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"abstract": "This is a case report of a patient who developed severe, irreversible hypocalcemia after receiving one dose of pamidronate 90 mg for hypercalcemia of malignancy. Hypocalcemia is a known risk of bisphosphonate treatments, but the incidence of severe hypocalcemia is rare, and the risk factors are well established. However, in the treatment of hypercalcemia of malignancy, the treatment objective is to reduce the elevated serum calcium level, and the bisphosphonate is usually given as one time dose only. The potential for developing severe hypocalcemia may not be considered a significant concern in this setting compared to the setting of the treatment of bone metastasis, where the baseline serum calcium level is not elevated and the bisphosphonate is administered at a regular interval of every three to four weeks. Furthermore, there is unawareness of prevalence of vitamin D deficiency in cancer patients, especially in those with advanced cancer, which may lead to inadvertent, severe hypocalcemia from bisphosphonate treatment. The objective of this case report is to bring awareness to the risk of severe hypocalcemia in patients with hypercalcemia of malignancy and the high prevalence of unrecognized vitamin D deficiency in cancer patients.",
"affiliations": "Department of Pharmacy, Princess Margaret Cancer Centre, Toronto, ON, Canada.",
"authors": "Kim|Sophie|S|",
"chemical_list": "D000077268:Pamidronate; D002118:Calcium",
"country": "England",
"delete": false,
"doi": "10.1177/1078155218812945",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "25(7)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Bisphosphonate; bone metastasis; hypercalcemia of malignancy; hypocalcemia; vitamin D deficiency",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D001859:Bone Neoplasms; D002118:Calcium; D006801:Humans; D006934:Hypercalcemia; D006996:Hypocalcemia; D008297:Male; D008875:Middle Aged; D000077268:Pamidronate; D012307:Risk Factors",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "1787-1793",
"pmc": null,
"pmid": "30419769",
"pubdate": "2019-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of severe, irreversible hypocalcemia after one dose of pamidronate administered for hypercalcemia of malignancy.",
"title_normalized": "a case of severe irreversible hypocalcemia after one dose of pamidronate administered for hypercalcemia of malignancy"
} | [
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"companynumb": "CA-TEVA-2019-CA-1121701",
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"occurcountry": "CA",
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"activesubstancename": "ATORVASTATIN"
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"abstract": "Transverse myelitis is a neurological disorder of the spinal cord that can have a variety of etiologies. Herpes simplex virus (HSV) infection has been described as one of the causes, most commonly HSV type 2. We report here a case of an 18 year old male who presented with weakness that started in his upper extremities and rapidly evolved to quadriplegia. Magnetic resonance imaging of spine was consistent with transverse myelitis. HSV type 1 PCR testing on cerebrospinal fluid (CSF) was positive. He was started on acyclovir and steroids, but despite therapy, patient did not recover motor function.",
"affiliations": "Department of Internal Medicine, Division of Infectious Disease, University of Florida, College of Medicine-Jacksonville, United States.;Department of Internal Medicine, Division of Infectious Disease, University of Florida, College of Medicine-Jacksonville, United States.;Department of Internal Medicine, Division of Infectious Disease, University of Florida, College of Medicine-Jacksonville, United States.;Department of Internal Medicine, Division of Infectious Disease, University of Florida, College of Medicine-Jacksonville, United States.",
"authors": "Figueroa|Danisha|D|;Isache|Carmen|C|;Sands|Michael|M|;Guzman|Nilmarie|N|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.idcr.2016.05.007",
"fulltext": "\n==== Front\nIDCasesIDCasesIDCases2214-2509Elsevier S2214-2509(16)30039-710.1016/j.idcr.2016.05.007Case ReportAn unusual case of acute transverse myelitis caused by HSV-1 infection Figueroa Danisha giselle-d80@hotmail.com⁎Isache Carmen Sands Michael Guzman Nilmarie Department of Internal Medicine, Division of Infectious Disease, University of Florida, College of Medicine-Jacksonville, United States⁎ Corresponding author. giselle-d80@hotmail.com22 6 2016 2016 22 6 2016 5 29 31 9 3 2016 29 5 2016 31 5 2016 © 2016 The Author(s)2016This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Transverse myelitis is a neurological disorder of the spinal cord that can have a variety of etiologies. Herpes simplex virus (HSV) infection has been described as one of the causes, most commonly HSV type 2.\n\nWe report here a case of an 18 year old male who presented with weakness that started in his upper extremities and rapidly evolved to quadriplegia. Magnetic resonance imaging of spine was consistent with transverse myelitis. HSV type 1 PCR testing on cerebrospinal fluid (CSF) was positive. He was started on acyclovir and steroids, but despite therapy, patient did not recover motor function.\n\nKeywords\nQuadriplegiaHerpes simplex virusTransverse myelitis\n==== Body\nIntroduction\nTransverse myelitis is a neurological disorder of the spinal cord caused by inflammation that typically has an acute presentation [1]. The etiology may be infectious, parainfectious, other systemic inflammatory disorders, a spinal form of multiple sclerosis or idiopathic.\n\nInfectious myelitis presents with fever and paraparesis, most commonly affecting the thoracic spinal cord. It can manifest as motor, sensory, and/or autonomic dysfunction of varying degrees. Symptoms develop over hours to days and worsen over days to weeks. Sensory symptoms usually present as ascending paresthesias, with or without back pain at or near the level of the myelitis. Motor symptoms often include weakness that preferentially affects the flexors of the legs and the extensors of the arms and can include sphincter dysfunction. Autonomic involvement manifests with bowel and bladder dysfunction, temperature dysregulation or bouts of hypertension.\n\nWe present a case of infectious transverse myelitis secondary to HSV-1 with an unusual presentation of descending paralysis, who despite appropriate therapy did not recover motor function.\n\nCase\nOn arrival to the hospital, the patient was talking and moving his upper extremities. He was afebrile, tachycardic (106 bpm) and tachypneic (25 bpm). During initial evaluation, patient suddenly became unable to talk or move any of his extremities. He was intubated and placed on mechanical ventilation for airway protection. He remained fully conscious.\n\nOn physical exam, strength was 0/5 in all four extremities. Sensation was intact over the head and neck, decreased 3/5 in the right arm and absent over the rest of his body. Complete blood count and comprehensive metabolic panels were normal. Computer tomography of his head without intravenous contrast showed no hemorrhage or midline shift.\n\nLumbar puncture (LP) was done on admission and CSF analysis showed 49 red blood cells, one white blood cell, normal protein and normal glucose. CSF HSV PCR was negative. Magnetic resonance imaging (MRI) of the spine showed segmental increase in T2 and STIR signal with associated mild expansion of the spinal cord (Fig. 1), consistent with possible transverse myelitis. Patient was started on high dose methylprednisone. Toxicology screen including lead, arsenic, cadmium and mercury was negative. Tests for lupus, neuronal potassium channel antibodies, anti-calcium-channel antibodies, anti-Purkinje-cell antibodies, anti-chromatin antibodies, anti-glial antibodies, anti-neuronal antibodies, Rheumatoid arthritis latex turbid test, Lyme serology, Mycoplasma antibodies and quantitative HIV RT-PCR were all negative.\n\nLP was repeated after one week and CSF analysis showed this time 92,000 red cells/cubic cm, 40 white cells/cubic cm with 88% neutrophils, glucose 72 mg/dL and protein 209 mg/dL. CSF aerobic and fungal cultures, Enterovirus RT-PCR, West Nile virus IgM and IgG, VDRL, oligoclonal bands and NMO/AQP4 were negative. Repeat HSV-1 PCR was positive.\n\nAfter repeat LP, intravenous dexamethasone 6 g every 4 h was initiated, followed by a taper. In addition patient received intravenous acyclovir 1 g every 8 h and was given also IVIG, but his symptoms failed to improve.\n\nOf note, during his hospital stay, patient also underwent plasma exchange every other day for 5 days without signs of improvement. This was done due to suspicion of possible Guillain Barre syndrome, prior to repeating the LP.\n\nRepeat spine MRI done 12 days from admission showed interval increase in abnormal signal intensity of cervical cord, acute cervical cord edema with associated diffuse intramedullary enhancement with complete effacement of the CSF space surrounding the cervical spinal cord. There were also areas suggestive of possible spinal cord hemorrhages (Fig. 2). A follow up MRI done at 51 days showed marked improvement in the focal expansile appearance of upper cervical cord and abnormal T2 signal within the spinal cord and slightly decreased in craniocaudal extent, improved in cystic myelomalacia with T2 signal changes and minimal persistent enhancement.\n\nDespite completing three weeks of intravenous acyclovir, high dose steroids, IVIG and plasma exchange patient did not recover motor function.\n\nDiscussion\nSeveral viruses have been associated with infectious transverse myelitis, most commonly enteroviruses, HSV type 2 and varicella-zoster virus. Klastersky et al. reported the first case of HSV myelitis in 1972 [2], [3]. HSV, most frequently HSV type 2, has been reported since as the causative agent in several other cases of transverse myelitis. It can affect all ages, but seems to be more common in the10-19 years old and 30–39 years old age groups. HSV myelitis has been described mostly in immunocompromised patients, but it has also been reported in immunocompetent patients [3]. Patients may or may not present with HSV skin manifestations at the time of neurological symptoms.\n\nIt has been hypothesized that the pathogenesis of HSV myelitis starts with HSV latent infection of the dorsal root ganglion at the level of the lumbosacral spinal cord which reactivates. This leads to invasion of the spinal cord, forming of necrotizing lesions and sometimes spread to the cervico-thoracic spinal cord. Related to the localization of the latent HSV infection, it has been described that HSV type 1 more often produces myelitis involving the cervical to the thoracic segment, while HSV type 2 involves the whole spinal cord or just the lumbosacral segment [4].\n\nThe initial symptoms of HSV myelitis are sensory-motor disturbances of the lower limbs and urinary disturbance [1]. The ascending necrotizing form often presents with encephalitis, quadriplegia or respiratory muscle paralysis which makes the prognosis poor. Necrotic cord changes are common, and hemorrhagic lesions are occasionally seen [2].\n\nAscending paralysis has been described as the most common presentation of transverse myelitis secondary to HSV type 2 infection. In contrast, Nakajima and Shoji et. al described cases of transverse myelitis secondary to HSV type 1 infection where a non-ascending paralysis pattern was observed [2]. Initial diagnosis is made by imaging. Magnetic resonance imaging is the most specific test and may reveal signs of demyelination with or without necrosis. Histopathologic findings include marked necrosis of both gray and white matters, hemorrhage, perivascular lymphocyte infiltration and vascular necrosis. Progression may be prevented by administration of antiviral agents and steroids which lower mortality and improve neurological symptoms [3].\n\nIn this case, presentation was unusual with initial complaints of weakness in his upper extremity, followed by rapid progression to quadriplegia. The first CSF HSV PCR was negative, but subsequent repeat CSF HSV PCR was positive for HSV type 1. After administration of acyclovir, steroids, IVIG and plasma exchange, MRI of spine showed improvement of the lesions, but at four month follow-up, the patient had not recovered any of his motor function.\n\nFig 1 MRI of cervical spine with intravenous contrast done on admission with cord enhancement and possible hemorrhage indicated by the arrow.\n\nFig 1Fig. 2 MRI of cervical spine with intravenous contrast done after 12 days with cystic myelomalacia indicated by the arrow.\n\nFig. 2\n==== Refs\nReferences\n1 Jacob A. Weinshenker B. An approach to the diagnosis of acute transverse myelitis Semin Liver Dis 28 February (1) 2008 105 120 \n2 Nakajima H. Shoji H. Herpes simplex myelitis: differences in clinical manifestations between herpes simplex virus type 1 and type 2 Pathog Enceph 2011 153 168 \n3 Nakajima H. Furutama D. Herpes simplex virus myelitis: diagnosis by the polymerase chain reaction method Eur Neurol 39 1998 163 167 9605393 \n4 Yoshimoto A. Nshimura M. Herpes simplex virus type 1 myelitis with a favorable outcome Intern Med 40 10 2001 1068 1069 11688837\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-2509",
"issue": "5()",
"journal": "IDCases",
"keywords": "Herpes simplex virus; Quadriplegia; Transverse myelitis",
"medline_ta": "IDCases",
"mesh_terms": null,
"nlm_unique_id": "101634540",
"other_id": null,
"pages": "29-31",
"pmc": null,
"pmid": "27419072",
"pubdate": "2016",
"publication_types": "D016428:Journal Article; D002363:Case Reports",
"references": "11688837;18256991;9605393",
"title": "An unusual case of acute transverse myelitis caused by HSV-1 infection.",
"title_normalized": "an unusual case of acute transverse myelitis caused by hsv 1 infection"
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"companynumb": "US-GLAXOSMITHKLINE-US2016128971",
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"activesubstancename": "DEXAMETHASONE"
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"abstract": "Oculogyric crisis (OGC) is an often recurrent dystonic adverse effect of antipsychotic treatment characterized by a sustained fixed upward gaze lasting minutes to hours. The risk of OGC has not been established. We prospectively estimated the incidence rate of OGC in an early intervention service for psychosis and provided details regarding the antipsychotics implicated, clinical presentation, and long-term outcomes of OGC. The Nova Scotia Early Psychosis Program provides comprehensive, team-based care to youth and young adults with schizophrenia spectrum disorder. For 6 years (April 2008 to March 2014), 452 new patients were admitted to the program and participated in an individualized program of care. Eight patients (4 females; mean age, 19.8 years) developed recurrent episodes of OGC after 3 months to 2 years of treatment with 1 or more second-generation antipsychotics, yielding an incidence rate of 1.8% (95% confidence interval, 0.9%-3.4%). Risperidone or olanzapine (alone or in combination with a second antipsychotic) seemed causative in each case. Also implicated in the onset or recurrence of oculogyric episodes were ziprasidone, quetiapine, clozapine, aripiprazole, and the first-generation antipsychotic loxapine. Follow-up ranged between 2 and 7 years. Episodes stopped after switching antipsychotic treatment in 4 cases and after stopping antipsychotic treatment in 2 cases. In the other 2 cases, recurrences were ongoing at last follow-up 2 and 6 years after onset with antipsychotic treatment continuing. We observed a high rate of tardive-onset, recurrent, and potentially chronic ocular dystonias in patients with first-episode psychosis caused by the use of second-generation antipsychotics.",
"affiliations": "From the *Department of Psychiatry, Dalhousie University; and †Nova Scotia Early Psychosis Program, Nova Scotia Health Authority, Nova Scotia, Canada.",
"authors": "Gardner|David M|DM|;Abidi|Sabina|S|;Ursuliak|Zenovia|Z|;Morrison|Jason|J|;Teehan|Michael D|MD|;Tibbo|Philip G|PG|",
"chemical_list": "D014150:Antipsychotic Agents",
"country": "United States",
"delete": false,
"doi": "10.1097/JCP.0000000000000411",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0271-0749",
"issue": "35(6)",
"journal": "Journal of clinical psychopharmacology",
"keywords": null,
"medline_ta": "J Clin Psychopharmacol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D014150:Antipsychotic Agents; D004421:Dystonia; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D008297:Male; D009674:Nova Scotia; D015835:Ocular Motility Disorders; D017063:Outcome Assessment, Health Care; D011618:Psychotic Disorders; D012008:Recurrence; D012559:Schizophrenia; D055815:Young Adult",
"nlm_unique_id": "8109496",
"other_id": null,
"pages": "715-8",
"pmc": null,
"pmid": "26485339",
"pubdate": "2015-12",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Incidence of Oculogyric Crisis and Long-Term Outcomes With Second-Generation Antipsychotics in a First-Episode Psychosis Program.",
"title_normalized": "incidence of oculogyric crisis and long term outcomes with second generation antipsychotics in a first episode psychosis program"
} | [
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"companynumb": "CA-LUPIN PHARMACEUTICALS INC.-2015-03572",
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"abstract": "To analyze the factors associated with response to anti-tumor necrosis factor (anti-TNF) treatment and compare the efficacy and safety of infliximab (IFX) and adalimumab (ADA) in patients with refractory noninfectious uveitis.\n\n\n\nThis was a multicenter observational study of 160 patients (39% men and 61% women; median age 31 years [interquartile range 21-42]) with uveitis that had been refractory to other therapies, who were treated with anti-TNF (IFX 5 mg/kg at weeks 0, 2, 6, and then every 5-6 weeks [n = 98] or ADA 40 mg every 2 weeks [n = 62]). Factors associated with complete response were assessed by multivariate analysis. Efficacy and safety of IFX versus ADA were compared using a propensity score approach with baseline characteristics taken into account. Subdistribution hazard ratios (SHRs) and 95% confidence intervals (95% CIs) were calculated.\n\n\n\nThe main etiologies of uveitis included Behçet's disease (BD) (36%), juvenile idiopathic arthritis (22%), spondyloarthropathy (10%), and sarcoidosis (6%). The overall response rate at 6 and 12 months was 87% (26% with complete response) and 93% (28% with complete response), respectively. The median time to complete response was 2 months. In multivariate analysis, BD and occurrence of >5 uveitis flares before anti-TNF initiation were associated with complete response to anti-TNF (SHR 2.52 [95% CI 1.35-4.71], P = 0.004 and SHR 1.97 [95% CI 1.02-3.84], P = 0.045, respectively). Side effects were reported in 28% of patients, including serious adverse events in 13%. IFX and ADA did not differ significantly in terms of occurrence of complete response (SHR 0.65 [95% CI 0.25-1.71], P = 0.39), serious side effects (SHR 0.22 [95% CI 0.04-1.25], P = 0.089), or event-free survival (SHR 0.55 [95% CI 0.28-1.08], P = 0.083).\n\n\n\nAnti-TNF treatment is highly effective in refractory inflammatory uveitis. BD is associated with increased odds of response. IFX and ADA appear to be equivalent in terms of efficacy.",
"affiliations": "Hôpital Pitié-Salpêtrière, AP-HP, Centre National de Référence Maladies Systémiques et Autoimmunes Rares, and Université Paris VI, Paris, France.;Hôpital Croix Rousse, Lyon, France.;Hôpital Saint Louis and Le Centre de Recherche INSERM, Paris Sorbonne Cité, UMR 1153, Paris, France.;Hôpital Jean Verdier, Bondy, France.;Centre Hospitalier Universitaire (CHU) de Dijon, Dijon, France.;Hôpital Edouard Herriot, Lyon, France.;CHU de Caen, Caen, France.;Hôpital Avicenne, Bobigny, France.;Hôpital Pitié-Salpêtrière, AP-HP, Centre National de Référence Maladies Systémiques et Autoimmunes Rares, and Université Paris VI, Paris, France.;CHU de Grenoble-Hôpital Michallon, Grenoble, France.;Hôpital Lariboisière, AP-HP, Paris, France.;CHU de Rennes, Rennes, France.;CHU de Rouen, Rouen, France.;Hôpital Croix Rousse, Lyon, France.;Eric Hachulla, MD, PhD: Centre Hospitalier Régional Universitaire de Lille, Lille, France.;Hôpital Saint Antoine, AP-HP, Paris, France.;A. Rothschild Foundation, Paris, France.;CHU de Montpellier, Montpellier, France.;Hôpital Saint Louis and Le Centre de Recherche INSERM, Paris Sorbonne Cité, UMR 1153, Paris, France.;CHU de Rouen, Rouen, France.;CHU de Toulouse-Hôpital Purpan, INSERM UMR 1027, Toulouse, France.;Hôpital Pitié-Salpêtrière, AP-HP, Paris, France.;Hôpital Saint Louis and Le Centre de Recherche INSERM, Paris Sorbonne Cité, UMR 1153, Paris, France.;Hôpital Pitié-Salpêtrière, AP-HP, Centre National de Référence Maladies Systémiques et Autoimmunes Rares, and Université Paris VI, Paris, France.;Hôpital Pitié-Salpêtrière, AP-HP, Paris, France.;Hôpital Pitié-Salpêtrière, AP-HP, Centre National de Référence Maladies Systémiques et Autoimmunes Rares, and Université Paris VI, Paris, France.",
"authors": "Vallet|Hélène|H|;Seve|Pascal|P|;Biard|Lucie|L|;Baptiste Fraison|Jean|J|;Bielefeld|Philip|P|;Perard|Laurent|L|;Bienvenu|Boris|B|;Abad|Sébastien|S|;Rigolet|Aude|A|;Deroux|Alban|A|;Sene|Damien|D|;Perlat|Antoinette|A|;Marie|Isabelle|I|;Feurer|Elodie|E|;Hachulla|Eric|E|;Fain|Olivier|O|;Clavel|Gaëlle|G|;Riviere|Sophie|S|;Bouche|Pierre-Alban|PA|;Gueudry|Julie|J|;Pugnet|Gregory|G|;Le Hoang|Phuc|P|;Resche Rigon|Matthieu|M|;Cacoub|Patrice|P|;Bodaghi|Bahram|B|;Saadoun|David|D|;|||",
"chemical_list": "D000893:Anti-Inflammatory Agents; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000068879:Adalimumab",
"country": "United States",
"delete": false,
"doi": "10.1002/art.39667",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2326-5191",
"issue": "68(6)",
"journal": "Arthritis & rheumatology (Hoboken, N.J.)",
"keywords": null,
"medline_ta": "Arthritis Rheumatol",
"mesh_terms": "D000068879:Adalimumab; D000328:Adult; D000893:Anti-Inflammatory Agents; D001528:Behcet Syndrome; D005260:Female; D006801:Humans; D000069285:Infliximab; D008297:Male; D012074:Remission Induction; D014409:Tumor Necrosis Factor-alpha; D014605:Uveitis; D055815:Young Adult",
"nlm_unique_id": "101623795",
"other_id": null,
"pages": "1522-30",
"pmc": null,
"pmid": "27015607",
"pubdate": "2016-06",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study",
"references": null,
"title": "Infliximab Versus Adalimumab in the Treatment of Refractory Inflammatory Uveitis: A Multicenter Study From the French Uveitis Network.",
"title_normalized": "infliximab versus adalimumab in the treatment of refractory inflammatory uveitis a multicenter study from the french uveitis network"
} | [
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"companynumb": "FR-JNJFOC-20160606695",
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"actiondrug": "1",
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"activesubstancename": "INFLIXIMAB"
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{
"abstract": "EGFR tyrosine kinase inhibitors (TKIs) are the front-line treatment in EGFR mutation positive advanced non-small cell lung cancer (aNSCLC) patients. Generally, they are well-tolerated but skin toxicity is common (45-100% of patients) and may adversely affect quality of life. Pathogenesis of cutaneous side effects is usually linked to EGFR expression in normal cells of the epidermis and not immune-related. Subacute cutaneous lupus erythematosus (SCLE) is an autoimmune disease and about 40% of SCLE cases are drug related, but no reports are available involving osimertinib. Our report depicts a drug induced-SCLE (DI-SCLE) caused by erlotinib and worsened by osimertinib. The adverse event is characterized by the absence of systemic symptoms. Diagnosis has been performed by skin biopsy and the conditions improved with systemic steroids administration and EGFR-TKIs discontinuation. The report underlines the importance of a complete dermatologic diagnosis of skin lesions induced by EGFR inhibitors, according to symptom severity and timing of improving with standard clinical management. The diagnosis of immune-related skin toxicity in this context affects the treatment and the outcome of skin toxicity and must be taken into account when planning subsequent treatments, potentially including immune checkpoint inhibitors (ICIs).",
"affiliations": "Department of Surgery, Oncology and Gastroenterology, Università degli Studi di Padova, Padova, Italy.;Melanoma and Sarcoma Surgical Oncology Unit - Veneto Institute of Oncology, IOV-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padua, Italy.;Medical Oncology 2, Istituto Oncologico Veneto Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padova, Italy.;Medical Oncology 2, Istituto Oncologico Veneto Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padova, Italy.;Department of Surgery, Oncology and Gastroenterology, Università degli Studi di Padova, Padova, Italy.;Department of Surgery, Oncology and Gastroenterology, Università degli Studi di Padova, Padova, Italy.;Unit of Dermatology, University of Padua, Padua, Italy.;Medical Oncology 2, Istituto Oncologico Veneto Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padova, Italy.",
"authors": "Ferro|Alessandra|A|;Filoni|Angela|A|;Pavan|Alberto|A|;Pasello|Giulia|G|;Guarneri|Valentina|V|;Conte|PierFranco|P|;Alaibac|Mauro|M|;Bonanno|Laura|L|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fmed.2021.570921",
"fulltext": "\n==== Front\nFront Med (Lausanne)\nFront Med (Lausanne)\nFront. Med.\nFrontiers in Medicine\n2296-858X\nFrontiers Media S.A.\n\n10.3389/fmed.2021.570921\nMedicine\nCase Report\nSubacute Cutaneous Lupus Erythematosus-Like Eruption Induced by EGFR -Tyrosine Kinase Inhibitor in EGFR-Mutated Non-small Cell Lung Cancer: A Case Report\nFerro Alessandra 12†\n\nFiloni Angela 3†\nPavan Alberto 2\n\nPasello Giulia 2\n\nGuarneri Valentina 12\nConte PierFranco 12\nAlaibac Mauro 4†\nBonanno Laura 2*†\n\n1Department of Surgery, Oncology and Gastroenterology, Università degli Studi di Padova, Padova, Italy\n2Medical Oncology 2, Istituto Oncologico Veneto Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padova, Italy\n3Melanoma and Sarcoma Surgical Oncology Unit - Veneto Institute of Oncology, IOV-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padua, Italy\n4Unit of Dermatology, University of Padua, Padua, Italy\nEdited by: Oleg E. Akilov, University of Pittsburgh, United States\n\nReviewed by: Timothy F. Burns, University of Pittsburgh, United States; Alessandro Russo, A. O. Papardo, Italy\n\n*Correspondence: Laura Bonanno laura.bonanno@iov.veneto.it\nThis article was submitted to Dermatology, a section of the journal Frontiers in Medicine\n\n†These authors have contributed equally to this work\n\n04 6 2021\n2021\n8 57092107 4 2021\n13 5 2021\nCopyright © 2021 Ferro, Filoni, Pavan, Pasello, Guarneri, Conte, Alaibac and Bonanno.\n2021\nFerro, Filoni, Pavan, Pasello, Guarneri, Conte, Alaibac and Bonanno\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nEGFR tyrosine kinase inhibitors (TKIs) are the front-line treatment in EGFR mutation positive advanced non-small cell lung cancer (aNSCLC) patients. Generally, they are well-tolerated but skin toxicity is common (45–100% of patients) and may adversely affect quality of life. Pathogenesis of cutaneous side effects is usually linked to EGFR expression in normal cells of the epidermis and not immune-related. Subacute cutaneous lupus erythematosus (SCLE) is an autoimmune disease and about 40% of SCLE cases are drug related, but no reports are available involving osimertinib. Our report depicts a drug induced-SCLE (DI-SCLE) caused by erlotinib and worsened by osimertinib. The adverse event is characterized by the absence of systemic symptoms. Diagnosis has been performed by skin biopsy and the conditions improved with systemic steroids administration and EGFR-TKIs discontinuation. The report underlines the importance of a complete dermatologic diagnosis of skin lesions induced by EGFR inhibitors, according to symptom severity and timing of improving with standard clinical management. The diagnosis of immune-related skin toxicity in this context affects the treatment and the outcome of skin toxicity and must be taken into account when planning subsequent treatments, potentially including immune checkpoint inhibitors (ICIs).\n\nosimertinib\nimmunotherapy\ntargeted therapy\ncutaneous drug reactions\nimmune- related adverse events\n==== Body\nIntroduction\n\nEpidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are currently the standard of care for front-line treatment in advanced non-small cell lung cancer (NSCLC) patients carrying EGFR sensitizing mutations. Both first and second generation TKIs demonstrated to be superior to chemotherapy in terms of response rate (RR) and progression-free survival (PFS) (1–8). A third-generation irreversible EGFR TKI, osimertinib, has been developed to overcome acquired resistance to EGFR TKI driven by EGFR T790M mutation (9). Subsequently, because of its superiority to first generation EGFR TKIs in terms of RR, PFS and overall survival (OS), independently from the presence of T790M mutation, it has been recently approved as first-line treatment for advanced EGFR-mutated NSCLC (10, 11).\n\nThe most common drug-related side effects of EGFR TKIs are acneiform skin rash, follicular papulopustular eruption, xerosis, diarrhea, and paronychia (12). Cutaneous toxicity is usually a dose-dependent skin drug reaction, which develops after 1–2 weeks of treatment, peaks at 3–4 weeks on therapy, and its intensity decreases after 2 weeks but can often persist over some months (13). Despite lower systemic toxicity than conventional chemotherapy, the majority of patients treated with these agents experiences cutaneous disorders, because of the ubiquitous presence of EGFR in the skin and its involvement in maintaining the integrity of the tissue. Specifically, EGFR is expressed in undifferentiated, proliferating keratinocytes in the basal and suprabasal layers of the epidermis. The inhibition of EGFR catalytic activity induces growth arrest and apoptosis, decreased cell migration, increased cell attachment and differentiation and also stimulates inflammation, resulting in typical cutaneous lesions (14).\n\nSubacute cutaneous lupus erythematosus (SCLE) is a subtype of cutaneous lupus erythematosus that was first described in 1979 by Sontheimer et al. (15). Skin lesions typically manifest as papulosquamous or annular eruptions developing in sun-exposed areas. SCLE usually occurs in genetically predisposed individuals, primarily in young to middle aged women, frequently associated with the presence of the anti-Ro (SS-A) autoantibody, a positive antinuclear antibody (ANA) reaction and human leukocyte antigens B8, DR3, DRw52, and DQ1 (16).\n\nAbout 40% of SCLE cases may be drug related (DI-SCLE) (17). Proton pump inhibitors, antifungal medications, hydrochlorothiazide and calcium channel blockers are the most common drugs involved, but some chemotherapeutic agents have been more recently implicated (18, 19). To the best of our knowledge, in literature there is only one other case report of SCLE-like eruption induced by an EGFR TKI (erlotinib) and no one linked to osimertinib (20). Moreover, clinical manifestation of this immune-related toxicity is different from the previously reported one and has important implications in clinical management.\n\nCase Report\n\nIn July 2018, a 71-year-old woman with no smoking habit and few comorbidities (arterial hypertension and autoimmune hypothyroidism) was diagnosed with stage IV lung adenocarcinoma with metastases to lung, liver, bone, adrenal glands and lymph nodes (T4N3M1c according to 8th edition of TNM) (21). A tissue-based mutation testing by using Real-time PCR (Easy EGFR, Diatech Pharmacogenetics) showed an EGFR mutation in exon 21 (L858R point mutation).\n\nA targeted therapy with erlotinib 150 mg daily was started and since the second cycle the patient experienced severe pruritus and developed a grade 2 cutaneous adverse event (AE), characterized by the appearance of an annular eruption involving the chest and upper arms (Figure 1). The toxicity was managed with the administration of topical corticosteroids (betamethasone dipropionate 0.05% ointment) and oral antihistamine (cetirizine 10 mg/daily) with partial clinical benefit. After three cycles the radiological evaluation with computerized tomography (CT) scan showed a partial response according to the Response evaluation criteria in solid tumors (RECIST) v1.1 (22).\n\nFigure 1 Timeline of disease status, corresponding treatments administered and development of skin toxicity.\n\nIn November 2018, because of the persistence of the cutaneous toxicity, the patient underwent first dermatologic consultation: the skin lesions were considered as related to erlotinib and topical corticosteroids were administered. However, the skin disorder worsened, evolving to a grade 3 maculopapular rash, seriously affecting her quality of life. Therefore, erlotinib was temporarily discontinued and new dermatologic evaluation was planned after 1 week. Physical examination revealed numerous annular lesions, with raised pink borders and central clearing on the chest and upper arms (Figure 2A). After treatment interruption and topic treatment, the rash improved and the treatment was resumed.\n\nFigure 2 (A) Cutaneous eruption composed of annular, palpable, pink, scaly plaques on the patient's upper chest, and arms. (B) Numerous erythematous annular plaques on the chest and arms with a typically photo distributed pattern.\n\nIn January 2019, skin lesions worsened again and erlotinib was prescribed at reduced dose of 100 mg daily. In addition, given clinical suspicion of DI-SCLE, in January 2019 a biopsy of a right supraclavicular cutaneous lesion was performed. The pathology report revealed the presence of interface dermatitis with parakeratosis and focally thinning of the epidermis and a diffuse dyskeratosis. A perivascular and interstitial lymphocytic infiltrate and vacuolar degeneration of the basal layer was described in the dermis. Furthermore, laboratory findings revealed speckled-pattern antinuclear antibodies (ANA) at 1: 160 (normal >1: 40) and anti-endomysial antibody (EMA) positivity. This set of morphological features together with the clinical-anamnestic characteristics suggested a diagnosis of DI-SCLE-like eruption. For this reason, the patient was prescribed a course of systemic corticosteroids (prednisone 25 mg/daily) and antihistamine in combination with topical steroids. This treatment was effective, providing a prompt reduction of symptoms and signs, allowing for progressive steroid tapering and discontinuation.\n\nIn March 2019, after 10 cycles of erlotinib treatment, the CT scan showed disease progression. According to guidelines, a liquid biopsy was thus performed and EGFR T790M acquired resistance mutation was detected in circulating tumor DNA by using Real-time PCR (Cobas cfDNA Roche). Based on this result, second line treatment with the third generation TKI osimertinib was initiated (Figure 1).\n\nSince the first cycle, the patient underwent a dramatic exacerbation of the itchy, erythematous and desquamating skin lesions, which involved the face and the chest (Figure 2B). Osimertinib was the only identifiable precipitant of the cutaneous AE. The dermatologist prescribed a systemic therapy with prednisone 25 mg per day, antihistamine and a short-course of antibiotic therapy with minocycline 100 mg bid in association with topical steroid treatment. Again, the prompt relief of the clinical manifestation led to steroid tapering and antihistamine interruption.\n\nIn June 2019 the first radiological revaluation showed a progressive disease, so a third line therapy with carboplatin and gemcitabine was started. After one cycle of chemotherapy the patient experienced a recurrence of skin lesions and she underwent a new dermatological evaluation. Systemic therapy with prednisone 25 mg per day for 2 weeks was prescribed and skin lesions progressively improved (Figure 1).\n\nAfter five cycles of therapy the patient underwent a sudden clinical worsening and extensive liver disease progression, resulting in decline of patient's general condition and death.\n\nIn April 2019 the patient provided written informed consent to the publication of her anonymous case report including photos and details about her disease.\n\nDiscussion and Conclusions\n\nSince DI-SCLE was first described, several drugs have been identified as involved with its development. Among oncological treatment, some chemotherapeutic agents, such as taxanes, pyrimidine analogs, gemcitabine, and anthracyclines have been identified as sources/causative agents of SCLE (23, 24). More recently also some cases of lupus erythematosus-like eruption induced by targeted therapies have been reported: one related to the multikinase inhibitor pazopanib, another one related to the cyclin-dependent kinases 4 and 6 inhibitor palbociclib and two associated with the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab (25, 26).\n\nIn the era of personalized medicine, the use of targeted therapies has led to a therapeutic revolution in particular for molecularly defined subsets of NSCLC. Despite lower systemic side effects than chemotherapy, TKIs may cause different cutaneous AEs including dry skin, dermatitis acneiform, folliculitis, paronychia, alopecia, pruritus, and xerosis. The discomfort caused by these AEs can reduce compliance to anti-EGFR therapy and therefore affect patients' outcome. For this reason, prompt and proper management of skin toxicity is essential in clinical practice. International guidelines do not consider skin lesions biopsy as necessary for toxicity management (27).\n\nDI-SCLE is an autoimmune disease that manifests especially on the upper body including face, neck and trunk (sun-exposed areas) with annular or papulosquamous presentation with histologic findings of interface dermatitis with focal vacuolization of the epidermal basal layer associated with a perivascular dermal lymphocytic infiltrate. The pathogenic mechanisms involved in DI-SCLE remains unclear: several hypotheses have been proposed, including genetic predisposition, drug biotransformation, and epigenetic dysregulation in immune cells (28).\n\nIn our case, the SCLE-like lesions were likely to be induced by osimertinib therapy. Even though the mechanism is not known, a potential involvement of EGFR TKIs in the pathogenesis of SCLE might be related to the inflammation induced by apoptosis and cellular stressing conditions following EGFR inhibition in subjects with self-reactive predisposition of the immune system (Figure 3).\n\nFigure 3 A model for potential involvement of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) in the pathogenesis of Subacute Cutaneous Lupus Erythematosus. EGFR TKIs bind EGFR expressed in keratinocytes (KCs) in the basal and suprabasal layers of the epidermis (1). The inhibition of EGFR catalytic activity induces apoptosis or could sensitize KCs to agents inducing cellular stressing conditions (2). This causes the ignition of an inflammatory microenvironment, with recruitment of different immune cells. A self-reactive predisposition of the immune system (e.g., certain MHC polymorphisms) (3) may confer susceptibility to subacute cutaneous lupus erythematosus (SCLE) development (4). CK, cytokines; pDC, plasmacytoid dendritic cell.\n\nAlthough our patient did not perform serological dosage of Anti-Ro/SSa antibodies, the clinical picture and skin biopsy was consistent with DI-SCLE-like eruption and the most likely cause of the exacerbation of skin lesions was the administration of osimertinib after erlotinib, on the basis of the close temporal relationship between drug exposure and symptoms' onset.\n\nTo our knowledge, only another case of SCLE -like eruption related to anti-EGFR therapy has been reported: Takeda et al. described the case of a patient diagnosed with EGFR-mutated NSCLC who received erlotinib (150 mg daily) as a third-line therapy (20). After 2 weeks of treatment, she manifested fever, multiple erythematous patches over her upper chest and upper limbs, and prominent butterfly-shaped plaque erythema over her malar eminences that was categorized as lupus erythematosus-like eruption (Grade 3). A skin biopsy specimen from the upper chest revealed superficial perivascular dermatitis with a vacuolar change consistent with cutaneous lupus erythematosus. Also in this patient anti-Ro/SSa antibodies were not examined.\n\nOur case suggests novel issues. The patient had no systemic symptoms and no butterfly-shaped erythema, thus underlining the importance of considering skin lesions biopsy in case of persistent skin toxicity, after dermatologic evaluation and multidisciplinary discussion. In addition, the toxicity worsened with the administration of osimertinib, usually associated with more favorable skin toxicity profile when compared to first- and second-generation EGFR TKIs.\n\nThe potential involvement of osimertinib in the pathogenesis of an autoimmune disorder (Figure 3) is particularly relevant. Indeed, nowadays osimertinib represents a standard of care in first-line setting for advanced EGFR-mutated NSCLC (10, 11). Moreover, EGFR-mutated patients might be also considered for a treatment with immune checkpoint inhibitors (ICIs) following EGFR TKI. Even though EGFR mutations are generally associated with less effectiveness of ICIs, these drugs might be considered after EGFR TKIs and at least one chemotherapy treatment (29, 30). Furthermore, atezolizumab in combination with bevacizumab, paclitaxel and carboplatin might also have a role for patients progressing to first or second line osimertinib (31).\n\nIt is well-known that the blockade of regulatory immune checkpoint can result in aberrant immune activation leading to undesirable inflammation and autoimmunity (32). Recently, SCLE has been reported to occur during anti-PD-1 and anti-PD-L1 immunotherapy (33–35). In this context, the diagnosis of previous immune-related toxicity associated with EGFR TKI should be taken into account in decision making for systemic treatment in patients progressing to osimertinib and caution is needed in order to avoid serious immune-related AEs during treatment with ICIs.\n\nIn conclusion, we describe immune-related skin toxicity induced by erlotinib and worsened by osimertinib. The observation suggests the importance of multidisciplinary evaluation in case of persistent moderate-severe skin toxicity. Considering skin biopsy and potential immune-related pathogenesis is important not only for the management of skin toxicity and subsequently the compliance to EGFR TKI treatment, but also in planning further lines of treatment, potentially including immunotherapy.\n\nData Availability Statement\n\nThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.\n\nEthics Statement\n\nThe patient provided written informed consent to the publication of her anonymous case report including photos and details about her disease.\n\nAuthor Contributions\n\nAFe and LB conceived the manuscript. AFe, AP, and LB collected clinical, radiological data, and wrote the manuscript. LB and GP were responsible for the patient' care. AFi and MA were the dermatologists in charge of the patient, provided imaging, and critical review. VG and PC performed editing and critical review. All the authors read and approved the manuscript.\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n==== Refs\nReferences\n\n1. Mok TS Wu Y-L Thongprasert S Yang C-H Chu D-T Saijo N . Gefitinib or carboplatin–paclitaxel in pulmonary adenocarcinoma. N Engl J Med. (2009) 361 :947–57. 10.1056/NEJMoa0810699 19692680\n2. Mitsudomi T Morita S Yatabe Y Negoro S Okamoto I Tsurutani J . Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. (2010) 11 :121–8. 10.1016/S1470-2045(09)70364-X 20022809\n3. Maemondo M Inoue A Kobayashi K Sugawara S Oizumi S Isobe H . Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. (2010) 362 :2380–8. 10.1056/NEJMoa0909530 20573926\n4. Zhou C Wu YL Chen G Feng J Liu XQ Wang C . Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. (2011) 12 :735–42. 10.1016/S1470-2045(11)70184-X 21783417\n5. Rosell R Carcereny E Gervais R Vergnenegre A Massuti B Felip E . Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. (2012) 13 :239–46. 10.1016/S1470-2045(11)70393-X 22285168\n6. Wu Y Zhou C Liam C Wu G Liu X Zhong Z . First-line erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation-positive non-small-cell lung cancer: analyses from the phase III, randomized, open-label, ENSURE study. Ann Oncol. (2015) 26 :1883–9. 10.1093/annonc/mdv270 26105600\n7. Sequist LV. Yang JCH Yamamoto N O'Byrne K Hirsh V Mok T . Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. (2013) 31 :3327–34. 10.1200/JCO.2012.44.2806 23816960\n8. Wu YL Zhou C Hu CP Feng J Lu S Huang Y . Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol. (2014) 15 :213–22. 10.1016/S1470-2045(13)70604-1 24439929\n9. Mok TS Wu Y-L Ahn M-J Garassino MC Kim HR Ramalingam SS . Osimertinib or platinum–pemetrexed in EGFR T790M–positive lung cancer. N Engl J Med. (2017) 376 :629–40. 10.1056/NEJMoa1612674 27959700\n10. Soria J-C Ohe Y Vansteenkiste J Reungwetwattana T Chewaskulyong B Lee KH . Osimertinib in untreated EGFR-mutated advanced non–small-cell lung cancer. N Engl J Med. (2018) 378 :113–25. 10.1056/NEJMoa1713137 29151359\n11. Ramalingam SS Vansteenkiste J Planchard D Cho BC Gray JE Ohe Y . Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med. (2020) 382 :41–50. 10.1056/NEJMoa1913662 31751012\n12. Hsu W-H Yang JC-H Mok TS Loong HH . Overview of current systemic management of EGFR-mutant NSCLC. Ann Oncol Off J Eur Soc Med Oncol. (2018) 29 (suppl.1 ):i3–9. 10.1093/annonc/mdx702 29462253\n13. Fabbrocini G Panariello L Caro G Cacciapuoti S . Acneiform rash induced by EGFR inhibitors: review of the literature and new insights. Ski Appendage Disord. (2015) 1 :31–7. 10.1159/000371821 27171241\n14. Lacouture ME . Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev Cancer. (2006). 2006 :803–12. 10.1038/nrc1970 16990857\n15. Sontheimer RD Thomas JR Gilliam JN . Subacute cutaneous lupus erythematosus: a cutaneous marker for a distinct lupus erythematosus subset. Arch Dermatol. (1979) 115 :1409–15. 10.1001/archderm.115.12.1409 533284\n16. Okon LG Werth VP . Cutaneous lupus erythematosus: diagnosis and treatment. Best Practice Res Clin Rheumatol. (2013) 27 :391–404. 10.1016/j.berh.2013.07.008\n17. Rosenbach M Fernandes NF Elenitsas R Kist JM . Subacute cutaneous lupus erythematosus associated with capecitabine monotherapy. Archiv Dermatol. (2009) 145 :340–1. 10.1001/archdermatol.2008.619 19289781\n18. Laurinaviciene R Sandholdt LH Bygum A . Drug-induced cutaneous lupus erythematosus: 88 new cases. Eur J Dermatology. (2017) 27 :28–33. 10.1684/ejd.2016.2912 27799135\n19. Floristan U Feltes RA Sendagorta E Feito-Rodriguez M Ramírez-Marín P Vidaurrázaga C . Subacute cutaneous lupus erythematosus induced by capecitabine. Clin Exp Dermatol. (2009) 34 :e328–9. 10.1111/j.1365-2230.2009.03280.x 19456774\n20. Takeda M Okamoto I Tsurutani J Oiso N Kawada A Nakagawa K . Clinical impact of switching to a second EGFR-TKI after a severe AE related to a first EGFR-TKI in EGFR-mutated NSCLC. Jpn J Clin Oncol. (2012) 42 :528–33. 10.1093/jjco/hys042 22457323\n21. Chansky K Detterbeck FC Nicholson AG Rusch VW Vallières E Groome P . The IASLC lung cancer staging project: external validation of the revision of the TNM stage groupings in the eighth edition of the TNM classification of lung cancer. J Thorac Oncol. (2017) 12 :1109–21. 10.1016/j.jtho.2017.04.011 28461257\n22. Eisenhauer EA Therasse P Bogaerts J Schwartz LH Sargent D Ford R . New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. (2009) 45 :228–47. 10.1016/j.ejca.2008.10.026 19097774\n23. Choi JN . Chemotherapy-induced iatrogenic injury of skin: new drugs and new concepts. Clin Dermatol. (2011) 29 :587–601. 10.1016/j.clindermatol.2011.08.032 22014981\n24. Wiznia LE Subtil A Choi JN . Subacute cutaneous lupus erythematosus induced by chemotherapy: gemcitabine as a causative agent. JAMA Dermatol. (2013) 149 :1071–5. 10.1001/jamadermatol.2013.4957 23842655\n25. Casado-Verrier B Pérez-Santos S Delgado-Mucientes C Beato-Merino M . Subacute cutaneous lupus erythematosus induced by the new multikinase inhibitor pazopanib. Br J Dermatol. (2014) 171 :1559–61. 10.1111/bjd.13175 24909204\n26. Pinard J Patel M Granter SR Vleugels RA Merola JF . Subacute cutaneous lupus erythematosus induced by palbociclib. J Cutan Med Surg. (2018) 22 :341–3. 10.1177/1203475417752369 29307217\n27. Aw DCW Tan EH Chin TM Lim HL Lee HY Soo RA . Management of epidermal growth factor receptor tyrosine kinase inhibitor-related cutaneous and gastrointestinal toxicities. Asia-Pacific J Clin Oncol. (2018) 14 :23–31. 10.1111/ajco.12687 28464435\n28. He Y Sawalha AH . Drug-induced lupus erythematosus: an update on drugs and mechanisms. Curr Opin Rheumatol. (2018) 30 :490–7. 10.1097/BOR.0000000000000522 29870500\n29. Lee CK Man J Lord S Links M Gebski V Mok T . Checkpoint inhibitors in metastatic EGFR-mutated non–small cell lung cancer—a meta-analysis. J Thorac Oncol. (2017) 12 :403–7. 10.1016/j.jtho.2016.10.007 27765535\n30. Garassino MC Cho BC Kim JH Mazières J Vansteenkiste J Lena H . Durvalumab as third-line or later treatment for advanced non-small-cell lung cancer (ATLANTIC): an open-label, single-arm, phase 2 study. Lancet Oncol. (2018) 19 :521–36. 10.1016/S1470-2045(18)30144-X 29545095\n31. Socinski MA Jotte RM Cappuzzo F Orlandi F Stroyakovskiy D Nogami N . Atezolizumab for first-line treatment of metastatic non-squamous NSCLC. N Engl J Med. (2018) 378 :2288–301. 10.1056/NEJMoa1716948 29863955\n32. Postow MA Sidlow R Hellmann MD . Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med. (2018) 378 :158–68. 10.1056/NEJMra1703481 29320654\n33. Blakeway EA Elshimy N Muinonen-Martin A Marples M Mathew B Mitra A . Cutaneous lupus associated with pembrolizumab therapy for advanced melanoma: a report of three cases. Melanoma Res. (2019) 29 :338–41. 10.1097/CMR.0000000000000587 30762712\n34. Michot JM Fusellier M Champiat S Velter C Baldini C Voisin AL . Drug-induced lupus erythematosus following immunotherapy with anti-programmed death-(ligand) 1. Ann Rheumatic Dis. (2019) 78 :e67. 10.1136/annrheumdis-2018-213677 29934372\n35. Zitouni NB Arnault JP Dadban A Attencourt C Lok CC Chaby G . Subacute cutaneous lupus erythematosus induced by nivolumab: two case reports and a literature review. Melanoma Res. (2019) 29 :212–5. 10.1097/CMR.0000000000000536 30489484\n\n",
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"title": "Subacute Cutaneous Lupus Erythematosus-Like Eruption Induced by EGFR -Tyrosine Kinase Inhibitor in EGFR-Mutated Non-small Cell Lung Cancer: A Case Report.",
"title_normalized": "subacute cutaneous lupus erythematosus like eruption induced by egfr tyrosine kinase inhibitor in egfr mutated non small cell lung cancer a case report"
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"abstract": "After near-drowning following a car accident, a 27-year-old man developed severe ARDS. Six days later Aspergillus fumigatus was isolated in his sputum, and invasive pulmonary aspergillosis developed thereafter. Aspergillus titre increased, and chest tomograms revealed cavities in both lungs. The treatment consisted essentially of Amphotericin B and 5 fluorocytosine, intravenously and by inhalation, intensive postural drainage and mechanical ventilation with PEEP. After 41 days he was cured and discharged from the ICU. Six months later he returned to his job and clinical examination was normal.",
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"abstract": "Left ventricular hypertrophy (LVH) regression after kidney transplantation may be influenced by immunosuppression. In a 24-month open-label, multicenter, phase-IV study, 71 kidney allograft recipients without previous acute rejection, showing eGFR >40 ml/min and proteinuria <500 mg/day and between 6 months and 3 years post-transplantation, were randomized to receive everolimus (EVR) + mycophenolic acid (MPA) or were maintained on tacrolimus (TAC) + MPA. The aim was to assess whether the conversion to EVR could reduce left ventricular mass index (LVMi) at month-24. LVMi at month-24 decreased without differences between groups (TAC: 54.0 vs. 48.2 g/m2.7 ; EVR: 53.4 vs. 49.4 g/m2.7 ). The LVH prevalence at baseline and month-24 was 59.4% and 40.6% in TAC group and 57.1% and 50.0% in EVR group. EVR conversion was associated with nearly disappearance of concentric LVH and concentric remodeling pattern. The procollagen type I N-terminal propeptide at month-24 showed greater reduction in EVR group (51.6 vs. 58.2 mg/l; P = 0.004). Conversion from TAC to EVR was associated with a significant improvement of eGFR (P = 0.0315, ancova). Adverse events were similar between groups without rejection episode or graft loss. Conversion from TAC to EVR did not further reduce LVMi after 24 months, although its effect on concentric LVH deserves further investigation (NCT01169701).",
"affiliations": "Nephrology Department, IDIBELL, Hospital de Bellvitge, Barcelona, Spain.;Nephrology Department, Hospital del Mar, Barcelona, Spain.;Nephrology Department, Hospital Clínico San Carlos, Madrid, Spain.;Nephrology Department, Hospital Vall Hebron, Barcelona, Spain.;Nephrology Department, Fundació Puigvert, Barcelona, Spain.;Nephrology Department, Hospital Gregorio Marañón, Madrid, Spain.;Kidney Transplant Department, Hospital Clínic i Provincial de Barcelona, Barcelona, Spain.;Nephrology Department, Hospital Carlos Haya, Málaga, Spain.;Medical Department, Novartis Farmacéutica, Barcelona, Spain.;Medical Department, Novartis Farmacéutica, Barcelona, Spain.;Nephrology Department, Hospital 12 Octubre, Madrid, Spain.",
"authors": "Cruzado|Josep M|JM|;Pascual|Julio|J|;Sánchez-Fructuoso|Ana|A|;Serón|Daniel|D|;Díaz|Joan M|JM|;Rengel|Manuel|M|;Oppenheimer|Federico|F|;Hernández|Domingo|D|;Paravisini|Alexandra|A|;Saval|Núria|N|;Morales|José M|JM|;|||",
"chemical_list": "D015415:Biomarkers; D007166:Immunosuppressive Agents; D000068338:Everolimus; D009173:Mycophenolic Acid; D016559:Tacrolimus",
"country": "England",
"delete": false,
"doi": "10.1111/tri.12862",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0934-0874",
"issue": "29(12)",
"journal": "Transplant international : official journal of the European Society for Organ Transplantation",
"keywords": "cardiovascular profile; everolimus; left ventricular hypertrophy; tacrolimus",
"medline_ta": "Transpl Int",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers; D001794:Blood Pressure; D016903:Drug Monitoring; D000068338:Everolimus; D005260:Female; D005919:Glomerular Filtration Rate; D006084:Graft Rejection; D006085:Graft Survival; D006352:Heart Ventricles; D006801:Humans; D007166:Immunosuppressive Agents; D007677:Kidney Function Tests; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D061214:Patient Safety; D051437:Renal Insufficiency; D012307:Risk Factors; D016559:Tacrolimus; D055815:Young Adult",
"nlm_unique_id": "8908516",
"other_id": null,
"pages": "1317-1328",
"pmc": null,
"pmid": "27648523",
"pubdate": "2016-12",
"publication_types": "D017429:Clinical Trial, Phase IV; D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": null,
"title": "Controlled randomized study comparing the cardiovascular profile of everolimus with tacrolimus in renal transplantation.",
"title_normalized": "controlled randomized study comparing the cardiovascular profile of everolimus with tacrolimus in renal transplantation"
} | [
{
"companynumb": "ES-ASTELLAS-2016US039756",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
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{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MYCOPHENOLIC ACID"
},
"drugadditional": null,
... |
{
"abstract": "Incidence of Burkitt's lymphoma post-transplant lymphoproliferative disorder (BL-PTLD) in solid organ transplant (SOT) recipients in 1.4%-1.6% with unknown cure rate. We report a case of Epstein-Barr virus (EBV) positive, late-onset BL-PTLD in a 24-year-old EBV donor positive/recipient negative female. This is the first reported case of advanced BL-PTLD post-heart transplant in an adult. This is also the first reported case of treatment of advanced BL-PTLD in a heart transplant recipient with a combined chemotherapy regimen without anthracyclines to avoid cardiotoxicity. The patient received 6 cycles of R-COEP (rituximab with cyclophosphamide, vincristine, etoposide, prednisone) over 6 months and subsequently 3 cycles of high-dose methotrexate (MTX) over 3 months for CNS prophylaxis. She remains without evidence of disease at 19 months post-treatment. This case demonstrates that an anthracycline-free regimen can be the therapy option for patients with BL-PTLD after heart transplantation.",
"affiliations": "Virginia Commonwealth University School of Medicine, Richmond, Virginia.;INOVA Hematology Oncology, Falls Church, Virginia.;Inova Heart & Vascular Institute, Falls Church, Virginia.;Inova Heart & Vascular Institute, Falls Church, Virginia.",
"authors": "AbdelHameid|Duaa|D|;Felice|Anthony|A|;Cooper|Lauren B|LB|;Katugaha|Shalika B|SB|https://orcid.org/0000-0002-7163-0734",
"chemical_list": "D018943:Anthracyclines",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.13265",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "22(4)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "Burkitt's lymphoma; anthracycline sparing; heart transplant; post-transplant lymphoproliferative disorder",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000328:Adult; D018943:Anthracyclines; D000971:Antineoplastic Combined Chemotherapy Protocols; D002051:Burkitt Lymphoma; D004359:Drug Therapy, Combination; D020031:Epstein-Barr Virus Infections; D005260:Female; D016027:Heart Transplantation; D006801:Humans; D008232:Lymphoproliferative Disorders; D066027:Transplant Recipients",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e13265",
"pmc": null,
"pmid": "32077552",
"pubdate": "2020-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Long-term remission in an adult heart transplant recipient with advanced Burkitt's lymphoma post-transplant lymphoproliferative disorder after anthracycline-free chemotherapy: A case report and literature review.",
"title_normalized": "long term remission in an adult heart transplant recipient with advanced burkitt s lymphoma post transplant lymphoproliferative disorder after anthracycline free chemotherapy a case report and literature review"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/20/0120963",
"fulfillexpeditecriteria": "1",
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MYCOPHENOLIC ACID"
},
"drugadditional": ... |
{
"abstract": "The second generation antipsychotic risperidone is generally considered to have low cardiac adverse events, with an increased risk of ventricular arrhythmias being reported only rarely in literature. We report here the case of a patient with a significant history of alcohol dependence, yet with no previous cardiac history, who had previously tolerated risperidone well, but had experienced isolated sinus tachycardia in the post detox period, following the reinitiation of risperidone therapy. The Naranjo Adverse Drug Reaction (ADR) probability scale rating for this being a medication adverse event (AE) was 4, thus indicating that this patient's AE was associated with risperidone therapy. This case report will contribute to the limited evidence of adverse cardiac events associated with risperidone therapy, with particular emphasis on the susceptibility of patients in a state of autonomic hypersensitivity.",
"affiliations": "Department of Psychiatry, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania, United States.;Department of Psychiatry, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania, United States.;Department of Psychiatry, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania, United States.",
"authors": "Grubisha|Melanie J|MJ|;Brennan|Jessica L|JL|;Douaihy|Antoine|A|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/0976-500X.149147",
"fulltext": "\n==== Front\nJ Pharmacol PharmacotherJ Pharmacol PharmacotherJPPJournal of Pharmacology & Pharmacotherapeutics0976-500X0976-5018Medknow Publications & Media Pvt Ltd India JPP-6-4210.4103/0976-500X.149147Case ReportIsolated sinus tachycardia following reinitiation of risperidone in a patient with suspected autonomic hypersensitivity Grubisha Melanie J Brennan Jessica L Douaihy Antoine Department of Psychiatry, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania, United StatesAddress for correspondence: Melanie J Grubisha, 3501 O’Hara Street, Pittsburgh, Pennsylvania - 15213, United States. E-mail: grubisham@upmc.eduJan-Mar 2015 6 1 42 44 24 1 2014 02 5 2014 28 6 2014 Copyright: © Journal of Pharmacology and Pharmacotherapeutics2015This 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.The second generation antipsychotic risperidone is generally considered to have low cardiac adverse events, with an increased risk of ventricular arrhythmias being reported only rarely in literature. We report here the case of a patient with a significant history of alcohol dependence, yet with no previous cardiac history, who had previously tolerated risperidone well, but had experienced isolated sinus tachycardia in the post detox period, following the reinitiation of risperidone therapy. The Naranjo Adverse Drug Reaction (ADR) probability scale rating for this being a medication adverse event (AE) was 4, thus indicating that this patient's AE was associated with risperidone therapy. This case report will contribute to the limited evidence of adverse cardiac events associated with risperidone therapy, with particular emphasis on the susceptibility of patients in a state of autonomic hypersensitivity.\n\nAutonomic hypersensitivityautonomic instabilitycardiotoxicitydual diagnosisrisperidonesinus tachycardia\n==== Body\nINTRODUCTION\nIn patients withdrawing from alcohol or benzodiazepine abuse, autonomic instability is common. It usually begins within the first six to thirty-six hours, and typically peaks in severity 72 to 120 hours after cessation of drinking, and thus, protocols exist to limit this dangerous dysautonomia over the detox period.[1] However, we suggest that continued autonomic hypersensitivity may exist, which can influence a response to medications in dually diagnosed patients.\n\nThe atypical antipsychotic risperidone (Risperdal®) is generally considered to have a low cardiotoxic profile.[2] We report here a case of sinus tachycardia without QT-interval (QTc) prolongation in a recently detoxed, dually diagnosed patient, treated with risperidone, who had previously tolerated risperidone during a period of sobriety.\n\nCASE REPORT\nA 25-year-old Caucasian male, with a past psychiatric history of bipolar disorder, not otherwise specified (NOS), opioid dependence, and alcohol dependence began inpatient treatment at a psychiatric hospital on day zero. He was admitted on the basis of inability to care for self, secondary to depressive symptoms from his bipolar disorder, and he required concomitant detoxification from alcohol and opiates. His past medical history was not significant for any history of cardiac disease and his thyroid (Thyroid Stimulating Hormone (TSH) 0.51), liver function (Aspartate Transaminase (AST) 13, Alanine Transaminase (ALT) 23, Alkaline phosphatase 95), and kidney (Blood Urea Nitrogen (BUN) 19, Creatinine (Cr) 0.84) testing were normal within the last two months. On admission, his substance-use history was positive for benzodiazepines (last use three days before admission), alcohol (last use one day before admission), and IV heroin (last use two days before admission). He was placed on a Withdrawal-from-Alcohol Scale (referred to as a WAS at our institution) with as-needed oxazepam (Serax) based on the scoring of the WAS,[1] in addition to a five day oxazepam taper. A Clinical Opiate Withdrawal Scale (COWS) was also initiated.[1] These were continued for the first week of his inpatient treatment and then discontinued. Records indicate that he was scoring mostly zeros on both scales, except during the 24 hours surrounding the incident described below. Vital signs at the time of admission were: A pulse of 99 and blood pressure (BP) of 128/87, both recorded in standard units of beats per minute and mm/Hg, respectively.\n\nInitially, the patient refused medications prescribed for his depressive symptoms. On day five of admission, following completion of his oxazepam taper, he was amenable to starting risperidone 2 mg p.o. BID, to help with mood stabilization. He had been treated with risperidone in the past at this same dosage and reportedly tolerated it well. He was non-adherent with his medications over the long term, as he preferred illicit drug use and alcohol to treat his symptoms. He received his first dose on the evening of day five and his second dose on the morning of day six. Within two hours of his second dose, he reported feeling dizzy, a racing heart, and chest tightness. At that time he was found to be tachycardic at 126 bpm and hypertensive at 163/86. Although nine days had passed since his last substance use, 15 mg of oxazepam was administered out of concern for the possibility of ongoing withdrawal based on his WAS score of 17. His BP decreased to 138/88; however, the patient's heart rate did not respond to the oxazepam and continued to increase, fluctuating between 130 and 154 bpm with the BP remaining normotensive. He was given scheduled doses of both diazepam (Valium) and lorazepam (Ativan) throughout the remainder of day six, totaling to 60 mg and 2 mg, respectively. Even as he remained normotensive, his heart rate did not decrease and remained elevated above 130 bpm throughout day six.\n\nInitially, with only isolated tachycardia, recent substance abuse, and no cardiac history, there was low concern for an acute cardiac etiology. However, when the tachycardia did not resolve, electrocardiography (EKG) was performed two hours after symptom onset. This showed sinus tachycardia (145 bpm) without ST-segment changes and without QTc prolongation (QTc 412 ms). The chart review revealed that the recent TSH screening level was within normal limits. Stat laboratories for electrolytes, blood urea nitrogen (BUN)/Creatinine, and Complete Blood Count (CBC) with differential were drawn, to rule out electrolyte abnormalities, depleted volume status, and infection, as being the precipitators of his isolated tachycardia. All the laboratory values were within normal limits, and were unchanged from his admission laboratories seven days prior. Risperidone was discontinued and the patient was monitored. On day seven of admission, 23 hours after his last risperidone dose, his heart rate was 86, BP was 106/74, and he had no subjective symptoms. A repeat EKG showed normal sinus rhythm, without any other abnormalities.\n\nDISCUSSION\nRisperidone has an oral bioavailability of 70% and reaches maximum plasma concentration within one hour of ingestion.[3] Within two hours of ingesting his second dose, our patient began feeling tachycardic. This time coincided with what was likely to be his peak plasma concentration window. His tachycardia worsened, was unresponsive to benzodiazepines, and persisted for 24 hours after his risperidone dose. Failure of the benzodiazepines to lower his heart rate made it unlikely that his tachycardia was the result of anyongoing withdrawal. Furthermore, the patient was not taking any other medications concomitantly, thus ruling out other potential pharmacological causes of his tachycardia.\n\nRisperidone is hepatically metabolized, exclusively through CYP2D6, with an elimination half-life of two to twenty hours for oral administration.[3] The resolution of his tachycardia within 24 hours of his last risperidone dose temporally correlates with the elimination half-life of the drug. Even as a genetic polymorphism impairing the metabolic functioning of CYP2D6 could explain an adverse effect at a therapeutic dosage,[4] our patient reportedly tolerated therapeutic dosages of risperidone in the past, without consequence. Thus, it is unlikely that he had genetically impaired CYP2D6 function, and his lack of concomitant medication use that could potentially alter the CYP2D6 function further argues against a deficit in metabolism underlying this adverse event. Furthermore, while chronic alcohol intake has been shown to induce hepatic metabolism, it has primarily been shown to affect the CYP2E1 isoform.[5] As risperidone is exclusively CYP2D6 metabolized, it is unlikely that this patient's ongoing alcohol consumption, prior to this reinitiation of risperidone, was contributing to this adverse effect. Rather, we postulate that the nature of this AE was due in a large part to a state of autonomic hypersensitivity in a susceptible patient.\n\nAutonomic instability is a hallmark of alcohol withdrawal, with the initial onset at six to thirty-six hours. It can become life-threatening (delirium tremens or DTs) when hallucinations, disorientation, and severe dysautonomia are present. This generally occurs 72-120 hours after cessation of alcohol ingestion.[6] Benzodiazepines will both prevent and treat the autonomic instability caused by alcohol withdrawal, and thus, their use during the first 48-72 hours can prevent the escalation to DTs.[1] Our patient was managed appropriately with an oxazepam taper for five days to treat his high risk for dysautonomia from his alcohol withdrawal, and his vital signs throughout those first five days were all within normal limits. The timing of his tachycardia seven days after his last drink was not consistent with acute alcohol withdrawal.\n\nEven as the antipsychotic activity of risperidone is thought to be related primarily to its 5HT-2 and D2 receptor antagonism, it is also known to exert some α1 and α2 receptor affinity.[7] Antagonism of the α1 receptor causes a decrease in blood pressure and reflex tachycardia. In cases with underlying autonomic hypersensitivity, such as is seen in patients who have recently undergone alcohol detoxification, this small amount of α receptor activity may lead to an exaggerated response.\n\nAccording to the package insert, results from a double-blind placebo-controlled trial demonstrated tachycardia in 0.01% of patients treated with risperidone, compared to none in the controls.[8] However, our patient had previously tolerated risperidone without experiencing sinus tachycardia. His current state of recent alcohol detoxification, however, placed him in a state of autonomic hypersensitivity, which may have led to isolated sinus tachycardia related to the reinitiation of a therapeutic dose of risperidone.\n\nWe have presented here, the case of isolated sinus tachycardia in response to initiation of risperidone therapy in a young patient with a recent history of alcohol detoxification, but otherwise no cardiac history. The Naranjo ADR probability rating scale assesses the likelihood of an event being associated with a medication, and in this case it has indicated a possible association, with a score of 4.[9] This case will add to the limited body of evidence for possible cardiac adverse events of risperidone treatment, particularly in autonomically sensitive patients. Substance abuse is commonly comorbid with other psychiatric disorders, thus, providers must be aware of the increased risk for autonomic side effects of medications, when initiating therapy in this patient population.\n\nSource of Support: Nil\n\nConflict of Interest: None declared.\n==== Refs\nREFERENCES\n1 Kosten TR O’Connor PG Management of drug and alcohol withdrawal N Engl J Med 2003 348 1786 95 12724485 \n2 Hasnain M Vieweg WV Hollett B Weight gain and glucose dysregulation with second-generation antipsychotics and antidepressants: A review for primary care physicians Postgrad Med 2012 124 154 67 22913904 \n3 He H Richardson JS A pharmacological, pharmacokinetic and clinical overview of risperidone, a new antipsychotic that blocks serotonin 5-HT2 and dopamine D2 receptors Int Clin Psychopharmacol 1995 10 19 30 7542676 \n4 Llerena A Berecz R Peñas-Lledó E Süveges A Fariñas H Pharmacogenetics of clinical response to risperidone Pharmacogenomics 2013 14 177 94 23327578 \n5 Klotz U Ammon E Clinical and toxicological consequences of the inductive potential of ethanol Eur J Clin Pharmacol 1998 54 7 12 9591923 \n6 Turner RC Lichstein PR Peden JG Jr Busher JT Waivers LE Alcohol withdrawal syndromes: A review of pathophysiology, clinical presentation, and treatment J Gen Intern Med 1989 4 432 44 2677272 \n7 Cohen LJ Risperidone Pharmacotherapy 1994 14 253 65 7524043 \n8 Risperidone 1993 Last accessed on 2014 May 6 Janssen PharmaceuticalsInc Available from:\nhttp://www.dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=7e117c7e-02fc-4343-92a1-230061dfc5e0 \n9 Naranjo CA Busto U Sellers EM Sandor P Ruiz I Roberts EA A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 239 45 7249508\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0976-500X",
"issue": "6(1)",
"journal": "Journal of pharmacology & pharmacotherapeutics",
"keywords": "Autonomic hypersensitivity; autonomic instability; cardiotoxicity; dual diagnosis; risperidone; sinus tachycardia",
"medline_ta": "J Pharmacol Pharmacother",
"mesh_terms": null,
"nlm_unique_id": "101552113",
"other_id": null,
"pages": "42-4",
"pmc": null,
"pmid": "25709354",
"pubdate": "2015",
"publication_types": "D002363:Case Reports",
"references": "9591923;12724485;23327578;7249508;2677272;7542676;7524043;22913904",
"title": "Isolated sinus tachycardia following reinitiation of risperidone in a patient with suspected autonomic hypersensitivity.",
"title_normalized": "isolated sinus tachycardia following reinitiation of risperidone in a patient with suspected autonomic hypersensitivity"
} | [
{
"companynumb": "US-APOTEX-2015AP007019",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
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"drugadministrationroute": null,
"drugauthori... |
{
"abstract": "OBJECTIVE\nTo assess the prevalence of gastrointestinal (GI) bleeding in patients after orthognathic surgery and its relation to known risk factors.\n\n\nMETHODS\nWith institutional review board approval, a single-center case series was conducted with data collected retrospectively from orthognathic surgical patients' medical records from 1990 to 2010. All patients were treated by 1 primary surgeon, were limited to 21 years or younger at the time of surgery, and had no coagulopathy. The authors' hypothesis was that patients concurrently exposed to mechanical ventilation and dual anti-inflammatory drugs in the postoperative period would be at a greater risk for clinically significant GI bleeding according to the American Society of Health-System Pharmacists guideline compared with those exposed to fewer risk factors. Its prevalence and relation to known risk factors were analyzed.\n\n\nRESULTS\nIn total 498 orthognathic cases consisting of 220 male patients (median age, 17 yr; age range, 3 to 21 yr) and 262 female patients (median age, 17 yr; age range, 10 to 21 yr) were reviewed. Of 17 patients admitted to intensive care unit level of care postoperatively, 4 patients were exposed to concomitant administration of ketorolac and steroids while being mechanically ventilated. Two of these 4 patients developed esophagogastroduodenoscopy-confirmed upper GI bleeding (UGIB). There was no incidence of UGIB in patients not exposed to all 3 risk factors concurrently.\n\n\nCONCLUSIONS\nPostoperative GI bleeding complication is rare in orthognathic surgical patients, with an estimated prevalence of 0.4%. Based on these observations, orthognathic surgical patients who require mechanical ventilation and are receiving anti-inflammatory medications may have an increased risk of GI bleeding. In the absence of active bleeding from the surgical site, persistent decrease in hemoglobin concentration should alert one to consider the possibility of UGIB.",
"affiliations": "Resident, Division of Oral and Maxillofacial Surgery, Department of Surgery, Mayo Clinic, Rochester, MN. Electronic address: han.james@mayo.edu.;Consultant, Division of Oral and Maxillofacial Surgery, Department of Surgery; Professor of Surgery, Mayo Clinic College of Medicine, Rochester, MN.;Chair, Pediatric Gastroenterology, Pediatric and Adolescent Medicine; Assistant Professor of Pediatrics, Mayo Clinic College of Medicine, Rochester, MN.",
"authors": "Han|James B|JB|;Keller|Eugene E|EE|;Grothe|Rayna M|RM|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D000894:Anti-Inflammatory Agents, Non-Steroidal; D020910:Ketorolac",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0278-2391",
"issue": "72(10)",
"journal": "Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons",
"keywords": null,
"medline_ta": "J Oral Maxillofac Surg",
"mesh_terms": "D000293:Adolescent; D000305:Adrenal Cortex Hormones; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016025:Bone Transplantation; D002648:Child; D002675:Child, Preschool; D003422:Critical Care; D016145:Endoscopy, Digestive System; D005260:Female; D006471:Gastrointestinal Hemorrhage; D006801:Humans; D020910:Ketorolac; D008297:Male; D008910:Minnesota; D056948:Orthognathic Surgical Procedures; D019340:Osteotomy, Le Fort; D059229:Osteotomy, Sagittal Split Ramus; D019106:Postoperative Hemorrhage; D015995:Prevalence; D012121:Respiration, Artificial; D012189:Retrospective Studies; D012307:Risk Factors; D055815:Young Adult",
"nlm_unique_id": "8206428",
"other_id": null,
"pages": "2043-51",
"pmc": null,
"pmid": "24997023",
"pubdate": "2014-10",
"publication_types": "D002363:Case Reports; D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Postoperative gastrointestinal bleeding in orthognathic surgery patients: its estimated prevalence and possible association to known risk factors.",
"title_normalized": "postoperative gastrointestinal bleeding in orthognathic surgery patients its estimated prevalence and possible association to known risk factors"
} | [
{
"companynumb": "US-H14001-14-00320",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FAMOTIDINE"
},
"drugadditional": null,
"d... |
{
"abstract": "OBJECTIVE\nBecause treatment with tumor necrosis factor (TNF) antagonists may increase the risk of tuberculosis (TB), and because knowledge of the risk of TB in rheumatoid arthritis (RA) not treated with biologics is scarce and of uncertain generalizability to low-risk populations, this study sought to determine the risk of TB among Swedish patients with RA.\n\n\nMETHODS\nUsing data from Swedish nationwide and population-based registers and data from an ongoing monitoring program of TNF antagonists, the relative risks of TB in patients with RA (versus the general population) and of TB associated with TNF antagonists (versus RA patients not treated with biologics) were determined by comparing the incidence of hospitalization for TB in 3 RA cohorts and 2 general population cohorts from 1999 to 2001. We also reviewed the characteristics of all reported cases of TB in RA patients treated with TNF antagonists in Sweden and calculated the incidence of TB per type of TNF antagonist between 1999 and 2004.\n\n\nRESULTS\nDuring 1999-2001, RA patients who were not treated with TNF antagonists were at increased risk of TB versus the general population (relative risk 2.0, 95% confidence interval [95% CI] 1.2-3.4). RA patients treated with TNF antagonists had a 4-fold increased risk of TB (relative risk 4.0, 95% CI 1.3-12) versus RA patients not treated with TNF antagonists. The reported TB cases during 1999-2004 in RA patients exposed to TNF antagonists (9 infliximab, 4 etanercept, 2 both) were predominantly pulmonary. TB occurred up to 3 years following the start of treatment.\n\n\nCONCLUSIONS\nIrrespective of whether TNF antagonists are administered, Swedish patients with RA are at increased risk of TB. During 1999-2001, TNF antagonists were associated with an increased risk of TB, up to 4-fold in magnitude. This increased risk may persist over time during treatment and is related to both infliximab and etanercept.",
"affiliations": "Clinical Epidemiology Unit, Department of Medicine, Karolinska University Hospital Solna, Karolinska Institute, Stockholm, Sweden. johan.askling@medks.ki.se",
"authors": "Askling|Johan|J|;Fored|C Michael|CM|;Brandt|Lena|L|;Baecklund|Eva|E|;Bertilsson|Lennart|L|;Cöster|Lars|L|;Geborek|Pierre|P|;Jacobsson|Lennart T|LT|;Lindblad|Staffan|S|;Lysholm|Jörgen|J|;Rantapää-Dahlqvist|Solbritt|S|;Saxne|Tore|T|;Romanus|Victoria|V|;Klareskog|Lars|L|;Feltelius|Nils|N|",
"chemical_list": "D000911:Antibodies, Monoclonal; D014409:Tumor Necrosis Factor-alpha",
"country": "United States",
"delete": false,
"doi": "10.1002/art.21137",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0004-3591",
"issue": "52(7)",
"journal": "Arthritis and rheumatism",
"keywords": null,
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"mesh_terms": "D000293:Adolescent; D000328:Adult; D016907:Adverse Drug Reaction Reporting Systems; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal; D001172:Arthritis, Rheumatoid; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy; D008297:Male; D008875:Middle Aged; D012042:Registries; D012307:Risk Factors; D013548:Sweden; D014397:Tuberculosis, Pulmonary; D014409:Tumor Necrosis Factor-alpha",
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"abstract": "West Nile virus (WNV) is a single-stranded RNA arbovirus of Flavivirus genus that is endemic to the United States and known to cause neuroinvasive disease. Diagnosis is confirmed by the presence of WNV-specific IgM antibodies within serum or cerebrospinal fluid (CSF). Radiologically, it presents as hyperintense T2 signal within deep brain structures (ie, thalami and mid-brain) with or without cerebral peduncle and substantia nigra involvement. On diffusion-weighted imaging, restricted diffusion is reported in basal ganglia and disseminated throughout the white matter. In this report, we describe the imaging findings for 2 cases of WNV from our institution; a 56-year-old female and a 34-year-old female. Increased vigilance for WNV is warranted, particularly in immunosuppressed patients presenting with a clinical picture of viral meningoencephalitis despite initial negative magnetic resonance imaging or CSF analysis. A high suspicion for WNV disease should prompt repeat imaging or laboratory workup.",
"affiliations": "Department of Radiology, Detroit Medical Center, Wayne State University, Detroit, MI.;Department of Radiology, Detroit Medical Center, Wayne State University, Detroit, MI.;Department of Neurology, Rockefeller Neuroscience Institute, School of Medicine, West Virginia University, Morgantown, WV.;Army College of Medical Sciences, Base Hospital, New Delhi, India.;Department of Radiology, School of Medicine, West Virginia University, Morgantown, WV.;Department of Neurology, Rockefeller Neuroscience Institute, School of Medicine, West Virginia University, Morgantown, WV.",
"authors": "Bailey|Christopher|C|;Mach|John|J|;Kataria|Saurabh|S|;Tandon|Medha|M|;Lakhani|Dhairya A|DA|;Sriwastava|Shitiz|S|",
