitis C (CHC) dual infection was defined as anti-HCV-positive with detectable HCV RNA accompanying by positive HBsAg/anti-HBc with HBV DNA levels either >2000 IU/mL or <2000 IU/mL (inactive HBV carriers). Acute HCV superinfection was defined as documented anti-HCV detection in patients with known CHB. Acute HBV superinfection was defined as documented HBsAg/anti-HBc detection in patients with known CHC.\n\nHepatitis C sustained virological response (SVR) was defined as serum HCV RNA undetectability by qualitative polymerase chain reaction (PCR) at 6 months (SVR24) after stopping treatment with interferon and ribavirin, or at 3 months after (SVR12) stopping treatment with direct-acting antivirals (DAAs). Patients with undetectable serum HCV RNA at the end and detectable HCV RNA after the end of treatment were considered as relapse responders and patients with detectable serum HCV RNA at the end of treatment as non-responders. Treatment response in HBV infection was defined as HBsAg clearance. HBV reactivation after DAA treatment was defined as a >1 log increase in HBV DNA accompanying by a ≥3-fold increase in baseline levels of alanine aminotransferase (ALT). Increases >1 log in HBV DNA levels that did not led to clinical acute hepatitis (≥3-fold increase in ALT) were considered as HBV DNA flares of no clinical significance.\n\nLaboratory methods\nHematological and biochemical parameters were determined using commercially available assays. The upper limit of normal for both ALT and aspartate aminotransferase was 40 IU/L. Commercially available enzyme immunoassays were used for detection of anti-HCV, while quantitative determination of HCV RNA and HBV DNA were performed using quantitative real-time PCR (Quantiplex HCV RNA, Chiron Co and COBAS Taqman HBV Test; Roche Diagnostics). HCV genotype was also determined by a commercially available assay (InnoLipa; Innogenetics).\n\nStatistical analysis\nAll statistical analyses were carried out using SPSS (version 21.0, SPSS Inc., Chicago, IL, USA). General descriptive methods, including frequencies and mean values ± standard deviation, were used to express percentages and continuous variables.\n\nResults\nWe included 40 patients with HBV/HCV coinfection. Their mean age was 47±15 years and 65% of them were male. The majority (87.5%) were Greeks. About half of the patients (52.5%) had a history of parenteral drug use, while 11 patients (27.5%) were cirrhotics. The mean follow-up time was 50.5±7 months. HBeAg was positive in 13/40 (32.5%) patients (7 patients with acute HBV superinfection, 5 patients with CHB/CHC dual infection and one patient with acute HCV superinfection). Mean ALT levels were 171±336 IU/L, mean HCV RNA levels were 1×106±2×106 IU/mL and mean HBV DNA levels were 1×108±36×107 IU/mL (Table 1).\n\nTable 1 Baseline demographic and clinical characteristics\n\nBaseline data in subgroups\nCHB/CHC dual infection was present in 25/40 (62.5%) patients, of whom 14 (56%) had long-term normal aminotransferases and low or undetectable HBV DNA (inactive HBV carriers). Acute HCV superinfection was found in 5/40 (12.5%) patients and acute HBV superinfection in 10/40 (25%) patients (Table 1).\n\nTreatment decision and outcome\nOf the 40 patients, 25 (62.5%) were treated for HCV and/or HBV. According to each treating physician’s decision, 16 (64%) of the 25 patients received treatment with (peg)IFN ± ribavirin (IFN-based), 4 (16%) patients were treated with nucleot(s)ide analogs (NUCs) and 5 (20%) patients were treated with DAAs.\n\nCHB/CHC patients\nTwenty-one (84%) of this subgroup of 25 patients were treated: 13/21 (62%) with IFN-based treatment, resulting in both HBsAg clearance and HCV eradication in 4 patients (31%); 3/21 (14%) with NUCs and no HBsAg clearance or HCV eradication; and 5/21 (24%) with DAAs, resulting in HCV eradication in 3 patients (60%) with no HBsAg clearance.\n\nAcute HCV superinfection\nOnly 2/25 (8%) patients of this subgroup were treated: 2/2 (100%) with IFN-based treatment, resulting in both HBsAg clearance and HCV eradication in both patients (100%).\n\nAcute HBV superinfection\nOnly 2/25 (8%) patients of this subgroup were treated: 1 patient (50%) with IFN-based treatment, with no HBsAg clearance or HCV eradication, and 1 patient (50%) with NUC, resulting in both HBsAg clearance and HCV eradication.\n\nClearance\nAmong 16 patients treated with IFN based therapy, 6 (37.5%) achieved both SVR and HBsAg clearance. Of the 4 patients treated with NUCs, 1 patient (25%) who presented with acute HBV superinfection achieved both SVR and HBsAg clearance. Among 5 patients treated with DAAs, all cases (100%) achieved SVR12. One case of HBV reactivation was recorded among these 5 patients who achieved SVR with DAAs. He was a cirrhotic 55-year-old Caucasian male with genotype 1b CHC/inactive HBV carrier (baseline HBV DNA levels: 215 IU/mL), initially treated with ledipasvir/sofosbuvir and ribavirin. He achieved SVR12, but one month later he experienced HBV reactivation, with HBV DNA levels of 460,000 IU/mL, accompanied by clinical hepatitis (ALT levels of 352 IU/L). Antiviral therapy with tenofovir disoproxil fumarate (TDF, 300 mg once daily) was initiated. Six months later, ALT levels were within normal range and serum HBV DNA was undetectable. We also recorded a case of HBV DNA flare. She was a 57-year-old Caucasian female with genotype 1a CHC/CHB (HBeAg-positive with baseline HBV DNA levels 1,000,000 IU/mL), treated with peg-IFN plus ribavirin for 48 weeks. She achieved SVR24 accompanying by <1 log increase in HBV DNA levels (3,070,000 IU/mL) without clinical or laboratory findings of acute hepatitis. The patient did not receive treatment for HBV and is still HBeAg-positive without any increases in ALT levels (Table 2).\n\nTable 2 Outcomes according to initial clinical features among treated patients (N=25)\n\nNon-treated patients\nA significant proportion of this cohort, 15/40 patients (37.5%), did not receive any treatment, mainly because of the physician’s decision or a contraindication (12/15; 80%). Eight of these patients (53.5%) presented with acute HBV superinfection: spontaneous HCV clearance was recorded in 5/8 (62.5%), while HBsAg clearance occurred in 6/8 (75%). Three of them (20%) presented with acute HCV superinfection: spontaneous HCV clearance was recorded in one of them (33.5%). Four patients (26.5%) presented with dual HBV/HCV infection: two of them (50%) did not receive any treatment due to contraindication, one patient (25%) did not wish to receive treatment and one patient (25%) was lost during the follow up (Table 3).\n\nTable 3 Outcomes according to initial clinical features among non-treated patients (N=15)\n\nDiscussion\nThe worldwide prevalence of HBV/HCV coinfection is unknown and may be underestimated, while the disease outcomes, including cirrhosis, are more severe than in patients with mono-infection [11]. HBV/HCV coinfection is frequently found in several high-risk populations, such as PWID [12]. Unfortunately, HBV/HCV-coinfected patients have very heterogeneous clinical manifestations. There is either HCV predominance, with high HCV RNA levels and low HBV DNA levels, or HBV predominance, with high HBV DNA levels and low HCV RNA levels. It seems that the time of acquisition of each infection is crucial for the prevalence of one virus over the other. In areas with a high prevalence of HBV infection, such as Asia-Pacific countries, patients may have acquired HBV infection at birth, with HCV occurring later as a superinfection, while most patients from Europe and the USA present HBV superinfection on CHC [13]. However, most cases are characterized by an inhibition of HBV replication. In accordance with these reports, most of our HBV/HCV-coinfected patients (14/25; 56%) presented with HCV predominance as HBV replication was suppressed. However, a significant proportion of our patients presented either with dually active HBV/HCV infection (11/25; 44%) or with acute HBV superinfection (10/40; 25%), indicating a significant role for HBV in our cohort. This finding can be explained by the fact that, while Greece has been associated with intermediate endemicity for HBV infection, a significant number of HBsAg/HBeAg-positive immigrants have registered in our country during the last two decades, changing the epidemiology of HBV infection [14]. In Greece, as in most countries with intermediate endemicity for HBV infection, most of these infections occurred through horizontal transmission during infancy or early childhood; thus, patients had HBV infection for many years before being infected by HCV. As proposed by Chen et al, patients who acquired HCV infection later than HBV infection have a minority of hepatocytes uninfected by HBV and thus “available” for HCV superinfection; this unequal distribution of the coinfection leads to HBV dominance [15].\n\nDetailed serological and virological evaluations are required for coinfected patients before the initiation of antiviral therapy. It has been demonstrated that IFN-based therapies are safe and can achieve SVR rates comparable to those expected with HCV mono-infection, leading to a reduction in liver-related complications [16-18]. Our cohort included 25 treated patients. The majority (64%) were treated with IFN-based therapies. Both HBsAg clearance and HCV eradication were documented in 37.5% of them. We also observed both HBsAg clearance and HCV eradication in a patient treated with NUC. However, this patient presented with acute HBV superinfection. Sagnelli et al conducted a long-term follow-up study in Italy of HBV superinfection in CHC patients. In that study, more than 90% of patients cleared HBsAg, while all patients had undetectable HCV RNA during acute hepatitis B [19]. Several case reports suggested the dominant role of HBV leading to HCV clearance after HBV superinfection [8]. There is a hypothesis that HCV eradication in HBV superinfection is favorable because the T-cell response targets HBV [20]. Thus, the role of NUC treatment in this patient’s HBV/HCV clearance is unclear. Furthermore, our data indicate the favorable role of acute HBV superinfection in HBsAg and HCV clearance; we recorded 75% HBsAg clearance and 50% HCV spontaneous eradication in eight untreated patients with HBV superinfection.\n\nRecently, several cases of HBV reactivation have been reported in HBV/HCV-coinfected patients receiving DAAs, raising potential safety concerns [21-24]. HBV reactivation according to various definitions may occur in >50% of HBsAg-positive patients who receive treatment with DAAs for CHC, but is very rare in patients with resolved HBV hepatitis (HBsAg-negative/antiHBc-positive) [23]. On the other hand, recently published data showed frequent HBV reactivations in CHB/CHC patients, but no signs of clinical flares, while none of the patients required antiviral treatment for HBV [25]. HBV reactivation in HBV/HCV dually infected patients was initially described with IFN-based treatment several years ago [26]. It seems that HBV reactivation may occur much earlier after treatment with DAAs compared to IFN-based treatment [23]. As a result, the US Food and Drug Administration issued a warning about the risk of HBV reactivation and suggests screening and monitoring for HBV in all patients receiving DDA treatment [27-28]. Recently published recommendations from the European Association for the Study of the Liver (EASL) regarding the treatment of hepatitis C indicate that patients with HBV/HCV coinfection should be treated with the same regimens, following the same rules as HCV mono-infected patients, and if active CHB or “occult” HBV infection is detected, concurrent NUC therapy is indicated [29]. However, more recently published EASL recommendations for the treatment of hepatitis B indicate that HBsAg-negative/anti-HBc-positive patients undergoing DAA treatment should be monitored and tested for HBV reactivation only in case of ALT elevation [30]. Consistently with these reports, one of our patients experienced HBV reactivation after DAA treatment. As described above, he was treated with TDF for HBV reactivation without any signs of liver function deterioration, despite the fact he was cirrhotic. Six months later he achieved complete viral suppression with normal liver function tests and undetectable HBV DNA. In fact, according to the EASL published guidelines, HBsAg-positive cirrhotic patients with detectable HBV DNA levels at baseline require antiviral treatment with NUC even before DAA treatment, regardless of ALT levels [30].\n\nSummary Box\nWhat is already known:\n\n\nLiver disease activity and progression are generally more severe in hepatitis B (HBV) and C (HCV)-coinfected patients\n\nViral interference usually leads to a predominance of one of the two viruses, which in most cases is HCV\n\nTreatment-induced eradication of each virus could lead to reactivation of the other; several cases of HBV reactivation have been reported in HBV/HCV-coinfected patients receiving direct-acting antivirals (DAAs)\n\n\n\n\nWhat the new findings are:\n\n\nAs Greece has been associated with intermediate endemicity for HBV infection, a significant proportion of our patients presented either with dually-active HBV/HCV infection or with acute HBV superinfection, indicating a significant role for HBV in our cohort\n\nA significant proportion of this cohort (37.5%) did not receive any treatment\n\nOur data indicate the favorable role of acute HBV superinfection in HBsAg and HCV clearance; we recorded 75% HBsAg clearance and 50% HCV spontaneous eradication in eight untreated patients with HBV superinfection\n\nTreatment with DAAs seems to be efficacious in HCV eradication; however, one of our five treated patients with DAAs experienced HBV reactivation and he was successfully treated with tenofovir disoproxil fumarate\n\n\n\n\nBecause of the retrospective design of our study, we unfortunately did not have frequent follow-up data regarding concurrent measurements of HBV DNA and HCV RNA during follow up, which could have been helpful for a better understanding of the viral interactions without or during antiviral treatment. However, prospective studies are not easy to perform, because of the small number of cases and the high heterogeneity of the clinical presentations.\n\nIn conclusion, although HCV dominance was documented, a significant proportion of our patients presented with active HBV replication, either as dually active HBV/HCV infection or as acute HBV superinfection over CHC. Treatment with DAAs seems to be efficacious in HCV eradication. However, clinicians should be alert for HBV reactivation after DAA therapy and all patients with HCV/HBV coinfection should be closely monitored. Finally, acute HBV superinfection may lead to both HBsAg and HCV clearance.\n\nConflict of Interest: None\n\n417 Army Share Fund Hospital of Athens; Medical School National and Kapodistrian University of Athens, Hippokration Hospital; Medical School of National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece\n==== Refs\nReferences\n1 Chakravarti A Verma V Jain M Kar P Characteristics of dual infection of hepatitis B and C viruses among patients with chronic liver disease:a study from tertiary care hospital Trop Gastroenterol 2005 26 183 187 16737047 \n2 Mekky MA Nasr AM Saleh MA Virologic and histologic characterisation of dual hepatitis B and C co-infection in Egyptian patients Arab J Gastroenterol 2013 14 143 147 24433642 \n3 Gaeta GB Stornaiuolo G Precone DF Epidemiological and clinical burden of chronic hepatitis B virus/hepatitis C virus infection. A multicenter Italian study J Hepatol 2003 39 1036 1041 14642623 \n4 Alberti A Pontisso P Chemello L The interaction between hepatitis B virus and hepatitis C virus in acute and chronic liver disease J Hepatol 1995 22 38 41 7602074 \n5 Senturk H Tahan V Canbakan B Clinicopathologic features of dual chronic hepatitis B and C infection:a comparison with single hepatitis B, C and delta infections Ann Hepatol 2008 7 52 58 18376366 \n6 Konstantinou D Deutsch M The spectrum of HBV/HCV coinfection:epidemiology, clinical characteristics, viral interactions and management Ann Gastroenterol 2015 28 221 228 25830779 \n7 Liaw YF Hepatitis C virus superinfection in patients with chronic hepatitis B virus infection J Gastroenterol 2002 37 Suppl 13 65 68 12109669 \n8 Liaw YF Yeh CT Tsai SL Impact of acute hepatitis B virus superinfection on chronic hepatitis C virus infection Am J Gastroenterol 2000 95 2978 2980 11051381 \n9 Yan BM Lee SS Acute coinfection with hepatitis B and hepatitis C viruses Can J Gastroenterol 2005 19 729 730 16341313 \n10 Liu CJ Chen PJ Chen DS Dual chronic hepatitis B virus and hepatitis C virus infection Hepatol Int 2009 3 517 525 19669238 \n11 Liu CJ Liou JM Chen DS Chen PJ Natural course and treatment of dual hepatitis B virus and hepatitis C virus infections J Formos Med Assoc 2005 104 783 791 16496056 \n12 Pallás JR Fariñas-Alvarez C Prieto D Delgado-Rodríguez M Coinfections by HIV, hepatitis B and hepatitis C in imprisoned injecting drug users Eur J Epidemiol 1999 15 699 704 10555612 \n13 Nguyen LH Ko S Wong SS Ethnic differences in viral dominance patterns in patients with hepatitis B virus and hepatitis C virus dual infection Hepatology 2011 53 1839 1845 21425314 \n14 Raptopoulou M Papatheodoridis G Antoniou A Epidemiology, course and disease burden of chronic hepatitis B virus infection. HEPNET study for chronic hepatitis B:a multicentre Greek study J Viral Hepat 2009 16 195 202 19175881 \n15 Chen F Zhang J Wen B HBV/HCV dual infection impacts viral load, antibody response, and cytokine expression differently from HBV or HCV single infection Sci Rep 2016 6 39409 28009018 \n16 Liu CJ Chu YT Shau WY Kuo RN Chen PJ Lai MS Treatment of patients with dual hepatitis C and B by peginterferon αand ribavirin reduced risk of hepatocellular carcinoma and mortality Gut 2014 63 506 514 23676440 \n17 Liu CJ Chen PJ Lai MY Kao JH Jeng YM Chen DS Ribavirin and interferon is effective for hepatitis C virus clearance in hepatitis B and C dually infected patients Hepatology 2003 37 568 576 12601355 \n18 Liu CJ Chuang WL Lee CM Peginterferon alfa-2a plus ribavirin for the treatment of dual chronic infection with hepatitis B and C viruses Gastroenterology 2009 136 496 504 19084016 \n19 Sagnelli E Coppola N Pisaturo M HBV superinfection in HCV chronic carriers:a disease that is frequently severe but associated with the eradication of HCV Hepatology 2009 49 1090 1097 19263473 \n20 Gruener NH Jung MC Ulsenheimer A Hepatitis C virus eradication associated with hepatitis B virus superinfection and development of a hepatitis B virus specific T cell response J Hepatol 2002 37 866 869 12445431 \n21 Collins JM Raphael KL Terry C Hepatitis B virus reactivation during successful treatment of hepatitis C virus with sofosbuvir and simeprevir Clin Infect Dis 2015 61 1304 1306 26082511 \n22 Belperio PS Shahoumian TA Mole LA Backus LI Evaluation of hepatitis B reactivation among 62,920 veterans treated with oral hepatitis C antivirals Hepatology 2017 66 27 36 28240789 \n23 Chen G Wang C Chen J Hepatitis B reactivation in hepatitis B and C coinfected patients treated with antiviral agents:a systematic review and meta-analysis Hepatology 2017 66 13 26 28195337 \n24 Mücke VT Mücke MM Peiffer KH No evidence of hepatitis B virus reactivation in patients with resolved infection treated with direct-acting antivirals for hepatitis C in a large real-world cohort Aliment Pharmacol Ther 2017 46 432 439 28627791 \n25 Londoño MC Lens S Mariño Z Hepatitis B reactivation in patients with chronic hepatitis C undergoing anti-viral therapy with an interferon-free regimen Aliment Pharmacol Ther 2017 45 1156 1161 28206681 \n26 Potthoff A Berg T Wedemeyer H HEP-NET B/C Coinfection Study Group Late hepatitis B virus relapse in patients co-infected with hepatitis B virus and hepatitis C virus after antiviral treatment with pegylated interferon-a2b and ribavirin Scand J Gastroenterol 2009 44 1487 1490 19900055 \n27 Accessed March 5 2018 http://www.fda.gov/downloads/Drugs/DrugSafety/UCM523499.pdf \n28 Bersoff-Matcha SJ Cao K Jason M Hepatitis B virus reactivation associated with direct-acting antiviral therapy for chronic hepatitis C virus:a review of cases reported to the U.S. food and drug administration adverse event reporting system Ann Intern Med 2017 166 792 798 28437794 \n29 European Association for the Study of the Liver EASL Recommendations on treatment of hepatitis C 2016 J Hepatol 2017 66 153 194 27667367 \n30 European Association for the Study of the Liver EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection J Hepatol 2017 67 370 398 28427875\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "1108-7471",
"issue": "31(3)",
"journal": "Annals of gastroenterology",
"keywords": "Hepatitis B; direct-acting antivirals; hepatitis C; interferon",
"medline_ta": "Ann Gastroenterol",
"mesh_terms": null,
"nlm_unique_id": "101121847",
"other_id": null,
"pages": "365-370",
"pmc": null,
"pmid": "29720863",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": "16341313;26082511;19669238;27667367;25830779;28195337;24433642;10555612;28240789;11051381;12445431;19263473;7602074;28009018;16496056;18376366;28627791;19900055;28437794;19084016;19175881;14642623;12109669;28206681;16737047;23676440;12601355;21425314;28427875",
"title": "Hepatitis B and C coinfection in a real-life setting: viral interactions and treatment issues.",
"title_normalized": "hepatitis b and c coinfection in a real life setting viral interactions and treatment issues"
} | [
{
"companynumb": "GR-GILEAD-2018-0343301",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RIBAVIRIN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nTramadol is a centrally acting analgesic with opioid and nonopioid properties, which extensively used in the relief of mild to moderate pain. Tramadol poisoning is a common cause of acute pharmaceutical poisoning in Iran. There are a few studies about clinical and laboratory findings related to acute tramadol poisoning. Therefore, the aim of this study was to demonstrate the clinical and laboratory findings in tramadol acute poisoning cases.\n\n\nMETHODS\nThis was a retrospective descriptive study of patients with acute tramadol poisoning who referred to Loghman Hakim Hospital Poison Center during January to April 2012. Data such as patient's age, sex, time of ingestion, ingested dose, cause of poisoning, mean duration of hospitalization, patient's clinical presentations, laboratory findings, therapeutic measures, and patient's outcome have collected in a predesigned checklist.\n\n\nRESULTS\nA total of 144 patients including 111 men (77%) and 33 women (23%) with acute tramadol poisoning was included in this study. The mean ingested dose was 1971.2 mg (100-20000 mg). Seizure (47.91%) was the most frequent clinical symptom. Blood gas on admission showed pH (7.3 ± 0.1), PCO2 (49.7 ± 8.6 mmHg) and HCO3 (-) (24.1 ± 3.8 mEq/L), indicating pure acute respiratory acidosis may be occurred in tramadol-intoxicated patients. There were significant differences between tramadol-intoxicated cases with and without a seizure with regard to the time interval between ingestion and admission on hospital, ingested dose and PCO2.\n\n\nCONCLUSIONS\nSeizure and rise of PCO2 were the most findings in this study.",
"affiliations": "Department of Toxicology and Pharmacology, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran.;Legal Medicine Research Center, Legal Medicine Organization, Tehran, Iran.;Excellent Center of Clinical Toxicology, Toxicology Research Center, Department of Clinical Toxicology, Loghman Hakim Hospital, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.",
"authors": "Rahimi|Hamid Reza|HR|;Soltaninejad|Kambiz|K|;Shadnia|Shahin|S|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": null,
"fulltext": "\n==== Front\nJ Res Med SciJ Res Med SciJRMSJournal of Research in Medical Sciences : The Official Journal of Isfahan University of Medical Sciences1735-19951735-7136Medknow Publications & Media Pvt Ltd India JRMS-19-855Original ArticleAcute tramadol poisoning and its clinical and laboratory findings Rahimi Hamid Reza Soltaninejad Kambiz 1Shadnia Shahin 2Department of Toxicology and Pharmacology, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran1 Legal Medicine Research Center, Legal Medicine Organization, Tehran, Iran2 Excellent Center of Clinical Toxicology, Toxicology Research Center, Department of Clinical Toxicology, Loghman Hakim Hospital, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, IranAddress for correspondence: Dr. Shahin Shadnia, Department of Clinical Toxicology, Loghman Hakim Hospital Poison Center, Kamali Avenue, South Karegar Street, Tehran - 1333431151, Iran. E-mail: shahin1380@yahoo.com9 2014 19 9 855 859 16 4 2014 08 6 2014 11 9 2014 Copyright: © Journal of Research in Medical Sciences2014This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background:\nTramadol is a centrally acting analgesic with opioid and nonopioid properties, which extensively used in the relief of mild to moderate pain. Tramadol poisoning is a common cause of acute pharmaceutical poisoning in Iran. There are a few studies about clinical and laboratory findings related to acute tramadol poisoning. Therefore, the aim of this study was to demonstrate the clinical and laboratory findings in tramadol acute poisoning cases.\n\nMaterials and Methods:\nThis was a retrospective descriptive study of patients with acute tramadol poisoning who referred to Loghman Hakim Hospital Poison Center during January to April 2012. Data such as patient's age, sex, time of ingestion, ingested dose, cause of poisoning, mean duration of hospitalization, patient's clinical presentations, laboratory findings, therapeutic measures, and patient's outcome have collected in a predesigned checklist.\n\nResults:\nA total of 144 patients including 111 men (77%) and 33 women (23%) with acute tramadol poisoning was included in this study. The mean ingested dose was 1971.2 mg (100-20000 mg). Seizure (47.91%) was the most frequent clinical symptom. Blood gas on admission showed pH (7.3 ± 0.1), PCO2 (49.7 ± 8.6 mmHg) and HCO3− (24.1 ± 3.8 mEq/L), indicating pure acute respiratory acidosis may be occurred in tramadol-intoxicated patients. There were significant differences between tramadol-intoxicated cases with and without a seizure with regard to the time interval between ingestion and admission on hospital, ingested dose and PCO2.\n\nConclusion:\nSeizure and rise of PCO2 were the most findings in this study.\n\nClinical manifestationslaboratorypoisoningseizuretramadol\n==== Body\nINTRODUCTION\nTramadol is a synthetic, centrally acting analgesic with opioid and nonopioid properties.[12] Tramadol has low affinity for μ- and κ-opioid receptors and inhibits the reuptake of both nor-epinephrine and serotonin (5-hydroxytryptamine) neurotransmitters.[2] It stimulates the dopamine (D2) receptors and also inhibits the gamma amino butyric acid release in central nervous system.[34] Furthermore, it has some N-methyl-D-aspartate antagonistic properties.[56]\n\nIt is available as parenteral and oral pharmaceutical dosage forms. Common therapeutic doses of tramadol are 50 mg orally and 100 mg with parenteral and rectal route of administration up to 400 mg/day.[27]\n\nTramadol has been included in Iran National Drug List since 2003.[8] Recently, tramadol abuse, misuse, and overdose have been increased in Iran.[91011] The main adverse drug reactions of tramadol are nausea, dizziness, somnolence, drowsiness, increased sweating, vomiting, and dry mouth.[1213] Seizure and apnea are the most important life-threatening clinical presentations of tramadol in therapeutic and toxic doses.[91114] Liver and kidney dysfunctions have been reported during tramadol chronic use.[15] From this view, evaluation of laboratory findings including plasma electrolytes, kidney and liver function tests, and blood gas analysis have a critical role for patient monitoring.\n\nAs there are few studies about laboratory findings in tramadol acute poisoning, we evaluated the clinical and laboratory findings in acute tramadol-intoxicated cases and their role in the prediction of seizure.\n\nMETHODS\nThis was a retrospective study on patients with acute tramadol poisoning who referred to Loghman Hakim Hospital Poison Center, Tehran, Iran from January to April 2012. The exclusion criteria were co-ingestion, intoxication with unknown dose of tramadol, uncertainty about time of tramadol ingestion, onset of a seizure before admission on hospital, the past medical history of epilepsy and history of drug/substance abuse.\n\nData such as patients’ age, sex, time of ingestion, ingested dose, cause of intoxication, respiratory rate, pulse rate, systolic and diastolic blood pressure, temperature, coma grade scale on admission time, and therapeutic interventions and patients’ outcome were extracted from the medical records. Laboratory findings including blood sugar, blood urea nitrogen (BUN), creatinin (Cr), sodium (Na+), potassium (K+), liver function tests, cell blood count, and blood gas on admission time were retrieved from patients’ medical records.\n\nStatistical analyses\nThe data were expressed as mean ± standard deviation/standard error (SE) for continuous or discrete variables and as frequency and percentage for categorical variables. Chi-square test was used for statistical comparison of qualitative variables. We used the Student's t-test and Mann–Whitney U-test for statistical analyses of continuous variables with and without normal distribution, respectively. P =0.05 or less were considered statistically significant. Linear correlations between variables were assessed by Spearman and expressed as the Spearman correlation coefficient. Furthermore, we used binary logistic regression analysis to determine the predictor variables. We used SPSS software (version 13, SPSS Inc., Chicago, IL, USA).\n\nRESULTS\nA total of 144 patients including 111 men (77%) and 33 (23%) women with the mean age of 23.7 ± 6.9 (range = 15-57) years old included in this study. The average time between ingestion and admission on hospital (mean ± SE) was 292.2 ± 30 min (range = 30-3600 min). Mean duration of hospitalization was 17.9 ± 10.6 h (range = 3.6-80 h). In all of the cases, the route of exposure was oral, and the most drug dosage form was tablet (n = 142) and then capsule (n = 2). The mean ingested dose (mean ± SE) was 1971.2 ± 233.4 mg (range = 100-20000 mg). In most of the cases (n = 99, 68.8%) the cause of intoxication was suicide and then abuse (n = 45, 31.2%) [Table 1]. There was no mortality among the patients.\n\nTable 1 Demographic findings in tramadol-intoxicated patients\n\nMajor cases had stable vital signs on admission and the related data are summarized in Table 2. 128 (88.9%) of patients were conscious, and 16 of them had a decreased level of consciousness. Seizure (47.9%), nausea (29.9%), vomiting (22.2%), drowsiness (20.1%), dizziness (18.1%), lethargy (6.3%), apnea (5.6%), agitation (4.2%), headache (1.4%), blurred vision (1.4%), ataxia (0.7%), anxiety (0.7%), sweating (0.7%), and nystagmus (0.7%) were the most clinical findings in tramadol-intoxicated patients [Table 2]. Laboratory findings on admission time in the intoxicated patients have been summarized in Table 3.\n\nTable 2 Clinical findings in tramadol-intoxicated patients on admission time\n\nTable 3 Laboratory findings in tramadol-intoxicated patients on admission time\n\nWe divided the cases with regard to occurrence of seizure during hospitalization. The results showed that there were significant differences between cases with seizure and cases without seizure according to time interval between tramadol ingestion and hospital admission (TIBTIHA) (mean ± SE) (330.3 ± 53.2 vs. 257.3 ± 30.1 min, P = 0.01), ingested dose (mean ± SE) (1395.7 ± 218.3 vs. 2500.7 ± 390.7 mg, P = 0.006), with odds ratio 2.7 (1.03-7.09, 95% confidence interval [CI]), dizziness (3 cases vs. 23 cases, P = <0.0001), with odds ratio 0.1 (0.29-0.36, 95% CI), PCO2 (51.2 ± 8.5 vs. 48.4 ± 8.6 mmHg, P = 0.03), with odds ratio 0.58 (0.27-1.24, 95% CI), and total bilirubin (0.5 ± 0.2 vs. 0.7 ± 0.4 mg/dL, P = 0.002). There was a correlation between ingested dose (r = −0.2, P = 0.006), PaCO2 (r = 0.2, P = 0.03), TIBTIHA (r = 0.2, P = 0.01), total bilirubin (r = −0.3, P = 0.002), dizziness (r = −0.3, P = 0.000), and seizure.\n\nDISCUSSION\nTramadol abuse and overdose is one of the most frequent health problems in Iran and worldwide.[9101116] In this study, we report clinical and paraclinical findings in 144 cases with pure tramadol poisoning who referred to a referral-poisoning center in Tehran, Iran. Young male adults were the major patients in our study. This result is in accordance with previous studies.[1011] Furthermore, the results indicated that oral route is the most common route of exposure, which is similar with the findings of our previous studies.[910]\n\nSeizure was the most common symptom among tramadol-intoxicated cases in this study. This result is in concordance with previous studies too.[9101718] Jovanovic-Cupic et al. reported higher seizure frequency (54.4%) in their study.[14] The frequency of other clinical manifestations including lethargy, coma, nausea, vomiting, agitation, and respiratory depression in our study were different with previous studies.[1619] Tramadol is metabolized by cytochrome P450 (CYP450) enzymes (mainly 2D6 isoenzyme) to its active metabolites M1 (O-desmethyl tramadol), M2 (N-desmethyl tramadol), M3 (N, N-didesmethyl tramadol), M4 (O, N, N-tridesmethyl tramadol), and M5 (O, N-didesmethyl tramadol). M1 metabolite has more affinity (200 times) for the μ-opioid receptors and also it has more inhibitory effect on biogenic amine reuptake than that of parent drug molecule and may be responsible for tramadol induce analgesia or seizure in intoxicated patients. In this regard, genetic polymorphism in humans may affect the tramadol metabolism and its peak blood concentration resulting to a different frequency of tramadol adverse effects or clinical presentations during therapeutic doses or intoxication.[2021]\n\nAlthough the increasing of liver function tests, serum BUN and Cr due to liver and kidney damage have been demonstrated in chronic administration of tramadol in experimental model,[15] but in our study due to acute onset of toxicity we did not observe any increase in liver function tests, BUN and Cr and this is in concordance of the previous study.[11]\n\nRhabdomyolysis and rise of creatine phosphokinase (CPK) have been reported as a rare and serious complication in tramadol intoxication in the previous studies, which was observed in our study too. Although in the previous studies, prolong immobilization and multiple seizures have been described as one of the reasons for the rise of CPK and rhabdomyolysis,[2223] but in our study there was no significant difference in level of CPK in the tramadol-intoxicated patients with seizure in comparison to cases without seizure.\n\nLe Berre et al., reported tramadol induced hyponatremia which described as a result of inappropriate antidiuretic hormone secretion.[24] In this study, the level of Na, and K was within the normal range.\n\nThe PCO2 level was above normal range which could be attributed to tramadol-induced respiratory depression, which has been reported previously.[25]\n\nIn this study, the mean of ingested dose in the seizure group was less than those cases without seizure which is in contrasts with the result of the previous study.[26] One of the explanations is the difference between two groups with regard to TIBTIHA, which was significantly longer in seizure group. Furthermore, as mentioned previously, the other reason could be the genetic polymorphism in patients.\n\nThe main limitation of this study is its retrospective design, which should be considered in the interpretation of the results. With this regard, prospective study could be considered.\n\nCONCLUSION\nSeizure is the most clinical manifestation in tramadol poisoning. There were significant differences between seizure and nonseizure cases with regard to TIBTIHA, ingested dose, and PCO2. Furthermore, we showed poor correlation between tramadol ingested dose, TIBTIHA, PCO2, and seizure in tramadol-intoxicated cases.\n\nAUTHOR'S CONTRIBUTION\nHRR involving in the data collection and data analysis. SS and KSN involving in the study design, conducting of the study and data analysis. The manuscript was drafted by HRR and SS and KSN reviewed the manuscript. Finally, all the authors read and approved the final version of the manuscript.\n\nACKNOWLEDGMENT\nOur thanks are due to Mr. Atari, who works at archive center of Loghman Hakim hospital for his corporations.\n\nSource of Support: Nil\n\nConflict of Interest: None declared.\n==== Refs\nREFERENCES\n1 Shipton EA Tramadol – Present and future Anaesth Intensive Care 2000 28 363 74 10969362 \n2 Grond S Sablotzki A Clinical pharmacology of tramadol Clin Pharmacokinet 2004 43 879 923 15509185 \n3 Nakamura A Narita M Miyoshi K Shindo K Okutsu D Suzuki M Changes in the rewarding effects induced by tramadol and its active metabolite M1 after sciatic nerve injury in mice Psychopharmacology (Berl) 2008 200 307 16 18758760 \n4 Rehni AK Singh I Kumar M Tramadol-induced seizurogenic effect: A possible role of opioid-dependent gamma-aminobutyric acid inhibitory pathway Basic Clin Pharmacol Toxicol 2008 103 262 6 18684224 \n5 Nagakannan P Shivasharan BD Thippeswamy BS Veerapur VP Effect of tramadol on behavioral alterations and lipid peroxidation after transient forebrain ischemia in rats Toxicol Mech Methods 2012 22 674 8 22871232 \n6 Chaparro LE Wiffen PJ Moore RA Gilron I Combination pharmacotherapy for the treatment of neuropathic pain in adults Cochrane Database Syst Rev 2012 7 CD008943 22786518 \n7 Scott LJ Perry CM Tramadol: A review of its use in perioperative pain Drugs 2000 60 139 76 10929933 \n8 Gholami K Shalviri G Zarbakhsh A Daryabari N Yousefian S New guideline for tramadol usage following adverse drug reactions reported to the Iranian Pharmacovigilance Center Pharmacoepidemiol Drug Saf 2007 16 229 37 17063533 \n9 Shadnia S Soltaninejad K Heydari K Sasanian G Abdollahi M Tramadol intoxication: A review of 114 cases Hum Exp Toxicol 2008 27 201 5 18650251 \n10 Shadnia S Brent J Mousavi-Fatemi K Hafezi P Soltaninejad K Recurrent seizures in tramadol intoxication: Implications for therapy based on 100 patients Basic Clin Pharmacol Toxicol 2012 111 133 6 22364547 \n11 Hassanian-Moghaddam H Farajidana H Sarjami S Owliaey H Tramadol-induced apnea Am J Emerg Med 2013 31 26 31 22809771 \n12 Götrick B Tobin G The xerogenic potency and mechanism of action of tramadol inhibition of salivary secretion in rats Arch Oral Biol 2004 49 969 73 15485638 \n13 Rawal N Macquaire V Catalá E Berti M Costa R Wietlisbach M Tramadol/paracetamol combination tablet for postoperative pain following ambulatory hand surgery: A double-blind, double-dummy, randomized, parallel-group trial J Pain Res 2011 4 103 10 21559356 \n14 Jovanovic-Cupic V Martinovic Z Nesic N Seizures associated with intoxication and abuse of tramadol Clin Toxicol (Phila) 2006 44 143 6 16615669 \n15 Atici S Cinel I Cinel L Doruk N Eskandari G Oral U Liver and kidney toxicity in chronic use of opioids: An experimental long term treatment model J Biosci 2005 30 245 52 15886461 \n16 Marquardt KA Alsop JA Albertson TE Tramadol exposures reported to statewide poison control system Ann Pharmacother 2005 39 1039 44 15870139 \n17 Eizadi-Mood N Ozcan D Sabzghabaee AM Mirmoghtadaee P Hedaiaty M Does naloxone prevent seizure in tramadol intoxicated patients? Int J Prev Med 2014 5 302 7 24829714 \n18 Eizadi-Mood N Safdari A Yaraghi A Sabzghabaee AM Clinical signs, hospitalization duration and outcome of tramadol intoxication JIMS 2010 28 1187 93 \n19 Spiller HA Gorman SE Villalobos D Benson BE Ruskosky DR Stancavage MM Prospective multicenter evaluation of tramadol exposure J Toxicol Clin Toxicol 1997 35 361 4 9204095 \n20 Raffa RB Basic pharmacology relevant to drug abuse assessment: Tramadol as example J Clin Pharm Ther 2008 33 101 8 18315774 \n21 Raffa RB Stone DJ Jr Unexceptional seizure potential of tramadol or its enantiomers or metabolites in mice J Pharmacol Exp Ther 2008 325 500 6 18292293 \n22 Afshari R Ghooshkhanehee H Tramadol overdose induced seizure, dramatic rise of CPK and acute renal failure J Pak Med Assoc 2009 59 178 19288949 \n23 Yousef Khan F Yousef H Errayes M Tramadol toxicity-induced rhabdomyolysis J Emerg Trauma Shock 2010 3 421 2 21063575 \n24 Le Berre JP Desramé J Lecoules S Coutant G Béchade D Algayres JP Hyponatremia due to tramadol Rev Med Interne 2007 28 888 9 17624638 \n25 Tantry TP Kadam D Shetty P Adappa KK Tramadol-induced respiratory depression in a morbidly obese patient with normal renal function Indian J Anaesth 2011 55 318 20 21808420 \n26 Taghaddosinejad F Mehrpour O Afshari R Seghatoleslami A Abdollahi M Dart RC Factors related to seizure in tramadol poisoning and its blood concentration J Med Toxicol 2011 7 183 8 21735309\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "1735-1995",
"issue": "19(9)",
"journal": "Journal of research in medical sciences : the official journal of Isfahan University of Medical Sciences",
"keywords": "Clinical manifestations; laboratory; poisoning; seizure; tramadol",
"medline_ta": "J Res Med Sci",
"mesh_terms": null,
"nlm_unique_id": "101235599",
"other_id": null,
"pages": "855-9",
"pmc": null,
"pmid": "25535500",
"pubdate": "2014-09",
"publication_types": "D016428:Journal Article",
"references": "24829714;18315774;18292293;15870139;10969362;15886461;21808420;10929933;21735309;15509185;17624638;17063533;21063575;9204095;18650251;22786518;16615669;22809771;22364547;15485638;22871232;18684224;21559356;18758760;19288949",
"title": "Acute tramadol poisoning and its clinical and laboratory findings.",
"title_normalized": "acute tramadol poisoning and its clinical and laboratory findings"
} | [
{
"companynumb": "IR-JNJFOC-20141212816",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRAMADOL HYDROCHLORIDE"
},
"drugadditional": null... |
{
"abstract": "Pseudomyogenic hemangioendothelioma (PMH) is a recently described, indolent vascular tumor that usually presents in the distal extremities. PMH typically has a multi-focal presentation and can involve several tissue planes including the dermis, subcutis, muscle, and bone. This soft tissue tumor predominantly affects men between 20 and 50 years of age. PMH tumors typically are resected but frequently recur locally; thus, more efficacious treatment options are needed. Herein, we report two cases of patients with PMH who were treated with systemic therapy. To the best of our knowledge, our report is the first to describe a response of PMH either to gemcitabine/taxane cytotoxic chemotherapy or to a mammalian target of rapamycin inhibitor. In the first case, a 45-year-old man with PMH of the right ilium was treated with gemcitabine plus docetaxel. Although chemotherapy was ultimately halted owing to gemcitabine-induced pulmonary toxicity, positron emission tomography-computer tomography scans taken after three cycles of gemcitabine plus docetaxel illustrated a noticeable response to the regimen. In the second case, a 22-year-old man with PMH of the right distal femur and metastases in the left ilium showed no response to gemcitabine plus docetaxel therapy, but underwent surgical resection after cisplatin and doxorubicin resulted in stable disease. DNA sequencing of his tumor revealed the presence of a tuberous sclerosis 1 (TSC1) mutation, so daily everolimus, which inhibits mammalian target of rapamycin, was started. Two months after beginning everolimus, the patient underwent magnetic resonance imaging of the pelvis, which revealed mild shrinkage of PMH metastases in the left iliac bone. Despite the apparent heterogeneity of response to gemcitabine/taxane chemotherapy in our two patients, these two cases indicate that gemcitabine/taxane and mammalian target of rapamycin inhibitor may serve as systemic treatment options for PMH and warrant further investigation.",
"affiliations": "Department of Sarcoma Medical Oncology, Unit 0450, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030 USA.;Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX USA.;Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX USA.;Department of Sarcoma Medical Oncology, Unit 0450, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030 USA.;Department of Sarcoma Medical Oncology, Unit 0450, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030 USA.;Department of Sarcoma Medical Oncology, Unit 0450, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030 USA.;Department of Sarcoma Medical Oncology, Unit 0450, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030 USA.",
"authors": "Joseph|Jason|J|;Wang|Wei-Lien|WL|;Patnana|Madhavi|M|;Ramesh|Naveen|N|;Benjamin|Robert|R|;Patel|Shreyaskumar|S|;Ravi|Vinod|V|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s13569-015-0037-8",
"fulltext": "\n==== Front\nClin Sarcoma ResClin Sarcoma ResClinical Sarcoma Research2045-3329BioMed Central London 3710.1186/s13569-015-0037-8Case ReportCytotoxic and targeted therapy for treatment of pseudomyogenic hemangioendothelioma Joseph Jason jason.m.joseph@uth.tmc.edu Wang Wei-lien wlwang@mdanderson.org Patnana Madhavi madhavi.patnana@mdanderson.org Ramesh Naveen nramesh@mdanderson.org Benjamin Robert rbenjamin@mdanderson.org Patel Shreyaskumar spatel@mdanderson.org Ravi Vinod 713-792-3626vravi@mdanderson.org Department of Sarcoma Medical Oncology, Unit 0450, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030 USA Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX USA Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX USA 19 10 2015 19 10 2015 2015 5 223 7 2015 30 9 2015 © Joseph et al. 2015\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Pseudomyogenic hemangioendothelioma (PMH) is a recently described, indolent vascular tumor that usually presents in the distal extremities. PMH typically has a multi-focal presentation and can involve several tissue planes including the dermis, subcutis, muscle, and bone. This soft tissue tumor predominantly affects men between 20 and 50 years of age. PMH tumors typically are resected but frequently recur locally; thus, more efficacious treatment options are needed. Herein, we report two cases of patients with PMH who were treated with systemic therapy. To the best of our knowledge, our report is the first to describe a response of PMH either to gemcitabine/taxane cytotoxic chemotherapy or to a mammalian target of rapamycin inhibitor. In the first case, a 45-year-old man with PMH of the right ilium was treated with gemcitabine plus docetaxel. Although chemotherapy was ultimately halted owing to gemcitabine-induced pulmonary toxicity, positron emission tomography-computer tomography scans taken after three cycles of gemcitabine plus docetaxel illustrated a noticeable response to the regimen. In the second case, a 22-year-old man with PMH of the right distal femur and metastases in the left ilium showed no response to gemcitabine plus docetaxel therapy, but underwent surgical resection after cisplatin and doxorubicin resulted in stable disease. DNA sequencing of his tumor revealed the presence of a tuberous sclerosis 1 (TSC1) mutation, so daily everolimus, which inhibits mammalian target of rapamycin, was started. Two months after beginning everolimus, the patient underwent magnetic resonance imaging of the pelvis, which revealed mild shrinkage of PMH metastases in the left iliac bone. Despite the apparent heterogeneity of response to gemcitabine/taxane chemotherapy in our two patients, these two cases indicate that gemcitabine/taxane and mammalian target of rapamycin inhibitor may serve as systemic treatment options for PMH and warrant further investigation.\n\nKeywords\nPseudomyogenicHemangioendotheliomaSoft tissue tumorSarcomamTOR inhibitorissue-copyright-statement© The Author(s) 2015\n==== Body\nBackground\nPseudomyogenic hemangioendothelioma (PMH) is a rare indolent vascular tumor that typically presents in the distal extremities and may present in multiple tissue planes, including the dermis, subcutis, muscle, and bone [1, 2]. Over the last three decades, PMH has been determined to be the same pathological entity as epithelioid sarcoma-like hemangioendothelioma and fibroma-like variant of epithelioid sarcoma [2–5]. The tumor has a 4.6:1 male predominance and typically occurs in men between 20 and 50 years of age. Histopathologically, PMH resembles a myogenic neoplasm with a striking rhabdomyoblast appearance and spindle cell morphology. However, PMH lacks true muscle markers such as desmin and has an immunophenotype and highly membranous pattern in line with endothelial differentiation [2, 5]. PMH has recently been characterized molecularly to have a balanced t(7;19) translocation resulting in a SERPINE1-FOSB fusion [6]. PMH does not typically transform into high-grade disease or metastasize. However, PMH frequently recurs locally after excision [2].\n\nWhile much has been published concerning the characterization of PMH, much remains to be learned about the natural history of the disease and efficacy of treatment. In the majority of PMH cases, excision is the management modality of choice, but over a third of patients experience local recurrence or new nodules in adjacent soft tissue during follow up [2]. Previous accounts demonstrate an indolent course of disease and most studies have shown that the disease does not progress before or after therapy. In a large case series (n = 50), only one patient died of PMH. Nevertheless, since PMH presents as multifocal tumors in 70 % of patients, systemic therapy options are acutely needed [2].\n\nTo the best of our knowledge, only two published reports [5, 7] in the literature discuss a response by PMH to therapeutic options other than excision.\n\nHere, we report two cases of patients who had PMH that responded to systemic therapy: one patient exhibited a noticeable response to gemcitabine plus docetaxel and one patient demonstrated a response to everolimus, a mammalian target of rapamycin (mTOR) inhibitor.\n\nCase presentation\nCase 1\nIn October 2010, a 45-year-old man presented to his local physician with pain in his right groin, which the patient attributed to a muscle strain from playing soccer. As his pain worsened, the patient went to an orthopedic surgeon who obtained a magnetic resonance imaging (MRI) study that showed a mass within the right anterior ilium. In December 2010, the patient was examined by physicians in the Department of Orthopaedic Oncology at The University of Texas MD Anderson Cancer Center, and a biopsy of the right ilium mass revealed a malignant epithelioid and spindle cell neoplasm most consistent with PMH. The patient was treated with two cycles of intra-arterial cisplatin (120 mg/m2) administered every 3 weeks. Due to hearing loss, administration was modified to intravenously with a slow infusion rate over 24 h for the next two cycles. Restaging positron emission tomography-computed tomography (PET-CT) studies revealed a minor tumor response to cisplatin.\n\nBecause the patient’s hearing loss worsened, therapy was switched to a combination of gemcitabine (900 mg/m2) and docetaxel (100 mg/m2) administered in 3 week cycles, beginning 3 weeks after cessation of cisplatin. Restaging PET-CT studies performed after completion of the third cycle revealed that the PMH had significantly responded to gemcitabine plus docetaxel (Fig. 1). Unfortunately, despite this significant improvement, there was evidence of gemcitabine-induced pulmonary toxicity. Therefore, cytotoxic chemotherapy was halted, and a tapering dose of steroids was given to the patient to treat the pulmonary toxicity. The patient’s edema was managed with furosemide and amiloride.Fig. 1 Imaging studies for 45-year-old patient (“Case 1”) with pseudomyogenic hemangioendothelioma. a Baseline fat saturated T1-weighted axial magnetic resonance image with intravenous contrast enhancement of the pelvis demonstrates multiple enhancing tumor foci in the right iliac bone (white arrow). b Positron emission tomography-computed tomography (PET-CT) fusion image through the pelvis demonstrates diffuse metabolic activity in the right anterior iliac bone (disease in the right posterior iliac bone at the level of the sacroiliac joint was also present but is not shown). This image was obtained 1 month before the patient began gemcitabine/docetaxel. c PET-CT fusion image through the pelvis after three cycles of gemcitabine/docetaxel demonstrates a significant metabolic response\n\n\n\nDuring a follow-up visit 3 months after cessation of gemcitabine and docetaxel, the patient’s PET-CT scans showed mild progression of disease in the right iliac bone with enlarging lucencies. This finding suggested that the PMH progressed in the absence of gemcitabine and docetaxel treatment. Therapy with weekly paclitaxel (80 mg/m2) was therefore started. However, after 4 months of paclitaxel, therapy was discontinued because the patient experienced hearing loss, rhinitis, and neuropathy characterized by tingling of the hands and feet. Restaging studies performed 16 months following cessation of cytotoxic chemotherapy revealed stable disease.\n\nThe tumor response to the combination of gemcitabine and a taxane was clearly demonstrated on the PET-CT scans. PMH progressed once chemotherapy was stopped, and taxane treatment led to disease stability, suggesting that gemcitabine plus taxane could be an effective treatment for PMH.\n\nCase 2\nIn June 2011, a 22-year-old man presented to his local physician with a painless, dime-shaped nodule in his right lateral thigh. Approximately 1 year later, the mass began to enlarge and induce pain, and the patient saw a dermatologist who performed a punch biopsy that was inconclusive. In September 2012, an excisional biopsy was performed at MD Anderson Cancer Center, and the pathologist concluded that the mass was consistent with PMH originating from the right femur. Baseline imaging included MRI of the right thigh which showed multiple enhancing lesions in the distal right femur and lateral soft tissues, extending for a length of 6.8 cm and centered approximately 7 cm proximal to the articular surface of the lateral femoral condyle. A baseline PET-CT study revealed a hypermetabolic mass in the right distal femur (standardized uptake value, maximum of 15.2) and a 1.3 cm left acetabular lytic lesion (standardized uptake value, maximum of 7.9), suspicious for metastatic disease (Fig. 2). After the patient was evaluated by physicians in the Department of Sarcoma Medical Oncology at MD Anderson, therapy with gemcitabine (900 mg/m2) and docetaxel (75 mg/m2) was started and given in 3 week cycles. The cytotoxic chemotherapy was well tolerated. However, imaging showed no evidence of tumor response after two cycles, and treatment was halted.Fig. 2 Baseline magnetic resonance imaging (MRI) and positron emission tomography-computed tomography (PET-CT) studies for a 22-year-old man (“Case 2”) with pseudomyogenic hemangioendothelioma. a Baseline contrast-enhanced, fat-saturated T1-weighted axial MR image of the right thigh demonstrates multifocal enhancing lesions in the distal femoral metadiaphysis (short white arrow) and vastus intermedius muscle and subcutaneous fat. b PET-CT fusion image through the distal femurs demonstrates corresponding hypermetabolic activity. Restaging examinations after two cycles of gemcitabine and docetaxel (not shown) did not demonstrate any significant response\n\n\n\nTherapy was then changed to doxorubicin (90 mg/m2 as a continuous infusion over 72 h) and cisplatin (120 mg/m2 as an intravenous infusion over 4 h), but the patient had mucositis, tinnitus, neutropenic fever, and ototoxicity during the first cycle. The cisplatin dose was reduced to 100 mg/m2 as a slow infusion over 24 h to prevent ototoxicity and doxorubicin was changed to bolus doxorubicin with dexrazoxane (90 mg/m2) in a 3 week cycle to reduce mucositis caused by continuous intravenous infusion of doxorubicin. The patient tolerated the regimen better during the second cycle, and the PMH remained stable.\n\nIn July 2013, the patient underwent surgical resection to remove the right distal femoral lesion. DNA sequencing of the tumor revealed the presence of a tuberous sclerosis 1 (TSC1):c.1760A >Gp.K587R mutation. Owing to the TSC1 mutation, therapy with everolimus (10 mg/day) was started. Two months later, the patient underwent MRI of the pelvis, which revealed mild interval healing of the small intramedullary metastases in the supra-acetabular region of the left iliac bone (Fig. 3).Fig. 3 Imaging studies obtained during treatment for a 22-year-old man (“Case 2”) with pseudomyogenic hemangioendothelioma. a Fat-saturated T1-weighted axial magnetic resonance image with intravenous contrast enhancement of the pelvis demonstrates a solitary enhancing tumor focus in the supra-acetabular region of the left iliac bone (white arrow), before everolimus treatment. b Positron emission tomography-computed tomography fusion image through the pelvis demonstrates corresponding metabolic activity. This image was obtained before the patient began everolimus treatment. c Fat-saturated T1-weighted axial MR image with intravenous contrast enhancement of the pelvis obtained after 2 months of everolimus demonstrates partial response of the solitary enhancing tumor focus in the supra-acetabular region of the left iliac bone\n\n\n\nRestaging MRI studies of the pelvis were performed 5 months after the start of everolimus treatment and revealed generally stable disease and no evidence of recurrent disease in the thigh. Owing to the stability of the disease, the patient decided to cease everolimus therapy and pursue cryotherapy. Overall, the mTOR inhibitor provided a noticeable response in the tumor, which had not responded to doxorubicin and cisplatin. Thus, targeted therapy could serve as a viable treatment option for PMH.\n\nDiscussion\nTo the best of our knowledge, only two previous descriptions of outcomes from PMH therapy other than resection have been published [5, 7]. The first report described a 36-year-old man with multiple lesions in his right lower leg treated with isolated limb perfusion (melphalan and tumor necrosis factor alpha) followed by four cycles of ifosfamide and doxorubicin. The treatment did not elicit significant shrinkage of the tumor, but the lesion remained stable after 9 months of follow-up [5]. The second study reported a response of PMH to metronomic oral cyclophosphamide and prednisolone. The patient’s lesion decreased in size after 10 months of therapy before the patient became non-compliant; however, the report did not include any quantifiable data or imaging concerning lesion size and progression [7].\n\nA review of all published literature on pseudomyogenic hemangioendothelioma was performed to summarize major findings of this newly characterized soft tissue tumor. Of the 63 total reported cases, 78 % of patients were males. PMH presented in the extremities in 79 % of cases and was multifocal at diagnosis in over two-thirds of patients. 90 % of cases utilized excision as the treatment modality of choice (Table 1).Table 1 Reported cases of pseudomyogenic hemangioendothelioma\n\nReferences\tCases (N)\tSex\tTumor location\tMultifocality at diagnosis\tManagement\t\nSheng [1]\t1\tMale: 100 % (1of 1)\nFemale: 0 % (0 of 1)\tExtremity: 100 % (1 of 1)\t100 % (1 of 1)\tExcision: 100 % (1 of 1)\t\nHornick and Fletcher [2]\t50\tMale: 82 % (41 of 50)\nFemale: 18 % (9 of 50)\tExtremity: 78 % (39 of 50)\nTrunk: 18 % (9 of 50)\nHead and neck: 4 % (2 of 50)\t66 % (33 of 50)\tExcision: 92 % (46 of 50)\nPost-operative radiation: 16 % (8 of 50)\nChemotherapy: 12 % (6 of 50)\t\nAmary et al. [5]\t5 (1 case included in Hornick was excluded)a\n\tMale: 50 % (2 of 4)\nFemale: 50 % (2 of 4)\tExtremity: 100 % (4 of 4)\t75 % (3 of 4)\tExcision: 75 % (3of 4)\nChemotherapy: 25 % (1 of 4)\t\nStuart et al. [7]\t1\tMale: 100 % (1 of 1)\nFemale: 0 % (0 of 1)\tExtremity: 100 % (1 of 1)\t100 % (1 of 1)\tChemotherapy: 100 % (1 of 1)\t\nSheng and Wang [9]\t1\tMale: 0 % (0 of 1)\nFemale: 100 % (1 of 1)\tExtremity: 100 % (1 of 1)\t100 % (1 of 1)\tExcision: 100 % (1 of 1)\t\nRequena et al. [10]\t2\tMale: 50 % (1 of 2)\nFemale: 50 % (1 of 2)\tExtremity: 50 % (1 of 2)\nHead and neck: 50 % (1 of 2)\t100 % (2 of 2)\tExcision: 100 % (2 of 2)\t\nRighi [11]\t2\tMale: 50 % (1 of 2)\nFemale: 50 % (1 of 2)\tExtremity: 100 % (2 of 2)\t100 % (2 of 2)\tExcision: 100 % (2 of 2)\t\nKarakasli et al. [12]\t1\tMale: 100 % (1 of 1)\tExtremity: 100 % (1 of 1)\t0 % (0 of 1)\tExcision: 100 % (1 of 1)\t\nMcGinity [13]\t1\tMale: 100 % (1 of 1)\nFemale: 0 % (0 of 1)\tExtremity: 0 % (0 of 1)\nTrunk: 100 % (1 of 1)\t0 % (0 of 1)\tExcision: 100 % (1 of 1)\t\nTotal\t63\tMale: 78 % (49 of 63)\nFemale: 22 % (14 of 63)\tExtremity: 79 % (50 of 63)\nTrunk: 16 % (10 of 63)\nHead and neck: 5 % (3 of 63)\tMultifocality at diagnosis: 68 % (43 of 63)\tExcision: 90 % (57 of 63)\nPost-op radiation: 13 % (8 of 63)\nChemotherapy: 13 % (8 of 63)\t\n\naPatient 5 of this report was already accounted for in the series by Hornick et al. [2]\n\n\n\nIn the first of our cases, the patient exhibited a noticeable treatment response to gemcitabine plus docetaxel. As the 3 month follow-up PET-CT scans clearly indicate, a significant tumor response was achieved following therapy (Fig. 1). The progression of the tumor 3 months after cessation of chemotherapy suggests that the tumor response directly resulted from the gemcitabine and docetaxel therapy. Furthermore, the resumption of a taxane led to disease stability, suggesting that gemcitabine plus a taxane could be an effective treatment for PMH.\n\nUnlike patient 1, patient 2’s tumor did not respond to gemcitabine plus docetaxel but ultimately showed stability following treatment with cisplatin and doxorubicin. The differing outcomes following gemcitabine plus docetaxel treatment in the two cases reflect PMH’s heterogeneity of response to cytotoxic chemotherapy. The discovery of a TSC1 mutation in patient 2’s tumor prompted the use of an mTOR inhibitor. An mTOR inhibitor was selected due to its potential to inhibit aberrant mTOR signaling in perivascular epithelioid cell tumors with similar TSC1 mutations [8]. The mTOR inhibitor used in case 2 provided a noticeable response in the PMH metastases in the supra-acetabular region of the left iliac bone. Thus, systemic therapy targeted to the mutations detected by DNA sequencing could be a promising option for PMH that warrants further investigation.\n\nConclusion\nTo the best of our knowledge, our report is the first to describe a response of PMH either to gemcitabine/taxane chemotherapy or to an mTOR inhibitor. These observations are especially noteworthy because previous treatment options have typically dealt with local excision and a high rate of recurrence or chemotherapeutic approaches which lack a significant response. There is much to be learned about systemic treatment of pseudomyogenic hemagioendothelioma, but these two cases demonstrate two distinct treatment approaches that warrant further investigation.\n\nConsent\nWritten informed consent was obtained from the patients for publication of this case report and any accompanying images. A copy of the written consent is available for review.\n\nAbbreviations\nMRImagnetic resonance imaging\n\nmTORmammalian target of rapamycin\n\nPET-CTpositron emission tomography-computed tomography\n\nPMHpseudomyogenic hemangioendothelioma\n\nTSC1tuberous sclerosis 1\n\nAuthors’ contributions\nJJ compiled all patient data, completed a literature review and wrote the manuscript, VR conceived of the study, participated in its design and coordination, and helped draft the manuscript, RB helped conceive of the study and gave valuable insight while drafting the manuscript, MP aided in choosing and interpreting all PET/CT and MRI images, NR aided in analyzing and interpreting data used in the manuscript, SP helped conceive of the study and gave valuable insight while drafting the manuscript, WW confirmed histopathological diagnosis for both cases. All authors read and approved the final manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Sheng WQ Wang J Primary pseudomyogenic haemangioendothelioma of bone Histopathology 2012 61 6 1219 1224 10.1111/j.1365-2559.2012.04347.x 22963723 \n2. Hornick JL Fletcher CD Pseudomyogenic hemangioendothelioma: a distinctive, often multicentric tumor with indolent behavior Am J Surg Pathol 2011 35 2 190 201 10.1097/PAS.0b013e3181ff0901 21263239 \n3. Billings SD Folpe AL Weiss SW Epithelioid sarcoma-like hemangioendothelioma Am J Surg Pathol 2003 27 1 48 57 10.1097/00000478-200301000-00006 12502927 \n4. Mirra JM Kessler S Bhuta S Eckardt J The fibroma-like variant of epithelioid sarcoma. A fibrohistiocytic/myoid cell lesion often confused with benign and malignant spindle cell tumors Cancer 1992 69 6 1382 1395 10.1002/1097-0142(19920315)69:6<1382::AID-CNCR2820690614>3.0.CO;2-Y 1371711 \n5. Amary MF O’Donnell P Berisha F Tirabosco R Briggs T Pollock R Pseudomyogenic (epithelioid sarcoma-like) hemangioendothelioma: characterization of five cases Skelet Radiol 2013 42 7 947 957 10.1007/s00256-013-1577-8 \n6. Walther C Tayebwa J Lilljebjörn H Magnusson L Nilsson J von Steyern FV Øra I Domanski HA Fioretos T Nord KH Fletcher CD Mertens F A novel SERPINE1-FOSB fusion gene results in transcriptional up-regulation of FOSB in pseudomyogenic haemangioendothelioma J Pathol 2014 232 5 534 540 10.1002/path.4322 24374978 \n7. Stuart LN Gardner JM Lauer SR Monson DK Parker DC Edgar MA Epithelioid sarcoma-like (pseudomyogenic) hemangioendothelioma, clinically mimicking dermatofibroma, diagnosed by skin biopsy in a 30-year-old man J Cutan Pathol 2013 40 10 909 913 24033835 \n8. Wagner AJ Malinowska-Kolodziej I Morgan JA Qin W Fletcher CD Vena N Ligon AH Antonescu CR Ramaiya NH Demetri GD Kwiatkowski DJ Maki RG Clinical activity of mTOR inhibition with sirolimus in malignant perivascular epithelioid cell tumors: targeting the pathogenic activation of mTORC1 in tumors J Clin Oncol 2010 28 5 835 840 10.1200/JCO.2009.25.2981 20048174 \n9. Sheng W Pan Y Wang J Pseudomyogenic hemangioendothelioma: report of an additional case with aggressive clinical course Am J Dermatopathol 2013 35 5 597 600 10.1097/DAD.0b013e31827c8051 23475148 \n10. Requena L Santonja C Martinez-Amo JL Saus C Kutzner H Cutaneous epithelioid sarcomalike (pseudomyogenic) hemangioendothelioma: a little-known low-grade cutaneous vascular neoplasm JAMA Dermatol 2013 149 4 459 465 10.1001/jamadermatol.2013.3190 23715533 \n11. Righi A Gambarotti M Picci P Dei Tos AP Vanel D Primary pseudomyogenic haemangioendothelioma of bone: report of two cases Skelet Radiol 2014 44 5 727 731 10.1007/s00256-014-2024-1 \n12. Karakasli A Karaaslan A Erduran M Capkin S Tuna EB Havitcioglu H Pseudomyogenic (epithelioid sarcoma-like) hemangioendothelioma with bone invasion J Orthop 2014 11 4 197 199 10.1016/j.jor.2014.06.019 25561757 \n13. McGinity M Bartanusz V Dengler B Birnbaum L Henry J Pseudomyogenic hemangioendothelioma (epithelioid sarcoma-like hemangioendothelioma, fibroma-like variant of epithelioid sarcoma) of the thoracic spine Eur Spine J 2013 22 Suppl 3 S506 S511 10.1007/s00586-013-2727-3 23435749\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2045-3329",
"issue": "5()",
"journal": "Clinical sarcoma research",
"keywords": "Hemangioendothelioma; Pseudomyogenic; Sarcoma; Soft tissue tumor; mTOR inhibitor",
"medline_ta": "Clin Sarcoma Res",
"mesh_terms": null,
"nlm_unique_id": "101577890",
"other_id": null,
"pages": "22",
"pmc": null,
"pmid": "26500758",
"pubdate": "2015",
"publication_types": "D002363:Case Reports",
"references": "25300339;22963723;25561757;24374978;24033835;20048174;23475148;23435749;1371711;21263239;12502927;23715533;23381465",
"title": "Cytotoxic and targeted therapy for treatment of pseudomyogenic hemangioendothelioma.",
"title_normalized": "cytotoxic and targeted therapy for treatment of pseudomyogenic hemangioendothelioma"
} | [
{
"companynumb": "US-JNJFOC-20151105444",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional": n... |
{
"abstract": "BACKGROUND\nEndothelial growth factor receptor (EGFR) mutations are an essential driver of personalized therapy for patients with lung cancer and are detected in approximately 15% of Caucasian and 50% of Asian patients. EGFR tyrosine kinase inhibitors have been developed and used for this set of patients. T790M mutation in exon 20 is usually associated with secondary resistance to EGFR tyrosine kinase inhibitors therapy but is also present in treatment-naïve patients. The frequency for baseline T790M mutation varies from 4 to 35% according to the detection method used. Newer techniques have yielded higher rates, but concerns about false-positive results have been raised. Compound mutations account for 4-14% of all EGFR-mutated tumors, with no studies yet to provide a frequency rate for T790M + 19 deletion association due to the small number of cases. However, there are reports that pretreatment T790M + L858R association is significantly more frequent compared to T790M + exon 19 deletion mutations. Diagnostic challenges, current knowledge on the subject, and therapeutic decisions are discussed.\n\n\nMETHODS\nWe present the case of a 43-year-old Hispanic woman, a treatment-naïve patient, with metastasized lung cancer adenocarcinoma harboring a T790M deletion along with the classic 19 mutation. The initial symptoms were monoparesis of her left leg, associated with hyperreflexia, and hypoesthesia. In the absence of third-generation tyrosine kinase inhibitors, a platinum-based therapy was initiated with no response and she died 4 months after diagnosis.\n\n\nCONCLUSIONS\nOsimertinib seems to be a suitable therapy for treatment-naïve patients with sensitizing and resistant compound EGFR mutations. More studies regarding the clinical characteristics of these patients and the appropriate management of this condition are needed to provide the highest standard of care.",
"affiliations": "Hematology-Oncology department, Fundacion Valle del Lili, Carrera 98 No. 18-49, Fundacion Valle del Lili, Cali, Colombia.;Internal Medicine department, Fundacion Valle del Lili, Carrera 98 No. 18-49, Cali, Colombia.;Hematology-Oncology department, Fundacion Valle del Lili, Carrera 98 No. 18-49, Fundacion Valle del Lili, Cali, Colombia.;Human Genetics department, Fundacion Valle del Lili, Carrera 98 No. 18-49, Cali, Colombia.;Pathology department, Fundacion Valle del Lili, Carrera 98 No. 18-49, Cali, Colombia.;Hematology-Oncology department, Fundacion Valle del Lili, Carrera 98 No. 18-49, Fundacion Valle del Lili, Cali, Colombia. harveyangie@yahoo.com.",
"authors": "Falla-Martinez|Juan C|JC|;Espinosa|Daniela|D|;Baena|Juan C|JC|;Rodriguez|Lisa X|LX|;Sua|Luz F|LF|;Zambrano|Angela R|AR|http://orcid.org/0000-0003-0846-8129",
"chemical_list": "D047428:Protein Kinase Inhibitors; C512478:EGFR protein, human; D066246:ErbB Receptors",
"country": "England",
"delete": false,
"doi": "10.1186/s13256-019-2075-y",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 207510.1186/s13256-019-2075-yCase ReportAn endothelial growth factor receptor compound mutation of T790M substitution with exon 19 deletion in a previously untreated patient: a case report Falla-Martinez Juan C. juancfalla@gmail.com 1Espinosa Daniela dani.espinosa816@gmail.com 2Baena Juan C. jenseitsdesgrabes@hotmail.com 1Rodriguez Lisa X. lixiro@gmail.com 3Sua Luz F. lufer24@hotmail.com 4http://orcid.org/0000-0003-0846-8129Zambrano Angela R. +57(2)3319090harveyangie@yahoo.com 11 grid.477264.4Hematology-Oncology department, Fundacion Valle del Lili, Carrera 98 No. 18-49, Fundacion Valle del Lili, Cali, Colombia 2 grid.477264.4Internal Medicine department, Fundacion Valle del Lili, Carrera 98 No. 18-49, Cali, Colombia 3 grid.477264.4Human Genetics department, Fundacion Valle del Lili, Carrera 98 No. 18-49, Cali, Colombia 4 grid.477264.4Pathology department, Fundacion Valle del Lili, Carrera 98 No. 18-49, Cali, Colombia 15 5 2019 15 5 2019 2019 13 1443 8 2018 8 4 2019 © The Author(s). 2019Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nEndothelial growth factor receptor (EGFR) mutations are an essential driver of personalized therapy for patients with lung cancer and are detected in approximately 15% of Caucasian and 50% of Asian patients. EGFR tyrosine kinase inhibitors have been developed and used for this set of patients. T790M mutation in exon 20 is usually associated with secondary resistance to EGFR tyrosine kinase inhibitors therapy but is also present in treatment-naïve patients. The frequency for baseline T790M mutation varies from 4 to 35% according to the detection method used. Newer techniques have yielded higher rates, but concerns about false-positive results have been raised. Compound mutations account for 4–14% of all EGFR-mutated tumors, with no studies yet to provide a frequency rate for T790M + 19 deletion association due to the small number of cases. However, there are reports that pretreatment T790M + L858R association is significantly more frequent compared to T790M + exon 19 deletion mutations. Diagnostic challenges, current knowledge on the subject, and therapeutic decisions are discussed.\n\nCase presentation\nWe present the case of a 43-year-old Hispanic woman, a treatment-naïve patient, with metastasized lung cancer adenocarcinoma harboring a T790M deletion along with the classic 19 mutation. The initial symptoms were monoparesis of her left leg, associated with hyperreflexia, and hypoesthesia. In the absence of third-generation tyrosine kinase inhibitors, a platinum-based therapy was initiated with no response and she died 4 months after diagnosis.\n\nConclusions\nOsimertinib seems to be a suitable therapy for treatment-naïve patients with sensitizing and resistant compound EGFR mutations. More studies regarding the clinical characteristics of these patients and the appropriate management of this condition are needed to provide the highest standard of care.\n\nKeywords\nLung neoplasmsEGFR proteinAdenocarcinoma of the lungCompound mutationissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nNon-small cell lung cancer (NSCLC) accounts for the majority of lung neoplasms and its mortality in advanced stages is very high, compared with other cancer types [1, 2]. Driver mutations can be found in a high percentage of these cases, including endothelial growth factor receptor (EGFR) alterations [3–5]. However, compound mutations in treatment-naïve patients are rare, even more so if the association is that of a T790M mutation and an exon 19 deletion (19-Del) [5, 6]. There are very few cases of this compound mutation found in the literature.\n\nWe present the case of a 43-year-old, treatment-naïve, woman with metastasized lung cancer adenocarcinoma harboring a T790M deletion along with the classic 19-Del. The importance of this case lies in the rareness of this compound mutation, the ample variation of T790M incidence in the literature, and the multiple treatment difficulties that arise when, for a particular reason, including no availability, a third-generation EGFR tyrosine kinase inhibitor (TKI) cannot be used.\n\nCase presentation\nA 43-year-old Hispanic woman with no past medical or family history of importance, presented to our emergency room (ER) with progressive lumbar pain for the past 4 months, 10/10 in intensity, which irradiated to her left lower limb limiting her functionality. She also referred weakness of her left leg, associated with loss of sensitivity, and had experienced night fevers, chills, and a 23 kg (50 pound) weight loss. A physical examination revealed monoparesis of her left leg, associated with hyperreflexia, and hypoesthesia.\n\nA contrasted pelvis and lumbar magnetic resonance imaging (MRI) showed a solid infiltrative mass in her left sacral and iliac bones, compromising the left sacroiliac joint, the ipsilateral sacral nerve roots, and the pyramidalis and gluteus medius muscles. Other bone lesions compromised the left femoral neck and the right femoral diaphysis (Fig. 1).Fig. 1 Pelvic magnetic resonance imaging. Infiltrative mass with areas of cystic appearance in the left sacral bone, extending to the sacroiliac joint and left iliac bone, obliterating the left neural foramina. Measures 6.2 × 7.9 × 5.3 cm\n\n\n\nThe hypothesis was that these lesions were metastatic, so further studies were ordered. Breast ultrasonography revealed a mass of 2 cm by 3 cm in her left breast, but a subsequent fine-needle biopsy showed benign histopathology. A computed tomography (CT) scan revealed masses in both her liver and lung (Fig. 2). A bronchoalveolar wash was negative for malignancy, and so was a transbronchial biopsy. A decision was made to do a CT-guided percutaneous biopsy of the sacral lesion; the results revealed a metastasized lung adenocarcinoma (Fig. 3), negative for ALK mutation but with a complex mutation of the EGFR gene: a 19-Del associated with a T790M (exon 20) mutation. The genetic assay used was cobas® EGFR Mutation Test v2 (Roche®). The target deoxyribonucleic acid (DNA) was amplified and detected on the cobas® 480 system which measures the fluorescence generated by specific polymerase chain reaction (PCR) products, using the amplification and detection reagents provided in the cobas® EGFR mutation test kit (lightmix®).Fig. 2 Thorax computed tomography. Solid mass with heterogenic enhancement, with well-defined intrapulmonary spiculated contours in the anteromedial segment of the lower lobe of the left lung of 4.7 × 3.3 cm (anteroposterior × transverse)\n\nFig. 3 Metastasized lung adenocarcinoma in sacral bone. Sacral bone biopsy. a Hematoxylin and eosin stain, solid pattern metastatic adenocarcinoma of the lung (× 10). b, c Positive thyroid transcription factor 1 and napsin A immunohistochemistry stain (× 10). d Negative immunohistochemistry stain for EML-4, ALK, and programmed death-ligand 1 rearrangements\n\n\n\nStage IV lung adenocarcinoma was diagnosed. In the absence of third-generation EGFR-TKIs (not approved by the local drug and food administration at the time) and taking into account the performance status of our patient, which was Eastern Cooperative Oncology Group (ECOG) 2, platinum-based chemotherapy of gemcitabine (1000 mg/m2 day 1 and 8) with carboplatin (AUC 6) was initiated. Only grade 1 toxicities were observed.\n\nOur patient suffered from a severe headache 25 days after admission, with no response to analgesia, and a CT scan of her brain was done; the CT scan revealed intraparenchymal bleeding on the left cerebellar hemisphere, with fourth ventricle compression and non-communicant acute hydrocephalus. A brain MRI showed a lesion in the cerebellum, thought to be a metastasis (Fig. 4). After stabilization of the clinical status, whole brain irradiation with three-dimensional conformational radiotherapy (CRT) was done (3 Gy fractions for a total dose of 30 Gy). Radiation therapy (three-dimensional CRT) was also administered to her left sacral and iliac bones for pain management (4 Gy fractions for a total dose of 20 Gy). She died 4 months after diagnosis.Fig. 4 Brain magnetic resonance imaging. A nodular lesion with a cystic component of intra-axial location in the left cerebellar hemisphere is observed, whose enhancement component measures 23 × 31 mm (anteroposterior × transverse), is associated with vasogenic edema in the periphery and conditions the mass effect\n\n\n\nDiscussion\nNSCLC accounts for nearly 85% of all lung neoplasms, and its 5-year survival rate is still low, around 17% dropping to 5%, if the disease is categorized as stage IV [1, 2]. As many as 80% of cases of lung adenocarcinoma have a driver mutation contributing to early carcinogenesis [7]; the identification of these mutations has allowed for a more personalized therapy, improving outcomes in relevant populations. EGFR mutations, detected in approximately 15% of Caucasian and 50% of Asian patients [3, 4], have been targeted since 2004, resulting in EGFR-TKIs such as erlotinib and gefitinib.\n\nEGFR mutations are more frequent in tumors with adenocarcinoma histology, in never-smokers or light smokers of tobacco, in women with NSCLC, and in patients with East Asian ethnicities [8]. The two most common EGFR mutations, also called classic mutations, are the 19-Del and the L858R substitution in exon 21 [9], both of them regarded as positive predictive biomarkers for response to EGFR-TKIs [10]. These mutations are oncogenic because they favor the active state of the kinase, inducing EGFR-mediated antiapoptotic and prosurvival proteins specifically in the Akt/STAT and MAPK signaling pathways [11].\n\nT790M mutation in exon 20 is usually associated with secondary resistance to EGFR-TKIs therapy, being responsible for approximately 50 to 60% of these cases [12, 13]. This point mutation increases the affinity of EGFR for adenosine triphosphate (ATP) and decreases drug binding through steric hindrance, consequently diminishing the binding efficacy of EGFR-TKIs [12, 14–16]. If this mutation is present before treatment, then it becomes a rare EGFR mutation. The frequency of this mutation in treatment-naïve patients varies significantly according to the population screened and the method used for detection. The rate fluctuates between 1 and 3% when direct sequencing is used [16]. However, when newer techniques like real-time (RT) PCR, next-generation sequencing (NGS), and highly sensitive matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) are used, the frequency rises to 25 to 35% [17, 18]. One study reported a rate of 79% using colony hybridization [19]. However, there are reports of false-positive results with the newer techniques, especially when the sample tested is formalin-fixed paraffin-embedded tumor tissue [20–22].\n\nEven rarer than an uncommon mutation is a compound mutation. This entails a dual mutation on the EGFR gene, comprising a sensitizing mutation (usually 19-Del or a 21 substitution) along with a rare mutation involving other residues of the tyrosine kinase domain of EGFR [5]. In our case, the double mutation was found to be a coexistence of 19-Del and the exon 20 T790M mutation. Compound mutations account for 4–14% of all EGFR-mutated tumors [5, 23, 24]. This frequency variation is due most likely to the fact that multiple methods for mutation detection are used among the studies. One article has independently associated the T790M and drug-sensitive EGFR mutations, establishing the hypothesis that these mutations themselves cause genetic instability, predisposing the cell to more DNA changes [25]. However, there seem to be some combinations that occur more often than others. Some studies have concluded that pretreatment T790M point mutation is significantly more frequent in patients carrying the L858R mutation compared to those harboring deletions in exon 19 [6], making this case even more unusual. Very few case reports of this compound mutation are published. Sakashita et al. [26] presented three cases of EGFR compound mutation, one of them a 19-Del + T790M alteration; their approach was a pathological one. Lou et al. [27] published one similar case but with no clinical description, and Khan et al. published a short report about a 57-year woman harboring the same mutation, with a good response to osimertinib [28]. A summary of cases reported in descriptive studies is presented in Table 1.Table 1 Cases of exon 19 deletion + T790M in the literature\n\nAuthor\tYear\tType of assay\tNumber of samples\tExon 19 deletion + T790M\t\nYu et al. [29]\t2018\tARMS-PCR\t3925\t43 (1.09%)\t\nIllei et al. [30]\t2017\tNGS\t1006\t1 (0.09%)\t\nTezel et al. [31]\t2017\tPCR\t959\t2 (0.2%)\t\nTu et al. [32]\t2017\tARMS-PCR / Sanger\t5363\t11 (0.2%)\t\nTang et al. [33]\t2016\tARMS-PCR\t3894\t8 (0.2%)\t\nARMS-PCR amplification refractory mutation system technology, NGS next-generation sequencing, PCR polymerase chain reaction\n\n\n\nThere is a paucity of literature about the clinical profile of patients with de novo T790M mutation. Studies in Korea and Japan [34, 35] have described characteristics that are similar to those of patients with an EGFR mutation, regardless of the mutation: female gender, < 65 years of age, never-smoker of tobacco, and adenocarcinoma histology. The differences found were mainly a higher never-smoker of tobacco representation and more brain metastasis. All of these characteristics, including brain metastasis, were present in our patient.\n\nDespite some studies concluding that first-line TKI therapy could benefit patients with a compound mutation harboring a T790M substitution [19, 36], the majority of the literature suggests that compound de novo T790M mutations confer resistance to TKI therapy. Poorer response rates to first-generation and second-generation EGFR-TKIs, along with similar response rates to platinum-based chemotherapy, have been described in this population. However, even though these patients have worse progression-free survival (PFS), there is no statistically significant difference in overall survival (OS) [17, 18, 32, 34–37]. New therapeutic molecules called third-generation EGFR-TKIs could be the solution for this set of patients, namely osimertinib.\n\nOsimertinib is an orally administered, irreversible EGFR-TKI that is selective for activating EGFR mutations including 19-Del, L858R in exon 21, as well as the common T790M gatekeeper mutation mediating acquired resistance to early generation EGFR-TKIs [38]. Its potency is almost 200-times greater against L858R/T790M than the wild-type EGFR, which minimizes toxicity in patients [39].\n\nIts clinical efficacy has been shown in multiple international trials, namely the AURA1 [40], AURA2 [41], AURA3 [42], and FLAURA [43] trials. The international phase I/II AURA clinical trial (NCT01802632) included patients with locally advanced or metastatic NSCLC with documented EGFR mutation or prior benefit to EGFR-targeted therapy following progression on at least one prior EGFR-TKI. The AURA phase II extension study established the safety and efficacy of osimertinib 80 mg daily as either second-line or third-line therapy in patients with EGFR-mutated NSCLC with confirmed T790M mutation. A pooled study of both the AURA1 extension and the AURA2 revealed a median duration of osimertinib treatment to be 16.4 months, with an improvement in the overall response rate (ORR) which was 66% (262 of 398 patients; 95% CI, 61–70%) and PFS [44]. Of note, there was a trend toward an increased response rate in patients who had co-occurring EGFR T790M mutations with 19-Dels versus EGFR T790M mutations with leucine-to-arginine at codon 858 (L858R) mutations (70 versus 57%) [44].\n\nThe AURA3 trial was a randomized international phase III study comparing osimertinib to platinum-pemetrexed chemotherapy combination in patients with T790M-mutated NSCLC following progression on prior EGFR-TKIs [42]. Osimertinib was superior, with a higher ORR (71 versus 31%; p < 0.001) and improved median PFS (10.1 versus 4.4 months, hazard ratio 0.30; 95% CI, 0.23–0.41; p < 0.0001) [42]. Nowadays, upon availability, osimertinib is the therapy of choice for this set of patients.\n\nThe FLAURA phase III, double-blinded, international clinical trial compared osimertinib to either gefitinib or erlotinib as initial therapy for patients with advanced EGFR-mutated NSCLC [43]. Longer median PFS was achieved in the osimertinib compared with treatment with standard-of-care first-line EGFR-TKIs (18.9 versus 10.2 months, hazard ratio, 0.46; 95% CI, 0.37 to 0.57; p < 0.001). However, no significant difference in the ORR was seen (80 versus 76%), but the median duration of response was longer with osimertinib (17.2 months) over standard EGFR-TKIs (8.5 months) [43]. Just as in the previous trials, patients with central nervous system (CNS) metastases had a better response to osimertinib. A study evaluating post-progression outcomes with first-line osimertinib versus standard-of-care EGFR-TKIs, provided further confidence in the interim OS data of the FLAURA study and advocated use of osimertinib as first-line therapy for EGFR mutant (EGFRm) advanced NSCLC [45]. The ELIOS trial (NCT03239340), which is ongoing, will assess the tumor genetic and proteomic markers at the point of disease progression in patients with EGFRm NSCLC who receive first-line osimertinib, hopefully providing better guidelines for the use of this drug as first-line treatment. However, further studies comparing second-generation EGFR-TKIs and osimertinib, and a more mature OS data for osimertinib, are needed to make a final decision [46, 47].\n\nVery few data are available regarding the effectiveness of osimertinib in compound mutated EGFR NSCLC, at least in treatment-naïve patients with T790M/19-Del mutated tumors. Zhang et al. stated that first-generation TKIs, including gefitinib, erlotinib, and icotinib, are ineffective even with the presence of sensitive mutations when accompanied by a resistant mutation, while osimertinib carries survival benefits for those patients [48]. Yu et al. found a PFS of only 1.5 months for patients with sensitive and resistant compound mutation treated with first-generation and second-generation EGFR-TKIs [49]. Similar results were also observed in another prospective study, where the ORR and PFS were only 14.3% and 2.9 months, respectively for this set of patients [50]. With these results in mind, using osimertinib as a first line of treatment for patients with NSCLC harboring de novo compound T790M/19-Del mutation, like the one presented in this report, appears to be a sensible decision.\n\nA choice for platinum-based chemotherapy was made for this patient due to the unavailability of third-generation TKIs, a baseline T790M mutation, the presence of multiple metastases, and a high tumor burden.\n\nConclusion\nEven though the rate of baseline T790M mutation is apparently higher than previously known, compound mutations harboring this point substitution are very rare, more so when accompanied by a 19-Del, making this set of patients particularly hard to manage. Osimertinib seems a good choice of treatment for these patients, but in its absence, and until more mature OS data are available and more comparative studies are made, first-line treatment can continue to be platinum-based chemotherapy, especially if there is a high tumor burden. More studies regarding the clinical characteristics of these patients and the appropriate management of this condition are needed to provide the highest standard of care.\n\nFunding\nNot applicable.\n\nAvailability of data and materials\nNot applicable.\n\nAuthors’ contributions\nARZ was the primary caregiver of this oncological patient and was involved in the making of the manuscript. LXR was the geneticist in charge of the diagnostic test and was involved in the making of the manuscript. LFS was the pathologist in charge of the histopathologic diagnostic and was involved in the making of the manuscript. JCB, DE, and JCF were in charge of gathering the information and making the manuscript. All authors read and approved the final manuscript.\n\nEthics approval\nNot applicable.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Ramalingam SS Owonikoko TK Khuri FR Lung cancer: New biological insights and recent therapeutic advances CA Cancer J Clin 2011 61 2 91 112 10.3322/caac.20102 21303969 \n2. O’Kane GM Bradbury PA Feld R Uncommon EGFR mutations in advanced non-small cell lung cancer Lung Cancer 2017 109 137 144 10.1016/j.lungcan.2017.04.016 28577943 \n3. Shi Y Au JS Thongprasert S A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER) J Thorac Oncol 2014 9 2 154 162 10.1097/JTO.0000000000000033 24419411 \n4. Rosell R Moran T Queralt C Screening for Epidermal Growth Factor Receptor Mutations in Lung Cancer N Engl J Med 2009 361 10 958 967 10.1056/NEJMoa0904554 19692684 \n5. Kobayashi S Canepa HM Bailey AS Compound EGFR mutations and response to EGFR tyrosine kinase inhibitors J Thorac Oncol 2013 8 1 118 122 10.1097/JTO.0b013e3182781e35 \n6. Chen LY Molina-Vila MA Ruan SY Coexistence of EGFR T790M mutation and common activating mutations in pretreatment non-small cell lung cancer: A systematic review and meta-analysis Lung Cancer 2016 94 46 53 10.1016/j.lungcan.2016.01.019 26973206 \n7. Dearden S Stevens J Wu YL Blowers D Mutation incidence and coincidence in non small-cell lung cancer: Meta-analyses by ethnicity and histology (mutMap) Ann Oncol 2013 24 9 2371 2376 10.1093/annonc/mdt205 23723294 \n8. Shigematsu H Lin L Takahashi T Clinical and Biological Features Associated With Epidermal Growth Factor Receptor Gene Mutations in Lung Cancers JNCI J Natl Cancer Inst 2005 97 5 339 346 10.1093/jnci/dji055 15741570 \n9. Jorge SEDC Kobayashi SS Costa DB Epidermal growth factor receptor (EGFR) mutations in lung cancer: preclinical and clinical data Braz J Med Biol Res 2014 47 11 929 939 10.1590/1414-431X20144099 25296354 \n10. Paez JG Jänne PA Lee JC EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy Science. 2004 304 5676 1497 1500 10.1126/science.1099314 15118125 \n11. Sharma SV Bell DW Settleman J Haber DA Epidermal growth factor receptor mutations in lung cancer Nat Rev Cancer 2007 7 3 169 181 10.1038/nrc2088 17318210 \n12. Kobayashi S Boggon TJ Dayaram T EGFR Mutation and Resistance of Non–Small-Cell Lung Cancer to Gefitinib N Engl J Med 2005 352 8 786 792 10.1056/NEJMoa044238 15728811 \n13. Yu HA Arcila ME Rekhtman N Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers Clin Cancer Res 2013 19 8 2240 2247 10.1158/1078-0432.CCR-12-2246 23470965 \n14. Morgillo F Della Corte CM Fasano M Ciardiello F Mechanisms of resistance to EGFR-targeted drugs: lung cancer ESMO Open 2016 1 3 e000060 10.1136/esmoopen-2016-000060 27843613 \n15. Yun C-H Mengwasser KE Toms AV The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP Proc Natl Acad Sci 2008 105 6 2070 2075 10.1073/pnas.0709662105 18227510 \n16. Yu HA Arcila ME Hellmann MD Kris MG Ladanyi M Riely GJ Poor response to erlotinib in patients with tumors containing baseline EGFR T790M mutations found by routine clinical molecular testing Ann Oncol 2014 25 2 423 428 10.1093/annonc/mdt573 24478319 \n17. Su KY Chen HY Li KC Pretreatment Epidermal Growth Factor Receptor (EGFR) T790M mutation predicts shorter EGFR tyrosine kinase inhibitor response duration in patients with non-small-cell lung cancer J Clin Oncol 2012 30 4 433 440 10.1200/JCO.2011.38.3224 22215752 \n18. Rosell R Molina MA Costa C Pretreatment EGFR T790M Mutation and BRCA1 mRNA Expression in Erlotinib-Treated Advanced Non-Small-Cell Lung Cancer Patients with EGFR Mutations Clin Cancer Res 2011 17 5 1160 1168 10.1158/1078-0432.CCR-10-2158 21233402 \n19. Fujita Y Suda K Kimura H Highly sensitive detection of EGFR T790M mutation using colony hybridization predicts favorable prognosis of patients with lung cancer harboring activating EGFR mutation J Thorac Oncol 2012 7 11 1640 1644 10.1097/JTO.0b013e3182653d7f 22899358 \n20. Roma Cristin Esposito Claudia Rachiglio Anna Maria Pasquale Raffaella Iannaccone Alessia Chicchinelli Nicoletta Franco Renato Mancini Rita Pisconti Salvatore De Luca Antonella Botti Gerardo Morabito Alessandro Normanno Nicola Detection of EGFR Mutations by TaqMan Mutation Detection Assays Powered by Competitive Allele-Specific TaqMan PCR Technology BioMed Research International 2013 2013 1 9 10.1155/2013/385087 \n21. Jenkins Suzanne Yang James C-H. Ramalingam Suresh S. Yu Karen Patel Sabina Weston Susie Hodge Rachel Cantarini Mireille Jänne Pasi A. Mitsudomi Tetsuya Goss Glenwood D. Plasma ctDNA Analysis for Detection of the EGFR T790M Mutation in Patients with Advanced Non–Small Cell Lung Cancer Journal of Thoracic Oncology 2017 12 7 1061 1070 10.1016/j.jtho.2017.04.003 28428148 \n22. Tatematsu T Okuda K Suzuki A The detectability of the pretreatment EGFR T790M mutations in lung adenocarcinoma using CAST-PCR and digital PCR J Thorac Dis 2017 9 8 2397 2403 10.21037/jtd.2017.07.02 28932544 \n23. Wu J-Y Yu C-J Chang Y-C Yang C-H Shih J-Y Yang P-C Effectiveness of tyrosine kinase inhibitors on “uncommon” epidermal growth factor receptor mutations of unknown clinical significance in non-small cell lung cancer Clin Cancer Res 2011 17 11 3812 3821 10.1158/1078-0432.CCR-10-3408 21531810 \n24. Kosaka T Yatabe Y Endoh H Kuwano H Takahashi T Mitsudomi T Mutations of the epidermal growth factor receptor gene in lung cancer: Biological and clinical implications Cancer Res 2004 64 24 8919 8923 10.1158/0008-5472.CAN-04-2818 15604253 \n25. Hashida S Soh J Toyooka S Presence of the minor EGFR T790M mutation is associated with drug-sensitive EGFR mutations in lung adenocarcinoma patients Oncol Rep 2014 32 1 145 152 10.3892/or.2014.3197 24842519 \n26. Sakashita S Shiba-Ishii A Murata Y Sekimoto R Minami Y Sato Y Case report of three EGFR TKI naïve lung adenocarcinoma containing double EGFR mutations (L858R/T790M or Exon 19 Deletion/T790M); Comparing genetic information and histology Pathol Res Pract 2018 214 1224 1230 10.1016/j.prp.2018.05.016 29887244 \n27. Lou Y Pecot CV Tran HT DeVito VJ Tang XM Heymach JV Germline Mutation of T790M and Dual/Multiple EGFR Mutations in Patients With Lung Adenocarcinoma Clin Lung Cancer. 2016 17 e5 11 10.1016/j.cllc.2015.11.003 26700910 \n28. Khan J Pritchard CC Martins RG Tissue Is the Issue for Diagnosis of EGFR T790M Mutation J Thorac Oncol 2016 11 7 e91 e92 10.1016/j.jtho.2016.03.017 27339415 \n29. Yu X Zhang X Zhang Z Lin Y Wen Y Chen Y First-generation EGFR tyrosine kinase inhibitor therapy in 106 patients with compound EGFR-mutated lung cancer: A single institution’s clinical practice experience Cancer Commun 2018 38 1 1 13 10.1186/s40880-018-0270-7 \n30. Illei PB Belchis D Tseng L-H Nguyen D De Marchi F Haley L Clinical mutational profiling of 1006 lung cancers by next generation sequencing Oncotarget. 2017 8 57 96684 96696 10.18632/oncotarget.18042 29228562 \n31. Tezel GG Şener E Aydın Ç Önder S Prevalence of epidermal growth factor receptor mutations in patients with non-small cell lung cancer in Turkish population Balkan Med J 2017 34 6 567 571 10.4274/balkanmedj.2017.0297 28832323 \n32. Tu H-Y Ke E-E Yang J-J A comprehensive review of uncommon EGFR mutations in patients with non-small cell lung cancer Lung Cancer 2017 114 November 96 102 10.1016/j.lungcan.2017.11.005 29173773 \n33. Tang Y Wang WY Zheng K Jiang L Zou Y Su XY EGFR mutations in non-small cell lung cancer: an audit from West China Hospital Expert Rev Mol Diagn 2016 16 8 915 919 10.1080/14737159.2016.1199961 27348572 \n34. Kawamura Takahisa Kenmotsu Hirotsugu Omori Shota Nakashima Kazuhisa Wakuda Kazushige Ono Akira Naito Tateaki Murakami Haruyasu Omae Katsuhiro Mori Keita Tanigawara Yusuke Nakajima Takashi Ohde Yasuhisa Endo Masahiro Takahashi Toshiaki Clinical Factors Predicting Detection of T790M Mutation in Rebiopsy for EGFR-Mutant Non–small-cell Lung Cancer Clinical Lung Cancer 2018 19 2 e247 e252 10.1016/j.cllc.2017.07.002 28866043 \n35. Lee Y Lee GK Hwang JA Yun T Kim HT Lee JS Clinical likelihood of sporadic primary EGFR T790M Mutation in EGFR-mutant Lung Cancer Clin Lung Cancer 2015 16 1 46 50 10.1016/j.cllc.2014.09.002 25450875 \n36. Fukuoka M Wu YL Thongprasert S Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS) J Clin Oncol 2011 29 21 2866 2874 10.1200/JCO.2010.33.4235 21670455 \n37. Inukai M Toyooka S Ito S Presence of epidermal growth factor receptor gene T790M mutation as a minor clone in non-small cell lung cancer Cancer Res 2006 66 16 7854 7858 10.1158/0008-5472.CAN-06-1951 16912157 \n38. Carlisle J Ramalingam S Role of osimertinib in the treatment of EGFR-mutation positive non-small-cell lung cancer Future Oncol 2019 15 805 816 10.2217/fon-2018-0626 30657347 \n39. Cross DA Ashton SE Ghiorghiu S AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer Cancer Discov 2014 4 9 1046 1061 10.1158/2159-8290.CD-14-0337 24893891 \n40. Janne PA Yang JC Kim DW AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer N Engl J Med 2015 372 18 1689 1699 10.1056/NEJMoa1411817 25923549 \n41. Yang JC Ahn MJ Kim DW Osimertinib in pretreated T790M-positive advanced non-small-cell lung cancer: AURA study Phase II extension component J Clin Oncol 2017 35 12 1288 1296 10.1200/JCO.2016.70.3223 28221867 \n42. Mok T Wu YL Ahn MJ Garassino MC Kim HR Ramalingam S Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer N Engl J Med 2017 376 629 640 10.1056/NEJMoa1612674 27959700 \n43. Soria JC Ohe Y Vansteenkiste J Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer N Engl J Med 2018 378 2 113 125 10.1056/NEJMoa1713137 29151359 \n44. Ahn MY Tsai CM Shepherd FA Bazhenova L Sequist LV Hida T Osimertinib in Patients With T790M Mutation-Positive, Advanced Non-Small Cell Lung Cancer: Long-Term Follow-Up From a Pooled Analysis of 2 Phase 2 Studies Cancer. 2019 125 892 901 10.1002/cncr.31891 30512189 \n45. Planchard D Boyer MJ Lee JS Dechaphunkul A Cheema PK Takahashi T Post-Progression Outcomes for Osimertinib versus Standard-of-Care EGFR-TKI in Patients with Previously Untreated EGFR-3 Mutated Advanced Non-Small Cell Lung Cancer Clin Cancer Res 2019 25 2058 2063 10.1158/1078-0432.CCR-18-3325 30659024 \n46. Roeper J Griesinger F Epidermal growth factor receptor tyrosine kinase inhibitors in advanced non-small cell lung cancer: what is the preferred first-line therapy? Curr Opin Oncol 2019 31 1 1 7 30451714 \n47. Scott LJ Osimertinib as first-line therapy in advanced NSCLC: a profile of its use Drugs Ther Perspect 2018 34 8 351 357 10.1007/s40267-018-0536-9 30631243 \n48. Zhang B Xu JL Zhang X Gu P Wang HM Wang SY Coexistence of sensitive and resistant epidermal growth factor receptor (EGFR) mutations in pretreatment non-small cell lung cancer (NSCLC) patients: First or third generation tyrosine kinase inhibitors (TKIs)? Lung Cancer 2018 117 1 27 31 29496252 \n49. Yu HA Arcila ME Hellmann MD Poor response to erlotinib in patients with tumors containing baseline EGFR T790M mutations found by routine clinical molecular testing Ann Oncol 2014 25 1 423 428 10.1093/annonc/mdt573 24478319 \n50. Yang JC Sequist LV Geater SL Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6 Lancet Oncol 2015 16 7 830 838 10.1016/S1470-2045(15)00026-1 26051236\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1752-1947",