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"fulltext": "\n==== Front\nRadiol Case Rep\nRadiol Case Rep\nRadiology Case Reports\n1930-0433 Elsevier \n\nS1930-0433(20)30496-9\n10.1016/j.radcr.2020.09.023\nCase Report\nWest Nile virus encephalitis: A report of two cases and review of neuroradiological features\nBailey Christopher DOa Mach John DO, MPHa Kataria Saurabh MDb Tandon Medha MDc Lakhani Dhairya A. MDd Sriwastava Shitiz MDsks00002@hsc.wvu.edub⁎ a Department of Radiology, Detroit Medical Center, Wayne State University, Detroit, MI\nb Department of Neurology, Rockefeller Neuroscience Institute, School of Medicine, West Virginia University, Morgantown, WV\nc Army College of Medical Sciences, Base Hospital, New Delhi, India\nd Department of Radiology, School of Medicine, West Virginia University, Morgantown, WV\n⁎ Corresponding author. sks00002@hsc.wvu.edu\n23 9 2020 \n11 2020 \n23 9 2020 \n15 11 2422 2426\n13 8 2020 13 9 2020 15 9 2020 © 2020 The Authors. Published by Elsevier Inc. on behalf of University of Washington.2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).West Nile virus (WNV) is a single-stranded RNA arbovirus of Flavivirus genus that is endemic to the United States and known to cause neuroinvasive disease. Diagnosis is confirmed by the presence of WNV-specific IgM antibodies within serum or cerebrospinal fluid (CSF). Radiologically, it presents as hyperintense T2 signal within deep brain structures (ie, thalami and mid-brain) with or without cerebral peduncle and substantia nigra involvement. On diffusion-weighted imaging, restricted diffusion is reported in basal ganglia and disseminated throughout the white matter. In this report, we describe the imaging findings for 2 cases of WNV from our institution; a 56-year-old female and a 34-year-old female. Increased vigilance for WNV is warranted, particularly in immunosuppressed patients presenting with a clinical picture of viral meningoencephalitis despite initial negative magnetic resonance imaging or CSF analysis. A high suspicion for WNV disease should prompt repeat imaging or laboratory workup.\n\nKeywords\nWest Nile virusMeningoencephalitisAbbreviations\nWNV, West Nile virusPCR, polymerase chain reactionMRI, magnetic resonance imagingIVIG, intravenous immunoglobulinWNND, West Nile neuroinvasive disease\n==== Body\nBackground\nWest Nile virus (WNV) is an RNA virus belonging to the Flaviviridae family transmitted by the Culex mosquito, endemic to East Africa, Europe, West Asia, and North America [1]. Although the majority of infected patients develop a mild self-resolving form of illness, severe meningoencephilitis may occur in a minority of cases with the very young, elderly, and immunocompromised at greatest risk [1,2]. Although the virus can affect any part of the neural axis, there is a predilection for the brainstem, cerebellum, and anterior horn cells of the spinal cord [1]. Neuroinvasive variants of WNV are seen in less than 1% of cases, but the mortality may be up to 10% [3].\n\nThe neurological manifestations of WNV includes: (1) Neuromuscular involvement, that is, poliomyelitis-like syndrome resulting in asymmetric flaccid paralysis of one or more limbs, (2) encephalitis, meningitis or encephalomeningitis. These clinical syndromes, however, can have significantly overlapping features and mimic other conditions such as Guillain-Barré s Syndrome [1,4,5]. In rare cases, spinal cord involvement has been reported with WNV infection [3]. The diagnosis is confirmed with presence of WNV-specific IgM antibodies either from serum or cerebrospinal fluid (CSF).\n\nRadiologically, it presents as hyperintense T2 signal within deep brain structures (ie, basal ganglia especially thalami and mid-brain) with or without cerebral peduncle and substantia nigra involvement. On diffusion weighted imaging, restricted diffusion is reported in basal ganglia and disseminated throughout the white matter [6].\n\nIn this report we describe imaging findings in 2 cases of West Nile encephalitis that we from our institution with a range of characteristic MRI findings with the goal of increasing radiologic and clinical diagnosis of the condition.\n\nCase 1\nA 56-year-old African-American woman with past medical history significant for multiple sclerosis and chronic kidney disease status postrenal and pancreatic transplant 10 years prior on mycophenolate and cyclosporine, presented in September with worsening left lower extremity weakness. Her hospital course was complicated by the fever of unknown origin with a sudden decline in mentation and severe brainstem dysfunction, requiring mechanical ventilation. Meningitis was suspected and empiric antibiotic therapy was initiated. Initial serum and CSF analysis was nonconclusive and a viral panel was negative. Initial MRI brain demonstrated nonspecific white matter changes.\n\nOne-week follow-up CSF analysis demonstrated elevated white blood cell count with lymphocytic pleocytosis. Repeat magnetic resonance imaging (MRI) of the brain demonstrated new symmetric T2-hyperintense signal in the bilateral thalami, with associated diffusion restriction and mild abnormal contrast enhancement (Fig. 1). In addition to viral encephalitis, the possibility of deep cerebral venous thrombosis was considered, however a subsequent magnetic resonance venogram was negative. One-week follow-up WNV serology ultimately returned positive with elevated IgM antibodies definitively establishing the diagnosis of WNV. Unfortunately, the patient's condition progressively deteriorated and she was discharged home with hospice.Fig. 1 One-week follow-up magnetic resonance imaging (MRI) of the brain for Case 1, obtained 10 days after onset of symptoms. Diffusion Weighted Imaging demonstrates symmetric restricted diffusion (hyperintense signal) in bilateral thalami (Fig. 1A), with corresponding hypointense signal on apparent diffusion coefficient (ADC) (Fig. 1B), T2-weighted (Fig. 1C) and FLAIR sequences (Fig. 1D) demonstrates corresponding hyperintense signal in thalami.T1-weighted precontrast (Fig. 1E) and postcontrast (Fig. 1F) demonstrates abnormal contrast enhancement in the bilateral thalami.\n\nFig 1\n\nCase 2\nA 34-year-old Caucasian female with past medical history significant for hypertension and end stage renal disease, status post renal transplantation presented in late September with light headedness, abdominal pain, weakness, and fever. The patient's medication regimen included Mycophenolate mofetil, Prednisone, Tacrolimus, Valganciclovir, Trimethoprim, and Sulfamethoxazole. On the fifth day of admission, her mental status rapidly declined with diminished alertness and increasing lethargy, eventually requiring intubation for hypoxic respiratory failure. Initial CSF analysis was unremarkable, including a negative viral panel. WNV for next generation sequencing was sent to an outside laboratory. Neurological exam further declined as the she became responsive to painful stimuli only and developed a left gaze palsy. Repeat CSF analysis performed 8 days after initial CSF sampling revealed an elevated cell count with lymphocytic pleocytosis, elevated protein, low-normal glucose, and a negative viral panel.\n\nInitial brain MRI revealed only chronic microvascular ischemic changes. Repeat imaging 9 days later demonstrated diffusion restriction and T2W and FLAIR hyperintense signal with expansile changes within the bilateral centrum semiovale, corona radiata, deep gray nuclei, deep white matter tracts, midbrain, bilateral superior cerebellar peduncles, and left cerebellar hemisphere. Additionally, there was faint postcontrast enhancement within the right thalamus (Fig. 2).Fig. 2 MRI for Case 2, obtained 14 days after onset of symptoms. Diffusion weighted imaging demonstrates restricted diffusion (hyperintense signal) in bilateral medial lentiform nuclei and lateral thalami (Fig. 2A), with corresponding hypointense signal on ADC (Fig. 2B); T2-weighted (Fig. 2C) and FLAIR sequences (Fig. 2D) demonstrate corresponding hyperintense signal in bilateral medial lentiform nuclei, lateral thalami, posterior limbs of the internal capsules and callosal splenium; T1-weighted precontrast (Fig. 2E) and postcontrast (Fig. 2F) demonstrates abnormal right thalamic enhancement.\n\nFig. 2\n\nWNV polymerase chain reaction and next generation sequencing returned positive, with negative CSF IgG and IgM. Despite initiation of intravenous immunoglobulin (IVIG) therapy, the patient's neurologic status continued to deteriorate including absent gag and corneal reflexes, very mild oculocephalic reflex, absent extremity motor response, and hyporeflexia. A tracheostomy was performed, and she was eventually discharged to a long-term acute care facility.\n\nDiscussion\nMost cases of WNV are either asymptomatic or mild and present with low-grade fever, headache, rash, myalgia, and malaise lasting 3 to 10 days following an incubation period of 3 to 14 days [1,2]. Despite representing a minority of infections, severe neuroinvasive disease may occur, particularly in immunocompromised individuals, and result in a wide spectrum of clinical features leading to irreversible cognitive impairment, coma, or death [2,5].\n\nIncreased vigilance for WNV is warranted during the late summer months when most outbreaks of WNV in the United States occur [2,7]. Findings suspicious for CNS involvement of WNV should prompt evaluation of CSF for WNV IgM antibodies on MAC-ELISA to establish the diagnosis [8,9]. The use of polymerase chain reaction is generally reserved for immunocompromised individuals who may lack sufficient antibody formation against the virus [6,10]. When these methods fail to identify an etiology in immunocompromised patients, but WNV encephalitis is highly suspected, genomic sequencing of RNA from the CSF may identify the viral pathogen as was performed in Case 2 [11].\n\nNeuroradiological findings during active West Nile Virus neuroinvasive disease (WNND) vary, but often correlate with clinical manifestations of the disease. CT of the brain is typically normal [2]. MRI abnormalities usually appear within several weeks after onset of illness. Onset of MRI features may be delayed in immunocompromised patients [2,12]. Patients with meningitis secondary to WNV may show meningeal involvement in the form of leptomeningeal enhancement [2,12]. Early signs of West Nile encephalitis likely first appear as diffusion restriction, followed by hyperintense signal abnormality on T2 weighted and FLAIR sequences most commonly involving the bilateral thalami, basal ganglia, posterior limb of the internal capsule, midbrain, and pons [2,12,13]. Less commonly, high signal T2W, and FLAIR abnormalities are seen involving the cerebral white matter, cerebellar peduncles, and cerebellar hemispheres [13]. Diffusion restriction may be the first MR feature to normalize on follow-up examinations [14]. Moreover, the presence of diffusion restriction only may portend a favorable neurologic prognosis when compared to those with abnormalities on diffusion-weighted imaging and T2/FLAIR [12].\n\nOur cases demonstrated symmetric thalamic, basal ganglia, and brainstem involvement. The collective presence of these features is important to differentiate from other diagnoses via imaging and clinical history. Bilateral thalamic lesions have been described in a variety of neoplastic, metabolic, infectious, and vascular conditions [7]. Wernicke's encephalopathy for example, commonly presents with dorsomedial thalamic FLAIR hyperintensity, but is often distinguished by concomitant presence of FLAIR hyperintensity of the mammillary bodies and periaqueductal gray as well as history of nutritional deficiency or alcoholism [7,15]. Thrombosis of deep cerebral veins may also exhibit expansile thalami with hyperintense T2/FLAIR signal as seen in Case 1, but is differentiated by lack of signal intensity within deep venous sinuses on magnetic resonancevenography [7].\n\nIntraspinal WNND involvement may be seen as focal T2 abnormalities, typically within the ventral horns, and manifest as acute flaccid paralysis syndrome. Such lesions have been reported within the thoracolumbar spine as well as conus medullaris and cauda equina and mimic transverse myelitis [2].\n\nAn estimated 48% of patients with WNND die within 90 days of disease onset [16]. Of those who survive to discharge, roughly 10% die within the convalescent phase [16]. Individuals, who survive beyond the convalescent phase, are more likely to suffer from long-term cognitive dysfunction. Follow-up MRI often shows permanent cortical thinning and regional atrophy compared to age and gender controls [17].\n\nThe imaging and clinical features of WNV encephalitis are considerably variable and overlapping with other conditions ranging from acute and chronic demyelinating disorders to other viral illnesses. Increased vigilance for WNV is warranted, particularly in immunosuppressed patients presenting with a clinical picture of viral meningoencephalitis despite initial negative MRI or CSF analysis. A high suspicion for WNV disease may prompt repeat imaging or more in-depth laboratory workup such as with next generation sequencing to obtain the diagnosis. The following MRI features should raise suspicion for WNV infection: hyperintense T2 signal within deep brain structures (ie, basal ganglia especially thalami and mid-brain) with or without cerebral peduncle and substantia nigra involvement and diffusion restriction in basal ganglia.\n\nPatient consent statement: This work contains no identifiable information or images of included patients. The work was deemed IRB exempt by the Wayne State University IRB Review Board.\n\nConflict of interest: No Conflicts of interest to declare.\n==== Refs\nReferences\n1 DeBiasi RL West Nile virus neuroinvasive disease Curr infect Dis Rep 13 2011 350 359 21544522 \n2 Zak IT Altinok D Merline JR Chander S Kish KK West Nile virus infection Am J Roentgenol 184 3 2005 957 961 15728624 \n3 Sejvar JJ. Clinical manifestations and outcomes of West Nile virus infection Viruses 6 2014 606‐623 10.3390/v6020606 24509812 \n4 Davis LE DeBiasi R Goade DE Haaland KY Harrington JA Harnar JB West Nile virus neuroinvasive disease Ann Neurol 60 2006 286 300 16983682 \n5 Sejvar JJ Haddad MB Tierney BC Campbell GL Marfin A Van Gerpen JA Neurologic manifestations and outcome of West Nile virus infection JAMA 290 4 2003 511 515 12876094 \n6 Petersen LR Brault AC Nasci RS West Nile virus: review of the literature JAMA 310 3 2013 308 315 10.1001/jama.2013.8042 23860989 \n7 Smith AB Smirniotopoulos JG Rushing EJ Goldstein SJ Bilateral thalamic lesions AJR Am J Roentgenol 192 2 2009 W53 W62 19155381 \n8 Debiasi RL Tyler KL West Nile virus meningoencephalitis Nat Clin Pract Neurol 2 5 2006 264‐275 10.1038/ncpneuro0176 16932563 \n9 Long MT Jeter W Hernandez J Sellon DC Gosche D Gillis K Diagnostic performance of the equine IgM capture ELISA for serodiagnosis of West Nile virus infection J Vet Intern Med 20 3 2006 608 613 16734097 \n10 Arboviral Diseases, Neuroinvasive and Non-neuroinvasive 2015 Case Definition. https://www.cdc.gov/westnile/symptoms/index.html\n11 Wilson MR Zimmermann LL Crawford ED Sample HA Soni PR Baker AN Acute West Nile virus meningoencephalitis diagnosed via metagenomic deep sequencing of cerebrospinal fluid in a renal transplant patient Am J Transplant 17 3 2017 803 808 27647685 \n12 Ali M Safriel Y Sohi J Llave A Weathers S West Nile virus infection: MR imaging findings in the nervous system AJNR Am J Neuroradiol 26 2 2005 289 297 15709126 \n13 Petropoulou KA Gordon SM Prayson RA Ruggierri PM West Nile virus meningoencephalitis: MR imaging findings AJNR Am J Neuroradiol 26 8 2005 1986 1995 16155147 \n14 Nouranifar RK Ali M Nath J The earliest manifestation of focal encephalitis on diffusion-weighted MRI Clin Imaging 27 5 2003 316 320 12932681 \n15 Zuccoli G Santa Cruz D Bertolini M Rovira A Galluci M Carollo C MR imaging findings in 56 patients with Wernicke encephalopathy: nonalcoholics may differ from alcoholics AJNR Am J Neuroradiol 30 2009 171 176 18945789 \n16 Philpott D Nolan MS Evert N Mayes B Hesalroad D Fronken E Acute and delayed deaths after West Nile virus infection, Texas, USA, 2002–2012 Emerg Infect Dis 25 2 2019 256 264 10.3201/eid2502.181250 \n17 Murray KO Nolan MS Ronca SE Datta S Govindarajan K Narayana PA The neurocognitive and MRI outcomes of West Nile virus infection: preliminary analysis using an external control group Front Neurol 9 2018 111 29636722\n\n",
"fulltext_license": "CC BY-NC-ND",
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"issue": "15(11)",
"journal": "Radiology case reports",
"keywords": "IVIG, intravenous immunoglobulin; MRI, magnetic resonance imaging; Meningoencephalitis; PCR, polymerase chain reaction; WNND, West Nile neuroinvasive disease; WNV, West Nile virus; West Nile virus",
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"title": "West Nile virus encephalitis: A report of two cases and review of neuroradiological features.",
"title_normalized": "west nile virus encephalitis a report of two cases and review of neuroradiological features"
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"abstract": "Discontinuation of denosumab is associated with the increase of bone turnover markers to above-baseline levels (so-called rebound in bone turnover) and rapid bone loss. Several studies have reported vertebral fractures (VFs), particularly multiple spontaneous clinical VFs (MSCVFs), occurring after discontinuation of denosumab. There is currently no recommendation for the management of VFs including MSCVFs. Presently, romosozumab is the strongest anti-osteoporotic agent that inhibits sclerostin and rapidly increases bone mass, but it is uncertain that romosozumab is an effective treatment choice to treat VFs occurring after discontinuation of denosumab. Herein we reported a novel case of a 60-year-old woman who was treated with romosozumab after discontinuation of denosumab and subsequently suffered MSCVFs under romosozumab treatment. She had a history of two osteoporotic VFs (T6 and T8) and received five doses of 60 mg denosumab every 6 months following the osteoporosis diagnosis. As per the patient's convenience, the sixth denosumab injection was postponed. To improve the persistent low bone mass in the lumbar spine (T-score -3.8), 210 mg romosozumab was administered monthly after 9 months following the last denosumab injection. At the first romosozumab injection, she had no clinical symptoms such as low back pain, but her bone formation and resorption marker levels elevated compared with those treated with denosumab. After three doses of romosozumab, spontaneous severe low back pain occurred, and time-course radiographs revealed five new VFs (T12, L2, L3, L4, and L5). Romosozumab administration had no suppressive effect on bone resorption during the rebound in bone turnover after discontinuation of denosumab. This case suggests that romosozumab is not effective in preventing VFs or MSCVFs after denosumab discontinuation.",
"affiliations": "Department of Orthopedic Surgery, Toyonaka Municipal Hospital, Toyonaka, Osaka, Japan.;Department of Musculoskeletal Regenerative Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.;Department of Orthopedic Surgery, Toyonaka Municipal Hospital, Toyonaka, Osaka, Japan.;Department of Orthopedic Surgery, Toyonaka Municipal Hospital, Toyonaka, Osaka, Japan.",
"authors": "Kashii|Masafumi|M|;Ebina|Kosuke|K|;Kitaguchi|Kazuma|K|;Yoshikawa|Hideki|H|",
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"fulltext": "\n==== Front\nBone Rep\nBone Rep\nBone Reports\n2352-1872 Elsevier \n\nS2352-1872(20)30048-6\n10.1016/j.bonr.2020.100288\n100288\nArticle\nRomosozumab was not effective in preventing multiple spontaneous clinical vertebral fractures after denosumab discontinuation: A case report\nKashii Masafumi mkashii-osk@umin.ac.jpa⁎ Ebina Kosuke k-ebina@umin.ac.jpb Kitaguchi Kazuma kitaguchi-osk@umin.ac.jpa Yoshikawa Hideki yhideki@chp.toyonaka.osaka.jpa a Department of Orthopedic Surgery, Toyonaka Municipal Hospital, Toyonaka, Osaka, Japan\nb Department of Musculoskeletal Regenerative Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan\n⁎ Corresponding author at: Department of Orthopedic Surgery, Toyonaka Municipal Hospital, 4-14-1 Shibaharacho, Toyonaka, Osaka 560-8565, Japan. mkashii-osk@umin.ac.jp\n05 6 2020 \n12 2020 \n05 6 2020 \n13 10028814 4 2020 27 5 2020 2 6 2020 © 2020 The Authors2020This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Discontinuation of denosumab is associated with the increase of bone turnover markers to above-baseline levels (so-called rebound in bone turnover) and rapid bone loss. Several studies have reported vertebral fractures (VFs), particularly multiple spontaneous clinical VFs (MSCVFs), occurring after discontinuation of denosumab. There is currently no recommendation for the management of VFs including MSCVFs. Presently, romosozumab is the strongest anti-osteoporotic agent that inhibits sclerostin and rapidly increases bone mass, but it is uncertain that romosozumab is an effective treatment choice to treat VFs occurring after discontinuation of denosumab. Herein we reported a novel case of a 60-year-old woman who was treated with romosozumab after discontinuation of denosumab and subsequently suffered MSCVFs under romosozumab treatment. She had a history of two osteoporotic VFs (T6 and T8) and received five doses of 60 mg denosumab every 6 months following the osteoporosis diagnosis. As per the patient's convenience, the sixth denosumab injection was postponed. To improve the persistent low bone mass in the lumbar spine (T-score −3.8), 210 mg romosozumab was administered monthly after 9 months following the last denosumab injection. At the first romosozumab injection, she had no clinical symptoms such as low back pain, but her bone formation and resorption marker levels elevated compared with those treated with denosumab. After three doses of romosozumab, spontaneous severe low back pain occurred, and time-course radiographs revealed five new VFs (T12, L2, L3, L4, and L5). Romosozumab administration had no suppressive effect on bone resorption during the rebound in bone turnover after discontinuation of denosumab. This case suggests that romosozumab is not effective in preventing VFs or MSCVFs after denosumab discontinuation.\n\nKeywords\nDenosumabRomosozumabVertebral fracturesDiscontinuation\n==== Body\n1 Introduction\nBisphosphonates remain in the skeletal bone even after their discontinuation because of their high affinity to skeletal bone (Meier et al., 2017). However, the clinical benefit of other anti-osteoporosis agents, except bisphosphonates, diminishes over time following discontinuation. Discontinuation of denosumab has been known to be associated with the increase of bone turnover markers to above-baseline levels (rebound in bone turnover) and rapid bone loss (Bone et al., 2011; Popp et al., 2018), and recent reports have demonstrated vertebral fractures (VFs), particularly multiple spontaneous clinical VFs (MSCVFs), occurring after discontinuation of denosumab (Anastasilakis et al., 2017; Tripto-Shkolnik et al., 2018; Lamy et al., 2019). There is currently no recommendation for the management of VFs including MSCVFs (Lamy et al., 2019). A bone anabolic agent such as teriparatide seems to be an effective treatment choice to treat VFs occurring after discontinuation of denosumab. However, switching therapy from denosumab to teriparatide results in transient bone loss in the spine and hip with the rebound in the bone turnover (Leder et al., 2015).\n\nSclerostin is an antagonist for canonical Wnt/β-catenin signaling that regulates bone mass, and it is a therapeutic target for the treatment of osteoporosis (Delgado-Calle et al., 2017). Romosozumab, which became available in March 2019, is a monoclonal anti-sclerostin antibody that rapidly increases bone mass through the following dual effects on the bone: increasing bone formation and decreasing bone resorption (Padhi et al., 2011; McClung et al., 2014). In a randomized controlled trial that compared romosozumab with placebo, treatment with romosozumab for 12 months showed a dramatic increase in bone mass and significant reduction of the risk of new VFs and clinical fractures among postmenopausal women with osteoporosis (Cosman et al., 2016). Furthermore, treatment with romosozumab is reported to significantly increase bone mass among women with postmenopausal osteoporosis transitioning from alendronate treatment (Langdahl et al., 2017). The second course of romosozumab transitioning from treatment with denosumab increased bone mass in the spine, maintained bone mass in the hip, and was well tolerated (Kendler et al., 2019). Presently, romosozumab is the strongest anti-osteoporotic agent that rapidly increases bone mass when compared with other agents, but it is uncertain that romosozumab is an effective treatment choice to treat VFs or MSCVFs occurring after discontinuation of denosumab.\n\nTo the best of our knowledge, this is the first reported case of a 60-year-old woman who was treated with romosozumab after discontinuation of denosumab and subsequently suffered MSCVFs under romosozumab treatment.\n\n2 Case presentation\nThis 60-year-old woman was firstly diagnosed with osteoporosis at the age of 57. She had a history of two VFs in the thoracic spine (T6 and T8) after lifting a heavy load. She had no other comorbidities such as cardiovascular diseases, osteomalacia, hyperthyroidism, and hyperparathyroidism. She also took no medicines which induce medication-related osteoporosis. During her first hospital visit, dual-energy absorptiometry (DXA) revealed severe osteoporosis with low bone mineral density (BMD) in the lumbar spine (T-score of −4.4) and low BMD in the femoral neck (T-score of −2.7) (Fig. 1). Initially, we strongly recommended the usage of teriparatide to increase the lumbar spine BMD, but she felt uncomfortable with self-injection. As a result, 60 mg denosumab was subcutaneously administered every 6 months, which prevented further fractures. After five denosumab injections, her lumbar spine BMD increased by 26%; however, no increase was observed within the past year (Fig. 1). Before the sixth denosumab injection in April 2019, she became sick and could not visit our hospital. Unfortunately, denosumab treatment was discontinued although we instructed her not to miss her routine visit every 6 months. The switching therapy from denosumab to romosozumab is not a standard treatment, but romosozumab was recommended in order to improve the persistent low bone mass in lumbar spine BMD. There was a 9 month-interval between the last denosumab administration and the first romosozumab administration; 210 mg Romosozumab was administered monthly since July 2019 (Fig. 1). At the first romosozumab injection, she had no clinical symptoms such as low back pain, but she experienced spontaneous severe low back pain after three doses of romosozumab. Spine radiographs did not show any vertebral deformities just after she complained severe back pain (Fig. 2B). Due to claustrophobia, earlier diagnosis using magnetic resonance images could not be performed; however, time-course radiographs revealed five new VFs (at the T12, L2, L3, L4, and L5) (Fig. 2C). Spine radiographs revealed MSCVFs and denosumab treatment was resumed after discontinuation of romosozumab.Fig. 1 Treatment progress of switching from denosumab to romosozumab with changes of bone turnover markers and bone mineral density (BMD) in the lumbar spine and hip.\n\nFN femoral neck, LS lumbar spine, P1NP intact N-terminal propeptide of type I procollagen, TH total hip, TRACP-5b tartrate-resistant acid phosphatase 5b.\n\nFig. 1Fig. 2 Lateral spine radiographs with the patient standing. (A) Before romosozumab treatment, (B) 2 months after romosozumab treatment, (C) 4 months after romosozumab treatment. Time-course radiographs revealed five new vertebral fractures with vertebral deformity (T12, L2, L3, L4, and L5). Dot lines show the outline of L5 vertebral body.\n\nFig. 2\n\nAt the first presentation, blood and urine tests were performed to rule out secondary osteoporosis and other bone diseases. Her serum alkaline phosphatase level was high (612 IU/L) due to bone healing after two thoracic VFs. The levels of serum calcium, blood urea nitrogen, creatinine, estimated glomerular filtration rate, and intact parathyroid hormone were within the normal range. Her serum intact N-terminal propeptide of type I procollagen (P1NP) (standard range, 26.4–98.2 μg/L) was high (111 μg/L) due to bone healing after two thoracic VFs. The tartrate-resistant acid phosphatase 5b (TRACP-5b) (standard range, 120–420 mU/dL) level was also high (863 mU/dL) (Fig. 1). During the treatment with denosumab, serum P1NP and TRACP-5b levels were lower, suggesting that denosumab efficiently suppresses bone turnover. However, discontinuation of denosumab for 3 months induced the rebound in bone turnover with the rapid increase of serum P1NP and TRACP-5b levels (P1NP, 35.7 μg/L and TRACP-5b, 370 mU/dL). At the second romosozumab injection, the serum TRACP-5b level did not decrease (before the first injection, 370 mU/dL; before the second injection, 393 mU/dL). After six doses of romosozumab, DXA revealed no increased lumbar spine BMD when compared with that obtained during the first initiation of romosozumab administration (Fig. 1). Serum P1NP and TRACP-5b levels were noted to be even higher (P1NP, 95.7 μg/L and TRACP-5b, 769 mU/dL) at 6 months after the treatment with romosozumab (Fig. 1).\n\n3 Discussion\nDiscontinuation of denosumab is associated with the rebound in bone turnover and rapid bone loss (Bone et al., 2011; Popp et al., 2018). The incidence of VFs after denosumab discontinuation is uncertain; however, MSCVFs frequently occur (≥1/100 and <1/10) in patients not treated with bisphosphonate (Uebelhart et al., 2017). In a recent review, 70 patients (69 women and one man; average age, 67.3 years) experienced 399 spontaneous VFs (median 5) within 7 and 20 (median 11) months after their last denosumab injection (Lamy et al., 2019). Younger women tend to be at a higher risk of MSCVFs (Lamy et al., 2019). Several studies have argued that bisphosphonate treatment before the denosumab administration can possibly reduce the risk of MSCVFs, and a sequential treatment with bisphosphonates after discontinuation of denosumab can also possibly reduce the risk (Uebelhart et al., 2017; Tripto-Shkolnik et al., 2018; Lamy et al., 2019). The present patient, who experienced five spontaneous VFs 11 months after the last denosumab injection was relatively young and had not been previously treated with bisphosphonate. These characteristics highly agree with those reported by other studies (Anastasilakis et al., 2017; Tripto-Shkolnik et al., 2018; Lamy et al., 2019). We firmly believe that 9 months interval between the last denosumab injection and the initiation of romosozumab treatment induced the rebound in bone turnover and this patient experienced MSCVFs after discontinuation of denosumab, even under romosozumab treatment.\n\nPresently, the management for VFs occurring after discontinuation of denosumab remains to be elucidated (Lamy et al., 2019). The management should be started in the early stages and earlier diagnosis is necessary. Magnetic resonance imaging (MRI) has a high degree of accuracy for making a definite diagnosis of acute VF. MRI is useful tool to detect VF in the early stages (Anastasilakis et al., 2020b). There is a possibility that repetitive MSCVFs in a patient who had previous MSCVFs after stopping denosumab (Niimi et al., 2020; Anastasilakis et al., 2020a). Delayed additional denosumab administration do not completely eliminate the risk of VFs or MSCVFs occurring after discontinuation of denosumab (Niimi et al., 2020). Bone anabolic agents such as teriparatide and romosozumab appear to be one of the treatment choices. However, both teriparatide and romosozumab as a sequential therapy after the treatment with denosumab temporarily decrease bone loss in the spine and hip (Leder et al., 2015; Kendler et al., 2019). A subsequent negative chain of multiple VFs was not prevented by romosozumab treatment in this patient. The activation of canonical Wnt/β-catenin signaling may decrease osteoclastogenesis both through osteoprotegerin produced by osteoblasts and through a direct effect on osteoclasts (Lerner and Ohlsson, 2015; Delgado-Calle et al., 2017). However, the serum TRACP-5b level in this case did not decrease at the second romosozumab injection, the time before she complained low back pain. This revealed that activation of canonical Wnt/β-catenin signaling by romosozumab cannot show its suppressive effect on bone resorption during the rebound in bone turnover after discontinuation of denosumab. Serum P1NP and TRACP-5b levels were even higher at 6 months after the treatment with romosozumab. It is thought that bone healing process after MSCVFs have greatly affected the increase of serum P1NP and TRACP-5b levels.\n\nTo the best of our knowledge, this is the first case report of a patient who experienced MSCVFs under romosozumab treatment after discontinuation of denosumab immediately after the availability of romosozumab in the market. However, no cases of MSCVFs occurring after switching from denosumab to teriparatide were reported. There are two possible reasons for this difference. 1) Physicians rarely use teriparatide after denosumab except in the case of osteonecrosis of jaw or atypical femoral fracture occurred under denosumab treatment. Teriparatide was put on the market at 2002 in USA earlier than denosumab, and the DATA-switch study showed the transient bone loss of switching therapy from denosumab to teriparatide (Leder et al., 2015). However, up to date there were no reported cases with MSCVFs after switching from denosumab to teriparatide. 2) The difference in the pharmacological action between teriparatide and romosozumab may be associated with MSCVFs. Lamy et al. argued that microdamage accumulation in the cancellous bone brought by extremely high bone turnover induce fractures in spine, which are rich in cancellous bone (Lamy et al., 2019). Teriparatide has been shown to accelerate fracture healing in animal studies (Mognetti et al., 2011; Shi et al., 2016), which has also been confirmed in humans (Kitaguchi et al., 2019). Anti-sclerostin antibody has also been reported to accelerate fracture healing in animal models (Ominsky et al., 2011); however, its effect on cancellous bone regeneration is weaker than that of teriparatide, which has more powerful effects on the mesenchymal stem cell differentiation in osteoblasts and adipocytokine inhibition (Agholme et al., 2014). The difference in repair ability for microcracks may be associated with the occurrence of MSCVFs.\n\n4 Conclusion\nThis is the only a case report and it's difficult to draw a definitive conclusion from this case. However, the findings of this case suggested that romosozumab cannot demonstrate its strong dual effects on the bone during the rebound in bone turnover after discontinuation of denosumab. The least clinicians can do is to initiate the therapy at 6 months after the last denosumab injection when considering the switching therapy from denosumab to romosozumab.\n\nTransparency document\nTransparency document\n\nImage 1 \n\nFunding source\nNone.\n\nDeclaration of competing interest\nAll authors declare that they have no conflicts of interest.\n\nAcknowledgments\nThe authors would like to thank Enago (www.enago.jp) for the English language review.\n\nData availability statement\nNot applicable.\n\nInformed consent\nInformed consent was obtained from the participants included in the study.\n\nCredit authorship contribution statement\nMasafumi Kashii: Conceptualization, Data curation, Writing - original draft, Writing - review&editing.\n\nKosuke Ebina: Writing - review&editing.\n\nKazuma Kitaguchi: Writing - review&editing.\n\nHideki Yoshikawa: Writing - review&editing.\n\nThe Transparency document associated with this article can be found, in online version.\n==== Refs\nReferences\nAgholme, F., Macias, FB, Hamang, M., Lucchesi, J., Adrian, M.D., Kuhstoss, S., Harvey, A., Sato, M., Aspenberg, P., 2014. Efficacy of a sclerostin antibody compared to a low dose of PTH on metaphyseal bone healing. J. Orthop. Res. 32, 471–476. doi:10.1002/jor.22525 .\nAnastasilakis A.D. Polyzos S.A. Makras P. Aubry-Rozier B. Kaouri S. Lamy O. Clinical features of 24 patients with rebound-associated vertebral fractures after denosumab discontinuation: systematic review and additional cases J. Bone Miner. Res. 32 2017 1291 1296 10.1002/jbmr.3110 28240371 \nAnastasilakis A.D. Evangelatos G. Makras P. Iliopoulos A. Rebound-associated vertebral fractures may occur in sequential time points following denosumab discontinuation: need for prompt treatment re-initiation Bone Rep 12 2020 100267 10.1016/j.bonr.2020.100267 32373677 \nAnastasilakis A.D. Evangelatos G. Makras P. Iliopoulos A. Magnetic resonance imaging has an advantage over conventional spine X-rays in the evaluation of rebound-associated vertebral fractures following denosumab discontinuation Endocrine 2020 10.1007/s12020-020-02333-1 \nBone H.G. Bolognese M.A. Yuen C.K. Kendler D.L. Miller P.D. Yang Y.C. Grazette L. San Martin J. Gallagher J.C. Effects of denosumab treatment and discontinuation on bone mineral density and bone turn-over markers in postmenopausal women with low bone mass J. Clin. Endocrinol. Metab. 96 2011 972 980 10.1210/jc.2010-1502 21289258 \nCosman F. Crittenden D.B. Adachi J.D. Binkley N. Czerwinski E. Ferrari S. Hofbauer L.C. Lau E. Lewiecki E.M. Miyauchi A. Zerbini C.A. Milmont C.E. Chen L. Maddox J. Meisner P.D. Libanati C. Grauer A. Romosozumab treatment in postmenopausal women with osteoporosis N. Engl. J. Med. 375 2016 1532 1543 10.1056/NEJMoa1607948 27641143 \nDelgado-Calle J. Sato A.Y. Bellido T. Role and mechanism of action of sclerostin in bone Bone 96 2017 29 37 10.1016/j.bone.2016.10.007 27742498 \nKendler D.L. Bone H.G. Massari F. Gielen E. Palacios S. Maddox J. Yan C. Yue S. Dinavahi R.V. Libanati C. Grauer A. Bone mineral density gains with a second 12-month course of romosozumab therapy following placebo or denosumab Osteoporos. Int. 30 2019 2437 2448 10.1007/s00198-019-05146-9 31628490 \nKitaguchi K. Kashii M. Ebina K. Sasaki S. Tsukamoto Y. Yoshikawa H. Murase T. Effects of weekly teriparatide administration for vertebral stability and bony union in patients with acute osteoporotic vertebral fractures Asian Spine J 13 2019 763 771 10.31616/asj.2018.0311 31000686 \nLamy O. Stoll D. Aubry-Rozier B. Gonzalez-Rodriguez E. Stopping denosumab Current Osteoporosis Reports 17 2019 8 15 10.1007/s11914-019-00502-4 30659428 \nLangdahl B.L. Libanati C. Crittenden D.B. Bolognese M.A. Brown J.P. Daizadeh N.S. Romosozumab (sclerostinmonoclonal antibody) versus teriparatide in postmenopausal women with osteoporosis transitioning from oral bisphosphonate therapy: a randomised, open-label, phase 3 trial Lancet 390 2017 1585 1594 10.1016/S0140-6736(17)31613-6 28755782 \nLeder B.Z. Tsai J.N. Uihlein A.V. Wallace P.M. Lee H. Neer R.M. Burnett-Bowie S.A. Denosumab and teriparatide transitions in postmenopausal osteoporosis (the DATA-switch study): extension of a randomised controlled trial Lancet 386 2015 1147 1155 10.1016/S0140-6736(15)61120-5 26144908 \nLerner U.H. Ohlsson C. The WNT system: background and its role in bone J. Intern. Med. 277 2015 630 649 10.1111/joim.12368 25845559 \nMcClung M.R. Grauer A. Boonen S. Bolognese M.A. Brown J.P. Diez-Perez A. Langdahl B.L. Reginster J.Y. Zanchetta J.R. Wasserman S.M. Katz L. Maddox J. Yang Y.C. Libanati Y.C. Bone Y.C. Romosozumab in postmenopausal women with low bone mineral density N. Engl. J. Med. 370 2014 412 420 10.1056/NEJMoa1305224 24382002 \nMeier C. Uebelhart B. Aubry-Rozier B. Birkhäuser M. Bischoff-Ferrari H.A. Frey D. Kressig R.W. Lamy O. Lippuner K. Stute P. Suhm N. Ferrari S. Osteoporosis drug treatment: duration and management after discontinuation. A position statement from the SVGO/ASCO Swiss Med. Wkly. 147 2017 w14484 10.4414/smw.2017.14484 28871570 \nMognetti B. Marino S. Barberis A. Martin A.S. Bala Y. Di Carlo F. Boivin G. Barbos M.P. Experimental stimulation of bone healing with teriparatide: histomorphometric and microhardness analysis in a mouse model of closed fracture Calcif. Tissue Int. 89 2011 163 171 10.1007/s00223-011-9503-3 21701938 \nNiimi R. Kono T. Nishihara A. Hasegawa M. Kono T. Sudo A. Second rebound-associated vertebral fractures after denosumab discontinuation Arch. Osteoporos. 15 2020 7 10.1007/s11657-019-0676-0 31898803 \nOminsky M.S. Li C. Li X. Tan H.L. Lee E. Barrero M. Asuncion F.J. Dwyer D. Han C.Y. Vlasseros F. Samadfam R. Jolette J. Smith S.Y. Stolina M. Lacey D.L. Simonet W.S. Paszty C. Li G. Ke H.Z. Inhibition of sclerostin by monoclonal antibody enhances bone healing and improves bone density and strength of nonfractured bones J. Bone Miner. Res. 26 2011 1012 1021 10.1002/jbmr.307 21542004 \nPadhi D. Jang G. Stouch B. Fang L. Posvar E. Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody J. Bone Miner. Res. 26 2011 19 26 10.1002/jbmr.173 20593411 \nPopp A.W. Varathan N. Buffat H. Senn C. Perrelet R. Lippuner K. Bone mineral density changes after 1 year of denosumab discontinuation in postmenopausal women with long-term denosumab treatment for osteoporosis Calcif. Tissue Int. 103 2018 50 54 10.1007/s00223-018-0394-4 29380013 \nShi Z. Zhou H. Pan B. Lu L. Liu J. Kang Y. Yao X. Feng S. Effectiveness of teriparatide on fracture healing: a systematic review and meta-analysis PLoS One 11 2016 e0168691 10.1371/journal.pone.0168691 \nTripto-Shkolnik L. Rouach V. Marcus Y. Rotman-Pikielny P. Benbassat C. Vered I. Vertebral fractures following denosumab discontinuation in patients with prolonged exposure to bisphosphonates Calcif. Tissue Int. 103 2018 44 49 10.1007/s00223-018-0389-1 29396698 \nUebelhart B. Rizzoli R. Ferrari S.L. Retrospective evaluation of serum CTX levels after denosumab discontinuation in patients with or without prior exposure to bisphosphonates Osteoporos. Int. 28 2017 2701 2705 10.1007/s00198-017-4080-6 28540505\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2352-1872",
"issue": "13()",
"journal": "Bone reports",
"keywords": "Denosumab; Discontinuation; Romosozumab; Vertebral fractures",
"medline_ta": "Bone Rep",
"mesh_terms": null,
"nlm_unique_id": "101646176",
"other_id": null,
"pages": "100288",
"pmc": null,
"pmid": "32548215",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports",
"references": "21289258;31628490;24382002;27997614;28755782;29380013;28871570;21542004;31898803;24243768;27742498;27641143;21701938;26144908;30659428;29396698;25845559;31000686;28540505;20593411;32373677;32441026;28240371",
"title": "Romosozumab was not effective in preventing multiple spontaneous clinical vertebral fractures after denosumab discontinuation: A case report.",
"title_normalized": "romosozumab was not effective in preventing multiple spontaneous clinical vertebral fractures after denosumab discontinuation a case report"
} | [
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"companynumb": "JP-AMGEN-JPNSP2019182898",
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"activesubstancename": "CALCIUM ASPARTATE"
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"abstract": "OBJECTIVE\nTo analyse emergency department (ED) presentations related to acute medical problems after recreational use of prescription/over-the-counter (OTC) drugs in two major Swiss hospitals in order to identify the prevalence of specific drugs, vulnerable groups, time trends and local differences which could have major public health implications.\n\n\nMETHODS\nRetrospective analysis of cases presenting with signs/symptoms consistent with acute toxicity due to recreational use of prescription/OTC drugs from May 2012 to August 2017 at the ED of the University Hospital of Bern and from October 2013 to July 2017 at the ED of the University Hospital Basel. We investigated time trends, sex differences, patient characteristics and consumption patterns within three age groups (≥16 to <36 years; ≥36 to <56 years; ≥56 years).\n\n\nRESULTS\nDuring the study period, 344 cases were included out of 1715 ED attendances due to acute drug toxicity and a total of 412,557 ED presentations. The use of prescription drugs in conjunction with illegal drugs was reported in nearly half the cases. The most frequently reported prescription drugs were benzodiazepines (64%, n = 220) and methadone (13%, n = 45). Forty-eight percent (n = 166) of all presentations occurred within the youngest age group. The analysis of time trends showed a significant increase in presentations in the youngest and the oldest groups in Basel (both p <0.05), while the trend remained stable over time in Bern for all age groups. While the number of presentations remained constant over time for men and women in Bern, a significant increase was found for the female cohort in Basel (p <0.05). Patients in all age groups presented with toxicities of predominantly minor severity.\n\n\nCONCLUSIONS\nThe prescription/OTC drugs most frequently leading to ED presentations after recreational use were sedative substances. A large proportion of the patients belonged to the youngest age group. A significant increase in presentations was seen in the youngest and oldest age groups and within women in Basel. This information can be used to inform health care providers so that they can adapt their prevention and treatment strategies in their communities.",
"affiliations": "Clinical Pharmacology and Toxicology, Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland / Institute of Pharmacology, University of Bern, Switzerland.;Division of Clinical Pharmacology and Toxicology, University Hospital and University of Basel, Switzerland.;Emergency Department, Inselspital, Bern University Hospital, University of Bern, Switzerland.;Clinical Pharmacology and Toxicology, Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland / Institute of Pharmacology, University of Bern, Switzerland.;Division of Clinical Pharmacology and Toxicology, University Hospital and University of Basel, Switzerland.;Clinical Pharmacology and Toxicology, Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland / Institute of Pharmacology, University of Bern, Switzerland.",
"authors": "Scholz|Irene|I|;Schmid|Yasmin|Y|;Exadaktylos|Aristomenis K|AK|;Haschke|Manuel|M|;Liechti|Matthias E|ME|;Liakoni|Evangelia|E|",
"chemical_list": "D000928:Antidepressive Agents; D000697:Central Nervous System Stimulants; D013287:Illicit Drugs; D004366:Nonprescription Drugs; D001569:Benzodiazepines; D008774:Methylphenidate; D008691:Methadone",
"country": "Switzerland",
"delete": false,
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"issn_linking": "0036-7672",
"issue": "149()",
"journal": "Swiss medical weekly",
"keywords": null,
"medline_ta": "Swiss Med Wkly",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D017677:Age Distribution; D000368:Aged; D000428:Alcohol Drinking; D000928:Antidepressive Agents; D001569:Benzodiazepines; D000697:Central Nervous System Stimulants; D004636:Emergency Service, Hospital; D005260:Female; D006801:Humans; D013287:Illicit Drugs; D008297:Male; D008691:Methadone; D008774:Methylphenidate; D008875:Middle Aged; D004366:Nonprescription Drugs; D012189:Retrospective Studies; D019966:Substance-Related Disorders; D013557:Switzerland; D055815:Young Adult",
"nlm_unique_id": "100970884",
"other_id": null,
"pages": "w20056",
"pmc": null,
"pmid": "31340053",
"pubdate": "2019-07-15",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Emergency department presentations related to abuse of prescription and over-the-counter drugs in Switzerland: time trends, sex and age distribution.",
"title_normalized": "emergency department presentations related to abuse of prescription and over the counter drugs in switzerland time trends sex and age distribution"
} | [
{
"companynumb": "CH-ALKEM LABORATORIES LIMITED-CH-ALKEM-2019-07171",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
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"activesubstance": {
"activesubstancename": "METHADONE HYDROCHLORIDE"
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... |
{
"abstract": "Ketamine is a promising alternative agent for pain control that offers benefit to traditional strategies, particularly in the setting of rib fracture. Current pharmacologic therapies have clear adverse effects, and other options may be invasive, cost prohibitive, or marginally effective. We describe three consecutive patients with traumatic injuries including rib fracture for which a ketamine infusion was utilized as part of their pain control strategy. For each patient, use of a ketamine infusion trended toward reduced opioid requirements with stable pain scores. One patient experienced a dissociative adverse effect prompting decrease and discontinuation of ketamine. No pulmonary complications in the form of emergent intubation or new diagnosis of pneumonia were observed. We believe the addition of ketamine infusion to be a valid alternative strategy for managing pain associated with rib fracture.",
"affiliations": "Pharmacy Services, Sanford Health, Fargo ND, USA.;Pharmacy Services, Sanford Health, Fargo ND, USA.;Pharmacy Services, Sanford Health, Fargo ND, USA.;Department of Trauma and Acute Care Surgery, Sanford Health, Fargo ND, USA.;Pharmacy Services, Sanford Health, Fargo ND, USA.",
"authors": "Losing|Ashley K|AK|;Jones|Justin M|JM|;Keric|Adis|A|;Briggs|Steven E|SE|;Leedahl|David D|DD|",
"chemical_list": null,
"country": "Iran",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2322-2522",
"issue": "4(3)",
"journal": "Bulletin of emergency and trauma",
"keywords": "Ketamine; Pain management; Rib fracture; Thoracic injury",
"medline_ta": "Bull Emerg Trauma",
"mesh_terms": null,
"nlm_unique_id": "101614018",
"other_id": null,
"pages": "165-9",
"pmc": null,
"pmid": "27540552",
"pubdate": "2016-07",
"publication_types": "D002363:Case Reports",
"references": "23857159;15920221;21716105;27162892;20847690;26659198;12853057;23663314;26543461;10730829;27225735;17937714;20567973",
"title": "Ketamine Infusion Therapy as an Alternative Pain Control Strategy in Patients with Multi-Trauma including Rib Fracture; Case Report and Literature Review.",
"title_normalized": "ketamine infusion therapy as an alternative pain control strategy in patients with multi trauma including rib fracture case report and literature review"
} | [
{
"companynumb": "US-NOVEL LABORATORIES, INC-2016-04041",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "MORPHINE"
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"drugadditional": n... |
{
"abstract": "The autopsy of a 65-year-old diabetic African American male revealed significant left myocardial involvement by adult T-cell leukemia/lymphoma (ATLL) despite normal pre-mortem fluorodeoxyglucose (FDG) uptake by positron emission tomography/computed tomography (PET/CT). Due to pre-existing diabetic cardiomyopathy with reduced ejection fraction (EF) and compatible imaging studies, cardiac lymphomatous involvement was not suspected. While peripheral blood was negative for leukemia, next-generation sequencing of a lymph node revealed at least eight novel mutations (AXIN1, R712Q, BARD1 R749K, CTNNB1 I315V, CUX1 P102T, DNMT3A S199R, FGFR2 S431L, LRP1B Y2560C and STAG2 I771M). These findings underscore a diagnostic pitfall in a rare lymphomatous variant of ATLL infiltrating myocardium and contribute to its molecular characterization.",
"affiliations": "Pathology and Laboratory Service, Veterans Affairs Medical Center, 50 Irving Street, NW, Washington, DC 20422, USA.;Pathology and Laboratory Service, Veterans Affairs Medical Center, 50 Irving Street, NW, Washington, DC 20422, USA.;Calcium Signaling Laboratory, Veterans Affairs Medical Center, 50 Irving Street, NW, Washington, DC 20422, USA.;Pathology and Laboratory Service, Veterans Affairs Medical Center, 50 Irving Street, NW, Washington, DC 20422, USA.",
"authors": "Hashemi Zonouz|Taraneh|T|;Abdulbaki|Rami|R|;Bandyopadhyay|Bidhan C|BC|0000-0003-2364-8945;Nava|Victor E|VE|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/curroncol28010079",
"fulltext": "\n==== Front\nCurr Oncol\nCurr Oncol\ncurroncol\nCurrent Oncology\n1198-0052\n1718-7729\nMDPI\n\n33562071\n10.3390/curroncol28010079\ncurroncol-28-00079\nCase Report\nNovel Mutations in a Lethal Case of Lymphomatous Adult T Cell Lymphoma with Cryptic Myocardial Involvement\nHashemi Zonouz Taraneh 12\nAbdulbaki Rami 12\nhttps://orcid.org/0000-0003-2364-8945\nBandyopadhyay Bidhan C. 34\nNava Victor E. 12*\n1 Pathology and Laboratory Service, Veterans Affairs Medical Center, 50 Irving Street, NW, Washington, DC 20422, USA; thz62@email.gwu.edu (T.H.Z.); Rabdulbaki@gwu.edu (R.A.)\n2 Department of Pathology, George Washington University, Washington, DC 20037, USA\n3 Calcium Signaling Laboratory, Veterans Affairs Medical Center, 50 Irving Street, NW, Washington, DC 20422, USA; bidhan.bandyopadhyay@va.gov\n4 Division of Renal Diseases & Hypertension, Department of Medicine, The George Washington University, Washington, DC 20037, USA\n* Correspondence: Victor.Nava@va.gov\n06 2 2021\n2 2021\n28 1 818824\n17 12 2020\n01 2 2021\n© 2021 by the authors.\n2021\nLicensee 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/).\nThe autopsy of a 65-year-old diabetic African American male revealed significant left myocardial involvement by adult T-cell leukemia/lymphoma (ATLL) despite normal pre-mortem fluorodeoxyglucose (FDG) uptake by positron emission tomography/computed tomography (PET/CT). Due to pre-existing diabetic cardiomyopathy with reduced ejection fraction (EF) and compatible imaging studies, cardiac lymphomatous involvement was not suspected. While peripheral blood was negative for leukemia, next-generation sequencing of a lymph node revealed at least eight novel mutations (AXIN1, R712Q, BARD1 R749K, CTNNB1 I315V, CUX1 P102T, DNMT3A S199R, FGFR2 S431L, LRP1B Y2560C and STAG2 I771M). These findings underscore a diagnostic pitfall in a rare lymphomatous variant of ATLL infiltrating myocardium and contribute to its molecular characterization.\n\nadult T-cell leukemia/lymphoma\ndiabetic cardiomyopathy\nnext-generation sequencing\npoint mutations\nTCR/NF-kB\n==== Body\n1. Introduction\n\nThe World Health Organization (WHO) defines adult T-cell leukemia/lymphoma (ATLL) as a mature T-cell neoplasm composed of highly pleomorphic lymphoid cells and thought to be initiated by the retrovirus human T-cell leukemia virus type-1 (HTLV-1), which is necessary but not sufficient for its pathogenesis [1,2]. In North America, out of the four clinical variants of the disease (acute, lymphomatous, chronic and smoldering), the first two are the most common (~90% of cases) and carry a worse prognosis [3]. The lymphomatous type is characterized by prominent lymphadenopathy without peripheral blood involvement and by less frequent dermatologic manifestations or hypercalcemia [3]. Heart involvement by ATLL tends to be asymptomatic or oligosymptomatic. In autopsy series, few patients show cardiac symptoms like shortness of breath or palpitations, and massive cardiomegaly with extensive myocardial lymphomatous infiltration has seldom been reported [4,5,6].\n\nThe epidemiology of HTLV-1 in ATLL has been extensively studied. Geographic ATLL clustering overlaps endemic areas for the virus, such as southwestern Japan, the Caribbean basin and parts of central Africa. HTLV-1 is transmitted through blood products and breast feeding, and development of the disease follows a long (over 30 years) latency period after infection [7], which suggest that besides the causal role of viral oncogenes, host genetic and epigenetic factors are also necessary for tumorigenesis [8]. Two HTLV-1 proteins Tax and basic leucine zipper (HBZ) lead to transcriptional activation and T-cell proliferation, and both are able to transform in mouse models [9,10]. Tax-induced T-cell receptor (TCR)/nuclear factor kB (NF-kB) signaling has been well-documented in the development of ATLL [11]. However, Tax expression is silenced in a high proportion of ATLL cases, which illustrates its dispensable role in lymphomagenesis. In contrast, HBZ is the only viral protein consistently expressed in ATLL, and plays pleotropic roles modulating cell growth, T-cell differentiation and immune response, which contribute to oncogenesis. While most studies on the genetic alterations in ATLL have focused on Asian cases, recently, North American cases were analyzed in detail, demonstrating a unique frequency of epigenetic and histone modifying gene changes [12]. Conversely, the frequency of mutations in the JAK/STAT and the TCR/NF-kB pathway genes were lower when compared with the Japanese cases [12]. Therefore, it would be important to further analyze North American cases to confirm these findings, and to identify preclinical druggable target candidates. Here we present a lethal lymphomatous case of North American ATLL with extensive cardiac involvement and next-generation sequencing (NGS) data demonstrating several novel mutations that may hold promise in the diagnostic and therapeutic strategy.\n\n2. Result\n\nA 65-year-old diabetic African American male followed at the Washington DC Veterans Affairs Medical Center for hypertension and complications of diabetes mellitus, including heart failure with 40% ejection fraction (EF), chronic renal failure and neuropathy, developed poor appetite, abdominal pain and weight loss of 15 pounds (6.8 kg) in May 2019. The patient was hospitalized due to exertional orthopnea, severe gastrointestinal reflux disease and worsening shortness of breath.\n\nPhysical examination revealed mild obesity, unremarkable pulmonary and cardiovascular examination and no organomegaly or palpable lymphadenopathy. Imaging studies (including CT of the abdomen and pelvis with contrast) revealed infiltrating hypodense masses involving both kidneys, mesenteric lymphadenopathy and innumerable ground glass nodules with random distribution in the lung bases. The electrocardiogram was unremarkable. Multigated acquisition scan showed concentric left ventricular wall hypertrophy and hypokinesia, compatible with known cardiomyopathy. PET scan revealed innumerable foci of intense fluorodeoxyglucose (FDG) uptake in lungs, peritoneal cavity, kidneys, nodal basins (above and below the diaphragm), subcutaneous soft tissues and bones. However, normal FDG uptake within the myocardium was detected. Peripheral white blood cell counts were within the normal range. Serum calcium, sodium and potassium were also normal. Lactate dehydrogenase was markedly elevated at 1600 U/L, and serum HTLV-I antibody test was positive.\n\nAn enlarged supraclavicular lymph node was excised, and the diagnosis of ATLL was made based on histomorphology and positivity for CD45, CD2, CD3, CD4 and CD25 by immunohistochemistry. Ki-67 proliferative rate was very high (>80%). Other markers, including CD7 (aberrant loss), CD8, CD10, CD56, EBV and CD30, were negative. Careful examination of peripheral blood failed to detect atypical large lymphocytes, which was confirmed by a flow cytometric analysis showing no lymphomatous involvement. The diagnosis of lymphomatous variant of ATLL was confirmed, and NGS was performed by Foundation Medicine (comprehensive DNA and RNA analysis) and interpreted following the guidelines of the American College of Medical Genetics. This analysis revealed an intermediate tumor mutational burden (nine mutations per megabase) and stable microsatellite status. The following somatic mutations (Table 1) were also identified: AXIN1 R712Q, BARD1 R749K, CBL H42_L43insH, CD36 amplification, CDK6 amplification, CTNNB1 I315V, CUX1 (P102T and R44W), DNMT3A S199R, FAS D228fs*2, FGFR2 S431L, GATA3 loss exons 4–6, HGF amplification, HIST1H2AM loss, HIST1H2BO loss, IRF4 amplification, LRP1B (D1063N and Y2560C), NF1 S665F, PCLO amplification, SDHD F34C, SMO G24A, STAG2 I771M and TP53 H193L.\n\nThe patient underwent two cycles of chemotherapy (ESHAP-etoposide, methylprednisolone, cytarabine and cisplatin), but unfortunately had a complicated post-treatment course and developed tumor lysis syndrome, gastrointestinal bleeding, exacerbation of heart failure and unresolved acute kidney injury. Despite intensive care and cardiopulmonary resuscitation, the patient developed cardiac arrest and died 45 days after hospitalization. An autopsy revealed extensive lymphomatous involvement of multiple lymph nodes, including mesenteric, mediastinal, retroperitoneal, cervical and periaortic. In addition, significant involvement of the left myocardium (Figure 1) and multiple other organs (bilateral lungs, stomach, bowels, pancreas, bilateral kidneys, bilateral adrenals and prostate) and patchy involvement of diaphragm, skin and muscle was demonstrated by histomorphology and immunohistochemistry (including sections from the cardiac lymphoma shown in Figure 2).\n\n3. Discussion\n\nATLL is a malignant lymphoproliferative neoplasm of mature T-cells initiated by monoclonal integration of HTLV-1 in the genome of lymphocytes, which leads to complex multistep events occurring during a long latency period. Despite a greater understanding of the pathogenesis of ATLL, curative treatment is lacking, and the overall prognosis remains dismal.\n\nAccording to the Shimoyama classification, four variants of ATLL are recognized: acute, lymphomatous, chronic and smoldering [3]. The lymphomatous form is usually clinically aggressive and presents with advanced disease, including prominent lymphadenopathy and infrequent hypercalcemia, as seen in our patient. Although extensive involvement of the spleen and skin are common in lymphomatous ATLL, we did not observe these features. Instead, we detected patchy dermal involvement and extensive myocardial infiltration by ATLL, a rare event typically associated with ominous prognosis and concomitant lymphomatous involvement of the lung [6], as our necropsy illustrated. Of note, cardiac ATLL can be commonly missed pre-mortem even with modern imaging (as performed here) and is associated with chemoresistance [6]. Cutaneous involvement in our case was subclinical, as demonstrated by immunohistochemistry of a few tiny lymphoid aggregates found by microscopic examination, which is also unusual in lymphomatous ATLL.\n\nDespite substantial progress in recent years, the molecular pathogenesis of ATLL remains unclear. After monoclonal integration of HTLV-1 and expression of viral oncogenes, such as Tax and HBZ, dysregulation of signaling pathways related to T-cell proliferation/differentiation and immune surveillance leads to leukemogenesis. Interestingly, Tax is dispensable for transformation and inactivated in a high proportion of cases [9]. However, HBZ is the only viral protein that remains consistently expressed in ATLL cases. Activation of PI3K, JAK/STAT and TCR/NF-kB pathways by genetic and epigenetic mechanisms seem to be crucial for tumor progression, and specific genes are commonly mutated, including CARD22, CCR4, CCR7, CDKN2A (p16), CDK2B (p15), EP300, FAS, FYN, GATA3, IRF4, PLCG1, PRKCB, TP53, STAT3 and VAV1. Accordingly, we observed mutations in genes of the TCR/NF-κB pathway (CBL, CUX1 and FAS), implicated in unrestricted and persistent NF-κB activation leading to the development of autoimmune diseases and neoplasms [13]. Such disbalance between T-cell activation and excessive NF-κB stimulation may have initiated deleterious consequences of TCR signaling, which, without negative regulation of nuclear signaling, may contribute to tumor progression. Interestingly, genetic alterations in genes associated with WNT/beta-catenin (AXIN1, CTNNB1 and SMO) and the RAS/MAPK (NF1), which are less commonly associated with ATLL, were also detected, suggesting possible unique pathogenic associations. As expected, several mutated genes that play a role in genomic stability (BARD1, TP53 and STAG2) and/or transcriptional regulation (HIST1H2AM, HIST1H2BO, IRF4 and GATA3) were seen. Also, genes directly involved in cell cycle control (CDK6) and soluble growth factors (HCF) had mutations in this tumor. Furthermore, trophic pathways related to surface receptors seem to be involved in our case, as suggested by mutations in CD36 (a lipid scavenger receptor) [14], LRP1B (a member of the low-density lipoprotein receptor family) [15] and FGFR2 (fibroblast growth factor receptor 2/CD332) [12]. Furthermore, additional epigenetic regulation may be represented by mutations in DNMT3A, a methyltransferase that may modulate gene expression by altering histones [16]. Finally, we found alterations in genes that have an unclear oncogenic mechanism of action, such as SDHD (a well-known driver gene in Cowden/Cowden-like syndromes) [17] and PCLO (a scaffold protein of the presynaptic cytomatrix at the active zone) [18].\n\nMutations in some of these genes (CBL, CDK6, DNMT3A, FAS, FGFR2, GATA3, HGF, IRF4, TP53 and STAG2) are well known in association with ATLL [12], but the specific alterations found are novel (CBL H42_L43insH, DNMT3A S199R, FGFR2 S431L, GATA3 loss of exons 4–6 and STAG2 I771M). Other genes have been described [18,19,20] in association with different hematopoietic or solid tumors (AXIN1, BARD1, CUX1, NF1, PCLO, SDHD and SMO), but are reported here for the first time in association with ATLL. Of interest, eight mutations (AXIN1, R712Q, BARD1 R749K, CTNNB1 I315V, CUX1 P102T, DNMT3A S199R, FGFR2 S431L, LRP1B Y2560C and STAG2 I771M) have not been reported before to the best of our knowledge after extensive literature/database searches. Current molecular pathogenesis of ATLL postulates important processes related to HTLV-1-mediated proliferation and immune evasion based on unclear stochastic genetic alterations necessary for full-blown disease. Accordingly, mutations belonging to major well-characterized pathways were found in this study. Focusing on the novel point mutations in the TCR/NF-kB (CUX1 P102T), epigenetic/methylation regulatory (DNMT3A S199R) and genetic stability (BARD1 and STAG2) pathways, our findings suggest commonalities with prior reports [12]. Similarly, various novel mutations belonging to the category of trophic proliferative signaling (FGFR2 S431L and LRP1B Y2560C) were sequenced. However, we also found novel mutations in the WNT/beta-catenin pathway (AXIN1, R712Q and CTNNB1 I315V), which is underappreciated in ATLL. Overexpression of Wnt5a (an activator of beta-catenin/CTNNB1 not found in our case) has been proposed as a mediator of hypercalcemia [21] and suggests that the beta-catenin (CTNNB1 I315V) defect we observed may have abrogated this mechanism, since our patient remained normocalcemic. Likewise, AXIN1 inactivation may have contributed to such normocalcemic phenotype, since this tumor suppressor regulates G-protein coupled signaling upstream of beta-catenin [20].\n\nIn summary, we present a clinically unusual lethal case of ATLL with several novel mutations (AXIN1, R712Q, BARD1 R749K, CTNNB1 I315V, CUX1 P102T, DNMT3A S199R, FGFR2 S431L, LRP1B Y2560C and STAG2 I771M) and unexpected myocardial involvement, which probably contributed to the fatal outcome.\n\nAuthor Contributions\n\nConceptualization, V.E.N.; methodology, R.A. and T.H.Z.; formal analysis R.A. and T.H.Z.; investigation, V.E.N., R.A., T.H.Z. and B.C.B.; data curation, R.A.; writing—original draft preparation, T.H.Z.; writing—review and editing, R.A., V.E.N. and B.C.B. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research received no external funding.\n\nConflicts of Interest\n\nThe authors declare no conflict of interest.\n\nFigure 1 Gross appearance of the heart. The left myocardium shows and focal thickening and white-brown discoloration (arrow) that corresponds to leukemic infiltration.\n\nFigure 2 (A) Adult T-cell leukemia/lymphoma (ATLL) infiltration of endocardium and myocardium (H&E, 20×). (B) Higher magnification of infiltrating lymphoma showing pleomorphism, scant eosinophilic cytoplasm, irregular nuclear contours with coarse chromatin and variably prominent nucleoli (H&E, 200×). The lymphoma cells were strongly positive for CD4 (C) and CD25 (D) by immunohistochemistry (20×).\n\ncurroncol-28-00079-t001_Table 1 Table 1 Somatic mutations identified by next-generation sequencing (NGS).\n\nGene\tSomatic Mutation\tAllele Frequency (%)\t\nAXIN1\tR712Q\t44.94\t\nBARD1\tR749K\t24.75\t\nCBL\tH42_L43insH\t17.61\t\nCTNNB1\tI315V\t76.45\t\nCUX1\tR44W\t36.15\t\nCUX1\tP102T\t26.84\t\nDNMT3A\tS199R\t39.04\t\nFAS\tD228fs*2\t45.37\t\nFGFR2\tS431L\t26.61\t\nLRP1B\tD1063N\t68.28\t\nLRP1B\tY2560C\t46.64\t\nNF1\tS665F\t31.97\t\nSDHD\tF34C\t29.79\t\nSMO\tG24A\t48.98\t\nSTAG2\tI771M\t40.98\t\nTP53\tH193L\t70.02\t\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Ohshima K. Jaffe E. Yoshino T. Siebert R. Adult T-cell leukemia/lymphoma World Health Organization Classification of Tumours Revised 4th ed. Swerdlow S.H. Campo C.E. Harris N.L. IARC press Lyon, France 2017 363 367\n2. Ishitsuka K. Tamura K. Human T-cell leukaemia virus type I and adult T-cell leukaemia-lymphoma Lancet Oncol. 2014 15 e517 e526 10.1016/S1470-2045(14)70202-5 25281470\n3. Shimoyama M. Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma Br. J. Haematol. 1991 79 428 437 10.1111/j.1365-2141.1991.tb08051.x 1751370\n4. Furihata M. Ido E. Iwata J. Sonobe H. Ohtsuki Y. Takata J. Chikamori T. Doi Y. Adult T cell leukemia/lymphoma with massive involvement of cardiac muscle and valves Pathol. Int. 1998 48 221 224 10.1111/j.1440-1827.1998.tb03896.x 9589491\n5. Iemura A. Yano H. Kojiro M. Nouno R. Kouno K. Massive cardiac involvement of adult T-cell leukemia/lymphoma. An autopsy case Arch. Pathol. Lab. Med. 1991 115 1052 1054 1898236\n6. O’Mahony D. Debnath I. Janik J. Aisner D. Jaffe E. Waldmann T. Morris J.C. Cardiac involvement with human T-cell lymphotrophic virus type-1-associated adult T-cell leukemia/lymphoma: The NIH experience Leuk. Lymphoma 2008 49 439 446 10.1080/10428190701809164 18297519\n7. Tajima K. Hinuma Y. Epidemiology of HTLV-I/II in Japan and in the world Advances in Adult T-Cell Leukemia and HTLV-1 Research (Gann Monograph on Cancer Research) Takatsuki K. Hinuma Y. Yoshida M. Japan Scientific Societies Press Tokyo, Japan 1992 129 149\n8. Matsuoka M. Jeang K.-T. Human T-cell leukaemia virus type 1 (HTLV-1) infectivity and cellular transformation Nat. Rev. Cancer 2007 7 270 280 10.1038/nrc2111 17384582\n9. Franchini G. Molecular mechanisms of human T-cell leukemia/lymphotropic virus type I infection Blood 1995 86 3619 3639 10.1182/blood.V86.10.3619.bloodjournal86103619 7579327\n10. Satou Y. Yasunaga J.-I. Yoshida M. Matsuoka M. HTLV-I basic leucine zipper factor gene mRNA supports proliferation of adult T cell leukemia cells Proc. Natl. Acad. Sci. USA 2006 103 720 725 10.1073/pnas.0507631103 16407133\n11. Kataoka K. Nagata Y. Kitanaka A. Shiraishi Y. Shimamura T. Yasunaga J.-I. Totoki Y. Chiba K. Sato-Otsubo A. Nagae G. Integrated molecular analysis of adult T cell leukemia/lymphoma Nat. Genet. 2015 47 1304 1315 10.1038/ng.3415 26437031\n12. Shah U.A. Chung E.Y. Giricz O. Pradhan K. Kataoka K. Gordon-Mitchell S. Bhagat T.D. Mai Y. Wei Y. Ishida E. North American ATLL has a distinct mutational and transcriptional profile and responds to epigenetic therapies Blood 2018 132 1507 1518 10.1182/blood-2018-01-824607 30104217\n13. Paul S. Schaefer B.C. A new look at T cell receptor signaling to nuclear factor-κB Trends Immunol. 2013 34 269 281 10.1016/j.it.2013.02.002 23474202\n14. DeRosa P. Nava V. Comment on Aasebø, E.; et al. The Progression of Acute Myeloid Leukemia from First Diagnosis to Chemoresistant Relapse: A Comparison of Proteomic and Phosphoproteomic Profiles. Cancers 2020, 12, 1466 Cancers 2020 12 2461 10.3390/cancers12092461 32512867\n15. Liu C.-X. Li Y. Obermoeller-McCormick L.M. Schwartz A.L. Bu G. The Putative Tumor Suppressor LRP1B, a Novel Member of the Low Density Lipoprotein (LDL) Receptor Family, Exhibits Both Overlapping and Distinct Properties with the LDL Receptor-related Protein J. Biol. Chem. 2001 276 28889 28896 10.1074/jbc.M102727200 11384978\n16. Yeh C.-H. Bai X.T. Moles R. Ratner L. Waldmann T.A. Watanabe T. Nicot C. Mutation of epigenetic regulators TET2 and MLL3 in patients with HTLV-I-induced acute adult T-cell leukemia Mol. Cancer 2016 15 1 7 10.1186/s12943-016-0500-z 26728659\n17. Renella R. Carnevale J. Schneider K.A. Hornick J.L. Rana H.Q. Janeway K.A. Exploring the association of succinate dehydrogenase complex mutations with lymphoid malignancies Fam. Cancer 2014 13 507 511 10.1007/s10689-014-9725-4 24781345\n18. Schatz J.H. Horwitz S.M. Teruya-Feldstein J. Lunning M.A. Viale A. Huberman K. Socci N.D. Lailler N. Heguy A. Dolgalev I. Targeted mutational profiling of peripheral T-cell lymphoma not otherwise specified highlights new mechanisms in a heterogeneous pathogenesis Leukemia 2014 29 237 241 10.1038/leu.2014.261 25257991\n19. Feigenbaum L. Fujita K. Collins F.S. Jay G. Repression of the NF1 gene by Tax may expain the development of neurofibromas in human T-lymphotropic virus type 1 transgenic mice J. Virol. 1996 70 3280 3285 10.1128/JVI.70.5.3280-3285.1996 8627811\n20. Salahshor S. Woodgett J.R. The links between axin and carcinogenesis J. Clin. Pathol. 2005 58 225 236 10.1136/jcp.2003.009506 15735151\n21. Bellon M. Ko N.L. Lee M.-J. Yao Y. Waldmann T.A. Trepel J.B. Nicot C. Adult T-cell leukemia cells overexpress Wnt5a and promote osteoclast differentiation Blood 2013 121 5045 5054 10.1182/blood-2012-07-439109 23660959\n\n",
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"issn_linking": "1198-0052",
"issue": "28(1)",
"journal": "Current oncology (Toronto, Ont.)",
"keywords": "TCR/NF-kB; adult T-cell leukemia/lymphoma; diabetic cardiomyopathy; next-generation sequencing; point mutations",
"medline_ta": "Curr Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell; D008223:Lymphoma; D016399:Lymphoma, T-Cell; D008297:Male; D009154:Mutation; D009206:Myocardium; D000072078:Positron Emission Tomography Computed Tomography",
"nlm_unique_id": "9502503",
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"pages": "818-824",
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"pmid": "33562071",
"pubdate": "2021-02-06",
"publication_types": "D002363:Case Reports",
"references": "25281470;11384978;26880370;15735151;23660959;18297519;32878013;1898236;8627811;25257991;1751370;30104217;7579327;23474202;17384582;9589491;24781345;26437031;16407133",
"title": "Novel Mutations in a Lethal Case of Lymphomatous Adult T Cell Lymphoma with Cryptic Myocardial Involvement.",
"title_normalized": "novel mutations in a lethal case of lymphomatous adult t cell lymphoma with cryptic myocardial involvement"
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"abstract": "We report a 53-year-old man diagnosed with Richter syndrome. He was heavily pretreated and was refractory to prior therapy. He received rituximab and ibrutinib, and achieved a significant response after 1 month of therapy. Our case illustrates the importance of investigation of rituximab and ibrutinib in Richter's syndrome.",
"affiliations": "Comprehensive Cancer Center, Wake Forest University Medical Center Boulevard, Winston-Salem, North Carolina, 27157.;Department of Pharmacy, Wake Forest Baptist Health Medical Center Boulevard, Winston-Salem, North Carolina, 27157.;Comprehensive Cancer Center, Wake Forest University Medical Center Boulevard, Winston-Salem, North Carolina, 27157.;Comprehensive Cancer Center, Wake Forest University Medical Center Boulevard, Winston-Salem, North Carolina, 27157.;Comprehensive Cancer Center, Wake Forest University Medical Center Boulevard, Winston-Salem, North Carolina, 27157.;Comprehensive Cancer Center, Wake Forest University Medical Center Boulevard, Winston-Salem, North Carolina, 27157.;Comprehensive Cancer Center, Wake Forest University Medical Center Boulevard, Winston-Salem, North Carolina, 27157.",
"authors": "Lamar|Zanetta|Z|;Kennedy|LeAnne|L|;Kennedy|Brooke|B|;Lynch|Mary|M|;Goad|Amanda|A|;Hurd|David|D|;McIver|Zachariah|Z|",
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"fulltext": "\n==== Front\nClin Case RepClin Case Repccr3Clinical Case Reports2050-09042050-0904John Wiley & Sons, Ltd Chichester, UK 10.1002/ccr3.269Case ReportsIbrutinib and rituximab induced rapid response in refractory Richter syndrome Lamar Zanetta 1Kennedy LeAnne 2Kennedy Brooke 1Lynch Mary 1Goad Amanda 1Hurd David 1McIver Zachariah 11 Comprehensive Cancer Center, Wake Forest UniversityMedical Center Boulevard, Winston-Salem, North Carolina, 271572 Department of Pharmacy, Wake Forest Baptist HealthMedical Center Boulevard, Winston-Salem, North Carolina, 27157Correspondence Zanetta Lamar, Section of Hematology-Oncology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157. Tel: 336 716 5847; Fax: 336 716 5687; E-mail: zlamar@wakehealth.eduFunding Information No sources of funding were declared for this study\n\n7 2015 05 6 2015 3 7 615 617 22 8 2014 29 12 2014 03 3 2015 © 2015 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.2015This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Key Clinical Message\nWe report a 53-year-old man diagnosed with Richter syndrome. He was heavily pretreated and was refractory to prior therapy. He received rituximab and ibrutinib, and achieved a significant response after 1 month of therapy. Our case illustrates the importance of investigation of rituximab and ibrutinib in Richter’s syndrome.\n\nIbrutinibRichterRichter syndromeRichter’s transformationrituximab\n==== Body\nCase Presentation\nWe report a 53-year-old man who was diagnosed with chronic lymphocytic leukemia (CLL) in 2012, after presenting to the emergency room with a white blood cell count of 23,200 with 78% lymphocytes and enlarged cervical nodes. A bone marrow biopsy was performed; pathologic findings were consistent with CLL without cytogenetic or FISH abnormalities. Immunoglobulin heavy chain testing was not performed. He completed six cycles of fludarabine, cyclophosphamide, and rituximab (FCR). However, a CT scan 3 months after treatment completion showed extensive cervical, axillary, mediastinal, and retroperitoneal adenopathy. He was then started on rituximab and bendamustine, but treatment was discontinued early because of rash. Figure1, panel A, shows the PET scan performed prior to starting third line therapy with single agent ofatumumab. Due to concern about possible transformation, he was then started on a dose-adjusted rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin, (R-EPOCH) regimen, with persistent disease. Biopsy of a left axillary lymph axillary node confirmed transformation to diffuse large B cell lymphoma, nongerminal center origin. Richter score at the time of confirmed transformation was 1. He was then treated with rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) and rituximab, dexamethasone, high dose cytarabine, and carboplatin (R-DHAC) and high-dose cyclophosphamide, with suboptimal response (Fig.1, Panel B). Treatment regimens are shown in Table1.\n\nTable 1 Diagnosis and treatment timeline\n\nAug-12\tFeb-13\tMay-13\tJun-13\tSep-13\tNov-13\tJan-14\tFeb-14\tApr-14\tMay-14\tJun-14\t\nDiagnosed with CLL\tFCR × 6 cycles\tCT scan demonstrated recurrence\tRituximab and Bendamustine × 2 cycles\tOfatumumab × 5 cycles\tR-EPOCH × 4 cycles\tRichter confirmed. PET scan no response\tR-ICE × 1 cycle; R-DHAC × 3\tPET scan without response\tIbrutinib 420 mg daily and Rituximab weekly × 5\tPET response – eligible for transplant\t\nCLL, chronic lymphocytic leukemia; FCR, fludarabine, cyclophosphamide, and rituximab.\n\nFigure 1 PET scan with arrows pointing to areas of maximum standardized uptake value (SUV).\n\nThe patient then began taking a combination of rituximab (375 mg/m2 weekly) and ibrutinib (420 mg daily). Within one month of starting therapy, no lymph nodes were clinically palpable and PET scan showed significant response in the majority of involved lymph nodes (Fig.1, panel C). He never developed ibrutinib-associated lymphocytosis. The response continued for 3 months. During evaluation for allogeneic transplant, he developed progressive disease and elected to forego further therapy and later died.\n\nDiscussion\nRichter syndrome describes the transformation of CLL into an aggressive lymphoma. It is considered to have a worse prognosis than either CLL or de novo diffuse large B cell lymphoma. About 1% of CLL cases annually transform to a more aggressive lymphoma. While most transformations are to diffuse large B cell lymphoma, transformations to other disorders, such as Hodgkin lymphoma, have been reported 1. Risk factors for transformation include advanced Rai stage at diagnosis and lymph nodes >3 cm on physical examination 2. Since Richter syndrome may not involve all lymph nodes simultaneously, it is important to obtain a PET scan to guide biopsy of suspected areas prior to initiation of therapy 2. A standard uptake value (SUV) max of ≥5 is sensitive and specific for diagnosing Richter syndrome; however an SUV max of ≥10 is independently associated with a shorter overall survival 3. The prognosis for patients with Richter syndrome is poor, and hematopoietic transplant is recommended in patients who do respond to therapy. Our patient had a Richter score of 1 at diagnosis which correlates with a median survival of 1.12 years 4. In addition, he had no response to multiple regimens, and the combination of ibrutinib and rituximab was initially given with palliative intent.\n\nIbrutinib is an oral covalent inhibitor of Bruton’s tyrosine kinase. This kinase is located downstream from the B cell receptor and is necessary for the activation of pathways linked to CLL cell survival 5. Several recently published studies reported better progression-free and overall survival and response rates in patients with CLL without evidence of transformation 6,7. An unpublished phase 1b/II trial was conducted to study the combination of ofatumumab and ibrutinib reported a partial response in 2 of 3 study participants with Richter syndrome 8. Further, ibrutinib has shown activity combined with rituximab and bendamustine in diffuse large B cell lymphoma 9. We speculate ibrutinib may inhibit downstream signals important for malignant B cell proliferation; however the effect was not durable possibly due to the development of acquired resistance to ibrutinib 10. Importantly, our patient did not have lymphocytosis during therapy and previous data has suggested that prolonged lymphocytosis may decrease risk of relapse 10. To our knowledge, no previous reports have described using the combination of ibrutinib and rituximab in a heavily pretreated patient with Richter syndrome. In this patient, lymphadenopathy rapidly diminished after 4 weeks of a combined regimen of rituximab and ibrutinib.\n\nConclusion\nThis case highlights the importance of further investigation of combined ibrutinib and rituximab for patients with Richter syndrome.\n\nConflict of Interest\nNone declared.\n==== Refs\nReferences\nTsimberidou AM O’Brien S Kantarjian HM Koller C Hagemeister FB Fayad L Hodgkin transformation of chronic lymphocytic leukemia: the M. D. Anderson Cancer Center experience Cancer 2006 107 1294 1302 16902984 \nParikh SA Kay NE Shanafelt TD How we treat Richter syndrome Blood 2014 123 1647 1657 24421328 \nFalchi L Keating MJ Marom EM Truong MT Schlette EJ Sargent RL Correlation between FDG/PET, histology, characteristics, and survival in 332 patients with chronic lymphoid leukemia Blood 2014 123 2783 2790 24615780 \nTsimberidou AM O’Brien S Khouri I Giles FJ Kantarjian HM Champlin R Clinical outcomes and prognostic factors in patients with Richter’s syndrome treated with chemotherapy or chemoimmunotherapy with or without stem-cell transplantation J. Clin. Oncol 2006 24 2343 2351 16710033 \nHerman SE Mustafa RZ Gyamfi JA Pittaluga S Chang S Chang B Ibrutinib inhibits BCR and NF-kappaB signaling and reduces tumor proliferation in tissue-resident cells of patients with CLL Blood 2014 123 3286 3295 24659631 \nByrd JC Brown JR O’Brien S Barrientos JC Kay NE Reddy NM Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia N. Engl. J. Med 2014 371 213 223 24881631 \nByrd JC Furman RR Coutre SE Flinn IW Burger JA Blum KA Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia N. Engl. J. Med 2013 369 32 42 23782158 \nJaglowski SM Jones JA Flynn J Andritsos LA Maddocks K Blum K A phase Ib/II study evaluating activity and tolerability of BTK inhibitor PCI-32765 and Ofatumumab in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and related diseases J. Clin. Oncol 2012 30 (suppl; abstr 6508) \nMaddocks K Christian B Jaglowski S Flynn J Jones JA Porcu P A phase 1/1b study of rituximab, bendamustine, and ibrutinib in patients with untreated and relapsed/refractory non-Hodgkin lymphoma Blood 2015 125 242 248 25355819 \nWoyach JA Furman RR Liu TM Ozer HG Zapatka M Ruppert AS Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib N. Engl. J. Med 2014 370 2286 2294 24869598\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2050-0904",
"issue": "3(7)",
"journal": "Clinical case reports",
"keywords": "Ibrutinib; Richter; Richter syndrome; Richter’s transformation; rituximab",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "615-7",
"pmc": null,
"pmid": "26273453",
"pubdate": "2015-07",
"publication_types": "D002363:Case Reports",
"references": "24615780;23782158;16902984;24421328;25355819;24659631;24881631;16710033;24869598",
"title": "Ibrutinib and rituximab induced rapid response in refractory Richter syndrome.",
"title_normalized": "ibrutinib and rituximab induced rapid response in refractory richter syndrome"
} | [
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"companynumb": "US-ROCHE-1864663",
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"activesubstancename": "RITUXIMAB"
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"drugadditional": null,
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{
"abstract": "OBJECTIVE\nAntibiotic-associated diarrhea (AAD) and Clostridium difficile infection (CDI) are well-known outcomes from antibiotic administration. Because emergency department (ED) visits frequently result in antibiotic use, we evaluated the frequency of AAD/CDI in adults treated and discharged home with new prescriptions for antibiotics to identify risk factors for acquiring AAD/CDI.\n\n\nMETHODS\nThis prospective multicenter cohort study enrolled adult patients who received antibiotics in the ED and were discharged with a new prescription for antibiotics. Antibiotic-associated diarrhea was defined as 3 or more loose stools for 2 days or more within 30 days of starting the antibiotic. C difficile infection was defined by the detection of toxin A or B within this same period. We used multivariate logistic regression to assess predictors of developing AAD.\n\n\nRESULTS\nWe enrolled and followed 247 patients; 45 (18%) developed AAD, and 2 (1%) developed CDI. Patients who received intravenous (IV) antibiotics in the ED were more likely to develop AAD/CDI than patients who did not: 25.7% (95% confidence interval [CI], 17.4-34.0) vs 12.3% (95% CI, 6.8-17.9). Intravenous antibiotics had adjusted odds ratio of 2.73 (95% CI, 1.38-5.43), and Hispanic ethnicity had adjusted odds ratio of 3.04 (95% CI, 1.40-6.58). Both patients with CDI had received IV doses of broad-spectrum antibiotics.\n\n\nCONCLUSIONS\nIntravenous antibiotic therapy administered to ED patients before discharge was associated with higher rates of AAD and with 2 cases of CDI. Care should be taken when deciding to use broad-spectrum IV antibiotics to treat ED patients before discharge home.",
"affiliations": "Department of Emergency Medicine, University of Massachusetts Medical School, Worcester, MA. Electronic address: johnpharan@gmail.com.;Department of Emergency Medicine, Alpert Medical School of Brown University, Providence, RI.;Department of Emergency Medicine, University of Massachusetts Medical School, Worcester, MA.;Department of Emergency Medicine, Alpert Medical School of Brown University, Providence, RI.;Division of Biostatistics and Health Services Research, Department of Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, MA.;Department of Pediatrics and Division of Global Health, Harvard Medical School, Boston, MA.;Laboratory of Nucleic Acid Vaccines, Department of Medicine, University of Massachusetts Medical School, Worcester, MA.;Department of Emergency Medicine, University of Massachusetts Medical School, Worcester, MA.",
"authors": "Haran|John Patrick|JP|;Hayward|Gregory|G|;Skinner|Stephen|S|;Merritt|Chris|C|;Hoaglin|David C|DC|;Hibberd|Patricia L|PL|;Lu|Shan|S|;Boyer|Edward W|EW|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-6757",
"issue": "32(10)",
"journal": "The American journal of emergency medicine",
"keywords": null,
"medline_ta": "Am J Emerg Med",
"mesh_terms": "D061605:Administration, Intravenous; D000284:Administration, Oral; D000328:Adult; D001741:African Americans; D000900:Anti-Bacterial Agents; D015331:Cohort Studies; D003967:Diarrhea; D004636:Emergency Service, Hospital; D004761:Enterocolitis, Pseudomembranous; D005260:Female; D006630:Hispanic or Latino; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016017:Odds Ratio; D011446:Prospective Studies; D012307:Risk Factors; D044465:Whites",
"nlm_unique_id": "8309942",
"other_id": null,
"pages": "1195-9",
"pmc": null,
"pmid": "25149599",
"pubdate": "2014-10",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": "21694803;11152430;9777516;19359104;1420669;22047560;16635227;22491338;16514124;16514122;11821511;18929686;18971494;23177601;2911306;23103666;3846592;1753154;23158603;9892789;26038491;21935398;19049438;9630371;20153547",
"title": "Factors influencing the development of antibiotic associated diarrhea in ED patients discharged home: risk of administering IV antibiotics.",
"title_normalized": "factors influencing the development of antibiotic associated diarrhea in ed patients discharged home risk of administering iv antibiotics"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2016SP003476",
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"activesubstance": {
"activesubstancename": "UNSPECIFIED INGREDIENT"
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"abstract": "Due to rarity of insulin-producing pancreatic neuroendocrine carcinomas, no large, nor randomized studies of the clinical course, treatment options and outcome are available. Therefore, we want to share our personal experience and we retrospectively reviewed a cohort of five patients.\n\n\n\nThis study reports on the clinical characteristics, disease course, management and outcome of five patients with an advanced pancreatic neuroendocrine carcinoma with insulin production, which we followed recently in our center (between 2006 and 2015). Extraordinary for our cohort is that, except for one patient, which was diagnosed with a de novo malignant insulinoma, all other patients were diagnosed with a non-functional pancreatic neuroendocrine tumor which evolved during the disease course to a malignant insulinoma.\n\n\n\nAlthough various treatment strategies, both surgical and medical, are used to prolong survival and prevent hypoglycemic events, long-term prognosis of these patients remains poor, especially after transformation of a non-functional pancreatic neuroendocrine tumor to an insulin-producing neuroendocrine carcinoma. Of all five patients, only one is still alive, the other four died 25, 17, 3 and 1 month(s) after diagnosis of the malignant insulinoma. In general, prognosis is determined by early diagnosis and treatment, and by resectability of the tumor and its biological behavior.\n\n\n\nManagement of a malignant insulinoma is very challenging and a better understanding of the underlying mechanisms of this disease entity and its biological behavior is absolutely necessary to improve diagnostic tools, treatment and outcome in the future. (Acta gastro-enterol. belg., 2016, 79, 321-327).",
"affiliations": null,
"authors": "Lowette|K|K|;Verslype|C|C|;Van Cutsem|E|E|",
"chemical_list": "D007328:Insulin",
"country": "Belgium",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1784-3227",
"issue": "79(2)",
"journal": "Acta gastro-enterologica Belgica",
"keywords": null,
"medline_ta": "Acta Gastroenterol Belg",
"mesh_terms": "D018278:Carcinoma, Neuroendocrine; D005500:Follow-Up Studies; D006801:Humans; D007328:Insulin; D007340:Insulinoma; D010190:Pancreatic Neoplasms; D011379:Prognosis",
"nlm_unique_id": "0414075",
"other_id": null,
"pages": "321-327",
"pmc": null,
"pmid": "27821028",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical characteristics and management of insulin-producing neuroendocrine carcinomas.",
"title_normalized": "clinical characteristics and management of insulin producing neuroendocrine carcinomas"
} | [
{
"companynumb": "BE-MYLANLABS-2017M1015415",
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"activesubstance": {
"activesubstancename": "OXALIPLATIN"
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... |
{
"abstract": "Ruxolitinib is a potent inhibitor of JAK1/2 with proven efficacy in myelofibrosis. In recent years, research in graft versus host disease (GVHD) has revealed the role of activation of JAK pathways in alloreactive lymphocytes. Some reports have shown significant responses in refractory GVHD patients.\n\n\n\nIn this report we present our experience in 8 patients with acute or chronic GVHD with refractoriness to steroids and extracorporeal photopheresis treated with ruxolitinib. Three patients had acute GVHD (1 pulmonary, 2 cutaneous, 1 multi-systemic) and 5 had chronic GVHD (3 cutaneous); 85% obtained an overall response and 50% a complete response with a tolerable toxicity profile.\n\n\n\nIn our series, Ruxolitinib was very active as a rescue therapy for patients with acute or chronic GVHD refractory to standard treatment.",
"affiliations": "Adult Hematopoietic Stem Cell Transplantation Program, Pontificia Universidad Católica de Chile, Diagonal Paraguay 362, 6th Floor, ZC 832000 Santiago, RM Chile.;School of Medicine, Universidad Austral de Chile, Independencia 641, Valdivia, Chile.;Adult Hematopoietic Stem Cell Transplantation Program, Pontificia Universidad Católica de Chile, Diagonal Paraguay 362, 6th Floor, ZC 832000 Santiago, RM Chile.;Adult Hematopoietic Stem Cell Transplantation Program, Pontificia Universidad Católica de Chile, Diagonal Paraguay 362, 6th Floor, ZC 832000 Santiago, RM Chile.;Adult Hematopoietic Stem Cell Transplantation Program, Pontificia Universidad Católica de Chile, Diagonal Paraguay 362, 6th Floor, ZC 832000 Santiago, RM Chile.;Adult Hematopoietic Stem Cell Transplantation Program, Pontificia Universidad Católica de Chile, Diagonal Paraguay 362, 6th Floor, ZC 832000 Santiago, RM Chile.;Adult Hematopoietic Stem Cell Transplantation Program, Pontificia Universidad Católica de Chile, Diagonal Paraguay 362, 6th Floor, ZC 832000 Santiago, RM Chile.;Department of Hematology, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS/CSIC), Manuel Siurot 41013, Seville, Spain.",
"authors": "Sarmiento Maldonado|Mauricio|M|0000-0003-3715-9886;Ramírez Villanueva|Pablo|P|;Bertín Cortes-Monroy|Pablo|P|;Jara Arias|Veronica|V|;Soto Donoso|Katherine|K|;Uribe Gonzalez|Pablo|P|;Ocqueteau Tachini|Mauricio|M|;Perez-Simón|Jose Antonio|JA|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s40164-017-0092-3",
"fulltext": "\n==== Front\nExp Hematol OncolExp Hematol OncolExperimental Hematology & Oncology2162-3619BioMed Central London 292141169210.1186/s40164-017-0092-3Case ReportCompassionate use of ruxolitinib in acute and chronic graft versus host disease refractory both to corticosteroids and extracorporeal photopheresis http://orcid.org/0000-0003-3715-9886Sarmiento Maldonado Mauricio 223542615mauriciosarmiento@hotmail.com 1Ramírez Villanueva Pablo pramirezv2@gmail.com 2Bertín Cortes-Monroy Pablo pbertin@med.puc.cl 1Jara Arias Veronica vjara@med.puc.cl 1Soto Donoso Katherine ksotod@med.puc.cl 1Uribe Gonzalez Pablo puribeg@med.puc.cl 1Ocqueteau Tachini Mauricio moqueteau@med.puc.cl 1Perez-Simón Jose Antonio josea.perez.simon.sspa@juntadeandalucia.es 31 0000 0001 2157 0406grid.7870.8Adult Hematopoietic Stem Cell Transplantation Program, Pontificia Universidad Católica de Chile, Diagonal Paraguay 362, 6th Floor, ZC 832000 Santiago, RM Chile 2 0000 0004 0487 459Xgrid.7119.eSchool of Medicine, Universidad Austral de Chile, Independencia 641, Valdivia, Chile 3 0000 0000 9542 1158grid.411109.cDepartment of Hematology, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS/CSIC), Manuel Siurot 41013, Seville, Spain 2 12 2017 2 12 2017 2017 6 3211 11 2017 25 11 2017 © The Author(s) 2017Open 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\nRuxolitinib is a potent inhibitor of JAK1/2 with proven efficacy in myelofibrosis. In recent years, research in graft versus host disease (GVHD) has revealed the role of activation of JAK pathways in alloreactive lymphocytes. Some reports have shown significant responses in refractory GVHD patients.\n\nCases presentation\nIn this report we present our experience in 8 patients with acute or chronic GVHD with refractoriness to steroids and extracorporeal photopheresis treated with ruxolitinib. Three patients had acute GVHD (1 pulmonary, 2 cutaneous, 1 multi-systemic) and 5 had chronic GVHD (3 cutaneous); 85% obtained an overall response and 50% a complete response with a tolerable toxicity profile.\n\nConclusions\nIn our series, Ruxolitinib was very active as a rescue therapy for patients with acute or chronic GVHD refractory to standard treatment.\n\nKeywords\nRuxolitinibGraft versus host diseaseCorticoid refractorinessExtracorporeal photopheresisissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nAllogeneic transplantation remains the only curative strategy for many patients with hematologic malignancies including leukemias and myelodysplastic syndromes [1, 2]. Graft vs. host disease (GVHD) is one of the most frequent complications with high morbidity and mortality. First-line treatment with corticosteroids allows to obtain a response rate that varies between 50 and 70% [3]; however patients who did not respond have a poor response rate to second line regimens and have a high mortality [4–6]. Extracorporeal photopheresis (EP) has been consolidated in recent years as strategy second line treatment option for corticosteroid-refractory patients, allowing GVHD control in up to 70% of cases with cutaneous involvement with mild immunosuppressive effect and low rates of opportunistic infections [7]. Unfortunately, some patients are still refractory to corticosteroids and photopheresis, becoming a therapeutic challenge since no standard treatment has been identified. Ruxolitinib is a janus kinase (JAK1/2) inhibitor designed for the treatment of myelofibrosis, and in comparison with placebo or best available treatment, reduce spleen size and transfusional requirements [8]. In a murine model ruxolitinib has shown to induce an intense reduction of IL-1β, IL-6, or IFN-γ and TNF and other cytokines implicated in lymphocyte activation, which is a distinctive of GVHD [9]. With this background, ruxolitinib has been used in patients with refractory GVHD with overall responses in acute or chronic GVHD of 85 and 25% of complete remission. In this report we show our experience of ruxolitinib use in 8 patients with severe manifestations of acute and chronic GVHD who did not respond to EP.\n\nCase presentations\nCase 1\nA 54-year-old male was diagnosed with Philadelphia (−) acute B lymphoblastic leukemia in 2015. A relapse with central nervous system involvement was demonstrated 4 months after ending Hyper CVAD chemotherapy. He received intrathecal methotrexate with FLAGIDA chemotherapy achieving a second complete remission (CR) followed by a haploidentical myeloablative transplant with cyclophosphamide and total body irradiation (TBI) using peripheral blood hematopoietic stem cell transplantation (PBSCT) from a 3/6 HLA matched sibling. GVHD prophylaxis consisted of post transplant cyclophosphamide (days +3 and +4), tacrolimus and mycophenolate mofetil. 1 week post transplantation he developed febrile neutropenia and a progressive hepatic failure. After engraftment on day 12, he developed a progressive respiratory failure and required invasive mechanical ventilation. At day 14 an evanescent rash was noticed and the skin biopsy showed grade 3 aGVHD. Chest CT Scan showed an interstitial pattern of infiltration without images suggesting fungal infection. BAL was performed an all assays were negative (bacterial cultures, CMV PCR, EBV PCR, aspergillus test, no cardial test). He was started on high doses of methylprednisolone (1.5 g total dose) followed by prednisone 2 mg/kg/day without improvement after 14 days of treatment. A diagnosis of corticoid refractory acute GVHD NIH grade 3 was established and EP was started. During the first session of apheresis, his respiratory function worsened. We started low doses of ruxolitinib (5 mg BID), and after 2 weeks of treatment all cutaneous and hepatic alterations resolved and chest CT scan showed a significant resolution of the interstitial pattern. This allowed the weaning of the 2-month mechanical ventilation. After 12 months of treatment the patient have normal lung function and no other signs of GVHD nor leukemia relapse (Fig. 1).Fig. 1 Chest CT scans. Left panel shows an interstitial infiltrate previous to ruxolitinib. Right panel shows 1-month chest CT scan follow-up with nearly complete resolution of the pulmonary infiltrates\n\n\n\n\nCase 2\nA 28 year old male was diagnosed in 2014 with stage IVB, Hanseclever PS score of 5 classical nodular sclerosis Hodgkin´s disease. He was treated with 3 cycles of ABVD and and interim PET CT showed progressive disease. He then received 2 cycles of ICE (ifosfamide, carboplatine, etoposide) chemotherapy followed by autologous hematopoietic stem cell transplantation (auto-SCT). After 3 month post auto-SCT he was in CR but 6 months later he relapsed. Brentuximab–bendamustine rescue was started and after 4 months of treatment he achieved a second complete remission. Haploidentical transplant with reduced intensity conditioning was performed. At day 45, he developed and intense bloody diarrhea of 2–3 L/day. Endoscopic duodenal biopsy showed a severe GVHD NIH grade 3 (Fig. 2). He received a full dose of corticosteroids during 2 weeks without response, followed by 8 EP sessions, two per week, without clinical improvement. Progressive malnutrition was detected and parenteral nutrition was started. Ruxolitinib was initiated at 10 mg QD, and after 3 weeks of treatment diarrhea was controlled and all of nutritional parameters were improved. After 12 months of treatment with Ruxolitinib, he has normal nutritional parameters, no signs of GVHD and remains in CR.Fig. 2 Left panel shows colonoscopy with erythema and inflammation of duodenum. Right panel show a complete resolution of GVHD, 4 weeks after Ruxolitinib\n\n\n\n\nCase 3\nA 56-year-old male was diagnosed with germinal mediastinal tumor in 2011 and was treated with 3 cycles of bleomycin etoposide and platinum obtaining CR. A secondary acute myeloid leukemia was diagnosed in 2015. After standard induction with cytarabine and daunorubicin, he underwent a reduced intensity conditioning haploidentical transplantation but a relapse was diagnosed 14 months post transplant. Mixed chimerism with 46% recipient cellularity was found so a first infusion of donor lymphocytes (DLI) at a dose of 1 × 105 CD3/kg was performed. One month later a second DLI of 1 × 106 CD3/kg was performed, which resulted in severe erythroderma with mucosal involvement (Fig. 3). A skin biopsy was performed confirming aGVHD NIH grade 3. 6-Methyl-methylprednisolone was administered without clinical response. After 8 days of treatment he was started on EP twice a week without response. Ruxolitinib was started at a dose of 5 mg BID with significant improvement of his clinical condition. Ruxolitinib is currently being in use 6 months after transplantation. He is in CR and chimerism assay showed 90% donor hematopoiesis.Fig. 3 a Erythroderma at diagnosis of aGVHD. b Regression of cutaneous aGVHD after 2 weeks of treatment with ruxolitinib\n\n\n\n\nCase 4\nA 26-year-old female was diagnosed in 2015 with stage IVB (lung and bone involvement) nodular sclerosis Hodgkin’s lymphoma. She was treated with ABVD chemotherapy. An interim PET/CT scan after 4 cycles showed progressive disease. She received ESHAP chemotherapy with no response after 2 cycles. She received ICE chemotherapy, obtaining CR after 3 cycles. She underwent reduced intensity conditioning haploidentical transplantation in September 2015. 8 months after transplant she developed cGVHD NIH grade 1 with liver involvement (AST 150 μ/L, ALT 190 μ/L, GGT 210 U/L, FA 250 μ/L, normal bilirubin). Other causes of liver injury including hepatotropic viruses, autoimmunity tests, and other parasitic or bacterial infections were ruled out. 6-methylprednisolone 1 mg/kg was initiated. Liver tests remained abnormal. One month later vesicular lesions appeared in the oral mucosa. Biopsy showed mucoceles and inflammation compatible with cGVHD NIH 2. Her liver function progressively worsened and progressive malnutrition was confirmed. She required parenteral nutritional support and ECP was started, but after 8 sessions there was no response. Ruxolitinib 10 mg QD was initiated and after 2 months of treatment the liver tests returned to normal and the oral lesions partially remitted allowing her to satisfactory feeding (Fig. 4).Fig. 4 a Several mucosal lesions compatibles with mucocele. b A nearly complete remission of mucoceles, after treatment with ruxolitinib\n\n\n\n\nCase 5\nA 52-year-old male patient was diagnosed with Acute Lymphoblastic Leukemia philadelphia (+) in November of 2012. He was treated with HyperCVAD and dasatinib, obtaining complete molecular remission. He received a 5/6 mismatched unrelated donor transplant after myeloablative conditioning. After 2 years of transplantation he developed a progressive rash, xerophthalmia, xerostomia and oral ulcerations. Besides of cutaneous disease he developed liver malfunction with AST/ALT 4 times above normal values and total bilirubin of 8 mg/dL, concordant with a cGVHD NIH grade 3. 6-Methylprednisolone at 1 mg/kg was started. After 1 month of therapy, liver tests and cutaneous lesions were controlled, but oral lesions worsened. Clobetasol mouthwash was administered without improvement. Malnutrition was evident at this point and ECP was started. After 8 ECP procedures oropharyngeal ulcerations had not improved. We started Ruxolitinib 5 mg BID and after 4 months of therapy a progressive improvement of ulceration was evident. After 2 years of treatment, the patient has mild xerostomia without other signs or symptom of cGVHD.\n\nCase 6\nA 36-year-old woman was diagnosed with Ph (+) acute lymphoblastic leukemia in 2013. She was treated with HyperCVAD chemotherapy and dasatinib, with complete molecular remission after 4 months of treatment. She received a PBSCT from her HLA identical brother after a myeloablative conditioning (CY-TBI) and GVHD prophylaxis with methotrexate and cyclosporine. She developed aGVHD NIH grade 1 with intestinal involvement initially treated with budesonide. 24 months later she started with hyperpigmentation in thorax and severe and rapidly progressive sclerodermoid features in the legs, arms and neck, with deep panniculitis and fasciitis-like sclerotic cGVHD NIH grade 3. Skin biopsy confirmed cGVHD, and systemic corticosteroids and low-dose oral methotrexate were started, with only partial response after 2 months of therapy. There was no clinical improvement after 4 months with progression of her scleroderma with severe involvement of movement in the legs and hip rotation. There was no response to ECP 12 sessions. Ruxolitinib 10 mg QD was started and scleroderma improved significantly after 3 months allowing a normal deambulation. After 11 months of ruxolitinib, sclerodermic form persists but in lower grade and normalization of skin changes. Modified Rodnan score improved from 26 to 16 (Fig. 5).Fig. 5 Left panels show intense sclerotic features of cGVHD in hands and neck. Right panel shows some improvement in hands and nearly complete resolution in neck after ruxolitinib treatment\n\n\n\n\nCase 7\nA 46 year old male was diagnosed with AML del11q23 in 1996. He received chemotherapy followed by autoSCT. In 2012 he showed a progressive leukocytosis and AML with del 7 was diagnosed. He received induction chemotherapy with daunorubicin and cytarabine and obtained a 2nd complete remission. He received a PBSCT from an 8/8 HLA identical unrelated donor after myeloablative conditioning. He developed progressive scleroderma, non infectious hepatitis and mild diarrhea 2 years after transplantation with 18 kg of weight loss. Intense xerophthalmia, xerostomia and skin involvement was observed. He had alopecia, disabling acral erythema and desquamation, following development of lichen sclerosus-like lesions upon his trunk, arms, legs and ears. He developed severe sclerodactyly, resorption of distal phalanges and anonychia, with important functional impairment. Endoscopic study and biopsy confirmed cGVHD NIH grade 3. He was started on corticosteroids, tacrolimus, thalidomide, azathioprine, clofazimine without any response. Between December 2013 and October 2014, he was treated with ECP, with a transient intestinal and cutaneous response and a subsequent flare of cGVHD manifestations. A short cycle of methotrexate was inefficient; afterwards imatinib therapy during 6 months was also used without any improvement (A summarized information of all patients is showed in Table 1).Table 1 Patients characteristics\n\nCase\tGender/age\tNIH GVHD grade\tSites involved\tPrevious treatment\tTime to diagnosis to ruxolitinib\tResponse obtained\tFollow up (years)\tDose adjustments of ruxolitinib due to adverse events\t\n1\tMale/51\t3 acute\tSkin\nLung\tTacrolimus\nMycophenolate\nCorticosteroids\nExtracorporeal photopheresis\t21 days\tPartial remission\t2\tNo\t\n2\tMale/28\t3 acute\tDuodenal\tTacrolimus\nMycophenolate\nCorticosteroids\nExtracorporeal photopheresis\t5 weeks\tComplete remission\t2\tNo\t\n3\tMale/56\t3 acute\tSkin\tCyclosporine\nMethotrexate\nCorticosteroids\nExtracorporeal photopheresis\t5 weeks\tComplete remission\t1\tNo\t\n4\tFemale/26\t3 chronic\tSkin\nOral mucosa\nLung\tTacrolimus\nMycophenolate\nCorticosteroids\nExtracorporeal photopheresis\t3 months\tPartial remission\t1\tYes\n50% reduction for neutropenia grade 2\t\n5\tMale/52\t3 chronic\tSkin\nLiver\nOral mucosa\tTacrolimus\nMycophenolate\nCorticosteroids\nExtracorporeal photopheresis\t3 months\tPartial remission\t1\tNo\t\n6\tFemale/36\t3 chronic\tSkin\tCyclosporine\nMethotrexate\nCorticosteroids\nExtracorporeal photopheresis\t10 months\tPartial remission\t1\tNo\t\n7\tMale/46\t3 chronic\tSkin\nLiver\tCyclosporine\nMethotrexate\nCorticosteroids\nImatinib\nExtracorporeal photopheresis\t18 months\tPartial remission\t1\tNo\t\n8\tFemale/26\t2 chronic\tLung\tTacrolimus\nMycophenolate\nCorticosteroids\nExtracorporeal photopheresis\t6 months\tComplete remission\t1\tYes\n75% reduction for neutropenia grade 2\t\n\n\nHe started ruxolitinib 10 mg BID, and after 3 months hepatitis features resolved and diarrhea stopped. After 6 months of treatment he shows a significant improvement of scleroderma, he recovered his basal weight and shows a complete improvement of ocular GVHD (Fig. 6).Fig. 6 Left panels show intense sclerotic features of cGVHD in both hands and feet. Right panel shows a nearly complete resolution after ruxolitinib treatment\n\n\n\n\nCase 8\nA 28 years old female was diagnosed with IV B classical Hodgkin lymphoma in 2014, and was treated with ABVD schema obtaining a complete remission. She relapsed in 2016 and after a first attempt of ICE chemotherapy no response was observed and brentuximab rescue was planned. She completed 3 months of treatment and attained a 2nd complete response. She received a PBSCT from a haploidentical donor after reduced intensity conditioning. 6 months post transplantation she developed a progressive hypoxemic pulmonary insufficiency and CT scan shows a nodular pattern. Bronchioloalveolar lavage was performed which ruled out any infection. A lung biopsy showed an inflammatory pattern compatible with GVHD NIH grade 3. There was no response to corticosteroid therapy and ECP was started without significant improvement after 12 sessions. Ruxolitinib 10 mg BID was started and after 3 months of therapy his CT Scan showed a complete remission of lung nodular infiltrates (Fig. 7).Fig. 7 Left Pannel shows CT Scan at diagnosis of chronic lung GVHD. Right panel shows CT scan 3 months after ruxolitinb treatment\n\n\n\n\nDiscussion\nGVHD is a potentially lethal complication after hematopoietic stem cell transplantation [3]. The absence of response to corticosteroids is associated with an increased risk of death. EP has allowed treating patients who do not respond to corticosteroids, with the advantage of being less immunosuppressive as compared to other strategies such as ATG, imatinib, pentostatin, alemtuzumab, rituximab, etc. However, patients who do not respond to corticosteroids and EP are in a very unfavorable situation. Usually these patients have been treated with different immunosuppressive treatments without a consistent response.\n\nRuxolitinib has emerged in recent years as an excellent strategy for the control of refractory patients [9]. Previously, preclinical studies showed that ruxolitinib have a potent immunomodulatory and anti-inflammatory effects with decrease of proinflammatory cytokines [10]. More recently, a cooperative study [11] showed a multicentric analysis of 54 patients with aGVHD refractory to corticosteroid treatment and 41 with cGVHD with overall response rate of 81.5% (44/54) in aGVHD including 25 complete responses (46.3%) and an ORR of 85.4% (35/41) in cGVHD, with a low GVHD relapse rate. This outstanding outcomes have also been reported in treatment of sclerotic forms of the disease, a condition that usually has poor response rates [12, 13]. Not only in adult transplantation has been reported this remarkable response. Recently a pediatric group showed a 45% overall response in 13 children’s with refractory GVHD [14]. Based on these encouraging results prospective randomized trials are ongoing in order to confirm the efficacy of ruxolitinib in acute and cGVHD. Also, a new JAK2/FLT3 inhibitor, pacritinib, has recently shown promising results in xenograft mouse models of JAK2V617F-driven diseases [15]. Likewise, there is a growing interest in developing other JAK pathway inhibitors in GVHD, such as momelotinib, bacritinib and itacitinib [16, 17]. To the best of our knowledge, our report is the first to show experience in the use of ruxolitinib in patients refractory or resistant to corticosteroids and EP. In our patients who have received this agent within a compassionate use, an overall response rate of 90% was observed. Another interesting report from our series is that, even in patients with digestive GVHD responses have been observed, despite the doubts regarding the bioavailability of oral drugs in patients with high-flow diarrhea [18]. In addition, we observed a favorable response in pulmonary GVHD, the most severe and with the highest mortality [19]. So far all of our patients continue to use the drug, with good tolerance and without major adverse effects. Only in two of them was it necessary to adjust the dosage due to haematological toxicity, mainly mild neutropenia, which was recovered when establishing the appropriate dose. Our report shows a satisfactory experience in controlling this serious condition among patients failing to corticosteroids and EP. According to our experience, it could be thought that it is better to use ruxolitinib as a second-line medication for the treatment of refractory GVHD. Randomized studies are necessary to answer this and generate a treatment algorithm.\n\nConclusions\nRuxolitinib has shown a remarkable and hopeful response in patients with GVHD refractory to corticosteroids in recent years. Our report shows that in patients with refractoriness to corticoids and extracorporeal photopheresis also has excellent results with good tolerance and minimal adverse effects, even in difficult cases such as sclerodermiform forms and lung disease.\n\nAbbreviations\nAMLacute myeloid leukemia\n\nABVDchemotherapy protocol with doxorrubicina, bleomycin, vinblastine, dacarbazine\n\nCRcomplete remission\n\nCMVCytomegalovirus\n\nEBVEpstein Barr virus\n\nEPextracorporeal photoapheresis\n\nFLAGIDAchemotherapy protocol with fludarabina, idarrubicin, cytarabine, filgrastim\n\nGVHDgraft versus host disease\n\nHyperCVADchemotherapy protocol with cytarabine, vincristine, doxorrubicin, dexamethasone, methotrexate\n\nICEchemotherapy with ifosfamide, carboplatine, etoposide\n\nILinterleukin\n\nIFNinterferon\n\nJAK2janus kinase\n\nPBSCTperipheral blood hematopoietic stem cell transplantation\n\nPET/CTpositron emission tomography\n\nAuthors’ contributions\nAll authors participated with contributions to the conception of the work; acquisition, analysis, and interpretation of data drafting the work or revising it critically for important intellectual content. All authors read approved the final manuscript.\n\nAcknowledgements\nNot applicable.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAvailability of data and materials\nNot applicable.\n\nEthics approval and consent to participate\nThe ethical committee of our institution approved this manuscript. The information of patient’s data was kept under confidentiality and a consent for publication was obtained.\n\nFunding\nNot applicable.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Passweg JR Baldomero H Bader P Bonini C Cesaro S Dreger P Hematopoietic stem cell transplantation in Europe 2014: more than 40 000 transplants annually Bone Marrow Transplant 2016 51 6 786 792 10.1038/bmt.2016.20 26901709 \n2. Sureda A Bader P Cesaro S Dreger P Duarte RF Dufour C Indications for allo- and auto-SCT for haematological diseases, solid tumours and immune disorders: current practice in Europe, 2015 Bone Marrow Transplant. 2015 50 8 1037 1056 10.1038/bmt.2015.6 25798672 \n3. Presland RB Biology of chronic graft-vs-host disease: immune mechanisms and progress in biomarker discovery World J Transplant. 2016 6 4 608 619 10.5500/wjt.v6.i4.608 28058210 \n4. Levine JE Logan B Wu J Alousi AM Ho V Bolanos-Meade J Weisdorf D Graft-versus-host disease treatment: predictors of survival Biol Blood Marrow Transplant 2010 16 12 1693 1699 10.1016/j.bbmt.2010.05.019 20541024 \n5. Nassereddine S Rafei H Elbahesh E Tabbara I Acute graft versus host disease: a comprehensive review Anticancer Res 2017 37 4 1547 1555 10.21873/anticanres.11483 28373413 \n6. Abu-Dalle I Reljic T Nishihori T Antar A Bazarbachi A Djulbegovic B Extracorporeal photopheresis in steroid-refractory acute or chronic graft-versus-host disease: results of a systematic review of prospective studies Biol Blood Marrow Transplant 2014 20 11 1677 1686 10.1016/j.bbmt.2014.05.017 24867779 \n7. Bittenbring J Reichrath J Extracorporeal photopheresis for non-skin GvHD Anticancer Res 2016 36 3 1395 1396 26977041 \n8. Verstovsek S Mesa RA Gotlib J Gupta V DiPersio JF Catalano JV Long-term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial J Hematol Oncol. 2017 10 1 55 10.1186/s13045-017-0417-z 28228106 \n9. Carniti C Gimondi S Vendramin A Recordati C Confalonieri D Bermema A Pharmacologic inhibition of JAK1/JAK2 signaling reduces experimental murine acute GVHD while preserving GVT effects Clin Cancer Res. 2015 21 16 3740 3749 10.1158/1078-0432.CCR-14-2758 25977345 \n10. Shanavas M Popat U Michaelis LC Fauble V McLornan D Klisovic R Outcomes of allogeneic hematopoietic cell transplantation in patients with myelofibrosis with prior exposure to janus kinase 1/2 inhibitors Biol Blood Marrow Transplant 2016 22 3 432 440 10.1016/j.bbmt.2015.10.005 26493563 \n11. Zeiser R Burchert A Lengerke C Verbeek M Maas-Bauer K Metzelder SK Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter survey Leukemia 2015 29 10 2062 2068 10.1038/leu.2015.212 26228813 \n12. Hurabielle C Sicre de Fontbrune F Moins-Teisserenc H Robin M Jachiet M Coman T Efficacy and tolerance of ruxolitinib in refractory sclerodermatous chronic graft-versus-host disease Br J Dermatol 2017 28422274 \n13. Choi J Cooper ML Alahmari B Ritchey J Collins L Holt M DiPersio JF Pharmacologic blockade of JAK1/JAK2 reduces GvHD and preserves the graft-versus-leukemia effect PLoS ONE 2014 9 10 e109799 10.1371/journal.pone.0109799 25289677 \n14. Khandelwal P Teusink-Cross A Davies SM Nelson AS Dandoy CE El-Bietar J Ruxolitinib as salvage therapy in steroid-refractory acute graft-versus-host disease in pediatric hematopoietic stem cell transplant patients Biol Blood Marrow Transplant 2017 23 7 1122 1127 10.1016/j.bbmt.2017.03.029 28344057 \n15. Hart S Goh KC Novotny-Diermayr V Hu CY Hentze H Tan YC SB1518, a novel macrocyclic pyrimidine-based JAK2 inhibitor for the treatment of myeloid and lymphoid malignancies Leukemia 2011 25 1751 1759 10.1038/leu.2011.148 21691275 \n16. Okiyama N Furumoto Y Villarroel VA Linton JT Tsai WL Gutermuth J Reversal of CD8 T-cell-mediated mucocutaneous graft-versus-host-like disease by the JAK inhibitor tofacitinib J Invest Dermatol. 2014 134 4 992 1000 10.1038/jid.2013.476 24213371 \n17. Kheirkhah A Di Zazzo A Satitpitakul V Fernandez M Magilavy D Dana R A pilot randomized trial on safety and efficacy of a novel topical combined inhibitor of janus kinase 1/3 and spleen tyrosine kinase for GVHD-associated ocular surface disease Cornea. 2017 36 799 804 10.1097/ICO.0000000000001206 28445193 \n18. Akpek G Chinratanalab W Lee LA Torbenson M Hallick JP Gastrointestinal involvement in chronic graft versus host disease: a clinicopathologic study Biol Blood Marrow Transplant. 2003 9 1 46 51 10.1053/bbmt.2003.49999 12533741 \n19. Palmer J Williams K Inamoto Y ChaiX Martin PJ Tomas LS Pulmonary symptoms measured by the national institutes of health lung score predict overall survival, non relapse mortality, and patient-reported outcomes in chronic graft-versus host-disease Biol Blood Marrow Transplant. 2014 20 33 337 344 10.1016/j.bbmt.2013.11.025 24315845\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2162-3619",
"issue": "6()",
"journal": "Experimental hematology & oncology",
"keywords": "Corticoid refractoriness; Extracorporeal photopheresis; Graft versus host disease; Ruxolitinib",
"medline_ta": "Exp Hematol Oncol",
"mesh_terms": null,
"nlm_unique_id": "101590676",
"other_id": null,
"pages": "32",
"pmc": null,
"pmid": "29214116",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "26493563;25798672;24867779;28228106;26901709;28058210;26228813;24315845;21691275;25977345;24213371;26977041;12533741;28344057;20541024;28373413;25289677;28445193;28422274",
"title": "Compassionate use of ruxolitinib in acute and chronic graft versus host disease refractory both to corticosteroids and extracorporeal photopheresis.",
"title_normalized": "compassionate use of ruxolitinib in acute and chronic graft versus host disease refractory both to corticosteroids and extracorporeal photopheresis"
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"abstract": "We report a case of a new diagnosis of systemic lupus erythematosus (SLE) in a patient with HIV who presented to the outpatient department with a fever, headache and lymphadenopathy. Cerebrospinal fluid analysis showed lymphocytic pleocytosis. Initial concerns were for an infectious process, and investigations for systemic and central nervous system infection were negative. Serum testing for ANA, dsDNA, nucleosome, anti-histone and ribosomal-P antibodies was positive. A magnetic brain imaging scan of the brain showed a well-circumscribed lesion in the right cerebellar peduncle on T2/FLAIR. The patient was commenced on prednisolone and rituximab, and had a good clinical response. The cerebellar lesion resolved and has not recurred with sequential imaging. SLE and HIV are both multi-systemic diseases which rarely co-occur. Autoimmune processes should be considered in HIV patients with multi-systemic symptoms and signs.",
"affiliations": "Beaumont Hospital, Dublin, Ireland.;Beaumont Hospital, Dublin, Ireland.;Beaumont Hospital, Dublin, Ireland.;Beaumont Hospital, Dublin, Ireland.",
"authors": "O'Kelly|Brendan|B|https://orcid.org/0000-0001-9367-6576;McNally|Cora|C|;McConkey|Sam|S|;Durcan|Laura|L|",
"chemical_list": "D000974:Antibodies, Antinuclear; D009707:Nucleosomes; D000069283:Rituximab; D004247:DNA; D011239:Prednisolone",
"country": "England",
"delete": false,
"doi": "10.1177/0961203320934851",
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"issue": "29(9)",
"journal": "Lupus",
"keywords": "HIV; Kikuchi disease; Systemic lupus erythematosus; central nervous system lupus; lupus nephritis",
"medline_ta": "Lupus",
"mesh_terms": "D000328:Adult; D000974:Antibodies, Antinuclear; D001921:Brain; D004247:DNA; D005260:Female; D005334:Fever; D015658:HIV Infections; D006261:Headache; D006801:Humans; D008180:Lupus Erythematosus, Systemic; D000072281:Lymphadenopathy; D008279:Magnetic Resonance Imaging; D009707:Nucleosomes; D011239:Prednisolone; D000069283:Rituximab",
"nlm_unique_id": "9204265",
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"pages": "1130-1132",
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"pmid": "32571141",
"pubdate": "2020-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "HIV and systemic lupus erythematosus: where immunodeficiency meets autoimmunity.",
"title_normalized": "hiv and systemic lupus erythematosus where immunodeficiency meets autoimmunity"
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"abstract": "While the COVID-19 epidemic occurred since December 2019, as of end April 2020, no treatment has been validated or invalidated by accurate clinical trials. Use of hydroxychloroquine has been popularised on mass media and put forward as a valid treatment option without strong evidence of efficacy. Hydroxychloroquine (HCQ) has its own side effects, some of which are very serious like acute haemolysis in glucose-6-phosphate dehydrogenase (G6PD) deficient patients. Side effects may be worse than the disease itself. Belgian national treatment guidelines recommend the use of HCQ in mild to severe COVID-19 disease. As opinions, politics, media and beliefs are governing COVID-19 therapy, performance of randomised controlled blinded clinical trials became difficult. Results of sound clinical trials are eagerly awaited. We report a case of acute haemolysis leading to admission in intensive care unit and renal failure in a patient with uncovered G6PD deficiency.",
"affiliations": "Infectious Diseases Clinic, University Hospital Brugmann, Brussels, Belgium.;Infectious Diseases Clinic, University Hospital Brugmann, Brussels, Belgium.;Infectious Diseases Clinic, University Hospital Brugmann, Brussels, Belgium.;Internal Medicine Department, University Hospital Brugmann, Brussels, Belgium.;Brussels Academic Hospital Laboratory, Brussels, Belgium.;Internal Medicine Department, University Hospital Brugmann, Brussels, Belgium.;Intensive Care Unit, University Hospital Brugmann, Brussels, Belgium.;Infectious Diseases Clinic, University Hospital Brugmann, Brussels, Belgium.",
"authors": "Maillart|E|E|;Leemans|S|S|;Van Noten|H|H|;Vandergraesen|T|T|;Mahadeb|B|B|;Salaouatchi|M T|MT|;De Bels|D|D|0000-0001-9324-5768;Clevenbergh|P|P|",
"chemical_list": "D004791:Enzyme Inhibitors; D006242:Haptoglobins; D006886:Hydroxychloroquine; D017963:Azithromycin",
"country": "England",
"delete": false,
"doi": "10.1080/23744235.2020.1774644",
"fulltext": null,
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"issn_linking": "2374-4243",
"issue": "52(9)",
"journal": "Infectious diseases (London, England)",
"keywords": "Covid-19; adverse event; evidence-based medicine; glucose-6-phosphate dehydrogenase (G6PD) deficiency; haemolysis; hydroxychloroquine",
"medline_ta": "Infect Dis (Lond)",
"mesh_terms": "D000368:Aged; D017963:Azithromycin; D000073640:Betacoronavirus; D001803:Blood Transfusion; D000086382:COVID-19; D000079664:Continuous Renal Replacement Therapy; D018352:Coronavirus Infections; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors; D005955:Glucosephosphate Dehydrogenase Deficiency; D006242:Haptoglobins; D006461:Hemolysis; D006801:Humans; D006886:Hydroxychloroquine; D000860:Hypoxia; D008297:Male; D009305:Nasopharynx; D058873:Pandemics; D011024:Pneumonia, Viral; D012128:Respiratory Distress Syndrome; D045473:SARS Virus; D000086402:SARS-CoV-2",
"nlm_unique_id": "101650235",
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"pages": "659-661",
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"pubdate": "2020-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "32335561;31612996;32240719;32145363;28556555;32330521;32330122;32324284;31860324",
"title": "A case report of serious haemolysis in a glucose-6-phosphate dehydrogenase-deficient COVID-19 patient receiving hydroxychloroquine.",
"title_normalized": "a case report of serious haemolysis in a glucose 6 phosphate dehydrogenase deficient covid 19 patient receiving hydroxychloroquine"
} | [
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"companynumb": "BE-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-250027",
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"drug": [
{
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"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE"
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{
"abstract": "A 22-year-old woman presented with high fever, chest tightness and cough in January 20XX. Since CT scans revealed an anterior mediastinal mass, percutaneous needle biopsies of the mass were performed and she was diagnosed with T-cell lymphoblastic lymphoma (T-LBL). After the immunophenotype of lymphocytes in her pleural effusion had been identified, she received CHOP therapy because her dyspnea worsened, and induction therapy for acute lymphoblastic leukemia was subsequently performed after confirmation of her diagnosis as T-LBL. During this induction therapy, she developed paralytic ileus. One week thereafter, she suddenly exhibited visual disturbance, headache and nausea. Her cerebrospinal fluid was normal. Magnetic resonance imaging showed symmetrical high signal intensities on T2-weighted and fluid-attenuated inversion recovery images, and low signal intensities on T1-weighted images in the cortical and subcortical white matter of the posterior parietal and occipital lobes. Based on these findings, she was diagnosed as having posterior reversible encephalopathy syndrome (PRES). During chemotherapy for hematologic malignancies, some patients with PRES reportedly develop paralytic ileus or tumor lysis syndrome. PRES should be considered in patients with neurological abnormalities following such complications during chemotherapy.",
"affiliations": "Department of Hematology, Hokkaido University Graduate School of Medicine.",
"authors": "Hayase|Eiko|E|;Sugita|Junichi|J|;Fujimoto|Katsuya|K|;Ebata|Ko|K|;Yamakawa|Tomohiro|T|;Yoshida|Miho|M|;Takemura|Ryo|R|;Iwasaki|Junko|J|;Takahashi|Shojiro|S|;Shiratori|Souichi|S|;Kondo|Takeshi|T|;Tanaka|Junji|J|;Teshima|Takanori|T|",
"chemical_list": "D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "Japan",
"delete": false,
"doi": null,
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"issn_linking": "0485-1439",
"issue": "55(2)",
"journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology",
"keywords": null,
"medline_ta": "Rinsho Ketsueki",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D004317:Doxorubicin; D005260:Female; D006801:Humans; D060828:Induction Chemotherapy; D007418:Intestinal Pseudo-Obstruction; D008279:Magnetic Resonance Imaging; D008479:Mediastinal Neoplasms; D054038:Posterior Leukoencephalopathy Syndrome; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; D011241:Prednisone; D014750:Vincristine; D055815:Young Adult",
"nlm_unique_id": "2984782R",
"other_id": null,
"pages": "249-53",
"pmc": null,
"pmid": "24598194",
"pubdate": "2014-02",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Posterior reversible encephalopathy syndrome following paralytic ileus caused by vincristine in a patient with T cell lymphoblastic lymphoma.",
"title_normalized": "posterior reversible encephalopathy syndrome following paralytic ileus caused by vincristine in a patient with t cell lymphoblastic lymphoma"
} | [
{
"companynumb": "JP-WATSON-2014-13745",
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"activesubstancename": "VINCRISTINE"
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{
"abstract": "Ulcerative colitis often develops in the reproductive age women and can cause exacerbation by pregnancy. Mesalazine (5-aminosalicylic acid) is recommended as a safe anti-inflammatory drug during pregnancy. However, maternal mesalazine is transferred to the fetus through the placenta and may cause allergic events. A pregnant woman with severe ulcerative colitis was treated with a dose of mesalazine 4,000 mg/day from early gestation to delivery. Immediately after birth, the preterm neonate vomited bloody contents and discharged massive gross haematochezia. Serum concentrations of mesalazine and its main metabolite were high in the mother and the umbilical cord. Faecal eosinophils and drug-induced lymphocyte stimulation test suggested possibility that sensitisation with mesalazine in utero caused allergic enterocolitis like food protein-induced allergic proctocolitis. Maternal mesalazine has a potential of fetal sensitisation and cause allergic disease.",
"affiliations": "Department of Neonatology, Shikoku Medical Center for Children and Adults, Zentsuji, Kagawa, Japan knii0704@gmail.com.;Division of Neonatology, Tokyo Metropolitan Children's Medical Center, Fuchu, Tokyo, Japan.;Department of Pediatrics, Kagawa University, Miki-cho, kitagun, Kagawa, Japan.;Department of Neonatology, Shikoku Medical Center for Children and Adults, Zentsuji, Kagawa, Japan.",
"authors": "Nii|Kohichiroh|K|http://orcid.org/0000-0003-2519-1360;Okazaki|Kaoru|K|;Okada|Hitoshi|H|;Kuboi|Toru|T|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D019804:Mesalamine",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-238743",
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"issue": "14(4)",
"journal": "BMJ case reports",
"keywords": "GI bleeding; drugs: obstetrics and gynaecology; immunology; neonatal intensive care; pharmacodynamics",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D003093:Colitis, Ulcerative; D005260:Female; D006471:Gastrointestinal Hemorrhage; D006801:Humans; D007231:Infant, Newborn; D019804:Mesalamine; D011247:Pregnancy",
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"abstract": "For advanced-stage Hodgkin lymphoma (HL), front-line chemotherapy, alone or in combination with radiotherapy, leads to 5-year progression-free survival (PFS) rates and freedom-from-treatment failure (FFTF) rates of 70-85%, regardless of the chemotherapy regimen applied. Patients with HL experiencing disease progression during or within 3 months of front-line therapy (primary refractory) and patients whose disease relapses after a complete response have a second chance of treatment. The standard of care for relapsed or refractory HL is second-line chemotherapy followed by autologous stem cell transplantation (ASCT), which can induce long-term remission in approximately 40-50% of patients. However, HL recurrence occurs in about 50% of patients after ASCT, usually within the first year, and represents a significant therapeutic challenge. Allogeneic transplantation from HLA-matched donors represents the standard of care for patients with HL relapsing after- or refractory to ASCT.",
"affiliations": "Department of Hematology and Stem Cell Transplant, Presidio Ospedaliero Vito Fazzi, Lecce, Italy. direnzo.ematolecce@gmail.com.;Department of Emergency and Transplantation, Hematology Section, University of Bari Medical School, Italy. francesco.gaudio@policlinico.ba.it.;Department of Hematology and Oncology, Humanitas Cancer Center, Humanitas Clinical and Research Center - IRCCS, Rozzano (MI), Italy; Department of Biomedical Sciences, Humanitas University, Rozzano, Milano, Italy. carmelo.carlostella@hunimed.eu.;Bone Marrow Transplant Center, R. Binaghi Hospital, ASL 8, Cagliari, Italy. saraoppi@tiscali.it.;Hematology Division, Pisa University Hospital, Pisa, Italy. mpelo78@hotmail.com.;Division of Hematology, A.O. Santi Croce e Carle, Cuneo, Italy. sorasio.r@ospedale.cuneo.it.;Division of Hematology, Azienda Ospedaliera \"Bianchi Melacrino Morelli\", Reggio Calabria, Italy. caterinastelitano27@gmail.com.;Haematology Unit and Bone Marrow Transplant Unit, San Camillo Forlanini Hospital, Rome, Italy. luigi.rigacci@unifi.it.",
"authors": "Di Renzo|Nicola|N|;Gaudio|Francesco|F|;Carlo Stella|Carmelo|C|;Oppi|Sara|S|;Pelosini|Matteo|M|;Sorasio|Roberto|R|;Stelitano|Caterina|C|;Rigacci|Luigi|L|",
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"doi": "10.23750/abm.v91iS-5.9912",
"fulltext": "\n==== Front\nActa Biomed\nActa Biomed\nActa Bio Medica : Atenei Parmensis\n0392-4203\n2531-6745\nMattioli 1885 Italy\n\n32525132\nACTA-91-30\n10.23750/abm.v91iS-5.9912\nHow I Treat\nRelapsing/refractory HL after autotransplantation: which treatment?\nDi Renzo Nicola 1\nGaudio Francesco 2\nCarlo Stella Carmelo 3\nOppi Sara 4\nPelosini Matteo 5\nSorasio Roberto 6\nStelitano Caterina 7\nRigacci Luigi 8\n1 Department of Hematology and Stem Cell Transplant, Presidio Ospedaliero Vito Fazzi, Lecce, Italy\n2 Department of Emergency and Transplantation, Hematology Section, University of Bari Medical School, Italy\n3 Department of Hematology and Oncology, Humanitas Cancer Center, Humanitas Clinical and Research Center - IRCCS, Rozzano (MI), Italy; Department of Biomedical Sciences, Humanitas University, Rozzano, Milano, Italy\n4 Bone Marrow Transplant Center, R. Binaghi Hospital, ASL 8, Cagliari, Italy\n5 Hematology Division, Pisa University Hospital, Pisa, Italy\n6 Division of Hematology, A.O. Santi Croce e Carle, Cuneo, Italy\n7 Division of Hematology, Azienda Ospedaliera “Bianchi Melacrino Morelli”, Reggio Calabria, Italy\n8 Haematology Unit and Bone Marrow Transplant Unit, San Camillo Forlanini Hospital, Rome, Italy\nCorrespondence: Nicola Di Renzo E-mail: direnzo.ematolecce@gmail.com\n2020\n25 5 2020\n91 Suppl 5 3040\n02 5 2020\n25 5 2020\nCopyright: © 2020 ACTA BIO MEDICA SOCIETY OF MEDICINE AND NATURAL SCIENCES OF PARMA\n2020\nThis work is licensed under a Creative Commons Attribution 4.0 International License\nFor advanced-stage Hodgkin lymphoma (HL), front-line chemotherapy, alone or in combination with radiotherapy, leads to 5-year progression-free survival (PFS) rates and freedom-from-treatment failure (FFTF) rates of 70-85%, regardless of the chemotherapy regimen applied. Patients with HL experiencing disease progression during or within 3 months of front-line therapy (primary refractory) and patients whose disease relapses after a complete response have a second chance of treatment. The standard of care for relapsed or refractory HL is second-line chemotherapy followed by autologous stem cell transplantation (ASCT), which can induce long-term remission in approximately 40-50% of patients. However, HL recurrence occurs in about 50% of patients after ASCT, usually within the first year, and represents a significant therapeutic challenge. Allogeneic transplantation from HLA-matched donors represents the standard of care for patients with HL relapsing after- or refractory to ASCT.\n\nHodgkin Lymphoma\nRelapsing/refractory HL\nautologous transplantation\n==== Body\nIntroduction\n\nFor advanced-stage Hodgkin lymphoma (HL), front-line chemotherapy, alone or in combination with radiotherapy (RT), leads to 5-year progression-free survival (PFS) rates and freedom-from-treatment failure (FFTF) rates of 70-85%, regardless of the chemotherapy regimen applied. Patients with HL experiencing disease progression (DP) during or within 3 months of front-line therapy (primary refractory), and patients whose disease relapses after a complete response, have a second chance of treatment. The standard of care for relapsed or refractory HL is second-line chemotherapy followed by autologous stem cell transplantation (ASCT), which can induce a long-term remission in approximately 40-50% of patients. However, HL recurrence occurs in about 50% of patients after ASCT, usually within the first year, and represents a significant therapeutic challenge.\n\nSeveral factors have been associated with an increased risk of relapse following ASCT, including the number of prior regimens, less than a complete remission to salvage treatment prior to ASCT evaluated by PET-CT scan, the short duration of first remission, the poor performance status and extranodal involvement. Many regimens or single agents have been tested in patients with relapse after ASCT, showing an overall response rate of 20- 86%, including a complete response of 4-50%, with a short median duration of response, usually ranging from 5 to 20 months.\n\nAllogeneic transplantation from HLA-matched donors represents the standard of care for patients with HL relapsing after or refractory to ASCT. Unfortunately, not all the patients are eligible for this potentially curative therapeutic approach because of donors’ unavailability, advanced age and/or comorbidities. Although a second ASCT may be an option in patients who do not have a donor for an allogeneic stem cell transplantation (allo-SCT), it is not routinely recommended, especially nowadays that new drugs such as brentuximab vedotin (BV) and the checkpoint inhibitors (CPI) nivolumab and pembrolizumab are available. How these drugs should be integrated in the therapeutic strategy for treatment of patients with HL relapsing after ASCT will be discussed.\n\nDo we trust in PET scans?\n\nCase report 1\n\nA 25-year-old man was diagnosed with stage IIA classical Hodgkin lymphoma (cHL) involving bilateral cervical nodes and mediastinum (bulky). A staging PET/CT scan revealed a 2 x 3.9 cm right cervical node, with a standardized uptake value (SUV) of 10.5, a 1.9 x 2.5 cm right paratracheal node with a SUV of 8.0, and a 10.3 x 5.7 cm bulky mediastinic involvement with a SUV of 12.6. The therapeutic program was ABVD regimen for 4 cycles with an interim PET scan evaluation and Involved-field radiotherapy (IFRT). PET/CT scan performed after 2 cycles of the ABVD regimen demonstrated a persistent positivity on mediastinum (Deauville score: 4), with decreased mediastinal mass at CT scan. Therefore, the treatment was shifted to the BEACOPP regimen. Two cycles of BEACOPP and RT were scheduled. After 2 cycles, the PET/CT scan was persistently positive, with a Deauville score of 4 in the residual mediastinal mass, which was further reduced at CT scan. A CT scan guided biopsy of the positive PET area did not show any evidence of lymphoma. The patient was treated with 4 cycles of therapy following the BeGEV scheme, with stem cell collection after the second cycle. Pre-transplantation PET/CT scan showed again a persistent mediastinal PET scan positivity; a new biopsy was performed, suggesting again fibrotic tissue, in absence of lymphoproliferative disease. The patient received a high dose chemotherapy and ASCT, followed by a consolidation RT on mediastinal bulk. A CT scan after 45 days showed a reduction of the residual mass (3.8 x 2 cm) and a PET/CT scan performed after 3 months showed a reduction of the SUVmax and a Deauville score of 3. A new CT scan was performed after 3 months and showed a further minimal reduction of the residual mediastinal mass. No signs of active disease were observed during the follow-up.\n\nDiscussion\n\nFluorodeoxyglucose-positron emission tomography (FDG-PET) scan is without any doubt the best currently available predictor for HL patients. However, it should be used carefully due to the well-known false positivity issues.\n\nOur case clearly points out the wide variability of PET scan interpretation before and after stem cell transplantation, which could possibly lead to overtreat the patient or, by the contrary, underestimate a PET scan positive signal. According to the wide literature data, we probably overtreat some interim PET scan-positive patients (10-15%) or undertreat some interim PET scan-negative patients (5- 10%) (1-3).\n\nThe role of interim PET scan in advanced HL has been supported by several prospective studies, confirming that an early intensification in interim PET scan-positive patients significantly improves PFS (4-7). Moreover, with the interim FDG-PET scan evaluation, we avoid to use in all the patients a very intensive treatment such as the BEACOPP regimen.\n\nIn localized-stage HL patients, the role of FDG-PET scan is less consolidated and the literature data are conflicting (8-10). In particular, in bulky disease we can frequently observe a persistence of positivity either in interim PET scan or in end-of-treatment PET scan (11).\n\nSeveral papers and clinical trials tried to understand whether the PET scan results could be used to spare RT in HL patients. However, the chemotherapy in association with RT still remain the golden standard (12,13).\n\nIn uncertain cases, a CT scan-guided biopsy is mandatory in order to demonstrate the presence of residual disease. The possibility of PET scan false positivity is well known and reported in several studies, and every clinical decision should be supported whenever possible by a CT scan-guided biopsy. The possibility to overtreat patients should be considered in particular in localized-stage with bulky mass, due to the high frequency of false positive PET scans. Unfortunately, the persistence of positivity, even if intense, is usually very limited, the attempt to perform a biopsy to identify the cause very often fails, and in a CT scan-guided biopsy this result cannot be considered certain. The only reliable technique is the PET/CT scan-guided biopsy, but it is not applicable in all the centers (14,15).\n\nThus, a biopsy result suggesting the absence of lym- phoma should always be carefully discussed, in order to exclude a false negative specimen and not to lose or undertreat the patient.\n\nAnother issue about the PET-CT scan is its role in the peri-transplantation period. The literature has focused on pre-transplant PET scan, which is known to be important and predictive of good clinical outcomes: several authors reported a better PFS obtained with high dose chemotherapy with a negative PET scan (16). The role of PET scans after transplantation is more controversial (17,18). Some studies reported that persistence of PET scan positivity is associated with lower PFS and OS (19), however the data in this field are still limited. As a matter of fact, post-transplantation management, such as maintenance BV, is so far guided by pre-transplantation patient’s characteristics (20). Therefore, PET scan interpretation is a really critical issue, because it is not known which patients could be treated with RT only, or could be rescued by new agents, or in which patients an allo-SCT would be indicated (21,22).\n\nAfter an allo-SCT, the PET scan role is far more complicated, as false positivity has been described in case of graft versus host disease (GVHD) and other transplantation-associated complications (23,24). The case we described here is paradigmatic of all PET scan issues discussed above. The patient was probably overtreated. We should have continued with the scheduled therapy also with a PET scan positivity and with a Deauville score of 4 on bulky mass, considering that RT is curative in HL, omitting the high dose chemotherapy. In that moment, we had a persistent PET scan positivity on residual bulky disease, with a negative histological test, which however did not guarantee the absence of disease. However, considering the increasing SUVmax of the mediastinal mass, the young age and the very good conditions of the patient, and the global low therapeutic load as well, we proceeded to intensification. Clearly, the interim PET scan positivity could underlie a spread of the disease due to an insensitivity to chemotherapy, but this situation is much more likely with a Deauville score of 5 (25-27), when all the statements about PET scan false positivity are not applicable.\n\nIn the case we described, even the peri-transplantation PET scan was meaningful, in the era of post-transplantation maintenance with BV. Pre-transplantation PET scan was still positive, again with a negative biopsy. High dose chemotherapy was performed, but a softer approach, with strict clinical follow-up and PET scan, should have been another rational approach, as clearly demonstrated in the post-transplantation follow-up.\n\nPost-transplantation PET scan showed a SUV reduction of the known lesion, which was treated with local RT on initial bulky mass, showing a progressive disappearance in the follow-up. It could be speculated that a follow-up-based approach could have led to the same result.\n\nIn summary, the answer to the starting question is that, in our opinion, we can trust in PET scan, even if not blindly, and we should have a good knowledge of PET imaging technique and of PET scan interpretation.\n\nIn a localized stage with bulky disease, an interim positive PET scan with a Deauville score of 4 suggests to proceed with the scheduled therapy with a new PET evaluation before the start of RT. In our opinion, in case of PET scan positivity, and regardless of biopsy result, the patient should be treated with RT at the end of the pharmacological treatment. In case of persistent positivity at the end of treatment, a CT or PET/CT scan guided biopsy is mandatory, and if positivity is confirmed, the patient should undergo a salvage treatment. If the biopsy is negative, without any other sign or symptom of active disease, it could be useful to repeat a PET/CT scan after 2 or 3 months.\n\nPost-autotransplantation therapy: which treatment?\n\nCase report 2 Post-autotranplantation brentuximab\n\nOn February 2017, a 36-year-old male presented weight loss, low-grade fever and sweating. A CT scan revealed a voluminous enlargement of all lymph nodes (left LC, axillary and inguinal lymph nodes, with a maximum diameter of 5 cm, and right LC with a 9 cm diameter), with bilateral pulmonary micronodules; in the spleen was 3 cm and in the liver 2 cm, without parenchymal lesions. All lesions were PET scan-positive, and the patient was diagnosed with stage IVB cNS HL, type 2 BNLI. In March 2017, the patient started a treatment with the ABVD regimen; during the second cycle, despite a reduction of superficial nodes (diameter 3 cm), a fast progression of the disease was observed, with discomfort and enlargement of LC nodes (7 cm). Therefore, the treatment was switched to BEACOPP escalated for 3 cycles, with stem cell mobilization. After an initial significant node reduction, during the third cycle a new enlargement was observed, with a PET scan result of partial response (PR). In July 2017, the patient started 3 cycles of BeGV, and in October the PET scan was negative. HLA investigation identified a matched sibling donor. During pre-transplantation exams, a biopsy of the right LC node revealed a new progression. A treatment with 2 cycles of brentuximab was started, with PR. After the addition of bendamustine for 2 additional cycles, PET and abdomen ultrasound scans resulted negative. In May, the patient underwent autotransplantation with complete remission (CR), but he presented a symptomatic relapse after 2 months, with PET scan positive for nodes, bones, spleen and liver. CT and NMR scans revealed a diffuse positivity for nodes (max 3 cm), spleen hypodense lesions (max 2.6 cm), focal liver lesions (max 1.6 cm), and intertrochanteric femoral lesion (2 cm). In September, a new PET scan revealed a further increase of dimension and metabolic activity of part of the abdominal nodes, with new vertebral lesions (D9, D10, L2, L4), and with a slight regression of other sites. Four cycles of brentuximab were scheduled, with a concomitant administration of low dose corticosteroid. In December 2018, a treatment with nivolumab was started, with a good clinical response and symptoms regression, and the corticosteroid administration was discontinued. After 4 cycles of nivolumab, a DP (affecting spleen, liver, bones, and mediastinal, abdominal, LC and axillary nodes) was revealed by PET scan and confirmed by NMR.\n\nNivolumab therapy is currently ongoing. A hepatic bi- opsy was scheduled but not performed as no lesions were identified with ultrasound scan. The patient is currently free from systemic symptoms. A PET scan re-evaluation is scheduled, and a HLA identical donor is currently available.\n\nDiscussion\n\nBefore the development of BV and CPI, the median survival of HL patients relapsing after ASCT was 25 months (28). Allo -SCT could potentially cure about 40% of these patients, particularly when performed in the setting of a chemosensitive disease (29).\n\nIn patients relapsed after ASCT, BV demonstrated an Overall Response Rate (ORR) of 74% with 34% of cases with a CR; estimated PFS and Overall Survival (OS) were 9.3 and 40.5 months, respectively, with longer survivals in CR patients (30). Moreover, Chen et al. showed that BV- treated patients had a better 2-year PFS after allo-SCT compared to patients re-induced with standard chemotherapy (59.3% vs. 26.1%), with reduced cumulative incidence of relapse or progression (23.8% vs. 5.65%) due to better disease control prior to allo-SCT (31).\n\nBV could be considered the most suitable drug to “bridge” the patients to allo-SCT. However, 38% of complete BV responders could maintain a sustained response over time, also without allo-SCT consolidation (30). For this reason, a delay of allo-SCT to the time of DP during or after the BV treatment is now considered reasonable, provided that a salvage treatment with a CPI (nivolumab and pembrolizumab) is available. In this setting, pembrolizumab demonstrated an ORR of 73.9%, with 21.7% CR (32), and nivolumab an ORR of 68%, with 13% CR (33).\n\nNevertheless, only a minority of CPI-responding patients obtain a long-term remission, and allo-SCT remains the only potentially curative therapy. However, its timing in patients treated with CPI is matter of debate. Patients undergoing allo-SCT after CPI appeared at increased risk of grade 4 acute graft versus host disease (GVHD), veno-occlusive disease (VOD), and noninfectious febrile syndrome, requiring a prolonged steroid treatment. It should be underlined that the relapse rate was lower than previously reported (16% at 1 year), with an encouraging 1 year PFS of 74% (34). Recently, a large pooled analysis suggested that allo-SCT after CPI is feasible and not associated with higher mortality, provided that a careful consideration is given to prevention, early detection and treatment of GVHD (35). As questioned by Broccoli and Zinzani in a recent review, should allo-SCT be performed only in patients achieving a CR, in all patients with at least stable disease, or only in patients progressing while on CPI? (36). Herbaux and colleagues suggest keeping CR and PR patients on therapy instead of stopping it to proceed to allo-SCT (37). This is motivated, on one hand, by the relative safety of CPI compared to allo-SCT and, on the other, by the possibility to reinduce remission after CPI failure. In a retrospective analysis, salvage chemotherapy following CPI resulted in an ORR of 53% (38,39). Nevertheless, the authors recommend referral to a transplantation center for a potential transplantation at the time of CPI failure, considering an early allo-SCT only for patients in remission, with heavily pretreated refractory disease and no viable post–CPI salvage options. Shah and Moskowitz proposed an algorithm (40) where the patients achieving CR continue the CPI therapy for 3 additional months: if the CR is maintained, the authors suggest to stop the therapy and restart only in case of progression. For PR patients, the authors continue the therapy due to a possible late conversion to CR, but consider allo-SCT sooner. Finally, if there is stable disease on CPI treatment, the authors suggest to continue the therapy until DP, followed by an alkylator-based therapy or a clinical trial as a bridge to allo-SCT in case of responding disease. If allo-SCT is scheduled, CPI treatment should be hold for 6 weeks before transplantation. A reduced intensity conditioning, a bone marrow source and a post-transplantation cyclophosphamide treatment should be considered to minimize the risk of GVHD and VOD (37). Interestingly, these algorithms take into account the response to CPI treatment as outlined by PET/CT scans. However, CPI-induced activation of antitumor immune cells could theoretically increase the 18F-FDG uptake, masking the CPI efficacy. This so-called pseudoprogression, with imaging findings suggestive of progression, followed by later response, has been described in solid tumors and confirmed in HL patients. In 2016, the LYmphoma Re- sponse to Immunomodulatory therapy Criteria (LYR-IC) introduced the concept of indeterminate response to indicate the time interval until a biopsy or subsequent imaging confirm either a pseudoprogression or a true progression (41). On the other hand, hyperprogression, a condition in which CPI initiation leads to a paradoxal increase in tumor growth rate, seems to be associated with a worse prognosis (42). The literature data reported above led us to continue the CPI treatment in our patient, due to a satisfactory clinical response despite the progression at first PET/CT scan re-evaluation, but also to schedule allo-SCT despite the subsequent response, in consideration of the high probability of relapse and of the lack of suitable salvage therapy.\n\nPost-allotransplantation therapy: which treatment?\n\nCase report 3:Post-allotransplantation brentuximab (with lymphocytes infusion)\n\nA 22-year-young boy was diagnosed with stage IIIA cHL (mixed cellularity). He started the ABVD chemotherapy. The PET/CT scan after 2 cycles revealed a partial response, with residue in right retroclavicular lymph node, bilateral laterocervical and mediastinum. Therefore, he received 4 BEACOPP escalated cycles achieving RC (no evidence of hypermetabolic disease localization with PET/CT scan) and then other 4 BEACOPP baseline cycles. PET/CT scan showed CR.\n\nFour months after the end of therapy, the PET/TC scan revealed a relapse. A novel excisional biopsy (axillary node) confirmed cHL (nodular sclerosis). The patient was treated with 4 IGEV cycles (achieving PR) and with 4 cycles of BV infusion and subsequent ASCT with FEAM conditioning (CD34+ PBSC: 5x106/Kg).\n\nThe post-ASCT PET scan revealed a good but partial response to treatment (persistent uptake in bilateral submandibular lymph nodes, considerable reduction in laterocervical nodes, resolution of other nodal sites: mediastinal, axillary, jugular nodes).\n\nWithin 3 months before the SCT, the patient received another brentuximab infusion and RT (30 Gy in bilateral sub- mandibular and laterocervical nodes).\n\nThe patient underwent allogeneic haploidentical stem cell transplantation, fludarabine (30 mg/m2/day, from day -6 to day -2), cyclophosphamide (450 mg/m2/day, on days -6 and -5) and TBI 2 Gy (on day -1) conditioning, achieving a complete allogeneic engraftment. The patient received GVHD prophylaxis with CSA, MMF and cyclophosphamide. He did not present acute GVHD but the hospitalization was complicated by haemorrhagic cystitis and by cytomegalovirus reactivation.\n\nAfter 11 months, the disease relapsed (mixed cellularity with scleronodular areas at biopsy). The PET/CT scan showed a relapse in multiple lymph nodes above and under diaphragm, in pectoralis muscle and in spleen.\n\nThe patient started a treatment with bendamustine (90 mg/m2 on day +1 and +2) and brentuximab (1,8 mg/kg on day +1) every 21 days for 4 cycles.\n\nThe PET/CT scan revealed a CR. Brentuximab was well tolerated, Bendamustine determined third and fourth grade hematologic toxicity.\n\nThe patient continued the treatment combining brentuximab infusion (day +1, 1.8 mg/Kg every 21 days) with donor lymphocyte infusion (DLI) administration (day +8, in increasing doses) in alternating regimen. Treatment was repeated every 28 days. The patient received 8 brentuximab infusions on day +1 (3 in association with bendamustine) with 5 DLI (day +8, increasing doses: the first two at the dose of 1x105/kg, the third and the fourth at the dose 5x105/kg, the fifth at 1x106/Kg).\n\nThe treatment was well tolerated and stopped on April 14, 2015. The patient did not experience any no side effect. One month after the end of the therapy, the patient presented pruriginous maculopapular erythema on hand and feet palm, volar forearm and neck, treated with a steroid cream. After 5 months, a treatment with cyclosporine (with an initial dose of 3mg/Kg/day, reduced to 0.5mg/kg/day) was started for limited chronic cutaneous GVHD on hands and nails (nail dystrophy).\n\nForty-eight months after the end of therapy, the patient is still in CR and presents limited chronic GVHD, well controlled with cyclosporine at the dose of 0.5 mg/Kg/day.\n\nDiscussion\n\nFor patients developing disease recurrence or progression after allo-SCT, the prognosis is fatal and the treatment is challenging because most of these subjects are heavily pretreated and often are affected by a chemotherapy- resistant disease (43-46).\n\nCPI are increasingly used in this setting and appear to be highly effective, although with conflicting safety results as they can be complicated by the rapid onset of transplantation disease against the severely affected and treatment-resistant host (GVHD) (47,48). Anecdotal reports and some small series of cases suggested that BV, alone (49,50) or in combination with DLI, could be effective in a post-allograft setting (51).\n\nIt is interesting to note that the BV ORR was not in- fluenced by whether or not the patients received BV before undergoing allo-SCT, suggesting that rechallenge with BV could be advantageous in HL patients developing recurrent disease after allo-SCT, although theyhave received BV before transplantation.\n\nTreatment of HL patients developing recurrence or DP after allo-SCT remains a real challenge and an unmet medical need (43-46).\n\nDLI, with or without previous chemotherapy, resulted in a response rate ranging from 43% to 56%, at the expense of a grade 2-4 GVHD, ranging from 32% to 38% (52,53).\n\nCurrently, the treatment options for HL patients failing the allo-SCT are BV, with or without DLI, or CPI.\n\nThere is a shortage of data on the efficacy and safety of BV, either alone or in combination with DLI, for the treatment or prevention of relapse after allo-SCT.\n\nIn a recent study, the administration of BV after allo- SCT to 16 high-risk and highlypretreated HL patients led to an objective response rate of 73% (51). This high efficacy rate should not be attributed only to BV but rather to the combination of BV and DLI. The safety and efficacy of BV after allo-SCT were evaluated in a prospective study of 25 BV-naive patients with recurrent HL. Toxicity was minimal and easily manageable, while the overall response and CR rate were 50% and 38%, respectively. Median PFS was 7.8 months while the median OS was not achieved at the time of publication (49).\n\nIn another study, 16 previously BV-naive patients with recurrent HL after allo-SCT were included in a program of compassionate use. The treatment was safe, with anemia, neutropenia, thrombocytopenia and peripheral sensory neuropathy reported as the most frequent side effects. ORR was 69%, with five patients achieving CR. Median PFS and OS were 7 and 25 months, respectively (50).\n\nBoth the association of chronic GVHD with reduced incidence of relapse and the efficacy of DLI in inducing remissions in patients with relapsing HL after allo- SCT support the concept of a graft effect with respect to the HL effect (45, 46).\n\nThe largest body of data on the efficacy of DLI in HL patients comes from the cooperative study group in the United Kingdom. Seventy-six consecutive patients with relapsed/refractory HL underwent allo-SCT following reduced intensity conditioning. DLI was effective in restoring donor chimerism to 86% of patients. A lasting response to DLI was observed in 79% of patients treated for relapse, while DLI-related 3-year mortality was 7% and was mainly attributed to GVHD (54).\n\nHowever, it should be noted that these results were not reproduced from other studies evaluating the efficacy of DLI in the treatment of progressive or recurrent HL disease after allo-SCT. In these studies, the responses to the DLI were inconsistent and of short duration, as no patient reached a PFS in the long term (52, 55, 56).\n\nIn conclusion, the administration of BV in combination with DLI is safe and induces a significant anti-HL activity. Furthermore, it is strongly suggested that a BV-induced immunomodulatory effect resulted in a reduction in the incidence and severity of GVHD associated with DLI. The combination of BV plus DLI should be prospectively tested in a greater number of patients with high-risk HL after allo-SCT. It is conceivable that this approach will be more effective if used as a consolidation therapy for HL in response to allo-SCT rather than as a treatment for a confirmed relapse or a post-SCT progressive disease.\n\nThe working hypothesis supporting the combined BV-DLI treatment suggests that selective targeting of lymphoma cells could improve the graft response against leukemia by inducing immunogenic cell death (57). Furthermore, BV could potentially reduce GVHD by targeting CD30+ T cells (58). Adverse events were generally manageable and were not worse than expected in heavily pretreated patients. The most common events were generally of grade 1 or 2. Based on the hypothesis that antigen targeting on activated T cells could further compromise cell-mediated immunity in this high-risk population, particular attention was paid to a close monitoring of clinical infection. No grade III or IV infections were recorded and no CMV reactivation occurred. BV is a highly effective therapy with a good toxicity profile that can be offered to HL patients with relapse or progression after allo-SCT, in order to achieve an effective but transient disease control. Future studies should explore the combination of BV with DLI, conventional chemotherapy (e.g. bendamustine) or targeted agents (eg PI3K inhibitors or anti-PD-1 agents), to improve the tumor burden reduction and increase the rate of CR, thereby improving the disease control. The BV therapy, with or without DLI, could also be considered a prophylaxis strategy in patients at high risk of relapse after allo-SCT. Recent data regarding the reprocessing of BV support this therapeutic approach in patients that have previously received BV regimens during the course of the disease (59). Future studies could be justified to explore these new BV-based strategies in BV-naive and BV-sensitive patients.\n\nCase report 4: Post allotransplantation nivolumab\n\nIn 2012, a 49-year-old male patient with Parkinson’s disease in his past medical history, was diagnosed with stage IIIB cHL, and with International Prognostic Score of 4. He received 5 therapy lines: 6 cycles of ABVD regimen, resulting in a PR, 4 cycles of IGEV regimen followed by ASCT, with PR, 4 cycles of BV, resulting in DP, and then 6 cycles of bendamustine, with no response, showing a chemorefractory disease. Therefore, in 2014 we performed an allo-SCT from a matched sibling donor, due to the lack of other treatment options. The patient achieved a PR, that lasted for 28 months after allo-SCT. Subsequently, DP required additional treatments. The patient started a treatment with the anti-PD-1 nivolumab, at the standard dose of 3 mg/kg every 2 weeks. After 3 cycles, the patient developed a grade 2 elevation of liver enzymes and a grade 2 cutaneous and ocular GVHD. The nivolumab treatment was discontinued and corticosteroid treatment started, with a consequent normalization of the liver enzymes and the regression of cutaneous and ocular signs after 4 months. At that time, disease revaluation showed a CR.\n\nDiscussion\n\nAllo-SCT is a treatment option for patients with re- lapsed or refractory HL, when a previous autologous transplantation failed. Since the allo-SCT -related mortality continues to decline, with preparative regimens characterized by a lower-intensity and a better supportive care, the treatment of relapsed disease is increasing. Approximately 30% of allografted lymphoma patients relapse after allo-SCT (43).\n\nFor patients who develop disease recurrence or progression after allo-SCT, the prognosis is unfavorable and the treatment is challenging as most patients are heavily pretreated, and often have a chemotherapy-refractory disease.\n\nAside from rapidly minimizing the systemic immunosuppression, no standard strategy is currently available.\n\nThe scientific basis for the use of CPI in HL is real and strong. In tumor tissue, HL cells are scanty and surrounded by a large number of inflammatory tumor-infiltrating lymphocytes. In particular, Reed-Sternberg cells are characterized by the 9p24 amplification, encoding for both the PD-1-/PD-2-ligands and for the Janus kinase (JAK)-2. The latter activates the JAK/STAT pathway (60), leading to a further enhancement of PD ligand expression on Reed-Sternberg cells. Additionally, around 40% of patients with cHL are positive for Epstein-Barr virus, which is associated with high expression of PD-1 and PD-2 ligands (61).\n\nRecently, early-phase clinical trials on PD-1–blocking antibodies nivolumab and pembrolizumab showed a substantial therapeutic activity and an acceptable safety profile in patients with relapsed or refractory HL (62-64).\n\nOf note, both trials excluded patients with a previous history of allo-SCT, because of concerns about GVHD reactivation.\n\nCurrent strategies for relapsed HL after allo-SCT are discouraging (50,65). Using different approaches (DLI with or without chemo- therapy, BV, or bendamustine), poor results were reported, with a median PFS ranging from 6 to 18 months.\n\nThe immune-mediated graft-versus-tumor (GVT) effect endows the allo-SCT with the potential to cure malignancies refractory to all other treatments. Nevertheless, it is associated with the risk of donor cell-mediated GVHD, which mainly contributes to its relevant morbidity and mortality. In theory, the GVT effect might be enhanced by immune CPI such as ipilimumab (anti-cytotoxic T-lymphocyte-associated protein 4), nivolumab (anti-PD-1) or pembrolizumab (anti-PD-1), by releasing the brakes on GVT conveying tumor-suppressed lymphocytes. Nevertheless, severe GVHD reactions might be unleashed as well.\n\nCPI administration has also been tested for post allo-SCT relapse, and, although the response rates are high, the toxicity is substantial as well. A multicenter retrospective trial of 31 lymphoma patients, 29 with HL, treated either with nivolumab or with pembrolizumab after allo-SCT relapse, found a high ORR of 77%. However, a treatment-related GVHD occurred in 55% of patients and tended to be highly refractory to conventional GVHD management, with a mortality of 26% (48). Another retrospective trial on 20 HL patients receiving nivolumab after allo-SCT found an ORR of 95%, with a 30% incidence of GVHD, and 10% of the patients died of GVHD (47).\n\nWhile the preliminary data demonstrated no significantly increased GVHD in patients treated with ipilimumab post allo-SCT, there is still a substantial concern regarding the safety of PD-1 inhibitors in this setting. In fact, increased GVHD-related lethality has been demonstrated in a murine model of acute GVHD when blocking PD-L1 (66).\n\nThere is a possibility that anti–PD-1 administration during the early phase of transplantation would trigger severe GVHD secondary to decreased PD-1/PD-L1 ligation soon after the allo-SCT (67).\n\nDonor source, type of GVHD prophylaxis, history of GVHD, dose and timing of anti–PD-1 therapy, and immunosuppression at time of anti–PD-1 administration should be considered as variables potentially influencing the development of GVHD in clinical trials that evaluate the treatment with checkpoint blockade after allo-SCT.\n\nIn phase 1 studies with nivolumab and pembrolizumab for treatment of relapsed and refractory HL, grade 3 hepatic and dermatologic toxicities were observed in 5% of patients, and there were no drug-related grade 4-5 events (62-64).\n\nOne case of fatal hepatic toxicity has been reported in a lung cancer patient after the treatment with an anti-PD-1 monoclonal antibody (68).\n\nNevertheless, early onset of severe and fatal events occurred more frequently than expected when anti–PD-1 monoclonal antibodies were administered post allo-SCT.\n\nThere are context-dependent functions of the PD-1/PD-L1 axis in allo-SCT, including timing of pathway activation and organ-specific immunogenicity, donor vs. host expression, and peripheral tolerance, which affect the risk of aGVHD and cGVHD.\n\nHowever, while reversing the suppression of allogeneic GVT effects with PD-1 inhibition appears particularly appealing, special caution has to be taken in the context of an allogeneic immune system, given the role of the PD-1 axis in the pathophysiology of GVHD as well. In conclusion, CPI are increasingly being used in this setting and appear to be effective, although with conflicting safety results, because their administration can be complicated by the rapid onset of severe and treatment-refractory GVHD.\n\nConflict of interest:\n\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\n\n1 Bröckelmann PJ Sasse S Engert A Balancing risk and benefit in early-stage classical Hodgkin lymphoma Blood 2018 131 15 1666 1678 29500174\n2 Adams HJ Kwee TC Controversies on the prognostic value of in-terim FDG-PET in advanced-stage Hodgkin lymphoma Eur J Hae-matol 2016 97 6 491 498\n3 Rigacci L Puccini B Zinzani PL Clinical Characteristics of patients with negative interim-PET and positive final PET: data from the prospective PET-oriented HD0801 study by Fondazione Italiana Linfomi (FIL) Hematological Oncology 2017 35 S2\n4 Gallamini A Tarella C Viviani S Early Chemotherapy Intensification With Escalated BEACOPP in Patients With Advanced-Stage Hodgkin Lymphoma With a Posi-tive Interim Positron Emission Tomography/Computed Tomog-raphy Scan After Two ABVD Cycles: Long-Term Results of the GITIL/FIL HD 0607 Trial J Clin Oncol 2018 36 5 454 462 29360414\n5 Dann EJ Bairey O Bar-Shalom R Modification of initial therapy in early and advanced Hodgkin lymphoma, based on in-terim PET/CT is beneficial: a prospective multicentre trial of 355 patients Br J Haematol 2017 178 5 709 718 28589704\n6 Borchmann P Haverkamp H Lohri A Progression-free sur-vival of early interim PET-positive patients with advanced stage Hodgkin’s lymphoma treated with BEACOPP escalated alone or in combination with rituximab (HD18): an open-label, international, randomised phase 3 study by the German Hodgkin Study Group Lancet Oncol 2017 18 4 454 463 28236583\n7 Zinzani PL Broccoli A Gioia DM Interim Positron Emis-sion Tomography Response-Adapted Therapy in Advanced-Stage Hodgkin Lymphoma: Final Results of the Phase II Part of the HD0801 Study J Clin Oncol 2016 34 12 1376 1385 26884559\n8 Rigacci L Puccini B Zinzani PL The prognostic value of positron emission tomography performed after two courses (IN-TERIM-PET) of standard therapy on treatment outcome in early stage Hodgkin lymphoma: A multicentric study by the fondazione italiana linfomi (FIL) Am J Hematol 2015 90 6 499 503 25720750\n9 Ciammella P Filippi AR Simontacchi G Post-ABVD/pre-ra-diotherapy (18)F-FDG-PET provides additional prognostic infor-mation for early-stage Hodgkin lymphoma: a retrospective analysis on 165 patients Br J Radiol 2016 89 1061 20150983 27022777\n10 Simontacchi G Filippi AR Ciammella P Interim PET Af-ter Two ABVD Cycles in Early-Stage Hodgkin Lymphoma: Out-comes Following the Continuation of Chemotherapy Plus Radio-therapy Int J Radiat Oncol Biol Phys 2015 92 5 1077 1083 26031367\n11 Keresztes K Lengyel Z Devenyi K Vadasz G Miltenyi Z Illes A Mediastinal bulky tumour in Hodgkin’s disease and prognostic value of positron emission tomography in the evaluation of post-treatment residual masses Acta Haematol 2004 112 4 194 199 15564730\n12 Sickinger MT von Tresckow B Kobe C Borchmann P Engert A Skoetz N PET-adapted omission of radiotherapy in early stage Hodgkin lymphoma-a systematic review and meta-analysis Crit Rev Oncol Hematol 2016 101 86 92 26971064\n13 Sickinger MT von Tresckow B Kobe C Engert A Borchmann P Skoetz N Positron emission tomography-adapted therapy for first-line treatment in individuals with Hodgkin lymphoma Cochrane Database Syst Rev 2015 9 1 CD010533\n14 Adams HJA de Klerk JMH Regelink JC Heggelman BGF Dubois SV Kwee TC Radiation-Induced Giant Cell Granuloma Mimick-ing Relapsed Hodgkin Lymphoma at FDG-PET/CT Nucl Med Mol Imaging 2017 51 4 371 373 29242737\n15 Radhakrishnan RK Mittal BR Basher RK Prakash G Malhotra P Kalra N Das A Post-therapy lesions in patients with non-Hodgkin’s lymphoma characterized by 18F-FDG PET/CT-guided biopsy using automated robotic biopsy arm Nucl Med Commun 2018 39 1 74 82 29189443\n16 Adams HJ Kwee TC Prognostic value of pretransplant FDG-PET in refractory/relapsed Hodgkin lymphoma treated with autologous stem cell transplantation: systematic review and meta-analysis Ann Hematol 2016 95 5 695 706 26931115\n17 Filmont JE Gisselbrecht C Cuenca X Deville L Ertault M Brice P The impact of pre-and post-transplantation positron emis-sion tomography using 18-fluorodeoxyglucose on poor-prognosis lymphoma patients undergoing autologous stem cell transplantation Cancer 2007 110 6 1361 1369 17623832\n18 Ying Z Mi L Wang X Zhang Y Yang Z Song Y Prognos-tic value of pre-and post-transplantation 18F-fluorodeoxyglucose positron emission tomography results in non-Hodgkin lymphoma patients receiving autologous stem cell transplantation Cancer Res 2017 29 6 561 571\n19 Sucak GT Özkurt ZN Suyani E Yaşar DG Akdemir ÖÜ Aki Z Early post-transplantation positron emission tomography in patients with Hodgkin lymphoma is an independent prog-nostic factor with an impact on overall survival Ann Hematol 2011 90 11 1329 1336 21437590\n20 Moskowitz CH Nademanee A Masszi T Agura E Holowiecki J Abidi MH Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin’s lymphoma at risk of relapse or progression (AETHERA): a ran-domised, double-blind, placebo-controlled, phase 3 trial Lancet 2015 385 9980 1853 1862 25796459\n21 Bair SM Strelec L Nagle SJ Nasta SD Landsburg DJ Mato AR Outcomes of patients with relapsed/refractory Hodgkin lympho-ma progressing after autologous stem cell transplant in the current era of novel therapeutics: A retrospective analysis Am J Hematol 2017 92 9 879 884 28512788\n22 Wilke C Cao Q Dusenbery KE Bachanova V Lazaryan A Lee CK Role of Consolidative Radiation Therapy After Autolo-gous Hematopoietic Cell Transplantation for the Treatment of Re-lapsed or Refractory Hodgkin Lymphoma Int J Radiat Oncol Biol Phys 2017 99 1 94 102 28816170\n23 Dejanovic D Amtoft A Loft A F 18 F-FDG PET/CT in Exten-sive Graft-Versus-Host Disease of the Gastrointestinal Tract Fol-lowing Autologous Stem Cell Transplantation Diagnostics (Basel) 2018 8 4 72\n24 Bouard L Bodet-Milin C Bailly C Guillaume T Peterlin P Garnier A Deauville Scores 4 or 5 Assessed by Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Early Post-Allotransplant Is Highly Predictive of Re-lapse in Lymphoma Patients Biol Blood Marrow Transplant 2019 May 25 5 906 911 30481598\n25 Kurch L Hasenclever D Kluge R Georgi T Tchavdarova L Golombeck M Only strongly enhanced residual FDG up-take in early response PET (Deauville 5 or qPET ≥ 2) is prognostic in pediatric Hodgkin lymphoma: Results of the GPOH-HD2002 trial Pediatr Blood Cancer 2019 66 3 e27539 30426671\n26 Milgrom SA Dong W Akhtari M Smith GL Pinnix CC Maw-lawi O Chemotherapy Response Assessment by FDG-PET-CT in Early-stage Classical Hodgkin Lymphoma: Moving Beyond the Five-Point Deauville Score Int J Radiat Oncol Biol Phys 2017 97 2 333 338 28068241\n27 Kluge R Chavdarova L Hoffmann M Kobe C Malkowski B Montravers F Inter-Reader Reliability of Early FDG-PET/ CT Response Assessment Using the DeauvilleScale after 2 Cycles of Intensive Chemotherapy (OEPA) in Hodgkin’s Lymphoma PLoS One 2016 11 3 e0149072 26963909\n28 Moskowitz AJ Outcomes for patients who fail high dose chemoradiotherapy and autologous stem cell rescue for relapsed and primary refractory Hodgkin lymphoma BJH 2009 146 2 158 163 19438504\n29 Giaccone L Long-term follow-up of allogeneic stem cell trans-plantation in relapsed/refractory Hodgkin lymphoma Bone Mar-row Transplantation 2017 52 1208 1211\n30 Chen R Five-year survival and durability results of brentuxi-mab vedotin in patients with relapsed or refractory Hodgkin lym-phoma Blood 2016 128 12 1562 1566 27432875\n31 Chen R Brentuximab vedotin is associated with improved progression-free survival after allogeneic transplantation for Hodg-kin lymphoma Biology of Blood and Marrow Transplantation 2014 20 1864 1868 25008328\n32 Chen R Phase II Study of the Efficacy and Safety of Pembroli-zumab for Relapsed/Refractory Classic Hodgkin Lymphoma JCO 2017 35 19 2125 2132\n33 Armand P Nivolumab for Relapsed/Refractory Classic Hodg-kin Lymphoma After Failure of Autologous Hematopoietic Cell Transplantation: Extended Follow-Up of the Multicohort.Single-Arm Phase II CheckMate 205 Trial JCO 2018 36 14 1428 1439\n34 Merryman RW Safety and efficacy of allogeneic hematopoi-etic stem cell transplant after PD-1 blockade in relapsed/refractory lymphoma Blood 2017 129 10 1380 1388 28073785\n35 Dada R Usman B Allogeneic hematopoietic stem cell transplan-tation in r/r Hodgkin lymphoma after treatment with checkpoint in-hibitors: Feasibility and safety Eur J Haematol 2019 102 2 150 156 30341987\n36 Broccoli A Zinzani PL The role of transplantation in Hodgkin lymphoma British Journal of Hamatology 2019 184 1 93 104\n37 Herbaux C Recommendations for managing PD-1 blockade in the context of allogeneic HCT in Hodgkin lymphoma: taming a necessary evil Blood 2018 132 1 9 16 29720488\n38 Rossi C Efficacy of chemotherapy or chemo-anti-PD-1 com-bination after failed anti-PD-1 therapy for relapsed and refractory Hodgkin Lymphoma: A series from lysa centers Am J Hematol 2018 93 1042 1049\n39 Carlo Stella C Nivolumab restores sensitivity to chemotherapy in chemorefractory classical Hodgkin Lymphoma patients EHA 2018 poster PS1175\n40 Shah GL Moskowitz CH Transplant strategies in relapsed/ refractory Hodgkin Lymphoma Blood 2018 131 15 1689 1697 29500170\n41 Cheson BD Refinement of the Lugano classification response criteria for lymphoma in the era of immunomodulatory therapy Blood 2016 128 2489 2496 27574190\n42 Champiat S Hyperprogressive disease (HPD) is a new pattern of progression in cancer patients treated by anti-PD-1/PD-L1 Clin Cancer Res 2017 23 1920 1928 27827313\n43 Gaudio F Mazza P Carella AM Mele A Outcomes of Re-duced Intensity Conditioning Allogeneic Hematopoietic Stem Cell Transplantation for Hodgkin Lymphomas: A Retrospective Multi-center Experience by the Rete Ematologica Pugliese (REP) Clin Lymphoma Myeloma Leuk 2019 Jan 19 1 35 40 30293754\n44 Gaudio F Mazza P Mele A Brentuximab vedotin prior to allogeneic stem cell transplantation increases survival in chem-orefractory Hodgkin’s lymphoma patients Ann Hematol 2019 Jun 98 6 1449 1455 30868307\n45 Robinson SP Sureda A Canals C Lymphoma Working Party of the EBMT. Reduced intensity conditioning allogeneic stem cell transplantation for Hodgkin’s lymphoma: identification of prognos-tic factors predicting outcome Haematologica 2009 94 230 238 19066328\n46 Sureda A Robinson S Canals C Reduced-intensity condi-tioning compared with conventional allogeneic stem-cell transplan-tation in relapsed or refractory Hodgkin’s lymphoma: an analysis from the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation J Clin Oncol 2008 26 455 462 18086796\n47 Herbaux C Gauthier J Brice P Efficacy and tolerability of nivolumab after allogeneic transplantation for relapsed Hodgkin lymphoma Blood 2017 129 2471 2478 28270452\n48 Haverkos BM Abbott D Hamadani M PD-1 blockade for relapsed lymphoma post-allogeneic hematopoietic cell transplant: high response rate but frequent GVHD Blood 2017 130 221 228 28468799\n49 Gopal AK Ramchandren R O’Connor OA Safety and effi-cacy of brentuximab vedotin for Hodgkin lymphoma recurring after allogeneic stem cell transplantation Blood 2012 120 560 568 22510871\n50 Carlo-Stella C Ricci F Dalto S Brentuximab vedotin in pa-tients with Hodgkin lymphoma and a failed allogeneic stem cell transplantation: results from a named patient program at four Ital-ian centers Oncologist 2015 20 323 328 25669663\n51 Tsirigotis P Danylesko I Gkirkas K Brentuximab vedotin in combination with or without donor lymphocyte infusion for pa-tients with Hodgkin lymphoma after allogeneic stem cell transplan-tation Bone Marrow Transplant 2016 51 1313 1317 27183095\n52 Anderlini P Saliba R Acholonu S Fludarabine-melphalan as a preparative regimen for reduced-intensity conditioning alloge-neic stem cell transplantation in relapsed and refractory Hodgkin’s lymphoma: the updated M.D. Anderson Cancer Center experience Haematologica 2008 93 257 264 18223284\n53 Przepiorka D Weisdorf D Martin P Consensus conference on acute GVHD grading Bone Marrow Transplant 1995 15 825 828 7581076\n54 Peggs KS Kayani I Edwards N Kottaridis P Goldstone AH Linch DC Donor lymphocyte infusions modulate relapse risk in mixed chimeras and induce durable salvage in relapsed patients after T-cell-depleted allogeneic transplantation for Hodgkin’s lym-phoma J Clin Oncol 2011 29 971 978 21282545\n55 Alvarez I Sureda A Caballero MD Urbano-Ispizua A Ribera JM Canales M Nonmyeloablative stem cell transplantat on is an effective therapy for refractory or relapsed Hodgkin lymphoma: results of a Spanish prospective cooperative protocol Biol Blood Marrow Transplant 2006 12 172 183 16443515\n56 Anderlini P Saliba R Acholonu S Okoroji GJ Ledesma C An-dersson BS Donor leukocyte infusions (DLIs) in recurrent Hodgkin lymphoma (HL) following allogeneic stem cell transplan-tation: ten-year experience at the M.D. Anderson Cancer Center Leuk Lymphoma 2012 53 1239 1241 22132837\n57 Theurich S Malcher J Wennhold K Brentuximab vedotin combined with donor lymphocyte infusions for early relapse of-Hodgkin lymphoma after allogeneic stem-cell transplantation in-duces tumor-specific immunity and sustained clinical remission J Clin Oncol 2013 31 e59 e63 23269992\n58 Chen YB McDonough S Hasserjian R Expression of CD30 in patients with acute graft versus-host disease Blood 2012 120 691 696 22661699\n59 Bartlett NL Chen R Fanale MA Retreatment with brentuxi-mab vedotin in patients with CD30-positive hematologic malig-nancies J Hematol Oncol 2014 7 24 24642247\n60 Ok CY Young KH Targeting the programmed death-1 pathway in lymphoid neoplasms Cancer Treat Rev 2017 54 99 109 28242522\n61 Paydas S Bagir E Seydaoglu G Ercolak V Ergin M Programmed death-1 (PD-1), programmed death-ligand 1 (PDL1), and EBV-encoded RNA (EBER) expression in Hodgkin lymphoma Ann Hematol 2015 94 9 1545 1552 26004934\n62 Ansell SM Lesokhin AM Borrello I PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma N Engl J Med 2015 372 4 311 319 25482239\n63 Younes A Santoro A Shipp M Nivolumab for classical Hodg-kin’s lymphoma after failure of both autologous stem-cell transplan-tation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial Lancet Oncol 2016 17 9 1283 1294 27451390\n64 Armand P Shipp MA Ribrag V Programmed death-1 block-ade with pembrolizumab in patients with classical Hodgkin lym-phoma after brentuximab vedotin failure J Clin Oncol 2016 Nov 1 34 31 3733 3739 27354476\n65 Anastasia A Carlo-Stella C Corradini P Bendamustine for Hodgkin lymphoma patients failing autologous or autologous and allogeneic stem cell transplantation: a retrospective study of the Fondazione Italiana Linfomi Br J Haematol 2014 166 1 140 142 24606548\n66 Saha A Aoyama K Taylor PA Koehn BH Veenstra RG Panoskalt-sis-Mortari Host programmed death ligand 1 is dominant over programmed death ligand 2 expression in regulating graft-versus-host disease lethality Blood 2013 122 3062 3073 24030385\n67 Schade H Sen S Neff CP Programmed death 1 expression on CD41 T cells predicts mortality after allogeneic stem cell trans-plantation Biol Blood Marrow Transplant 2016 22 12 2172 2179 27519280\n68 Sarmen S Tara S Acute liver failure from Anti-PD-1 antibody nivolumab in a patient with metastatic lung squamous cell carci-noma Austin Oncol 2016 1 2 1006\n\n",