"issue": "13(1)",
"journal": "Journal of medical case reports",
"keywords": "Adenocarcinoma of the lung; Compound mutation; EGFR protein; Lung neoplasms",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D000077192:Adenocarcinoma of Lung; D000328:Adult; D001859:Bone Neoplasms; D004252:DNA Mutational Analysis; D066246:ErbB Receptors; D005091:Exons; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D006987:Hypesthesia; D035002:Lower Extremity; D008175:Lung Neoplasms; D008279:Magnetic Resonance Imaging; D047428:Protein Kinase Inhibitors; D012021:Reflex, Abnormal; D017384:Sequence Deletion",
"nlm_unique_id": "101293382",
"other_id": null,
"pages": "144",
"pmc": null,
"pmid": "31088573",
"pubdate": "2019-05-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15118125;15604253;15728811;15741570;16912157;17318210;18227510;19692684;21233402;21303969;21531810;21670455;22215752;22899358;23242437;23470965;23723294;24364033;24419411;24478319;24842519;24893891;25296354;25450875;25923549;26051236;26700910;26973206;27339415;27348572;27843613;27959700;28221867;28428148;28577943;28832323;28866043;28932544;29151359;29173773;29228562;29496252;29887244;30055651;30451714;30512189;30631243;30657347;30659024",
"title": "An endothelial growth factor receptor compound mutation of T790M substitution with exon 19 deletion in a previously untreated patient: a case report.",
"title_normalized": "an endothelial growth factor receptor compound mutation of t790m substitution with exon 19 deletion in a previously untreated patient a case report"
} | [
{
"companynumb": "CO-PFIZER INC-2019243682",
"fulfillexpeditecriteria": "1",
"occurcountry": "CO",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": "3",
... |
{
"abstract": "Diabetic ketoacidosis (DKA) occurs frequently among children and adolescents with type 1 diabetes. Although a number of complications may occur during episodes of DKA, significant cardiac arrhythmias are uncommon. We present the case of an adolescent who presented with severe DKA and wide complex tachycardia that was unresponsive to multiple doses of adenosine and ultimately required synchronized cardioversion. This case reminds the clinician of the importance of cardiac monitoring in children with DKA, particularly in the setting of hyperkalemia.",
"affiliations": "Department of Pediatric Emergency Medicine, Children's Minnesota, Minneapolis, MN, USA. Electronic address: kelly.bergmann@childrensmn.org.;Department of Pediatric Emergency Medicine, Children's Minnesota, Minneapolis, MN, USA.",
"authors": "Bergmann|Kelly R|KR|;Whitcomb|Valerie|V|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajem.2020.12.029",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-6757",
"issue": "45()",
"journal": "The American journal of emergency medicine",
"keywords": "Arrhythmia; Cardioversion; Diabetic ketoacidosis; Ventricular tachycardia",
"medline_ta": "Am J Emerg Med",
"mesh_terms": "D000293:Adolescent; D003922:Diabetes Mellitus, Type 1; D016883:Diabetic Ketoacidosis; D004554:Electric Countershock; D004562:Electrocardiography; D006801:Humans; D008297:Male; D017180:Tachycardia, Ventricular",
"nlm_unique_id": "8309942",
"other_id": null,
"pages": "683.e1-683.e3",
"pmc": null,
"pmid": "33376006",
"pubdate": "2021-07",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Ventricular tachycardia in an adolescent with severe diabetic ketoacidosis.",
"title_normalized": "ventricular tachycardia in an adolescent with severe diabetic ketoacidosis"
} | [
{
"companynumb": "US-MYLANLABS-2021M1075818",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ADENOSINE"
},
"drugadditional": "3",
... |
{
"abstract": "Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) is a potent fixed-dose, once-daily regimen for HIV-1 treatment and has rare emergence of drug resistance. We report a potential drug-drug interaction in 2 female patients both receiving treatment for HIV and cerebral toxoplasmosis: one case between E/C/F/TAF with calcium carbonate and a second case involving leucovorin as calcium salt. Both cases resulted in rise in HIV RNA levels and emergence of M184 V mutation and resistance to elvitegravir and raltegravir. To the best of our knowledge, these 2 cases are the first reports of rapid emergence of mutation from coadministration of E/C/F/TAF and calcium.",
"affiliations": "1 Immunology Clinic, Ventura County Medical Center, Ventura, CA, USA.;1 Immunology Clinic, Ventura County Medical Center, Ventura, CA, USA.;1 Immunology Clinic, Ventura County Medical Center, Ventura, CA, USA.",
"authors": "Kang-Birken|S Lena|SL|0000-0002-0620-0922;El-Sayed|Dena|D|;Prichard|John|J|",
"chemical_list": "D019380:Anti-HIV Agents; D015363:Quinolones; C509700:elvitegravir; D000068698:Tenofovir; D000068679:Emtricitabine; D002119:Calcium Carbonate; D000069547:Cobicistat; D002955:Leucovorin; D002118:Calcium",
"country": "United States",
"delete": false,
"doi": "10.1177/2325958218821653",
"fulltext": "\n==== Front\nJ Int Assoc Provid AIDS CareJ Int Assoc Provid AIDS CareJIAspjiaJournal of the International Association of Providers of AIDS Care2325-95742325-9582SAGE Publications Sage CA: Los Angeles, CA 3079867910.1177/232595821882165310.1177_2325958218821653Case ReportHIV Viral Rebound Due to a Possible Drug–Drug Interaction between Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide and Calcium-Containing Products: Report of 2 Cases https://orcid.org/0000-0002-0620-0922Kang-Birken S. Lena PharmD12El-sayed Dena MD1Prichard John MD1\n1 Immunology Clinic, Ventura County Medical Center, Ventura, CA, USA\n2 Thomas J. Long School of Pharmacy and Health Sciences, University of the Pacific, Stockton, CA, USAS. Lena Kang-Birken, Thomas J Long School of Pharmacy and Health Sciences, University of the Pacific, 3601 Pacific Avenue, Stockton, CA 95211, USA. Email: lbirken@pacific.edu07 1 2019 Jan-Dec 2019 18 2325958218821653© The Author(s) 20192019SAGE Publications Inc. unless otherwise noted. Manuscript content on this site is licensed under Creative Commons LicensesThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (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).Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) is a potent fixed-dose, once-daily regimen for HIV-1 treatment and has rare emergence of drug resistance. We report a potential drug–drug interaction in 2 female patients both receiving treatment for HIV and cerebral toxoplasmosis: one case between E/C/F/TAF with calcium carbonate and a second case involving leucovorin as calcium salt. Both cases resulted in rise in HIV RNA levels and emergence of M184 V mutation and resistance to elvitegravir and raltegravir. To the best of our knowledge, these 2 cases are the first reports of rapid emergence of mutation from coadministration of E/C/F/TAF and calcium.\n\nHIV/AIDSelvitegravir/cobicistat/emtricitabine/tenofovir alafenamidecalciummutation emergenceresistancecover-dateJanuary-December 2019\n==== Body\nWhat Do We Already Know about This Topic?\nThe manufacturer of elvitegravir recommends separation of administration from aluminum, magnesium or calcium-containing antacids without providing specific data regarding calcium salts.\n\nHow Does Your Research Contribute to the Field?\nThe cases describe new data on clinically significant drug interaction between elvitegravir and simultaneously administered calcium, leading to resistance-associated mutations and ultimately, treatment failure.\n\nWhat Are Your Research’s Implications toward Theory, Practice, or Policy?\nClinicians should check for all forms of calcium for possible drug interaction with elvitegravir while advising the patient to separate the administration of the 2 medications.\n\nIntroduction\nElvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg (E/C/F/TAF) is a relatively new antiretroviral combination having potent and durable activity against HIV-1.1,2 It is a single tablet, once-daily (QD) regimen containing an integrase strand transfer inhibitor, a pharmacokinetic booster, and inhibitor of CYP3A, and 2 nucleoside/nucleotide reverse transcriptase inhibitors (NNRTIs). It was well tolerated and showed a low frequency of emerging resistance during clinical trials.3,4 Drug–drug interactions have been described including aluminum and magnesium hydroxide-containing antacids, which decrease the absorption of elvitegravir.5 The package insert recommends separating the administration of antacids containing aluminum, magnesium hydroxide, or calcium carbonate from E/C/F/TAF by at least 2 hours.6 We encountered 2 cases wherein resistance to E/C/F/TAF unexpectedly emerged during treatment of HIV-1. Both patients were also being managed for cerebral toxoplasmosis. We speculate that coadministered calcium may have limited absorption of the anti-retroviral, leading to acquired resistance.\n\nCase 1\nA 42-year-old woman with no known history of HIV infection or treatment, presented to the hospital in January 2017, following a near syncopal episode and chronic generalized weakness. Brain magnetic resonance imaging (MRI) showed multiple ring-enhancing lesions in the right internal capsule and basal ganglia with extensive vasogenic edema and a midline shift of 7 mm. She had an emergent left frontal burr hole and a placement of left extraventricular drain for hydrocephalus and a stereotactic needle biopsy of the brain confirmed cerebral toxoplasmosis. She was also diagnosed with HIV at this time and her plasma HIV viral load in January 2017 was 66 500 copies/mL and her CD4 T-cell count was 10 cells/mm3. The genotype at this time demonstrated no reverse transcriptase (RT) gene mutations, but the following protease gene mutations: L10V, M36I, L63P, H69H/Y, A71T/A, and I93L. Integrase genotype was not performed as there have been no reports of resistance to integrase inhibitors among treatment naive individuals.\n\nOn admission in January, the patient was started on oral sulfadiazine 1000 mg every 6 hours, pyrimethamine 75 mg daily, and leucovorin 15 mg daily. She quickly developed profound neutropenia and the regimen was changed to oral atovaquone 1500 mg twice daily (BID) and clindamycin 600 mg intravenous (IV) every 6 hours. The patient tolerated the new treatment regimen, and in February 2017, E/C/F/TAF was started. One month later in March 2017, the HIV viral load decreased to 347 copies/mL and CD4 T-cell count increased to 36 cell/µL.\n\nIn March 2017, the patient’s symptoms improved, and she was discharged to a skilled nursing facility to continue the treatment of toxoplasmosis with IV clindamycin and oral atovaquone which also served as Pneumocystis jirovecii pneumonia (PJP) prophylaxis, E/C/F/TAF for HIV, and fluoxetine for depression. In April 2017, her HIV viral load further declined to 64 copies/mL.\n\nIn May 2017, per institution’s protocol, the patient was started on oral supplement of calcium carbonate 1500 mg (600-mg elemental calcium) QD at the same time as E/C/F/TAF every morning without our knowledge. In July 2017, the HIV viral load increased to 4,840 copies/mL with the CD4 T-cell count of 106 cells/mm3. The HIV genotype at this time reported the RT gene mutations M184V and L100L/F, conferring resistance to emtricitabine and lamivudine, and protease gene mutations L10V, M36I/M, K43R, L63P, H69Y, A71A/V, and I93L. Resistance to protease inhibitors was not predicted as these were minor mutations that do not have substantial effect on phenotype. The virus also exhibited probable resistance to raltegravir, predicted resistance to elvitegravir, and no predicted resistance to dolutegravir. All medications were reviewed for potential drug interactions, and good adherence was corroborated by the staff and the medication administration record. In August 2017, the regimen was subsequently changed to rilpivirine 25 mg/emtricitabine 200 mg/tenofovir alafenamide 25mg (RPV/F/TAF) and darunavir 800 mg/cobicistat 150 mg, and her repeat HIV viral load was <40 copies/mL with a CD4 T-cell count of 312 cells/mm3 after 3 months on the new regimen.\n\nCase 2\nA 35-year-old HIV-1-infected Hispanic woman with no history of AIDS-defining opportunistic illnesses had been prescribed efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg (EFV/FTC/TDF) when she established care in December 2010. The genotype report at that time showed protease gene mutations L63P and V77I, and the patient had prior exposure to zidovudine, lamivudine, didanosine, and nevirapine, since her diagnosis in 2004. Between December 2010 and January 2015, the patient experienced no medical complications and claimed 100% compliance to EFV/FTC/TDF during each visit which was supported by her HIV viral load consistently <20 copies/mL over these years. In 2015, the patient was lost to followup. Unfortunately, she discontinued her medication in June 2016 as she was dealing with an unexpected death of a close family member. The patient reestablished care in October 2016 at which time she was asymptomatic with a HIV viral load of 325 000 copies/mL, and the CD4 T-cell count was 68 cells/mm3. Atovaquone 1500 mg daily was initiated for PJP prophylaxis as the patient reported having extensive rash with trimethoprim/sulfamethoxazole in the past. The genotype performed at this time showed the following protease inhibitor gene mutations: I13I/V, E35D, D60E, L63P, I64V, and V77I and RT mutation V106I/V/M conferring resistance to efavirenz and nevirapine. Based on genotype and the patient’s history of exposure to multiple medications, an integrase genotype was subsequently ordered in January 2017. There was no predicted resistance to raltegravir, elvitegravir, or dolutegravir. In the meantime, the elevated AST and ALT of 299 IU/L and 475 IU/L prompted an ultrasound of the abdomen, which showed increased echogenicity compatible with a fatty liver. With subsequent improvement of transaminase levels, the patient was started on E/C/F/TAF in March 2017.\n\nOne week later, she was admitted with progressively worsening headache for several days with some neck stiffness but without fever, visual disturbances or focal neurological findings. The Toxoplasma antibody (immunoglobulin G) was elevated at >5.0 IU/mL, and the brain MRI showed several ring-enhancing lesions consistent with cerebral toxoplasmosis. Because the patient was noted to have developed a diffuse rash along with leukopenia in the past to sulfa-containing medications, she was initially treated with clindamycin 600 mg IV every 6 hours and pyrimethamine 75 mg orally daily along with leucovorin calcium 25 mg daily. At the time of her admission, her HIV viral load had quickly declined to 2500 copies/mL after 1 week of E/C/F/TAF without any notable adverse reactions. However, E/C/F/TAF was temporarily suspended upon admission to avoid further exacerbation of toxoplasmosis-associated immune reconstitution inflammatory syndrome as well as possible drug–drug interactions. Within a week of toxoplasmosis treatment, pancytopenia was noted and leucovorin calcium was increased to 50 mg BID (8 mg elemental calcium). On hospital day 10, the patient developed diffuse morbilliform rash, fever, and transaminase elevation suspected to be secondary to clindamycin. Clindamycin was discontinued and the regimen was changed to atovaquone 1500 mg BID orally and the same doses of pyrimethamine with leucovorin calcium. The patient became afebrile and the symptoms began to resolve within the next 24 hours.\n\nThe patient was discharged from the hospital in April 2017 with atovaquone, pyrimethamine, and leucovorin calcium only, and E/C/F/TAF was restarted. In July 2017, her CD4 T-cell count was 265 cells/mm3 but HIV viral load increased to 91 300 copies/mL. A repeat genotype performed at this time showed the M184I mutation, conferring resistance to lamivudine and emtricitabine, and probable resistance to raltegravir, predicted resistance to elvitegravir but no predicted dolutegravir resistance. The patient adamantly and repeatedly confirmed 100% adherence to both the antiretroviral and toxoplasmosis regimens. She confirmed taking E/C/F/TAF with breakfast every morning along with leucovorin calcium, atovaquone, and pyrimethamine. She denied use of magnesium/aluminum hydroxide or calcium carbonate antacids, vitamins, herbal supplements, or any other medications that had not been prescribed. She was no longer symptomatic from toxoplasmosis, and the repeat brain MRI showed interval decrease in size of the ring-enhancing lesions and complete resolution of vasogenic edema, suggesting adherence to her toxoplasmosis medications and adequate absorption. In August 2017, her regimen was changed to RPV/F/TAF and atazanavir 300 mg/cobicistat 150 mg. Based on her impressive history of allergic reactions to sulfa-containing medications and clindamycin, any sulfa-containing medication including darunavir was avoided. In January 2018, the HIV viral load was <40 copies/mL and CD4 T-cell count of 317 cells/mm3.\n\nDiscussion\nTwo cases are presented wherein resistance to E/C/F/TAF emerged during treatment of an HIV infection. Both patients had been treated for cerebral toxoplasmosis, had clinically improved, and brain imaging demonstrated progressive resolution of lesions. All medications were reviewed in detail, and both patients were interviewed carefully to assess their compliance and administration of the medication with food. Pharmacy refill records and the medication administration records from the nursing facility were examined, and there were no indications of lapses in dosing.\n\nVirologic failure was, in both cases, unexpected. We considered several possible explanations. In our first case, resistance to integrase inhibitors was not evaluated at baseline. As such, we cannot exclude primary integrase resistance. However, we have not observed primary integrase resistance in our clinic population, and transmitted integrase resistant HIV-1 is extremely rare in the literature.4 Our second patient discontinued her antiretroviral medications for a minimum of 4 months, which resulted in RT mutation V106, conferring resistance to NNRTIs. Although M184V/I was not reported at this time, it was possible that this mutation was archived. Once E/C/F/TAF was initiated, M184V/I may have reemerged, causing resistance to emtricitabine. This less than optimal regimen may have led to the emergence of elvitegravir resistance mutation. Phase 3 studies have, however, reported a 0.9% overall emergence of resistance to integrase inhibitor after 144 weeks of E/C/F/TAF.4\n\n\nWe speculate, however, that coadministration of calcium may have affected absorption of the antiviral agents. In general, serum concentrations of integrase inhibitors are decreased by compounds that contain metal cations, such as those found in multivitamins and antacids, if they are taken concurrently or in a close time frame.7-9 Divalent and trivalent cations bind to elvitegravir, forming an insoluble chelate complex and cause decreased absorption of elvitegravir. Simultaneous administration of elvitegravir with a single dose of antacid-containing aluminum and magnesium resulted in reduction in the serum concentration of elvitegravir by more than 40%, in comparison to elvitegravir alone.7 When aluminum or magnesium-containing antacid was dosed 4 hours apart from elvitegravir, the effect was minimal. Coadministration of calcium with elvitegravir has not been studied, specifically. Similar reductions in serum concentrations have been described with raltegravir and 1200-mg elemental calcium, as well as dolutegravir and 500-mg elemental calcium.8,9 As such, the manufacturer of E/C/F/TAF recommends the staggered dosing of any antacid including calcium from E/C/F/TAF.6 This recommendation was communicated to the skilled nursing team to avoid concurrent administration in the future. The second patient only received calcium in the form of leucovorin calcium salt. The patient’s daily dose of leucovorin 100 mg contained approximately 8 mg of elemental calcium.10 It may be argued that such a small amount of calcium would not result in a clinically significant interaction. However, having reviewed other plausible causes including nonadherence, malabsorption, and other drug interactions, this possibility remains. Of note, it is estimated that 50% of medications are manufactured as salt forms to improve pharmaceutical properties as in atorvastatin calcium and omeprazole magnesium.11\n\n\nPrevious studies with the integrase inhibitors raltegravir, elvitegravir, and dolutegravir have shown significant effects of concomitant administration with antacids. However, clinical relevance of this interaction has not been described. To the best of our knowledge, these 2 cases are the first reports of rapid emergence of mutation and HIV viral rebound from coadministration of E/C/F/TAF and calcium, possibly even at low doses. It may be prudent to avoid simultaneous coadministration of E/C/F/TAF with any form of calcium and to check the salt forms of all the medications.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nORCID iD: S. Lena Kang-Birken \nhttps://orcid.org/0000-0002-0620-0922\n==== Refs\nReferences\n1 \nSax PE Wohl D Yin MT \nTenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: two randomized, double-blind, phase 3, non-inferiority trials . Lancet . 2015 ;385 (9987 ):2606 –2615 .25890673 \n2 \nArribas JR Thompson M Sax PE \nBrief report: randomized, double-blind comparison of tenofovir alafenamide (TAF) vs tenofovir disoproxil fumarate (TDF), each coformulated with elvitegravir, cobicistat, and emtricitabine (E/C/F) for initial HIV-1 treatment: week 144 results . J Acquir Immune Defic Syndr \n2017 ;75 (2 ):211 –218 .28282300 \n3 \nWhite K Kulkarni R Miller MD \nAnalysis of early resistance development at the first failure timepoint in elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate-treated patients . J Antimicrob Chemother . 2015 ;70 (9 ):2632 –2638 .26108607 \n4 \nMargot NA Cox S Das M McCallister S Miller MD Callebaut C \nRare emergence of drug resistance in HIV-1 treatment-naïve patients receiving elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide for 144 weeks . J Clin Virol . 2018 ;103 :37 –42 .29627709 \n5 \nRamanathan S Mathias A Wei X \nPharmacokinetics of once-daily boosted elvitegravir when administered in combination with acid-reducing agents . J Acquir Immune Defic Syndr . 2013 ;64 (1 ):45 –50 .23774876 \n6 \nGilead Sciences, Inc . Genvoya [package insert] . Foster City, CA : Gilead Sciences, Inc ; 2015 .\n7 \nRamanathan S Mathias AA German P Kearney BP \nClinical pharmacokinetic and pharmacodynamics profile of the HIV integrase inhibitor elvitegravir . Clin Pharmacokinet . 2011 ;50 (4 ):229 –244 .21348537 \n8 \nSong I Borland J Arya N Wynne B Piscitelli S \nPharmacokinetics of dolutegravir when administered with mineral supplements in healthy adults subjects . J Clin Pharmacol . 2015 ;55 (5 ):490 –496 .25449994 \n9 \nKiser JJ Bumpass B Meditz AL \nEffect of antacids on the pharmacokinetics of raltegravir in human immunodeficiency virus-seronegative volunteers . Antimicrob Agents Chemother . 2010 ;54 (12 ):4999 –5003 .20921313 \n10 \nTeva Pharmaceuticals, Inc . Leucovorin Calcium [package insert] . North Wales, PA : Teva Pharmaceuticals, Inc ; 2016 .\n11 \nMcDougall D Hoehns JD Feller TT Witry MJ \nInclusion of salt form on prescription medication labeling as a source of patient confusion: a pilot study . Pharmacy Practice \n2016 ;14 (1 ):677 –681 .27011777\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2325-9574",
"issue": "18()",
"journal": "Journal of the International Association of Providers of AIDS Care",
"keywords": "HIV/AIDS; calcium; elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide; mutation emergence; resistance",
"medline_ta": "J Int Assoc Provid AIDS Care",
"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D002118:Calcium; D002119:Calcium Carbonate; D000069547:Cobicistat; D004347:Drug Interactions; D024882:Drug Resistance, Viral; D000068679:Emtricitabine; D005260:Female; D015658:HIV Infections; D015497:HIV-1; D006801:Humans; D002955:Leucovorin; D015363:Quinolones; D000068698:Tenofovir; D016781:Toxoplasmosis, Cerebral; D019562:Viral Load; D014775:Virus Activation",
"nlm_unique_id": "101603896",
"other_id": null,
"pages": "2325958218821653",
"pmc": null,
"pmid": "30798679",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "27011777;20921313;28282300;25449994;26108607;29627709;23774876;21348537;25890673",
"title": "HIV Viral Rebound Due to a Possible Drug-Drug Interaction between Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide and Calcium-Containing Products: Report of 2 Cases.",
"title_normalized": "hiv viral rebound due to a possible drug drug interaction between elvitegravir cobicistat emtricitabine tenofovir alafenamide and calcium containing products report of 2 cases"
} | [
{
"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-19-01708",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PYRIMETHAMINE"
},
... |
{
"abstract": "Control of the agitated patient in the emergency department is challenging. Many options exist for chemical sedation, but most have suboptimal pharmacodynamic action, and many have undesirable adverse effects. There are reports of ketamine administration for control of agitation prehospital and in traumatically injured patients. Ketamine is a noncompetitive N-methyl-D-aspartic acid receptor antagonist, making it an effective dissociative agent. We present 5 cases of ketamine administration to manage agitated adolescent patients with underlying psychiatric disease and/or drug intoxication. Ketamine, as a dissociative agent, may be an alternative pharmacological consideration for the control of agitation in patients with undifferentiated agitated delirium.",
"affiliations": "From the *Division of Medical Toxicology, Einstein Medical Center Philadelphia, Philadelphia, PA; †Duke University Medical Center, Durham, NC; and ‡Division of Emergency Medicine and §The Poison Control Center, The Children's Hospital of Philadelphia, Philadelphia, PA.",
"authors": "Kowalski|J Michael|JM|;Kopec|Kathryn T|KT|;Lavelle|Jane|J|;Osterhoudt|Kevin|K|",
"chemical_list": "D000778:Anesthetics, Dissociative; D007649:Ketamine",
"country": "United States",
"delete": false,
"doi": "10.1097/PEC.0000000000000578",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0749-5161",
"issue": "33(9)",
"journal": "Pediatric emergency care",
"keywords": null,
"medline_ta": "Pediatr Emerg Care",
"mesh_terms": "D000293:Adolescent; D000778:Anesthetics, Dissociative; D003693:Delirium; D004636:Emergency Service, Hospital; D005260:Female; D006801:Humans; D007273:Injections, Intramuscular; D007649:Ketamine; D008297:Male; D011595:Psychomotor Agitation",
"nlm_unique_id": "8507560",
"other_id": null,
"pages": "e58-e62",
"pmc": null,
"pmid": "26466151",
"pubdate": "2017-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Novel Agent for Management of Agitated Delirium: A Case Series of Ketamine Utilization in the Pediatric Emergency Department.",
"title_normalized": "a novel agent for management of agitated delirium a case series of ketamine utilization in the pediatric emergency department"
} | [
{
"companynumb": "US-TEVA-2017-US-829939",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "KETAMINE"
},
"drugadditional": "3",
"d... |
{
"abstract": "Preoperative neoadjuvant therapy for colorectal liver metastases (CRLM) is increasing in use and can lead to chemotherapy-induced damage to sinusoidal integrity, namely sinusoidal obstruction syndrome (SOS). SOS has been associated with an increased need for intraoperative blood transfusions, increased length of hospitalization post-surgery, decreased tumor response, and a shorter overall survival after resection due to liver insufficiency. It is critical for clinicians and pathologists to be aware of this type of liver injury, and for pathologists to include the status of the background, non-neoplastic liver parenchyma in their pathology reports. In this study, expression of CD34 by sinusoidal endothelial cells (SECs), increased expression of smooth muscle actin (SMA) by hepatic stellate cells (HSCs), and aberrant expression of glutamine synthetase (GS) by noncentrizonal hepatocytes were semiquantitatively evaluated in liver resection or biopsy specimens from patients with CRLM to determine their diagnostic value for assessing chemotherapy-induced sinusoidal injury (CSI).\n\n\n\nThe expression of each marker was compared among 22 patients with CRLM with histologically evident SOS (SOS+) and 8 patients with CRLM who had not undergone chemotherapy. Each case was given a histologic grade using the sinusoidal obstruction syndrome index score (SOS-I) to assess the likelihood of SOS. Cases were also given an immunohistochemical grade using the total CSI score calculated as the sum of CD34, SMA, and GS scores.\n\n\n\nAbnormal staining patterns for CD34 and SMA were significantly more frequent and extensive in SOS+ cases than in the controls (81.8% vs. 25%, P < 0.01; 72.7% vs. 25%, P = 0.03). Aberrant GS expression in midzonal and periportal hepatocytes was only observed in SOS+ cases (31.8% vs. 0%), but this difference did not reach statistical significance. The CSI score was significantly higher in the SOS+ cases when compared to controls (P < 0.01), and was associated with a higher SOS histologic grade (P = 0.02).\n\n\n\nThe CSI score, calculated using an immunohistochemical panel consisting of CD34, SMA, and GS, may serve as an objective marker of chemotherapy-induced sinusoidal injury and could help diagnose this peculiar form of liver injury.",
"affiliations": "Department of Pathology, The University of Texas Medical Branch, John Sealy Annex Building - Room 2.148, 301 University Blvd., Galveston, TX, 77555-0588, USA.;Department of Pathology, The University of Texas Medical Branch, John Sealy Annex Building, 301 University Blvd., Galveston, TX, 77555-0588, USA.;Department of Pathology, The University of Texas Medical Branch, John Sealy Annex Building - Room 2.148, 301 University Blvd., Galveston, TX, 77555-0588, USA. sasatomi@med.unc.edu.",
"authors": "Stevenson|Heather L|HL|;Prats|Mariana M|MM|;Sasatomi|Eizaburo|E|0000-0002-5925-422X",
"chemical_list": "D000199:Actins; D018952:Antigens, CD34; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D005974:Glutamate-Ammonia Ligase; D002955:Leucovorin; D005472:Fluorouracil",
"country": "England",
"delete": false,
"doi": "10.1186/s12885-016-2998-2",
"fulltext": "\n==== Front\nBMC CancerBMC CancerBMC Cancer1471-2407BioMed Central London 299810.1186/s12885-016-2998-2Research ArticleChemotherapy-induced Sinusoidal Injury (CSI) score: a novel histologic assessment of chemotherapy-related hepatic sinusoidal injury in patients with colorectal liver metastasis Stevenson Heather L. 409-772-8554hlsteven@utmb.edu 1Prats Mariana M. 409-772-8554marimore@utmb.edu 2http://orcid.org/0000-0002-5925-422XSasatomi Eizaburo 984-974-9146sasatomi@med.unc.edu 131 Department of Pathology, The University of Texas Medical Branch, John Sealy Annex Building - Room 2.148, 301 University Blvd., Galveston, TX 77555-0588 USA 2 Department of Pathology, The University of Texas Medical Branch, John Sealy Annex Building, 301 University Blvd., Galveston, TX 77555-0588 USA 3 Department of Pathology and Laboratory Medicine, The University of North Carolina at Chapel Hill Women’s & Children’s Hospitals, Room 30212, 101 Manning Drive, Chapel Hill, NC 27514 USA 7 1 2017 7 1 2017 2017 17 3511 5 2016 13 12 2016 © The Author(s). 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nPreoperative neoadjuvant therapy for colorectal liver metastases (CRLM) is increasing in use and can lead to chemotherapy-induced damage to sinusoidal integrity, namely sinusoidal obstruction syndrome (SOS). SOS has been associated with an increased need for intraoperative blood transfusions, increased length of hospitalization post-surgery, decreased tumor response, and a shorter overall survival after resection due to liver insufficiency. It is critical for clinicians and pathologists to be aware of this type of liver injury, and for pathologists to include the status of the background, non-neoplastic liver parenchyma in their pathology reports. In this study, expression of CD34 by sinusoidal endothelial cells (SECs), increased expression of smooth muscle actin (SMA) by hepatic stellate cells (HSCs), and aberrant expression of glutamine synthetase (GS) by noncentrizonal hepatocytes were semiquantitatively evaluated in liver resection or biopsy specimens from patients with CRLM to determine their diagnostic value for assessing chemotherapy-induced sinusoidal injury (CSI).\n\nMethods\nThe expression of each marker was compared among 22 patients with CRLM with histologically evident SOS (SOS+) and 8 patients with CRLM who had not undergone chemotherapy. Each case was given a histologic grade using the sinusoidal obstruction syndrome index score (SOS-I) to assess the likelihood of SOS. Cases were also given an immunohistochemical grade using the total CSI score calculated as the sum of CD34, SMA, and GS scores.\n\nResults\nAbnormal staining patterns for CD34 and SMA were significantly more frequent and extensive in SOS+ cases than in the controls (81.8% vs. 25%, P < 0.01; 72.7% vs. 25%, P = 0.03). Aberrant GS expression in midzonal and periportal hepatocytes was only observed in SOS+ cases (31.8% vs. 0%), but this difference did not reach statistical significance. The CSI score was significantly higher in the SOS+ cases when compared to controls (P < 0.01), and was associated with a higher SOS histologic grade (P = 0.02).\n\nConclusions\nThe CSI score, calculated using an immunohistochemical panel consisting of CD34, SMA, and GS, may serve as an objective marker of chemotherapy-induced sinusoidal injury and could help diagnose this peculiar form of liver injury.\n\nKeywords\nColorectal liver metastasisSinusoidal obstruction syndromeOxaliplatinFOLFOXImpaired liver functionissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nThe liver is the most frequent site of colorectal cancer metastases. Approximately 15 to 25% of patients present with synchronous, and 25 to 30% develop metachronous liver metastasis [1]. Curative metastasectomy is possible in the setting of liver-limited metastases; however, only 15 to 20% of patients are considered candidates for hepatic resection at the time of presentation. Systemic chemotherapy in the preoperative setting is increasingly used to improve the potential benefit of surgery and to downstage initially unresectable disease, allowing for potentially curative surgery [2, 3]. The latter strategy, referred to as “conversion chemotherapy” or “downsizing therapy,” is a major reason for the yearly increase in the number of liver resections for colorectal liver metastases (CRLM). The most commonly used CRLM chemotherapy regimens include oxaliplatin (OX) plus 5-fluorouracil (5-FU) and leucovorin (FOLFOX) and irinotecan plus 5-FU and leucovorin (FOLFIRI). As chemotherapy is often administered prior to hepatic resection, adverse effects on the background liver parenchyma of CRLM patients are increasingly recognized [4, 5]. Recent meta-analysis studies have demonstrated that the nature of preoperative chemotherapy liver injury is a regimen-specific phenomenon [6]. For example, OX-based regimens are associated with sinusoidal injury, whereas irinotecan-based regimens are associated with steatohepatitis. In the context of liver surgery, chemotherapy-induced liver injury could increase the risks of intra- and postoperative complications and postoperative liver insufficiency [7].\n\nSinusoidal obstruction syndrome (SOS), previously termed veno-occlusive disease (VOD), is considered the result of severe toxic injury affecting hepatic sinusoidal endothelial cells (SECs). SOS has been associated with the use of OX-based systemic chemotherapy, cytoreductive therapy prior to hematopoietic stem cell transplantation, hepatic irradiation, pyrrolizidine alkaloid-containing herbal remedies, liver transplantation, and a rare autosomal recessive disorder of the liver and immune system (hepatic veno-occlusive disease with immunodeficiency) [8]. Macroscopically, the affected liver typically has a characteristic bluish-red marbled appearance and therefore, has been called “blue liver syndrome”. Histologically, SOS is characterized by distinct areas of dilated sinusoids with congestion, which may be associated with liver cell plate atrophy. In severe cases, it can also be associated with perisinusoidal fibrosis, nodular regenerative hyperplasia (NRH), obstruction of centrilobular veins, and peliotic change [9]. The reported incidence of OX-induced SOS varies between 8.3 and 54% [9, 10]. Patients with OX-induced SOS in the setting of CRLM have significantly impaired functional hepatic reserve and are predisposed to increased blood transfusions and higher morbidity after the hepatic resection [7]. Recent studies have demonstrated that SOS induced by OX-based chemotherapy might diminish the response to chemotherapy in patients with CRLM [11, 12]. SOS may also compromise liver regeneration in patients undergoing hepatectomy [13]. Therefore, both pathologists and clinicians should be aware of this syndrome as it has a relatively high prevalence and may affect patient outcomes.\n\n“Sinusoidal capillarization” is the altered phenotype of SECs characterized by increased CD34 expression, basement membrane formation, and decreased fenestrae numbers, and is typically seen at the periphery of cirrhotic nodules. In cases of OX-induced liver injury, increased CD34 expression by SECs has been associated with the severity of sinusoidal injury and deterioration of hepatic functional reserve [14, 15]. It is well known that hepatic stellate cells (HSCs) transform from a quiescent vitamin A-rich type to a myofibroblastic fibrogenic phenotype that can produce excessive amounts of extracellular matrix, leading to perisinusoidal fibrosis [16]. While centrilobular perisinusoidal/venular fibrosis is often reported in cases with OX-induced liver injury, the expression status of SMA by HSCs has only been sporadically described in this clinical setting [17, 18]. In the normal liver, GS is expressed exclusively in a narrow rim of pericentral hepatocytes; however, the area of GS-expressing hepatocytes has recently been shown to be significantly expanded in several pathologic conditions including focal nodular hyperplasia (FNH), liver cirrhosis of various etiologies, and idiopathic portal hypertension [19–22]. Because these conditions are associated with altered intrahepatic blood flow caused by shunt vessels or the presence of aberrant vasculature, impaired sinusoidal microcirculation in SOS may also lead to altered GS expression in the hepatic lobules.\n\nThe primary objective of this study was to assess the value of immunohistochemical labeling for CD34, SMA, and GS in the diagnosis of SOS after chemotherapy for CRLM and to develop a scoring system that could be easily implemented by pathologists. Each case was given a histologic grade using the sinusoidal obstruction syndrome index score (SOS-I) to assess the likelihood of SOS. Cases were also given an immunohistochemical grade using the total chemotherapy-induced sinusoidal injury (CSI) score calculated as the sum of CD34, SMA, and GS scores. The relationship between the CSI score and histologic disease severity was also assessed.\n\nMethods\nPatient and tissue selection\nFollowing institutional review board approval, this study was conducted in the Department of Pathology at the University of Pittsburgh Medical Center (UPMC), Presbyterian Hospital. Between January 2012 and December 2013, 121 patients (74 males and 47 females, aged 28 to 91 years, median: 60 years) underwent liver resection for either synchronous or metachronous CRLM or liver biopsy to evaluate the background liver parenchyma. Before the procedure, 72 patients were treated with OX-based chemotherapy, 16 patients were initially treated with OX-based chemotherapy and later converted to irinotecan-based chemotherapy, 9 were treated with irinotecan-based chemotherapy, and 13 were treated with either 5-FU or oral capecitabine alone. Eleven subjects received no chemotherapy. Among these patients, routine histology slides were available in 107 cases. For these cases, hematoxylin & eosin (H&E)-stained non-neoplastic liver parenchyma slides were blindly and independently evaluated by two hepatopathologists (H.L.S. and E.S.). Three exclusion criteria were applied to minimize confounding effects of other possible significant liver injuries and secondary changes resulting from surgery and/or a possible tumor mass effect. These included: 1) the presence of moderate to severe steatosis (steatosis involving greater than 33% of hepatocytes) 2) cases in which the only non-neoplastic liver parenchyma was within 1.5 cm of the cauterized margin or tumor nodules, and 3) cases with well-developed bridging fibrosis or nodule formation. As a result, 40 cases with available slides not meeting the above criteria were excluded from the remainder of the study. For the remaining 67 cases, the likelihood of SOS was assessed based on: 1) the degree of sinusoidal injury, 2) the presence or absence of NRH, and 3) the presence or absence of partial or total venous obstruction as shown in Table 1. The SOS-I was then calculated by summing the sinusoidal injury, NRH, and venous occlusion scores in each case similar to that described previously by Rubbia-Brandt et al. [9]. For those with an SOS-I ≥2 and 0/1, the cases were classified as SOS+ and SOS–, respectively. Of the 67 cases evaluated, all 11 control cases were SOS–. Among the cases treated with chemotherapy, 31 (55.4%) cases were SOS– and 25 (44.6%) cases were SOS+. Of these cases, tissue blocks were available for 8 controls and 22 SOS+ cases. Masson’s trichrome and immunohistochemical stains for CD34, SMA, and GS were performed in these cases. The trichrome stain was blindly evaluated by two hepatopathologists (H.L.S. and E.S.) and scored as 0 or 1, as shown Table 2.Table 1 Histologic grading of sinusoidal obstruction syndrome\n\nSinusoidal Injury (SI)\t\n 0 - No sinusoidal dilatation or congestion\t\n 1 - patchy/confluent areas of sinusoidal dilatation/congestion without hepatocyte atrophy\t\n 2 - patchy/confluent areas of sinusoidal dilatation/congestion with associated mild hepatocyte atrophy\t\n 3 - patchy/confluent areas of sinusoidal dilatation/congestion with associated moderate or severe hepatocyte atrophy\t\nNodular Regenerative Hyperplasia (NRH)\t\n 0 - absent\t\n 1 - present\t\nVenous Obstruction (VO)\t\n 0 - absent\t\n 1 - present, partial obstruction of central venule(s)\t\n 2 - present, total occlusion of central venule(s)\t\nAdapted from Rubbia-Brandt et al. [9]\n\n\nTable 2 Grading of trichrome stain\n\n0 - no perisinusoidal fibrosis\t\n1 - perisinusoidal fibrosis in the areas of sinusoidal dilatation/hepatocyte atrophy\t\n\n\n\nImmunohistochemistry\nRoutinely formalin-fixed and paraffin-embedded liver samples were immunostained with indirect immunohistochemistry using monoclonal antibodies to CD34, SMA, and GS, followed by the appropriate secondary antibodies. The details of the primary antibodies used, their dilutions, and the procedure for antigen retrieval are summarized in Table 3. The reactions were revealed with 3-amino-9-ethylcarbazol (ScyTek Laboratories, West Logan, UT, USA) as a chromogen and then lightly counterstained with modified Gill’s hematoxylin (Ventana Medical Systems, Tucson, AZ, USA). The immunohistochemical stains for CD34, SMA, and GS were blindly evaluated by one of the authors (E.S.) in a semiquantitative manner as shown in Table 4. Briefly, each stain was evaluated and given a staining intensity score of 0 to 3; the results of which were summed to give the CSI score.Table 3 Antibodies used in the study and their specifications\n\nAntibody\tCat number/clone\tSource\tDilution\tAntigen retrieval\t\nCD34\tM7165/clone QBEnd-10\tDAKO (Carpinteria, CA, USA)\t1:25\tSteam slides in preheated Target Retrieval Solution, pH 9 (Carpinteria, CA, USA) for 30 min\t\nSMA\tM0851/clone 1A4\tDAKO (Carpinteria, CA, USA)\t1:50\tNone\t\nGS\tMAB302/clone GS-6\tEMD Millipore (Billerica, MA, USA)\t1:2000\tSteam slides in pre-heated Target Retrieval Solution, Citrate pH 6 (Carpinteria, CA, USA) for 60 min\t\n\nTable 4 Grading of CD34, smooth muscle actin and glutamine synthetase staining\n\nCD34\t\t\n 0 - no periportal sinusoidal staining or focal, (non-circumferential) periportal sinusoidal staining\t\t\n 1 - circumferential periportal sinusoidal staining present\t\t\n 2 - bridging (zone 1 to zone 1) sinusoidal staining present\t\t\n 3 - 2 and midzonal to centrizonal (zone 2 to zone 3) staining\t\t\nSmooth Muscle Actin\t\t\n 0 - no apparent staining or rare isolated positive cells in the perisinusoidal space\t\t\n 1 - many positive cells without linear/continuous pattern of perisinusoidal staining\t\t\n 2 - focal linear/continuous pattern of perisinusoidal staining\t\t\n 3 - multifocal linear/continuous perisinusoidal staining\t\t\nGlutasmine Synthetase\t\t\n 0 - normal perivenular staining pattern\t\t\n 1 - focal midzonal (zone 2) staining present\t\t\n 2 - multifocal midzonal (zone 2) staining present\t\t\n 3 - unequivocal confluent midzonal to periportal staining, if any\t\t\n\n\n\nStatistics\nComparisons between the two groups were carried out with Mann–Whitney U test or Fisher’s exact test using StatPlus:mac Pro (Version 6.1, AnalystSoft Inc., Walnut, CA). Differences were considered significant at P < 0.05.\n\nResults\nHistological evaluation\nThe histologic grade and chemotherapy details in each of these 30 cases are summarized in Table 5. The histologic findings of representative cases are shown in Fig. 1a (control) and Fig. 2a-d (SOS+ cases). Of the 22 SOS+ cases, 17 were treated with OX-based chemotherapy, 4 were initially treated with OX-based chemotherapy and later converted to irinotecan-based chemotherapy, and 1 was principally treated with irinotecan-based chemotherapy. The number of treatment cycles with OX-based chemotherapy was available in 15 cases, and the average was 5.5. In our series, unequivocal venous occlusion was found in only one SOS+ case treated with a FOLFOX regimen (4.5%) (Table 5, Case 14; see also Fig. 2d), and most cases were categorized as SOS+ based on a combination of sinusoidal injury and NRH scores (63.6%) or sinusoidal injury score alone (31.8%). The SOS-I score of the control cases was less than 2 in all cases, and the majority had an SOS-I of score 1 (75%, 6/8), mostly due to sinusoidal dilatation and congestion without significant hepatocyte atrophy. The trichrome stain highlighted perisinusoidal fibrosis in 59% (13/22) of SOS+ cases and 37.5% (3/8) of control cases. There was no statistical difference in the trichrome staining results between the SOS+ and control groups (P = 0.42).Table 5 Expression of CD34, smooth muscle actin and glutamine synthetase in patients with chemotherapy-induced SOS\n\nCase\t\tHistologic Grade\tTrichrome\tImmunohistochemistry Grade\t\t\t\nNo.\tAgea\n\tSI\tNRH\tVO\tSOS-I\t\tCD34\tSMA\tGS\tCSI score\tChemotherapy (cycle #)\t\n1\t70–74\t3\t1\t0\t4\t1\t3\t3\t0\t6\tcapecitabine and oxaliplatin (2)\t\n2\t65–69\t3\t1\t0\t4\t1\t3\t3\t0\t6\tFOLFOX (4)\t\n3\t65–69\t3\t1\t0\t4\t0\t3\t3\t0\t6\tcapecitabin, oxaliplatin (2) and cetuximab\t\n4\t55–59\t3\t1\t0\t4\t0\t3\t1\t3\t7\tFOLFOX (*) and bevacizumab\t\n5\t65–69\t3\t1\t0\t4\t1\t3\t2\t3\t8\tFOLFOX (*)\t\n6\t60–64\t3\t1\t0\t4\t1\t3\t3\t3\t9\tFOLFOX (6)\t\n7\t70–74\t3\t1\t0\t4\t0\t2\t3\t0\t5\tFOLFOX and bevacizumab (6)\t\n8\t50–54\t2\t1\t0\t3\t1\t0\t0\t0\t0\tFOLFOX (6)\t\n9\t70–74\t2\t1\t0\t3\t1\t2\t0\t0\t2\tFOLFOX (*)\t\n10\t65–69\t2\t1\t0\t3\t0\t2\t3\t0\t5\tFOLFOX (*) and bevacizumab\t\n11\t65–69\t3\t0\t0\t3\t1\t3\t3\t2\t8\tFOLFOX (4)\t\n12\t55–59\t3\t0\t0\t3\t1\t3\t3\t1\t7\tFOLFOX (3) and bevacizumab\t\n13\t75–79\t2\t1\t0\t3\t0\t3\t0\t0\t3\tFOLFOX (*)\t\n14\t70–74\t0\t1\t2\t3\t1\t0\t3\t3\t6\tFOLFOX (12)\t\n15\t30–34\t1\t1\t0\t2\t0\t2\t3\t0\t5\tFOLFOX (8), converted to FOLFIRI and bevacizumab\t\n16\t50–54\t2\t0\t0\t2\t1\t2\t3\t0\t5\tFOLFOX (6) and cetuximab\t\n17\t50–54\t2\t0\t0\t2\t0\t0\t0\t0\t0\tFOLFOX (8), converted to FOLFIRI, bevacizumab and cetuximab\t\n18\t55–59\t2\t0\t0\t2\t0\t0\t3\t0\t3\tFOLFOX (4) and bevacizumab\t\n19\t45–49\t2\t0\t0\t2\t1\t1\t3\t3\t7\tFOLFOX (5) and cetuximab converted to FOLFIRI\t\n20\t55–59\t1\t1\t0\t2\t0\t1\t0\t0\t1\tFOLFOX (6)\t\n21\t55–59\t2\t0\t0\t2\t1\t2\t3\t0\t5\tFOLFOX (*), converted to FOLFIRI, avastin and cetuximab\t\n22\t50–54\t1\t1\t0\t2\t1\t2\t0\t0\t2\tFOLFIRI and cetuximab\t\n23\t55–59\t1\t0\t0\t1\t1\t0\t2\t0\t2\tnone\t\n24\t60–64\t1\t0\t0\t1\t0\t1\t0\t0\t1\tnone\t\n25\t50–54\t0\t1\t0\t1\t1\t2\t0\t0\t2\tnone\t\n26\t70–74\t1\t0\t0\t1\t0\t0\t0\t0\t0\tnone\t\n27\t60–64\t1\t0\t0\t1\t1\t0\t3\t0\t3\tnone\t\n28\t55–59\t1\t0\t0\t1\t0\t0\t0\t0\t0\tnone\t\n29\t85–89\t0\t0\t0\t0\t0\t0\t0\t0\t0\tnone\t\n30\t75–79\t0\t0\t0\t0\t0\t0\t0\t0\t0\tnone\t\n\naAges were replaced by age ranges to maintain partient confidentiality\n\n\nSOS sinusoidal obstruction syndrome, SI sinusoidal injury, NRH nodular regenerative hyperplasia, VO venous obstruction, SOS-I SOS index, SMA smooth muscle actin, GS glutamine synthetase, CSI score chemotherapy-induced sinusoidal injury score, OX oxaliplatin, *unknown cycle\n\n\nFig. 1 An example of a control group (case 29 in Table 5) in which a patient with CLRM did not receive chemotherapy prior to resection. a This case showed no significant sinusoidal dilatation, congestion, or parenchymal nodularity (H&E, ×40). b An immunohistochemical stain for CD34 showed the normal staining pattern with only focal weak sinusoidal staining around the portal tracts (arrows, ×200). c Positive immunoreactivity for smooth muscle actin (SMA) was seen in the portal blood vessels, bile ducts, and central venules. No SMA-positive stellate cells were present in the lobules (×200). d An immunohistochemical stain for GS revealed a normal perivenular staining pattern (×100)\n\n\nFig. 2 Common histologic features of SOS. a Shown are changes typical of sinusoidal obstruction (Case 12). Bridging bands of congestion were observed connecting centrizonal areas (H&E, ×40). b In the same case, a trichrome stain highlights prominent fibrosis extending along centrilobular sinusoids and also shows atrophic hepatocyte trabeculae (trichrome stain, ×200). c Nodular regenerative hyperplasia. In some cases (e.g., Case 6), the hepatic parenchyma showed diffuse transformation into small nodules with little to no fibrosis (reticulin stain, ×40). d Venous occlusion. Case 14 showed complete fibrous obliteration of the central veins (H&E, ×100), which was further confirmed with Verhoeff–Van Gieson staining (inset, ×100)\n\n\n\n\nStaining profile for CD34, SMA, and GS\nThe immunohistochemical results for CD34, SMA, and GS are summarized in Table 5. The normal staining patterns of CD34, SMA, and GS in a control case are shown in Fig. 1, and the abnormal staining patterns of CD34, SMA, and GS observed in representative SOS+ cases are shown in Fig. 3. Aberrant CD34 expression in sinusoidal lining cells was significantly more frequent in SOS+ cases (81.8%, 18/22) than in controls 25% (2/8) (P < 0.01), and the CD34 score of SOS+ cases was also significantly higher than that of the controls (P < 0.01). As reflected in the scoring system (see Table 4), the areas of aberrant CD34 expression in SECs first appear in the periportal area and then coalesce into periportal to periportal bridging and further extend to the midzonal and centrizonal areas (Fig. 3a). The areas of aberrant CD34 expression, when present, were observed in multiple areas within the examined samples and were not limited to the areas with histologically recognizable sinusoidal dilatation/congestion. Conversely, SMA expression in perisinusoidal HSCs was more frequently observed in the centrizonal and midzonal areas than in periportal areas. SMA-positive HSCs varied in size and shape but often showed stretched, long cytoplasmic processes that resulted in a confluent linear staining pattern along the perisinusoidal space of Disse (Fig. 3b). The areas showing SMA overexpression in HSCs were multifocal and not limited to the areas with histologically evident sinusoidal dilatation/congestion. SMA expression in HSCs was significantly more frequent in the SOS+ group (72.7%, 16/22) than in the control group (25%, 2/8) (P = 0.03), and the SOS+ group SMA score was higher (P = 0.02). Aberrant GS expression in the midzonal and periportal hepatocytes was less frequent compared to CD34 and SMA. All GS-positive cases were SOS+ (31.8%, 7 of 22) (Fig. 3c and d), and none of the control cases showed aberrant GS expression in either midzonal or periportal hepatocytes (0%, 0 of 8), but this difference did not reach statistical significance (P = 0.14). Notably, 6/7 GS-positive cases showed relatively high SOS-I (SOS-I of 3 or 4) including one case with VOD.Fig. 3 Aberrant expression of CD34, SMA, and GS in cases with sinusoidal obstruction syndrome were used to calculate the CSI score. a In case 12, the immunohistochemistry for CD34 showed confluent sinusoidal staining extending from the periportal to midzonal and centrizonal areas (×100). This is an example of a immunohistochemistry grade 3 for CD34. b Immunohistochemical stain for SMA in the same case showed confluent subsinusoidal staining in multiple areas (×200), which is also an example of a grade 3 staining intensity. c Immunohistochemistry conducted on case 14 showed GS expression adjacent to an obliterated sublobular vein (arrow) that was expanded (×100) compared to the normal perivenular GS staining pattern and was also give an immunohistochemistry score of 3. d In Case 19, aberrant confluent GS expression is seen in midzonal and periportal areas; another example of a grade 3 pattern of staining (asterisks, central veins; arrow, portal tract; ×100)\n\n\n\n\nChemotherapy-induced sinusoidal injury (CSI) score\nThe CSI score was calculated as the sum of the CD34, SMA, and GS scores. The CSI score of the SOS+ group (mean ± standard deviation, 4.82 ± 2.60) was significantly higher than that of the control group (1 ± 1.20) (P < 0.01, Fig. 4a). Within the SOS+ group, the cases with the highest SOS-I (SOS-I = 4) showed significantly higher CSI scores (6.71 ± 1.38) than cases with lower SOS-I (SOS-I = 2 or 3) (3.93 ± 2.56) (P = 0.02, Fig. 4b).Fig. 4 CSI score. Comparison of CSI scores between the SOS+ and control groups (a). Comparison of CSI score between the cases with the highest (SOS-I = 4) and lower SOS-I scores within the SOS+ group (b)\n\n\n\n\nDiscussion\nChemotherapy for CRLM has dramatically improved over the past 15 years, with tumor response rates increasing from 20% with 5-FU alone to 60 to 70% using variable combinations of new chemotherapeutic agents [3]. The current mainstay of chemotherapy for CRLM is FOLFIRI or FOLFOX and the standard chemotherapy backbone in first-line treatment has gradually been shifting from FOLFIRI to FOLFOX during the last decade [23, 24]. While the use of modern chemotherapy regimens has dramatically improved the CRLM response rate, its toxicity on the background liver parenchyma is becoming more recognized. OX-based regimens are associated with SEC injury, which may manifest as SOS, centrilobular, perisinusoidal, or venular fibrosis, NRH, and peliosis-like changes in severe cases [6, 25]. SOS has been associated with an increased need for intraoperative blood transfusions, an increase in the length of stay in the hospital after surgery [7], a decrease in response to chemotherapy [11, 12], early recurrence after resection and a short overall survival after resection due to liver insufficiency [26, 27].\n\nSOS was originally termed hepatic VOD; however, recent experimental studies in pyrrolizidine alkaloid (monocrotaline)-treated rats have clarified that the main injury occurs at the level of the hepatic sinusoids, indicating that central vein involvement is not essential for SOS development [28]. SOS is caused by toxic injury to SECs and loss of sinusoidal wall integrity with subsequent sinusoid blockage by embolized sinusoidal lining cells. Impaired sinusoidal microcirculation leads to metabolic dysfunction and ischemic damage of adjacent liver cell plates, which may cause atrophy and/or dissociation of liver cell plates and further focal hepatocellular necrosis/dropout.\n\nThe histopathologic spectrum of OX-associated liver lesions was extensively investigated by Rubbia-Brandt et al. in a large series of surgically resected CRLM [9]. According to their study, 54% of patients treated with OX-based regimens had moderate/severe SOS, 47% showed centrilobular perisinusoidal/venular fibrosis, 24.5% developed NRH, and 10.6% manifested peliosis hepatis, while the 111 patients treated by surgery alone had no such lesions. Although the histologic spectrum of OX-associated liver lesions has been well documented, the precise histopathologic diagnosis of OX-associated liver injury in the setting of CRLM can be potentially difficult, due to several reasons. First, surgically resected liver specimens for CRLM contain tumor nodules of varying sizes; therefore, the histologic changes of OX-associated liver injury might be obscured by or misinterpreted as local mechanical and/or hemodynamic changes caused by tumor mass effect. This is why it is critical to sample the non-neoplastic liver away from the tumor/tumors; ideally we suggest greater than 1.5 cm away from the metastatic lesions. Second, SOS lesions can be patchy and more prominent in the subcapsular region. Uneven lesion distribution may make diagnosis difficult, particularly in biopsy samples. Even in resection specimens, it may be difficult to differentiate whether focally enhanced sinusoidal dilatation/congestion is clinically an irrelevant localized change or a true manifestation of SOS. Our stains appeared to detect SOS lesions diffusely throughout the liver parenchyma and may reduce this potential sampling error. Third, the histologic detection of perisinusoidal fibrosis and NRH changes might potentially be difficult to detect by inexperienced pathologists, especially without the use of special stains such as trichrome and reticulin, which are not routinely performed on CRLM specimens. While awareness of the histologic spectrum of OX-induced liver injury, careful examination of precise areas, and appropriate use of special stains would reduce diagnostic errors, additional markers of sinusoidal endothelial injury would further improve the diagnosis and provide a more objective assessment of this unusual type of liver injury.\n\nHepatic SECs are highly specialized endothelial cells characterized by fenestrations and the absence of an organized basement membrane. Fenestrae are grouped into sieve plates and control the exchange of fluids, solutes, and particles between the sinusoidal blood and the space of Disse, which contains numerous protruding microvilli of hepatocytes. Unlike vascular endothelium elsewhere in the body (except for splenic sinusoids), hepatic SECs do not express CD34 other than the small areas directly adjacent to portal tracts [29]. In normal conditions, hepatocytes and HSCs maintain the normal SEC phenotype; however, in chronic liver disease, the SECs undergo a phenotypic shift to regular vascular endothelium that is termed “sinusoidal capillarization” [30]. In such conditions, capillarized SECs lack fenestration, develop an organized basement membrane, and express CD34. Sinusoidal capillarization by means of immunohistochemistry for CD34 was observed in 81.8% of SOS+ cases, which was statistically more frequent and more extensive than in controls. To date, immunohistochemical CD34 assessment of sinusoidal capillarization in the setting of chemotherapy-induced liver injury in patients with CRLM has only been reported in a few studies. According to Narita et al., SOS was found in 39 of 80 patients treated with hepatic resection for CRLM after chemotherapy, of which 33 (85%) showed sinusoidal CD34 overexpression [14]. They also found that age over 70 years, male sex, and the presence of SOS were independent factors associated with CD34 overexpression. Nalbantoglu et al. demonstrated aberrant capillarization of the sinusoids by CD34 labeling in 98% (45/46) of cases treated with hepatic resection for CRLM after OX-based chemotherapy, and 41% (19/46) showed extensive staining throughout the lobule [15]. In their series, the overall frequency of sinusoidal capillarization by CD34 was much more frequent than that of histologically recognized OX-induced liver injury (68.1%, 32/47), and extensive multifocal CD34 expression was associated with liver injury severity. As evidenced by our study and others, sinusoidal capillarization is quite frequent in patients with CSI and CRLM and appears to be a fairly early event in the SOS disease process.\n\nWhile SMA upregulation in activated HSCs has been sporadically reported in VOD of the liver after allogeneic bone marrow transplantation, SMA expression status in the setting of chemotherapy-induced sinusoidal endothelial injury in CRLM has only rarely been described [17, 18]. Sato et al. described that the area of activated HSCs significantly increased in zones 1 and 2, was more prominent in zone 3 of the hepatic lobules after bone marrow transplantation compared to normal liver tissues, and was much larger in zone 3 of liver tissues with VOD [31]. Rubbia-Brandt et al. reported strong SMA reactivity in almost all HSCs within the lobules, both along the dilated and intact sinusoids in OX-induced SOS in patients with CRLM, while sparse HSCs were SMA-positive in a small proportion of control liver lobules [18]. In our study, SMA expression in perisinusoidal HSCs was seen in 72.7% of SOS+ cases, which was more frequent and extensive than in the control group. These results are in agreement with previous descriptions and indicate that HSC activation is a salient feature of SOS.\n\nRecent experimental studies have suggested that normal SECs of the liver function as a gatekeeper, preventing HSC activation; however, once the SEC capillarizes, it no longer prevents HSC activation and permits or promotes HSC activation and subsequent fibrosis [30]. Because drugs and toxins that cause SOS are selectively more toxic to SECs than to hepatocytes, the disease is initiated by damage at the sinusoid level. If present, prolonged loss of normal SEC with capillarization permits HSC activation and perisinusoidal fibrosis and fibrous occlusion of central venules in severe cases. Thus, given the recent experimental evidence that aberrant CD34 expression by SECs and subsequent SMA overexpression by perisinusoidal HSCs are essential in SOS initiation and development, immunohistochemical labeling for CD34 and SMA appear to be a reasonable and effective tool to identify CSI in patients with CRLM. The frequent overexpression of these markers in cases with histologically evident SOS in ours and a few other observational studies further support the feasibility of these markers as diagnostic aids in this setting.\n\nGS is exclusively expressed in a subpopulation of hepatocytes situated adjacent to the central veins, and its peculiar zonated distribution is considered to represent a “fail-safe” mechanism for ammonia detoxification in mammals [32]. Ammonia, arriving from the intestine via the portal vein, is first metabolized by periportal hepatocytes through a low-affinity but high-capacity system involving carbamoyl phosphate synthetase and arginase 1 to generate urea. If any ammonia escapes the periportal hepatocytes, it can be scavenged and detoxified by perivenular hepatocytes through a high-affinity but low-capacity system involving GS [33]. Recently, significant expansion of the area of GS-expressing hepatocytes in human liver has been demonstrated in certain circumstances such as FNH, cirrhosis due to various causes, and idiopathic portal hypertension [19–22]. Because these conditions are well known to have altered microcirculation due to the presence of shunt vessels or abnormalities in venous and/or arterial vessels, we tested the GS expression status based on the assumption that an impaired sinusoidal microcirculation in CSI may lead to altered GS expression. In SOS, there appears to be reduced plasma access to hepatocytes due to SEC defenestration, basement membrane formation, and perisinusoidal fibrosis. In severe cases, sinusoidal perfusion might also be impaired due to microthrombi and partial or total fibrous obliteration of the central venules. Considering the fact that perivenular GS plays an important physiological role as a downstream scavenger for ammonia, it is conceivable that aberrant expression of GS in the midzonal and periportal hepatocytes in SOS may possibly represent protective recruitment of hepatocytes upstream from the perivenular area to maintain overall hepatic ammonia disposal. In our study, aberrant GS expression in the midzonal and periportal hepatocytes was observed in 31.8% of SOS+ cases. Interestingly, most GS-positive cases showed relatively high SOS-I, and none of the control cases showed aberrant GS expression, but these differences did not reach statistical significance. One limitation of our study, was a low number of control cases that had not received neoadjuvant chemotherapy prior to resection. This further supports how commonly these agents are used, and with a larger population of patients GS staining would have likely reached statistical significance.\n\nThe diagnosis of CSI should not be made based solely on the histopathologic findings. The diagnosis of CSI/SOS depends on a high index of clinical suspicion, after the clinical exclusion of other potential mimicking causes of liver injury. Several clinical features, such as hyperbilirubinemia, hepatomegaly, ascites, weight gain, and splenomegaly, have been associated with the development of SOS [34, 35], although their sensitivity and specificity have not been well defined. In the appropriate clinical setting, histological examination of the background liver of the patients with CRLM using SOS-I and the CSI scoring system would certainly increase the diagnostic accuracy of CSI. The major limitation of our study was that it compared CRLM SOS+ cases that received chemotherapy with control CRLM cases that did not. Future studies should use our panel to compare CRLM patients that received chemotherapy and are SOS positive with those that received chemotherapy and are SOS negative. This will ensure that chemotherapy use alone does not result in a positive staining pattern with our panel and an elevated CSI score. These studies, combined with correlation of CIS score to clinical features, will provide additional valuable information for the assessment of sensitivity and specificity of CIS score for clinically significant chemotherapy-related liver injury.\n\nConclusions\nThe CSI score, calculated using an immunohistochemical panel consisting of CD34, SMA, and GS, may serve as an objective marker of chemotherapy-induced sinusoidal injury. The uniqueness of our study is although there are a few others reports using these individual markers (SMA, and CD34) as indicators of sinusoidal liver injury, ours is the first to combine them and add GS into a scoring system that can successfully diagnose CSI in liver biopsies and resection specimens in patients with CRLM. Aberrant CD34 expression by SECs and the increase in SMA-positive HSCs seem to represent the pathologic consequences of sinusoidal endothelial injury, and the altered distribution pattern of GS-expressing hepatocytes may represent an adaptive process reflecting impaired sinusoidal microcirculation. Notably, the abnormal staining patterns for CD34, SMA, and GS were not necessarily limited to the areas with sinusoidal dilatation/congestion and appear less susceptible to sampling variability in comparison with histologic evidence of sinusoidal dilatation/congestion. Therefore, the simultaneous use of these markers may increase the sensitivity for detecting CSI.\n\nAbbreviations\n5-FU5-fluorouracil\n\nCRLMColorectal liver metastases\n\nCSIChemotherapy-induced sinusoidal injury\n\nFNHFocal nodular hyperplasia\n\nGSGlutamine synthetase\n\nHSCsHepatic stellate cells\n\nNRHNodular regenerative hyperplasia\n\nOXOxaliplatin\n\nSECsSinusoidal endothelial cells\n\nSMASmooth muscle actin\n\nSOSSinusoidal obstruction syndrome\n\nSOS-ISinusoidal obstruction syndrome index score\n\nVODVeno-occlusive disease\n\nAcknowledgements\nWe thank Dr. Yan Xie (Department of Pathology, University of Texas Medical Branch) for statistical analysis support.\n\nFunding\nThis work did not receive funding.\n\nAvailability of data and materials\nThe primary datasets supporting the conclusions of this article are included within the article (Table 5).\n\nAuthors’ contributions\nES and HLS participated in the design of the study. MMP performed the statistical analyses. All authors participated in discussion and contributed to interpretation of data. All authors were involved in manuscript writing and approved the final manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent for publication\nNot applicable.\n\nEthics approval and consent to participate\nThe ethics board of the University of Pittsburgh Medical Center recognized this retrospective study was for quality-improvement purposes and did not require ethics approval. This study was approved by Total Quality Council at the Pittsburgh Medical Center, which waived the requirement for patients’ consent.\n==== Refs\nReferences\n1. Schlag PM Benhidjeb T Stroszczynski C Resection and local therapy for liver metastases Best Pract Res Clin Gastroenterol 2002 16 299 317 10.1053/bega.2002.0286 11969240 \n2. Bartlett DL Chu E Can metastatic colorectal cancer be cured? Oncology (Williston Park) 2012 26 266 75 22545311 \n3. Folprecht G Gruenberger T Bechstein W Raab HR Weitz J Lordick F Hartmann JT Stoehlmacher-Williams J Lang H Trarbach T Liersch T Ockert D Jaeger D Steger U Suedhoff T Rentsch A Köhne CH Survival of patients with initially unresectable colorectal liver metastases treated with FOLFOX/cetuximab or FOLFIRI/cetuximab in a multidisciplinary concept (CELIM study) Ann Oncol 2014 25 1018 25 10.1093/annonc/mdu088 24585720 \n4. McWhirter D Kitteringham N Jones RP Malik H Park K Palmer D Chemotherapy induced hepatotoxicity in metastatic colorectal cancer: a review of mechanisms and outcomes Crit Rev Oncol Hematol 2013 88 404 15 10.1016/j.critrevonc.2013.05.011 23786843 \n5. Nguyen-Khac E, Lobry C, Chatelain D, Fuks D, Joly JP, Brevet M, Tramier B, Mouly C, Hautefeuille V, Chauffert B, Regimbeau JM. A reappraisal of chemotherapy-induced liver injury in colorectal liver metastases before the era of antiangiogenics. Int J Hepatol. 2013;2013(314868):11.\n6. Robinson SM Wilson CH Burt AD Manas DM White SA Chemotherapy-associated liver injury in patients with colorectal liver metastases: a systematic review and meta-analysis Ann Surg Oncol 2012 19 4287 99 10.1245/s10434-012-2438-8 22766981 \n7. Kneuertz PJ Maithel SK Staley CA Kooby DA Chemotherapy-associated liver injury: impact on surgical management of colorectal cancer liver metastases Ann Surg Oncol 2011 18 181 90 10.1245/s10434-010-1201-2 20645011 \n8. Fan CQ Crawford JM Sinusoidal obstruction syndrome (hepatic veno-occlusive disease) J Clin Exp Hepatol 2014 4 332 46 10.1016/j.jceh.2014.10.002 25755580 \n9. Rubbia-Brandt L Lauwers GY Wang H Majno PE Tanabe K Zhu AX Brezault C Soubrane O Abdalla EK Vauthey JN Mentha G Terris B Sinusoidal obstruction syndrome and nodular regenerative hyperplasia are frequent oxaliplatin-associated liver lesions and partially prevented by bevacizumab in patients with hepatic colorectal metastasis Histopathology 2010 56 430 9 10.1111/j.1365-2559.2010.03511.x 20459550 \n10. Morine Y Shimada M Utsunomiya T Evaluation and management of hepatic injury induced by oxaliplatin-based chemotherapy in patients with hepatic resection for colorectal liver metastasis Hepatol Res 2014 44 59 69 10.1111/hepr.12107 23551330 \n11. Vreuls CP Van Den Broek MA Winstanley A Koek GH Wisse E Dejong CH Olde Damink SW Bosman FT Driessen A Hepatic sinusoidal obstruction syndrome (SOS) reduces the effect of oxaliplatin in colorectal liver metastases Histopathology 2012 61 314 8 10.1111/j.1365-2559.2012.04208.x 22571348 \n12. Viganò L Capussotti L De Rosa G De Saussure WO Mentha G Rubbia-Brandt L Liver resection for colorectal metastases after chemotherapy: impact of chemotherapy-related liver injuries, pathological tumor response, and micrometastases on long-term survival Ann Surg 2013 258 731 40 10.1097/SLA.0b013e3182a6183e 24045448 \n13. Narita M Oussoultzoglou E Chenard MP Rosso E Casnedi S Pessaux P Bachellier P Jaeck D Sinusoidal obstruction syndrome compromises liver regeneration in patients undergoing two-stage hepatectomy with portal vein embolization Surg Today 2011 41 7 17 10.1007/s00595-010-4414-x 21191686 \n14. Narita M Oussoultzoglou E Chenard MP Fuchshuber P Rather M Rosso E Addeo P Jaeck D Bachellier P Liver injury due to chemotherapy-induced sinusoidal obstruction syndrome is associated with sinusoidal capillarization Ann Surg Oncol 2012 19 2230 7 10.1245/s10434-011-2112-6 22402811 \n15. Nalbantoglu IL Tan BR Jr Linehan DC Gao F Brunt EM Histological features and severity of oxaliplatin-induced liver injury and clinical associations J Dig Dis 2014 15 553 60 10.1111/1751-2980.12177 25060628 \n16. Blomhoff R Wake K Perisinusoidal stellate cells of the liver: important roles in retinol metabolism and fibrosis FASEB J 1991 5 271 7 2001786 \n17. Kang GH Moon HS Lee ES Kim SH Sung JK Lee BS Jeong HY Lee HY Kang DY A case of liver fibrosis with splenomegaly after oxaliplatin-based adjuvant chemotherapy for colon cancer J Korean Med Sci 2013 28 1835 8 10.3346/jkms.2013.28.12.1835 24339718 \n18. Rubbia-Brandt L Audard V Sartoretti P Roth AD Brezault C Le Charpentier M Dousset B Morel P Soubrane O Chaussade S Mentha G Terris B Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer Ann Oncol 2004 15 460 6 10.1093/annonc/mdh095 14998849 \n19. Bioulac-Sage P Laumonier H Rullier A Cubel G Laurent C Zucman-Rossi J Balabaud C Over-expression of glutamine synthetase in focal nodular hyperplasia: a novel easy diagnostic tool in surgical pathology Liver Int 2009 29 459 65 10.1111/j.1478-3231.2008.01849.x 18803590 \n20. Joseph NM Ferrell LD Jain D Torbenson MS Wu TT Yeh MM Kakar S Diagnostic utility and limitations of glutamine synthetase and serum amyloid-associated protein immunohistochemistry in the distinction of focal nodular hyperplasia and inflammatory hepatocellular adenoma Mod Pathol 2014 27 62 72 10.1038/modpathol.2013.114 23807780 \n21. Fleming KE Wanless IR Glutamine synthetase expression in activated hepatocyte progenitor cells and loss of hepatocellular expression in congestion and cirrhosis Liver Int 2013 33 525 34 10.1111/liv.12099 23362937 \n22. Sato Y Harada K Sasaki M Nakanuma Y Altered intrahepatic microcirculation of idiopathic portal hypertension in relation to glutamine synthetase expression Hepatol Res 2015 45 1323 30 10.1111/hepr.12506 25692330 \n23. Song X Zhao Z Barber B Gregory C Wang PF Long SR Treatment patterns and metastasectomy among mCRC patients receiving chemotherapy and biologics Curr Med Res Opin 2011 27 123 30 10.1185/03007995.2010.536912 21128878 \n24. Hess GP Wang PF Quach D Barber B Zhao Z Systemic therapy for metastatic colorectal cancer: patterns of chemotherapy and biologic therapy use in US medical oncology practice J Oncol Pract 2010 6 301 7 10.1200/JOP.2010.000072 21358960 \n25. Schwarz RE Berlin JD Lenz HJ Nordlinger B Rubbia-Brandt L Choti MA Systemic cytotoxic and biological therapies of colorectal liver metastases: expert consensus statement HPB (Oxford) 2013 15 106 15 10.1111/j.1477-2574.2012.00558.x 23297721 \n26. Nakano H Oussoultzoglou E Rosso E Casnedi S Chenard-Neu MP Dufour P Bachellier P Jaeck D Sinusoidal injury increases morbidity after major hepatectomy in patients with colorectal liver metastases receiving preoperative chemotherapy Ann Surg 2008 247 118 24 10.1097/SLA.0b013e31815774de 18156931 \n27. Tamandl D Klinger M Eipeldauer S Herberger B Kaczirek K Gruenberger B Gruenberger T Sinusoidal obstruction syndrome impairs long-term outcome of colorectal liver metastases treated with resection after neoadjuvant chemotherapy Ann Surg Oncol 2011 18 421 30 10.1245/s10434-010-1317-4 20844968 \n28. DeLeve LD Shulman HM McDonald GB Toxic injury to hepatic sinusoids: sinusoidal obstruction syndrome (veno-occlusive disease) Semin Liver Dis 2002 22 27 42 10.1055/s-2002-23204 11928077 \n29. Pusztaszeri MP Seelentag W Bosman FT Immunohistochemical expression of endothelial markers CD31, CD34, von Willebrand factor, and Fli-1 in normal human tissues J Histochem Cytochem 2006 54 385 95 10.1369/jhc.4A6514.2005 16234507 \n30. DeLeve LD Liver sinusoidal endothelial cells in hepatic fibrosis Hepatology 2015 61 1740 6 10.1002/hep.27376 25131509 \n31. Sato Y Asada Y Hara S Marutsuka K Tamura K Hayashi T Sumiyoshi A Hepatic stellate cells (Ito cells) in veno-occlusive disease of the liver after allogeneic bone marrow transplantation Histopathology 1999 34 66 70 10.1046/j.1365-2559.1999.00569.x 9934587 \n32. Gebhardt R Baldysiak-Figiel A Krügel V Ueberham E Gaunitz F Hepatocellular expression of glutamine synthetase: an indicator of morphogen actions as master regulators of zonation in adult liver Prog Histochem Cytochem 2007 41 201 66 10.1016/j.proghi.2006.12.001 17368308 \n33. Colnot S Perret C Monga SPS Liver zonation Molecular pathology of liver diseases 2011 New York Springer 7 29 \n34. Dignan FL Wynn RF Hadzic N Karani J Quaglia A Pagliuca A Veys P Potter MN Haemato-oncology Task Force of British Committee for Standards in Haematology; British Society for Blood and Marrow Transplantation BCSH/BSBMT guideline: diagnosis and management of veno-occlusive disease (sinusoidal obstruction syndrome) following haematopoietic stem cell transplantation Br J Haematol 2013 163 444 57 10.1111/bjh.12558 24102514 \n35. Overman MJ Maru DM Charnsangavej C Loyer EM Wang H Pathak P Eng C Hoff PM Vauthey JN Wolff RA Kopetz S Oxaliplatin-mediated increase in spleen size as a biomarker for the development of hepatic sinusoidal injury J Clin Oncol 2010 28 2549 55 10.1200/JCO.2009.27.5701 20406923\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2407",
"issue": "17(1)",
"journal": "BMC cancer",
"keywords": "Colorectal liver metastasis; FOLFOX; Impaired liver function; Oxaliplatin; Sinusoidal obstruction syndrome",
"medline_ta": "BMC Cancer",
"mesh_terms": "D000199:Actins; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018952:Antigens, CD34; D000971:Antineoplastic Combined Chemotherapy Protocols; D015179:Colorectal Neoplasms; D005260:Female; D005472:Fluorouracil; D005974:Glutamate-Ammonia Ligase; D006498:Hepatectomy; D006504:Hepatic Veno-Occlusive Disease; D006801:Humans; D002955:Leucovorin; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin",
"nlm_unique_id": "100967800",
"other_id": null,
"pages": "35",
"pmc": null,
"pmid": "28061766",
"pubdate": "2017-01-07",
"publication_types": "D016428:Journal Article",
"references": "23533786;18803590;25692330;18156931;21128878;24102514;20406923;25060628;22571348;25755580;21191686;20645011;2001786;17368308;24045448;16234507;9934587;11928077;23362937;11969240;25131509;23551330;14998849;23786843;22402811;22545311;22766981;21358960;20459550;23807780;23297721;24339718;24585720;20844968",
"title": "Chemotherapy-induced Sinusoidal Injury (CSI) score: a novel histologic assessment of chemotherapy-related hepatic sinusoidal injury in patients with colorectal liver metastasis.",
"title_normalized": "chemotherapy induced sinusoidal injury csi score a novel histologic assessment of chemotherapy related hepatic sinusoidal injury in patients with colorectal liver metastasis"
} | [
{
"companynumb": "US-ROCHE-1905091",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"drugadditional": "3",
"drug... |
{
"abstract": "Infective endocarditis (IE) secondary to rat-bite fever (RBF) is rare but potentially lethal. Rapid diagnosis is of utmost prognostic importance. However, the diagnosis of RBF is challenging because Streptobacillus moniliformis does not grow under conventional culture conditions.\nA 65-year-old male without previous cardiac history presented with sudden onset of balance problems and facial palsy. For 2 weeks, he had experienced intermittent fever and myalgia. Transoesophageal echocardiography (TOE) revealed severe mitral and aortic valve IE with aortic root abscess. The patient underwent a double biological valve replacement. Blood cultures remained negative after 9 days of incubation. However, sub-cultivation on solid media demonstrated the growth of pleomorphic Gram-negative rods, identified as S. moniliformis. After 4 weeks of antibiotic therapy, he was discharged. One month later, control TOE showed valve excrescences and aortic annular aneurysm. Despite comprehensive surgery, antibiotic treatment, and intensive care, the patient died 1 week after reoperation.\nA fatal outcome of S. moniliformis IE is rare. The majority of previous cases describe underlying valvular abnormalities or death due to insufficient antimicrobial therapy. Here, the patient had no prehistory of valvular heart disease and despite appropriate antibiotics, the outcome was fatal. Rapid diagnosis of RBF IE has prognostic implications. Identification of S. moniliformis is, however, difficult, because the bacterium is fastidious and does not grow under standard laboratory conditions. Therefore, diagnosis often relies on clinical symptoms or a history of rodent exposure. Close attention to this disease by clinicians, in addition to, dialogue with clinical microbiologists is essential.",
"affiliations": "Department of Clinical Microbiology, Aarhus University Hospital, Palle Juul-Jensens Blvd. 99, 8200, Aarhus, Denmark.;Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark.;Department of Clinical Microbiology, Aalborg University Hospital, Denmark.;Department of Clinical Microbiology, Aalborg University Hospital, Denmark.",
"authors": "Winther|Mette|M|0000-0001-9814-4448;Jensen|Hanne Sortsøe|HS|0000-0002-8611-1427;Harder Tarpgaard|Irene|I|0000-0001-5723-1609;Nielsen|Hans Linde|HL|0000-0002-2370-417X",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/ehjcr/ytaa254",