"fulltext_license": "CC BY-NC-SA",
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"issue": "91(S-5)",
"journal": "Acta bio-medica : Atenei Parmensis",
"keywords": null,
"medline_ta": "Acta Biomed",
"mesh_terms": "D000328:Adult; D006689:Hodgkin Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D033581:Stem Cell Transplantation; D014182:Transplantation, Autologous; D055815:Young Adult",
"nlm_unique_id": "101295064",
"other_id": null,
"pages": "30-40",
"pmc": null,
"pmid": "32525132",
"pubdate": "2020-05-25",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15564730;27183095;21282545;30868307;27827313;26963909;25482239;23269992;16443515;30341987;29584546;26884559;28068241;25720750;28242522;27528557;25669663;30481598;17623832;29500174;19066328;27451390;29500170;29360414;30326627;28270452;29353979;18086796;25796459;24030385;29242737;27574190;7581076;27432875;28073785;28468799;21437590;29720488;30293754;25572491;25008328;28441111;22510871;26004934;19438504;28816170;29189443;30407612;28236583;22661699;26931115;24606548;22132837;18223284;26971064;30426671;26031367;28581461;27519280;28589704;27354476;29884994;28512788;27022777;24642247",
"title": "Relapsing/refractory HL after autotransplantation: which treatment?",
"title_normalized": "relapsing refractory hl after autotransplantation which treatment"
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"companynumb": "IT-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-297134",
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"abstract": "In this article we describe the developments of two patients who were hospitalized after a quetiapine overdose, subsequently developing delirium. Delirium occurred several hours after ingestion and lasted several days. Laboratory blood testing revealed a slower decline in quetiapine plasma concentration than expected when compared to the standardized half-life averages of therapeutic doses of quetiapine. The clinical state during the first hours after ingestion does not sufficiently predict further clinical outcome. The changes in pharmacokinetics due to the intoxication, so-called toxicokinetics, are the underlying cause.",
"affiliations": null,
"authors": "Baptist|E|E|;de Graaf|I C|IC|;Bannink|M|M|",
"chemical_list": "D014150:Antipsychotic Agents; D000069348:Quetiapine Fumarate",
"country": "Netherlands",
"delete": false,
"doi": null,
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"issn_linking": "0303-7339",
"issue": "60(8)",
"journal": "Tijdschrift voor psychiatrie",
"keywords": null,
"medline_ta": "Tijdschr Psychiatr",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D003693:Delirium; D062787:Drug Overdose; D005260:Female; D006801:Humans; D008297:Male; D000069348:Quetiapine Fumarate",
"nlm_unique_id": "0423731",
"other_id": null,
"pages": "548-551",
"pmc": null,
"pmid": "30132584",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Delirium as a late onset manifestation of quetiapine intoxication.",
"title_normalized": "delirium as a late onset manifestation of quetiapine intoxication"
} | [
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"companynumb": "NL-ALKEM LABORATORIES LIMITED-NL-ALKEM-2018-08144",
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"activesubstancename": "QUETIAPINE FUMARATE"
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... |
{
"abstract": "To assess the outcomes and toxicity of first-line methotrexate (MTX) chemotherapy in low-risk postmolar gestational trophoblastic neoplasia (GTN) patients receiving 8-day methotrexate or one-day methotrexate infusion regimens.\n\n\n\nThis retrospective cohort study was conducted at the New England Trophoblastic Disease Center (NETDC), between 1974 and 2014, and included 325 patients with FIGO-defined low-risk postmolar GTN receiving first-line 8-day MTX/folinic acid (FA) or one-day MTX infusion and FA. Demographics, disease presentation, initial treatment plan, treatment outcome, and treatment-related adverse events were assessed.\n\n\n\nSustained remission (84% vs 62%, p<0.001) and need to switch to second-line therapy due to treatment-related adverse events (5.3% vs 0%, p=0.001) were higher for 8-day MTX/FA compared to one-day MTX infusion. MTX resistance, however, was more frequent with one-day MTX (34.5%) than with 8-day MTX/FA (7.3%, p<0.001). Relapse rates were similar with both regimens (3.0%). Compared to one-day MTX infusion, 8-day MTX/FA was associated with significantly higher gastrointestinal disorders (48% vs 24%), abnormal laboratory findings (48% vs 28%), eye disorders (37% vs 19%) and general disorders (22% vs 5%) (p<0.001). Only infection frequency did not differ between 8-day MTX/FA and one-day MTX infusion (20% vs 12%, p=0.083).\n\n\n\nThis is one of the largest studies to comprehensively catalogue toxicities associated with 8-day MTX/FA and one-day MTX infusion. Although treatment-related adverse events were more frequent with 8-day MTX/FA, these were all self-limited and resolved with no long-term sequelae. Given this and its higher effectiveness, 8-day MTX/FA remains the treatment of choice at NETDC for patients with low-risk postmolar GTN.",
"affiliations": "Department of Gynecology and Obstetrics, Botucatu Medical School, UNESP-Sao Paulo State University, Botucatu, SP, Brazil; Trophoblastic Diseases Center of the Botucatu Medical School, UNESP-Sao Paulo State University, Botucatu, SP, Brazil; Postgraduate Program of Gynecology, Obstetrics and Mastology of Botucatu Medical School, UNESP-São Paulo State University, Botucatu, SP, Brazil.. Electronic address: imaesta@fmb.unesp.br.;Department of Obstetrics and Gynecology, Brigham and Women's Hospital Boston, MA, USA.;Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Brigham and Women's Hospital, Boston, MA, USA; New England Trophoblastic Disease Center, Donald P. Goldstein M.D. Tumor Registry, Boston, MA, USA; Dana Farber Cancer Institute/Harvard Cancer Center, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.;Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Brigham and Women's Hospital, Boston, MA, USA; New England Trophoblastic Disease Center, Donald P. Goldstein M.D. Tumor Registry, Boston, MA, USA; Dana Farber Cancer Institute/Harvard Cancer Center, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.;Department of Gynecology and Obstetrics, Botucatu Medical School, UNESP-Sao Paulo State University, Botucatu, SP, Brazil; Trophoblastic Diseases Center of the Botucatu Medical School, UNESP-Sao Paulo State University, Botucatu, SP, Brazil; Postgraduate Program of Gynecology, Obstetrics and Mastology of Botucatu Medical School, UNESP-São Paulo State University, Botucatu, SP, Brazil.;Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Brigham and Women's Hospital, Boston, MA, USA; New England Trophoblastic Disease Center, Donald P. Goldstein M.D. Tumor Registry, Boston, MA, USA; Dana Farber Cancer Institute/Harvard Cancer Center, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.;Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Brigham and Women's Hospital, Boston, MA, USA; New England Trophoblastic Disease Center, Donald P. Goldstein M.D. Tumor Registry, Boston, MA, USA; Dana Farber Cancer Institute/Harvard Cancer Center, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.",
"authors": "Maestá|Izildinha|I|;Nitecki|Roni|R|;Horowitz|Neil S|NS|;Goldstein|Donald P|DP|;de Freitas Segalla Moreira|Marjory|M|;Elias|Kevin M|KM|;Berkowitz|Ross S|RS|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D006063:Chorionic Gonadotropin; D002955:Leucovorin; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ygyno.2017.10.028",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0090-8258",
"issue": "148(1)",
"journal": "Gynecologic oncology",
"keywords": "Effectiveness; First-line methotrexate chemotherapy; Low-risk gestational trophoblastic neoplasia; Toxicity",
"medline_ta": "Gynecol Oncol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000964:Antimetabolites, Antineoplastic; D006063:Chorionic Gonadotropin; D015331:Cohort Studies; D005260:Female; D031901:Gestational Trophoblastic Disease; D006801:Humans; D006828:Hydatidiform Mole; D007262:Infusions, Intravenous; D002955:Leucovorin; D008727:Methotrexate; D008875:Middle Aged; D009367:Neoplasm Staging; D011247:Pregnancy; D012189:Retrospective Studies; D012307:Risk Factors; D055815:Young Adult",
"nlm_unique_id": "0365304",
"other_id": null,
"pages": "161-167",
"pmc": null,
"pmid": "29092742",
"pubdate": "2018-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Effectiveness and toxicity of first-line methotrexate chemotherapy in low-risk postmolar gestational trophoblastic neoplasia: The New England Trophoblastic Disease Center experience.",
"title_normalized": "effectiveness and toxicity of first line methotrexate chemotherapy in low risk postmolar gestational trophoblastic neoplasia the new england trophoblastic disease center experience"
} | [
{
"companynumb": "BR-MYLANLABS-2018M1008569",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": "3",
... |
{
"abstract": "Vitamin D3 is a secosteroid hormone produced in the skin in amounts estimated up to 25,000 international units (IUs) a day by the action of UVB radiation on 7-dehydrocholesterol. Vitamin D deficiency is common due to both lack of adequate sun exposure to the skin, and because vitamin D is present in very few food sources. Deficiency is strongly linked to increased risk for a multitude of diseases, several of which have historically been shown to improve dramatically with either adequate UVB exposure to the skin, or to oral or topical supplementation with vitamin D. These diseases include asthma, psoriasis, rheumatoid arthritis, rickets and tuberculosis. All patients in our hospital have been routinely screened on admission for vitamin D deficiency since July 2011, and offered supplementation to either correct or prevent deficiency. During this time, we have admitted over 4700 patients, the vast majority of whom agreed to supplementation with either 5000 or 10,000 IUs/day. Due to disease concerns, a few agreed to larger amounts, ranging from 20,000 to 50,000 IUs/day. There have been no cases of vitamin D3 induced hypercalcemia or any adverse events attributable to vitamin D3 supplementation in any patient. Three patients with psoriasis showed marked clinical improvement in their skin using 20,000 to 50,000 IUs/day. Analysis of 777 recently tested patients (new and long-term) not on D3 revealed 28.7% with 25-hydroxyvitaminD3 (25OHD3) blood levels < 20 ng/ml, 64.1% < 30 ng/ml, a mean 25OHD3 level of 27.1 ng/ml, with a range from 4.9 to 74.8 ng/ml. Analysis of 418 inpatients on D3 long enough to develop 25OHD3 blood levels > 74.4 ng/ml showed a mean 25OHD3 level of 118.9 ng/ml, with a range from 74.4 to 384.8 ng/ml. The average serum calcium level in these 2 groups was 9.5 (no D3) vs 9.6 (D3), with ranges of 8.4 to 10.7 (no D3) vs 8.6 to 10.7 mg/dl (D3), after excluding patients with other causes of hypercalcemia. The average intact parathyroid hormone levels were 24.2 pg/ml (D3) vs. 30.2 pg/ml (no D3). In summary, long-term supplementation with vitamin D3 in doses ranging from 5000 to 50,000 IUs/day appears to be safe.",
"affiliations": "Department of Psychiatry, Wright State University School of Medicine, Dayton, OH, 45435, United States; Summit Behavioral Healthcare, Cincinnati, OH, 45237, United States. Electronic address: pmccullough1@cinci.rr.com.;Department of Psychiatry, Wright State University School of Medicine, Dayton, OH, 45435, United States; Summit Behavioral Healthcare, Cincinnati, OH, 45237, United States.;Summit Behavioral Healthcare, Cincinnati, OH, 45237, United States.",
"authors": "McCullough|Patrick J|PJ|;Lehrer|Douglas S|DS|;Amend|Jeffrey|J|",
"chemical_list": "D014815:Vitamins; D002762:Cholecalciferol",
"country": "England",
"delete": false,
"doi": "10.1016/j.jsbmb.2018.12.010",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0960-0760",
"issue": "189()",
"journal": "The Journal of steroid biochemistry and molecular biology",
"keywords": "Adverse events; Intact parathyroid hormone; Long-term supplementation",
"medline_ta": "J Steroid Biochem Mol Biol",
"mesh_terms": "D000328:Adult; D000368:Aged; D002762:Cholecalciferol; D005260:Female; D006760:Hospitalization; D006801:Humans; D006934:Hypercalcemia; D008297:Male; D008875:Middle Aged; D014808:Vitamin D Deficiency; D014815:Vitamins; D055815:Young Adult",
"nlm_unique_id": "9015483",
"other_id": null,
"pages": "228-239",
"pmc": null,
"pmid": "30611908",
"pubdate": "2019-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Daily oral dosing of vitamin D3 using 5000 TO 50,000 international units a day in long-term hospitalized patients: Insights from a seven year experience.",
"title_normalized": "daily oral dosing of vitamin d3 using 5000 to 50 000 international units a day in long term hospitalized patients insights from a seven year experience"
} | [
{
"companynumb": "NVSC2019US061713",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HYDROCHLOROTHIAZIDE"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nBecause acute liver failure (ALF) patients share many clinical features with severe sepsis and septic shock, identifying bacterial infection clinically in ALF patients is challenging. Procalcitonin (PCT) has proven to be a useful marker in detecting bacterial infection. We sought to determine whether PCT discriminated between presence and absence of infection in patients with ALF.\n\n\nMETHODS\nRetrospective analysis of data and samples of 115 ALF patients from the United States Acute Liver Failure Study Group randomly selected from 1863 patients were classified for disease severity and ALF etiology. Twenty uninfected chronic liver disease (CLD) subjects served as controls.\n\n\nRESULTS\nProcalcitonin concentrations in most samples were elevated, with median values for all ALF groups near or above a 2.0 ng/mL cut-off that generally indicates severe sepsis. While PCT concentrations increased somewhat with apparent liver injury severity, there were no differences in PCT levels between the pre-defined severity groups-non-SIRS and SIRS groups with no documented infections and Severe Sepsis and Septic Shock groups with documented infections, (p = 0.169). PCT values from CLD patients differed from all ALF groups (median CLD PCT value 0.104 ng/mL, (p ≤0.001)). Subjects with acetaminophen (APAP) toxicity, many without evidence of infection, demonstrated median PCT >2.0 ng/mL, regardless of SIRS features, while some culture positive subjects had PCT values <2.0 ng/mL.\n\n\nCONCLUSIONS\nWhile PCT appears to be a robust assay for detecting bacterial infection in the general population, there was poor discrimination between ALF patients with or without bacterial infection presumably because of the massive inflammation observed. Severe hepatocyte necrosis with inflammation results in elevated PCT levels, rendering this biomarker unreliable in the ALF setting.",
"affiliations": "Department of Internal Medicine, Division of Digestive Diseases, UT Southwestern Medical Center, Dallas, Texas, United States of America; Department of Clinical Laboratory Sciences, School of Allied Health, Virginia Commonwealth University, Richmond, Virginia, United States of America.;Department of Clinical Sciences and Department of Psychiatry, Division of Biostatistics, UT Southwestern Medical Center, Dallas, Texas, United States of America.;Department of Internal Medicine, Division of Digestive Diseases, UT Southwestern Medical Center, Dallas, Texas, United States of America.;Department of Internal Medicine, Division of Digestive Diseases, UT Southwestern Medical Center, Dallas, Texas, United States of America.;Department of Clinical Laboratory Sciences, School of Allied Health, Virginia Commonwealth University, Richmond, Virginia, United States of America.;Department of Internal Medicine, Division of Digestive Diseases, UT Southwestern Medical Center, Dallas, Texas, United States of America.",
"authors": "Rule|Jody A|JA|;Hynan|Linda S|LS|;Attar|Nahid|N|;Sanders|Corron|C|;Korzun|William J|WJ|;Lee|William M|WM|;|||",
"chemical_list": "D015415:Biomarkers; C000606589:CALCA protein, human; D011498:Protein Precursors; D002116:Calcitonin; D015740:Calcitonin Gene-Related Peptide",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0138566",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 2639392410.1371/journal.pone.0138566PONE-D-15-16182Research ArticleProcalcitonin Identifies Cell Injury, Not Bacterial Infection, in Acute Liver Failure Procalcitonin and Acute Liver FailureRule Jody A. \n1\n\n3\n*Hynan Linda S. \n2\nAttar Nahid \n1\n\n‡\nSanders Corron \n1\n\n‡\nKorzun William J. \n3\nLee William M. \n1\nAcute Liver Failure Study Group \n¶\n\n1 \nDepartment of Internal Medicine, Division of Digestive Diseases, UT Southwestern Medical Center, Dallas, Texas, United States of America\n\n2 \nDepartment of Clinical Sciences and Department of Psychiatry, Division of Biostatistics, UT Southwestern Medical Center, Dallas, Texas, United States of America\n\n3 \nDepartment of Clinical Laboratory Sciences, School of Allied Health, Virginia Commonwealth University, Richmond, Virginia, United States of America\nBruns Helge Editor\nUniversity Hospital Oldenburg, GERMANY\nCompeting Interests: Siemens Healthcare Diagnostics provided instrumentation and reagents only for this study. The authors have no other relevant declarations relating to Siemens Healthcare Diagnostics. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.\n\nConceived and designed the experiments: JAR LSH WJK WML. Performed the experiments: JAR. Analyzed the data: JAR LSH WML. Contributed reagents/materials/analysis tools: JAR LSH. Wrote the paper: JAR LSH. Sample and data selection and procurement: NA CS.\n\n‡ These authors also contributed equally to this work.\n\n¶ Membership of the Acute Liver Failure Study Group is listed in the Acknowledgments.\n\n* E-mail: jody.rule@utsouthwestern.edu22 9 2015 2015 10 9 e013856614 4 2015 1 9 2015 © 2015 Rule et al2015Rule et alThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.Background\nBecause acute liver failure (ALF) patients share many clinical features with severe sepsis and septic shock, identifying bacterial infection clinically in ALF patients is challenging. Procalcitonin (PCT) has proven to be a useful marker in detecting bacterial infection. We sought to determine whether PCT discriminated between presence and absence of infection in patients with ALF.\n\nMethod\nRetrospective analysis of data and samples of 115 ALF patients from the United States Acute Liver Failure Study Group randomly selected from 1863 patients were classified for disease severity and ALF etiology. Twenty uninfected chronic liver disease (CLD) subjects served as controls.\n\nResults\nProcalcitonin concentrations in most samples were elevated, with median values for all ALF groups near or above a 2.0 ng/mL cut-off that generally indicates severe sepsis. While PCT concentrations increased somewhat with apparent liver injury severity, there were no differences in PCT levels between the pre-defined severity groups–non-SIRS and SIRS groups with no documented infections and Severe Sepsis and Septic Shock groups with documented infections, (p = 0.169). PCT values from CLD patients differed from all ALF groups (median CLD PCT value 0.104 ng/mL, (p ≤0.001)). Subjects with acetaminophen (APAP) toxicity, many without evidence of infection, demonstrated median PCT >2.0 ng/mL, regardless of SIRS features, while some culture positive subjects had PCT values <2.0 ng/mL.\n\nSummary/Conclusions\nWhile PCT appears to be a robust assay for detecting bacterial infection in the general population, there was poor discrimination between ALF patients with or without bacterial infection presumably because of the massive inflammation observed. Severe hepatocyte necrosis with inflammation results in elevated PCT levels, rendering this biomarker unreliable in the ALF setting.\n\nThis work was supported by the National Institutes of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health, W. M. Lee, Principal Investigator [grant U-01 DK58369]. Additional support was provided by Siemens Healthcare Diagnostics, Tarrytown, NY. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data AvailabilityAll relevant data are contained within the supporting information file.Data Availability\nAll relevant data are contained within the supporting information file.\n==== Body\nIntroduction\nPatients with acute liver failure (ALF) have an increased risk of infection approaching 80% thus predisposing to sepsis-related multi-organ failure [1–3]. Infections have been shown to worsen hepatic encephalopathy (HE) and are one of the most common causes of multi-organ dysfunction and death in ALF [3, 4].\n\nSigns and symptoms of ALF closely mimic those of sepsis making it difficult to accurately identify infection in this setting. The diagnosis of infection or sepsis (usually based upon a positive culture) is often delayed or not detected, even when presumptive evidence is very strong. Identification of a bacterial infection by culture requires 48–72 hours to complete and the efficacy of prophylactic antibiotics to contain an established infection remains difficult to prove. A more rapid method to identify infection is a worthwhile goal.\n\nProcalcitonin (PCT) is a biomarker for detection of bacterial infection that has shown early promise. PCT consists of 116 amino acids and has a MW of 14.5 kDa. A precursor of calcitonin, the primary source of PCT is the parafollicular C cells of the thyroid gland. Calcitonin has a hypocalcemic and hypophosphatemic effect that inhibits bone resorption and stimulates excretion of phosphorus, calcium, and sodium by the kidney and is used as a biomarker of medullary thyroid cancer but its relation to systemic inflammation remains unclear [5–8].\n\nIn studies of patients with sepsis, pneumonia, and other types of infections, PCT has been shown to be a reliable and rapidly available indicator of bacterial infection, useful in guiding antimicrobial therapy. PCT has been examined in patients who have had a liver transplant and in patients hospitalized with chronic liver disease (cirrhosis; CLD), but there are few studies of patients with ALF. [9–14].\n\nIn this study, we sought to determine whether PCT would aid in the identification of infection in ALF patients, since distinguishing sepsis from ALF without infection has prognostic and therapeutic implications. We utilized the extensive registry and serum bank of the U. S. Acute Liver Failure Study Group (USALFSG) as well as 2 local repositories for CLD control sera, to address this question.\n\nMaterials and Methods\nStudy Population\nThis study included patients prospectively enrolled in the US Acute Liver Failure Study (established in January 1998). Additionally, data and sera from two other repositories related to CLD were accessed to provide control groups. A total of 1863 adult ALF patients were enrolled from 23 tertiary care centers within the US between Jan. 1998 and Oct. 2010. Inclusion criteria defining ALF were the presence of coagulopathy (PT > 15 seconds or INR ≥1.5 IU) and any grade of hepatic encephalopathy (HE) that had occurred within 26 weeks of the first onset of symptoms. Enrolled patients may not have any CLD or cirrhosis, with the exception of certain patients with chronic hepatitis B or Wilson’s disease [15]. Written informed consent was obtained for each subject from the next of kin because of altered mental status due to HE. All centers were in compliance with their local institutional review board requirements. After informed consent was obtained, serum samples and clinical data were collected daily for up to 7 consecutive days. Sample collection ended when one of the following events occurred: the subject was discharged, transplanted, died, or completed the 7th study day. Serum samples were stored frozen at -70° until testing.\n\nThe Chronic Liver Disease (CLDD; PI–William M. Lee, MD) and the Nucleic Acid, Serum, and Tissue Repository for the Study of Liver Diseases Database and sample repositories (NSTLD; PI–Marlyn Mayo, MD) are principal investigator-initiated studies at UT Southwestern Medical Center (UTSW) in Dallas, TX. After written informed consent was obtained, sera were obtained and frozen at -70° until testing.\n\nThis retrospective analysis received Institutional Review Board (IRB) approval from the University of Texas Southwestern Medical Center (IRB#STU092010-126) and Virginia Commonwealth University (IRB#HM13517).\n\nAll study subjects were categorized into infection groups using modified definitions from the 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference definitions of systemic inflammatory response syndrome (SIRS), severe sepsis, and septic shock [9, 10, 16] based upon available data from the USALFSG database. Subjects with SIRS had to have two or more of the following signs or symptoms: body temperature >38°C or <36°C, heart rate >90 bpm, respiration rate >20 breaths/min, PCO2 level <32 mm Hg, WBC >12,000 or <4,000, or bands (immature granulocytic white blood cells) >10%. Severe sepsis was defined as organ failure in the presence of sepsis (SIRS plus a documented infection defined as a positive culture (blood, trachea, wound, catheter or urine) up to 2 days prior to the blood sample). Septic shock was defined as the presence of severe persistent hypotension (mean arterial pressure <60 mmHg) despite adequate volume resuscitation and pressor therapy in the presence of sepsis [16]. Non-infected/non-SIRS (non-SIRS) samples were selected from patients who met no more than one of the SIRS criteria.\n\nFor the 1,863 patients enrolled in the ALF study, 12,492 days of demographic and bio-data were sorted into 1 of the 4 groups: non-SIRS (n = 628), SIRS (n = 1407), severe sepsis (n = 387), and septic shock (n = 31). Because the USALFSG is an observational study not specifically designed to study SIRS or infections, some data parameters noted in the 4 different SIRS categories were either not captured by the ALF CRF or were not routinely collected on all patient days (examples: cell differential, urine output, tachypnea, and cardiac index). Thus, each patient day was categorized into a SIRS category based upon available data (i.e., if a lab value was missing, it was considered to be negative for that parameter and, if present, considered positive if the parameter met positive criteria). Samples for the non-SIRS category were only selected from days that had all available data and were negative for each parameter. Once sorted into the 4 SIRS categories, 115 subjects were randomly selected, based upon sample availability and maintaining a balance between the etiologies of their acute liver failure (acetaminophen toxicity, viral hepatitis or other etiologies). Currently, 46% of all ALF cases (in both the USALFSG and the US) result from APAP toxicity, either suicidal overdoses or unintentional excessive dosing [15]. To ensure a balanced distribution of etiologies, an equal number of samples were requested for each etiology.\n\nIn addition, 10 subjects from each of the CLDD and NSTLD repositories were randomly selected as negative controls. These subjects were ambulatory patients with CLD who had provided a screening blood sample during a routine clinic visit without symptoms. Limited bio-data were available for this group. These subjects were considered to be non-SIRS and had no clinical or laboratory evidence of bacterial infection.\n\nImmunoassay testing\nThe ADVIA Centaur BRAHMS PCT assay [17] is a sandwich immunoassay utilizing a monoclonal mouse antibody to fluorescein covalently linked to paramagnetic particles, a monoclonal mouse antibody to procalcitonin that is labeled with acridinium ester and a second monoclonal mouse antibody to procalcitonin labeled with fluorescein.\n\nAll testing was performed at Siemens Healthcare Diagnostics in Tarrytown, NY on a single ADVIA Centaur. Siemens Healthcare Diagnostics, Tarrytown, NY, provided all reagents required for testing.\n\nStatistical Analyses\nDescriptive statistics (median and range) are provided for all analyzed samples by group. A Kruskal-Wallis test with post hoc testing (Dunn Method) was used to determine the utility of PCT to detect infection, to examine possible measurement differences in PCT between patients with CLD and ALF, and to determine the existence of a dose affect between PCT values and severity of infection in ALF patients [18]. A Chi-square test was used as an alternative method for analyzing patient groups and infection status. PCT values were categorized into infection and non-infection groups using ROC analyses [19]. A 2-way analysis of variance was performed to examine the difference in PCT by type of culture (blood vs. all other culture types), severity categories (severe sepsis and septic shock), and the interaction of these two factors.\n\nThe median PCT values for the CLD, non-SIRS, and SIRS groups were compared to the reference range of the PCT assay. An expected reference value of <0.1 ng/mL had been previously calculated from PCT values from a population of 456 normal subjects. The 95% confidence interval for the mean concentration was 0.023 to 0.028 ng/mL [17]. SPSS version 20.0 (SPSS, Chicago, IL) and SAS version 9.2 (Cary, NC) were used for statistical analyses.\n\nResults\nStudy group characteristics based upon disease severity\nAvailable demographic and laboratory data for the 115 study subjects and control groups are shown in Tables 1 and 2. No discernible differences were apparent between the groups studied, except that the CLD group was somewhat older and the overall ALF group contained more women. Laboratory and certain clinical values differed significantly across the various study groups generally reflecting severity of illness: WBC, platelets, INR, AST, ALT, creatinine, lactate, pO2, O2 saturation, pCO2, pulse, respiration, and MAP.\n\n10.1371/journal.pone.0138566.t001Table 1 Demographic Data for Patients Based Upon Severity of Illness Classifications.\nMean (± SD) or\tCLD\tnon-SIRS\tSIRS\tSevere Sepsis\tSeptic Shock\t\t\nNumber (%)\tn = 20\tn = 30\tn = 29\tn = 40\tn = 16\tp-value\t\nAge (years)\t51 (29–71)\t49 (19–86)\t37 (18–66)\t41 (17–73)\t41 (19–71)\t0.044\t\nGender\t\t\t\t\t\t\t\n Female\t10 (50)\t15 (50)\t21 (72.4)\t33 (82.5)\t12 (75)\t0.019\t\nEthnicity*\n\t\t\t\t\t\t\t\n Hispanic\t\t5 (16.7)\t5 (17.2)\t5 (12.5)\t1 (6.7)\t\t\nRace**\n\t\t\t\t\t\t0.672\t\n White\t14 (77.8)\t21 (66.7)\t23 (79.3)\t33 (82.5)\t14 (87.5)\t\t\n African American\t1 (5.6)\t5 (16.7)\t5 (17.2)\t4 (10.0)\t1 (6.2)\t\t\n Asian\t2 (11.1)\t2 (6.7)\t1 (3.4)\t2 (5.0)\t1 (6.2)\t\t\n Hawaiian\t\t1 (3)\t\t\t\t\t\n Other\t1 (5.6)\t1 (3)\t\t1 (2.5)\t\t\t\nDiagnosis\t\t\t\t\t\t\t\n APAP\t\t10 (33.3)\t10 (34.5)\t16 (40.0)\t5 (31.2)\t\t\n Viral Hepatitis\t10 (50)\t10 (33.3)\t10 (34.5)\t7 (17.5)\t1 (6.2)\t\t\n Other\t10 (50)\t10 (33.3)\t9 (31.0)\t17 (42.5)\t10 (62.5)\t\t\nOutcome (TFS)\t\t\t\t\t\t\t\n APAP\t\t6 (20)\t5 (17.2)\t12 (30.0)\t1 (6.2)\t\t\n Viral Hepatitis\t\t4 (13.3)\t2 (6.9)\t2 (7.4)\t\t\t\n Other\t\t1 (3.3)\t4 (13.8)\t5 (12.5)\t1 (6.2)\t\t\nComa Grade\t\t\t\t\t\t\t\n Not Reported / 0\t20 (100)\t\t4 (13.8)\t3 (7.5)\t\t\t\n 1\t\t11 (36.7)\t1 (3.4)\t4 (10.0)\t\t\t\n 2\t\t11 (36.7)\t8 (27.6)\t1 (2.5)\t\t\t\n 3\t\t4 (13.3)\t5 (17.2)\t11 (27.5)\t1 (6.2)\t\t\n 4\t\t4 (13.3)\t11 (37.9)\t21 (52.5)\t15 (93.8)\t\t\nCulture Types\t\t\t\t\t\t\t\n Blood\t\t\t\t6\t5\t\t\n Tracheal\t\t\t\t12\t4\t\t\n Urine\t\t\t\t5\t3\t\t\n Wound\t\t\t\t3\t1\t\t\n Catheter\t\t\t\t1\t\t\t\n Multiple w Blood\t\t\t\t10\t2\t\t\n Multiple w/o Blood\t\t\t\t3\t1\t\t\nAntibiotics Used\t\t19 (63.3)\t23 (79.3)\t33 (82.5)\t13 (81.2)\t0.294\t\nProphylaxis\t\t15 (50)\t17 (58.6)\t19 (47.5)\t10 (62.5)\t0.673\t\nTherapy\t\t7 (23)\t12 (41.4)\t22 (55.0)\t7 (43.8)\t0.069\t\nAge of Sample (years)\t9 (1–15)\t7 (2–13)\t7 (2–13)\t6 (2–13)\t6.5 (2–11)\t0.872\t\nAfter Hospital Admission (days)\t\t2 (0–11)\t3 (0–51)\t2 (0–22)\t3 (0–16)\t0.557\t\n*Ethnicity: O were reported in the CLD group; 15 of 16 were reported in the Septic Shock group\n\n**Race: 18 of 20 reported in the CLD group / p-value reported for white vs. all other races.\n\n10.1371/journal.pone.0138566.t002Table 2 Biodata and Laboratory values for Patients Based Upon Severity of Illness Classifications.\n\tCLD\tnon-SIRS\tSIRS\tSevere Sepsis\tSeptic Shock\t\t\nMedian\tn = 20\tn = 30\tn = 29\tn = 40\tn = 16\tp-value\t\nPulse [bpm]\t\t80\t96\t108\t112\t<0.001\t\nRespiration [breaths/min]\t\t18\t23\t22\t22\t0.005\t\nMAP [mmHg]\t\t90.0\t81.5\t89.5\t57.5\t0.472*\n\t\nMin Temp [°C]\t\t36.6\t35.9\t36.5\t36.0\t0.200\t\nMax Temp [°C]\t\t36.8\t36.7\t37.4\t34.3\t0.101\t\nLaboratory values\t\t\t\t\t\t\t\n PCT [ng/mL]\t0.104\t1.57\t2.29\t2.51\t5.89\t<0.001\t\n AST [IU/L]\t\t787\t360\t292\t3069\t<0.001\t\n ALT [IU/L]\t\t1894\t775\t750\t1520\t0.030\t\n WBC [x 103 /uL]\t\t8.0\t14.0\t14.0\t17.00\t<0.001\t\n Platelets[x 103 /uL]\t\t143\t88\t115\t61\t0.002\t\n Prothrombin time [secs]\t\t27.5\t25.0\t21.0\t25.0\t0.124\t\n INR [ratio]\t\t3.0\t2.0\t2.0\t3.0\t0.030\t\n Bilirubin [mg/dL]\t\t15.0\t10.0\t10.0\t12.5\t0.902\t\n Glucose [mg/dL]\t\t122\t103\t110\t145\t0.997\t\n Creatinine [mg/dL]\t\t1.00\t2.00\t1.00\t3.00\t0.003\t\n Lactate [mg/dL]\t\t3.00\t6.00\t8.00\t14.00\t0.024\t\n pO2 [mmHg]\t\t117\t86\t107\t93\t0.025\t\n pCO2 [mmHg]\t\t34\t27\t27\t25\t<0.001\t\n O2_saturation [%]\t\t98\t96\t98\t95\t0.001\t\n FiO2 [%]\t\t28\t40\t40\t50\t0.056\t\n pO2/FiO2 [ratio]\t\t334\t306.7\t306.7\t172.5\t0.195\t\n*Septic Shock was not included as MAP is defined by the category.\n\nWithin the group of 115 ALF patients examined, all 56 with severe sepsis or septic shock had demonstrated positive bacterial cultures (Table 1), and the CLD, non-SIRS, and SIRS groups had no reported positive cultures on or prior to the study day. Blood stream infections (with or without other positive cultures) were present in 23 of the 56, with the majority of the remaining infections being tracheal, urinary tract or multiple without blood stream infection (n = 16, 8 and 4 respectively).\n\n\nFig 1 and Table 2 present the median results for the PCT assay across all categories. There was a significant difference between the CLD, non-SIRS and SIRS groups with a Chi-square = 43.68 (df = 2, p-value <0.001) as well as between the CLD group and either the non-SIRS or the SIRS groups (both p-values <0.001). However, there was no significant difference between the non-SIRS and SIRS groups (p-value >0.05). When PCT results for CLD, non-SIRS, and SIRS groups combined were compared to the documented reference value of the PCT assay (<0.1 ng/mL—(17)), the median PCT value (0.97 ng/mL) was significantly higher than the reference value (p <0.001). Results for the CLD group (median = 0.104 ng/mL) considered separately did not differ from the published reference range (p = 0.985), while results from each of the other two groups (non-SIRS–median = 1.57 ng/mL and SIRS–median = 2.29 ng/mL) were significantly higher than the reference and the CLD median value (p <0.001 for both).\n\n10.1371/journal.pone.0138566.g001Fig 1 Median PCT Values by Category.\nThis graph represents the median PCT values for the five patient severity groups. The lower dashed horizontal line represents the 0.1 ng/mL PCT cut-off value indicative of no infection. The upper dotted horizontal line represents the 2.0 ng/mL PCT cut-off value indicative of severe sepsis.\n\nWhen PCT concentrations were compared across all categories, there was a significant difference between the CLD group and the four ALF categories (Chi-square = 53.98, p-value <0.001). Post hoc pairwise testing indicated that the median PCT of the CLD group was significantly different from each of the ALF categories (p<0.001). However, there were no significant differences observed (p = 0.169) between the four ALF categories themselves (non-SIRS, SIRS, severe sepsis and septic shock). When we compared the PCT values between ALF subjects without a documented infection (non-SIRS and SIRS) to those with a documented infection (severe sepsis and septic shock), there was no difference between the 2 groups (p = 0.082).\n\nSubjects in severe sepsis and septic shock categories were examined based upon types of cultures: blood cultures vs. all other culture types. There were no significant differences observed for any of the 3 interactions: type of culture (p = 0.224), severity categories (p = 0.309), or the interaction between these two factors (p = 0.241). There was also no difference observed between the median PCT levels for subjects with positive blood cultures and those with positive cultures from other sources.\n\nStudy group characteristics based upon PCT cut-off value\nIn previous studies, values of PCT above 2.0 ng/mL were considered to be associated with bacterial infection. While our non-SIRS and SIRS categories lacked evidence of infection, both demonstrated median PCT values near or slightly above the 2.0 ng/mL cut-off, 1.57 and 2.29 respectively. Given the uncertainty concerning what a reasonable cut-off value for infection should be for this population, we used a receiver operator characteristic (ROC) analysis, in which the optimal area under the curve (AUC) was equal to 0.697 (95% CI: 0.609–0.784), with a cut-off value of 1.62 ng/mL, somewhat below the 2.0 ng/mL level (Fig 2). The cut-off value determined from this set of data was made using a combination of criteria: 1) the point on the curve that was at the greatest distance (0.186) from the 0.5 reference line at a 45° angle to the line, 2) accuracy, 3) sensitivity (0.643), 4) specificity (0.620), and 5) likelihood ratio (1.693). We used this 1.62 ng/mL cut-off for subsequent analyses.\n\n10.1371/journal.pone.0138566.g002Fig 2 Receiver Operator Curve for the Detection of Infection in ALF and ALI patients Using PCT.\nThe ROC analysis resulted in an AUC of 0.697 with a sensitivity of 64.3% and a specificity of 62.0% for the use of PCT in the detection of infection this population of ALF patients.\n\nWhen additional biochemical data ALF between subjects with a PCT that was <1.62 ng/mL and from those with a PCT that was ≥1.62 ng/mL were compared, platelet, creatinine, AST, ALT, and bilirubin showed significant differences between the theoretically ‘infected’ (above the cut-off) and ‘non-infected’ (below the cut-off) groups (Table 3). Of interest, 85.4% of all APAP subjects had values above the 1.62 ng/mL level while only 21 of 41 (51.2%) of the APAP subjects had a documented bacterial infection. In the non-APAP subjects, 43.2% had values above 1.62 ng/mL with documented bacterial infection in 35 of 74 (47.3%) of the subjects.\n\n10.1371/journal.pone.0138566.t003Table 3 Demographic and Biodata Results Based Upon the Calculated Infection Cut-off Value of 1.62 ng/mL.\nMedian or Number (%)\tPCTs < 1.62 ng/mL n = 48\tPCT ≥ 1.62 ng/mL n = 67\tp-value\t\nALF Etiology\t\t\t\t\n APAP\t6 (12.5)\t35 (52.2)\t\t\n Viral hepatitis\t17 (34.7)\t11 (16.4)\t\t\n Other\t25 (51.0)\t21 (31.3)\t\t\nOutcome (TFS)\t\t\t\t\n APAP\t3 (6.2)\t21 (31.3)\t\t\n Viral Hepatitis\t5 (10.4)\t3 (4.4)\t\t\n Other\t5 (10.4)\t6 (9.0)\t\t\nProcalcitonin [ng/mL]\t0.6904\t5.325\t<0.001\t\nWBC [x 103 /uL]\t13.0\t13.0\t0.740\t\nPlatelets [x 103 /uL]\t135\t92\t0.019\t\nINR [ratio]\t2.0\t2.0\t0.786\t\nGlucose [mg/dL]\t115.5\t120.0\t0.787\t\nCreatinine [mg/dL]\t1.0\t2.0\t<0.001\t\nAST [IU/L]\t337\t913\t0.06\t\nALT [IU/L]\t684\t1759\t0.07\t\nLactate [mg/dL]\t3.5\t6.0\t0.230\t\nBilirubin [mg/dL]\t19.0\t7.0\t<0.001\t\npO2 [mmHg]\t92.5\t103.0\t0.707\t\npCO2 [mmHg]\t29.0\t27.0\t0.108\t\nPulse [bpm]\t84\t68\t0.084\t\nRespiration [breaths/min]\t17\t13\t0.094\t\nMin Temp [°C]\t36.0\t37.0\t0.298\t\nMax Temp [°C]\t37.0\t37.0\t0.298\t\nComa Grade\t\t\t\t\n 0 / Not reported\t3\t4\t\t\n 1\t7\t9\t\t\n 2\t12\t8\t\t\n 3\t9\t12\t\t\n 4\t18\t33\t\t\nSamples were resorted based upon the cut-off value of 1.62 ng/mL and demographic and biodata were re-examined.\n\nWhen PCT results were examined based solely upon etiology, median values for subjects with APAP toxicity were typically much higher, between 3.0 and 6.6 times higher than the results observed for the same severity category for subjects with non-APAP etiologies (Fig 3).\n\n10.1371/journal.pone.0138566.g003Fig 3 Median APAP vs All Other Etiologies PCT values by Category.\nThis graph represents the median PCT values for the four ALF patient severity groups sorted by etiologies: APAP and All Others etiologies (combined viral and other) with the lower dashed line indicative of no infection (0.1 ng/mL) and the upper dotted line indicative of severe sepsis (2.0 ng/mL).\n\nDiscussion\nIn this study of ALF patients selected for increasing severity of SIRS features and for the presence of bacterial infection, PCT measurement disclosed markedly elevated values but did not provide any direct correlation to presence or absence of infection. Determining the presence with certainty of systemic infection in those with advance SIRS features is problematic in a retrospective study; we assumed that the presence of advanced SIRS features plus positive cultures was the best surrogate for systemic infection and this may not be the case in every instance. However, virtually all ALF subjects displayed PCT values well above both the 0.1 ng/mL reference value and the median value observed in the CLD controls, regardless of any evidence for infection, particularly high values being observed in a large group that demonstrated no evidence for infection. The differences in PCT levels between severity categories among ALF patients were not significant due apparently to elevated levels in the absence of infection. Thus, both the non-SIRS and SIRS categories that would be expected to show low or normal PCT levels demonstrated PCT levels approximating those that have been observed previously in other studies during active bacterial infection in a non-ALF setting.\n\nUsing a cut-off value determined by the ROC analysis, the presumed uninfected categories (non-SIRS and SIRS) included 31 patients with elevated PCTs (≥1.62 ng/mL). Of these subjects, 13 demonstrated signs of infection (bacterial or fungal, n = 5 each) 1 or more days after the PCT sample was collected or other evidence of infection upon closer examination of the each subject’s case report form (CRF), including pancreatitis, tooth abscess or ventilator acquired pneumonia with infiltrate on x-ray. Subjects with fungal infections were classified as culture negative since values of PCT in yeast and fungal infections have been observed to be lower than those seen with most bacterial infections [20].\n\nThe median PCT values in the severe sepsis and septic shock categories (3.46 ng/mL and 589 ng/mL, respectively), were both well above the 1.62 ng/mL calculated cut-off and 2.0 ng/mL literature cut-off for severe sepsis [10], but these were not significantly different from the median PCT values in non-SIRS and SIRS patients without documented infection. Of interest, 17 of 40 severe sepsis subjects and 3 of 16 septic shock subjects had PCT values below the 1.62 ng/mL cut-off. Prophylactic antibiotics might provide a partial explanation for lower PCT values during a documented infection but, overall, the decreased results remain unexplained. Full bacterial culture reports were not collected as part of the USALFSG study nor did the study case report forms capture information related to quantity of bacterial growth or antibiotic sensitivities that might have helped determine some the differences among the various severity groups.\n\nUpon examining results according to etiology, subjects with APAP toxicity demonstrated much higher PCT levels than any other etiologies. It seems likely that the elevated PCT values in these subjects are not indicative of infection. Rather, APAP toxicity unleashes an inflammatory response, with macrophage activation, release of cytokines and pro-inflammatory regulators including TNF-alpha that may secondarily contribute to liver injury and the appearance of a septic milieu [21, 22]. While the exact origin and pathogenic pathway of PCT stimulation is still unknown, it has been suggested that PCT is produced by neuroendocrine cells in the liver while other data suggest that it is released by macrophages [23]. It is also possible that increases in PCT may be initiated by TNF-alpha and IL-1b [24, 25]. It appears that in the acute liver failure setting PCT is increased due in large part to the massive inflammatory response to liver injury, particularly in the case of acetaminophen toxicity. While we did see higher PCT levels in patients with bacterial infections, if PCT is to be useful in this population, a better understanding of the mechanism of PCT production will need to be ascertained.\n\nPrior studies examining PCT values in the acute liver failure setting have been limited. Studies in patients with chronic liver disease (cirrhosis) [26–29], liver metastasis of non-liver primary solid tumors [23], and other acute and chronic liver diseases have been performed [30]. While baseline PCT values increased as the severity of the underlying liver disease increased, an elevated PCT was indicative of bacterial infection. A previous study of PCT use in ALF patients due to APAP toxicity also showed increased PCT values in subjects without evidence of bacterial infection [14], similar to our findings.\n\nWe considered whether the use of older retrospective samples from the ALFSG repository might affect results, since long-term sample storage may decrease observed PCT levels. Schuetz, et al. studied two sets of samples that were stored at -80°C for 4.8 to 5.5 years and 3.3 to 4.6 years [31]. The PCTs for each set decreased by 11.4% and 13.5% respectively. Samples used in this study had been stored an average of approximately 6.75 years at -80°C. While it is assumed that the length of time in storage might have decreased the PCT values obtained, the exact amount of decrease is unknown and an estimate of the extent of the effect cannot be calculated. However, since each sample group had similarly aged samples, this would appear to negate a specific effect on the overall study results (Table 1).\n\nConclusion\nProcalcitonin detects bacterial infection and sepsis in the general population, but appears to be a more general marker of moderate to severe inflammation. As such, it has limited value as a single marker to discriminate between the presence or absence of bacterial infection in the setting of acute liver failure but may be of value in combination with other markers. PCT elevations appeared to be roughly proportional to the degree of hepatic necrosis. A prospective study with a larger sample size employing prospective determination of infection and standardized antibiotic usage might provide additional information regarding the relationship between PCT and severe liver injury, particularly APAP toxicity.\n\nSupporting Information\nS1 Data Study Clinical and Laboratory Data.\n(XLSX)\n\nClick here for additional data file.\n\n Members and institutions participating in the Acute Liver Failure Study Group 1998–2011 are as follow: William M. Lee, M.D. (Principal Investigator), The University of Texas Southwestern Medical Center, Dallas, TX; Anne M. Larson, M.D., Iris Liou, M.D., University of Washington, Seattle, WA; Timothy Davern, M.D., University of California, San Francisco, CA (current address: California Pacific Medical Center, San Francisco, CA), Oren Fix, M.D., University of California, San Francisco; Michael Schilsky, M.D., Mount Sinai School of Medicine, New York, NY (current address: Yale University, New Haven, CT); Timothy McCashland, M.D., University of Nebraska, Omaha, NE; J. Eileen Hay, M.B.B.S., Mayo Clinic, Rochester, MN; Natalie Murray, M.D., Baylor University Medical Center, Dallas, TX; A. Obaid S. Shaikh, M.D., University of Pittsburgh, Pittsburgh, PA; Andres Blei, M.D., Northwestern University, Chicago, IL (deceased), Daniel Ganger, M.D., Northwestern University, Chicago, IL; Atif Zaman, M.D., University of Oregon, Portland, OR; Steven H.B. Han, M.D., University of California, Los Angeles, CA; Robert Fontana, M.D., University of Michigan, Ann Arbor, MI; Brendan McGuire, M.D., University of Alabama, Birmingham, AL; Raymond T. Chung, M.D., Massachusetts General Hospital, Boston, MA; Alastair Smith, M.B., Ch.B., Duke University Medical Center, Durham, NC; Robert Brown, M.D., Cornell/Columbia University, New York, NY; Jeffrey Crippin, M.D., Washington University, St Louis, MO; Edwyn Harrison, Mayo Clinic, Scottsdale, AZ; Adrian Reuben, M.B.B.S., Medical University of South Carolina, Charleston, SC; Santiago Munoz, M.D., Albert Einstein Medical Center, Philadelphia, PA; Rajender Reddy, M.D., University of Pennsylvania, Philadelphia, PA; R. Todd Stravitz, M.D., Virginia Commonwealth University, Richmond, VA; Lorenzo Rossaro, M.D., University of California Davis, Sacramento, CA; Raj Satyanarayana, M.D., Mayo Clinic, Jacksonville, FL; and Tarek Hassanein, M.D., University of California, San Diego, CA. The University of Texas Southwestern Administrative Group included Grace Samuel, Ezmina Lalani, Carla Pezzia, and Corron Sanders, Ph.D., Nahid Attar, Jody A. Balko, Ph.D., the University of Texas Southwestern Statistics and Data Management Group included Joan Reisch, PhD, Linda Hynan, PhD, Janet P. Smith, Joe W. Webster, and Mechelle Murry, and the Medical University of South Carolina Data Coordination Unit included Valerie Durkalski, Ph.D., Wenle Zhao, Ph.D., Catherine Dillon, Holly Battenhouse and Tomoko Goddard.\n\nAbbreviations\nALFacute liver failure\n\nALTalanine aminotransferase\n\nAPAPacetaminophen\n\nASTaspartate aminotransferase\n\nAUCarea under the receiver operator characteristic curve\n\nCLDchronic liver disease\n\nCRFcase report form\n\nHBVhepatitis B virus\n\nHEhepatic encephalopathy\n\nINRInternational Normalized Ratio of prothrombin time\n\nLLDlower limit of detection\n\nLTliver transplantation\n\nMAPmean arterial pressure\n\nPCTprocalcitonin\n\nPTprothrombin time\n\nROCreceiver operator characteristic curve\n\nSIRSsystemic inflammatory response syndrome\n\nTFStransplant-free survival\n\nWBCwhite blood cell count\n==== Refs\nReferences\n1 \nRolando N , Wade J , Davalos M , Wendon J , Philpott-Howard J , Williams R . The systemic inflammatory response syndrome in acute liver failure . Hepatology , 2000 ; 32 (4 ): 734 –739 .\n11003617 \n2 \nRolando N , Wade J , Davalos M , Wendon J , Philpott-Howard J , Williams R . Timing and aetiology of bacterial infections in a liver intensive care unit . J Hosp Infect , 2003 ; 53 (2 ): 144 –146 .\n12586576 \n3 \nStravitz RT . Critical management decisions in patients with acute liver failure . Chest , 2008 ; 134 : 1092 –1102 . 10.1378/chest.08-1071 \n18988787 \n4 \nVaquero J , Polson J , Chung C , Helenowski I , Schiodt FV , Reisch J , et al\nInfection and the progression of hepatic encephalopathy in acute liver failure . Gastroenterology , 2003 ; 125 (3 ): 755 –764 .\n12949721 \n5 \nBecker KL , Nylen ES , White JC , Muller B , Snider RH , Jr. Procalcitonin and the calcitonin gene family of peptides in inflammation, infection, and sepsis: A journey from calcitonin back to its precursors . J Clin Endocrinol Metab , 2004 ; 89 (4 ): 1512 –1525 .\n15070906 \n6 \nBracq S , Machairas M , Clement B , Pidoux E , Andreoletti M , Mokhtar MS , et al\nCalcitonin gene expression in normal human liver . FEBS Letters , 1993 ; 331 (1,2 ): 15 –18 .8405394 \n7 \nCarrol ED , Thomson APJ , Hart CA . Procalcitonin as a marker of sepsis . Int J Antimicrob Agents , 2002 ; 20 : 1 –9 .\n12127705 \n8 \nMuller B , Becker KL . (2001). Procalcitonin: How a hormone became a marker and mediator of sepsis . Swiss Medi Wkly , 2001 ; 131 (41–42 ): 595 –602 .\n9 \nBrunkhorst FM , Wegscheider K , Forycki ZF , Brunkhorst R . Procalcitonin for early diagnosis and differentiation of SIRS, sepsis, severe sepsis, and septic shock . Intensive Care Med , 2000 ; 26 : S148 –S152 . 10.1007/BF02900728 \n18470710 \n10 \nHarbarth S , Holeckova K , Froidevaux C , Pittet D , Ricou B , Grau GE , et al\nDiagnostic value of procalcitonin, interleukin-6, and interleukin-8 in critically ill patients admitted with suspected sepsis . American Journal of Respiratory Critical Care Medicine , 2001 ; 164 : 396 –402 .\n11500339 \n11 \nBrunkhorst FM , Eberhard OK , Brunkhorst R . Discrimination of infectious and noninfectious causes of early acute respiratory distress syndrome by procalcitonin . Crit Care Med , 1999 ; 27 (10 ): 2172 –2176 .\n10548201 \n12 \nLuyt C , Guerin V , Combes A , Trouillet J , Ayed SB , Bernard M , et al\nProcalcitonin kinetics as a prognostic marker of ventilator-associated pneumonia . Am J Respir Crit Care Med , 2005 ; 171 : 48 –53 .\n15447947 \n13 \nMeisner M , Tschaikowsky K , Hutzler A , Schick C , Schuttler J . Postoperative plasma concentrations of procalcitonin after different types of surgery . Intensive Care Med , 1998 ; 24 : 680 –684 .\n9722037 \n14 \nJackson N , Batouche S , Sherwood R , Wendon J . Serial plasma procalcitonin levels in patients requiring admission to liver ITU with paracetamol induced acute liver failure . Abstract Brit J Anaesth , 2000 ; 84 (5 ): 92P .\n15 \nLee WM , Squires RH Jr, Nyberg SL , Doo E , Hoofnagle JH . Acute liver failure: Summary of a workshop . Hepatology , 2008 ; 47 : 1401 –1415 . 10.1002/hep.22177 \n18318440 \n16 \nLevy MM , Fink MP , Marshall JC , Abraham E , Angus D , Cook D , et al\n2001 SCCM/ESICM/ACCP/ATS/SIS international sepsis definitions conference . Crit Care Med , 2003 ; 31 (4 ): 1250 –1256 .\n12682500 \n17 Siemens Healthcare Diagnostics, Ltd. Advia centaur and advia centaur XP systems—procalcitonin (PCT). Frimley, Camberley, UK; 2010. Rev B.\n18 \nElliot AC , Hynan LS . A SAS® macro implementation of a multiple comparison post hoc test for a Kruskal-Wallis analysis . Comput Methods Programs Biomed , 2011 ; 102 (1 ): 75 –80 . 10.1016/j.cmpb.2010.11.002 \n21146248 \n19 \nRiffenburgh RH . Statistics in Medicine . Second Edition \nNew York, NY , Elsevier , 2006 .\n20 \nNakamura A , Wada S , Takeda T , Nobori T . Efficacy of procalcitonin in the early diagnosis of bacterial infections in a critical care unit . Shock , 2009 ; 31 (6 ): 586 –591 . 10.1097/SHK.0b013e31819716fa \n19060784 \n21 \nDragomir A-C , Laskin JD , Laskin DL . Macrophage activation by factors released from acetaminophen-injured hepatocytes: Potential role of HMGB-1 . Toxicol Appl Pharmacol , 2011 ; 253 : 170 –177 . 10.1016/j.taap.2011.04.003 \n21513726 \n22 \nJaeschke H , McGill MR , Ramachandran A . Oxidant stress, mitochondria, and cell death mechanisms in drug-induced liver injury: Lessons learned from acetaminophen hepatotoxicity . Drug Metab Rev , 2012 ; 44 (1 ): 88 –106 . 10.3109/03602532.2011.602688 \n22229890 \n23 \nMatzaraki V , Alexandraki KI , Venetsanou K , Piperi C , Myrianthefs P , Malamos N , et al\nEvaluation of serum procalcitonin and interleukin-6 levels as markers of liver metastasis . Clin Biochem , 2007 ; 40 : 336 –342 .\n17306245 \n24 \nWhang KT , Vath SD , Nylen ES , Muller B , Li Q , Tamarkin L , et al\nProcalcitonin and proinflammatory cytokine interactions in sepsis . Shock , 1999 ; 12 (4 ): 268 –273 .\n10509628 \n25 \nDomenech VS , Nylen ES , White JC , Snider RH Jr, Becker KL , Landmann R , et al\nCalcitonin gene-related peptide expression in sepsis: Postulation of microbial infection-specific response elements within the calcitonin I gene promoter . J Investig Med , 2001 ; 49 (6 ): 514 –521 .\n11730087 \n26 \nBota DP , Van Nuffelen M , Zakariah AN , Vincent JL . Serum levels of C-reactive protein and procalcitonin in critically ill patients with cirrhosis of the liver . J Lab Clin Med , 2005 ; 146 (6 ): 347 –351 .\n16310518 \n27 \nConnert S , Stremmel W , Eising C . Procalcitonin is a valid marker of infection in decompensated cirrhosis . Abstract Z Gastroenterol , 2003 ; 41 (2 ): 165 –170 .\n28 \nSpahr L , Morard I , Hadengue A , Vadas L , Pugin J . Procalcitonin is not an accurate marker of spontaneous bacterial peritonitis in patients with cirrhosis . Hepatogastroenterology , 2001 ; 48 (38 ): 502 –505 .\n11379342 \n29 \nViallon A , Zeni F , Pouzet V , Lambert C , Quenet S , Tardy B , et al\nSerum and ascitic procalcitonin levels in cirrhotic patients with spontaneous bacterial peritonitis: Diagnostic value and relationship to pro-inflammatory cytokines . Intensive Care Med , 2000 ; 26 : 1082 –1086 .\n11030164 \n30 \nElefsiniotis IS , Skounakis M , Vezali E , Pantazis KD , Petrocheilou A , Pirounaki M , et al\nClinical significance of serum procalcitonin levels in patients with acute or chronic liver disease . Eur J Gastroenterol Hepatol , 2006 ; 18 (5 ): 525 –530 .\n16607149 \n31 \nSchuetz P , Christ-Crain M , Huber AR , Muller B . Long-term stability of procalcitonin in frozen samples and comparison of kryptor and VIDAS automated immunoassays . Clin Biochem , 2010 ; 43 (3 ): 341 –344 . 10.1016/j.clinbiochem.2009.08.029 \n19747473\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1932-6203",
"issue": "10(9)",
"journal": "PloS one",
"keywords": null,
"medline_ta": "PLoS One",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001424:Bacterial Infections; D015415:Biomarkers; D002116:Calcitonin; D015740:Calcitonin Gene-Related Peptide; D005260:Female; D006801:Humans; D007249:Inflammation; D017114:Liver Failure, Acute; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011498:Protein Precursors; D012189:Retrospective Studies; D018805:Sepsis; D012720:Severity of Illness Index; D012772:Shock, Septic; D018746:Systemic Inflammatory Response Syndrome; D055815:Young Adult",
"nlm_unique_id": "101285081",
"other_id": null,
"pages": "e0138566",
"pmc": null,
"pmid": "26393924",
"pubdate": "2015",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "18318440;17306245;18988787;19060784;19747473;21146248;21513726;22229890;10548201;11003617;11030164;11379342;11500339;12127705;11820070;11730087;12586576;12592597;12682500;12949721;15070906;8405394;9722037;10509628;15447947;16310518;16607149;18470710",
"title": "Procalcitonin Identifies Cell Injury, Not Bacterial Infection, in Acute Liver Failure.",
"title_normalized": "procalcitonin identifies cell injury not bacterial infection in acute liver failure"
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"abstract": "OBJECTIVE\nFebrile neutropenia (FN) is a common and serious complication of myelosuppressive chemotherapy. Guidelines recommend primary granulocyte colony-stimulating factors (G-CSF) prophylaxis (PPG) in patients with a high risk (HR, >20 %) of developing FN. We performed a retrospective analysis using a subset of the Medicare 5 % database to assess patterns of G-CSF use and FN occurrence among elderly cancer patients receiving myelosuppressive chemotherapy.\n\n\nMETHODS\nChemotherapy courses for patients aged 65+ years were identified; only the first course was used for this analysis. Using clinical guidelines, chemotherapy regimens were classified as HR or intermediate risk (IR) for FN. The first administration of G-CSF was classified as either PPG (within the first 5 days of the first cycle), secondary prophylaxis, or reactive.\n\n\nRESULTS\nTwelve thousand seven hundred seven courses across five tumor types were classified as having a HR or IR regimen. G-CSF was used in 24.5-73.8 % of patients receiving a HR FN regimen, with the highest use in breast cancer or NHL. Except for breast cancer (where PPG was used in 52.1 %), PPG was given in less than half of patients receiving a HR regimen. Depending on the tumor type, 4.8-22.6 % of patients with a HR regimen had a neutropenia-related hospitalization.\n\n\nCONCLUSIONS\nGuidelines recommend PPG with HR FN regimens and older age (>65 years), an important risk factor for developing severe neutropenic complications. However, our results show that in this elderly population, PPG was not routinely used (range 4.8-52.1 %) in patients receiving HR FN regimens. Careful attention to FN risk factors, including chemotherapy regimen and patient age, is needed when planning treatment strategies.",
"affiliations": "Amgen Inc., One Amgen Center Drive, M/S 17-1-A, Thousand Oaks, CA, 91320, USA.",
"authors": "Choi|Mi Rim|MR|;Solid|Craig A|CA|;Chia|Victoria M|VM|;Blaes|Anne H|AH|;Page|John H|JH|;Barron|Richard|R|;Arneson|Thomas J|TJ|",
"chemical_list": "D016179:Granulocyte Colony-Stimulating Factor",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00520-014-2121-7",
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"issn_linking": "0941-4355",
"issue": "22(6)",
"journal": "Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer",
"keywords": null,
"medline_ta": "Support Care Cancer",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D064146:Chemotherapy-Induced Febrile Neutropenia; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D008297:Male; D009369:Neoplasms; D012189:Retrospective Studies; D012307:Risk Factors",
"nlm_unique_id": "9302957",
"other_id": null,
"pages": "1619-28",
"pmc": null,
"pmid": "24492928",
"pubdate": "2014-06",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "15751024;17634496;16682719;16492793;21095116;20715160;21509769;7964965;21402294;21091127;20840455;14556916;21378538;16633911;21670423;16314624;15967836;19637341;16575919;17506600;10764438;10928394;21584667;12488407",
"title": "Granulocyte colony-stimulating factor (G-CSF) patterns of use in cancer patients receiving myelosuppressive chemotherapy.",
"title_normalized": "granulocyte colony stimulating factor g csf patterns of use in cancer patients receiving myelosuppressive chemotherapy"
} | [
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"abstract": "Radiation recall dermatitis (RRD) is a phenomenon that occurs in previously irradiated areas shortly after administration of a chemotherapeutic agent. As the use of sorafenib expands, the incidence of radiation recall dermatitis induced by sorafenib will likely increase. Here, we report on a patient who developed RRD and describe his clinical characteristics along with a review of the literature.\nOur patient was treated with palliative radiation therapy (RT) to a painful metastatic hepatocellular carcinoma lesion in the right forearm. He completed his radiation course with grade 1 dermatitis, which had resolved by the time he was started on sorafenib 400 mg twice daily 7 days afterwards. On the 21st day after RT, he presented with desquamation and erythema in the previously irradiated area of the right forearm, consistent with RRD. The sorafenib was discontinued and his symptoms subsequently resolved with conservative topical management.\nAlthough the pathophysiologic mechanism of sorafenib-related radiation recall dermatitis remains to be investigated, practitioners should be aware of its presence and management in order to improve clinical outcomes.",
"affiliations": "Department of Radiation Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA.;Department of Medical Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA.;Department of Radiation Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA.;Department of Radiation Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA.;Department of Radiation Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA.",
"authors": "Mehta|Keyur|K|0000-0003-2113-617X;Kaubisch|Andreas|A|;Tang|Justin|J|;Pirlamarla|Aneesh|A|;Kalnicki|Shalom|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2018/2171062",
"fulltext": "\n==== Front\nCase Rep Oncol MedCase Rep Oncol MedCRIONMCase Reports in Oncological Medicine2090-67062090-6714Hindawi 10.1155/2018/2171062Case ReportRadiation Recall Dermatitis in Patients Treated with Sorafenib http://orcid.org/0000-0003-2113-617XMehta Keyur kmehta@montefiore.org\n1\nKaubisch Andreas \n2\nTang Justin \n1\nPirlamarla Aneesh \n1\nKalnicki Shalom \n1\n\n1Department of Radiation Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA\n2Department of Medical Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USAAcademic Editor: Peter F. Lenehan\n\n2018 24 1 2018 2018 21710621 12 2017 10 1 2018 Copyright © 2018 Keyur Mehta et al.2018This 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.Introduction\n Radiation recall dermatitis (RRD) is a phenomenon that occurs in previously irradiated areas shortly after administration of a chemotherapeutic agent. As the use of sorafenib expands, the incidence of radiation recall dermatitis induced by sorafenib will likely increase. Here, we report on a patient who developed RRD and describe his clinical characteristics along with a review of the literature. \n\nCase Presentation\n Our patient was treated with palliative radiation therapy (RT) to a painful metastatic hepatocellular carcinoma lesion in the right forearm. He completed his radiation course with grade 1 dermatitis, which had resolved by the time he was started on sorafenib 400 mg twice daily 7 days afterwards. On the 21st day after RT, he presented with desquamation and erythema in the previously irradiated area of the right forearm, consistent with RRD. The sorafenib was discontinued and his symptoms subsequently resolved with conservative topical management. \n\nConclusions\n Although the pathophysiologic mechanism of sorafenib-related radiation recall dermatitis remains to be investigated, practitioners should be aware of its presence and management in order to improve clinical outcomes.\n==== Body\n1. Introduction\nRadiation recall dermatitis (RRD) is a phenomenon that occurs in previously irradiated areas shortly after administration of a chemotherapeutic agent. Radiation recall dermatitis has been reported with usage of cisplatin, docetaxel, and trastuzumab. Sorafenib is a tyrosine kinase inhibitor that has been commonly used in locally advanced and metastatic hepatocellular carcinoma (HCC) with phase III clinical trial showing improvement in overall survival in patients with inoperable HCC [1].\n\nApplication of radiation therapy in HCC has increased with the advent of advanced radiation planning techniques such as stereotactic body radiation therapy. As a result, the clinical application of radiation therapy with sorafenib continues to increase. While the side-effect profile of sorafenib as monotherapy has been well described, the cumulative effects with radiation therapy are less clear. RRD triggered by sorafenib is rare, and only few cases have been reported [2, 3]. Here, we report a case of sorafenib-induced radiation recall dermatitis along with a review of the literature.\n\n2. Case Report\nA 59-year-old man with hepatitis C presented with an enlarging right forearm lesion that was gradually becoming more painful. Biopsy of the painful lesion showed metastatic hepatocellular carcinoma. On PET/CT imaging, he was shown to have several hepatic lesions and a FDG avid lesion in the right forearm. His right forearm lesion received radiofrequency ablation and was followed by palliative radiation therapy. The patient received a total dose of 30 Gy in 10 fractions using two oblique fields (Figure 1). The mean dose of the skin was 13.1 Gy, and the maximum dose was 29.4 Gy. The skin contour extended 3 cm superior and inferior to the gross tumor volume. The skin D50% was 15.2 Gy. The patient's tumor decreased in size with improvement in his range of motion. He developed grade 1 dermatitis while receiving radiation therapy, but this had resolved prior to initiation of sorafenib.\n\nThe patient was started on sorafenib 400 mg twice daily after resolution of his grade 1 dermatitis and seven days after radiation therapy. When evaluated in follow-up 21 days after completion of radiation therapy, he was noted to have marked erythema and dry desquamation in the previously irradiated area with sharp demarcation of the adjacent skin, consistent with RRD (Figure 2). He did not have pruritus, pain, or tenderness associated with the RRD. He was determined to have grade 1 RRD.\n\nThe sorafenib was held, and the patient was started on topical antibiotics for prophylaxis and topical steroids for symptom management. Shortly afterwards, his dermatitis improved, and the patient was restarted on reduced dose sorafenib 200 mg daily with no further complications.\n\n3. Discussion\nThe multimodality approach to cancer patients often involves a combination of chemotherapy and radiation therapy in a concomitant or sequential course. Radiation recall reactions are inflammatory states triggered by a systemic agent in a previously irradiated field. These reactions can manifest in internal organs and muscles but are most commonly seen as dermatologic effects. RRD has been described as a side effect for many systemic agents, such as docetaxel, paclitaxel, gemcitabine, pemetrexed, doxorubicin, and tamoxifen [4]. To date, RRD with sorafenib treatment has only been described in five other cases [2, 3, 5, 6].\n\nIn our patient, the skin reaction was observed 21 days after completion of radiation therapy. The acute reaction that was observed shortly after completion of radiation therapy was likely due to acute radiation dermatitis. However, that quickly resolved by itself. The second manifestation of dermatitis in the same area after initiation of sorafenib is more consistent with RRD. While the affected skin appears to have completely healed during the short one-week interval between RT and exposure of sorafenib, it is possible that there may be subdermal effects that are still in the process of healing. Therefore, it is possible that the presentation may also have a component of acute radiation dermatitis due to sensitization by sorafenib.\n\nRRD typically appears after a dermatitis-free interval subsequent to the completion of radiation treatments. The possibility of RRD should be considered in anyone who developed a skin reaction in a previously irradiated area that was normal prior to the initiation of a new drug. This is inclusive of patients with distant history of radiation therapy, as the radiation-to-drug interval can range from days to years, who were administered a dose between 10 and 81 Gy [7].\n\nThe presentation of RRD is similar to the dermatologic reaction seen during active radiation therapy, namely, erythema, edema, desquamation, hemorrhage, and necrosis. These can be categorized in the RTOG acute toxicity definition of radiation dermatitis. However, Camidge and Price fashioned a new categorization of RRD that includes pruritus, urticaria, and vesiculation (Table 1) [8].\n\nThe exact mechanism of RRD is unknown, but hypotheses have focused on vascular damage, drug hypersensitivity, or stem cell inadequacy or sensitivity [7–9]. The histopathologic findings of RRD were described by Smith et al. in 10 patients who underwent a biopsy of affected areas [10]. Included in their findings were descriptions of hyperkeratosis, epidermal acanthosis, disordered proliferation with increased mitotic figures, follicular hyperkeratosis, follicular pustules, psoriasiform changes, dermal sclerosis, vascular dilatation, endothelial atypia, and stromal cell atypia [10].\n\nThe RRD described in our patient is typical of the recall reactions demonstrated with systemic agents that have been in use for many years. Our patient was managed with topical antibiotics for prophylaxis and topical steroids for inflammation. The general management of RRD is to discontinue the offending agents and offer supportive care as most symptoms self-resolve with time. Therefore, the prompt recognition of RRD and the offending agent is important in management.\n\n4. Conclusion\nSince sorafenib is used in patients with advanced carcinomas, it is not unlikely that these patients have received or will receive radiation therapy for primary or metastatic lesions. Although our patient had only mild dermatologic reactions, other agents have resulted in grade 3 and 4 RRD that require swift attention. This report of radiation recall dermatitis associated with sorafenib should prompt clinicians to carefully question and examine their patients who are at risk of RRD.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest.\n\nFigure 1 Radiotherapy planning with two oblique fields. Radiotherapy field with (a) three-dimensional model view, (b) axial view, and (c) coronal view. (d) Dose-volume curve demonstrates that the skin D50% was 15.2 Gy. Mean dose of skin was 13.1 Gy, and the maximum dose was 29.4 Gy.\n\nFigure 2 RRD demonstrated on previously irradiated area of the right forearm. RRD, radiation recall dermatitis.\n\nTable 1 Radiation recall dermatitis toxicity grading.\n\nGrade\tReaction\t\n1\tErythema ± pruritus ± dry desquamation\t\n2\tPain ± edema ± uricaria or vesiculation\t\n3\tMoist desquamation\t\n4\tNecrosis, ulceration or hemorrhage\n==== Refs\n1 Llovet J. Ricci S. Mazzaferro V. Randomized phase III trial of sorafenib versus placebo in patients with advanced hepatocellular carcinoma (HCC) Journal of Clinical Oncology 2007 25 18 10.1200/jco.2007.25.18_suppl.lba1 \n2 Chung C. Dawson L. A. Joshua A. M. Brade A. M. Radiation recall dermatitis triggered by multi-targeted tyrosine kinase inhibitors: sunitinib and sorafenib Anti-Cancer Drugs 2010 21 2 206 209 10.1097/cad.0b013e328333d679 2-s2.0-76149123563 19952730 \n3 Oh D. Park H. C. Lim H. Y. Yoo B. C. Sorafenib-triggered radiation recall dermatitis with a disseminated exanthematous reaction Radiation Oncology Journal 2013 31 3 171 174 10.3857/roj.2013.31.3.171 2-s2.0-84885771954 24137563 \n4 Burris H. A. Hurtig J. Radiation recall with anticancer agents Oncologist 2010 15 11 1227 1237 10.1634/theoncologist.2009-0090 2-s2.0-78649921480 21045191 \n5 Hsieh C. H. Lin S.-C. Shueng P.-W. Kuo D.-Y. Recall radiation dermatitis by sorafenib following stereotactic body radiation therapy OncoTargets and Therapy 2014 7 1111 1114 10.2147/ott.s64706 2-s2.0-84902982360 24971021 \n6 Stieb S. Riesterer O. Brüssow C. Pestalozzi B. Guckenberger M. Weiler S. Radiation recall dermatitis induced by sorafenib: a case study and review of the literature Strahlentherapie und Onkologie 2016 192 5 342 348 10.1007/s00066-016-0950-7 2-s2.0-84959153021 26907093 \n7 Azria D. Magné N. Zouhair A. Radiation recall: a well recognized but neglected phenomenon Cancer Treatment Reviews 2005 31 7 555 570 10.1016/j.ctrv.2005.07.008 2-s2.0-27744599575 16168567 \n8 Camidge R. Price A. Characterizing the phenomenon of radiation recall dermatitis Radiotherapy and Oncology 2001 59 3 237 245 10.1016/s0167-8140(01)00328-0 2-s2.0-0035370503 11369064 \n9 Ristic B. Radiation recall dermatitis International Journal of Dermatology 2004 43 9 627 631 10.1111/j.1365-4632.2004.02406.x 2-s2.0-4644281310 15357739 \n10 Smith K. J. Germain M. Skelton H. Histopathologic features seen with radiation recall or enhancement eruptions Journal of Cutaneous Medicine and Surgery 2002 6 6 535 540 10.1007/s10227-001-0156-0 2-s2.0-0036872943 12362258\n\n",
"fulltext_license": "CC BY",
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"issue": "2018()",
"journal": "Case reports in oncological medicine",
"keywords": null,
"medline_ta": "Case Rep Oncol Med",
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"nlm_unique_id": "101581035",
"other_id": null,
"pages": "2171062",
"pmc": null,
"pmid": "29670787",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "16168567;19952730;24137563;11369064;24971021;26907093;15357739;21045191;12362258",
"title": "Radiation Recall Dermatitis in Patients Treated with Sorafenib.",
"title_normalized": "radiation recall dermatitis in patients treated with sorafenib"
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"abstract": "Ursodeoxycholic acid (UDCA) might prevent progression of cystic fibrosis liver disease, but objective parameters for its effect are lacking.\n\n\n\nWe used liver stiffness measurements to evaluate the effect of Ursodeoxycholic acid.\n\n\n\nPaired measurements of liver stiffness were done in 73 patients without UDCA and in 32 patients with UDCA. In the latter group, 6 patients had cirrhosis; in 15 patients, UDCA was started based on Colombo criteria, and in 11 patients for other reasons. In patients without UDCA, liver stiffness increased: 0.19 (-0.03 to 0.59)kPa/year. Liver stiffness also increased in patients with cirrhosis: 4.6 (0.67-12.4)kPa/year. In patients who had UDCA based on Colombo criteria, a decrease of liver stiffness was observed: 0.70 (-1.6 to 0.55)kPa/year (P=0.01). In patients on UDCA for other reasons, liver stiffness increased: 0.23 (-0.20 to 0.51)kPa/year.\n\n\n\nUDCA reduced liver stiffness in patients with well-defined, mild liver disease.",
"affiliations": "Department of Pediatric Gastroenterology, University Medical Center Utrecht, Utrecht, The Netherlands.;Department of Pediatric Gastroenterology, University Medical Center Utrecht, Utrecht, The Netherlands; Department of Pediatric Gastroenterology, University Medical Center Groningen, Groningen, The Netherlands.;Department of Pediatric Pulmonology, University Medical Center Utrecht, Utrecht, The Netherlands.;Department of Pediatric Gastroenterology, University Medical Center Utrecht, Utrecht, The Netherlands. Electronic address: r.h.j.houwen@umcutrecht.nl.",
"authors": "van der Feen|Cathelijne|C|;van der Doef|Hubert P J|HP|;van der Ent|Cornelis K|CK|;Houwen|Roderick H J|RH|",
"chemical_list": "D002756:Cholagogues and Choleretics; D014580:Ursodeoxycholic Acid",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jcf.2016.07.009",
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"issn_linking": "1569-1993",
"issue": "15(6)",
"journal": "Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society",
"keywords": "Cystic fibrosis liver disease; Fibroscan; Liver stiffness measurement; Ursodeoxycholic acid",
"medline_ta": "J Cyst Fibros",
"mesh_terms": "D000293:Adolescent; D002648:Child; D002756:Cholagogues and Choleretics; D003550:Cystic Fibrosis; D016903:Drug Monitoring; D054459:Elasticity Imaging Techniques; D005260:Female; D006801:Humans; D008099:Liver; D008103:Liver Cirrhosis; D008111:Liver Function Tests; D008297:Male; D009426:Netherlands; D016896:Treatment Outcome; D014463:Ultrasonography; D014580:Ursodeoxycholic Acid",
"nlm_unique_id": "101128966",
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"pages": "834-838",
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"publication_types": "D016428:Journal Article; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Ursodeoxycholic acid treatment is associated with improvement of liver stiffness in cystic fibrosis patients.",
"title_normalized": "ursodeoxycholic acid treatment is associated with improvement of liver stiffness in cystic fibrosis patients"
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"dr... |
{
"abstract": "Pirarubicin (tetrahydropyranyl adriamycin [THP]) is an anthracyclin with less cardiotoxicity than doxorubicin (DOX). We previously reported the efficacy and safety of R-THP-COP consisting of rituximab (R), THP, cyclophosphamide (CPA), vincristine (VCR), and prednisolone (PSL) for diffuse large B cell lymphoma (DLBCL) in phase 2 studies. Here, we prospectively compared the efficacy and safety of the R-THP-COP and standard R-CHOP regimen (consisting of R, CPA, DOX, VCR, and PSL) in a noninferiority phase 3 trial. This prospective, randomized phase 3 study included patients younger than 70 years of age with previously untreated DLBCL. The regimen consisted of R (day 1), DOX, or THP (day 3), CPA (day 3), VCR (day 3), and PSL for 5 days every 3 weeks for 6 to 8 cycles. Between July 5, 2006 and June 11, 2013, 81 patients were randomly assigned to the treatment groups (R-CHOP group, 40 patients; R-THP-COP group, 41 patients). R-THP-COP was noninferior to R-CHOP, as assessed by the primary endpoint of complete response rate (85% vs 85% respectively). With a median follow-up of 75.2 months, the 5-year overall survival was 87% in the R-CHOP group and 82% in the R-THP-COP group (hazard ratio [HR]: 0.89, 95% confidence interval [CI]: 0.31-2.49; P = .82). The 5-year progression-free survival was 74% in the R-CHOP group and 79% in the R-THP-COP group (HR: 1.37, 95% CI: 0.56-3.55; P = .49). No grade 3 cardiac side effects were observed in either group. No serious late adverse reactions were observed in either group, with the exception of therapy-related acute myeloid leukemia in the R-THP-COP group. These data indicate that R-THP-COP is noninferior to R-CHOP with regard to clinical response, and has an acceptable safety profile. Thus, this regimen may be an alternative therapy to R-CHOP.",
"affiliations": "First Department of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.;First Department of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.;Division of Hematology, Gifu Municipal Hospital, Gifu, Japan.;Department of Hematology, Gifu Red-Cross Hospital, Gifu, Japan.;Department of Hematology, Gifu Prefectural General Medical Center, Gifu, Japan.;First Department of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.;Division of Hematology, Gifu Municipal Hospital, Gifu, Japan.;First Department of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.;First Department of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.;Department of Internal Medicine, Kisogawa Municipal Hospital, Kisogawa, Japan.;First Department of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.;First Department of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.;First Department of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.;First Department of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.;First Department of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.;First Department of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.;Department of Internal Medicine, Chuno Kosei Hospital, Seki, Japan.;Department of Hematology, Matsunami General Hospital, Kasamatsu, Japan.;Department of Pathology and Translational Research, Gifu University Graduate School of Medicine, Gifu, Japan.;Department of Pathology and Translational Research, Gifu University Graduate School of Medicine, Gifu, Japan.;Pathology Division, Gifu University Hospital, Gifu, Japan.;Department of Pathology and Translational Research, Gifu University Graduate School of Medicine, Gifu, Japan.;First Department of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.;First Department of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.",
"authors": "Hara|Takeshi|T|;Yoshikawa|Takeshi|T|;Goto|Hideko|H|;Sawada|Michio|M|;Yamada|Toshiki|T|;Fukuno|Kenji|K|;Kasahara|Senji|S|;Shibata|Yuhei|Y|;Matsumoto|Takuro|T|;Mabuchi|Ryoko|R|;Nakamura|Nobuhiko|N|;Nakamura|Hiroshi|H|;Ninomiya|Soranobu|S|;Kitagawa|Junichi|J|;Kanemura|Nobuhiro|N|;Nannya|Yasuhito|Y|;Katsumura|Naoki|N|;Takahashi|Takeshi|T|;Kito|Yusuke|Y|;Takami|Tsuyoshi|T|;Miyazaki|Tatsuhiko|T|;Takeuchi|Tamotsu|T|;Shimizu|Masahito|M|;Tsurumi|Hisashi|H|http://orcid.org/0000-0002-9262-5790",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011239:Prednisolone; C027260:pirarubicin; D011241:Prednisone",
"country": "England",
"delete": false,
"doi": "10.1002/hon.2524",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0278-0232",
"issue": "36(4)",
"journal": "Hematological oncology",
"keywords": "R-CHOP; R-THP-COP; diffuse large B cell lymphoma (DLBCL); non-Hodgkin's lymphoma (NHL); pirarubicin (THP)",
"medline_ta": "Hematol Oncol",
"mesh_terms": "D000328:Adult; D000367:Age Factors; D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D018572:Disease-Free Survival; D004317:Doxorubicin; D005260:Female; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008875:Middle Aged; D011239:Prednisolone; D011241:Prednisone; D011446:Prospective Studies; D000069283:Rituximab; D015996:Survival Rate; D014750:Vincristine",
"nlm_unique_id": "8307268",
"other_id": null,
"pages": "638-644",
"pmc": null,
"pmid": "29882279",
"pubdate": "2018-10",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": null,
"title": "R-THP-COP versus R-CHOP in patients younger than 70 years with untreated diffuse large B cell lymphoma: A randomized, open-label, noninferiority phase 3 trial.",
"title_normalized": "r thp cop versus r chop in patients younger than 70 years with untreated diffuse large b cell lymphoma a randomized open label noninferiority phase 3 trial"
} | [
{
"companynumb": "JP-EDENBRIDGE PHARMACEUTICALS, LLC-JP-2018EDE000376",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PREDNISOLONE SODIUM PHOSPHATE"
... |
{
"abstract": "Cytomegalovirus (CMV) is the most important opportunistic pathogen associated with transplant. The objective of this study was the characterization of CMV resistance mutations in allogeneic haematopoietic cell transplant recipients (allo-TPH) and the study of associated factors.\n\n\n\nA retrospective study of a cohort of allo-TPH recipients with post-transplant CMV reactivations with stable or increasing viral loads (CV), despite adequate antiviral treatment for at least 2weeks. The study of resistance mutations of the UL97 and UL54 genes was carried out by Sanger sequencing.\n\n\n\nRefractory CMV infection in our group of allo-TPH patients corresponded with a 21.43% rate of resistant virus infection (3 of 14 patients). All patients with resistance mutations had multiple reactivation episodes (P-value .01). The mutations found were A594V and H520Q in the UL97 gene that confers high-grade resistance to ganciclovir (GCV). One of the 3 cases with antiviral resistance was documented with a low VL (< 1000 copies/ml) and short accumulated GCV treatment (41 days).\n\n\n\nMost of the failures in the treatment of CMV were possibly due to clinical resistance; the lack of satisfactory response to antiviral treatment is not always accompanied by virological resistance. However, the appearance of resistances can occur early after the start of the treatment and with VL below 1000 copies / ml. The number of episodes of reactivation was higher among patients with virological resistance than those who did not.",