"fulltext": "\n==== Front\nEur Heart J Case Rep\nEur Heart J Case Rep\nehjcr\nEuropean Heart Journal: Case Reports\n2514-2119 Oxford University Press \n\n10.1093/ehjcr/ytaa254\nytaa254\nCase Reports\nOther\nAcademicSubjects/MED00200\nCase report: A fatal case of aortic and mitral valve endocarditis caused by Streptobacillus moniliformis\nhttp://orcid.org/0000-0001-9814-4448Winther Mette \nDepartment of Clinical Microbiology, Aarhus University Hospital, Palle Juul-Jensens Blvd. 99, 8200, Aarhus, Denmark\n\nDepartment of Clinical Microbiology, Aalborg University Hospital, Denmark\n http://orcid.org/0000-0002-8611-1427Jensen Hanne Sortsøe \nDepartment of Cardiology, Aalborg University Hospital, Aalborg, Denmark\n http://orcid.org/0000-0001-5723-1609Harder Tarpgaard Irene \nDepartment of Clinical Microbiology, Aalborg University Hospital, Denmark\n http://orcid.org/0000-0002-2370-417XNielsen Hans Linde \nDepartment of Clinical Microbiology, Aalborg University Hospital, Denmark\n\nDepartment of Clinical Medicine, Aalborg University, Aalborg, Denmark\n Khan Tina Handling Editor Simovic Stefan Editor Miglioranza Marcelo Haertel Editor Abdulhak Aref Bin Editor Patel Peysh A Editor Corresponding author. Tel: +45 27 26 68 77, Email: mettejoh@rm.dk, mjmail12@gmail.com\n10 2020 \n09 9 2020 \n09 9 2020 \n4 5 1 6\n11 1 2020 2 3 2020 13 7 2020 © The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.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\nBackground\nInfective endocarditis (IE) secondary to rat-bite fever (RBF) is rare but potentially lethal. Rapid diagnosis is of utmost prognostic importance. However, the diagnosis of RBF is challenging because Streptobacillus moniliformis does not grow under conventional culture conditions.\n\nCase summary\nA 65-year-old male without previous cardiac history presented with sudden onset of balance problems and facial palsy. For 2 weeks, he had experienced intermittent fever and myalgia. Transoesophageal echocardiography (TOE) revealed severe mitral and aortic valve IE with aortic root abscess. The patient underwent a double biological valve replacement. Blood cultures remained negative after 9 days of incubation. However, sub-cultivation on solid media demonstrated the growth of pleomorphic Gram-negative rods, identified as S. moniliformis. After 4 weeks of antibiotic therapy, he was discharged. One month later, control TOE showed valve excrescences and aortic annular aneurysm. Despite comprehensive surgery, antibiotic treatment, and intensive care, the patient died 1 week after reoperation.\n\nDiscussion\nA fatal outcome of S. moniliformis IE is rare. The majority of previous cases describe underlying valvular abnormalities or death due to insufficient antimicrobial therapy. Here, the patient had no prehistory of valvular heart disease and despite appropriate antibiotics, the outcome was fatal. Rapid diagnosis of RBF IE has prognostic implications. Identification of S. moniliformis is, however, difficult, because the bacterium is fastidious and does not grow under standard laboratory conditions. Therefore, diagnosis often relies on clinical symptoms or a history of rodent exposure. Close attention to this disease by clinicians, in addition to, dialogue with clinical microbiologists is essential.\n\nStreptobacillus moniliformisInfective endocarditisFatal outcomeRat-bite feverZoonotic infectionCase report\n==== Body\nLearning points\nPossible rodent exposure several months before the diagnosis of infective endocarditis (IE) should be thoroughly explored.\n\nTo prevent complications and a delayed diagnosis, collaboration between clinicians and clinical microbiologists is essential to improve Streptobacillus moniliformis identification as the bacteria cannot be grown under standard laboratory conditions.\n\nClose follow-up and extension of antibiotic therapy may be considered in patients with severe rat-bite fever IE.\n\n\n\n\nIntroduction\n\nStreptobacillus moniliformis is the causative pathogen of rat-bite fever (RBF) in Europe and North America.1 The bacterium is a fastidious Gram-negative bacillus found as a normal part of the oro- and nasopharyngeal microbiota of rats and transmission to humans occurs through contact with infected rodents.1,2\n\nRat-bite fever is a rare zoonosis that manifests as an acute systemic disease. Symptoms are characterized by fever, headache, maculopapular rash, and migratory polyarthritis.1 Reported complications include meningitis, focal abscesses, and infective endocarditis (IE).3 The estimated overall mortality rate of untreated RBF is 7–13%.1,4,5\n\nAs RBF IE is potentially lethal, the diagnosis of streptobacillosis has important prognostic implications. However, identification of S. moniliformis is challenging as the bacterium does not grow under standard laboratory conditions. Therefore, diagnosis depends on clinical symptoms in combination with a history of relevant exposure. Here, we report a fatal case of native aortic and mitral valve IE secondary to S. moniliformis bacteraemia.\n\nTimeline\nApproximately 2 months prior to admission\t Rate bite in several toes\t\nDay 1\tAdmission to hospital.\t\nDay 6\tTransoesophageal echocardiography (TOE) revealed severe infective endocarditis (IE). Initiation of intravenous meropenem 2 g two times daily for blood culture-negative IE.\t\nDay 7\tSurgical management of IE.\t\nDay 13\tIncreased meropenem dosage to 2 g three times daily and the addition of gentamicin 3 mg/kg (according to Danish guidelines on blood culture-negative IE).\t\nDay 17\tIdentification of Streptobacillus moniliformis (by sub-cultivation).\t\nDay 19\tAntibiotic treatment was switched to benzylpenicillin 3 g four times daily plus gentamicin 3 mg/kg.\t\nDay 34\tCompletion of the antibiotic course. The patient was discharged without clinical or TOE signs of infection to a rehabilitation facility.\t\nDay 66\tControl TOE revealed valve excrescences, aortic annular aneurysm, and loosening of the mitral valve prosthesis.\t\nAdministration of benzylpenicillin 3 g four times daily plus gentamicin 3 mg/kg was initiated.\t\nDay 74\tReoperation.\t\nDay 81\tPatient died.\t\nCase presentation\nA 65-year-old Danish male with a medical history of type 2 diabetes and hypertension was admitted to the hospital with suspicion of ischaemic stroke due to sudden onset of balance problems and facial palsy. For 2 weeks, the patient had experienced discomfort, intermittent fever, and myalgia. On examination, he was afebrile and vital parameters were normal. The patient presented no cardiovascular symptoms, and the cardiovascular examination was normal. Electrocardiogram showed sinus rhythm and right bundle branch block (Figure 1).\n\nFigure 1 Initial electrocardiogram showed sinus rhythm and right bundle branch block.\n\nBlood tests showed a C-reactive protein level of 135 mg/L, haemoglobin 7.3 mmol/L, and creatinine 141 µmol/L, but normal leucocyte and platelet count of 6.4 × 109/L and 167 × 109/L, respectively. Other laboratory results were also within the normal range. Magnetic resonance imaging of the brain demonstrated ischaemic changes involving both the cerebellar hemispheres and the right frontal lobe (Figure 2). Computed tomography (CT) of the chest, abdomen, and pelvis showed a minor splenic abscess and intravenous cefuroxime 3 g every 8 h was initiated on suspicion of acute cardioembolic cerebral infarction given the manifestations in the brain and spleen. Six days after admission, a transoesophageal echocardiography (TOE) verified severe mitral valve and aortic valve IE with aortic root abscess (Figure 3A, Videos 1 and 2), and the antibiotic therapy was changed to intravenous meropenem 2 g every 12 h for presumed blood culture-negative IE (BCNIE). The following day, the patient underwent double biological valve replacement, debridement, and irrigation of the aortic root abscess.\n\nFigure 2 Magnetic resonance imaging of the brain (T2 FLAIR) demonstrated ischaemic changes in the cerebellar hemispheres.\n\nFigure 3 (A) Diagnostic transoesophageal echocardiography revealed severe aortic valve and mitral valve infective endocarditis as well as aortic root abscess. (B) Transoesophageal echocardiography before discharge showed no pendulous excrescences. (C, D) Control transoesophageal echocardiography 4 weeks after discharge showed severe valve excrescences, aortic annular aneurysm, and loosening of the mitral valve prosthesis.\n\nIn total, one blood culture set was obtained prior to the initiation of antibiotic treatment and two sets after antibiotic administration. After 9 days of incubation, blood cultures (BD BACTECTM FX) remained negative, but a sub-cultivation of one primary aerobic bottle onto solid media (10% horse blood agar plates, incubated at 35°C in 5% CO2) was performed and yielded growth of Gram-negative pleomorphic rods 4 days hereafter. By the use of MALDI TOF-MS (Biotyper 3.1, Bruker Daltonik, Germany), the bacterium was identified to species-level as S. moniliformis (log-score 2.410) and whole-genome-sequencing was performed using the Illumina MiSeq instrument, confirming the isolate as S. moniliformis (data not shown). In addition, S. moniliformis was detected on both heart valves by 16S rRNA sequencing. Antimicrobial susceptibility testing was performed by using Etest (BioMérieux, Marcy l’Etoile, France) according to the EUCAST pharmacokinetics/pharmacodynamics (non-species related) breakpoints. The isolate was susceptible to benzylpenicillin (MIC: 0.016 mg/L) and ceftriaxone (MIC: 0.016 mg/L).\n\nOn further questioning after S. moniliformis identification, the patient recalled having been bitten by rats in several toes ∼2 months prior to admission. Intravenous meropenem was later increased to 2 g every 8 h in combination with intravenous gentamicin 3 mg/kg every 24 h. Administration of gentamicin was terminated after 10 days due to high serum-gentamicin levels (data not shown). Hereafter treatment was switched to definitive therapy with intravenous benzylpenicillin 3 g every 6 h.\n\nThe post-operative course was complicated by third-degree atrioventricular-block with the need for permanent pacemaker implantation. After 4 weeks of antibiotic treatment, control TOE showed no pendulous excrescences (Figure 3B), and the patient was discharged. However, at 1-month follow-up visit a TOE revealed severe valve excrescences, aortic annular aneurysm, and loosening of the mitral valve prosthesis (Figure 3C,D). Cardiac CT showed severe tissue destruction in the aorto-mitral area (Figure 4). Blood cultures, in addition to, sub-cultivation on solid media were performed, but the growth of S. moniliformis was not detected. One week later, reoperation was performed including double valve replacement. Post-operatively, the patient developed biventricular heart failure requiring veno-arterial extracorporeal membrane oxygenation. Despite comprehensive intensive care, the patient died 1 week post-operatively.\n\n\nFigure 4 Cardiac computed tomography showed severe tissue destruction in the aorto-mitral area. Left anterior descending artery (LAD).\n\nDiscussion\nThis is the first fatal case of IE caused by S. moniliformis in Denmark, and to our current knowledge, the first fatal case treated with antimicrobial agents in Europe. The prevalence of RBF is rare. The disease may, however, be underdiagnosed due to a lack of information on rodent contact and presentation of non-species-specific clinical symptoms.\n\nThe prevalence of IE secondary to RBF is rare but uncertain. Nevertheless, this complication is the best described with a reported mortality rate as high as 53%.1,5,6 A majority of previous reports have described underlying cardiac valvular abnormalities, mostly rheumatic, or death as outcome in absence of effective antibiotic therapy or inadequate antibiotic dosing.1,6–8 In literature, only 26 cases with native valve RBF IE have been reported.5\n\nIsolation and identification of S. moniliformis from clinical samples have recently been thoroughly reviewed by Eisenberg et al.9 Sodium polyanethol sulfonate, an anticoagulant, present in most commercial blood culture bottles inhibits the growth of S. moniliformis and therefore challenges isolation from routine blood cultures.9,10 In addition, S. moniliformis is a fastidious bacterium requiring microaerophilic growth conditions and benefits from added CO2 (5–10%). For optimal cultivation, enriched artificial media is preferable.\n\nIn the present case, all aerobic and anaerobic blood cultures remained negative in the BACTECTM FX blood culture system after 14 days of incubation. Due to clinical suspicion of IE, sub-cultivation was performed in order to detect potentially fastidious microorganisms. This method is described in the 2015 ESC Guidelines for the management of IE.11 In addition, the guideline proposes a diagnostic strategy for BCNIE including serological testing as well as rheumatoid factors and polymerase chain reaction. Several studies have shown that serological evaluation may aid in diagnosis in BCNIE.12,13 However, no serological tests for RBF are available. A reliable method for species identification of S. moniliformis is the use of MALDI TOF-MS.9 16S rRNA gene sequencing can be used, but insufficient species resolution of 16S rRNA gene sequencing is possible.5,9\n\nDue to the rarity of RBF IE, no treatment guidelines exist. However, high-dose benzylpenicillin (12 g/day) for 4 weeks in combination with gentamicin for the initial 2 weeks has been recommended.1 Our isolate was fully susceptible to penicillin, and therefore interpreted as fully susceptible to carbapenem. According to literature, no in vitro resistance to penicillin has been described.\n\nIn the present case, the patient was not known with a prehistory of valvular heart disease and despite apparent in vitro susceptibility, treatment failed. The cause of this failure is uncertain. Nevertheless, even though identification of S. moniliformis was successful, the diagnosis was delayed due to lack of an exposure history, non-specific symptoms, and difficulties in culture diagnosis, i.e., lack of growth in blood cultures under standard conditions. Due to the fatal outcome presented here, we advocate for a treatment duration of 6 weeks, in addition to, a closer follow-up regimen.\n\nConclusion\nGiven the risk of complications and potential lethal outcomes of RBF, the diagnosis of streptobacillosis has important prognostic implications. Identification of S. moniliformis is, however, difficult as the bacterium does not grow under standard laboratory conditions. Therefore, close attention to this disease by clinicians including exposure history in patients with severe IE along with a dialogue with clinical microbiologists is of utmost importance.\n\nLead author biography\n\n\n\n\nMette Winther is a graduate from Medical School at Aarhus University, Denmark, in 2009. In 2016, she earned her PhD from Aarhus University and is currently a specialty trainee at Department of Clinical Microbiology at Aarhus University Hospital, Denmark. Microbiological areas of particular interest to Mette Winther include bacteria associated with IE. In addition, she is a board member of Danish Society of Clinical Microbiology.\n\nSupplementary Material\nytaa254_Supplemntary_Data Click here for additional data file.\n\n Acknowledgements\nThe authors thank David Fuglsang-Damgaard for technical support and laboratory staff for excellent assistance. \n\nSupplementary material \n\nSupplementary material is available at European Heart Journal - Case Reports online.\n\n\nSlide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data. \n\n\nConsent: The authors confirm that written informed consent for publication of this case report including images had been obtained from the patient in line with COPE guidance. \n\n\nConflict of interest: none declared.\n==== Refs\nReferences\n1 \nElliott SP. \nRat bite fever and Streptobacillus moniliformis\n. Clin Microbiol Rev 2007 ;20 :13 –22\n.17223620 \n2 \nWullenweber M. \n\nStreptobacillus moniliformis—a zoonotic pathogen. Taxonomic considerations, host species, diagnosis, therapy, geographical distribution\n. Lab Anim 1995 ;29 :1 –15\n.7707673 \n3 \nBennett JE , Dolin R , Blaser MJ. \nMandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases , 8th ed \nNew York, NY : \nElsevier, Saunders ; 2015 .\n4 \nHagelskjaer L , Sorensen I , Randers E. \n\nStreptobacillus moniliformis infection: 2 cases and a literature review\n. Scand J Infect Dis 1998 ;30 :309 –311\n.9790145 \n5 \nTorres-Miranda D , Moshgriz M , Siegel M. \n\nStreptobacillus moniliformis mitral valve endocarditis and septic arthritis: the challenges of diagnosing rat-bite fever endocarditis\n. Infect Dis Rep 2018 ;10 :7731 .30344968 \n6 \nRupp ME. \n\nStreptobacillus moniliformis endocarditis: case report and review\n. Clin Infect Dis 1992 ;14 :769 –772\n.1562665 \n7 \nChen PL , Lee NY , Yan JJ , Yang YJ , Chen HM , Chang CM , et alProsthetic valve endocarditis caused by Streptobacillus moniliformis: a case of rat bite fever\n. J Clin Microbiol 2007 ;45 :3125 –3126\n.17652475 \n8 \nRordorf T , Zuger C , Zbinden R , von Graevenitz A , Pirovino M. \n\nStreptobacillus moniliformis endocarditis in an HIV-positive patient\n. Infection 2000 ;28 :393 –394\n.11139161 \n9 \nEisenberg T , Ewers C , Rau J , Akimkin V , Nicklas W. \nApproved and novel strategies in diagnostics of rat bite fever and other Streptobacillus infections in humans and animals\n. Virulence 2016 ;7 :630 –648\n.27088660 \n10 \nLambe DW Jr, McPhedran AM , Mertz JA , Stewart P. \n\nStreptobacillus moniliformis isolated from a case of Haverhill fever: biochemical characterization and inhibitory effect of sodium polyanethol sulfonate\n. Am J Clin Pathol 1973 ;60 :854 –860\n.4586017 \n11 \nHabib G , Lancellotti P , Antunes MJ , Bongiorni MG , Casalta JP , Del Zotti F , et al2015 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\n). Eur Heart J 2015 ;36 :3075 –3128\n.26320109 \n12 \nBin Abdulhak AA , Qazi AH , Tleyjeh IM. \nWorkup and management of native and prosthetic valve endocarditis\n. Curr Treat Options Cardio Med 2018 ;20 :73 .\n13 \nLiesman RM , Pritt BS , Maleszewski JJ , Patel R. \nLaboratory diagnosis of infective endocarditis\n. J Clin Microbiol 2017 ;55 :2599 –2608\n.28659319\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2514-2119",
"issue": "4(5)",
"journal": "European heart journal. Case reports",
"keywords": "Case report; Fatal outcome; Infective endocarditis; Rat-bite fever; Streptobacillus moniliformis; Zoonotic infection",
"medline_ta": "Eur Heart J Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101730741",
"other_id": null,
"pages": "1-6",
"pmc": null,
"pmid": "33426458",
"pubdate": "2020-10",
"publication_types": "D002363:Case Reports",
"references": "11139161;30083823;1562665;4586017;17223620;26320109;28659319;27088660;7707673;17652475;30344968;9790145",
"title": "Case report: A fatal case of aortic and mitral valve endocarditis caused by Streptobacillus moniliformis.",
"title_normalized": "case report a fatal case of aortic and mitral valve endocarditis caused by streptobacillus moniliformis"
} | [
{
"companynumb": "DK-PFIZER INC-2021423121",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CEFUROXIME"
},
"drugadditional": null,
... |
{
"abstract": "A 68-year-old man was treated with FAM (5-fluorouracil, doxorubicin [Adriamycin], mitomycin-C) for metastic gastric adenocarcinoma. Twelve months later while in complete clinical remission, pulmonary hypertension and microangiopathic hemolytic anemia were recognized, progressed, and ended in his demise 6 months later. At necropsy, minimal residual cancer and severe pulmonary veno-occlusive disease was found. Pulmonary veno-occlusive disease may occur in association with microangiopathic hemolytic anemia and cancer chemotherapy.",
"affiliations": null,
"authors": "Waldhorn|R E|RE|;Tsou|E|E|;Smith|F P|FP|;Kerwin|D M|DM|",
"chemical_list": "D008937:Mitomycins; D016685:Mitomycin; D004317:Doxorubicin; D005472:Fluorouracil",
"country": "United States",
"delete": false,
"doi": "10.1002/mpo.2950120607",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0098-1532",
"issue": "12(6)",
"journal": "Medical and pediatric oncology",
"keywords": null,
"medline_ta": "Med Pediatr Oncol",
"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D000743:Anemia, Hemolytic; D000971:Antineoplastic Combined Chemotherapy Protocols; D004317:Doxorubicin; D005472:Fluorouracil; D006801:Humans; D006976:Hypertension, Pulmonary; D008297:Male; D016685:Mitomycin; D008937:Mitomycins; D011652:Pulmonary Circulation; D013274:Stomach Neoplasms",
"nlm_unique_id": "7506654",
"other_id": null,
"pages": "394-6",
"pmc": null,
"pmid": "6548790",
"pubdate": "1984",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pulmonary veno-occlusive disease associated with microangiopathic hemolytic anemia and chemotherapy of gastric adenocarcinoma.",
"title_normalized": "pulmonary veno occlusive disease associated with microangiopathic hemolytic anemia and chemotherapy of gastric adenocarcinoma"
} | [
{
"companynumb": "US-PFIZER INC-2015274467",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MITOMYCIN"
},
"drugadditional": null,
... |
{
"abstract": "Xeroderma pigmentosum is a genodermatosis characterized by defects in the DNA nucleotide excision repair pathway, which increases the risk of suffering skin cancers. There is lack of information about the efficacy and toxicity of chemotherapy and radiotherapy in the treatment of these patients. We present the case of a xeroderma pigmentosum patient with a neck node recurrence of a squamous cell skin carcinoma that achieved a good response and survival with cetuximab.",
"affiliations": "Department of Medical Oncology, Catalan Institute of Oncology, Hospital Josep Trueta, AV Francia s/n 17007 Girona, Spain. jrubio@ico.scs.es",
"authors": "Rubió Casadevall|Jordi|J|;Graña-Suárez|Begoña|B|;Hernandez-Yagüe|Xavier|X|;Vayreda Ribera|Jordi|J|;Huc Grasa|Oscar|O|;Brunet Vidal|Joan|J|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000068818:Cetuximab",
"country": "France",
"delete": false,
"doi": "10.1684/ejd.2008.0574",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1167-1122",
"issue": "19(2)",
"journal": "European journal of dermatology : EJD",
"keywords": null,
"medline_ta": "Eur J Dermatol",
"mesh_terms": "D000328:Adult; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D002294:Carcinoma, Squamous Cell; D000068818:Cetuximab; D003131:Combined Modality Therapy; D017809:Fatal Outcome; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D009333:Neck; D012878:Skin Neoplasms; D014983:Xeroderma Pigmentosum",
"nlm_unique_id": "9206420",
"other_id": null,
"pages": "163-5",
"pmc": null,
"pmid": "19106040",
"pubdate": "2009",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Xeroderma pigmentosum: neck lymph node metastasis of a squamous cell carcinoma of the skin treated with cetuximab.",
"title_normalized": "xeroderma pigmentosum neck lymph node metastasis of a squamous cell carcinoma of the skin treated with cetuximab"
} | [
{
"companynumb": "ES-PFIZER INC-202101612272",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": "1",
... |
{
"abstract": "We presented the cases of three children with coeliac disease who despite good adherence to a glutenfree diet remained non-responsive to treatment. Two patients, one of them with IgA deficiency, were successfully treated by complete gluten exclusion with enteral nutrition. However the third child with a severe coeliac disease did not achieve clinical and histologic improvement, even on immunosuppressive treatment. If no hidden sources of gluten can be identified, other causes of persistent villous atrophy, dierent from coeliac disease, have to be considered. They include e.g. inflammatory, immune and endocrine diseases of the digestive tract. In severe cases of childhood coeliac disease not responding to a gluten free diet, autoimmune enteropathy and refractory coeliac disease must be taken into account.",
"affiliations": "Department of Gastroenterology, Hepatology and Eating Disorders, The Children's Memorial Health Institute, Warsaw, Poland.;Department of Pediatrics Leiden University Medical Center, The Netherlands.;Department of Pediatrics Leiden University Medical Center, The Netherlands.;Department of Gastroenterology, Hepatology and Eating Disorders, The Children's Memorial Health Institute, Warsaw, Poland.;Department of Gastroenterology, Hepatology and Eating Disorders, The Children's Memorial Health Institute, Warsaw, Poland.;Department of Pediatrics Leiden University Medical Center, The Netherlands.",
"authors": "Janczyk|Wojciech|W|;de Roo|J H C|JH|;Schweizer|Joachim|J|;Socha|Jerzy|J|;Socha|Piotr|P|;Mearin|M Luisa|ML|",
"chemical_list": null,
"country": "Poland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1428-345X",
"issue": "19(2)",
"journal": "Developmental period medicine",
"keywords": null,
"medline_ta": "Dev Period Med",
"mesh_terms": "D002446:Celiac Disease; D002648:Child; D055050:Diet, Gluten-Free; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D017211:Treatment Failure",
"nlm_unique_id": "101636421",
"other_id": null,
"pages": "162-6",
"pmc": null,
"pmid": "26384116",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Coeliac disease not responding to a gluten-free diet in children: case studies and literature review.",
"title_normalized": "coeliac disease not responding to a gluten free diet in children case studies and literature review"
} | [
{
"companynumb": "PHHY2016PL002814",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": null,
"dr... |
{
"abstract": "Objectives. To describe clinical manifestations and performed diagnostic workup, focusing drug challenge tests (DCT), in patients with drug allergy. Methods. Retrospective study including all patients with skin tests (STs) or DCT-based drug allergy diagnosis, between 01/2014 - 06/2018 in a Portuguese allergy unit. Data were collected from electronic and paper-based clinical records. Results. We had 75 drug allergy diagnoses. Most index reactions were mild and major or equal 1 hour after drug intake. 59 (78%) diagnoses were based on DCTs, all based on multistep protocols with major or equal 3 predicted steps. Only 10% of the DCT were positive during up-dosing; timing and severity of the index reaction predicted DCT interruption during up-dosing. Conclusions. Most drug allergy diagnoses were based on multistep DCT. The identified predictors of DCT interruption during up-dosing can support the development of more personalized DCTs protocols.",
"affiliations": "Otorhinolaryngology Unit, Casa di Cura Villa Montallegro, Genoa, Italy.;Otorhinolaryngology Unit, Casa di Cura Villa Montallegro, Genoa, Italy.;Otorhinolaryngology Unit, Casa di Cura Villa Montallegro, Genoa, Italy.;Otorhinolaryngology Unit, Casa di Cura Villa Montallegro, Genoa, Italy.",
"authors": "Pereira|A M|AM|;Couto|M|M|;Pereira|M|M|;Araújo|L|L|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.23822/EurAnnACI.1764-1489.107",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1764-1489",
"issue": "52(2)",
"journal": "European annals of allergy and clinical immunology",
"keywords": "decision tree; drug allergy; drug challenge test; predictors; skin tests",
"medline_ta": "Eur Ann Allergy Clin Immunol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000465:Algorithms; D004342:Drug Hypersensitivity; D005260:Female; D006801:Humans; D007114:Immunization; D008297:Male; D008875:Middle Aged; D011174:Portugal; D057285:Precision Medicine; D011237:Predictive Value of Tests; D012189:Retrospective Studies; D012882:Skin Tests; D055815:Young Adult",
"nlm_unique_id": "101466614",
"other_id": null,
"pages": "74-83",
"pmc": null,
"pmid": "31594290",
"pubdate": "2020-03",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Skin tests and challenge-based drug allergy diagnosis: a retrospective study of patients with confirmed drug allergy.",
"title_normalized": "skin tests and challenge based drug allergy diagnosis a retrospective study of patients with confirmed drug allergy"
} | [
{
"companynumb": "PT-JNJFOC-20200418104",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nThe purpose of this study is to report the use of intravitreal triamcinolone for treatment of cancer-associated retinopathy (CAR) refractory to systemic therapy.\n\n\nMETHODS\nThis was a retrospective chart review study.\n\n\nRESULTS\nA 67-year-old man presented with cancer-associated retinopathy with antibodies against a 46-kDa retinal protein, alpha enolase. There was disease progression despite therapy with mycophenolate and intravenous immunoglobulin. Serial intravitreal injections of triamcinolone resulted in restoration of photoreceptor anatomy on optical coherence tomography and visual improvement. The patient's vision was preserved at 20/40 OD and 20/32 OS until his death from lung cancer 31 months after CAR diagnosis.\n\n\nCONCLUSIONS\nIntravitreal triamcinolone may be beneficial for maintenance of vision in patients with CAR.",
"affiliations": "Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, 243 Charles Street, Boston, MA, 02114, USA.",
"authors": "Huynh|Nancy|N|;Shildkrot|Yevgeniy|Y|;Lobo|Ann-Marie|AM|;Sobrin|Lucia|L|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s12348-012-0067-9",
"fulltext": "\n==== Front\nJ Ophthalmic Inflamm Infect\nJ Ophthalmic Inflamm Infect\nJournal of Ophthalmic Inflammation and Infection\n1869-5760\nSpringer-Verlag Berlin/Heidelberg\n\n67\n10.1007/s12348-012-0067-9\nBrief Report\nIntravitreal triamcinolone for cancer-associated retinopathy refractory to systemic therapy\nHuynh Nancy\nShildkrot Yevgeniy\nLobo Ann-Marie\nSobrin Lucia +1-617-5734279 +1-617-5733698 lucia_sobrin@meei.harvard.edu\n\nMassachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, 243 Charles Street, Boston, MA 02114 USA\n14 3 2012\n14 3 2012\n9 2012\n2 3 169171\n20 2 2012\n27 2 2012\n© The Author(s) 2012\nPurpose\n\nThe purpose of this study is to report the use of intravitreal triamcinolone for treatment of cancer-associated retinopathy (CAR) refractory to systemic therapy.\n\nMethods\n\nThis was a retrospective chart review study.\n\nResults\n\nA 67-year-old man presented with cancer-associated retinopathy with antibodies against a 46-kDa retinal protein, alpha enolase. There was disease progression despite therapy with mycophenolate and intravenous immunoglobulin. Serial intravitreal injections of triamcinolone resulted in restoration of photoreceptor anatomy on optical coherence tomography and visual improvement. The patient’s vision was preserved at 20/40 OD and 20/32 OS until his death from lung cancer 31 months after CAR diagnosis.\n\nConclusions\n\nIntravitreal triamcinolone may be beneficial for maintenance of vision in patients with CAR.\n\nKeywords\n\nCancer-associated retinopathy\nTriamcinolone\nSteroids\nIntravitreal injection\nissue-copyright-statement© Springer-Verlag 2012\n==== Body\nIntroduction\n\nCancer-associated retinopathy (CAR) is a paraneoplastic process caused by autoantibodies against retinal proteins, including recoverin and alpha enolase [1, 2]. Approximately 50 % of patients with CAR present with visual symptoms before the diagnosis of a malignancy is made [3]. CAR is rare, and there are currently no standard treatment regimens for the condition [4]. Systemic corticosteroids, steroid-sparing immunosuppression, and non-traditional immunomodulatory therapies including intravenous immunoglobulin (IVIg) have been shown to variably preserve or improve vision [5–7]. Cystoid macular edema (CME) has been reported in patients with non-paraneoplastic autoimmune retinopathy (npAIR) but is less common with CAR [2]. We report a patient with CAR in whom serial intravitreal steroid injections resulted in maintenance of visual function for more than 2 years until his death.\n\nCase report\n\nA 67-year-old man presented with decreased vision, photopsias, and nyctalopia. Examination revealed best corrected visual acuities of 20/32 in the right eye and 20/25 in the left eye. Dilated fundus exam was remarkable for bilateral CME and arteriolar narrowing (Fig. 1a). Fluorescein angiography (FA) revealed petalloid leakage at the fovea, perivascular leakage, and disk staining bilaterally (Fig. 1b). Multifocal and full-field electroretinography (ERG) revealed severely decreased scotopic and photopic responses but no negative ERG pattern. Serologic testing revealed the presence of antibodies to a 46-kDa retinal protein that was confirmed to be alpha enolase. Systemic evaluation for malignancy uncovered poorly differentiated squamous cell carcinoma of the lung. Chemotherapy was initiated with carboplatin and paclitaxel. For his eye disease, the patient was initially treated with intravenous methylprednisolone, 1 g/day for 3 days, followed by oral prednisone (initial dose of 80 mg/day and then a taper over 2 months) with decreased retinal vascular leakage and CME.Fig. 1 a Fundus photos showing macular edema and arteriolar narrowing. b Fluorescein angiography showing petalloid leakage in the macula, perivascular leakage, and disk staining\n\nThe patient’s visual acuities worsened to 20/125 OD and 20/60 OS with tapering of the prednisone, and FA showed worsening retinal vasculitis. Steroid-sparing treatment was attempted first with mycophenolate mofetil (2 g/day) and then with four doses of IVIg, with no response to either therapy. FA continued to show CME and diffuse retinal vasculitis. Intravitreal triamcinolone (IVTA) was administered bilaterally, with vision improving to 20/40 OD and 20/32 OS and resolution of cystic changes. Over the ensuing 2.5 years, the patient received four additional IVTA injections bilaterally. When the IVTA effect waned, his vision diminished to as low as 20/70 in the right eye and hand motions in the left eye. After the initial injection, there were no retinal cystic changes or significant retinal thickening on optical coherence tomography (OCT) at the subsequent visits, yet the patient periodically reported visual deterioration and had objectively diminished visual acuity with disruption of photoreceptor anatomy on OCT (Fig. 2a). The vision and anatomical changes improved with IVTA (Fig. 2b). His visual acuities were 20/40 OD and 20/32 OS after the most recent IVTA injections. The patient developed steroid response intraocular pressure rises in both eyes that decreased with topical antihypertensive therapy. No other complications of IVTA injections occurred. He passed away from complications of his lung cancer 31 months after his CAR diagnosis.Fig. 2 a OCT of left eye showing loss of the inner segment/outer segment (IS/OS) junction subfoveally (arrow) and hyperreflective areas along the photoreceptor layer (arrowheads), possibly indicative of foci of active inflammation. The patient’s vision was hand motions. b OCT 1 month after intravitreal steroid injection. The IS/OS junction has been restored subfoveally (arrow) and the hyperreflective areas have largely resolved, with vision improving to 20/32\n\nDiscussion\n\nThis report describes the successful treatment of CAR with intravitreal steroids. The treatment of CAR is often challenging. Treatment of the underlying malignancy alone does not alter the course of the ocular disease. Various treatment modalities have been tried in patients with CAR, including oral and intravenous steroids, plasmapheresis, IVIg, rituximab, azathioprine, cyclosporine, and mycophenolate mofetil [2, 6–8]. Despite treatment with these systemic medications, it is not unusual to have a progressive decline in vision with this disease. Our patient responded initially to systemic steroids but did not have an alteration of his disease course with mycophenolate mofetil or IVIg. After initiation of IVTA injections, his vision improved. Vision improvement in CAR is unusual; vision stabilization is often the best that can be hoped for. In this patient, there was strong evidence for a causal relationship between the injections and visual improvement. When the intravitreal triamcinolone wore off, his vision declined. With his initial injections, the improvement in vision could be attributed, at least in part, to treatment of the CME. But subsequent injections were given when there were no retinal cystic changes or thickening present on OCT and yet reinjection led to marked subjective and objective improvement. The improvement was likely due to suppression of inflammation around the photoreceptors as evidenced by restoration of inner segment/outer segment junction and resolution of hyperreflective lesions along the photoreceptor layer on OCT after the injections. In one such instance, his vision recovered from hand motions to 20/32 OS.\n\nCME and periphlebitis can be seen in patients with npAIR but is less common with CAR. There is one case report of retinal periphlebitis associated with CAR in a patient with ovarian cancer [9]. In the presence of CME, intravitreal steroids have previously been shown to be effective in patients with npAIR [2]. The unique presentation of CAR with CME and vasculitis in our patient motivated the use of intraocular triamcinolone, but there was evidence for an effect on the course of CAR directly given the visual improvements even when IVTA injected in the absence of CME. The presence of anti-retinal antibodies in the sera of patients with CAR suggests the need for systemic intervention in general, but this patient’s course suggests that a subset of CAR patients might be successfully treated with local therapy. The OCT photoreceptor findings in this patient pre- and post-injection indicate that intravitreal steroids may be able to successfully suppress inflammation and apoptosis induced by the autoantibodies at the level of the photoreceptors despite ongoing systemic production and/or circulation of antibodies. Some authors caution that readministration of intravitreal steroid for recurrent CME in npAIR and CAR is best done early when cystic changes are just starting to recur to avoid cycles of retinal cyst expansion and collapse which may cause retinal damage [2, 10]. Similarly, CAR patients without CME being treated with intravitreal steroids should be followed closely with OCT imaging and retreated promptly when evidence of photoreceptor layer disruption becomes apparent to avoid permanent photoreceptor damage.\n\nIn summary, intravitreal steroids should be considered in patients with CAR who do not respond to systemic therapy. In our patient, serial IVTA injections led to preservation of vision for almost 3 years.\n\nOpen Access\n\nThis article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution and reproduction in any medium, provided the original author(s) and source are credited.\n==== Refs\nReferences\n\n1. Adamus G Ren G Weleber RG Autoantibodies against retinal proteins in paraneoplastic and autoimmune retinopathy BMC Ophthalmol 2004 4 5 14 10.1186/1471-2415-4-5 15180904\n2. Ferreyra HA Jayasundera T Khan NW He S Lu Y Heckenlively JR Management of autoimmune retinopathies with immunosuppression Arch Ophthalmol 2009 127 390 397 10.1001/archophthalmol.2009.24 19365013\n3. Khan N Huang JJ Foster CS Cancer associated retinopathy (CAR): an autoimmune-mediated paraneoplastic syndrome Semin Ophthalmol 2006 21 135 141 10.1080/08820530500350662 16912011\n4. Chan JW Paraneoplastic retinopathies and optic neuropathies Surv Ophthalmol 2003 48 12 38 10.1016/S0039-6257(02)00416-2 12559325\n5. Kashiwabara K Nakamura H Kishi K Yagyu H Sarashina G Kobayashi K Matsuoka T Cancer-associated retinopathy during treatment for small-cell lung carcinoma Intern Med 1999 38 597 601 10.2169/internalmedicine.38.597 10435368\n6. Guy J Aptsiauri N Treatment of paraneoplastic visual loss with intravenous immunoglobulin Arch Ophthalmol 1999 127 612 614 10.1016/S0002-9394(98)00431-0\n7. Shildkrot Y Sobrin L Gragoudas ES Cancer-associated retinopathy: update on pathogenesis and therapy Sem Ophthalmol 2011 26 321 328 10.3109/08820538.2011.588657\n8. Mahdi N Faia LJ Goodwin J Nussenblatt RB Sen HN A case of autoimmune retinopathy associated with thyroid carcinoma Ocul Immunol Inflamm 2010 18 322 323 10.3109/09273941003802379 20662664\n9. Kim SJ Toma HS Thirkill CE Dunn JP Cancer-associated retinopathy with retinal periphlebitis in a patient with ovarian cancer Ocul Immunol Inflamm 2010 18 107 109 10.3109/09273940903457441 20370338\n10. Jr H Ferreyra HA Autoimmune retinopathy: a review and summary Semin Immunopathol 2008 30 127 134 10.1007/s00281-008-0114-7 18408929\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1869-5760",
"issue": "2(3)",
"journal": "Journal of ophthalmic inflammation and infection",
"keywords": null,
"medline_ta": "J Ophthalmic Inflamm Infect",
"mesh_terms": null,
"nlm_unique_id": "101553216",
"other_id": null,
"pages": "169-71",
"pmc": null,
"pmid": "22415770",
"pubdate": "2012-09",
"publication_types": "D016428:Journal Article",
"references": "16912011;15180904;10206574;18408929;21958182;20370338;10435368;20662664;19365013;12559325",
"title": "Intravitreal triamcinolone for cancer-associated retinopathy refractory to systemic therapy.",
"title_normalized": "intravitreal triamcinolone for cancer associated retinopathy refractory to systemic therapy"
} | [
{
"companynumb": "PHHY2015US007366",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TRIAMCINOLONE"
},
"drugadditional": null,
"... |
{
"abstract": "Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder punctuated by varied multiorgan complications all along the course of its natural history. Lymphoma represents a relatively well-recognized malignant phenomenon associated with lupus. The cause and effect relationships of lymphoma in SLE have been subject to extensive scrutiny with several studies reporting on clinic-pathologic characteristics and risk factors predicting lymphoma development in SLE. However, the pathogenic role of immunosuppressives in SLE-related lymphoma still remains unclear, and indices to help guide diagnosis, prognostication, therapy, and posttreatment monitoring are yet to be established. In this review, we describe 3 SLE patients who developed non-Hodgkin's lymphoma at different time points of their disease. Through a careful dissection of the aforementioned cases, we intend to apprise readers of the currently available literature surrounding risk factors, management, and prognosis in SLE-related lymphoma. We will also review and discuss the implications of immunosuppressives in SLE-related lymphoma and the role of mycophenolate mofetil in SLE-related primary CNS lymphoma development.",
"affiliations": "Department of Internal Medicine, Advocate Illinois Masonic Medical Center, 836 W. Wellington Avenue, Chicago, IL 60657, USA.;Department of Internal Medicine, Advocate Illinois Masonic Medical Center, 836 W. Wellington Avenue, Chicago, IL 60657, USA.;Department of Rheumatology, Rush University Medical Center, 1725 West Harrison Street, Chicago, IL 60612, USA.;Department of Rheumatology, Rush University Medical Center, 1725 West Harrison Street, Chicago, IL 60612, USA.",
"authors": "Boddu|Prajwal|P|0000-0003-4594-1704;Mohammed|Abdul S|AS|0000-0003-1061-0497;Annem|Chandrahasa|C|;Sequeira|Winston|W|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2017/1658473",
"fulltext": "\n==== Front\nCase Rep RheumatolCase Rep RheumatolCRIRHCase Reports in Rheumatology2090-68892090-6897Hindawi 10.1155/2017/1658473Case ReportSLE and Non-Hodgkin's Lymphoma: A Case Series and Review of the Literature http://orcid.org/0000-0003-4594-1704Boddu Prajwal \n1\nhttp://orcid.org/0000-0003-1061-0497Mohammed Abdul S. \n1\n\n*\nAnnem Chandrahasa \n2\nSequeira Winston \n2\n1Department of Internal Medicine, Advocate Illinois Masonic Medical Center, 836 W. Wellington Avenue, Chicago, IL 60657, USA2Department of Rheumatology, Rush University Medical Center, 1725 West Harrison Street, Chicago, IL 60612, USA*Abdul S. Mohammed: mabdulsalman@gmail.comAcademic Editor: Ruben Burgos-Vargas\n\n2017 27 3 2017 2017 16584739 12 2016 16 3 2017 Copyright © 2017 Prajwal Boddu et al.2017This 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. Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder punctuated by varied multiorgan complications all along the course of its natural history. Lymphoma represents a relatively well-recognized malignant phenomenon associated with lupus. The cause and effect relationships of lymphoma in SLE have been subject to extensive scrutiny with several studies reporting on clinic-pathologic characteristics and risk factors predicting lymphoma development in SLE. However, the pathogenic role of immunosuppressives in SLE-related lymphoma still remains unclear, and indices to help guide diagnosis, prognostication, therapy, and posttreatment monitoring are yet to be established. In this review, we describe 3 SLE patients who developed non-Hodgkin's lymphoma at different time points of their disease. Through a careful dissection of the aforementioned cases, we intend to apprise readers of the currently available literature surrounding risk factors, management, and prognosis in SLE-related lymphoma. We will also review and discuss the implications of immunosuppressives in SLE-related lymphoma and the role of mycophenolate mofetil in SLE-related primary CNS lymphoma development.\n==== Body\n1. Introduction\nSystemic lupus erythematosus (SLE) is an autoimmune disease with myriad presentations and multisystem complications arising from both underlying disease activity and therapy-related side effects. SLE's association with lymphoma is a well-established phenomenon. A number of studies have reported a higher incidence of lymphoma in the SLE population compared with healthy cohorts [1–3]. The effects of lymphoma development in SLE and its impact on modifying the disease's natural history are a matter of great interest amongst both clinicians and researchers. This has spawned a proliferation of studies examining predictors of lymphoma development, its effect on SLE prognosis, and optimal treatment strategies in its management. In this article, we describe 3 SLE patients who developed lymphoma at different time points of their disease. Of note, all these patients were diagnosed with SLE based on fulfilling the 1997 American College of Rheumatology (ACR) criteria. We will attempt to understand potential factors that may have contributed to disease development in each of the three patients, rationalize treatment strategies that they had received, and identify clinicopathological indices predicting lymphoma development by reviewing the currently updated literature.\n\n2. Case #1\nA 36-year-old Asian female presented to our hospital with complaints of one month of progressive back pain and two weeks of left lower extremity numbness, cramps, and weakness. She endorsed a two-week history of bowel and bladder retention. She was diagnosed with SLE, over 10 years ago, and was on hydroxychloroquine with reasonable control of her symptoms until a month prior to hospitalization. Her past medical history was also significant for intermittent autoimmune neutropenia. Physical exam at initial evaluation was remarkable for 4/5 strength in both lower extremities with an associated left foot drop. Labs including blood counts and routine serum chemistries were unremarkable at presentation. An MRI of lumbar spine was performed and revealed two peripherally enhancing extradural/subdural masses in the lumbar spinal canal at the L2 and L3-L4 level with additional nodular and linear enhancement of cauda equina nerve roots. A lumbar puncture performed revealed normal CSF cell count, protein 227 mg/dL, and glucose 24 mg/dL; cytopathology was positive for atypical mononuclear cells confirming leptomeningeal involvement. The patient was treated over three days with emergent radiation therapy along with intravenous dexamethasone (10 mg followed by 16 mg daily in divided doses) without further tissue confirmation. Flow cytometry on repeat lumbar puncture, postradiation therapy, showed no diagnostic abnormalities. A L3-vertebral tissue biopsy was performed a day later and showed chronic inflammatory cells and CD20+ necrotic cells consistent with a vanishing lymphoma. Staging with PET and bone marrow biopsy was negative for disseminated lymphomatous involvement. Given the severity of presentation, the patient was treated further with 5 cycles of high dose methotrexate, alternating with rituximab and intrathecal methotrexate. She was started on entecavir, for positive hepatitis B antibody serologies, to prevent possible reactivation of hepatitis while receiving Rituxan. The patient improved clinically over her three-month chemotherapy course after which a restaging PET was performed that showed mild hyper enhancement in the L2 vertebral region. The hyperenhancement on PET was deemed to be postsurgical, based on a preceding core biopsy that was negative for malignancy, and hence an open biopsy was deferred. She completed her localized radiation therapy sessions and proceeded to receive two cycles of consolidation chemotherapy with cytarabine three months later. Six months after her last Rituxan dose, repeat hepatitis B quantitative titers and liver enzymes were negative/normal and entecavir was discontinued. On her most recent follow-up, she continues to make progress and is planned for surveillance monitoring with regular lab work and MRI every 6 months to monitor for disease status and treatment related toxicities.\n\n3. Case #2\nA 57-year-old African American female presented to the hospital with complaints of headache, fevers, dysarthria, and tremors. She had a 19-year long history of SLE complicated by Class IIIA + Class V lupus nephritis requiring treatment with cyclophosphamide and mycophenolate (MMF). She was also on hydroxychloroquine and had a prolonged course of prednisone (5–10 mg/day). Her other past medical history included anemia of chronic disease, hypertension, hypothyroidism, and listeria meningitis (five months prior to this hospital presentation). Her other relevant medications included trimethoprim sulfa for PJP prophylaxis. Labs at presentation were significant for a Hgb 9 gm/dL, normal WBC and platelet counts, creatinine 2.12 mg/dL, albumin 3.6 mg/dL, bilirubin 0.21 mg/dL, ALP 71 IU/L, ALT 32 IU/L, AST 31 IU/L, LDH 772 IU/L, and uric acid 6.6 mg/dL. Brain MRI was performed for her neurological symptoms and revealed T2-hyperintensive periventricular lesions extending into the corona radiata and internal capsule. A stereotactic brain biopsy was performed which showed large discohesive neoplastic lymphoid cells forming characteristic perivascular cuffing which stained positive for CD20 suggestive of diffuse large B cell lymphoma (DLBCL). Staging PET/CT showed hyper metabolic mediastinal nodes and nodules in the left lower lobe, lesions that were biopsied and showed Cryptococcus neoformans. There was no evidence of lymphoma on bone marrow biopsies. A repeat MRI, one month later, demonstrated interval increase in the size of periventricular lesions. A lumbar puncture at this time showed normal cell count with no abnormal cell morphology or flow cytometry. She was started on allopurinol for tumor lysis prophylaxis and fluconazole for recently diagnosed cryptococcosis. She received adjusted high dose intravenous methotrexate for her DLBCL. Her neurological symptoms began to improve after her first session of treatment. At the time of this writing, she is planned to receive further cycles of methotrexate treatment.\n\n4. Case #3\nA 50-year-old African American male presented to the emergency department with complaints of fever and progressive fatigue over a month. He reported fevers, night sweats, and 17-pound weight loss over this period. His past medical history was significant for SLE with Class II lupus glomerulonephritis and chronic lupus interstitial nephritis for which he was being treated with azathioprine and hydroxychloroquine. Labs at presentation revealed pancytopenia, Hgb 5.6 gm/dL, WBC 3700/mm3, and platelets 90000/mm3. CT scans of the chest, abdomen, and pelvis demonstrated diffuse lymphadenopathy above and below the diaphragm with no evidence of involvement of extranodal sites. A bone marrow biopsy was performed which showed a hypocellular (30%) marrow with 15–20% of involvement of marrow cells by large CD5, CD19, CD20 positive; Cyclin D1, BCL6 negative B cells with lambda light chain restriction consistent with diffuse large B cell lymphoma. Azathioprine was promptly discontinued. He was determined to have a good prognostic, revised international prognostic index category (R-IPI) Stage IVB DLBCL and treated with 6 cycles of R-CHOP regimen. First chemotherapy cycle was complicated by neutropenic fevers (requiring broad spectrum antibiotics) and progression of kidney disease to end-stage renal disease (ESRD) requiring hemodialysis. Fortunately, he completed the other five cycles without incident. Interim CTs and post-chemo-CT scans with bone marrow biopsy showed complete response with no evidence of residual disease. On repeat evaluation during her follow-up visit, a month after completing treatment, she is asymptomatic with a good recovery of her peripheral blood counts (Hgb 10.2 gm/dL, platelets 195 K/microL, and WBC 3470/mm3).\n\n5. Summary of the Cases\nIn summary, patient #1, with a 10-year history of SLE and chronic hepatitis B, presented with primary CNS lymphoma (PCNSL) of leptomeningeal/spinal type and was treated successfully with high dose methotrexate and rituximab. Patient #2 had a 19-year long history of SLE and also presented with a localized CNS lymphoma. Importantly, she was on mycophenolate mofetil (MMF) and cyclophosphamide at the time of her presentation. Mycophenolate therapy was discontinued soon after diagnosis. She was treated with high dose intravenous methotrexate. Patient #3 presented with DLBCL while he was being treated with azathioprine which was later discontinued. He showed good clinical response to chemotherapy and was in complete remission at the end of his R-CHOP regimen. Two of our patients presented with a primary CNS lymphoma, a rare and unusual presentation in SLE patients. Of note, all patients were diagnosed with SLE based on the 1997 ACR criteria.\n\n6. Discussion\n6.1. Incidence and Epidemiology\nThe association between lymphoma and SLE has been examined in varied detail and studies have reported an increased incidence of lymphoma in SLE [1–3]. Immune dysregulation coupled with the use of immunosuppression may account for the increased incidence of cancer (and lymphoma) in SLE. A recent meta-analysis which included 16 observational studies showed a mildly increased risk of overall cancer in SLE compared with the general population [1]. This risk is most pronounced in SLE-related non-Hodgkin's lymphoma with reported relative risk estimates ranging widely from 4.39 to 44.4 in various studies [1–3].\n\nBased on two studies with a total of 37 patients, SLE patients presenting with lymphoma typically age between 57 and 61 years with the majority of them being women [10, 13]. In a study involving 11 SLE-NHL patients, the mean duration of SLE at the time of NHL diagnosis was found to be 18 years, but cases of NHL occurring prior to concurrently with a diagnosis of SLE have also been reported [5, 7]. Unlike the increased overall cancer risk which is generally confined to Caucasian SLE patients, lymphoma risk in SLE is uniformly higher across all ethnicities [14].\n\n6.2. Pathology\nThe most common histological type of NHL in SLE is the DLBCL type constituting 50–65% of the SLE-lymphoma cases [5, 10, 13]. Gene expression profiling in DLBCL has revealed at least three different subgroups, each driven by different pathophysiological mechanisms and characterized by different responses to therapy. Of these, the “activated B-cell-like DLBCL” type is derived from postgerminal center B cells while the “germinal center B-cell-like DLBCL” type originates from germinal center B cells. DLBCL of the activated B cell type carries a worse prognosis compared with DLBCL of the germinal type (GCB) [10, 15]. Importantly, DLBCL arising in patients with a history of SLE showed an enrichment of non-GCB subtype, and this has potential implications on therapy and prognosis.\n\n6.3. Clinical and Laboratory Features\nSigns and symptoms like fever and adenopathy are shared clinical features in SLE-related lymphoma and infections complicating SLE. However, a thorough assessment of the duration of lymphadenopathy and chronicity of symptoms, exhaustive exclusion of potential infectious etiologies, and examination of tissue and bone marrow biopsies are essential in arriving at the right diagnosis [16, 17]. Though NHL in SLE is predominantly nodal, extranodal involvement may also occur. Prognosis of NHL in SLE is heavily weighted upon the stage of the disease, with a higher stage predicting for a worsened outcome [18, 19]. Early stage lymphoma can share similar clinical and hematological findings observed in SLE. In addition, lymphadenopathy is very common in SLE, occurring in up to 67% of patients [20]. Hence, the diagnosis often hinges upon a lymph node biopsy or peripheral blood sampling for immunophenotyping to detect a monoclonal cell expansion consistent with lymphoma.\n\nA study examining predictors of increased lymphoma risk in systemic lupus suggested a potential role of cyclophosphamide and high cumulative steroid use [21]. In their sample, disease activity was found to be associated with increased lymphoma risk. A study on Sjogren's syndrome patients with lymphoma identified simple hematological factors such as neutropenia, low complement, and cryoglobulinemia as highly predictive factors in the development of NHL [21]. Of note, we observed our three study patients to have either bicytopenia or pancytopenia for a brief time period just prior to the diagnosis of lymphoma.\n\n6.4. Role of Immunosuppressives\nMost SLE patients are on potent immunosuppressives for the management of lupus and its complications. Pertinent concerns have been raised against the plausible role of immunosuppressives in lymphomagenesis. The potential association between cyclophosphamide and azathioprine use and lymphoma in SLE has been widely studied in literature. Most of the evidence suggests that immunosuppressives do not increase the incidence of lymphoma [4–12]. Studies, in fact, have shown conflicting results and failed to demonstrate a significant risk of lymphoma with use of cyclophosphamide and azathioprine (see Table 1). The role of other agents like MMF is detailed in the following sections.\n\n6.5. Pathophysiology\nBiological mechanisms behind lymphomagenesis in SLE remain to be better defined. Constitutive immune activation from prolonged antigen stimulation may result in active lymphocyte proliferation which can eventually terminate into a lymphoma. Bone marrow derived naïve B cells ingress into the lymph node and enter a germinal center reaction, after antigen stimulation, where they proliferate rapidly and undergo class switching and somatic hypermutation [22]. DLBCL subtype is derived from activated B cells suggesting that an increased incidence of lymphoma may be a secondary effect of chronic inflammation in this subgroup [23]. Activating mutations in multi-proto-oncogenes have been reported in DLBCL [24]. It is noteworthy to mention that chromosomal translocation break points in SLE DLBCL have been shown to occur in the very same regions as non-SLE DLBCL [25–27].\n\nEpstein Barr virus (EBV) infection is being increasingly recognized as a potential pathogenetic link to lymphomagenesis. It has been observed that EBV antigens share structural similarities with certain SLE antigens. Additionally, SLE patients tend to have frequent viral reactivations as suggested by higher EBV seroconversion rates [28]. These reactivations are partly the effect of defective EBV-specific T cell suppression allowing enhanced expression of viral genes [28, 29] in SLE patients. It is also interesting to note that EBV infection of B cells upregulates the expression of enzymes like cytidine deaminase expression, an essential mediator in the process of somatic hypermutation [30].\n\n6.6. Primary CNS Lymphoma\nPrimary CNS lymphoma (PCNSL) is a regional type of non-Hodgkin lymphoma and is defined by central nervous system involvement without evidence of concomitant systemic disease. The diagnosis of PCNSL carries a worse prognosis compared with its systemic counterpart [31]. Histologically, about 95% of PCNSL is CD20+ DLBCL type [32]. Immunodeficiency predisposes to PCNSL development; however, it has also been associated independently with the presence of autoimmune diseases [33]. Almost all cases of PCSNL reported in SLE patients are associated with the use of immunosuppressives [33–38]. As alluded above, patient #1 was treated with endeavor to prevent hepatitis B reactivation, a potential complication while receiving rituximab [39]. Hepatitis B independently associates with increased PCSNL risk and may be due to HBV causing chronic antigenic stimulation [40, 41]. However, our patient was HBsAg negative and anti-HBs Ab positive, an association not likely associated with an increased risk of PCSNL [40]. This patient was only on hydroxychloroquine, a weak immunosuppressant, when she presented with PCSNL. It is worth mentioning that the use of hydroxychloroquine may actually positively influence the cancer risk in SLE patients [42]. An observational prospective study involving 235 SLE patients with a median 10-year follow-up (156 on hydroxychloroquine) determined a decreased cancer incidence while on hydroxychloroquine [adjusted hazard ratio 0.15 (95% CI 0.02 to 0.99)]. Finally, it currently remains unknown if SLE has an immunosuppressive-independent association with primary CNS lymphoma.\n\nPCNSL in SLE is being diagnosed more frequently since the introduction of MMF in the management of lupus nephritis and post-transplant [35–38]. All case studies including ours were treated long term with mycophenolate indicating that prolonged immunosuppression may be one of the prerequisites for PCNSL development [23, 36–38]. All reported patients had at least 5 years of autoimmune disease. All patients were on mycophenolate 1 gram twice daily dosing for 8 months to 46 months prior to diagnosis. Of the five patients, including ours, three were diagnosed with DLBCL and two had polymorphous B cell lymphoproliferative disorder. Three patients went into complete remission after steroid/rituximab regimen; one patient had progressive disease on the same. Our patient was not assessed for CD20 marker status. MMF induces a compromise in T cell immune function thereby likely causing dysregulated B cell proliferation in the setting of chronic antigen stimulation. In all the reports mentioned above, patients had tumors which were positive for EBV, a factor which may well have contributed to chronic antigen stimulation. The EBV status of our patient's tumor was not evaluated. In this context, EBV episomes tend to be absent in immunocompetent PCNSL patients, and other mechanisms of disease induction might be responsible for lymphomagenesis [43]. Finally, PCNSL in SLE without mycophenolate has also been rarely described [34].\n\nAll patients were diagnosed with PCNSL within 1–3 months of onset of neurological symptoms. Rapid onset of neurological symptoms in SLE patients on long term immunosuppressives, especially MMF, should raise concern for PCNSL.\n\n6.7. Management and Prognosis\nDiffuse large B cell lymphoma is highly aggressive but responds well to the traditional CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone) [44]. Addition of rituximab to CHOP improves response rates and survival outcomes [45]. The optimal regimen for PCSNL is unestablished, with the traditional CHOP regimens generally proving ineffective due to poor penetrance through the blood brain barrier. Hence intrathecal chemotherapy involving high dose methotrexate and rituximab now forms the standard first line regimen in PCSNL [46]. Patient #1 responded well to the combined high dose methotrexate and rituximab regimen with complete response after completion of his chemotherapy.\n\nCourse of these patients has not been well studied and may be poor given the relatively higher proportion of DLBCL non-GCB types and higher disease stage at presenting diagnosis. Rossi et al. reported on the outcomes of 5 patients, who on attaining complete remission after treatment with high dose chemotherapy found that 3 of the 4 patients continued to have persistent autoantibody elevation with frequent lupus flares [19]. The potential of stem cell transplantation in serving a potentially curative role not only in the management of DLBCL but also in inducing prolonged serological remissions of autoimmune disease should be explored in future studies [19, 47, 48].\n\n7. Conclusion\nThere has been a wealth of progress in the understanding of SLE-related lymphoma in the past two decades. The availability of simple hematological/laboratory indices predicting lymphoma development can facilitate early identification of disease and warrant further evaluation in future studies. Although immunosuppressives have no clear role in the pathogenesis of SLE-related lymphoma, reports including ours suggest an etiological role of mycophenolate in PCNSL development. The therapeutic role of allogenic stem cell transplant in curing both lymphoma and SLE holds promise and prognostic risk stratification studies are required to identify patients who best benefit from this therapeutic approach.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest.\n\nTable 1 Studies on the role of cyclophosphamide and azathioprine on SLE-related lymphomagenesis.\n\nRef.\tStudy design\tPt follow-up\tNumber of patients with lymphoma/hematological malignancies\tDrugs studied\tComments\tOutcomes\t\n[4]\tProspective observational\t68592 patient months\t3\tAzathioprine & cyclophosphamide\t3/914 patients had lymphoma. 1 was on AZT, 1 on CYP, and 1 on both.\n348/911 were on AZT, 188/911 on CYP\tNo association\t\n\n\n\t\n [5]\tRetrospective\t2020\t11\tAzathioprine & CYP\t1 on CYP,\n0 on AZT\tNo association\t\n\n\n\t\n[6]\tRetrospective\t219\t1\tAzathioprine & CYP\t0 on immunosuppressives\tNo association\t\n\n\n\t\n [7]\tRetrospective\t 784 \n 246 cancer cases and 538 controls without cancer\t46\tAzathioprine & CYP\tCyclophosphamide: 17.5% of 538 cancer free patients, 7.4% of 246 cancer patients; azathioprine: 34.9% of 538 cancer free patients, 25.0% of 246 cancer patients\tNo association Cyclophosphamide 2.09 (0.69–6.30)\nAzathioprine 1.19 (0.48–2.92)\t\n\n\n\t\n[8]\tRetrospective\t864\t8\tAzathioprine & CYP\t11 of 28 cancer patients on CYP, 12 of 28 cancer patients on AZP\tNo association\t\n\n\n\t\n[9]\tRetrospective\t5036\t75\tAzathioprine, CYP, MMF, and prednisone\t75 lymphoma cases, only 15 had prior exposure to CYP, 19 to AZA,\n9 to methotrexate, and 6 to MMF\tNo association Cyclophosphamide ever used 2.80 (0.87 to 8.98) Azathioprine (AZA) ever used fully adjusted 0.84 (0.32 to 2.25)\t\n\n\n\t\n [10]\t Retrospective\t6438\t16\tAzathioprine, CYP\tCyclophosphamide: 2/16 in patients with NHL, 3/26 in patients without NHL\nAzathioprine: 5/16 in patients with NHL, 9/26 in patients without NHL\tNo association\nCYP (RR 0.3–3.3)\nAZP RR 0.9 [0.4–2.1]\t\n\n\n\t\n[11]\tProspective\t5976 patient years\t1\tCYP\t1/49 on CYP developed NHL\tNo association\t\n\n\n\t\n[12]\tProspective\t17376 patient years\t3\tAZT, CYP\tNone on CYP or AZT\tNo association\n==== Refs\n1 Cao L. Tong H. Xu G. Systemic lupus erythematous and malignancy risk: a meta-analysis PLoS ONE 2015 10 4 e0122964 10.1371/journal.pone.0122964 2-s2.0-84929465044 \n2 Bernatsky S. Ramsey-Goldman R. Labrecque J. Cancer risk in systemic lupus: an updated international multi-centre cohort study Journal of Autoimmunity 2013 42 130 135 10.1016/j.jaut.2012.12.009 2-s2.0-84877148183 23410586 \n3 Pettersson T. Pukkala E. Teppo L. Friman C. Increased risk of cancer in patients with systemic lupus erythematosus Annals of the Rheumatic Diseases 1992 51 4 437 439 10.1136/ard.51.4.437 2-s2.0-0026550809 1586239 \n4 Kang K. Y. Kim H. O. Yoon H. S. Incidence of cancer among female patients with systemic lupus erythematosus in Korea Clinical Rheumatology 2010 29 4 381 388 10.1007/s10067-009-1332-7 2-s2.0-77950865019 20041274 \n5 King J. K. Costenbader K. H. Characteristics of patients with systemic lupus erythematosus (SLE) and non-Hodgkin's lymphoma (NHL) Clinical Rheumatology 2007 26 9 1491 1494 10.1007/s10067-006-0532-7 2-s2.0-34547556504 17297594 \n6 Sweeney D. M. Manzi S. Janosky J. Risk of malignancy in women with systemic lupus erythematosus Journal of Rheumatology 1995 22 8 1478 1482 2-s2.0-0029088161 7473469 \n7 Bernatsky S. Joseph L. Boivin J.-F. The relationship between cancer and medication exposures in systemic lupus erythaematosus: a case-cohort study Annals of the Rheumatic Diseases 2008 67 1 74 79 10.1136/ard.2006.069039 2-s2.0-37749038302 17545189 \n8 Tarr T. Gyorfy B. Szekanecz É. Occurrence of malignancies in Hungarian patients with systemic lupus erythematosus: results from a single center Annals of the New York Academy of Sciences 2007 1108 76 82 10.1196/annals.1422.008 2-s2.0-34948884016 17893972 \n9 Bernatsky S. Ramsey-Goldman R. Clarke A. E. Malignancy in systemic lupus erythematosus: what have we learned? Best Practice and Research: Clinical Rheumatology 2009 23 4 539 547 10.1016/j.berh.2008.12.007 2-s2.0-67649757164 19591783 \n10 Löfström B. Backlin C. Sundström C. Ekbom A. Lundberg I. E. A closer look at non-Hodgkin's lymphoma cases in a national Swedish systemic lupus erythematosus cohort: a nested case-control study Annals of the Rheumatic Diseases 2007 66 12 1627 1632 10.1136/ard.2006.067108 2-s2.0-35548969613 17517757 \n11 Sultan S. M. Ioannou Y. Isenberg D. A. Is there an association of malignancy with systemic lupus erythematosus? An analysis of 276 patients under long-term review Rheumatology 2000 39 10 1147 1152 10.1093/rheumatology/39.10.1147 2-s2.0-0033782917 11035137 \n12 Abu-Shakra M. Gladman D. D. Urowitz M. B. Malignancy in systemic lupus erythematosus Arthritis & Rheumatism 1996 39 6 1050 1054 10.1002/art.1780390625 2-s2.0-0029897564 8651970 \n13 Bernatsky S. Ramsey-Goldman R. Rajan R. Non-Hodgkin's lymphoma in systemic lupus erythematosus Annals of the Rheumatic Diseases 2005 64 10 1507 1509 10.1136/ard.2004.034504 2-s2.0-27744486101 16162903 \n14 Bernatsky S. Boivin J. F. Joseph L. Race/ethnicity and cancer occurrence in systemic lupus erythematosus Arthritis Care and Research 2005 53 5 781 784 10.1002/art.21458 2-s2.0-26844439111 16208671 \n15 Hassan U. Mushtaq S. Mamoon N. Hussain Asghar A. Ishtiaq S. Prognostic sub-grouping of diffuse large B-cell lymphomas into germinal centre and post germinal centre groups by immunohistochemistry after 6 cycles of chemotherapy Asian Pacific Journal of Cancer Prevention 2012 13 4 1341 1347 10.7314/APJCP.2012.13.4.1341 2-s2.0-84873178458 22799329 \n16 Gillmore R. Sin W. Y. Systemic lupus erythematosus mimicking lymphoma: the relevance of the clinical background in interpreting imaging studies BMJ Case Reports 2014 10.1136/bcr-2013-201802 \n17 Bernatsky S. Ramsey-Goldman R. Lachance S. Pineau C. A. Clarke A. E. Lymphoma in a patient with systemic lupus erythematosus Nature Clinical Practice Rheumatology 2006 2 10 570 574 10.1038/ncprheum0295 2-s2.0-33749353234 \n18 Fisher R. I. Overview of non-Hodgkin's lymphoma: biology, staging, and treatment Seminars in Oncology 2003 30 2, supplement 4 3 9 10.1016/s0093-7754(03)70019-0 2-s2.0-0037395994 \n19 Rossi E. Catania G. Truini M. Ravetti G. L. Grassia L. Marmont A. M. Patients with systemic lupus erythematosus (SLE) having developed malignant lymphomas. Complete remission of lymphoma following high-dose chemotherapy, but not of SLE Clinical and Experimental Rheumatology 2011 29 3 555 559 2-s2.0-80052047062 21722503 \n20 Brown J. R. Skarin A. T. Clinical mimics of lymphoma The Oncologist 2004 9 4 406 416 10.1634/theoncologist.9-4-406 2-s2.0-3543020899 15266094 \n21 Bernatsky S. Ramsey-Goldman R. Joseph L. Lymphoma risk in systemic lupus: effects of disease activity versus treatment Annals of the Rheumatic Diseases 2014 73 1 138 142 10.1136/annrheumdis-2012-202099 2-s2.0-84889686638 23303389 \n22 Browning J. L. B cells move to centre stage: novel opportunities for autoimmune disease treatment Nature Reviews Drug Discovery 2006 5 7 564 576 10.1038/nrd2085 2-s2.0-33745662565 16816838 \n23 Jaffe E. S. Harris N. L. Stein H. Vardiman J. W. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues 2001 Lyon, France IARC Press \n24 Pasqualucci L. Neumeister P. Goossens T. Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas Nature 2001 412 6844 341 346 10.1038/35085588 2-s2.0-0035913362 11460166 \n25 Papavasiliou F. N. Schatz D. G. Somatic hypermutation of immunoglobulin genes: merging mechanisms for genetic diversity Cell 2002 109 2, supplement 1 S35 S44 10.1016/s0092-8674(02)00706-7 2-s2.0-0036234455 11983151 \n26 Montesinos-Rongen M. Van Roost D. Schaller C. Wiestler O. D. Deckert M. Primary diffuse large B-cell lymphomas of the central nervous system are targeted by aberrant somatic hypermutation Blood 2004 103 5 1869 1875 10.1182/blood-2003-05-1465 2-s2.0-1442307976 14592832 \n27 Küppers R. Klein U. Hansmann M.-L. Rajewsky K. Cellular origin of human B-cell lymphomas New England Journal of Medicine 1999 341 20 1520 1529 10.1056/NEJM199911113412007 2-s2.0-0033547310 10559454 \n28 James J. A. Robertson J. M. Lupus and epstein-barr Current Opinion in Rheumatology 2012 24 4 383 388 10.1097/bor.0b013e3283535801 22504579 \n29 Draborg A. H. Duus K. Houen G. Epstein-barr virus and systemic lupus erythematosus Clinical and Developmental Immunology 2012 2012 370516 10.1155/2012/370516 2-s2.0-84864924195 \n30 Epeldegui M. Hung Y. P. McQuay A. Ambinder R. F. Martínez-Maza O. Infection of human B cells with Epstein-Barr virus results in the expression of somatic hypermutation-inducing molecules and in the accrual of oncogene mutations Molecular Immunology 2007 44 5 934 942 10.1016/j.molimm.2006.03.018 2-s2.0-33748789332 16730063 \n31 Bailey P. Intracranial sarcomatous tumors of leptomeningeal origin Archives of Surgery 1929 18 4 1359 1402 10.1001/archsurg.1929.01140130449031 \n32 Shenkier T. N. Blay J.-Y. O'Neill B. P. Primary CNS lymphoma of T-cell origin: a descriptive analysis from the international primary CNS lymphoma collaborative group Journal of Clinical Oncology 2005 23 10 2233 2239 10.1200/jco.2005.07.109 2-s2.0-20244383617 15800313 \n33 Hochberg F. H. Miller D. C. Primary central nervous system lymphoma Journal of Neurosurgery 1988 68 6 835 853 10.3171/jns.1988.68.6.0835 2-s2.0-0023891187 3286832 \n34 Pisoni C. N. Grinberg A. R. Plana J. L. Freue R. D. Manni J. A. Paz L. Primary central nervous system lymphoma in a patient with systemic lupus erythematosus Medicina 2003 63 3 221 223 2-s2.0-0037702119 12876906 \n35 Svobodova B. Hruskova Z. Rysava R. Tesar V. Brain diffuse large B-cell lymphoma in a systemic lupus erythematosus patient treated with immunosuppressive agents including mycophenolate mofetil Lupus 2011 20 13 1452 1454 10.1177/0961203311412413 2-s2.0-81555220938 21868432 \n36 Tsang H. H. L. Trendell-Smith N. J. Wu A. K. P. Mok M. Y. Diffuse large B-cell lymphoma of the central nervous system in mycophenolate mofetil-treated patients with systemic lupus erythematosus Lupus 2010 19 3 330 333 10.1177/0961203309347921 2-s2.0-77749292033 19897521 \n37 Finelli P. F. Naik K. DiGiuseppe J. A. Prasad A. Primary lymphoma of CNS, mycophenolate mofetil and lupus Lupus 2006 15 12 886 888 10.1177/0961203306071431 2-s2.0-33846006249 17211996 \n38 Dasgupta N. Gelber A. C. Racke F. Fine D. M. Central nervous system lymphoma associated with mycophenolate mofetil in lupus nephritis Lupus 2005 14 11 910 913 10.1191/0961203303lu2179cr 2-s2.0-28444471591 16335585 \n39 Kim M.-G. Park S. Y. Kim E. J. Hepatitis B virus reactivation in a primary central nervous system lymphoma patient following intrathecal rituximab treatment Acta Haematologica 2011 125 3 121 124 10.1159/000321792 2-s2.0-78649777371 21150178 \n40 Meng Y. He S. Liu Q. Xu D. Zhang T. Chen Z. High prevalence of hepatitis B virus infection in primary central nervous system lymphoma International Journal of Clinical and Experimental Medicine 2015 8 6 9937 9942 2-s2.0-84938379372 26309679 \n41 Bracci P. M. Obesity and hepatitis B infection and risk of primary CNS lymphoma Blood 2013 122 21 \n42 Ruiz-Irastorza G. Ugarte A. Egurbide M. V. Antimalarials may influence the risk of malignancy in systemic lupus erythematosus Annals of the Rheumatic Diseases 2007 66 6 815 817 10.1136/ard.2006.067777 2-s2.0-34249801215 17204564 \n43 Ambinder R. F. Gammaherpesviruses and “hit-and-run” oncogenesis American Journal of Pathology 2000 156 1 1 3 10.1016/s0002-9440(10)64697-4 2-s2.0-0033895812 10623645 \n44 Zinzani P. L. Broccoli A. Stefoni V. Immunophenotype and intermediate-high international prognostic index score are prognostic factors for therapy in diffuse large B-cell lymphoma patients Cancer 2010 116 24 5667 5675 10.1002/cncr.25307 2-s2.0-78650158119 20737566 \n45 Lin T. Y. Zhang H. Y. Huang Y. Comparison between R-CHOP regimen and CHOP regimen in treating naive diffuse large B-cell lymphoma in China—a multi-center randomized trial Ai Zheng 2005 24 12 1421 1426 16351785 \n46 Holdhoff M. Ambady P. Abdelaziz A. High-dose methotrexate with or without rituximab in newly diagnosed primary CNS lymphoma Neurology 2014 83 3 235 239 10.1212/WNL.0000000000000593 2-s2.0-84905864491 24928128 \n47 Alchi B. Jayne D. Labopin M. Autologous haematopoietic stem cell transplantation for systemic lupus erythematosus: data from the European Group for Blood and Marrow Transplantation registry Lupus 2013 22 3 245 253 10.1177/0961203312470729 2-s2.0-84874424391 23257404 \n48 Klyuchnikov E. Bacher U. Kroll T. Allogeneic hematopoietic cell transplantation for diffuse large B cell lymphoma: who, when and how? Bone Marrow Transplantation 2014 49 1 1 7 10.1038/bmt.2013.72 2-s2.0-84891874313 23708703\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6897",
"issue": "2017()",
"journal": "Case reports in rheumatology",
"keywords": null,
"medline_ta": "Case Rep Rheumatol",
"mesh_terms": null,
"nlm_unique_id": "101585353",
"other_id": null,
"pages": "1658473",
"pmc": null,
"pmid": "28428903",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "17204564;11035137;22504579;23410586;21722503;3286832;16816838;16208671;26309679;1586239;17893972;23303389;24928128;20737566;10623645;24577173;16335585;14592832;22799329;16730063;20041274;12728402;15800313;7473469;17517757;17016483;19591783;16162903;23708703;11460166;21868432;23257404;19897521;25885411;11983151;17211996;10559454;15266094;21150178;22811739;16351785;17297594;8651970;12876906;17545189",
"title": "SLE and Non-Hodgkin's Lymphoma: A Case Series and Review of the Literature.",
"title_normalized": "sle and non hodgkin s lymphoma a case series and review of the literature"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2021-06547",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
... |
{
"abstract": "While opioid-induced myoclonus is well described, there are limited reports of opioid-induced chorea. Here we present the first case of chorea as a manifestation of opioid neurotoxicity due to hydromorphone.\n\n\n\nA 20-year-old woman presenting with fevers and cutaneous lesions was diagnosed with hemophagocytic lymphohistiocytosis secondary to primary cutaneous lymphoma. Surgical resection of a cutaneous lesion was complicated by severe postoperative pain requiring rapid opioid dose escalation. Seven days after hydromorphone was initiated, she developed positive myoclonus, hallucinations, delirium, and involuntary, flowing movements consistent with chorea. She had no personal or family history of nervous system disorders and was not taking any medications associated with drug-induced chorea. Case management: The remainder of her neurologic examination was unremarkable. Her renal function was normal and no etiology was found on neuroimaging or laboratory workup. Hydromorphone was discontinued and pain control was achieved with fentanyl. Case outcome: The patient's neurotoxic symptoms including chorea resolved within 72 h of hydromorphone discontinuation.\n\n\n\nFurther studies are needed to determine which patients have a unique sensitivity to opioids predisposing them to chorea. Clinicians should be aware that chorea may be a sign of such toxicity so that rapid corrective action can be taken.",
"affiliations": "1 Moores Cancer Center, University of California-San Diego, La Jolla, CA, USA.;2 University of Colorado, Anschutz Medical Campus, Denver, CO, USA.;3 Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California-San Diego, La Jolla, CA, USA.;1 Moores Cancer Center, University of California-San Diego, La Jolla, CA, USA.;1 Moores Cancer Center, University of California-San Diego, La Jolla, CA, USA.;1 Moores Cancer Center, University of California-San Diego, La Jolla, CA, USA.",
"authors": "Martin|Emily J|EJ|0000-0003-1413-482X;Vaughan|Christina L|CL|;Atayee|Rabia|R|;Hirst|Jeremy M|JM|;O'Donnell|Kaitlyn|K|;Edmonds|Kyle P|KP|",
"chemical_list": "D000701:Analgesics, Opioid; D004091:Hydromorphone; D005283:Fentanyl",
"country": "England",
"delete": false,
"doi": "10.1177/0269216318786861",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-2163",
"issue": "32(9)",
"journal": "Palliative medicine",
"keywords": "Hydromorphone; analgesics; case report; chorea; movement disorders; neurotoxicity syndromes; opioid",
"medline_ta": "Palliat Med",
"mesh_terms": "D000701:Analgesics, Opioid; D002819:Chorea; D005260:Female; D005283:Fentanyl; D006801:Humans; D004091:Hydromorphone; D020258:Neurotoxicity Syndromes; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "8704926",
"other_id": null,
"pages": "1529-1532",
"pmc": null,
"pmid": "30004301",
"pubdate": "2018-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hydromorphone-induced chorea as an atypical presentation of opioid neurotoxicity: A case report and review of the literature.",
"title_normalized": "hydromorphone induced chorea as an atypical presentation of opioid neurotoxicity a case report and review of the literature"
} | [
{
"companynumb": "US-PFIZER INC-2018287454",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": null,
... |
{
"abstract": "Acne fulminans is a rare and severe form of acne that may evolve from acne vulgaris, especially in male adolescents, or occur as an adverse effect of oral isotretinoin. Arthritis is a serious clinical manifestation when the musculoskeletal system is compromised by AF and has been reported as a rare adverse effect of isotretinoin. Involvement of the sacroiliac joints occurs in 21% of acne fulminans cases. We present the case of a 18-year-old male patient in whom acne fulminans evolved from acne vulgaris grade IV and after inflammation resolution started treatment with oral isotretinoin. Within a 30-day period of retinoid treatment he presented with back pain followed by rapid, progressive inability to deambulate.",
"affiliations": "Fundação de Dermatologia e Venereologia Alfredo da Matta, ManausAM, Brazil.;Fundação de Dermatologia e Venereologia Alfredo da Matta, ManausAM, Brazil.",
"authors": "Geller|Ariane Silva Bastos|AS|;Alagia|Roberta Ferreira Nazareth|RF|",
"chemical_list": "D003879:Dermatologic Agents; D015474:Isotretinoin",
"country": "Spain",
"delete": false,
"doi": null,
"fulltext": "\n==== Front\nAn Bras DermatolAn Bras DermatolAn Bras DermatolAnais Brasileiros de Dermatologia0365-05961806-4841Sociedade Brasileira de Dermatologia 2434691710.1590/abd1806-4841.20132500Case ReportSacroiliitis after use of oral isotretinoin - association\nwith acne fulminans or adverse effect?*\n Sacroileíte após uso de isotretinoína oral - associação com acne\nfulminans ou efeito adverso? Geller Ariane Silva Bastos 1Alagia Roberta Ferreira Nazareth 21 MD, PhD program student - Resident at Fundação de Dermatologia e Venereologia Alfredo da\nMatta (FUAM) - Manaus (AM), Brazil.\n.2 MD, residence in Dermatology - Fundação de Dermatologia e Venereologia Alfredo da Matta (FUAM) - Manaus (AM), Brazil\n.Mailing address: Ariane Silva Bastos Geller, Av Codajás, 24 -\nCachoeirinha, 69.065-130 - Manaus - AM, Brazil. E-mail:\narianegeller@hotmail.comNov-Dec 2013 88 6 Suppl 1 193 196 30 1 2013 17 3 2013 ©2013 by Anais Brasileiros de\nDermatologiaThis is an Open Access article distributed under the terms of the Creative\nCommons Attribution Non-Commercial License, which permits unrestricted\nnon-commercial use, distribution, and reproduction in any medium, provided the\noriginal work is properly cited.Acne fulminans is a rare and severe form of acne that may evolve from acne vulgaris,\nespecially in male adolescents, or occur as an adverse effect of oral isotretinoin.\nArthritis is a serious clinical manifestation when the musculoskeletal system is\ncompromised by AF and has been reported as a rare adverse effect of isotretinoin.\nInvolvement of the sacroiliac joints occurs in 21% of acne fulminans cases. We\npresent the case of a 18-year-old male patient in whom acne fulminans evolved from\nacne vulgaris grade IV and after inflammation resolution started treatment with oral\nisotretinoin. Within a 30-day period of retinoid treatment he presented with back\npain followed by rapid, progressive inability to deambulate.\n\nAcne fulminans é uma forma grave e rara de acne que pode ser evolução da acne vulgar,\nprincipalmente em adolescentes do sexo masculino, ou ser precipitada durante o\ntratamento com isotretinoína oral. A artrite pode ocorrer como grave complicação na\nacne fulminans e já foi relatada como efeito adverso raro da isotretinoína. O\nacometimento das articulações sacroilíacas ocorre em 21% das artrites associadas à\nacne fulminans. Relatase caso de paciente masculino, 18 anos, que desenvolveu acne\nfulminans a partir de acne vulgar grau IV/conglobata e após resolução do quadro\ninflamatório, foi iniciado tratamento da acne com isotretinoína. Com 30 dias de uso\ndo retinóide, o paciente iniciou dor lombar com piora rápida, progressiva que o\nincapacitou de deambular.\n\nAcne vulgarisArthritisIsotretinoinSacroiliitis\n==== Body\nINTRODUCTION\nIsotretinoin is a safe and effective drug that has been used for over thirty years in\nthe treatment of acne. The more frequent adverse effects are related to skin and mucous\nmembranes.1Arthralgias, and more rarely\nsacroiliitis and polyneuropathy, signal musculoskeletal system involvement.2\n\n\nLikewise, the acne fulminans (AF) described by Plewig and Kligman in 1975 is\ncharacterized by sudden onset of ulcerous/crusted acne and systemic symptoms, including\nfever and weight loss, osteoarticular signs and laboratory tests alterations. It can\nalso be triggered by isotretinoin and has sacroiliitis as a clinical manifestation.1,2,3This is the report of a\ncase of an adolescent who developed acne fulminans from grade IV acne\nvulgaris, and after resolution of the inflammatory process, while initiating treatment\nwith oral isotretinoin, presented with bilateral sacroiliitis after 30 days of\ntreatment. The association of the retinoid with the clinical picture developed is\ndiscussed in this report.\n\nCASE REPORT\nAn 18-year-old male patient had the onset of acne 3 years ago, with worsening in the 40\ndays that preceded the examination at the outpatient clinic. He presented fever and\narthralgias for 7 days, more intense on the sternal region and left shoulder, associated\nwith pustules and confluent nodules which formed crusted erythematous plaques in the\nmalar region, with formation of fistulous tracts in the bilateral mandibular region,\nextending to the preauricular area with purulent secretion (Figure 1). However, there were no thorax nor dorsum lesions.\nLaboratory exams showed leucocytosis 22,640/mm3 with 78.8% neutrophils,\nwithout hepatic or lipid profile alterations. The drugs in use (topic betamethasone,\ngentamicin and benzoyl peroxide) were suspended and dapsone 100mg/day and minocycline\n100mg/day prescribed for 21 days. With the clinical improvement and normalization of the\nhemogram, oral isotretinoin, 40mg/day (0.67mg/Kg/day) was prescribed. After 30 days\nthere was significant improvement of cutaneous lesions, with pustules more concentrated\non the perioral region, in addition to papules and erythema in the malar and mandibular\nregion, which already showed healing of the fistulous tracts (Figure 2). At the same time, the patient reported intense lumbar\npain of quick progression, which prevented ambulation, resulting in hospitalization,\nsuspension of isotretinoin and use of analgesics and non-steroidal anti-inflammatory.\nThe lumbar spine radiography and MRI, performed during hospitalization, did not show\nalterations that could explain the clinical condition. After hospital discharge, the\npatient returned to the outpatient clinic using a wheelchair, and an orthopedic\nevaluation was requested. The non-steroidal anti-inflammatory was continued and a bone\nscintigraphy was requested. Bone scintigraphy, done after hospitalization, when the\npatient was already walking with the aid of crutches, detected the radiopharmaceutical\ntrapped in the sacroiliac articulations, which was conclusive for light bilateral\nsacroiliitis (Figure 3). The HLA-B27 antigen was\nnegative. The patient maintained improvement of the articular condition, with\nprogressive recovery of ambulation after the use of orthesis and physical therapy. The\nacne condition presented excellent results with the use of oral isotretinoin for 30 days\nand after its suspension, benzoyl peroxide 5% associated with adapalene 0.1% and\nintermittent oral antibiotic therapy, showing few inflammatory lesions and residual\nerythema (Figure 4).\n\nFIGURE 1 Presence of pustules, nodules and crusts on face, predominantly in the malar\nregion\n\nFIGURE 2 Improvement of condition 30 days after use of oral isotretinoin. A) presence\nof pustules, erythema and papules; B) Pustules, erythema and fistulous\ntract\n\nFIGURE 3 Bone scintigraphy showing light bilateral sacroiliitis (arrows)\n\nFIGURE 4 Patient under maintenance acne treatment with improvement of clinical\ncondition. A e B: presence of multiple scars\n\nDISCUSSION\nAcne vulgaris, in all its clinical variables, involves 80% of young people and has in\nacne fulminans, which affects 1% of this population, its most severe\nform. It predominates in men between 13 and 22 years of age and is characterized by\nabscesses, crusted hemorrhagic ulcerative lesions and purulent areas that invariably\ninvolve the trunk with less intense facial involvement, associated with sudden systemic\nmanifestations like high fever, weight loss, asthenia, adenopathies and osteoarticular\ninvolvement that affects mainly big articulations.4,5Clinically, it differs\nfrom grade IV or conglobata acne, for even of the latter presents nodule-cystical\neruptive lesions, there is no systemic symptomatology. Laboratory exams show that with\nacne fulminans there is evident leucocytosis, with left deviation and\nincreased erythrocyte sedimentation speed.4Despite the absence of extra-facial involvement in the reported patient, the\npresence of signs and systemic symptoms of sudden onset accompanied by expressive\nleucocytosis, besides the worsening and characteristics of the facial cutaneous lesions,\nsupported the diagnosis of acne fulminans. \n\nAs previously mentioned, acne fulminans can involve the musculoskeletal\nsystem and more commonly causes bone pain, arthralgias and arthritis. When accompanied\nby arthritis, the sacroiliac articulations are involved in 21% of the cases reported on\nthe literature.5,6There are reports of acne fulminans caused by\nisotretinoin, however in none of them it is related to the antigen HLA-B27.7,8\n\n\nOral isotretinoin is a drug largely employed in dermatology. This oral retinoid is\nindicated for the treatment of grade III/nodular acne and grade IV/conglobata or\nfulminans and presents as the most common adverse effect drying of\nskin and mucous membranes.1Rare situations like\npolyneuropathy and seronegative sacroiliitis can occur, as in the described case.2,7,8As a pathogenic\nmechanism, it was suggested that isotretinoin could induce solubilization of the\nliposomal membrane and consequently cytopathic destruction of the synovium, causing\narthritis as an adverse effect.9Ekisioglu and\nothers (2007) suggested that the positivity of antigen HLA-B27 renders the patient\nsusceptible to the development of sacroiliitis; however, the other cases described in\nthe literature do not corroborate this statement.7,8,10\n\n\nIn the case presented, bilateral sacroiliitis occurred only after the introduction of\noral isotretinoin, when the acne fulminans condition was resolved, with\nnormalized hemogram and clinical absence of inflammation. Based on the chronology of\nevents and expressive improvement of arthritis after suspension of oral isotretinoin, in\nthe described case the sacroiliitis was associated with the retinoid. However, it is\nknown that this type of clinical manifestation can occur late when associated with acne\nfulminans and it is not possible to exclude this possibility.\nWhatever the case, the investigation of rheumatological associations and careful\nfollow-up of patients that show osteoarticular involvement are indispensable, especially\nin sacroiliitis, an arthritis that involves the axial skeleton and is thus considered\nsevere.\n\n* Work performed at Dermatology and Venereology Foundation Alfredo da Matta (FUAM) -\nManaus (AM), Brazil.\n\nConflict of interest: None\n\nFinancial Support: None\n==== Refs\nREFERENCES \n1 Montagner S Costa A Diretrizes modernas no tratamento da acne vulgar\nabordagem inicial à manutenção dos benefícios clínicos Surg Cosmet Dermatol 2010 2 205 213 \n2 Eksioglu E Oztekin F Unlu E Cakci A Keyik B Karadavut IK Sacroiliitis and polyneuropathy during isotretinoin\ntreatment Clin Exp Dermatol 2007 33 122 124 17725657 \n3 Plewig G Kligman AM Acne: Morphogenesis and treatment Berlin Springer 1975 \n4 Romiti R Jansen T Plewig G Acne fulminans An Bras Dermatol 2000 75 611 617 \n5 Zanelato TP Gontijo GM Alves CA Pinto JC Cunha PR Acne fulminans incapacitante An Bras Dermatol 2011 86 S9 12 22068759 \n6 Knitzer RH Needleman BW Musculoskeletal syndromes associated with\nacne Semin Arthritis Rheum 1991 20 247 255 1828308 \n7 Bachmeyer C Charoud A Turc Y Callot V Blum L Aractingi S Isotretinoin-induced bilateral\nsacroiliitis Dermatology 2003 206 285 286 12673094 \n8 Barbareschi M Paresce E Chiaratti A Ferla Lodigiani A Clerici G Greppi F Unilateral sacroiliitis associated with systemic\nisotretinoin treatment Int J Dermatol 2010 49 331 333 20465675 \n9 De Francesco V Stinco G Campanella M Acute arthritis during isotretinoin treatment for acne\nconglobata Dermatology 1997 194 195 \n10 Rozin AP Kagna O Shiller Y Sacroiliitis and severe disability due to isotretinoin\ntherapy Rheumatol Int 2010 30 985 986 19533139\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0365-0596",
"issue": "88(6 Suppl 1)",
"journal": "Anais brasileiros de dermatologia",
"keywords": null,
"medline_ta": "An Bras Dermatol",
"mesh_terms": "D000152:Acne Vulgaris; D000293:Adolescent; D003879:Dermatologic Agents; D006801:Humans; D015474:Isotretinoin; D008297:Male; D011877:Radionuclide Imaging; D058566:Sacroiliitis; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "0067662",
"other_id": null,
"pages": "193-6",
"pmc": null,
"pmid": "24346917",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12673094;20465675;17725657;9094477;19533139;22068759;1828308",
"title": "Sacroiliitis after use of oral isotretinoin--association with acne fulminans or adverse effect?",
"title_normalized": "sacroiliitis after use of oral isotretinoin association with acne fulminans or adverse effect"
} | [
{
"companynumb": "BR-RANBAXY-2014R1-77953",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ISOTRETINOIN"
},
"drugadditional": null,
... |
{
"abstract": "Most of the patients with iliofemoral thrombosis treated with anticoagulants only are affected with postthrombotic syndrome (PTS) that worsens the patients' quality of life. In the acute phase of proximal deep venous thrombosis (DVT) catheter-directed (CDT) and pharmacomechanical thrombolysis may be a reasonable alternative therapeutic method. Our aim was to summarize our results using these methods.\n\n\n\nSince 2009 twenty-four patients with iliofemoral DVT were treated with these endovascular procedures and with stenting at our Institution.\n\n\n\nThe median age of the patients was 35.83 ± 15.9 years, the female: male ratio was approximately 2:1. The mean time between the onset of the symptoms and the procedures was eleven days. CDT alone was performed in 8 patients, thrombus aspiration in addition to CDT using AngioJet device in 16 patients; in 19 cases the procedure was completed with venous stenting. During the follow-up we performed US examinations and estimated the severity of PTS by Villalta-scale. The total recanalization-rate was more than 50%, which even improved during the follow-up. The total lysis time and the amount of used recombinant tissue plasminogen activator decreased significantly by applying the AngioJet. We did not find any severe PTS among our patients during the follow-up visits.\n\n\n\nOur data suggests that these methods can be used efficiently and safely in the treatment of acute iliofemoral DVT.",
"affiliations": "Érsebészeti Tanszék, Semmelweis Egyetem, Városmajori Szív- és Érgyógyászati Klinika 1122 Budapest, Városmajor u. 68.;Érsebészeti Tanszék, Semmelweis Egyetem, Városmajori Szív- és Érgyógyászati Klinika 1122 Budapest, Városmajor u. 68.;Kardiológiai Központ, Semmelweis Egyetem, Városmajori Szív- és Érgyógyászati Klinika Budapest.;Kardiológiai Központ, Semmelweis Egyetem, Városmajori Szív- és Érgyógyászati Klinika Budapest.;Érsebészeti Tanszék, Semmelweis Egyetem, Városmajori Szív- és Érgyógyászati Klinika 1122 Budapest, Városmajor u. 68.;Érsebészeti Tanszék, Semmelweis Egyetem, Városmajori Szív- és Érgyógyászati Klinika 1122 Budapest, Városmajor u. 68.;Érsebészeti Tanszék, Semmelweis Egyetem, Városmajori Szív- és Érgyógyászati Klinika 1122 Budapest, Városmajor u. 68.;Érsebészeti Tanszék, Semmelweis Egyetem, Városmajori Szív- és Érgyógyászati Klinika 1122 Budapest, Városmajor u. 68.;Érsebészeti Tanszék, Semmelweis Egyetem, Városmajori Szív- és Érgyógyászati Klinika 1122 Budapest, Városmajor u. 68.",
"authors": "Berencsi|Anikó|A|;Dósa|Edit|E|;Nemes|Balázs|B|;Hüttl|Kálmán|K|;Legeza|Péter|P|;Oláh|Zoltán|Z|;Kristóf|Vera|V|;Acsády|György|G|;Sótonyi|Péter|P|",
"chemical_list": "D005343:Fibrinolytic Agents",
"country": "Hungary",
"delete": false,
"doi": "10.1556/1046.70.2017.1.4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0025-0295",
"issue": "70(1)",
"journal": "Magyar sebeszet",
"keywords": "catheter-directed thrombolysis; iliofemoral deep venous thrombosis; lokális katéteres lysis; pharmacomechanical thrombectomy; postthrombotic syndrome; postthromboticus szindróma; proximális mélyvénás thrombosis; thrombusaspiráció; venous stenting; vénás stent",
"medline_ta": "Magy Seb",
"mesh_terms": "D002406:Catheterization, Peripheral; D057510:Endovascular Procedures; D005260:Female; D005268:Femoral Vein; D005343:Fibrinolytic Agents; D006801:Humans; D007084:Iliac Vein; D008297:Male; D054070:Postthrombotic Syndrome; D011788:Quality of Life; D015607:Stents; D017131:Thrombectomy; D015912:Thrombolytic Therapy; D016896:Treatment Outcome; D018084:Ultrasonography, Interventional; D014654:Vascular Patency; D020246:Venous Thrombosis",
"nlm_unique_id": "18420110R",
"other_id": null,
"pages": "24-31",
"pmc": null,
"pmid": "28294670",
"pubdate": "2017-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Endovascular treatment of acute iliofemoral deep venous thrombosis - our results with catheter-directed thrombolysis and AngioJet.",
"title_normalized": "endovascular treatment of acute iliofemoral deep venous thrombosis our results with catheter directed thrombolysis and angiojet"
} | [
{
"companynumb": "HU-ROCHE-1919104",
"fulfillexpeditecriteria": "1",
"occurcountry": "HU",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": null,
... |
{
"abstract": "Hepatocellular carcinoma (HCC) is more common in patients with chronic viral hepatitis infection and cirrhosis. Transarterial chemoembolization (TACE) is an effective treatment method for unresectable HCC. A rare complication of TACE is the development of bloodstream infection. We present a fatal case of sepsis due to Anaerococcus nagyae after TACE.",
"affiliations": "Marmara University School of Medicine, Department of Microbiology, Istanbul, Turkey. Electronic address: nulger@marmara.edu.tr.;Marmara University Pendik Training and Research Hospital, Laboratory of Microbiology, Istanbul, Turkey.;Marmara University School of Medicine, Department of Microbiology, Istanbul, Turkey.;Marmara University Pendik Training and Research Hospital, Emergency Medicine Department, Istanbul, Turkey.",
"authors": "Toprak|Nurver Ulger|NU|;Sayin|Elvan|E|;Akilli|Fatih Mehmet|FM|;Gundogdu|Abidin|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.anaerobe.2021.102464",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1075-9964",
"issue": "72()",
"journal": "Anaerobe",
"keywords": "Anaerococcus nagyae; Hepatocellular carcinoma; Sepsis; Transarterial chemoembolization",
"medline_ta": "Anaerobe",
"mesh_terms": null,
"nlm_unique_id": "9505216",
"other_id": null,
"pages": "102464",
"pmc": null,
"pmid": "34597796",
"pubdate": "2021-09-28",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Sepsis caused by Anaerococcus nagyae after transarterial-chemoembolization for hepatocellular carcinoma: Case report and literature review.",
"title_normalized": "sepsis caused by anaerococcus nagyae after transarterial chemoembolization for hepatocellular carcinoma case report and literature review"
} | [
{
"companynumb": "TR-LUPIN PHARMACEUTICALS INC.-2022-04677",
"fulfillexpeditecriteria": "2",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional... |
{
"abstract": "BACKGROUND\nSerotonin syndrome (SS) is a drug-induced constellation of various clinical features that result from excess central serotonergic tone. The clinical features range from barely perceptible to life-threatening conditions.\n\n\nMETHODS\nWe describe four patients with acute headache (four days to three weeks) who were receiving serotonergic drugs for other indications. There was a temporal relation between the administration of the serotonergic drugs and the development of the headaches. All four patients fulfilled the Hunter Serotonin Toxicity Criteria for SS. In parallel, two patients fulfilled the Sternbach's criteria for SS. Discontinuation of the serotonergic drugs and the administration of cyprohepatadine led to complete improvement in three to seven days in all four patients.\n\n\nCONCLUSIONS\nA review of the literature suggests that some overlaps exist in the pathophysiology between SS and headache disorders, including medication-overuse headache. The overlap is also in the management. The drugs found to be effective in SS (cyproheptadine, chlorpromazine, olanzapine, etc.) are also known to have positive effects on some headache disorders.\n\n\nCONCLUSIONS\nPhysicians should consider the diagnosis of SS in patients with new onset or worsening headache after the addition of serotonergic drugs, especially in the presence of objective signs on examination suggestive of the disorder such as tremor, fever, hyperreflexia, diaphoresis or tachycardia.",
"affiliations": "Department of Neurology, Medical College, SSG Hospital, India.",
"authors": "Prakash|Sanjay|S|;Belani|Pooja|P|;Trivedi|Aditi|A|",
"chemical_list": "D000701:Analgesics, Opioid; D000928:Antidepressive Agents; D018490:Serotonin Agents; D012701:Serotonin; D014147:Tramadol",
"country": "England",
"delete": false,
"doi": "10.1177/0333102413495968",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0333-1024",
"issue": "34(2)",
"journal": "Cephalalgia : an international journal of headache",
"keywords": "Headache; antidepressant; drug-induced headache; serotonin; serotonin syndrome",
"medline_ta": "Cephalalgia",
"mesh_terms": "D000328:Adult; D000701:Analgesics, Opioid; D000928:Antidepressive Agents; D005260:Female; D006261:Headache; D006801:Humans; D007049:Iatrogenic Disease; D008297:Male; D008875:Middle Aged; D012701:Serotonin; D018490:Serotonin Agents; D020230:Serotonin Syndrome; D014147:Tramadol; D055815:Young Adult",
"nlm_unique_id": "8200710",
"other_id": null,
"pages": "148-53",
"pmc": null,
"pmid": "23827981",
"pubdate": "2014-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Headache as a presenting feature in patients with serotonin syndrome: a case series.",
"title_normalized": "headache as a presenting feature in patients with serotonin syndrome a case series"
} | [
{
"companynumb": "IN-DRREDDYS-USA/IND/14/0042075",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN\\TRAMADOL"
},
"drugadditi... |
{
"abstract": "Background: Common variable immunodeficiency disorder (CVID) is one of the most frequent inborn errors of immunity, increased occurrence of malignancies, particularly lymphomas, and gastric cancers, has long been noted among CVID patients. Multifactorial etiology, including immune dysregulation, infections, chronic inflammation, or genetic background, is suggested to contribute to tumor development. Here, we present the results of the first Czech nationwide study focused on epidemiology, immunology and genetic background in a cohort of CVID patients who also developed tumors Methods: The cohort consisted of 295 CVID patients followed for 3,070 patient/years. Standardized incidence ratio (SIR) was calculated to determine the risk of cancer, and Risk ratio (RR) was established to evaluate the significance of comorbidities. Moreover, immunophenotyping, including immunoglobulin levels and lymphocyte populations, was assessed. Finally, Whole exome sequencing (WES) was performed in all patients with lymphoma to investigate the genetic background. Results: Twenty-five malignancies were diagnosed in 22 patients in a cohort of 295 CVID patients. SIR was more than 6 times greater in comparison to the general population. The most common neoplasias were gastric cancers and lymphomas. History of Immune thrombocytopenic purpura (ITP) was established as a potential risk factor, with over 3 times higher risk of cancer development. The B cell count at diagnosis of lymphoma was reduced in the lymphoma group; moreover, post-treatment B and T cell lymphopenia, associated with poorer outcome, was found in a majority of the patients. Intriguingly, no NK cell depression was observed after the chemotherapy. WES revealed heterogeneous genetic background among CVID patients with tumors, identifying gene variants associated with primary immunodeficiencies (such as CTLA4, PIK3CD, PMS2) and/or increased cancer susceptibility (including BRCA1, RABEP1, EP300, KDM5A). Conclusions: The incidence of malignancy in our CVID cohort was found to be more than 6 times greater compared to the general population. Gastric cancers and lymphomas were the most frequently diagnosed tumors. ITP was identified as a risk factor for malignancy in CVID patients. WES analysis confirmed a wide genetic heterogeneity among CVID patients. The identified causative or modifying gene variants pointed to errors in mechanisms contributing to both immunodeficiency and malignancy.",
"affiliations": "Department of Allergology and Clinical Immunology, Faculty of Medicine, Charles University and University Hospital in Hradec Kralove, Hradec Kralove, Czechia.;Department of Immunology, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czechia.;Department of Allergology nad Clinical Immunology, Faculty of Medicine, Masaryk University and St Anne's University Hospital in Brno, Brno, Czechia.;Department of Allergology and Clinical Immunology, Faculty of Medicine in Pilsen, Charles University and University Hospital Pilsen, Pilsen, Czechia.;Department of Allergology and Clinical Immunology, Institute of Health, Usti nad Labem, Czechia.;Institute of Immunology and Microbiology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czechia.;Department of Clinical Immunology and Allergology, Institute for Clinical and Experimental Medicine, Prague, Czechia.;Department of Pneumology, Regional Thomas Bata Hospital, Zlin, Czechia.;Childhood Leukemia Investigation Prague, Second Faculty of Medicine, Charles University, Prague, Czechia.;Childhood Leukemia Investigation Prague, Second Faculty of Medicine, Charles University, Prague, Czechia.;Childhood Leukemia Investigation Prague, Second Faculty of Medicine, Charles University, Prague, Czechia.;Department of Immunology, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czechia.;Department of Immunology, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czechia.;Department of Immunology, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czechia.;Department of Informatics and Quantitative Methods, Faculty of Informatics and Management, University of Hradec Kralove, Hradec Kralove, Czechia.;Childhood Leukemia Investigation Prague, Second Faculty of Medicine, Charles University, Prague, Czechia.;Department of Immunology, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czechia.",
"authors": "Kralickova|Pavlina|P|;Milota|Tomas|T|;Litzman|Jiri|J|;Malkusova|Ivana|I|;Jilek|Dalibor|D|;Petanova|Jitka|J|;Vydlakova|Jana|J|;Zimulova|Alena|A|;Fronkova|Eva|E|;Svaton|Michael|M|;Kanderova|Veronika|V|;Bloomfield|Marketa|M|;Parackova|Zuzana|Z|;Klocperk|Adam|A|;Haviger|Jiri|J|;Kalina|Tomas|T|;Sediva|Anna|A|",
"chemical_list": "D014408:Biomarkers, Tumor",
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fimmu.2018.03135",
"fulltext": "\n==== Front\nFront ImmunolFront ImmunolFront. Immunol.Frontiers in Immunology1664-3224Frontiers Media S.A. 10.3389/fimmu.2018.03135ImmunologyOriginal ResearchCVID-Associated Tumors: Czech Nationwide Study Focused on Epidemiology, Immunology, and Genetic Background in a Cohort of Patients With CVID Kralickova Pavlina 1†Milota Tomas 2*†Litzman Jiri 3Malkusova Ivana 4Jilek Dalibor 5Petanova Jitka 6Vydlakova Jana 7Zimulova Alena 8Fronkova Eva 9Svaton Michael 9Kanderova Veronika 9Bloomfield Marketa 2Parackova Zuzana 2Klocperk Adam 2Haviger Jiri 10Kalina Tomas 9Sediva Anna 21Department of Allergology and Clinical Immunology, Faculty of Medicine, Charles University and University Hospital in Hradec Kralove, Hradec Kralove, Czechia2Department of Immunology, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czechia3Department of Allergology nad Clinical Immunology, Faculty of Medicine, Masaryk University and St Anne's University Hospital in Brno, Brno, Czechia4Department of Allergology and Clinical Immunology, Faculty of Medicine in Pilsen, Charles University and University Hospital Pilsen, Pilsen, Czechia5Department of Allergology and Clinical Immunology, Institute of Health, Usti nad Labem, Czechia6Institute of Immunology and Microbiology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czechia7Department of Clinical Immunology and Allergology, Institute for Clinical and Experimental Medicine, Prague, Czechia8Department of Pneumology, Regional Thomas Bata Hospital, Zlin, Czechia9Childhood Leukemia Investigation Prague, Second Faculty of Medicine, Charles University, Prague, Czechia10Department of Informatics and Quantitative Methods, Faculty of Informatics and Management, University of Hradec Kralove, Hradec Kralove, CzechiaEdited by: Fabian Hauck, LMU München, Germany\n\nReviewed by: Roshini Sarah Abraham, Nationwide Children's Hospital, United States; Jolan Eszter Walter, University of South Florida, United States\n\n*Correspondence: Tomas Milota tomas.milota@fnmotol.czThis article was submitted to Primary Immunodeficiencies, a section of the journal Frontiers in Immunology\n\n†These authors have contributed equally to this work\n\n22 1 2019 2018 9 313511 9 2018 19 12 2018 Copyright © 2019 Kralickova, Milota, Litzman, Malkusova, Jilek, Petanova, Vydlakova, Zimulova, Fronkova, Svaton, Kanderova, Bloomfield, Parackova, Klocperk, Haviger, Kalina and Sediva.2019Kralickova, Milota, Litzman, Malkusova, Jilek, Petanova, Vydlakova, Zimulova, Fronkova, Svaton, Kanderova, Bloomfield, Parackova, Klocperk, Haviger, Kalina and SedivaThis 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.Background: Common variable immunodeficiency disorder (CVID) is one of the most frequent inborn errors of immunity, increased occurrence of malignancies, particularly lymphomas, and gastric cancers, has long been noted among CVID patients. Multifactorial etiology, including immune dysregulation, infections, chronic inflammation, or genetic background, is suggested to contribute to tumor development. Here, we present the results of the first Czech nationwide study focused on epidemiology, immunology and genetic background in a cohort of CVID patients who also developed tumors\n\nMethods: The cohort consisted of 295 CVID patients followed for 3,070 patient/years. Standardized incidence ratio (SIR) was calculated to determine the risk of cancer, and Risk ratio (RR) was established to evaluate the significance of comorbidities. Moreover, immunophenotyping, including immunoglobulin levels and lymphocyte populations, was assessed. Finally, Whole exome sequencing (WES) was performed in all patients with lymphoma to investigate the genetic background.\n\nResults: Twenty-five malignancies were diagnosed in 22 patients in a cohort of 295 CVID patients. SIR was more than 6 times greater in comparison to the general population. The most common neoplasias were gastric cancers and lymphomas. History of Immune thrombocytopenic purpura (ITP) was established as a potential risk factor, with over 3 times higher risk of cancer development. The B cell count at diagnosis of lymphoma was reduced in the lymphoma group; moreover, post-treatment B and T cell lymphopenia, associated with poorer outcome, was found in a majority of the patients. Intriguingly, no NK cell depression was observed after the chemotherapy. WES revealed heterogeneous genetic background among CVID patients with tumors, identifying gene variants associated with primary immunodeficiencies (such as CTLA4, PIK3CD, PMS2) and/or increased cancer susceptibility (including BRCA1, RABEP1, EP300, KDM5A).\n\nConclusions: The incidence of malignancy in our CVID cohort was found to be more than 6 times greater compared to the general population. Gastric cancers and lymphomas were the most frequently diagnosed tumors. ITP was identified as a risk factor for malignancy in CVID patients. WES analysis confirmed a wide genetic heterogeneity among CVID patients. The identified causative or modifying gene variants pointed to errors in mechanisms contributing to both immunodeficiency and malignancy.\n\ncommon variable immunodeficiencymalignancylymphomagastric cancerwhole exome sequencingGrantová Agentura, Univerzita Karlova10.13039/100007543Agentura Pro Zdravotnický Výzkum Ceské Republiky10.13039/501100009553\n==== Body\nIntroduction\nImmune control of tumor development and growth requires a functional immune system capable of complex immune responses necessary for recognition and elimination of malignant cells. As such, inborn errors resulting in immunodeficiencies may convey an increased risk of cancer. In general, the spectrum of malignancies in primary immunodeficiency (PID) patients is clearly biased when compared to malignant diseases in the general population. Malignancies in PIDs tend to be restricted to certain oncological entities, and their pathophysiology is often linked to the mechanism underlying the particular immunodeficiency (1). For example, immunodeficiencies associated with gain-of-function mutations in PIK3 are associated with a high risk of lymphoma (2). The role of this signaling pathway in cancer genesis and immunodeficiency is validated by therapeutic success of targeted PI3K/mTOR pathway inhibition used in activating PIK3 syndrome, as well as in malignant diseases (3). Similarly, immunodeficiencies arising from developmental defects of stem cells, myeloid cells or lymphocytes are associated with an increased incidence of leukemia or lymphomas, implying errors in the corresponding pathways (1). Recent advances in understanding of molecular mechanisms underlying primary immunodeficiencies, as well as tumors, has provided evidence for such associations. However, in immunodeficiencies that are not yet precisely defined by their molecular/genetic cause, the situation is more complex. Common variable immunodeficiency disorder (CVID) is one of the most frequent forms of antibody deficiencies; yet, its pathophysiology remains largely unknown. The hallmark of CVID is the impairment of the B cell compartment, typically manifesting as a reduction of mature forms of B cells and expansion of less differentiated stages of B lymphocytes (4). The T cell compartment is also usually skewed in CVID, specifically toward terminally differentiated forms, including senescent cells, typically affecting both CD4and CD8 T cells, which are crucial for anti-tumor immunity (5). The mechanisms of B cell involvement in anti-tumor immunity are largely unknown. B cells may promote both pro-tumourigenic responses (e.g., specific subsets of B cells may produce IL-10 or TGF-beta with immunosuppressive properties, B cells may promote tumor genesis and tumor progression by alteration of the angiogenic and proinflammatory microenvironment), as well as anti-tumourigenic responses (e.g., B cells may enhance cytotoxic T cell activity, indirectly mediate antibody dependent cytotoxic mechanisms or serve as professional antigen-presenting cells, initiating the T cell response) (6). Inborn impairment of the B cell lineage, along with T cell dysregulation, may facilitate the genesis of tumors in CVID patients. Furthermore, the immunologic defect is accentuated by recurrent and chronic infections. Chronic viral infections, particularly EBV, are strongly associated with lymphoproliferative diseases and lymphoma (7). Additionally, chronic inflammatory response, per se, represents a risk factor for tumor development, especially in patients genetically predisposed to malignancy.\n\nEfforts made to establish the genetic etiology of CVID have thus far been successful in 2–10% of CVID patients (known CVID-associated gene variants are shown in Table 1) (8). Some of the CVID-associated genes represent a clear predisposition to cancer, as described in previously published CVID cohorts; most prominently, these mutations are in genes causing alterations in the NFkB or PI3k pathways or in genes affecting B cell receptors (3, 9, 10).\n\nTable 1 List of genes associated with Common variable immunodeficiency (monogenic causes and modifier genes) and their prevalence, adjusted according to Bogaert et al. (8).\n\nGene\tPrevalence (%)\t\nMONOGENIC CAUSE OF CVID: 2–10%\t\nPIK3CD\t26.74\t\nLRBA\t26.74\t\nCTLA4\t6.42\t\nNFKB2\t5.35\t\nTNFRSF7 (CD27)\t4.81\t\nPIK3R1\t4.81\t\nICOS\t3.74\t\nCD19\t3.74\t\nIL-21R\t3.21\t\nIKZF1 (IKAROS)\t3.21\t\nPRKCD\t2.14\t\nPLCG2\t2.14\t\nNFKB1\t1.6\t\nCR2 (CD21)\t1.7\t\nMODIFIER GENES: UNKNOWN PREVALENCE\t\nTNFRSF13B (TACI), TNFRSF13C (BAFF-R), MSH2, MSH5, CLECG1, MLH1, RAD50, ORC4L, FCGR2A.\t\nOverall, the factors contributing to increased incidence of malignancy in CVID are complex, encompassing genetics, immune response dysregulation, infections, inflammation, and perhaps other not yet elucidated mechanisms.\n\nHere, we present the results of a complex study on a Czech national cohort of CVID patients who also presented with malignancy. National epidemiological data were collected, immune profiles were analyzed and, in a subgroup of CVID patients with lymphoma, Whole exome sequencing (WES) was performed.\n\nMethods\nThis study was approved by local ethics committee of Motol University Hospital. Written informed consents were obtained from all enrolled patients.\n\nData Collection\nRetrospective clinical and laboratory data of 295 enrolled patients were obtained from medical records of national referral centers for the treatment of adult patients with primary immunodeficiency diseases. The collected data covered the period from 1997 to 2016. They included a total amount and a length of surveillance of all CVID patients fulfilling ESID/PAGID criteria, a number of CVID cancer patients and patient-specific data: year of birth, age at first symptoms associated with CVID and their nature, clinical comorbidities, age at cancer diagnosis, type of cancer, therapeutic regimens, survival rates, cause of death (if applicable), and specific details of cancer diagnostics.\n\nA more detailed set of clinical data was obtained from 11 CVID patients with cancer and from 160 randomly selected cancer-free CVID patients, who represented the reference group. This cohort included 95 females and 65 males with a median age of 48 years (range 19–88). Czech general population data on occurrence of malignancy were obtained from the Czech National Cancer Registry and covered the period from 1994 to 2014 (the last available reports).\n\nEpidemiology\nPrevalence and SIR were calculated to express the probability of cancer diagnosis in a CVID cohort compared to the general population. RR was used to assess the significance of comorbidities in CVID patients with cancer. Confidence intervals (95% CIs) were determined for both parameters. All results for which number 1 was beyond the 95% CI were accepted as statistically significant (11).\n\nImmunophenotyping\nSerum levels of IgM, IgG, IgA were evaluated by nephelometric method using Image 800 systems (Beckman-Coulter, Brea, CA, USA). Basic lymphocyte subpopulations, including T cells, T helper cells, T cytotoxic cells, B cells and NK cells, were distinguished by FACS based on the expression of specific cell surface membrane markers using fluorochrome-conjugated monoclonal antibodies CD3-FITC, CD4-PE/Cy, CD8-APC/Cy,CD19-APC, CD16-PE, CD56-PE; KOMBITEST, Exbio, Prague, Czech Republic. B cell subpopulations (including CD21low, naive, transitional, marginal zone-like, class-switched cells, and plasmablasts) and T cell subpopulations (recent thymic emigrants-RTE, naïve, central memory-CM, effector memory-EM, effector memory expressing CD45RA-TEMRA, activated T cells) were performed using antibody-fluorochrome conjugates: CD45-APC-H7, CD3-APC, CD4-PerCP-Cy5.5, CD16-PE, CD56-PE, TCRgd-PE-Cy7, CD38-FITC, CD21-APC, IgM-FITC, CD8-Horizon V-500, CD45RA-PE-Cy7 (BD Biosciences, San Jose, CA, USA), CD5-PE,CD8-FITC, CD27-Brilliant Violet 421, IgM-Brilliant Violet 510, IgD-PerCP-Cy5.5, CD4-Brilliant Violet 510, CD62L-Brilliant Violet 421, HLA-DR-PerCP-Cy5.5 (Biolegend, San Diego, CA), CD19-PE-Cy7, CD24-PE, CD24-APC-Alexa Fluor 750, CD8-APC-Alexa Fluor 750 (Beckman Coulter, Miami, FL, USA), CD27-Pacific Blue, CD38-Alexa Fluor 700, CD45RO-FITC, CD31-PE, CD4-Alexa Fluor 700 (Exbio, Vestec, Czech Republic), CCR7-PE (MiltenyiBiotec, BergischGladbach, Germany), CD3-PerCP-Cy5.5 (Affymetrix eBioscience, ThermoFisher Scientific, Waltham, MA, USA), and IgD biotin (SouthernBiotech, Birmingham, AL, USA) followed by Streptavidin-Qdot 605 (Invitrogen, ThermoFisher Scientific, Waltham, MA, USA).\n\nThe absolute and relative counts were assessed for all subpopulations. Examinations of the basic subpopulations and immunoglobulin levels were performed at the time of diagnosis of CVID and at the time of diagnosis of lymphoma. The B and T cell subpopulations were measured prior to the genetic testing. All parameters were compared to the control cohort of 20 randomly selected CVID patients without lymphoma. All obtained data were statistically evaluated. A non-parametric Mann-Whitney test was used to compare independent samples, and a non-parametric Wilcoxon matched-pairs signed rank test was used to compare dependent samples; differences of p < 0.05 were regarded as significant. Median and 95% CIs were calculated for all analyzed parameters.\n\nCTLA-4 Expression\nCTLA-4 expression was assessed in patient with novel mutations using FACS. Intracellular CTLA-4 was detected 16 h following anti-CD3/CD28 stimulation (Dynabeads, Thermo Fisher Scientific, MA, USA) using CTLA4-APC antibody together with the FOXP3 Fix/Perm Buffer set (BioLegend, San Diego, CA, USA) in CD4+CD127dimCD25+ T regulatory cells (Tregs). CD45-APC-H7, CD4-Brilliant Violet 510, and CD127-Brilliant Violet 421 (BD Biosciences, San Jose, CA, USA), CD25-PE-Cy7 and CD8-FITC (Exbio, Vestec, Czech Republic) antibodies were used for detection of Tregs.\n\nWhole Exome Sequencing\nSequencing libraries were prepared using a SureSelectXT Human All Exon V6+UTR kit (Agilent Technologies, Santa Clara, CA) from DNA isolated from patients' peripheral blood with a QIAamp DNA Blood Mini Kit (Qiagen, Hilden, Germany). Sequencing was performed by our facility on the NextSeq 500 (Illumina, San Diego, CA) instrument according to the manufacturer's protocols. The reads in resulting Fastq files were aligned against the human reference genome hg19 with BWA (12). Genomic variants were called with samtools and VarScan (13). Variant annotation was performed using SnpEff (14). Variant filtering was performed with Ingenuity® Variant Analysis™ (IVA) software (www.qiagen.com/Ingenuity, QIAGEN). Only variants with read depths of at least 10 and allele frequencies of at least 0.3 were evaluated. Common variants with allele population frequencies of more than 0.1% or homozygous counts of 5 or more in the ExAC or gnomAD databases were filtered out unless reported as disease-causing in the HGMD® (BIOBASE GmbH) or dbSNP databases (15, 16). Variants predicted to have low impact by at least 2 out of 3 scores calculated by SIFT, PolyPhen2, or CADD and present in population databases were also discarded (17–19). Remaining variants were manually evaluated in Integrative Genomics Viewer (http://www.broadinstitute.org/igv) to exclude variants in reads with low mapping quality (20). The analysis was then focused on variants in genes reported as causative for inborn errors of immunity in the last International Union of Immunological Societies (IUIS) guidelines, cancer-predisposition genes in children and in-house lists of genes possibly leading to immune dysregulation based on recent publications and close interactions with causative genes reported by IUIS (21, 22).\n\nResults\nEpidemiology and Clinical Manifestation\nOur cohort of patients included 295 patients followed for 3,070 patient/years in total. The average ages at the first CVID-related symptoms and at the time of CVID diagnosis in a subgroup of CVID patients with malignancy were 34.2 and 38.3 years, respectively. A total of 25 malignancies were found in 22 patients (7.4% of all included patients) with SIR 6.3 (95% CI: 4.08–9.31). These cases included 6/25 (24.0%) gastric carcinoma (GC): SIR 5.7, 95% CI: 2.08–12.32, 4/25 (16.0%), B cell Non-Hodgkin lymphoma (B-NHL): SIR 5.5, 95% CI: 1.50–14.09, 5/25 (20.0%), Hodgkin lymphoma (HL):SIR 30.0, 95% CI: 9.73–69.93 and 10/24 (41.7%) other cancers (SIR 5.0, 95% CI: 2.40–9.16). These were two cases of spinocellular carcinoma, basocellular carcinoma, and T-cell lymphoma, and a single case each of tonsillar carcinoma, breast carcinoma, renal carcinoma and urine bladder cancer. Cancer duplicity was observed in 3 patients (gastric and tonsillar carcinoma, breast cancer and urothelial carcinoma, spinocellular, and gastric carcinoma). Malignancies were diagnosed in 16 males and 6 females; the average age at diagnosis was 52.3 years (15 years after the diagnosis of CVID and 19 years after the first symptoms). The average ages of manifestation of GC, B-NHL, and HL in CVID cancer group were 55–59, 35–39, and 40–44 years, respectively.\n\nAutoimmune cytopaenias, including Immune thrombocytopenic purpura (ITP) and Autoimmune hemolytic anemia (AIHA), were the most common complications in CVID both with and without malignancy. They were found in 8/22 (36.4%) and 27/160 (16.9%), respectively. Interestingly, a strikingly increased risk of malignancy was detected in a subgroup of CVID patients with a history of ITP (RR 3.52, 95% CI 1.42–7.26). Cumulative risk (RR 4.53, 95% CI 1.23–11.59) observed for B-NHL and HL together was similar. However, no risk increase was observed for isolated HL, B-NHL, and GC, probably due to the small number of cancer events and because the direct association with other documented CVID-related comorbidities was not significant (data not shown).\n\nAs mentioned above, lymphomas and GC represent the most frequent malignancies diagnosed in CVID patients in our cohort. While five out of six patients with GC (4 males, 2 females) underwent surgery, one received palliative chemotherapy with FLOX regimen (fluorouracil, leucovorin, oxaliplatin) due to highly progressed disease at the time of diagnosis. Five out of six patients had deceased before the study initiation, 2/6 (33.3%) due to disease progression, 2/6 (33.3%) passed away after achieving more than 10 years survival, and one patient died because of malnutrition due to severe enteropathy 2 years after the diagnosis of lymphoma. All patients suffered from various gastrointestinal complications related to CVID, and the majority of them also had splenomegaly.\n\nAll 5 patients (4 males, 1 female) with HL received chemotherapy. The following chemotherapeutic regimens were used: R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) in 2/5 (40%) of patients, BEACOPP (bleomycine, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone), eBEACOPP respectively, in 2/5 (40%) and DBVE-PC (adriamycin, bleomycine, vincristine, etoposide, prednisone, cyclophosphamide) in 1 patient (20%). No therapy-associated deaths or unexpected toxicities were noted. One patient died 3 years after treatment because of severe enteropathy, and 4/5 (80%) patients are still surviving today. All patients had previously described splenomegaly, and 3/5 (60%) had lymphadenopathy described prior to cancer diagnosis.\n\nSimilarly, all 4 patients (3 males, 1 female) with B-NHL received chemotherapy; no therapy-associated deaths or unexpected toxicities were noted. The following chemotherapeutic regimens were used: R-CHOP/CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone in 3/4 (75%) patients−2 with DLBCL (Diffuse large B-cell lymphoma) and in 1 patient with MALT (Mucosa-associated lymphoid tissue] lymphoma. A GMALL (German multicenter ALL) regimen was used in 1 patient with Burkitt lymphoma. Two of these patients had been regularly followed even prior to the diagnosis of B-NHL for lymphadenopathy and previously reported splenomegaly. All patients are still alive. T-NHL was diagnosed in 2 patients. The clinical features of CVID patients in whom lymphomas were diagnosed are summarized in Tables 2, 3. In this cohort, WES and detailed immunophenotyping were performed as part of further investigation (results presented further).\n\nTable 2 Characteristics of the cohort of 11 CVID patients with lymphoma (M, Male; F, Female; LYM, Lymphadenopathy; SPLE, Splenomegaly; ITP, Idiopathic thrombocytopenic purpura; RTI, Respiratory tract infections; DBLCL lymphoma, Diffuse large B-cell lymphoma; MALT lymphoma, Mucosa-associated lymphoid tissue lymphoma; PTCL, Peripheral T-cell lymphoma; N/A, not applicable; Y, Yes; N, No; chemotherapeutic regimens are described in the results).\n\nPatient Nr.\tGender\tAge at diagnosis of CVID\tManifestation\tIgG serum level\tAge at diagnosis of lymphoma\tType of lymphoma\tCause of death\tSurvival interval\tStaging\tTherapy\t\n1\tM\t35 years\tRTI\t1.9 g/l\t57 years\tT lymphoma\tInfection\t0 month\tDied before staging\tDied before treatment\t\n2\tM\t53 years\tLYM, SPLE\t1.15 g/l\t64 years\tHL\tEnteropathy\t36 months\tIVB\tBEACOPP\t\n3\tF\t41 years\tITP\t3.89 g/l\t58 years\tHL\tAlive\t4 months\tIIA\tR-CHOP\t\n4\tM\t18 years\tRTI\t2.43 g/l\t45 years\tDBLCL lymphoma\tAlive\t9 months\tIIA\tR-CHOP\t\n5\tM\t39 years\tLYM, SPLE\t0.03 g/l\t35 years\tDBLCL lymphoma\tAlive\t96 months\tIVB\tR-CHOP\t\n6\tM\t37 years\tITP\t4.1 g/l\t40 years\tHL\tAlive\t12 months\tIVA\tR-CHOP\t\n7\tM\t36 years\tRTI\t4.1 g/l\t42 years\tHL\tAlive\t6 months\tIIIB\teBEACOPP\t\n8\tM\t26 years\tITP\t4.88 g/l\t36 years\tBurkitt lymphoma\tAlive\t25 months\tIIIA\tB-NHL GMALL\t\n9\tF\t25 years\tRTI\t2.88 g/l\t36 years\tMALT lymphoma\tAlive\t145 months\tIVA\tR-CHOP\t\n10\tM\t11 years\tRTI\t4.48 g/l\t11 years\tHL\tAlive\t204 months\tIIIA\tDBVE-PC\t\n11\tM\t25 years\tRTI\t1.76 g/l\t30 years\tPTCL\tInfection\t9 months\tIVA\tCHOP\t\nTable 3 Characteristics of CVID-related complications in a cohort of 11 patients with lymphoma (ITP, Immune thrombocytopenic purpura; AIHA, Autoimmune hemolytic anemia; RA, Rheumatoid arthritis; LIPS, Lymphocytic interstitial pneumonia; BE, Bronchiectasis; ACOS, Asthma-COPD overlap syndrome; EAA, Exogenous allergic alveolitis; NLH, Nodular lymphoid hyperplasia; IBD, Intestinal bowel disease; CG, Chronic gstritis; Y, Yes; N, No).\n\nPatient Nr.\tAutoimmunity\tChronic lung disease\tEnteropathy\tGranulomatous complications\tLymph-adenopathy\tSpleno-megaly\t\n1\tAI thyreoiditis\tLIPS\tNLH\tN\tN\tY\t\n2\tN\tBE\tCeliac-like disease\tN\tY\tY\t\n3\tITP\tBE\tN\tN\tY\tY\t\n4\tITP, AIHA\tLIPS\tCeliac-like disease\tN\tY\tY\t\n5\tN\tN\tN\tN\tY\tY\t\n6\tITP\tN\tN\tN\tN\tY\t\n7\tRA\tN\tN\tN\tN\tY\t\n8\tITP, psoriasis\tACOS\tN\tN\tN\tY\t\n9\tN\tEAA\tIBD-like disease\tN\tY\tN\t\n10\tN\tBE, NLH\tNLH, CG\tN\tY\tY\t\n11\tN\tBE\tNLH\tN\tY\tN\t\nImmunophenotype\nParameters of cellular immunity were investigated, including T cell (CD4 T helpers as well as CD8 T cytotoxic cells), B cell and NK cell counts. No significant differences were registered between the absolute counts of T cells, T helper cells and T cytotoxic cells at the time of diagnosis of CVID in a cohort of patients with lymphoma compared to those without lymphoma. The T cellcounts were also well within the normal reference ranges (T cells 0.8−2.10E9/l, T helper cells 0.3−2.8E9/l, T cytotoxic cells 0.2−1.0E9/l). Unsurprisingly, the chemotherapeutic regiments for lymphoma led to skewing of T cell numbers (median 0.65E9/l, 95% CI 0.46–0.75 vs. 1.22E9/l, 95% CI 1.07–1.47, ***p = 0.0004), specifically T helper cells (median 0.34E9/l, 95% CI 0.14–0.36 vs. 0.56E9/l, 95% CI 0.53–0.76, ***p = 0.0004) and T cytotoxic cells (0.26E9/l, 95% CI 0.14–0.36 vs. 0.54E9/l, 95% CI 0.41–0.64, **p = 0.006).\n\nThe number of total B cells at the diagnosis of CVID did not differ significantly from the control group of CVID patients without lymphoma and from normal ranges. No significant difference was noted in the serum levels of IgG in the group of CVID patients with lymphoma (median 2.88 g/l, 95% CI 1.83–3.91, normal values 7.65–13.6 g/l) compared to the CVID control group (median 2.02 g/l, 95% CI1.63–3.24). In contrast, the number of total B cells at the diagnosis of lymphoma was reduced in the lymphoma group (median 0.01E9/l, 95% CI 0–0.13 vs. 0.195E9/l, 95% CI 0.16–0.29, **p = 0.006). Absolute B cell counts were further depleted by the chemotherapy (median 0.11E9/l, 95% CI 0–0.46 vs. 0.08E9/l, 95% CI 0.03–0.197, *p = 0.02). Post-therapeutic B cell lymphopenia (B cells count ≤ 0.03E9/l) was found in 6 patients. A complete total B cell count reconstitution was achieved in only 3 patients (median 0.33E9/l, range 0.137–0.654); however, mature forms of B cells, including marginal zone-like, class-switched cells and plasmablasts, remained reduced in these subjects (mean interval after chemotherapy 102 months, range 6–204). The remaining 3 patients failed to re-establish their B cell populations and continued to maintain severely reduced B cell compartments (mean 0.02E9/l, range 0.001–0.08; mean interval after chemotherapy 39 months, range 4–145). Concerning NK cells, their absolute counts were similar to CVID patients without lymphoma and the general population (normal range 0.05–1.0 E9/l) and remained unchanged throughout the disease course. Curiously, no NK cell depression was observed after the chemotherapy. The immunophenotype profiles are summarized in Figure 1, and the B cell subpopulations are shown in detail in Table 4 and Figure 2.\n\nFigure 1 Absolute counts of (A) T (CD3+) cells, (B) B (CD19+) cells, and (C) NK (CD16+, CD56+) cells in a cohort of CVID patients with lymphoma at the time of diagnosis of CVID (CVID-dg), at the time of diagnosis of lymphoma (CVID-ly) and current values (CVID-curr) compared to the control group of CVID patients without lymphoma (CVID-cg);median and 95% CI are shown.\n\nTable 4 B cell subpopulations in CVID patients with lymphoma post-chemotherapy (absolute counts in E9/L; reference values for general population in brackets; (↓), decreased count; (↑), increased count; N/A, value not available).\n\nPatient Nr.\tCD21low (0.01–0.02)\tNaïve (0.06–0.47)\tTransitional (0.0–0.03)\tMZ-like (0.01–0.08)\tClass-switched (0.02–0.09)\t\n1\tN/A\tN/A\tN/A\tN/A\tN/A\t\n2\t0.0252 (↑)\t0.069\t0.004\t0.009 (↓)\t0.002 (↓)\t\n3\tN/A\tN/A\tN/A\tN/A\tN/A\t\n4\t0.001 (↓)\t0.005 (↓)\t0.002\t0 (↓)\t0 (↓)\t\n5\t0.216 (↑)\t0.614 (↑)\t0.137 (↑)\t0.022\t0.001 (↓)\t\n6\t0 (↓)\t0 (↓)\t0\t0 (↓)\t0 (↓)\t\n7\t0.005 (↓)\t0.2\t0.045 (↑)\t0.003 (↓)\t0 (↓)\t\n8\t0.004 (↓)\t0.0076 (↓)\t0\t0.0013 (↓)\t0 (↓)\t\n9\t0.0002 (↓)\t0.002 (↓)\t0\t0 (↓)\t0 (↓)\t\n10\t0.011\t0.069 (↓)\t0.059 (↑)\t0.008 (↓)\t0.009 (↓)\t\nFigure 2 Absolute counts of (A) Naïve B cells, (B) CD21low B cells, (C) Marginal Zone-like B cells, and (D) Class-switched B cells in CVID patients with lymphoma upon chemotherapy (CVID-ly) compared to the compared to the control group of CVID patients without lymphoma (CVID-cg) and healthy controls (HC); median and 95% are shown.\n\nWhole Exome Sequencing\nWES was performed in 10 out of 11 CVID patients with lymphoma in whom biological material for genetic testing was available. The WES results were divided into 5 groups. Gene variants previously described in association with CVID or in patients with inborn error of immunity (Group 1) were found in 4 patients. A novel heterozygous missense variant in CTLA4 was identified inpatient Nr. 9, who developed B—NHL (MALT) at the age of 36 years. She was also followed and treated for lymphadenopathy and enteropathy (with features of IBD-like disease), which is in concordance with the expected phenotype of CTLA4 deficiency. The deleterious effect of the mutation was verified by determination of decreased basal and stimulated (CD3/CD28) expression of CTLA4 protein in the patient's T regulatory cells (CD4+CD127dimCD25+) (Supplementary Figure 1).\n\nAnother type of B—NHL (DBLCL) was diagnosed in patient Nr. 4 at the age of 45 years. A genetic variant in PMS2 was found, which has an important role in the mismatch repair system and class switch recombination (23, 24). In addition to the lymphoma, the patient also manifested with a broad spectrum of non-infectious complications, including autoimmune cytopaenias (both AIHA as well as ITP), celiac–like disease and generalized lymphoproliferation, including lymphadenopathy, splenomegaly, and lymphocytic interstitial pneumonia.\n\nThe clinical manifestation of patient Nr. 10, who was found to harbor a PIK3CD mutation, corresponded with the previously described APDS (activated PI3K-delta syndrome) phenotype due to an activating mutation (2). He has been followed for generalized lymphadenopathy, splenomegaly, and nodular lymphoid hyperplasia (NLH) of the lungs and gastrointestinal tract since his childhood. This patient developed Hodgkin lymphoma at the age of 11 years.\n\nNodular lymphoid hyperplasia and lymphocytic interstitial pneumonia were also noted in patient Nr. 1, who was followed and treated for splenomegaly and autoimmune thyroiditis before the diagnosis of T cell lymphoma, which developed at the age of 57. A gene variant in TNFRSF13B (TACI), known to increase susceptibility to CVID, was found. TACI variants are not regarded as disease-causing but rather as modifying (Group 2) (8).\n\nFurthermore, several heterozygous variants were identified in genes associated with known primary immunodeficiencies that are inherited in an autosomal recessive manner, such as LYST, LRBA, RAG1, EXTL3, and STX11 (Group 4). The clinical phenotype of these patients did not match the respective disease; nevertheless, we report these variants because of their rarity in the healthy population and their potentially damaging character predicted by in silico tools. Functional assays, which would elucidate the impact of these variants on protein function, were not performed, as they exceeded the scope of this study. The tumor DNA was not available for analysis of somatic “second-hit” mutations, which might explain the pathogenesis of some of the malignancies.\n\nVariants in genes previously described in association with cancer susceptibility or as likely to increase the risk of cancer development, such as BRCA1, RABEP1, EP300, KDM5A, and others, were found in 6 out of 10 patients. They were divided into variants reported as pathogenic (Group 3) and variants of unknown significance and novel variants predicted as damaging in-silico (Group 5).The summary of WES results and a detailed description of the gene variants is presented in Table 5 and in Supplementary Table 1.\n\nTable 5 Summary of whole exome sequencing results performed in CVID patients with lymphoma.\n\nPatient Nr.\tChromo-some\tGene symbol\tTranscript variant\tProtein variant\tGeno- type\tSIFT function prediction\tSIFT score\tPolyphen-2 function prediction\tCADD score\tExAC Freq.\tGnomAD Freq.\tHGMD accession\t\nGROUP 1: VARIANTS IN IUIS-CLASSIFIED GENES WITH LINKS TO CVID\t\n4\t7\tPMS2\tc.1687C>T\tp.R563*\tHet\t\t\t\t34.000\t0.002\t0.001\tCM102799\t\n9\t2\tCTLA4\tc.515C>G\tp.S172W\tHet\tDamaging\t0.00\tPossibly Damaging\t28.700\t\t\t\t\n10\t1\tPIK3CD\tc.3061G>A\tp.E1021K\tHet\tTolerated\t0.07\tProbably Damaging\t31.000\t\t0.000\tCM067447\t\nGROUP 2: MODIFIER GENES\t\n1\t17\tTACI\tc.310T>C\tp.C104R\tHet\tDamaging\t0.00\tProbably Damaging\t25.900\t0.321\t0.346\tCM052924\t\nGROUP 3: CANCER SUSCEPTIBILITY GENES\t\n3\t17\tBRCA1\tc.547+14delG\t\tHet\t\t\t\t0.424\t0.012\t0.009\tCD176513\t\n6\t17\tBRCA1\tc.5263_5264insC\tp.Q652fs*74\tHet\t\t\t\t35.000\t0.016\t0.016\tCI941841\t\nDiscussion\nImmune dysregulation associated with primary immunodeficiencies represents an increased risk of cancer development. We aimed to search for the occurrence of malignant diseases in a nationwide cohort of CVID patients, taking into account relevant epidemiology, immunophenotype, and the genetic background of the patients.\n\nSimilarly to published studies, we detected a higher incidence of malignancies among our CVID cohort (25–30). Also in alignment with previous reports, we noted a distinct spectrum of tumors in CVID patients, with Hodgkin and Non-Hodgkin lymphomas and gastric cancers being the most prevalent malignancies (Table 6 and Supplementary Table 2). The overall risk of malignancy was more than 6 times greater in comparison to the general population, while the specific risk of HL was as much as 30 times greater. Curiously, an over 3 times greater risk of malignancy was determined in a subgroup of CVID patients with a history of ITP. Moreover, we noted that the diagnosis of GC (average age 55–59 years vs. 70–74 in general population) and B-NHL (35–39 years vs. 65–69) was established at a much younger age compared to the Czech general population, while HL developed later in life compared to the healthy population (40–44 years vs. 30–34).\n\nTable 6 Summary of tumor prevalence and SIR (Standardized Incidence Ratio, median and 95% Confidence Intervals (CIs) shown) in a cohort of 295 CVID patients.\n\nTumor\tPrevalence\tSIR (95% CI)\t\nAll tumors\t25/295 (8.5%)\t6.3 (4.08–9.31)\t\nB cell lymphoma (all types)\t9/295 (3.0%)\t10.1 (4.61–19.12)\t\nB cell non-Hodgkin lymphoma\t4/295 (1.4%)\t5.50 (1.50–14.09)\t\nHodgkin lymphoma\t5/295 (1.7%)\t30.0 (9.73–69.93)\t\nGastric cancer\t6/295 (2.0%)\t5.70 (2.08–12.32)\t\nOther types of cancer\t10/295 (3.4%)\t5.0 (2.40–9.16)\t\nPatients with CVID present with a characteristic immunophenotypic profile that is reflected in the diagnostic criteria of CVID. In this context, we specifically searched for potential differences between CVID patients with tumors and CVID patients who did not develop a malignant disease. Malignant hematologic diseases may, in general, reduce lymphocyte counts in up to 60% of patients, and lymphoma in particular may affect an entire spectrum of lymphocyte subpopulations, including CD4+, CD8+, CD19+, and CD56+ cells (31, 32). Nevertheless, in our cohort of CVID patients, we did not observe any significant differences between absolute or relative counts of CD3+, CD4+, CD8+, and CD56+ cells measured at the time of diagnosis of immunodeficiency and those measured at the time of diagnosis of lymphoma. Furthermore, the values of all T cell subpopulations and NK cells were similar to the control group of CVID patients without malignancy. In contrast, chemotherapy regimens had significant impacts on the CD4+ and CD8+ cell counts. A similar observation has already been published in patients with lymphomas without underlying primary immunodeficiencies who underwent chemotherapy with an R-CHOP protocol. In the study, a reduction of CD4+ absolute counts to values <0.343 × 109/l was declared an independent negative prognostic factor with a significant impact on 5-year progression-free survival and overall survival (33). Indeed, in our CVID cohort with lymphoma, the median level of post-chemotherapy absolute numbers of CD4+ was very low, 0.343 × 109/l, 95% CI 0.14–0.36 (R-CHOP being the regiment used in 5 out of 11 patient), which implies that a CVID population treated with chemotherapy should be prognostically regarded as a higher risk group. Quite unexpectedly, NK cell counts were not affected by the chemotherapy. However, the B cell compartment was profoundly depleted in all CVID patients who underwent chemotherapy. The total B cell count normalized in only 3/10 patients. However, even in those, selective reductions of mature forms (including class-switched, marginal zone-like B cells and plasmablasts) persisted. This observation was in striking contrast to patients with autoimmune diseases receiving anti-CD20 therapy (rituximab), in whom the reconstitution is achieved within 5–9 months in up to 90% of patients (34).\n\nB cell deficiency seems to be the hallmark in CVID patients with lymphoma, as they presented with reduced B cell count even at the time of diagnosis of lymphoma, which decreased and remained persistently lower after chemotherapy. Despite this, neither B cell nor T cell detailed immunophenotyping provided a strong enough predictive tool for assessment of the cancerogenic predisposition of CVID patients. Therefore, we set out to search for possible genetic causes of malignancies in CVID using massive parallel sequencing. Out of 10 patients who were available for testing, we identified gene variants previously classified as associated with CVID in 4 patients, namely, CTLR4, PIK3CD, PMS2, and TNFRSF13B. It is noteworthy that mutations in CTLA4 and PIK3CD, which account for the majority of currently known molecular causes of CVID (8), were both found among our small cohort of CVID patients.\n\nCTLA4 heterozygous mutation was first described as a cause of CVID-like syndrome that displayed a significant overlap with CVID phenotype, including hypogammaglobulinemia, low B cell counts and immune dysregulation with variable organ involvement (35). The clinical and laboratory spectra of CTLA4 haploinsufficiency were described in detail in a recently published cohort of 133 patients. In this cohort, 8 mutation carriers developed lymphoma, and 3 had gastric cancer. Thus, our finding of a singleCTLA4 mutation among our small cohort corresponds well with this report. Furthermore, this particular patient also presented with IBD-like gastrointestinal disease that was retrospectively reclassified as a CTLA4-related gastrointestinal presentation. Interestingly, the spectrum of tumors found in the above mentioned CTLA4 study was limited to lymphomas and gastric carcinomas, which also correlates with our findings.\n\nPIK3CD is a well-established genetic cause of APDS, activated PI3K-delta syndrome. Similarly toCLTA4, the clinical presentation of APDS overlaps significantly with the CVID phenotype, and a number of patients originally diagnosed with CVID were found to harbor mutations in PIK3CD. A large study including 53 patients with APDS reported lymphoma occurrence in 13% of patients (36). Furthermore, somatic mutations of PIK3 were found in several types of HL and NHL, thus suggesting the role of PI3K signaling in tumorigenesis.\n\nFinally, the PMS2 protein is involved in complex mechanisms of DNA repair. As such, mutations in PMS2 are directly associated with an increased risk of cancer (37). At the same time, mutations in PMS2 were also implicated in class-switch recombination defects and impaired immunoglobulin production (36). Therefore, our finding of PMS2 mutation among CVID patients with lymphoma corresponds well with these reports.\n\nOverall, we suggest that each of these CVID-associated genes may also convey a predisposition to tumor development.\n\nThe role of the TNFSF13B molecule, also known as TACI, in CVID has long been discussed. TACI variants have been found to be associated with autoimmune complications in CVID (38). Moreover, given the involvement of TACI in B cell activation, its mutations might contribute to immune dysregulation and lymphoma development (39). However, TACI variants are regarded as modifier genes rather than a monogenic cause of CVID.\n\nApart of the above mentioned genetic findings, we identified several variants in genes involved in lymphogenesis and immune system regulation. Although sufficient data to postulate their role in immune deficiency or tumorigenesis are lacking, we report them along with our results for the sake of completeness, reflecting the previously described roles of heterozygous mutations in PID and possible epistatic roles of various genes in immune dysregulation (40–42).\n\nFinally, we also detected several variants in genes involved in tumor surveillance in our cohort, such as BRCA1 and others listed in Supplementary Table 1. These variants were previously reported in patients with a broad spectrum of solid tumors (including breast, ovarian, colorectal cancer, and others) and may therefore represent another contributory mechanism of malignant susceptibility.\n\nConclusion\nMalignancies belong to the most severe non-infectious complications of common variable immunodeficiency disorder. The prevalence of malignancy in our CVID cohort was found to be more than 6 times greater than in the general population. The spectrum of cancers was characteristically narrow, involving mostly gastric cancers and lymphomas. Moreover, ITP was elucidated as a novel risk factor for malignancy in CVID patients. Post-treatment T and B cell lymphopaenias, associated with poorer prognosis, were found in a majority of CVID patients who received chemotherapy. Surprisingly, NK cells remained unaffected. WES analysis illustrated a wide heterogeneity of potential genetic background of the oncogenic predisposition among CVID patients and identified several causative or contributing gene variants, pointing toward immune system dysregulation. In the future, modern genetic analytic approaches applied on larger cohorts of CVID patients, along with the use of oncogenomic tools, will undoubtedly enable the identification of other CVID-associated genes with increased risk of cancer and elucidate their roles in tumorigenesis.\n\nAuthor Contributions\nPK and TM conceived and designed the study, collected data, and drafted manuscript. JL, IM, DJ, JP, JV, AZ, MB, ZP, and AK collected and provided primary patient data. EF and MS performed analysis and interpretation of data from genetic testing (Whole exome sequencing). VK performed analysis and interpretation of immunophenotyping data. JH provided statistical analysis of the obtained data and its interpretation. TK and AS provided critical revisions of the manuscript and final approval of the version to be published.\n\nConflict of Interest Statement\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nThis study was supported by grants from the Grant Agency Charles University in Prague (GAUK) nr. 2120217 and the Czech Health Research Council (AZV) nr.NV18-05-00162.\n\nSupplementary Material\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2018.03135/full#supplementary-material\n\nClick here for additional data file.\n\n Click here for additional data file.\n\n Click here for additional data file.\n==== Refs\nReferences\n1. Hauck F Voss R Urban C Seidel MG . Intrinsic and extrinsic causes of malignancies in patients with primary immunodeficiency disorders . J Allergy Clin Immunol. (2018 ) 141 :59 –68.e4 . 10.1016/j.jaci.2017.06.009 28669558 \n2. Coulter TI Chandra A Bacon CM Babar J Curtis J Screaton N . Clinical spectrum and features of activated phosphoinositide 3-kinase delta syndrome: a large patient cohort study . J Allergy Clin Immunol. (2017 ) 139 :597 –606.e4 . 10.1016/j.jaci.2016.06.021 27555459 \n3. Dornan GL Burke JE . Molecular mechanisms of human disease mediated by oncogenic and primary immunodeficiency mutations in class IA phosphoinositide 3-kinases . Front Immunol. (2018 ) 9 :575 . 10.3389/fimmu.2018.00575 29616047 \n4. Warnatz K Schlesier M . Flowcytometric phenotyping of common variable immunodeficiency . Cytometry B Clin Cytom. (2008 ) 74 :261 –71 . 10.1002/cyto.b.20432 18561200 \n5. Wong GK Huissoon AP . T-cell abnormalities in common variable immunodeficiency: the hidden defect . J Clin Pathol. (2016 ) 69 :672 –6 . 10.1136/jclinpath-2015-203351 27153873 \n6. Tsou P Katayama H Ostrin EJ Hanash SM . The emerging role of B cells in tumor immunity . Cancer Res. (2016 ) 76 :5597 –601 . 10.1158/0008-5472.CAN-16-0431 27634765 \n7. Latour S Winter S . Inherited immunodeficiencies with high predisposition to epstein-barr virus-driven lymphoproliferative diseases . Front Immunol. (2018 ) 9 :1103 . 10.3389/fimmu.2018.01103 29942301 \n8. Bogaert DJ Dullaers M Lambrecht BN Vermaelen KY De Baere E Haerynck F . Genes associated with common variable immunodeficiency: one diagnosis to rule them all? \nJ Med Genet . (2016 ) 53 :575 –90 . 10.1136/jmedgenet-2015-103690 27250108 \n9. Fliegauf M Bryant VL Frede N Slade C Woon ST Lehnert K . Haploinsufficiency of the NF-kappaB1 subunit p50 in common variable immunodeficiency . Am J Hum Genet. (2015 ) 97 :389 –403 . 10.1016/j.ajhg.2015.07.008 26279205 \n10. Hildebrand JM Luo Z Manske MK Price-Troska T Ziesmer SC Lin W . A BAFF-R mutation associated with non-Hodgkin lymphoma alters TRAF recruitment and reveals new insights into BAFF-R signaling . J Exp Med. (2010 ) 207 :2569 –79 . 10.1084/jem.20100857 21041452 \n11. Ressing M Blettner M Klug SJ . Data analysis of epidemiological studies: part 11 of a series on evaluation of scientific publications . Dtsch Arztebl Int . (2010 ) 107 :187 –92 . 10.3238/arztebl.2010.0187 20386677 \n12. Li H Durbin R . Fast and accurate short read alignment with Burrows-Wheeler transform . Bioinformatics (2009 ) 25 :1754 –60 . 10.1093/bioinformatics/btp324 19451168 \n13. Li H Handsaker B Wysoker A Fennell T Ruan J Homer N . The sequence alignment/map format and SAMtools . Bioinformatics (2009 ) 25 :2078 –9 . 10.1093/bioinformatics/btp352 19505943 \n14. Cingolani P Patel VM Coon M Nguyen T Land SJ Ruden DM . Using Drosophila melanogaster as a model for genotoxic chemical mutational studies with a new program, SnpSift . Front Genet. (2012 ) 3 :35 . 10.3389/fgene.2012.00035 22435069 \n15. Lek M Karczewski KJ Minikel EV Samocha KE Banks E Fennell T . Analysis of protein-coding genetic variation in 60,706 humans . Nature (2016 ) 536 :285 –91 . 10.1038/nature19057 27535533 \n16. Sherry ST Ward MH Kholodov M Baker J Phan L Smigielski EM . dbSNP: the NCBI database of genetic variation . Nucleic Acids Res. (2001 ) 29 :308 –11 . 10.1093/nar/29.1.308 11125122 \n17. Adzhubei IA Schmidt S Peshkin L Ramensky VE Gerasimova A Bork P . A method and server for predicting damaging missense mutations . Nat Methods (2010 ) 7 :248 –9 . 10.1038/nmeth0410-248 20354512 \n18. Kircher M Witten DM Jain P O'Roak BJ Cooper GM Shendure J . A general framework for estimating the relative pathogenicity of human genetic variants . Nat Genet. (2014 ) 46 :310 –5 . 10.1038/ng.2892 24487276 \n19. Ng PC Henikoff S . SIFT: predicting amino acid changes that affect protein function . Nucleic Acids Res. (2003 ) 31 :3812 –4 . 10.1093/nar/gkg509 12824425 \n20. Thorvaldsdóttir H Robinson JT Mesirov JP . Integrative Genomics Viewer (IGV): high-performance genomics data visualization and exploration . Brief Bioinform. (2013 ) 14 :178 –92 . 10.1093/bib/bbs017 22517427 \n21. Picard C Bobby Gaspar H Al-Herz W Bousfiha A Casanova JL Chatila T . International union of immunological societies: 2017 primary immunodeficiency diseases committee report on inborn errors of immunity . J Clin Immunol . (2018 ) 38 :96 –128 . 10.1007/s10875-017-0464-9 29226302 \n22. Zhang J Walsh MF Wu G Edmonson MN Gruber TA Easton J . Germline mutations in predisposition genes in pediatric cancer . N Engl J Med. (2015 ) 373 :2336 –46 . 10.1056/NEJMoa1508054 26580448 \n23. Hendriks YM Jagmohan-Changur S van der Klift HM Morreau H van Puijenbroek M Tops C . Heterozygous mutations in PMS2 cause hereditary nonpolyposis colorectal carcinoma (Lynch syndrome) . Gastroenterology (2006 ) 130 :312 –22 . 10.1053/j.gastro.2005.10.052 16472587 \n24. Nicolaides NC Papadopoulos N Liu B Wei YF Carter KC Ruben SM . Mutations of two PMS homologues in hereditary nonpolyposis colon cancer . Nature (1994 ) 371 :75 –80 . 10.1038/371075a0 8072530 \n25. Gathmann B Mahlaoui N Gérard L Oksenhendler E Warnatz K . Clinical picture and treatment of 2212 patients with common variable immunodeficiency . J Allergy Clin Immunol. (2014 ) 134 :116 –26 . 10.1016/j.jaci.2013.12.1077 24582312 \n26. Kinlen LJ Webster AD Bird AG Haile R Peto J Soothill JF . Prospective study of cancer in patients with hypogammaglobulinaemia . Lancet (1985 ) 1 :263 –6 . 10.1016/S0140-6736(85)91037-2 2857327 \n27. Kokron CM Errante PR Barros MT Baracho GV Camargo MM Kalil J . Clinical and laboratory aspects of common variable immunodeficiency . An Acad Bras Cienc. (2004 ) 76 :707 –26 . 10.1590/S0001-37652004000400007 15558152 \n28. Oksenhendler E Gérard L Fieschi C Malphettes M Mouillot G Jaussaud R . Infections in 252 patients with common variable immunodeficiency . Clin Infect Dis. (2008 ) 46 :1547 –54 . 10.1086/587669 18419489 \n29. Quinti I Soresina A Spadaro G Martino S Donnanno S Agostini C . Long-term follow-up and outcome of a large cohort of patients with common variable immunodeficiency . J Clin Immunol. (2007 ) 27 :308 –16 . 10.1007/s10875-007-9075-1 17510807 \n30. Resnick ES Moshier EL Godbold JH Cunningham-Rundles C . Morbidity and mortality in common variable immune deficiency over 4 decades . Blood (2012 ) 119 :1650 –7 . 10.1182/blood-2011-09-377945 22180439 \n31. Plonquet A Haioun C Jais JP Debard AL Salles G Bene MC . Peripheral blood natural killer cell count is associated with clinical outcome in patients with aaIPI 2-3 diffuse large B-cell lymphoma . Ann Oncol. (2007 ) 18 :1209 –15 . 10.1093/annonc/mdm110 17496307 \n32. Tadmor T Bari A Marcheselli L Sacchi S Aviv A Baldini L . Absolute monocyte count and lymphocyte-monocyte ratio predict outcome in nodular sclerosis hodgkin lymphoma: evaluation based on data from 1450 patients . Mayo Clin Proc. (2015 ) 90 :756 –64 . 10.1016/j.mayocp.2015.03.025 26046410 \n33. Kusano Y Yokoyama M Terui Y Nishimura N Mishima Y Ueda K \nLow absolute peripheral blood CD4+ T-cell count predicts poor prognosis in R-CHOP-treated patients with diffuse large B-cell lymphoma . Blood Cancer J. (2017 ) 7 :e561 \n10.1038/bcj.2017.43 28498371 \n34. Worch J Makarova O Burkhardt B . Immunreconstitution and infectious complications after rituximab treatment in children and adolescents: what do we know and what can we learn from adults? \nCancers (2015 ) 7 :305 –28 . 10.3390/cancers7010305 25643241 \n35. Kuehn HS Ouyang W Lo B Deenick EK Niemela JE Avery DT . Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4 . Science (2014 ) 345 :1623 –7 . 10.1126/science.1255904 25213377 \n36. Péron S Metin A Gardès P Alyanakian MA Sheridan E Kratz CP . Human PMS2 deficiency is associated with impaired immunoglobulin class switch recombination . J Exp Med. (2008 ) 205 :2465 –72 . 10.1084/jem.20080789 18824584 \n37. ten Broeke SW Brohet RM Tops CM van der Klift HM Velthuizen ME Bernstein I . Lynch syndrome caused by germline PMS2 mutations: delineating the cancer risk . J Clin Oncol. (2015 ) 33 :319 –25 . 10.1200/JCO.2014.57.8088 25512458 \n38. Romberg N Virdee M Chamberlain N Oe T Schickel JN Perkins T . TNF receptor superfamily member 13b (TNFRSF13B) hemizygosity reveals transmembrane activator and CAML interactor haploinsufficiency at later stages of B-cell development . J Allergy Clin Immunol. (2015 ) 136 :1315 –25 . 10.1016/j.jaci.2015.05.012 26100089 \n39. Meinl E Thaler FS Lichtenthaler SF . Shedding of BAFF/APRIL receptors controls B cells . Trends Immunol. (2018 ) 39 :673 –6 . 10.1016/j.it.2018.07.002 30072119 \n40. Abraham RS Recher M Giliani S Walter JE Lee YN Frugoni F . Adult-onset manifestation of idiopathic T-cell lymphopenia due to a heterozygous RAG1 mutation . J Allergy Clin Immunol. (2013 ) 131 :1421 –3 . 10.1016/j.jaci.2012.09.016 23122631 \n41. Sic H Speletas M Cornacchione V Seidl M Beibel M Linghu B . An activating janus kinase-3 mutation is associated with cytotoxic T lymphocyte antigen-4-dependent immune dysregulation syndrome . Front Immunol. (2017 ) 8 :1824 . 10.3389/fimmu.2017.01824 29375547 \n42. Ameratunga R Koopmans W Woon ST Leung E Lehnert K Slade CA . Epistatic interactions between mutations of TACI (TNFRSF13B) and TCF3 result in a severe primary immunodeficiency disorder and systemic lupus erythematosus . Clin Transl Immunol. (2017 ) 6 :e159 . 10.1038/cti.2017.41 29114388\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1664-3224",
"issue": "9()",
"journal": "Frontiers in immunology",
"keywords": "common variable immunodeficiency; gastric cancer; lymphoma; malignancy; whole exome sequencing",
"medline_ta": "Front Immunol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D017074:Common Variable Immunodeficiency; D018153:Czech Republic; D004198:Disease Susceptibility; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D016130:Immunophenotyping; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D011159:Population Surveillance; D015995:Prevalence; D018570:Risk Assessment; D012307:Risk Factors; D000073359:Whole Exome Sequencing; D055815:Young Adult",
"nlm_unique_id": "101560960",
"other_id": null,
"pages": "3135",
"pmc": null,
"pmid": "30723478",
"pubdate": "2018",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "16472587;29375547;21041452;29616047;11125122;27153873;25512458;17496307;22435069;26100089;27250108;25213377;15558152;20354512;20386677;30072119;19451168;24582312;26279205;12824425;23122631;17510807;26580448;18561200;26046410;25643241;28498371;18419489;22180439;27634765;27535533;28669558;24487276;18824584;29114388;27555459;8072530;29226302;19505943;2857327;29942301;22517427",
"title": "CVID-Associated Tumors: Czech Nationwide Study Focused on Epidemiology, Immunology, and Genetic Background in a Cohort of Patients With CVID.",
"title_normalized": "cvid associated tumors czech nationwide study focused on epidemiology immunology and genetic background in a cohort of patients with cvid"
} | [
{
"companynumb": "CZ-CELLTRION INC.-2019CZ021787",
"fulfillexpeditecriteria": "1",
"occurcountry": "CZ",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nAcute pyelonephritis (APN) generally involves a single kidney, but it can be bilateral. The aim of the present study was to evaluate differences in clinical presentation, progress and outcome for bilateral APN compared with unilateral APN.\n\n\nMETHODS\nThe medical records of all patients over 19 years of age, hospitalised for APN and who underwent abdominal enhanced CT at Samsung Changwon Hospital between January 2009 and August 2012 were retrospectively reviewed. Patients were divided into two groups according to whether unilateral or bilateral lesions were identified on the CT scan.\n\n\nRESULTS\nOf the 296 patients, 99 had bilateral APN. Only 64/86 (74.4%) patients with clear tenderness in the bilateral APN group had bilateral tenderness. Patients with bilateral APN had more severe abnormalities, based on the results of laboratory tests. Leukocytosis, thrombocytopenia, bacteraemia, acute kidney injury, shock and death occurred more frequently in bilateral than in unilateral APN. In the bilateral APN group, broad spectrum antibiotics were used more frequently as an initial antibiotic treatment. A history of stroke or diabetes mellitus, and duration of symptoms before admission, were independent risk factors associated with bilateral APN.\n\n\nCONCLUSIONS\nPatients with bilateral APN experienced more severe clinical and laboratory manifestations and had a poorer outcome than those with unilateral APN. Early imaging tests can be considered to discriminate unilateral from bilateral APN, especially in those with a history of stroke or diabetes and with a longer duration of symptoms. Moreover, initial use of broader spectrum antibiotics can be considered in patients with bilateral APN.",
"affiliations": "Department of Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, , Changwon, Korea.",
"authors": "Lee|Yu-Ji|YJ|;Cho|Seong|S|;Kim|Sung Rok|SR|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "England",
"delete": false,
"doi": "10.1136/postgradmedj-2013-131935",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0032-5473",
"issue": "90(1060)",
"journal": "Postgraduate medical journal",
"keywords": null,
"medline_ta": "Postgrad Med J",
"mesh_terms": "D000208:Acute Disease; D058186:Acute Kidney Injury; D000328:Adult; D000900:Anti-Bacterial Agents; D016470:Bacteremia; D003920:Diabetes Mellitus; D018450:Disease Progression; D005260:Female; D006801:Humans; D007964:Leukocytosis; D008297:Male; D008875:Middle Aged; D011704:Pyelonephritis; D012079:Renal Circulation; D012189:Retrospective Studies; D012720:Severity of Illness Index; D012769:Shock; D013921:Thrombocytopenia; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "0234135",
"other_id": null,
"pages": "80-5",
"pmc": null,
"pmid": "24255118",
"pubdate": "2014-02",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Unilateral and bilateral acute pyelonephritis: differences in clinical presentation, progress and outcome.",
"title_normalized": "unilateral and bilateral acute pyelonephritis differences in clinical presentation progress and outcome"
} | [
{
"companynumb": "KR-ROCHE-1454195",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PIPERACILLIN SODIUM\\TAZOBACTAM SODIUM"
},
"drugaddit... |
{
"abstract": "BACKGROUND\nAbout 30% of patients with chronic urticaria experience flares of hives and/or angioedema after ingesting either aspirin or nonsteroidal anti-inflammatory drugs. In such patients, cross-reactivity to all NSAIDs seems to occur suggesting a mechanism dependent on cyclooxygenase inhibition.\n\n\nOBJECTIVE\nTo evaluate the preventive effect of leukotriene receptor antagonists on urticaria exacerbations induced by NSAIDs in a patient with chronic urticaria.\n\n\nMETHODS\nA 59-year-old woman with a 2-year history of recurrent urticaria exacerbated by different NSAIDs including aspirin 500 mg (2 episodes), piroxicam 20 mg, and nimesulide 100 mg (1 episode each) was studied. Acetaminophen 375 mg and floctafenine 50 mg induced a marked flare of urticaria/angioedema in a single-blind, placebo-controlled challenge.\n\n\nRESULTS\nThe patient was totally urticaria free during a 3-week course of montelukast 10 mg once a day. After montelukast withdrawal, a gradual relapse of urticaria/angioedema occurred along with a further acute urticaria/angioedema episode after a single piroxicam, 20-mg tablet. Zafirlukast 20 mg twice daily was started. After some days the patient was urticaria-free again, and after 3 weeks she tolerated a 6-day course of injective piroxicam (20 mg once a day) without any problem. To date the patient is still urticaria-free.\n\n\nCONCLUSIONS\nLeukotriene receptor antagonists may prevent the severe urticaria/angioedema exacerbations which follow the use of NSAIDs in some patients with chronic urticaria.",
"affiliations": "Caduti Bollatesi Hospital, Milan, Italy.",
"authors": "Asero|R|R|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D020024:Leukotriene Antagonists",
"country": "United States",
"delete": false,
"doi": "10.1016/S1081-1206(10)62457-X",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1081-1206",
"issue": "85(2)",
"journal": "Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology",
"keywords": null,
"medline_ta": "Ann Allergy Asthma Immunol",
"mesh_terms": "D000799:Angioedema; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002908:Chronic Disease; D005260:Female; D006801:Humans; D020024:Leukotriene Antagonists; D008875:Middle Aged; D014581:Urticaria",
"nlm_unique_id": "9503580",
"other_id": null,
"pages": "156-7",
"pmc": null,
"pmid": "10982225",
"pubdate": "2000-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Leukotriene receptor antagonists may prevent NSAID-induced exacerbations in patients with chronic urticaria.",
"title_normalized": "leukotriene receptor antagonists may prevent nsaid induced exacerbations in patients with chronic urticaria"
} | [
{
"companynumb": "IT-RANBAXY-2014RR-91550",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NIMESULIDE"
},
"drugadditional": null,
... |
{
"abstract": "Due to improvements in earlier detection and expansions in available treatments, the number of individuals surviving with cancer is steadily increasing. Sexual dysfunction is a common and often persistent complication for cancer survivors, affecting >60% of women diagnosed with cancer. Although highly prevalent, issues related to sexual health are often not addressed among survivors, with women reporting less discussion with providers compared to men.\n\n\n\nIn this narrative review, we present a case series of three women seen in a psycho-oncology clinic who experienced sexual dysfunction following a cancer diagnosis. We then review existing literature on the presentation and management of sexual issues associated with cancer and its treatment.\n\n\n\nThe three cases highlight different mechanisms of sexual dysfunction after cancer, including anatomic changes, hormonal alterations, psychiatric conditions and medication side effects. The literature review includes discussion of the prevalence and course of sexual dysfunction in female cancer survivors. Tools for screening and assessment are then reviewed, as well as contributing factors and common presenting symptoms. We conclude with a discussion of both pharmacologic and non-pharmacologic approaches to management.\n\n\n\nDespite its high prevalence and considerable impact on quality of life, the complication of sexual dysfunction after cancer diagnosis and treatment is still under recognized and undertreated. Improving awareness, communication, and screening, as well as appropriate referral to treatment, could have a profound impact on the ever growing number of women surviving with cancer with sexual health concerns.",
"affiliations": "University of Pittsburgh Medical Center, United States of America. Electronic address: valpeyre@upmc.edu.;University of Pittsburgh Medical Center, United States of America.;University of Pittsburgh School of Medicine, United States of America.",
"authors": "Valpey|Robin|R|;Kucherer|Shelly|S|;Nguyen|Julia|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.genhosppsych.2019.04.003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0163-8343",
"issue": "60()",
"journal": "General hospital psychiatry",
"keywords": null,
"medline_ta": "Gen Hosp Psychiatry",
"mesh_terms": "D000328:Adult; D001943:Breast Neoplasms; D000073116:Cancer Survivors; D005260:Female; D006801:Humans; D008875:Middle Aged; D012735:Sexual Dysfunction, Physiological; D014565:Urogenital Neoplasms",
"nlm_unique_id": "7905527",
"other_id": null,
"pages": "141-147",
"pmc": null,
"pmid": "31030966",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Sexual dysfunction in female cancer survivors: A narrative review.",
"title_normalized": "sexual dysfunction in female cancer survivors a narrative review"
} | [
{
"companynumb": "US-APOTEX-2019AP024174",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BUPROPION"
},
"drugadditional": "3",
"... |
{
"abstract": "Apatinib showed efficacy in non-small cell lung cancer (NSCLC). We conducted this phase II clinical study to assess the efficacy and safety of apatinib in combination with pemetrexed-platinum chemotherapy in non-squamous NSCLC (Clinical Trial Registration: ChiCTR1800015920).\n\n\n\nPatients received oral apatinib (250 mg/d) with intravenous pemetrexed (500 mg/m2)-platinum (carboplatin AUC = 5 or cisplatin 75 mg/m2) chemotherapy every 21 days for 6 treatment cycles, and then maintained with apatinib 250 mg/d until progressive disease or intolerable toxicity. The primary endpoint was the objective response rate (ORR). The secondary endpoints included the progression-free survival (PFS), disease control rate (DCR), overall survival (OS) and safety.\n\n\n\nTwenty advanced and chemo-naive non-squamous NSCLC patients were enrolled and evaluated. The ORR and DCR was 80% and 100%, respectively. The median PFS (mPFS) and median OS (mOS) for total patients was 7.7 (95%CI: 3.1-12.3) and 20.1 (95%CI: not available, NA) months. In the TKI-pretreated and treatment-naive subgroup, the ORR was 90% vs.70%, and the mPFS was 8.9 (95%CI: 5.5-12.3) vs.5.7 (95%CI: 0.1-11.3) months, respectively (P = 0.433). The mPFS in the responders without central nervous system (CNS) metastasis at baseline was 10.0 (95%CI: 6.1-13.9) months, and it was 3.8 (95%CI: 0.9-6.7) months in those with presence of CNS metastasis at baseline (P = 0.041, HR = 0.283, 95%CI: 0.084-0.948). Toxicities mainly included grade I-II hand-foot syndrome, hypertension, proteinuria and myelosuppression.\n\n\n\nApatinib in combination with pemetrexed-platinum chemotherapy showed good efficacy and tolerable toxicity in advanced non-squamous NSCLC, especially for those who failed to prior TKI targeted therapies.",
"affiliations": "Department of Medical Oncology, National Cancer Center/ National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.;Department of Comprehensive Oncology, National Cancer Center/ National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.;Department of Medical Oncology, National Cancer Center/ National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.;Department of Medical Oncology, National Cancer Center/ National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.;Department of Medical Oncology, National Cancer Center/ National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.;Department of Medical Oncology, National Cancer Center/ National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.;Department of Medical Oncology, National Cancer Center/ National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China. Electronic address: wangyanyifu@163.com.",
"authors": "Yang|Guangjian|G|;Xu|Haiyan|H|;Yang|Lu|L|;Xu|Fei|F|;Zhang|Shuyang|S|;Yang|Yaning|Y|;Wang|Yan|Y|",
"chemical_list": "D011725:Pyridines; D000068437:Pemetrexed; D010984:Platinum; C553458:apatinib",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.lungcan.2020.07.024",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0169-5002",
"issue": "147()",
"journal": "Lung cancer (Amsterdam, Netherlands)",
"keywords": "Apatinib; Chemotherapy; Non-small cell lung cancer; Pemetrexed; Tyrosine kinase inhibitor",
"medline_ta": "Lung Cancer",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D002289:Carcinoma, Non-Small-Cell Lung; D006801:Humans; D008175:Lung Neoplasms; D000068437:Pemetrexed; D010984:Platinum; D011725:Pyridines; D016896:Treatment Outcome",
"nlm_unique_id": "8800805",
"other_id": null,
"pages": "229-236",
"pmc": null,
"pmid": "32739743",
"pubdate": "2020-09",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Apatinib in combination with pemetrexed-platinum chemotherapy for chemo-naive non-squamous non-small cell lung cancer: a phase II clinical study.",
"title_normalized": "apatinib in combination with pemetrexed platinum chemotherapy for chemo naive non squamous non small cell lung cancer a phase ii clinical study"
} | [
{
"companynumb": "CN-ASTRAZENECA-2020SF13480",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GEFITINIB"
},
"drugadditional": "3",
... |
{
"abstract": "We present a patient with coeliac disease who developed refractory coeliac disease II, which was complicated by the development of metachronous lymphomas.",
"affiliations": "Department of Gastroenterology, AMNCH, Dublin, Ireland.;Department of Pathology, AMNCH, Dublin, Ireland.;Department of Gastroenterology, AMNCH, Dublin, Ireland.",
"authors": "Parihar|Vikrant|V|;Crotty|Paul|P|;McNamara|Deidre|D|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000481162",
"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 10.1159/000481162crg-0011-0593Single CaseA Tale of Two Lymphomas Parihar Vikrant a*Crotty Paul bMcNamara Deidre acdaDepartment of Gastroenterology, AMNCH, Dublin, IrelandbDepartment of Pathology, AMNCH, Dublin, IrelandcTrinity College Dublin, Dublin, IrelanddTAGG (Trinity Academic Gastroenterology Group), Dublin, Ireland*Dr. Vikrant Parihar, Department of Gastroenterology, AMNCH, Tallaght, Dublin 24 (Ireland), E-Mail Vikpar37@yahoo.comSep-Dec 2017 6 10 2017 6 10 2017 11 3 593 598 26 6 2017 29 8 2017 Copyright © 2017 by S. Karger AG, Basel2017This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.We present a patient with coeliac disease who developed refractory coeliac disease II, which was complicated by the development of metachronous lymphomas.\n\nKeywords\nRefractory coeliac diseaseLymphomaMassive gastrointestinal bleeding\n==== Body\nIntroduction\nRefractory coeliac disease (RCD) is a rare disease of the gastrointestinal tract characterised by crampy abdominal pain, diarrhoea, gastrointestinal bleeding, and weight loss in patients with coeliac disease (CD) and is associated with loss of response to standard therapy which is gluten-free diet (GFD). It occurs as type I and II, with type II having a poor outcome due to the development of complications. We present a patient with CD who went on to develop RCDII despite strict adherence to a GFD. The case was complicated by the development of metachronous lymphomas and massive gastrointestinal bleeding. This case emphasises the challenges in the diagnosis of RCD and the need for increased awareness of this entity. This will improve early recognition with possibly better outcomes.\n\nCase Report\nA 69-year-old male presented with a 3-month history of weight loss, watery non-bloody diarrhoea, low energy, and pain in the left hip radiating to the leg. His history consisted of stroke with no residual deficit 6 years ago and non-deforming rheumatoid arthritis. He was on aspirin and sulfasalazine. He was a smoker of 20 pack-years having stopped 7 years ago. He consumed alcohol socially.\n\nSystemic examination was normal. He had recently been diagnosed with CD and commenced a GFD. MRI followed by a PET scan showed a mass at the fourth lumbar vertebra with no disease elsewhere, and the subsequent biopsy revealed a diagnosis of T-cell lymphoma with anaplastic large cell morphology, CD30 positive and ALK-1 negative. The patient was treated with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) × 8 cycles and radiotherapy 40 Gy/20 fractions. A follow-up PET scan 6 months after completion of therapy suggested a residual soft tissue mass in the left posterior element of L4 with minimal FDG accumulation (residual disease). However, a repeat L4 biopsy showed therapy-related changes only, with no evidence of lymphoma. The patient was admitted again 24 months later with diarrhoea and 2-stone weight loss. He looked cachectic with generalised oedema, but on examination, there was no lymphadenopathy or organomegaly. His laboratory work-up revealed a normocytic anaemia, hypoalbuminaemia with normal anti-transglutaminase antibody titre (Table 1). Given significant risk of enteropathy-associated T-cell lymphoma (EATL), investigations to exclude this diagnosis were performed. Scans including whole-body CT and PET showed no evidence of recurrence of his anaplastic large cell lymphoma, but an MRI of the small bowel showed mildly thickened loops of the jejunum in the central abdomen and right flank without dilatation. Oesophagogastroduodenoscopy revealed severely active CD (Fig. 1), and colonoscopy was macroscopically normal with normal colonic and terminal ileal biopsies. Biopsy results from the second part of the duodenum showed total villus atrophy with intraepithelial lymphocytes that were within normal limits. Subsequent immunostaining confirmed a normal number of aberrant intraepithelial T lymphocytes (IELs) (Fig. 2). A diagnosis of RCDII was made, and the patient was treated with total parenteral nutrition, blood products (red cell concentrate, platelet, fibrinogen, albumin), parenteral steroids followed by “naked” unencapsulated budesonide. He was later treated with oral cladribine, a synthetic purine nucleoside homologue with cytotoxic activity, but was not considered a candidate for autologous stem cell transplant given his age and poor performance status. He did not respond to cladribine, and developed a catastrophic upper gastrointestinal bleed 4 weeks after admission which could not be controlled endoscopically. A mesenteric angiogram with embolisation of jejunal branches was performed, and haemostasis was achieved (Fig. 3). Unfortunately, he went on to develop severe systemic sepsis with multiple organ dysfunction after the procedure. Given the poor prognosis, treatment was not escalated, and he died 3 days later. A limited post-mortem examination (requested by next of kin) showed axillary lymph node T-cell lymphoma likely related to the CD.\n\nDiscussion\nCD is a T-cell mediated reversible enteropathy induced by ingestion of gluten with a significant intestinal injury. CD is associated with a doubling of non-Hodgkin lymphoma (NHL) risk, with an OR of 2.1. The OR for diffuse large B-cell lymphoma is 2.8 in contrast to an OR of 17 for T-cell lymphoma [1].\n\nRCD is a subset of the disease, which is characterised by a continuous gluten independent immune response that does not respond to standard treatment with a GFD [2]. RFD is typically divided into 2 subgroups – RCDI and RCDII, differentiated by the presence or absence of abnormal IELs on mucosal biopsy [3]. In RCDI, the IEL phenotype is normal, whereas the abnormal phenotype in RCDII is supported by the loss of normal surface markers CD3, CD4, and CD8 with preserved expression of intracytoplasmic CD3.\n\nProgress to EATL occurs in 60–80% of RCDII sufferers within 5 years [4]. Survival rates for patients with EATL are low, at 11–20% at 5 years [4]. However, non-intestinal B-cell and T-cell NHL together constitute the majority of CD-associated malignant lymphomas [5]. “Naked” budesonide, as used in this case, assists with the enteric delivery of an active steroid, rather than standard steroid formulations and can be utilised initially to manage the disease. Autologous stem cell treatment is now the standard of care in patients with RCDII to prevent progression [6]. Mesenchymal stem cell infusions and calamine (anti-IL-15) are newer experimental modalities being tried [7]. On the other hand, RCDI is managed with immunosuppressive therapy, such as prednisolone/budesonide in combination with azathioprine.\n\nOur case is unusual in the development of metachronous lymphomas at 2 different locations. He initially appears to have had a responsive disease when he had a non-intestinal T-cell lymphoma, not typical EATL, and only in the terminal phase did he have evidence of refractory coeliac/ulcerative jejunitis with additional post-mortem diagnosis of axillary lymph node T-cell lymphoma. However, there is always a possibility that given the multifocal nature of the condition, his RCD might have been missed at the index gastroscopy. So, in summary, the unique features and teaching points of this case are the occurrences of 2 different metachronous lymphomas in 1 patient. We need to be cognizant of the need to look for RCDII if patients with the coeliac disease develop non-GI lymphoma disease. Also, RCDII has significant morbidity in its own right due to bleeding and malabsorption; so, early referral for autologous stem cell transplant is mandatory. However, due to the rarity of the disorder, further large-scale studies are needed, and multi-centre cooperation will be essential to achieve meaningful results.\n\nStatement of Ethics\nThe authors have no ethical conflicts to disclose.\n\nDisclosure Statement\nNo financial disclosures for any of the authors.\n\nFig. 1. Endoscopic duodenal appearance.\n\nFig. 2. a Duodenal biopsy with villous atrophy. ×100. b Immunostaining with retention of CD3. ×100. c Immunostaining with loss of CD8. ×100.\n\nFig. 3. a Mesenteric angiogram demonstrating bleeding from jejunal branches. b Coiling of bleeding branches.\n\nTable 1 Laboratory values\n\nHb\t9.6 (13.0–17.5)\t\nMCV\t80 fL (79.0–96.0)\t\nWhite cell count\t8 × 109/L (4.0–11.0)\t\nPlatelet count\t350 × 109/L (140–400)\t\nLFTs and U and E\tnormal\t\nAlbumin\t19 (35–45)\t\nStool C+S\tnegative\t\nTTG\t4.1 and 3.5 (0.0–3.9 U/mL)\t\nLDH\t159 (<250)\t\nVit D\t12 (>50)\n==== Refs\nReferences\n1 Smedby KE Åkerman M Hildebrand H Glimelius B Ekbom A Askling J Malignant lymphomas in coeliac disease: evidence of increased risks for lymphoma types other than enteropathy-type T cell lymphoma Gut 2005 32 54 59 \n2 Dewar DH Donnelly SC McLaughlin SD Johnson MW Ellis HJ Ciclitira PJ Celiac disease: management of persistent symptoms in patients on a gluten-free diet World J Gastroenterol 2012 32 1348 1356 \n3 Rubio-Tapia A Murray J Recent advances in clinical practice: classification and management of refractory coeliac disease Gut 2010 32 547 557 \n4 Al-Toma A Verbeek WH Hadithi M von Blomberg BM Mulder CJ Survival in refractory coeliac disease and enteropathy-associated T-cell lymphoma: retrospective evaluation of single-centre experience Gut 2007 32 1373 1378 \n5 Halfdanarson TR Litzow MR Murray JA Hematologic manifestations of celiac disease Blood 2007 32 412 421 \n6 Tack GJ Wondergem MJ Al-Toma A Verbeek WH Schmittel A Machado MV Perri F Ossenkoppele GJ Huijgens PC Schreurs MW Mulder CJ Auto-SCT in refractory celiac disease type II patients unresponsive to cladribine therapy Bone Marrow Transplant 2011 32 840 846 \n7 Meresse B Korneychuk N Malamut G Cerf-Bensussan N Interleukin-15, a master piece in the immunological jigsaw of celiac disease Dig Dis 2015 32 122 130\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-0631",
"issue": "11(3)",
"journal": "Case reports in gastroenterology",
"keywords": "Lymphoma; Massive gastrointestinal bleeding; Refractory coeliac disease",
"medline_ta": "Case Rep Gastroenterol",
"mesh_terms": null,
"nlm_unique_id": "101474819",
"other_id": null,
"pages": "593-598",
"pmc": null,
"pmid": "29118688",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "16973955;20332526;25925912;20818442;22493548;15591504;17470479",
"title": "A Tale of Two Lymphomas.",
"title_normalized": "a tale of two lymphomas"
} | [
{
"companynumb": "IE-BAYER-2018-027244",
"fulfillexpeditecriteria": "1",
"occurcountry": "IE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SULFASALAZINE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nThe national protocol aimed to improve the outcome of the high risk neuroblastoma patients by high-dose chemotherapy and stem cell rescue with intensive multimodal therapy.\n\n\nMETHODS\nAfter the 6 induction chemotherapy cycles, patients without disease progression were nonrandomly (by physicians' and/or parent's choices) allocated into two treatment arms, which were designed to continue the conventional chemotherapy (CCT), or myeloablative therapy with autologous stem cell rescue (ASCR).\n\n\nRESULTS\nFifty-six percent (272 patients) of patients was evaluated as high risk. Response rate to induction chemotherapy was 71%. Overall event-free survival (EFS) and overall survival (OS) at 5 years were 28% and 36%, respectively. \"As treated\" analysis documented postinduction EFS of 41% in CCT arm (n = 138) and 29% in ASCR group (n = 47) (P = 0.042); whereas, OS was 45% and 39%, respectively (P = 0.05). Thirty-one patients (11%) died of treatment-related complications.\n\n\nCONCLUSIONS\nSurvival rates of high-risk neuroblastoma have improved in Turkey. Myeloablative chemotherapy with ASCR has not augmented the therapeutic end point in our country's circumstances. The adequate supportive care and the higher patients' compliance are attained, the better survival rates might be obtained in high-risk neuroblastoma patients received myeloablative chemotherapy and ASCR.",
"affiliations": "Department of Pediatric Hematology-Oncology, Ege University Faculty of Medicine, Izmir, Turkey.;Department of Pediatric Oncology, Hacettepe University Faculty of Medicine, Ankara, Turkey.;Department of Pediatric Hematology, Behcet Uz Training and Research Hospital, Izmir, Turkey.;Department of Pediatric Oncology, Akdeniz University Faculty of Medicine, Antalya, Turkey.;Department of Pediatric Oncology, Kanuni Sultan Suleyman Training and Research Hospital, Istanbul, Turkey.;Department of Pediatric Oncology, Ondokuz Mayis University Faculty of Medicine, Samsun, Turkey.;Department of Pediatric Oncology, Ataturk University Faculty of Medicine, Erzurum, Turkey.;Department of Pediatric Oncology, Istanbul University Institute of Oncology, Istanbul, Turkey.;Department of Pediatric Oncology, Karadeniz Technical University Faculty of Medicine, Trabzon, Turkey.;Department of Pediatric Oncology, Uludag University Faculty of Medicine, Bursa, Turkey.;Department of Pediatric Oncology, Ankara University Institute of Oncology, Ankara, Turkey.;Department of Pediatric Oncology, Sisli Etfal Training and Research Hospital, Istanbul, Turkey.;Department of Pediatric Oncology, Gaziantep University Institute of Oncology, Gaziantep, Turkey.;Department of Pediatric Oncology, Istanbul University Cerrahpaşa Medical Faculty, Istanbul, Turkey.;Department of Pediatric Oncology, Tepecik Training and Research Hospital, Izmir, Turkey.;Department of Pediatric Oncology, Gazi University Faculty of Medicine, Ankara, Turkey.;Department of Pediatric Oncology, Marmara University Faculty of Medicine, Istanbul, Turkey.;Department of Pediatric Oncology, Istanbul University Faculty of Medicine, Istanbul, Turkey.;Department of Pediatric Oncology, Dr. Abdurrahman Yurtaslan Oncology Training and Research Hospital, Ankara, Turkey.;Department of Pediatric Oncology, Dokuz Eylul University Institute of Oncology, Izmir, Turkey.;Department of Pediatric Oncology, Adnan Menderes University Faculty of Medicine, Aydin, Turkey.;Department of Pediatric Oncology, Dokuz Eylul University Institute of Oncology, Izmir, Turkey.",
"authors": "Aksoylar|Serap|S|;Varan|Ali|A|;Vergin|Canan|C|;Hazar|Volkan|V|;Akici|Ferhan|F|;Dagdemir|Ayhan|A|;Buyukavci|Mustafa|M|;Kebudi|Rejin|R|;Kurucu|Nilgun|N|;Sevinir|Betul|B|;Unal|Emel|E|;Vural|Sema|S|;Guler|Elif|E|;Apak|Hilmi|H|;Oniz|Haldun|H|;Karadeniz|Ceyda|C|;Canpolat|Cengiz|C|;Anak|Sema|S|;Ilhan|Inci|I|;Ince|Dilek|D|;Cecen|Emre|E|;Olgun|Nur|N|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/0973-1482.183205",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1998-4138",
"issue": "13(2)",
"journal": "Journal of cancer research and therapeutics",
"keywords": null,
"medline_ta": "J Cancer Res Ther",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002985:Clinical Protocols; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009447:Neuroblastoma; D033581:Stem Cell Transplantation; D019172:Transplantation Conditioning; D014421:Turkey; D055815:Young Adult",
"nlm_unique_id": "101249598",
"other_id": null,
"pages": "284-290",
"pmc": null,
"pmid": "28643749",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Treatment of high-risk neuroblastoma: National protocol results of the Turkish Pediatric Oncology Group.",
"title_normalized": "treatment of high risk neuroblastoma national protocol results of the turkish pediatric oncology group"
} | [
{
"companynumb": "TR-JNJFOC-20170718474",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional": n... |
{
"abstract": "We report the case of a 50-year-old man with allergic bronchopulmonary mycosis (ABPM) complicated with bilateral septic arthritis of the knees caused by Methicillin-resistant Staphylococcus aureus (MRSA). He had a background of bronchial asthma and end-stage renal failure on maintenance dialysis. He was treated with 30 mg/day of prednisolone for 14 days for ABPM. He developed bilateral septic arthritis of the knees, caused by MRSA during prednisolone treatment. He underwent bilateral arthroscopic washout with a 2-week course of intra-articular arbekacin, concomitantly treated with a 6-week course of intravenous teicoplanin and oral rifampicin, subsequently followed by oral linezolid treatment. However, he suffered exacerbation of ABPM during treatment of septic arthritis. Because of these serious infectious complications, he was treated with mepolizumab instead of corticosteroids for the ABPM, which resolved all symptoms and clinical features. This case highlights mepolizumab treatment as an alternative to corticosteroid therapy for treatment of ABPM in patients with comorbidities such as infection.",
"affiliations": "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 Clinical Infectious Diseases, 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 Orthopedics, Hamanomachi Hospital, Fukuoka, 810-8539, Japan.;Department of Orthopedics, Hamanomachi Hospital, Fukuoka, 810-8539, Japan.;Department of Respiratory Medicine, Hamanomachi Hospital, Fukuoka, 810-8539, Japan.",
"authors": "Yanagihara|Toyoshi|T|;Hirota|Mao|M|;Egashira|Ayaka|A|;Harada|Yukiko|Y|;Ogo|Naruhiko|N|;Asoh|Tatsuma|T|;Kuramoto|Takahumi|T|;Matsui|Gen|G|;Maeyama|Takashige|T|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.rmcr.2020.101316",