"affiliations": "Servicio de Microbiología, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria, Hospital Universitario de La Princesa, Madrid, España. Electronic address: alba_guiu@hotmail.com.;Servicio de Microbiología, Hospital Clínic, ISGlobal (Instituto de Salud Global de Barcelona), Barcelona, España.;Servicio de Microbiología, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria, Hospital Universitario de La Princesa, Madrid, España.;Servicio de Microbiología, Hospital Clínic, ISGlobal (Instituto de Salud Global de Barcelona), Barcelona, España.;Servicio de Hematología, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria, Hospital Universitario de La Princesa, Madrid, España.;Servicio de Microbiología, Hospital Clínic, ISGlobal (Instituto de Salud Global de Barcelona), Barcelona, España.",
"authors": "Guiu|Alba|A|;López-Aladid|Rubén|R|;Cardeñoso|Laura|L|;Mosquera|Maria Mar|MM|;de la Cámara|Rafael|R|;Marcos|Maria Angeles|MA|",
"chemical_list": "D000998:Antiviral Agents; D015774:Ganciclovir",
"country": "Spain",
"delete": false,
"doi": "10.1016/j.medcli.2019.07.027",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0025-7753",
"issue": "154(11)",
"journal": "Medicina clinica",
"keywords": "Allogeneic haematopoietic cell transplant; Citomegalovirus; Cytomegalovirus; Mutaciones de resistencia; Resistance mutations; Trasplante alogénico de progenitores hematopoyéticos",
"medline_ta": "Med Clin (Barc)",
"mesh_terms": "D000998:Antiviral Agents; D003587:Cytomegalovirus; D024882:Drug Resistance, Viral; D015774:Ganciclovir; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D009154:Mutation; D012189:Retrospective Studies; D066027:Transplant Recipients",
"nlm_unique_id": "0376377",
"other_id": null,
"pages": "433-439",
"pmc": null,
"pmid": "31785805",
"pubdate": "2020-06-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Study of cytomegalovirus resistance in allogeneic hematopoietic cell transplant recipients.",
"title_normalized": "study of cytomegalovirus resistance in allogeneic hematopoietic cell transplant recipients"
} | [
{
"companynumb": "ES-CHEPLA-C20202827_01",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "GANCICLOVIR"
},
"drugadditional": null,
... |
{
"abstract": "A 93-year-old man was admitted with 1 week of frank jaundice and abdominal pain. His medical history included diffuse large B-cell lymphoma treated with rituximab and cyclophosphamide, hydroxydaunomycin, oncovin and prednisolone (R-CHOP) chemotherapy 10 months prior. His investigations revealed marked hyperbilirubinemia with a total bilirubin of 355 μmol/L, along with a 17-fold elevation in alanine transaminase and impaired hepatic synthetic function. He tested hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody (HBsAb) negative, hepatitis B core antibody (HBcAb) positive and had elevated hepatitis B virus DNA level at 13 691 IU/L. This was in the setting of radiological evidence of suspected cirrhosis. He was later found to have tested positive for HBcAb and negative for HBsAg and HBsAb prior to chemotherapy, but had not received antiviral prophylaxis. He was diagnosed with fulminant hepatitis secondary to delayed hepatitis B reactivation in the setting of rituximab. Hepatitis B reactivation and the role of screening and antiviral prophylaxis in isolated HBcAb-positive patients is reviewed.",
"affiliations": "General Medicine, Austin Health, Heidelberg, Victoria, Australia borojevicbranko2@gmail.com.;General Medicine, Eastern Health, Box Hill, Victoria, Australia.;Gastroenterology and General Medicine, Austin Health, Heidelberg, Victoria, Australia.",
"authors": "Borojevic|Branko|B|;Chauhan|Ayushi|A|;Patterson|Scott|S|",
"chemical_list": "D006514:Hepatitis B Surface Antigens; D000069283:Rituximab",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2021-243526",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(7)",
"journal": "BMJ case reports",
"keywords": "chemotherapy; haematology (incl blood transfusion); hepatitis B; liver disease",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D006509:Hepatitis B; D006514:Hepatitis B Surface Antigens; D006515:Hepatitis B virus; D006801:Humans; D017093:Liver Failure; D008297:Male; D000069283:Rituximab; D014775:Virus Activation",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34244190",
"pubdate": "2021-07-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Liver failure from delayed hepatitis B reactivation in anti-HBc-positive patient following rituximab for B-cell lymphoma.",
"title_normalized": "liver failure from delayed hepatitis b reactivation in anti hbc positive patient following rituximab for b cell lymphoma"
} | [
{
"companynumb": "AU-BAXTER-2021BAX024453",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "A case of driving under the influence of drugs with an extremely high blood fentanyl concentration and concomitant use of methamphetamine is presented. As the increase of the appearance of fentanyl in drug seizures continues, the likelihood of tolerant users increases as well. Data presented on fentanyl in antemortem cases over time from several regions of North America show geographic differences on whether fentanyl concentrations are increasing. This case is an example of a blood concentration that could have been assumed to be fatal if presented on its own, a reminder that concentrations, especially those of opioids, must be interpreted with care.",
"affiliations": "Orange County Sheriff Coroner Department, Orange County Crime Laboratory, 550 North Flower Street, Santa Ana, CA 92703, USA.;Bureau of Forensic Services, Solano County Office of the District Attorney, 2201 Courage Dr, Suite 2119, Fairfield, CA 94533, USA.",
"authors": "Mata|Dani C|DC|;Coleman|Dan|D|0000-0002-8298-0377",
"chemical_list": "D000701:Analgesics, Opioid; D008694:Methamphetamine; D005283:Fentanyl",
"country": "England",
"delete": false,
"doi": "10.1093/jat/bkab050",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0146-4760",
"issue": "45(8)",
"journal": "Journal of analytical toxicology",
"keywords": null,
"medline_ta": "J Anal Toxicol",
"mesh_terms": "D000328:Adult; D000701:Analgesics, Opioid; D001334:Automobile Driving; D062787:Drug Overdose; D005283:Fentanyl; D006801:Humans; D008297:Male; D008694:Methamphetamine",
"nlm_unique_id": "7705085",
"other_id": null,
"pages": "847-850",
"pmc": null,
"pmid": "34008031",
"pubdate": "2021-09-17",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Unusually High Concentration of Fentanyl in a Driver: A Case Report.",
"title_normalized": "unusually high concentration of fentanyl in a driver a case report"
} | [
{
"companynumb": "US-TAKEDA-2021TUS035271",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DIAMORPHINE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nSeveral regimens for treating hematologic malignancies are given inpatient due to multiple factors. Many clinicians are evaluating methods to deliver traditionally inpatient regimens in the outpatient setting to increase patient satisfaction, improve access to therapy, and reduce costs. A regimen traditionally administered inpatient, dexamethasone, cytarabine, and cisplatin (DHAP) is a common and effective salvage regimen for relapsed/refractory non-Hodgkin's lymphoma. DHAX, which substitutes oxaliplatin for cisplatin, has been identified as a reasonable alternative to DHAP and offers the potential for tolerable administration in the outpatient setting as well.\n\n\nMETHODS\nA 74-year-old patient with double hit relapsed/refractory diffuse large B cell lymphoma was given rituximab, dexamethasone, high-dose cytarabine, and oxaliplatin (R-DHAX) in our outpatient clinic; however, this regimen is traditionally administered in the inpatient setting. Our main obstacle being cytarabine doses traditionally given 12 h apart. The outpatient regimen given to our patient was rituximab and oxaliplatin on day 1, cytarabine dose one late afternoon on day 2, cytarabine dose two early morning on day 3, and dexamethasone on days 1-4. Doses of oxaliplatin and cytarabine were reduced due to thrombocytopenia experienced with Cycle 1. He did not experience any increased toxicities or complications associated with the regimen moving forward.\n\n\nCONCLUSIONS\nThis illustrates a unique administration of R-DHAX in an infusion center that operates during typical outpatient clinic hours. Both DHAP and DHAX, with or without rituximab, administered in the outpatient setting may be options to consider in relapsed/refractory non-Hodgkin's lymphoma.",
"affiliations": "Department of Pharmacy, Carolinas Medical Center, Atrium Health, Charlotte, USA.;Department of Pharmacy, Levine Cancer Institute, Atrium Health, Charlotte, USA.;Levine Cancer Institute, Atrium Health, Concord, USA.;Department of Pharmacy, Levine Cancer Institute, Atrium Health, Concord, USA.;Levine Cancer Institute, Atrium Health, Concord, USA.;Levine Cancer Institute, Atrium Health, Concord, USA.;Department of Pharmacy, Levine Cancer Institute, Atrium Health, Charlotte, USA.;Department of Pharmacy, Inova Fairfax Hospital, Falls Church, USA.;Department of Pharmacy, Levine Cancer Institute, Atrium Health, Concord, USA.;Levine Cancer Institute, Atrium Health, Concord, USA.",
"authors": "Hill|Hailey|H|;Arnall|Justin|J|;Janes|Amanda|A|;Hatley|Crystal|C|;Swift|Kristen|K|;Hargett|Christy|C|;Howell|Theresa|T|;Griffin|Sarah|S|;Larck|Christopher|C|;Park|Stephen|S|",
"chemical_list": "D003561:Cytarabine; D000077150:Oxaliplatin; D000069283:Rituximab; D003907:Dexamethasone; D002945:Cisplatin",
"country": "England",
"delete": false,
"doi": "10.1177/1078155218820108",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "25(8)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Chemotherapy; R-DHAX; lymphoma; outpatient",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002945:Cisplatin; D003561:Cytarabine; D003907:Dexamethasone; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D009364:Neoplasm Recurrence, Local; D010045:Outpatients; D000077150:Oxaliplatin; D000069283:Rituximab; D016879:Salvage Therapy; D013921:Thrombocytopenia",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "2041-2044",
"pmc": null,
"pmid": "30616469",
"pubdate": "2019-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A review of R-DHAP administration in the outpatient setting and a case of the alternative regimen R-DHAX given outpatient for refractory diffuse large B-cell lymphoma.",
"title_normalized": "a review of r dhap administration in the outpatient setting and a case of the alternative regimen r dhax given outpatient for refractory diffuse large b cell lymphoma"
} | [
{
"companynumb": "NVSC2019US041975",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": "3",
"dr... |
{
"abstract": "Background: High dose methotrexate (HDMTX) is used for the treatment of pediatric hemato-oncological diseases. HDMTX can induce acute kidney injury in cases of delayed elimination. The use of leucovorin remains the most effective rescue action. Further treatment options are of difficult access in the rare cases where leucovorin fails to prevent renal failure from occurring. Glucarpidase is an effective treatment in cases of methotrexate (MTX) delayed elimination, but cost is high and availability is limited. Charcoal hemoperfusion (CHP) is a very efficient procedure to remove protein-bound drugs, promoting fast MTX elimination, but is rarely considered as a treatment option. Methods: We present three pediatric cases with prolonged exposure to MTX after HDMTX and delayed elimination in which hemoperfusion was performed as rescue treatment for methotrexate intoxication. Results: Charcoal hemoperfusion was performed with positive results and no complications as bridging until glucarpidase was available in two cases and in one case where two doses of glucarpidase led to insufficient reduction of MTX levels. Conclusions: CHP can be considered as a rescue treatment option in MTX intoxication, since it is an effective and safe extracorporeal method for removing MTX, in cases where rescue with leucovorin is insufficient and glucarpidase is not available or while waiting for delivery.",
"affiliations": "Department of Pediatrics, Medical University Innsbruck, Innsbruck, Austria.;Pediatric Nephrology, University Hospital Sant Joan de Deu, University of Barcelona, Barcelona, Spain.;Pediatric Nephrology, Vall d'Hebron Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.;Pediatric Oncology and Hematology Department, Vall d'Hebron Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.;Pediatric Nephrology, Vall d'Hebron Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.",
"authors": "Rosales|Alejandra|A|;Madrid|Alvaro|A|;Muñoz|Marina|M|;Dapena|Jose Luis|JL|;Ariceta|Gema|G|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fped.2021.635152",
"fulltext": "\n==== Front\nFront Pediatr\nFront Pediatr\nFront. Pediatr.\nFrontiers in Pediatrics\n2296-2360\nFrontiers Media S.A.\n\n10.3389/fped.2021.635152\nPediatrics\nBrief Research Report\nCharcoal Hemoperfusion for Methotrexate Toxicity: A Safe and Effective Life-Rescue Alternative When Glucarpidase Is Not Available\nRosales Alejandra 1 *\n\nMadrid Alvaro 2\nMuñoz Marina 3\nDapena Jose Luis 4 5\nAriceta Gema 3\n1Department of Pediatrics, Medical University Innsbruck, Innsbruck, Austria\n2Pediatric Nephrology, University Hospital Sant Joan de Deu, University of Barcelona, Barcelona, Spain\n3Pediatric Nephrology, Vall d'Hebron Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain\n4Pediatric Oncology and Hematology Department, Vall d'Hebron Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain\n5Pediatric Oncology and Hematology Department, University Hospital Sant Joan de Deu, University of Barcelona, Barcelona, Spain\nEdited by: Jakub Zieg, University Hospital in Motol, Czechia\n\nReviewed by: Dominique Leveque, Hôpital d'Hautepierre, France; Alka Khadwal, Post Graduate Institute of Medical Education & Research, India\n\n*Correspondence: Alejandra Rosales alejandra.rosales@i-med.ac.atorcid.org/0000-0002-8819-5302\nThis article was submitted to Pediatric Nephrology, a section of the journal Frontiers in Pediatrics\n\n19 8 2021\n2021\n9 63515229 11 2020\n25 5 2021\nCopyright © 2021 Rosales, Madrid, Muñoz, Dapena and Ariceta.\n2021\nRosales, Madrid, Muñoz, Dapena and Ariceta\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nBackground: High dose methotrexate (HDMTX) is used for the treatment of pediatric hemato-oncological diseases. HDMTX can induce acute kidney injury in cases of delayed elimination. The use of leucovorin remains the most effective rescue action. Further treatment options are of difficult access in the rare cases where leucovorin fails to prevent renal failure from occurring. Glucarpidase is an effective treatment in cases of methotrexate (MTX) delayed elimination, but cost is high and availability is limited. Charcoal hemoperfusion (CHP) is a very efficient procedure to remove protein-bound drugs, promoting fast MTX elimination, but is rarely considered as a treatment option.\n\nMethods: We present three pediatric cases with prolonged exposure to MTX after HDMTX and delayed elimination in which hemoperfusion was performed as rescue treatment for methotrexate intoxication.\n\nResults: Charcoal hemoperfusion was performed with positive results and no complications as bridging until glucarpidase was available in two cases and in one case where two doses of glucarpidase led to insufficient reduction of MTX levels.\n\nConclusions: CHP can be considered as a rescue treatment option in MTX intoxication, since it is an effective and safe extracorporeal method for removing MTX, in cases where rescue with leucovorin is insufficient and glucarpidase is not available or while waiting for delivery.\n\ncharcoal\nhemoperfusion\nmethotrexate\nhigh dose methotrexate\nglucarpidase\nmethotrexate toxicity\n==== Body\npmcIntroduction\n\nMethotrexate (MTX) is administered in high doses (HDMTX, dose > 500 mg/m2) for the treatment of several hemato-oncological diseases in the pediatric age (including lymphoblastic leukemia, lymphoma and osteosarcoma). MTX is a folate analog antimetabolite that interferes with folate metabolism impeding purine and thymidine synthesis and DNA production promoting cell death. MTX action is cell-cycle dependent, acting specifically during DNA-synthesis and making tissues with high turnover more susceptible to cytotoxicity. Fifty percent of circulating MTX is bound to proteins, mostly albumin, regardless of its concentration in serum. MTX molecules are 454 Da, and MTX has a distribution volume of 0.4/0.8 L/kg (1, 2). Elimination occurs through glomerular filtration and tubular secretion. At a urinary pH <7, MTX and its metabolites precipitate in renal tubules leading to delayed elimination and prolonged exposure times, causing further MTX precipitation and perpetuating renal damage (3).\n\nHDMTX regimens include intensive hydration and urine alkalinization to prevent acute kidney injury (4, 5). Monitoring of plasma MTX levels, monitoring diuresis and urinary pH are mandatory to prevent toxicity. Nevertheless, inadequately high MTX levels are observed in 0.5–1.8% patients, increasing the risk of MTX toxicity (4, 6, 7). Factors such as impaired renal function, presence of ascites, pleural effusion or bowel obstruction, or concomitant administration of certain drugs (such as antibiotics, aspirin, probenecid, and proton pump inhibitors), increase the risk of MTX toxicity (4). Prolonged exposure to MTX results not only in renal impairment but also in gastrointestinal distress, hepatic insufficiency, and bone marrow suppression (8).\n\nLeucovorin (folinic acid) competes with MTX and prevents this drug toxicity in normal cells: it provides reduced folates to bypass the metabolic blockage produced by MTX (9). Leucovorin remains one of the cornerstones of preventing MTX toxicity, since it is the only available approach that acts intracellularly. Treatment protocols with HDMTX include a 2–3 days period of multiple leucovorin doses. Safety of HDMTX regimens requires careful monitoring of blood MTX levels for the adjustment of leucovorin doses. Hydration and alkalinization should be continued and adjusted, since successful rescue with leucovorin depends on patient renal elimination of MTX (10).\n\nGlucarpidase (Voraxaze™, a recombinant bacterial carboxypeptidase G2) is a very effective treatment option for MTX poisoning. Glucarpidase provides an enzymatic method for MTX cleavage into non-toxic metabolites, 2, 4-diamino-N(10)-methylpteroic acid (DAMPA) and glutamate. A single dose of glucarpidase can reduce MTX level by >95% in 15 min, but it has no influence in intracellular MTX levels. Cost is elevated and availability limited (in the European Union only on compassionate use) often causing delays in the start of treatment (10).\n\nDiverse reports exist on the use of extracorporeal treatments for MTX intoxication. The choice of a treatment method for drug removal depends on molecular weight of the drug, protein binding, volume of distribution, treatment availability, and expertise in the center. Hemodialysis is a suitable method for low molecular weight, water soluble molecules. Larger size molecules, such as MTX, are insufficiently removed by standard HD and require high flux filters (11). High-flux hemodialysis is the most frequently implemented extracorporeal therapy in cases of MTX toxicity but efficacy is limited (12). MTX redistribution from the cellular compartment or third space may result in a rebound of MTX levels after treatment discontinuation, requiring repeated dialysis or CHP sessions (10).\n\nCharcoal hemoperfusion (CHP) is a successful extracorporeal method for the removal of a variety of toxins. It is a suitable method for toxins with high molecular weight, a low volume of distribution and high protein binding, where hemodialysis is less effective. Table 1 shows previous reports on the use of CHP in cases of MTX toxicity alone or combined with other extracorporeal treatments and they results (Table 1). We present three pediatric cases in which CHP was used successfully for the treatment of MTX intoxication when glucarpidase was not available.\n\nTable 1 Existing reports on the use of hemoperfusion in MTX toxicity cases.\n\nReferences\tCase number (age, gender)\tIndication (treatment protocol)\tMTX dose\tSupportive treatment\tExtracorporeal method\tResults\t\nDjerassi et al. (13)\t4 (?)\tOsteosarcoma\t300 mg/kg\tCitrovorum Factor\tCHP and/or iHD\tCHP more effective than IHD at low MTX levels\t\nGibson et al. (14)\t1 (56 y, f)\tBreast carcinoma\t600 mg\tLeucovorin\tHP (Amberlite XAD-4 Column)\tAmberlite XAD-4 hemoperfusion effective\nCharcoal more effective than XAD-4 in vitro\nRebound after treatment observed, no sustained effect\t\nBouffet et al. (15)\t3 (71, 7, 52 y)\t?\t1.5 and 3 g/m2\t?\tCHP, iHD, PE\tCHP efficient, no complications observed\nPlasma exchange less effective\nHD did not decrease MTX levels but corrected renal failure.\t\nMolina et al. (16)\t1 (60 y, m)\tLymphocytic lymphoma\t130 mg/m2\tAllopurinol, urine alkalinization, citrovorum\tiHD + CHP\tSustained reduction of MTX levels using sequential HD and CHP.\t\nRelling et al. (17)\t1 (15 y, f)\tOsteosarcoma (OS-86)\t(12 g/m2)\tHydration, urine alkalinization, Leucovorin, Thymidine\tiHD + CHP Thymidine\tCombined HD-CHP more effective than HP only.\t\nGrimes et al. (18)\t1 (18 y, f)\tOsteosarcoma\t8 g/m2\tUrine alkalinization, leucovorin, oral activated charcoal\tCHP, iHD\tRebound of MTX levels after CHP and HD. Authors attribute more success to supportive treatment than extracorporeal therapies.\t\nMcIvor (19)\t1 (39 y, m)\tBurkitt Lymphoma\t3 g/m2\tAllopurinol, urine alkalinization, leucovorin\tCHP\tRapid reduction of MTX level after CHP. No complications.\t\nNowicki et al. (20)\t1 (10 y, m)\tOsteosarcoma\t12 g/m2\tHydration, urine alkalinization, leucovorin\tiHD and CHP, glucarpidase\tHD due to hyperkalemia, followed by CHP. Significant reduction of MTX levels using HD, HP and glucarpidase.\t\nNemoto et al. (21)\t1 (12 y, f)\tOsteosarcoma\t10 g/m2\tHydration, urine alkalinization, leucovorin\tHP, iHD and PE\tEffective removal of MTX using CHP. HDF due to renal failure. PE due to liver failure.\nSignificant reduction in MTX level after CHP, no significant reduction after PE\t\nGrafft et al. (22)\t1 (64 y, f)\tB-cell lymphoma\t8 g/m2\tHydration, urine alkalinization, leucovorin\tCHP and high dose CVVH\tCVVH combined with CHP not more effective than CVVH alone.\t\nChan and Hui (11)\t1 (11 y, f)\tOsteosarcoma (HKPSOSG)\t12 g/m2\tHydration, urine alkalinization, leucovorin\tSPAD + CHP\tFaster drop in MTX level after sequential use of SPAD and CHP than using only leucovorin\t\n\nMaterials and Methods\n\nThree pediatric cases which presented delayed MTX elimination after HDMTX during the treatment of different oncological diseases are presented in this report. The clinical and laboratory data were analyzed retrospectively. Details on treatment protocol, definition of toxic range and leucovorin rescue are presented in Table 2.\n\nTable 2 Detailed information on treatment protocols.\n\nStudy, References\tMTX dose\tDuration of infusion\tHyperhydration\tLeucovorin\tTime to first leucovorin\tMTX at 24 h\t\nEURAMOS (23)\t12 g/m2\t4 h\t3,000 ml/m2\t15 mg/m2, adjusted to nomogram\t24 h\t<8.5 μmol/L\t\nEuro LB 02 (24)\t5 g/m2\t24 h\t3,000 ml/m2\t15 mg/m2\t42 h\t<150 μmol/L\t\nALL SEHOP/PETHEMA 2013 HR (25)\t5 g/m2\t24 h\t3,000 ml/m2\t15 mg/m2\t42 h\t<150 μmol/L\t\n\nMTX levels were measured using the Architect Methotrexate chemiluminescent assay (Abbott Diagnostics, IL, USA) on the Architect i2000SR (Abbott Diagnostics). Plasma MTX levels may be overestimated in this report, since the method measures not only MTX but also its metabolites due to antibody cross reactivity.\n\nHemoperfusion was performed using the Prismaflex® system CHP with Adsorba® C 300 kit (cellulose-coated activated charcoal). The procedure required a central venous access using a dual-lumen hemodialysis catheter. Anticoagulation was performed with heparin. Sessions lasted 2.5–3 h.\n\nAll the procedures being performed were part of the routine care and were performed in accordance to relevant guidelines and regulations. In view of the retrospective nature of the study, the need for informed consent was waived by the local ethics committee.\n\nResults\n\nPatient 1\n\nAn 11-year-old male (41.1 kg, 151 cm, BSA 1.32 m2) treated for second malignant disease (an osteoblastic osteosarcoma involving the facial bones), and previous history of radiotherapy and chemotherapy due to bilateral retinoblastoma during the 1st year of life. He received his first course of HDMTX according to protocol EURAMOS 1 in an external center (EURAMOS 1) (23). Before receiving HDMTX, he showed correct renal and liver function and normal serum albumin. Prehydration (3 L/m2) and urine alkalinization were performed as recommended (EURAMOS 1). HDMTX (12 g/m2 e.v. over 4 h) was administered with a short interruption due to exanthema during infusion, which improved with antihistaminics and cortisone (MTX at 4 h 1,081 μmol/L, creatinine 0.81). The serum MTX level 24 h after infusion was with 491 μmol/L clearly in toxic range (toxic >8.5 μmol/L, serum creatinine 1.73 mg/dl). An intensification of hyperhydration (5 L/m2), forced diuresis (furosemide), urine alkalinization and intensification of treatment with leucovorin (250 mg/m2/3 h) were performed. Forty-eight hours after infusion and despite of intensified treatment, MTX levels remained persistently high (202 μmol/L, toxic >1 μmol/L) and the patient developed leukocytosis (34.5 × 109/l), progressive acute renal failure (increase of serum creatinine to 2.94 mg/dL, eGFR 21 ml/min/1.73 m2), liver failure with elevated liver enzymes (AST 125 UI/L, ALT 193 UI/L) and coagulopathy (Quick 47%) treated with vitamin K and plasma. Nevertheless, the patient was clinically stable, showed no hypertension, no mucositis and besides erythema and emesis no further symptoms. Due to temporary unavailability of glucarpidase, the patient was referred to our center where one session of CHP was performed at his arrival, as bridge until glucarpidase became available. The first CHP session started 52 h after start of MTX infusion. A significant reduction of MTX level from 202 to 124 μmol/L was achieved using CHP, and the procedure was performed without complications. Further, glucarpidase (50 U/kg) was administered as soon as available (54 h after MTX infusion), which led to a reduction of MTX level to 8.09 μmol/L. Due to persistent elevated MTX levels 96 h after MTX infusion (5.29 μmol/L, toxic >1 μmol/L) the patient received a second glucarpidase dose leading to a sufficient reduction of MTX level. Later on, treatment with leucovorin was maintained until day 31 (MTX <1 μmol/L). Diuresis was preserved and a progressive recovery of renal (creatinine 0.86 mg/dL, eGFR 72 ml/min/1.73 m2), normalization of liver function and blood count were observed during the follow-up (Figure 1A).\n\nFigure 1 This figure shows the progression of MTX and creatinine levels after HDMTX in the three presented cases [(A) patient 1, (B) patient 2, and (C) patient 3]. Furthermore, the applied supportive treatments are depicted. The dotted line represents the toxic MTX level according to each treatment protocol.\n\nPatient 2\n\nA 12 years old male (34.5 kg, 139 cm, BSA 1.15 m2) with pre-B lymphoblastic lymphoma, previously healthy and with normal renal function and serum albumin at the start of treatment (creatinine 0,48 mg/dl at 0 h). The patient received the second HDMTX course (5 g/m2 e.v., in 24 h), 14 days after first course (which had been well-tolerated), according to Protocol Euro LB 02 (24) after adequate prehydration and urine alkalinization. During the first 24 h after the initiation of MTX infusion the patient developed non-oliguric acute renal failure (creatinine 3.13 mg/dL, eGFR 18 ml/min/1.73 m2). An elevated MTX level was observed with 180 μmol/L after 24 h (toxic >150 μmol/L) that was managed by intensification of hydration (4,000 mL/m2/day) and leucovorin rescue (100 mg/m2/3 h). At 36 h MTX level remained persistently high with 85 μmol/L (toxic > 3 μmol/L) and the patient was referred to our center to start treatment with CHP due the unavailability of glucarpidase. The patient presented clinically stable with abdominal pain and vomiting, epistaxis, no cutaneous lesions, no neurological symptoms, no hypertension. After the first session of CHP (48 h after start of MTX infusion) a decrease of MTX level to 43 μmol/L (toxic > 0.4 μmol/L) was observed, and after the second session an MTX level of 20 μmol/L achieved. Anemia (hemoglobin 6.4 g/dL) and thrombocytopenia (37 × 109/l) were observed at this point, needing blood cell and platelet transfusions. Glucarpidase was administered as soon as available (82 h after start of MTX infusion), decreasing MTX to 0.96 μmol/L. Subsequently, we observed a recovery of renal function (creatinine 0.55 mg/dL, eGFR 104 ml/min/1.73 m2) remission of gastrointestinal symptoms and normal blood count (Figure 1B).\n\nPatient 3\n\nAn 11 years old male (46.2 kg, 142 cm, BSA 1.36 m2) with T-cell acute lymphoblastic leukemia, under treatment according to protocol ALL SEHOP/PETHEMA 2013 HR (25). The patient had no history of previous diseases, with normal renal and liver function and serum albumin at the start of treatment. During the first course of HDMTX (5 g/m2 e.v., in 24 h) with adequate previous hydration and urine alkalinization an elevated MTX level was detected 24 h after starting infusion (190 μmol/L, toxic > 150 μmol/L). Despite adequate treatment with hydration (3,000 ml/m2/24 h) and leucovorin rescue (30 mg/m2/6 h), the patient presented persistently elevated MTX levels after 36 and 48 h (620 and 510 μmol/L). In addition, non-oliguric renal failure with creatinine increase to 2.36 mg/dL (eGFR 34.5 ml/min/1.73 m2) was observed. The patient received the first dose of glucarpidase (50 U/kg) 48 h and second dose 96 h after starting MTX infusion, nevertheless an insufficient decrease in MTX levels was observed (Figure 1). MTX levels continued persistently high (MTX at 100 h 3.8 μmol/L, toxic >0.4) despite two doses of glucarpidase, hydration, urine alkalinization and leucovorin rescue. Glucarpidase was no further available. The patient presented in reduced general status, in the absence of diarrhea, mucositis, or other symptoms such as hypertension. Persistent renal failure (with maintained diuresis) and increasing creatinine (max. creatinine 3.45 mg/dL at day 9 after MTX) was observed at admission. Leukopenia (1.4 × 109/l) was observed too. Rescue treatment with hemoperfusion was indicated. CHP was performed without complications on days 9, 10, 11, and 12 after MTX infusion with no complications other than slight anemia (hemoglobin 8 g/dl) and thrombocytopenia (100 × 109/l). Progressive improvement was achieved under treatment with CHP, with reduction in MTX levels, recovery of renal function and normalization of blood count (Figure 1C).\n\nDiscussion\n\nHigh-dose methotrexate-induced toxicity is an oncologic emergency that can potentially result in serious organ damage and life threat. The introduction of standardized supportive care measures such as hyperhydration, urine alkalinization, and leucovorin rescue has dramatically reduced the risk of MTX toxicity (6). In the rare cases where pharmacokinetically guided leucovorine rescue is insufficient, glucarpidase has become the treatment of choice (10). However, delays in drug availability may happen. Extracorporeal treatments can be used as a bridge in cases where glucarpidase is not available or insufficiently effective. Studies assessing the efficacy of different extracorporeal treatment approaches for MTX poisoning show mixed results, reporting mostly of isolated cases, presenting no control patients and using differing concomitant interventions.\n\nThe election of an extracorporeal treatment method for drug intoxication should rely on the pharmacological characteristics of the toxin, the antagonist availability, and the expertise of the center. Charcoal hemoperfusion (CHP) is based in the adsorption of toxins to charcoal particles, which makes it a suitable method for protein bound toxins, liposoluble toxins and toxins which have high molecular weight, such as MTX. Common side effects are thrombocytopenia, hypocalcemia and hypoglycemia. In the three presented cases CHP was a safe and well-tolerated method leading to a significant reduction in MTX levels.\n\nDespite fast efficacy and improved tolerance with less hypersensitivity reactions and charcoal embolization nowadays, since cellulose coated charcoal filters were introduced, and in parallel with the advance of hemodialysis techniques and availability of high efficacy filters, CHP has lost popularity (11). Decline in the use of CHP relies on the high cost of the columns, which become saturated and loose effectiveness during the treatment, and short expiration time. In contrast to intermittent hemodialysis (iHD), CHP does not contribute to normalize electrolyte or fluid disbalances, and therefore cannot replace acute dialysis if needed (26). Reversely, CHP will cause less electrolyte imbalance in those intoxicated patients with preserved renal function.\n\nCurrently, iHD is often used for extracorporeal toxic removal, since it is an effective procedure for a broad range of toxins with low molecular weight and which are water-soluble. However, iHD is less suitable for protein bound toxins depuration, such as MTX. iHD also serves as treatment for fluid and electrolyte disbalances in those patients, who often present acute renal failure. Furthermore, iHD is more frequently available and lower-priced than CHP (26). Reports on the use of iHD in HDMTX toxicity show variable results. Many patients experience a rebound in MTX levels after iHD, probably due to multicompartmental distribution of MTX and slow redistribution from tissues to blood stream (14, 18). Avoiding delays in the initiation of treatment could prevent distribution of MTX in intracellular compartment and maximize removal through extracorporeal treatment (27). High-dose continuous venovenous hemofiltration (CVVHDF) may prevent rebound of plasma drug levels as well (22). Lack of trials comparing CHP vs. iHD efficacy and adverse events in MTX removal does not support an evidenced-based decision process between those procedures.\n\nWe report our experience with CHP in MTX toxicity after a regional transient lack of availability of glucarpidase, and as a life-saving treatment in a patient with limited response to the drug. In cases 1 and 2 successful stabilization and reduction of MTX levels were achieved after 1 or 2 sessions of CHP. Glucarpidase was administered as soon as available, leading to a significant reduction of MTX levels. That fast and good outcome indicates that possibly both patients would had responded to glucarpidase if available, but CHP facilitated a fast MTX removal and the achievement of low-risk levels. In comparison, case 3 presented with persistent elevated MTX levels despite 2 doses of glucarpidase, although we have to mention that MTX levels after glucarpidase may be overestimated due to the cross reactivity with its metabolites using an immunoassay for measurement. We could have probably avoided to repeat glucarpidase doses at high cost if a more specific measurement method for MTX would have been available. Treatment with CHP was considered since glucarpidase was no longer available for few days, and the patient remained in a critical situation. Fortunately, under treatment with daily CHP sessions we observed a decrease in MTX levels and normalization of renal function. Unfortunately, leucovorin levels were not measured before and after CHP sessions and could be reduced through CHP leading to insufficient protection during CHP sessions.\n\nLeucovorin rescue was continued in all patients, in parallel to glucarpidase treatment and CHP, since it is the most effective resource to protect cells from MTX toxicity. Leucovorin rescue should be maintained until negative MTX levels are reached as described and replaced after dialysis may be removed through HD and CHP (17). Leucovorin should not be given until 2 h after glucarpidase administration since it could interfere with the cleavage of MTX (28).\n\nGlucarpidase should remain the first line treatment in cases of MTX delayed elimination, even if only insufficient quantity of glucarpidase available, since its efficacy is not dose dependent (29). Recommendations in cases of insufficient decrease in MTX levels after use of glucarpidase are missing. Existing reports refer of no further reduction in MTX levels after extra doses of glucarpidase within 48 h of MTX infusion. The benefit of administering glucarpidase after >60 h can be discussed, since lasting toxicities may not be undone beyond this point (28). In our patients the use of glucarpidase led to further decrease of MTX levels, despite the time of administration. One should consider the possible overestimation of MTX levels after glucarpidase infusion, since most laboratories measure MTX with immunoassay, which shows a cross reactivity with its metabolite DAMPA (30). MTX levels after use of glucarpidase may be overestimated in this report. We could have probably avoid the second dose of glucarpidase and the use of CHP in case 3 if a more specific method for measuring MTX levels, as HPLC, would have been available.\n\nThese three cases show that CHP is an eligible bridging rescue treatment approach for life-threatening MTX intoxications in the absence of glucarpidase or after lack of response. Despite limitations such as small sample size, or lack of comparison with iHD, our experience shows a fast and positive response to few CHP sessions in severe cases with MTX toxicity, in the absence of significant adverse events or technical issues, but venous central access requirement. Acute renal failure was successfully managed by conservative treatment in all cases, and renal function recovered spontaneously in parallel to MTX level reduction.\n\nTherefore, and based on MTX body distribution, we favor the use of CHP instead of iHD as recue treatment of refractory MTX toxicity. CHP does not replace supportive measures or rescue with leucovorin but should be considered in centers with expertise in the method and available cartridges since it leads to a significant reduction of MTX levels with concomitant improvement of renal function.\n\nUp-to-date treatment recommendations for MTX toxicity are urgently needed. The international EXTRIP (extracorporeal treatments in poisoning workgroup) reviewed the use of extracorporeal treatments for MTX toxicity recently, a report on the results should be available soon. Furthermore, we retrospectively evaluated the course of MTX levels in our patients using the MTXPK.org tool, which is very practical and easy to use resource for clinical decision making (31).\n\nData Availability Statement\n\nThe data analyzed in this study is subject to the following licenses/restrictions: Data out of patients' clinical records. Requests to access these datasets should be directed to alejandra.rosales@i-med.ac.at.\n\nEthics Statement\n\nEthical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent from the participants' legal guardian/next of kin was not required to participate in this study in accordance with the national legislation and the institutional requirements.\n\nAuthor Contributions\n\nAR analyzed and interpreted the data, drafted the article, and approved the final version. AM, MM, and JD provided content of critical importance, revised the article, and approved the final version. GA conceived the study, drafted and revised the article, provided content of critical importance, and approved the final version. All authors contributed to the article and approved the submitted version.\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nPublisher's Note\n\nAll claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.\n==== Refs\nReferences\n\n1. Bleyer WA . Methotrexate: clinical pharmacology, current status and therapeutic guidelines. Cancer Treat Rev. (1977) 4 :87–101. 10.1016/S0305-7372(77)80007-8 329989\n2. Howard SC McCormick J Pui CH Buddington RK Harvey RD . Preventing and managing toxicities of high-dose methotrexate. Oncologist. (2016) 21 :1471–82. 10.1634/theoncologist.2015-0164 27496039\n3. Buchen S Ngampolo D Melton RG Hasan C Zoubek A Henze G . Carboxypeptidase G2 rescue in patients with methotrexate intoxication and renal failure. Br J Cancer. (2005) 92 :480–7. 10.1038/sj.bjc.6602337 15668713\n4. Svahn T Mellgren K Harila-Saari A Åsberg A Kanerva J Jónsson Ó . Delayed elimination of high-dose methotrexate and use of carboxypeptidase G2 in pediatric patients during treatment for acute lymphoblastic leukemia. Pediatr Blood Cancer. (2017) 64 :26395. 10.1002/pbc.26395 27966809\n5. Izzedine H Perazella MA . Anticancer drug-induced acute kidney injury. Kidney Int Rep. (2017) 2 :504–14. 10.1016/j.ekir.2017.02.008 29318217\n6. Widemann BC Balis FM Kempf-Bielack B Bielack S Pratt CB Ferrari S . High-dose methotrexate-induced nephrotoxicity in patients with osteosarcoma. Cancer. (2004) 100 :2222–32. 10.1002/cncr.20255 15139068\n7. May J Carson KR Butler S Liu W Bartlett NL Wagner-Johnston ND . High incidence of methotrexate associated renal toxicity in patients with lymphoma: a retrospective analysis. Leuk Lymphoma. (2014) 55 :1345–9. 10.3109/10428194.2013.840780 24004183\n8. Ranchon F Vantard N Henin E Bachy E Sarkozy C Karlin L . Delayed methotrexate elimination: Incidence, interaction with antacid drugs, and clinical consequences? Hematol Oncol. (2018) 36 :399–406. 10.1002/hon.2479 28983943\n9. Fertel BS Nelson LS Goldfarb DS . Extracorporeal removal techniques for the poisoned patient: a review for the intensivist. J Intensive Care Med. (2010) 25 :139–48. 10.1177/0885066609359592 20444738\n10. Widemann BC Adamson PC . Understanding and managing methotrexate nephrotoxicity. Oncologist. (2006) 11 :694–703. 10.1634/theoncologist.11-6-694 16794248\n11. Chan WK Hui WF . Sequential use of hemoperfusion and single-pass albumin dialysis can safely reverse methotrexate nephrotoxicity. Pediatr Nephrol. (2016) 31 :1699–703. 10.1007/s00467-016-3389-2 27335061\n12. Wall SM Johansen MJ Molony DA DuBose TD Jaffe N Madden T . Effective clearance of methotrexate using high-flux hemodialysis membranes. Am J Kidney Dis. (1996) 28 :846–54. 10.1016/S0272-6386(96)90384-4 8957036\n13. Djerassi I Ciesielka W Kim JS . Removal of methotrexate by filtration-adsorption using charcoal filters or by hemodialysis. Cancer Treat Rep. (1977) 61 :751–2. 889610\n14. Gibson TP Reich SD Krumlovsky FA Ivanovich P Gonczy C . Hemoperfusion for methotrexate removal. Clin Pharmacol Ther. (1978) 23 :351–5. 10.1002/cpt1978233351 627142\n15. Bouffet E Frappaz D Laville M Finaz J Pinkerton CR Philip T . Charcoal haemoperfusion and methotrexate toxicity. Lancet. (1986) 1 :1497. 10.1016/S0140-6736(86)91528-X\n16. Molina R Fabian C Cowley B . Use of charcoal hemoperfusion with sequential hemodialysis to reduce serum methotrexate levels in a patient with acute renal insufficiency. Am J Med. (1987) 82 :350–2. 10.1016/0002-9343(87)90085-4 3812535\n17. Relling MV Stapleton FB Ochs J Jones DP Meyer W Wainer IW . Removal of methotrexate, leucovorin, and their metabolites by combined hemodialysis and hemoperfusion. Cancer. (1988) 62 :884–8. 10.1002/1097-0142(19880901)62:5<884::AID-CNCR2820620506>3.0.CO;2-A 3261621\n18. Grimes DJ Bowles MR Buttsworth JA Thomson DB Ravenscroft PJ Nixon PF . Survival after unexpected high serum methotrexate concentrations in a patient with osteogenic sarcoma. Drug Saf. (1990) 5 :447–54. 10.2165/00002018-199005060-00005 2285498\n19. McIvor A . Charcoal hemoperfusion and methotrexate toxicity. Nephron. (1991) 58 :378. 10.1159/000186462 1896111\n20. Nowicki TS Bjornard K Kudlowitz D Sandoval C Jayabose S . Early recognition of renal toxicity of high-dose methotrexate therapy: a case report. J Pediatr Hematol Oncol. (1998) 30 :950–2. 10.1097/MPH.0b013e318182e73e 19131789\n21. Nemoto T Imai C Kaneko U Takachi T Iwabuchi H Tanaka A . Effect of charcoal hemoperfusion for removal of plasma methotrexate in a patient with acute renal failure. Pediatr Hematol Oncol. (1999) 26 :520–5. 10.1080/08880010902976023 19863208\n22. Grafft C Gunderson H Langman L Farmer JC Leung N . High-dose continuous venovenous hemofiltration combined with charcoal hemoperfusion for methotrexate removal. NDT Plus. (2011) 4 :87–9. 10.1093/ndtplus/sfr002 25984119\n23. Marina NM Smeland S Bielack SS Bernstein M Jovic G Krailo MD . Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomised controlled trial. Lancet Oncol. (2016) 17 :1396–408. 10.1016/S1470-2045(16)30214-5 27569442\n24. Landmann E Burkhardt B Zimmermann M Meyer U Woessmann W Klapper W . Results and conclusions of the European Intergroup EURO-LB02 trial in children and adolescents with lymphoblastic lymphoma. Haematologica. (2017) 102 :2086–96. 10.3324/haematol.2015.139162 28983060\n25. Badell Serra I . Tratamiento de la Leucemia Aguda Linfoblástica de Nuevo Diagnóstico, Recomendaciones terapéuticas LAL/SEHOP-PETHEMA 2013 Versión 2.0. Sociedad Española de Hematología y Hemoterapia. (2014). Available online at: https://www.sehh.es/images/stories/recursos/2014/documentos/guias/LAL_SEHOP_PETHEMA_2013.pdf (accessed November 2020).\n26. Bouchard J Lavergne V Roberts DM Cormier M Morissette G Ghannoum M . Availability and cost of extracorporeal treatments for poisonings and other emergency indications: a worldwide survey. Nephrol Dial Transplant. (2017) 32 :699–706. 10.1093/ndt/gfw456 28339843\n27. Saland JM Leavey PJ Bash RO Hansch E Arbus GS Quigley R . Effective removal of methotrexate by high-flux hemodialysis. Pediatr Nephrol. (2002) 7 :825–9. 10.1007/s00467-002-0946-7 12376811\n28. Ramsey LB Balis FM O'Brien MM Schmiegelow K Pauley JL Bleyer A . Consensus guideline for use of glucarpidase in patients with high-dose methotrexate induced acute kidney injury and delayed methotrexate clearance. Oncologist. (2018) 23 :52–61. 10.1634/theoncologist.2017-0243 29079637\n29. Scott JR Crews KR . Reply to: glucarpidase for the treatment of methotrexate-induced renal dysfunction and delayed methotrexate excretion. Pediatr Blood Cancer. (2016) 63 :365. 10.1002/pbc.25800 26488798\n30. Christensen AM Pauley JL Molinelli AR Panetta JC Ward DA Stewart CF . Resumption of high-dose methotrexate after acute kidney injury and glucarpidase use in pediatric oncology patients. Cancer. (2012) 118 :4321–30. 10.1002/cncr.27378 22252903\n31. Taylor ZL Mizuno T Punt NC Baskaran B Navarro Sainz A Shuman W . MTXPKorg: a clinical decision support tool evaluating high-dose methotrexate pharmacokinetics to inform post-infusion care and use of glucarpidase. Clin Pharmacol Ther. (2020) 108 :635–43. 10.1002/cpt.1957 32558929\n\n",
"fulltext_license": "CC BY",
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"journal": "Frontiers in pediatrics",
"keywords": "charcoal; glucarpidase; hemoperfusion; high dose methotrexate; methotrexate; methotrexate toxicity",
"medline_ta": "Front Pediatr",
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"title": "Charcoal Hemoperfusion for Methotrexate Toxicity: A Safe and Effective Life-Rescue Alternative When Glucarpidase Is Not Available.",
"title_normalized": "charcoal hemoperfusion for methotrexate toxicity a safe and effective life rescue alternative when glucarpidase is not available"
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"abstract": "Drug-induced pulmonary arterial hypertension (PAH) is constantly evolving as new drugs are developed. Carfilzomib is a recently approved therapy for relapsed and refractory multiple myeloma. While it has been associated with cardiovascular adverse events, such as ischemic heart disease and heart failure, PAH has not been a well-described side effect. We present two patients who developed PAH associated with initiation of carfilzomib. They both initially presented with severe dyspnea, had elevated right ventricular systolic pressure on transthoracic echocardiography and ultimately underwent right heart catheterization. With discontinuation of carfilzomib, both patients had improvement in hemodynamics. However, one patient required initiation of PAH-targeted therapies and has had worsening right ventricular function again despite permanent discontinuation of carfilzomib. It is important to recognize the association between carfilzomib and PAH. Echocardiography can be an important initial screening tool. PAH from carfilzomib therapy may be reversible, especially if diagnosed early; however, extended follow-up is essential.",
"affiliations": "Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California San Diego, La Jolla, CA, USA.;Department of Medicine, University of California San Diego, La Jolla, CA, USA.;Division of Cardiovascular Medicine, Department of Medicine, University of California San Diego, La Jolla, CA, USA.;Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California San Diego, La Jolla, CA, USA.",
"authors": "Yang|Jenny Z|JZ|https://orcid.org/0000-0002-4844-8715;Buckstaff|Taylor|T|;Narezkina|Anna|A|;Fernandes|Timothy M|TM|",
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"fulltext": "\n==== Front\nPulm Circ\nPulm Circ\nPUL\nsppul\nPulmonary Circulation\n2045-8932\n2045-8940\nSAGE Publications Sage UK: London, England\n\n10.1177/20458940211049300\n10.1177_20458940211049300\nCase Report\nCarfilzomib-associated pulmonary arterial hypertension in multiple myeloma\nhttps://orcid.org/0000-0002-4844-8715\nYang Jenny Z. 1\nBuckstaff Taylor 2\nNarezkina Anna 3\nFernandes Timothy M. 1\n1 Division of Pulmonary, Critical Care and Sleep Medicine, 8784 Department of Medicine, 8784 University of California San Diego , La Jolla, CA, USA\n2 Department of Medicine, 8784 University of California San Diego, La Jolla, CA, USA\n3 Division of Cardiovascular Medicine, 8784 Department of Medicine, University of California San Diego, La Jolla, CA, USA\nJenny Z. Yang, Division of Pulmonary, Critical Care and Sleep Medicine, University of California San Diego, 9300 Campus Point Drive, MC 7381, La Jolla, CA 92037, USA. Email: jey052@health.ucsd.edu\n29 9 2021\nOct-Dec 2021\n11 4 2045894021104930016 7 2021\n7 9 2021\n© The Author(s) 2021\n2021\nSAGE Publications Ltd, or Pulmonary Vascular Research Institute, unless otherwise noted. Manuscript content on this site is licensed under Creative Commons Licenses\nhttps://creativecommons.org/licenses/by-nc/4.0/ Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).\nDrug-induced pulmonary arterial hypertension (PAH) is constantly evolving as new drugs are developed. Carfilzomib is a recently approved therapy for relapsed and refractory multiple myeloma. While it has been associated with cardiovascular adverse events, such as ischemic heart disease and heart failure, PAH has not been a well-described side effect. We present two patients who developed PAH associated with initiation of carfilzomib. They both initially presented with severe dyspnea, had elevated right ventricular systolic pressure on transthoracic echocardiography and ultimately underwent right heart catheterization. With discontinuation of carfilzomib, both patients had improvement in hemodynamics. However, one patient required initiation of PAH-targeted therapies and has had worsening right ventricular function again despite permanent discontinuation of carfilzomib. It is important to recognize the association between carfilzomib and PAH. Echocardiography can be an important initial screening tool. PAH from carfilzomib therapy may be reversible, especially if diagnosed early; however, extended follow-up is essential.\n\ncardio-oncology\ndrug toxicity\nmultiple myeloma\npulmonary hypertension\ncover-dateOctober-December 2021\ntypesetterts2\n==== Body\npmcIntroduction\n\nOur understanding of drugs linked with the development of pulmonary arterial hypertension (PAH) continues to evolve. For many years, anorexigens were the main culprits, but as research and awareness surrounding PAH increase, other drugs have been reported to cause PAH as well.\n\nCarfilzomib is a second-generation selective proteasome inhibitor and was approved in 2012 for the treatment of relapsed and refractory multiple myeloma. Carfilzomib is increasingly used in regimens for multiple myeloma, as studies have shown improved complete response rates, progression-free survival, and reduced risk of death compared to prior treatment regimens.1 However, cardiovascular adverse effects have also been reported with carfilzomib.2 Herein, we present two cases of carfilzomib-associated PAH.\n\nCase 1\n\nA 59-year-old woman with multiple myeloma was referred for an abnormal transthoracic echocardiogram (TTE). A year prior to her presentation, she had received an autologous stem cell transplant for multiple myeloma. However, she had relapse of her disease approximately 10 months later, so was started on salvage therapy, which consisted of carfilzomib, daratumumab, and dexamethasone. Prior treatments had included bortezomib and lenalidomide. TTE prior to initiating this regimen showed normal right ventricular systolic function and a right ventricular systolic pressure (RVSP) of 34 mmHg.\n\nAfter the fourth cycle of carfilzomib, the patient noted dyspnea on exertion. A new TTE was obtained, which demonstrated reduced right ventricular systolic function with a RVSP of 74 mmHg (Video 1(a) and (b)). Therefore, she was referred to the pulmonary vascular clinic. Vitals were normal and she had a room air saturation of 97%. Physical examination was unremarkable. Hemoglobin was 14.8 gm/dL, platelets were 140,000 mm,3 and creatinine was 0.74 mg/dL. Electrocardiography confirmed a normal sinus rhythm without signs of ischemia, and ventilation-perfusion scan was not consistent with thromboembolic disease. On further review of her TTE, there was consideration for amyloidosis given interventricular septal thickening, so she was referred for right heart catheterization with possible cardiac biopsy. Carfilzomib was discontinued, and no PAH-targeted therapies were started. Right heart catheterization performed approximately one month later showed resolution of pulmonary hypertension (Table 1). She also reported improvement in her symptoms, and three months later, her dyspnea entirely resolved.\n\nTable 1. Results of right heart catheterization.\n\nPatient\tTiming of RHC\tRA (mmHg)\tPAP, sys/dias (mmHg)\tMean PAP (mmHg)\tPCWP (mmHg)\tCO (L/min)\tCI (L/min/m2)\tPVR (WU)\t\n1\t1 month after carfilzomib\t4\t39/14\t23\t10\t3.6\t2.3\t3.6\t\n2\tOn carfilzomib\t12\t85/33\t52\t11\t2.7\t1.8\t15.2\t\nCI: cardiac index; CO: cardiac output; L/min: liters/minute; mmHg: millimeters of Mercury; PAP: pulmonary artery pressures; PCWP: pulmonary capillary wedge pressure; PVR: pulmonary vascular resistance; RA: right atrial pressure; RHC: right heart catheterization; Sys/dias: systolic/diastolic; WU: Wood units.\n\nCase 2\n\nA 56-year-old woman with multiple myeloma was evaluated for dyspnea. She had underwent an autologous stem cell transplant several years prior but had relapse of disease approximately two years later. Subsequently, she was treated with multiple regimens, including bortezomib, chimeric antigen receptor T-cell therapy, and most recently carfilzomib.\n\nAfter four months of treatment with carfilzomib, she developed significant dyspnea. TTE showed RVSP of 120 mmHg with severely enlarged right ventricle and depressed function (Video 2(a) to (c)). Her baseline TTE had normal right ventricular size and function, with RVSP of 43 mmHg. Given her TTE findings and worsening symptoms, she was admitted for urgent work up. Vital signs were within normal limits. Physical examination revealed elevated jugular venous pressure and mild abdominal distention. Hemoglobin was 8.6 gm/dL, platelets 87,000 mm3, and creatinine 0.77 mg/dL which were all near her baseline. Chest radiography reported no cardiopulmonary abnormality; ventilation-perfusion scan was not consistent with thromboembolic disease; and electrocardiography showed normal sinus rhythm with a rightward axis. Right heart catheterization confirmed PAH (Table 1). Combination PAH-targeted therapy was started with sildenafil and macitentan, and carfilzomib was discontinued.\n\nAt two-month follow-up, the patient’s dyspnea had resolved. Repeat TTE showed a RVSP of 38 mmHg, normalization of right ventricular size and function (Video 3(a) and (b)), and improved tricuspid annular plane systolic excursion from 1.37 cm to 2.33 cm. Macitentan was discontinued. One month later, repeat TTE showed an increased RVSP to 70 mmHg with enlarged right ventricular size. Therefore, she was restarted on macitentan and has ongoing follow-up with the pulmonary vascular clinic.\n\nDiscussion\n\nCarfilzomib has improved the treatment of relapsed and refractory multiple myeloma. However, serious adverse events have been observed, especially related to the cardiovascular system. Prior reports have described heart failure, hypertension, and ischemic heart disease related to carfilzomib.2,3 While there are several mechanisms for pulmonary hypertension in multiple myeloma,4 including thromboembolic disease and amyloidosis, drug-associated pulmonary arterial hypertension may become increasingly common, especially as novel medications are emerging. These two cases demonstrate that in addition to ruling out other causes of pulmonary hypertension related to multiple myeloma, drug therapy for myeloma should be carefully monitored.\n\nAlthough there are reports of bortezomib associated with PAH,5 the temporal correlation of PAH in both patients appeared to be with carfilzomib. The underlying mechanism of carfilzomib-induced PAH is unclear. One hypothesis is that carfilzomib may lead to dose-dependent changes in endothelial nitric oxide synthase activity, leading to less bioavailable nitric oxide and thus impairing vasodilation.2 Patient 1 had a cumulative carfilzomib dose of 496 mg/m2 while patient 2 had received a cumulative dose of 6133 mg/m2 of carfilzomib. Given this theory of dose-dependent changes in nitric oxide synthase activity, the higher total cumulative dose of carfilzomib in patient 2 may have contributed to why her PAH was not reversible with drug cessation alone. An alternative theory is that the non-targeted proteasome inhibition of the endothelium and subsequent oxidative stress lead to vascular dysfunction and increased vascular tone.6 Although the pathogenesis of carfilzomib-induced PAH remains unclear, the growing number of case reports7,8 highlights the importance of screening echocardiograms and close symptom monitoring after initiation of carfilzomib.\n\nGiven the limited cases of PAH associated with carfilzomib, prognosis and treatment are ill-defined. Our first patient highlights that PAH associated with carfilzomib may be potentially reversible if diagnosed early and the offending agent is stopped. She had complete resolution of pulmonary hypertension with just discontinuation of carfilzomib. On the contrary, PAH-targeted therapies were prescribed in our second patient. Despite permanent discontinuation of carfilzomib, she failed a trial off combination PAH therapies. Similarly, in the experience with dasatinib-induced PAH, about a third of patients had persistent PAH despite discontinuation of dasatinib.9 Therefore, extended follow-up of these patients is essential. We acknowledge the lack of complete hemodynamics in both patients before and after carfilzomib cessation is a limitation in this series, but believe this is still an important association to highlight.\n\nConclusion\n\nCarfilzomib has been revolutionary for patients with multiple myeloma, but there is an emerging association with PAH. These cases highlight the importance of echocardiographic and symptom screening during treatment with carfilzomib, as well as the need for extended follow-up for these patients even after discontinuation of carfilzomib. While pulmonary hypertension associated with carfilzomib may be reversible with drug discontinuation, there may also be patients who require long-term treatment with PAH-targeted therapies. Larger studies are needed to help further define the incidence, characteristics, and long-term effects of pulmonary hypertension in this population.\n\nSupplemental Material\n\nsj-pdf-1-pul-10.1177_20458940211049300 - Supplemental material for Carfilzomib-associated pulmonary arterial hypertension in multiple myeloma\n\nClick here for additional data file.\n\nSupplemental material, sj-pdf-1-pul-10.1177_20458940211049300 for Carfilzomib-associated pulmonary arterial hypertension in multiple myeloma by Jenny Z. Yang, Taylor Buckstaff, Anna Narezkina and Timothy M. Fernandes in Pulmonary Circulation\n\nConflict of interest: The author(s) declare that there is no conflict of interest.\n\nFunding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\n\nORCID iD: Jenny Z. Yang https://orcid.org/0000-0002-4844-8715\n\nSupplemental Material: Supplemental material for this article is available online.\n==== Refs\nReferences\n\n1 Dimopoulos MA Moreau P Palumbo A , et al . Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): and randomised, phase 3, open-label, multicentre study. Lancet Oncol 2016; 17 : 27–38.26671818\n2 Chari A Hajje D. Case series discussion of cardiac and vascular events following carfilzomib treatment: possible mechanism, screening, and monitoring. BMC Cancer 2014; 14 : 915.25471129\n3 Chari A Keith Stewart A Russell SD , et al . Analysis of carfilzomib cardiovascular safety profile across relapsed and/or refractory multiple myeloma clinical trials. Blood Adv 2018; 2 : 1633–1644.29991494\n4 Krishnan U Mark TM Niesvizky R , et al . Pulmonary hypertension complicating multiple myeloma. Pulm Circ 2015; 5 : 590–597.26401262\n5 Akosman C Ordu C Eroglu E , et al . Development of acute pulmonary hypertension after bortezomib treatment in a patient with multiple myeloma: a case report and the review of the literature. Am J Ther 2015; 22 : e88–e92.24100255\n6 McGregor PC Boosalis V Aragam J. Carfilzomib-induced pulmonary hypertension with associated right ventricular dysfunction: a case report. SAGE Open Med Case Rep 2021; 9: 1–4.\n7 Mathur P Thanendrarajan S Lopez-Candales A. Severe right-sided heart failure and pulmonary hypertension with carfilzomib treatment in multiple myeloma. Heart Views 2020; 21 : 296.33986932\n8 Rago A Siniscalchi A Tordi A , et al . Pulmonary arterial hypertension in a patient with multiple myeloma during carfilzomib treatment: in search of better management. Tumori. Epub ahead of print 1 February 2021. DOI: 10.1177/0300891621990427.\n9 Weatherald J Chaumais MC Savale L , et al . Long-term outcomes of dasatinib-induced pulmonary arterial hypertension: a population-based study. Eur Respir J 2017; 50 : 1700217.28751413\n\n",
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"issue": "11(4)",
"journal": "Pulmonary circulation",
"keywords": "cardio-oncology; drug toxicity; multiple myeloma; pulmonary hypertension",
"medline_ta": "Pulm Circ",
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"title": "Carfilzomib-associated pulmonary arterial hypertension in multiple myeloma.",
"title_normalized": "carfilzomib associated pulmonary arterial hypertension in multiple myeloma"
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"abstract": "Despite an established history of intraocular antivascular endothelial growth factor (anti-VEGF) agents therapy in a variety of ocular pathologies as well as other cancer forms, use in the primary treatment of uveal melanoma has not been well assessed. This was a two-stage therapeutic and exploratory phase II, non-randomised, single centre trial involving intraocular treatment with 0.5 mg in 0.05 ml of ranibizumab via six intravitreous injections over 6 months in patients with primary ocular melanoma that otherwise required radical surgery because of tumour size. Seven patients were recruited with a median age of 66 years. At baseline, the longest basal diameter was 15.1 mm (mean, range 10-20.4 mm) with a height measured by ultrasonography of 9.2 mm (mean, range 6.6-12.7 mm). No patients achieved complete or partial response at any visit. All required enucleation. Histopathological analysis revealed mixed cell melanoma in 5/7 (71%) and spindle cell morphology in 2/7 (29%) with ciliary body involvement in 4/7 (57%) and the presence of closed loops also in 4/7 (57%). Genetic analysis demonstrated loss of chromosome 3 in 5/7 (71%) but abnormalities in chromosome 1,6 or 8 in all cases. Our study was terminated early as alternative treatments were clearly superior for local tumour control. There continues to be a role of intravitreal anti-VEGF for the treatment of the sequelae of local radiotherapy in the form of radiation retinopathy and so these agents may be used as adjuncts in the treatment of uveal melanoma rather than as a primary treatment.",
"affiliations": "Liverpool Ocular Oncology Centre, St Pauls Eye Unit, Royal Liverpool University Hospital, Liverpool, UK.",
"authors": "Hussain|Rumana N|RN|;Heimann|Heinrich|H|;Damato|Bertil|B|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D000069579:Ranibizumab",
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"issue": "30(1)",
"journal": "Melanoma research",
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"medline_ta": "Melanoma Res",
"mesh_terms": "D000368:Aged; D020533:Angiogenesis Inhibitors; D005128:Eye Diseases; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D000069579:Ranibizumab; D012878:Skin Neoplasms",
"nlm_unique_id": "9109623",
"other_id": null,
"pages": "102-106",
"pmc": null,
"pmid": "31425478",
"pubdate": "2020-02",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Neoadjuvant intravitreal ranibizumab treatment in high-risk ocular melanoma patients: a two-stage single-centre phase II single-arm study.",
"title_normalized": "neoadjuvant intravitreal ranibizumab treatment in high risk ocular melanoma patients a two stage single centre phase ii single arm study"
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"abstract": "BACKGROUND\nOur objective was to assess therapeutic non-inferiority of dual treatment with lopinavir-ritonavir and lamivudine to triple treatment with lopinavir-ritonavir plus two nucleos(t)ides for maintenance of HIV-1 viral suppression.\n\n\nMETHODS\nIn this randomised, open-label, non-inferiority trial, we recruited patients from 32 HIV units in hospitals in Spain and France. Eligible patients were HIV-infected adults (aged ≥18 years) with HIV-1 RNA of less than 50 copies per mL, for at least 6 months on triple treatment with lopinavir-ritonavir (twice daily) plus lamivudine or emtricitabine and a second nucleos(t)ide, with no resistance or virological failure to these drugs, and no positive hepatitis B serum surface antigen. Investigators at each centre randomly assigned patients (1:1; block size of four; stratified by time to suppression [<1 year or >1 year] and nadir CD4 cell count [<100 cells per μL or >100 cells per μL]; computer-generated random sequence) to continue triple treatment or switch to dual treatment (oral lopinavir 400 mg and oral ritonavir 100 mg twice daily plus oral lamivudine 300 mg once daily). The primary endpoint was response to treatment in the intention-to-treat population (all randomised patients) at 48 weeks. The non-inferiority margin was 12%. This study is registered with ClinicalTrials.gov, number NCT01471821.\n\n\nRESULTS\nBetween Oct 1, 2011, and April 1, 2013, we randomly assigned 250 participants to continue triple treatment (127 [51%] patients) or switch to dual treatment (123 [49%] patients). In the intention-to-treat population, 110 (86·6%) of 127 patients in the triple-treatment group responded to treatment versus 108 (87·8%) of 123 in the dual-treatment group (difference -1·2% [95% CI -9·6 to 7·3]; p=0·92), meeting the criteria for non-inferiority. Serious adverse events occurred in eight (7%) patients in the triple-treatment group and five (4%) in the dual-treatment group (p=0·515), and study drug discontinuations due to adverse events occurred in four (3%) in the triple-treatment group and one (1%) in the dual-treatment group (p=0·223).\n\n\nCONCLUSIONS\nDual treatment with lopinavir-ritonavir plus lamivudine has non-inferior therapeutic efficacy and is similarly tolerated to triple treatment.\n\n\nBACKGROUND\nAbbVie and Red Temática Cooperativa de Investigación en Sida.",
"affiliations": "Hospital La Paz, Instituto de Investigation Sanitaria del Hospital Universitario La Paz, Madrid, Spain. Electronic address: joser.arribas@salud.madrid.org.;Hôpital Saint-Antoine, Assistance Publique - Hôpitaux de Paris, Institut National de la Santé et de la Recherche Médicale UMR_S 1136, Paris, France.;Hôpital Bichat-Claude Bernard, AP-HP, and Institut National de la Santé et de la Recherche Médicale UMR 1137, Paris, France.;Hospital Clínic/Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain.;Hospital Clínic/Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain.;Hospital Clínic/Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain.;Hospital La Paz, Instituto de Investigation Sanitaria del Hospital Universitario La Paz, Madrid, Spain.;Hospital Clínico San Carlos, Madrid, Spain.;Hospital Vall d'Hebrón, Barcelona, Spain.;Hospital Universitario de Bellvitge, Barcelona, Spain.;Hospital General Universitario de Alicante, Alicante, Spain.;Hospital Universitario Ramón y Cajal, Madrid, Spain.;Hospital de Donostia, Donostia, Spain.;Hospital de Sant Pau, Barcelona, Spain.;Hospital Universitario Doce de Octubre, i+12, Madrid, Spain.;Hospital La Fe, Valencia, Spain.;Hospital del Mar, Barcelona, Spain.;CHU de Martinique-Institut National de la Santé et de la Recherche Médicale CIC1224, Fort-de-France, France.;Assistance Publique - Hôpitaux de Paris, Hôpital Européen Georges Pompidou, and Université Paris Descartes, Sorbonne Paris-Cité, Paris, France.;Hospital Clínic/Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain.",
"authors": "Arribas|José R|JR|;Girard|Pierre-Marie|PM|;Landman|Roland|R|;Pich|Judit|J|;Mallolas|Josep|J|;Martínez-Rebollar|María|M|;Zamora|Francisco X|FX|;Estrada|Vicente|V|;Crespo|Manuel|M|;Podzamczer|Daniel|D|;Portilla|Joaquín|J|;Dronda|Fernando|F|;Iribarren|José A|JA|;Domingo|Pere|P|;Pulido|Federico|F|;Montero|Marta|M|;Knobel|Hernando|H|;Cabié|André|A|;Weiss|Laurence|L|;Gatell|José M|JM|;|||",
"chemical_list": "D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D003841:Deoxycytidine; D061466:Lopinavir; D019259:Lamivudine; D000068679:Emtricitabine; D019438:Ritonavir",
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"issn_linking": "1473-3099",
"issue": "15(7)",
"journal": "The Lancet. Infectious diseases",
"keywords": null,
"medline_ta": "Lancet Infect Dis",
"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D018791:CD4 Lymphocyte Count; D003841:Deoxycytidine; D004359:Drug Therapy, Combination; D000068679:Emtricitabine; D005260:Female; D015658:HIV Infections; D017320:HIV Protease Inhibitors; D015497:HIV-1; D006801:Humans; D057194:Intention to Treat Analysis; D019259:Lamivudine; D061466:Lopinavir; D060046:Maintenance Chemotherapy; D008297:Male; D008875:Middle Aged; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D019438:Ritonavir; D019562:Viral Load",
"nlm_unique_id": "101130150",
"other_id": null,
"pages": "785-92",
"pmc": null,
"pmid": "26062880",
"pubdate": "2015-07",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Dual treatment with lopinavir-ritonavir plus lamivudine versus triple treatment with lopinavir-ritonavir plus lamivudine or emtricitabine and a second nucleos(t)ide reverse transcriptase inhibitor for maintenance of HIV-1 viral suppression (OLE): a randomised, open-label, non-inferiority trial.",
"title_normalized": "dual treatment with lopinavir ritonavir plus lamivudine versus triple treatment with lopinavir ritonavir plus lamivudine or emtricitabine and a second nucleos t ide reverse transcriptase inhibitor for maintenance of hiv 1 viral suppression ole a randomised open label non inferiority trial"
} | [
{
"companynumb": "ES-CIPLA LTD.-2015ES05660",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "LAMIVUDINE"
},
"drugadditional": null,
... |
{
"abstract": "Brain metastases (BM) frequently develop in patients with melanoma and are associated with a poor prognosis. Whole brain radiation therapy (WBRT) is a standard intervention for intracranial disease, particularly in patients with multiple BM. Ipilimumab improves survival in patients with advanced melanoma. The purpose of this study is to investigate the safety and efficacy of concurrent WBRT and ipilimumab. A retrospective analysis was conducted of 13 consecutive patients treated with WBRT within 30 days of ipilimumab administration. Radiographic response, as measured by serial magnetic resonance imaging scans post-treatment, was graded by modified World Health Organization (mWHO) and immune-related response criteria (irRC) in the 9 patients with follow-up imaging. Treatment-related toxicity was prospectively assessed during treatment. Four of nine patients (44 %) experienced partial response or stable central nervous system (CNS) disease as measured by mWHO criteria. This number increased to 5 patients (56 %) when irRC criteria were used. Rates of treatment-related neurologic toxicity were low with only one patient experiencing grade 3-4 neurologic toxicity. There was a high rate of intratumoral hemorrhage in this patient population, with 10 of 10 patients with post-treatment imaging demonstrating new or increased intratumoral bleeding after WBRT. This retrospective study demonstrates that the primary pattern of CNS response to WBRT and ipilimumab is stable disease and not regression of BM. Furthermore, while the combination of WBRT and ipilimumab may offer promising efficacy, prospective studies are needed to further assess efficacy and toxicity.",
"affiliations": "Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY, 10065, USA.",
"authors": "Gerber|Naamit K|NK|;Young|Robert J|RJ|;Barker|Christopher A|CA|;Wolchok|Jedd D|JD|;Chan|Timothy A|TA|;Yamada|Yoshiya|Y|;Friguglietti|Leigh|L|;Beal|Kathryn|K|",
"chemical_list": "D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000074324:Ipilimumab",
"country": "United States",
"delete": false,
"doi": "10.1007/s11060-014-1617-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0167-594X",
"issue": "121(1)",
"journal": "Journal of neuro-oncology",
"keywords": null,
"medline_ta": "J Neurooncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D001921:Brain; D001932:Brain Neoplasms; D003131:Combined Modality Therapy; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D000074324:Ipilimumab; D008279:Magnetic Resonance Imaging; D008297:Male; D008545:Melanoma; D008875:Middle Aged; D011446:Prospective Studies; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "8309335",
"other_id": null,
"pages": "159-65",
"pmc": null,
"pmid": "25273687",
"pubdate": "2015-01",
"publication_types": "D016428:Journal Article",
"references": "6678974;2405271;19018089;12569292;9420067;22456429;20440079;19934295;19733017;22527228;22051508;20372154;17142742;18287337;11163501;15325032;20977700;23462208;12407517;20525992;15158627;22203767;22857154;15051777;22820413;7484597;21639810;23068052;21737504;8851427;24661650;22702482",
"title": "Ipilimumab and whole brain radiation therapy for melanoma brain metastases.",
"title_normalized": "ipilimumab and whole brain radiation therapy for melanoma brain metastases"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2017-003824",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IPILIMUMAB"
},
"drugadd... |
{
"abstract": "OBJECTIVE\nDaratumumab is a promising novel agent for relapsed/refractory multiple myeloma (RRMM). However, there are limited data on its efficacy and toxicity profiles in real-world patients, especially in the Asian population.\n\n\nMETHODS\nThis was a multicenter, retrospective, longitudinal cohort study set between January 2017 and April 2019. We collected and analyzed clinical and survival data of 21 patients treated with daratumumab monotherapy. All patients were previously exposed to proteasome inhibitors and immunomodulatory drugs.\n\n\nRESULTS\nThe overall response rate was 42.1%, including one complete remission (4.8%) and three very good partial responses (14.3%). The cycles of daratumumab delivered were three (range=1-10 cycles) and the median progression-free survival was 6 months, while the overall survival was not reached. Infusion reaction was observed in nine patients (42.9%), and one discontinued permanently. Fatigue was the most common adverse event (52.4%), and there were five cases of documented infection during daratumumab treatment, two of them leading to the death of the patient.\n\n\nCONCLUSIONS\nDaratumumab monotherapy showed fairly promising activity with modest tolerance in heavily treated Asian RRMM patients.",
"affiliations": "Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea.;Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea ssysmc@snu.ac.kr.;Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea.;Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea.;Department of Internal Medicine, Jeju National University Hospital, Jeju, Republic of Korea.;Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Republic of Korea.;Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.;Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.",
"authors": "Byun|Ja Min|JM|;Yoon|Sung-Soo|SS|;Koh|Youngil|Y|;Kim|Inho|I|;Jo|Jaemin|J|;Park|Hyunkyung|H|;Lee|Jeong-Ok|JO|;Lee|Jiyun|J|",
"chemical_list": "D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C556306:daratumumab",
"country": "Greece",
"delete": false,
"doi": "10.21873/anticanres.13712",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0250-7005",
"issue": "39(9)",
"journal": "Anticancer research",
"keywords": "Asian; Daratumumab; multiple myeloma; real-world; relapsed",
"medline_ta": "Anticancer Res",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D001208:Asia; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D012008:Recurrence; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "8102988",
"other_id": null,
"pages": "5165-5170",
"pmc": null,
"pmid": "31519629",
"pubdate": "2019-09",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Daratumumab Monotherapy in Heavily Pretreated Asian Patients With Relapsed and Refractory Multiple Myeloma: A Real-world Experience.",
"title_normalized": "daratumumab monotherapy in heavily pretreated asian patients with relapsed and refractory multiple myeloma a real world experience"
} | [
{
"companynumb": "KR-JNJFOC-20191002186",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DARATUMUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nTo compare the safety and effectiveness of three methods of reversing coagulopathic effects of warfarin in patients with potentially life-threatening intracranial hemorrhage.\n\n\nMETHODS\nA retrospective electronic medical record review of 63 patients with warfarin-related intracranial hemorrhage between 2007 and 2010 in an integrated health care delivery system was conducted. The three methods of rapid warfarin reversal were fresh-frozen plasma (FFP), activated factor VII (FVIIa; NovoSevenRT [Novo Nordisk, Bagsværd, Denmark]), and prothrombin complex concentrate (PCC; BebulinVH [Baxter, Westlake Village, California, USA], ProfilnineSD [Grifols, North Carolina, USA]), each used adjunctively with vitamin K (Vit K, phytonadione). We determined times from reversal agent order to laboratory evidence of warfarin reversal (international normalized ratio [INR]) in the first 48 hours and compared INR rebound rates and complications in the first 48 hours.\n\n\nRESULTS\nReversal with FFP took more than twice as long compared with FVIIa or PCC. To reach an INR of 1.3, mean (±SD) reversal times were 1933 ± 905 minutes for FFP, 784 ± 926 minutes for FVIIa, and 980 ± 1021 minutes for PCC (P < 0.001; P < 0.01 between FFP and FVIIa, P < 0.05 between FFP and PCC). INR rebound occurred in 0 of 31 patients for FFP, 4 of 8 for FVIIa, and 0 of 7 for PCC (P = 0.001). Complications were uncommon. FVIIa was 15 and 3.5 times as expensive as FFP and PCC, respectively.\n\n\nCONCLUSIONS\nAs an adjunct to Vit K for rapid warfarin reversal, FVIIa and PCC appear more effective than FFP. Either FVIIa or PCC are reasonable options for reversal, but FVIIa is considerably more expensive and may have greater risk of INR rebound.",
"affiliations": "Department of Pharmacy, Kaiser Permanente Medical Center, San Francisco, California, USA. Electronic address: Carolyn.H.Woo@kp.org.;Department of Neurosurgery/Neuroscience, Kaiser Permanente Medical Center, Redwood City, California, USA.;Division of Research, Kaiser Permanente Medical Center, Oakland, California, USA.;Department of Neurosurgery/Neuroscience, Kaiser Permanente Medical Center, Redwood City, California, USA.;Department of Neurosurgery/Neuroscience, Kaiser Permanente Medical Center, Redwood City, California, USA.;Department of Neurosurgery/Neuroscience, Kaiser Permanente Medical Center, Redwood City, California, USA.;Department of Neurosurgery/Neuroscience, Kaiser Permanente Medical Center, Redwood City, California, USA.;Department of Neurosurgery, Kaiser Permanente Medical Center, Sacramento, California, USA.;Department of Neurosurgery, Kaiser Permanente Medical Center, Sacramento, California, USA.;Department of Neurosurgery/Neuroscience, Kaiser Permanente Medical Center, Redwood City, California, USA.;Department of Neurosurgery/Neuroscience, Kaiser Permanente Medical Center, Redwood City, California, USA.;Department of Neurosurgery/Neuroscience, Kaiser Permanente Medical Center, Redwood City, California, USA.",
"authors": "Woo|Carolyn H|CH|;Patel|Nihar|N|;Conell|Carol|C|;Rao|Vivek A|VA|;Faigeles|Bonnie S|BS|;Patel|Minal C|MC|;Pombra|Jasmeen|J|;Akins|Paul T|PT|;Axelrod|Yekaterina K|YK|;Ge|Ivy Y|IY|;Sheridan|William F|WF|;Flint|Alexander C|AC|",
"chemical_list": "D000925:Anticoagulants; D001779:Blood Coagulation Factors; D011994:Recombinant Proteins; D014812:Vitamin K; C025667:prothrombin complex concentrates; D014859:Warfarin; D005167:Factor VII",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-8750",
"issue": "81(1)",
"journal": "World neurosurgery",
"keywords": "Intracranial hemorrhage; Plasma; Prothrombin complex concentrate; Recombinant activated factor vii; Reversal; Warfarin",
"medline_ta": "World Neurosurg",
"mesh_terms": "D000368:Aged; D000925:Anticoagulants; D001778:Blood Coagulation Disorders; D001779:Blood Coagulation Factors; D057286:Electronic Health Records; D004632:Emergency Medical Services; D005167:Factor VII; D005260:Female; D006801:Humans; D019934:International Normalized Ratio; D020300:Intracranial Hemorrhages; D008297:Male; D008875:Middle Aged; D019635:Neurosurgical Procedures; D010949:Plasma; D011994:Recombinant Proteins; D012189:Retrospective Studies; D014812:Vitamin K; D014859:Warfarin",
"nlm_unique_id": "101528275",
"other_id": null,
"pages": "110-5",
"pmc": null,
"pmid": "23220122",
"pubdate": "2014-01",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Rapid Warfarin reversal in the setting of intracranial hemorrhage: a comparison of plasma, recombinant activated factor VII, and prothrombin complex concentrate.",
"title_normalized": "rapid warfarin reversal in the setting of intracranial hemorrhage a comparison of plasma recombinant activated factor vii and prothrombin complex concentrate"
} | [
{
"companynumb": "US-TEVA-620892USA",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "WARFARIN"
},
"drugadditional": null,
"druga... |
{
"abstract": "Dupilumab is a receptor antagonist binding to the alpha subunit of the interleukin-4 receptor. Through binding to it, dupilumab inhibits signaling of both IL-4 and IL-13, the representative Th2 biomarkers. Recently, in addition to the treatment effects for atopic dermatitis (AD), there is an emerging adverse event as facial erythema.\nA twenty-seven-year-old female patient developed erythema and desquamation on the face and neck after dupilumab administration. She had AD on her arms, legs, and trunk before the treatment but there was no atopic clinical feature in her face and neck. With the treatment of dupilumab, her skin lesions of the body have improved from the beginning of the treatment. In the patch test, including dupilumab, there was no specific finding other than the 1+ response to neomycin on day 2. In the intradermal test to dupilumab, a positive result was observed 15 min later, but negative both days 1 and 2. The blood examination showed an elevation of both ANA as 1:80 and anti-phospholipid antibodies (Anti-cardiolipin IgM, IgG, and Anti- beta 2 GPI IgG). She was diagnosed with Systemic lupus erythematosus (SLE) based on diagnostic criteria by a rheumatologist.\nDupilumab is an emerging therapeutic agent for AD, and treatment cases are increasing in Korea. However, there are several adverse events during the treatment of dupilumab. Herein, we report the unexpected adverse event during the treatment of dupilumab in SLE patients.",
"affiliations": "Department of Dermatology, National Medical Center, 245 Eulji-ro, Jung-gu, Seoul, 04564 Korea.;Department of Dermatology, National Medical Center, 245 Eulji-ro, Jung-gu, Seoul, 04564 Korea.;Department of Dermatology, National Medical Center, 245 Eulji-ro, Jung-gu, Seoul, 04564 Korea.;Department of Dermatology, National Medical Center, 245 Eulji-ro, Jung-gu, Seoul, 04564 Korea.;Department of Dermatology, National Medical Center, 245 Eulji-ro, Jung-gu, Seoul, 04564 Korea.;Department of Dermatology, National Medical Center, 245 Eulji-ro, Jung-gu, Seoul, 04564 Korea.",
"authors": "Jang|Dong Hyek|DH|;Lee|Jae In|JI|;Bae|Joo Yoon|JY|;Jung|Hye Jung|HJ|;Park|Mi Yeon|MY|;Ahn|Jiyoung|J|0000-0002-6766-9978",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s13223-020-00458-6",