"fulltext": "\n==== Front\nRespir Med Case Rep\nRespir Med Case Rep\nRespiratory Medicine Case Reports\n2213-0071 Elsevier \n\nS2213-0071(20)30530-X\n10.1016/j.rmcr.2020.101316\n101316\nCase Report\nSuccessful treatment with mepolizumab for allergic bronchopulmonary mycosis complicated with bilateral septic arthritis of the knee joints caused by Methicillin-resistant Staphylococcus aureus\nYanagihara Toyoshi yanagiha@kokyu.med.kyushu-u.ac.jpa∗ Hirota Mao a Egashira Ayaka a Harada Yukiko b Ogo Naruhiko a Asoh Tatsuma a Kuramoto Takahumi c Matsui Gen c Maeyama Takashige a a Department of Respiratory Medicine, Hamanomachi Hospital, Fukuoka, 810-8539, Japan\nb Department of Clinical Infectious Diseases, Hamanomachi Hospital, Fukuoka, 810-8539, Japan\nc Department of Orthopedics, Hamanomachi Hospital, Fukuoka, 810-8539, Japan\n∗ Corresponding author. yanagiha@kokyu.med.kyushu-u.ac.jp\n04 12 2020 \n2020 \n04 12 2020 \n31 1013162 10 2020 27 11 2020 2 12 2020 © 2020 The Author(s)2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).We report the case of a 50-year-old man with allergic bronchopulmonary mycosis (ABPM) complicated with bilateral septic arthritis of the knees caused by Methicillin-resistant Staphylococcus aureus (MRSA). He had a background of bronchial asthma and end-stage renal failure on maintenance dialysis. He was treated with 30 mg/day of prednisolone for 14 days for ABPM. He developed bilateral septic arthritis of the knees, caused by MRSA during prednisolone treatment. He underwent bilateral arthroscopic washout with a 2-week course of intra-articular arbekacin, concomitantly treated with a 6-week course of intravenous teicoplanin and oral rifampicin, subsequently followed by oral linezolid treatment. However, he suffered exacerbation of ABPM during treatment of septic arthritis. Because of these serious infectious complications, he was treated with mepolizumab instead of corticosteroids for the ABPM, which resolved all symptoms and clinical features. This case highlights mepolizumab treatment as an alternative to corticosteroid therapy for treatment of ABPM in patients with comorbidities such as infection.\n\nKeywords\nAllergic bronchopulmonary mycosisAllergic bronchopulmonary aspergillosisBronchial asthmaMepolizumabSeptic arthritisMRSA\n==== Body\n1 Introduction\nAllergic bronchopulmonary aspergillosis (ABPA) is an eosinophilic pulmonary disease resulting from a hypersensitivity reaction to Aspergillus species colonizing the airways, predominantly in patients with asthma or cystic fibrosis [1,2]. Recently, it has been recognized that fungi other than Aspergillus species can cause the same symptoms, and collectively these diseases are called allergic bronchopulmonary mycosis (ABPM) [3]. Because ABPM is caused by a hypersensitivity reaction to bronchial colonization by some fungi, standard treatment comprises a combination of systemic corticosteroids and anti-fungal agents. Some patients with ABPM, however, do not respond or are intolerant of this standard therapy due to comorbidities. In this report, we describe a case of ABPM successfully treated with mepolizumab, a humanized anti-IL-5 antibody. This treatment was selected due to complications with bilateral septic arthritis of the knees caused by Methicillin-resistant Staphylococcus aureus (MRSA).\n\n2 Case report\nA 50-year-old man was admitted to Hamanomachi Hospital with a three-week history of painful bilateral knee joints. He claimed that his knee pain started after repeated jet-skiing. He underwent acupuncture treatment around both knee joints, but knee pain was exacerbated. His medical history includes end-stage renal failure due to focal glomerulosclerosis and maintenance dialysis for more than a year, and bronchial asthma over twenty years. He was treated with fluticasone furoate and vilanterol trifenatate. He did not smoke and had no history of dust exposure.\n\nHe complained of a persistent cough with sputum since one month before admission. Physical examination revealed rhonchi and crackles. His chest X-ray image showed newly emerging club-shaped masses in both lung fields (Fig. 1). Chest computed tomography (CT) showed central bronchiectasis, mucoid impaction, and tree-in-bud opacities (Fig. 2A). Densities of mucoid impactions were higher than those of paravertebral muscles (80–90 Hounsfield Unit [HU] vs. 40–60 HU, respectively). Laboratory examination showed peripheral blood eosinophilia (1906/μL) and an extremely elevated total serum IgE value of 6000 IU/mL. Specific IgE against Aspergillus fumigatus later proved positive (26.8 UA/mL). Pulmonary function testing was unavailable due to the global Coronavirus pandemic (COVID-19). He was clinically diagnosed with allergic bronchopulmonary aspergillosis/mycosis (ABPA/ABPM) (Table 1) and treatment was initiated with 30 mg/day of prednisolone 12 days before admission (Fig. 3). Mucus plugs were later confirmed by bronchoscopy after admission (Fig. 4), although fungal hyphae were not detected, presumably because of the effect of treatment. Aspergillus fumigatus was the most suspect allergen in this case, based on the specific IgE result, but we prefer to consider the condition as ABPM, because of the lack of a positive culture for Aspergillus species.Fig. 1 Chest radiographic images of the patient. Chest X-ray images 4 months before admission (A), 4 weeks before admission (B), on admission (C), and admission on day 14 (D). Arrows indicate newly emerging club-shaped masses in both lungs. The image on day 14 was performed by bedside X-ray in the anteroposterior (AP) sitting position.\n\nFig. 1Fig. 2 Chest CT images of the patient. (A) Mucus plugging and tree-in-bud opacities were apparent before prednisolone treatment and (B) at the time of mepolizumab treatment. (C) Mucus plugging was resolved 43 days after mepolizumab treatment.\n\nFig. 2Table 1 Application of new clinical diagnostic criteria for allergic bronchopulmonary mycosis to this case. Diagnosis for ABPM: meet 6 or more of the criteria below, proposed by the Japan ABPM research program [4]. This case met 7 criteria.\n\nTable 1\tTHIS CASE\tCRITERIA\t\n1\t○\tCurrent or previous history of asthma or asthmatic symptoms\t\n2\t○\tPeripheral blood eosinophilia (≧ 500 cells/mm3)\t\n3\t○\tElevated total serum immunoglobulin E levels (IgE ≧ 417 IU/mL)\t\n4\t○\tImmediate cutaneous hypersensitivity or specific IgE for filamentous fungi\t\n5\t\tPresence of precipitins or specific IgG for filamentous fungi\t\n6\t\tFilamentous fungal growth in sputum cultures or bronchial lavage fluid\t\n7\t\tPresence of fungal hyphae in bronchial mucus plugs\t\n8\t○\tCentral bronchiectasis on computed tomography (CT)\t\n9\t○\tPresence of mucus plugs in central bronchi, based on CT or mucus plug expectoration history\t\n10\t○\tHigh attenuation mucus in the bronchi on CT\t\nFig. 3 Clinical course of the case. The patient was treated with 30 mg/day of prednisolone (PSL) for ABPM starting 12 days before admission. He developed bilateral septic arthritis of the knees caused by Methicillin-resistant Staphylococcus aureus (MRSA) during prednisolone treatment. He underwent bilateral arthroscopic washout with a 2-week course of intra-articular arbekacin (ABK), concomitantly treated with a 6-week course of intravenous teicoplanin (TEIC) and oral rifampicin (RFP). He suffered exacerbation of ABPM during treatment of the septic arthritis and was treated with mepolizumab on admission day 15. Garenoxacin (GRNX) followed by tazobactam/piperacillin (TAZ/PIPC) was transiently administered for the treatment of bronchopneumonia by Pseudomonas aeruginosa from day 16 to day 27. He was discharged on day 43.\n\nFig. 3Fig. 4 Bronchoscopic findings showing a mucoid plug in the left lingular bronchus.\n\nFig. 4\n\nOn admission, he had a temperature of 36.5 °C (afebrile, possibly because of prednisolone treatment), blood pressure of 138/77 mmHg, a heart rate of 86 beats per minute, oxygen saturation of 98% under room air. Chest auscultation revealed no murmur nor wheezes. Both of his knees were swollen and warm. He had difficulty in bearing weight on his knees and exhibited tenderness in both. Hip and ankle joints were normal. Laboratory examination revealed elevated inflammatory markers, with a white blood cell (WBC) count of 12.8 × 103/μL (Neutrophils 10.7 × 103/μL, Eosinophils 500/μL) and C-reactive protein (CRP) of 17.20 mg/dL. Although his chest X-ray showed persistent club-shaped masses in both lung fields (Fig. 1C), no abnormal respiratory sounds with improved eosinophilia (Fig. 3) suggested the partial effect of prednisolone treatment for ABPM. An MRI of the right knee revealed a small amount of fluid retention in the knee joint and a hyperintense signal in soft tissues of the medial aspect of the lower leg by T2 weighted-image sequencing (Fig. 5A). There was also synovitis around the suprapatellar capsule. A needle aspiration from the right knee revealed thick, cloudy pus with Gram-positive cocci being phagocytosed by neutrophils (Fig. 5B). which proved to be MRSA. Blood cultures were also positive for MRSA. Empirical intravenous ceftriaxone and teicoplanin (TEIC) were administered, but ceftriaxone was discontinued on day 3, when the culture results proved positive for MRSA.Fig. 5 Clinical features of septic arthritis of the knee. (A) An MRI of the right knee revealed a small amount of joint fluid retention in the knee and a hyperintense signal in the soft tissues of the medial aspect of the lower leg, based on T2 weighted-image sequencing. (B) Gram stain of knee synovial fluid showed Gram-positive cocci being phagocytosed by neutrophils.\n\nFig. 5\n\nHe was then given bilateral knee arthroscopies and washouts on day 3. Cultures from the left synovial fluid were also positive with MRSA. He was thus diagnosed with bilateral septic arthritis of the knees caused by MRSA. He underwent a 2-week course of intra-articular arbekacin with oral rifampicin. An echocardiogram revealed no vegetations, and subsequent blood cultures were negative.\n\nHe suffered shortness of breath with wheezing from day 9. Considering the exacerbation of ABPM, he was treated with 200 mg of itraconazole, which did not improve his symptoms. Eosinophil cell count rose linearly, reaching 2966/μL on day 14 (Fig. 3). Laboratory examination showed sustained elevation of CRP level (16.9 mg/dL). His oxygen saturation dropped below 90% in room air on day 14. His chest X-ray showed newly emerging lung infiltration in the right lower lung field compared to that on admission (Fig. 1D). Cultures from sputum on day 13 were positive with Pseudomonas aeruginosa. Causes of respiratory deterioration were clinically indistinguishable from exacerbation of ABPM and bronchopneumonia caused by Pseudomonas aeruginosa. We therefore decided to address both possible situations. One of the reasons for this was the difficulty in assessing the presence of respiratory infections serologically due to the complication of bilateral septic arthritis. We used mepolizumab instead of systemic corticosteroid for exacerbation of ABPM. Garenoxacin followed by tazobactam/piperacillin was transiently administered for treatment of Pseudomonas aeruginosa bronchopneumonia from day 15 to day 27 (Fig. 3). Eosinophil cell count dramatically decreased after mepolizumab administration. Accordingly, his respiratory symptoms and oxygen saturation gradually improved.\n\nHe showed a good recovery with a 6-week course of intravenous teicoplanin and oral rifampicin for his septic arthritis. He was discharged on day 43, replacing intravenous teicoplanin with oral linezolid. The IgE level tended to decrease at 5220 IU/mL, and mucus plugging was resolved 43 days after mepolizumab treatment (Fig. 2C). No relapse of septic arthritis nor exacerbation of ABPM was observed for two months after discharge.\n\n3 Discussion\nWe report a case of ABPM, complicated with bilateral septic arthritis of the knee joints, that was successfully treated with mepolizumab. First, we employed new diagnostic criteria for ABPM proposed by the Japan ABPM research program [4]. The new criteria showed higher sensitivity and specificity for ABPM (94.4% and 96.0%, respectively), compared to the Rosenberg-Patterson criteria proposed in 1977, or the International Society for Human and Animal Mycology (ISHAM) criteria proposed in 2013 [4]. Moreover, the new criteria are practical for ABPM screening since they show improved AUC (= 0.95) for ROC curve analysis, compared to previous criteria, even in the absence of pathological examinations of mucus plugs [4]. Indeed, in this case we were able to diagnose ABPM without positive fungal hyphae in mucus plugs.\n\nIn general, systemic corticosteroids are considered the mainstay of treatment of acute ABPM, based on results of case series and studies [[5], [6], [7]]. Because of the serious infectious disease, however, it was difficult to use systemic corticosteroids for exacerbation of the ABPM. Since antifungal therapy is reportedly effective [2,[7], [8], [9]], we then chose itraconazole as a second choice for the exacerbated ABPM; however, it resulted in no improvement at all. Molecular targeted drugs have been used for refractory asthma, including omalizumab (anti-IgE), mepolizumab (anti-IL-5), and dupilumab (anti-IL-4R) [10]. These drugs have potential to improve ABPM, and several case reports found omalizumab, mepolizumab, or dupilumab efficacious for treatment of ABPM.\n\nOmalizumab, a humanized anti-IgE monoclonal antibody, is reportedly beneficial in treatment of ABPM in cases of uncontrolled asthma [11,12]. Dosing of omalizumab follows a nomogram based on weight and total serum IgE levels. However, the nomogram may be difficult to apply to ABPM due to high levels of serum IgE. The level of serum IgE was over 6000 IU/mL (out of range) in this case, calling for doses above the nomogram-based upper limit. Indeed, some case reports describe an insufficient efficacy of omalizumab for ABPM [13]. We thus doubted the efficacy of omalizumab in this case and decided not to use it.\n\nMepolizumab, a humanized monoclonal antibody against IL-5, inhibits binding of IL-5 to its receptor, leading to suppression of eosinophil activation. Therefore, we expected mepolizumab to be efficacious for treatment of ABPM. Several cases of ABPM treated with mepolizumab have been reported so far [[14], [15], [16], [17], [18], [19], [20]]. All were controlled, and none of these patients experienced adverse events with mepolizumab. Activated eosinophils can reveal a non-apoptotic cell death pathway, named eosinophil extracellular trap cell death (EETosis) that mediates eosinophil cytolytic degranulation [21]. EETosis contributes to formation of mucoid impaction [21] and trapping of fungi. As Hirota et al. reported [14], inhibition of eosinophilic activation by mepolizumab might lead to suppression of mucoid impaction, which resulted in improvement of ABPM.\n\nDupilumab, a humanized monoclonal antibody against IL-4 receptor, also has potential for treatment of ABPM [13,22]. We had no idea whether mepolizumab or dupilumab was preferable for this case from the perspective of biological effects. We chose mepolizumab just because of the longer treatment interval (mepolizumab every four weeks, dupilumab every two weeks). As with application of different biologics in severe asthma, there are problems related to selection criteria. Further study will be needed to determine the appropriate role and selection guidelines of biologics in ABPM.\n\nIn this case, the patient was on maintenance dialysis. Based on population pharmacokinetic analyses, mepolizumab clearance was similar between patients of hyper-eosinophilic syndrome with creatinine clearance values between 50 and 80 mL/min and patients with normal renal function [23]. Although there are no data available in subjects with creatinine clearance values less than 50 mL/min, renal impairment should not affect mepolizumab pharmacokinetics, as mepolizumab is not filtered by the kidney due to its high molecular weight, as with other biologics [24]. Mepolizumab is thought to be metabolized by ubiquitous proteolytic enzymes [24].\n\nSeptic arthritis is an infection in a joint, often destructive, and usually caused by bacteria. Predisposing factors include advanced age, pre-existing joint disease, skin or soft tissue infection, intravenous drug use, immunosuppression, and recent joint surgery or injection [[25], [26], [27], [28]]. Although the knee is the most common joint involved in septic arthritis (>50%) [29], bilateral involvement is rare. In this case, the patient's background of end-stage renal failure on maintenance dialysis may have increased the chance of hematogenous seeding of MRSA from the skin, providing an immune-suppressed condition. Treatment with prednisolone further suppressed the immune system. Injury of the knees by repeated jet-skiing probably increased the chance of MRSA to adhere to synovial tissues. Acupuncture treatment around both knee joints may have seeded bacteria into the joint, as previously reported [30]. All of these conditions synergistically resulted in severe bilateral septic arthritis, which complicated therapy.\n\nIn conclusion, this case highlights biologic treatment such as mepolizumab as an alternative to corticosteroid therapy for treatment of ABPM in patients with infections.\n\nPatient consent for publication\nWritten informed consent was obtained from the patient.\n\nDeclaration of competing interest\nThe authors declare no conflict of interest.\n\nConflicts of interest\nAll authors of the manuscript declare that there are no conflicts of interest.\n==== Refs\nReferences\n1 P.A. Greenberger, R.K. Bush, J.G. Demain, A. Luong, R.G. Slavin, A.P. Knutsen, Allergic bronchopulmonary aspergillosis., J. Allergy Clin. Immunol. Pract. 2 (n.d.) 703–8. 10.1016/j.jaip.2014.08.007 .\n2 Agarwal R. Allergic bronchopulmonary aspergillosis Chest 135 2009 805 826 10.1378/chest.08-2586 19265090 \n3 Asano K. Kamei K. Hebisawa A. Allergic bronchopulmonary mycosis – pathophysiology, histology, diagnosis, and treatment, Asia Pac Allergy 8 2018 1 14 10.5415/apallergy.2018.8.e24 \n4 Asano K. Hebisawa A. Ishiguro T. Takayanagi N. Nakamura Y. Suzuki J. Okada N. Tanaka J. Fukutomi Y. Ueki S. Fukunaga K. Konno S. Matsuse H. Kamei K. Taniguchi M. Shimoda T. Oguma T. New clinical diagnostic criteria for allergic bronchopulmonary aspergillosis/mycosis and its validation J. Allergy Clin. Immunol. 2020 10.1016/j.jaci.2020.08.029 \n5 Patterson R. Allergic bronchopulmonary aspergillosis Arch. Intern. Med. 146 1986 916 10.1001/archinte.1986.00360170130020 3516103 \n6 Agarwal R. Gupta D. Aggarwal A.N. Behera D. Jindal S.K. Allergic bronchopulmonary aspergillosis: lessons from 126 patients attending a chest clinic in North India Chest 130 2006 442 448 10.1378/chest.130.2.442 16899843 \n7 Moss R.B. Treatment options in severe fungal asthma and allergic bronchopulmonary aspergillosis Eur. Respir. J. 43 2014 1487 1500 10.1183/09031936.00139513 24311776 \n8 Stevens D.A. Schwartz H.J. Lee J.Y. Moskovitz B.L. Jerome D.C. Catanzaro A. Bamberger D.M. Weinmann A.J. Tuazon C.U. Judson M.A. Platts-Mills T.A.E. Degraff A.C. Grossman J. Slavin R.G. Reuman P. A randomized trial of itraconazole in allergic bronchopulmonary aspergillosis N. Engl. J. Med. 342 2000 756 762 10.1056/NEJM200003163421102 10717010 \n9 Agarwal R. Chakrabarti A. Shah A. Gupta D. Meis J.F. Guleria R. Moss R. Denning D.W. Allergic bronchopulmonary aspergillosis: review of literature and proposal of new diagnostic and classification criteria Clin. Exp. Allergy 43 2013 850 873 10.1111/cea.12141 23889240 \n10 McGregor M.C. Krings J.G. Nair P. Castro M. Role of biologics in asthma Am. J. Respir. Crit. Care Med. 199 2019 433 445 10.1164/rccm.201810-1944CI 30525902 \n11 Li J.X. Fan L.C. Li M.H. Cao W.J. Xu J.F. Beneficial effects of Omalizumab therapy in allergic bronchopulmonary aspergillosis: a synthesis review of published literature Respir. Med. 122 2017 33 42 10.1016/j.rmed.2016.11.019 27993289 \n12 Voskamp A.L. Gillman A. Symons K. Sandrini A. Rolland J.M. O'Hehir R.E. Douglass J.A. Clinical efficacy and immunologic effects of omalizumab in allergic bronchopulmonary aspergillosis J. Allergy Clin. Immunol. Pract. 3 2015 192 199 10.1016/j.jaip.2014.12.008 25640470 \n13 Mümmler C. Mümmler C. Kemmerich B. Behr J. Behr J. Kneidinger N. Kneidinger N. Milger K. Milger K. Differential response to biologics in a patient with severe asthma and ABPA: a role for dupilumab? Allergy Asthma Clin. Immunol. 16 2020 1 4 10.1186/s13223-020-00454-w 31911804 \n14 Hirota S. Kobayashi Y. Ishiguro T. Nishida T. Kagiyama N. Shimizu Y. Takayanagi N. Allergic bronchopulmonary aspergillosis successfully treated with mepolizumab: case report and review of the literature Respir. Med. Case Reports. 26 2019 59 62 10.1016/j.rmcr.2018.11.013 \n15 Terashima T. Shinozaki T. Iwami E. Nakajima T. Matsuzaki T. A case of allergic bronchopulmonary aspergillosis successfully treated with mepolizumab BMC Pulm. Med. 18 2018 1 5 10.1186/s12890-018-0617-5 29301525 \n16 Oda N. Miyahara N. Senoo S. Itano J. Taniguchi A. Morichika D. Fujii U. Maeda Y. Kiura K. Kanehiro A. Severe asthma concomitant with allergic bronchopulmonary aspergillosis successfully treated with mepolizumab Allergol. Int. 67 2018 521 523 10.1016/j.alit.2018.03.004 29665990 \n17 Altman M.C. Lenington J. Bronson S. Ayars A.G. Combination omalizumab and mepolizumab therapy for refractory allergic bronchopulmonary aspergillosis J. Allergy Clin. Immunol. Pract. 5 2017 1137 1139 10.1016/j.jaip.2017.01.013 28279664 \n18 Soeda S. To M. Kono Y. Yamawaki S. Tsuzuki R. Katsube O. Watanabe N. To Y. Case series of allergic bronchopulmonary aspergillosis treated successfully and safely with long-term mepolizumab Allergol. Int. 68 2019 377 379 10.1016/j.alit.2018.12.008 30704844 \n19 Tsubouchi H. Tsuchida S. Yanagi S. Shigekusa T. Miura M. Sakaguchi K. Matsumoto N. Nakazato M. Successful treatment with mepolizumab in a case of allergic bronchopulmonary aspergillosis complicated with nontuberculous mycobacterial infection Respir. Med. Case Reports. 28 2019 100875 10.1016/j.rmcr.2019.100875 \n20 Matsumoto N. Shigekusa T. Matsuo A. Tsubouchi H. Yanagi S. Nakazato M. Allergic bronchopulmonary aspergillosis complicated by eosinophilic chronic rhinosinusitis successfully treated with mepolizumab Respirol. Case Reports. 7 2019 1 3 10.1002/rcr2.465 \n21 Ueki S. Melo R.C.N. Ghiran I. Spencer L.A. Dvorak A.M. Weller P.F. Eosinophil extracellular DNA trap cell death mediates lytic release of free secretion-competent eosinophil granules in humans Blood 121 2013 10.1182/blood-2012-05-432088 2074–2083 \n22 Ramonell R.P. Lee F.E.H. Swenson C. Kuruvilla M. Dupilumab treatment for allergic bronchopulmonary aspergillosis: a case series J. Allergy Clin. Immunol. Pract. 8 2020 742 743 10.1016/j.jaip.2019.11.031 31811944 \n23 Smith D.A. Minthorn E.A. Beerahee M. Pharmacokinetics and pharmacodynamics of mepolizumab, an anti-interleukin-5 monoclonal antibody Clin. Pharmacokinet. 50 2011 215 227 10.2165/11584340-000000000-00000 21348536 \n24 Bagnasco D. Heffler E. Testino E. Passalacqua G. Canonica G.W. Pharmacokinetics and pharmacodynamics of monoclonal antibodies for asthma treatment Expet Opin. Drug Metabol. Toxicol. 15 2019 113 120 10.1080/17425255.2019.1568409 \n25 Margaretten M.E. Kohlwes J. Moore D. Bent S. Does this adult patient have septic arthritis? J. Am. Med. Assoc. 297 2007 1478 1488 10.1001/jama.297.13.1478 \n26 Mathews C.J. Coakley G. Septic arthritis: current diagnostic and therapeutic algorithm Curr. Opin. Rheumatol. 20 2008 457 462 10.1097/BOR.0b013e3283036975 18525361 \n27 Borzio R. Mulchandani N. Pivec R. Kapadia B.H. Leven D. Harwin S.F. Urban W.P. Predictors of septic arthritis in the adult population Orthopedics 39 2016 e657 e663 10.3928/01477447-20160606-05 27286047 \n28 Carpenter C.R. Schuur J.D. Everett W.W. Pines J.M. Evidence-based diagnostics: adult septic arthritis Acad. Emerg. Med. 18 2011 781 796 10.1111/j.1553-2712.2011.01121.x 21843213 \n29 Goldenberg D.L. Septic arthritis and other infections of rheumatologic significance Rheum. Dis. Clin. N. Am. 17 1991 149 156 http://www.ncbi.nlm.nih.gov/pubmed/2041884 \n30 Robinson A. Lind C.R.P. Smith R.J. Kodali V. Atlanto-axial infection after acupuncture BMJ Case Rep. 2015 1 3 10.1136/bcr-2015-212110 2015\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2213-0071",
"issue": "31()",
"journal": "Respiratory medicine case reports",
"keywords": "Allergic bronchopulmonary aspergillosis; Allergic bronchopulmonary mycosis; Bronchial asthma; MRSA; Mepolizumab; Septic arthritis",
"medline_ta": "Respir Med Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101604463",
"other_id": null,
"pages": "101316",
"pmc": null,
"pmid": "33318922",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "21348536;30079302;16899843;30632416;10717010;23889240;29587693;23303825;32944023;3516103;2041884;30704844;25640470;17405973;31811944;32920094;31205860;19265090;18525361;29665990;26655668;31346471;30533379;25439360;30525902;24311776;27286047;27993289;21843213;28279664",
"title": "Successful treatment with mepolizumab for allergic bronchopulmonary mycosis complicated with bilateral septic arthritis of the knee joints caused by Methicillin-resistant Staphylococcus aureus.",
"title_normalized": "successful treatment with mepolizumab for allergic bronchopulmonary mycosis complicated with bilateral septic arthritis of the knee joints caused by methicillin resistant staphylococcus aureus"
} | [
{
"companynumb": "JP-TEVA-2021-JP-1867229",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "We report a case of a rupture of the common carotid artery caused by the medication of lenvatinib. The patient, 70-yearold female, was referred to our hospital by unresectable papillary thyroid cancer infiltrated the left common carotid artery. Externalbeam radiotherapy and radioiodine therapy were undergone after totalthyroidectomy. After 1 year 7 months from operation, she admitted our hospital due to left shoulder pain and dysphagia caused by the growing left cervical tumor. The medication of lenvatinib was decided after the careful informed consent. Computed tomography on the eighth day of lenvatinib medication showed the existence of air infiltration into the tumor surrounded left common carotid artery. So, a discontinuance of lenvatinib medication was decided immediately. But, on the ninth day, a rupture of the left common carotid artery occurred and on the tenth day, she died. Lenvatinib medication for the patient with the tumor surrounded artery should be decided carefully.",
"affiliations": "Dept. of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine.",
"authors": "Nishi|Takashi|T|;Igawa|Akiko|A|;Nishimura|Akimasa|A|;Hakamada|Kenichi|K|",
"chemical_list": "D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D011804:Quinolines; C531958:lenvatinib",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "44(12)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D002291:Carcinoma, Papillary; D002340:Carotid Artery Diseases; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D010671:Phenylurea Compounds; D011804:Quinolines; D012421:Rupture; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "1610-1612",
"pmc": null,
"pmid": "29394718",
"pubdate": "2017-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of a Rupture of the Carotid Artery Caused by the Lenvatinib Medication.",
"title_normalized": "a case of a rupture of the carotid artery caused by the lenvatinib medication"
} | [
{
"companynumb": "JP-EISAI MEDICAL RESEARCH-EC-2016-020395",
"fulfillexpeditecriteria": "2",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LENVATINIB"
},
"drugadditional... |
{
"abstract": "BACKGROUND\nAbdominal abscess that result from bowel injury may require treatment with percutaneous drainage. In some cases, an abscess-associated fistula develops between the injured bowel and the drainage catheter. Fistulas that fail to resolve may require surgery; however, fibrin glue therapy (FGT) may be a suitable alternative.\n\n\nMETHODS\nWe retrospectively identified patients undergoing FGT for an abscess-associated enteric fistula between 2004 and 2015. Success was defined as closure of the fistula tract without need for additional intervention. A multivariable logistic regression analysis was utilized to identify factors associated with success.\n\n\nRESULTS\nWe identified 34 patients with a median age of 54 (23-87) years and 24 (71 %) males. FGT was successful in 23 (67 %) patients. On multivariate analysis, a tract width less than 5 mm (OR 19.2, 95 % CI 1.7-214.5) and removal of the drain (OR 13.8, 95 % CI 1.2-157.6) predicted FGT success. The time from initial FGT to resolution was significantly decreased for the patients who were successfully treated compared to those who failed 24 (14-38) days vs. 99 (71-175) days, respectively (p < 0.001).\n\n\nCONCLUSIONS\nFibrin glue therapy for abscess-associated enteric fistula results in successful and accelerated healing in the majority of cases. Factors associated with successful fibrin glue therapy were identified.",
"affiliations": "Department of Surgery, University of Colorado School of Medicine, 12631 E. 17th Ave. C313, Aurora, CO, 80045, USA. brandon.chapman@ucdenver.edu.;Department of Surgery, University of Colorado School of Medicine, 12631 E. 17th Ave. C313, Aurora, CO, 80045, USA.;Department of Surgery, University of Colorado School of Medicine, 12631 E. 17th Ave. C313, Aurora, CO, 80045, USA.;Department of Surgery, University of Colorado School of Medicine, 12631 E. 17th Ave. C313, Aurora, CO, 80045, USA.;Department of Surgery, University of Colorado School of Medicine, 12631 E. 17th Ave. C313, Aurora, CO, 80045, USA.;Department of Surgery, University of Colorado School of Medicine, 12631 E. 17th Ave. C313, Aurora, CO, 80045, USA.;Department of Surgery, University of Colorado School of Medicine, 12631 E. 17th Ave. C313, Aurora, CO, 80045, USA.",
"authors": "Chapman|B C|BC|;Merkow|J|J|;Paniccia|A|A|;Overbey|D M|DM|;Gipson|M|M|;Stiegmann|G|G|;Vogel|J D|JD|",
"chemical_list": "D003287:Contrast Media; D015718:Fibrin Tissue Adhesive",
"country": "Italy",
"delete": false,
"doi": "10.1007/s10151-016-1512-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1123-6337",
"issue": "20(9)",
"journal": "Techniques in coloproctology",
"keywords": "Abdominal abscess; Fibrin glue; Fistula",
"medline_ta": "Tech Coloproctol",
"mesh_terms": "D000038:Abscess; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003287:Contrast Media; D005260:Female; D015718:Fibrin Tissue Adhesive; D006801:Humans; D007412:Intestinal Fistula; D008297:Male; D008875:Middle Aged; D015641:Radiography, Interventional; D012189:Retrospective Studies; D016896:Treatment Outcome; D014945:Wound Healing",
"nlm_unique_id": "9613614",
"other_id": null,
"pages": "641-6",
"pmc": null,
"pmid": "27522598",
"pubdate": "2016-09",
"publication_types": "D016428:Journal Article",
"references": "1376932;20093605;16741596;7266601;23408085;21190028;7283510;1947068;21679776;24183344;1627886;24509449;15784040;20533600;2031543;3337483;12093344",
"title": "Efficacy of fibrin glue therapy for abscess-associated enteric fistulas.",
"title_normalized": "efficacy of fibrin glue therapy for abscess associated enteric fistulas"
} | [
{
"companynumb": "US-JNJFOC-20160620129",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FIBRINOGEN HUMAN\\THROMBIN HUMAN"
},
"drugadditi... |
{
"abstract": "Rapidly progressive interstitial lung disease (RP-ILD) and its distinctive cutaneous features are highly associated with the presence of anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibody in patients with dermatomyositis (DM), leading to a poor prognosis. We describe the case of a 25-year-old man who developed progressive proximal muscle weakness with RP-ILD and had unusual cutaneous findings (cutaneous ulcerations and livedo reticularis) accompanied by classical cutaneous features (heliotrope rash, Gottron's papules, Gottron's sign, and flagellate erythema). Blood test was positive for anti-MDA5 antibody. He was treated with intravenous corticosteroids and immunoglobulin, but passed away due to respiratory failure within 1 month after admission. Our case highlights that the presence of cutaneous ulcerations and livedo reticularis, in addition to RP-ILD, are useful clinical clues that may aid in the detection of anti-MDA5 antibody, early initiation of combined immunosuppressants, and prognosis prediction in patients with classical DM.",
"affiliations": "Division of Dermatology, Department of Medicine, Faculty of Medicine, Srinagarind Hospital, Khon Kaen University, Khon Kaen, Thailand.;Division of Dermatology, Department of Medicine, Faculty of Medicine, Srinagarind Hospital, Khon Kaen University, Khon Kaen, Thailand.;Division of Dermatology, Department of Medicine, Faculty of Medicine, Srinagarind Hospital, Khon Kaen University, Khon Kaen, Thailand.;Division of Sleep Medicine, Department of Medicine, Faculty of Medicine, Srinagarind Hospital, Khon Kaen University, Khon Kaen, Thailand.;Division of Rheumatology, Department of Medicine, Faculty of Medicine, Srinagarind Hospital, Khon Kaen University, Khon Kaen, Thailand.;Division of Rheumatology, Department of Medicine, Faculty of Medicine, Srinagarind Hospital, Khon Kaen University, Khon Kaen, Thailand.",
"authors": "Wongjirattikarn|Rachot|R|;Chaowattanapanit|Suteeraporn|S|;Choonhakarn|Charoen|C|;So-Ngern|Apichart|A|;Mahakkanukrauh|Ajanee|A|;Foocharoen|Chingching|C|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000506668",
"fulltext": "\n==== Front\nCase Rep Dermatol\nCase Rep Dermatol\nCDE\nCase Reports in Dermatology\n1662-6567 S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com \n\n10.1159/000506668\ncde-0012-0057\nSingle Case\nAcral Cutaneous Ulcerations and Livedo Reticularis with Rapidly Progressive Interstitial Lung Disease in Anti-MDA5 Antibody-Positive Classical Dermatomyositis\nWongjirattikarn Rachot a Chaowattanapanit Suteeraporn a* Choonhakarn Charoen a So-ngern Apichart b Mahakkanukrauh Ajanee c Foocharoen Chingching c aDivision of Dermatology, Department of Medicine, Faculty of Medicine, Srinagarind Hospital, Khon Kaen University, Khon Kaen, Thailand\nbDivision of Sleep Medicine, Department of Medicine, Faculty of Medicine, Srinagarind Hospital, Khon Kaen University, Khon Kaen, Thailand\ncDivision of Rheumatology, Department of Medicine, Faculty of Medicine, Srinagarind Hospital, Khon Kaen University, Khon Kaen, Thailand\n*Suteeraporn Chaowattanapanit, MD, Division of Dermatology, Department of Medicine, Faculty of Medicine, Srinagarind Hospital, Khon Kaen University, Khon Kaen 40002 (Thailand), csuteeraporn@yahoo.com\nJan-Apr 2020 \n20 3 2020 \n20 3 2020 \n12 1 57 63\n27 12 2019 19 2 2020 2020 Copyright © 2020 by S. Karger AG, Basel2020This 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.Rapidly progressive interstitial lung disease (RP-ILD) and its distinctive cutaneous features are highly associated with the presence of anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibody in patients with dermatomyositis (DM), leading to a poor prognosis. We describe the case of a 25-year-old man who developed progressive proximal muscle weakness with RP-ILD and had unusual cutaneous findings (cutaneous ulcerations and livedo reticularis) accompanied by classical cutaneous features (heliotrope rash, Gottron's papules, Gottron's sign, and flagellate erythema). Blood test was positive for anti-MDA5 antibody. He was treated with intravenous corticosteroids and immunoglobulin, but passed away due to respiratory failure within 1 month after admission. Our case highlights that the presence of cutaneous ulcerations and livedo reticularis, in addition to RP-ILD, are useful clinical clues that may aid in the detection of anti-MDA5 antibody, early initiation of combined immunosuppressants, and prognosis prediction in patients with classical DM.\n\nKeywords\nCutaneous ulcerationLivedo reticularisDermatomyositis\n==== Body\nIntroduction\nDermatomyositis (DM) is a systemic autoimmune disease typically characterized by chronic inflammation of muscle and skin. However, 5–46% of patients with DM can also develop interstitial lung disease (ILD) [1]. Diagnosis is based on clinical manifestations of characteristic cutaneous eruption (heliotrope sign, Gottron's papules, and Gottron's sign) with or without proximal muscle weakness and supportive laboratory findings including electromyographic or histopathological muscle findings, and those regarding muscle enzymes or myositis-specific antibodies (MSAs). Although the estimated rates of MSA positivity in DM range from just 20 to 50%, MSA tests have increasingly been used to help diagnose DM, predict prognosis, and guide treatment [2]. However, the presence of MSAs usually correlates with that of distinct clinical features. We report a case of classical DM presenting with rapidly progressive ILD (RP-ILD) and unusual cutaneous features (ulcerations on Gottron's papules and the palmar surfaces of the interphalangeal joints and livedo reticularis on the palmar surfaces of the index fingers) associated with anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibody.\n\nCase Report\nA 25-year-old healthy Thai man presented with progressive dyspnea for 1 month. Four months earlier, the patient had developed generalized myalgia without clinical weakness that was predominant on both thighs (pain score 7/10) and a low-grade fever. Two months later, the fever persisted and he complained of difficulty climbing stairs. He had occasional knee pain on both sides and weight loss from 65 to 60 kg in 3 months. One month later, he developed rapidly progressive dyspnea and noticed a new-onset periorbital rash, which brought him to the hospital.\n\nVital signs on admission were temperature of 36.7°C, blood pressure of 115/75 mm Hg, pulse rate of 119 beats/min, respiratory rate of 30 breaths/min, and severe hypoxemia (SpO2 74% in room air). Physical examination revealed erythematous to violaceous patches on the periorbital areas (heliotrope rash), red to violaceous papules (Gottron's papules) with overlying ulcerations and crusts on the right 3rd metacarpophalangeal joint and 4th proximal interphalangeal joint, ill-defined violaceous erythema (Gottron's sign) on the left 3rd metacarpophalangeal joint, tender erythematous papules, and ulcerations on the palmar surfaces of the distal interphalangeal joints of both hands and medial aspect of the index fingers. Livedo reticularis was also detected on the palmar surfaces of the index fingers of both hands, and erythematous linear plaques (flagellate erythema) were noticed on both inner thighs (Fig. 1). Mechanic's hands were not found. Chest auscultation was notable for bilateral basal lung crepitation. He had bilateral proximal muscle weakness grade IV/V at both the upper and lower extremities. No signs of arthritis were detected. Other findings were unremarkable.\n\nLaboratory investigations showed mild anemia (Hb 9.1 g/dL), a white blood cell count of 10,370/µL (neutrophils 85%, lymphocytes 8%, monocytes 4%, eosinophils 3%), a C-reactive protein level of 3.53 mg/dL, and an erythrocyte sedimentation rate of 68 mm/h. Creatine kinase and aspartate aminotransferase were high at 505 mg/dL and 105 IU/L, respectively. Alanine aminotransferase was normal (20 IU/L). The anti-nuclear antibody titer was 1:80 (fine speckle type and cytoplasmic pattern), and anti-Ro-52 was positive. Anti-MDA5 antibody was positive, whereas anti-Jo-1, anti-Mi-2, and anti-SRP antibodies as well as other myositis panels were negative which were detected by Western blot.\n\nAn anteroposterior chest X-ray showed bilateral interstitial infiltration at both lungs. A high-resolution CT scan of the chest revealed multifocal areas of ground glass attenuation and alveolar opacity throughout the lung parenchyma and predominately at the peripheral and peribronchiolar regions (Fig. 2). Electromyographic findings suggested inflammatory myositis. Histopathological findings from the right 3rd knuckle revealed interface changes with sparse inflammatory cell infiltrate (Fig. 2).\n\nThe patient was diagnosed with RP-ILD with anti-MDA5 antibody-positive classical DM. He was initially treated with intravenous hydrocortisone (300 mg/day) and 125 g of intravenous immunoglobulin (0.4 g/kg/day) divided over 5 days due to impending respiratory failure. However, his condition deteriorated. He developed new-onset fever on the 7th day after admission and a chest X-ray showed progressive alveolar infiltration. Meropenem was administered intravenously at a dose of 1 g every 8 h. Bronchoalveolar lavage was performed and bronchoalveolar lavage fluid cultures were negative for microorganisms. Pathological transbronchial biopsy results revealed benign bronchial epithelium with fibrinous material and no malignancy. Dexamethasone was administered intravenously at a dosage of 20 mg per day in addition to the patient's existing treatment regimen. However, his status progressed towards respiratory failure, and he required ventilator support. He died due to respiratory failure on day 22.\n\nDiscussion\nILD is the most common systemic manifestation in DM and is commonly associated with high mortality rates. It can develop in various myositis subtypes, but is most highly associated with antisynthetase syndrome and anti-MDA5 antibody-positive DM. Antisynthetase syndrome is characterized by the presence of antisynthetase antibodies that are directed against aminoacyl-tRNA synthetase enzymes (ARS antibodies) and a group of symptoms that include ILD, myositis, polyarthritis, fever, Raynaud phenomenon, and mechanic's hands [3]. Among the eight specific anti-ARS antibodies (anti-Jo-1, anti-PL7, anti-PL12, anti-EJ, anti-OJ, anti-KS, anti-Zo, and anti-Ha/YRS) that share some clinical features, anti-Jo-1 is the one most commonly associated with ILD and mechanic's hands [4] and is also highly associated with myositis [5]. However, other anti-ARS antibodies are also associated with ILD. The clinical presentation of ILD in patients with anti-synthetase syndrome can range from no symptoms to acute respiratory failure, requiring a combination of corticosteroids and immunosuppressive agents [6]. However, anti-synthetase syndrome-associated ILD responds better to therapy and has a higher survival rate than anti-MDA5-associated ILD [7].\n\nAnti-MDA5 antibody-positive DM is a unique DM subtype characterized by distinct cutaneous and systemic manifestations, of which ILD is the most common systemic complication. Anti-MDA5 antibody is associated with an increased the risk of developing fatal acute-onset ILD and RP-ILD, especially in Asian populations, and is highly associated with clinically amyopathic DM [2, 8]. However, anti-MDA5 antibody is also present in classical DM patients [9]. A previous study reported that 79% of anti-MDA5 antibody-positive DM patients developed RP-ILD, 50% of whom died from respiratory failure, and that 82% of anti-MDA5 antibody-positive DM patients were diagnosed with clinically amyopathic DM [10]. Apart from typical cutaneous manifestations, the most common cutaneous signs of anti-MDA5 antibody-positive DM are cutaneous ulceration and painful palmar papules, with an estimated prevalence of 40–82% and 20–60%, respectively [9]. Cutaneous ulceration commonly occurs on Gottron's papules, the elbows and knees, and in periungual areas [2, 9, 11]. Recent studies have shown that presence of anti-MDA5 antibodies and cutaneous ulceration are strong risk factors for RP-ILD [12, 13]. Palmar papules are usually painful and commonly occur on the metacarpophalangeal and interphalangeal joint creases of the palms [9]. These findings are thought to be due to vasculopathy [14, 15]. Other findings that have been reported in anti-MDA5 antibody-positive DM patients are nonscarring alopecia, panniculitis, mechanic's hand, and oral ulcers [2, 9].\n\nOur patient presented with clinical rapidly progressive dyspnea within 1 month with clinical signs of impending respiratory failure and severe hypoxemia, which is compatible with RP-ILD. This was confirmed by high-resolution CT of the chest. The patient also had proximal muscle weakness with elevated muscle enzymes and typical cutaneous manifestations that were compatible with classical DM. The differential diagnosis included anti-MDA5 antibody-positive DM and antisynthetase syndrome. In addition to the typical cutaneous features of DM, our patient also had cutaneous ulcerations and livedo reticularis on the index fingers, with absence of mechanic's hand and Raynaud phenomenon. These findings led to an initial diagnosis of anti-MDA5 antibody-positive DM, which was later confirmed by a blood test that was positive for anti-MDA5 antibody. Other systemic symptoms that have been reported in anti-MDA5 antibody-positive DM patients, such as arthralgia and fever, were also present in our patient. We performed a skin biopsy at the right 3rd knuckle near the ulceration to identify its pathology, but the histopathological results showed only interface changes and sparse inflammatory cell infiltrate without vascular or perivascular abnormality.\n\nRP-ILD accompanied by anti-MDA5 antibodies is an aggressive form of DM that has a poor prognosis, especially in the presence of high anti-MDA5 autoantibody titers. Treatment of this condition is challenging and there is no standard regimen. Typically, RP-ILD requires initial high-dose glucocorticoid combined with other immunosuppressive agents such as cyclophosphamide, rituximab, and calcineurin inhibitors (including cyclosporin A and tacrolimus) [16, 17]. A recent multicenter prospective study demonstrated that a combination of immunosuppressive drugs, consisting of high-dose glucocorticoid, tacrolimus, and intravenous cyclophosphamide, was significantly more effective in patients with anti-MDA5-positive DM with ILD than step-up treatment (high-dose glucocorticoid and stepwise addition of immunosuppressive drugs) [18]. Although our patient received a combination of high-dose intravenous corticosteroids and immunoglobulin, his condition worsened, and he passed away due to respiratory failure.\n\nIn conclusion, we describe the case of a patient with anti-MDA5 antibody-positive classical DM who developed RP-ILD and had cutaneous ulceration and livedo reticularis on both hands. The cutaneous ulceration and livedo reticularis were crucial clues that prompted clinicians to test for anti-MDA5 antibody and initiate early aggressive treatment for RP-ILD associated with classical DM.\n\nStatement of Ethics\nThis case report was reviewed and approved by the Ethics Committee in Human Research, Khon Kaen University, Thailand (HE 621535). The patient's parents gave their written informed consent for publication of the case, including images. The authors have no ethical conflicts to disclose.\n\nDisclosure Statement\nThe authors declare no conflicts of interest.\n\nFunding Sources\nNone.\n\nAuthor Contributions\nAll named authors meet the International Committee of Medical Journal Editors criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and gave their approval for this version to be published.\n\nAcknowledgements\nThe authors would like to thank Dr. Dylan Southard for assistance with the English language presentation of the manuscript under Research Affairs, Faculty of Medicine, Khon Kaen University.\n\nFig. 1 a Heliotrope rash on the periorbital areas. b, c Painful, erythematous papules and ulcerations on the palmar surfaces of the distal interphalangeal joints of both hands and medial aspects of the index fingers. Livedo reticularis was also noticed on the index fingers of both hands (arrows). d Flagellate erythema on both inner thighs. e Gottron's sign on the left 3rd metacarpophalangeal joint. f Gottron's papules with central ulcerations and crusts on the right 3rd metacarpophalangeal joint and 4th proximal interphalangeal joint.\n\nFig. 2 a High-resolution CT of the chest showed multifocal areas of ground-glass attenuation. b A skin biopsy specimen from the right 3rd knuckle showed focal interface changes with sparse inflammatory cell infiltrate (hematoxylin and eosin staining, original magnification ×100).\n==== Refs\nReferences\n1 Fathi M Lundberg IE Interstitial lung disease in polymyositis and dermatomyositis Curr Opin Rheumatol 2005 11 17 (6) 701 6 16224246 \n2 DeWane ME Waldman R Lu J Dermatomyositis Part I: Clinical Features and Pathogenesis J Am Acad Dermatol 2020 2 82 (2) 267 81 31279808 \n3 Connors GR Christopher-Stine L Oddis CV Danoff SK Interstitial lung disease associated with the idiopathic inflammatory myopathies: what progress has been made in the past 35 years? Chest 2010 12 138 (6) 1464 74 21138882 \n4 Srivastava P Dwivedi S Misra R Myositis-specific and myositis-associated autoantibodies in Indian patients with inflammatory myositis Rheumatol Int 2016 7 36 (7) 935 43 27193471 \n5 Hamaguchi Y Fujimoto M Matsushita T Kaji K Komura K Hasegawa M Common and distinct clinical features in adult patients with anti-aminoacyl-tRNA synthetase antibodies: heterogeneity within the syndrome PLoS One 2013 8 (4) e60442 23573256 \n6 Maturu VN Lakshman A Bal A Dhir V Sharma A Garg M Antisynthetase syndrome: an under-recognized cause of interstitial lung disease Lung India 2016 Jan-Feb 33 (1) 20 6 26933302 \n7 Isoda K Kotani T Takeuchi T Kiboshi T Hata K Ishida T Comparison of long-term prognosis and relapse of dermatomyositis complicated with interstitial pneumonia according to autoantibodies: anti-aminoacyl tRNA synthetase antibodies versus anti-melanoma differentiation-associated gene 5 antibody Rheumatol Int 2017 8 37 (8) 1335 40 28451794 \n8 Fujimoto M Watanabe R Ishitsuka Y Okiyama N Recent advances in dermatomyositis-specific autoantibodies Curr Opin Rheumatol 2016 11 28 (6) 636 44 27533321 \n9 Kurtzman DJ Vleugels RA Anti-melanoma differentiation-associated gene 5 (MDA5) dermatomyositis: A concise review with an emphasis on distinctive clinical features J Am Acad Dermatol 2018 4 78 (4) 776 85 29229575 \n10 Koga T Fujikawa K Horai Y Okada A Kawashiri SY Iwamoto N The diagnostic utility of anti-melanoma differentiation-associated gene 5 antibody testing for predicting the prognosis of Japanese patients with DM Rheumatology (Oxford) 2012 7 51 (7) 1278 84 22378718 \n11 Wolstencroft PW Fiorentino DF Dermatomyositis Clinical and Pathological Phenotypes Associated with Myositis-Specific Autoantibodies Curr Rheumatol Rep 2018 4 20 (5) 28 29637414 \n12 Xu Y Yang CS Li YJ Liu XD Wang JN Zhao Q Predictive factors of rapidly progressive-interstitial lung disease in patients with clinically amyopathic dermatomyositis Clin Rheumatol 2016 1 35 (1) 113 6 26660480 \n13 Narang NS Casciola-Rosen L Li S Chung L Fiorentino DF Cutaneous ulceration in dermatomyositis: association with anti-melanoma differentiation-associated gene 5 antibodies and interstitial lung disease Arthritis Care Res (Hoboken) 2015 5 67 (5) 667 72 25331610 \n14 Fiorentino D Chung L Zwerner J Rosen A Casciola-Rosen L The mucocutaneous and systemic phenotype of dermatomyositis patients with antibodies to MDA5 (CADM-140): a retrospective study J Am Acad Dermatol 2011 7 65 (1) 25 34 21531040 \n15 Okiyama N Yamaguchi Y Kodera M Hamaguchi Y Yokozeki H Ishiguro N Distinct Histopathologic Patterns of Finger Eruptions in Dermatomyositis Based on Myositis-Specific Autoantibody Profiles JAMA Dermatol 2019 7 155 (9) 1080 \n16 Morisset J Johnson C Rich E Collard HR Lee JS Management of Myositis-Related Interstitial Lung Disease Chest 2016 11 150 (5) 1118 28 27102182 \n17 Long K Danoff SK Interstitial Lung Disease in Polymyositis and Dermatomyositis Clin Chest Med 2019 9 40 (3) 561 72 31376891 \n18 Tsuji H Nakashima R Hosono Y Imura Y Yagita M Yoshifuji H Multicenter Prospective Study of the Efficacy and Safety of Combined Immunosuppressive Therapy With High-Dose Glucocorticoid, Tacrolimus, and Cyclophosphamide in Interstitial Lung Diseases Accompanied by Anti-Melanoma Differentiation-Associated Gene 5-Positive Dermatomyositis Arthritis Rheumatol 2020 3 72 (3) 488 98 31524333\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6567",
"issue": "12(1)",
"journal": "Case reports in dermatology",
"keywords": "Cutaneous ulceration; Dermatomyositis; Livedo reticularis",
"medline_ta": "Case Rep Dermatol",
"mesh_terms": null,
"nlm_unique_id": "101517685",
"other_id": null,
"pages": "57-63",
"pmc": null,
"pmid": "32308577",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "21531040;31290941;27533321;27102182;26660480;29229575;22378718;28451794;27193471;29637414;31279808;31376891;16224246;25331610;31524333;26933302;23573256;21138882",
"title": "Acral Cutaneous Ulcerations and Livedo Reticularis with Rapidly Progressive Interstitial Lung Disease in Anti-MDA5 Antibody-Positive Classical Dermatomyositis.",
"title_normalized": "acral cutaneous ulcerations and livedo reticularis with rapidly progressive interstitial lung disease in anti mda5 antibody positive classical dermatomyositis"
} | [
{
"companynumb": "TH-PFIZER INC-2020250521",
"fulfillexpeditecriteria": "1",
"occurcountry": "TH",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MEROPENEM"
},
"drugadditional": "3",
... |
{
"abstract": "Recently, an expandable cage equipped with rectangular footplates has been used for anterior vertebral replacement in osteoporotic vertebral fracture (OVF). However, the postoperative changes in global alignment have not been elucidated. The purpose of this study was to evaluate local and global spinal alignment after anterior and posterior spinal fixation (APSF) using an expandable cage in elderly OVF patients. This retrospective multicenter review assessed 54 consecutive patients who underwent APSF for OVF. Clinical outcomes were compared between postoperative sagittal vertical axis (SVA) > 95 mm and ≤95 mm groups to investigate the impact of malalignment. SVA improved by only 18.7 mm (from 111.8 mm to 93.1 mm). VAS score of back pain at final follow-up was significantly higher in patients with SVA > 95 mm than SVA ≤ 95 mm (42.4 vs. 22.6, p = 0.007). Adjacent vertebral fracture after surgery was significantly more frequent in the SVA > 95 mm (37% vs. 11%, p = 0.038). Multiple logistic regression showed significantly increased OR for developing adjacent vertebral fracture (OR = 4.76, 95% CI 1.10-20.58). APSF using the newly developed cage improves local kyphotic angle but not SVA. The main cause for the spinal malalignment after surgery was postoperative development of adjacent vertebral fractures.",
"affiliations": "Department of Orthopaedic Surgery, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.;Department of Orthopaedic Surgery, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.;Department of Orthopaedic Surgery, Osaka General Hospital of West Japan Railway Company, Osaka 545-0053, Japan.;Department of Orthopaedic Surgery, Osaka General Hospital of West Japan Railway Company, Osaka 545-0053, Japan.;Department of Orthopaedic Surgery, Ishikiri Seiki Hospital, Osaka 579-8026, Japan.;Department of Orthopaedic Surgery, Ishikiri Seiki Hospital, Osaka 579-8026, Japan.;Department of Orthopaedic Surgery, Osaka City General Hospital, Osaka 534-0021, Japan.;Department of Orthopaedic Surgery, Osaka City General Hospital, Osaka 534-0021, Japan.;Department of Orthopaedic Surgery, Osaka City General Hospital, Osaka 534-0021, Japan.;Department of Orthopaedic Surgery, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.;Department of Orthopaedic Surgery, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.;Department of Orthopaedic Surgery, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.;Department of Orthopaedic Surgery, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.;Department of Orthopaedic Surgery, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.",
"authors": "Terai|Hidetomi|H|;Takahashi|Shinji|S|0000-0002-6906-5406;Yasuda|Hiroyuki|H|;Konishi|Sadahiko|S|;Maeno|Takafumi|T|;Kono|Hiroshi|H|;Matsumura|Akira|A|;Namikawa|Takashi|T|;Kato|Minori|M|;Hoshino|Masatoshi|M|;Tamai|Koji|K|0000-0003-1467-2599;Toyoda|Hiromitsu|H|0000-0002-3126-0046;Suzuki|Akinobu|A|0000-0003-4800-9226;Nakamura|Hiroaki|H|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/jcm10174012",
"fulltext": "\n==== Front\nJ Clin Med\nJ Clin Med\njcm\nJournal of Clinical Medicine\n2077-0383\nMDPI\n\n10.3390/jcm10174012\njcm-10-04012\nArticle\nDirect Lateral Corpectomy and Reconstruction Using an Expandable Cage Improves Local Kyphosis but Not Global Sagittal Alignment\nTerai Hidetomi 1\nhttps://orcid.org/0000-0002-6906-5406\nTakahashi Shinji 1*†\nYasuda Hiroyuki 2\nKonishi Sadahiko 2\nMaeno Takafumi 3\nKono Hiroshi 3\nMatsumura Akira 4\nNamikawa Takashi 4\nKato Minori 4\nHoshino Masatoshi 1\nhttps://orcid.org/0000-0003-1467-2599\nTamai Koji 1\nhttps://orcid.org/0000-0002-3126-0046\nToyoda Hiromitsu 1\nhttps://orcid.org/0000-0003-4800-9226\nSuzuki Akinobu 1\nNakamura Hiroaki 1\nCarulli Christian Academic Editor\n1 Department of Orthopaedic Surgery, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan; hterai@med.osaka-cu.ac.jp (H.T.); hoshino717@gmail.com (M.H.); koji.tamai.707@gmail.com (K.T.); h-toyoda@msic.med.osaka-cu.ac.jp (H.T.); a-suzuki@msic.med.osaka-cu.ac.jp (A.S.); hnakamura@med.osaka-cu.ac.jp (H.N.)\n2 Department of Orthopaedic Surgery, Osaka General Hospital of West Japan Railway Company, Osaka 545-0053, Japan; hiroyuki19780728@yahoo.co.jp (H.Y.); m1378921@med.osaka-cu.ac.jp (S.K.)\n3 Department of Orthopaedic Surgery, Ishikiri Seiki Hospital, Osaka 579-8026, Japan; dzm02716@nifty.ne.jp (T.M.); hiroshikishikiri@gmail.com (H.K.)\n4 Department of Orthopaedic Surgery, Osaka City General Hospital, Osaka 534-0021, Japan; amatsumura@med.osaka-cu.ac.jp (A.M.); namikawa@msic.med.osaka-cu.ac.jp (T.N.); minori202048@gmail.com (M.K.)\n* Correspondence: shinji@med.osaka-cu.ac.jp; Tel.: +81-06-6645-3851\n† Current Address: 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.\n\n05 9 2021\n9 2021\n10 17 401205 7 2021\n03 9 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nRecently, an expandable cage equipped with rectangular footplates has been used for anterior vertebral replacement in osteoporotic vertebral fracture (OVF). However, the postoperative changes in global alignment have not been elucidated. The purpose of this study was to evaluate local and global spinal alignment after anterior and posterior spinal fixation (APSF) using an expandable cage in elderly OVF patients. This retrospective multicenter review assessed 54 consecutive patients who underwent APSF for OVF. Clinical outcomes were compared between postoperative sagittal vertical axis (SVA) > 95 mm and ≤95 mm groups to investigate the impact of malalignment. SVA improved by only 18.7 mm (from 111.8 mm to 93.1 mm). VAS score of back pain at final follow-up was significantly higher in patients with SVA > 95 mm than SVA ≤ 95 mm (42.4 vs. 22.6, p = 0.007). Adjacent vertebral fracture after surgery was significantly more frequent in the SVA > 95 mm (37% vs. 11%, p = 0.038). Multiple logistic regression showed significantly increased OR for developing adjacent vertebral fracture (OR = 4.76, 95% CI 1.10–20.58). APSF using the newly developed cage improves local kyphotic angle but not SVA. The main cause for the spinal malalignment after surgery was postoperative development of adjacent vertebral fractures.\n\ndirect lateral corpectomy\nexpandable cage\nglobal alignment\nlocal kyphosis\nosteoporosis vertebral fracture\n==== Body\npmc1. Introduction\n\nMaintenance of global sagittal balance in the standing position is important for minimizing energy expenditure and load on the musculoskeletal system [1]. Many mechanisms work together to maintain balance in the normal spine and extremities, including some compensatory mechanisms. However, once the compensatory mechanisms break down, there is severe deterioration in the patient’s condition, pain, and reduction of quality of life (QOL) [2]. Other reports have shown that osteoporotic vertebral fracture (OVF) is strongly related to sagittal spinal imbalance in aged patients [3,4,5]. Several reports suggest that reduced muscle volume (i.e., sarcopenia) is one of the major causes of sagittal imbalance, causing reduction in the QOL of OVF patients [6,7,8]. Sarcopenia and osteoporosis show a high prevalence in old age and incur a high risk for falls, fractures, and further functional decline [9]. The term osteosarcopenia has been proposed to describe individuals suffering from both diseases [10]. With the aging of society and the associated increase in the amount of osteosarcopenia [11], the number of patients presenting with problems associated with an imbalanced sagittal spine is also likely to increase in the near future.\n\nOVF mainly occurs at the thoracolumbar junction and negatively affects spinal alignment and QOL [5]. There are many surgical methods for the treatment of OVF, such as vertebroplasty (VP), balloon kyphoplasty (BKP), anterior vertebral replacement and posterior spinal fixation (APSF), and posterior osteotomy (PO) including posterior vertebral column resection (pVCR) [12,13]. The choice of surgical method is based on the goal of surgery, the patients’ symptoms, the degree of deformity, the global spinal alignment, and the flexibility. However, few reports have described the correlation between local kyphotic changes and changes in global alignment after OVF surgery.\n\nRecently, a newly developed expandable cage equipped with rectangular footplates has overcome the subsidence that is thought to be a disadvantage of anterior surgery for OVF. In addition, recent advances in the lateral approach enable minimally invasive anterior spinal reconstruction of thoracolumbar and lumbar lesions in elderly patients. Taiji et al. in a cohort of 16 OVF patients treated with the wide-foot-plate expandable cage reported a 30% correction loss (local kyphotic angle 22.6° before surgery, −1.5° immediately after surgery, and 7.0° at the final observation) [14]. However, there have been no reports about the changes in global alignment after anterior surgery for OVF. Our major clinical question in this study was whether sagittal imbalance following OVF could be improved by the anterior surgery or not. Therefore, the aim of this study was to report the correlation between local kyphotic changes and global spinal alignment after APSF in elderly OVF patients and to investigate the impact of global malalignment.\n\n2. Materials and Methods\n\nThis multicenter retrospective cohort study was conducted at four institutions. Consecutive patients who underwent APSF for intra- or intervertebral instability after OVF were reviewed retrospectively.\n\nThe following were required of all patients eligible for participation in this retrospective study. (1) Osteoporotic vertebral fracture; (2) Intra- or intervertebral instability; (3) Neurologic deficit or severe back pain; and (4) Improvement of these symptoms in the supine position. Finally, the patients who were followed-up for at least 1 year were analyzed. Among them, patients with data of global spinal alignment before surgery and at final follow-up were included in the analysis. This study was approved by the institutional review board of our institution (approval no. 3170). The need to obtain informed consent was waived based on the retrospective design and anonymization of patient identifiers.\n\nPatients’ clinical records were reviewed for demographic data, instability type, operation time (min), estimated blood loss (mL), performance status (PS, Common Toxicity Criteria, version 2.0), comorbidities, and perioperative complications. Bone mineral density (BMD) at the femoral neck was determined using dual-energy x-ray absorptiometry. Information on previous surgeries at the corpectomy site was obtained and divided into lumbar decompression, VP/BKP, and posterior instrumentation. The severity of pain was subjectively assessed by the patients on a visual analogue scale (VAS), which was based on the average level of back pain that the patient felt over the previous week. The VAS was measured before surgery and at final follow-up. The rate of minimal clinically important differences (MCID) was evaluated. MCID score for lumbar fusion surgery [15] was used (≥21 mm) because there have been no reports about MCID for OVF treatment. The fracture level was divided into thoracolumbar (T11–L2) and lumbar (L3–L5) regions.\n\nRadiographic evaluation was performed via whole spine x-ray on all patients before surgery and at final follow-up and included analysis of sagittal alignment (sagittal vertical axis: SVA; pelvic incidence: PI; lumbar lordosis: LL; sacral slope: SS; pelvic tilt: PT; thoracic kyphosis: TK; T1 pelvic angle: TPA) and incidence of cage subsidence. Local kyphotic angle was defined as the angle between the inferior endplate of the vertebra above and the superior endplate of the vertebra below the fractured vertebra and was given a negative value in patients with kyphotic deformity. Intravertebral instability was defined as angular motion of the fractured vertebral body with intravertebral cleft between flexed and extended positions. Intervertebral instability was defined as a change in disc height of >2 mm with deformation of the vertebral body between flexed and extended positions.\n\n2.1. Surgical Indications and Techniques\n\nThe patient was placed in a lateral position and a true lateral film was obtained with fluoroscopy. The affected vertebral body and the upper and lower discs were exposed per transthoracic retropleural or retroperitoneal approaches. After removal of discs above and below the affected vertebral body and the ligation or coagulation of segmental vessels, corpectomy was performed using a large osteotome. The cartilaginous endplate was carefully removed by a disc knife and ring curettage to prevent inadvertent endplate violation. The vertebral segment was reconstructed with an expandable titanium cage comprising rectangular footplates (X-Core2®; NuVasive, San Diego, CA, USA). Bone grafting was performed inside and outside of the cage using artificial tricalcium phosphate particles, resected vertebral body, and resected rib fragments. After position change, posterior percutaneous pedicle screw fixation (PPS) fixation was performed without decompression. The range of posterior fixation was unregulated and depended on the surgeon’s preference.\n\n2.2. Statistical Analysis\n\nClinical outcomes were compared between postoperative SVA > 95 mm and ≤95 mm groups to investigate the impact of malalignment in patients who underwent this surgery [16]. In addition, baseline data, radiological parameters before surgery, and surgical complications were compared between SVA > 95 mm and ≤95 mm groups to investigate the factors related to SVA > 95 mm. Multiple logistic regression analysis was used to calculate odds ratios of variables for SVA > 95 mm. The model included age and variables with p-values < 0.10 in univariate analysis. The data on medication for osteoporosis including teriparatide, romosozumab, bisphosphonate, denosumab, and vitamin D within a month before index surgery were collected. We divided them into two groups in the analysis: bone-forming agents (teriparatide, romosozumab) and others.\n\nShapiro–Wilk tests were used to check normality assumptions for all parameters. The normality was confirmed in all continuous variables except for the VAS of back pain. The t-test (normality) or Mann–Whitney U test (non-normality) was used to compare continuous variables. The χ2 test or Fisher’s exact test was used for categorical variables. To establish whether significant differences existed in postoperative clinical or radiologic outcomes between the two group, a restricted maximum likelihood, mixed-model regression was used. Statistical test results were considered significant for values of p < 0.05. All p-values were two-sided. All analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA).\n\n3. Results\n\nA total of 72 patients were enrolled in this study. Two patients were lost to follow-up and one patient died two months after surgery due to pneumonitis. Fifteen patients were excluded due to insufficient radiological data. Finally, 54 patients were included in the analysis. Patients with a mean age of 76.3 years ± standard deviation 6.1 were followed-up for 25.3 months ± 12.6. Twelve patients (22%) had a history of thoracic or lumbar surgery. Regarding medication for osteoporosis, 32 patients (59%) were treated by teriparatide, 3 patients (6%) by romosozumab, 8 patients (15%) by bisphosphonate, 4 patients (7%) by denosumab, and 7 patients (13%) by only vitamin D. Mean operative time and estimated blood loss was 269.8 ± 79.8 min and 289.5 ± 289.5 mL, respectively. Regarding fixation range, 32 patients (59%) were one above and one below fixation. Adjacent vertebral fractures were observed in 11 patients (20%) after surgery.\n\nTable 1 shows the radiological parameters before and after surgery. Local kyphosis, thoracic kyphosis, lumbar lordosis, SVA, TPA and PI-LL significantly improved at final follow-up compared with before surgery, although there was no improvement in PT and SS. Local kyphosis improved from −17.5 degrees to 4.1 degrees immediately after surgery but was −0.6 degrees at final follow-up with 22.4% of correction loss. SVA was improved by only 18.7 mm (from 111.8 mm to 93.1 mm).\n\nNineteen of the 54 patients (35%) showed global malalignment (SVA > 95 mm) postoperatively. Table 2 shows a comparison of baseline data, radiological parameters before surgery, and surgical complications between SVA > 95 mm and ≤95 mm groups. Adjacent vertebral fracture after surgery was significantly more frequent in the SVA > 95 mm group than in the SVA ≤ 95 mm group (37% vs. 11%, p = 0.038). TPA before surgery tended to be higher in the SVA > 95 mm group. Table 3 shows a comparison of clinical outcomes between SVA > 95 mm and ≤95 mm groups. VAS of back pain at final follow-up was significantly higher in patients with SVA > 95 mm than those in whom SVA was ≤95 mm (42.4 vs. 22.6, p = 0.015). Regarding the MCID, the better improvement was also observed in patients with SVA ≤ 95 mm (83% vs. 58%, p = 0.046). Multiple logistic regression showed a significantly increased odds ratio (OR) of adjacent vertebral fracture presence and TPA increase (OR = 4.76, 95% CI 1.10–20.58 and OR = 1.07, 1.00–1.14, respectively) (Table 4).\n\n4. Discussion\n\nThis is the first study to reveal details about changes in sagittal balance following the minimally invasive procedure of corpectomy and reconstruction using an expandable cage with rectangular foot plates (APSF). Although there was 22.4% correction loss, local kyphotic changes using this system was 21.7°, which was better than the previous reports for APSF [17,18,19]. As well, Kanayama et al. reported that 80% of patients with OVF could be successfully treated using Kaneda instrumentation without the need for posterior reinforcement [20]. However, nearly 40% of correction loss was observed at the final follow-up. Suk et al. compared anterior-posterior surgery versus closing wedge osteotomy for kyphotic OVF and reported that the correction loss of anterior-posterior surgery was 27.3% with a mean blood loss of 2892 mL, whereas that of posterior closing wedge osteotomy was 10.8% with a mean blood loss of 1930 mL [21]. Posterior closing wedge osteotomy might offer better kyphosis correction. However, the procedure is technically demanding with more blood loss compared with the system in this study.\n\nAlthough it is reported that anatomical and biomechanical restoration of vertebra is an advantage of anterior surgery resulting from the placement of anterior struts, our results indicated that restoration of sagittal alignment was not achieved by anterior surgery with 1–2 level posterior fixation in OVF patients. The parameters of SVA and TPA were used to evaluate sagittal spinal balance in this study. SVA increases with aging, and it is affected by movement of the hip and knee joint, such as “sway back” TPA, which combines information of SVA and PT and is a reliable indicator to address sagittal balance, including pelvic inclination [22]. TPA in this series was 33.2° preoperatively and 30.1° postoperatively. Thus, the improvement in TPA might not be significant. Ryan et al. demonstrated that TPA > 20° was the severe deformity threshold [23]. The main reason for this observation in our study was postoperative development of adjacent vertebral fracture. Low BMD, older age, an upper instrumented vertebra (UIV) level at the thoracolumbar spine, and a high preoperative SVA have been reported as risk factors for proximal junctional failure following surgical treatment for adult spinal deformity [24]. In the current series, BMD, medicine for osteoporosis, and level of surgery was not different between SVA > 95 mm and SVA ≤ 95 mm groups, probably because all the patients had comparatively severe osteoporosis. Posterior tethers and vertebral augmentation might be effective in preventing the failure of instrumentation, especially in patients with a high risk for proximal junctional kyphosis [25].\n\nThe relationship between PI and LL (PI-LL) is also considered an important parameter to evaluate sagittal spinal balance. Schwab et al. reported that SVA of 47 mm or more, PI-LL > 11° or more, and PT < 22° predicted severe disability (ODI > 40) [26]. Yamato et al. [31] described that the ideal LL angle can be determined using the equation ‘LL = 0.45 × PI + 31.8’. Inami et al. [27] reported that the optimum value of PI-LL is inconsistent, in that it depends on the individual PI. [28]. In this study, although PI-LL improved significantly (from 35.1° to 24.2°), the final PI-LL did not reach the ideal value. In addition, the preoperative decrease in SS did not change postoperatively, indicating absence of improvement of pelvic retroversion. If lumbar lordosis is restored by surgery, the retroverted sacrum must be improved to maintain spino-pelvic harmony. Otherwise, reciprocal changes in the thoracic spine might develop to maintain sagittal balance [29,30]. Our results showed an increase in TK from 26.8°to 32.8°, which concurred with the theory mentioned above. This reciprocal change might be one of the reasons SVA did not change significantly in the OVF patients in our study. Improvement of the retroverted sacrum requires extension of the hip joint, with the erector spinae and gluteus muscles playing an important role in this action. In aged OVF patients, weakness of these muscles is responsible for the pelvic retroversion [8,31]. The average age of patients in this study was 76.3 years; hence, although we did not measure muscle volumes in these patients, they might have had age-related muscle wasting and weakness. A retroverted pelvis can be managed surgically by osteotomy of the lower lumbar vertebra or long fixation involving the pelvis. However, these are extremely invasive surgeries and it is not clear whether such invasive correction surgery is necessary for aged OVF patients.\n\nSVA changed from 111.8 mm to 93.1 mm, which, although a statistically significant change, might be an insufficient improvement to correct malalignment. Based on the classification of Scoliosis Research Society [16], SVA (>95 mm) was reported as a risk factor with the deterioration of QOL measures [32]. In the current study, the number of patients who acquired one or more level improvement of PS was 15/19 (78.9%) in SVA > 95 mm and 33/35 (94.3%) in SVA ≤ 95 mm groups, which although better in the SVA ≤ 95 mm group, was not significantly different. Postoperative VAS was better in the SVA ≤ 95 mm than the SVA > 95 mm group. As also reported by Hu et al. [5]. SVA correlated with back pain in this study, which significantly improved after surgery. However, age and preoperative comorbidities influence the complication rate in deformity surgery [33]. Thus, we thought that the strategy for aged OVF patients should differ from those in ASD patients to relieve pain and improve mobility. Our results also showed the significant improvement of JOA score and VAS even in the SVA > 95 mm group compared with those before surgery. It is not always necessary to restore sagittal imbalance in aged OVF patients to the same level as in young people, although the clinical results are worse in patients with SVA > 95 mm.\n\nThere are some limitations to this study. First, the number of patients was small because some patients were excluded due to lack of data from standing whole spine X-ray films before surgery because of intractable back pain. Second, due to the lack of apparatus, we did not take whole spine X-rays including the lower extremity. Hence, we could not evaluate knee and hip joint flexion, which might have been used to compensate for sagittal imbalance [34]. Despite these limitations, this is the first report describing the correlation between anterior spinal surgery and changes in sagittal alignment, which might contribute to preoperative planning in OVF patients. For further study, the prediction methods for postoperative sagittal balance are necessary, since this might contribute to decision-making in the surgical planning for OVF patients.\n\n5. Conclusions\n\nThis study demonstrated the clinical and radiological outcomes of combined anterior–posterior procedures via a lateral corpectomy, vertebral reconstruction using an expandable cage with rectangular footplates and posterior percutaneous pedicle screw fixation. The procedure, which includes short segment fixation, did not improve global spinal alignment and pelvic retroversion. However, the procedure achieved significant reduction of local kyphosis and VAS of back pain. This indicated that the procedure is effective in elderly patients with severe back pain due to spinal deformity and instability caused by OVF despite the global spinal malalignment.\n\nAuthor Contributions\n\nConceptualization, H.T. (Hidetomi Terai) and H.N.; methodology, H.Y., S.K., T.M. and H.K.; formal analysis, S.T.; data curation, A.M., T.N., M.K., M.H., K.T., H.T. (Hiromitsu Toyoda), and A.S.; writing—original draft preparation, H.T. (Hidetomi Terai); writing—review and editing, H.T. (Hiromitsu Toyoda); supervision, H.N. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nNo funds were received in support of this work.\n\nInstitutional Review Board Statement\n\nThe study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board of Osaka city university (protocol code 3170 and date of approval 30 June 2015).\n\nInformed Consent Statement\n\nThe need to obtain informed consent was waived based on the retrospective design and anonymization of patient identifiers.\n\nConflicts of Interest\n\nA.S. received fee for Speakers Bureaus. The other authors declare that they have no conflicts of interest.\n\njcm-10-04012-t001_Table 1 Table 1 Comparison of local and global alignment pre- and postoperatively.\n\n\tMean (SD)\tp-Value\t\nLocal kyphosis\t\t\t\t\n Preop\t−17.5\t(19.2)\t\t\n Immediate postop\t4.1\t(13.1)\t\t\n Final\t−0.6\t(14.8)\t\t\n Δ (preop-final)\t21.7\t(13.3)\t<0.001\t\n Correction loss (%)\t22.4\t(42.5)\t<0.001\t\nTK\t\t\t\t\n Preop\t26.8\t(17.1)\t\t\n Final\t32.8\t(12.3)\t\t\n Δ (preop-final)\t6.1\t(15.2)\t<0.001\t\nLL\t\t\t\t\n Preop\t14.6\t(16.9)\t\t\n Final\t25.5\t(13.8)\t\t\n Δ (preop-final)\t10.9\t(14.7)\t<0.001\t\nSVA\t\t\t\t\n Preop\t111.8\t(45.6)\t\t\n Final\t93.1\t(46.6)\t\t\n Δ (preop-final)\t18.7\t(56.7)\t0.018\t\nPT\t\t\t\t\n Preop\t28.4\t(7.9)\t\t\n Final\t27\t(8.2)\t\t\n Δ (preop-final)\t1.4\t(8)\t0.209\t\nSS\t\t\t\t\n Preop\t21.5\t9.8\t\t\n Final\t22.8\t10.0\t\t\n Δ (preop-final)\t1.2\t7.4\t0.229\t\nTPA\t\t\t\t\n Preop\t33.2\t(10.4)\t\t\n Final\t30.1\t(9.3)\t\t\n Δ (preop-final)\t3.1\t(9.5)\t0.019\t\nPI-LL\t\t\t\t\n Preop\t35.1\t(17.7)\t\t\n Final\t24.2\t(14.4)\t\t\n Δ (preop-final)\t10.9\t(14.7)\t<0.001\t\nSD, standard deviation; TK, Thoracic kyphosis; LL, Lumbar lordosis; SVA, Sagittal vertical axis; PT, Pelvic tilt; SS, sacral slope; TPA, T1 Pelvic Angle; PI-LL, Pelvic incidence- Lumbar lordosis.\n\njcm-10-04012-t002_Table 2 Table 2 Comparison between SVA > 95 mm and ≤95 mm groups by univariate analysis.\n\n\tSVA > 95 mm (n = 19)\tSVA ≤ 95 mm (n = 35)\tp-Value\t\nMean or N (SD or %)\tMean or N (SD or %)\t\nAge\t76.9\t(5.8)\t76\t(6.2)\t0.577\t\nGender\t13\t(68)\t26\t(74)\t0.646\t\nFollow-up period (months)\t28.9\t(13.4)\t23.3\t(11.8)\t0.121\t\nBMD (T-score)\t−2.4\t(0.5)\t−2.1\t(0.9)\t0.251\t\nMedication for osteoporosis\t\t\t\t\t\t\n Teriparatide/Romosozumab\t13\t(68)\t22\t(63)\t0.683\t\nPrevious surgery\t\t\t\t\t\t\n Lumbar decompression\t1\t(5)\t4\t(11)\t\t\n Vertebral augmentation\t1\t(5)\t1\t(3)\t\t\n Posterior instrumentation\t1\t(5)\t4\t(11)\t0.781\t\nLevel\t\t\t\t\t\t\n Thoracolumbar\t10\t(53)\t17\t(49)\t\t\n Lumbar\t9\t(47)\t18\t(51)\t1.000\t\nProximal fixation range\t\t\t\t\t\t\n 1\t11\t(58)\t21\t(60)\t\t\n >1\t8\t(42)\t14\t(40)\t1.000\t\nDistal fixation range\t\t\t\t\t\t\n 1\t13\t(68)\t24\t(69)\t\t\n >1\t6\t(32)\t11\t(31)\t1.000\t\nAdjacent vertebral fracture\t7\t(37)\t4\t(11)\t0.038\t\nInfection\t1\t(5)\t1\t(3)\t1.000\t\nReoperation\t3\t(16)\t2\t(6)\t0.332\t\nCage subsidence\t9\t(47)\t15\t(43)\t0.750\t\nLocal kyphosis preop\t−21.7\t(15.3)\t−15.3\t(20.8)\t0.248\t\nLocal kyphosis at final FU\t−2.2\t(12)\t0.3\t(16.2)\t0.549\t\nLL preop\t9.8\t(17.8)\t17.2\t(16)\t0.126\t\nPT preop\t30.6\t(7.7)\t27.1\t(7.9)\t0.127\t\nPI preop\t52.1\t(10.7)\t48.4\t(9.5)\t0.190\t\nSVA preop\t122.4\t(45.4)\t106.1\t(45.4)\t0.217\t\nTK preop\t21.5\t(16.6)\t29.6\t(17)\t0.100\t\nTPA preop\t36.9\t(10.6)\t31.2\t(9.9)\t0.052\t\nSD, standard deviation; BMD, Bone marrow density; TK, Thoracic kyphosis; LL, Lumbar lordosis; SVA, Sagittal vertical axis; PT, Pelvic tilt; SS, sacral slope; TPA, T1 Pelvic Angle; PI-LL, Pelvic incidence- Lumbar lordosis.\n\njcm-10-04012-t003_Table 3 Table 3 Comparison of clinical outcomes between SVA > 95 mm and ≤95 mm groups.\n\n\tSVA > 95 mm (n = 19)\tSVA ≤ 95 mm (n = 35)\tp-Value\t\nMean or N (SD or %)\tMean or N (SD or %)\t\nPS improvement (N)\t15\t(79)\t33\t(94)\t0.087\t\nJOA score\t\t\t\t\t\t\n Preop\t10.9\t(5.1)\t9.5\t(4.8)\t0.311\t\n Final\t19.2 *\t(5.4)\t20.5 *\t(4.7)\t0.361\t\n Improvement ratio\t46.1\t(19.8)\t54.8\t(28.7)\t0.248\t\nVAS of back pain\t\t\t\t\t\t\n Preop\t73.7\t(17.8)\t77.3\t(23)\t0.301\t\n Final\t42.4 *\t(28.7)\t22.6 *\t(23)\t0.015\t\n Δ (preop-final)\t31.4\t(23.2)\t54.7\t(30.8)\t0.008\t\n MCID (≥21 mm)\t11\t(58)\t29\t(83)\t0.046\t\nSD, standard deviation; PS, Performance Status; JOA score, The Japanese Orthopaedic Association score; MCID, minimal clinically important difference. * There were significant differences between preop and final scores of JOA score and VAS of back pain.\n\njcm-10-04012-t004_Table 4 Table 4 Adjusted odds ratio for SVA > 95 mm at final follow-up.\n\n\tAdjusted OR *\t95% CI\t\tp-Value\t\nTPA preop (per 1 degree)\t1.07\t1.00\t1.14\t0.047\t\nAdjacent vertebral fracture\t4.76\t1.10\t20.58\t0.037\t\nTPA, T1 Pelvic Angle; OR, odds ratio. * The odds ratio was adjusted for age, preoperative TPA and adjacent vertebral fracture.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Dubousset J. Three-dimensional analysis of the scoliotic deformity The Pediatric Spine: Principles and Practice Weinstein S.L. Raven Press Ltd. New York, NY, USA 1994 479 496\n2. Miyakoshi N. Hongo M. Kobayashi T. Abe T. Abe E. Shimada Y. Improvement of spinal alignment and quality of life after corrective surgery for spinal kyphosis in patients with osteoporosis: A comparative study with non-operated patients Osteoporos. Int. 2015 26 2657 2664 10.1007/s00198-015-3163-5 25963236\n3. Dai J. Yu X. Huang S. Fan L. Zhu G. Sun H. Tang X. Relationship between sagittal spinal alignment and the incidence of vertebral fracture in menopausal women with osteoporosis: A multicenter longitudinal follow-up study Eur. Spine J. 2015 24 737 743 10.1007/s00586-014-3637-8 25374300\n4. Ohnishi T. Iwata A. Kanayama M. Oha F. Hashimoto T. Iwasaki N. Impact of spino-pelvic and global spinal alignment on the risk of osteoporotic vertebral collapse Spine Surg. Relat. Res. 2018 2 72 76 10.22603/ssrr.2017-0046 31440650\n5. Hu Z. Man G.C.W. Kwok A.K.L. Law S.W. Chu W.W.C. Cheung W.H. Qiu Y. Cheng J.C. Global sagittal alignment in elderly patients with osteoporosis and its relationship with severity of vertebral fracture and quality of life Arch. Osteoporos. 2018 13 95 10.1007/s11657-018-0512-y 30194552\n6. Menezes-Reis R. Bonugli G.P. Salmon C.E.G. Mazoroski D. Herrero C. Nogueira-Barbosa M.H. Relationship of spinal alignment with muscular volume and fat infiltration of lumbar trunk muscles PLoS ONE 2018 13 e0200198 10.1371/journal.pone.0200198 29975763\n7. Yagi M. Hosogane N. Watanabe K. Asazuma T. Matsumoto M. The paravertebral muscle and psoas for the maintenance of global spinal alignment in patient with degenerative lumbar scoliosis Spine J. 2016 16 451 458 10.1016/j.spinee.2015.07.001 26165478\n8. Takayama K. Kita T. Nakamura H. Kanematsu F. Yasunami T. Sakanaka H. Yamano Y. New Predictive Index for Lumbar Paraspinal Muscle Degeneration Associated With Aging Spine 2016 41 E84 E90 10.1097/BRS.0000000000001154 26335668\n9. Drey M. Sieber C.C. Bertsch T. Bauer J.M. Schmidmaier R. The FiAT Intervention Group Osteosarcopenia is more than sarcopenia and osteopenia alone Aging Clin. Exp. Res. 2016 28 895 899 10.1007/s40520-015-0494-1 26563287\n10. Hirschfeld H.P. Kinsella R. Duque G. Osteosarcopenia: Where bone, muscle, and fat collide Osteoporos. Int. 2017 28 2781 2790 10.1007/s00198-017-4151-8 28733716\n11. Cooper C. Cole Z.A. Holroyd C.R. Earl S.C. Harvey N.C. Dennison E.M. Melton L.J. Cummings S.R. Kanis J.A. Secular trends in the incidence of hip and other osteoporotic fractures Osteoporos. Int. 2011 22 1277 1288 10.1007/s00198-011-1601-6 21461721\n12. Hosogane N. Nojiri K. Suzuki S. Funao H. Okada E. Isogai N. Ueda S. Hikata T. Shiono Y. Watanabe K. Surgical Treatment of Osteoporotic Vertebral Fracture with Neurological Deficit-A Nationwide Multicenter Study in Japan Spine Surg. Relat. Res. 2019 3 361 367 10.22603/ssrr.2019-0004 31768457\n13. Watanabe K. Katsumi K. Ohashi M. Shibuya Y. Hirano T. Endo N. Kaito T. Yamashita T. Fujiwara H. Nagamoto Y. Surgical outcomes of spinal fusion for osteoporotic vertebral fracture in the thoracolumbar spine: Comprehensive evaluations of 5 typical surgical fusion techniques J. Orthop. Sci. 2019 24 1020 1026 10.1016/j.jos.2019.07.018 31445858\n14. Taiji R. Takami M. Yukawa Y. Hashizume H. Minamide A. Nakagawa Y. Nishi H. Iwasaki H. Tsutsui S. Okada M. A short-segment fusion strategy using a wide-foot-plate expandable cage for vertebral pseudarthrosis after an osteoporotic vertebral fracture J. Neurosurg. Spine 2020 33 862 869 10.3171/2020.5.SPINE2062\n15. Parker S.L. Adogwa O. Paul A.R. Anderson W.N. Aaronson O. Cheng J.S. McGirt M.J. Utility of minimum clinically important difference in assessing pain, disability, and health state after transforaminal lumbar interbody fusion for degenerative lumbar spondylolisthesis J. Neurosurg. Spine 2011 14 598 604 10.3171/2010.12.SPINE10472 21332281\n16. Schwab F. Ungar B. Blondel B. Buchowski J. Coe J. Deinlein D. DeWald C. Mehdian H. Shaffrey C. Tribus C. Scoliosis Research Society-Schwab adult spinal deformity classification: A validation study Spine 2012 37 1077 1082 10.1097/BRS.0b013e31823e15e2 22045006\n17. Kashii M. Yamazaki R. Yamashita T. Okuda S. Fujimori T. Nagamoto Y. Tamura Y. Oda T. Ohwada T. Yoshikawa H. Surgical treatment for osteoporotic vertebral collapse with neurological deficits: Retrospective comparative study of three procedures—Anterior surgery versus posterior spinal shorting osteotomy versus posterior spinal fusion using vertebroplasty Eur. Spine J. 2013 22 1633 1642 10.1007/s00586-013-2759-8 23549907\n18. Takenaka S. Mukai Y. Hosono N. Fuji T. Major surgical treatment of osteoporotic vertebral fractures in the elderly: A comparison of anterior spinal fusion, anterior-posterior combined surgery and posterior closing wedge osteotomy Asian Spine J. 2014 8 322 330 10.4184/asj.2014.8.3.322 24967046\n19. Uchida K. Kobayashi S. Nakajima H. Kokubo Y. Yayama T. Sato R. Timbihurira G. Baba H. Anterior expandable strut cage replacement for osteoporotic thoracolumbar vertebral collapse J. Neurosurg. Spine 2006 4 454 462 10.3171/spi.2006.4.6.454 16776356\n20. Kanayama M. Ishida T. Hashimoto T. Shigenobu K. Togawa D. Oha F. Kaneda K. Role of major spine surgery using Kaneda anterior instrumentation for osteoporotic vertebral collapse J. Spinal Disord. Tech. 2010 23 53 56 10.1097/BSD.0b013e318193e3a5 20065870\n21. Suk S.I. Kim J.H. Lee S.M. Chung E.R. Lee J.H. Anterior-posterior surgery versus posterior closing wedge osteotomy in posttraumatic kyphosis with neurologic compromised osteoporotic fracture Spine 2003 28 2170 2175 10.1097/01.BRS.0000090889.45158.5A 14501932\n22. Qiao J. Zhu F. Xu L. Liu Z. Zhu Z. Qian B. Sun X. Qiu Y. T1 pelvic angle: A new predictor for postoperative sagittal balance and clinical outcomes in adult scoliosis Spine 2014 39 2103 2107 10.1097/BRS.0000000000000635 25271508\n23. Ryan D.J. Protopsaltis T.S. Ames C.P. Hostin R. Klineberg E. Mundis G.M. Obeid I. Kebaish K. Smith J.S. Boachie-Adjei O. T1 pelvic angle (TPA) effectively evaluates sagittal deformity and assesses radiographical surgical outcomes longitudinally Spine 2014 39 1203 1210 10.1097/BRS.0000000000000382 25171068\n24. Yagi M. Fujita N. Okada E. Tsuji O. Nagoshi N. Asazuma T. Ishii K. Nakamura M. Matsumoto M. Watanabe K. Fine-tuning the Predictive Model for Proximal Junctional Failure in Surgically Treated Patients With Adult Spinal Deformity Spine 2018 43 767 773 10.1097/BRS.0000000000002415 28902106\n25. Yagi M. Nakahira Y. Watanabe K. Nakamura M. Matsumoto M. Iwamoto M. The effect of posterior tethers on the biomechanics of proximal junctional kyphosis: The whole human finite element model analysis Sci. Rep. 2020 10 3433 10.1038/s41598-020-59179-w 32103040\n26. Schwab F.J. Blondel B. Bess S. Hostin R. Shaffrey C.I. Smith J.S. Boachie-Adjei O. Burton D.C. Akbarnia B.A. Mundis G.M. Radiographical spinopelvic parameters and disability in the setting of adult spinal deformity: A prospective multicenter analysis Spine 2013 38 E803 E812 10.1097/BRS.0b013e318292b7b9 23722572\n27. Yamato Y. Hasegawa T. Kobayashi S. Yasuda T. Togawa D. Arima H. Oe S. Iida T. Matsumura A. Hosogane N. Calculation of the Target Lumbar Lordosis Angle for Restoring an Optimal Pelvic Tilt in Elderly Patients With Adult Spinal Deformity Spine 2016 41 E211 E217 10.1097/BRS.0000000000001209 26571165\n28. Inami S. Moridaira H. Takeuchi D. Shiba Y. Nohara Y. Taneichi H. Optimum pelvic incidence minus lumbar lordosis value can be determined by individual pelvic incidence Eur. Spine J. 2016 25 3638 3643 10.1007/s00586-016-4563-8 27072550\n29. Klineberg E. Schwab F. Ames C. Hostin R. Bess S. Smith J.S. Gupta M.C. Boachie O. Hart R.A. Akbarnia B.A. Acute reciprocal changes distant from the site of spinal osteotomies affect global postoperative alignment Adv. Orthop. 2011 2011 415946 10.4061/2011/415946 22007318\n30. Ferrero E. Liabaud B. Challier V. Lafage R. Diebo B.G. Vira S. Liu S. Vital J.M. Ilharreborde B. Protopsaltis T.S. Role of pelvic translation and lower-extremity compensation to maintain gravity line position in spinal deformity J. Neurosurg. Spine 2016 24 436 446 10.3171/2015.5.SPINE14989 26565764\n31. Li Q. Sun J. Cui X. Jiang Z. Li T. Analysis of correlation between degeneration of lower lumbar paraspinal muscles and spinopelvic alignment in patients with osteoporotic vertebral compression fracture J. Back Musculoskelet. Rehabil. 2017 30 1209 1214 10.3233/BMR-150506 29154265\n32. Banno T. Togawa D. Arima H. Hasegawa T. Yamato Y. Kobayashi S. Yasuda T. Oe S. Hoshino H. Matsuyama Y. The cohort study for the determination of reference values for spinopelvic parameters (T1 pelvic angle and global tilt) in elderly volunteers Eur. Spine J. 2016 25 3687 3693 10.1007/s00586-016-4411-x 26831540\n33. Yoshida G. Hasegawa T. Yamato Y. Kobayashi S. Oe S. Banno T. Mihara Y. Arima H. Ushirozako H. Yasuda T. Predicting Perioperative Complications in Adult Spinal Deformity Surgery Using a Simple Sliding Scale Spine 2018 43 562 570 10.1097/BRS.0000000000002411 28885286\n34. Bailey J.F. Matthew R.P. Seko S. Curran P. Chu L. Berven S.H. Deviren V. Burch S. Lotz J.C. ISSLS PRIZE IN BIOENGINEERING SCIENCE 2019: Biomechanical changes in dynamic sagittal balance and lower limb compensatory strategies following realignment surgery in adult spinal deformity patients Eur. Spine J. 2019 28 905 913 10.1007/s00586-019-05925-2 30826876\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2077-0383",
"issue": "10(17)",
"journal": "Journal of clinical medicine",
"keywords": "direct lateral corpectomy; expandable cage; global alignment; local kyphosis; osteoporosis vertebral fracture",
"medline_ta": "J Clin Med",
"mesh_terms": null,
"nlm_unique_id": "101606588",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34501460",
"pubdate": "2021-09-05",
"publication_types": "D016428:Journal Article",
"references": "27072550;28902106;25271508;32103040;26565764;22007318;20065870;26165478;31440650;25374300;26571165;30194552;31445858;26335668;29154265;25963236;26563287;28885286;16776356;23722572;25171068;28733716;22045006;26831540;23549907;21461721;30826876;32823261;29975763;21332281;31768457;14501932;24967046",
"title": "Direct Lateral Corpectomy and Reconstruction Using an Expandable Cage Improves Local Kyphosis but Not Global Sagittal Alignment.",
"title_normalized": "direct lateral corpectomy and reconstruction using an expandable cage improves local kyphosis but not global sagittal alignment"
} | [
{
"companynumb": "JP-AMGEN-JPNSP2021192690",
"fulfillexpeditecriteria": "2",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ROMOSOZUMAB"
},
"drugadditional": "4",
... |
{
"abstract": "Patients with HIV are at risk of both primary and secondary haematological disorders. We report two cases of patients with HIV and cryptococcal meningitis who developed severe haemolytic anaemia, thrombocytopenia, renal failure and lactic acidosis while on treatment with amphotericin B and co-trimoxazole.",
"affiliations": "Servicio de Neurologia, Hospital Universitario \"Dr. José E. González\", Universidad Autónoma de Nuevo León, Monterrey, México crcamara83@hotmail.com.;Servicio de Neurologia, Hospital Universitario \"Dr. José E. González\", Universidad Autónoma de Nuevo León, Monterrey, México.;Servicio de Neurologia, Hospital Universitario \"Dr. José E. González\", Universidad Autónoma de Nuevo León, Monterrey, México.;Servicio de Neurologia, Hospital Universitario \"Dr. José E. González\", Universidad Autónoma de Nuevo León, Monterrey, México.;Servicio de Neurologia, Hospital Universitario \"Dr. José E. González\", Universidad Autónoma de Nuevo León, Monterrey, México.",
"authors": "Camara-Lemarroy|Carlos R|CR|;Flores-Cantu|Hazael|H|;Calderon-Hernandez|Hector J|HJ|;Diaz-Torres|Marco A|MA|;Villareal-Velazquez|Hector J|HJ|",
"chemical_list": "D000935:Antifungal Agents; D000666:Amphotericin B; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"country": "England",
"delete": false,
"doi": "10.1177/0956462414567547",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0956-4624",
"issue": "26(14)",
"journal": "International journal of STD & AIDS",
"keywords": "AIDS; Cryptococcal meningitis; HIV; Haemolysis; cryptococcosis; lactic acidosis; renal failure; thrombocytopenia",
"medline_ta": "Int J STD AIDS",
"mesh_terms": "D017088:AIDS-Related Opportunistic Infections; D000140:Acidosis, Lactic; D000328:Adult; D000666:Amphotericin B; D000743:Anemia, Hemolytic; D000935:Antifungal Agents; D003455:Cryptococcus neoformans; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D016919:Meningitis, Cryptococcal; D051437:Renal Insufficiency; D013921:Thrombocytopenia; D016896:Treatment Outcome; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"nlm_unique_id": "9007917",
"other_id": null,
"pages": "1052-4",
"pmc": null,
"pmid": "25614519",
"pubdate": "2015-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Drug-induced haemolysis, renal failure, thrombocytopenia and lactic acidosis in patients with HIV and cryptococcal meningitis: a diagnostic challenge.",
"title_normalized": "drug induced haemolysis renal failure thrombocytopenia and lactic acidosis in patients with hiv and cryptococcal meningitis a diagnostic challenge"
} | [
{
"companynumb": "PHHY2015MX158629",
"fulfillexpeditecriteria": "1",
"occurcountry": "MX",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AMPHOTERICIN B"
},
"drugadditional": null,
"... |
{
"abstract": "This is the first reported case of pineal lymphoma with concomitant prolactin-producing pituitary adenoma.A 51-year-old male experienced worsening headaches accompanied by nausea, diplopia, and memory loss for 1 month. Cranial nerve examination revealed bilateral upward gaze limitation with convergence impairment, which is known as Parinaud syndrome. Magnetic resonance images revealed a mass in the pineal gland with a coexisting mass within the enlarged sella fossa. Hormone analysis revealed hyperprolactinemia. The pineal mass was removed without injuring the hypothalamus, brain stem, or any neighboring vessels. Pathology examination confirmed the diagnosis of diffuse large B-cell lymphoma (DLBCL) involving the pineal gland. After further studies, the pineal lymphoma was determined to be a secondary tumor from a gastric primary tumor. The patient died 6 months after diagnosis due to systemic progression of DLBCL.Although the mechanistic link between hyperprolactinemia and lymphoma progression has not been clarified on a clinical basis, high prolactin levels may contribute to the rapid progression and therapeutic resistance of the lymphoma.",
"affiliations": "From the Department of Neurosurgery (Y-JK, SJ, K-SM); Department of Internal Medicine (HKK, D-HY); and Departments of Pathology, Chonnam National University Research Institute of Medical Sciences (M-GN, J-HL, K-HL), Chonnam National University Hwasun Hospital and Medical School, Hwasun-gun, Jeollanamdo, South Korea.",
"authors": "Kim|Yeong-Jin|YJ|;Kim|Hee Kyung|HK|;Yang|Deok-Hwan|DH|;Jung|Shin|S|;Noh|Myung-Giun|MG|;Lee|Jae-Hyuk|JH|;Lee|Kyung-Hwa|KH|;Moon|Kyung-Sub|KS|",
"chemical_list": "D003287:Contrast Media",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000002923",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 10.1097/MD.0000000000002923029235700Research ArticleClinical Case ReportPineal Diffuse Large B-Cell Lymphoma Concomitant With Pituitary Prolactinoma: Possible Correlation Between 2 Distinguished Pathologies A Case ReportKim Yeong-Jin MDKim Hee Kyung MD, PhDYang Deok-Hwan MD, PhDJung Shin MD, PhDNoh Myung-Giun MDLee Jae-Hyuk MD, PhDLee Kyung-Hwa MD, PhDMoon Kyung-Sub MD, PhDCao. Chun-xia From the Department of Neurosurgery (Y-JK, SJ, K-SM); Department of Internal Medicine (HKK, D-HY); and Departments of Pathology, Chonnam National University Research Institute of Medical Sciences (M-GN, J-HL, K-HL), Chonnam National University Hwasun Hospital and Medical School, Hwasun-gun, Jeollanamdo, South Korea.Correspondence: Kyung-Sub Moon, Department of Neurosurgery, Brain Tumor Clinic and Gamma Knife Center, Chonnam National University Hwasun Hospital and Medical School, 322 Seoyang-ro, Hwasun-eup, Hwasun-gun, Jeollanam-do 519-763, South Korea (e-mail: moonks@chonnam.ac.kr).Kyung-Hwa Lee, Department of Pathology, Chonnam National University Hwasun Hospital and Medical School, 322 Seoyang-ro, Hwasun-eup, Hwasun-gun, Jeollanam-do 519-763, South Korea (e-mail: mdkaylee@jnu.ac.kr).2 2016 03 3 2016 95 8 e29231 12 2015 1 2 2016 2 2 2016 Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.2016This is an open access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0, where it is permissible to download, share and reproduce the work in any medium, provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0Abstract\nThis is the first reported case of pineal lymphoma with concomitant prolactin-producing pituitary adenoma.\n\nA 51-year-old male experienced worsening headaches accompanied by nausea, diplopia, and memory loss for 1 month. Cranial nerve examination revealed bilateral upward gaze limitation with convergence impairment, which is known as Parinaud syndrome. Magnetic resonance images revealed a mass in the pineal gland with a coexisting mass within the enlarged sella fossa. Hormone analysis revealed hyperprolactinemia. The pineal mass was removed without injuring the hypothalamus, brain stem, or any neighboring vessels. Pathology examination confirmed the diagnosis of diffuse large B-cell lymphoma (DLBCL) involving the pineal gland. After further studies, the pineal lymphoma was determined to be a secondary tumor from a gastric primary tumor. The patient died 6 months after diagnosis due to systemic progression of DLBCL.\n\nAlthough the mechanistic link between hyperprolactinemia and lymphoma progression has not been clarified on a clinical basis, high prolactin levels may contribute to the rapid progression and therapeutic resistance of the lymphoma.\n\nOPEN-ACCESSTRUE\n==== Body\nINTRODUCTION\nCerebral lymphoma is a malignant lymphocytic neoplasm that can occur as a primary tumor or as a secondary manifestation of systemic disease. Once considered a rare neoplasm, the incidence of central nervous system (CNS) lymphoma has increased significantly in recent decades.1 At initial diagnosis, a primary CNS lesion appears in approximately 1% to 2% of patients with non-Hodgkin lymphoma.2 Systemic lymphoma spreads to the CNS in 5.5% to 9.4% of cases and is associated with a poor prognosis.3,4 The occurrence of malignant lymphoma in the pineal region is extremely rare. Only 10 cases of primary or secondary pineal lymphomas, including the case in this study, have been reported in the literature to date.5–13\n\nNeuroendocrine and immune responses mutually affect each other via various interactions between the hormones/respective receptors and the immune system.14 Furthermore, elevated prolactin (PRL) levels are associated with the progression of hematologic diseases including multiple myeloma, acute myeloid leukemia, and non-Hodgkin lymphoma.15–17 Here, we report a case of pineal lymphoma as the first manifestation of gastric lymphoma and discuss the possible role of concomitant pituitary prolactinoma on lymphoma.\n\nCASE PRESENTATION\nA 51-year-old male experienced worsening headaches for 1 month, which were accompanied by nausea, diplopia, and mild memory loss. He had no significant medical history and was not taking any medications including antipsychotics. On admission, the liver and spleen were not palpable, and there were no palpable superficial lymph nodes. Neurological examination revealed no evidence of impaired mental status, gait difficulties, or sensory or motor deficits. Positive neurological findings included bilateral upward gaze limitation with convergence impairment, also called Parinaud syndrome. Magnetic resonance (MR) image of the brain revealed a 2 × 2 × 2 cm mass in the pineal gland with a concomitant 1.5 × 1.5 × 1.2 cm mass within the enlarged pituitary fossa (Figure 1A–D). The pineal mass showed iso- to hypointensity on T1- and T2-weighted MR images and heterogeneous enhancement by gadolinium administration. It was a multilobulated mass that extended into the hypothalamus and midbrain. The lesion showed perilesional edema and internal calcification. Obstructive hydrocephalus due to stenosis of the aqueduct of Sylvius was also seen. Laboratory findings upon admission included a 6.7 × 103/mm3 white blood cell count with a normal differentiation, a hemoglobin level of 10.8 g/dL, and a platelet count of 360 × 103/mm3. Hormonal analysis indicated hyperprolactinemia (977.7 ng/mL; normal, 2.8–29.3 ng/mL). The patient's serum thyroid-stimulating hormone (TSH) and free T4 values were 0.652 μIU/mL (normal, 0.8–1.71 μIU/mL) and 0.770 ng/dL (normal, 0.4–4.8 ng/dL). Coagulation, hepatic, and renal profiles were within normal limits. A serologic study for human immunodeficiency virus was negative. Tumor markers for a pineal mass, such as α-fetoprotein, human chorionic gonadotropin, and carcinoembryonic antigen, were within normal ranges. Due to the presumptive diagnosis of a nongerminomatous, parenchymal, or glial tumor on the pineal gland, surgery was performed using the occipital transtentorial approach. A slightly hard, dark red mass was located in the pineal gland and posterior third ventricle. The mass had internal calcification and was easily demarcated from the peritumoral brain parenchyma. Some portions of the mass that adhered to surrounding venous structures required sharp dissection. Frozen biopsy diagnosis of the pineal lesion suggested a pineoblastoma. The mass was removed completely without injuring the hypothalamus, brain stem, or any neighboring vessels.\n\nFIGURE 1 Preoperative magnetic resonance (MR) imaging. (A) A hypo- to isointense mass was detected at the pineal region on the T1-weighted image. (B) Marked peritumoral edema was shown surrounding the pineal mass on the T2-weighted image. (C) Axial image with gadolinium enhancement demonstrated multilobulation and heterogenous enhancement of the pineal mass, with a margin indistinct from the surrounding hypothalamus and midbrain, and hydrocephalus caused by obstruction of the aqueduct of Sylvius. (D) Note a strongly enhanced mass located entirely within the enlarged sellar turcica (asterisk).\n\nHistopathology revealed diffuse infiltration of large lymphocytes with vesicular nuclei, prominent nucleoli, and abundant cytoplasm. In some portions, the cells were arranged in sheets with a prominent starry-sky pattern and geographic coagulative necrosis. Interestingly, the well-known characteristics of perivascular infiltration of tumor cells were not identified, since the pineal parenchyma was almost completely replaced by neoplastic lymphocytes. An initial immunohistochemistry (IHC) panel was performed to exclude the diagnostic possibility of pineoblastoma and other germ cell tumors that frequently develop in the pineal gland. The tumor cells were all negative for synaptophysin, glial fibrillary acidic protein, pan-cytokeratin, and placental alkaline phosphatase. Instead, tumor cells showed strong positivity for B-cell markers including CD79a and CD20 but were negative for T-cell markers including CD3 and CD45RO. BCL2 was also positive, and the Ki-67 labeling proliferation index exceeded 50%. Pathology confirmed a diffuse large B cell lymphoma (DLBCL) involving the pineal gland. Additional IHC panel for DLBCL subdivision revealed BCL6 positivity, and CD10 and MUM1 nonreactivity (Figure 2A–D). Consequently, the immunohistochemical subgroup of the lymphoma was a germinal center-like DLBCL.18\n\nFIGURE 2 Microscopic characteristics of the pineal and gastric diffuse large B-cell lymphoma (DLBCL). (A) The pineal mass was composed of enlarged lymphocytes and scattered pale histiocytes featuring a starry-sky appearance (hematoxylin and eosin [H&E] staining, original magnification × 200). (B) The tumor cells were diffusely positive for CD20 (immunohistochemistry, × 400). (C) Approximately 40% of the tumor cells showed positivity for BCL6 (immunohistochemistry, × 400). (D) The Ki-67 proliferation index of the tumor exceeded 50% (immunohistochemistry, × 400). (E) The lymphoma cells were densely infiltrated between the remaining gastric glands (H&E stain, × 200). (F) The gastric lymphoma cells showed strong staining for CD79a (immunohistochemistry, × 400).\n\nTwo weeks after the operation, the patient complained of gastric fullness and aggravated vomiting. Abdominal computed tomography revealed concentric wall thickening in the lower portion of the lesser curvature of the gastric body, but there was no evidence of enlarged lymph nodes or hepatosplenomegaly. Upper esophagogastroduodenoscopy showed a diffuse ulceroinfiltrative mass in the lesser curvature of the gastric body (Figure 3). Pathological diagnosis was DLBCL, identical to that of the previously removed pineal mass (Figure 2E and F). Other systemic evaluations, including chest and neck computed tomography scans and bone marrow biopsy, were normal. The PRL level gradually dropped to 459 ng/mL 3 months after the brain operation. After removal of the pineal gland mass, the patient was treated with 2 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by 1 cycle of high-dose methotrexate (3.5 g/m2) chemotherapy. The patient was originally planned to be treated with 2 cycles of R-CHOP, followed by 4th infusion of high-dose MTX-based chemotherapy and additional 4 cycles of R-CHOP chemotherapy. However, further chemotherapy had to be discontinued after 1 cycle of high-dose MTX chemotherapy since the patient had neutropenia and general weakness. Two months after the brain operation, the patient underwent an emergent operation for mechanical ileus due to a newly developed mass. Subsequently, the patient had aspiration pneumonia and showed progression of the brain lesion aggravated by CSF seeding. The patient died 6 months after initial diagnosis.\n\nFIGURE 3 Esophagogastroduodenoscopy (EGD) showed a diffuse infiltrative mass with central ulceration (indicated by arrowheads) located in the lesser curvature of the gastric body.\n\nTo evaluate the contribution of elevated PRL levels on the rapid progression of DLBCL, PRL expression in lymphoma cells was investigated by IHC. Both the pineal and gastric lesions were repeatedly negative for PRL staining (Figure 4A). For further evaluation of PRL receptor (PRL-R) expression, IHC and Western blot (WB) analysis were performed (dilution 1:200 for IHC, 1:2000 for WB; clone B6.2, catalogue no. MA5-11955, Thermo Fisher Scientific, Rockford, IL). WB was performed as described previously.19 To validate the results, WB analysis using a representative lymphoma cell line, EG7 (kindly provided by Dr Yang Deok-Hwan, Chonnam National University), and IHC staining for PRL-R were performed in an additional 10 DLBCL cases (Table 1). As shown in Figure 4A, surgical samples from primary gastric and metastatic pineal lesions stained positive for PRL-R. PRL-R expression in lymphoma cells was also shown in the EG7 lymphoma cell line by WB (Figure 4B). In addition, 9 of 10 cases displayed diffuse or patchy strong PRL-R positivity (Figure 5), and the remaining case showed localized immunoreactivity around the vessels. The patients provided signed, informed consent, and the study was approved by the Institutional Review Board of the Chonnam National University Hwasun Hospital.\n\nTABLE 1 Brief Summary of Additional 10 Cases of DLBCL\n\nFIGURE 4 Expression of prolactin receptor (PRL-R) in the current case. (A) Immunohistochemistry of PRL-R revealed a strong positivity in both primary gastric and metastatic pineal lymphomas (immunohistochemistry, × 200 and × 400, respectively). There was no expression of prolactin in the same samples (immunohistochemistry, × 200 and × 400, respectively). (B) Western blot analysis revealed PRL-R expression in the pineal lymphoma. This positive reaction was also noted in the lymphoma cell line EG7.\n\nFIGURE 5 Immunohistochemistry of the prolactin receptor (PRL-R) in additional diffuse large B-cell lymphoma samples. Nine out of 10 selected cases showed positive immunoreactivity with variable portions of tumor components.\n\nDISCUSSION\nPrimary CNS lymphomas (PCNSL) are supratentorial in approximately 60% of patients.20 Despite the more common location of PCNSL in the supratentorial region, involvement of the pineal gland is extremely rare. In a meta-analysis of PCNSL, only 0.5% of enrolled cases (2 of 424 cases) had tumors in the pineal location.21 Secondary CNS involvement is infrequent in DLBCL, with an incidence range of 5% to 25% reported in studies assessing different risk factors and diagnostic tools.22–24\n\nThe pineal region is one of the rarest locations for intracranial metastasis of systemic malignancies, with an incidence range of 1.8% to 4% of all intracranial metastases.25–28 Approximately half of the cases have no other metastases within the brain, as in this case.25 Hematogenous spread through the posterior choroidal artery is suggested as the pathomechanism for pineal metastasis, given that the pineal gland is a circumventricular organ of the brain lacking a blood–brain barrier.28,29 Even though it is an isolated event, CNS involvement represents widespread disease progression and has the worst clinical outcome, with less than 10% of patients surviving 1 year.4,30,31 Of the 10 reported cases of pineal lymphoma, 6 involved multiple locations, and 2 were secondary, with 1 retroperitoneal primary and 1 gastric primary (Table 2). The majority of the cases (6 out of 8 with determined histological types) were of a B-cell lineage, and the overall clinical progression seemed to be fatal, but follow-up information was insufficient.\n\nTABLE 2 Clinoco-Radiological Characteristics of Reported Cases of Pineal Lymphoma\n\nIn CNS lymphoma, concurrent brain tumor types including astrocytoma,32 meningioma,33 and pituitary adenoma34–36 have been reported. Interruption of the inhibitory pathway between the hypothalamus and pituitary gland was proposed as the putative pathogenesis for the development of pituitary adenoma in hypothalamic PCNSL.34 In contrast, lymphoma development may be stimulated by microenvironmental alterations or hormones produced by the pituitary adenoma.35 Another reported case of intermingled adenoma with lymphoma suggested a strong connection between pituitary adenoma and lymphoma in the same location.36\n\nWhereas PRL-R is expressed in immune cells universally, the expression of human PRL is found mainly in T lymphocytes.37 In addition, PRL production is evident in normal extrapituitary sites, including the decidua, myometrium, breast, prostate, brain, and malignant cells.38,39 Although the precise function of PRL in immune cells is not clear, PRL has an important role in immunomodulation and lymphoid cell proliferation, in addition to the promotion of normal hematopoiesis.40–42 PRL promotes both cell-mediated and humoral immune responses through signaling pathways, including JAK/STAT and mitogen-activated protein kinase, resulting in target gene expression,43 stimulation of B- and T-cell proliferation, proinflammatory cytokine production, and B-cell growth arrest.14 PRL can act as a survival (antiapoptotic) factor or as a mitogen, as exemplified in the lactating mammary gland, Nb2 lymphoma cells, and breast cancer cells.38\n\nThe presence of elevated serum PRL levels in the context of hematological malignancy is still controversial. A small number of previous studies reported elevated PRL levels in lymphoma patients,16,44 as well as in acute myeloid leukemia patients.17,45 Pathological hyperprolactinemia was shown to be associated with a reduction in natural killer cell number and function.46 In addition to a direct mitogenic effect, PRL also has the capacity to inhibit cell death induced by cisplatin, doxorubicin, taxol, and other agents in cancer cells as exemplified by breast cancer research,47,48 through drug detoxification arising from PRL-induced activation of glutathione S-transferase,48 or potentially via PRL-mediated upregulation of antiapoptotic proteins such as BCL2.49\n\nIn this case, the endosellar mass was diagnosed as a prolactinoma based on an elevated PRL > 300 ng/mL and relevant MR imaging,50,51 even without pathological confirmation. There were a couple of reasons for that the pituitary tumor was prolactinoma. First, IHC staining using PRL antibody was repeatedly negative in the pineal and gastric lesions. It seemed unlikely that PRL was massively secreted from the pituitary lesion if the pituitary gland also had a lymphoma. Second, serum PRL levels exceeding 300 ng/mL are almost always caused by a pure prolactinoma or a mixed pituitary adenoma with a lactotrophic component.50,51 There are variable causes of hyperprolactinemia including drugs, pregnancy, nipple stimulation, and pituitary PRL secreting adenoma. Serum PRL levels in patients with prolactinoma can range from minimally elevated to 50,000 ng/mL, but the PRL levels rarely exceed 200 ng/mL in hyperprolactinemia due to other causes. Three months after complete removal of the pineal lymphoma, the PRL level gradually dropped to 459 ng/mL without specific treatment for the prolactinoma. This finding corroborated a previous report that hyperprolactinemia is associated with lymphoma.16,44 The studies described above showed that certain subpopulations of lymphocytes synthesize and secrete biologically active PRL and that PRL can act as an autocrine and/or paracrine factor to modulate the activities of cells of the immune system. Despite repeated immunostaining in the current case, the tumor cells did not stain for PRL. In comparison, some lymphoma samples showed PRL-R expression. Presumably, shrinkage of the lymphoma volume may have affected the functional aspects of the prolactinoma. In addition, it is likely that the persistent hyperprolactinemia may have affected the chemoresistance of the DLBCL and have contributed to the fatal deterioration of the patient's condition.\n\nIn conclusion, this is the 1st clinical report of concurrent prolactinoma and pineal lymphoma to our knowledge. This report raises questions about the mutual interaction between lymphoma progression and hyperprolactinemia. The occurrence of lymphoma in the clinical context of hyperprolactinemia may have important implications. Any clinical condition that results in elevated PRL levels needs to be controlled. In small clinical studies on breast cancer, patients treated with antiprolactinemic agents in combination with docetaxel responded better than those treated with docetaxel alone.52,53 Additional research and clinical data are required to clarify the exact correlation between DLBCL progression and hyperprolactinemia.\n\nAbbreviations: CNS = central nervous system, DLBCL = diffuse large B-cell lymphoma, IHC = immunohistochemistry, MR = magnetic resonance, PRL = prolactin, PRL-R = prolactin receptor.\n\nThis work was supported by the National R&D Program for Cancer Control, Ministry of Health & Welfare (0720570).\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nREFERENCES\n1. Gerstner ER Batchelor TT \nWinn HR \nCentral nervous system lymphoma . Youmans Neurological Surgery . Philadelphia : Saunders ; 2011 \n1400 –1409 .\n2. Loeffler JS Ervin TJ Mauch P \nPrimary lymphomas of the central nervous system: patterns of failure and factors that influence survival . J Clin Oncol \n1985 ; 3 :490 –494 .3981223 \n3. Liang RH Woo EK Yu YL \nCentral nervous system involvement in non-Hodgkin's lymphoma . Eur J Cancer Clin Oncol \n1989 ; 25 :703 –710 .2714346 \n4. Hollender A Kvaloy S Lote K \nPrognostic factors in 140 adult patients with non-Hodgkin's lymphoma with systemic central nervous system (CNS) involvement. A single centre analysis . Eur J Cancer \n2000 ; 36 :1762 –1768 .10974623 \n5. Pantanowitz L Freedman SJ Dezube BJ \nNovember 2002: a 72-year-old woman with a pineal gland mass . Brain Pathol \n2003 ; 13 :235 –236 .239 .12744478 \n6. Grimoldi N Tomei G Stankov B \nNeuroendocrine, immunohistochemical, and ultrastructural study of pineal region tumors . J Pineal Res \n1998 ; 25 :147 –158 .9745983 \n7. Amagasa M Kawase M Sato S \nSpinal malignant lymphoma appearing after radiation and chemotherapy of a pineal region tumor . Surg Neurol \n1996 ; 45 :167 –169 .discussion 169–171 .8607068 \n8. Matsuno A Hashizume K Tsuzuki N \n[A case of primary intracranial T cell type malignant lymphoma, radiologically resembling germ cell tumor and presenting hypopituitarism] . No Shinkei Geka \n1993 ; 21 :551 –555 .8393152 \n9. Popovic EA Kelly PJ \nStereotactic procedures for lesions of the pineal region . Mayo Clin Proc \n1993 ; 68 :965 –970 .8412362 \n10. Endo H Fujimura M Kumabe T \nApplication of high-definition flexible neuroendoscopic system to the treatment of primary pineal malignant B-cell lymphoma . Surg Neurol \n2009 ; 71 :344 –348 .18207502 \n11. Karikari IO Thomas KK Lagoo A \nPrimary cerebral ALK-1-positive anaplastic large cell lymphoma in a child. Case report and literature review . Pediatric Neurosurg \n2007 ; 43 :516 –521 .\n12. Yoshida T Tezuka Y Hirosawa T \nPineal malignant B-cell lymphoma with lower cranial nerve involvement . Intern Med (Tokyo, Japan) \n2014 ; 53 :1205 –1208 .\n13. Vasudevan JA Nair RA Nair SG \nPrimary diffuse large B-cell lymphoma of the central nervous system in pineal gland: report of a rare case with review of literature . Indian J Pathol Microbiol \n2015 ; 58 :412 –413 .26275286 \n14. McMurray RW \nEstrogen, prolactin, and autoimmunity: actions and interactions . Int Immunopharmacol \n2001 ; 1 :995 –1008 .11407318 \n15. Gado K Pallinger E Kovacs P \nProlactin influences proliferation and apoptosis of a human IgE secreting myeloma cell line, U266 . Immunol Lett \n2002 ; 82 :191 –196 .12036601 \n16. Grobe N Ruhle H Eckelmann G \n[Hyperprolactinemia in malignant lymphomas] . Dtsch Med Wochenschr \n1990 ; 115 :1825 –1827 .2245764 \n17. Hatfill SJ Kirby R Hanley M \nHyperprolactinemia in acute myeloid leukemia and indication of ectopic expression of human prolactin in blast cells of a patient of subtype M4 . Leuk Res \n1990 ; 14 :57 –62 .1968111 \n18. Stein H Warnke RA Chan WC \nSwerdllow SH Campo E Harris NL \nDiffuse large B-cell lymphoma, not otherwise specified. \nWHO Classification of Tumours of Haematopoietic and Lymphoid Tissues \n4th ed Lyon : IARC Press ; 2008 \n233 –237 .\n19. Lee KH Ahn EJ Oh SJ \nKITENIN promotes glioma invasiveness and progression, associated with the induction of EMT and stemness markers . Oncotarget \n2015 ; 6 :3240 –3253 .25605251 \n20. Deckert M Paulus W \nLouis DN Ohgaki H Wiestler OD Cavenee WK \nMalignant lymphomas . WHO Classification of Tumours of the Central Nervous System \n4th ed Lyon, France : International Agency for Research on Cancer ; 2007 \n188 –192 .\n21. Murray K Kun L Cox J \nPrimary malignant lymphoma of the central nervous system. Results of treatment of 11 cases and review of the literature . J Neurosurg \n1986 ; 65 :600 –607 .3772445 \n22. Bierman P Giglio P \nDiagnosis and treatment of central nervous system involvement in non-Hodgkin's lymphoma . Hematol Oncol Clin North Am \n2005 ; 19 :597 –609 .v .16083825 \n23. Hegde U Filie A Little RF \nHigh incidence of occult leptomeningeal disease detected by flow cytometry in newly diagnosed aggressive B-cell lymphomas at risk for central nervous system involvement: the role of flow cytometry versus cytology . Blood \n2005 ; 105 :496 –502 .15358629 \n24. Villa D Connors JM Shenkier TN \nIncidence and risk factors for central nervous system relapse in patients with diffuse large B-cell lymphoma: the impact of the addition of rituximab to CHOP chemotherapy . Ann Oncol \n2010 ; 21 :1046 –1052 .19861575 \n25. Hirato J Nakazato Y \nPathology of pineal region tumors . J Neurooncol \n2001 ; 54 :239 –249 .11767290 \n26. Chason JL Walker FB Landers JW \nMetastatic carcinoma in the central nervous system and dorsal root ganglia. A prospective autopsy study . Cancer \n1963 ; 16 :781 –787 .14020314 \n27. France LH \nContribution to the study of 150 cases of cerebral metastases. II. Neuropathological study . J Neurosurg Sci \n1975 ; 19 :189 –210 .1232094 \n28. Ortega P Malamud N Shimkin MB \nMetastasis to the pineal body . AMA Arch Pathol \n1951 ; 52 :518 –528 .14877387 \n29. Freedman SJ Pantanowitz L Joseph JT \nUnusual locations for lymphomas. Case 2. Pineal lymphoma . J Clin Oncol \n2001 ; 19 :2960 –2963 .11387370 \n30. van Besien K Gisselbrecht C Pfreundschuh M \nSecondary lymphomas of the central nervous system: risk, prophylaxis and treatment . Leuk Lymphoma \n2008 ; 49 \n(Suppl 1) :52 –58 .18821433 \n31. Aviles A Jesus Nambo M Neri N \nCentral nervous system prophylaxis in patients with aggressive diffuse large B cell lymphoma: an analysis of 3,258 patients in a single center . Med Oncol \n2013 ; 30 :520 .23456620 \n32. Giromini D Peiffer J Tzonos T \nOccurrence of a primary Burkitt-type lymphoma of the central nervous system in an astrocytoma patient. A case report . Acta Neuropathol \n1981 ; 54 :165 –167 .7246058 \n33. Slowik F Jellinger K \nAssociation of primary cerebral lymphoma with meningioma: report of two cases . Clin Neuropathol \n1990 ; 9 :69 –73 .2187641 \n34. Roggli VL Suzuki M Armstrong D \nPituitary microadenoma and primary lymphoma of brain associated with hypothalamic invasion . Am J Clin Pathol \n1979 ; 71 :724 –727 .377944 \n35. Kuhn D Buchfelder M Brabletz T \nIntrasellar malignant lymphoma developing within pituitary adenoma . Acta Neuropathol \n1999 ; 97 :311 –316 .10090680 \n36. Au WY Kwong YL Shek TW \nDiffuse large-cell B-cell lymphoma in a pituitary adenoma: an unusual cause of pituitary apoplexy . Am J Hematol \n2000 ; 63 :231 –232 .10706771 \n37. Pellegrini I Lebrun JJ Ali S \nExpression of prolactin and its receptor in human lymphoid cells . Mol Endocrinol (Baltimore, MD) \n1992 ; 6 :1023 –1031 .\n38. Ben-Jonathan N Liby K McFarland M \nProlactin as an autocrine/paracrine growth factor in human cancer . Trends Endocrinol Metab \n2002 ; 13 :245 –250 .12128285 \n39. Ben-Jonathan N Mershon JL Allen DL \nExtrapituitary prolactin: distribution, regulation, functions, and clinical aspects . Endocr Rev \n1996 ; 17 :639 –669 .8969972 \n40. Yu-Lee LY \nMolecular actions of prolactin in the immune system . Proc Soc Exp Biol Med \n1997 ; 215 :35 –52 .9142136 \n41. Berczi I Nagy E de Toledo SM \nPituitary hormones regulate c-myc and DNA synthesis in lymphoid tissue . J Immunol (Baltimore, MD: 1950) \n1991 ; 146 :2201 –2206 .\n42. Velkeniers B Dogusan Z Naessens F \nProlactin, growth hormone and the immune system in humans . Cell Mol Life Sci \n1998 ; 54 :1102 –1108 .9817989 \n43. Yu-Lee L Luo G Moutoussamy S \nProlactin and growth hormone signal transduction in lymphohaemopoietic cells . Cell Mol Life Sci \n1998 ; 54 :1067 –1075 .9817985 \n44. Hill RW Grebe SK Dady PJ \n[Hyperprolactinemia in malignant lymphomas] . Dtsch Med Wochenschr \n1992 ; 117 :198 .1735383 \n45. Kooijman R Gerlo S Coppens A \nMyeloid leukemic cells express and secrete bioactive pituitary-sized 23 kDa prolactin . J Neuroimmunol \n2000 ; 110 :252 –258 .11024557 \n46. Gerli R Rambotti P Nicoletti I \nReduced number of natural killer cells in patients with pathological hyperprolactinemia . Clin Exp Immunol \n1986 ; 64 :399 –406 .3091304 \n47. Howell SJ Anderson E Hunter T \nProlactin receptor antagonism reduces the clonogenic capacity of breast cancer cells and potentiates doxorubicin and paclitaxel cytotoxicity . Breast Cancer Res \n2008 ; 10 :R68 .18681966 \n48. LaPensee EW Schwemberger SJ LaPensee CR \nProlactin confers resistance against cisplatin in breast cancer cells by activating glutathione-S-transferase . Carcinogenesis \n2009 ; 30 :1298 –1304 .19443905 \n49. Peirce SK Chen WY \nHuman prolactin and its antagonist, hPRL-G129R, regulate bax and bcl-2 gene expression in human breast cancer cells and transgenic mice . Oncogene \n2004 ; 23 :1248 –1255 .14647416 \n50. Vance ML Thorner MO \nProlactinomas . Endocrinol Metab Clin North Am \n1987 ; 16 :731 –753 .3319600 \n51. Weiss MH Teal J Gott P \nNatural history of microprolactinomas: six-year follow-up . Neurosurgery \n1983 ; 12 :180 –183 .6682188 \n52. Lissoni P Bucovec R Malugani F \nA clinical study of taxotere versus taxotere plus the antiprolactinemic agent bromocriptine in metastatic breast cancer pretreated with anthracyclines . Anticancer Res \n2002 ; 22 \n(2b) :1131 –1134 .12168912 \n53. Frontini L Lissoni P Vaghi M \nEnhancement of the efficacy of weekly low-dose taxotere by the long acting anti-prolactinemic drug cabergoline in pretreated metastatic breast cancer . Anticancer Res \n2004 ; 24 :4223 –4226 .15736476\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0025-7974",
"issue": "95(8)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D003287:Contrast Media; D003937:Diagnosis, Differential; D017809:Fatal Outcome; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D010871:Pinealoma; D010911:Pituitary Neoplasms; D015175:Prolactinoma; D013274:Stomach Neoplasms",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e2923",
"pmc": null,
"pmid": "26937937",
"pubdate": "2016-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "2245764;7246058;11024557;1232094;2187641;12744478;11767290;12036601;14877387;2005393;18821433;12128285;8607068;25605251;8412362;10090680;18207502;8969972;14647416;14020314;16083825;9745983;23456620;9142136;2714346;6682188;11387370;10974623;3981223;10706771;19443905;9817985;11407318;1735383;1508218;15736476;9817989;17992044;18681966;1968111;26275286;377944;15358629;24881750;12168912;19861575;8393152;3319600;3772445;3091304",
"title": "Pineal Diffuse Large B-Cell Lymphoma Concomitant With Pituitary Prolactinoma: Possible Correlation Between 2 Distinguished Pathologies: A Case Report.",
"title_normalized": "pineal diffuse large b cell lymphoma concomitant with pituitary prolactinoma possible correlation between 2 distinguished pathologies a case report"
} | [
{
"companynumb": "KR-BAUSCH-BL-2016-009259",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "One of the most used cephalosporin in clinical practice is ceftriaxone. Anaphylaxis due to the administration of ceftriaxone is considered a rare event. Here, we report a case of fatal anaphylactic shock after the administration of ceftriaxone in a child who had tolerated the drug in past exposures. The allergic pathogenesis is sustained by the clinical data (short time between the inoculation of the drug and the onset of the symptoms; past exposure to the same molecule and probable sensitization) and the postmortem examination findings (polivisceral congestion and intense eosinophilia found in the histological examination).",
"affiliations": "From the *Department of Clinical and Experimental Medicine, Section of Pharmacology; †Department of Clinical and Experimental Medicine, School and Unit of Allergy and Clinical Immunology, University of Messina, Messina; ‡Department of Biotechnology and Legal Medicine, Section of Legal Medicine, University of Palermo, Palermo; §Department of Drug Sciences and Health Products, University of Messina; ∥IRCCS Centro Neurolesi \"Bonino-Pulejo\", Messina; and ¶Institute of Biomedicine and MolecularImmunology \"A. Monroy\" (IBIM)-Consiglio Nazionale delle Ricerche (CNR), Palermo, Italy.",
"authors": "Calapai|Gioacchino|G|;Imbesi|Selene|S|;Ventura-Spagnolo|Elvira|E|;Cafeo|Viviana|V|;Milone|Livio|L|;Navarra|Michele|M|;Gangemi|Sebastiano|S|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002443:Ceftriaxone",
"country": "United States",
"delete": false,
"doi": "10.1097/PEC.0000000000000311",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0749-5161",
"issue": "32(1)",
"journal": "Pediatric emergency care",
"keywords": null,
"medline_ta": "Pediatr Emerg Care",
"mesh_terms": "D000707:Anaphylaxis; D000900:Anti-Bacterial Agents; D001344:Autopsy; D002443:Ceftriaxone; D002675:Child, Preschool; D004342:Drug Hypersensitivity; D017809:Fatal Outcome; D006801:Humans; D008297:Male; D012189:Retrospective Studies",
"nlm_unique_id": "8507560",
"other_id": null,
"pages": "32-3",
"pmc": null,
"pmid": "25513979",
"pubdate": "2016-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fatal Anaphylactic Shock Ceftriaxone-Induced in a 4-Year-Old Child.",
"title_normalized": "fatal anaphylactic shock ceftriaxone induced in a 4 year old child"
} | [
{
"companynumb": "IT-LUPIN PHARMACEUTICALS INC.-2016-00443",
"fulfillexpeditecriteria": "2",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CEFTRIAXONE"
},
"drugadditiona... |
{
"abstract": "Intravenous thrombolysis with alteplase alone cannot reperfuse most large-artery strokes. We aimed to determine whether mechanical thrombectomy in addition to intravenous thrombolysis improves clinical outcome in patients with acute ischaemic stroke.\n\n\n\nTHRACE is a randomised controlled trial done in 26 centres in France. Patients aged 18-80 years with acute ischaemic stroke and proximal cerebral artery occlusion were randomly assigned to receive either intravenous thrombolysis alone (IVT group) or intravenous thrombolysis plus mechanical thrombectomy (IVTMT group). Intravenous thrombolysis (alteplase 0·9 mg/kg [maximum 90 mg], with an initial bolus of 10% of the total dose followed by infusion of the remaining dose over 60 min) had to be started within 4 h and thrombectomy within 5 h of symptom onset. Occlusions had to be confirmed by CT or magnetic resonance angiography. Randomisation was done centrally with a computer-generated sequential minimisation method and was stratified by centre. The primary outcome was the proportion of patients achieving functional independence at 3 months, defined by a score of 0-2 on the modified Rankin scale, assessed in the modified intention-to-treat population (ie, patients lost to follow-up and those with missing data were excluded). Safety outcomes were analysed in the per-protocol population (ie, all patients who did not follow the protocol of their randomisation group precisely were excluded from the analysis). THRACE is registered with ClinicalTrials.gov, NCT01062698.\n\n\n\nBetween June 1, 2010, and Feb 22, 2015, 414 patients were randomly assigned to the IVT group (n=208) or the IVTMT group (n=204). Four patients (two in each group) lost to follow-up and six (four in the IVT group and two in the IVTMT group) with missing data were excluded. 85 (42%) of 202 patients in the IVT group and 106 (53%) of 200 patients in the IVTMT group achieved functional independence at 3 months (odds ratio 1·55, 95% CI 1·05-2·30; p=0·028). The two groups had no significant differences in mortality at 3 months (24 [12%] deaths of 202 patients vs 27 [13%] of 206; p=0·70) or symptomatic intracranial haemorrhage at 24 h (four [2%] of 185 vs three [2%] of 192; p=0·71). Common adverse events related to thrombectomy were vasospasm (33 [23%] patients) and embolisation in a new territory (nine [6%]).\n\n\n\nMechanical thrombectomy combined with standard intravenous thrombolysis improves functional independence in patients with acute cerebral ischaemia, with no evidence of increased mortality. Bridging therapy should be considered for patients with large-vessel occlusions of the anterior circulation.\n\n\n\nFrench Ministry for Health.",
"affiliations": "Department of Diagnostic and Interventional Neuroradiology, INSERM U 947, University of Lorraine and University Hospital of Nancy, Nancy, France. Electronic address: s.bracard@chu-nancy.fr.;Department of Neurology, University of Lorraine and University Hospital of Nancy, Nancy, France.;Department of Neurology, Sainte-Anne Hospital and Paris-Descartes University, INSERM U894, Paris, France.;Department of Clinical Epidemiology, INSERM CIC-EC 1433, University of Lorraine and University Hospital of Nancy, Nancy, France.;Department of Neuroradiology, Sainte-Anne Hospital and Paris-Descartes University, INSERM U894, Paris, France.;Department of Neurology, University Hospital of Besançon, Besançon, France.;Department of Clinical Epidemiology, INSERM CIC-EC 1433, University of Lorraine and University Hospital of Nancy, Nancy, France.",
"authors": "Bracard|Serge|S|;Ducrocq|Xavier|X|;Mas|Jean Louis|JL|;Soudant|Marc|M|;Oppenheim|Catherine|C|;Moulin|Thierry|T|;Guillemin|Francis|F|;|||",
"chemical_list": "D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1474-4422",
"issue": "15(11)",
"journal": "The Lancet. Neurology",
"keywords": null,
"medline_ta": "Lancet Neurol",
"mesh_terms": "D000368:Aged; D002545:Brain Ischemia; D003131:Combined Modality Therapy; D005260:Female; D005343:Fibrinolytic Agents; D006801:Humans; D008297:Male; D061185:Mechanical Thrombolysis; D008875:Middle Aged; D017063:Outcome Assessment, Health Care; D020521:Stroke; D010959:Tissue Plasminogen Activator",
"nlm_unique_id": "101139309",
"other_id": null,
"pages": "1138-47",
"pmc": null,
"pmid": "27567239",
"pubdate": "2016-10",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": null,
"title": "Mechanical thrombectomy after intravenous alteplase versus alteplase alone after stroke (THRACE): a randomised controlled trial.",
"title_normalized": "mechanical thrombectomy after intravenous alteplase versus alteplase alone after stroke thrace a randomised controlled trial"
} | [
{
"companynumb": "FR-ROCHE-1824259",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALTEPLASE"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "BACKGROUND\nCutaneous angiosarcoma presents clinically in numerous ways, and can be mistaken for a different clinical entity, particularly when arising at unusual anatomic locations such as the eyelid.\n\n\nMETHODS\nA 57-year-old woman presented with a 1-year history of eyelid swelling. Concurrent imaging was also suggestive of an edematous process. Multiple superficial biopsies showed nonspecific dermal inflammation and interstitial edema. A diagnosis of Morbihan disease (chronic and idiopathic lymphedema of the eyelid) was rendered, and the patient was treated with compression and local therapy without clinical improvement. Three years after initial presentation, a diagnostic blepharoplasty was performed revealing a deep dermal vascular proliferation composed of anastomosing vascular channels with an atypical endothelial lining. A diagnosis of cutaneous angiosarcoma was ultimately made.\n\n\nCONCLUSIONS\nThis case illustrates a unique presentation of cutaneous angiosarcoma and the implications of different biopsy techniques in acquiring the correct diagnosis.",
"affiliations": "Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN.;Department of Ophthalmology and Visual Sciences, Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN.;Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN.",
"authors": "Ferguson|Donna C|DC|;Mawn|Louise A|LA|;Al-Rohil|Rami N|RN|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/DAD.0000000000001096",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0193-1091",
"issue": "40(8)",
"journal": "The American Journal of dermatopathology",
"keywords": null,
"medline_ta": "Am J Dermatopathol",
"mesh_terms": "D001706:Biopsy; D003937:Diagnosis, Differential; D003951:Diagnostic Errors; D005142:Eyelid Neoplasms; D005260:Female; D006394:Hemangiosarcoma; D006801:Humans; D008209:Lymphedema; D008875:Middle Aged; D012878:Skin Neoplasms",
"nlm_unique_id": "7911005",
"other_id": null,
"pages": "617-620",
"pmc": null,
"pmid": "29329133",
"pubdate": "2018-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cutaneous Angiosarcoma of the Eyelid Mimicking Morbihan Disease.",
"title_normalized": "cutaneous angiosarcoma of the eyelid mimicking morbihan disease"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/19/0113828",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nIbrutinib, an oral inhibitor of Bruton's tyrosine kinase, has altered the treatment perspective of chronic lymphocytic leukemia and showed modest activity against several types of non-Hodgkin's lymphomas. According to phase studies and real-world data, reported serious adverse effects included atrial fibrillation, diarrhea, and bleeding diathesis. However, heart failure was not reported to be a probable adverse effect linked with ibrutinib.\n\n\nMETHODS\nIn this paper, we present a 66-year-old female chronic lymphocytic leukemia patient who developed significant and symptomatic left ventricular dysfunction at the 13th month of ibrutinib treatment.\nFollowing cessation of ibrutinib, ejection fraction and clinical findings of the left ventricular dysfunction alleviated.\n\n\nCONCLUSIONS\nAlthough the use of ibrutinib is generally well tolerated, cardiac functions should be monitored occasionally in all patients.",
"affiliations": "Faculty of Medicine, Department of Hematology, Edirne, Turkey.;Faculty of Medicine, Department of Hematology, Edirne, Turkey.;Faculty of Medicine, Department of Hematology, Edirne, Turkey.;Faculty of Medicine, Department of Hematology, Edirne, Turkey.;Faculty of Medicine, Department of Hematology, Edirne, Turkey.;Faculty of Medicine, Department of Hematology, Edirne, Turkey.;Faculty of Medicine, Department of Hematology, Edirne, Turkey.",
"authors": "Gülsaran|Sedanur K|SK|;Baysal|Mehmet|M|https://orcid.org/0000-0001-7681-4623;Demirci|Ufuk|U|;Baş|Volkan|V|;Kirkizlar|Hakkı O|HO|;Umit|Elif|E|https://orcid.org/0000-0001-5589-3000;Demir|Ahmet M|AM|",
"chemical_list": "D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; D000225:Adenine",
"country": "England",
"delete": false,
"doi": "10.1177/1078155219852146",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "26(2)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "CLL; Ibrutinib; cardiomyopathy; left ventricular dysfunction",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000225:Adenine; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000368:Aged; D009202:Cardiomyopathies; D005260:Female; D006801:Humans; D000067562:Late Onset Disorders; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D018487:Ventricular Dysfunction, Left",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "478-480",
"pmc": null,
"pmid": "31142233",
"pubdate": "2020-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Late onset left ventricular dysfunction and cardiomyopathy induced with ibrutinib.",
"title_normalized": "late onset left ventricular dysfunction and cardiomyopathy induced with ibrutinib"
} | [
{
"companynumb": "TR-ABBVIE-20K-161-3327947-00",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METOPROLOL"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nPoly (ADP-ribose) polymerase (PARP) inhibitors are approved for the treatment of breast cancer susceptibility genes 1 and 2 (BRCA1/2) mutant ovarian and breast cancers, and are now being evaluated in metastatic castration-resistant prostate cancer (mCRPC). Reversion mutations that restore BRCA1/2 function have been shown to be responsible for resistance to platinum-based chemotherapy and PARP inhibitors, however there is no information on the sequential use of these agents in prostate cancer.\n\n\nMETHODS\nA patient with mCRPC associated with a germline BRCA2 mutation was sequentially treated with carboplatin and the PARP inhibitor rucaparib. Genomic profiling of the available baseline tumor and progression blood samples using next-generation sequencing panel tests identified polyclonal BRCA2 reversion mutations post carboplatin treatment but prior to rucaparib treatment. A total of 12 somatic reversion mutations were detected and ranged from small indels to larger deletions of up to 387 amino acids. These alterations are all predicted to restore the BRCA2 open reading frame and potentially protein function. The patient received limited benefit while on rucaparib, likely due to these reversion mutations observed prior to treatment.\n\n\nCONCLUSIONS\nHere we report a case of a patient with prostate cancer who received a platinum agent and PARP inhibitor sequentially and in whom polyclonal BRCA2 reversion mutations were identified as the likely mechanism of acquired resistance to carboplatin and primary resistance to PARP inhibition. These findings suggest caution is warranted in sequencing these agents.",
"affiliations": "Translational Medicine, Clovis Oncology, Inc., 5500 Flatiron Parkway, Suite 100, Boulder, CO, 80301, USA.;Translational Medicine, Clovis Oncology, Inc., 5500 Flatiron Parkway, Suite 100, Boulder, CO, 80301, USA.;Berkshire Cancer Centre, Royal Berkshire NHS Foundation Trust, 5 Redlands Rd, Reading, RG15AQ, UK. eliaspintus@nhs.net.",
"authors": "Simmons|Andrew D|AD|;Nguyen|Minh|M|;Pintus|Elias|E|http://orcid.org/0000-0001-5123-1835",
"chemical_list": "D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D007211:Indoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C531549:rucaparib; D016190:Carboplatin",
"country": "England",
"delete": false,
"doi": "10.1186/s12885-020-6657-2",
"fulltext": "\n==== Front\nBMC Cancer\nBMC Cancer\nBMC Cancer\n1471-2407 BioMed Central London \n\n6657\n10.1186/s12885-020-6657-2\nCase Report\nPolyclonal BRCA2 mutations following carboplatin treatment confer resistance to the PARP inhibitor rucaparib in a patient with mCRPC: a case report\nSimmons Andrew D. asimmons@clovisoncology.com 1 Nguyen Minh mnguyen@clovisoncology.com 1 http://orcid.org/0000-0001-5123-1835Pintus Elias eliaspintus@nhs.net 23 1 grid.428464.8Translational Medicine, Clovis Oncology, Inc., 5500 Flatiron Parkway, Suite 100, Boulder, CO 80301 USA \n2 grid.419297.00000 0000 8487 8355Berkshire Cancer Centre, Royal Berkshire NHS Foundation Trust, 5 Redlands Rd, Reading, RG15AQ UK \n3 grid.239826.4Guy’s Hospital, Great Maze Pond, London, SE19RT UK \n14 3 2020 \n14 3 2020 \n2020 \n20 21524 6 2019 18 2 2020 © The Author(s). 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nPoly (ADP-ribose) polymerase (PARP) inhibitors are approved for the treatment of breast cancer susceptibility genes 1 and 2 (BRCA1/2) mutant ovarian and breast cancers, and are now being evaluated in metastatic castration-resistant prostate cancer (mCRPC). Reversion mutations that restore BRCA1/2 function have been shown to be responsible for resistance to platinum-based chemotherapy and PARP inhibitors, however there is no information on the sequential use of these agents in prostate cancer.\n\nCase presentation\nA patient with mCRPC associated with a germline BRCA2 mutation was sequentially treated with carboplatin and the PARP inhibitor rucaparib. Genomic profiling of the available baseline tumor and progression blood samples using next-generation sequencing panel tests identified polyclonal BRCA2 reversion mutations post carboplatin treatment but prior to rucaparib treatment. A total of 12 somatic reversion mutations were detected and ranged from small indels to larger deletions of up to 387 amino acids. These alterations are all predicted to restore the BRCA2 open reading frame and potentially protein function. The patient received limited benefit while on rucaparib, likely due to these reversion mutations observed prior to treatment.\n\nConclusions\nHere we report a case of a patient with prostate cancer who received a platinum agent and PARP inhibitor sequentially and in whom polyclonal BRCA2 reversion mutations were identified as the likely mechanism of acquired resistance to carboplatin and primary resistance to PARP inhibition. These findings suggest caution is warranted in sequencing these agents.\n\nKeywords\nBRCAProstate cancerPARP inhibitorPoly (ADP-ribose) polymeraseClovis Oncology IncN/aissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nResults from the phase 2 TOPARP study (NCT01682772) suggest that the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib has activity in men with metastatic castration-resistant prostate cancer (mCRPC) who have a deleterious alteration in a DNA damage repair gene, such as BRCA2 [1]. Recently, preliminary results of the TRITON2 study (NCT02952534) showed that 52 and 44% of evaluable mCRPC patients with a deleterious BRCA1/2 mutation had a prostate-specific antigen (PSA) response and Response Evaluation Criteria In Solid Tumors response, respectively, when treated with the PARP inhibitor rucaparib [2]. Based on these encouraging results, the U.S. Food and Drug Administration granted Breakthrough Therapy designation to both olaparib and rucaparib in mCRPC, and there are many ongoing studies evaluating these and other PARP inhibitors in patients with prostate cancer.\n\nPARP inhibitors have been approved for the treatment of BRCA1/2 mutant ovarian and breast cancers. A key mechanism of resistance to PARP inhibitors and platinum-based chemotherapy in these cancers is the acquisition of reversion mutations in BRCA1/2 that restore protein function [3, 4]. Reversion mutations in BRCA2 have also been observed in a small number of mCRPC patients treated with PARP inhibitors or carboplatin [5–8]. Acquired reversion mutations in BRCA1/2 resulting from exposure to platinum chemotherapy are likely to render tumors less sensitive to PARP inhibitor treatment. In a recent study of patients with ovarian cancer treated with rucaparib following platinum, patients without BRCA1/2 reversion mutations had a significantly longer median progression-free survival than patients with reversion mutations (9.0 vs. 1.8 months; hazard ratio, 0.12; P < 0.0001) [3]. However, there are limited data on the combination or sequential use of platinum and PARP inhibitors in prostate cancer.\n\nIn this manuscript, we describe a patient with mCRPC and a germline BRCA2 mutation who was sequentially treated with carboplatin and the PARP inhibitor rucaparib. We profiled the available baseline tumor and progression blood samples using next-generation sequencing panel tests and identified polyclonal BRCA2 reversion mutations post carboplatin treatment but prior to rucaparib treatment. The patient received limited benefit while on rucaparib, likely due to these reversion mutations observed prior to treatment.\n\nCase presentation\nIn May 2016, a 58-year-old patient presented with hematuria and rectal tenesmus. Baseline staging showed prostate cancer invading the mesorectum, pelvic lymphadenopathies, and high-volume bone metastases (T4N1M1); his serum PSA was 136 ng/mL, and his alkaline phosphatase (ALP) was 1106 IU/L (Fig. 1). A prostatic biopsy revealed a Gleason’s 5 + 5 prostate adenocarcinoma. His comorbidities included moderate aortic stenosis, left ventricular hypertrophy, left atrial dilatation, diabetes, hypercholesterolemia, and vitiligo. His Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) was 1.\nFig. 1 Clinical treatment course and PSA and ALP responses. Treatment and duration of treatment are denoted as arrows or colored areas, and time of sampling as diamonds. ALP, alkaline phosphatase; LHRH, luteinizing hormone-releasing hormone; PSA, prostate-specific antigen; RT, palliative radiotherapy\n\n\n\nIn June 2016, he commenced on luteinizing hormone-releasing hormone agonists with bicalutamide cover (PSA, 20 ng/mL; ALP, 1567 IU/L) and received his first cycle of docetaxel chemotherapy. In October 2016, docetaxel was discontinued after four cycles due to clinical and biochemical progression. Serum PSA was 41 ng/mL and ALP was 292 IU/L. In November 2016, the patient started on enzalutamide and shortly after received palliative radiotherapy to the lumbosacral spine and started zoledronic acid for prevention of skeletal-related events. He had a marked response to enzalutamide in terms of pain control and PSA and ALP decline (Fig. 1) until August 2017, when due to bone-related pain and PSA and ALP rise, treatment was stopped.\n\nFrom August to November 2017, the patient received six cycles of second-line cabazitaxel chemotherapy, which were discontinued due to clinical and radiological progression. His ECOG Performance Status for the first time since his diagnosis declined to 2. Based on family history and the aggressive clinical behavior of the disease, in January 2018 he commenced third-line carboplatin chemotherapy (area under the concentration-time curve 5). His initial PSA and ALP levels were 24 ng/mL and 113 IU/L and reached a nadir of 10 ng/mL and 85 IU/L, respectively. Chemotherapy allowed better pain control and improved general condition. He received a total of six cycles of carboplatin, the last given in April 2018. Chemotherapy was discontinued for symptomatic progression and PSA progression, despite a stable ALP level (91 IU/L).\n\nIn May 2018, molecular testing was performed on the prostatic sample taken in June 2016 to determine if the patient was eligible for clinical trials. FoundationONE CDx (version T7) testing [9] identified a deleterious BRCA2 c.5727_5728insG (N1910fs*2) mutation in the original tumor biopsy (Fig. 2). This alteration was later confirmed to be a germline pathogenic variant in BRCA2 by Hereditary Cancer Solution testing. Based on published data suggesting that PARP inhibitors are active in patients with BRCA1/2-mutant mCRPC [1], in June 2018 the patient commenced on rucaparib 600 mg twice daily (BID) under a compassionate use program due to the lack of an approved standard of care or access to a clinical trial at that time. A baseline plasma sample for circulating tumor DNA (ctDNA) analysis was collected prior to the patient starting rucaparib and profiled using the FoundationACT assay [10]. In addition to the germline BRCA2 alteration, 12 other BRCA2 alterations were also observed. Six of the alterations were in close proximity (within ≈10 amino acids) of the original alteration (Fig. 2a, Table 1). All six alterations reestablished the BRCA2 open reading frame (ORF) by substitutions or short in-frame deletions. Five additional alterations were longer in-frame deletions ranging from 46 to 386 amino acids, four of which resulted in partial or complete loss of the BRC repeat sequences BRC5, BRC6, BRC7, and/or BRC8 (Fig. 2b). These alterations are also predicted to restore the BRCA2 ORF. The final BRCA2 alteration extended across the exon/intron border: nucleotides 5333–6841 of the coding region and the first 197 nucleotides of the intron (5333_6841 + 197del1706; Table 1). The 1509 base pair deletion within the coding region (6841–5333 + 1) would potentially remove the original mutation as part of an in-frame 503 amino acid deletion.\nFig. 2 BRCA2 reversion mutations. Schematic of small indel (a) and large deletion mutations (b) detected. BRC repeats, interacting regions, and sequences are represented as yellow, blue, and orange boxes, respectively. Substitutions and deletions are represented as red text and black lines, respectively\n\nTable 1 BRCA2 and CDKN2A mutations and corresponding variant allele fractions\n\nGene\tProtein\tCoding change\tVariant allele fraction %\t\nBRCA2\tN1910fs*2\t5727_5728insG\t83.7\t\nBRCA2\tA1843_S1985del\t5528_5956del429\t0.53\t\nBRCA2\tA1891_M1936del\t5671_5808del138\t0.54\t\nBRCA2\tD1909_D1911 > EDY\t5727_5731TAATG > AGACT\t0.64\t\nBRCA2\tD1909_E1912 > V\t5726_5735ATAATGATGA > T\t0.13\t\nBRCA2\tI1664_V2049del\t4989_6146del1158\t0.18\t\nBRCA2\tI1903_D1909 > M\t5709_5727TCTTCATAACTCTCTAGAT > G\t0.11\t\nBRCA2\tL1908_N1910del\t5722_5730delCTAGATAAT\t0.33\t\nBRCA2\tL1908_S1917del\t5721_5750del30\t1.8\t\nBRCA2\tN1766_Q2009del\t5292_6025 > CA\t1.3\t\nBRCA2\tN1910_D1911del\t5728_5733delAATGAT\t3.3\t\nBRCA2\tS1788_P2114 > DTT\t5362_6340 > GATACCA\t1.2\t\nBRCA2\tUnknown\tsplice site 5333_6841 + 197del1706\t4.8\t\nCDKN2A\tP114L\t341C > T\t10.0\t\n\n\nThe FoundationACT assay reported the variant allele fraction (VAF) for the detected alterations (Fig. 3, Table 1). The VAF for the baseline BRCA2 N1910fs*2 mutation was 83.7%, consistent with the confirmed germline alteration. The VAF of the reversion mutations ranged from 0.11–4.8%, with a total of 14.9%. A CDKN2A P114L alteration was observed at a VAF of 10.0%.\nFig. 3 Graph of variant allele fractions for BRCA2 and CDKN2A mutations. BRCA2 reversion mutations are represented in legend\n\n\n\nThe patient received rucaparib 600 mg BID for a total of 47 days from June to July 2018. His general condition gradually deteriorated. Following hospital admission with sepsis and uncontrolled back pain, imaging confirmed disease progression (new nodal, pulmonary, and hepatic lesions), and rucaparib was discontinued permanently.\n\nDiscussion and conclusions\nWe report a case of a patient with mCRPC and a germline truncating mutation in BRCA2 who developed 12 different somatic reversion mutations that restored the protein ORF and would be expected to render the tumor insensitive to platinum-based chemotherapy or PARP inhibitor treatment. Consistent with this hypothesis, the patient had a limited response to subsequent treatment with rucaparib.\n\nAlthough no definitive conclusions can be made due to the limited sampling, it is likely that the reversion mutations resulted from the 4-month course of carboplatin, as the reversion mutations were not detected in the tumor tissue sample obtained at primary diagnosis. We are also not aware of any reports describing de novo BRCA2 reversion mutations prior to platinum-based chemotherapy or PARP inhibitor treatment. The emergence of reversion mutations in BRCA1/2 has been associated with platinum drugs based on their mechanism of action of forming DNA-platinum adducts that leads to DNA lesions [11], whereas it has not been reported in patients treated with taxanes. Although anecdotal, it is remarkable that our patient developed reversion mutations after such a limited exposure to platinum, which suggests a different genomic or biological context in inducing secondary mutations among patients with prostate cancer compared to those with ovarian cancer.\n\nAll of the reversion mutations would result in unique, non-wild-type proteins that would restore the C-terminal end of BRCA2, including the DNA binding domains, the tower domain, oligonucleotide/oligosaccharide-binding folds, and nuclear localization sequence. However, several of the mutations resulted in large BRCA2 deletions (up to 387 amino acids), encompassing one or more of the BRC repeats BRC5–8. This region is known to stabilize the RAD51 filament and promote homologous recombination repair upon DNA damage [12]. A previous report suggests that BRC5–8 deletion may confer partial resistance to the DNA damaging agent mitomycin C using BRCA2-mutant cell lines [13]. Although the functional consequences of each of the reversion mutations cannot be determined without additional investigation, it is likely that many or all of them restore BRCA2 function.\n\nThe VAF for the BRCA2 reversion mutations ranged from 0.11 to 4.8%, totaling 14.9% overall. Although the limited activity observed with rucaparib cannot definitively be attributed to these low allele frequency reversion mutations, the identification of polyclonal reversion mutations in prostate cancer patients is consistent with that in other reports [5–8] and highlights the strong selective pressure to restore BRCA2 function. It is not possible to determine if these alterations are clonal or multiple reversion alterations in a single tumor cell, because shedding may not be similar from each tumor deposit. Interestingly, the patient’s PSA levels remained stable (ranging between 27 and 31 ng/L) throughout rucaparib treatment, indicating that perhaps not all tumor clones contained a reversion mutation and some were responding to treatment.\n\nAnother acquired alteration detected in ctDNA following carboplatin treatment was a CDKN2A P114L variant with a VAF of 10%, suggesting that it may have been a somatic tumor-specific variant. The CDKN2A gene encodes the p16(INK4A) and p14(ARF) proteins, which both function as tumor suppressors [14]. The P114L (c.341C > T) loss-of-function mutation would prevent p16 from inhibiting CDK4 and inducing cell cycle arrest [15]. CDKN2A is commonly altered in patients with metastatic melanoma and cutaneous squamous cell carcinoma [16, 17]. Although CDKN2A mutations are rarely observed in prostate cancer, a recent case study reported a CDKN2A P81L mutation (which would render the protein functionally defective) as the proposed mechanism underlying acquired resistance to enzalutamide in a patient with CRPC [18]. The emergence of the CDKN2A P114L alternation in our patient could have occurred during enzalutamide treatment. However, because the ctDNA sample was obtained after multiple therapies, including carboplatin and cabazitaxel, we cannot rule out the possibility that other agents may have caused the emergence of the CDKN2A mutation. Upregulation of cell-cycle pathway observed in patients resistant to enzalutamide along with genomic aberrations in the cell-cycle pathway observed in patients with prostate cancer (such as RB1 loss and CCDN1 amplification) suggest the potential importance of cell-cycle kinases in the development of prostate carcinoma and resistance to enzalutamide [19].\n\nWe acknowledge several limitations of our study regarding correlation to patient response. First, the patient’s ECOG PS at the start of rucaparib treatment was 2, and there are limited data on the effectiveness of PARP inhibitors in patients with an ECOG PS > 1. In addition, the patient was exposed to rucaparib for only 6 weeks. Although there is limited information on the time required for mCRPC patients to demonstrate a tumour response to a PARP inhibitor, it has previously been reported that 76% (19/25) of patients with a BRCA1/2 alteration treated with rucaparib in the TRITON2 trial had a radiographic response within 8 weeks of starting rucaparib [2].\n\nThe PARP inhibitor rucaparib is currently being evaluated in patients with mCRPC, where it has shown encouraging antitumor activity. An important question is how to use PARP inhibitors, as well as platinum-based chemotherapies, to maximize the clinical benefit in patients with mCRPC. This case study suggests that caution may be warranted in sequencing these agents.\n\nAbbreviations\nALPAlkaline phosphatase\n\nBIDTwice daily\n\nBRCA1Breast cancer susceptibility gene 1\n\nBRCA2Breast cancer susceptibility gene 2\n\nCDKN2ACyclin-dependent kinase inhibitor 2A\n\nctDNACirculating-tumor DNA\n\nECOGEastern Cooperative Oncology Group\n\nLHRHLuteinizing hormone-releasing hormone\n\nmCRPCMetastatic castration-resistant prostate cancer\n\nORFOpen reading frame\n\nPARPPoly (ADP-ribose) polymerase\n\nPSAProstate-specific antigen\n\nRTPalliative radiotherapy\n\nVAFVariant allele fraction\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nWe thank Linda Kelly and Catherine Smith for patient care, as well as Simon Watkins for his assistance in providing rucaparib for this patient. We appreciate Cheryl Chun of Clovis Oncology for her help in reviewing the manuscript. We thank the patient’s family for giving their consent to publish his case. Copy editing assistance funded by Clovis Oncology was provided by Shannon Davis of Ashfield Healthcare Communications (Middletown, CT, USA).\n\nAuthors’ contributions\nEP was the treating physician, conceived of the case, and collected and assembled the data. ADS, MN, and EP analyzed and interpretated the data, drafted and revised the manuscript, and read and approved the final manuscript.\n\nFunding\nWe would like to thank Clovis Oncology for funding the analysis of the ctDNA samples and Oxford University Hospitals NHS Foundation Trust for funding the germline analysis of the tumor DNA.\n\nAvailability of data and materials\nAll available data generated or analyzed during this study are included in this published article.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nPatient written informed consent has been obtained. A copy of the consent form is available for review by the Editor of this journal.\n\nCompeting interests\nADS and MN are employees of Clovis Oncology. EP reports a consulting or advisory role for Clovis Oncology; honoraria from Clovis Oncology, Astellas, Bristol-Myers Squibb, and Janssen; and travel support from Clovis Oncology, Astellas, Ipsen, and Janssen.\n==== Refs\nReferences\n1. Mateo J Carreira S Sandhu S Miranda S Mossop H Perez-Lopez R DNA-repair defects and olaparib in metastatic prostate cancer N Engl J Med 2015 373 18 1697 1708 26510020 \n2. Abida W Campbell D Patnaik A Preliminary results from the TRITON2 study of rucaparib in patients (pts) with DNA damage repair (DDR)-deficient metastatic castration-resistant prostate cancer (mCRPC): Updated analyses Ann Oncol 2019 30 suppl 5 abst 846PD \n3. Lin KK Harrell MI Oza AM Oaknin A Ray-Coquard I Tinker AV BRCA reversion mutations in circulating tumor DNA predict primary and acquired resistance to the PARP inhibitor rucaparib in high-grade ovarian carcinoma Cancer Discov. 2019 9 2 210 219 30425037 \n4. Norquist B Wurz KA Pennil CC Garcia R Gross J Sakai W Secondary somatic mutations restoring BRCA1/2 predict chemotherapy resistance in hereditary ovarian carcinomas J Clin Oncol 2011 29 22 3008 3015 21709188 \n5. Goodall J Mateo J Yuan W Mossop H Porta N Miranda S Circulating cell-free DNA to guide prostate cancer treatment with PARP inhibition Cancer Discov. 2017 7 9 1006 1017 28450425 \n6. Quigley D Alumkal JJ Wyatt AW Kothari V Foye A Lloyd P Analysis of circulating cell-free DNA identifies multiclonal heterogeneity of BRCA2 reversion mutations associated with resistance to PARP inhibitors Cancer Discov 2017 7 9 999 1005 28450426 \n7. Carneiro BA Collier KA Nagy RJ Pamarthy S Sagar V Fairclough S Acquired resistance to poly (ADP-ribose) polymerase inhibitor olaparib in BRCA2-associated prostate cancer resulting from biallelic BRCA2 reversion mutations restores both germline and somatic loss-of-function mutations JCO Precis Oncol 2018 2 1 8 30949620 \n8. Cheng HH Salipante SJ Nelson PS Montgomery B Pritchard CC Polyclonal BRCA2 reversion mutations detected in circulating tumor DNA after platinum chemotherapy in a patient with metastatic prostate cancer JCO Precis Oncol 2018 2 1 5 30949620 \n9. Frampton GM Fichtenholtz A Otto GA Wang K Downing SR He J Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing Nat Biotechnol 2013 31 11 1023 1031 24142049 \n10. Clark TA Chung JH Kennedy M Hughes JD Chennagiri N Lieber DS Analytical validation of a hybrid capture-based next-generation sequencing clinical assay for genomic profiling of cell-free circulating tumor DNA J Mol Diagn 2018 20 5 686 702 29936259 \n11. Shen DW Pouliot LM Hall MD Gottesman MM Cisplatin resistance: a cellular self-defense mechanism resulting from multiple epigenetic and genetic changes Pharmacol Rev 2012 64 3 706 721 22659329 \n12. Carreira A Kowalczykowski SC Two classes of BRC repeats in BRCA2 promote RAD51 nucleoprotein filament function by distinct mechanisms Proc Natl Acad Sci U S A 2011 108 26 10448 10453 21670257 \n13. Chatterjee G Jimenez-Sainz J Presti T Nguyen T Jensen RB Distinct binding of BRCA2 BRC repeats to RAD51 generates differential DNA damage sensitivity Nucleic Acids Res 2016 44 11 5256 5270 27084934 \n14. Zhao R Choi BY Lee MH Bode AM Dong Z Implications of genetic and epigenetic alterations of CDKN2A (p16(INK4a)) in cancer EBioMedicine. 2016 8 30 39 27428416 \n15. Koh J Enders GH Dynlacht BD Harlow E Tumour-derived p16 alleles encoding proteins defective in cell-cycle inhibition Nature. 1995 375 6531 506 510 7777061 \n16. Brown VL Harwood CA Crook T Cronin JG Kelsell DP Proby CM p16INK4a and p14ARF tumor suppressor genes are commonly inactivated in cutaneous squamous cell carcinoma J Invest Dermatol 2004 122 5 1284 1292 15140233 \n17. Helgadottir H, Ghiorzo P, van Doorn R, Puig S, Levin M, Kefford R, et al. Efficacy of novel immunotherapy regimens in patients with metastatic melanoma with germline CDKN2A mutations. J Med Genet. 2018. [Epub ahead of print]. 10.1136/jmedgenet-2018-105610.\n18. Han GC Hwang J Wankowicz SAM Zhang Z Liu D Cibulskis C Genomic resistance patterns to second-generation androgen blockade in paired tumor biopsies of metastatic castration-resistant prostate cancer JCO Precis Oncol 2017 1 1 11 \n19. Robinson D Van Allen EM Wu YM Schultz N Lonigro RJ Mosquera JM Integrative clinical genomics of advanced prostate cancer Cell. 2015 162 2 454 28843286\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2407",
"issue": "20(1)",
"journal": "BMC cancer",
"keywords": "BRCA; PARP inhibitor; Poly (ADP-ribose) polymerase; Prostate cancer",
"medline_ta": "BMC Cancer",
"mesh_terms": "D024682:BRCA2 Protein; D016190:Carboplatin; D019008:Drug Resistance, Neoplasm; D024522:Genes, BRCA2; D018095:Germ-Line Mutation; D006801:Humans; D007211:Indoles; D008297:Male; D008875:Middle Aged; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D064129:Prostatic Neoplasms, Castration-Resistant; D016896:Treatment Outcome",
"nlm_unique_id": "100967800",
"other_id": null,
"pages": "215",
"pmc": null,
"pmid": "32171277",
"pubdate": "2020-03-14",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24142049;27084934;21709188;31501807;27428416;28450425;7777061;28450426;22659329;30291219;29936259;21670257;30425037;15140233;26510020;28843286",
"title": "Polyclonal BRCA2 mutations following carboplatin treatment confer resistance to the PARP inhibitor rucaparib in a patient with mCRPC: a case report.",
"title_normalized": "polyclonal brca2 mutations following carboplatin treatment confer resistance to the parp inhibitor rucaparib in a patient with mcrpc a case report"
} | [
{
"companynumb": "US-PFIZER INC-2020139009",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": "2",
... |
{
"abstract": "BACKGROUND\nAs neonatal central diabetes insipidus is rare in preterm neonates with intraventricular hemorrhage (IVH), very little is known about dosing and the route of administration of desmopressin treatment.\n\n\nMETHODS\nWe present a preterm neonate born at 29 weeks' gestation. Within 24 h, she developed bilateral IVH with subsequent post-hemorrhagic hydrocephalus. On the 3rd postnatal day, she developed diabetes insipidus for which she was intranasally administered 0.2 mg desmopressin. This resulted in oliguria with several hours of anuria and a 25-point drop in sodium levels within 15 h.\n\n\nCONCLUSIONS\nThe determination of the desmopressin dose in a preterm neonate is a challenge and there is no consistent literature about the dosing or the route of administration. We suggest starting with a low dose of intranasal desmopressin (0.05-0.1 μg) and titrate in accordance with clinical and laboratory parameters.",
"affiliations": null,
"authors": "Van der Kaay|Danielle C M|DC|;Van Heel|Willemijn J M|WJ|;Dudink|Jeroen|J|;van den Akker|Erica L T|EL|",
"chemical_list": "D003894:Deamino Arginine Vasopressin",
"country": "Germany",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0334-018X",
"issue": "27(7-8)",
"journal": "Journal of pediatric endocrinology & metabolism : JPEM",
"keywords": null,
"medline_ta": "J Pediatr Endocrinol Metab",
"mesh_terms": "D000281:Administration, Intranasal; D002543:Cerebral Hemorrhage; D003894:Deamino Arginine Vasopressin; D003919:Diabetes Insipidus; D005260:Female; D006801:Humans; D006849:Hydrocephalus; D007231:Infant, Newborn; D007234:Infant, Premature; D007235:Infant, Premature, Diseases",
"nlm_unique_id": "9508900",
"other_id": null,
"pages": "769-71",
"pmc": null,
"pmid": "24670345",
"pubdate": "2014-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Transient diabetes insipidus in a preterm neonate and the challenge of desmopressin dosing.",
"title_normalized": "transient diabetes insipidus in a preterm neonate and the challenge of desmopressin dosing"
} | [
{
"companynumb": "NL-SA-2014SA043583",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "DESMOPRESSIN ACETATE"
},
"drugadditional": null,
... |
{
"abstract": "Rheumatoid meningitis (RM) is a rare central nervous system (CNS) manifestation of rheumatoid arthritis (RA) with a wide spectrum of symptoms. We present a review of the literature with a rare illustrative case of a 61-year-old man with a history of seropositive rheumatoid arthritis (RA) who presented headaches, stroke-like symptoms and seizures. MRI revealed the leptomeningeal enhancement in the right hemisphere. As cerebromeningeal fluid showed increased level of protein and was positive for Candida mannan, the initial clinical diagnosis was fungal meningitis. Despite the antifungal treatment the patient's clinical condition did not improve. Detailed laboratory, radiologic and histopathological diagnostics enabled the diagnosis of RM. In conclusion is worth to highlight that presentation of RM is variable and complex, diagnosing it is a big dilemma which is why it must be considered in the differential in a patient with long-standing seropositive RA.",
"affiliations": "Student Clinical Rheumatology Circle, Medical University of Gdansk, Poland.;Department of Internal Medicine, Connective Tissue Diseases and Geriatrics, Medical University of Gdansk, Poland.;Department of Internal Medicine, Connective Tissue Diseases and Geriatrics, Medical University of Gdansk, Poland.",
"authors": "Joshi|Sanyukta|S|;Masiak|Anna|A|;Zdrojewski|Zbigniew|Z|",
"chemical_list": null,
"country": "Poland",
"delete": false,
"doi": "10.5114/reum.2020.95368",
"fulltext": "\n==== Front\nReumatologia\nReumatologia\nRU\nReumatologia\n0034-6233 2084-9834 Narodowy Instytut Geriatrii, Reumatologii i Rehabilitacji w Warszawie \n\n32476685\n95368\n10.5114/reum.2020.95368\nCase-Based Review\nRheumatoid arthritis with pachymeningitis – a case presentation and review of the literature\nJoshi Sanyukta 1 Masiak Anna 2 Zdrojewski Zbigniew 2 1 Student Clinical Rheumatology Circle, Medical University of Gdansk, Poland\n2 Department of Internal Medicine, Connective Tissue Diseases and Geriatrics, Medical University of Gdansk, Poland\nAddress for correspondence: Anna Masiak, Department of Internal Medicine, Connective Tissue Diseases and Geriatrics, Medical University of Gdansk, 7 Dębinki St., 80-211 Gdansk, Poland, e-mail: anna.masiak@wp.pl\n30 4 2020 \n2020 \n58 2 116 122\n14 1 2020 09 4 2020 Copyright © 2020 Narodowy Instytut Geriatrii, Reumatologii i Rehabilitacji w Warszawie2020This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0). License (http://creativecommons.org/licenses/by-nc-sa/4.0/)Rheumatoid meningitis (RM) is a rare central nervous system (CNS) manifestation of rheumatoid arthritis (RA) with a wide spectrum of symptoms. We present a review of the literature with a rare illustrative case of a 61-year-old man with a history of seropositive rheumatoid arthritis (RA) who presented headaches, stroke-like symptoms and seizures. MRI revealed the leptomeningeal enhancement in the right hemisphere. As cerebromeningeal fluid showed increased level of protein and was positive for Candida mannan, the initial clinical diagnosis was fungal meningitis. Despite the antifungal treatment the patient’s clinical condition did not improve. Detailed laboratory, radiologic and histopathological diagnostics enabled the diagnosis of RM.\n\nIn conclusion is worth to highlight that presentation of RM is variable and complex, diagnosing it is a big dilemma which is why it must be considered in the differential in a patient with long-standing seropositive RA.\n\nrheumatoid arthritisrheumatoid meningitisstroke-like symptomscentral system involvement\n==== Body\nIntroduction\nRheumatoid arthritis (RA) is a multifactorial, autoimmune systemic inflammatory disease which most commonly affects synovial joints. It presents with pain and stiffness of multiple joints which commonly involve proximal interphalangeal (PIP) and metacarpophalangeal (MCP) joints. The disease is estimated to affect 1% of the population predominantly women [1].\n\nRheumatoid arthritis has several extra-articular manifestations like rheumatoid vasculitis, nodules, interstitial pulmonary fibrosis, ocular manifestations (e.g. scleritis) or renal involvement. Nervous system manifestations of RA include peripheral neuropathies, mononeuritis multiplex, cervical myelopathy due to atlanto-axial subluxation and rheumatoid meningitis (RM) [2].\n\nRheumatoid meningitis is a rare central nervous system (CNS) manifestation of RA with symptoms ranging from headaches and seizures to deafness, speech impairment and stroke-like symptoms for instance hemi-paresis, cognitive impairment, focal neurological deficits which makes diagnosing it a challenge.\n\nMaterial and methods\nWe analyzed studies reporting neurological manifestations of rheumatoid arthritis from PubMed and Google Scholar databases as a key words using a combination of search terms such as: rheumatoid arthritis with pachymeningitis.\n\nUsing a combination of presented search terms, we undertook a systematic review of the literature for discussion and analysis of studies reporting neurological manifestations of rheumatoid arthritis from PubMed and Google Scholar databases especially focusing on pachymeningitis.\n\nCase description\nA 61-year old man with speech impairment, left-sided paresis and generalized seizures was admitted to the neurology department with the suspicion of stroke. The patient suffered from coronary heart disease for seventeen years and RA for 10 years which was being treated with methylprednisolone (8 mg/day) and methotrexate (20 mg/week). Neurological symptoms were preceded by severe headache, right tinnitus and increased blood pressure (max 220/100 mm Hg). MRI of the head (Fig. 1)showed hyper-intense signaling and diffusion restriction from the fronto-parieto-temporal region, additionally contrast studies showed leptomeningeal enhancement in the right hemisphere.\n\nFig. 1 MRI scan of the brain on first admission to the hospital. The study description was prepared by prof. Edyta Szurowska. Axial TIRM dark fluid sequence – cerebral cortex oedema in the frontoparietal region of the right hemisphere with clamping grooves of brain and increase of their signal (A); axial DWI sequence – minor foci of diffusion reduction in the right parietal lobe (B); axial, contrast-enhanced T1 –dependent images- distinct enhancement of dura mater and pia mater in frontoparietal area (C).\n\nTranscranial USG revealed atherosclerotic lesions that were hemodynamically insignificant which lead to exclusion of stroke. Lumbar puncture was performed for further assessment which revealed pleocytosis (7 cells/µl), increased level of protein and was positive for Candida mannan which lead to a suspicion of fungal meningitis. Moreover, presence of IgG oligoclonal bands were present in both cerebrospinal fluid (CSF) and serum, suggesting passive diffusion between them. Additionally, a brain biopsy affirmed lymphoid infiltration of the meninges with histiocytes containing PAS+ substance. Due to suspicion of fungal etiology the patient was treated with fluconazole for 3 months, but clinical condition did not improve.\n\nThe patient reported back after 3 months with severe headache (VAS 10/10), dizziness, sleeplessness and mood disorders. Laboratory tests showed mild normocytic anemia (Hgb 11.6 g/dl), thrombocytopenia (PLT 122 G/l), lymphopenia (0,42 G/l) and low inflammation markers (ESR 8 mm/h, CRP 3.6 mg/l). Immunological assessment reveal the presence of anti-nuclear autoantibodies (ANA HEp-2 1 : 320 homogenous type, > 1 : 2560 speckled type; ANA-immunoblot: anti-SSA-Ro60 and anti-SSA-Ro52; anti-SS-A (154 IU/ml; n< 20.0 IU/ml), RF (229 IU/ml, n< 30 IU/ml) and ACPA antibodies (76 U/ml; n< 5 U/ml). Anti-neutrophil antibodies (ANCA), anti-endothelial cell antibodies or antiphospholipid antibodies were negative (Table I). There were no symptoms of active vasculitis in other organs (physical examination, chest CT, abdominal USG, urine test). Follow-up MRI revealed no visible regression of previously described changes. Fungal etiology seemed unlikely in this situation.\n\nTable I Laboratory results\n\nCSF analysis\t\nParameters tested\tResult\tReference values\t\nChlorides (mmol/l)\t115\t115–130\t\nAlbumin (mg/l)\t771.04\t< 350\t\nTotal Protein (g/l)\t1.11\t0.15–0.40\t\nGlucose (mg/dl)\t63\t40–70\t\nCell count (cells/µl)\t8\t< 3\t\nErythrocytes (per high power field)\t1–3\tAbsent\t\nLeukocytes (per high power field)\t0–1\tAbsent\t\nBorrelia antibodies\tNegative\tNegative\t\nAspergillosis antibodies\tNegative\tNegative\t\nCandida mannan antibodies\tPositive\tNegative\t\nImmunoglobulin (IgG) (mg/l)\t36.10\tAbsent\t\nSerology\t\nParameters tested\tResult\tReference values\t\nHemoglobin (g/dl)\t11.6\t13–17\t\nHematocrit (%)\t35.8\t40–50\t\nBasophils (%)\t0.0\t0–2\t\nEosinophils (%)\t0.0\t0–6\t\nNeutrophils (%)\t83.6\t40–70\t\nMonocytes (%)\t6.2\t4–8\t\nLymphocytes (%)\t10.0\t20–50\t\nMCV (fl)\t86.1\t80–100\t\nGlucose (mg/dl)\t140\t60–99\t\nCRP (mg/l)\t3.6\t0–5\t\nESR (mm/h)\t8\t< 15\t\nACPA (U/ml)\t76\t< 5\t\nRF (IU/ml)\t229\t< 30\t\nACPA – anti-cycliccitrullinatedpeptide, CRP – C-reactive protein, CSF – cerebrospinal fluid analysis, ESR – erythrocytesedimentationrate, MCV – meancorpuscularvolume, RF – rheumatoidfactor.\n\nThe neuropathological consultation of brain samples (Fig. 2), combined with the clinical presentation and laboratory results allowed to diagnose chronic rheumatoid meningitis and CNS vasculitis in the course of RA. Additionally, the diagnosis of secondary Sjögren’s syndrome (sSS) was based on a positive Schirmer’s test, symptoms of dry mouth (unstimulated salivary flow) and presence of anti-SSA antibodies in the immunological assessment.\n\nFig. 2 Histopathology of cerebro-meningeal biopsy. The study description was prepared by prof. Ewa Iżycka-Świeszewska. Intense chronic inflammation with vasculitis and granulation tissue within leptomeninges and subarachnoid space as well as slight vasculitis of cortical vessels (HE, 100 ×) (A); fibrosing granulation tissue with histiocytic multinucleated cell necrotizing granuloma and hyalinization of blood vessels walls (HE, 200 ×) (B); inflammatory infiltrate made of foamy and multinucleated histiocytes, lymphocytes and plasmocytes (HE, 400 ×) (C); chronic meningitis with active vasculitis in form of dense intraparietal and perivascular lympho-plasmocytic infiltrates, old extravasations with hemosiderin- laden macrophages and collagen fibers deposition (HE, 400 ×) (D).\n\nImmunosuppressive treatment with methylprednisolone (total 3 g IV), followed by oral prednisone 0.5 mg/kg QD and IV cyclophosphamide every 3 weeks for 8 months (total dose 7.2 g) was administered. Currently after 4 years the patient is in good condition with episodic headaches of low intensity (VAS 2/10). The control MRI (Fig. 3) revealed a decrease in temporal enhancement of the meninges. The patients were treated with methotrexate in current dose 15 mg per week.\n\nFig. 3 MRI scan of the brain after 6 months of immunosuppressive treatment. The study description was prepared by prof. Edyta Szurowska. Axial FLAIR sequence – regression of cerebral cortex oedema placed in the frontoparietal region of the right hemisphere, grooves of brain of proper width, visible only band-like area of gliosis in the area of surgical access (A); axial, contrast-enhanced T1 – dependent images – distinct regression of meninges enhancement in frontoparietal area, minor enhancement of post-biopsy site (B).\n\nResults of data searching\nWe analyzed similar clinical problems in the literature. Since 2012 there have been 28 different case reports published about pachymeningitis in a course of RA. Out of these, 5 of them reported patients with seronegative RA in whom pachymeningitis was the first clinical manifestation of the autoimmune disease (Fig. 4) [3–8].\n\nFig. 4 Results of data searching.\n\nDiscussion\nPachymeningitis is the inflammation of the most superficial layer of the meninges-dura mater [1]. In some cases, the inflammation can reach the leptomeninges and the brain parenchyma [3]. The etiology of pachymeningitis ranges from infectious causes (like syphilis, fungal or viral), lymphomas, drug-induced to auto-immune (like vasculitis or RA) and IgG4-related pathologies [4, 9]. Extremely rare cause of hypertrophic pachymeningitis is primary Sjögren’s syndrome (SS). Nakano et al. [10] report only a single case of patient with primary SS who developed pachymeningitis. There have not been any cases of patients with secondary SS associated with pachymeningitis. This variety of causes lead to considerable diagnostic difficulties. Identifying the cause of changes in the CNS is crucial to implement proper treatment and avoid complications.\n\nCervical myelopathy due to atlanto-axial subluxation is the most well-known CNS manifestation in the course of RA, others include spinal cord compression, subdural hematoma [11], cerebral vasculitis, rheumatoid nodule formation and pachymeningitis [12]. The first suggestion of pachymeningitis due to RA was by Wells [13] in 1969, since then there have been a number of reviews and reports which showed CNS involvement in RA patients.\n\nWhile common neurological symptoms like headaches, seizures, focal neurological deficits, altered mental condition and cranial nerve palsies that present as blindness or sensorineural deafness were reported over the years [12, 14], some rare symptoms have been described in the recent times which include neuropsychiatric presentation [5] and acute parkinsonism [15]. Due to these varied neurological symptoms and a multitude of etiologies for pachymeningitis, diagnosis of rheumatoid meningitis is challenging.\n\nDiagnosis of RM depends on a combination of clinical presentation, lumbar puncture, brain MRI and biopsy along with exclusion of other etiologies [3]. The CSF analysis on lumbar puncture may have mild pleocytosis with predominant lymphocytes, increased protein and increased or normal glucose. To exclude any infections, CSF cultures should be negative.\n\nIn our case, the cultures were negative for bacteria, borreliosis and aspergillosis, but was positive for Candida mannan due to which a suspicion of fungal etiology arose. MRI with DWI sequence shows meningeal thickening and sometimes there maybe presence of rheumatoid nodules with contrast enhancement. But these tests are non-specific for RM and a biopsy for establish the diagnosis is necessary. In the histopathological assessment were nonspecific meningeal inflammation, presence of nodules and vasculitis [16].\n\nMagaki et al. [6] stated that the most characteristic histological findings in brain biopsy of described patients are picture of pachymeningitis or leptomeningitis with rheumatoid nodules (typical presentation) and vasculitis affected a smaller parenchymal and meningeal arteries. The mononuclear cells, especially plasma cells, multinucleated giant cells, neutrophils (less commonly) and occasional necrosis formed inflammatory infiltrates. The authors suggested that the autoimmunity of collagen may be a main cause of inflammatory changes in the meninges.\n\nSerological findings in a patient with RM include elevated CRP, ESR, RF and ACPA antibodies, out of these the latter two are considered specific, all of which were elevated in our patient [1]. ACPA antibodies titer has been a novel tool to check the disease advancement as its presence is associated with severe extra-articular manifestations and progressive damage to the joint [17]. Moreover, some case reports suggest presence of RF in the CSF as a possible diagnostic finding, although we did not assess this in our patient [17]. Currently there are no specific biomarkers or guidelines to detecting RM.\n\nTay et al. [18] conducted a meta-analysis assessing association of anti-N-methyl-D-aspartate (anti-NMDA) receptor antibodies and neuropsychiatric (NP) syndromes in systemic lupus erythematosus (SLE) and SS which added another potential serological marker [19]. Their study showed that presence of anti-NMDA receptor antibodies in the serum could be used in diagnosing NP syndromes in SLE and SS, but it did not help in distinguishing the type of NP manifestation. However, no such data is available for patients with RA or other rheumatological diseases which also has NP manifestations and further studies need to be done to establish anti-NMDA antibody as a promising diagnostic marker.\n\nNo definitive treatment for RM currently exists due to its rarity and diverse clinical presentation but previous case reports and studies have used a combination of corticosteroids, immune modulating drugs, cyclophosphamide and rituximab successfully [19–21]. However occurrence of PM in the course of treatment with biologics was also described [22].\n\nMost cases of RM have occurred in patients with seropositive RA, however this may occur in patients at any stage of the disease [6, 8]. In some case reports, RM was observed in patients as the first clinical manifestation of RA [4, 23]. In our case, the patient had been diagnosed with seropositive RA for 10 years.\n\nThe pathogenesis of remains unclear, although many case reports over the years suggest the use of tumor necrosis factor inhibitor as a treatment for RA was the cause of RM [24–27]. It is hypothesized that these drugs induce development of accelerated nodulosis by various mechanisms like induction of cytokine expression modulation in particularly interferon [25].\n\nOther theories include failure of inhibition of apoptosis in component cells or failure of interferon gamma inhibition which could promote granulomatosis [23]. Our patient was being treated with glucorticosteroids and methotrexate which may be the reason for development of RM as suggested by Huys et al. [25] in their study.\n\nWe analyzed 28 different case reports published about pachymeningitis due to RA. Five of them described patients without diagnosis of RA at the beginning with symptoms of pachymeningitis as the first clinical manifestation of the autoimmune disease [3–8] although both the patients in the Magaki et al. [6] report had a strong family history of RA. Most recurring clinical presentation in all these cases are stroke like symptoms, headaches, speech impairment, recurring seizures and most of these manifestations are progressive over a period of weeks to months. Thus, such varied presentation over a period leads to misdiagnosis.\n\nThe rest of the articles report cases in patients with seropositive RA most of whom were being treated for it with a combination of methotrexate and corticosteroids additionally some of them were being treated with TNF-α blockers [20, 22, 24–27] sulfasalazine [28, 29], a gold salt [30], iguratimod, a methanesulfonanilide [14, 31].\n\nThe imaging results rarely revealed pathology in CT scans, but findings in MRI aided towards the diagnosis of RM. Most of the cases showed abnormal signaling in MRI without contrast, it was necessary to perform contrast MRI to visualize the lepto- or pachymeningeal uptake and enhancement.\n\nOther MRI sequences (FLAIR, DWI) showed hyperintense signals over the meninges. Some cases the first MRI performed did not show any pathological abnormalities [24, 32, 33] but after progression of the disease similar findings were noted. Unfortunately, there are no findings that exist in imaging which are specific for RM, so imaging is useful in excluding etiologies like malignancies, ischemic stroke or hemorrhage.\n\nLaboratory tests, which include serum inflammatory markers (CRP, ESR), were persistently elevated in most of the patients leaving 13 cases where these were either not reported or were normal. But these inflammatory markers can be elevated in several systemic diseases. CSF findings were persistent in almost all the cases with pleocytosis and increased protein content as the characteristic findings leaving 2 cases where it was normal [5, 30].\n\nIn some cases there was presence of RF or ACPA [3, 34, 35] antibodies in undiluted CSF therefore presence of RF or ACPA antibodies in the CSF could be a good diagnostic marker of RM, but these are not present in all the cases. Current biomarkers include serum RF, ACPA and these findings are quite persistent in RM patients with either one or both being present in all the 29 cases.\n\nIn addition to these, Tsuzaki et al. [24] reported elevated antinuclear antibodies (ANA), Anti-Sjögren’s-syndrome-related antigen A/Anti-Ro (SS-A), Anti-La (SS-B) antibodies, chemokine ligand 13 (CXCL13) and Akamatsu et al. [36] reported elevated interleukin 6 (IL-6) while one patient had negative serum RF, ANA and ANCA [4]. Elevated IL-6 has been reported very rarely in previous literature. Biopsy findings in all the cases are very similar and lead to confirmed diagnosis of RM which typically showed granulomatous inflammation of the meninges with lymphoplasmacytic infiltrate, perivascular inflammation and presence of rheumatoid nodules in some cases. As of today, meningeal biopsy is the most accurate diagnostic test for RM, but due to its’ invasive nature it shouldn’t be performed unless all other etiologies have been excluded.\n\nPreferred treatment method was intravenous methylprednisolone followed by oral prednisolone. Treatment for RA was continued or was changed to rituximab which successfully managed the RA progression [1, 3, 7, 25, 35]. Elevated serum ACE and β-2 microglobulin were reported by Pellerin et al. [15] and McKenna et al. [8] although, these findings haven’t been clearly associated with RM [8, 15]. Some patients had pulmonary manifestations in the form of nodules or pleural effusions which were attributed as extra-articular manifestations of RA after examinations [22, 32, 35].\n\nConclusions\nPreviously RM was identified during autopsies, but recently due to the advancement in imaging techniques and diagnostic procedures, it has been possible to detect it early and start the appropriate treatment. This review establishes that the incidence of pachymeningitis in the course of RA is quite rare but is still increasing and there is a need to find more specific tests or biomarkers which could facilitate differential diagnostics of this disease.\n\nAcknowledgements\nThe authors want to thank prof. EwaIżycka-Świeszewska and prof. Edyta Szurowska for their help in preparing histopathology and imaging tests.\n\nThe authors declare no conflict of interest.\n==== Refs\n1 Scheitel M , Ives ST , Nasr R , Nolan MW \nWhen the Plot Thickens: A Rare Complication of Rheumatoid Arthritis\n. J Community Hosp Intern Med Perspect \n2019 ; 9 : 143 -146\n, DOI: 10.1080/20009666.2019.1593780 .31044046 \n2 Muravyev YV \nExtra-articular Manifestations of Rheumatoid Arthritis\n. Nauchno-Prakticheskaya Revmatol \n2018 ; 56 : 356 -362\n, DOI: 10.14412/1995-4484-2018-356-362 .\n3 Lee Ching C , Kenyon L , Berk M , Park C \nRheumatoid Meningitis Sine Arthritis\n. J Neuroimmunol \n2019 ; 328 : 73 -75\n, DOI: 10.1016/j.jneuroim.2018.12.001 .30597393 \n4 Parsons AM , Zuniga LA , Hoxworth JM , et al \nRheumatoid Meningitis: A Case Review\n. Neurologist \n2018 ; 23 : 83 -85\n, DOI: 10.1097/NRL.0000000000000158 .29722740 \n5 Lubomski M , Sy J , Buckland M , et al \nRheumatoid Leptomeningitis Presenting With an Acute Neuropsychiatric Disorder\n. Pract Neurol \n2019 ; 19 : 68 -71\n, DOI: 10.1136/practneurol-2018-001978 .30097553 \n6 Magaki S , Chang E , Hammond RR , et al \nTwo Cases of Rheumatoid Meningitis\n. Neuropathology \n2016 ; 36 : 93 -102\n, DOI: 10.1111/neup.12238 .26350538 \n7 Schuster S , Braass H , Iking-Konert C , et al \nRheumatoid Meningitis: A Rare Cause of Aseptic Meningitis With Frequently Stroke-Like Episodes\n. Neurol Clin Pract \n2018 ; 8 : 451 -455\n, DOI: 10.1212/CPJ.0000000000000504 .30564500 \n8 McKenna MC , Vaughan D , Bermingham N , Cronin S \nRheumatoid Arthritis Presenting as Rheumatoid Meningitis\n. BMJ Case Rep \n2019 ; 12 : bcr-2018-226649 , DOI: 10.1136/bcr-2018-226649 .\n9 Wallace ZS , Carruthers MN , Khosroshahi A , et al \nIgG4-related Disease and Hypertrophic Pachymeningitis\n. Medicine (Baltimore) \n2013 ; 92 : 206 -216\n, DOI: 10.1097/MD.0b013e31829cce35 .23793110 \n10 Nakano Y , Yamamoto M , Komatsu K , et al \nHypertrophic Pachymeningitis in Sjögren’s Syndrome\n. Intern Med \n2018 ; 57 : 413 -415\n, DOI: 10.2169/internalmedicine.9406-17 .29093421 \n11 Yagita K , Shinde A , Suenaga T \nRheumatoid meningitis can present MRI findings that mimic chronic subdural haematoma\n. BMJ Case Rep \n2019 ; 12 : e229642 , DOI: 10.1136/bcr-2019-229642 .\n12 Tan HJ , Raymond AA , Phadke PP , Rozman Z \nRheumatoid pachymeningitis\n. Singapore Med J \n2004 ; 45 : 337 -339\n.15221051 \n13 Wells AL \nExtra-articular manifestations of rheumatoid arthritis\n. Br Med J \n1969 , 4 : 173 , DOI: 10.1136/bmj.4.5676.173-c .\n14 DeQuattro K , Imboden JB \nNeurologic Manifestations of Rheumatoid Arthritis\n. Rheum Dis Clin North Am \n2017 ; 43 : 561 -571\n, DOI: 10.1016/j.rdc.2017.06.005 .29061242 \n15 Pellerin D , Wodkowski M , Guiot MC , et al \nRheumatoid Meningitis Presenting With Acute Parkinsonism and Protracted Non-convulsive Seizures: An Unusual Case Presentation and Review of Treatment Strategies\n. Front Neurol \n2019 ; 10 : 163 , DOI: 10.3389/fneur.2019.00163 .30873111 \n16 Grose D , Linger M , Tinni S , Sahathevan R \nRheumatoid meningitis: a rare cause of unilateral pachymeningitis\n. BMJ Case Rep \n2019 ; 12 , e227905 , DOI: 10.1136/bcr-2018-227905 .\n17 Kim HY , Park JH , Oh HE , et al \nA case of rheumatoid meningitis: Pathologic and magnetic resonance imaging findings\n. Neurol Sci \n2011 ; 32 : 1191 -1194\n, DOI: 10.1007/s10072-011-0727-9 .21863270 \n18 Tay SH , Fairhurst AM , Mak A \nClinical utility of circulating anti-N-methyl-d-aspartate receptor subunits NR2A/B antibody for the diagnosis of neuropsychiatric syndromes in systemic lupus erythematosus and Sjögren’s syndrome: An updated meta-analysis\n. Autoimmun Rev \n2017 ; 16 : 114 -122\n, DOI: 10.1016/j.autrev.2016.12.002 .27988431 \n19 Degboé Y , Fajadet B , Laurent C , et al \nA rare case of rheumatoid pachyleptomeningitis successfully treated with rituximab\n. Rheumatology (Oxford) \n2017 ; 56 : 1238 -1240\n, DOI: 10.1093/rheumatology/kex059 .28340133 \n20 Harrison NS , Kishore S , Majithia V \nRheumatoid meningitis: successful remission with rituximab\n. BMJ Case Rep \n2018 ; 11 : e226642 , DOI: 10.1136/bcr-2018-226642 .\n21 Moeyersoons A , Verschueren P , Tousseyn T , De Langhe E \nRheumatoid granulomatous disease and pachymeningitis successfully treated with rituximab\n. Acta Clin Belg \n2018 ; 73 : 307 -312\n, DOI: 10.1080/17843286.2017.1375193 .28901842 \n22 Gherghel N , Stan A , Stan H \nPearls & Oy-sters: Rheumatoid meningitis occurring during treatment with etanercept\n. Neurology \n2018 ; 91 : 806 -808\n, DOI: 10.1212/WNL.0000000000006397 .30348854 \n23 Atzeni F , Talotta R , Masala IF , et al \nCentral nervous system involvement in rheumatoid arthritis patients and the potential implications of using biological agents\n. Best Pract Res Clin Rheumatol \n2018 ; 432 : 500 -510\n, DOI: 10.1016/j.berh.2019.02.003 .\n24 Tsuzaki K , Nakamura T , Okumura H , et al \nRheumatoid Meningitis Occurring during Etanercept Treatment\n. Case Rep Neurol Med \n2017 ; 2017 : 7638539 , DOI: 10.1155/2017/7638539 .28286682 \n25 Huys AC , Guerne PA , Horvath J \nRheumatoid meningitis occurring during adalimumab and methotrexate treatment\n. Joint Bone Spine \n2012 ; 79 : 90 -92\n, DOI: 10.1016/j.jbspin.2011.07.008 .21962388 \n26 Koopmansch C , D’Haene N , Hastir D , et al \nA 63-Year-Old Woman with a Right Frontal Lesion\n. Brain Pathol \n2016 ; 26 : 555 -556\n, DOI: 10.1111/bpa.12393 .27322935 \n27 Nihat A , Chinthapalli K , Bridges L , et al \nRheumatoid meningitis\n. Pract Neurol \n2016 ; 16 : 312 -324\n, DOI: 10.1136/practneurol-2015-001306 .27029468 \n28 Roy B , Uphoff DF , Silverman IE \nRheumatoid Meningitis Presenting With Multiple Strokelike Episodes\n. JAMA Neurol \n2015 ; 72 : 1073 -1076\n, DOI:10.1001/jamaneurol.2015.1105 .26368353 \n29 Mason A , Chan C , Pengas G , Holroyd C \nRheumatoid pachymeningitis: a rare extra-articular manifestation of rheumatoid arthritis\n. Rheumatol Adv Pract \n2018 ; 2 (Suppl 1 ), rky033.023 , DOI: 10.1093/rap/rky033.023 .\n30 Lu L , Chwalisz B , Pfannl R , Narayanaswami P \nRheumatoid meningitis: a rare complication of rheumatoid arthritis\n. BMJ Case Rep \n2015 ; 2015 : bcr2014208745 , DOI: 10.1136/bcr-2014-208745 .\n31 Matsuda S , Yoshida S , Takeuchi T , et al \nAsymptomatic rheumatoid meningitis revealed by magnetic resonance imaging, followed by systemic rheumatic vasculitis: A case report and a review of the literature\n. Mod Rheumatol \n2019 ; 29 : 370 -376\n, DOI: 10.1080/14397595.2016.1232333 .27659704 \n32 Duray MC , Marchand E , Gohy S , et al \nGranulomatous meningitis due to rheumatoid arthritis\n. Acta Neurol Belg \n2012 ; 112 : 193 -197\n, DOI: 10.1007/s13760-012-0021-5 .22426662 \n33 Krysl D , Zamecnik J , Senolt L , Marusic P \nChronic repetitive nonprogressive epilepsiapartialis continua due to rheumatoid meningitis\n. Seizure \n2013 ; 22 : 80 -82\n, DOI: 10.1016/j.seizure.2012.10.006 .23122511 \n34 Choi SJ , Ho Park Y , Kim JA , et al \nPearls & Oy-sters: Asymmetric meningeal involvement is a common feature of rheumatoid meningitis\n. Neurology \n2017 ; 88 : e108 -e110\n, DOI: 10.1212/WNL.0000000000003744 .28320928 \n35 Nissen MS , Nilsson AC , Forsberg J , et al \nUse of Cerebrospinal Fluid Biomarkers in Diagnosis and Monitoring of Rheumatoid Meningitis\n. Front Neurol \n2019 ; 10 : 666 ,31293505 \n36 Akamatsu M , Maki F , Akiyama H , et al \nRheumatoid meningitis presenting with a stroke-like attack treated with recombinant tissue plasminogen activator: a case presentation\n. BMC Neurol \n2018 ; 18 : 139, DOI: 10.1186/s12883-018-1143-z .\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0034-6233",