"fulltext": "\n==== Front\nAllergy Asthma Clin Immunol\nAllergy Asthma Clin Immunol\nAllergy, Asthma, and Clinical Immunology : Official Journal of the Canadian Society of Allergy and Clinical Immunology\n1710-1484 1710-1492 BioMed Central London \n\n458\n10.1186/s13223-020-00458-6\nCase Report\nFacial erythema after the treatment of dupilumab in SLE patient\nJang Dong Hyek Lee Jae In Bae Joo Yoon Jung Hye Jung Park Mi Yeon http://orcid.org/0000-0002-6766-9978Ahn Jiyoung jiyoung.ahn@nmc.or.kr grid.415619.e0000 0004 1773 6903Department of Dermatology, National Medical Center, 245 Eulji-ro, Jung-gu, Seoul, 04564 Korea \n3 7 2020 \n3 7 2020 \n2020 \n16 6024 2 2020 26 6 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. 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\nDupilumab is a receptor antagonist binding to the alpha subunit of the interleukin-4 receptor. Through binding to it, dupilumab inhibits signaling of both IL-4 and IL-13, the representative Th2 biomarkers. Recently, in addition to the treatment effects for atopic dermatitis (AD), there is an emerging adverse event as facial erythema.\n\nCase presentation\nA twenty-seven-year-old female patient developed erythema and desquamation on the face and neck after dupilumab administration. She had AD on her arms, legs, and trunk before the treatment but there was no atopic clinical feature in her face and neck. With the treatment of dupilumab, her skin lesions of the body have improved from the beginning of the treatment. In the patch test, including dupilumab, there was no specific finding other than the 1+ response to neomycin on day 2. In the intradermal test to dupilumab, a positive result was observed 15 min later, but negative both days 1 and 2. The blood examination showed an elevation of both ANA as 1:80 and anti-phospholipid antibodies (Anti-cardiolipin IgM, IgG, and Anti- beta 2 GPI IgG). She was diagnosed with Systemic lupus erythematosus (SLE) based on diagnostic criteria by a rheumatologist.\n\nConclusion\nDupilumab is an emerging therapeutic agent for AD, and treatment cases are increasing in Korea. However, there are several adverse events during the treatment of dupilumab. Herein, we report the unexpected adverse event during the treatment of dupilumab in SLE patients.\n\nKeywords\nAtopic dermatitisDupilumabFacial erythemaSLEissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nAtopic dermatitis (AD) is a chronic inflammatory disease accompanied by itching, which often occurs at any age and gradually improves but sometimes worsens. Mainly, adult atopic dermatitis affects the quality of life because the degree of dermatitis is so severe that healthy daily life cannot be guaranteed. Therefore, there has been much effort in developing treatments for adult atopic dermatitis. Currently, dupilumab (an anti-IL-4R alpha monoclonal antibody [1]) is already an excellent treatment option. Although dupilumab has been very effective in clinical trials and real-world data, there are some treatment-related adverse events. Among them, facial erythema after dupilumab treatment is an emerging adverse event. It has recently been reported frequently at home and abroad [2–4].\n\nCase presentation\nA twenty-seven-year-old female patient developed erythema and desquamation on the face and neck after dupilumab treatment (nasolabial fold was spared). She received first dupilumab treatment at another tertiary hospital with her initial EASI (Eczema Area and Severity Index) score of 16.5 and transferred to our dermatologic clinic. She did not have the symptoms before dupilumab treatment, and they gradually improved after a week (Fig. 1). The same symptoms repeated every time the treatment was administered. Previously she used topical steroid and topical calcineurin inhibitor, but she never used systemic steroid or immunosuppressant such as cyclosporine. She had AD lesions on her arms, legs, and trunk before the treatment, but her face and neck showed no AD lesion at that time. Dupilumab was administered every 2 weeks, and atopic lesions of the body improved from the beginning of the treatment (showed an improvement in the EASI score to 5.5). To identify the cause of the facial erythema after dupilumab treatment, we performed several tests. The patch test, including dupilumab showed negative response except for the 1+ response to neomycin on day 2, which may be thought of as non-specific finding. In the intradermal test (ID test) to dupilumab, a positive result was observed after 15 min (the wheal size of dupilumab was the same as that of histamine). However, negative results were observed on both days 1 and 2 (Fig. 2). Although the ID test showed an immediate reaction, the patient had not experienced any immediate reactions after any dupilumab treatments. Moreover, a delayed reaction was not observed in the patch test or ID test on days 1 and 2, suggesting that the possibility of any hypersensitivity to dupilumab was highly unlikely.Fig. 1 a, b 2 days after fourth injection (c, d) 6 days after fourth injection\n\nFig. 2 Interdermal test (a) 15 min, Dupilumab (3+, same wheal size as histamine) (b) 1 day, Dupilumab (−) (c) 2 day, Dupilumab (−)\n\n\n\nThe blood examination results showed elevation of both ANA to 1:80 (speckled type) consistent with the previous result as ANA as 1:320 and anti-phospholipid antibodies (Anti-cardiolipin IgM, IgG, and Anti- beta 2 GPI IgG). However, other autoantibodies were negative, including anti-histone antibody. We consulted a rheumatologist, under the suspicion of Anti-phospholipid antibody syndrome. Also, intermittent leukopenia, the elevation of anti-phospholipid antibodies after three months, and low complement level (C3) were identified. She complained of intermittent pain of both knee joints showing the joint space narrowing on knee x-ray. We recommended a skin biopsy to confirm whether the facial erythema is cutaneous lupus or not, but she refused it. According to SLICC (Systemic Lupus Erythematosus International Collaborating Clinics) criteria [5], she was diagnosed with SLE (Arthritis and Leukopenia in clinical criteria and ANA, Anti-phospholipid antibody and Low complement in immunologic criteria). She took a low dose of aspirin and hydroxychloroquine for SLE. She maintained the dupilumab treatment for AD as her EASI score has improved with the treatment.\n\nDiscussion and conclusions\nErythema of the face after treatment with dupilumab can be caused by (1) worsening of the existing atopic dermatitis lesions, (2) withdrawal of systemic steroid [6] or immuno-suppressant, (3) concomitant allergic contact dermatitis (ACD) [7, 8] or other eczematous skin diseases, (4) a seborrheic dermatitis-like reaction to facial Malassezia species [3] and (5) adverse effects of dupilumab. Our patient did not have any AD lesions on the face at first. Besides, the facial and neck lesions were different from those of flare-up of atopic dermatitis. After the administration of dupilumab, the remaining lesions of the body improved. Nevertheless, the face and neck had worsened with erythema and desquamation. The patient used only topical agents for maintenance during the treatment of dupilumab, so the rebound effect due to the withdrawal of systemic agents can be excluded. We can also exclude allergic contact eczema due to the result of no delayed response in the patch test and intradermal test. Moreover, there have been some cases of ACD treated with dupilumab [8], implying that our patient’s erythema might not have been a lesion of ACD. The following excluded the possibility of seborrheic dermatitis-like reaction: the lesion did not occur in seborrheic areas and showed improvement without topical ketoconazole. The erythema and desquamation after treatment with dupilumab were not reported in previous clinical trials [1]. These reasons caused us to consider another cause of the erythema of the face after treatment with dupilumab. Besides, in one case reported in the United States, facial erythema was reported after the administration of dupilumab [4]. The elevation of ANA was reported in that patient.\n\nThis case is the first case of facial erythema after treatment with dupilumab for AD accompanied with SLE. Both AD and SLE are immune diseases involving interactions between genes and the environment [9, 10]. A previous study reported epidemiological correlations and a substantial pathophysiological relationship between AD and SLE [10]. In patients with AD, various autoantibodies have been identified [11–13]. Significant associations between AD and SLE have been reported, implying a shared autoimmune mechanism [11].\n\nRecently, there was a case that showed an erythrodermic psoriasis in a patient treated with dupilumab [14]. It is thought that the opposing shift toward Th1 and Th17 cells by the blockade in the Th2 inflammatory cascades causes a psoriasiform eruption. Guimarães et al. suggested that Th1 and Th17 interaction with lowered Th2 activity is essential in SLE [15]. Therefore, we assumed that the immune shift toward Th1 and Th17 by dupilumab resulted in the facial erythema as a form of cutaneous lupus in our patient.\n\nHowever, there is a possibility that the facial erythema is the skin manifestation of drug-induced lupus (DIL) caused by dupilumab. Although DIL to an existing commonly known drug-like procainamide mostly has positive anti-histone antibody, a newly developed drug-like biologic agent often shows negative anti-histone antibody [16]. One of the main ways to diagnose DIL is improvement after discontinuing suspicious agents. Unfortunately, our patient did not want to discontinue the treatment of dupilumab. Therefore, we can’t entirely exclude the possibility of DIL. Further studies on erythema after treatment with dupilumab in patients with SLE will be necessary in the future.\n\nAs treatment with dupilumab has increased, various treatment-related cases are expected to be reported. We believe that our case will help understand one of the causes of facial erythema after dupilumab treatment.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNone.\n\nAuthors’ contributions\nDHJ and JA wrote the manuscript. JIL, JYB, HJJ and MYP discussed case and collection and assembly of data. JA conception, design reviewed and revised the manuscript. All authors read and approved the final manuscript.\n\nFunding\nNone.\n\nAvailability of data and materials\nNot applicable.\n\nEthics approval and consent to participate\nWritten and informed consent was obtained from the patient.\n\nConsent for publication\nInformed consent was obtained from the patient.\n\nCompeting interests\nThe authors have no competing interests.\n==== Refs\nReferences\n1. Eric S Thomas B Emma G Lisa B Andrew B Michael C Two phases 3 trials of dupilumab versus placebo in atopic dermatitis N Engl J Med 2016 375 2335 2348 10.1056/NEJMoa1610020 27690741 \n2. Fleur B Daphne B Inge H Lieneke A Jorien S Marijke D Dupilumab facial redness: positive effect of itraconazole J Am Acad Dermatol Case Rep 2019 5 10 888 891 10.1016/j.jdcr.2019.07.020 \n3. Waldman R DeWane M Sloan B Grant J Characterizing dupilumab facial redness: a multi-institution retrospective medical record review J Am Acad Dermatol 2020 82 1 230 232 10.1016/j.jaad.2019.06.026 31228530 \n4. Dalia Y, Marchese S. Case report: first reported case of facial rash after Dupilumab therapy, Call for abstracts. Practical Dermatology. https://practicaldermatology.com/articles/2018-apr/case-report-first-reported-case-of-facial-rash-after-dupilumab-therapy-call-for-abstracts. Accessed May 3, 2019.\n5. Michelle P Ana O Graciela A Caroline G Joan M Paul F Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus Arthritis Rheum 2012 64 2677 2686 10.1002/art.34473 22553077 \n6. Arnold K Treister A Lio P Dupilumab in the management of topical corticosteroid withdrawal in atopic dermatitis: a retrospective case series J Am Acad Dermatol Case Rep 2018 4 9 860 862 \n7. Suresh R Murase J The role of expanded series patch testing in identifying causality of residual facial dermatitis following initiation of dupilumab therapy J Am Acad Dermatol Case Rep 2018 4 9 899 904 \n8. Stout M Silverberg J Variable impact of dupilumab on patch testing results and allergic contact dermatitis in adults with atopic dermatitis J Am Acad Dermatol 2019 10.1016/j.jaad 30885752 \n9. Rahman A Isenberg D Systemic lupus erythematosus N Engl J Med 2008 358 929 939 10.1056/NEJMra071297 18305268 \n10. Matsui S Kitaba S Itoi S Kijima A Murota H Tani M A case of disseminated DLE complicated by atopic dermatitis and Sjogren’s syndrome: link between hypohidrosis and skin manifestations Mod Rheumatol 2011 21 101 105 10.3109/s10165-010-0352-0 20824298 \n11. Hsiao Y Tsai J Muo C Tsai C Sung F Liao Y Atopic diseases and systemic lupus erythematosus: an epidemiological study of the risks and correlations Int J Environ Res Public Health 2014 11 8112 8122 10.3390/ijerph110808112 25111878 \n12. Halken S Prevention of allergic disease in childhood: clinical and epidemiological aspects of primary and secondary allergy prevention Pediatr Allergy Immunol 2004 15 S9 S32 10.1111/j.1399-3038.2004.0148b.x \n13. David D Munther K Graham H Systemic lupus erythematosus Lancet 2007 369 587 596 10.1016/S0140-6736(07)60279-7 17307106 \n14. Tracey E Elston C Feasel P Piliang M Michael M Vij A Erythrodermic presentation of psoriasis in a patient treated with dupilumab J Am Acad Dermatol Case Rep 2018 4 7 708 710 \n15. Guimarães P Scavuzzi B Stadtlober N Franchi S Lozovoy M Iriyoda T Cytokines in systemic lupus erythematosus: far beyond Th1/Th2 dualism lupus: cytokine profiles Immunol Cell Biol 2017 95 9 824 831 10.1038/icb.2017.53 28649995 \n16. Camilla V Micol G Donatella S Giampiero G Drug-induced lupus erythematosus Arch Dermatol Res 2009 301 99 105 10.1007/s00403-008-0895-5 18797892\n\n",
"fulltext_license": "CC BY",
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"journal": "Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology",
"keywords": "Atopic dermatitis; Dupilumab; Facial erythema; SLE",
"medline_ta": "Allergy Asthma Clin Immunol",
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"title": "Facial erythema after the treatment of dupilumab in SLE patient.",
"title_normalized": "facial erythema after the treatment of dupilumab in sle patient"
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"abstract": "BACKGROUND\nDense deposit disease (DDD) (also known as membranoproliferative glomerulonephritis type II) in childhood is a rare glomerulonephritis with frequent progression to end-stage renal disease (ESRD) and a high recurrence after kidney transplantation. The pathophysiologic basis of DDD is associated with the uncontrolled systemic activation of the alternative pathway (AP) of the complement cascade.\n\n\nMETHODS\nA 14-year-old girl presented with edema and nephrotic range proteinuria. Blood tests showed hypoalbuminemia, nephrotic range proteinuria, normal renal function, and a low C3 level. Renal biopsy confirmed the diagnosis of crescentic DDD. Complement analysis revealed strong AP activation (low C3), positive C3 nephritic factor (C3NeF), and a decreased complement factor H (CFH) levels with CFH polymorphisms. Therapy with eculizumab was considered after the failure of corticosteroid and plasmapheresis to modulate the ongoing massive proteinuria and persistence of low serum C3 levels. There was a marked clinical and biochemical response following the administration of eculizumab.\n\n\nCONCLUSIONS\nOur case emphasizes the efficacy of eculizumab in the management of crescentic DDD in a patient with a normal renal function, in a short follow-up period. Considering previously reported cases, it appears that eculizumab represents a promising new approach which may prevent progression to ESRD in a subset of patients with DDD.",
"affiliations": "Pediatric Nephrology Department, Ondokuz Mayis University Faculty of Medicine, Kurupelit, Samsun, Turkey.",
"authors": "Ozkaya|Ozan|O|;Nalcacioglu|Hulya|H|;Tekcan|Demet|D|;Genc|Gurkan|G|;Meydan|Bilge Can|BC|;Ozdemir|B Handan|BH|;Baysal|M Kemal|MK|;Keceligil|Hasan Tahsin|HT|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D003176:Complement C3; D003178:Complement C3 Nephritic Factor; D017242:Complement Factor H; C481642:eculizumab",
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"mesh_terms": "D000293:Adolescent; D061067:Antibodies, Monoclonal, Humanized; D003176:Complement C3; D003178:Complement C3 Nephritic Factor; D017242:Complement Factor H; D003170:Complement Pathway, Alternative; D005260:Female; D015432:Glomerulonephritis, Membranoproliferative; D006801:Humans; D008060:Lipodystrophy",
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"title": "Eculizumab therapy in a patient with dense-deposit disease associated with partial lipodystropy.",
"title_normalized": "eculizumab therapy in a patient with dense deposit disease associated with partial lipodystropy"
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"abstract": "The opioid epidemic is currently a leading health crisis in the United States, and evidence supports Medication for Opioid Use Disorder (MOUD) as the most effective treatment (2). In our EMS system we are observing an ever increasing number of patients who, due to refusing transport after naloxone rescue, represent an access void at the point of overdose. We present a case series to illustrate a new treatment paradigm utilizing front line EMS paramedic units and high dose buprenorphine to treat withdrawal symptoms with next day bridge to long term care. The three patients described are exemplary cases, meant to represent overall characteristics of the intervention prior to complete data collection. Each patient was revived from opioid overdose with naloxone. Paramedics then treated each patient with 16 mg of buprenorphine to relieve and prevent withdrawal symptoms. Patients were provided with outpatient follow up irrespective of ED transport. To the best of our knowledge, this is the first EMS agency in the United States providing MOUD in the prehospital setting at the point of overdose. This innovative program provides EMS with education and tools to promote patient engagement. While still in its infancy, this approach utilizes existing EMS resources to bring MOUD to the prehospital setting, offering a new avenue to long term care. Keywords: Opioid, buprenorphine, emergency medical services, medication assisted therapy, naloxone, overdose.",
"affiliations": null,
"authors": "Carroll|Gerard G|GG|;Wasserman|Deena D|DD|;Shah|Aman A|AA|;Salzman|Matthew S|MS|;Baston|Kaitlan E|KE|;Rohrbach|Rick A|RA|;Jones|Iris L|IL|;Haroz|Rachel|R|",
"chemical_list": "D009292:Narcotic Antagonists; D009270:Naloxone; D002047:Buprenorphine",
"country": "England",
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"issue": "25(2)",
"journal": "Prehospital emergency care : official journal of the National Association of EMS Physicians and the National Association of State EMS Directors",
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"mesh_terms": "D002047:Buprenorphine; D062787:Drug Overdose; D004632:Emergency Medical Services; D006801:Humans; D009270:Naloxone; D009292:Narcotic Antagonists; D009293:Opioid-Related Disorders; D014481:United States",
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"title": "Buprenorphine Field Initiation of ReScue Treatment by Emergency Medical Services (Bupe FIRST EMS): A Case Series.",
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"abstract": "We present a case where we evaluated the effectiveness of nebulized fentanyl in the treatment of refractive dyspnea in a patient with chronic obstructive pulmonary disease (COPD) with major complications and comorbidities. Nebulized fentanyl was used to successfully decrease the subjective symptoms of refractory dyspnea in this given patient. Nebulized fentanyl appears to be a cost-effective treatment option in patients that experience episodes of severe shortness of breath (SOB).",
"affiliations": "Medical University of South Carolina, 171 Ashley Ave, Charleston, SC, 29425, USA.;Medical University of South Carolina, 171 Ashley Ave, Charleston, SC, 29425, USA.;Medical University of South Carolina, 171 Ashley Ave, Charleston, SC, 29425, USA.",
"authors": "Hildreth|Leah|L|;Pett|Danielle|D|;Higgins|Elizabeth|E|",
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"doi": "10.1016/j.rmcr.2020.101251",
"fulltext": "\n==== Front\nRespir Med Case Rep\nRespir Med Case Rep\nRespiratory Medicine Case Reports\n2213-0071 Elsevier \n\nS2213-0071(20)30465-2\n10.1016/j.rmcr.2020.101251\n101251\nCase Report\nNebulized fentanyl for refractory dyspnea secondary to chronic obstructive pulmonary disease (COPD): A case report\nHildreth Leah hildretl@musc.edu∗ Pett Danielle pettd@musc.edu Higgins Elizabeth higginel@musc.edu Medical University of South Carolina, 171 Ashley Ave, Charleston, SC, 29425, USA\n∗ Corresponding author. hildretl@musc.edu\n12 10 2020 \n2020 \n12 10 2020 \n31 10125129 11 2019 19 8 2020 7 10 2020 © 2020 Published by Elsevier Ltd.2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).We present a case where we evaluated the effectiveness of nebulized fentanyl in the treatment of refractive dyspnea in a patient with chronic obstructive pulmonary disease (COPD) with major complications and comorbidities. Nebulized fentanyl was used to successfully decrease the subjective symptoms of refractory dyspnea in this given patient. Nebulized fentanyl appears to be a cost-effective treatment option in patients that experience episodes of severe shortness of breath (SOB).\n\nKeywords\nCOPDDyspneaNebulized fentanyl\n==== Body\n1 Introduction\nDyspnea is a common and debilitating symptom of cardiopulmonary and neuromuscular diseases [1]. Appropriate diagnosis and treatment of the underlying cause of dyspnea would be ideal but is not always a possibility [1]. Some patients experience idiopathic dyspnea, in which the etiology is unclear. Other patients continue to experience dyspnea even with appropriate treatment regimens; this is deemed “refractory dyspnea” [2]. Dyspnea is a common and debilitating effect of severe COPD, and a significant number of patients eventually fall into the “refractory dyspnea” category [2]. In advanced COPD, up to 94% of patients report that dyspnea significantly impacts their quality of life [3]. While some individuals with COPD may stabilize over time without significant symptoms, COPD is still the 4th leading cause of death worldwide and is often manifested as a progressive pulmonary disease that inevitably leads to palliation. Therefore it is important to be able to provide these patients with alternative treatment options in order to manage their symptoms [4]. In palliative care, innovative methods are often implemented to assist patients living with chronic diseases in reducing or relieving symptoms and ultimately improving quality of life.\n\nIn the terminally ill, systemic opioids are often administered as a treatment modality for dyspnea. Their mechanism of action works by decreasing spontaneous respiratory drive, modulating cortical activity, and diminishing the brainstem chemoreceptors response to hypoxia and hypercapnia [5]. Systemic opioids are associated with a plethora of adverse effects including: sedation, dizziness, nausea, vomiting, constipation, physical dependence, tolerance and respiratory depression [6]. With the pathophysiologic knowledge that the lung contains active peptides (enzymes necessary for activation of opioids) and opioid receptors (μ, κ, and δ), it was presumed that nebulization of opioids would be effective by acting on those local peripheral neural receptors in the small airways of the lungs [2,5,7]. This local activity could reduce the incidence of adverse effects associated with systemic administration [5,7].\n\nFor well over 20 years, morphine has been noted as the main stay of opioid therapy for refractory dyspnea [8]. However, few studies have evaluated other opioid agents for this indication. As of yet, there are no systematic reviews or randomized controlled trials showing a clear benefit of one inhaled opioid compared to another. Although there is limited data in the literature, nebulized fentanyl has been noted to have a positive impact on resolving dyspnea [9]. This case report explores the use of nebulized fentanyl in order to broaden therapy options for those experiencing refractory dyspnea.\n\n2 Materials and methods\nA retrospective electronic medical record chart review was performed in order to assess the symptom improvement after nebulized fentanyl administration in this patient case.\n\n3 Results\nRS is an 86-year-old male with a history of chronic obstructive pulmonary disease (COPD) (FEV1 32%) with major complications and comorbidities of: tracheobronchiomalacia, bronchiectasis, paroxysmal atrial fibrillation, hyperlipidemia, prostate cancer s/p prostatectomy, mild dementia, and gastroesophageal reflux disease who presented with acute on chronic respiratory failure. He was admitted 4 times over the course of a month and 8 times within the past calendar year, all with similar presentations. His typical presentation was tachypneic with a respiration rate in the upper 30's, decreased bilateral breath sounds, accessory muscle usage, and wheezing. His respiratory failure was accompanied by a productive cough with green sputum that was chronic and present for months. Arterial blood gas results (ABG) had shown respiratory alkalosis on multiple previous admissions. On this admission, the ABG was as follows: pH 7.58, partial pressure of carbon dioxide 22 mmHg, partial pressure of oxygen 189 mmHg, bicarbonate 20 mEq/L. Electrolytes tested on admission were as follows: sodium 139 mEq/L, chloride 111 mEq/L, bicarbonate 21 mEq/L, and potassium 4.5 mEq/L. RS had been intubated 3 times in the past for reported COPD exacerbations. On this admission, he was at 100% oxygen saturation on 40% FiO2. There was no evidence of bacterial infection and all respiratory virus panels were negative to date. RS had an extensive workup to assess metabolic, endocrine, infectious, and central causes of hyperventilation but no source of tachypnea was discovered.\n\nAt home, RS was initially managed on home nebulizers of sodium chloride, albuterol, and budesonide/formoterol. However, he continued to present to the ED when the nebulizers failed to relieve SOB symptoms. Between discharges, his therapy began to intensify with the addition of supportive home O2 as needed (PRN) and PO morphine 5 mg q6hrs PRN air hunger. At the most recent discharge, RS was managed on sodium chloride nebulizer solution, morphine 100mg/5 mL concentrated solution (0.3 mL PO Q6HRS PRN), levalbuterol nebulizer solution, and Symbicort. The patient's home tested negative for mold and harmful air quality, and plans to remove carpeting to reduce irritant exposure were in place.\n\nIn order to manage RS's symptoms inpatient, he often required bilevel positive airway pressure (BiPAP), that was weaned down to continuous positive airway pressure (CPAP) (used nocturnally), high flow nasal canula (HFNC), and then to room air. He completed various rounds of chest physiotherapy supplemented with humidified and heated air, fan-to-face, and breathing exercises. RS failed various therapies of bronchodilator treatments, mucolytic treatments, hypertonic saline, and corticosteroid inhalation treatments. Precedex was trialed with no improvement in symptoms; Precedex was then discontinued due to the anticholinergic risk associated with the medication. PRN 5mg IV morphine Q6hrs was used on admission to decrease agitation and assist in decreasing air hunger; however, it showed inconsistent benefit in relieving his SOB. This dose of morphine is within the normal range of morphine used for dyspnea as it may alleviate symptoms while potentially avoiding respiratory depression [10]. A psychiatry consult was conducted due to suspicions for anxiety as a cause of SOB, but it was concluded that RS did not suffer from depression or anxiety. However, there were still suspicions that situational anxiety caused the patient to further decompensate during his tachypnic episodes. Therefore, RS was trialed on a single dose of 0.1 mg oral lorazepam during an episode of dyspnea with improvement in symptoms. He was later started on a daily dose of 0.25 mg of oral clonazepam that was titrated up to the patient's most recent dose of 0.5 mg daily.\n\nPRN intravenous (IV) fentanyl was attempted with a reported adverse event of hallucinations. However, the patient noted that fentanyl provided the biggest improvement in subjective symptoms when compared to albuterol and morphine. A trial of nebulized fentanyl (25 mcg every 3–4 hours while awake PRN) was initiated due to the patient's beneficial response to fentanyl, already owning a nebulizer at home, and the need to manage the acute and sudden onset of symptoms that arose without noted trigger. The nebulizer used was the AeroEclipse ® II Breath Actuated Nebulizer. This nebulizer is reported to deliver medication with a mass median aerodynamic diameter of 2.8 μm (μm) [11]. Prior to nebulized fentanyl administration, RS scored a 10/10 on the Edmonton Assessment Scale; this assessment was either not repeated or not charted after medication administration. RS experienced significant subjective improvement in symptoms when nebulized fentanyl was administered.\n\nAfter several instances of beneficial nebulized fentanyl administration, the patient requested to be sent home with a prescription for nebulized fentanyl in order to manage his symptoms in the outpatient setting and prevent further hospital admissions. RS and his caregiver noted on multiple instances that nebulized fentanyl had the biggest improvement on his symptoms. The caregiver was given education on the preparation and administration of nebulized fentanyl solution for home use. However, the patient presented to the Emergency Department with similar symptoms after his discharge; additional education was given at that time, as there was concern that the concentration administered at home was not accurate. The dose of his outpatient nebulized fentanyl was increased to 50 mcg every 4 hours. After the most recent education, the patient had not re-presented to the ED within 6 months.\n\n4 Discussion\nThis case used a novel therapeutic approach of using nebulized fentanyl for refractory dyspnea in a patient with COPD with multiple comorbidities and complications. This patient continued to have dyspnea despite treatment with levalbuterol, concentrated morphine, and supplemental oxygen. Administration of nebulized fentanyl, an opioid agonist, could possibly decrease the incidence of potential adverse effects such as nausea, vomiting, and constipation associated with systemic opioid administration. As with this patient, and many others with debilitating chronic diseases, medication regimens are often extensive with the risk of each drug exhibiting side effects that further complicate patient care. Avoidance of adverse effects, which are often additive in nature, can be crucial in these patient populations.\n\nEven with the positive effects reported by the patient and his caregiver (wife), it is important to take note of the limitations seen in this case report. By nature, a retrospective chart review is limited to what may be found in a patient's chart. A significant limitation in this chart review is the inability to quantify how RS′ dyspnea changed after medication administration as the Edmonton score was not reported after medication administration. Another limitation in this report is the patient's diagnosis of mild dementia. With this diagnosis, it is unclear how able RS was to accurately compare the perceived benefit from nebulized fentanyl compared to his other treatment modalities. However, the nurses and caregiver noted benefit in his SOB and he did not re-appear to the hospital after being discharged with nebulized fentanyl. These factors increase the reliability of the findings that this patient benefitted from nebulized fentanyl.\n\nMedication cost can play a vital role in selecting drug therapies. The price for the vials of fentanyl is fairly cost effective. The wholesale acquisition price (WAC) for our given institution's outpatient departments is $1.14 for fentanyl citrate 50mcg/mL in 2 mL single use vials. In the case that insurance does not cover the cost of fentanyl vials, a pack of 25 vials would be sold for $44.00. The inpatient WAC price is $0.55 per vial. Nebulized fentanyl is similarly priced to oral morphine, which has been used for air hunger over the past few decades. Concentrated morphine sulfate oral solution 100 mg/5mL costs an average of $0.84 per mL at our given institution. Utilizing this patient's previously failed outpatient regimen of morphine sulfate 100mg/5mL taking 0.3 mL every 6 hours as needed, an estimated monthly cost would be approximately $30.24. Avoiding the astronomical prices that are often associated with novel drug therapies is an added benefit for utilizing nebulized fentanyl. Nebulized fentanyl could be beneficial in a palliative care setting, where patients have refractive dyspnea that has failed other therapies.\n\n5 Conclusions\nIn conclusion, this report evaluated the subjective benefits of administering nebulized fentanyl in a patient with refractory dyspnea from COPD. The patient and his caretaker (wife) in this case reported improvement in his SOB, and therefore increased quality of life. Administration by the nebulized route avoided the systemic adverse effects that are often associated with opioids. The cost effectiveness of nebulized fentanyl is an additional benefit. Further studies are warranted to determine the benefit of nebulized fentanyl in decreasing dyspnea symptoms in palliative patients refractory to established treatment modalities.\n\nFunding\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nDeclaration of competing interest\nThe authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.\n==== Refs\nReferences\n1 Parshall M.B. Schwartzstein R.M. Adams L. An official American Thoracic Society statement: update on the mechanisms, assessment, and management of dyspnea Am. J. Respir. Crit. Care Med. 185 4 2012 435 452 22336677 \n2 Uronis H. Currow D. Abernethy A. Palliative management of refractory dyspnea in COPD Chron Obstruct Pulmon Dis. 1 3 2006 289 304 \n3 Blinderman C. Homel P. Billings J. Symptom distress and quality of life in patients with advanced chronic obstructive pulmonary disease J. Pain Symptom Manag. 38 2009 115 123 \n4 Lozano R. Naghavi M. Foreman K. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010 Lancet 380 9859 2012 2095 2128 23245604 \n5 Afolabi T.M. Nahata M.C. Pai V. Nebulized opioids for the palliation of dyspnea in terminally ill patients Am. J. Health Syst. Pharm. 74 14 2017 1053 1061 28687551 \n6 Benyamin R. Trescot A.M. Datta S. Opioid complications and side effects Pain Physician 11 2 Suppl 2008 S105 S120 18443635 \n7 Krajnik M. Jassem E. Sobanski P. Opioid receptor bronchial tree: current science Curr. Opin. Support. Palliat. Care 8 3 2014 191 199 25010531 \n8 Boyden J.Y. Connor S.R. Otolorin L. Nebulized medications for the treatment of dyspnea: a literature review J. Aerosol Med. Pulm. Drug Deliv. 28 1 2015 1 19 24914770 \n9 Coyne P.J. The use of nebulized fentanyl for the management of dyspnea Clin. J. Oncol. Nurs. 7 3 2003 334 335 12793342 \n10 Soffler M. Rose A. Hayes M.M. Treatment of acute dyspnea with morphine to avert respiratory failure Ann Am Thorac Soc. 14 4 2017 584 588 28362540 \n11 Nagel M.W. Doyle C.C. Bates S.L. Nebulizer Dose Comparison : Aerosol Laboratory Report 2006 Monaghan Medical Corporation ©\n\n",
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"title": "Nebulized fentanyl for refractory dyspnea secondary to chronic obstructive pulmonary disease (COPD): A case report.",
"title_normalized": "nebulized fentanyl for refractory dyspnea secondary to chronic obstructive pulmonary disease copd a case report"
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... |
{
"abstract": "Ibandronate is considered to be a safe drug, and the few reported side-effects in the digestive system are usually related to the upper gastrointestinal tract. Large bowel lesions associated to ibandronate use in humans have not been reported. We describe the case of a 52-year-old female with two episodes of lower abdominal pain after the intake of oral ibandronate. The second pain episode was followed by hematochezia with endoscopic and histological evidence of sigmoid ischemia. No other possible causes of colonic ischemia were found. After a short hospital admission, there was a complete clinical, endoscopic and histological recovery. Ibandronate was withdrawn and the patient reported no further gastrointestinal complaints. This is the first reported case of colon bleeding related to the use of Ibandronate.",
"affiliations": null,
"authors": "Vitor|Sofia|S|;Nunes|Ana|A|;Fonseca|Cristina|C|;Freitas|João|J|",
"chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D000077557:Ibandronic Acid",
"country": "Portugal",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0303-464X",
"issue": "37(4)",
"journal": "Acta reumatologica portuguesa",
"keywords": null,
"medline_ta": "Acta Reumatol Port",
"mesh_terms": "D050071:Bone Density Conservation Agents; D017091:Colitis, Ischemic; D004164:Diphosphonates; D005260:Female; D006801:Humans; D000077557:Ibandronic Acid; D008875:Middle Aged",
"nlm_unique_id": "0431702",
"other_id": null,
"pages": "342-4",
"pmc": null,
"pmid": "24126426",
"pubdate": "2012",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Ibandronate-associated ischemic colitis: case report.",
"title_normalized": "ibandronate associated ischemic colitis case report"
} | [
{
"companynumb": "PT-MYLANLABS-2014M1005542",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OMEPRAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "Primary bone marrow lymphoma is a rare disease and remains undiagnosed due to deceptive clinical presentation. Here, we report four cases of primary bone marrow B-cell non-Hodgkin lymphoma, which presented with cytopenias without any lymphadenopathy or organomegaly. Bone marrow examination revealed large atypical B-cells with a reactive T-cell infiltrate with suppression of the normal hematopoietic elements. This lymphoma is known to have a poor prognosis. Inspite of treatment, two of our patients died during chemotherapy. Two patients relapsed, of which one showed an early relapse after two months and was put on an alternative regimen. The other patient relapsed twice at an interval of 4 and 5 years, respectively, following which he remained in remission for another 5 years and had recently shown a relapse for the third time. Review of literature revealed seven case series and 11 case reports of primary bone marrow lymphoma in the last five decades.",
"affiliations": "Departments of Hematology and Internal Medicine, PGIMER, Chandigarh, India.;Departments of Hematology and Internal Medicine, PGIMER, Chandigarh, India.;Departments of Hematology and Internal Medicine, PGIMER, Chandigarh, India.;Departments of Hematology and Internal Medicine, PGIMER, Chandigarh, India.;Departments of Hematology and Internal Medicine, PGIMER, Chandigarh, India.;Departments of Hematology and Internal Medicine, PGIMER, Chandigarh, India.;Departments of Hematology and Internal Medicine, PGIMER, Chandigarh, India.;Departments of Hematology and Internal Medicine, PGIMER, Chandigarh, India.;Departments of Hematology and Internal Medicine, PGIMER, Chandigarh, India.",
"authors": "Bhagat|Priyanka|P|;Sachdeva|Man Updesh Singh|MU|;Sharma|Prashant|P|;Naseem|Shano|S|;Ahluwalia|Jasmina|J|;Das|Reena|R|;Varma|Neelam|N|;Law|Arjun|A|;Malhotra|Pankaj|P|",
"chemical_list": "D002699:Chlorambucil; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011239:Prednisolone; D011241:Prednisone",
"country": "England",
"delete": false,
"doi": "10.1002/hon.2178",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0278-0232",
"issue": "34(1)",
"journal": "Hematological oncology",
"keywords": "bone marrow biopsy; immunohistochemistry; non-Hodgkin lymphoma; primary bone marrow lymphoma",
"medline_ta": "Hematol Oncol",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001402:B-Lymphocytes; D001706:Biopsy; D001853:Bone Marrow; D001856:Bone Marrow Examination; D019046:Bone Marrow Neoplasms; D002699:Chlorambucil; D003520:Cyclophosphamide; D004317:Doxorubicin; D005260:Female; D006801:Humans; D007194:India; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008875:Middle Aged; D011239:Prednisolone; D011241:Prednisone; D011379:Prognosis; D012008:Recurrence; D000069283:Rituximab; D062606:Tertiary Care Centers; D016896:Treatment Outcome; D014750:Vincristine",
"nlm_unique_id": "8307268",
"other_id": null,
"pages": "42-8",
"pmc": null,
"pmid": "25407700",
"pubdate": "2016-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Primary bone marrow lymphoma is a rare neoplasm with poor outcome: case series from single tertiary care centre and review of literature.",
"title_normalized": "primary bone marrow lymphoma is a rare neoplasm with poor outcome case series from single tertiary care centre and review of literature"
} | [
{
"companynumb": "IN-JNJFOC-20160406883",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "Granuloma annulare (GA) is a benign, granulomatous cutaneous disease without clear etiology. Disseminated and drug induced granuloma annulare is a rare presentation. We present a 47-year-old woman with diffuse circular erythematous eruptions following treatment with levetiracetam. Her clinical and histopathological findings were compatible with the diagnosis of granuloma annulare. To the best of our knowledge, there is no previous report of this skin disease as a result of levetiracetam use. We report this case to highlight this antiepileptic drug as a possible etiologic agent in disseminated granuloma annulare.",
"affiliations": "a Dermatology, Abant Izzet Baysal University Medical Faculty , Bolu , Turkey.;a Dermatology, Abant Izzet Baysal University Medical Faculty , Bolu , Turkey.;b Pathology, Abant Izzet Baysal Universitesi , Bolu , Turkey , and.;c Neurology, Abant Izzet Baysal Universitesi , Bolu , Turkey.",
"authors": "Sereflican|Betul|B|;Karapinar|Tekden|T|;Duzcu|Selma Erdogan|SE|;Turkoglu|Şule Aydin|ŞA|",
"chemical_list": "D000927:Anticonvulsants; D000077287:Levetiracetam; D010889:Piracetam",
"country": "England",
"delete": false,
"doi": "10.1080/15569527.2016.1269336",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-9527",
"issue": "36(3)",
"journal": "Cutaneous and ocular toxicology",
"keywords": "Disseminated; drug; eruptive; granuloma annulare; levetiracetam",
"medline_ta": "Cutan Ocul Toxicol",
"mesh_terms": "D000927:Anticonvulsants; D005260:Female; D016460:Granuloma Annulare; D006801:Humans; D000077287:Levetiracetam; D008875:Middle Aged; D010889:Piracetam; D012867:Skin",
"nlm_unique_id": "101266892",
"other_id": null,
"pages": "300-301",
"pmc": null,
"pmid": "28095713",
"pubdate": "2017-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Disseminated eruptive granuloma annulare induced by levetiracetam.",
"title_normalized": "disseminated eruptive granuloma annulare induced by levetiracetam"
} | [
{
"companynumb": "TR-CIPLA LTD.-2017TR01411",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": "3",
... |
{
"abstract": "The aim of this study was to evaluate quality of life (QOL) and adherence to the therapy in patients with chronic myeloid leukemia in chronic phase treated with nilotinib as second-line therapy.\n\n\n\nA multicenter, prospective, observational trial with 6 time points was conducted; 177 patients were recruited in 23 centers in Poland who were treated with nilotinib as second-line therapy because of the ineffectiveness or intolerance of their previous therapy. QOL was evaluated with the standard European Organization for Research and Treatment of Cancer Core Quality of Life questionnaire. Adherence to the therapy was assessed using the 4-item Morisky Medication Adherence Scale by patients and their physicians.\n\n\n\nThe average QOL in patients who completed the study was significantly higher during the last visit (69.4 ± 17.4) than at the start of the study (59.1 ± 18.8; P < .001). At their first visit, 120 (83.2%) patients assessed themselves as highly compliant and 135 (93.4%) at the fifth visit. Low-compliance patients represented 3 (1.7% of the total) during visit 1; none of the patients self-assessed as low compliance since the fourth visit. At the first visit 151 (85.3%) patients were categorized by their physicians as highly compliant and 138 (96.0%) during the last 3 visits. Patients' and their physicians' assessments were significantly correlated.\n\n\n\nThe QOL among patients receiving nilotinib administered as second-line therapy was very good and adherence to the treatment was high. The efficacy and safety of the drug were confirmed in the real-life setting.",
"affiliations": "Department of Hematology, Jagiellonian University Hospital, Kraków, Poland. Electronic address: sachatom@gmail.com.;Institute of Hematology and Transfusion Medicine, Warszawa, Poland.;Novartis Poland, Warszawa, Poland.;Department of Hematology and Bone Marrow Transplantation, Silesian Medical University, Katowice, Poland.;Department of Hematology, Malignant Blood Diseases and Bone Marrow Transplantation, Wroclaw Medical University, Wrocław, Poland.;Department of Hematology, Pomeranian Medical University in Szczecin, Szczecin, Poland.;Department of Hematology and Bone Marrow Transplantation, Silesian Medical University, Katowice, Poland.;Novartis Poland, Warszawa, Poland.;Department of Hematology, Jagiellonian University Hospital, Kraków, Poland.;Department of Hematology and Transplantology, Gdansk Medical University, Gdańsk, Poland.",
"authors": "Sacha|Tomasz|T|;Góra-Tybor|Joanna|J|;Wąsak-Szulkowska|Ewa|E|;Kyrcz-Krzemień|Sławomira|S|;Mędraś|Ewa|E|;Becht|Rafał|R|;Bober|Grażyna|G|;Kotowska|Aneta|A|;Wącław|Joanna|J|;Hellmann|Andrzej|A|",
"chemical_list": "C498826:4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide; D000970:Antineoplastic Agents; D011743:Pyrimidines",
"country": "United States",
"delete": false,
"doi": "10.1016/j.clml.2017.01.001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2152-2669",
"issue": "17(5)",
"journal": "Clinical lymphoma, myeloma & leukemia",
"keywords": "CML; Drug compliance; Second generation tyrosine kinase inhibitor treatment; Therapy outcome on doctor's perspective; Therapy outcome on patient's perspective",
"medline_ta": "Clin Lymphoma Myeloma Leuk",
"mesh_terms": "D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D005260:Female; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008297:Male; D055118:Medication Adherence; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D011446:Prospective Studies; D011743:Pyrimidines; D011788:Quality of Life; D016879:Salvage Therapy; D011795:Surveys and Questionnaires",
"nlm_unique_id": "101525386",
"other_id": null,
"pages": "283-295",
"pmc": null,
"pmid": "28185798",
"pubdate": "2017-05",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study",
"references": null,
"title": "Quality of Life and Adherence to Therapy in Patients With Chronic Myeloid Leukemia Treated With Nilotinib as a Second-Line Therapy: A Multicenter Prospective Observational Study.",
"title_normalized": "quality of life and adherence to therapy in patients with chronic myeloid leukemia treated with nilotinib as a second line therapy a multicenter prospective observational study"
} | [
{
"companynumb": "PHHY2017PL076109",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NILOTINIB"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "Sorafenib followed by fractionated radiotherapy (RT) has been shown to decrease the phagocytic and candidacidal activities of antifungal agents due to radiosensitization. Moreover, sorafenib has been shown to suppress the immune system, thereby increasing the risk for candida colonization and infection. In this study, we present the 2 hepatocellular carcinoma (HCC) patients suffered from epigastric distress caused by esophageal candidiasis who received sorafenib plus RT. Two patients who had received sorafenib and RT for HCC with bone metastasis presented with hiccups, gastric ulcer, epigastric distress, anorexia, heart burn, and fatigue. Empiric antiemetic agents, antacids, and pain killers were ineffective at relieving symptoms. Panendoscopy revealed diffuse white lesions in the esophagus. Candida esophagitis was suspected. Results of periodic acid-Schiff staining were diagnostic of candidiasis. Oral fluconazole (150 mg) twice daily and proton-pump inhibitors were prescribed. At 2-weak follow-up, esophagitis had resolved and both patients were free of gastrointestinal symptoms. Physicians should be aware that sorafenib combined with RT may induce an immunosuppressive state in patients with HCC, thereby increasing their risk of developing esophagitis due to candida species.",
"affiliations": "From the Department of Surgery (K-HC), Department of Internal Medicine (M-TW), Department of Anatomical Pathology (Y-HC), Division of Radiation Oncology, Department of Radiology, Far Eastern Memorial Hospital, New Taipei City (Y-FL, C-HH), Department of Electrical Engineering (K-HC), Department of Chemical Engineering & Materials Science, Yuan-Ze University, Taoyuan (M-TW), Department of Medicine (C-HH), and Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan (C-HH).",
"authors": "Chen|Kuo-Hsin|KH|;Weng|Meng-Tzu|MT|;Chou|Yueh-Hung|YH|;Lu|Yueh-Feng|YF|;Hsieh|Chen-Hsi|CH|",
"chemical_list": "D000935:Antifungal Agents; D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D054328:Proton Pump Inhibitors; D009536:Niacinamide; D015725:Fluconazole; D000077157:Sorafenib",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000003133",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 2698616810.1097/MD.0000000000003133031334500Research ArticleClinical Case ReportEpigastric Distress Caused by Esophageal Candidiasis in 2 Patients Who Received Sorafenib Plus Radiotherapy for Hepatocellular Carcinoma: Case Report Chen Kuo-Hsin MDWeng Meng-Tzu MDChou Yueh-Hung MDLu Yueh-Feng MDHsieh Chen-Hsi MD, PhDBabic. Zarko From the Department of Surgery (K-HC), Department of Internal Medicine (M-TW), Department of Anatomical Pathology (Y-HC), Division of Radiation Oncology, Department of Radiology, Far Eastern Memorial Hospital, New Taipei City (Y-FL, C-HH), Department of Electrical Engineering (K-HC), Department of Chemical Engineering & Materials Science, Yuan-Ze University, Taoyuan (M-TW), Department of Medicine (C-HH), and Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan (C-HH).Correspondence: Chen-Hsi Hsieh, Division of Radiation Oncology, Department of Radiology, Far Eastern Memorial Hospital, 21 Sec 2, Nanya S Road, Banciao District, New Taipei City 220, Taiwan (e-mail: chenciab@gmail.com).3 2016 18 3 2016 95 11 e313317 12 2015 18 2 2016 20 2 2016 Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.2016This is an open access article distributed under the Creative Commons Attribution License 4.0, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nSorafenib followed by fractionated radiotherapy (RT) has been shown to decrease the phagocytic and candidacidal activities of antifungal agents due to radiosensitization. Moreover, sorafenib has been shown to suppress the immune system, thereby increasing the risk for candida colonization and infection. In this study, we present the 2 hepatocellular carcinoma (HCC) patients suffered from epigastric distress caused by esophageal candidiasis who received sorafenib plus RT.\n\nTwo patients who had received sorafenib and RT for HCC with bone metastasis presented with hiccups, gastric ulcer, epigastric distress, anorexia, heart burn, and fatigue. Empiric antiemetic agents, antacids, and pain killers were ineffective at relieving symptoms. Panendoscopy revealed diffuse white lesions in the esophagus. Candida esophagitis was suspected. Results of periodic acid-Schiff staining were diagnostic of candidiasis. Oral fluconazole (150 mg) twice daily and proton-pump inhibitors were prescribed. At 2-weak follow-up, esophagitis had resolved and both patients were free of gastrointestinal symptoms.\n\nPhysicians should be aware that sorafenib combined with RT may induce an immunosuppressive state in patients with HCC, thereby increasing their risk of developing esophagitis due to candida species.\n\nOPEN-ACCESSTRUE\n==== Body\nINTRODUCTION\nCandida species are part of the normal gastrointestinal (GI) flora in humans; however, patients with impaired immunity, those with chronic diseases such as cancer and diabetes mellitus (DM), patients with a history of recurrent antibiotic usage, and those receiving chemotherapy and/or radiotherapy (RT) are at increased risk of developing candida esophagitis.1–4\n\nSorafenib is a kinase inhibitor commonly used as treatment for advanced renal cell carcinoma and hepatocellular carcinoma (HCC). The drug inhibits intracellular raf kinases (CRAF and BRAF) as well as cell surface kinase receptors such as Fms-like tyrosine kinase receptor 3 (Flt-3), c-kit, Ret, vascular endothelial growth factor (VEGF)-2, VEGFR-3, and platelet-derived growth factor receptor beta (PDGFR-beta).5,6 One of the most common adverse effects of sorafenib is upper and lower GI distress which manifests as reflux or dyspepsia and epigastric pain, causing appetite loss, weight loss, and fatigue.7,8\n\nSorafenib suppresses CD 4+ T-cell activation and induces T-cell cycle arrest9 and has been demonstrated to significantly enhance the sensitivity of human HCC cell lines to irradiation.10,11 A growing body of evidence shows that irradiation has direct DNA damage-dependent effects, sending signals to distant normal tissues via a process known as the abscopal effect.12,13 In addition, fractionated irradiation has been shown to suppress interferon-gamma (IFN-γ)14 and decrease the percentage of dendritic cells (DCs) and macrophages in vivo.15 Moreover, radiation therapy can modulate the pharmacokinetics of anticancer drugs.16 These lines of evidence support the possibility that sorafenib and RT can synergistically induce an immunosuppressive state, thereby increasing the risk for infection due to candida species.\n\nThe symptoms of candida esophagitis mimic those of GI upset in patients taking sorafenib, which can lead to misdiagnosis and inadequate treatment. Herein, we present 2 patients with HCC who received sorafenib concurrently with RT as well as after completion of RT. Both patients developed candida esophagitis, the symptoms of which were initially misdiagnosed as symptoms characteristic of sorafenib-induced GI distress.\n\nCASE REPORT\nCase 1\nA 71-year-old man with a history of chronic hepatitis C virus infection, DM, hypertension and benign prostate hypertrophy presented with a tender mass in the right subcostal area in June 2015. Results of needle biopsy were diagnostic of metastatic HCC. Laparoscopic right hepatectomy was performed in August, 2015 and histopathologic examination of resected specimens revealed HCC. Positron emission tomography–computed tomography (PET-CT) scan showed multiple bone metastases. A total radiation dose of 45 Gy was delivered in 15 fractions to the mass located near lumbar spine (L spine) 4 to 5 and a total dose of 39 Gy was delivered in 13 fractions to the right 7th rib. The radiation course began on September 9 and was completed on October 16, 2015. Sorafenib (200 mg) 400 mg twice daily was prescribed beginning on September 7, 2015. Approximately 1 week after beginning sorafenib, the patient began to complain of hiccups, epigastric distress, anorexia, heart burn, and fatigue. Empiric antiemetic agents, antacids, and pain killers were prescribed but the symptoms persisted. Panendoscopy revealed diffuse white lesions in the esophagus (Figure 1). A diagnosis of candida esophagitis, grade IV, was made according to Kodsi classification.17 Periodic acid-Schiff (PAS) staining was indicative of candidiasis involving the squamous epithelium of the esophageal mucosa (Figure 2). Fluconazole (150 mg) 300 mg per os (p.o.) quaque die (qd) in 1 week was prescribed. At 2-week follow-up, panendoscopy demonstrated regression of candida esophagitis (Figure 3). Physical examination at the same follow-up visit revealed complete resolution of hiccups and epigastric distress as well as significant weight gain.\n\nFIGURE 1 Esophagogastroduodenoscopy revealed diffuse white lesions in the esophagus characteristic of grade IV candida esophagitis according to Kodsi classification.\n\nFIGURE 2 Periodic acid-Schiff (PAS) staining is indicative of candidiasis involving the squamous epithelium of the esophageal mucosa (PAS stain, magnification ×200).\n\nFIGURE 3 Esophagogastroduodenoscopy at 2-week follow-up shows complete resolution of candida esophagitis.\n\nCase 2\nAn 80-year-old man with goiter and benign prostatic hyperplasia underwent laparoscopic segmentectomy for segment 5 of liver in October 2014 and cholecystectomy on November 11, 2014. Alpha-fetoprotein (AFP) level decreased from 265.2 ng/ml before surgery to 3.52 ng/ml after surgery; however, at follow-up in April 2015 the AFP level was 1260 ng/ml. PET-CT scan in May 2015 revealed multiple bone metastases, including metastasis to the right scapula, the left 7th rib, the 10th thoracic (T) spine, and the 1st lumbar (L) spine but no local recurrence. Sorafenib (200 mg) 400 mg twice a day was prescribed in addition to local radiation therapy comprising a total dose of 30 Gy in 10 fractions delivered to T12 to L2 in May 2015. Grade II hand-foot syndrome was noted during the course of sorafenib and RT. In August 2015, the patient presented with persistent bone pain and an AFP level of 31,526 ng/ml. A total dose of 30 Gy in 10 fractions was delivered to T10-L1 and a total dose of 39 Gy in 13 fractions was delivered to lesions in the right scapula and left 7th rib concurrent with sorafenib (200 mg) 400 mg per day beginning in September 2015. Epigastric pain, hiccups, anorexia, and tarry stool were noted during the periods of treatment. Empiric agents were administered but the patient still complained of retrosternal pain on swallowing and persistent hiccups. Panendoscopy revealed plaques in the upper and mid esophagus indicative of candida esophagitis as well as esophageal and gastric ulcers. An 1-week regimen of fluconazole (150 mg) 300 mg p.o. qd for candidiasis and Takepron, 30 mg p.o. qd for the esophageal and gastric ulcers was administered. Physical examination at 2-week follow-up revealed complete resolution of hiccups and epigastric distress as well as significant weight gain.\n\nThe need for informed consent was waived by the Institutional Review Board of the Far Eastern Memorial Hospital (FEMH-IRB-104172-C) and retrospective data were collected after receiving approval from the Institutional Review Board of the Far Eastern Memorial Hospital (FEMH-IRB-104172-C).\n\nDISCUSSION\nThe Sorafenib HCC Assessment Randomized Protocol (SHARP) and the Asian Pacific Trial demonstrated that sorafenib (Nexavar, Bayer Pharma AG, Berlin, Germany) was associated with significantly better survival of patients with HCC than placebo.7,8 RT combined with sorafenib results in marked tumor shrinkage but has been shown to be associated with systemic skin reactions.18,19 The results of a phase II trial showed that radiation therapy plus sorafenib results in a partial response rate of 55% in patients with unresectable HCC.20\n\nGrade 2 and 3 diarrhea was reported in 25% of patients who received radiation therapy concurrently with sorafenib and in 5.6% of patients who received radiation therapy after sorafenib. Moreover, grade 2/3 gastric or duodenal ulcer was reported in 8.4% of patients who received sequential use of sorafenib.20 However, the incidence of diarrhea of grade 3/4 ranged from 6% to 8% and the grade 3/4 of anorexia and nausea was 0% to 2% in patients treated with sorefenib only.7,8 These data suggest the percentage of GI adverse effects were higher in multiple modalities.\n\nThe classic symptoms of infectious esophagitis include dysphagia, odynophagia, and retrosternal pain on swallowing.4 It can cause candida esophagitis when patients with impaired immunity, with chronic disease or under medications, such as gastric acid suppression therapy, malignancy, human immunodeficiency virus disease, illnesses characterized by immunodeficiency, DM, corticosteroid therapy, recurrent antibiotic use, prescribed chemotherapy and/or RT, proton pump inhibitors, H2-receptor antagonists, and prior vagotomy produce hypochlorhydria, which alters the colonization of the stomach by oral cavity bacteria and yeast and is thought to increase the risk of infectious esophagitis.1–4,21,22 The prevalence of esophageal candidiasis is 0.8% to 1.2%.4,23 In the current report, both patients under concurrent RT and sorafenib suffered from hiccups, epigastric distress, anorexia, heart burn, or retrosternal pain on swallowing and fatigue that were similar those of GI upset caused by sorafenib. Furthermore, we reviewed the records for 44 patients under such schedule in our institute retrospectively, 3/44 (6.8%, including 2 patients reported here) had epigastric distress or anorexia with panendoscopy-proved esophageal candidiasis.\n\nZhao et al9 found that sorafenib suppressed CD 4+ T-cell activation, proliferation, and cytokine production and induced T-cell cycle arrest and apoptosis in a dose-dependent manner. Hipp et al24 observed that sorafenib inhibited DCs antigen presentation, DC migration and their capability to stimulate primary T-cell responses by reducing the secretion of cytokines and the expression of major histocompatibility complex and CD1a molecules. These inhibitory effects were found to be mediated by the inhibition of phosphatidylinositol 3-kinase (PI3K), mitogen-activated protein kinase (MAPK), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling. These findings provide evidence that sorafenib suppresses the immune system and therefore increases the risk for infections due to candida species.\n\nOpsonized candida species are ingested by both monocytes and monocyte-derived macrophages, but uptake of unopsonized candida is mediated only by monocyte-derived macrophages.25,26 Additionally, IFN-γ is one of the major factors that augment the phagocytic and candidacidal activities of human macrophages.27 Recently, Tsai et al16 reported that local irradiation, no matter daily dose or off-target dose, modulates the area under the concentration versus time curve of anticancer drugs in plasma. Furthermore, a growing body of evidence shows that irradiation has direct DNA damage-dependent effects, sending signals to distant normal tissues via a process known as the abscopal effect. The effect leads to overall genomic instability and radiation susceptibility in surrounding and distant normal tissues.12,13 Interestingly, fractionated irradiation has been shown in an animal model to suppress helper T1 (Th1) cytokine profiles, namely IFN-γ and the IFN-γ-inducible 10 kDa protein (IP-10).14 Song et al15 also found that the percentages of DCs and macrophages were also lower after fractionated irradiation in an animal model. After patients recovered from the episode and in the sequential maintaining course with sorafenib only, there was no recurrent esophageal candidiasis. Putting these published observations together, it is apparent that irradiation could modulate the concentration of anticancer drugs with abscopal effects that hint the effects of sorafenib may be modulated when concurrent with RT and it may cause the response of nonirradiation area similar with the irradiation area.\n\nSorafenib was shown to significantly enhance the sensitivity of the human HCC cell line SMMC-7721 to radiation in a schedule-dependent manner.10,11 Moreover, there is evidence that irradiation can induce the compensatory activation of multiple intracellular signaling pathway mediators, such as PI3K, MAPK, VEGF, c-jun N-terminal kinase (JNK), and NF-κB.28 The sorafenib-mediated blockade of the Raf/MAPK and VEGFR pathways therefore may enhance the efficacy of radiation.29 The evidence suggests that sorafenib with fractionated irradiation or sorafenib followed RT delivered sequentially provide better results but may enhance the adverse effects associated with each treatment modality, thereby decreasing the phagocytic and candidacidal activities of antifungal drugs due to radiosensitization.\n\nEsophagogastroduodenoscopy with brushings or biopsy is currently the most sensitive and specific method for diagnosing candida esophagitis. The infection is characterized by the presence of patchy, whitish plaques covering a friable, erythematous mucosa.23,30 For immunosuppressed patients with candida esophagitis, the recommended drug is oral fluconazole with a loading dose of 400 mg followed by 200 to 400 mg once daily for 2 to 3 weeks without local antifungal therapy.1,31 In our patients, the epigastric and chest distress was improved after prescribed oral fluconazole accordingly.\n\nCONCLUSION\nTo the best of our knowledge this is the first report to show that treatment with sorafenib concurrent with RT or following RT can result in candida esophagitis. Physicians should be aware that sorafenib and RT can synergistically induce an immunosuppressive state in patients with HCC, thereby increasing their risk for esophagitis due to candida species.\n\nAbbreviations: DCs = dendritic cells, DM = diabetes mellitus, Flt-3 = Fms-like tyrosine kinase receptor 3, GI = gastrointestinal, HCC = hepatocellular carcinoma, IFN-γ = interferon-gamma, L spine = lumbar spine, MAPK = mitogen-activated protein kinase, NF-κB = nuclear factor kappa-light-chain-enhancer of activated B cells, p.o. = per os, PAS = periodic acid-Schiff, PDGFR-beta = platelet-derived growth factor receptor beta, PET-CT = positron emission tomography–computed tomography, PI3K = phosphatidylinositol 3-kinase, qd = quaque die, RT = radiotherapy, SHARP = Sorafenib HCC Assessment Randomized Protocol, T spine = thoracic spine, VEGF = vascular endothelial growth factor\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nREFERENCES\n1. Rosolowski M Kierzkiewicz M \nEtiology, diagnosis and treatment of infectious esophagitis . Prz Gastroenterol \n2013 ; 8 :333 –337 .24868280 \n2. Kim KY Jang JY Kim JW \nAcid suppression therapy as a risk factor for Candida esophagitis . Dig Dis Sci \n2013 ; 58 :1282 –1286 .23306845 \n3. Chocarro Martinez A Galindo Tobal F Ruiz-Irastorza G \nRisk factors for esophageal candidiasis . Eur J Clin Microbiol Infect Dis \n2000 ; 19 :96 –100 .10746494 \n4. Underwood JA Williams JW Keate RF \nClinical findings and risk factors for Candida esophagitis in outpatients . Dis Esophagus \n2003 ; 16 :66 –69 .12823199 \n5. Hilger RA Scheulen ME Strumberg D \nThe Ras-Raf-MEK-ERK pathway in the treatment of cancer . Onkologie \n2002 ; 25 :511 –518 .12566895 \n6. Wilhelm S Chien DS \nBAY 43-9006: preclinical data . Curr Pharm Des \n2002 ; 8 :2255 –2257 .12369853 \n7. Llovet JM Ricci S Mazzaferro V \nSorafenib in advanced hepatocellular carcinoma . N Engl J Med \n2008 ; 359 :378 –390 .18650514 \n8. Cheng AL Kang YK Chen Z \nEfficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial . Lancet Oncol \n2009 ; 10 :25 –34 .19095497 \n9. Zhao W Gu YH Song R \nSorafenib inhibits activation of human peripheral blood T cells by targeting LCK phosphorylation . Leukemia \n2008 ; 22 :1226 –1233 .18337760 \n10. Dai XF Ding J Zhang RG \nRadiosensitivity enhancement of human hepatocellular carcinoma cell line SMMC-7721 by sorafenib through the MEK/ERK signal pathway . Int J Radiat Biol \n2013 ; 89 :724 –731 .23682582 \n11. Li Q Hu Y Xi M \nSorafenib modulates the radio sensitivity of hepatocellular carcinoma cells in vitro in a schedule-dependent manner . BMC Cancer \n2012 ; 12 :485 .23088517 \n12. Mole RH \nWhole body irradiation; radiobiology or medicine? \nBr J Radiol \n1953 ; 26 :234 –241 .13042090 \n13. Siva S MacManus MP Martin RF \nAbscopal effects of radiation therapy: a clinical review for the radiobiologist . Cancer Lett \n2015 ; 356 :82 –90 .24125863 \n14. Gremy O Benderitter M Linard C \nAcute and persisting Th2-like immune response after fractionated colorectal gamma-irradiation . World J Gastroenterol \n2008 ; 14 :7075 –7085 .19084914 \n15. Song KH Kim MH Kang SM \nAnalysis of immune cell populations and cytokine profiles in murine splenocytes exposed to whole-body low-dose irradiation . Int J Radiat Biol \n2015 ; 91 :795 –803 .26136089 \n16. Tsai TH Chen YJ Hou ML \nPelvic irradiation modulates the pharmacokinetics of cisplatin in the plasma and lymphatic system . Am J Transl Res \n2015 ; 7 :375 –384 .25901204 \n17. Kodsi BE Wickremesinghe C Kozinn PJ \nCandida esophagitis: a prospective study of 27 cases . Gastroenterology \n1976 ; 71 :715 –719 .964563 \n18. Hsieh CH Jeng KS Lin CC \nCombination of sorafenib and intensity modulated radiotherapy for unresectable hepatocellular carcinoma . Clin Drug Investig \n2009 ; 29 :65 –71 .\n19. Hsieh CH Lin SC Shueng PW \nRecall radiation dermatitis by sorafenib following stereotactic body radiation therapy . Onco Targets Ther \n2014 ; 7 :1111 –1114 .24971021 \n20. Chen SW Lin LC Kuo YC \nPhase 2 study of combined sorafenib and radiation therapy in patients with advanced hepatocellular carcinoma . Int J Radiat Oncol Biol Phys \n2014 ; 88 :1041 –1047 .24661657 \n21. Karmeli Y Stalnikowitz R Eliakim R \nConventional dose of omeprazole alters gastric flora . Dig Dis Sci \n1995 ; 40 :2070 –2073 .7555466 \n22. Brooks JR Smith HF Pease FB Jr \nBacteriology of the stomach immediately following vagotomy: the growth of Candida albicans . Ann Surg \n1974 ; 179 :859 –862 .4599845 \n23. Naito Y Yoshikawa T Oyamada H \nEsophageal candidiasis . Gastroenterol Jpn \n1988 ; 23 :363 –370 .3181663 \n24. Hipp MM Hilf N Walter S \nSorafenib, but not sunitinib, affects function of dendritic cells and induction of primary immune responses . Blood \n2008 ; 111 :5610 –5620 .18310500 \n25. Marodi L Johnston RB Jr \nEnhancement of macrophage candidacidal activity by interferon-gamma . Immunodeficiency \n1993 ; 4 :181 –185 .8167696 \n26. Marodi L Kaposzta R Campbell DE \nCandidacidal mechanisms in the human neonate. Impaired IFN-gamma activation of macrophages in newborn infants . J Immunol \n1994 ; 153 :5643 –5649 .7989763 \n27. Nathan CF Murray HW Wiebe ME \nIdentification of interferon-gamma as the lymphokine that activates human macrophage oxidative metabolism and antimicrobial activity . J Exp Med \n1983 ; 158 :670 –689 .6411853 \n28. Cheng JC Chou CH Kuo ML \nRadiation-enhanced hepatocellular carcinoma cell invasion with MMP-9 expression through PI3K/Akt/NF-kappaB signal transduction pathway . Oncogene \n2006 ; 25 :7009 –7018 .16732316 \n29. Zhao JD Liu J Ren ZG \nMaintenance of Sorafenib following combined therapy of three-dimensional conformal radiation therapy/intensity-modulated radiation therapy and transcatheter arterial chemoembolization in patients with locally advanced hepatocellular carcinoma: a phase I/II study . Radiat Oncol \n2010 ; 5 :12 .20149262 \n30. Baehr PH McDonald GB \nEsophageal infections: risk factors, presentation, diagnosis, and treatment . Gastroenterology \n1994 ; 106 :509 –532 .7980741 \n31. Darouiche RO \nOropharyngeal and esophageal candidiasis in immunocompromised patients: treatment issues . Clin Infect Dis \n1998 ; 26 :259 –272 .quiz 254–273 .9502438\n\n",
"fulltext_license": "CC BY",
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"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000935:Antifungal Agents; D000970:Antineoplastic Agents; D002177:Candidiasis; D006528:Carcinoma, Hepatocellular; D019583:Dose Fractionation, Radiation; D004941:Esophagitis; D015725:Fluconazole; D006356:Heartburn; D006606:Hiccup; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D009536:Niacinamide; D010671:Phenylurea Compounds; D054328:Proton Pump Inhibitors; D000077157:Sorafenib; D013276:Stomach Ulcer",
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"pubdate": "2016-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Epigastric Distress Caused by Esophageal Candidiasis in 2 Patients Who Received Sorafenib Plus Radiotherapy for Hepatocellular Carcinoma: Case Report.",
"title_normalized": "epigastric distress caused by esophageal candidiasis in 2 patients who received sorafenib plus radiotherapy for hepatocellular carcinoma case report"
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"abstract": "Kounis syndrome represents the concurrence of acute coronary syndromes or anginal pain with allergic, hypersensitivity, and anaphylactoid reactions that are increasingly found in clinical practice. We present a case of a young woman who experienced attacks of dyspnea, hypoxemia, and hypotension during and after spinal anesthesia. Based on the pattern of clinical symptoms and laboratory findings, she was retrospectively diagnosed with Kounis syndrome, even though no apparent trigger of hypersensitivity was found.",
"affiliations": "From the Department of Anesthesia, Instituto Guatemalteco de Seguridad Social, Guatemala City, Guatemala.",
"authors": "Mendoza Vásquez|Luis Eduardo|LE|",
"chemical_list": "D004837:Epinephrine",
"country": "United States",
"delete": false,
"doi": "10.1213/XAA.0000000000000768",
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"issn_linking": "2575-3126",
"issue": "11(6)",
"journal": "A&A practice",
"keywords": null,
"medline_ta": "A A Pract",
"mesh_terms": "D000328:Adult; D000775:Anesthesia, Spinal; D004837:Epinephrine; D017809:Fatal Outcome; D005260:Female; D050723:Fractures, Bone; D006801:Humans; D000074962:Kounis Syndrome; D008682:Metatarsal Bones",
"nlm_unique_id": "101714112",
"other_id": null,
"pages": "155-157",
"pmc": null,
"pmid": "29621013",
"pubdate": "2018-09-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Allergic Acute Coronary Syndrome (Kounis Syndrome) in a Young Woman During Spinal Anesthesia: A Case Report.",
"title_normalized": "allergic acute coronary syndrome kounis syndrome in a young woman during spinal anesthesia a case report"
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"companynumb": "GT-ELEFSEE PHARMACEUTICALS INTERNATIONAL-GT-2019WTD000007",
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"abstract": "A 59-year-old woman who had been diagnosed with cirrhotic primary biliary cholangitis (PBC) 5 years earlier was admitted for severe jaundice (total bilirubin: 30.1 mg/dL). We suspected that her cirrhotic PBC had deteriorated acutely for some reason. Her general condition deteriorated quickly, and she passed away on day 18 of admission. Hepatitis E virus (HEV)-IgA antibodies were positive, and Genotype 3b HEV involvement was confirmed from a blood sample taken on admission. Histopathological findings revealed cirrhosis and submassive loss and necrosis of hepatocytes. Clinicians should consider the possibility of acute HEV infection as a trigger for acute PBC exacerbation.",
"affiliations": "Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Japan.;Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Japan.;Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Japan.;Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Japan.;Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Japan.;Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Japan.;Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Japan.;Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Japan.;Department of Pathology, Shinshu University School of Medicine, Japan.;Department of Pathology, Shinshu University School of Medicine, Japan.;Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Japan.;Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Japan.;Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Japan.",
"authors": "Koyama|Mizuki|M|;Yamazaki|Tomoo|T|;Joshita|Satoru|S|;Ito|Akihiro|A|;Ono|Kazuyuki|K|;Watanabe|Takayuki|T|;Yamashita|Yuki|Y|;Sugiura|Ayumi|A|;Kobayashi|Mikiko|M|;Sato|Yoshinori|Y|;Takahashi|Masaharu|M|;Okamoto|Hiroaki|H|;Umemura|Takeji|T|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.6337-20",
"fulltext": "\n==== Front\nIntern Med\nIntern Med\nInternal Medicine\n0918-2918\n1349-7235\nThe Japanese Society of Internal Medicine\n\n33518570\n10.2169/internalmedicine.6337-20\nCase Report\nAn Autopsy Case of Primary Biliary Cholangitis with Histological Submassive Hepatic Necrosis Caused by Acute Hepatitis E Virus Infection\nKoyama Mizuki 1\nYamazaki Tomoo 1\nJoshita Satoru 1\nIto Akihiro 1\nOno Kazuyuki 1\nWatanabe Takayuki 1\nYamashita Yuki 1\nSugiura Ayumi 1\nKobayashi Mikiko 2\nSato Yoshinori 2\nTakahashi Masaharu 3\nOkamoto Hiroaki 3\nUmemura Takeji 14\n1 Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Japan\n2 Department of Pathology, Shinshu University School of Medicine, Japan\n3 Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Japan\n4 Department of Life Innovation, Institute for Biomedical Sciences, Shinshu University, Japan\nCorrespondence to Dr. Tomoo Yamazaki, ymzktm6@shinshu-u.ac.jp\n\n1 2 2021\n15 6 2021\n60 12 18631870\n18 9 2020\n6 12 2020\nCopyright © 2021 by The Japanese Society of Internal Medicine\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ The Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).\nA 59-year-old woman who had been diagnosed with cirrhotic primary biliary cholangitis (PBC) 5 years earlier was admitted for severe jaundice (total bilirubin: 30.1 mg/dL). We suspected that her cirrhotic PBC had deteriorated acutely for some reason. Her general condition deteriorated quickly, and she passed away on day 18 of admission. Hepatitis E virus (HEV)-IgA antibodies were positive, and Genotype 3b HEV involvement was confirmed from a blood sample taken on admission. Histopathological findings revealed cirrhosis and submassive loss and necrosis of hepatocytes. Clinicians should consider the possibility of acute HEV infection as a trigger for acute PBC exacerbation.\n\nprimary biliary cholangitis\nhepatitis E virus\n==== Body\nIntroduction\n\nPrimary biliary cholangitis (PBC) is a chronic and slowly progressive cholestatic autoimmune liver disease that is histopathologically characterized by an attack on the small intralobular bile duct by T lymphocytes (1). The precise etiology of PBC remains unknown but is related to genetic susceptibility environmental factors (2-4). Although most patients with PBC are asymptomatic and have a normal life expectancy, clinicians sometimes encounter symptomatic PBC cases with severe jaundice or liver failure as a result of the sustained loss of intralobular bile ducts in spite of ursodeoxycholic acid (UDCA) therapy (5,6). Patients with concomitant acute liver injury from autoimmune hepatitis show particularly rapid disease progression (7). The acute exacerbation of PBC from hepatitis virus co-infection is rare in the clinical setting.\n\nThe hepatitis E virus (HEV) is a quasi-enveloped, single-stranded RNA virus that causes acute or chronic hepatitis (8,9). With the increase in the number of hepatitis E cases, HEV antibody is now positive in approximately 5% of the general population in Japan (10,11). Among HEV-associated acute hepatitis cases, 0.5-4% of patients progress to fulminant hepatitis (12), leading to high mortality when intensive care and liver transplantation are unavailable. Rare cases of severe acute HEV hepatitis underlying such chronic liver diseases as alcoholic liver disease, nonalcoholic fatty liver disease, chronic viral hepatitis, and PBC have been documented as well (13-15). No autopsy PBC cases displaying acute exacerbation due to superimposed acute HEV infection have been reported to date.\n\nWe herein report the autopsy findings of a PBC case in the cirrhotic stage with histological submassive hepatic necrosis caused by acute HEV infection.\n\nCase Report\n\nA 59-year-old woman who had been serologically diagnosed with PBC after the detection of liver dysfunction 26 years earlier was admitted to our hospital for severe jaundice, brown urine, and leg edema. She had suffered from cold-like symptoms and skin jaundice for a month and had received antitussives and antibiotics (levofloxacin 500 mg/day) from her attending physician 2 weeks before admission. She had no symptoms of diarrhea, vomiting, or a history of eating raw meat. She reported no regular ethanol consumption or travel to a foreign country. Although she had been prescribed 600 mg/day UDCA and 400 mg/day bezafibrate for PBC, her medication compliance was extremely poor. She had persistent liver dysfunction [alanine aminotransferase (ALT) at around 100 U/L] and jaundice (total bilirubin at around 3 mg/dL). Eight years before admission, the histological findings of a liver biopsy specimen showed lymphocyte infiltration in the portal area and severe bile duct loss that were consistent with Nakanuma stage 3 (16) and Scheuer stage III (17) classifications (Fig. 1). Three years later, she was clinically diagnosed with cirrhosis-stage PBC. She had also undergone endoscopic gastric varices treatment one year before admission.\n\nFigure 1. Histological findings of a liver biopsy specimen obtained eight years before admission. a, b) Lymphocyte infiltration in the portal area and severe bile duct loss were observed (Hematoxylin and Eosin staining). c) Azan-Mallory staining showed moderate fibrosis in the liver that was consistent with Nakanuma stage 3 and Scheuer stage III classifications.\n\nOn an examination at the time of admission, the patient was 165 cm tall, weighed 68 kg, and had a body mass index of 25.0 kg/m2. Her vital signs included Glasgow Coma Scale score E4V5M6, body temperature 37.3 °C, and blood pressure 111/54 mmHg. She exhibited conjunctival and systemic jaundice and front chest vascular spider but no flapping tremor. Laboratory tests on admission revealed elevated serum aspartate aminotransferase (78 U/L), ALT (100 U/L), gamma-glutamyl transpeptidase (105 U/L), alkaline phosphatase (702 U/L), total bilirubin (30.1 mg/dL), and Mac-2-binding protein glycan isomer (M2BPGi) (7.4 C・O・I) but a reduced platelet count (7.2×104/μL), albumin (2.7 g/dL), and prothrombin time activity (67.7%) (Table 1). Testing for hepatitis A virus antibody (immunoglobulin M), hepatitis B virus surface antigen, and anti-hepatitis C virus (HCV) antibody was negative. Serum antibodies to the Epstein-Barr virus and cytomegalovirus both showed a historical infection pattern. Although serum alpha fetoprotein levels were within normal range, levels of protein induced by vitamin K absence or antagonist II were mildly elevated (152 mAU/mL). Among the autoantibodies tested, fluorescent anti-nuclear antibody (× 640) and anti-mitochondrial M2 antibody (168.1 Index) were positive.\n\nTable 1. Laboratory Findings on Admission.\n\nBlood\t\tChemistry / Serology\tViral markers\t\nWhite blood cell count\t5,760\t/μL\t\tTotal protein\t5.9\tg/dL\tIgM-HAV Ab\t(-)\t\t\nNeutrophils\t71.2\t%\t\tAlbumin\t2.7\tg/dL\tHBs-Ag\t0.001 (-)\tU/mL\t\nLymphocytes\t19.8\t%\t\tAST\t78\tU/L\tHBs-Ab\t0.4 (-)\tmIU/mL\t\nMonocytes\t5.7\t%\t\tALT\t100\tU/L\tHBc-Ab\t0.2 (-)\tC·O·I\t\nEosinophils\t3.0\t%\t\tTotal bilirubin\t30.14\tmg/dL\tIgM-HBc Ab\t(-)\t\t\nBasophils\t0.3\t%\t\tGGT\t105\tU/L\tHCV-Ab\t0.1 (-)\tC·O·I\t\nRed blood cell count\t418\t×104/μL\t\tALP\t702\tU/L\tIgM-EBV VCA Ab\t<10 (-)\t×\t\nHemoglobin\t13.1\tg/dL\t\tBUN\t12\tmg/dL\tIgG-EBV VCA Ab\t40 (+)\t\t\nHematocrit\t37.4\t%\t\tCreatinine\t0.59\tmg/dL\tEBV EBNA Ab\t<10 (-)\t×\t\nPlatelet count\t7.2\t×104/μL\t\tNH3\t29\tμg/dL\tIgM-CMV Ab\t0.29 (-)\tIndex\t\n\t\t\t\tCRP\t1.61\tmg/dL\tIgG-CMV Ab\t133.6 (+)\tAU/mL\t\nCoagulation\t\tHbA1c\t4.2\t%\tIgA-HEV Ab\t(+)\t\t\nPT\t67.7\t%\t\tIgM\t139\tmg/dL\t\t\t\t\nAPTT\t29.0\tsec\t\tIgA\t292\tmg/dL\tAutoimmune antibodies\t\nFibrinogen\t192.0\tmg/dL\t\tIgG\t1,156\tmg/dL\tFANA\t640\t×\t\nD-dimer\t2.3\tμg/mL\t\tM2BPGi\t7.4\tC·O·I\tAMA2\t168.1\tIndex\t\n\t\t\t\t\t\t\tAnti-centromere antibody\t(-)\t\t\n\t\t\t\tTumor markers\tLKM-1\t(-)\t\t\n\t\t\t\tAFP\t7.0\tng/mL\tASMA\t(-)\t\t\n\t\t\t\tPIVKA II\t152\tmAU/mL\t\t\t\t\nPT: prothrombin time, APTT: activated partial thromboplastin time, AST: aspartate aminotransferase, ALT: alanine aminotransferase, GGT: gamma-glutamyl transpeptidase, ALP: alkaline phosphatase, BUN: blood urea nitrogen, CRP: C-reactive protein, HbA1c: hemoglobin A1c, M2BPGi: Mac 2-Binding Protein Gylcan Isomer, AFP: alpha fetoprotein, PIVKA II: protein induced by vitamin K absence or antagonist II, FANA: fluorescent anti-nuclear antibody, AMA2: anti-mitochondrial M2 antibody, LKM-1: anti-liver/kidney microsome type 1 antibody, ASMA: anti-smooth muscle antibody, C·O·I: cut off index\n\nAbdominal ultrasonography showed surface irregularity and a coarse parenchyma echotexture of the liver, suggesting cirrhosis (Fig. 2a). Abdominal contrast-enhanced computed tomography portal phase images showed surface undulation of the liver, collateral circulation around the stomach and splenic hilum, and ascites on the surface of the liver and spleen (Fig. 2b). No evidence suggestive of acute hepatitis, such as periportal collar sign, gallbladder atrophy, or wall thickening, was observed, nor were any space-occupying lesions present in the liver.\n\nFigure 2. a) Abdominal ultrasonography showed liver surface irregularity (arrowheads) and a coarse parenchyma echotexture. b) Abdominal contrast-enhanced computed tomography portal phase images revealed surface undulation of the liver, collateral circulation around the stomach and splenic hilum (arrows), and ascites on the surface of the liver and spleen.\n\nBased on the patient’s clinical findings, we suspected that her cirrhotic PBC had deteriorated acutely for some reason. Although she did not meet the criteria for acute liver failure, the presence of severe jaundice and ascites indicated the need for liver transplantation. After being refused for this treatment, we provided supportive care, including bed rest, lactulose administration, and albumin replacement. On day 13 of admission, HEV-IgA antibody was found to be positive in an admission blood sample, suggesting an association between the exacerbation of her PBC and acute HEV infection. However, the patient’s liver atrophy and renal failure were beyond treatment. Her general condition progressively worsened, and she passed away on day 18 of admission. The entire clinical course is summarized in Fig. 3.\n\nFigure 3. Clinical course of the patient. ALT: alanine aminotransferase, PT: prothrombin time, T-Bil: Total bilirubin, Cre: Creatinine, HEV: Hepatitis E virus\n\nA pathological autopsy was performed after obtaining informed consent from her family. Macroscopically, the surface of the liver was atrophied in a nodular manner, indicating complete cirrhosis (Fig. 4a). Microscopic observation of the liver showed severe atrophy with submassive loss and necrosis of hepatocytes from Zone 3 to Zone 2 of the hepatic lobule (Fig. 4b). However, the distribution did not match the centrilobular necrosis typically observed in hepatic ischemia. In some areas, hepatocytes around the central vein were intact (Fig. 4c). In addition, there was no remarkable steatosis inside hepatocytes indicative of hypoxia (Fig. 4c). Based on these findings, hepatic ischemia was not considered as the main cause of submassive loss and necrosis in this case. Although cholestasis was prominent in the lobules, inflammatory cell infiltration related to acute hepatitis was not evident (Fig. 4b, c). Regenerated nodules and highly fibrous septum formation were found in the liver, which were histologically consistent with cirrhosis (Fig. 4d). In the portal area, the infiltration of mononuclear cells and disappearance of bile ducts suggested advanced PBC (Fig. 4e). Extensive bile duct loss was confirmed between the interlobular and septal bile duct levels.\n\nFigure 4. Autopsy findings. a) Macroscopically, the surface of the liver was atrophied in a nodular manner, indicating complete cirrhosis. b) Severe atrophy with submassive loss and necrosis of hepatocytes (red dotted lines) from Zone 3 to Zone 2 of the hepatic lobule were evident (Hematoxylin and Eosin staining). P: portal vein, C: central vein. c) In some areas, hepatocytes around the central vein were relatively intact, with no steatosis inside hepatocytes suggestive of hypoxia. Cholestasis was prominent in the lobules. Inflammatory cell infiltration indicative of acute hepatitis was not detected. d) On Elastica-Goldner staining, regenerated nodules and highly fibrous septum formation were found in the liver, findings that were histologically consistent with cirrhosis. e) In the portal area, infiltration of mononuclear cells and the disappearance of bile ducts were observed, suggesting advanced PBC. P: portal vein\n\nHEV antibodies (IgG, IgM, and IgA) were measured by an enzyme-linked immunosorbent assay using frozen serum samples according to a previously described method (18). The testing results are shown in Table 2 along with the corresponding hepatobiliary enzymes at each time point. HEV RNA was detected by the nested reverse-transcription polymerase chain reaction with primers targeting the open reading frame 2 (ORF2) region of the HEV genome (nucleotide position 5944-6355, excluding primer sequences at both ends: M73218), as described previously (19). HEV RNA, which had been negative at the last visit before admission, had become positive at admission along with increases in all classes of HEV antibodies. HEV RNA became undetectable during the deterioration of her condition, although a high antibody titer persisted. We determined her 412-nucleotide ORF2 sequence and constructed a molecular phylogenetic tree according to a previously described method (20) (Fig. 5). The HEV strain (HE-JA19-0280: DDBJ/EMBL/GenBank accession number LC581383) derived from this case belonged to genotype 3 (subgenotype 3b) and was closest to those of patients recovering from acute hepatitis E in Tokyo and Gunma Prefectures of Japan.\n\nFigure 5. Phylogenetic tree constructed by the neighbor-joining method based on the partial nucleotide sequence (412 nucleotides) of the open reading frame 2 region of hepatitis E virus (HEV) isolates. In addition to the HEV isolate (HE-JA19-0280) obtained in the present study (highlighted with a closed box), 33 representative genotype 3 isolates (subgenotype 3a: n=8, subgenotype 3b: n=22, and subgenotype 3e: n=3), whose entire genomic sequence is known, are included in the tree using the prototype HEV sequences of genotype 1 (M73218), genotype 2 (M74506), and genotype 4 (AJ272108) as outgroups. Three HEV isolates sharing the highest identity of 97.1-97.8% with the HE-JA19-0280 isolate are also included. Each reference sequence is shown with the genotype/subgenotype followed by the accession number, isolate name, and country in which it was isolated. The bootstrap values (>70%) are indicated for nodes as the percentage of data among 1,000 resampling procedures. The scale bar is in units of nuceotide substitutions per site.\n\nTable 2. Transition of Hepatobiliary Enzymes, HEV Antibodies, and HEV RNA.\n\nDay\tLaboratory data\tHEV antibodies\tHEV RNA\t\nAST\n(U/L)\tALT\n(U/L)\tGGT\n(U/L)\tALP\n(U/L)\tT-Bil\n(mg/dL)\tIgG (OD450)\tIgM (OD450)\tIgA (OD450)\t\nX - 80\t137\t111\t413\t940\t3.4\t0.010\t(-)\t0.046\t(-)\t0.020\t(-)\tNegative\t\nX (admission)\t78\t100\t105\t702\t30.1\t1.661\t(+)\t>3.000\t(+)\t2.374\t(+)\t+: 1.0×101 copies/mL\t\nX+1\t69\t80\t87\t588\t26.6\t1.578\t(+)\t>3.000\t(+)\t2.346\t(+)\t+: 1.2×101 copies/mL\t\nX+11\t43\t44\t64\t568\t39.7\t1.850\t(+)\t>3.000\t(+)\t2.002\t(+)\tNegative\t\nX+14\t61\t66\t78\t631\t46.7\t1.970\t(+)\t>3.000\t(+)\t1.768\t(+)\tNegative\t\nHEV: hepatitis E virus, AST: aspartate aminotransferase, ALT: alanine aminotransferase, GGT: gamma-glutamyl transpeptidase, ALP: alkaline phosphatase, T-Bil: total bilirubin\n\nDiscussion\n\nThe present autopsy case displayed histological evidence of submassive necrosis in the liver caused by acute HEV infection. The patient was presumed to have been at the liver cirrhosis stage of PBC but suddenly developed severe jaundice due to superimposed HEV infection and succumbed one month later to hepatic failure. The histopathological findings of severe liver atrophy with submassive loss and necrosis of hepatocytes could not be explained by ischemia only, strongly suggesting the involvement of genotype 3b HEV infection in her histopathological findings.\n\nAlthough PBC patients generally have a normal life expectancy, they sometimes show rapid disease exacerbation due to concomitant autoimmune hepatitis (7,21) or simultaneous HCV infection (22) as a trigger of PBC deterioration. One rare instance of PBC with acute HEV infection has been reported to date (15). To our knowledge, however, an autopsy case of rapid deterioration triggered by HEV infection has not yet been described. As the mechanism underlying PBC exacerbation due to viral hepatitis infection remains unknown, the present case may contribute to the body of knowledge concerning this condition.\n\nHEV is one of the most common causes of acute viral hepatitis (23). In addition to contaminated water, raw meat from pigs, boars, and deer is another common infection source (24-26). Recently, the prevalence of HEV cases without clinical symptoms as well as those of unknown transmission route has been increasing (27). The infection route in the present case could not be identified based on our medical interview. According to previous reports, pregnancy, old age, alcohol intake, and fatty liver are host factors associated with the aggravation of HEV, and co-infection with chronic liver disease is related to the risk of liver failure (13,14). Regarding the HEV genotype, HEV genotype 4 infection is reportedly associated with aggravation (26,28,29). Genotype 3 HEV, as detected in this case, is generally associated with a low tendency of severe clinical manifestations, although a rare case of progressive genotype 3 HEV infection has been reported (28). A mutation of V239A in the helicase region of the genotype 3 HEV genome has been associated with HEV infection aggravation (30). That mutant was absent in this case (data not shown). The patient had no other apparent host or viral factors associated with HEV severity. However, Wang et al. reported that the cirrhosis stage itself carries a potential risk of liver failure due to HEV infection, regardless of etiology; they further described the potentiation of the cirrhotic liver upon HEV infection and more aggressive immune- or inflammatory-mediated activation of cell death in a cirrhotic liver status as possible mechanisms of exacerbation (15). The above results suggested that even if patients have no documented risk factors of HEV aggravation, clinicians should bear in mind that HEV infection at a cirrhotic liver disease stage can become severe.\n\nThis patient had been diagnosed with PBC 26 years earlier based on serological criteria. Eight years before admission, she was already at an advanced stage of PBC, with Nakanuma stage 3 and Scheuer stage III classifications according to a liver biopsy. An autopsy specimen of the liver revealed obvious cirrhosis, which was consistent with the natural history of PBC as suggested by elevated serum surrogate markers of M2BPGi (31,32). However, the submassive loss and necrosis of hepatocytes could not solely be explained by the natural PBC history. Inflammatory cell infiltration suggesting acute hepatitis E (33) was not observed, which suggested a post-inflammatory status. Other general clinical features of acute hepatitis, including markedly elevated levels of liver enzymes, were absent as well. Her liver enzymes were only mildly elevated at day X-80, suggesting that asymptomatic hepatitis may have started at that point, followed by further increases in transaminase levels. Thus, one explanation as to why this case showed mild hepatitis was that the hepatitis had occurred after day X-80 and already peaked and ameliorated by the time of admission, such that jaundice represented the major feature. However, no clinical data were available between the patient’s last outpatient visit at day X-80 and her hospitalization. Another hypothesis was that this case had already reached the complete cirrhosis stage, as shown by the pathological findings, which could have induced mild liver enzyme elevations (34).\n\nPatients with hepatitis E sometimes show severe jaundice (35). Although the underlying mechanism is uncertain, HEV has been reported to exhibit not only hepatocytic but also biliary tropism and replicate within bile duct epithelial cells (36,37). The severe jaundice and cholestasis in this case might have been the result of HEV infection complicating the chronic cholestatic liver disease of PBC. The fact that jaundice was more pronounced than elevated liver enzyme levels may support this notion. Although drug-induced liver injury (levofloxacin 500 mg/day) cannot be ruled out, we suspected that HEV infection likely triggered the exacerbation of PBC due to her awareness of jaundice prior to drug administration and the histological considerations described above.\n\nIn conclusion, clinicians should consider the possibility of acute HEV infection as a trigger for the acute exacerbation of PBC. In such cases, it may be necessary to treat the patient with the anticipation of severe aggravation.\n\nThe authors state that they have no Conflict of Interest (COI).\n\nAcknowledgement\n\nWe thank Trevor Ralph for his English editorial assistance.\n==== Refs\n1. Kaplan MM , Gershwin ME . Primary biliary cirrhosis. N Engl J Med 353 : 1261-1273, 2005.16177252\n2. Joshita S , Umemura T , Yoshizawa K , et al . Association analysis of cytotoxic T-lymphocyte antigen 4 gene polymorphisms with primary biliary cirrhosis in Japanese patients. J Hepatol 53 : 537-541, 2010.20557968\n3. Joshita S , Umemura T , Tanaka E , Ota M . Genetics and epigenetics in the pathogenesis of primary biliary cholangitis. Clin J Gastroenterol 11 : 11-18, 2018.29159718\n4. Nakamura M , Nishida N , Kawashima M , et al . Genome-wide association study identifies TNFSF15 and POU2AF1 as susceptibility loci for primary biliary cirrhosis in the Japanese population. Am J Hum Genet 91 : 721-728, 2012.23000144\n5. Ludwig J . New concepts in biliary cirrhosis. Semin Liver Dis 7 : 293-301, 1987.3324348\n6. Joshita S , Umemura T , Yamashita Y , et al . Biochemical and plasma lipid responses to pemafibrate in patients with primary biliary cholangitis. Hepatol Res 49 : 1236-1243, 2019.31077509\n7. Chazouillères O , Wendum D , Serfaty L , Montembault S , Rosmorduc O , Poupon R . Primary biliary cirrhosis-autoimmune hepatitis overlap syndrome: clinical features and response to therapy. Hepatology 28 : 296-301, 1998.9695990\n8. Worm HC , Schlauder GG , Brandstätter G . Hepatitis E and its emergence in non-endemic areas. Wien Klini Wochenschr 114 : 663-670, 2002.\n9. Nagashima S , Takahashi M , Kobayashi T , et al . Characterization of the quasi-enveloped hepatitis E virus particles released by the cellular exosomal pathway. J Virol 91 : e00822-17, 2017.28878075\n10. Takahashi M , Tamura K , Hoshino Y , et al . A nationwide survey of hepatitis E virus infection in the general population of Japan. J Med Virol 82 : 271-281, 2010.20029817\n11. Tanaka E , Takeda N , Tian-Chen L , et al . Seroepidemiological study of hepatitis E virus infection in Japan using a newly developed antibody assay. J Gastroenterol 36 : 317-321, 2001.11388394\n12. Aggarwal R . Hepatitis E: clinical presentation in disease-endemic areas and diagnosis. Semin Liver Dis 33 : 30-40, 2013.23564387\n13. Hamid SS , Atiq M , Shehzad F , et al . Hepatitis E virus superinfection in patients with chronic liver disease. Hepatology 36 : 474-478, 2002.12143058\n14. Ramachandran J , Eapen CE , Kang G , et al . Hepatitis E superinfection produces severe decompensation in patients with chronic liver disease. J Gastroenterol Hepatol 19 : 134-138, 2004.14731121\n15. Wang Y , Liu H , Jiang Y , Pan Q , Zhao J . Poor outcomes of acute hepatitis E in patients with cirrhotic liver diseases regardless of etiology. Open Forum Infect Dis 7 : ofaa107, 2020.32355864\n16. Nakanuma Y , Zen Y , Harada K , et al . Application of a new histological staging and grading system for primary biliary cirrhosis to liver biopsy specimens: interobserver agreement. Pathol Int 60 : 167-174, 2010.20403042\n17. Scheuer P . Primary biliary cirrhosis. Proc R Soc Med 60 : 1257-1260, 1967.6066569\n18. Takahashi M , Kusakai S , Mizuo H , et al . Simultaneous detection of immunoglobulin A (IgA) and IgM antibodies against hepatitis E virus (HEV) is highly specific for diagnosis of acute HEV infection. J Clin Microbiol 43 : 49-56, 2005.15634950\n19. Mizuo H , Suzuki K , Takikawa Y , et al . Polyphyletic strains of hepatitis E virus are responsible for sporadic cases of acute hepatitis in Japan. J Clin Microbiol 40 : 3209-3218, 2002.12202555\n20. Yamazaki Y , Naganuma A , Arai Y , et al . Clinical and virological features of acute hepatitis E in Gunma prefecture, Japan between 2004 and 2015. Hepatol Res 47 : 435-445, 2017.27322051\n21. Martínez Casas OY , Díaz Ramírez GS , Marín Zuluaga JI , et al . Autoimmune hepatitis - primary biliary cholangitis overlap syndrome. Long-term outcomes of a retrospective cohort in a university hospital. Gastroenterol Hepatol 41 : 544-552, 2018.30017212\n22. Chen HW , Huang HH , Lai CH , et al . Hepatitis C virus infection in patients with primary biliary cirrhosis. Ann Hepatol 12 : 78-84, 2013.23293197\n23. Gupta DN , Smetana HF . The histopathology of viral hepatitis as seen in the Delhi epidemic (1955-56). Indian J Med Res 45 : 101-113, 1957.13438544\n24. Meng XJ . Swine hepatitis E virus: cross-species infection and risk in xenotransplantation. Curr Top Microbiol Immunol 278 : 185-216, 2003.12934945\n25. Ropp SL , Tam AW , Beames B , Purdy M , Frey TK . Expression of the hepatitis E virus ORF1. Arc Virol 145 : 1321-1337, 2000.\n26. Takahashi M , Okamoto H . Features of hepatitis E virus infection in humans and animals in Japan. Hepatol Res 44 : 43-58, 2014.23721425\n27. Meng XJ . Hepatitis E virus: animal reservoirs and zoonotic risk. Vet Microbiol 140 : 256-265, 2010.19361937\n28. Ohnishi S , Kang JH , Maekubo H , et al . Comparison of clinical features of acute hepatitis caused by hepatitis E virus (HEV) genotypes 3 and 4 in Sapporo, Japan. Hepatol Res 36 : 301-307, 2006.16971172\n29. Mizuo H , Yazaki Y , Sugawara K , et al . Possible risk factors for the transmission of hepatitis E virus and for the severe form of hepatitis E acquired locally in Hokkaido, Japan. J Med Virol 76 : 341-349, 2005.15902701\n30. Takahashi K , Okamoto H , Abe N , et al . Virulent strain of hepatitis E virus genotype 3, Japan. Emerg Infect Dis 15 : 704-709, 2009.19402955\n31. Umemura T , Joshita S , Sekiguchi T , et al . Serum wisteria floribunda agglutinin-positive Mac-2-binding protein level predicts liver fibrosis and prognosis in primary biliary cirrhosis. Am J Gastroenterol 110 : 857-864, 2015.25916223\n32. Joshita S , Yamashita Y , Sugiura A , et al . Clinical utility of FibroScan as a non-invasive diagnostic test for primary biliary cholangitis. J Gastroenterol Hepatol 35 : 1208-1214, 2020.31724755\n33. Malcolm P , Dalton H , Hussaini HS , Mathew J . The histology of acute autochthonous hepatitis E virus infection. Histopathology 51 : 190-194, 2007.17650215\n34. Starr SP , Raines D . Cirrhosis: diagnosis, management, and prevention. Am Fam Physician 84 : 1353-1359, 2011.22230269\n35. Xu B , Yu HB , Hui W , et al . Clinical features and risk factors of acute hepatitis E with severe jaundice. World J Gastroenterol 18 : 7279-7284, 2012.23326133\n36. Asher LV , Innis BL , Shrestha MP , Ticehurst J , Baze WB . Virus-like particles in the liver of a patient with fulminant hepatitis and antibody to hepatitis E virus. J Med Virol 31 : 229-233, 1990.2391510\n37. Kawai HF , Koji T , Iida F , Kaneko S , Kobayashi K , Nakane PK . Shift of hepatitis E virus RNA from hepatocytes to biliary epithelial cells during acute infection of rhesus monkey. J Viral Hepat 6 : 287-297, 1999.10607243\n\n",