"issue": "58(2)",
"journal": "Reumatologia",
"keywords": "central system involvement; rheumatoid arthritis; rheumatoid meningitis; stroke-like symptoms",
"medline_ta": "Reumatologia",
"mesh_terms": null,
"nlm_unique_id": "20130190R",
"other_id": null,
"pages": "116-122",
"pmc": null,
"pmid": "32476685",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "28901842;27322935;31293505;26135486;30635304;30873111;30564500;23122511;21863270;30597393;15221051;23793110;30189853;30948395;27659704;30097553;31444262;5823077;30348854;27029468;29093421;26368353;22426662;29061242;26350538;30598469;31174819;21962388;29722740;28320928;28340133;28286682;31044046;27988431",
"title": "Rheumatoid arthritis with pachymeningitis - a case presentation and review of the literature.",
"title_normalized": "rheumatoid arthritis with pachymeningitis a case presentation and review of the literature"
} | [
{
"companynumb": "PL-ACCORD-183828",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "We report two cases of doxycycline-induced solar urticaria that developed shortly after initiation of therapy with persistence despite discontinuation. Consequently, dermatologists should be aware of the association between doxycycline and solar urticaria and counsel their patients on the potential for this side effect when prescribing doxycycline.",
"affiliations": null,
"authors": "Bogner|Ryan R|RR|;Blixt|Elizabeth K|EK|;Bruce|Alison J|AJ|;Sciallis|Gabriel F|GF|",
"chemical_list": "D000900:Anti-Bacterial Agents; D004318:Doxycycline",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-9616",
"issue": "14(11)",
"journal": "Journal of drugs in dermatology : JDD",
"keywords": null,
"medline_ta": "J Drugs Dermatol",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D004318:Doxycycline; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D013472:Sunlight; D014581:Urticaria",
"nlm_unique_id": "101160020",
"other_id": null,
"pages": "1358-9",
"pmc": null,
"pmid": "26580888",
"pubdate": "2015-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Doxycycline-Induced Solar Urticaria: A Report of Two Cases.",
"title_normalized": "doxycycline induced solar urticaria a report of two cases"
} | [
{
"companynumb": "US-MAYNE PHARMA-2017MYN001768",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DOXYCYCLINE HYCLATE"
},
"drugadditional":... |
{
"abstract": "BACKGROUND\nAngiolymphoid hyperplasia with eosinophilia (ALHE) is a benign vascular proliferation characterized by dermal or subcutaneous red or brown papules or nodules, most commonly on the head and neck.\n\n\nOBJECTIVE\nThe aim of this study was to review the epidemiological and clinical characteristics of ALHE, focusing particularly on the histological and therapeutic features.\n\n\nMETHODS\nWe performed a retrospective study of all cases of ALHE diagnosed in our dermatology and pathology departments between 2004 and 2015.\n\n\nRESULTS\nOver 12 years, we collected nine cases of ALHE (0.75 case/year). There were four men and five women. The mean age was 43 years. Lesions presented as erythematous or violaceous papules or nodules in all cases, multiple in five cases, and localized on the head in eight cases or other sites in four cases. The diagnosis of ALHE was clinically suspected in only two cases. The histopathological findings showed an ill-circumscribed, intradermal slightly lobular proliferation of capillary-sized vessels around several central vessels. In all cases, the blood vessels were lined by large endothelial cells. An inflammatory infiltrate around the vessels was formed mainly of lymphocytes and eosinophils with isolated plasma cells and histiocytes. Surgery was the most common treatment in our series. Other local or general treatment has also been used with varying responses.\n\n\nCONCLUSIONS\nAngiolymphoid hyperplasia with eosinophilia is a rare epithelioid vascular tumor with a challenging clinical and histological diagnosis. Despite its benign nature, ALHE causes a therapeutic dilemma.",
"affiliations": "Department of Dermatology, Hedi Chaker Hospital, Sfax, Tunisia.;Department of Dermatology, Hedi Chaker Hospital, Sfax, Tunisia.;Department of Anatomopathology, Habib Bourguiba Hospital, Sfax, Tunisia.;Department of Anatomopathology, Habib Bourguiba Hospital, Sfax, Tunisia.;Department of Anatomopathology, Habib Bourguiba Hospital, Sfax, Tunisia.;Department of Anatomopathology, Habib Bourguiba Hospital, Sfax, Tunisia.;Department of Dermatology, Hedi Chaker Hospital, Sfax, Tunisia.",
"authors": "Bahloul|Emna|E|;Amouri|Meriem|M|;Charfi|Slim|S|;Boudawara|Ons|O|;Mnif|Hela|H|;Boudawara|Tahya|T|;Turki|Hamida|H|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/ijd.13800",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0011-9059",
"issue": "56(12)",
"journal": "International journal of dermatology",
"keywords": null,
"medline_ta": "Int J Dermatol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000796:Angiolymphoid Hyperplasia with Eosinophilia; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D012189:Retrospective Studies",
"nlm_unique_id": "0243704",
"other_id": null,
"pages": "1373-1378",
"pmc": null,
"pmid": "29057451",
"pubdate": "2017-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Angiolymphoid hyperplasia with eosinophilia: report of nine cases.",
"title_normalized": "angiolymphoid hyperplasia with eosinophilia report of nine cases"
} | [
{
"companynumb": "TN-BAUSCH-BL-2018-022303",
"fulfillexpeditecriteria": "1",
"occurcountry": "TN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "INTERFERON ALFA-2A OR INTERFERON ALFA-2B"
},
"... |
{
"abstract": "BACKGROUND\nPolypharmacy has become an emerging public health issue in recent years, since use of multiple medications or polypharmacy is beneficial for many conditions, but may also have negative effects like adverse drug reactions. The risk further increases in patients with chronic renal failure, a comorbidity very frequent in nursing home residents. Since more than 50% of all drugs were renally excreted, dose adjustments in patients with renal failure are required.\n\n\nOBJECTIVE\nTo assess polypharmacy in German nursing homes, in particular in residents with renal failure.\n\n\nMETHODS\nMulti-center cross-sectional study in 21 nursing homes in Bremen and Lower Saxony/Germany. Baseline data were analysed using descriptive statistics. Multivariable logistic regression model and 95% confidence intervals were used to study the association of renal failure and polypharmacy.\n\n\nRESULTS\nOf all 852 residents, the analysis comprised those 685 with at least one serum creatinine value so that the estimated creatinine clearance could be calculated. Of those, 436 (63.6%) had a severe or moderate renal failure, defined as estimated creatinine clearance <60 mL/min. Polypharmacy (5-9 drugs) was found in 365 (53.3%) and excessive polypharmacy (≥10 drugs) in 112 (16.4%) residents. Diuretics and psycholeptics were the most commonly used drug classes. Severe renal failure (estimated creatinine clearance <30 mL/min) was associated with polypharmacy (OR: 2.8, 95% CI 1.4-5.7).\n\n\nCONCLUSIONS\nBoth, polypharmacy and renal failure are common in German nursing home residents and an association of both could be found. Further studies are needed to assess the appropriateness of polypharmacy in these patients.",
"affiliations": "Department of Health Services Research, Carl von Ossietzky University Oldenburg, Ammerländer Heerstrasse 140, 26111, Oldenburg, Germany. michael.doerks@uni-oldenburg.de.;Department of Medicine, Rotes Kreuz Hospital, Bremen, Germany.;Department of Health Services Research, Institute for Public Health and Nursing Science, University of Bremen, Bremen, Germany.;Department of Health Services Research, Carl von Ossietzky University Oldenburg, Ammerländer Heerstrasse 140, 26111, Oldenburg, Germany.",
"authors": "Dörks|Michael|M|;Herget-Rosenthal|Stefan|S|;Schmiemann|Guido|G|;Hoffmann|Falk|F|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.1007/s40266-015-0333-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1170-229X",
"issue": "33(1)",
"journal": "Drugs & aging",
"keywords": null,
"medline_ta": "Drugs Aging",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D015897:Comorbidity; D003430:Cross-Sectional Studies; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D005858:Germany; D006801:Humans; D008297:Male; D009735:Nursing Homes; D019338:Polypharmacy; D051437:Renal Insufficiency; D012306:Risk",
"nlm_unique_id": "9102074",
"other_id": null,
"pages": "45-51",
"pmc": null,
"pmid": "26659732",
"pubdate": "2016-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "19284433;23283395;21450179;26025118;11083325;22698953;24647931;25962494;19187880;19795368;22935542;11234459;17164234;23027318;24350526;18457801;22219520;14717937;18622323;17727646;24348028;15485730;15599503;23864424;15386712;25869992;24245971;22223743;25402452;20959896",
"title": "Polypharmacy and Renal Failure in Nursing Home Residents: Results of the Inappropriate Medication in Patients with Renal Insufficiency in Nursing Homes (IMREN) Study.",
"title_normalized": "polypharmacy and renal failure in nursing home residents results of the inappropriate medication in patients with renal insufficiency in nursing homes imren study"
} | [
{
"companynumb": "DE-JNJFOC-20160310548",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "LACTULOSE"
},
"drugadditional": null,
"... |
{
"abstract": "BACKGROUND\nAlthough rare, cardiovascular involvement is the second most frequent cause of mortality in chronic relapsing polychondritis behind tracheobronchial tree chondritis. The most frequent cardiovascular complications are valvulopathy and aortic aneurysm.\n\n\nMETHODS\nWe report a case of chronic relapsing polychondritis with multiple aortic aneurysms that were clinically silent but continued to progress despite systemic corticosteroids and immunosuppressive therapy.\n\n\nCONCLUSIONS\nProgression of aortic aneurysms and extravascular disease do not appear to be correlated. Although the disease may appear to be in remission, vascular lesions can continue to progress independently. This case shows that medical treatment has little effect on the progression of these aneurysms. Consequently, it is necessary to opt for surgical therapy at the opportune moment.",
"affiliations": "Service de Dermatologie, AP-HP, Groupe Hospitalier Bichat Claude Bernard, Université Paris 7 Denis-Diderot, Paris.",
"authors": "Monsel|G|G|;Maubec|E|E|;Picard-Dahan|C|C|;Brocheriou|I|I|;Henry Feugeas|M-C|MC|;Kieffer|E|E|;Francès|C|C|;Crickx|B|B|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D007166:Immunosuppressive Agents",
"country": "France",
"delete": false,
"doi": "10.1016/s0151-9638(07)89267-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0151-9638",
"issue": "134(6-7)",
"journal": "Annales de dermatologie et de venereologie",
"keywords": null,
"medline_ta": "Ann Dermatol Venereol",
"mesh_terms": "D000293:Adolescent; D000305:Adrenal Cortex Hormones; D001014:Aortic Aneurysm; D017544:Aortic Aneurysm, Abdominal; D017545:Aortic Aneurysm, Thoracic; D004359:Drug Therapy, Combination; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D011081:Polychondritis, Relapsing; D016896:Treatment Outcome",
"nlm_unique_id": "7702013",
"other_id": null,
"pages": "552-4",
"pmc": null,
"pmid": "17657182",
"pubdate": "2007",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Multiple aortic aneurysms in chronic atrophic polychondritis.",
"title_normalized": "multiple aortic aneurysms in chronic atrophic polychondritis"
} | [
{
"companynumb": "FR-BAXTER-2019BAX013318",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "To demonstrate the successful use of pharmacogenomic testing to specifically tailor antifungal treatment to the phenotype of a patient with human immunodeficiency virus (HIV) and disseminated histoplasmosis who had clinical progression while on itraconazole and subsequently had insufficient therapeutic drug levels of voriconazole.\n\n\n\nWe present the case of a patient with HIV and disseminated histoplasmosis with a persistently elevated serum Histoplasma capsulatum antigen and subtherapeutic levels of voriconazole. Pharmacogenomic testing revealed he was a CYP2C19 rapid metabolizer, thus explaining his persistent, subtherapeutic levels of voriconazole and prompting a change in therapy.\n\n\n\nOur case illustrates the importance of pharmacogenomic testing as a tool to evaluate subtherapeutic itraconazole or voriconazole levels, especially in patients with failed clinical or Histoplasmosis Ag response despite reporting full adherence to prescribed therapy.",
"affiliations": null,
"authors": "Hanna|Kevin F|KF|;Havens|Joshua P|JP|;Bares|Sara H|SH|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.japh.2021.01.021",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1086-5802",
"issue": "61(3)",
"journal": "Journal of the American Pharmacists Association : JAPhA",
"keywords": null,
"medline_ta": "J Am Pharm Assoc (2003)",
"mesh_terms": "D006678:HIV; D015658:HIV Infections; D006658:Histoplasma; D006660:Histoplasmosis; D006801:Humans; D008297:Male; D000071185:Pharmacogenomic Testing",
"nlm_unique_id": "101176252",
"other_id": null,
"pages": "e152-e155",
"pmc": null,
"pmid": "33583749",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Successful application of pharmacogenomic testing in the evaluation and management of a patient with human immunodeficiency virus and disseminated histoplasmosis.",
"title_normalized": "successful application of pharmacogenomic testing in the evaluation and management of a patient with human immunodeficiency virus and disseminated histoplasmosis"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2021SP006654",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "ITRACONAZOLE"
},
"drugadditiona... |
{
"abstract": "Allometric scaling can be used for the extrapolation of pharmacokinetic parameters from adults to children. The objective of this study was to predict clearance of therapeutic proteins (monoclonal and polyclonal antibodies and non-antibody proteins) allometrically in preterm neonates to adolescents. There were 13 monoclonal antibodies, seven polyclonal antibodies, and nine therapeutic proteins (non-antibodies) in the study. The clearance of therapeutic proteins was predicted using the age dependent exponents (ADE) model and then compared with the observed clearance values. There were in total 29 therapeutic proteins in this study with 75 observations. The number of observations with ≤30%, ≤50%, and >50% prediction error was 60 (80%), 72 (96%), and 3 (4%), respectively. Overall, the predicted clearance values of therapeutic proteins in children was good. The allometric method proposed in this manuscript can be used to select first-in-pediatric dose of therapeutic proteins in pediatric clinical trials.",
"affiliations": "Mahmood Clinical Pharmacology, Consultancy, LLC, 1709, Piccard Dr, Rockville, MD 20850, USA.",
"authors": "Mahmood|Iftekhar|I|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/antib9030040",
"fulltext": "\n==== Front\nAntibodies (Basel)\nAntibodies (Basel)\nantibodies\nAntibodies\n2073-4468 MDPI \n\n32764408\n10.3390/antib9030040\nantibodies-09-00040\nCommunication\nPrediction of Clearance of Monoclonal and Polyclonal Antibodies and Non-Antibody Proteins in Children: Application of Allometric Scaling\nMahmood Iftekhar Mahmood Clinical Pharmacology, Consultancy, LLC, 1709, Piccard Dr, Rockville, MD 20850, USA; iftekharmahmood@aol.com; Tel.: +1-301-838-4555\n05 8 2020 \n9 2020 \n9 3 4009 6 2020 03 8 2020 © 2020 by the author.2020Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Allometric scaling can be used for the extrapolation of pharmacokinetic parameters from adults to children. The objective of this study was to predict clearance of therapeutic proteins (monoclonal and polyclonal antibodies and non-antibody proteins) allometrically in preterm neonates to adolescents. There were 13 monoclonal antibodies, seven polyclonal antibodies, and nine therapeutic proteins (non-antibodies) in the study. The clearance of therapeutic proteins was predicted using the age dependent exponents (ADE) model and then compared with the observed clearance values. There were in total 29 therapeutic proteins in this study with 75 observations. The number of observations with ≤30%, ≤50%, and >50% prediction error was 60 (80%), 72 (96%), and 3 (4%), respectively. Overall, the predicted clearance values of therapeutic proteins in children was good. The allometric method proposed in this manuscript can be used to select first-in-pediatric dose of therapeutic proteins in pediatric clinical trials.\n\nallometrychildrenclearancetherapeutic proteinsmonoclonal antibodiespolyclonal antibodies\n==== Body\n1. Introduction\nDuring drug development, whether it is in adults or pediatrics, the knowledge of a suitable starting dose is of immense importance. The pharmacokinetics (PK) of a drug is generally known in adults and, for the selection of first-in-pediatric dose, this PK knowledge in adults can be extrapolated to the pediatric population to initiate a clinical trial.\n\nThere are three important pharmacokinetic (clearance, volume of distribution, and half-life) parameters which are generally estimated in both adults and pediatrics. Of the three, clearance of a drug is very important because it represents exposure (area under the curve (AUC)) [1] as shown in Equation (1). Therefore, clearance (CL) of a drug can be used for the first-in-children dose selection in order to perform a clinical trial in pediatric population. CL can also be used for dosing in an individual child. Clearance can be calculated from the following Equation (1): CL = Dose/AUC(1) where AUC is the area under the curve.\n\nThe extrapolation of PK parameters, especially CL for small molecules from adults to children (neonates to adolescents) is well known but for macromolecules (antibodies and non-antibody therapeutic proteins) such extrapolations are not well established [2,3,4,5,6,7]. In a recent study, Mahmood [7] used an allometric approach to predict the clearance of coagulation factors for the initiation of pediatric clinical trials for coagulation factors.\n\nAllometry is the study of size and its consequences and generally used for the prediction of physiological as well as pharmacokinetic parameters [8]. The allometric equation can be generated by either of the following two methods:I. Using a power function as shown in Equation (2).\n\n\n Y = aWb(2) \nwhere Y is the parameter of interest (can be a physiological or PK), W is the body weight, “a” and “b” are the coefficient and exponent of the allometric equation, respectively.\n\nII. By linearization of Equation (2) using log transformation as shown in Equation (3).\n\n log Y = log a + b log W(3) \nwhere “a” is the intercept and “b” is the slope.\n\nAllometric scaling is regularly used to predict PK parameters such as clearance, volume of distribution {XE “volume of distribution”}, and half-life {XE “half-life”} from animals to humans (interspecies scaling) [8]. From the same token, the allometric principles can also be applied to scale physiological and PK parameters from preterm neonates to adolescents [2,3,4,5,6,7] from adult data. This approach is of practical value during drug development because it can provide some information for first-in-pediatric dose selection. Allometric scaling based on body weight is easy and simple and can be performed across age groups once PK information of a drug is available from adults.\n\nAs clearance is the most important PK parameter, using allometry, it is possible to predict clearance of drugs in children across the age groups from adult drug clearance values [2,3,4,5,6,7]. From these predicted clearance, one can project first-in-pediatric dose to initiate a clinical trial.\n\nThe objective of this study was to predict clearance of monoclonal and polyclonal antibodies and non-antibody proteins allometrically from neonates to adolescents using adult clearance values.\n\n2. Methods\nThe values for observed clearance of monoclonal and polyclonal antibodies and non-antibody proteins were obtained from the literature [9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51] and the predicted clearance values were compared with the observed values for each drug. In this study, there were 13 monoclonal antibodies, seven polyclonal antibodies, and nine therapeutic proteins (non-antibodies). The age stratification was preterm and term neonates (till ≤ 0.25 years), >0.25 to 2 years, >2 to ≤5 years, >5 to ≤12 years, and >12 to <18 years.\n\nData for basiliximab, canakinumab, gemtuzumab were extracted from the clearance vs. weight or age plots provided by the authors so that age could be stratified to a narrower range. The data extraction was done by digitizeit.\n\nFor two polyclonal antibodies Sandoglobulin [35] and Gamimune [36] the clearance values were calculated based on the mean concentration-time data provided by the authors. This was done because it was noted that the clearance values of these two polyclonal antibodies were absolute values rather than body weight adjusted as reported by the authors. The re-calculation of clearance of these two polyclonal antibodies indicated that indeed the clearance values were absolute values rather than body weight adjusted values as reported by the authors.\n\n2.1. Prediction of Clearance\nThe clearance values of therapeutic proteins were predicted using the age dependent exponents (ADE) model. The ADE model is based on variable exponents as a function of age [2,3,4,5,6,7]. Since the allometric exponents widely vary and are data-dependent, in this method, different allometric exponents were used for different age groups and clearance was predicted in a given age group according to Equation (4).\n CL = Adult CL × (WC/W70)b(4) \nwhere the “adult clearance” is the mean adult clearance of a given therapeutic protein obtained from the literature. WC is the weight of a child and W70 is the weight of an adult standardized to 70 kg.\n\nExponent “b” in Equation (4) is age dependent. The exponents used in Equation (4) were 1.2 for preterm and 1.1 for term neonates for age 0–3 months, 1.0, 0.9, and 0.75, >3 months–2 years, >2–5 years, and >5 years, respectively. The exponents selected in the ADE model are based from previous experience, observation, and data analysis. The exponents of the ADE model were previously applied to test the suitability of the exponents in the allometric model across the age group to predict the clearances of small molecule drugs and coagulation factors in children [2,3,4,5,6,7].\n\n2.2. Statistical Analysis\nPercent error between the observed and predicted values was calculated according to the following equation: %error = (Pr edicted – observed) ∗ 100/observed(5) \n\nGenerally, in the literature, a 2-fold prediction error is considered acceptable. This author, however, considers this magnitude of prediction error too high for any clinical use. Therefore, in this study, a prediction error of ≤50% and ≤30% was considered acceptable error.\n\n3. Results\n3.1. Monoclonal Antibodies\nA total of 13 monoclonal antibodies with different age groups were studied. The total number of observations was 33. The observed and predicted clearances in children for monoclonal antibodies are shown in Table 1. The prediction error ranged from 3% to 59%. The number of observations with ≤30%, ≤50%, and >50% was 30 (91%), 32 (97%), and 1 (3%), respectively. Overall, the prediction of clearance for monoclonal antibodies from infants (0.2 year) to adolescents from adult clearance using the ADE model was good.\n\n3.2. Polyclonal Antibodies\nThere were seven polyclonal antibodies (age range = preterm to adolescents) administered either by intravenous or subcutaneous route. The total number of observations was 21. The observed and predicted clearances in children for polyclonal antibodies are shown in Table 2. The prediction error ranged from 0% to 50%. The number of observations with ≤30%, ≤50%, and >50% was 17 (81%), 21 (100%), and 0 (0%), respectively. Overall, the prediction of clearance for polyclonal antibodies from preterm neonates to adolescents from adult clearance using ADE model was good.\n\n3.3. Therapeutic Proteins (Non-Antibodies)\nThere were nine therapeutic proteins with 21 observations. The age ranged from <30 days to adolescents. The observed and predicted clearances in children for therapeutic proteins are shown in Table 3. The prediction error ranged from 1% to 77%. The number of observations with ≤30%, ≤50%, and >50% was 13 (62%), 19 (90%), and 2 (10%), respectively. Overall, the prediction of clearance for therapeutic proteins from neonates to adolescents from adult clearance using ADE model was good.\n\nOverall, the ADE model provided a good prediction of monoclonal and polyclonal antibodies and non-antibody proteins from infants to adolescents. There were 29 macromolecules with 75 observations. The number of observations with ≤30%, ≤50%, and >50% was 60 (80%), 72 (96%), and 3 (4%), respectively (Table 4).\n\n4. Discussion\nAllometric scaling is a useful tool and can be used to predict PK parameters such as clearance, volume of distribution, and half-life in children from adult data [2,3,4,5,6,7,52,53,54,55]. Allometry has been successfully used for the prediction of clearance in children from adults for small molecules and coagulation factors [2,3,4,5,6,7,53,54,55].\n\nIn order to predict PK parameters from adults to children, it is important to consider ontogeny (growth and maturation). In neonates, infants, and toddlers, physiological changes develop very rapidly, and these changes are nonlinear. The physiological parameters of living organisms are allometrically related with body weights or age [8]. Therefore, the use of an allometric model to predict clearance of drugs across the age groups is scientifically and logically based and is not surprising that an allometric model provides a fairly accurate estimate of PK parameters across the age groups.\n\nConsidering that the allometric exponents widely vary and are data dependent, and the rapid physiological changes in children are nonlinear, a single exponent cannot be used to describe the clearance versus body weight data across all age groups (neonates to adults) [2,3,4,5,6,55]. Theoretical allometric exponents for clearance (0.75) and volume of distribution (1.0) cannot be used in children generally ≤2 years of age. Determination of the allometric exponents across the age groups (neonates to adults) indicated that the exponents of allometry change with body weight or age [52,56]. This change or difference in allometric exponents as a function of weight or age explains the allometric relationship with ontogeny or maturation for that particular age or body weight and belies the concept of a fixed theoretical exponent across all age groups. This observation led Mahmood to introduce the concept of the age dependent exponent (ADE) model for small and large molecules [2,3,4,5,6,7]. The application of the ADE model led to a substantial improvement in the prediction of drug clearance in children from neonates to adolescents as compared with a single theoretical exponent of 0.75. The theoretical exponent 0.75 substantially over-predicts the clearance of drugs in both preterm and term neonates, infants, and toddlers, hence, should not be used in these age groups.\n\nThis study is an attempt to predict clearance of monoclonal and polyclonal antibodies as well as non-antibodies (or therapeutic proteins) allometrically from adult data. In this study, overall, there were 29 therapeutic proteins with 75 observations (age ranging from preterm neonates to adolescents). The prediction error with ≤30%, and ≤50%, was 80% and 96% for 75 observations, respectively (Table 4). Overall, the prediction of the clearance of these macromolecules in children from adult clearance using an ADE model was good.\n\nIn this study, one of the issues related to the appropriate application of the exponents of ADE model was the wide range of the age lumped together for many macromolecules. For example, for Cetuximab the age range was 1–12 years (11). Some other examples were Infliximab (0.2–6.25 years) [14], Bivalirudin (1 month to <2 years) [37], and Darbepoetin alfa (1–17 years) [39]. Such study designs over such a wide age range and lumping the PK data together across all age groups is not appropriate since one may not detect the true age dependent PK differences for a given product. Furthermore, an appropriate allometric exponent based on the ADE model could not be applied due the age range and this in some instances might have compromised with the accuracy of the predicted clearance values.\n\nThere is paucity of data in preterm and term neonates and infants for macromolecules. In this study, there were two polycolonal antibodies (sandoglobulin and Gamimune) for which data in preterm and term neonates were available. The prediction in term neonates was fairly accurate (<20% prediction error) but in preterm neonates the prediction of clearance was underestimated (less than observed values) by 50% and 47% for sandoglobulin and Gamimune, respectively. Although, the prediction error was within the acceptable range, more data are needed to evaluate the predictive power of the ADE model for antibodies in the preterm and term neonates.\n\n5. Conclusions\nTo the best of the author’s knowledge, this is the first time that an allometric extrapolation has been used to predict clearance of therapeutic proteins (monoclonal and polyclonal antibodies, and non-antibody therapeutic proteins) in children from adult data. It is important to recognize that over the last decade pediatric drug development is on the rise. Therefore, the extrapolation of PK from adults to children is an important step to initiate a pediatric clinical trial. The results of this study indicate that the allometric extrapolation can be used to initiate a pediatric clinical trial with a reasonable initial dose right from the neonates to adolescents. This will save time, effort, and cost from conducting a pediatric clinical trial for rigorous dose finding. Allometric models due to their simplicity and comparable prediction accuracy are more attractive than many other complex models. Many clinical trials fail because the children do not receive an appropriate initial dose (mainly under-dosed due to being over-cautious) because the investigators do not have any clear idea about the first-in-children dose and mostly the dose selection is guess work. It should be, however, noted that the proposed method should only be used for the first-in-dose selection to initiate a pediatric clinical trial and is not in-lieu of a pediatric clinical trial.\n\nFunding\nThis work received no external funding.\n\nConflicts of Interest\nThe author declares that the research was conducted without any government or commercial financial support.\n\nantibodies-09-00040-t001_Table 1Table 1 Predicted and observed clearance of monoclonal antibodies in children of different ages.\n\nAge (Years)\tObserved CL\tPredicted CL\t% Error\t\n\nBasiliximab, Adult CL = 55 mL/h, Liver Transplantation\n\t\n<2\t19\t8\t−59\t\n3.5\t24\t18\t−26\t\n8.6\t28\t33\t17\t\n13.5\t49\t43\t−13\t\n\nBasiliximab, Adult CL = 37 mL/h, Renal Transplantation\n\t\n1–4 y\t15\t15\t−2\t\n6–12 y\t19\t24\t28\t\n14–16 y\t30\t31\t3\t\n\nCetuximab, Adult CL = 46 mL/h, Solid Tumors\n\t\n1–12 y\t18\t24\t35\t\n13–18 y\t32\t38\t20\t\n\nGemtuzumab, Adult CL = 270 mL/h, Refractory or Relapsed Acute Myeloid Leukemia\n\t\n1–5 y\t120\t87\t−27\t\n>5–12 y\t180\t161\t−11\t\n>12–16 y\t230\t225\t−2\t\n\nInfliximab, Healthy Adult CL = 9.5 mL/h, children = Kawasaki Disease\n\t\n0.7–3.1 y\t1.7\t2.0\t20\t\n0.2–6.25 y\t3.0\t2.7\t−10\t\n\nNatalizumab, Adult CL = 22 mL/h, Crohn Disease\n\t\n11–17 y\t18\t20\t12\t\n\nCanakinumab, Adult CL = 9 mL/h, Systemic Juvenile Idiopathic Arthritis (SJIA), SC\n\t\n0.7–1.7 y\t1.8\t1.3\t−27\t\n2.7–4.9 y\t4.6\t3.2\t−30\t\n5.9–11.1 y\t7.2\t5.9\t−17\t\n12–17.2 y\t8.3\t7.5\t−9\t\n\nCanakinumab, Adult CL = 9.5 mL/h, Cryopyrin-Associated Periodic Syndrome (CAPS), SC\n\t\nAge not known\t2.4\t2.7\t9\t\nyoungest may \t5.4\t5.1\t−6\t\nbe 4 years\t9.7\t6.9\t−29\t\n\nUrtoxazumab, Healthy Adult CL = 6 mL/h, children = Shiga-Like Toxin (Escherichia coli)\n\t\n2.9\t1.8\t1.9\t3\t\n\nTocilizumab, Adult CL = 20.3 mL/h, Polyarticular Juvenile Idiopathic Arthritis\n\t\n20 kg, age not known\t8.6\t7.9\t−8\t\n\nDaclizumab, Adult CL = 13 mL/h, Renal Transplant\n\t\n<5 y\t5.2\t3.2\t−38\t\n6–12 y\t10.8\t6.9\t−36\t\n13–17 y\t14.5\t10.4\t−28\t\n\nBelacept, Adult CL = 36 mL/h, Kidney Transplant\n\t\n13–17 y\t28\t32\t12\t\n\nMEDI8897, Healthy Adults (CL = 65 mL/day) and Healthy Infants, Intramuscular\n\t\nDose (mg/kg)/age at the time of study, CL is in mL/day\t\n10 (4.2 months)\t4.1\t5.3\t30\t\n25 (6.7 months)\t6.1\t6.3\t4\t\n50 (7 months)\t7.0\t6.6\t−6\t\n\nBevacizumab,\nAdult CL = 9.8 mL/h, Solid Tumors, Children = CNS Malignancies\n\t\n11–31 months\t2.8\t2.6\t−7\t\n\nPalivizumab, Adult CL = 198 mL/Day, Adult and Children = Respiratory Syncytial Virus, Intramuscular\n\t\n12.3 months\t11.0\t12.7\t15\t\nIf the route of administration not mentioned, then the antibodies were given by intravenous route.\n\nantibodies-09-00040-t002_Table 2Table 2 Predicted and observed clearance of polyclonal antibodies in children of different ages.\n\nAge (Years)\tObserved CL\tPredicted CL\t% Error\t\n\nPanzyga (IV), Adult CL = 101 mL/day, Baseline Uncorrected\n\t\n2–5.9\t48\t39\t−18\t\n6–11.9\t50\t48\t−4\t\n12–16 \t82\t78\t−4\t\n\nPanzyga (IV), Adult CL = 504 mL/day, Baseline Corrected\n\t\n2–5.9\t192\t197\t3\t\n6–11.9\t200\t240\t20\t\n12–16 \t504\t392\t−22\t\n\nGammaplex 10% (IV), Adult CL = 456 mL/day, Baseline Corrected\n\t\n2–5 \t114\t114\t0\t\n6–11 \t178\t181\t1\t\n12–15 \t381\t367\t−4\t\n\nGAMUNEX-C (IV), Adult CL = 101 mL/day, Baseline Uncorrected\n\t\n2–5 \t20\t26\t31\t\n6–11 \t44\t41\t−6\t\n12–16 \t84\t82\t−3\t\n\nCuvitru (subcutaneous), Adult CL = 150 mL/day, Baseline Uncorrected\n\t\n2–<5\t37\t37\t1\t\n5–<12\t48\t59\t22\t\n12–16 y\t103\t117\t14\t\n\nHizentra (subcutaneous), Adult CL = 161 mL/day, Baseline Uncorrected\n\t\n6–<12 y\t55\t74\t35\t\n12–<16 y\t119\t134\t13\t\n\nSandoglobulin, Adult CL = 110 mL/day, Baseline Uncorrected\n\t\nPreterm\t4.2\t2.1\t−50\t\n\nGamimune, Adult CL = 110 mL/day, Baseline Uncorrected\n\t\n250 (term)\t2.8\t3.1\t10\t\n500 (term)\t4.1\t3.3\t−18\t\n1000 (preterm)\t3.6\t1.9\t−47\t\nantibodies-09-00040-t003_Table 3Table 3 Predicted and observed clearance of therapeutic proteins (non-antibodies) in children of different ages.\n\nAge (Years)\tObserved CL\tPredicted CL\t% Error\t\n\nBivalirudin, Adult CL = 238 mL/min, Percutaneous Coronary Intervention\n\t\n<30 days\t40\t9\t−77\t\n31 days <2 \t83\t28\t−66\t\n2–<6 \t137\t86\t−37\t\n6–<16 \t245\t159\t−35\t\n\nDarbepoetin alfa, Adult CL = 112 mL/h, Chronic Kidney Disease\n\t\n1–17\t81\t67\t−17\t\n<12 \t55\t45\t−19\t\n>12 \t49\t64\t30\t\n\nErythropoietin, Adult CL = 361 mL/h, End Stage Renal Failure\n\t\n9–12 \t263\t177\t−33\t\n>12–16 \t429\t242\t−44\t\n\nInterleukin 11, Adult CL = 26 L/h, Solid Tumors or Lymphoma\n\t\n>1–3 \t4.9\t4.1\t−17\t\n>3–<13\t13.2\t12.5\t−5\t\n>13–<17\t23.8\t20.4\t−14\t\n\nDrotrecogin alfa (activated), Adult CL = 38 L/h, Chronic Kidney Disease\n\t\n<1 year\t3.4\t3.3\t−4\t\n1–8 year\t12\t18\t46\t\n\nGlulisine, SC, Adult CL = 53 mL/h, Type 1 Diabetes\n\t\n5–11 year \t45\t35\t−23\t\n11–17 year \t65\t50\t−24\t\n\nRegular Human Insulin, SC, Adult CL = 55 mL/h, Type 1 Diabetes\n\t\n5–11 year \t65\t36\t−44\t\n11–17 year \t63\t51\t−18\t\n\nGrowth Hormone (LB03002), Adult CL = 25 L/h, GH Deficiency\n\t\n7 years\t9.1\t11.5\t27\t\n\nEnfuvirtide, Adult CL = 1310 mL/h, HIV-1-Infected, SC\n\t\n>5–<12 year\t666\t640\t−3\t\n>12–<17 year\t970\t960\t−1\t\nantibodies-09-00040-t004_Table 4Table 4 Summary statistics of the analysis by the age dependent exponents (ADE) model.\n\nDescription\tMonoclonal\tPolyclonal\tNon-Antibodies\t\n# of drugs\t13\t7\t9\t\n# of observations\t33\t21\t21\t\n≤30% PE\t30 (91%)\t17 (81%)\t13 (62%)\t\n≤50% PE\t32 (97%)\t21 (100%)\t19 (90%)\t\n≥50% PE\t1 (3%)\t0 (0%)\t2 (10%)\t\n# All drugs\t29\t\n\t\n\t\n# of observations\t75\t\n\t\n\t\n≤30% PE\t60 (80%)\t\n\t\n\t\n≤50% PE\t72 (96%)\t\n\t\n\t\n≥50% PE\t3 (4%)\t\n\t\n\t\nPE = percent error; numbers in brackets are percent of total.\n==== Refs\nReferences\n1. Gibaldi M. Biopharmaceutics and Clinical Pharmacokinetics Lea & Febiger Philadelphia, PA, USA 1984 257 285 \n2. Mahmood I. Prediction of drug clearance in premature and mature neonates, infants, and children ≤ 2 years of age: A comparison of the predictive performance of 4 allometric models J. Clin. Pharmacol. 2016 56 733 739 10.1002/jcph.652 26437918 \n3. Mahmood I. Staschen C.M. Goteti K. Prediction of drug clearance in children: An evaluation of the predictive performance of several models AAPS J. 2014 16 334 343 10.1208/s12248-014-9667-7 25274608 \n4. Mahmood I. Mechanistic versus allometric models for the prediction of drug clearance in neonates (<3 months of age) J. Clin. Pharmacol. 2015 55 718 720 25943826 \n5. Mahmood I. Ahmad T. Mansoor N. Sharib S.M. Prediction of clearance in neonates and infants (≤3 months of age) for drugs that are glucuronidated: A comparative study between allometric scaling and physiologically based pharmacokinetic modeling J. Clin. Pharmacol. 2017 57 476 483 10.1002/jcph.837 27704554 \n6. Mahmood I. Tegenge M.A. A comparative study between allometric scaling and physiologically based pharmacokinetic modeling for the prediction of drug clearance from neonates to adolescents J. Clin. Pharmacol. 2019 59 189 197 10.1002/jcph.1310 30192373 \n7. Mahmood I. Initiation of pediatric clinical trials for coagulation factors: Application of pharmacokinetics and allometry to first-in-pediatric dose selection J. Clin. Pharmacol. 2019 59 829 834 10.1002/jcph.1371 30624769 \n8. Boxenbaum H. Interspecies pharmacokinetic scaling and the evolutionary-comparative paradigm Drug Metab. Rev. 1984 15 1071 10.3109/03602538409033558 6396053 \n9. Kovarik J.M. Gridelli B.G. Martin S. Rodeck B. Melter M. Dunn S.P. Merion R.M. Tzakis A.G. Alonso E. Bucuvalas J. Basiliximab in pediatric liver transplantation: A pharmacokinetic-derived dosing algorithm Pediatr. Transplant. 2002 6 224 230 10.1034/j.1399-3046.2002.01086.x 12100507 \n10. Kovarik J.M. Offner G. Broyer M. Niaudet P. Loirat C. Mentser M. Lemire J. Crocker J.F. Cochat P. Clark G. A rational dosing algorithm for basiliximab (Simulect) in pediatric renal transplantation based on pharmacokinetic-dynamic evaluations Transplantation 2002 74 966 971 10.1097/00007890-200210150-00011 12394838 \n11. Trippett T.M. Herzog C. Whitlock J.A. Wolff J. Kuttesch J. Bagatell R. Hunger S.P. Boklan J. Smith A.A. Arceci R.J. Phase I and pharmacokinetic study of cetuximab and irinotecan in children with refractory solid tumors: A study of the pediatric oncology experimental therapeutic investigators’ consortium J. Clin. Oncol. 2009 27 5102 5108 10.1200/JCO.2008.20.8975 19770383 \n12. Tan A.R. Moore D.F. Hidalgo M. Doroshow J.H. Poplin E.A. Goodin S. Mauro D. Rubin E.H. Pharmacokinetics of cetuximab after administration of escalating single dosing and weekly fixed dosing in patients with solid tumors Clin. Cancer Res. 2006 12 6517 6522 10.1158/1078-0432.CCR-06-0705 17065274 \n13. Buckwalter M. Dowell J.A. Korth-Bradley J. Gorovits B. Mayer P.R. Pharmacokinetics of gemtuzumab ozogamicin as a single-agent treatment of pediatric patients with refractory or relapsed acute myeloid leukemia J. Clin. Pharmacol. 2004 44 873 880 10.1177/0091270004267595 15286091 \n14. Burns J.C. Best B.M. Mejias A. Mahony L. Fixler D.E. Jafri H.S. Melish M.E. Jackson M.A. Asmar B.I. Lang D.J. Infliximab treatment of intravenous immunoglobulin-resistant Kawasaki disease J. Pediatr. 2008 153 833 838 10.1016/j.jpeds.2008.06.011 18672254 \n15. Shin D. Kim Y. Kim Y.S. Körnicke T. Fuhr R. A Randomized, Phase I Pharmacokinetic Study Comparing SB2 and Infliximab Reference Product (Remicade) in Healthy Subjects BioDrugs 2015 29 381 388 10.1007/s40259-015-0150-5 26577771 \n16. Hyams J.S. Wilson D.C. Thomas A. Heuschkel R. Mitton S. Mitchell B. Daniels R. Libonati M.A. Zanker S. Kugathasan S. International Natalizumab CD305 Trial Group. Natalizumab therapy for moderate to severe Crohn disease in adolescents J. Pediatr. Gastroenterol. Nutr. 2007 44 185 191 10.1097/01.mpg.0000252191.05170.e7 17255829 \n17. FDA Package Insert of Natalizumab for Adults in Crohn Disease Available online: https://www.medpagetoday.com/gastroenterology/inflammatoryboweldisease/7969 (accessed on 1 June 2020) \n18. Sun H. Van L.M. Floch D. Jiang X. Klein U.R. Abrams K. Sunkara G. Pharmacokinetics and Pharmacodynamics of Canakinumab in Patients with Systemic Juvenile Idiopathic Arthritis J. Clin. Pharmacol. 2016 56 1516 1527 10.1002/jcph.754 27119439 \n19. Kuemmerle-Deschner J.B. Ramos E. Blank N. Roesler J. Felix S.D. Jung T. Stricker K. Chakraborty A. Tannenbaum S. Wright A.M. Canakinumab (ACZ885, a fully human IgG1 anti-IL-1β mAb) induces sustained remission in pediatric patients with cryopyrin-associated periodic syndrome (CAPS) Arthritis Res. Ther. 2011 13 R34 10.1186/ar3266 21356079 \n20. López E.L. Contrini M.M. Glatstein E. González Ayala S. Santoro R. Allende D. Ezcurra G. Teplitz E. Koyama T. Matsumoto Y. Safety and pharmacokinetics of urtoxazumab, a humanized monoclonal antibody, against Shiga-like toxin 2 in healthy adults and in pediatric patients infected with Shiga-like toxin-producing Escherichia coli Antimicrob. Agents Chemother. 2010 54 239 243 10.1128/AAC.00343-09 19822704 \n21. FDA Package Insert of Toclizumab Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125276s092lbl.pdf (accessed on 1 June 2020) \n22. Pescovitz M.D. Knechtle S. Alexander S.R. Colombani P. Nevins T. Nieforth K. Bouw M.R. Safety and pharmacokinetics of daclizumab in pediatric renal transplant recipients Pediatr. Transplant. 2008 12 447 455 10.1111/j.1399-3046.2007.00830.x 18466432 \n23. Li J. Li X. Tan M. Lin B. Hou S. Qian W. Li B. Zhang D. Zhou B. Wang H. Two doses of humanized anti-CD25 antibody in renal transplantation: A preliminary comparative study MAbs 2009 1 49 55 10.4161/mabs.1.1.7399 20046574 \n24. Moudgil A. Dharnidharka V.R. Feig D.I. Warshaw B.L. Perera V. Murthy B. Roberts M.E. Polinsky M.S. Ettenger R.B. Phase I study of single-dose pharmacokinetics and pharmacodynamics of belatacept in adolescent kidney transplant recipients Am. J. Transplant. 2019 19 1218 1223 10.1111/ajt.15236 30582294 \n25. Griffin M.P. Khan A.A. Esser M.T. Jensen K. Takas T. Kankam M.K. Villafana T. Dubovsky F. Safety, Tolerability, and pharmacokinetics of MEDI8897, the respiratory syncytial virus prefusion F-targeting monoclonal antibody with an extended half-life, in healthy adults Antimicrob. Agents Chemother. 2017 61 e01714-16 10.1128/AAC.01714-16 27956428 \n26. Domachowske J.B. Khan A.A. Esser M.T. Jensen K. Takas T. Villafana T. Dubovsky F. Griffin M.P. Safety, tolerability and pharmacokinetics of MEDI8897, an extended half-life single-dose respiratory syncytial virus prefusion F-targeting monoclonal antibody administered as a single dose to healthy preterm infants Pediatr. Infect. Dis. J. 2018 37 886 892 10.1097/INF.0000000000001916 29373476 \n27. Lu J.F. Bruno R. Eppler S. Novotny W. Lum B. Gaudreault J. Clinical pharmacokinetics of bevacizumab in patients with solid tumors Cancer Chemother. Pharmacol. 2008 62 779 786 10.1007/s00280-007-0664-8 18205003 \n28. Gojo J. Sauermann R. Knaack U. Slavc I. Peyrl A. Pharmacokinetics of Bevacizumab in Three Patients Under the Age of 3 Years with CNS Malignancies Drugs R D 2017 17 469 474 10.1007/s40268-017-0190-z 28577293 \n29. Robbie G.J. Zhao L. Mondick J. Losonsky G. Roskos L.K. Population Pharmacokinetics of Palivizumab, a Humanized Anti-Respiratory Syncytial Virus Monoclonal Antibody, in Adults and Children Antimicrob. Agents Chemother. 2012 56 4927 4936 10.1128/AAC.06446-11 22802243 \n30. FDA Package Insert of Pangyza Available online: https://www.fda.gov/vaccines-blood-biologics (accessed on 1 June 2020) \n31. FDA Package Insert of Gamaplex 10% Available online: https://www.fda.gov/media/102800/download (accessed on 1 June 2020) \n32. FDA Package Insert of GAMUNEX-C Available online: https://www.fda.gov/media/70738/download (accessed on 1 June 2020) \n33. FDA Package Insert of Cuvitru Available online: https://www.fda.gov/media/100531/download (accessed on 1 June 2020) \n34. FDA Package Insert of Hizentra Available online: https://www.fda.gov/media/78466/download (accessed on 1 June 2020) \n35. Kyllonen K.S. Clapp D.W. Kliegman R.M. Baley J.E. Shenker N. Fanaroff A.A. Berger M. Dosage of intravenously administered immune globulin and dosing interval required to maintain target levels of immunoglobulin G in low birth weight infants J. Pediatr. 1989 115 1013 1016 10.1016/S0022-3476(89)80761-9 2511290 \n36. Weisman L.E. Fischer G.W. Marinelli P. Hemming V.G. Pierce J.R. Golden S.M. Peck C.C. Pharmacokinetics of intravenous immunoglobulin in neonates Vox Sang. 1989 57 243 248 10.1159/000461056 2694604 \n37. Forbes T.J. Hijazi Z.M. Young G. Ringewald J.M. Aquino P.M. Vincent R.N. Qureshi A.M. Rome J.J. Rhodes J.F. Jr. Jones T.K. Pediatric catheterization laboratory anticoagulation with bivalirudin Catheter. Cardiovasc. Interv. 2011 77 671 679 10.1002/ccd.22817 21433272 \n38. Robson R. White H. Aylward P. Frampton C. Bivalirudin pharmacokinetics and pharmacodynamics: Effect of renal function, dose, and gender Clin. Pharmacol. Ther. 2002 71 433 439 10.1067/mcp.2002.124522 12087346 \n39. Uemura O. Hattori M. Hataya H. Ito S. Ito N. Akizawa T. Pharmacokinetics of darbepoetin alfa after single, intravenous or subcutaneous administration in Japanese pediatric patients with chronic kidney disease Clin. Exp. Nephrol. 2014 18 932 938 10.1007/s10157-014-0936-7 24504705 \n40. Lerner G. Kale A.S. Warady B.A. Jabs K. Bunchman T.E. Heatherington A. Olson K. Messer-Mann L. Maroni B.J. Pharmacokinetics of darbepoetin alfa in pediatric patients with chronic kidney disease Pediatr. Nephrol. 2002 17 933 937 10.1007/s00467-002-0932-0 12432437 \n41. Evans J.H. Brocklebank J.T. Bowmer C.J. Ng P.C. Pharmacokinetics of recombinant human erythropoietin in children with renal failure Nephrol. Dial. Transplant. 1991 6 709 714 10.1093/ndt/6.10.709 1754107 \n42. Kindler J. Eckardt K.U. Ehmer B. Jandeleit K. Kurtz A. Schreiber A. Scigalla P. Sieberth H.G. Single-dose pharmacokinetics of recombinant human erythropoietin in patients with various degrees of renal failure Nephrol. Dial. Transplant. 1989 4 345 349 10.1093/oxfordjournals.ndt.a091888 2505184 \n43. Cairo M.S. Davenport V. Bessmertny O. Goldman S.C. Berg S.L. Kreissman S.G. Laver J. Shen V. Secola R. Van De Ven C. Phase I/II dose escalation study of recombinant human interleukin-11 following ifosfamide, carboplatin and etoposide in children, adolescents and young adults with solid tumours or lymphoma: A clinical, haematological and biological study Br. J. Haematol. 2005 128 49 58 10.1111/j.1365-2141.2004.05281.x 15606549 \n44. Barton P. Kalil A.C. Nadel S. Goldstein B. Okhuysen-Cawley R. Brilli R.J. Takano J.S. Martin L.D. Quint P. Yeh T.S. Safety, pharmacokinetics, and pharmacodynamics of drotrecogin alfa (activated) in children with severe sepsis Pediatrics 2004 113 7 17 10.1542/peds.113.1.7 14702440 \n45. Danne T. Becker R.H. Heise T. Bittner C. Frick A.D. Rave K. Pharmacokinetics, prandial glucose control, and safety of insulin glulisine in children and adolescents with type 1 diabetes Diabetes Care 2005 28 2100 2105 10.2337/diacare.28.9.2100 16123473 \n46. Rave K. Klein O. Frick A.D. Becker R.H. Advantage of premeal-injected insulin glulisine compared with regular human insulin in subjects with type 1 diabetes Diabetes Care 2006 29 1812 1817 10.2337/dc06-0383 16873785 \n47. Peter F. Savoy C. Ji H.J. Juhasz M. Bidlingmaier M. Saenger P. Pharmacokinetic and pharmacodynamic profile of a new sustained-release GH formulation, LB03002, in children with GH deficiency Eur. J. Endocrinol. 2009 160 349 355 10.1530/EJE-08-0703 19074465 \n48. Bidlingmaier M. Kim J. Savoy C. Kim M.J. Ebrecht N. de la Motte S. Strasburger C.J. Comparative pharmacokinetics and pharmacodynamics of a new sustained-release growth hormone (GH), LB03002, versus daily GH in adults with GH deficiency J. Clin. Endocrinol. Metab. 2006 91 2926 2930 10.1210/jc.2006-0514 16720652 \n49. Zhang X. Lin T. Bertasso A. Evans C. Dorr A. Kolis S.J. Salgo M. Patel I. T20-310/NV16056 Study Group Population pharmacokinetics of enfuvirtide in HIV-1-infected pediatric patients over 48 weeks of treatment J. Clin. Pharmacol. 2007 47 510 517 10.1177/0091270006299089 17389560 \n50. Bartelink I.H. Boelens J.J. Bredius R.G. Egberts A.C. Wang C. Bierings M.B. Shaw P.J. Nath C.E. Hempel G. Zwaveling J. Body weight-dependent pharmacokinetics of busulfan in paediatric haematopoietic stem cell transplantation patients: Towards individualized dosing Clin. Pharmacokinet. 2012 51 331 345 10.2165/11598180-000000000-00000 22455797 \n51. Wang C. Allegaert K. Peeters M.Y. Tibboel D. Danhof M. Knibbe C.A. The allometric exponent for scaling clearance varies with age: A study on seven propofol datasets ranging from preterm neonates to adults Br. J. Clin. Pharmacol. 2014 77 149 159 10.1111/bcp.12180 23772816 \n52. Momper J.D. Mulugeta Y. Green D.J. Karesh A. Krudys K.M. Sachs H.C. Yao L.P. Burckart G.J. Adolescent dosing and labeling since the Food and Drug Administration Amendments Act of 2007 JAMA Pediatr. 2013 167 926 932 10.1001/jamapediatrics.2013.465 23921678 \n53. Mahmood I. Tegenge M.A. A bodyweight-dependent allometric exponent model for scaling clearance of clotting factor VIII and IX from infants to adults Haemophilia 2016 22 e570 e573 10.1111/hae.13116 27868371 \n54. Mahmood I. Allometric Extrapolation of Factors VII, VIII, and IX Clearance in Children from Adults J. Thromb. Haemost. 2012 10 1609 1613 10.1111/j.1538-7836.2012.04787.x 22612736 \n55. Mahmood I. Prediction of Clearance, Volume of distribution, and Half-life of Drugs in Extremely Low to Low Birth Weight Neonates: An Allometric Approach Eur. J. Drug. Metab. Pharmacokinet. 2017 42 601 610 10.1007/s13318-016-0372-z 27562171 \n56. Wang C. Sadhavisvam S. Krekels E.H. Dahan A. Tibboel D. Danhof M. Vinks A.A. Knibbe C.A. Developmental changes in morphine clearance across the entire paediatric age range are best described by a bodyweight-dependent exponent model Clin. Drug. Investig. 2013 33 523 534 10.1007/s40261-013-0097-6\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2073-4468",
"issue": "9(3)",
"journal": "Antibodies (Basel, Switzerland)",
"keywords": "allometry; children; clearance; monoclonal antibodies; polyclonal antibodies; therapeutic proteins",
"medline_ta": "Antibodies (Basel)",
"mesh_terms": null,
"nlm_unique_id": "101587489",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32764408",
"pubdate": "2020-08-05",
"publication_types": "D016428:Journal Article",
"references": "27704554;2694604;1754107;26577771;17389560;27956428;2505184;22802243;25943826;15606549;19770383;27562171;22612736;26437918;6396053;16123473;30624769;30192373;23754691;16873785;21433272;30582294;21356079;18672254;27119439;19822704;16720652;14702440;23921678;20046574;28577293;12087346;2511290;22455797;12394838;25274608;12100507;19074465;23772816;18466432;18205003;15286091;12432437;17255829;27868371;24504705;29373476;17065274",
"title": "Prediction of Clearance of Monoclonal and Polyclonal Antibodies and Non-Antibody Proteins in Children: Application of Allometric Scaling.",
"title_normalized": "prediction of clearance of monoclonal and polyclonal antibodies and non antibody proteins in children application of allometric scaling"
} | [
{
"companynumb": "US-AMGEN-USASP2020158228",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DARBEPOETIN ALFA"
},
"drugadditional": "3",
... |
{
"abstract": "Stimulants-related bruxism has been previously reported; both diurnal and nocturnal. Here, authors report on a case of methylphenidate (MPH)-treated attention-deficit/hyperactivity disorder that developed nocturnal bruxism and failed multiple pharmacologic trials. Add-on clonidine has successfully helped with bruxisms while augmenting MPH response. This was achieved with great tolerability. This remains a viable option to deploy in such unusual clinical scenarios.",
"affiliations": "1 Al-Manara CAP Centre, Kuwait Centre for Mental Health (KCMH) , Shuwaikh, Kuwait .;2 Pediatrics Department, Cleveland Clinic Children's , Cleveland, Ohio.;3 Al-Manara CAP Centre, Kuwait Centre for Mental Health (KCMH) , Shuwaikh, Kuwait .",
"authors": "Naguy|Ahmed|A|;Elsori|Dalal|D|;Alamiri|Bibi|B|",
"chemical_list": "D000700:Analgesics; D000697:Central Nervous System Stimulants; D008774:Methylphenidate; D003000:Clonidine",
"country": "United States",
"delete": false,
"doi": "10.1089/cap.2018.0114",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1044-5463",
"issue": "29(1)",
"journal": "Journal of child and adolescent psychopharmacology",
"keywords": "bruxism; clonidine; methylphenidate",
"medline_ta": "J Child Adolesc Psychopharmacol",
"mesh_terms": "D000700:Analgesics; D001289:Attention Deficit Disorder with Hyperactivity; D000697:Central Nervous System Stimulants; D002648:Child; D003000:Clonidine; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007597:Jordan; D008774:Methylphenidate; D020186:Sleep Bruxism",
"nlm_unique_id": "9105358",
"other_id": null,
"pages": "75-76",
"pmc": null,
"pmid": "30575406",
"pubdate": "2019-02",
"publication_types": "D016422:Letter",
"references": null,
"title": "Methylphenidate-Induced Nocturnal Bruxism Alleviated by Adjunctive Clonidine.",
"title_normalized": "methylphenidate induced nocturnal bruxism alleviated by adjunctive clonidine"
} | [
{
"companynumb": "KW-PURDUE PHARMA-CAN-2019-0009662",
"fulfillexpeditecriteria": "1",
"occurcountry": "KW",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPHENIDATE HYDROCHLORIDE"
},
"dr... |
{
"abstract": "Mutations in the gene encoding epidermal growth factor receptor (EGFR) are the most frequent driver mutations in lung adenocarcinoma in Japan. Exon 19 deletion and L858R mutation in exon 21 are the most common EGFR mutations. Uncommon mutations, such as G719X, S768I, and L861Q, and compound mutations, combinations of 2 common or uncommon mutations, have also been reported. EGFR tyrosine kinase inhibitors (TKIs) are effective against cancers harboring common mutations; however, their efficacy against cancers with uncommon or compound mutations remains unclear. We report the case of a 67-year-old man with lung adenocarcinoma (clinical stage IIIA [cT1N2M0]), harboring an uncommon compound mutation, G719X and S768I. The cancer progressed within 2 months of initial chemoradiotherapy. Treatment with afatinib (40 mg/day) produced a partial response, which was maintained for 17 months with continued treatment. A literature review revealed that lung cancer with G719X/S768I compound mutation exhibited good response to EGFR-TKIs, even better than that of lung cancers with single uncommon mutations.",
"affiliations": "Division of Pulmonary Medicine, Department of Medicine, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan. ko-asano@tokai-u.jp.",
"authors": "Kutsuzawa|Naokata|N|;Takahashi|Fuminari|F|;Tomomatsu|Katsuyoshi|K|;Obayashi|Shohei|S|;Takeuchi|Tomoe|T|;Takihara|Takahisa|T|;Hayama|Naoki|N|;Oguma|Tsuyoshi|T|;Aoki|Takuya|T|;Asano|Koichiro|K|",
"chemical_list": "D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D000077716:Afatinib; C512478:EGFR protein, human; D066246:ErbB Receptors",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0005",
"issue": "45(3)",
"journal": "The Tokai journal of experimental and clinical medicine",
"keywords": null,
"medline_ta": "Tokai J Exp Clin Med",
"mesh_terms": "D000230:Adenocarcinoma; D000077716:Afatinib; D000368:Aged; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D005091:Exons; D017353:Gene Deletion; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D009154:Mutation; D047428:Protein Kinase Inhibitors; D016896:Treatment Outcome",
"nlm_unique_id": "7704186",
"other_id": null,
"pages": "113-116",
"pmc": null,
"pmid": "32901897",
"pubdate": "2020-09-20",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Successful Treatment of a Patient with Lung Adenocarcinoma Harboring Compound EGFR Gene Mutations, G719X and S768I, with Afatinib.",
"title_normalized": "successful treatment of a patient with lung adenocarcinoma harboring compound egfr gene mutations g719x and s768i with afatinib"
} | [
{
"companynumb": "JP-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2020-BI-054262",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"d... |
{
"abstract": "Amphotericin B is a powerful polyene antifungal drug used for treating systemic fungal infections and is usually administered for a short period. Side effects after prolonged use are unknown in humans. Here we report the case of a 28-year-old man suffering from chronic granulomatous disease (CGD), treated for invasive cerebral aspergillosis with liposomal amphotericin B (L-AmB) for a very long time (8 consecutive years). We describe the efficacy and safety of this treatment in the long term. Aspergillosis was kept under control as long as L-AmB therapy was maintained, but relapsed when the dose was reduced. No overt renal toxicity was noted. The patient gradually developed hepatosplenomegaly and pancytopenia. Abnormalities of bone marrow were similar to the sea-blue histiocyte syndrome. Liver biopsy showed images of nodular regenerative hyperplasia related to CGD as well as a histiocytic storage disease. We discuss the very prolonged use of L-AmB leading to the development of a lysosomal storage disease.",
"affiliations": "Assistance Publique - Hôpitaux de Paris, Service de Médecine Interne et Immunologie Clinique, Hôpital Universitaire Bicêtre, 94275 Le Kremlin-Bicêtre Cedex, France; Université Paris Sud XI, 63 rue Gabriel Péri, 94276 Le Kremlin-Bicêtre Cedex, France. Electronic address: jean-marie.michot@bct.aphp.fr.;Assistance Publique - Hôpitaux de Paris, Service de Médecine Interne et Immunologie Clinique, Hôpital Universitaire Bicêtre, 94275 Le Kremlin-Bicêtre Cedex, France.;Assistance Publique - Hôpitaux de Paris, Service de Médecine Interne et Immunologie Clinique, Hôpital Universitaire Bicêtre, 94275 Le Kremlin-Bicêtre Cedex, France.;Assistance Publique - Hôpitaux de Paris, Service de Médecine Interne et Immunologie Clinique, Hôpital Universitaire Bicêtre, 94275 Le Kremlin-Bicêtre Cedex, France; Université Paris Sud XI, 63 rue Gabriel Péri, 94276 Le Kremlin-Bicêtre Cedex, France.;Assistance Publique - Hôpitaux de Paris, Service de Médecine Interne et Immunologie Clinique, Hôpital Universitaire Bicêtre, 94275 Le Kremlin-Bicêtre Cedex, France.;Université Paris Sud XI, 63 rue Gabriel Péri, 94276 Le Kremlin-Bicêtre Cedex, France; Assistance Publique - Hôpitaux de Paris, Service de Mycologie et Parasitologie, Hôpital Universitaire Bicêtre, 94275 Le Kremlin-Bicêtre Cedex, France.;Assistance Publique - Hôpitaux de Paris, Service d'Immuno-hématologie pédiatrique, Hôpital Universitaire Necker-Enfants Malades, 75014 Paris, France.;Université Paris Descartes, Assistance Publique - Hôpitaux de Paris, Service de Maladies Infectieuses et Tropicales, Hôpital Universitaire Necker-Enfants Malades, Centre d'Infectiologie Necker-Pasteur, 75014 Paris, France; Institut Pasteur, Centre National de Référence Mycoses Invasives et Antifongiques, CNRS URA3012, 75015 Paris, France.;Assistance Publique - Hôpitaux de Paris, Centre hépato-biliaire, Hôpital Universitaire Paul Brousse, 94800 Villejuif, France.;Assistance Publique - Hôpitaux de Paris, Centre hépato-biliaire, Hôpital Universitaire Paul Brousse, 94800 Villejuif, France.;Assistance Publique - Hôpitaux de Paris, Service d'anatomopathologie, Hôpital Universitaire Bicêtre, 94275 Le Kremlin-Bicêtre Cedex, France.;Assistance Publique - Hôpitaux de Paris, Service d'anatomopathologie, Hôpital Universitaire Bicêtre, 94275 Le Kremlin-Bicêtre Cedex, France.;Assistance Publique - Hôpitaux de Paris, Service d'hématologie biologique, Hôpital Universitaire Bicêtre, 94275 Le Kremlin-Bicêtre Cedex, France.;Assistance Publique - Hôpitaux de Paris, Service de Médecine Interne et Immunologie Clinique, Hôpital Universitaire Bicêtre, 94275 Le Kremlin-Bicêtre Cedex, France; Université Paris Sud XI, 63 rue Gabriel Péri, 94276 Le Kremlin-Bicêtre Cedex, France.;Assistance Publique - Hôpitaux de Paris, Service de Médecine Interne et Immunologie Clinique, Hôpital Universitaire Bicêtre, 94275 Le Kremlin-Bicêtre Cedex, France; Université Paris Sud XI, 63 rue Gabriel Péri, 94276 Le Kremlin-Bicêtre Cedex, France.",
"authors": "Michot|J M|JM|;Gubavu|C|C|;Fourn|E|E|;Maigne|G|G|;Teicher|E|E|;Angoulvant|A|A|;Blanche|S|S|;Lortholary|O|O|;Coilly|A|A|;Duclos-Vallée|J C|JC|;Sebagh|M|M|;Guettier|C|C|;Aumont|C|C|;Delfraissy|J F|JF|;Lambotte|O|O|",
"chemical_list": "D000935:Antifungal Agents; C068538:liposomal amphotericin B; D000666:Amphotericin B",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0924-8579",
"issue": "43(6)",
"journal": "International journal of antimicrobial agents",
"keywords": "Antifungal agents; Chronic granulomatous disease; Neuroaspergillosis; Sea-blue histiocyte syndrome",
"medline_ta": "Int J Antimicrob Agents",
"mesh_terms": "D000328:Adult; D000666:Amphotericin B; D000935:Antifungal Agents; D001706:Biopsy; D006105:Granulomatous Disease, Chronic; D006651:Histocytochemistry; D006801:Humans; D008099:Liver; D016464:Lysosomal Storage Diseases; D008297:Male; D020953:Neuroaspergillosis",
"nlm_unique_id": "9111860",
"other_id": null,
"pages": "566-9",
"pmc": null,
"pmid": "24787480",
"pubdate": "2014-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Very prolonged liposomal amphotericin B use leading to a lysosomal storage disease.",
"title_normalized": "very prolonged liposomal amphotericin b use leading to a lysosomal storage disease"
} | [
{
"companynumb": "FR-MYLANLABS-2014S1015982",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "AMPHOTERICIN B"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nDespite the progress in protection and surgical techniques, the proponents of endovascular techniques for aortic arch repair still consider conventional arch replacement to be high risk, mostly due to deep hypothermia, which in the past was generally used for cerebral and organ protection. The aim of the study was to evaluate the operative results of open aortic arch replacement using current perfusion and surgical techniques in which deep hypothermia is avoided.\n\n\nMETHODS\nBetween October 2004 and February 2012, 131 consecutive patients with non-acute-dissected aortic arch pathology (mean age: 66 ± 11 years) were referred for surgery. All patients were operated on conventionally using circular aortic arch replacement with repair of one (10), two (58) or all arch branches (63). The adjacent aorta was replaced in all cases (ascending--115, descending--2 and both--14). Nine (6.9%) patients had previous neurological defects with residual symptoms and 17 (13.0%) had previous cardiac surgery.\n\n\nRESULTS\nEither unilateral (130) or bilateral (1) cerebral perfusion at a blood temperature of 28°C (mean duration 36 ± 14, range: 16-80 min) was performed for brain protection during circulatory arrest under mild-to-moderate hypothermia (mean rectal temperature 30.0 ± 1.6°C). Concomitant cardiac procedures, mostly on the aortic valve, were necessary in 121 (92%) patients. Among 114 patients needing aortic valve/root surgery, there were 70 aortic valve-preserving procedures. Permanent neurological deficit or temporary dysfunctions occurred in 1 (0.8%) and 6 patients (4.6%), respectively. No patient suffered from paraplegia. The postoperative 30-day mortality was 2.3% (3 patients). A total of 17 patients died during the follow-up time of up to 97 months (mean 37 ± 27 months), resulting in an actuarial survival of 81.9 ± 4.3% at 5 years. No patient needed any reoperation or new intervention on the repaired aorta.\n\n\nCONCLUSIONS\nConventional arch surgery offers definitive repair and can be safely performed using current perfusion and operative techniques. Open procedures ensure simultaneous aortic valve repair, which is frequently necessary, and can be performed by reconstruction in more than half of the cases. The use of refined surgical and cerebral perfusion techniques allows the avoidance of deep hypothermia with all its negative side effects and leads to excellent outcomes against which the results of alternative approaches should be compared.",
"affiliations": "Cardiovascular Clinic Bad Neustadt, Bad Neustadt, Germany. p.urbanski@kardiochirurg.de",
"authors": "Urbanski|Paul P|PP|;Raad|Mahli|M|;Lenos|Aristidis|A|;Bougioukakis|Petros|P|;Zacher|Michael|M|;Diegeler|Anno|A|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1093/ejcts/ezt030",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1010-7940",
"issue": "44(3)",
"journal": "European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery",
"keywords": "Aortic arch; Aortic surgery; Cerebral protection",
"medline_ta": "Eur J Cardiothorac Surg",
"mesh_terms": "D000368:Aged; D001011:Aorta; D019917:Blood Vessel Prosthesis Implantation; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015424:Reperfusion; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "8804069",
"other_id": null,
"pages": "431-6; discussion 436-7",
"pmc": null,
"pmid": "23425674",
"pubdate": "2013-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Open aortic arch replacement in the era of endovascular techniques.",
"title_normalized": "open aortic arch replacement in the era of endovascular techniques"
} | [
{
"companynumb": "PHHY2015DE016413",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nThrombotic microangiopathy (TMA) is characterized by endothelial cell injury and formation of fibrin thrombi within capillary and arterioles. In renal allograft recipients, TMA mainly presents as hemolytic uremic syndrome. Its occurrence is rare, and diagnosis requires a high degree of suspicion. Drug toxicity, in particular from calcineurin inhibitors (CNIs) and mTOR inhibitors (mTORi), is the most common cause posttransplant and has recently been emphasized in the setting of lung transplantation.\n\n\nOBJECTIVE\nThe goal of this study was to investigate the role of mTORi as an added risk factor in the development of TMA to propose strategies for modulation of immunosuppressive (IS) therapy.\n\n\nMETHODS\nFrom a database of 496 renal graft recipients, we analyzed 350 renal graft biopsy specimens gathered at our center from 1998 to 2012. In patients undergoing combined therapy with mTORi and CNI, we compared drugs levels in TMA-affected and TMA-free groups, using mTORi and CNI TLC and the summation of [everolimus TLC+(cyclosporine C2/100)] (Σ) as a surrogate marker of combined exposition to 2 drugs. Receiver-operating characteristic analysis of association of EVL TLC+(C2/100) was performed for patients exposed to mTORi.\n\n\nRESULTS\nHistologic features of TMA were found in 36 patients (prevalence of 7.3%). The caseload was divided into 2 groups: not drug-related TMA (n=19) and drug-related TMA (n=17). Despite the prevalence of TMA in patients exposed to mTORi being greater (8 of 153; prevalence, 5.3%) compared with therapies without mTORi (9 of 324; prevalence, 2.8%), statistical difference was not reached. Patients treated with mTORi who developed de novo drug-related TMA had higher blood levels of IS drugs compared with those who did not develop TMA. Receiver-operating characteristic analysis found a significant threshold of 12.5 ng/mL (area under the curve, 0.803; P=.006).\n\n\nCONCLUSIONS\nResults confirm the pivotal role of IS drugs in the onset of de novo TMA. On the basis of literature, we could speculate a sequence of endothelial damage by CNI, on which everolimus fits hindering the repair of endothelial injury. Therefore, high blood levels of CNI and mTORi seem to predispose patients to posttransplant TMA. Combined monitoring of these 2 drugs might be used to prevent the complication. Σ [everolimus TLC + (cyclosporine C2/100)]>12.5 ng/mL should be avoided as a surrogate risk factor for adverse effects.",
"affiliations": "Nephrology Dialysis and Kidney Transplantation, AOU Policlinico, Modena, Italy. Electronic address: fabio.nava24k@gmail.com.;Nephrology Dialysis and Kidney Transplantation, AOU Policlinico, Modena, Italy.;Nephrology Dialysis and Kidney Transplantation, AOU Policlinico, Modena, Italy.;Nephrology Dialysis and Kidney Transplantation, AOU Policlinico, Modena, Italy.;Nephrology Dialysis and Kidney Transplantation, AOU Policlinico, Modena, Italy.;Nephrology Dialysis and Kidney Transplantation, AOU Policlinico, Modena, Italy.;Nephrology Dialysis and Kidney Transplantation, AOU Policlinico, Modena, Italy.;Nephrology Dialysis and Kidney Transplantation, AOU Policlinico, Modena, Italy.;Nephrology Dialysis and Kidney Transplantation, AOU Policlinico, Modena, Italy.;Nephrology Dialysis and Kidney Transplantation, AOU Policlinico, Modena, Italy.",
"authors": "Nava|F|F|;Cappelli|G|G|;Mori|G|G|;Granito|M|M|;Magnoni|G|G|;Botta|C|C|;Solazzo|A|A|;Fontana|F|F|;Baisi|A|A|;Bonucchi|D|D|",
"chemical_list": "D007166:Immunosuppressive Agents; D016572:Cyclosporine; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "46(7)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000328:Adult; D000368:Aged; D016572:Cyclosporine; D000068338:Everolimus; D005260:Female; D006463:Hemolytic-Uremic Syndrome; D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012307:Risk Factors; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D057049:Thrombotic Microangiopathies",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "2263-8",
"pmc": null,
"pmid": "25242766",
"pubdate": "2014-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Everolimus, cyclosporine, and thrombotic microangiopathy: clinical role and preventive tools in renal transplantation.",
"title_normalized": "everolimus cyclosporine and thrombotic microangiopathy clinical role and preventive tools in renal transplantation"
} | [
{
"companynumb": "IT-MYLANLABS-2015M1032921",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
... |
{
"abstract": "Medulla oblongata myelinolysis is an extremely rare manifestation of extrapontine myelinolysis (EPM). Herein, we report a case of a 34-year-old man with a history of gout who presented repeated vomiting and diarrhea after ingesting 15 colchicine pills. A hyponatremia diagnosis was given and after an intensive treatment, his serum sodium level increased from 118 to 129 mmol/L within 24 hours. Brain magnetic resonance imaging (MRI) revealed a lesion in the medulla oblongata that appeared as a hypointense area in T1-weighted images and a hyperintense area in T2-weighted images. A diagnosis of medulla oblongata myelinolysis and colchicine poisoning was then given, and methylprednisolone therapy was initiated. Seventeen days later, the patient achieved a good outcome with methylprednisolone therapy. However, his medulla oblongata lesion remained detectable with MRI. Medulla oblongata myelinolysis is an extremely rare manifestation of EPM, and unique for being colchicine-induced. This case shows that colchicine poisoning can lead to hyponatremia, which in turn can induce myelinolysis if not treated correctly. As exemplified by our patient's case, desirable treatment outcomes are possible in such cases, although these outcomes may not be associated with a visible reduction of the brain lesions in MRI scans.",
"affiliations": "Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun, China.;Department of Neurosurgery, The First Hospital of Jilin University, Changchun, China.;Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun, China.;Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun, China.;Department of Ophthalmology, The Second Hospital of Jilin University, Changchun, China. 895222700@qq.com.;Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun, China. neuromdong@163.com.",
"authors": "Jiang|Wei|W|;Tan|Xuan-Yu|XY|;Li|Jia-Ai|JA|;Qu|Kang|K|;Yu|Peng|P|;Dong|Ming|M|",
"chemical_list": "D003078:Colchicine",
"country": "China",
"delete": false,
"doi": "10.21037/apm-19-627",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2224-5820",
"issue": "10(2)",
"journal": "Annals of palliative medicine",
"keywords": "Colchicine; case report; demyelinating diseases; medulla oblongata; myelin sheath",
"medline_ta": "Ann Palliat Med",
"mesh_terms": "D000328:Adult; D003078:Colchicine; D006801:Humans; D007010:Hyponatremia; D008279:Magnetic Resonance Imaging; D008297:Male; D008526:Medulla Oblongata; D017590:Myelinolysis, Central Pontine",
"nlm_unique_id": "101585484",
"other_id": null,
"pages": "2349-2353",
"pmc": null,
"pmid": "32527125",
"pubdate": "2021-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Colchicine poisoning complicated by medulla oblongata myelinolysis: a case report.",
"title_normalized": "colchicine poisoning complicated by medulla oblongata myelinolysis a case report"
} | [
{
"companynumb": "CN-TAKEDA-2020TJP012036",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "COLCHICINE"
},
"drugadditional": "3",
... |
{
"abstract": "Amidst the coronavirus (COVID-19) pandemic, the American Society for Transplant Surgeons has recommended that only urgent liver transplant with deceased donors should occur. However, young pediatric candidates rely on living donors for lifesaving transplant. We present a case of non-directed left lateral lobe living liver donor transplant for a 7-month-old child with biliary atresia experiencing repeated life-threatening episodes of sepsis and cholangitis from infected bile lakes. Using careful preoperative planning among the entire multidisciplinary team, paying meticulous attention to infection control pre- and post-operatively, and taking advantage of robust telehealth technology both in and out of the hospital, a successful transplant was achieved. Amidst the COVID pandemic, non-directed liver transplantation can be safely achieved for pediatric recipients.",
"affiliations": "Section of Gastroenterology, Hepatology and Nutrition and the Digestive Health Institute, University of Colorado School of Medicine, Anschutz Medical Campus & Children's Hospital Colorado, Aurora, Colorado, USA.;Division of Transplant Surgery, University of Colorado School of Medicine, Anschutz Medical Campus & Children's Hospital Colorado, Aurora, Colorado, USA.;Division of Transplant Surgery, University of Colorado School of Medicine, Anschutz Medical Campus & Children's Hospital Colorado, Aurora, Colorado, USA.;Section of Pediatric Infectious Diseases, University of Colorado School of Medicine, Anschutz Medical Campus & Children's Hospital Colorado, Aurora, Colorado, USA.;Transplant Surgery, Children's Hospital Colorado, Aurora, Colorado, USA.;Division of Gastroenterology & Hepatology, Department of Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado, USA.;Division of Transplant Surgery, University of Colorado School of Medicine, Anschutz Medical Campus & Children's Hospital Colorado, Aurora, Colorado, USA.;Section of Gastroenterology, Hepatology and Nutrition and the Digestive Health Institute, University of Colorado School of Medicine, Anschutz Medical Campus & Children's Hospital Colorado, Aurora, Colorado, USA.",
"authors": "Feldman|Amy G|AG|0000-0003-4021-5615;Adams|Megan A|MA|;Wachs|Michael E|ME|;Abzug|Mark J|MJ|;Pratscher|Lauren|L|;Jackson|Whitney E|WE|;Pomfret|Elizabeth A|EA|;Sundaram|Shikha S|SS|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.13816",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "24(8)",
"journal": "Pediatric transplantation",
"keywords": "COVID‐19; SARS; coronavirus",
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D001656:Biliary Atresia; D000086382:COVID-19; D005260:Female; D006801:Humans; D007223:Infant; D016031:Liver Transplantation; D019520:Living Donors; D012074:Remission Induction; D009927:Tissue and Organ Procurement; D016896:Treatment Outcome",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "e13816",
"pmc": null,
"pmid": "33460202",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "30811890;30882035;17204962;32196933;32281124;32278366",
"title": "Successful non-directed living liver donor transplant for an infant with biliary atresia during the COVID-19 pandemic.",
"title_normalized": "successful non directed living liver donor transplant for an infant with biliary atresia during the covid 19 pandemic"
} | [
{
"companynumb": "NVSC2020US228257",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
"druga... |
{
"abstract": "Aim: Angiotensin-converting enzyme inhibitors (ACEIs) are commonly used to treat hypertension. Although generally well tolerated, the adverse effects of ACEIs include hypotension, cough, acute kidney injury and hyperkalemia. Rare reports of ACEI-induced hepatotoxicity have been described, most notably a cholestatic pattern of injury related to captopril. A 67-year-old male presented to the emergency department with a three-week history of jaundice, pruritis and weakness. Eight weeks before, he began taking ramipril and clopidogrel. His past medical history was significant for previous acute cholestatic liver injury approximately 20 years earlier, which was attributed to methimazole. Abnormal blood work demonstrated aspartate aminotransferase (AST) 47 U/L, alanine aminotransferase (ALT) 46 U/L, total bilirubin 230 µmol/L, direct bilirubin 176 µmol/L, and alkaline phosphatase (ALP) 470 U/L. Abdominal ultrasound and magnetic resonance cholangiopancreatography showed no bile duct obstruction. Further work-up was negative for infectious, autoimmune, or other causes. Percutaneous liver biopsy showed marked cholestasis. With discontinuation of ramipril, the patient demonstrated prolonged cholestasis with partial biochemical improvement and was discharged after six weeks in hospital. This case represents the first described cross reactivity between ramipril and methimazole, illustrating the complex and poorly understood nature of DILI. Despite the relatively few instances of ACEI-induced liver hepatotoxicity, consideration should be given to discontinuation of ramipril in situations of unknown liver damage.",
"affiliations": "Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.;Division of Digestive Care and Endoscopy, Dalhousie University, Halifax, Nova Scotia.;Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.;Division of Digestive Care and Endoscopy, Dalhousie University, Halifax, Nova Scotia.;Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.",
"authors": "Forner|David|D|;Kulai|Tasha|T|;Arnason|Thomas|T|;E Gruchy|Steven|S|;MacLeod|Magnus|M|",
"chemical_list": null,
"country": "Iran",
"delete": false,
"doi": null,
"fulltext": "\n==== Front\nGastroenterol Hepatol Bed BenchGastroenterol Hepatol Bed BenchGHFBBGastroenterology and Hepatology From Bed to Bench2008-22582008-4234Shaheed Beheshti University of Medical Sciences Tehran, Iran GHFBB-10-143Case ReportRamipril-associated cholestasis in the setting of recurrent drug-induced liver injury Forner David 1Kulai Tasha 2Arnason Thomas 3E. Gruchy Steven 2MacLeod Magnus 11 Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada2 Division of Digestive Care and Endoscopy, Dalhousie University, Halifax, Nova Scotia3 Department of Pathology, Dalhousie University, Halifax, Nova Scotia, CanadaReprint or Correspondence: David Forner, BSc. Division of General Internal Medicine QEII - Bethune Building, Suite 406 Bethune Building, 1276 South Park Street Halifax, NS B3H 2Y9, Canada. E-mail: david.forner@dal.caSpring 2017 10 2 143 146 7 2 2017 20 3 2017 ©2017 RIGLD, Research Institute for Gastroenterology and Liver DiseasesThis is an Open Access article distributed under the terms of the Creative Commons Attribution License, (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nAim:\n\n\nAngiotensin-converting enzyme inhibitors (ACEIs) are commonly used to treat hypertension. Although generally well tolerated, the adverse effects of ACEIs include hypotension, cough, acute kidney injury and hyperkalemia. Rare reports of ACEI-induced hepatotoxicity have been described, most notably a cholestatic pattern of injury related to captopril. \n\nA 67-year-old male presented to the emergency department with a three-week history of jaundice, pruritis and weakness. Eight weeks before, he began taking ramipril and clopidogrel. His past medical history was significant for previous acute cholestatic liver injury approximately 20 years earlier, which was attributed to methimazole. Abnormal blood work demonstrated aspartate aminotransferase (AST) 47 U/L, alanine aminotransferase (ALT) 46 U/L, total bilirubin 230 µmol/L, direct bilirubin 176 µmol/L, and alkaline phosphatase (ALP) 470 U/L. Abdominal ultrasound and magnetic resonance cholangiopancreatography showed no bile duct obstruction. Further work-up was negative for infectious, autoimmune, or other causes. Percutaneous liver biopsy showed marked cholestasis. With discontinuation of ramipril, the patient demonstrated prolonged cholestasis with partial biochemical improvement and was discharged after six weeks in hospital. \n\nThis case represents the first described cross reactivity between ramipril and methimazole, illustrating the complex and poorly understood nature of DILI. Despite the relatively few instances of ACEI-induced liver hepatotoxicity, consideration should be given to discontinuation of ramipril in situations of unknown liver damage. \n\nKey Words\nDrug-induced liver injury (DILI)RamiprilAngiotensin-converting enzyme inhibitorsLiverCholestasisMethimazole\n==== Body\nIntroduction\n Angiotensin-converting enzyme inhibitors (ACEIs) are commonly used to treat hypertension. By inhibiting peptidyl dipeptidase and blocking the conversion of angiotensin I to angiotensin II, ACEIs block the renin angiotensin aldosterone system and inhibit bradykinin inactivation, resulting in an overall hypotensive effect. Ramipril is an oral prodrug that is de-esterified to ramiprilat through first pass effect by the liver, and as such is a long-acting member of the ACEI class. The prodrug and its metabolites are eliminated through combined kidney and biliary excretion. In fact, the kidney, with the exception of fosinopril and moexipril, eliminates all ACEIs (1). \n\nAlthough generally well tolerated, the adverse effects of ACEIs include hypotension, cough, acute kidney injury and hyperkalemia (1). Rare reports of ACEI-induced hepatotoxicity have been described, most notably a cholestatic pattern of injury related to captopril (2). \n\nCase Report\n A 67-year-old male presented to the emergency department with a three-week history of jaundice, pruritis and weakness. Eight weeks before, he began taking ramipril and clopidogrel after sustaining an inferior wall ST-elevation myocardial infarct. Changes to his original home medications also included increased dosing of bisoprolol and atorvastatin. He was first seen by outpatient internal medicine with the same symptoms two weeks before presenting to the emergency department and atorvastatin was discontinued; however, he continued to worsen clinically and biochemically. His past medical history was significant for previous acute cholestatic liver injury approximately 20 years earlier, which was attributed to methimazole after a negative work-up for causes of liver disease. \n\nPhysical examination revealed jaundice, but was otherwise unremarkable. Abnormal blood work demonstrated aspartate aminotransferase (AST) 47 U/L, alanine aminotransferase (ALT) 46 U/L, total bilirubin 230 µmol/L, direct bilirubin 176 µmol/L, alkaline phosphatase (ALP) 470 U/L, INR 1.4 and albumin 29 g/L. Abdominal ultrasound with Doppler and magnetic resonance cholangiopancreatography showed no bile duct obstruction. Further work-up was negative for infectious (Hepatitis A IgM, Hepatitis B surface antigen, Hepatitis C antibody screen, human immunodeficiency virus antibody and antigen screens, parvovirus B19 IgM, acute mononucleosis screen and Q Fever serology), autoimmune (anti-tissue transglutaminase IgA, immunoglobulins, anti-nuclear antibody screen, anti-mitochondrial antibody, anti-smooth muscle antibody and IgG-4 subclass serologies), and other (hereditary hemochromatosis) causes. Percutaneous liver biopsy showed marked cholestasis (Figure 1). There was minimal portal-based inflammation and no interface or lobular hepatitis. Features of large duct obstruction (portal edema, ductular reaction) were not apparent. There was no fibrosis on review of trichrome stains. The pathology was felt to be compatible with medication-induced cholestasis. His previous pathology report from 20 years earlier noted a similar histologic pattern of bland cholestasis. \n\nHis hospital stay was complicated by urinary retention, epididymitis and poor oral intake with subsequent orthostatic hypotension. With discontinuation of ramipril, the patient demonstrated prolonged cholestasis with partial biochemical improvement and was discharged after six weeks in hospital. One month after discharge, his total bilirubin had decreased to 35.5 µmol/L and ALP to 269 U/L\n\nDiscussion\nIdiosyncratic drug-induced liver injury (DILI) is rare, occurring at an incidence of 19 cases per 100,000 people per year according to a recent prospective population-based study from Iceland (3). Both genetics and environment are hypothesized to play a role in the development of DILI. For example, the HLA allele DRB1*1501 has been found to be associated with amoxicillin-clavulin derived cholestastic liver injury (4). Similarly, HLA DRB*0701 is associated with DILI due to ximelagatran (5). Several other risk factors have also been identified for the development of DILI, including age (above 55 years), gender (female), drug dose and alcohol use (6). Diagnosis can be challenging as the clinical presentation of DILI varies widely and confounding medications are often present. Here, causality assessment with the Council for International Organizations of Medical Sciences scale was 7 (probable) (7). \n\nThis case report is the fifth known case of ramipril-induced hepatotoxicity (2, 8). However, there have been over 50 reports of drug-induced hepatotoxicity associated with other ACEIs, the most common being captopril (8, 9). Cases varied in their symptomatic presentation, from incidental findings on blood work to jaundice and severe pruritus. Cholestasis appears to be the most common liver injury pattern in ACEI-induced hepatotoxicity, and this pattern has been evident in two previous cases of ramipril-induced liver injury with biopsies revealing cholestasis and bile duct necrosis (2). Following discontinuation of the offending agent, biochemical markers returned to near baseline at 6 and 14 months, respectively. In the case presented here, biopsy revealed bland cholestasis with no ductular changes and both alkaline phosphatase and bilirubin began declining promptly after discontinuation of ramipril. However, at one month post discharge, the patient’s biochemical markers had not yet returned to baseline.\n\nFigure 1 A liver biopsy shows canalicular cholestasis (at arrows) as well as cholestasis within hepatocytes in zone 3, near the central vein (CV). Some hepatocytes have edematous, vacuolated cytoplasm, which often occurs with cholestasis (hematoxylin and eosin, original magnification x 400\n\nThe remaining two previously reported cases of ramipril-induced liver injury manifested as unclassifiable and mixed. The unclassifiable case exhibited only mild increases in liver enzymes and a biopsy was not performed (2). The mixed pattern presented with markedly elevated ALT and ALP, with only minimal increases in bilirubin. Negative investigations prompted biopsy, revealing parenchymal inflammation. Re-institution resulted in an unintended positive rechallenge, confirming the diagnosis of ramipril-induced livery injury (8). The period of time from initiation of ramipril to presentation varied between cases, ranging from five weeks to 10 months. The current case is within this window, presenting eight weeks after beginning ramipril. \n\nThree key mechanisms have been previously suggested as the cause of ramipril-induced hepatotoxicity, including metabolic interaction, hypersensitivity, and bradykinin-mediated effects, although no model currently exists to confirm these hypotheses. In previous ramipiril-induced liver injury reports, both peripheral eosinophilia and biopsy proven eosinophil infiltration were seen, supporting the mechanism of hypersensitivity (2). However, no eosinophils were seen on biopsy in the current patient, nor was peripheral eosinophilia present. The majority of ACEIs differ only slightly in their chemical structure, supporting a possible metabolic interaction that is relatively conserved across the three structural classes by which ACEIs are categorized (10). Finally, similarly to other ACEIs, ramipril causes an increase in bradykinin through a reduction in bradykinin inactivation, resulting in an increase in prostaglandin synthesis. In turn, specific prostaglandins have been shown to cause decreased gallbladder contraction and bile stasis in humans (11). Similarly, the mechanism of methimazole-induced hepatotoxicity is unknown, although immune-mediated toxicity and reactive metabolite formation are suspected to be involved (12).\n\nRecurrent DILI is a rare and poorly understood phenomenon, occurring in 1.21% of patients who experience it (13). Immune cross-sensitization by the two implicated drugs is a potential mechanism. Additionally, shared structural or functional aspects of the medications themselves and genetic predisposition, such as the presence of particular major histocompatibility complex regions, may play a role. Recurrent hepatotoxicity of the same phenotype (cholestasis in this case) is typical for patients with a second episode of drug-induced liver injury, regardless of the causative medication, for unclear reasons (13). \n\nAlthough uncommon, the case of ramipril-induced livery injury described here illustrates the need for thoughtful consideration of all medications as potential causes of DILI. This case represents the first described cross reactivity between ramipril and methimazole, illustrating the complex and poorly understood nature of DILI. Despite the relatively few instances of ACEI-induced liver hepatotoxicity, consideration should be given to discontinuation of ramipril in situations of unknown liver damage.\n\nThis case represents a rare report of ACEI-induced cholestatic hepatotoxicity in a 67-year-old male with previous DILI, making this the first case of cross reactivity between ramipril and methimazole. The mechanism of hepatotoxicity is poorly understood in both medications. The cholestasis seen in ramipril-induced liver injury can be prolonged. In patients presenting with hepatotoxicity of an unclear etiology, a careful review of medications is warranted and discontinuation of potential offending drugs should be considered.\n\nConflict of interest\nThe authors declare that they have no conflict of interest.\n==== Refs\nReferences\n1 Katzung _BG Masters_ SB Trevor _AJ Basic & clinical pharmacology 2004 New York McGraw-Hill \n2 Yeung E Wong FS Wanless IR Shiota K Guindi M Joshi S Ramipril-associated hepatotoxicity Arch Pathol Lab Med 2003 12 1493 7 \n3 Bjornsson ES Bergmann OM Bjornsson HK Kvaran RB Olafsson S Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland Gastroenterology 2013 144 1419 25 23419359 \n4 O'Donohue J Oien K Donaldson P Underhill J Clare M MacSween R Co-amoxiclav jaundice: clinical and histological features and HLA class II association Gut 2000 47 717 20 11034591 \n5 Kindmark A Jawaid A Harbron C Barratt B Bengtsson O Andersson T Genome-wide pharmacogenetic investigation of a hepatic adverse event without clinical signs of immunopathology suggests an underlying immune pathogenesis Pharmacogenomics J 2008 8 186 95 17505501 \n6 Bleibel W Kim S D’Silva K Lemmer ER Drug-induced liver injury: review article Dig Dis Sci 2007 52 2463 71 17805971 \n7 Teschke R Wolff A Frenzel C Schwarzenboeck A Schulze J Eickhoff A Drug and herb induced liver injury: Council for International Organizations of Medical Sciences scale for causality assessment World J Hepatol 2014 6 17 32 24653791 \n8 Douros A Kauffmann W Bronder E Klimpel A Garbe E Kreutz R Ramipril-Induced Liver Injury: Case Report and Review of the Literature Am J Hypertens 2013 26 1070 5 23747952 \n9 Schattner A Kozak N Friedman J Captopril-induced jaundice: report of 2 cases and a review of 13 additional reports in the literature Am J Med Sci 2001 322 236 40 11678523 \n10 Ranadive SA Chen AX Serajuddin AT Relative lipophilicities and structural-pharmacological considerations of various angiotensin-converting enzyme (ACE) inhibitors Pharm RES 1992 9 1480 6 1475237 \n11 Pozo M Camello P Mawe G Chemical mediators of gallbladder dysmotility Curr Med Chem 2004 11 1801 12 15279583 \n12 Heidari R Niknahad H Jamshidzadeh A Abdoli N Factors affecting drug-induced liver injury: antithyroid drugs as instances Clin Mol Hepatol 2014 20 237 48 25320726 \n13 Lucena MI Kaplowitz N Hallal H Castiella A Garcia-Bengoechea M Otazua P Recurrent drug-induced liver injury (DILI) with different drugs in the Spanish Registry: the dilemma of the relationship to autoimmune hepatitis J Hepatol 2011 55 820 7 21338638\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2008-2258",
"issue": "10(2)",
"journal": "Gastroenterology and hepatology from bed to bench",
"keywords": "Angiotensin-converting enzyme inhibitors; Cholestasis; Drug-induced liver injury (DILI); Liver; Methimazole; Ramipril",
"medline_ta": "Gastroenterol Hepatol Bed Bench",
"mesh_terms": null,
"nlm_unique_id": "101525875",
"other_id": null,
"pages": "143-146",
"pmc": null,
"pmid": "28702139",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "24653791;23747952;11678523;11034591;25320726;15279583;14567716;1475237;23419359;17505501;17805971;21338638",
"title": "Ramipril-associated cholestasis in the setting of recurrent drug-induced liver injury.",
"title_normalized": "ramipril associated cholestasis in the setting of recurrent drug induced liver injury"
} | [
{
"companynumb": "CA-ACCORD-041662",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CLOPIDOGREL BISULFATE"
},
"drugadditional": null,
... |
{
"abstract": "A young man presented to the emergency department with seizures and recurrent episodes of polymorphic ventricular tachycardia (PMVT)/torsades de pointes (TdP) requiring cardioversion and administration of intravenous magnesium. A battery of tests performed to identify a cause for his arrhythmias and seizures were all normal. A revisit of history with family revealed he had consumed over 100 tablets/day of loperamide for the past 1 year. A prolonged QT interval on his ECG raised concerns for long QT syndrome (LQTS) (congenital or acquired). Our patient was suspected to have loperamide-induced cardiotoxicity. TdP is a specific PMVT that occurs with a prolonged QT interval and is usually drug-induced. Less frequently, congenital LQTS may be implicated. With supportive care, including mechanical ventilation, vasopressors and temporary transvenous overdrive pacing, our patient recovered completely. We describe the importance of a systematic and time-sensitive approach to diagnosing critical illness. Loperamide overdose may cause QT prolongation, life-threatening arrhythmias/cardiogenic shock, or cardiac arrest. Seizures/epilepsy may also be a manifestation in young patients. There is a substantial need to revisit the safety of over-the-counter medications and increasing awareness of manifestations of drug overdose.",
"affiliations": "Section of Cardiology, Department of Medicine, The Aga Khan University, Karachi, Pakistan sameeniqbal92@hotmail.com.;Section of Pulmonology & Critical Care Medicine, Department of Medicine, The Aga Khan University, Karachi, Pakistan.;Section of Cardiology, Department of Medicine, The Aga Khan University, Karachi, Pakistan.;Section of Pulmonology & Critical Care Medicine, Department of Medicine, The Aga Khan University, Karachi, Pakistan.",
"authors": "Iqbal|Sameen|S|http://orcid.org/0000-0002-2406-0855;Fayyaz|Sidra Malik|SM|http://orcid.org/0000-0003-4381-9342;Saeed|Yawer|Y|http://orcid.org/0000-0001-9408-6084;Aqeel|Masooma|M|",
"chemical_list": "D008139:Loperamide",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2021-243325",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(7)",
"journal": "BMJ case reports",
"keywords": "adult intensive care; arrhythmias; drug misuse (including addiction); pacing and electrophysiology; toxicology",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D062787:Drug Overdose; D004554:Electric Countershock; D004562:Electrocardiography; D006801:Humans; D008133:Long QT Syndrome; D008139:Loperamide; D008297:Male; D016171:Torsades de Pointes",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34290024",
"pubdate": "2021-07-21",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Loperamide-induced cardiotoxicity: a case overlooked?",
"title_normalized": "loperamide induced cardiotoxicity a case overlooked"
} | [
{
"companynumb": "PK-EDENBRIDGE PHARMACEUTICALS, LLC-PK-2022EDE000013",
"fulfillexpeditecriteria": "1",
"occurcountry": "PK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LOPERAMIDE"
},
"dru... |
{
"abstract": "This mono-institutional observational study was conducted to determine incidence, severity, risk factors, and outcome of sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) in high-risk Ewing sarcoma (ES) patients treated with intravenous busulfan and melphalan (BU-MEL) followed by autologous stem cell transplantation (ASCT). During the past 10 years, 75 consecutive ES patients resulted evaluable for the analysis. After diagnosis of SOS/VOD, defibrotide therapy was started as soon as the medication was available. The variables analyzed as potential risk factors were: gender, patient's age at diagnosis, primary tumor site, disease stage, and prior radiation therapy (RT) given, focusing on RT liver exposure. The median age at diagnosis was 18.8 years. Five patients developed moderate to severe SOS/VOD (cumulative incidence, 6.67%). None of 32 pediatric patients (≤17 years) developed SOS/VOD (p = 0.0674). In univariate analysis, prior RT liver exposure resulted statistically significant (p = 0.0496). There was one death due to severe SOS/VOD. This study reports the largest series of high-risk ES patients treated with intravenous BU-MEL before ASCT. The incidence of SOS/VOD was lower when compared with other studies that used oral busulfan. Any prior RT liver exposure should be avoided. Earlier defibrotide treatment confirms to be effective.",
"affiliations": "Chemotherapy Unit, Istituto Ortopedico Rizzoli, Bologna, Italy. massimo.abate@ior.it.;Chemotherapy Unit, Istituto Ortopedico Rizzoli, Bologna, Italy.;Radiation Oncology Center, Department of Experimental, Diagnostic and Specialty Medicine-DIMES, University of Bologna, Bologna, Italy.;Chemotherapy Unit, Istituto Ortopedico Rizzoli, Bologna, Italy.;Chemotherapy Unit, Istituto Ortopedico Rizzoli, Bologna, Italy.;Chemotherapy Unit, Istituto Ortopedico Rizzoli, Bologna, Italy.;Chemotherapy Unit, Istituto Ortopedico Rizzoli, Bologna, Italy.;PhD, Istituto Ortopedico Rizzoli, Bologna, Italy.;Laboratory of Experimental Oncology, Istituto Ortopedico Rizzoli, Bologna, Italy.;Unit of Internal Medicine, Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.",
"authors": "Abate|Massimo Eraldo|ME|http://orcid.org/0000-0003-1521-2930;Paioli|Anna|A|;Cammelli|Sivlia|S|;Cesari|Marilena|M|;Longhi|Alessandra|A|;Palmerini|Emanuela|E|;Ferrari|Stefano|S|;Carretta|Elisa|E|;Picci|Piero|P|;Piscaglia|Fabio|F|",
"chemical_list": "D011089:Polydeoxyribonucleotides; C036901:defibrotide; D002066:Busulfan; D008558:Melphalan",
"country": "England",
"delete": false,
"doi": "10.1038/s41409-017-0066-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0268-3369",
"issue": "53(5)",
"journal": "Bone marrow transplantation",
"keywords": null,
"medline_ta": "Bone Marrow Transplant",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D002066:Busulfan; D002648:Child; D002675:Child, Preschool; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006504:Hepatic Veno-Occlusive Disease; D006801:Humans; D008297:Male; D008558:Melphalan; D011089:Polydeoxyribonucleotides; D011878:Radiotherapy; D012307:Risk Factors; D012512:Sarcoma, Ewing; D016019:Survival Analysis; D019172:Transplantation Conditioning; D014182:Transplantation, Autologous; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "8702459",
"other_id": null,
"pages": "591-599",
"pmc": null,
"pmid": "29335623",
"pubdate": "2018-05",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Sinusoidal obstruction syndrome/veno-occlusive disease after high-dose intravenous busulfan/melphalan conditioning therapy in high-risk Ewing Sarcoma.",
"title_normalized": "sinusoidal obstruction syndrome veno occlusive disease after high dose intravenous busulfan melphalan conditioning therapy in high risk ewing sarcoma"
} | [
{
"companynumb": "IT-MYLANLABS-2019M1003774",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MELPHALAN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nGranulomatous reactions to silicone facial fillers are well described in the literature. Clinically, these reactions present as nodules or pseudotumors that are frequently described as silicone granulomas or siliconomas.\n\n\nOBJECTIVE\nWe want to report a peculiar form of granulomatous reaction to injected silicone characterized by recurrent episodes of facial edema.\n\n\nMETHODS\nWe collected silicone infiltrated patients with a similar clinical picture consisting of asymptomatic episodes of unilateral facial edema that had been recurring for months or years.\n\n\nRESULTS\nWe found four women with recurrent episodes of facial edema. They had been infiltrated with silicone in the face. Histology showed silicone deposits and a granulomatous infiltrate in all 4 cases.\n\n\nCONCLUSIONS\nWe describe and illustrate a new type of adverse reaction to injected silicone simulating orofacial granulomatosis. The reaction presents as recurrent, unilateral, asymmetric facial edema of the cheek in patients who have been injected with silicone in the face. Familiarity with this adverse reaction will help to prevent erroneous diagnoses such as idiopathic angioedema, Melkersson Rosenthal syndrome, and orofacial granulomatosis.",
"affiliations": "Department of Dermatology, Instituto Valenciano de Oncología, Valencia, Spain.",
"authors": "Requena|C|C|;Requena|L|L|;Alegre|V|V|;Serra|C|C|;Llombart|B|B|;Nagore|E|E|;Guillén|C|C|;Sanmartín|O|O|",
"chemical_list": "D000067548:Dermal Fillers; D012828:Silicones",
"country": "England",
"delete": false,
"doi": "10.1111/jdv.12522",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0926-9959",
"issue": "29(5)",
"journal": "Journal of the European Academy of Dermatology and Venereology : JEADV",
"keywords": null,
"medline_ta": "J Eur Acad Dermatol Venereol",
"mesh_terms": "D000368:Aged; D003357:Cosmetic Techniques; D000067548:Dermal Fillers; D005148:Facial Dermatoses; D005260:Female; D051261:Granulomatosis, Orofacial; D006801:Humans; D012828:Silicones",
"nlm_unique_id": "9216037",
"other_id": null,
"pages": "998-1001",
"pmc": null,
"pmid": "24750369",
"pubdate": "2015-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Adverse reaction to silicone simulating orofacial granulomatosis.",
"title_normalized": "adverse reaction to silicone simulating orofacial granulomatosis"
} | [
{
"companynumb": "PHHY2015ES155873",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CLOFAZIMINE"
},
"drugadditional": null,
"dru... |
{
"abstract": "We report a case of fatal adenovirus infection in a 37-year-old female who underwent allogeneic bone marrow transplantation (BMT) for acute myelogenous leukaemia (AML). Post BMT she developed acute grade II graft-vs.-host disease (aGVHD) requiring high-dose steroids and anti-thymocyte globulin. Additionally, her clinical course was complicated with adenovirus-associated haemorrhagic cystitis and viraemia. Intravenous ribavirin was obtained and administered for 5 days without success; the patient's mental status deteriorated rapidly and she died on day 69 post-transplant. Radiological imaging revealed diffuse cortical necrosis. At autopsy adenovirus was identified in her bladder, kidneys and lungs.",
"affiliations": "Division of Hematology/Oncology, College of Medicine, University of Florida, Gainsville 32610-0277, USA.",
"authors": "Mann|D|D|;Moreb|J|J|;Smith|S|S|;Gian|V|V|",
"chemical_list": "D000998:Antiviral Agents; D012254:Ribavirin",
"country": "England",
"delete": false,
"doi": "10.1016/s0163-4453(98)80021-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0163-4453",
"issue": "36(2)",
"journal": "The Journal of infection",
"keywords": null,
"medline_ta": "J Infect",
"mesh_terms": "D000258:Adenovirus Infections, Human; D000260:Adenoviruses, Human; D000328:Adult; D000998:Antiviral Agents; D016026:Bone Marrow Transplantation; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D015470:Leukemia, Myeloid, Acute; D012254:Ribavirin",
"nlm_unique_id": "7908424",
"other_id": null,
"pages": "227-8",
"pmc": null,
"pmid": "9570662",
"pubdate": "1998-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Failure of intravenous ribavirin in the treatment of invasive adenovirus infection following allogeneic bone marrow transplantation: a case report.",
"title_normalized": "failure of intravenous ribavirin in the treatment of invasive adenovirus infection following allogeneic bone marrow transplantation a case report"
} | [
{
"companynumb": "US-SA-2018SA081197",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,
... |
{
"abstract": "Carfilzomib has been established in previous years as a treatment for patients with relapsed and/or refractory multiple myeloma (RR-MM). A retrospective multicentre study to evaluate the clinical use of carfilzomib for RR-MM outside of a clinical trial setting was conducted by our group. One hundred and thirty-five patients were included. All patients had been previously exposed to bortezomib and 93% had also been treated with lenalidomide. The vast majority of patients received carfilzomib as part of a two- or three-drug combination. The overall response rate was 47·2%. Multivariate analysis revealed bortezomib resistance, lenalidomide resistance and albumin <35 g/l to negatively impact the likelihood of achieving response. The median duration of response was 8·4 months, and was significantly higher in patients receiving three-drug combination and patients presenting without extramedullary disease. The median progression-free survival and overall survival for the entire cohort was 4·9 months (95% confidence interval [CI] 3·8-6·4) and 12·2 months (95% CI 9-not reached), respectively. Toxicity was manageable, although treatment-related death was seen in 5% of patients. In the setting of progressive multiple myeloma, carfilzomib in a combination regimens yields effective results with a manageable toxicity.",
"affiliations": "Institute of Haematology, Rabin Medical Centre, Petah Tikva, Israel.;Department of Haematology, Hadassah Medical Centre, Jerusalem, Israel.;Department of Haematology, Soroka University Medical Centre, Negev Beer Sheva, Israel.;Department of Haematology, Shaare Zedek Medical Centre, Jerusalem, Israel.;Department of Haematology, HaEmek Medical Centre, Afula, Israel.;Department of Haematology, Galilee Medical Centre, Nahariya, Israel.;Haematology Unit, Bnai-Zion Medical Centre, Haifa, Israel.;Department of Haematology, Kaplan Medical Centre, Rehovot, Israel.;Department of Haematology, Rambam Health Care Campus, Haifa, Israel.;Statistical unit, Research department, Rabin Medical Centre, Petah-Tikva, Israel.;Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv, Israel.;Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv, Israel.;Institute of Haematology, Rabin Medical Centre, Petah Tikva, Israel.;Institute of Haematology, Rabin Medical Centre, Petah Tikva, Israel.",
"authors": "Muchtar|Eli|E|;Gatt|Moshe E|ME|;Rouvio|Ory|O|;Ganzel|Chezi|C|;Chubar|Evgeni|E|;Suriu|Celia|C|;Tadmor|Tamar|T|;Shevetz|Olga|O|;Lavi|Noa|N|;Shochat|Tzippy|T|;Cohen|Yael C|YC|;Avivi|Irit|I|;Raanani|Pia|P|;Magen|Hila|H|",
"chemical_list": "D000970:Antineoplastic Agents; D009842:Oligopeptides; D061988:Proteasome Inhibitors; C524865:carfilzomib",
"country": "England",
"delete": false,
"doi": "10.1111/bjh.13799",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-1048",
"issue": "172(1)",
"journal": "British journal of haematology",
"keywords": "carfilzomib; myeloma; relapse; resistance",
"medline_ta": "Br J Haematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D009367:Neoplasm Staging; D009842:Oligopeptides; D061988:Proteasome Inhibitors; D012008:Recurrence; D012189:Retrospective Studies; D016879:Salvage Therapy; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "0372544",
"other_id": null,
"pages": "89-96",
"pmc": null,
"pmid": "26567759",
"pubdate": "2016-01",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study",
"references": null,
"title": "Efficacy and safety of salvage therapy using Carfilzomib for relapsed or refractory multiple myeloma patients: a multicentre retrospective observational study.",
"title_normalized": "efficacy and safety of salvage therapy using carfilzomib for relapsed or refractory multiple myeloma patients a multicentre retrospective observational study"
} | [
{
"companynumb": "IL-AMGEN-ISRSP2016018630",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CARFILZOMIB"
},
"drugadditional": null,
... |
{
"abstract": "Anakinra is proven to be effective in controlled trials in terms of attack frequency and subclinical inflammation in colchicine-resistant patients. The objective of this study was to review the patients followed in our single centre with FMF who received anakinra because of insufficient colchicine response.\n\n\n\nThe study was conducted at a tertiary rheumatology centre experienced in autoinflammatory diseases. The patients were treated for at least 1 month with anakinra. Patients with amyloidosis and pregnancy were not included. Attack frequency, patient global assessment scales of disease severity and acute phase reactants were recorded before and throughout anakinra treatment. Criteria of treatment termination were side effects, disease remission, inadequate response, pregnancy plan and non-compliance.\n\n\n\nOne hundred and six patients diagnosed with FMF were treated with anakinra; 45.92% of the patients had a homozygous M694V mutation; 83 of the 98 patients tested for MEFV carried at least one copy of M694V. Attack frequency decreased while on anakinra treatment; in fact, no attacks were observed in 75 patients. Visual analogue scale score decreased from 7.49 (2.03) to 3.08 (2.82) (P = 0.001). Currently, 71 patients are still on anakinra treatment. Treatment of 34 patients was discontinued (32%). Insufficient response and side effects were the most common reasons for treatment discontinuation. All of the side effects observed were reversible and the patients alleviated after treatment cessation. In four patients, leukopenia was observed.\n\n\n\nIn patients who were refractory to colchicine, anti-IL-1 agent anakinra was shown to be effective and safe. The effectiveness of anakinra stems from preventing attacks and increasing the quality of life.",
"affiliations": "Division of Rheumatology, Department of Internal Medicine, Cerrahpasa Medical Faculty, Istanbul University-Cerrahpasa, Istanbul, Turkey.;Division of Rheumatology, Department of Internal Medicine, Cerrahpasa Medical Faculty, Istanbul University-Cerrahpasa, Istanbul, Turkey.;Division of Rheumatology, Department of Internal Medicine, Cerrahpasa Medical Faculty, Istanbul University-Cerrahpasa, Istanbul, Turkey.;Division of Rheumatology, Department of Internal Medicine, Cerrahpasa Medical Faculty, Istanbul University-Cerrahpasa, Istanbul, Turkey.;Division of Rheumatology, Department of Internal Medicine, Cerrahpasa Medical Faculty, Istanbul University-Cerrahpasa, Istanbul, Turkey.",
"authors": "Ugurlu|Serdal|S|0000-0002-9561-2282;Ergezen|Bilgesu|B|;Egeli|Bugra Han|BH|;Selvi|Oguzhan|O|;Ozdogan|Huri|H|",
"chemical_list": "D018501:Antirheumatic Agents; D053590:Interleukin 1 Receptor Antagonist Protein; D000071198:Pyrin; D003078:Colchicine",
"country": "England",
"delete": false,
"doi": "10.1093/rheumatology/keaa596",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1462-0324",
"issue": "60(5)",
"journal": "Rheumatology (Oxford, England)",
"keywords": "FMF; disease activity; treatment",
"medline_ta": "Rheumatology (Oxford)",
"mesh_terms": "D000328:Adult; D018501:Antirheumatic Agents; D003078:Colchicine; D010505:Familial Mediterranean Fever; D005260:Female; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D008297:Male; D008875:Middle Aged; D009154:Mutation; D000071198:Pyrin; D011788:Quality of Life; D012720:Severity of Illness Index; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "100883501",
"other_id": null,
"pages": "2327-2332",
"pmc": null,
"pmid": "33295622",
"pubdate": "2021-05-14",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Anakinra treatment in patients with familial Mediterranean fever: a single-centre experience.",
"title_normalized": "anakinra treatment in patients with familial mediterranean fever a single centre experience"
} | [
{
"companynumb": "TR-TAKEDA-2020TEU012322",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "COLCHICINE"
},
"drugadditional": null,
... |
{
"abstract": "Discontinuation of denosumab leads to a rapid reversal of its therapeutic effect. However, there are no data regarding how unintended delays or missed injections of denosumab impact bone mineral density (BMD) response.\n\n\n\nWe examined the association of delays in injections of denosumab with BMD change.\n\n\n\nWe used electronic medical records from two academic hospitals from 2010 to 2017.\n\n\n\nPatients older than 45 years of age and used at least 2 doses of 60 mg denosumab. Denosumab adherence was evaluated by the medication coverage ratio (MCR). Good adherence corresponds to a dosing interval ≤7 months (defined by MCR ≥93%), moderate adherence corresponds to an interval of 7 to 10 months (MCR 75%-93%), and poor adherence corresponds to an interval ≥10 months (MCR ≤75%).\n\n\n\nAnnualized percent BMD change from baseline at the lumbar spine, total hip, and femoral neck.\n\n\n\nWe identified 938 denosumab injections among 151 patients; the mean (SD) age was 69 (10) years, and 95% were female. Patients with good adherence had an annualized BMD increase of 3.9% at the lumbar spine, compared with patients with moderate (3.0%) or poor adherence (1.4%, P for trend .002). Patients with good adherence had an annualized BMD increase of 2.1% at the total hip, compared with patients with moderate (1.3%) or poor adherence (0.6%, P for trend .002).\n\n\n\nA longer interval between denosumab injections is associated with suboptimal BMD response at both spine and total hip. Strategies to improve the timely administration of denosumab in real-world settings are needed.",
"affiliations": "Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, Massachusetts, USA.;Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, Massachusetts, USA.;Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, Massachusetts, USA.;Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, Massachusetts, USA.;Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, Massachusetts, USA.;Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.;Harvard Medical School, Boston, Massachusetts, USA.;Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, Massachusetts, USA.",
"authors": "Lyu|Houchen|H|;Zhao|Sizheng S|SS|;Yoshida|Kazuki|K|;Tedeschi|Sara K|SK|;Xu|Chang|C|;Nigwekar|Sagar U|SU|;Leder|Benjamin Z|BZ|;Solomon|Daniel H|DH|",
"chemical_list": "D000069448:Denosumab",
"country": "United States",
"delete": false,
"doi": "10.1210/clinem/dgz321",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0021-972X",
"issue": "105(5)",
"journal": "The Journal of clinical endocrinology and metabolism",
"keywords": "Osteoporosis; bone mineral density; denosumab; dosing delay",
"medline_ta": "J Clin Endocrinol Metab",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D015519:Bone Density; D015331:Cohort Studies; D000069448:Denosumab; D004334:Drug Administration Schedule; D057286:Electronic Health Records; D005260:Female; D006801:Humans; D007267:Injections; D008297:Male; D008404:Massachusetts; D055118:Medication Adherence; D008875:Middle Aged; D010024:Osteoporosis; D012189:Retrospective Studies",
"nlm_unique_id": "0375362",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31894244",
"pubdate": "2020-05-01",
"publication_types": "D016428:Journal Article; D064888:Observational Study; D052061:Research Support, N.I.H., Extramural",
"references": "26510845;30674078;31894244;22543469;30535289;28058444;11346808;14500805;29691303;28789921;29105841;21289258;26694598;17476007;26881176;20827547;16495394;28546097;19671655;27681935;26018090;16224307;24535775;29258875;18237359;28643265;21927922;12578807;18539106;28240371",
"title": "Delayed Denosumab Injections and Bone Mineral Density Response: An Electronic Health Record-based Study.",
"title_normalized": "delayed denosumab injections and bone mineral density response an electronic health record based study"
} | [
{
"companynumb": "US-AMGEN-USASP2020004364",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DENOSUMAB"
},
"drugadditional": null,
... |
{
"abstract": "Osteoporosis is a common complication of cerebral palsy and Rett's syndrome. It is responsible for multiple fractures, bone pain, and impaired quality of life. In case of Rett's syndrome, a specific dysfunction of osteoblasts causes bone fragility. We observed the effects of annual zoledronic acid (ZA) infusion in a cohort of children with cerebral palsy and Rett's syndrome. 27 children under 18 years (19 with cerebral palsy and 8 girls with Rett syndrome confirmed by MCEP2 mutation) were treated with an annual injection of 0.1 mg/kg (max 4 mg) of ZA. Calcium and vitamin D were combined in all patients from the first injection of ZA. Dental examination was performed before treatment. Data were analyzed retrospectively. Bone mineral density was measured at diagnosis and yearly thereafter. Bone mass density (BMD) is decreased in patient with cerebral palsy and RS. One year after injection of ZA, we observe an increase of Lumbar spine BMD from - 2.99 to - 2.14 SD (p < 0.0001) and femoral BMD from - 4.26 to - 3.32 SD (p < 0.001) In the subgroup of patient with Rett syndrome, we also observe an increase from - 3.27 to 2.50 SD (p = 0.018) of Lumbar spine BMD. No fractures have been observed in our cohort since the first infusion. Side effects (flu-like syndrome and hypocalcemia) were more common in younger patients and after the first infusion. No serious complications were noticed. This study confirms the efficacy and the safety of an annual injection of ZA to improve bone status in children with cerebral palsy and Rett syndrome. No severe adverse effects were observed.",
"affiliations": "Centre de référence des erreurs innées du métabolisme, Hôpital d'Enfants, CHRU Nancy, Nancy, France. arnaud.wiedemann@gmail.com.;Service de Médecine Infantile, Hôpital d'enfants, CHRU Nancy, Nancy, France.;Service d'Odontologie, CHU Nancy, Nancy, France.;Service de Biochimie, CHU Nancy, Nancy, France.;Service de Médecine Infantile, Hôpital d'enfants, CHRU Nancy, Nancy, France.;Service de Génétique Clinique, CHU Nancy, Nancy, France.;Service d'Endocrinologie, CHU Nancy, Nancy, France.;Centre de référence des erreurs innées du métabolisme, Hôpital d'Enfants, CHRU Nancy, Nancy, France.",
"authors": "Wiedemann|Arnaud|A|;Renard|Emeline|E|;Hernandez|Magali|M|;Dousset|Brigitte|B|;Brezin|François|F|;Lambert|Laetitia|L|;Weryha|Georges|G|;Feillet|François|F|",
"chemical_list": "D050071:Bone Density Conservation Agents; D007093:Imidazoles; D000077211:Zoledronic Acid",
"country": "United States",
"delete": false,
"doi": "10.1007/s00223-018-0505-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0171-967X",
"issue": "104(4)",
"journal": "Calcified tissue international",
"keywords": null,
"medline_ta": "Calcif Tissue Int",
"mesh_terms": "D000293:Adolescent; D015519:Bone Density; D050071:Bone Density Conservation Agents; D001842:Bone and Bones; D002547:Cerebral Palsy; D002648:Child; D050723:Fractures, Bone; D006801:Humans; D007093:Imidazoles; D010024:Osteoporosis; D015518:Rett Syndrome; D013997:Time Factors; D000077211:Zoledronic Acid",
"nlm_unique_id": "7905481",
"other_id": null,
"pages": "355-363",
"pmc": null,
"pmid": "30554334",
"pubdate": "2019-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Annual Injection of Zoledronic Acid Improves Bone Status in Children with Cerebral Palsy and Rett Syndrome.",
"title_normalized": "annual injection of zoledronic acid improves bone status in children with cerebral palsy and rett syndrome"
} | [
{
"companynumb": "FR-MYLANLABS-2019M1036051",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CALCIUM"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nChemotherapy for unresectable pancreatic cancer should not only prolong survival but maintain quality of life, considering its limited life expectancy. To achieve these goals, biweekly gemcitabine plus S-1 was assessed in the clinical practice setting.\n\n\nMETHODS\nFifty-two patients with either locally advanced or metastatic pancreatic cancer who received biweekly gemcitabine plus S-1 as a first-line anti-cancer treatment were included in this study. Treatment delivery, toxicity, response, and survival were reviewed to assess the feasibility and efficacy.\n\n\nRESULTS\nThe completion rate of treatment delivery was 95.1%, with relative dose intensity of 97.1% for gemcitabine and 97.3% for S-1. Overall, grade 3 or worse adverse events were rare, with hematologic toxicities occurring in 5.8%. The objective response rate was 30.8%, and more than a 50% reduction of CA19-9 was observed in 77.1%. Surgical conversion was completed with a margin-negative resection in four patients whose tumor had shrunk for at least 6 months. The median progression-free and overall survivals were 10.4 and 18.2 months, respectively. Reduction of CA19-9 was associated with longer survival.\n\n\nCONCLUSIONS\nBiweekly gemcitabine plus S-1 may be a good alternative to current standard chemotherapies for unresectable pancreatic cancer with less toxicity and less treatment burden without losing efficacy.",
"affiliations": "Department of Surgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, 173-8605, Japan.;Department of Surgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, 173-8605, Japan.;Department of Surgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, 173-8605, Japan.;Department of Surgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, 173-8605, Japan.;Department of Surgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, 173-8605, Japan.;Department of Surgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, 173-8605, Japan.;Department of Surgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, 173-8605, Japan.;Department of Surgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, 173-8605, Japan.;Department of Surgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, 173-8605, Japan.;Department of Surgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, 173-8605, Japan.",
"authors": "Wada|Keita|K|;Sano|Keiji|K|;Amano|Hodaka|H|;Miura|Fumihiko|F|;Toyota|Naoyuki|N|;Ito|Hiromichi|H|;Shibuya|Makoto|M|;Ikeda|Yutaka|Y|;Kainuma|Masahiko|M|;Takada|Tadahiro|T|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; D003841:Deoxycytidine; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; C056507:gemcitabine",
"country": "Japan",
"delete": false,
"doi": "10.1002/jhbp.274",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1868-6974",
"issue": "22(9)",
"journal": "Journal of hepato-biliary-pancreatic sciences",
"keywords": "Chemotherapy; Gemcitabine; Pancreatic cancer; S-1",
"medline_ta": "J Hepatobiliary Pancreat Sci",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D005240:Feasibility Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D010094:Oxonic Acid; D010190:Pancreatic Neoplasms; D012189:Retrospective Studies; D005641:Tegafur; D016896:Treatment Outcome",
"nlm_unique_id": "101528587",
"other_id": null,
"pages": "692-8",
"pmc": null,
"pmid": "26136371",
"pubdate": "2015-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Biweekly gemcitabine plus S-1 for locally advanced and metastatic pancreatic cancer: a preliminary feasibility study.",
"title_normalized": "biweekly gemcitabine plus s 1 for locally advanced and metastatic pancreatic cancer a preliminary feasibility study"
} | [
{
"companynumb": "JP-CIPLA LTD.-2015JP07419",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GIMERACIL\\OTERACIL\\TEGAFUR"
},
"drugadditio... |
{
"abstract": "BACKGROUND\nconflicting evidence regarding the association of vancomycin serum concentrations with efficacy and toxicity has resulted in controversy regarding optimal target concentrations. Recent publications recommend attaining higher vancomycin trough concentrations of 15 to 20 mg/L for target infections, yet limited research is available assessing the correlation of vancomycin serum concentrations with toxicity. The aim of this study was to evaluate the association between vancomycin serum trough concentrations and nephrotoxicity.\n\n\nMETHODS\na 2-phase retrospective analysis was completed. Phase 1 evaluated 2493 courses of vancomycin completed between January 2003 and December 2007. The analysis describes a 5-year trend in vancomycin prescribing practices and assesses the association of nephrotoxicity with baseline serum creatinine, vancomycin serum trough concentrations, and duration of vancomycin therapy. Phase 2 examined patients receiving vancomycin therapy during 2007 to evaluate specific risk factors for development of nephrotoxicity.\n\n\nRESULTS\nthe proportion of vancomycin serum trough concentrations ≥ 15 mg/L and ≥ 20 mg/L increased significantly over time. Statistical analysis identified vancomycin serum trough concentrations ≥ 14 mg/L, duration of vancomycin therapy ≥ 7 days, and baseline serum creatinine levels ≥ 1.7 mg/dL as independent predictors of nephrotoxicity. Phase 2 analysis again implicated mean vancomycin serum trough concentration as a significant predictor of nephrotoxicity. Nephrotoxicity resolved in 81% (17/21) of cases evaluated.\n\n\nCONCLUSIONS\na higher vancomycin serum trough concentration and prolonged vancomycin therapy are associated with an increased risk of nephrotoxicity. The decision to target increased vancomycin trough concentrations should be based on an assessment of the severity of the infection and must consider the nephrotoxicity risk associated with increased vancomycin levels.",
"affiliations": "St. Louis College of Pharmacy, St. Louis, MO 63110-1088, USA. lprichard@stlcop.edu",
"authors": "Pritchard|Lindsey|L|;Baker|Catherine|C|;Leggett|James|J|;Sehdev|Paul|P|;Brown|Allen|A|;Bayley|K Bruce|KB|",
"chemical_list": "D000900:Anti-Bacterial Agents; D015415:Biomarkers; D014640:Vancomycin; D003404:Creatinine",
"country": "United States",
"delete": false,
"doi": "10.1016/j.amjmed.2010.07.025",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9343",
"issue": "123(12)",
"journal": "The American journal of medicine",
"keywords": null,
"medline_ta": "Am J Med",
"mesh_terms": "D058186:Acute Kidney Injury; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D000900:Anti-Bacterial Agents; D015415:Biomarkers; D003404:Creatinine; D005260:Female; D006801:Humans; D015994:Incidence; D007668:Kidney; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012307:Risk Factors; D014640:Vancomycin",
"nlm_unique_id": "0267200",
"other_id": null,
"pages": "1143-9",
"pmc": null,
"pmid": "21183005",
"pubdate": "2010-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Increasing vancomycin serum trough concentrations and incidence of nephrotoxicity.",
"title_normalized": "increasing vancomycin serum trough concentrations and incidence of nephrotoxicity"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2017SP000399",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional"... |
{
"abstract": "BACKGROUND\nDonor-derived Strongyloides stercoralis infection occurs rarely after transplantation, and the risk factors are not well understood. We present cases of two renal allograft recipients who developed Strongyloides hyperinfection syndrome after receipt of organs from a common deceased donor who received high-dose steroids as part of a preconditioning regimen.\n\n\nMETHODS\nThe two renal transplant patients who developed Strongyloides hyperinfection syndrome are reported in case study format with review of the literature.\n\n\nRESULTS\nMicroscopic examination of stool from one renal transplant patient and of tracheal and gastric aspirates from the other transplant patient revealed evidence of S. stercoralis larvae. Retrospective testing of serum from the deceased donor for Strongyloides antibodies by enzyme-linked immunosorbent assay was positive at 11.7 U/mL (Centers for Disease Control reference >1.7 U/mL positive). One patient was treated successfully with oral ivermectin. The other patient also had complete resolution of strongyloidiasis, but required a course of parenteral ivermectin because of malabsorption from severe gastrointestinal strongyloidiasis.\n\n\nCONCLUSIONS\nThese case studies provide some of the best evidence of transmission of S. stercoralis by renal transplantation. Because of the high risk of hyperinfection syndrome and its associated morbidity and mortality, high-risk donors and recipients should be screened for Strongyloides infection, so that appropriate treatment can be initiated before the development of disease. This study indicates that parenteral ivermectin can be used safely and effectively in patients in whom severe malabsorption would preclude the effective use of oral formulation. These cases also suggest that reconsideration should be given for the safety of steroids in donor-preconditioning regimens.",
"affiliations": "Division of Infectious Diseases, Department of Medicine, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA. Keith.hamilton@uphs.upenn.edu",
"authors": "Hamilton|Keith W|KW|;Abt|Peter L|PL|;Rosenbach|Misha A|MA|;Bleicher|Melissa B|MB|;Levine|Marc S|MS|;Mehta|Jimish|J|;Montgomery|Susan P|SP|;Hasz|Richard D|RD|;Bono|Bartholomew R|BR|;Tetzlaff|Michael T|MT|;Mildiner-Early|Shirly|S|;Introcaso|Camille E|CE|;Blumberg|Emily A|EA|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D000977:Antiparasitic Agents; D007559:Ivermectin",
"country": "United States",
"delete": false,
"doi": "10.1097/TP.0b013e3182115b7b",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1337",
"issue": "91(9)",
"journal": "Transplantation",
"keywords": null,
"medline_ta": "Transplantation",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000328:Adult; D000818:Animals; D000977:Antiparasitic Agents; D005260:Female; D006801:Humans; D007559:Ivermectin; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D017171:Strongyloides stercoralis; D013322:Strongyloidiasis; D014019:Tissue Donors; D019172:Transplantation Conditioning",
"nlm_unique_id": "0132144",
"other_id": null,
"pages": "1019-24",
"pmc": null,
"pmid": "21358367",
"pubdate": "2011-05-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Donor-derived Strongyloides stercoralis infections in renal transplant recipients.",
"title_normalized": "donor derived strongyloides stercoralis infections in renal transplant recipients"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2018-03502",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"druga... |
{
"abstract": "BACKGROUND\nLithium (Li) is an invaluable drug for the treatment of bipolar disorder. Long-term Li use is associated with renal complications including the formation of uncomplicated renal cysts caused by proliferation and expansion of collecting duct (CD) cells. We report six patients with complicated renal cysts in the context of Li nephropathy.\n\n\nMETHODS\nOver a time period of 15 years, we have identified six patients with one or more solid renal tumours in our population of approximately 50 patients with chronic Li nephropathy. In this study we describe the clinical and pathological characteristics of these Li-related tumours.\n\n\nRESULTS\nAll patients were on Li therapy for over 10 years and suffered from varying degrees of Li nephropathy. The tumours were all of CD origin and comprised both oncocytomas and collecting duct carcinomas. The CD carcinomas differed from the very rare \"classical\" CD cell carcinomas in histological appearance, multifocal presentation and non-aggressive clinical behaviour.\n\n\nCONCLUSIONS\nThe increased incidence of CD derived tumours and atypical presentation of CD cell carcinomas in patients with chronic Li nephropathy suggests that Li predisposes to the development of these tumours. We hypothesize that prolonged stimulation of CD cell proliferation and expansion by Li not only causes cyst formation, but can eventually induce the formation of adenomas and carcinomas. Increased awareness of a possible relationship between chronic Li therapy and renal neoplasms, will enhance the knowledge on epidemiology, clinical behavior and optimal therapy for the Li-related renal neoplasms.",
"affiliations": "Department of Nephrology and Hypertension , University Medical Center Utrecht , Utrecht , The Netherlands.;Department of Pathology , University Medical Center Utrecht , Utrecht , The Netherlands.;Department of Old-Age Psychiatry , GGZ Ingeest , Haarlem , The Netherlands.;Department of Nephrology and Hypertension , University Medical Center Utrecht , Utrecht , The Netherlands.",
"authors": "Rookmaaker|Maarten B|MB|;van Gerven|Heleen A J M|HA|;Goldschmeding|Roel|R|;Boer|Walther H|WH|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/ckj/sfs091",
"fulltext": "\n==== Front\nClin Kidney JClin Kidney JckjndtplusClinical Kidney Journal2048-85052048-8513Oxford University Press 10.1093/ckj/sfs091sfs091Original ContributionsOriginal ArticlesSolid renal tumours of collecting duct origin in patients on chronic lithium therapy Rookmaaker Maarten B. 1van Gerven Heleen A.J.M. 2Goldschmeding Roel 3Boer Walther H. 11 Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands2 Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands3 Department of Old-Age Psychiatry, GGZ Ingeest, Haarlem, The NetherlandsCorrespondence and offprint requests to: Maarten B. Rookmaaker; E-mail: m.rookmaaker@umcutrecht.nl10 2012 10 2012 5 5 412 415 28 6 2012 2 7 2012 © The Author 2012. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For permissions, please email: journals.permissions@oup.com2012This 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.comBackground\nLithium (Li) is an invaluable drug for the treatment of bipolar disorder. Long-term Li use is associated with renal complications including the formation of uncomplicated renal cysts caused by proliferation and expansion of collecting duct (CD) cells. We report six patients with complicated renal cysts in the context of Li nephropathy.\n\nMethods\nOver a time period of 15 years, we have identified six patients with one or more solid renal tumours in our population of approximately 50 patients with chronic Li nephropathy. In this study we describe the clinical and pathological characteristics of these Li-related tumours.\n\nResults\nAll patients were on Li therapy for over 10 years and suffered from varying degrees of Li nephropathy. The tumours were all of CD origin and comprised both oncocytomas and collecting duct carcinomas. The CD carcinomas differed from the very rare “classical” CD cell carcinomas in histological appearance, multifocal presentation and non-aggressive clinical behaviour\n\nConclusions\nThe increased incidence of CD derived tumours and atypical presentation of CD cell carcinomas in patients with chronic Li nephropathy suggests that Li predisposes to the development of these tumours. We hypothesize that prolonged stimulation of CD cell proliferation and expansion by Li not only causes cyst formation, but can eventually induce the formation of adenomas and carcinomas. Increased awareness of a possible relationship between chronic Li therapy and renal neoplasms, will enhance the knowledge on epidemiology, clinical behavior and optimal therapy for the Li-related renal neoplasms.\n\ncancercystlithium\n==== Body\nIntroduction\nLithium (Li) is an invaluable drug for the treatment of bipolar disorder, with 1:500 people using Li in Western societies. Chronic Li use is associated with several renal complications. Renal diabetes insipidus occurs in up to 40% of the patients and ∼20% develop chronic tubulointerstitial nephritis that is associated with slowly progressive renal failure. A third aspect of chronic renal Li toxicity, acquired polycystic kidney disease, has received little attention to date. Animal experiments have shown that Li induces a proliferative response in the kidneys, specifically in the CD, causing tubular dilation and cyst formation [1]. In patients with lithium nephropathy, abundant renal cysts are found using magnetic resonance imaging (MRI) and ultrasound [2]. In addition, dilation of CD and cyst formation are distinguishing features in kidney biopsies of these patients [3]. Until now, however, only uncomplicated renal cysts have been attributed to chronic Li use. Here, we report for the first time that complicated solid renal masses can occur in the context of Li nephropathy and show that these tumours are of CD origin.\n\nCases\nOver a time period of 15 years, we have identified six patients with one or more solid renal tumours in our population of ∼50 patients with chronic Li nephropathy (Table 1). All patients were on Li therapy for more than 10 years and suffered from varying degrees of chronic renal failure and renal diabetes insipidus. The renal tumours were incidental findings during work up for renal dysfunction (Patients 1, 4 and 5) or upon analysis of non-specific abdominal complaints (Patients 2, 3 and 6). The abdominal scans made to exclude regional metastases showed multiple uncomplicated renal cysts in all patients (Figure 1). In addition, a complicated cyst was found in the contralateral kidney in one patient (Patient 4).\nTable 1. Patient characteristics\n\nPatient no.\tAge (years)\tSex\tLi use (years)\tPlasma creatinine [µmol/L (mg/dL)]\tRadiological findings\tIntervention\tLithium\tFollow-up\t\n1\t69\tM\t17\t444 (5.0)\tSolid tumour L kidney (4.5 cm)\tNephrectomy, haemodialysis\tContinued\t1 year, died of unrelated cause\t\n2\t71\tF\t30\t125 (1.4)\tSolid tumour R kidney (4.0 cm)\tPartial nephrectomy\tContinued\t5 years, died of unrelated cause\t\n3\t59\tM\t12\t133 (1.5)\tSolid tumour R kidney (3.0 cm)\tNephrectomy\tContinued\t4 years, no recurrence\t\n4\t70\tM\t30\t765 (8.7)\tSolid tumour L kidney (3.0 cm), complicated cyst R kidney\tBiopsy tumour L kidney, radiological follow-up\tStopped\t2 years, no growth of lesions\t\n5\t61\tM\t15\t135 (1.5)\tSolid tumour L kidney (3.5 cm)\tBiopsy, awaiting surgery\tContinued\t4 months, no tumour growth\t\n6\t65\tF\t41\t135 (1.5)\tSolid tumour R Kidney (2.6 cm)\tBiopsy, radiological follow-up\tContinued\t4 months\t\n\nFig. 1. Typical MRI of a CD tumour in a patient on chronic lithium therapy. A large tumour can be seen in lower pole of the left kidney (arrow). In addition, numerous renal cysts are present in both kidneys (open arrows).\n\n\n\nHistological evaluation demonstrated that all tumours were of collecting duct (CD) origin (Table 2). In three patients, histology and immunohistochemistry showed the presence of a CD cell carcinoma (Patients 1, 3 and 5; Figure 2). In the three other patients, the tumours had the typical histological appearance of a renal oncocytoma (Figure 3). In the resection edge of the partial nephrectomy specimen of one of the latter patients (Patient 2), a CD cell carcinoma was found that had not been recognized on the computed tomographic (CT) scan.\nTable 2. Tumour characteristics\n\nPatient no.\tTumour, no.\tHistology\tCK 19\tVimentin\tOther markers present\t\n1\t1\tCD carcinoma\t+\t+\tCK8, 18 (CAM5.2), KL1; CK HMW; EMA\t\n2\t1\tOncocytoma\t\t\t\t\n\t2\tCD carcinoma\t+\t+\tCK8, 18 (CAM5.2); CD15\t\n3\t1\tCD carcinoma\t+\t+\tCK8, 18 (CAM5.2); CK HMW; CD15\t\n4\t1\tOncocytoma\t\t\t\t\n5\t1\tCD carcinoma\t+\t+\tEMA; CD15; CK HMW; CK7; CD10; E-cadherin\t\n6\t1\tOncocytoma\t\t\t\t\nCK, cytokeratin; EMA, epithelial membrane antigen; CK HMW, high-molecular-weight cytokeratin.\n\n\nFig. 2. Immunohistochemistry of the CD cell carcinomas. Cytokeratin 19 (A–D) and vimentin (E–H) staining of CD carcinomas (brown). A, E: Case 1; B, F: Case 2; C, G: Case 3, D, H: Case 5. Bar represents 50 μm.\n\n\nFig. 3. HE staining of renal oncocytomas. Large well-differentiated cells can be seen with eosinophilic granular cytoplasm in Cases 2, 4 and 6 (A–C).\n\n\n\nThe renal tissue surrounding the tumours showed dilation of the CD, abundant cyst formation and diffuse interstitial fibrosis and lymphocytic infiltration. In Patients 2 and 3, not only dilated CD and cysts were seen, but also papillary projections of the tubular epithelium into the lumen of several CDs or cysts (Figure 4).\nFig. 4. Cytokeratin 19 staining of the different parts of the same kidney (Case 3). (A) Normal renal tissue with cytokeratin 19 staining of the CD. (B) Cyst formation in cytokeratin 19-positive CD. (C) Cytokeratin 19-positive papillary structures within the cystic dilated CD. (D) Cytokeratin 19 staining of CD tumour. Bar represents 100 μm.\n\n\n\nNone of the patients had distant metastases on CT scanning and therapy varied from watchful waiting because of considerable comorbidity (Patients 4 and 6) to partial or complete unilateral nephrectomy (Table 1). Patient 1 became dialysis-dependent after nephrectomy. None of the patients died from renal malignancy, despite incomplete removal of a CD cell carcinoma (Patient 2), extension of the tumour into the perirenal fat (Patient 3), the presence of a contralateral complicated renal cyst (Patient 4) or the development of two complicated cysts in the contralateral kidney after unilateral nephrectomy (Patient 1). All patients except for one continued the use of Li because of inadequate psychiatric control on alternative pharmacotherapy.\n\nDiscussion\nWe report six patients who developed solid renal lesions of CD origin in the context of chronic Li nephropathy. The detection of these tumours in six patients among ∼50 patients with chronic Li nephropathy known at our department suggests that Li use predisposes to the development of CD neoplasms. Reports of renal neoplasms in patients on chronic Li therapy are very rare, and the connection with the use of Li was not made specifically. In a series of 24 renal biopsies in patients with Li nephropathy, Markowitz et al. [3] reported two tumours, of which one was a CD cell carcinoma. Because of limited immunohistochemical evaluation, the origin of the other tumour remained unresolved. In addition, in three unselected histology specimens of humans on Li therapy, Kjaersgaard et al. [4] described features of typical Li nephropathy in a kidney removed because of an unclassified renal carcinoma.\n\nCD cell carcinomas are derived from principal cells in the CD. Interestingly, Li can reach very high concentrations in the CD, exceeding that in plasma by 20- to 40-fold [5]. The principal cells in the CD express the epithelial sodium channel apically which has a considerable Li permeability, causing high intracellular Li concentrations [6]. Intracellular Li can inhibit the enzyme glycogen synthase kinase 3 beta (GSK-3β) by phosphorylation. In agreement with this, cells lining the renal microcysts in patients on chronic Li therapy contain phosphorylated GSK-3β [4]. GSK-3β regulates the breakdown of β-catenin; consequently, GSK-3β inhibition increases the availability of β-catenin. Indeed, it has been shown that Li increases β-catenin availability in principal cells [7]. Increased availability of β-catenin in tubular cells is associated with both increased cell proliferation and cyst formation [8]. We hypothesize that prolonged stimulation of principal cell proliferation by Li not only causes cyst formation, but can also eventually induce adenomas and carcinomas.\n\nThe CD cell carcinomas associated with Li use in our patients differ from the ‘classical’ CD cell carcinomas. The latter tumours are rare, with an incidence of less than 2 per 1 000 000 person years [9]. In contrast, the four CD cell carcinomas in our population of ∼50 patients with Li nephropathy suggest a much higher incidence in patients with Li nephropathy. Histologically, the Li-induced tumours show a more pronounced papillary growth, whereas the tumour cells do not always retain the hobnail appearance, typical of classical CD cell carcinomas. In addition, the lesions found in patients with Li nephropathy tend to occur multifocally (Patients 1, 2 and 4), which is not surprising in view of the widespread Li-induced proliferation in CD throughout both kidneys. Both multifocality and growth pattern are atypical for classical CD carcinomas. Finally, the clinical behaviour of the Li-associated CD cell tumours appears to be more benign than that of classical CD cell carcinomas. The latter are aggressive tumours with 80% lymph node metastases at presentation and a median survival of only 22 months [10]. In contrast, the tumours in our patients were subclinical, without metastases or recurrences during follow-up.\n\nThe pathophysiology of lithium-related oncocytomas exposure is less straight forward. Oncocytomas are mostly benign lesions comprising 3–7% of all renal tumours. Renal oncocytomas are derived from intercalated cells, which do not possess an entry mechanism for Li. It therefore appears unlikely that Li directly enhances the proliferation of intercalated cells. However, animal experiments have shown that Li treatment not only induces the proliferation of principal cells, but also causes an increase in the number of intercalated cells, possibly resulting from proliferation and differentiation of progenitor cells or the conversion of principal cells into intercalated cells [1]. Similar mechanisms may be involved in the development of oncocytomas in patients on Li therapy.\n\nOur data raise the question of whether patients with chronic Li nephropathy should be screened for renal cysts and which strategy should be applied in case a complex cyst or solid tumour is found. A subset of these tumours are oncocytomas, which are often slow-growing benign neoplasms that require only surgical intervention in the case of rapid growth or a large tumour volume [11]. Although the remainder of the Li-induced tumours are classified as CD cell carcinomas, these tumours appear to differ from ‘classical’ CD cell carcinomas, specifically with respect to their clinical behaviour. The benign clinical behaviour challenges the indication for surgery, which results in loss of renal mass in patients with already compromised renal function. The observation of multifocal Li-related renal masses in our cases makes the decision to perform surgery even more difficult. Until more information is obtained on the incidence and natural history of Li-related proliferative renal disease, we do not suggest radiological screening in patients with Li nephropathy. In the case of a renal mass found incidentally in a patient on chronic Li therapy, we would suggest a biopsy. If an oncocytoma is found, careful radiological follow-up would be sufficient. If a CD cell carcinoma is found, the same strategy could be considered in view of the benign clinical behaviour of the tumours in our cases. However, treatment should be individualized and surgical removal may be preferred if a biopsy is technically not feasible, the tumour grows rapidly or removal of the tumour would imply only minimal loss of renal mass. Although Li is often an indispensable drug in patients with psychiatric disease, we suggest that the use of lithium be stopped in patients with progressive cystic kidney disease or a complex renal cyst. This suggestion is supported by the observation that most patients have slowly progressive renal failure, which in itself forms an indication to stop the use of Li. Increased awareness of a possible relationship between chronic Li therapy and renal neoplasms will enhance the knowledge on epidemiology, clinical behaviour and optimal therapy for the Li-related renal neoplasms.\n\nConflict of interest statement\nNone declared.\n==== Refs\nReferences\n1 Christensen BM Kim YH Kwon TH Lithium treatment induces a marked proliferation of primarily principal cells in rat kidney inner medullary collecting duct Am J Physiol Renal Physiol 2006 291 F39 F48 16434572 \n2 Farres MT Ronco P Saadoun D Chronic lithium nephropathy: MR imaging for diagnosis Radiology 2003 229 570 574 14595154 \n3 Markowitz GS Radhakrishnan J Kambham N Lithium nephrotoxicity: a progressive combined glomerular and tubulointerstitial nephropathy J Am Soc Nephrol 2000 11 1439 1448 10906157 \n4 Kjaersgaard G Madsen K Marcussen N Tissue injury after lithium treatment in human and rat postnatal kidney involves glycogen synthase kinase 3beta-positive epithelium Am J Physiol Renal Physiol 2012 302 F455 F465 22088436 \n5 Birch NJ Hullin RP Lithium and the kidney Br Med J 1980 280 1148 1149 7427126 \n6 Kortenoeven ML Li Y Shaw S Amiloride blocks lithium entry through the sodium channel thereby attenuating the resultant nephrogenic diabetes insipidus Kidney Int 2009 76 44 53 19367330 \n7 Nielsen J Hoffert JD Knepper MA Proteomic analysis of lithium-induced nephrogenic diabetes insipidus: mechanisms for aquaporin 2 down-regulation and cellular proliferation Proc Natl Acad Sci USA 2008 105 3634 3639 18296634 \n8 Saadi-Kheddouci S Berrebi D Romagnolo B Early development of polycystic kidney disease in transgenic mice expressing an activated mutant of the beta-catenin gene Oncogene 2001 20 5972 5981 11593404 \n9 Storkel S Eble JN Adlakha K Classification of renal cell carcinoma: Workgroup No. 1. Union Internationale Contre le Cancer (UICC) and the American Joint Committee on Cancer (AJCC) Cancer 1997 80 987 989 9307203 \n10 Peyromaure M Thiounn N Scotte F Collecting duct carcinoma of the kidney: a clinicopathological study of 9 cases J Urol 2003 170 1138 1140 14501710 \n11 Chao DH Zisman A Pantuck AJ Changing concepts in the management of renal oncocytoma Urology 2002 59 635 642 11992832\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2048-8505",
"issue": "5(5)",
"journal": "Clinical kidney journal",
"keywords": "cancer; cyst; lithium",
"medline_ta": "Clin Kidney J",
"mesh_terms": null,
"nlm_unique_id": "101579321",
"other_id": null,
"pages": "412-5",
"pmc": null,
"pmid": "26019817",
"pubdate": "2012-10",
"publication_types": "D016428:Journal Article",
"references": "14595154;11593404;14501710;9307203;10906157;18296634;11992832;7427126;22088436;19367330;16434572",
"title": "Solid renal tumours of collecting duct origin in patients on chronic lithium therapy.",
"title_normalized": "solid renal tumours of collecting duct origin in patients on chronic lithium therapy"
} | [
{
"companynumb": "NL-APOTEX-2018AP020042",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "LITHIUM CARBONATE"
},
"drugadditional": null,
... |
{
"abstract": "Carfilzomib, a next-generation proteasome inhibitor, improves outcomes in patients with multiple myeloma (MM); however, a proportion of those treated develop renal failure due to adverse event, comorbidity, or myeloma progression. The rate of renal failure and associated risk factors remains unknown in real-world populations. Adults with relapsed/refractory MM who received carfilzomib between the years 2013 and 2016 were identified in the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked databases. Renal failure was defined using the corresponding International Classification of Diseases, Ninth Revision (ICD-9) and Tenth Revision (ICD-10) diagnostic codes and procedure codes for dialysis. Patients with a pre-existing diagnosis of renal failure were excluded to distinguish an adverse event from comorbidity. Multivariate cox regression analysis was performed to identify the variables independently associated with the development of renal failure among MM patients utilizing carfilzomib. A total of 1950 patients were included in the analysis. Renal failure developed in 22% of patients during the study period. The median time to development of renal failure from first carfilzomib administration was 1.6 months (range < 0.1-23.3). Increasing age (adjusted hazard ratio [aHR] 1.01 per year, p = 0.018), pre-existing heart failure (aHR 1.50, p = 0.005), and pre-existing chronic kidney disease (aHR 2.00, p < 0.001) were associated with a higher risk of developing renal failure. Renal failure occurred in up to 22% of patients on carfilzomib therapy. The exact cause and mechanism of renal failure cannot be determined from our study and may be multifactorial. Future studies are needed to further understand the cause of renal failure among patients on carfilzomib and devise strategies to mitigate the risk.",
"affiliations": "Department of Oncology, McMaster University, 699 Concession St., Hamilton, ON, L8V 5C2, Canada. mianh@mcmaster.ca.;Department of Medicine, Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO, USA.;Department of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.;Department of Medicine, Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO, USA.;Department of Medicine, Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO, USA.",
"authors": "Mian|Hira S|HS|http://orcid.org/0000-0003-1584-1067;Fiala|Mark A|MA|;Sanchez|Larysa|L|;Vij|Ravi|R|;Wildes|Tanya M|TM|",
"chemical_list": "D000970:Antineoplastic Agents; D009842:Oligopeptides; D061988:Proteasome Inhibitors; C524865:carfilzomib",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00277-021-04420-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0939-5555",
"issue": "100(5)",
"journal": "Annals of hematology",
"keywords": "Aged; Hematological malignancy; Multiple myeloma; Renal failure",
"medline_ta": "Ann Hematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D009842:Oligopeptides; D016016:Proportional Hazards Models; D061988:Proteasome Inhibitors; D051437:Renal Insufficiency; D012307:Risk Factors",
"nlm_unique_id": "9107334",
"other_id": null,
"pages": "1261-1266",
"pmc": null,
"pmid": "33475778",
"pubdate": "2021-05",
"publication_types": "D016428:Journal Article",
"references": "29341834;26671818;29465266;31721140;29296960;24518527;26771810;24390940;27654928;32382772;31722839;16641149;28886839;30819926;29285538;31188726;25071143;23445873;31099676;30478094;23364621",
"title": "Renal failure among multiple myeloma patients utilizing carfilzomib and associated factors in the \"real world\".",
"title_normalized": "renal failure among multiple myeloma patients utilizing carfilzomib and associated factors in the real world"
} | [
{
"companynumb": "CA-AMGEN-USASP2021013125",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARFILZOMIB"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nAs increasing frequency of serotonergic drug use, SS (serotonin syndrome) occurred more than ever. But clinicians have not enough knowledge and experience about SS as a potentially life-threatening condition. SS is usually caused by the increased serotonin activity in the central nervous system which may due to a serotonergic agent overdose or the concomitant use of 2 or more serotonergic antidepressants. We report a case of SS due to a normal dose of selective serotonin inhibitors (SSRIs) thus to remind clinicians to pay attention to such patients and make an early diagnosis and initiation of therapy in the clinical practice.\nWe report here a 49-year-old man presented with lethargic, less communicative, and insomnia for 20 days while a diagnosis of depression was considered and he was treated with SSRIs.\n\n\nMETHODS\nThe patient in our case fulfilled the 3 criteria existed now for diagnosing SS, including the Sternbach criteria, Radomski revised diagnostic criteria, and the Hunter serotonin toxicity criteria.\n\n\nMETHODS\nAll the antidepressants were stopped and cyproheptadine with an initial dose of 12 mg a day was started along with supportive care. The patient was also admitted to emergency intensive care unit for further treatment. He was sedated and paralyzed by intravenous Midazolam and Clonazepam along with physical cooling and supportive care.\n\n\nRESULTS\nAll of the patient's symptoms abated gradually and he soon could get off the bed and be communicative. Finally, the patient made a full recovery and he was discharged from the hospital.\n\n\nCONCLUSIONS\nOur case suggests an atypical clinical course while the medicine the patient takes was not in so much dose. We assumed that there may have been some variation in metabolism of these agents, resulting in increased possibility that led to the subsequent syndrome. Thus, it is essential for clinicians to keep in mind when patients taking serotonergic agents who demonstrate acute change in their mental status. Besides, clinicians should be aware of such patients who seem to be sensitive to SSRIs, who may require a genetic testing before the initiation of SSRI therapy.",
"affiliations": "Department of Emergency.;Department of Psychiatry, Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School, Nanjing, China.;Department of Emergency.;Department of Emergency.;Department of Emergency.;Department of Emergency.;Department of Emergency.;Department of Emergency.;Department of Emergency.",
"authors": "Liu|Yun|Y|;Yang|Hailong|H|;He|Fei|F|;Xu|Peng|P|;Tong|Hanwen|H|;Liu|Yao|Y|;Ni|Jie|J|;Zhang|Qiulin|Q|;Wang|Jun|J|",
"chemical_list": "D017367:Serotonin Uptake Inhibitors",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000015554",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 31083217MD-D-18-0838410.1097/MD.0000000000015554155545000Research ArticleClinical Case ReportAn atypical case of serotonin syndrome with normal dose of selective serotonin inhibitors A case reportLiu Yun MDaYang Hailong MDbHe Fei MDaXu Peng MDaTong Hanwen MDaLiu Yao MDaNi Jie MDaZhang Qiulin MDa∗Wang Jun MDa∗NA. a Department of Emergencyb Department of Psychiatry, Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School, Nanjing, China.∗ Correspondence: Jun Wang, Department of Emergency, Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School, Nanjing 210000, China (e-mail: wangjun691119@163.com); Qiulin Zhang, Department of Emergency, Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School, Nanjing 210000, China (e-mail: zzqqllnj@126.com).5 2019 13 5 2019 98 19 e1555430 11 2018 30 3 2019 10 4 2019 Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.2019This 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/4.0Abstract\nRationale:\nAs increasing frequency of serotonergic drug use, SS (serotonin syndrome) occurred more than ever. But clinicians have not enough knowledge and experience about SS as a potentially life-threatening condition. SS is usually caused by the increased serotonin activity in the central nervous system which may due to a serotonergic agent overdose or the concomitant use of 2 or more serotonergic antidepressants. We report a case of SS due to a normal dose of selective serotonin inhibitors (SSRIs) thus to remind clinicians to pay attention to such patients and make an early diagnosis and initiation of therapy in the clinical practice.\n\nPatient concerns:\nWe report here a 49-year-old man presented with lethargic, less communicative, and insomnia for 20 days while a diagnosis of depression was considered and he was treated with SSRIs.\n\nDiagnosis:\nThe patient in our case fulfilled the 3 criteria existed now for diagnosing SS, including the Sternbach criteria, Radomski revised diagnostic criteria, and the Hunter serotonin toxicity criteria.\n\nInterventions:\nAll the antidepressants were stopped and cyproheptadine with an initial dose of 12 mg a day was started along with supportive care. The patient was also admitted to emergency intensive care unit for further treatment. He was sedated and paralyzed by intravenous Midazolam and Clonazepam along with physical cooling and supportive care.\n\nOutcomes:\nAll of the patient's symptoms abated gradually and he soon could get off the bed and be communicative. Finally, the patient made a full recovery and he was discharged from the hospital.\n\nLessons:\nOur case suggests an atypical clinical course while the medicine the patient takes was not in so much dose. We assumed that there may have been some variation in metabolism of these agents, resulting in increased possibility that led to the subsequent syndrome. Thus, it is essential for clinicians to keep in mind when patients taking serotonergic agents who demonstrate acute change in their mental status. Besides, clinicians should be aware of such patients who seem to be sensitive to SSRIs, who may require a genetic testing before the initiation of SSRI therapy.\n\nKeywords\ncitalopramdonepezilNMSolanzapineP450 enzyme systemparoxetineSSSSRIsOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nSerotonin syndrome (SS) is an iatrogenic, drug-induced clinical syndrome which may be potentially life-threatening as increasing frequency of serotonergic drug use occurred more than ever .[1] SS is usually caused by the increased serotonin activity in the central nervous system which may due to a serotonergic agent overdose or the concomitant use of 2 or more serotonergic antidepressants .[1–5] But few cases have reported the SS caused by normal-dose of serotonergic agent since it was first reported in 1960 by Oates and Sjoerdsma.[6] SS is characterized by a triad symptom including autonomic instability (dilated unresponsive pupils, abdominal pain, profuse sweating, hyperthermia, tachycardia and flushing, etc.), neuromuscular hyperactivity (bilateral Babinski sign, bruxism. hyperreflexia, shivering and tremor, etc.), and mental status changes (agitation, hypomania, restless, disorientation, and confusion). The clinical manifestation of SS ranges from mild forms to fatal ones, patients with SS may not present with symptoms of all of the 3 categories mentioned above, while some patients may just show the symptom of increased neuromuscular excitability. Severe SS is medical emergency, thus, the early diagnosis and initiation of therapy is vital in the clinical practice. But the awareness of physicians, especially, of first-line physicians, is still inadequate, as 85% of physicians were unaware of SS as a clinical diagnosis.[7]\n\nWe present a case of SS caused by normal dose selective serotonin inhibitors (SSRIs), which fulfilled the Sternbachcriteria, Radomski's revised criteria and Hunter criteria. The patient in our case responded well to the withdraw of the relevant agents and the administration of cyproheptadine. In this case report, we also summarized the etiology, clinical presentation, diagnostic protocols, differential diagnosis of SS, and the gene polymorphisms involved in the metabolism of these drugs. We anticipate that our case report could provide more insight to clinicians to be aware of such syndrome.\n\n2 Case report\nA case of a 49-year-old man presented with lethargic, less communicative, and insomnia for 20 days was admitted into local hospital. The electroencephalogram showed a medium abnormality, while cranial computed tomography was normal. Therefore, wuling capsule, paroxetine (10 mg every day) were administrated to the patient, while 3 days later, the patient was presented with headache, nausea, and vomiting, then the medicine therapy was stopped and the patient was transferred to our hospital for further treatment on February 13, 2018. The patient had no history of drug or alcohol use, no medical history, and no drug allergies. The inpatient parameters were: body temperature 36.5°C, pulse 108 beats/min, blood pressure 153/97 mm Hg, and respiratory rate 20 breaths/min. On physical examination, no abnormalities were observed and neurological examination was normal. The results of cerebrospinal fluid (CSF) showed: the level of protein was 257.3 mg/L (normal range: 150–450 mg/L), glucose was 3.49 mmol/L (2.5–4.5 mmol/L), no white blood cell, and the culture of CSF was negative. Laboratory investigations including routine blood test revealed slightly increased white blood cell (9.6×109/L, normal range: 0–8×109/L). The thyroid function was normal. The manteaux test was negative. Examination and electroencephalogram were normal. Cranial magnetic resonance imaging was normal. ECG showed a sinus rhythm with a heart rate of 122 beats/min.\n\nOn admission, the body temperature of the patient reached to 37.8 °C, pulmonary computed tomography showed no signs of infection, so the diagnosis of encephalitis was suspected, and the empirical injectable acyclovir was started, along with 40mg methylprednisolone and CZX for antibiotic treatment. But the results of CSF were normal, thus the mental disorder cannot be excluded. Cipramil with a dose of 10 mg was started on 15th, Aricept with an initial dose of 5 mg was administrated on 15th, and Olanzapine with a starting dose of 2.5 mg was administrated on 18th to relieve the mental symptom but they did not work very well.\n\nThe symptom did not improve with consistent fever but no obvious infections were detected. The drug fever was considered while all intravenous medications were stopped on 20th, but the patient was still in hyperthermia and showed an increase in muscular tension. Sooner, the patient arose rigidity in extremities with trismus and shaking of 4 limbs, but he was still in consciousness and responsive. Due to the rigidity of extremities, a blood creatine phosphokinase (CPK) was checked on 24th, and it was 183 U/L (normal range: 55–170 U/L).\n\nThe symptom of the patient worsened day by day, he became more and more apathetic and exhibited a high fever (the heat peak reached to 39°C) coupled with photophobia, Estazolam was administrated to release symptom. After consulting psychiatry department, considering the medication history and clinical manifestation, the diagnosis of “serotonin syndrome” was considered. All the antidepressants were stopped on 22nd and Cyproheptadine with an initial dose of 12 mg a day was started along with supportive care. But the patient did not have any improvement in symptom but gradually accompanied by consciousness disturbance and further increased body temperature with diaphoresis and tachycardia. The patient was admitted to emergency intensive care unit for further treatment. He was sedated and paralyzed by intravenous Midazolam and Clonazepam along with physical cooling and supportive care. The patient was drowsy and appeared no more tremor and his body temperature decreased gradually. Oral Clonazepam was administrated 2 mg a day at first on 26th, then reduced to 1 mg a day, all of the patients’ symptom abated except slight fever and mild coma, then the patient was transferred to normal ward on February 28th. While on March 4th, the patient could get off the bed and be communicative, while the Cyproheptadine was reduced to 6 mg a day and Clonazepam reduced to 0.5 mg per night. On 9th, the patient made a full recovery and he was discharged from the hospital. The written informed consent was obtained from the patient for publication of the case report.\n\n3 Discussion\nAntidepressants are frequently used nowadays while SSRIs and serotonin-noradrenaline (SNRIs) are the major drugs.[8] Based on the French pharmacovigilance reports, SSRIs were involved in 42.1% of SS.[9] The SS is one of the adverse events (AEs) of SSRIs and SNRIs which can be fatal. The concomitant use of antidepressant and antipsychotic can cause this fata condition and neuroleptic malignant syndrome (NMS). Since there are no laboratory tests available in diagnosing SS, the diagnosis protocol is based on physical examination. There are 3 criteria exited for diagnosing SS, including Sternbach's serotonincriteria (1991), Radomski's revised criteria (2000), and Hunter SS toxicity criteria (2003), which have been listed in Table 1. SS may resolve within 24 hours of onset of symptoms but in severe cases it can be sustained for a long time and leads to death, serious cases may accompany with tachycardia, delirium, hypertonicity, muscular rigidity, and even renal failure. Mild cases may present with tachycardia, mydriasis, diaphoresis, and shivering while moderate may present with hyperreflexia and clonus of the lower extremities and mild agitation,[10] which can be overlooked sometimes. Clinicians may underdiagnose the syndrome due to the lack of certain experience, but it is vital to keep it in mind because it is potentially lethal if not appropriately treated.\n\nTable 1 The diagnosis criteria of serotonin syndrome.\n\nThe case described here followed an atypical course. The patient was admitted to the hospital for lethargic, less communicative, and insomnia for 20 days. He was taking 30 mg of Paroxetine in local hospital but presented with severe AEs including headache and vomiting. According to regional poison's center it was advised that doses of Paroxetine less than 600 mg were relatively safe and need no treatment.\n\nThus, he was transferred to our hospital. Considering the diagnosis of “depression,” the patient was administrated with Donepezil (35 mg), Olanzapine (12.5 mg), and Citalopram (80 mg) accordingly. In our case, the presentation of the patient worsened day by day, he was presented with lethargic and shivering first but soon developed to hyperthermia, tachycardia, myoclonusand confusion. We have used Naranjo Algorithm as a tool to evaluate the probability of adverse reaction (ADR) rather than the result of other factors. The score is 4, which indicates a possible ADR. After taking a thorough review of his history including the current medication, physical examination, and exclusion of other causes (encephalitis, septic conditions, and NMS), the diagnosis of SS can be confirmed regarding the presentations of our patient, which include rigidity, shivering, conscious disturbance, hyperthermia, diaphoresis, and tachycardia, which meet all the current 3 diagnosis criteria of SS.[11–13]Thus, we stopped all the antidepressants and neuroleptics the patient took and accompanied by other supportive care. Clonazepam was administrated in addition to Cyproheptadine. The symptom resolved after 6 days.\n\nThis case had 2 idiosyncratic features. Apart from the fact that the medication the patient took was not in so much dose, he took both serotonergic agents and antipsychotics. Thus, the diagnosis of NMS cannot be excluded. SSRIs are able to trigger SS because of their serotonergic activity that overstimulated the 5-HT1A receptors, which occurred predominantly in the brain. The Citalopram and Paroxetine all belong to SSRIs, but they were considered to be safer in overdose. Citalopram possesses a high selectivity for serotonin reuptake inhibition [14,15]and a weaker CYP450 inhibitory activity[16,17], thus it is considered to be the safest SSRIs. especially when our patient took a normal dose of Citalopram and Paroxetine (up to 30 times the regular daily dose is considered to be moderate overdose which may be associated with minor or no symptoms).[18] However, the patient of our case presented with serious clinical manifestations that included hyperthermia, status epilepticus, coma, muscle rigidity, and autonomic dysfunction. Thus, we have to exclude the possibility of the side effect caused by the combination of other drugs and possibility of NMS. SS and NMS can be overlapping in clinical features like fever, consciousness disturbance, autonomic symptoms, increased creatine phosphokinase levels, and muscular rigidity; we need to differentiate them sometimes.\n\nFirst, NMS is the AE of antipsychotics while SS is associated with the administration of serotogenic agents. NMS is caused by medications with dopamine blocking properties while the onset of certain symptom is slower and the duration after treatment is longer. NMS can last for several weeks and take 9 to 14 days to remit,[19] while SS can resolve within a few days, the characteristics of these 2 syndromes are summarized in Table 2. Therefore, careful observation of clinical signs and detailed medication history could help us in differentiating these 2 diseases. As for our patient, the medicine that involved includes Olanzapine and Donepezil. Olanzapine is an atypical antipsychotic drug with low potential for extrapyramidal effects and NMS have also been reported in several cases of Olanzapine-induced NMS.[20,21] But the evidence that supports the Olanzapine-induced SS is not enough; Haslett and Kumar have reported a case of Olanzapine-induced SS but was refuted as a misunderstanding of the behavioral serotonin syndrome of rodents and human being, thus the Olanzapine was still to be regarded as unlikely to cause SS.[22,23]\n\nTable 2 Characteristics of serotonin syndrome and neuroleptic malignant syndrome.\n\nDonepezil is an acetylcholinesterase inhibitor that inhibits the breakdown of acetylcholine and thus increases the availability; it is known to be metabolized mainly by CYP3A4 and to a lesser extent by CYP2D6. Warwick et al[24] have reported the case of a 78-year-old man, who had a pre-existing parkinsonian syndrome who experienced a variant of NMS after the combination use of olanzapine and donepezil . As for our case, the patient has no medical history and is not possible to have NMS after the small dose of olanzapine and donepezil use, considering the medication history and the typical SS, the patient remits after 6 days, thus we exclude the diagnosis of NMS.\n\nGiven that the patient was taking a relatively less dose of antidepressant and antipsychotics, could there have been some variation in metabolism of these agents, resulting in increased possibility that led to the subsequent syndrome? Thus, the assumption of the genetic individual vulnerability reported by Direk et al[25] that leads to the high susceptibility of such drugs cannot be excluded. As we know, all the drugs that the patient took are to be metabolized by the cytochrome P450 (CYP) enzyme system. Paroxetine is metabolized by the CYP2D6 system and Citalopram is metabolized by CYP3A4, 2C19, and CYP2D6. Olanzapine is metabolized by CYP2D6, CYP1A2 while donepezil is metabolized mainly by CYP3A4 and CYP2D6. There are 80 variant alleles for CYP2D6 which have been discovered while CYP2D6 gene polymorphisms are also a contributing factor in developing SS and for patients with genetic CYP3A4 variants the excessive level even treated with a normal therapeutic dose was reported too.[26] As to our case, the patient seems susceptible to Paroxetine, since he presented AE immediately after the Paroxetine intake, Paroxetine is reported to be the most potent CYP2D6 inhibitor of all antidepressants [27] when coadministered with drugs possessing serotonergic activity, the drug levels may increase to cause SS. Thus, the genetic testing was recommended to this patient, but he refused.\n\nIn our case, we suppose the sensitivity of SSRIs in our patient may increase serotonin transmission and result in higher serotonin activity ,[9,28,29] because the drug that was used in our patient was not in high dose, thus it is essential for clinicians to keep in mind when patients taking serotonergic agents who demonstrate acute change in their mental status. Besides, clinicians should be aware of such patients who seem to be sensitive to SSRIs, who may require a genetic testing before the initiation of SSRI therapy.\n\nAuthor contributions\nData curation: Jie Ni.\n\nMethodology: Fei He, Yao Liu.\n\nSupervision: Hanwen Tong.\n\nValidation: Peng Xu.\n\nWriting – original draft: Yun Liu.\n\nWriting – review & editing: Hailong Yang, Qiulin Zhang, Jun Wang.\n\nAbbreviations: ADR = adverse reaction, AE = adverse events, CPK = serum creatine phosphokinase, CSF = cerebrospinal fluid, NMS = neuroleptic malignant syndrome, SNRIs = serotonin-noradrenaline, SS = serotonin syndrome, SSRIs = selective serotonin inhibitors.\n\nYL and HY are the cowriter of the article.\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Isbister GK Buckley NA Whyte IM \nSerotonin toxicity: a practical approach to diagnosis and treatment . Med J Aust \n2007 ;187 :361–5 .17874986 \n[2] Fischer P \nSerotonin syndrome in the elderly after antidepressant monotherapy . J Clin Psychopharmacol \n1995 ;23 :440–2 .\n[3] Kolecki P \nIsolated venlafaxine-induced serotonin syndrome . J Emerg Med \n1997 ;15 :491–3 .9279702 \n[4] Lenzi A Raffaelli S Marazziti D \nSerotonin syndrome-like symptoms in a patient with obsessive-compulsive disorder, following inappropriate increase in fluvoxamine dosage . Pharmacopsychiatry \n1993 ;26 :100–1 .8415895 \n[5] Pao M Tipnis T \nSerotonin syndrome after sertraline overdose in a 5-year-old girl . Arch Pediatr Adolesc Med \n1997 ;151 :1064–7 .\n[6] Oates JA Sjoerdsma A \nNeurologic effects of tryptophan in patients receiving a monoamine oxidase inhibitor . Neurology \n1960 ;10 :1076–8 .13730138 \n[7] Mackay FJ Dunn NR Mann RD \nAntidepressants and the serotonin syndrome in general practice . Br J Gen Pract \n1999 ;49 :871–4 .10818650 \n[8] Abbing-Karahagopian V Huerta C Souverein PC \nAntidepressant prescribing in five European countries: application of common definitions to assess the prevalence, clinical observations, and methodological implications . Eur J Clin Pharmacol \n2014 ;70 :849–57 .24793010 \n[9] Abadie D Rousseau V Logerot S \nSerotonin syndrome: analysis of cases registered in the French pharmacovigilance database . J Clin Psychopharmacol \n2015 ;35 :382–8 .26082973 \n[10] Boyer EW Shannon M \nThe serotonin syndrome . N Engl J Med \n2005 ;352 :1112–20 .15784664 \n[11] Sternbach H \nThe serotonin syndrome . Am J Psychiatry \n1991 ;148 :705–13 .2035713 \n[12] Dunkley EJ Isbister GK Sibbritt D \nThe Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity . QJM \n2003 ;96 :635–42 .12925718 \n[13] Radomski JW Dursun SM Reveley MA \nAn exploratory approach to the serotonin syndrome: an update of clinical phenomenology and revised diagnostic criteria . Med Hypotheses \n2000 ;55 :218–24 .10985912 \n[14] Hiemke C Hartter S \nPharmacokinetics of selective serotonin reuptake inhibitors . Pharmacol Ther \n2000 ;85 :11–28 .10674711 \n[15] Rahola JG \nAntidepressants: pharmacological profile and clinical consequences . Int J Psyc Clin Pract \n2001 ;5 :19–28 .\n[16] Bezchlibnyk-Butler K Aleksic I Kennedy SH \nCitalopram—a review of pharmacological and clinical effects . J Psychiatry Neurosci \n2000 ;25 :241–54 .10863884 \n[17] Llorca PM Brousse G Schwan R \nEscitalopram for treatment of major depressive disorder in adults . Encephale \n2005 ;31 (4 pt 1) :490–501 .16389716 \n[18] Barbey JT Roose SP \nSSRI safety in overdose . J Clin Psychiatry \n1998 ;59 suppl 15 :42–8 .\n[19] Dosi et al.2014; Perry and Wilborn, 2012; Strawn et al.2007 .\n[20] Ananth J Parameswaran S Gunatilake S \nNeuroleptic malignant syndrome and atypical antipsychotic drugs . J Clin Psychiatry . 2004 ;65 : 464–470 .15119907 \n[21] Filice GA McDougall BC Ercan-Fang N \nNeuroleptic malignant syndrome associated with olanzapine . Ann Pharmacother \n1998 ;32 :1158–9 .9825080 \n[22] Haslett CD Kunar S \nCan olanzapine be implicated in causing serotonin syndrome? \nPsychiatry Clin Neurosci \n2002 ;56 :533–5 .12193243 \n[23] Isbister GK Downes F Whyte IM \nOlanzapine and serotonin toxicity . Psychiatry Clin Neurosci \n2003 ;57 :241–2 .12667176 \n[24] Warwick TC Moningi V Jami P \nNeuroleptic malignant syndrome variant in a patient receiving donepezil and olanzapine . Nat Clin Pract Neurol \n2008 ;4 :170–4 .18212788 \n[25] Direk MÇ Yildirim V Güneş S \nSerotonin syndrome after clomipramine overdose in a child . Clin Psychopharmacol Neurosci \n2016 ;14 :388–90 .27776393 \n[26] Alusik S Kalatova D Paluch Z \nSerotonin syndrome . Neuro Endocrinol Lett \n2014 ;35 :265–73 .25038602 \n[27] Carrasco JL Sandner C \nClinical effects of pharmacological variations in selective serotonin reuptake inhibitors: an overview . Int J ClinPract \n2005 ;59 :1428–34 .\n[28] Blier P de Montigny C Chaput Y \nA role for the serotonin system in the mechanism of action of antidepressant treatments: preclinical evidence . J Clin Psychiatry \n1990 ;51 suppl :14–20 .\n[29] Birmes P Coppin D Schmitt L \nSerotonin syndrome: a brief review . CMAJ \n2003 ;168 :1439–42 .12771076\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0025-7974",
"issue": "98(19)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D003937:Diagnosis, Differential; D006801:Humans; D008297:Male; D008875:Middle Aged; D020230:Serotonin Syndrome; D017367:Serotonin Uptake Inhibitors",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e15554",
"pmc": null,
"pmid": "31083217",
"pubdate": "2019-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "An atypical case of serotonin syndrome with normal dose of selective serotonin inhibitors: A case report.",
"title_normalized": "an atypical case of serotonin syndrome with normal dose of selective serotonin inhibitors a case report"
} | [
{
"companynumb": "CN-ACCORD-129672",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DONEPEZIL HYDROCHLORIDE"
},
"drugadditional": "1",
... |
{
"abstract": "Terbinafine is a common antifungal agent with few reports of liver injury. We present a 64-year-old man who developed terbinafine-induced liver injury. Drug-induced liver injury is an important cause of morbidity and an early diagnosis may prevent progression to severe and chronic forms of liver injury including fulminant hepatic failure.",
"affiliations": "Department of Medicine, Northern Railway Central Hospital, Basant Lane, New Delhi, India.;Department of Medicine, Northern Railway Central Hospital, Basant Lane, New Delhi, India.;Department of Medicine, Northern Railway Central Hospital, Basant Lane, New Delhi, India.;Department of Medicine, Northern Railway Central Hospital, Basant Lane, New Delhi, India.",
"authors": "Kaushal|Madhu|M|;Tolani|Priyanka|P|;Kumar|Navneet|N|;Sharma|Shiwani|S|",
"chemical_list": "D000935:Antifungal Agents; D002756:Cholagogues and Choleretics; D000077291:Terbinafine",
"country": "India",
"delete": false,
"doi": "10.4103/0970-258X.239071",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0970-258X",
"issue": "30(6)",
"journal": "The National medical journal of India",
"keywords": null,
"medline_ta": "Natl Med J India",
"mesh_terms": "D000935:Antifungal Agents; D056486:Chemical and Drug Induced Liver Injury; D002756:Cholagogues and Choleretics; D018450:Disease Progression; D006801:Humans; D008099:Liver; D008297:Male; D008875:Middle Aged; D000077291:Terbinafine; D014005:Tinea",
"nlm_unique_id": "8809315",
"other_id": null,
"pages": "321-323",
"pmc": null,
"pmid": "30117442",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Terbinafine-induced liver injury.",
"title_normalized": "terbinafine induced liver injury"
} | [
{
"companynumb": "IN-GLAXOSMITHKLINE-IN2018190126",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ATENOLOL"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nTo analyze the efficacy and safety of subcutaneous administration of bortezomib in the treatment of multiple myeloma (MM) patients.\n\n\nMETHODS\nA total of 26 MM patients were enrolled in this study and treated with BDT (bortezomib-dexamethasone-thalidomide). In the 26 MM patients, 12 patients received subcutaneous administration of Bortezomib while 14 patients received conventional intravenous administration. The outcomes and adverse effects of two groups were retrospectively evaluated and compared.\n\n\nRESULTS\nOverall response (OR) rates in the two groups were 75.00% and 71.43% respectively, in which complete remission (CR) plus very good complete remission (VGPR) rates were 50.00% and 47.14%, while CR rates were 16.67% and 28.57%. There were no statistically significant difference (P > 0.05). Time to achieve effectiveness in two groups was similar (P > 0.05). More than half patients in both groups achieved partial remission after the first treatment course and CR after the fourth course. Compared to the intravenous group, peripheral neuropathy rates remained significantly lower in subcutaneous group (16.67% vs. 64.29%, P = 0.021). The intravenous group had 7.14% grade 3 or worse, peripheral neuropathy but none found in the subcutaneous group. Rash occurred only in subcutaneous group (66.67%), but it was local, mild and transitional. No significant differences of other adverse events between the two groups were observed.\n\n\nCONCLUSIONS\nSubcutaneous administration of bortezomib offers similar efficacy to standard intravenous administration in the treatment of multiple myelom, with an improved safety for lower rate of peripheral neuropathy.",
"affiliations": null,
"authors": "Wang|Yan-sheng|YS|;Ding|Shi-hua|SH|;Wu|Fan|F|;Wang|Zhi-tao|ZT|;Wang|Qiang-sheng|QS|",
"chemical_list": "D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib; D003907:Dexamethasone",
"country": "China",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1672-173X",
"issue": "45(3)",
"journal": "Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition",
"keywords": null,
"medline_ta": "Sichuan Da Xue Xue Bao Yi Xue Ban",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001897:Boronic Acids; D000069286:Bortezomib; D003907:Dexamethasone; D006801:Humans; D007262:Infusions, Intravenous; D007279:Injections, Subcutaneous; D009101:Multiple Myeloma; D011719:Pyrazines; D012074:Remission Induction; D012189:Retrospective Studies",
"nlm_unique_id": "101162609",
"other_id": null,
"pages": "529-32",
"pmc": null,
"pmid": "24941833",
"pubdate": "2014-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Safety and efficacy of subcutaneous administration of bortezomib in the treatment of multiple myeloma.",
"title_normalized": "safety and efficacy of subcutaneous administration of bortezomib in the treatment of multiple myeloma"
} | [
{
"companynumb": "CN-TAKEDA-2015MPI005679",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "THALIDOMIDE"
},
"drugadditional": null,
... |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.