"fulltext_license": "CC BY-NC-ND",
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"issue": "60(12)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "hepatitis E virus; primary biliary cholangitis",
"medline_ta": "Intern Med",
"mesh_terms": "D001344:Autopsy; D002761:Cholangitis; D005260:Female; D016751:Hepatitis E; D016752:Hepatitis E virus; D006801:Humans; D008105:Liver Cirrhosis, Biliary; D047508:Massive Hepatic Necrosis; D008875:Middle Aged",
"nlm_unique_id": "9204241",
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"pmid": "33518570",
"pubdate": "2021-06-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "An Autopsy Case of Primary Biliary Cholangitis with Histological Submassive Hepatic Necrosis Caused by Acute Hepatitis E Virus Infection.",
"title_normalized": "an autopsy case of primary biliary cholangitis with histological submassive hepatic necrosis caused by acute hepatitis e virus infection"
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"abstract": "Acetaminophen toxicity is common and is characterized by hepatic failure. In cases that are not improving with standard medical therapy with N-acetylcysteine, some patients may require hepatic transplant. While there are various criteria to predict patients who might benefit from transplant, the King's College criteria remain one of the most widely used. However, the King's College criteria have several limitations and do not incorporate glucose, an important marker of hepatic function.\n\n\n\nThe primary objective of this study is to compare the presence of hypoglycemia, coagulopathy, and metabolic acidosis with the King's College criteria for predicting a composite endpoint of death or transplant.\n\n\n\nThis study is a retrospective cohort study of adult patients admitted with a discharge diagnosis of acetaminophen-induced liver failure.\n\n\n\nThe patients were admitted at one of six university-affiliated teaching hospitals in the United States.\n\n\n\nA total of 334 subjects were identified who met inclusion criteria. Fifty-one subjects (15.3%) met the composite endpoint of death or transplant. Ninety-six (28.7%) subjects met the King's College criteria for transplant. The presence of hypoglycemia increased the odds of reaching the composite endpoint by 3.39-fold. This model performed better than the King's College criteria (pseudo R2 for the area under the curve of 0.93 vs. 0.20 for the King's College criteria).\n\n\n\nThe combination of hypoglycemia, coagulopathy, and lactic acidosis performed better than the King's College criteria for predicting death or transplant.",
"affiliations": "a Department of Emergency Medicine, Division of Medical Toxicology , University of Southern California , Los Angeles , CA , USA.;b Department of Emergency Medicine, Division of Medical Toxicology , Regions Hospital , St. Paul , MN , USA.;c Department of Emergency Medicine, Division of Medical Toxicology , University of Pittsburgh , Pittsburgh , PA , USA.;d Department of Emergency Medicine , Massachusetts General Hospital , Boston , MA , USA.;e Department of Emergency Medicine, Division of Medical Toxicology , University of California , San Diego , CA , USA.;f Department of Emergency Medicine, Division of Medical Toxicology , University of Rochester , Rochester , NY , USA.;g Keck School of Medicine , University of Southern California , Los Angeles , CA , USA.;h Emergency Department , Hamad General Hospital, Hamad Medical Corporation , Doha , Qatar.",
"authors": "Levine|Michael|M|;Stellpflug|Samuel J|SJ|;Pizon|Anthony F|AF|;Peak|David A|DA|;Villano|Janna|J|;Wiegand|Timothy|T|;Dib|Christian|C|;Thomas|Stephen H|SH|",
"chemical_list": "D000082:Acetaminophen",
"country": "England",
"delete": false,
"doi": "10.1080/15563650.2017.1420193",
"fulltext": null,
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"issn_linking": "1556-3650",
"issue": "56(7)",
"journal": "Clinical toxicology (Philadelphia, Pa.)",
"keywords": "Hypoglycemia; Kings College; King’s College criteria; acetaminophen; acidosis; coagulopathy",
"medline_ta": "Clin Toxicol (Phila)",
"mesh_terms": "D000082:Acetaminophen; D000140:Acidosis, Lactic; D000328:Adult; D001778:Blood Coagulation Disorders; D056486:Chemical and Drug Induced Liver Injury; D005260:Female; D006801:Humans; D007003:Hypoglycemia; D017093:Liver Failure; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies",
"nlm_unique_id": "101241654",
"other_id": null,
"pages": "622-625",
"pmc": null,
"pmid": "29301418",
"pubdate": "2018-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Hypoglycemia and lactic acidosis outperform King's College criteria for predicting death or transplant in acetaminophen toxic patients.",
"title_normalized": "hypoglycemia and lactic acidosis outperform king s college criteria for predicting death or transplant in acetaminophen toxic patients"
} | [
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"companynumb": "US-JNJFOC-20180619509",
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"activesubstancename": "ACETAMINOPHEN"
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"abstract": "Fluoroquinolones increase the risk of peripheral neuropathy. The present work aims to report a case of fluoroquinolone-related severe axonal neuropathy. The subject of this study was a 62-year-old man who exhibited generalized sensory disturbances 4 days after treatment by ciprofloxacin prescribed for urinary infection. Electrodiagnostic studies revealed severe motor-sensory axonal neuropathy with widespread fibrillation potentials in support of generalized motor polyradiculopathy. There was no evidence of conduction blocks or albuminocytologic dissociation in favor of an autoimmune inflammatory reaction. The only pathological biomarker was the reduction of serum folate. According to this case, we suggest that folate level could be routinely measured and supplementation should be performed in patients with fluoroquinolone-induced neuropathy.",
"affiliations": "Victor Pauchet Clinics, Amiens, France.",
"authors": "Popescu|Cyprian|C|",
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"country": "Switzerland",
"delete": false,
"doi": "10.1159/000489303",
"fulltext": "\n==== Front\nCase Rep NeurolCase Rep NeurolCRNCase Reports in Neurology1662-680XS. 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 10.1159/000489303crn-0010-0124Case ReportSevere Acute Axonal Neuropathy Induced by Ciprofloxacin: A Case Report Popescu Cyprian *Victor Pauchet Clinics, Amiens, France*Dr. Cyprian Popescu, Victor Pauchet Clinics, 59 rue Alexandre Dumas, FR–80090 Amiens (France), E-Mail cimarpop@yahoo.frMay-Aug 2018 30 5 2018 30 5 2018 10 2 124 129 1 2 2018 16 4 2018 Copyright © 2018 by S. Karger AG, Basel2018This 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.Fluoroquinolones increase the risk of peripheral neuropathy. The present work aims to report a case of fluoroquinolone-related severe axonal neuropathy. The subject of this study was a 62-year-old man who exhibited generalized sensory disturbances 4 days after treatment by ciprofloxacin prescribed for urinary infection. Electrodiagnostic studies revealed severe motor-sensory axonal neuropathy with widespread fibrillation potentials in support of generalized motor polyradiculopathy. There was no evidence of conduction blocks or albuminocytologic dissociation in favor of an autoimmune inflammatory reaction. The only pathological biomarker was the reduction of serum folate. According to this case, we suggest that folate level could be routinely measured and supplementation should be performed in patients with fluoroquinolone-induced neuropathy.\n\nKeywords\nFluoroquinolonesTherapy-induced peripheral neuropathySide effectsAcute motor and sensory axonal neuropathyFolate deficiency\n==== Body\nIntroduction\nFluoroquinolones (FQs) are antibiotics that are widely used against urinary infections. Overall, the frequency and severity of adverse events are rather low [1]. Among the most serious adverse events are peripheral neurologic events [2, 3, 4, 5]; these are less common than central nervous system or gastrointestinal involvement, which occurs with an estimated frequency of 1 in 17,000 ciprofloxacin-treated patients [6]. We report an extremely rare case of axonal neuropathy induced by ciprofloxacin with peripheral nerve symptoms that lasted more than 6 months, while electrodiagnostic features have almost been normalized after 5 years of observation.\n\nCase Report\nA 62-year-old man was admitted to hospital with urinary infection 1 week after a surgical intervention for nephrolithiasis. He received ciprofloxacin 500 mg twice a day. Four days after the first intake of the antibiotic therapy, the patient started to present severe numbness in the feet gradually ascending towards the calves and sensory disturbances in the hands, but not flaccid paresis. During the examination of the patient, he had full strength in his extremities and only vibratory sensory distal deficit. Patellar and Achilles reflexes were absent. Cranial nerves were not involved, and no ataxic or autonomic features were reported. An electrodiagnostic test performed in the fourth week revealed that the peroneal and tibial nerves, as well as the sensory nerves in the lower limbs, were not excitable. In the upper limbs, the amplitudes of the compound motor action potentials (CMAPs) of the median and ulnar nerves were extremely low, less than 80% of the lower normal limit of motor amplitude, indicating axonal degeneration [7]. The sensory and motor nerve conduction velocity was severely diminished with temporal dispersion, especially at common entrapment sites, but no conduction blocks were registered (Table 1). Distal CMAP latencies in the median and ulnar nerves were prolonged as electrophysiological evidence of demyelination features [8]. The H reflex recorded from the soleus muscle after the stimulation of the tibial nerve was bilaterally abolished. The electromyography revealed active denervation with increased temporal recruitment in the distal part of the lower limbs with no neurogenic pattern in the proximal muscles. One month later, it was discovered that the same clinical phenotype with lack of tendon reflexes was present in the lower limbs. The electrodiagnostic test reported more than 50% reduction of normal values of the sensory amplitudes in the median and ulnar nerves and inexcitability of the sural nerve (Table 1). In our case, the involvement of the upper limbs was also prominent, even if the length-dependent pattern was respected. The fibular and tibial nerves became electrically excitable late in the disorder, but the compound motor action amplitudes were severely reduced with a comparatively lower reduction of motor conduction velocities. The subsequent reduction of nerve velocities of more than 30% and the increase in distal motor latencies of more than 50% fulfilled demyelination criteria [7]. Therefore, we concluded that the demyelination features were secondary to axonal degeneration.\n\nCerebrospinal fluid analysis did not detect albuminocytologic dissociation. The routine laboratory testing, including comprehensive metabolic profile, erythrocyte sedimentation rate, thyroid-stimulating hormone levels, and also vitamin B1, B12, and E, was normal. Furthermore, we found that the antibodies anti-GM1b and anti-GD1a were absent. The vitamin profile showed low amounts of serum folic acid at 2.7 ng/mL. The patient denied excessive alcohol consumption, which was confirmed by biological features. Additionally, there was no evidence that the neuropathy occurred secondary to other known causes. Despite the discontinuation of the antibiotics treatment, there was no relief of symptoms, and the patient was treated with pregabalin [9] and, at the same time, with oral folate supplementation for 3 months. The electrophysiological studies 6 months after the first ciprofloxacin intake showed an important improvement, particularly in the excitability of the sural nerve, which regained a normal amplitude, and also in the distal compound motor action latencies of the amplitudes of the peroneal, tibial, median, and ulnar nerves, respectively. The H reflex of the tibial nerve remained abolished. The serum folate level became normal again at 33.8 ng/mL. Acute inflammatory demyelinating polyradiculoneuropathy (AIDP) as a differential diagnosis was ruled out due to the lack of albuminocytologic dissociation. The clinical recovery lasted more than 6 months after drug intake.\n\nDiscussion\nThe occurrence of peripheral neuropathy has already been reported with FQs [2, 3, 4, 5]. Small-fiber neuropathy has been described as an adverse effect of ciprofloxacin [10] as well as Guillain-Barré syndrome (GBS) during treatment with ofloxacin [11]. In this study, we reported a case of severe FQ-induced peripheral neuropathy with long-term recovery. In our case, the time between the ciprofloxacin intake and the first symptoms was 4 days, knowing that in one-third of patients, the neuropathic symptoms occurred within 24 h of treatment initiation [5], and in more than two-thirds of patients within 1 week after the start of treatment [3]. The patient did not know whether this was his first FQ treatment, but probably that was the case, because new users have the highest risk of developing FQ-associated neuropathy [12]. There was no evidence of diabetes or other metabolic, hematological, or neoplastic conditions. The symptoms were solely sensitive; paresthesia with little objective sensory loss is regarded as the most common initial symptom of GBS [13]. However, this case is different from those reported concerning IDP, given its exclusive sensory clinical presentation, moderately reduced nerve conduction velocities, a marked reduction in the amplitude of motor and sensory nerve action potentials, and evidence of denervation on needle examination of the affected muscles [14]. The axonal degeneration is, therefore, the cause of secondary demyelination features, which explains the increase in distal motor latencies of more than 50% in relation to the normal values previously established [7]. Moreover, compared to our case, marked slowing of motor conduction is the essential feature of chronic IDP [15]. The electrophysiological features are, therefore, compatible with acute motor and sensory axonal neuropathy (AMSAN), defined as severe involvement of the motor and sensory nerves with more than 50% reduction of the amplitudes in at least 2 sensory nerves [16]. In AMSAN patients, the reduction of the sural nerve amplitude is more prominent than in AIDP patients, and sural sparing is considered a marker of demyelinating neuropathy [17]. Indeed, our electrophysiological features showed the inexcitability of the sensory nerves in the legs. Length-dependent conduction was also reported as an essential marker of the axonal type of GBS [8]; a drop of sensory nerve action potentials and CMAPs with only slightly diminished conduction velocities is required for the diagnosis of axonal neuropathies. Nine percent of patients with FQ neuropathy have the GBS phenotype [18]. Moreover, the laboratory findings did not show any evidence of albuminocytologic dissociation in favor of AIDP.\n\nAfter 5 years of observation without relapsing and remitting course, we noted that the monophasic course of this axonal neuropathy is in favor of axonal GBS. Although the antibiotic treatment was stopped, there was no prompt relief of symptoms, and sensory disturbances have continued for more than 6 months; this required treatment with pregabalin as the analgesic of choice [9]. Overall, reports showed variable recovery delays with neuropathic features lasting more than 3 months in 71% of cases and more than 1 year in 58% of cases [5]. Elderly patients with pre-existing risk factors are more frequently affected; age over 60 years and chronic renal diseases, as in our case, are considered as risk factors for FQ-induced side effects [19]. Possible FQ toxicity occurs more frequently in patients with diabetes, impaired renal function, hematological diseases, and neurotoxic-associated drugs [3].\n\nIt is worth to note that, in our case, folate deficiency without macrocytic anemia was probably due to a long-standing nutritional folate deficiency, which could be a possible enabling factor for FQ-induced neuropathy. Folate deficiency has been recognized as a risk factor for polyneuropathy [20, 21]. The phenotype of folate-deficiency neuropathy is predominantly deep sensory, slowly progressive, essentially axonal, and responding to folate supplementation [22]. Folate therapy significantly reversed abnormalities in motor and sensory nerve distal latencies in patients on long-term anticonvulsant therapy [23]. One-tenth of the neurological patients presented low serum folate levels [24]. FQs block the bacterial complex of DNA and DNA gyrase, but they are not involved in folate synthesis as a reductase inhibitor like other antibiotics [25]. We can speculate on the involvement of methylenetetrahydrofolate reductase (MTHFR) gene variants, which have already been associated with diabetic neuropathy [26, 27]. In this pathology, folic acid seems to have neuroprotective effects on experimental diabetic peripheral neuropathy [28]. Supplementation with folic acid may be a solution to facilitate the recovery of FQ-induced neuropathies, especially in those who experienced folate deficiency. The best choice of antibiotics, while respecting guidelines and contraindications, is necessary.\n\nWe reported a severe axonal GBS phenotype induced by ciprofloxacin. Considering the fact that the initial biological investigations revealed folate deficiency, we propose the supplementation of serum folate as an additive factor in order to hasten recovery. Clearly, it is difficult to conclusively demonstrate that FQ was the cause of neuropathy, but the chronological aspect and the peculiar features of electrodiagnostic tests are in favor of an axonal GBS-like phenotype with unobtainable sensory nerve action potentials, low CMAPs, and acute denervation.\n\nStatement of Ethics\nThe author has no ethical conflicts to disclose.\n\nDisclosure Statement\nThe author has no conflicts of interest to disclose.\n\nFunding Sources\nThe author received no financial support for the research, authorship, and publication of this article.\n\nAuthor Contributions\nThe author conceived and designed the study, examined and frequently monitored the patient, performed the electrophysiological studies, analyzed the data, and wrote the manuscript.\n\nTable 1 Electrophysiological findings\n\n\tMNCV, m/s (normal values)\tDistal latency, ms (normal values)\tCMAPs, mV (normal values)\tSensory amplitude, µV (SNAPs)\n(normal values)\t\n\tmedian\tulnar\tperoneal\tmedian\tulnar\tperoneal\tmedian\tulnar\tperoneal\tmedian\tsural\t\nTime after drug intake\t\n28 days\tR: 32.2\tR: 36.2\tR: 0\tR: 5.21\tR: 4.51\tR: 6.40\tR: 0.7\tR: 0.2\tR: 0\tR: 9.92\tR: 0\t\n\tL: 36.2\n(51.1±3.7)\tL: 37.2\n(52.4±3.5)\tL: 0\n(48.3±3.9)\tL: 7.23\n(1.82±0.19)\tL: 4.53\n(3.7±0.2)\tL: 6.11\n(3.9±0.8)\tL: 0.5\n(6±2.2)\tL: 0.2\n(52.5±3.8)\tL: 0\n(4.5±2.7)\tL: 7.73\n(24.4±3.3)\tL: 0\n(23.6±3.5)\t\n\t\n2 months\tR: 32.2\tR: 32.2\tR: 32.2\tR: 5.21\tR: 4.23\tR: 4.63\tR: 0.7\tR: 0.2\tR: 0.64\tR: 14.94\tR: 0\t\n\tL: 36.2\n(51.1±3.7)\tL: 36.2\n(52.4±3.5)\tL: 36.2\n(48.3±3.9)\tL: 7.23\n(1.82±0.19)\tL: 4.14\n(3.7±0.2)\tL: 5.21\n(3.9±0.8)\tL: 0.5\n(6±2.2)\tL: 0.2\n(52.5±3.8)\tL: 0.48\n(4.5±2.7)\tL: 12.65\n(24.4±3.3)\tL: 0\n(23.6±3.5)\t\n\t\n6 months\tR: 50.17\tR: 32.2\tR: 32.2\tR: 5.21\tR: 3.56\tR: 3.56\tR: 0.7\tR: 0.2\tR: 0.64\tR: 35.9\tR: 0\t\n\tL: 36.2\n(51.1±3.7)\tL: 36.2\n(52.4±3.5)\tL: 36.2\n(48.3±3.9)\tL: 7.23\n(1.82±0.19)\tL: 3.52\n(3.7±0.2)\tL: 3.71\n(3.9±0.8)\tL: 0.5\n(6±2.2)\tL: 0.2\n(52.5±3.8)\tL: 0.48\n(4.5±2.7)\tL: 34.3\n(24.4±3.3)\tL: 0\n(23.6±3.5)\t\nMNCV, motor nerve conduction velocity; SNAPs, sensory nerve action potentials; R, right; L, left.\n==== Refs\nReferences\n1 Ball P Mandell L Niki Y Tillotson G Comparative tolerability of the newer fluoroquinolone antibacterials Drug Saf 1999 11 21 (5) 407 21 10554054 \n2 Lietman PS Fluoroquinolone toxicities. An update Drugs 1995 49 Suppl 2 159 63 8549287 \n3 Hedenmalm K Spigset O Peripheral sensory disturbances related to treatment with fluoroquinolones J Antimicrob Chemother 1996 4 37 (4) 831 7 8722551 \n4 Zehnder D Hoigné R Neftel KA Sieber R Painful dysaesthesia with ciprofloxacin BMJ 1995 11 311 (7014) 1204 \n5 Cohen JS Peripheral neuropathy associated with fluoroquinolones Ann Pharmacother 2001 12 35 (12) 1540 7 11793615 \n6 Mandell L Tillotson G Safety of fluoroquinolones an update Can J Infect Dis 2002 1 13 (1) 54 61 18159374 \n7 Van den Bergh PY Piéret F Electrodiagnostic criteria for acute and chronic inflammatory demyelinating polyradiculoneuropathy Muscle Nerve 2004 4 29 (4) 565 74 15052622 \n8 Kokubun N Nishibayashi M Uncini A Odaka M Hirata K Yuki N Conduction block in acute motor axonal neuropathy Brain 2010 10 133 (10) 2897 908 20855419 \n9 Verma V Singh N Singh Jaggi A Pregabalin in neuropathic pain evidences and possible mechanisms Curr Neuropharmacol 2014 1 12 (1) 44 56 24533015 \n10 Jumma OK Dick J Marshall A Mellor K Ciprofloxacin induced acute small fibre neuropathy Case report Can J Neurol Sci 2013 1 40 (1) 127 8 23427360 \n11 Schmidt S Cordt-Schlegel A Heitmann R Guillain-Barré syndrome during treatment with ofloxacin J Neurol 1993 9 240 (8) 506 7 8263558 \n12 Etminan M Brophy JM Samii A Oral fluoroquinolone use and risk of peripheral neuropathy a pharmacoepidemiologic study Neurology 2014 9 83 (14) 1261 3 25150290 \n13 Barohn RJ Saperstein DS Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy Semin Neurol 1998 18 (1) 49 61 9562667 \n14 Van den Bergh PY Hadden RD Bouche P Cornblath DR Hahn A Illa I European Federation of Neurological Societies; Peripheral Nerve Society European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society - first revision Eur J Neurol 2010 3 17 (3) 356 63 20456730 \n15 McCombe PA Pollard JD McLeod JG Chronic inflammatory demyelinating polyradiculoneuropathy A clinical and electrophysiological study of 92 cases Brain 1987 12 110 (Pt 6) 1617 30 3427403 \n16 Rees JH Soudain SE Gregson NA Hughes RA Campylobacter jejuni infection and Guillain-Barré syndrome N Engl J Med 1995 11 333 (21) 1374 9 7477117 \n17 Gupta D Nair M Baheti NN Sarma PS Kuruvilla A Diplomate-American Board. Electrodiagnostic and clinical aspects of Guillain-Barré syndrome an analysis of 142 cases J Clin Neuromuscul Dis 2008 12 10 (2) 42 51 19169089 \n18 Ali AK Peripheral neuropathy and Guillain-Barré syndrome risks associated with exposure to systemic fluoroquinolones a pharmacovigilance analysis Ann Epidemiol 2014 4 24 (4) 279 85 24472364 \n19 Stahlmann R Lode H Fluoroquinolones in the elderly safety considerations Drugs Aging 2003 20 (4) 289 302 12641485 \n20 Manzoor M Runcie J Folate-responsive neuropathy report of 10 cases BMJ 1976 5 1 (6019) 1176 8 1268613 \n21 Botez MI Peyronnard JM Bachevalier J Charron L Polyneuropathy and folate deficiency Arch Neurol 1978 9 35 (9) 581 4 210747 \n22 Koike H Takahashi M Ohyama K Hashimoto R Kawagashira Y Iijima M Clinicopathologic features of folate-deficiency neuropathy Neurology 2015 3 84 (10) 1026 33 25663227 \n23 Martinez Figueroa A Johnson RH Lambie DG Shakir RA The role of folate deficiency in the development of peripheral neuropathy caused by anticonvulsants J Neurol Sci 1980 12 48 (3) 315 23 6255104 \n24 Yukawa M Naka H Murata Y Katayama S Kohriyama T Mimori Y Folic acid-responsive neurological diseases in Japan J Nutr Sci Vitaminol (Tokyo) 2001 6 47 (3) 181 7 11575572 \n25 Neu HC Gootz TD Chapter 11. Antimicrobial chemotherapy Baron S Medical microbiology 1996 4th ed Galveston (TX) University of Texas Medical Branch at Galveston \n26 Yigit S Karakus N Inanir A Association of MTHFR gene C677T mutation with diabetic peripheral neuropathy and diabetic retinopathy Mol Vis 2013 7 19 1626 30 23901246 \n27 Wu S Han Y Hu Q Zhang X Cui G Li Z Effects of common polymorphisms in the MTHFR and ACE genes on diabetic peripheral neuropathy progression a meta-analysis Mol Neurobiol 2017 5 54 (4) 2435 44 26971290 \n28 Yilmaz M Aktug H Oltulu F Erbas O Neuroprotective effects of folic acid on experimental diabetic peripheral neuropathy Toxicol Ind Health 2016 5 32 (5) 832 40 24311627\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-680X",
"issue": "10(2)",
"journal": "Case reports in neurology",
"keywords": "Acute motor and sensory axonal neuropathy; Fluoroquinolones; Folate deficiency; Side effects; Therapy-induced peripheral neuropathy",
"medline_ta": "Case Rep Neurol",
"mesh_terms": null,
"nlm_unique_id": "101517693",
"other_id": null,
"pages": "124-129",
"pmc": null,
"pmid": "29928218",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "19169089;7488901;20855419;11793615;11575572;6255104;26971290;8549287;3427403;24472364;25150290;1268613;7477117;24533015;24311627;20456730;8263558;12641485;23901246;23427360;10554054;25663227;18159374;8722551;15052622;9562667;210747",
"title": "Severe Acute Axonal Neuropathy Induced by Ciprofloxacin: A Case Report.",
"title_normalized": "severe acute axonal neuropathy induced by ciprofloxacin a case report"
} | [
{
"companynumb": "FR-SUN PHARMACEUTICAL INDUSTRIES LTD-2018RR-190671",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CIPROFLOXACIN"
},
"d... |
{
"abstract": "A 75-year-old woman with rheumatoid arthritis on rituximab presented with a 1-week history of constipation and abdominal distension. Subsequent workup showed presence of air in the bowel wall without perforation initially. Due to positive blood cultures, worsening leucocytosis and high suspicion for perforation, an exploratory laparotomy was performed revealing necrotic bowel, walled off perforation and abscess. Patient underwent right hemicolectomy with diversion loop ileostomy. Clinicians must recognise that monoclonal antibodies like rituximab can mask signs of inflammation and therefore should maintain a high index of suspicion for intestinal perforation when evaluating patients with minimal symptoms and pneumatosis intestinalis.",
"affiliations": "Department of Internal Medicine, Unity Hospital, Greece, New York, USA.;Department of Internal Medicine, Universidad Autonoma Metropolitana - Xochimilco, Coyoacan, Mexico.;Department of Internal Medicine, Unity Hospital, Greece, New York, USA.;Department of Pathology, Unity Hospital, Greece, New York, USA.",
"authors": "Tirumanisetty|Pratyusha|P|http://orcid.org/0000-0001-7497-9870;Sotelo|Jose William|JW|;Disalle|Michael|M|;Sharma|Meenal|M|",
"chemical_list": "D018501:Antirheumatic Agents; D000069283:Rituximab",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-229329",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(7)",
"journal": "BMJ case reports",
"keywords": "air leaks; gastroenterology; rheumatoid arthritis",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D003082:Colectomy; D005260:Female; D006801:Humans; D007081:Ileostomy; D007813:Laparotomy; D011006:Pneumatosis Cystoides Intestinalis; D000069283:Rituximab; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31366614",
"pubdate": "2019-07-30",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "1052668;3287869;23169717;22967460;22479281;25802792;21835823;29181149;4120645;9530294;20871638",
"title": "Pneumatosis intestinalis: cost paid for rheumatoid arthritis treatment.",
"title_normalized": "pneumatosis intestinalis cost paid for rheumatoid arthritis treatment"
} | [
{
"companynumb": "US-ROCHE-2388761",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
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{
"abstract": "OBJECTIVE\nThe aim of the present study was to assess the potential risk of hepatitis B virus (HBV) vertical transmission among Turkish parturient women and to evaluate the efficacy and safety of antiviral agents.\n\n\nMETHODS\nData were collected retrospectively from 114 HBV-infected pregnant women and their infants in eight health institutions in Turkey.\n\n\nRESULTS\nThe baseline characteristics of the women were: mean age, 28.3 ± 5.2 years; alanine aminotransferase, 57.4 ± 139.0 U/L; aspartate aminotransferase, 56.6 ± 150.0 U/L; and HBV DNA, 8.3 × 10(7) ± 2.6 × 10(8) copies/mL. Family history of HBV infection was detected in 53.5% (n = 61). In total, 60 (52.6%) pregnant women received tenofovir (60.0%), lamivudine (33.3%) or telbivudine (6.7%) therapy at the median gestational age of 22.2 ± 8.5 (1-36) weeks. All infants were vaccinated and hepatitis B immune globulin was administered, with 81 of them (71.1%) available for follow-up. After completion of HBV vaccination course, 71 (87.7%) infants had protective anti-HBs levels, three (3.7%) were hepatitis B surface antigen-positive, and seven (8.6%) were hepatitis B surface antigen-negative with nonprotective anti-HBs levels. Five of the infants had low gestational birthweight but no other birth defects were observed.\n\n\nCONCLUSIONS\nAccording to our results, viral load may not be the only effecting factor for transmission of HBV to children of infected mothers. Pregnant women with high viral load should be followed-up closely during pregnancy. They should begin to take tenofovir or telbivudine, which are category B drugs for pregnancy, at the beginning of the third trimester at the latest. We need new treatment strategies; and close follow-up of mothers and children is another important issue.",
"affiliations": "Department of Infectious Diseases and Clinical Microbiology, Faculty of Medicine, Harran University, Sanliurfa, Turkey.;Department of Infectious Diseases and Clinical Microbiology, Kartal Dr. Lutfi Kirdar Training and Research Hospital, Istanbul, Turkey.;Department of Infectious Diseases and Clinical Microbiology, Izmir Tepecik Training and Research Hospital, Izmir, Turkey.;Department of Infectious Diseases and Clinical Microbiology, Kocaeli University Faculty of Medicine, Kocaeli, Turkey.;Department of Infectious Diseases and Clinical Microbiology, Faculty of Medicine, Erciyes University, Kayseri, Turkey.;Department of Infectious Diseases and Clinical Microbiology, Ankara Training and Research Hospital, Ankara, Turkey.;Department of Infectious Diseases and Clinical Microbiology, Ankara Training and Research Hospital, Ankara, Turkey.;Department of Infectious Diseases and Clinical Microbiology, Ankara Training and Research Hospital, Ankara, Turkey.;Department of Infectious Diseases and Clinical Microbiology, Faculty of Medicine, Erciyes University, Kayseri, Turkey.;Department of Infectious Diseases and Clinical Microbiology, Kartal Yavuz Selim Training and Research Hospital, Istanbul, Turkey.;Department of Infectious Diseases and Clinical Microbiology, Faculty of Medicine, Abant Izzet Baysal University, Bolu, Turkey.;Department of Infectious Diseases and Clinical Microbiology, Kocaeli University Faculty of Medicine, Kocaeli, Turkey.",
"authors": "Tekin Koruk|Suda|S|;Batirel|Ayse|A|;Kose|Sukran|S|;Cetin Akhan|Sila|S|;Aygen|Bilgehan|B|;Tulek|Necla|N|;Hatipoglu|Çigdem|Ç|;Bulut|Cemal|C|;Yıldız|Orhan|O|;Sacligil|Cahide|C|;Sirmatel|Fatma|F|;Altunok|Elif|E|",
"chemical_list": "D000998:Antiviral Agents; D006514:Hepatitis B Surface Antigens",
"country": "Australia",
"delete": false,
"doi": "10.1111/jog.12821",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-8076",
"issue": "41(12)",
"journal": "The journal of obstetrics and gynaecology research",
"keywords": "antiviral therapy; hepatitis B; perinatal transmission; pregnancy",
"medline_ta": "J Obstet Gynaecol Res",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000998:Antiviral Agents; D005260:Female; D006509:Hepatitis B; D006514:Hepatitis B Surface Antigens; D006801:Humans; D018445:Infectious Disease Transmission, Vertical; D011247:Pregnancy; D012189:Retrospective Studies",
"nlm_unique_id": "9612761",
"other_id": null,
"pages": "1870-6",
"pmc": null,
"pmid": "26369498",
"pubdate": "2015-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Evaluation of hepatitis B virus transmission and antiviral therapy among hepatitis B surface antigen-positive pregnant women.",
"title_normalized": "evaluation of hepatitis b virus transmission and antiviral therapy among hepatitis b surface antigen positive pregnant women"
} | [
{
"companynumb": "TR-CIPLA LTD.-2015TR07696",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LAMIVUDINE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nDisulfiram is a potential cocaine addiction pharmacotherapy. Since dopamine deficiency has been found with cocaine addiction, our objective was to examine whether functional variants in the ankyrin repeat and kinase domain-containing 1 (ANKK1) and/or the dopamine receptor D2 (DRD2) genes interact with response to treatment with disulfiram.\n\n\nMETHODS\nCocaine and opioid codependent (DSM-IV) patients were stabilized on methadone and subsequently randomized into treatment groups - disulfiram (250 mg/day, N=31) or placebo (N=37). They were genotyped for ANKK1 (rs1800497) and DRD2 (rs2283265) polymorphisms, and the data were evaluated for an association between a cocaine-free state, as assessed by cocaine-free urine samples, and disulfiram treatment. Data were analyzed using repeated measures analysis of variance corrected for population structure.\n\n\nRESULTS\nPatients with CT or TT ANKK1 genotypes dropped from 80 to 52% cocaine-positive urines on disulfiram (N=13; P≤0.0001), whereas those on placebo (N=20) showed no treatment effect. Patients carrying the CC ANKK1 genotype showed no effect on treatment with disulfiram (N=18) or placebo (N=17). The GT/TT DRD2 genotype group showed a significant decrease in the number of cocaine-positive urine samples on disulfiram (N=9; 67-48%; P ≤ 0.0001), whereas the GG DRD2 genotype group showed only a marginal decrease (N=23; 84-63%; P=0.04). Genotype pattern analysis revealed that individuals carrying at least one minor allele in either gene responded better to disulfiram treatment (N=13; P ≤ 0.0001) compared with individuals carrying only the major alleles (N=17).\n\n\nCONCLUSIONS\nA patient's genotype for ANKK1, DRD2, or both, may be used to identify individuals for whom disulfiram may be an effective pharmacotherapy for cocaine dependence.",
"affiliations": "Menninger Department of Psychiatry and Behavioral Sciences, Michael E. DeBakey VA Medical Center, Baylor College of Medicine, Houston, Texas 77030, USA. spellicy@bcm.edu",
"authors": "Spellicy|Catherine J|CJ|;Kosten|Thomas R|TR|;Hamon|Sara C|SC|;Harding|Mark J|MJ|;Nielsen|David A|DA|",
"chemical_list": "C581293:DRD2 protein, human; D017448:Receptors, Dopamine D2; C489948:ANKK1 protein, human; D017346:Protein Serine-Threonine Kinases; D004221:Disulfiram; D008691:Methadone",
"country": "United States",
"delete": false,
"doi": "10.1097/FPC.0b013e328361c39d",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1744-6872",
"issue": "23(7)",
"journal": "Pharmacogenetics and genomics",
"keywords": null,
"medline_ta": "Pharmacogenet Genomics",
"mesh_terms": "D000328:Adult; D000483:Alleles; D019970:Cocaine-Related Disorders; D004221:Disulfiram; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008691:Methadone; D011110:Polymorphism, Genetic; D017346:Protein Serine-Threonine Kinases; D017448:Receptors, Dopamine D2",
"nlm_unique_id": "101231005",
"other_id": null,
"pages": "333-40",
"pmc": null,
"pmid": "23635803",
"pubdate": "2013-07",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't; D013486:Research Support, U.S. Gov't, Non-P.H.S.",
"references": "22925276;9692270;19853839;11015800;3661284;22893251;12587665;9636219;9881538;18828801;11343878;1318260;17543096;7851277;17085484;12814496;12804445;9241388;8807661;16427255;8261891;12762588;7882871;15146457;10395223;8289892;16163519;8685891;17615493;22906516;15370155;10723850;16503828;15995696;12875097;3343591;21150907;9337772;10862808;16829955;2700602;16766132;8894071;2069496;17850642;1969501;14993114;9672901;8974314;22382052;16395294;1839129;12076433;15027564;1334156;17761687;7832267;11054765;12511059;18698520;9429233;18077373;12044196;18332877;1832466;9311924;9848033",
"title": "ANKK1 and DRD2 pharmacogenetics of disulfiram treatment for cocaine abuse.",
"title_normalized": "ankk1 and drd2 pharmacogenetics of disulfiram treatment for cocaine abuse"
} | [
{
"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-20-04404",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHADONE HYDROCHLORIDE"
},... |
{
"abstract": "This report describes the occurrence of asymptomatic hyperkalemia induced by the sequential administration of metoprolol and carvedilol in an 81-year-old man with type II diabetes and stable stage III renal insufficiency. The potassium level rose to 5.6-5.7 mEq/L with metoprolol and normalized when the agent was discontinued. However, the potassium level rose again to 5.6 mEq/L after the administration of carvedilol but the level normalized by halving the dose. The observations of hyperkalemia induced by two different β-blocker drugs in the same patient confirm that this side effect is common to all β-blocker drugs.",
"affiliations": "Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.;San Diego Internal Medicine and Pediatrics Associates, San Diego, CA, USA.",
"authors": "Barold|S Serge|SS|0000-0003-4951-6465;Upton|Scott|S|",
"chemical_list": null,
"country": "United States",
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"fulltext": "\n==== Front\nCase Rep CardiolCase Rep CardiolCRICCase Reports in Cardiology2090-64042090-6412Hindawi 10.1155/2018/7686373Case ReportHyperkalemia Induced by the Sequential Administration of Metoprolol and Carvedilol http://orcid.org/0000-0003-4951-6465Barold S. Serge ssbarold@aol.com\n1\nUpton Scott \n2\n\n1Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA\n2San Diego Internal Medicine and Pediatrics Associates, San Diego, CA, USAAcademic Editor: Magnus Baumhäkel\n\n2018 15 10 2018 2018 768637323 7 2018 24 9 2018 Copyright © 2018 S. Serge Barold and Scott Upton.2018This 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.This report describes the occurrence of asymptomatic hyperkalemia induced by the sequential administration of metoprolol and carvedilol in an 81-year-old man with type II diabetes and stable stage III renal insufficiency. The potassium level rose to 5.6–5.7 mEq/L with metoprolol and normalized when the agent was discontinued. However, the potassium level rose again to 5.6 mEq/L after the administration of carvedilol but the level normalized by halving the dose. The observations of hyperkalemia induced by two different β-blocker drugs in the same patient confirm that this side effect is common to all β-blocker drugs.\n==== Body\n1. Introduction\nHyperkalemia is a rare side effect of β-blocker drugs [1–3]. In this report, we describe the occurrence of metoprolol-induced hyperkalemia in a patient with type 2 diabetes and stage III renal dysfunction. The potassium level normalized after metoprolol was discontinued, but the administration of carvedilol subsequently induced hyperkalemia. The development of hyperkalemia in the same patient induced by two different β-blocker drugs has not been previously reported.\n\n2. Case Report\nAn 81-year-old man presented with asymptomatic of hyperkalemia (5.7 mEq/L). The past history included mitral valve repair and coronary bypass surgery 27 years previously, mild type II diabetes for 12 years, renal insufficiency (stage III) with a stable creatinine level of 1.5 mg/dL for 8 years and prostatic hypertrophy. An echocardiogram performed 6 months previously revealed normal left ventricular function and minimal mitral regurgitation and an ECG documented sinus rhythm and complete left bundle branch block. Medications included Avodart 0.5 mg qd, atorvastatin 80 mg qd, aspirin 325 mg qd, Januvia 25 mg qd, and metoprolol tartrate 50 mg bid. The latter had been prescribed 6 years previously for frequent symptomatic atrial premature beats with an excellent clinical result so that metoprolol at the same dose (all tartrate preparation) was continued up to the most recent evaluation. The potassium level had always been normal before the administration of metoprolol. Afterwards, routine testing with serum electrolytes every 6 or 12 months consistently revealed a potassium level of 5.4 mEq/L. Then, for the last 2 years regular routine testing revealed a potassium level fluctuating between 5.6 and 5.7 mEq/L. Finally, metoprolol was discontinued and 18 days later the potassium level normalized at 4.2 mEq/L. Carvedilol was started and then increased to 12.5 mg bid. After about 10 days on this dose, the potassium level increased to 5.6 mEq/L. The dose of carvedilol was therefore reduced to 6.25 mg bid. A follow-up potassium level 2 weeks after the start of the lower carvedilol dose was 5.0 mEq/L which is at the upper limit of normal for the testing laboratory.\n\n3. Discussion\n\nβ-Blocker-induced hyperkalemia is a rare nonspecific side effect of β-blocker therapy as illustrated by the effect from two different β-blockers in the same patient. It appears from a review of the literature that a biological difference between the 2 available forms of metoprolol, tartrate or succinate, is unlikely.\n\n3.1. Metoprolol\nA 2018 FDA report evaluated the incidence of hyperkalemia (level not stated) in 24,296 patients taking metoprolol succinate and found 287 patients with hyperkalemia [4]. The patients with hyperkalemia were taking ramipil (41.5%) or spironolactone (10.4%). No other potassium-retaining drugs were taken. An increased creatinine was present in 20.56% and acute renal failure in 33.80% of the patients. The FDA report suggests that metoprolol-induced hyperkalemia occurs in about 0.5% of the patients without acute renal failure and can occur in patients without diabetes or renal dysfunction. Yet, there are only two Medline citations about this side effect of metoprolol. One case involved a 45-year-old hypertensive diabetic man with advanced renal failure on hemodialysis who developed marked recurrent hyperkalemia while on metoprolol therapy (full preparation not stated) [1]. The other case documented hyperkalemia as a result of a suicide with metoprolol [5].\n\n3.2. Propranolol\nPropranolol has rarely been reported to induce hyperkalemia in the adult patient, though it is well documented as a serious problem when it is used to treat hemangiomas in infants [3, 6, 7].\n\n3.3. Carvedilol\nIn our case, the potassium level rose to 5.6 mEq/L when the patient (with type III renal insufficiency) was on carvedilol 12.5 mg bid but it normalized (though at the upper limit of normal—5 mEq/L) when the dose of carvedilol was reduced to 6.25 mg bid. A similar observation was recently reported about carvedilol-induced hyperkalemia in a 69-year-old man with hypertension, type II diabetes, and stage III renal insufficiency who was hospitalized for abdominal pain [2]. He had been on carvedilol 3.125 mg bid and lisinopril 40 mg qd. The serum potassium was 4.8 mEq/L. When carvedilol was increased to 6.25 mg bid, the serum potassium rose to 6.7 mEq/L without any change in lisinopril dosage or administration of other potassium-retaining drugs. A simple reduction back to the original dose normalized the potassium level [2]. These two reports suggest that the development of hyperkalemia is dose dependent.\n\n3.4. Labetalol\nIntravenous labetalol has been associated with severe hyperkalemia for the treatment of acute hypertension in hemodialysis patients, renal transplant patients, and in preeclampsia [8–10].\n\n3.5. Timolol Eyedrops\nSevere hyperkalemia occurred in a patient with glaucoma following the use of timolol maleate eyedrops, but the serum potassium level normalized upon discontinuation of the eyedrops [11]. However, hyperkalemia recurred following a rechallenge with the same eyedrops and the potassium level normalized again when the eyedrops were withdrawn.\n\n4. Mechanisms\nIt is well known that adrenergic agents decrease serum potassium and hence are used to treat life-threatening hyperkalemia. β2 adrenergic agonists drive potassium into the cells by increasing the activity of the Na-K pump. Thus, a catecholamine surge tends to lower the serum potassium [12]. They also activate the inwardly directed Na-K-Cl cotransporter, a protein that aids in the active transport of sodium, potassium, and chloride into cells [12]. Yet, the opposite effect with the production of hyperkalemia by the inhibition of the sympathetic system as with β-blockers has only occasionally been reported. The propensity to hyperkalemia may be masked or unrecognized because β-blockers are commonly administered together with drugs that affect potassium balance.\n\nBarring the acute administration of a β-blocker drug, there are only 4 well-documented case reports of β-blocker-induced hyperkalemia from sustained therapy (3 from the literature and one described herein). Three cases had associated renal dysfunction and diabetes, while one had none of these associations. Insulin similar to epinephrine enhances the activity of the Na-K pump so that an anti-insulin effect in diabetes would favor the movement of potassium outside the cells [12]. Renal insufficiency decreases the cell membrane potential and thus leads to translocation of potassium to the extracellular fluid [13]. The above clinical cases confirm the FDA data that renal insufficiency is a strong predisposing factor to the development of β-blocker-induced hyperkalemia. These cases also suggest a probable association with diabetes, though the FDA data revealed a 10% incidence perhaps because of a different patient population. Finally, it is possible that hyperkalemia may be due to a genetic predisposition.\n\n5. Conclusion\nWe have reported metoprolol-induced and carvedilol-induced hyperkalemia. Such hyperkalemia is rare and seems to be a common side effect of β-blockers. Hyperkalemia is more common in patients with renal insufficiency and probably in those with diabetes. Identification of this form of hyperkalemia may avoid unnecessary investigations and prevent untoward effects. In patients with stable renal insufficiency, β-blocker-induced hyperkalemia should not be attributed to progression of kidney disease causing unwarranted alarm and inappropriate therapy. This form of hyperkalemia may be dose dependent so that normalization of the potassium level may not necessarily require complete withdrawal of therapy.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest.\n==== Refs\n1 Ashouri O. S. Metoprolol-induced hyperkalemia in a diabetic with advanced renal failure Archives of Internal Medicine 1985 145 3 p. 578 10.1001/archinte.1985.00360030230056 2-s2.0-0022038616 \n2 Hahn L. Hahn M. Carvedilol-induced hyperkalemia in a patient with chronic kidney disease Journal of Pharmacy Practice 2015 28 1 107 111 10.1177/0897190014566306 2-s2.0-84924910292 25715086 \n3 Mandić D. Nezić L. Skrbić R. Severe hyperkalemia induced by propranolol Medicinski Pregled 2014 67 5-6 181 184 10.2298/MPNS1406181M 2-s2.0-85005847961 25033579 \n4 Toprol and hyperkalemia From an FDA report May 2018, https://www.ehealthme.com/ds/metoprolol-succinate/hyperkalemia/ \n5 Delacour J. L. Blanc P. L. Wagschal G. Daoudal P. Hyperkalemie au cours d’une intoxication aigue par beta-blocqueur Presse Médicale 1988 15 p. 1377 \n6 Belen B. Oguz A. Okur A. Dalgic B. A complication to be aware of: hyperkalaemia following propranolol therapy for an infant with intestinal haemangiomatozis BMJ Case Reports 2014 2014 10.1136/bcr-2014-203746 2-s2.0-84901374637 24842358 \n7 Pavlakovic H. Kietz S. Lauerer P. Zutt M. Lakomek M. Hyperkalemia complicating propranolol treatment of an infantile hemangioma Pediatrics 2010 126 6 e1589 e1593 10.1542/peds.2010-0077 2-s2.0-78649651541 21115582 \n8 Thomas B. Abdul Rouf P. V. Kassem W. E. A case of probable labetalol induced hyperkalaemia in pre-eclampsia International Journal of Clinical Pharmacy 2014 36 6 1130 1133 10.1007/s11096-014-0021-z 2-s2.0-84922071258 25370900 \n9 Hamad A. Salameh M. Zihlif M. Feinfeld D. A. Carvounis C. P. Life-threatening hyperkalemia after intravenous labetolol injection for hypertensive emergency in a hemodialysis patient American Journal of Nephrology 2001 21 3 241 244 10.1159/000046255 2-s2.0-0034944819 11423696 \n10 Arthur S. Greenberg A. Hyperkalemia associated with intravenous labetalol therapy for acute hypertension in renal transplant recipients Clinical Nephrology 1990 33 6 269 271 2376088 \n11 Swenson E. R. Severe hyperkalemia as a complication of timolol, a topically applied β -adrenergic antagonist Archives of Internal Medicine 1986 146 6 1220 1221 10.1001/archinte.1986.00360180240037 2-s2.0-0022486432 3718111 \n12 Mount D. B. Brenner B. M. Disorders of potassium balance Brenner and Rector’s The Kidney 2016 10th Philadelphia, PA, USA WB Saunders Co 559 600 \n13 Cotton J. R. Woodard T. Carter N. W. Knochel J. P. Resting skeletal muscle membrane potential as an index of uremic toxicity: a proposed new method to assess adequacy of hemodialysis The Journal of Clinical Investigation 1979 63 3 501 506 10.1172/JCI109328 2-s2.0-0018344490 429569\n\n",
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"title": "Hyperkalemia Induced by the Sequential Administration of Metoprolol and Carvedilol.",
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"abstract": "Trigeminal neuralgia is a chronic and debilitating syndrome characterized by short paroxysms of lancinating facial pain. Patients may be medically managed; however, in cases of medically refractory trigeminal neuralgia, surgical management is often required. Our objective was to present and describe a technique for endoscopic microdissection of the infraorbital nerve, a peripheral method of management for refractory V2 trigeminal neuralgia in patients without evidence of neurovascular compression. The technique is designed to spare sensation in unaffected portions of the V2 distribution. We present 2 patients with medically refractory V2 trigeminal neuralgia localized to the lateral midface who underwent infraorbital microdissection. After first confirming that there was no neurovascular compression on imaging in these patients, we administered infraorbital bupivacaine injections to localize the symptomatic nerve. The nerve was then accessed via a 1.5-cm buccogingival incision, and the connective tissue sheath was incised. The nerve fascicles were bluntly separated, and the symptomatic branches were cauterized with fine-tipped monopolar cautery. Both patients reported complete resolution of their pain postoperatively and were pain free at last follow-up. They reported some hypoesthesia in the lateral face; however, they retained some sensation in the medial upper lip, midface, and nose. Infraorbital microdissection is a safe and effective technique for symptomatic management of V2 trigeminal neuralgia while sparing sensation in asymptomatic portions of the dermatome.",
"affiliations": "Medical Student, Department of Neurological Surgery, New Jersey Medical School, Newark, NJ. Electronic address: MaxWard94@gmail.com.;Neurosurgery Resident, Department of Neurological Surgery, New Jersey Medical School, Newark, NJ.;Assistant Professor of Neurosurgery, Department of Neurological Surgery, New Jersey Medical School, Newark, NJ.;Assistant Professor of Otolaryngology-Head and Neck Surgery, Department of Otolaryngology-Head and Neck Surgery, New Jersey Medical School, Newark, NJ.",
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"mesh_terms": "D004724:Endoscopy; D006801:Humans; D008442:Maxillary Nerve; D042282:Microdissection; D010146:Pain; D014276:Trigeminal Nerve; D014277:Trigeminal Neuralgia",
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"abstract": "We report 2 cases of metastatic rectal cancer patients who received chemotherapy with FOLFOXIRI plus bevacizumab(Bev). Case 1: A 54-year-old woman diagnosed with advanced rectal cancer with synchronous liver metastasis underwent a laparoscopic low anterior resection. After the operation, she received FOLFOXIRI plus Bev treatment, and experienced Grade 4 adverse events, including dyspnea and ventricular fibrillation(Vf). After chemotherapy, no other metastasis was detected except a liver metastasis, and partial resection of the liver was performed. Histopathological evaluation revealed that the effect of the chemotherapy was Grade 1a. After liver resection, FOLFOXIRI plus Bev was administered, and a recurrence of the rectal cancer was not detected. Case 2: A 44-year-old woman was diagnosed with advanced rectal cancer with synchronous liver metastasis, distant lymph nodes metastasis, and vaginal invasion. First a colostomy was performed and FOLFOXIRI plus Bev treatment was administered. Grade 3 adverse events, including tremor, neuralgia, and anemia occurred, and chemotherapy was stopped for 3 months. Her adverse events were not under control when progression of the disease was detected, and her treatment was changed to another chemotherapy regimen.",
"affiliations": "Dept. of Surgery, Fuchu Hospital.",
"authors": "Nishii|Takafumi|T|;Uchima|Yasutake|Y|;Yamakoshi|Yoshihito|Y|;Wang|En|E|;Nagashima|Daisuke|D|;Hirakawa|Toshiki|T|;Aomatsu|Naoki|N|;Iwauchi|Takehiko|T|;Morimoto|Junya|J|;Nakazawa|Kazunori|K|;Tei|Seika|S|;Takeuchi|Kazuhiro|K|",
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"title": "Two Cases of Metastatic Rectal Cancer Patients Who Received Chemotherapy with FOLFOXIRI plus Bevacizumab.",
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"abstract": "Practice guidelines recommend nonopioid medications in children after tonsillectomy, but to date, studies have not used recent national data to assess perioperative opioid prescribing patterns or the factors associated with these patterns in this population. Closing this knowledge gap may help in assessing whether such prescribing and prescription duration could be safely reduced.\nTo assess national perioperative opioid prescribing patterns, clinical and demographic factors associated with these patterns, and association between these patterns and complications in children after tonsillectomy compared with children not using opioids.\nThis cohort analysis used the 2016 to 2017 claims data from the database of a large national private insurer in the United States. Opioid-naive children aged 1 to 18 years with a claims code for tonsillectomy with or without adenoidectomy between April 1, 2016, and December 15, 2017, were identified (n = 22 567) and screened against the exclusion criteria. The final sample included 15 793 children.\nThe percentage of children with 1 or more perioperative fills (prescription drug claims for opioids between 7 days before to 1 day after tonsillectomy) was calculated, along with the duration of perioperative prescriptions (days supplied). Linear regression was used to identify the demographic and clinical factors associated with the duration of perioperative opioid prescriptions. Logistic regression was used to assess the association between having 1 or more perioperative fills and their duration and the risk of return visits 2 to 14 days after tonsillectomy for pain or dehydration, secondary hemorrhage, and constipation compared with children not using opioids.\nAmong 15 793 children, the mean (SD) age was 7.8 (4.2) years, 12 807 (81.1%) were younger than 12 years, 2986 (18.9%) were between 12 and 18 years of age, and 8289 (52.6%) were female. In total, 9411 (59.6%) children had 1 or more perioperative fills, and the median (25th-75th percentile) duration was 8 (6-10) days; 6382 had no perioperative fills. The probability of having 1 or more perioperative fills and the duration of prescription varied across US census divisions. Having 1 or more perioperative fills was not associated with return visits for pain or dehydration (adjusted odds ratio [AOR], 1.13; 95% CI, 0.95-1.34) or secondary hemorrhage (AOR, 0.90; 95% CI, 0.73-1.10) compared with children not using opioids, but it was associated with increased risk of return visits for constipation (AOR, 2.02; 95% CI, 1.24-3.28). Duration was not associated with return visits for complications.\nThese findings suggest that reducing perioperative opioid prescribing and the duration of perioperative opioid prescriptions may be possible without increasing the risk of these complications.",
"affiliations": "Department of Pediatrics, Susan B. Meister Child Health Evaluation and Research Center, University of Michigan, Ann Arbor.;National Clinician Scholars Program, Institute for Healthcare Policy and Innovation, University of Michigan, Ann Arbor.;Michigan Opioid Prescribing Engagement Network, Ann Arbor.;Department of Otolaryngology-Head and Neck Surgery, University of Michigan Medical School, Ann Arbor.;Department of Otolaryngology-Head and Neck Surgery, University of Michigan Medical School, Ann Arbor.;Department of Otolaryngology-Head and Neck Surgery, University of Michigan Medical School, Ann Arbor.;Department of Otolaryngology-Head and Neck Surgery, University of Michigan Medical School, Ann Arbor.",
"authors": "Chua|Kao-Ping|KP|;Harbaugh|Calista M|CM|;Brummett|Chad M|CM|;Bohm|Lauren A|LA|;Cooper|Karen A|KA|;Thatcher|Aaron L|AL|;Brenner|Michael J|MJ|",
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"title": "Association of Perioperative Opioid Prescriptions With Risk of Complications After Tonsillectomy in Children.",
"title_normalized": "association of perioperative opioid prescriptions with risk of complications after tonsillectomy in children"
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{
"abstract": "A patient developed marked cerebellar atrophy after a single suicidal intoxication with 7 grams phenytoin. The clinical signs of cerebellar dysfunction subsided very slowly and incompletely within 18 months. We documented the cerebellar atrophy by CTs 4 weeks and 1 year after the intoxication, and we suggest that a single severe acute intoxication with phenytoin may directly cause cerebellar degeneration.",
"affiliations": "Department of Neurology, University of Münster, FRG.",
"authors": "Masur|H|H|;Elger|C E|CE|;Ludolph|A C|AC|;Galanski|M|M|",
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"mesh_terms": "D000328:Adult; D001284:Atrophy; D002526:Cerebellar Diseases; D002531:Cerebellum; D006801:Humans; D008297:Male; D010672:Phenytoin; D014057:Tomography, X-Ray Computed",
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"title": "Cerebellar atrophy following acute intoxication with phenytoin.",
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"activesubstancename": "VALPROATE SODIUM"
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"abstract": "Several immune mechanisms are suspected in the unknown etiology of West syndrome (WS). We report a male infant who suffered from WS and X-linked T-B+NK- severe combined immunodeficiency (X-SCID) with a missense mutation of the IL2RG gene (c.202G>A, p.Glu68Lys). He promptly began vitamin B6 and valproic acid treatment, but infantile spasms (IS) and hypsarrhythmia persisted. Administration of intravenous immunoglobulin and the change to topiramate (TPM) at 7 months of age resulted in the rapid resolution of IS. The CD4/8 ratio in his peripheral blood increased from 0.04-0.09 to 0.20-1.95 following unrelated cord blood transplantation (UCBT). In vitro lymphocyte proliferation in response to phytohemagglutinin or concanavalin A and the ability of B lymphocytes to produce antibodies improved as well. Electroencephalogram findings became normal 1 month after UCBT. Thus, we consider that T-cell dysfunction and/or impairments in T-B cell interactions due to X-SCID may have played important roles in the onset of WS. Immune-modulating therapies along with the administration of TPM effectively treated this severe epileptic syndrome in our patient.",
"affiliations": "Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan.;Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan. Electronic address: inabay@shinshu-u.ac.jp.;Department of Neuropediatrics, Nagano Children's Hospital, Azumino, Japan.;Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan.;Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan.;Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan.;Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan.;Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan.;Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan.;Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan.;Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan.;Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan.;Department of Infection and Host Defense, Graduate School of Medicine, Shinshu University, Matsumoto, Japan.;Department of Family and Child Nursing, Shinshu University School of Medicine, Matsumoto, Japan.;Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan.",
"authors": "Motobayashi|Mitsuo|M|;Inaba|Yuji|Y|;Fukuyama|Tetsuhiro|T|;Kurata|Takashi|T|;Niimi|Taemi|T|;Saito|Shoji|S|;Shiba|Naoko|N|;Nishimura|Takafumi|T|;Shigemura|Tomonari|T|;Nakazawa|Yozo|Y|;Kobayashi|Norimoto|N|;Sakashita|Kazuo|K|;Agematsu|Kazunaga|K|;Ichikawa|Motoki|M|;Koike|Kenichi|K|",
"chemical_list": "D000927:Anticonvulsants; C507941:IL2RG protein, human; D016756:Immunoglobulins, Intravenous; D053631:Interleukin Receptor Common gamma Subunit; D000077236:Topiramate; D005632:Fructose",
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"keywords": "CD4/8; Hematopoietic stem cell transplantation; Intravenous injection of immunoglobulin; Severe combined immunodeficiency syndrome; West syndrome",
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"mesh_terms": "D000927:Anticonvulsants; D001402:B-Lymphocytes; D002675:Child, Preschool; D005632:Fructose; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007223:Infant; D007231:Infant, Newborn; D053631:Interleukin Receptor Common gamma Subunit; D008297:Male; D020125:Mutation, Missense; D016511:Severe Combined Immunodeficiency; D013036:Spasms, Infantile; D013601:T-Lymphocytes; D000077236:Topiramate",
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"title": "Successful treatment for West syndrome with severe combined immunodeficiency.",
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"abstract": "Interleukin 6 (IL-6) plays a main role in the immunopathogenesis of rheumatoid arthritis (RA). Tocilizumab (TCZ) is a humanized immunoglobulin G1 monoclonal antibody against the human IL-6. Warfarin sodium is an oral anticoagulant that is primarily metabolized by cytochrome P450 2C9 (CYP2C9). Impaired metabolism of this low therapeutic index drug is important as it may result in serious bleeding. In this article, we present a 56-year-old female patient with RA, treated with TCZ and warfarin sodium and presented spontaneous spinal epidural hematoma (SSEH) of thoracic spine although international normalized ratio levels were in normal ranges. One week after decompressive surgery for hematoma, a cervical spine abscess developed which resulted in her death. To the best of our knowledge, this is the first case of RA developing SSEH while taking TCZ and warfarin sodium together. Although it is difficult to attribute the severe bleeding to TCZ treatment, clinicians should be aware that concomitant use of oral anticoagulants and TCZ might result in potentially fatal complications in patients with RA.",
"affiliations": "Department of Physical Medicine and Rehabilitation, Ankara University Faculty of Medicine, Ankara, Turkey.;Department of Physical Medicine and Rehabilitation, Ankara University Faculty of Medicine, Ankara, Turkey.;Department of Physical Medicine and Rehabilitation, Division of Rheumatology, Ankara University Faculty of Medicine, Ankara, Turkey.;Department of Physical Medicine and Rehabilitation, Ankara University Faculty of Medicine, Ankara, Turkey.",
"authors": "Güneş|Seçilay|S|;Gök|Haydar|H|;Ataman|Şebnem|Ş|;Kutlay|Şehim|Ş|",
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"doi": "10.46497/ArchRheumatol.2020.7579",
"fulltext": "\n==== Front\nArch Rheumatol\nArch Rheumatol\narchrheum_pmc\nArchives of Rheumatology\n2148-5046\n2618-6500\nTurkish League Against Rheumatism\n\n10.46497/ArchRheumatol.2020.7579\nCase Report\nSpontaneous Spinal Epidural Hematoma During Simultaneous Tocilizumab and Warfarin Use in a Patient With Rheumatoid Arthritis: Is There a Drug Interaction Between Tocilizumab and Oral Anticoagulants?\nGÜNEŞ Seçilay 1\nGÖK Haydar 1\nATAMAN Şebnem 2\nKUTLAY Şehim 1\n1 Department of Physical Medicine and Rehabilitation, Ankara University Faculty of Medicine, Ankara, Turkey\n2 Department of Physical Medicine and Rehabilitation, Division of Rheumatology, Ankara University Faculty of Medicine, Ankara, Turkey\nSeçilay Güneş, MD. Ankara Üniversitesi Tıp Fakültesi, Fiziksel Tıp ve Rehabilitasyon Anabilim Dalı, 06590 Çankaya, Ankara, Türkiye. Tel: +90 312 - 508 28 22 secilaygunes@ankara.edu.tr.\n12 2020\n07 2 2020\n35 4 614617\n30 4 2019\n17 8 2019\nCopyright © 2020, Turkish League Against Rheumatism\n2020\nTurkish League Against Rheumatism\nThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.\nInterleukin 6 (IL-6) plays a main role in the immunopathogenesis of rheumatoid arthritis (RA). Tocilizumab (TCZ) is a humanized immunoglobulin G1 monoclonal antibody against the human IL-6. Warfarin sodium is an oral anticoagulant that is primarily metabolized by cytochrome P450 2C9 (CYP2C9). Impaired metabolism of this low therapeutic index drug is important as it may result in serious bleeding. In this article, we present a 56-year-old female patient with RA, treated with TCZ and warfarin sodium and presented spontaneous spinal epidural hematoma (SSEH) of thoracic spine although international normalized ratio levels were in normal ranges. One week after decompressive surgery for hematoma, a cervical spine abscess developed which resulted in her death. To the best of our knowledge, this is the first case of RA developing SSEH while taking TCZ and warfarin sodium together. Although it is difficult to attribute the severe bleeding to TCZ treatment, clinicians should be aware that concomitant use of oral anticoagulants and TCZ might result in potentially fatal complications in patients with RA.\n\nOral anticoagulant\nrheumatoid arthritis\nspinal epidural hematoma\ntocilizumab\n==== Body\nIntroduction\n\nSpontaneous spinal epidural hematoma (SSEH) is defined as blood within the epidural space without any known traumatic or iatrogenic cause and incidence of SSEH is 1:100,000/year.[1] SSEH is considered as a neurological emergency and many authors suggest a relationship between SSEH and arteriovenous malformations, anticoagulant use, underlying coagulopathy and vertebral hemangiomas.[2] Warfarin is the most commonly used oral anticoagulant, occurs as a pair of enantiomers that are differentially metabolized by human cytochromes P450 (CYP).[3] Tocilizumab (TCZ), which is a new drug targeting the interleukin 6 (IL-6) pathway, was approved by the Food and Drug Administration for the treatment of rheumatoid arthritis (RA). Some drug interaction studies have been reported on TCZ.[4] It has been highlighted that when starting or stopping therapy with TCZ, patients taking drugs metabolized via CYP450 3A4, 1A2 or 2C9 (atorvastatin, calcium channel blockers, theophylline, warfarin, phenytoin) should be monitored closely.[3,4] Although reduced simvastatin and omeprazole bioavailability has been shown under TCZ treatment, the bioavailability of warfarin is not clear in the literature.[4]\n\nIn this article, we present a case of RA under TCZ and warfarin sodium therapy, presenting SSEH of the thoracic spine while international normalized ratio (INR) levels were in normal ranges.\n\nCase Report\n\nA 56-year-old female patient with RA for the last 18 years had received methotrexate, methylprednisolone, leflunomide, etanercept, infliximab, and adalimumab in the past but all the drugs were discontinued due to inadequate response. TCZ therapy was started with an 8 mg/kg/month infusion. She had also been using warfarin sodium due to grade 2 aortic insufficiency and mitral valve prosthesis for five years. The patient did not use any other drugs. After the 20th day of the fourth trial of TCZ infusion, the patient was admitted to the emergency department with sudden back pain, weakness, and numbness in her legs, bladder and bowel dysfunction. There was no history of trauma. Her blood pressure was 130/90 mmHg. Neurological examination showed the presence of complete paraplegia. Laboratory findings were as follows: hemoglobin: 12.2 g/dL (normal), platelet: 193•109/L (normal), white blood count: 6•109/L (normal), aspartate aminotransferase: 55 U/L (high), alanine aminotransferase: 50 U/L (high), blood urea nitrogen: 16 mg/dL (normal), creatinine: 1.1 mg/dL (normal), INR: 2.1 (normal), C-reactive protein (CRP): 1.2 mg/L (normal). Peripheral blood smear was normal. Factor 13 and fibrinogen levels were normal too. Urgent magnetic resonance imaging (MRI) of the thoracolumbar spine demonstrated an elongated space-occupying mass with convexity to the spinal canal at the level of T8-T12 vertebra which was seen as a hyperintense mass on the T2 weighted images and hypointense on the T1 weighted images (Figure 1). It was observed via immediate exploratory surgery that there was blood in the epidural space and decompressive laminectomy was performed. A written informed consent was obtained from the relatives of patient.\n\nFigure 1 (a) Sagittal T2 weighted images: Hyperintense lesion between T8-T12 vertebra levels. (b) Axial T2 weighted images: Hematoma compressing spinal cord.\n\nSeven days after the surgery, her symptoms worsened and she also developed arm weakness. Cervical MRI revealed an intramedullary mass between the C5-C7 vertebra levels which was consistent with an abscess (Figure 2) although the CRP levels were within the normal range. She was re-operated and the intradural abscess was drained. The culture of pus from the abscess turned out to be negative. She developed severe pneumonia. The blood culture was negative. One month after the first surgery, Candida albicans was observed in the culture of sputum in the intensive care unit and patient died despite the antifungal treatment.\n\nFigure 2 T2 weighted images: Cervical abscess.\n\nDiscussion\n\nSpontaneous spinal epidural hematoma is an extremely rare entity. RA, Paget’s disease and ankylosing spondylitis are considered as risk factors for traumatic spinal epidural hematomas due to increased risk for compression fractures.[5] There was no history of trauma in our patient with RA. However, it is known that longstanding RA patients have increased risk for vasculopathy.[6] In addition, oral anticoagulation use is a risk factor for SSEH while the pathology is not clear. Some have argued that the risk of oral anticoagulation associated hemorrhage is not related to the intensity of anticoagulation.[7] There is no absolutely “safe” INR, and it is noteworthy that many of the reported cases were anticoagulated in the therapeutic range.[7] Therefore, any drug interactions altering the bioavailability of oral anticoagulants are important. TCZ inhibits the downregulation of the CYP2C9 which has a major role in warfarin metabolism. Aitken et al.[8] showed that IL-6 induced diminution of CYP2C9 protein level which was greater than that of CYP3A4 in vitro. This suggests that CYP2C9 activity may increase at greater extent than CYP3A4 with TCZ treatment, resulting in increased warfarin metabolism. The authors stated that clinically, this would result in patients requiring a smaller dose of warfarin and a possible need for more frequent INR monitoring.\n\nAnother risk of bleeding is thrombocytopenia due to TCZ treatment. One serious bleeding case with hemorrhagic stomatitis was reported.[9] Mokuda et al.[10] reported hematoma in a patient with hip pain and found a relationship between TCZ treatment and factor XIII deficiency and decreased fibrinogen. They reported that RA patients who are treated with TCZ are at risk for developing acquired factor XIII deficiency. However, the factor XIII level was normal in the current case.\n\nInhibiting IL-6 can also be an additional factor for bleeding, by decreasing plasma fibrinogen level in patients treated with TCZ which was within the normal range as it was in our case. Imamura et al.[11] showed that TCZ treatment is associated with reduced fibrinogen levels and increased blood loss after total knee arthroplasty in patients with RA.\n\nSpontaneous spinal epidural hematoma is a very rare and fatal condition. To the best of our knowledge, this is the first case of RA developing SSEH while taking TCZ and warfarin sodium together. Since the coagulation parameters were in the normal range, it is difficult to attribute the severe bleeding directly to the TCZ treatment. While the use of anticoagulants is a risk factor for SSEH, administering drugs affecting CYP metabolism causes additional risk for spontaneous bleeding. Although the effect of TCZ on coagulation parameters and CYP enzymes is still not well known, TCZ treatment must be administered carefully in the patients who have concomitant use of warfarin sodium even if the INR levels are in normal ranges.\n\nConflict of Interest: The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.\n\nFinancial Disclosure: The authors received no financial support for the research and/or authorship of this article.\n==== Refs\n1 Bhat KJ Kapoor S Watali YZ Sharma JR Spontaneous epidural hematoma of spine associated with clopidogrel: A case study and review of the literature Asian J Neurosurg 2015 10 54 54 25767588\n2 Zhong W Chen H You C Li J Liu Y Huang S Spontaneous spinal epidural hematoma J Clin Neurosci 2011 18 1490 1494 21920757\n3 Kaminsky LS Zhang ZY Human P450 metabolism of warfarin Pharmacol Ther 1997 73 67 74 9014207\n4 Kim S Östör AJ Nisar MK Interleukin-6 and cytochrome-P450, reason for concern Rheumatol Int 2012 32 2601 2604 22451032\n5 Yalbuzdağ ŞA Erol AM Çelik C Solum S Ankylosing spondylitis diagnosed after epidural hematoma and paraplegia: A case report Arch Rheumatol 2014 29 309 313\n6 Radic M Martinovic Kaliterna D Radic J Overview of vasculitis and vasculopathy in rheumatoid arthritis--something to think about Clin Rheumatol 2013 32 937 942 23649484\n7 Hart RG Boop BS Anderson DC Oral anticoagulants and intracranial hemorrhage. Facts and hypotheses Stroke 1995 26 1471 1477 7631356\n8 Aitken AE Morgan ET Gene-specific effects of inflammatory cytokines on cytochrome P450 2C, 2B6 and 3A4 mRNA levels in human hepatocytes Drug Metab Dispos 2007 35 1687 1693 17576808\n9 Schiff MH Kremer JM Jahreis A Vernon E Isaacs JD van Vollenhoven RF Integrated safety in tocilizumab clinical trials Arthritis Res Ther 2011 13 R141\n10 Mokuda S Murata Y Sawada N Matoba K Yamada A Onishi M Tocilizumab induced acquired factor XIII deficiency in patients with rheumatoid arthritis PLoS One 2013 8 e69944\n11 Imamura H Momohara S Yano K Sakuma Y Nakayama M Tobimatsu H Tocilizumab treatment in patients with rheumatoid arthritis is associated with reduced fibrinogen levels and increased blood loss after total knee arthroplasty Mod Rheumatol 2018 28 976 980 29325462\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2148-5046",
"issue": "35(4)",
"journal": "Archives of rheumatology",
"keywords": "Oral anticoagulant; rheumatoid arthritis; spinal epidural hematoma; tocilizumab",
"medline_ta": "Arch Rheumatol",
"mesh_terms": null,
"nlm_unique_id": "101639000",
"other_id": null,
"pages": "614-617",
"pmc": null,
"pmid": "33758819",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports",
"references": "25767588;21884601;9014207;29325462;23936360;22451032;21920757;7631356;23649484;17576808",
"title": "Spontaneous Spinal Epidural Hematoma During Simultaneous Tocilizumab and Warfarin Use in a Patient With Rheumatoid Arthritis: Is There a Drug Interaction Between Tocilizumab and Oral Anticoagulants?",
"title_normalized": "spontaneous spinal epidural hematoma during simultaneous tocilizumab and warfarin use in a patient with rheumatoid arthritis is there a drug interaction between tocilizumab and oral anticoagulants"
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"abstract": "BACKGROUND\nNeonatal lactic acidosis can be associated to severe inborn errors of metabolism. Rapid identification of the underlying disorder may improve the clinical management through reliable counseling of the parents and adaptation of the treatment.\n\n\nMETHODS\nWe present the case of a term newborn with persistent hypoglycemia on postnatal day 1, who developed severe lactic acidosis, aggravating under intravenous glucose administration. Routine metabolic investigations revealed elevated pyruvate and lactate levels in urine, and magnetic resonance spectroscopy showed a lactic acid peak and decreased N-acetylaspartate levels. Mitochondrial disorders, e.g., pyruvate dehydrogenase (PDH) deficiency, were the major differential diagnoses. However, both hypoglycemia and the elevated lactate to pyruvate ratio in serum (=55.2) were not typical for PDH deficiency. We used \"Mendeliome sequencing\", a next-generation sequencing approach targeting all genes which have been previously linked to single-gene disorders, to obtain the correct diagnosis.\n\n\nRESULTS\nOn day 27 of life, we identified a homozygous stop mutation in the PDHX gene, causing pyruvate dehydrogenase E3-binding protein deficiency. After starting the ketogenic diet, the infant recovered and is showing delayed but progressive development.\n\n\nCONCLUSIONS\nMendeliome sequencing was successfully used to disentangle the underlying cause of severe neonatal lactic acidosis. Indeed, it is one of several targeted sequencing approaches that allow rapid and reliable counseling of the parents, adaptation of the clinical management, and renunciation of unnecessary, potentially invasive and often costly diagnostic measures.",
"affiliations": "Department of Pediatrics, University Hospital Cologne, Kerpener Str. 62, 50937, Cologne, Germany.;Institute of Human Genetics, University Hospital Cologne, Cologne, Germany.;Department of Pediatrics, University Hospital Cologne, Kerpener Str. 62, 50937, Cologne, Germany.;Department of Pediatrics, University Hospital Cologne, Kerpener Str. 62, 50937, Cologne, Germany.;Department of Pediatrics, University Hospital Cologne, Kerpener Str. 62, 50937, Cologne, Germany.;Department of Pediatrics, University Hospital Cologne, Kerpener Str. 62, 50937, Cologne, Germany.;Department of Pediatrics, University Hospital Cologne, Kerpener Str. 62, 50937, Cologne, Germany. sebahattin.cirak@uk-koeln.de.",
"authors": "Fazeli|Walid|W|;Karakaya|Mert|M|;Herkenrath|Peter|P|;Vierzig|Anne|A|;Dötsch|Jörg|J|;von Kleist-Retzow|Jürgen-Christoph|JC|;Cirak|Sebahattin|S|",
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"doi": "10.1186/s40348-016-0050-x",
"fulltext": "\n==== Front\nMol Cell PediatrMol Cell PediatrMolecular and Cellular Pediatrics2194-7791Springer Berlin Heidelberg Berlin/Heidelberg 5010.1186/s40348-016-0050-xResearchMendeliome sequencing enables differential diagnosis and treatment of neonatal lactic acidosis Fazeli Walid Karakaya Mert Herkenrath Peter Vierzig Anne Dötsch Jörg von Kleist-Retzow Jürgen-Christoph Cirak Sebahattin +49-221-47886464+49-221-47886865sebahattin.cirak@uk-koeln.de Department of Pediatrics, University Hospital Cologne, Kerpener Str. 62, 50937 Cologne, Germany Institute of Human Genetics, University Hospital Cologne, Cologne, Germany Center for Molecular Medicine, University of Cologne, Cologne, Germany 17 6 2016 17 6 2016 12 2016 3 2230 12 2015 30 5 2016 © The Author(s). 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Background\nNeonatal lactic acidosis can be associated to severe inborn errors of metabolism. Rapid identification of the underlying disorder may improve the clinical management through reliable counseling of the parents and adaptation of the treatment.\n\nMethods\nWe present the case of a term newborn with persistent hypoglycemia on postnatal day 1, who developed severe lactic acidosis, aggravating under intravenous glucose administration. Routine metabolic investigations revealed elevated pyruvate and lactate levels in urine, and magnetic resonance spectroscopy showed a lactic acid peak and decreased N-acetylaspartate levels. Mitochondrial disorders, e.g., pyruvate dehydrogenase (PDH) deficiency, were the major differential diagnoses. However, both hypoglycemia and the elevated lactate to pyruvate ratio in serum (=55.2) were not typical for PDH deficiency. We used “Mendeliome sequencing”, a next-generation sequencing approach targeting all genes which have been previously linked to single-gene disorders, to obtain the correct diagnosis.\n\nResults\nOn day 27 of life, we identified a homozygous stop mutation in the PDHX gene, causing pyruvate dehydrogenase E3-binding protein deficiency. After starting the ketogenic diet, the infant recovered and is showing delayed but progressive development.\n\nConclusions\nMendeliome sequencing was successfully used to disentangle the underlying cause of severe neonatal lactic acidosis. Indeed, it is one of several targeted sequencing approaches that allow rapid and reliable counseling of the parents, adaptation of the clinical management, and renunciation of unnecessary, potentially invasive and often costly diagnostic measures.\n\nElectronic supplementary material\nThe online version of this article (doi:10.1186/s40348-016-0050-x) contains supplementary material, which is available to authorized users.\n\nKeywords\nMendeliome sequencingPDH deficiencyKetogenic dietPDHXhttp://dx.doi.org/10.13039/501100001659Deutsche ForschungsgemeinschaftDFG EN Grant CI 218/1-1Cirak Sebahattin issue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nNeonatal lactic acidosis can be associated to a heterogeneous spectrum of causes, ranging from benign (e.g., protracted postnatal adaptation) to severe, potentially life-threatening conditions, e.g., disorders of energy metabolism such as deficiency of the pyruvate dehydrogenase (PDH) complex. PDH deficiency is the most common biochemically proven cause of congenital lactic acidosis [1] and thus an important differential diagnosis, particularly as treatment approaches exist. The PDH complex is a large (approx. 8 MDa) nuclear-encoded multi-enzyme complex located in the mitochondrial matrix and formed by three functional subunits (E1, E2, and E3 plus the E3-binding protein (E3BP)). It catalyzes the oxidation of pyruvate to acetyl coenzyme A and thereby links cytoplasmic glycolysis to the intra-mitochondrial tricarboxylic acid cycle. Deficiency of the PDH complex leads to accumulation of pyruvate and lactic acid as well as impaired mitochondrial energy restoration which is particularly harmful to the brain leading to impaired life expectancy and neurocognitive development. PDH deficiency can be caused by mutations in several different genes (e.g., PDHA1 [OMIM 300502], PDHX [608769], PDHB [179060], DLAT [608770]; see [2] for overview). Additionally, an increasing number of mutations have been found in genes that encode for co-factors of pyruvate oxidation (e.g., thiamine), resembling the wide clinical spectrum of PDH deficiency [2] that embraces phenotypes which are primarily metabolic (i.e., severe neonatal lactic acidosis) and those which are rather neurologic (i.e., muscular hypotonia and congenital brain malformations, e.g., agenesis of corpus callosum). The E3BP of the PDH complex is encoded by the pyruvate dehydrogenase complex-component X (PDHX) gene. After PDHA1, PDHX is the second most commonly mutated gene in PDH deficiency [3]. So far, a genotype-phenotype correlation has not been established due to the different affected domains of E3BP and the heterogeneity of the clinical features [4].\n\nIn contrast to other possible causes of neonatal lactic acidosis, there is currently no fully satisfying treatment available for patients with PDH deficiency [5]. However, ketogenic diet (KD) has been shown to positively influence the outcome of patients with PDH deficiency as it provides an alternative energy source and thereby bypasses the detrimental energy deprivation [2, 6]. In case PDH deficiency underlies neonatal lactic acidosis, early initiation of KD supposedly correlates with improved long-term outcome [7]. Precise diagnosis before the start of KD is required as there are contra-indications in some cases of lactic acidosis; KD should be avoided in some defects of the mitochondrial respiratory chain [8, 9] and in pyruvate carboxylase deficiency [8, 10] as it can enhance lactic acidosis and deteriorate the clinical situation [9, 10]. Currently, the diagnostic approach to monogenetic disorders such as PDH deficiency is experiencing pivotal changes. While previously, newborns and infants often underwent invasive, time-consuming, and costly diagnostic procedures—yet in some cases with ambiguous and inconclusive results [11]—next-generation sequencing approaches are increasingly implemented in daily clinical practice. Here, we illustrate in a case of neonatal lactic acidosis that a disease gene panel based on a targeted next-generation sequencing (NGS) method—an approach that we term “Mendeliome sequencing”—can be successfully applied. This NGS approach allows targeted sequencing of all disease genes listed in the Online Mendelian Inheritance of Man (OMIM) database.\n\nMethods\nThe study was approved by the institutional review board of the Ethics Committee of the University Hospital of Cologne. Informed consent for research and publication was obtained from the family.\n\nCase description\nWe present the case of a male newborn of Turkish-origin parents who was born at term at a peripheral children’s hospital. The parents stated to be non-consanguineous but belonged both to an endogamic subpopulation from Turkey. The patient’s younger sister was healthy while the older sister suffered from agenesis of corpus callosum and severe psychomotor retardation; as the parents have been rejecting any genetic counseling, the etiology of her disease remains unknown. After a complicated pregnancy (maternal diabetes mellitus, placenta previa, HELLP syndrome), the boy was born by secondary caesarian section due to placental abruption. Initial postnatal adaptation was unremarkable, but routine check of blood sugar levels (in response to maternal diabetes mellitus) first revealed repetitive neonatal hypoglycemia (8 h of age) and later on spontaneous development of moderate lactic acidosis (13 h of age: lactic acid 8.6 mmol/l (normal, ≤ 2.1 mmol/l); pH 7336). As hypoglycemia did not improve under repetitive feeding, intravenous (i.v.) glucose administration (6 mg/kg body weight/min.) was necessary (starting at 14 h of age). However, after a bolus application of glucose (10 %, 2 ml/kg body weight), the patient developed hyperglycemia (max. 397 mg/dl) and further worsening of lactic acidosis (24 h of age: lactic acid 16 mmol/l; pH 7037) which barely improved despite subsequent reduction of glucose supply and buffering with bicarbonate. Thus, an inborn error of metabolism was suspected, and the boy was transferred to the University Children’s Hospital 25 h after birth. Though he remained clinically unimpaired, lactic acidosis worsened (27 h of age: pH 7.0, lactic acid 18 mmol/l, base excess −21). Further investigations showed ketone bodies in urine as well as mildly elevated liver enzyme and CRP levels, in response to which antibiotics were started (and again terminated 5 days later after exclusion of neonatal infection; cultures of blood and cerebrospinal fluid were unremarkable). Despite extensive metabolic screening, the diagnosis remained elusive (normal values for newborn screening, ammonium, serum acylcarnitines/carnitine, urine amino acids, urine organic acids, very long chain fatty acids (VLCFA), homocystein, purines/pyrimidines in urine; plasma amino acids: elevated alanine secondary to lactic acidosis [1054 μmol/l, normal <710 μmol/l]). A mitochondrial disorder was now suggested as the underlying cause for several reasons: aggravation of lactic acidosis under i.v. glucose supply; increased levels of pyruvate and lactic acid in urine (both >5000 mmol/mol creatinine, normal: lactic acid <285, pyruvate <130); and finally, the findings of a magnetic resonance (MR) spectroscopy performed on day 6 after birth, that showed lactic acid peaks in the right occipital and frontal cortical areas under involvement of the subcortical white matter. Alterations of brain morphology, in particular agenesis of corpus callosum as seen in his older sister and as previously described for PDH deficiency, were not present. Buffering via bicarbonate administration was stopped on postnatal day 3, and tentative treatment with thiamine (75 mg/kg body weight/day) and carnitine (100 mg/kg body weight/day) was started. However, two findings—the initially observed refractory hypoglycemia and the elevated lactate to pyruvate ratio in the blood (55.2 = 6.9 mmol/l [lactate] to 0.125 mmol/l [pyruvate] in blood samples taken simultaneously)—were not characteristic of PDH deficiency and could have been each of them caused by many other inborn errors of metabolism [2, 4]. On postnatal day 16, we therefore applied a genetic approach to identify the underlying disorder.\n\nSample preparation and sequencing analysis\nDNA was extracted from blood with standard protocols. We performed next-generation sequencing for Mendelian diseases—which we term Mendeliome sequencing—in order to clarify the diagnosis. Fifty nanogram of genomic DNA (gDNA) were used for the TruSight One Sequencing Panel (Illumina) library prep protocol (Number 15046433, 2013). After quality control and quantification, the library was pooled and enriched for 4813 genes associated to monogenetic disorders. The pool underwent qPCR as a final control step and was loaded on an Illumina MiSeq benchtop sequencer using v3 chemistry and a 2 × 150 bp read length. The Cologne Center for Genomics VARBANK pipeline v.2.12 (https://varbank.ccg.uni-koeln.de/) was used for data analysis (Table 1).Table 1 Pipeline and filter parameters used for Mendeliome sequencing (filter metrics)\n\nFilter parameter\tPatient\t\nReads variation allele frequency range\t75–100 %\t\nMaximal number of allowed variations per gene\t10\t\nMaximal number seen in epilepsy in-house DM (n = 511)\t5\t\nMaximal number seen in structural in-house DM (n = 611)\t10\t\nMaximal population variation frequency\t0.1 %\t\nMinimal read coverage\t6\t\nMinimal variation quality\t10\t\nMaximal target distance\t100\t\nTranscryptic biotypes\tprotein_coding\t\nVariation locations\tCOMPOSED (variation spans different parts of a gene), intron, CDS (coding sequence)\t\nConsequence types\tProtein structure affected; cryptic 5′SS/3′SS activation; strong 5′SS/3′SS effects\t\n\n\nResults\nGenetic work-up\nBy sequencing, a mean coverage of 82 % was reached, 10× coverage was 97.5 % for target sequences and 30× coverage was 87.1 % on target (Additional file 1: Table S1). After analysis by our in-house software VARBANK v.2.12 (https://varbank.ccg.uni-koeln.de/), we deciphered the underlying condition within 11 days, i.e., at postnatal day 27. Initially, we looked for homozygous variants located in the shared runs of homozygosity (ROH). For completion, we also performed a further analysis of other possible heterozygous variants which did not reveal any mutation that could explain the biochemical and clinical features in this newborn. After filters were applied, the number of variants was reduced to five. Further filtering was performed on the basis of quality of reads, frequency in the population, prediction of pathogenicity, and evolutionary conservation, leading to one disease-causing genetic variant (Table 2).Table 2 Sequentially listed filtering steps for homozygous analysis\n\nROH\t\t\nRare functional variants (RFV)\t5\t\nNon-synonymous coding, indels\t4\t\nRFVs in good sequence quality (Q > 100)\t4\t\nRFVs not reported in dbSNP database\t2\t\nNon-reported RFVs predicted to be disease causing\t1\t\n\nROH regions of homozygosity\n\n\n\nWe diagnosed pyruvate dehydrogenase E3-binding protein deficiency (OMIM 245349) by detecting a homozygous stop mutation in the PDHX gene (c.1336C>T in exon 11 causing p.R446* according to NM_003477.2) (Fig. 1). The PDHX variant was tested by Sanger sequencing, and the mutation was shown to be co-segregating within the family. The p.R446* allele was not present in the Exome Aggregation Consortium (http://exac.broadinstitute.org/) and the Exome Variant Server (http://evs.gs.washington.edu/EVS/). We show the excellent coverage of the Mendeliome sequencing for the PDHX gene in Additional file 2: Figure S1.Fig. 1 Mendeliome reads show PDHX mutation. Reads from the patient’s genome show homozygous change from C to T (https://varbank.ccg.uni-koeln.de/). Above in black capital letters are the genomic reference sequence and the hg19 coordinates. Below is the next-generation sequencing read alignment, small and capital letters correspond to different sequencing directions. The mutation is labeled in red\n\n\n\n\nDiscussion\nWe present a newborn with severe neonatal lactic acidosis in which we applied a NGS technique to identify pyruvate dehydrogenase E3-binding protein deficiency as the underlying disorder. Once the genetic diagnosis was made, KD (3:1) was started (on postnatal day 28) and lactic acid values were thereby normalized. Despite sufficient caloric intake (~180 kcal/kg body weight/day), the patient developed failure to thrive at the beginning of KD. Showing signs of exocrine pancreatic insufficiency (pancreatic elastase in stool, 72 μg/g stool; normal, >200), the boy received pancreatin as exogenous replacement therapy (for approximately 2 months). He profited of this treatment and showed adequate weight gain, even after termination of pancreatin treatment. In contrast to other rare forms of mitochondrial disorders, particularly Pearson syndrome [12], exocrine pancreas insufficiency has not been described in PDH deficiency. As discussed in a previous case report, this might represent a particular complication of KD treatment in very young infants [13]. At 7 months of age, our patient had developed a secondary microcephaly and had a moderate delay of motor development. Other comorbidities have not (yet) occurred.\n\nThe mutation (p.Arg446*) was recently described as a founder mutation in 60 % of the patients of the Roma population who presented with congenital lactic acidosis [14]. Later in life, these patients mostly suffer from spastic diplegia, epileptic seizures, cortical brain atrophy, ventricular enlargement, and mental retardation [14]. Though a genotype-phenotype correlation has not been well established for PDH deficiency, these findings suggest that this particular mutation could be associated to a severe outcome, underlining the need to counteract long-term developmental impairment as much as possible. Numerous case reports [7, 15] and a study in zebrafish [16] have shown the potential therapeutic benefit of KD in PDH deficiency. It has been suggested that early initiation of KD in PDH deficiency might improve patients’ long-term outcome [7]. This would also have socio-economic implications.\n\nHowever, rapid diagnosis of PDH deficiency is challenging as it is often not possible to separate it from other mitochondrial disorders by mere clinical observation and specific metabolites/biochemical findings [2]. Indeed, we were misled by the lactate/pyruvate ratio in the blood (=55.2) that was unusually high for PDH deficiency [2, 4] but could have fitted to defects of the mitochondrial respiratory chain complex I or IV [17]. This indicates that caution needs to be warranted in the interpretation of the L/P ratio, especially if the ratio was only measured once, as in our case. Previously, the diagnosis of PDH deficiency was primarily based on laborious biochemical enzymatic assays of, e.g., muscle tissue or cultured fibroblasts usually being both time-consuming and potentially inconclusive, in particular in very young infants under 3 months of age. Furthermore, depending on the X-inactivation pattern, cases of X-chromosomal PDHA1 deficiency can be missed with biochemical assays [2]. Thus, there is a need for fast and reliable methods to identify patients with PDH deficiency. Targeted next-generation sequencing panels have been shown to ease this need. Targeted gene sequencing panels may cover all (coding) exons of the human genome, i.e., whole-exome sequencing (WES), or a selection of exons in a limited number of relevant genes. Whole-genome sequencing (WGS) aims to cover the entire human genome including the non-coding regions. Recently, it has been shown that in child neurology practice, a substantial part of the patients profited from WGS because it led to the genetic identification of the underlying disorder [18]. The resulting implications are more than just therapeutic ones: the general clinical management of the patient and its family—e.g., by facilitating parents’ decision-making in end-of-life situations—may be substantially improved by fast genetic diagnoses. Targeted next-generation sequencing panels—such as for metabolic disorders, mitochondrial disorders or as in our case the Mendeliome—have several advantages. Compared to WGS or WES, a restriction to candidate genes—selected based on the clinical presentation of the patient and/or restricted to all known OMIM-listed genes—is cheaper and quicker and detects clinically relevant variant interpretation of known disease genes easier. From a broad perspective, sequencing off all OMIM-listed genes by the Mendeliome additionally offers the advantage to detect unusual links of clinical presentations and genetic mutations (genotype-phenotype correlations). Current studies of rapid WGS in neonatal settings show a high detection rate of deep intronic variants, which carries the problem of higher false positive rates and expensive, compelling, labor-intensive variant testing [19]. Targeted NGS panels (e.g., restricted on inborn errors of metabolism or the Mendeliome) have shorter turn-around times compared to standard WGS and WES. Rapid WGS however is comparably quick, providing the molecular diagnosis within 26 to 50 h [20–22]. However, this WGS approach needs expensive hardware and computational clusters that are only available in large genome centers of developed countries. Mendeliome sequencing has restrictions, of course. It has not been designed to detect deep intronic mutations, which currently can only be detected by WGS. Also, Mendeliome sequencing requires regular updates of the targeted genes. Further, low coverage in certain exons of a number of genes might lead to false negative results, requiring further technical optimization. However, our recent unpublished data shows that certain genomic regions are even elusive to WGS and can only be sequenced by special techniques (data not shown). Structural variants including copy number variants are difficult to detect with targeted gene panels using NGS. Although several algorithms based on coverage statistics have been developed, false positive and negative rates are very high in particular for heterozygous copy number variants. Further bioinformatic analysis with computational tools under development might make the identification of large structural variants and copy number variations more reliable in the future. In contrast, Mendeliome sequencing and other targeted NGS panels could be established in any molecular genetic laboratory and can be run by benchtop NGS machines while the data analysis can be performed on up-to-date standard computers.\n\nThe presented case shows that Mendeliome sequencing can be applied in case of neonatal lactic acidosis, providing the diagnosis and thereby enabling initiation of treatment. It took us 11 days from initiation of genetic investigation (on postnatal day 16) until finding of the diagnosis (on postnatal day 27). That was due to the fact that Mendeliome sequencing is not yet established in the daily clinical routine and that it is not a first-line diagnostic method. Thus, it was conducted in our research laboratory which obviously takes much longer. However, if this novel method is established in the clinical routine, Mendeliome sequencing is feasible within 72 h (Illumina Truesight One Manual 15046433, 2013). For cases of PDH deficiency in particular, Mendeliome sequencing is quicker than the previously used enzymatic assays. Our case of pyruvate dehydrogenase E3-binding protein deficiency could have equally been solved by targeted gene panels restricted on inborn errors of metabolism and/or mitochondrial disorders. The decision whether to choose smaller gene panels or the Mendeliome panel should be based on careful clinical judgment, which might also depend on the availability of subspecialty experts. Mendeliome sequencing is a novel diagnostic tool that might in the future become a valuable supplement to classical biochemical approaches. It is conceivable that Mendeliome could be preferentially applied in clinical settings with largely unspecific and undefined phenotypes and/or misleading biochemical findings (which we personally experienced in this particular case). The more specific a phenotype is (and the less ambiguous potential biochemical findings are), the more likely more restrictive targeted gene panels (e.g., for mitochondrial disorders) could potentially be used.\n\nConclusions\nIn summary, this case shows the feasibility of Mendeliome sequencing as a method that can be useful in patients with neonatal lactic acidosis to rapidly identify cases of pyruvate dehydrogenase deficiency. Thus, together with numerous previous NGS publications, our case indicates that rapid genetic diagnosis via targeted sequencing panels (e.g., Mendeliome sequencing) may improve the long-term outcome of patients with treatable metabolic or other inherited disorders. The utility of next-generation sequencing panels in comparison to conventional metabolic testing needs to be validated in the clinical routine settings.\n\nAdditional files\nAdditional file 1: Table S1. Total number of reads and coverage analysis of Mendeliome data.\n\nAdditional file 2: Figure S1. Coverage analysis of the PDHX gene.\n\n\n\nAbbreviations\nKDketogenic diet\n\nNGSnext-generation sequencing\n\nPDHpyruvate dehydrogenase\n\nWESwhole-exome sequencing\n\nWGSwhole-genome sequencing\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nWF collected and interpreted the clinical data and wrote the manuscript. MK analyzed the Mendeliome sequencing, performed the Sanger sequencing, and contributed to the writing of the manuscript. PH, AV, JD, and J-Cv. K-R collected and interpreted the clinical data. SC designed and led the study, supervised the genetic analysis, collected and interpreted the clinical data, and contributed to the writing of the manuscript. All authors read and approved the final manuscript.\n\nAcknowledgements\nWe thank the patient’s family for giving their consent to publication. We thank the Cologne Center for Genomics for the next-generation sequencing; Karin Oster and Frizzi Schneider for performing the dietary management of the patient; and the team of the Children Hospital Gummersbach for early postnatal as well as intermittent clinical care of the patient.\n\nS.C. received funding from the MDA and Deutsche Forschungsgemeinschaft (DFG) to support this work.\n==== Refs\nReferences\n1. Weber TA Antognetti MR Stacpoole PW Caveats when considering ketogenic diets for the treatment of pyruvate dehydrogenase complex deficiency J Pediatr 2001 138 390 395 10.1067/mpd.2001.111817 11241048 \n2. Sperl W Fleuren L Freisinger P The spectrum of pyruvate oxidation defects in the diagnosis of mitochondrial disorders J Inherit Metab Dis 2015 38 391 403 10.1007/s10545-014-9787-3 25526709 \n3. Miné M Brivet M Schiff M A novel gross deletion caused by non-homologous recombination of the PDHX gene in a patient with pyruvate dehydrogenase deficiency Mol Genet Metab 2006 89 106 110 10.1016/j.ymgme.2006.06.002 16843025 \n4. Patel KP O’Brien TW Subramony SH The spectrum of pyruvate dehydrogenase complex deficiency: clinical, biochemical and genetic features in 371 patients Mol Genet Metab 2012 106 385 394 10.1016/j.ymgme.2012.03.017 22896851 \n5. Morris AA Leonard JV The treatment of congenital lactic acidosis J Inherit Metab Dis 1996 19 573 80 10.1007/BF01799117 8884580 \n6. Klepper J Leiendecker B Riemann E Baumeister FAM Die ketogene Diät in den deutschsprachigen Ländern im Jahr 2003: Eine Standortbestimmung Klin Padiatr 2004 216 277 285 10.1055/s-2004-44906 15455294 \n7. Wexler ID Hemalatha SG McConnell J Outcome of pyruvate dehydrogenase deficiency treated with ketogenic diets. Studies in patients with identical mutations Neurology 1997 49 1655 61 10.1212/WNL.49.6.1655 9409363 \n8. Society for Neuropediatrics (2014) Guidelines for ketogenic diet. http://www.awmf.org/uploads/tx_szleitlinien/022-021l_S1_Ketogene_Diäten_2014-04.pdf.\n9. Kang H-C Lee Y-M Dong Kim H Safe and effective use of the ketogenic diet in children with epilepsy and mitochondrial respiratory chain complex defects Epilepsia 2007 48 82 88 17241212 \n10. Freeman J Veggiotti P Lanzi G The ketogenic diet: from molecular mechanisms to clinical effects Epilepsy Res 2006 68 145 180 10.1016/j.eplepsyres.2005.10.003 16523530 \n11. Willig LK Petrikin JE Smith LD Whole-genome sequencing for identification of Mendelian disorders in critically ill infants: a retrospective analysis of diagnostic and clinical findings Lancet Respir Med 2015 3 377 87 10.1016/S2213-2600(15)00139-3 25937001 \n12. Pearson HA Lobel JS Kocoshis SA A new syndrome of refractory sideroblastic anemia with vacuolization of marrow precursors and exocrine pancreatic dysfunction J Pediatr 1979 95 976 84 10.1016/S0022-3476(79)80286-3 501502 \n13. Goyens P De Laet C Ranguelov N Pitfalls of ketogenic diet in a neonate Pediatrics 2002 109 1185 6 10.1542/peds.109.6.1185 12042567 \n14. Ivanov IS Azmanov DN Ivanova MB Founder p.Arg 446* mutation in the PDHX gene explains over half of cases with congenital lactic acidosis in Roma children Mol Genet Metab 2014 113 76 83 10.1016/j.ymgme.2014.07.017 25087164 \n15. Falk RE Cederbaum SD Blass JP Ketonic diet in the management of pyruvate dehydrogenase deficiency Pediatrics 1976 58 713 21 824610 \n16. Taylor MR Hurley JB Van Epps HA Brockerhoff SE A zebrafish model for pyruvate dehydrogenase deficiency: rescue of neurological dysfunction and embryonic lethality using a ketogenic diet Proc Natl Acad Sci U S A 2004 101 4584 4589 10.1073/pnas.0307074101 15070761 \n17. Robinson BH Lactic acidemia and mitochondrial disease Mol Genet Metab 2006 89 3 13 10.1016/j.ymgme.2006.05.015 16854608 \n18. Srivastava S Cohen JS Vernon H Clinical whole exome sequencing in child neurology practice Ann Neurol 2014 76 473 483 10.1002/ana.24251 25131622 \n19. Petrikin JE Willig LK Smith LD Kingsmore SF Rapid whole genome sequencing and precision neonatology Semin Perinatol 2015 39 623 631 10.1053/j.semperi.2015.09.009 26521050 \n20. Saunders CJ Miller NA Soden SE Rapid whole-genome sequencing for genetic disease diagnosis in neonatal intensive care units Sci Transl Med 2012 4 154ra135 10.1126/scitranslmed.3004041 23035047 \n21. Soden SE Saunders CJ Willig LK Effectiveness of exome and genome sequencing guided by acuity of illness for diagnosis of neurodevelopmental disorders Sci Transl Med 2014 6 265ra168 10.1126/scitranslmed.3010076 25473036 \n22. Miller NA Farrow EG Gibson M A 26-hour system of highly sensitive whole genome sequencing for emergency management of genetic diseases Genome Med 2015 7 100 10.1186/s13073-015-0221-8 26419432\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2194-7791",
"issue": "3(1)",
"journal": "Molecular and cellular pediatrics",
"keywords": "Ketogenic diet; Mendeliome sequencing; PDH deficiency; PDHX",
"medline_ta": "Mol Cell Pediatr",
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"pubdate": "2016-12",
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"title": "Mendeliome sequencing enables differential diagnosis and treatment of neonatal lactic acidosis.",
"title_normalized": "mendeliome sequencing enables differential diagnosis and treatment of neonatal lactic acidosis"
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"abstract": "BACKGROUND\nSevere malaria is a potentially life-threatening infectious disease. It has been conclusively shown that artesunate compared to quinine is superior in antiparasitic efficacy and in lowering mortality showing a better short-term safety profile. Regarding longer-term effects, reports of delayed haemolysis after parenteral artesunate for severe malaria in returning travellers have been published recently. So far, delayed haemolysis has not been described after the use of parenteral quinine.\n\n\nMETHODS\nIn this retrospective study, all patients treated for severe malaria at the University Medical Centre Hamburg-Eppendorf were included between 2006 and 2012. The primary endpoint was the proportion of delayed haemolysis in patients treated with quinine versus those who received artesunate. As secondary endpoint, the proportion of any adverse event was assessed.\n\n\nRESULTS\nA total of 36 patients with severe malaria were included in the analysis. Of these, 16 patients contributed sufficient data to assess the endpoint delayed haemolysis. Twelve were treated primarily with intravenous quinine - with four patients having received intrarectal artesunate as an adjunct treatment - and five patients were treated primarily with artesunate. Five cases of delayed haemolysis could be detected - two in patients treated with quinine and intrarectal artesunate and three in patients treated with artesunate. No case of delayed haemolysis was detected in patients treated with quinine alone.While adverse events observed in patients treated with artesunate were limited to delayed haemolysis (three patients, 60%) and temporary deterioration in renal function (three patients, 60%), patients treated with quinine showed a more diverse picture of side effects with 22 patients (71%) experiencing at least one adverse event. The most common adverse events after quinine were hearing disturbances (12 patients, 37%), hypoglycaemia (10 patients, 32%) and cardiotoxicity (three patients, 14%).\n\n\nCONCLUSIONS\nThis study provides further evidence on delayed haemolysis after artesunate and underlines the importance of a standardized follow-up of patients treated with artesunate for severe malaria.",
"affiliations": "Department of Internal Medicine, Section Tropical Medicine University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.",
"authors": "Rolling|Thierry|T|;Wichmann|Dominic|D|;Schmiedel|Stefan|S|;Burchard|Gerd D|GD|;Kluge|Stefan|S|;Cramer|Jakob P|JP|",
"chemical_list": "D000962:Antimalarials; D037621:Artemisinins; D000077332:Artesunate; D011803:Quinine",
"country": "England",
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"doi": "10.1186/1475-2875-12-241",
"fulltext": "\n==== Front\nMalar JMalar. JMalaria Journal1475-2875BioMed Central 1475-2875-12-2412385574510.1186/1475-2875-12-241ResearchArtesunate versus quinine in the treatment of severe imported malaria: comparative analysis of adverse events focussing on delayed haemolysis Rolling Thierry 12t.rolling@uke.deWichmann Dominic 3d.wichmann@uke.deSchmiedel Stefan 1sschmiedel@bni-hamburg.deBurchard Gerd D 12gerd.burchard@bni-hamburg.deKluge Stefan 3s.kluge@uke.deCramer Jakob P 12cramer@bni-hamburg.de1 Department of Internal Medicine, Section Tropical Medicine University Medical Centre Hamburg-Eppendorf, Hamburg, Germany2 Department of Clinical Research, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany3 Department of Intensive Care Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany2013 15 7 2013 12 241 241 27 3 2013 23 6 2013 Copyright © 2013 Rolling et al.; licensee BioMed Central Ltd.2013Rolling et al.; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\nSevere malaria is a potentially life-threatening infectious disease. It has been conclusively shown that artesunate compared to quinine is superior in antiparasitic efficacy and in lowering mortality showing a better short-term safety profile. Regarding longer-term effects, reports of delayed haemolysis after parenteral artesunate for severe malaria in returning travellers have been published recently. So far, delayed haemolysis has not been described after the use of parenteral quinine.\n\nMethods\nIn this retrospective study, all patients treated for severe malaria at the University Medical Centre Hamburg-Eppendorf were included between 2006 and 2012. The primary endpoint was the proportion of delayed haemolysis in patients treated with quinine versus those who received artesunate. As secondary endpoint, the proportion of any adverse event was assessed.\n\nResults\nA total of 36 patients with severe malaria were included in the analysis. Of these, 16 patients contributed sufficient data to assess the endpoint delayed haemolysis. Twelve were treated primarily with intravenous quinine – with four patients having received intrarectal artesunate as an adjunct treatment – and five patients were treated primarily with artesunate. Five cases of delayed haemolysis could be detected – two in patients treated with quinine and intrarectal artesunate and three in patients treated with artesunate. No case of delayed haemolysis was detected in patients treated with quinine alone.\n\nWhile adverse events observed in patients treated with artesunate were limited to delayed haemolysis (three patients, 60%) and temporary deterioration in renal function (three patients, 60%), patients treated with quinine showed a more diverse picture of side effects with 22 patients (71%) experiencing at least one adverse event. The most common adverse events after quinine were hearing disturbances (12 patients, 37%), hypoglycaemia (10 patients, 32%) and cardiotoxicity (three patients, 14%).\n\nConclusions\nThis study provides further evidence on delayed haemolysis after artesunate and underlines the importance of a standardized follow-up of patients treated with artesunate for severe malaria.\n\nSevere malariaImported malariaArtesunateQuinineHaemolysisAdverse events\n==== Body\nBackground\nAround 5,000 cases of imported Plasmodium falciparum malaria are notified per year in the WHO European region with around 25 deaths\n[1]. 562 cases (all plasmodial species combined) were reported to the Robert-Koch-Institute (RKI, Berlin, Germany) in 2011 with only one death (0.2%)\n[2]. Plasmodium falciparum malaria is a potentially life-threatening disease in Europe and prompt treatment is essential\n[3]. In endemic areas it has been shown conclusively that artesunate is superior in antiparasitic efficacy and in lowering mortality due to severe malaria when compared to quinine – showing beneficial effects especially in hyperparasitaemic patients\n[4-6]. In one retrospective study, superior efficacy of artesunate could also be confirmed in a European health care system setting\n[7]. In the updated German guidelines on diagnosis and treatment of malaria parenteral artesunate and quinine are now considered both as equivalent first-line treatment options\n[8]. Recently, artesunate has been advocated as the sole first-line treatment in any geographical region\n[3,6,9].\n\nRegarding adverse events of parenteral artesunate, data is scarce so far\n[10]. This is in striking contrast to the existing safety evidence on quinine with its many known and well characterized adverse events such as cinchonism, hypoglycaemia or cardiotoxicity\n[11,12]. In the large multinational -QUAMAT trials, significantly less episodes of hypoglycaemia were observed after parenteral artesunate. However, while the rate of neurological sequelae was greater at discharge after artesunate, this difference waned over time and was attributed to the fact that a larger proportion of severely diseased patients with cerebral involvement survived after therapy with artesunate\n[5,6]. Recently, series of cases with delayed haemolysis in the second to third week after treatment with parenteral artesunate have been observed by several tropical medicine centres in hyperparasitaemic travellers returning to Europe\n[13-16]. This potential side-effect has not been reported in any of the large randomized trials comparing artesunate and quinine in endemic settings\n[4,5]. These trials were, however, not designed to detect any laboratory abnormalities in the follow-up period and the health care and social circumstances of malaria are not comparable to the situation in Europe\n[10].\n\nParenteral artesunate has received orphan drug designation for the treatment of malaria by the European Medicines Agency (EU/3/07/430 and EU/3/07/510). The orphan designation does not equate to a marketing authorization, but it offers incentives from the European Union to further develop and study a medicine for a rare disease such as malaria in Europe\n[17]. So far only artesunate produced by Guilin Pharmaceuticals (Shanghai, PR China) is available as WHO-confirmed Good Manufacturing Practice (GMP)-precertified drug. The French Medicines Agency has granted a temporary authorization of use with centralized data gathering in 2011\n[18]. The lack of full GMP certification of artesunate, however, poses some liability issues in other countries such as Germany, where artesunate can only be administered on an individual treatment basis. In this scenario knowledge about potential adverse events of both treatment options as well as the evidence of antiparasitic superiority of artesunate are essential for patients and physicians to reach an informed decision.\n\nThe aim of this retrospective study was to assess adverse events in all patients treated for severe malaria since 2006 in the University Medical Centre Hamburg-Eppendorf with a special focus on the occurrence of delayed haemolysis.\n\nMethods\nFor this retrospective study, data were analysed from adult (≥18 years) patients, hospitalized between January 2006 and December 2012 at the University Medical Centre Hamburg-Eppendorf with a discharge diagnosis of severe malaria. Until 2011, quinine was recommended as the primary anti-malarial in severe malaria according to national guidelines while in 2011, artesunate was added as a first-line treatment option\n[8]. Plasmodium falciparum malaria was diagnosed by thin and thick blood film. Severe malaria was defined according to national guidelines and major severity criteria are shown in Table \n1.\n\nTable 1 Severity criteria according to the 2006 German guidelines for diagnosis and treatment of malaria\n\nCriterion\tDefinition\t\nAnaemia\tHaemoglobin <8 g/dl\t\nAcute renal failure\tUrinary excretion <400 ml/24 h and/or creatinine >2,5 mg/dl or rapidly rising creatinine or Cystatin-C values\t\nHyperparasitaemia\t>5% infected erythrocytes or >100.000 parasites/μl\t\nIcterus\tBilirubin >3 mg/dl\t\nElevated liver function tests\t>3x upper normal value\t\nImpaired consciousness or convulsions\t \t\nRespiratory insufficiency or irregular respiration or hypoxia\t \t\nHypoglycaemia\tBlood glucose <40 mg/dl\t\nCirculatory shock\t \t\nSpontaneous bleeding\t \t\nAcidosis\tBase excess <-8 mmol/l\t\nHyperkalaemia\t>5,5 mmol/l\t\nIntravenous quinine (prepared by the pharmacy of the University Medical Centre Hamburg-Eppendorf) was given in combination with either oral doxycycline or oral clindamycin at a loading dose of 20 mg quinine dihydrochloride/kg (corresponding to 16,4 mg of quinine base) over four hours, followed by 10 mg quinine dihydrochloride/kg (corresponding to 8,2 mg of quinine base) every 8 hours until oral treatment was deemed possible with a total treatment period of seven days. Upon the discretion of the treating physician intrarectal artesunate (Plasmotrim®, Mepha Pharma, 5 doses of 200 mg) was added. Intravenous artesunate (Guilin Pharmaceuticals, Shanghai, China) was applied in four doses of 2,4 mg/kg (0 h, 12 h, 24 h, 48 h), followed by a full course of either oral mefloquine (3 doses every 8 hours of 750, 500 and 250 mg, respectively) or oral atovaquone/proguanil (1,000 mg/400 mg once daily for 3 days).\n\nPrimary endpoint was the proportion of delayed haemolysis in patients treated with quinine versus those who received artesunate. To detect delayed haemolysis and to separate this from haemolysis related to acute malaria, a case definition of a decrease in median haemoglobin (Hb) in combination with a rise in median lactate dehydrogenase (LDH) between week 2 (days 7 to 13) and week 3 (days 14 to 20) was chosen. Furthermore, the proportions of patients with additional side-effects likely associated with the anti-malarial medication were assessed.\n\nIndividual patient data were extracted retrospectively from paper charts until 2009. From 2010 onward individual patients’ data were retrieved from electronic hospital records. Patients’ records were screened for any disease- or treatment-related complications during the hospitalization and follow-up period. Laboratory parameters were entered into a database and analysed by SPSS 17.0 software package. Differences between groups were assessed by two-tailed Fisher’s exact test for categorical variables. Approval of the Ethics Committee of the Medical Council of Hamburg has been obtained.\n\nResults\nA total of 44 patients fulfilling the criteria of severe P. falciparum malaria have been treated in the study period at the University Medical Centre Hamburg-Eppendorf. Of these, five patients (11%) treated with oral mefloquine and three patients (7%) treated with oral atovaquone/proguanil only were excluded from further analysis. Therefore, 36 patients who received either intravenous quinine or intravenous artesunate or both as primary parenteral anti-malarial were included. Table \n2 shows all baseline demographic and clinical parameters. All patients acquired their plasmodial infection on the African continent. All but one patient (97%) returned from sub-Saharan Africa (25 from West Africa, five from Central Africa, three from Southern Africa and two from East Africa). Ghana (8) and Nigeria (6) were the most prevalent country destinations. One female Caucasian patient hospitalized for severe P. falciparum malaria in 2011 worked as a tourist guide and had travelled to several countries around the Mediterranean Sea including southern Europe, promed-note December 2010 (archive number: 2010121210.4401). Median length of hospital stay was 10 days (IQR: 7–18). Median baseline parasitaemia was 15,0% (IQR:7,0-25,0) and mean baseline Hb was 11,4 g/dl (95%CI: 10,2-12,6). Twenty-five patients (69%) were treated in an intensive care unit (ICU). One patient (3%) with an initial parasitaemia of 40% presenting with coma died. Despite rapid parasite clearance after treatment with intravenous quinine, intravenous doxycycline and intrarectal artesunate, he finally succumbed to multiple organ failure 36 days after initiation of anti-malarial treatment.\n\nTable 2 Baseline demographic and clinical parameters\n\nTreatment group\tAll\tPatients in whom delayed haemolysis could be assessed\t\n \tAll\tAll\tQuinine (iv)\tQuinine (iv) and artesunate (ir)\tArtesunate (iv)\t\nn\t36\t16\t8\t4\t4\t\nFemale\t13 (36)\t4 (25)\t2 (25)\t1 (25)\t1 (25)\t\nVisiting friends and relatives\t10 (28)\t5 (31)\t3 (38)\t1 (25)\t1 (25)\t\nTraveling from sub-Saharan Africa\t35 (97)\t16 (100)\t8 (100)\t4 (100)\t4 (100)\t\nICU treatment\t25 (69)\t12 (75)\t6 (75)\t4 (100)\t2 (50)\t\nDeaths\t1 (3)\t0 (0)\t0 (0)\t1 (25)\t0 (0)\t\nHospital stay duration in days, median (IQR)\t10 (7–18)\t17 (9–30)\t19 (11–30)\t17 (4–46)\t11 (6–16)\t\nAge in years, median (IQR)\t49 (35–55)\t48 (37–57)\t42 (35–48)\t55 (41–59)\t54 (28–62)\t\nTemperature in °C\t38.1 (37.5-38.6)\t38.1 (37.6 – 38.6)\t38.2 (37.4- 39.0)\t37.1 (37.0 – 37.2)\t38.5 (37.6 – 39.4)\t\nParasitaemia in%, median (IQR)\t15 (7–25)\t15 (7–24)\t12 (5–15)\t33 (26–39)\t17 (8,-21)\t\nHb (g/dl, normal range:12.0-16.0 )\t11.4 (10.2-12.5)\t11.4 (10.0 – 12.9)\t11.9 (9.4-14.3)\t9.8 (6.4-13.1)\t12.3 (7.7-16.9)\t\nWBC (1000/μl, normal range: 3.5 – 10.5)\t6.9 (5.4-8.4)\t8.1 (5.3-10.9)\t7.8 (4.6-11.0)\t11.6 (0.0-24.8)\t5.5 (1.1-9.9)\t\nCreatinine (mg/dl, normal range: 0.6 – 1.3)\t1.6 (1.0-2.2)\t2.0 (1.3-2.8)\t2.0 (0.7-3.3)\t1.7 (0.0-3.6)\t2.5 (0.6-4.4)\t\nBilirubin (mg/dl, normal range: <1.2)\t4.0 (2.7-5.2)\t5.0 (3.9-6.1)\t4.9 (3.0-6.8)\t4.2 (0.0-10.3)\t5.9 (3.3-8.5)\t\nGOT (U/l, normal range: <50)\t115 (71–158)\t153 (102–205)\t149 (46–251)\t163 (21–305)\t153 (55–251)\t\nGPT (U/l, normal range: <50)\t75 (52–98)\t84 (57–111)\t77 (40–115)\t65 (8–120)\t116 (4–228)\t\nC-Reactive Protein (mg/l, normal range:<5)\t182 (145–219)\t178 (130–226)\t187 (90–284)\t178 (25–331)\t163 (74–225)\t\nData are shown as number (%) or mean (with 95% standard deviation), if not indicated otherwise.\n\nTable \n3 summarizes the treatment regimens of patients included in this study. Thirty-one (86%) received intravenous quinine and five (14%) intravenous artesunate as their primary anti-malarial therapy. Data for Hb and LDH in weeks 2 and 3 were available for 16 patients (12 in the quinine group and four in the artesunate group) allowing the assessment of the primary endpoint definition of delayed haemolysis. In these 16 patients, five cases of delayed haemolysis were detected – two in patients treated primarily with quinine and three in patients treated primarily with artesunate. However, both patients developing delayed haemolysis after quinine had received additional intrarectal artesunate. Comparing the proportions of delayed haemolysis in patients who received intravenous artesunate with or without quinine (5/8, 63%) versus those who received intravenous quinine without artesunate (0/8, 0%), statistical significance was reached (p = 0,026). While delayed haemolysis was observed in patients treated with both, intravenous quinine and intrarectal artesunate, none of the patients treated with intravenous quinine without intrarectal artesunate showed the primary endpoint (2/4. 50%, versus 0/8, 0%; p = 0,091). Table \n4 provides characteristics and clinical parameters of patients affected by delayed haemolysis. Three patients needed transfusions of packed red blood cells between days 14 and 21 (2 with primary quinine and 1 with primary artesunate treatment). Figure \n1 illustrates the time course of Hb and LDH in patients having received any form of artesunate (intravenous or additionally intrarectal) and in patients having received quinine without any form of artesunate. Patients with delayed haemolysis reached their nadir in Hb around day 15 (range 15–17) in combination with a rise in haemolytic activity as shown by LDH peaks around day 15 (range 14–21). Direct Coombs test was performed in four of the five patients with delayed haemolysis. Two direct Coombs tests were negative; one showed a high titre of IgG warm-auto-antibodies and one a low titre of anti-E IgG antibodies. In the workup for haemolysis one patient was newly diagnosed with HIV. His CD4 count was 284 /μl with a viral load of 160,000 copies/μl.\n\nTable 3 Treatment regimens of study patients\n\nTreatment regimen\tAll patients\tPatients with delayed haemolysis,\t\n \tn = 36\tn = 5/16*\t\nQuinine (iv) + Clindamycin (po)\t9\t0/4\t\nQuinine (iv) + Doxycycline (po)\t16\t0/3\t\nQuinine (iv) monotherapy\t1\t0/1\t\nQuinine (iv) + Clindamycin (po) + Artesunate (ir)\t1\t1/1\t\nQuinine (iv) + Doxycycline (po) + Artesunate (ir)\t3\t1/2\t\nQuinine (iv) + Artesunate (ir)\t1\t0/1\t\nArtesunate (iv) with subsequent Atovaquone/Proguanil (po)\t4\t2/3\t\nArtesunate (iv) with subsequent Mefloquine (po)\t1\t1/1\t\n*a total of n = 16 contributed data for the primary endpoint assessment (delayed haemolysis).\n\nAbbreviation: iv intravenous, po orally, ir intrarectal.\n\nTable 4 Demographic and clinical parameters of patients with post-treatment haemolysis\n\nPatient\tGender\tTravel type\tCountry of infection\tAnti-malarial treatment\tBaseline parasitaemia\tOther complications\tPre-existing medical conditions\tCoombs test\tTransfusions for post-treatment haemolysis\t\n1\tf\tTourism\tBurkina Faso\tQuinine (iv) + Clindamycin (po) + Artesunate (ir)\t30%\tAcute renal failure (Peak creatinine: 8.5 mg/dl), QTc prolongation (550 ms)\tHypertension\tDCT negative\tDay 15 and Day 21 (2 units of packed red blood cells each)\t\n2\tm\tVFR\tBurkina Faso\tQuinine (iv) + Doxycycline (po) + Artesunate (ir)\t25%\tAcute renal failure (Peak creatinine: 2.2 mg/dl)\tNewly diagnosed HIV-1 infection\tDCT positive, warm auto-antibodies (IgG)\tDay 14 (2 units of packed red blood cells)\t\n3*\tf\tTourism\tUganda\tArtesunate (iv) + Mefloquine (po)\t14%\t-\t-\tDCT not done\tNone\t\n4*\tm\tTourism\tGambia\tArtesunate (iv) + Atovaquone/ Proguanil (po)\t21%\tAcute renal failure (peak creatinine: 6.5 mg/dl)\tHypertension\tDCT positive, Low titre of anti-E IgG antibodies\tDay 14 and Day 21, 2 units of packed red blood cells\t\n5*\tm\tTourism\tGambia/ Senegal\tArtesunate (iv) + Atovaquone/ Proguanil (po)\t20%\tAcute renal failure (peak creatinine: 7.0 mg/dl)\t-\tDCT negative\tNone\t\n*patients have been previously described in detail\n[15].\n\nAbbreviation: iv intravenous, po orally, ir intrarectal.\n\nFigure 1 Time course of median weekly Hb (A) and LDH (B) in patients treated with artesunate (n = 8) and in patients treated with quinine (n = 8). ir: intrarectal; iv: intravenous. Mean ± standard error of the mean is displayed.\n\nFurther adverse events are described in Table \n5. The only complications recorded in patients treated with artesunate were delayed haemolysis and deterioration in renal function. In contrast, several complications were recorded in patients after quinine treatment: One or more adverse events were recorded in 22 (71%) quinine patients. Complications were manifold with 10 (32%) cases of hypoglycaemia requiring specific therapy, 12 (38%) cases of hearing disturbances and one case (3%) of visual impairment. In three patients with QTc-interval prolongation on ECG the quinine dose had to be reduced. Eight patients (26%) developed acute renal failure with four patients requiring haemodialysis. One patient (treated with doxycycline as combination drug) showed an increase in liver function tests (LFTs) during treatment and doxycycline had to be stopped – prompting a normalization of LFTs. One patient developed a syndrome of inappropriate antidiuretic hormone secretion (SIADH) and one patient developed an aseptic eosinophilic pneumonitis. These cases are described in more detail in Additional files\n1 and\n2.\n\nTable 5 Reported adverse events other than delayed haemolysis in patients treated with a primary regimen of quinine and of patients treated with a primary regimen of artesunate\n\nPrimary treatment\tQuinine\tArtesunate\t\n \tn = 31\tn = 5\t\nAny adverse event\t22 (71%)\t3 (60%)\t\nHypoglycaemia (<50 mg/dl)\t10 (32%)\t0 (0%)\t\nHearing disturbances\t12 (38%)\t0 (0%)\t\nVisual disturbances\t1 (3%)\t0 (0%)\t\nHepatotoxicity\t1 (3%)*\t0 (0%)\t\nProlongation of the QTc-interval (>500 ms)\t3 (10%)\t0 (0%)\t\nAcute renal failure\t8 (26%)\t3 (60%)\t\nOther**\t2 (6%)\t0 (0%)\t\n* treated with quinine and doxycycline.\n\n*** 1 patient with SIADH, 1 patient with clindamycin-induced eosinophilic pneumonitis.\n\nAll p-values for between-group differences >0,05 by Fisher’s exact test.\n\nDiscussion\nDelayed haemolysis was found only in hyperparasitaemic patients treated with artesunate (alone or in combination with quinine) but not in patients with quinine (and other partner drugs). After intravenous artesunate was established as a first-line treatment option for severe malaria in the University Medical Centre Hamburg-Eppendorf, active follow-up to detect haemolysis once a week for a total of four weeks after treatment initiation was implemented. The possibility that some cases of delayed haemolysis had been missed in quinine patients before establishing these active follow-up procedures cannot be ruled out. It appears realistic, however, to assume that delayed haemolysis would have been recognized passively in quinine patients if it was as frequent and clinically relevant. In addition, there are no other reports of delayed haemolysis after quinine available up to date. In contrast, increasing evidence indicates that delayed haemolysis occurs comparatively frequently after parenteral artesunate\n[13-16]. Interestingly we could detect delayed haemolysis also in two patients treated with intrarectal artesunate – a finding which had not previously been reported. It has to be noted that patients treated with quinine and additional intrarectal artesunate were more severely ill and had higher initial parasite densities than patients treated primarily with quinine. As hyperparasitaemia has been implicated as a risk factor for delayed haemolysis, parasite densities might be a confounder\n[14-16,19].\n\nThe aetiology of delayed haemolysis remains unknown. The fact that mainly hyperparasitaemic patients develop haemolysis may point to the contribution of a mechanism called ‘pitting’. After extraction of blood stage parasites during splenic passage, these once-infected erythrocytes have a reduced life-span compared to naïve erythrocytes with a mean life-span of around 180 hours and with a total removal of pitted erythrocytes after 28 days\n[20,21]. One could postulate an increase of haemolytic activity two weeks after acute malaria due to more or less synchronized destruction of pitted erythrocytes. The proportion of pitted erythrocytes seems to be higher after the use of artemisinins than after quinine – potentially explaining the absence of this adverse effect after use of quinine\n[20,21]. Immune-mediated haemolysis may be another explanation – although Coombs testing in the reports published so far has remained inconclusive. Coombs tests were negative in three patients in the case series by Zoller et al.[16]. In the Belgian-Dutch cohort, half of the tested patients had a positive Coombs test\n[14]. In the present study, half of the tested patients had positive direct Coombs test – albeit with different specificity (anti-E and warm autoantibodies). HIV-infection induced immunologic dysfunctions might have played a further role in the development of delayed haemolysis in one patient in this study. Further appropriately designed studies are necessary to clarify the pathophysiological mechanisms behind delayed haemolysis.\n\nIt is important to separate the haemolysis of acute malaria from delayed haemolysis after parasitological cure. Also, Hb levels can remain decreased during weeks two or three in patients slowly recovering from severe malarial anaemia without showing a new onset of haemolytic activity. It is, therefore, relevant to precisely define delayed haemolysis by applying biochemical parameters over time. In this study, delayed haemolysis was defined as a decrease in Hb (median Hb of week three lower than in week two) in combination with a rise in median LDH (median LDH of week three higher than in week two). This definition was selected based on the known time course of delayed haemolysis in the case series reported recently\n[13-16]. Median values of one week were used to correct for any potential outliers (e.g. transfusions or fluid resuscitation), which would have inappropriately influenced the mean values of one week.\n\nThe only other adverse event seen in patients treated with artesunate was development of acute renal failure after treatment was started. Renal failure might be due to malaria itself\n[22]. In an animal model, however, it was shown that intravenous artesunate leads to increased diuresis and decreased glomerular filtration rate\n[23]. Two case reports confirmed an increased diuresis in humans after infusion of intravenous artesunate – but no decrease in renal function was seen\n[24]. Creatinine levels in the three patients with acute renal failure after parenteral artesunate in this report normalized rapidly in the first week and no dialysis was necessary.\n\nQuinine confers the risk of a wide spectrum of adverse events and complications. Cinchonism consisting of gastrointestinal disturbances, tinnitus, hearing loss, vasodilatation and headaches are comparatively common and reversible soon after the drug exposure has discontinued\n[12]. A potentially dangerous adverse event is hypoglycaemia – which occurred in every third patient in this study. Hypoglycaemic episodes are significantly more frequent in patients treated with quinine than in patients treated with artesunate\n[6]. Quinine (as well as quinidine – the prototypic drug of class Ia antiarrythmics) leads to changes in cardiac electrophysiology – mainly in a prolongation of the ventricular repolarization as emphasized by a prolongation of the corrected QT-interval and predisposing to the development of potentially lethal torsade de pointe arrhythmia\n[25]. Three patients developed prolongation of the QT-interval and the dose of quinine had to be reduced.\n\nSeveral factors limit this study. Adverse events might be underreported in a retrospective chart review – either because patients do not or are unable to mention onset of new signs and symptoms because active screening is incomplete or simply because of incomplete chart entries. Furthermore, follow-up was not standardized for all patients which might hamper comparison between groups. Patients who were initially severely ill tended to have more extensive follow-up and adverse events might have been detected more frequently. These aspects may limit the generalizability of findings to patients with severe malaria. Moreover, the sample size was relatively small. A multi-centre retrospective approach might provide a larger sample size, although further heterogeneity in treatment regimens could add a further limitation. To define severe malaria, the German guidelines for the diagnosis and treatment of malaria issued in 2006 were used. In 2011, a new updated guideline has been published. In this revised guideline, elevated bilirubin and elevated LFTs have been omitted as severity criteria\n[8]. The 2006 guidelines were consistently applied for this study because it was the aim to yield a homogenous study population and because the majority of patients were treated prior to 2011.\n\nConclusion\nDelayed haemolysis seems to be a comparatively frequent as well as clinically relevant complication in severe malaria patients treated with parenteral artesunate. Yet, the fast and reliable antiparasitic action of artesunate outweighs the risks associated with delayed haemolysis including the necessity of blood transfusion, in particular in high standard medical care systems. While delayed haemolysis was not seen in patients treated with intravenous quinine (and partner drugs other than artesunate), quinine or respective partner drugs or both carry a significantly higher risk of adverse events and complications that may per se become life-threatening. Nevertheless, prolonged monitoring in particular for haematologic complications during at least one month after antiparasitic treatment initiation is strongly recommended after parenteral artesunate in patients with severe malaria. If this is warranted, parenteral artesunate should be used – if available – as the first-line treatment for severe malaria especially in hyperparasitaemic patients – despite lacking full GMP-conform production and licensure.\n\nWritten informed consent\nConsent was obtained from the patients for the publication of the two individual case reports.\n\nCompeting interests\nThe authors declare that they have no competing interest.\n\nAuthors’ contributions\nTR and JPC designed the study, analyzed the data and wrote the first draft with contributions from all other authors. All authors were involved in the direct patient care of patients included in this study. All authors have read and approved the final manuscript.\n\nSupplementary Material\nAdditional file 1\nCase description – patient 1 [26]-[29].\n\nClick here for file\n\n Additional file 2\nCase description – patient 2 [30]-[33].\n\nClick here for file\n\n Acknowledgements\nTR has been supported by the Clinical Leave Programme of the German Centre for Infectious Diseases Research (DZIF), German Federal Ministry of Education and Research/BMBF grant number: 8000-202-2.\n==== Refs\nCentralized information system for infectious dieases (CISID) http://data.euro.who.int/cisid \nRobert-Koch-Institut Infektionepidemiologisches Jahrbuch meldepflichtiger Krankheiten für 2011 2012 Berlin, Germany \nAskling H Bruneel F Burchard G Castelli F Chiodini P Grobusch M Lopez-Velez R Paul M Petersen E Popescu C Ramharter M Schlagenhauf P European Society for Clinical Microbiology and Infectious Diseases Study Group on Clinical Parasitology Management of imported malaria in Europe Malar J 2012 11 328 10.1186/1475-2875-11-328 22985344 \nDondorp A Nosten F Stepniewska K Day N White N Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial Lancet 2005 366 717 725 16125588 \nDondorp AM Fanello CI Hendriksen IC Gomes E Seni A Chhaganlal KD Bojang K Olaosebikan R Anunobi N Maitland K Kivaya E Agbenyega T Nguah SB Evans J Gesase S Kahabuka C Mtove G Nadjm B Deen J Mwanga-Amumpaire J Nansumba M Karema C Umulisa N Uwimana A Mokuolu OA Adedoyin OT Johnson WB Tshefu AK Onyamboko MA Sakulthaew T Ngum WP Silamut K Stepniewska K Woodrow CJ Bethell D Wills B Oneko M Peto TE von Seidlein L Day NP White NJ AQUAMAT group Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial Lancet 2010 376 1647 1657 10.1016/S0140-6736(10)61924-1 21062666 \nSinclair D Donegan S Isba R Lalloo DG Artesunate versus quinine for treating severe malaria Cochrane Database Syst Rev 2012 6 CD005967 \nEder M Farne H Cargill T Abbara A Davidson RN Intravenous artesunate versus intravenous quinine in the treatment of severe falciparum malaria: a retrospective evaluation from a UK centre Pathog Glob Health 2012 106 181 187 10.1179/2047773212Y.0000000032 23265377 \nLeitlinie Diagnostik und Therapie der Malaria http://www.awmf.org/uploads/tx_szleitlinien/042-001l_S1_Malaria_2013-01.pdf \nWHO WHO Guidelines for the treatment of malaria 2010 2 Geneva, Switzerland: World Health Organization \nCramer JP Lopez-Velez R Burchard GD Grobusch MP de Vries PJ Treatment of imported severe malaria with artesunate instead of quinine–more evidence needed? Malar J 2011 10 256 10.1186/1475-2875-10-256 21899729 \nWolf LR Otten EJ Spadafora MP Cinchonism: two case reports and review of acute quinine toxicity and treatment J Emerg Med 1992 10 295 301 10.1016/0736-4679(92)90336-R 1624742 \nAlKadi HO Antimalarial drug toxicity: a review Chemotherapy 2007 53 385 391 10.1159/000109767 17934257 \nCaramello P Balbiano R De Blasi T Chiriotto M Deagostini M Calleri G Severe malaria, artesunate and haemolysis J Antimicrob Chemother 2012 67 2053 2054 10.1093/jac/dks139 22523307 \nKreeftmeijer-Vegter AR van Genderen PJ Visser LG Bierman WF Clerinx J van Veldhuizen CK de Vries PJ Treatment outcome of intravenous artesunate in patients with severe malaria in the Netherlands and Belgium Malar J 2012 11 102 10.1186/1475-2875-11-102 22462806 \nRolling T Schmiedel S Wichmann D Wittkopf D Burchard GD Cramer JP Post-treatment haemolysis in severe imported malaria after intravenous artesunate: case report of three patients with hyperparasitaemia Malar J 2012 11 169 10.1186/1475-2875-11-169 22594446 \nZoller T Junghanss T Kapaun A Gjorup I Richter J Hugo-Persson M Morch K Foroutan B Suttorp N Yurek S Flick H Intravenous artesunate for severe malaria in travelers, Europe Emerg Infect Dis 2011 17 771 777 10.3201/eid1705.101229 21529383 \nRare disease (orphan) designations http://www.ema.europa.eu/docs/en_GB/document_library/Brochure/2011/03/WC500104234.pdf \nATU nominative, protocole d’utilisation thérapeutique et de recueil d’informations, Malacef® (artésunate) 60mg, poudre et solvant pour solution injectable http://www.ansm.sante.fr/Activites/Autorisations-Temporairesd-Utilisation-ATU/Protocoles-d-utilisation-therapeutique/Liste-des-specialites-soumises-a-un-protocole-dutilisation-therapeutique/MALACEF-60-mg-poudre-et-solvant-pour-solution-injectable/(language)/fre-FR \nCentres for Disease C, Prevention Published reports of delayed hemolytic anemia after treatment with artesunate for severe malaria - worldwide, 2010–2012 MMWR Morb Mortal Wkly Rep 2013 62 5 8 23302816 \nAngus BJ Chotivanich K Udomsangpetch R White NJ In vivo removal of malaria parasites from red blood cells without their destruction in acute falciparum malaria Blood 1997 90 2037 2040 9292540 \nChotivanich K Udomsangpetch R Dondorp A Williams T Angus B Simpson JA Pukrittayakamee S Looareesuwan S Newbold CI White NJ The mechanisms of parasite clearance after antimalarial treatment of Plasmodium falciparum malaria J Infect Dis 2000 182 629 633 10.1086/315718 10915102 \nDas BS Renal failure in malaria J Vector Borne Dis 2008 45 83 97 18592837 \nCampos SB Rouch LHK Seguro AC Effects of sodium artesunate, a new antimalarial drug, on renal function Kidney Int 2001 59 1044 1051 10.1046/j.1523-1755.2001.0590031044.x 11231359 \nSeguro AC Campos SB Diuretic effect of sodium artesunate in patients with malaria AmJTrop Med Hyg 2002 67 473 474 \nWhite NJ Cardiotoxicity of antimalarial drugs Lancet Infect Dis 2007 7 549 10.1016/S1473-3099(07)70187-1 17646028 \nSterns RH Basow DF, Waltham MA Evaluation of the patient with hyponatremia 2013 Waltham, MA: UpToDate \nEllison DH Berl T Clinical practice. The syndrome of inappropriate antidiuresis N Engl J Med 2007 356 2064 2072 10.1056/NEJMcp066837 17507705 \nHoorn EJ van Wolfswinkel ME Hesselink DA de Rijke YB Koelewijn R van Hellemond JJ van Genderen PJJ Hyponatraemia in imported malaria: the pathophysiological role of vasopressin Malar J 2012 11 26 10.1186/1475-2875-11-26 22280539 \nHolst FG Hemmer CJ Kern P Dietrich M Inappropriate secretion of antidiuretic hormone and hyponatremia in severe falciparum malaria AmJTrop Med Hyg 1994 50 602 607 \nAkuthota P Weller PF Eosinophilic pneumonias Clin Microbiol Rev 2012 25 649 660 10.1128/CMR.00025-12 23034324 \nSolomon J Schwarz M Drug-, toxin-, and radiation therapy-induced eosinophilic pneumonia Semin Respir Crit Care Med 2006 27 192 197 10.1055/s-2006-939522 16612770 \nKohno S Yamaguchi K Yasuoka A Koga H Hayashi T Komori K Hara K Clinical evaluation of 12 cases of antimicrobial drug-induced pneumonitis Jpn J Med 1990 29 248 254 10.2169/internalmedicine1962.29.248 2273603 \nPneumotox v2.0 http://www.pneumotox.com\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1475-2875",
"issue": "12()",
"journal": "Malaria journal",
"keywords": null,
"medline_ta": "Malar J",
"mesh_terms": "D000328:Adult; D000743:Anemia, Hemolytic; D000962:Antimalarials; D037621:Artemisinins; D000077332:Artesunate; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D005858:Germany; D063426:Human Migration; D006801:Humans; D008288:Malaria; D008297:Male; D008875:Middle Aged; D011803:Quinine; D012189:Retrospective Studies",
"nlm_unique_id": "101139802",
"other_id": null,
"pages": "241",
"pmc": null,
"pmid": "23855745",
"pubdate": "2013-07-15",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "22462806;21529383;16612770;2273603;17934257;23034324;22985344;23302816;18592837;17507705;21899729;22280539;22523307;16125588;23265377;8203710;22594446;9292540;17646028;22696354;12479546;10915102;21062666;11231359;1624742",
"title": "Artesunate versus quinine in the treatment of severe imported malaria: comparative analysis of adverse events focussing on delayed haemolysis.",
"title_normalized": "artesunate versus quinine in the treatment of severe imported malaria comparative analysis of adverse events focussing on delayed haemolysis"
} | [
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"companynumb": "DE-MYLANLABS-2014M1014587",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "QUININE"
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{
"abstract": "Zolpidem is a commonly prescribed hypnotic used to treat insomnia. However, its potential for abuse and dependence has recently become controversial. Although over-the-counter (OTC) medications are widely used, their abuse potential has not received much research attention. We report a case of comorbid zolpidem and OTC compound analgesic abuse. OTC analgesics may serve as gateway drugs, and physicians must be cautious about this issue, especially when prescribing hypnotics or benzodiazepines.",
"affiliations": "Department of Psychiatry, Korea University Ansan Hospital, Korea University College of Medicine.;Department of Psychiatry, Korea University Ansan Hospital, Korea University College of Medicine.;Department of Psychiatry, Korea University Ansan Hospital, Korea University College of Medicine.;Department of Psychiatry, Korea University Ansan Hospital, Korea University College of Medicine.",
"authors": "Kim|Hyounwook|H|;Shin|Cheolmin|C|;Ko|Young-Hoon|YH|;Han|Changsu|C|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.9758/cpn.2019.17.2.323",
"fulltext": "\n==== Front\nClin Psychopharmacol NeurosciClin Psychopharmacol NeurosciClinical Psychopharmacology and Neuroscience1738-10882093-4327Korean College of Neuropsychopharmacology 3090513410.9758/cpn.2019.17.2.323cpn-17-323Case ReportComorbid Zolpidem Dependence and Over-the-Counter Compound Analgesic Abuse Kim Hyounwook Shin Cheolmin Ko Young-hoon Han Changsu Department of Psychiatry, Korea University Ansan Hospital, Korea University College of Medicine, Seoul, \nKoreaAddress for correspondence: Changsu Han, MD, PhD, MHS, Department of Psychiatry, Korea University Ansan Hospital, Korea University College of Medicine, 123 Jeokgeum-ro, Danwon-gu, Ansan 15355, Korea, Tel: +82-31-412-5140, Fax: +82-31-412-5144, E-mail: hancs@korea.ac.kr, ORCID: https://orcid.org/0000-0002-4021-89073 2019 30 4 2019 17 2 323 325 17 5 2017 02 6 2017 03 6 2017 Copyright © 2019, Korean College of Neuropsychopharmacology2019This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Zolpidem is a commonly prescribed hypnotic used to treat insomnia. However, its potential for abuse and dependence has recently become controversial. Although over-the-counter (OTC) medications are widely used, their abuse potential has not received much research attention. We report a case of comorbid zolpidem and OTC compound analgesic abuse. OTC analgesics may serve as gateway drugs, and physicians must be cautious about this issue, especially when prescribing hypnotics or benzodiazepines.\n\nZolpidemDependenceOver the counter drugsAbuse\n==== Body\nINTRODUCTION\nZolpidem, an imidazopyridine agent, is an agonist of the γ-aminobutyric acid (GABA)A-receptor complex.1) It is among the most commonly prescribed hypnotics2) due to its rapid onset, short duration of action, relatively few side effects compared with benzodiazepines,3) and minimal abuse and dependence potential.1,4,5) These advantages are thought to derive primarily from its selective binding to the α1 subunit-containing GABAA receptor.6–8)\n\nHowever, a series of studies reported that the abuse and dependence potential of zolpidem is similar to that of other benzodiazepines,2,9) rendering the use of this medication controversial.\n\nOver-the-counter (OTC) medications are widely used and perceived to be safer than prescription medication.10,11) Pain relievers are the best-selling OTC drugs,12) and 85% of all analgesics are sold OTC.13) There has been increasing concern about the abuse potential of OTC analgesics, but very little is known about this issue. Moreover, as patients tend to underreport OTC analgesic use, a significant proportion of individuals who abuse or are dependent on these substances may remain unidentified.14) Several studies have reported an association between OTC medication abuse (mainly dextromethorphan) and abuse of other substances. Bryner et al.15) reported that 20.1% of adolescent dextromethorphan abusers engaged in polysubstance abuse. Falck et al.16) reported that adolescent dextromethorphan abusers smoked more cigarettes and marijuana, consumed more alcohol, and abused more LSD, psilocybin, and 3,4-methylenedioxymethamphetamine.\n\nWe present a case of a patient hospitalized and treated for zolpidem dependence with comorbid OTC compound analgesic abuse.\n\nCASE\nA 69-year-old female visited the outpatient psychiatric clinic at our hospital with complaints of headache, insomnia, and zolpidem overuse. The patient had been suffering from headaches and insomnia for 12 years following her husband’s death. This patient started taking Panpyrin® (PR; Dong-A Pharm, Seoul, Korea), an OTC oral liquid analgesic comprising 200 mg acetaminophen, 100 mg etenzamide, 30 mg caffeine dehydrate, and 2 mg chlorpheniramine since the onset of the headaches, consuming more than five bottles of PR daily.\n\nBecause the patient’s headaches and insomnia persisted and worsened despite her continuous overuse of PR, the patient visited a local psychiatric clinic 5 years before her first visit to our hospital and started taking zolpidem 10 mg daily. Because of sustained insomnia, the patient increased her dose of zolpidem against her physician’s advice. After her physician refused to renew her prescription for zolpidem, she visited a number of clinics (including non-psychiatric ones), where her prescription was filled by proxy.\n\nFour years later, the patient was taking 50–60 mg of zolpidem daily and was experiencing confusion, sleep walking, and falling at night. The patient’s family persuaded her to decrease the dose of zolpidem to 10 mg daily, but the patient self-medicated with PR (2 bottles) and OTC diphenhydramine, an antihistamine agent (100–250 mg; normal dose, 25–50 mg) on a daily basis for headaches and insomnia. The patient visited the psychiatric department of our hospital and was admitted.\n\nThe patient was educated about her dependence and the risks of drug overdose, and then agreed to follow our plan to taper off of zolpidem, PR, and diphenhydramine. The patient was initially given 1 mg clonazepam, 50 mg quetiapine, 10 mg zolpidem, and 30 mg duloxetine. Zolpidem was tapered for 14 days while the quetiapine was increased to 100 mg and 2 mg melatonin was added. Whenever the patient did not fall asleep within 1 hour after taking her regular medication, she was allowed to take one additional 12.5-mg dose of quetiapine per day. The patient was also allowed to take 650 mg acetaminophen up to twice daily for headache. The patient eventually maintained a fair quality of sleep without zolpidem or other additional hypnotics and was discharged on hospital day 17. The patient continued outpatient treatment, experiencing several episodes of PR and zolpidem use, each of which lasted a maximum of one month.\n\nDISCUSSION\nThis report describes a vulnerable patient who abused multiple easily available substances. Her first drug of abuse was the OTC analgesic, PR, which she took in response to headaches and insomnia following the death of her husband. PR was an attractive choice as it is an OTC medication that is easy to obtain and generally considered to be safe. However, the patient’s superstitious beliefs about the effect of medication led to repetitive medication overuse. Moreover, there was no opportunity to educate the patient about her medication regimen because a prescription is not required for PR. Additionally, the patient did not attend to the drug label, which contains information about the recommended dosage, side effects, and so on. The patient took PR not only for headaches but also for insomnia. Abbott and Fraser17) described two types of OTC analgesic users; one type seeks to alleviate pain, and the other type seeks to treat stress, anxiety, depression, and sleep disturbances.\n\nRelapsing insomnia led the patient to seek and eventually abuse a more specialized medication, zolpidem. As one of the most commonly used hypnotics by both psychiatrists and non-psychiatrists, zolpidem is also relatively easily accessible. Additionally, we carefully suggest the possibility that the patient should have antidepressant effect of zolpidem which then would have contribute the patient’s dependence on it. Licata et al.18) found that zolpidem in the presence of SSRIs may have therapeutic effects in depression by elevating GABA. Ghosh et al.19) reported a case of an old male who abused baclofen, a GABA B receptor agonist, due to its hypomanic effect. This patient’s overuse of zolpidem caused obvious side effects, including nighttime confusion, sleep walking, and falls, leading the patient and her family members to seek medical and psychiatric services. While attempting to reduce her zolpidem use on her own, the patient overused another OTC medication, which contained diphenhydramine. This episode reflects the patient’s vulnerability to relapse. OTC medication may serve as a gateway drug, and abusers of these substances may also be vulnerable to abusing psychotropic agents or other substances. Agley et al.20) evaluated OTC medication as an initiator of drug-use sequences in adolescents but no other studies have been published on this subject.\n\nBased on this case, we suggest that clinicians who prescribe hypnotics or benzodiazepines should 1) identify all medication currently prescribed for the patient; 2) thoroughly investigate the patient’s history of OTC medication; and 3) consider short-term admission and readjustment of the patient’s extant drug regimen according to the severity of the patient’s dependence. Further longitudinal studies should address the association between OTC analgesic abuse and the abuse of other substances, including psychotropic agents.\n\nAcknowledgments\nThis research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HC15C1405).\n==== Refs\nREFERENCES\n1 Holm KJ Goa KL Zolpidem: an update of its pharmacology, therapeutic efficacy and tolerability in the treatment of insomnia Drugs 2000 59 865 889 10.2165/00003495-200059040-00014 10804040 \n2 Rush CR Baker RW Wright K Acute behavioral effects and abuse potential of trazodone, zolpidem and triazolam in humans Psychopharmacology (Berl) 1999 144 220 233 10.1007/s002130050997 10435388 \n3 Merlotti L Roehrs T Koshorek G Zorick F Lamphere J Roth T The dose effects of zolpidem on the sleep of healthy normals J Clin Psychopharmacol 1989 9 9 14 10.1097/00004714-198902000-00003 2651493 \n4 Langtry HD Benfield P Zolpidem. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential Drugs 1990 40 291 313 10.2165/00003495-199040020-00008 2226217 \n5 Salvà P Costa J Clinical pharmacokinetics and pharmacodynamics of zolpidem. Therapeutic implications Clin Pharmacokinet 1995 29 142 153 10.2165/00003088-199529030-00002 8521677 \n6 Korpi ER Mattila MJ Wisden W Lüddens H GABA(A)-receptor subtypes: clinical efficacy and selectivity of benzodiazepine site ligands Ann Med 1997 29 275 282 10.3109/07853899708999348 9375983 \n7 Lancel M Role of GABAA receptors in the regulation of sleep: initial sleep responses to peripherally administered modulators and agonists Sleep 1999 22 33 42 10.1093/sleep/22.1.33 9989364 \n8 Mitler MM Nonselective and selective benzodiazepine receptor agonists--where are we today? Sleep 2000 23 Suppl 1 S39 S47 10755807 \n9 Evans SM Funderburk FR Griffiths RR Zolpidem and triazolam in humans: behavioral and subjective effects and abuse liability J Pharmacol Exp Ther 1990 255 1246 1255 2262904 \n10 Bissell P Ward PR Noyce PR The dependent consumer: reflections on accounts of the risks of non-prescription medicines Health 2001 5 5 30 10.1177/136345930100500101 \n11 Roumie CL Griffin MR Over-the-counter analgesics in older adults: a call for improved labelling and consumer education Drugs Aging 2004 21 485 498 10.2165/00002512-200421080-00001 15182214 \n12 Bush PJ Rabin DL Who’s using nonprescribed medicines? Med Care 1976 14 1014 1023 10.1097/00005650-197612000-00005 1004035 \n13 Pommer W Glaeske G Molzahn M The analgesic problem in the Federal Republic of Germany: analgesic consumption, frequency of analgesic nephropathy and regional differences Clin Nephrol 1986 26 273 278 3802594 \n14 Cooper RJ ‘I can’t be an addict. I am.’ Over-the-counter medicine abuse: a qualitative study BMJ Open 2013 3 e002913 10.1136/bmjopen-2013-002913 \n15 Bryner JK Wang UK Hui JW Bedodo M MacDougall C Anderson IB Dextromethorphan abuse in adolescence: an increasing trend: 1999–2004 Arch Pediatr Adolesc Med 2006 160 1217 1222 10.1001/archpedi.160.12.1217 17146018 \n16 Falck R Li L Carlson R Wang J The prevalence of dextromethorphan abuse among high school students Pediatrics 2006 118 2267 2269 10.1542/peds.2006-2050 17079611 \n17 Abbott FV Fraser MI Use and abuse of over-the-counter analgesic agents J Psychiatry Neurosci 1998 23 13 34 9505057 \n18 Licata SC Jensen JE Conn NA Winer JP Lukas SE Zolpidem increases GABA in depressed volunteers maintained on SSRIs Psychiatry Res 2014 224 28 33 10.1016/j.pscychresns.2014.05.009 25082715 \n19 Ghosh S Bhuyan D Baclofen abuse due to its hypomanic effect in patients with alcohol dependence and comorbid major depressive disorder Clin Psychopharmacol Neurosci 2017 15 187 189 10.9758/cpn.2017.15.2.187 28449569 \n20 Agley J Gassman R YoussefAgha A Jun M Torabi M Jayawardene W Examining sequences of adolescent substance use initiation involving over-the-counter (OTC) drug abuse J Child Adoles Subst 2015 24 212 219 10.1080/1067828X.2013.812528\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1738-1088",
"issue": "17(2)",
"journal": "Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology",
"keywords": "Abuse; Dependence; Over the counter drugs; Zolpidem",
"medline_ta": "Clin Psychopharmacol Neurosci",
"mesh_terms": null,
"nlm_unique_id": "101207332",
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"pages": "323-325",
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"pubdate": "2019-05-31",
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"title": "Comorbid Zolpidem Dependence and Over-the-Counter Compound Analgesic Abuse.",
"title_normalized": "comorbid zolpidem dependence and over the counter compound analgesic abuse"
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"abstract": "BACKGROUND\nAtypical hemolytic uremic syndrome (aHUS) is associated with significant morbidity and mortality and occurs due to genetic or acquired abnormalities that result in the dysregulation of the alternative complement pathway.\n\n\nMETHODS\nWe report a case of post-living kidney transplantation de novo aHUS in a setting of heterozygous deletion in the complement factor H-related protein (CFHR)3-CFHR1 gene. The aHUS episode was possibly triggered by antibody-mediated rejection or tacrolimus. The patient responded well to eculizumab and substituting belatacept for tacrolimus. Her serum creatinine level was stable at 1.5 mg/dL after 2.5 years of follow-up.\n\n\nCONCLUSIONS\nThis case highlights the success of using a strategy that combines eculizumab and belatacept, as an alternative to calcineurin inhibitors, in treating aHUS in a patient with heterozygous deletion in the CFHR3-CFHR1 gene.",
"affiliations": "Division of Nephrology and Hypertension, University of Cincinnati, Cincinnati, Ohio, United States. Electronic address: drparasdedhia@gmail.com.;Division of Nephrology and Hypertension, University of Cincinnati, Cincinnati, Ohio, United States.;Division of Nephrology and Hypertension, University of Cincinnati, Cincinnati, Ohio, United States.;Division of Nephrology and Hypertension, University of Cincinnati, Cincinnati, Ohio, United States.;Division of Transplant Surgery, University of Cincinnati, Cincinnati, Ohio, United States.;Division of Nephrology and Hypertension, University of Cincinnati, Cincinnati, Ohio, United States.",
"authors": "Dedhia|P|P|;Govil|A|A|;Mogilishetty|G|G|;Alloway|R R|RR|;Woodle|E S|ES|;Abu Jawdeh|B G|BG|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D001798:Blood Proteins; C517621:CFHR1 protein, human; C105970:CFHR3 protein, human; D003180:Complement C3b Inactivator Proteins; D051056:Complement Inactivating Agents; D007166:Immunosuppressive Agents; D000069594:Abatacept; C481642:eculizumab; D016559:Tacrolimus",
"country": "United States",
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"doi": "10.1016/j.transproceed.2016.11.008",
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"issn_linking": "0041-1345",
"issue": "49(1)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000069594:Abatacept; D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D065766:Atypical Hemolytic Uremic Syndrome; D001798:Blood Proteins; D003180:Complement C3b Inactivator Proteins; D051056:Complement Inactivating Agents; D005260:Female; D006084:Graft Rejection; D006579:Heterozygote; D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D011183:Postoperative Complications; D016559:Tacrolimus",
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"references": null,
"title": "Eculizumab and Belatacept for De Novo Atypical Hemolytic Uremic Syndrome Associated With CFHR3-CFHR1 Deletion in a Kidney Transplant Recipient: A Case Report.",
"title_normalized": "eculizumab and belatacept for de novo atypical hemolytic uremic syndrome associated with cfhr3 cfhr1 deletion in a kidney transplant recipient a case report"
} | [
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"abstract": "We present a case of hypotension developing after reperfusion of a living-donor kidney transplant and performing a graft nephrectomy and successful retransplant with the same kidney 12 hours later. Preemptive kidney transplant was performed on a 51-year-old woman who had a chronic kidney disease because of hypertension. Her 55-year-old husband was the living kidney donor. The patient was stable before reperfusion. After declamping, pink color of the transplanted kidney, thrill from the renal artery, and urinary output were seen. But shortly after reperfusion, the invasive arterial blood pressure of the patient abruptly decreased from 130/70 mm Hg to 70/40 mm Hg, her pulse was approximately 80 to 110 beats/minute. The thrill disappeared from the renal artery, but blood flow continued. A graft nephrectomy was performed 45 minutes after reperfusion. Invasive arterial blood pressure of the patient was stabilized at approximately 110/70 mm Hg in the intensive care unit, and the patient was retransplanted with the same kidney. The patient was well, with a serum creatinine level of 1.4 mg/dL, 12 months after the operation. Resistant hypotension that occurs after kidney transplant may cause a loss of the graft and the patient. To prevent graft loss, and to stabilize the patient, a graft nephrectomy and retransplant of the graft under suitable circumstances may be considered.",
"affiliations": "From the Diyarbakir Education and Research Hospital, Transplantation Center, Diyarbakir, Turkey.",
"authors": "Ay|Nurettin|N|;Kaya|Sedat|S|;Anil|Melih|M|;Alp|Vahhac|V|;Sevuk|Utkan|U|;Danis|Ramazan|R|",
"chemical_list": "D014662:Vasoconstrictor Agents",
"country": "Turkey",
"delete": false,
"doi": "10.6002/ect.2015.0179",
"fulltext": null,
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"issn_linking": "1304-0855",
"issue": "16(1)",
"journal": "Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation",
"keywords": null,
"medline_ta": "Exp Clin Transplant",
"mesh_terms": "D001794:Blood Pressure; D004351:Drug Resistance; D005260:Female; D006085:Graft Survival; D006801:Humans; D007022:Hypotension; D016030:Kidney Transplantation; D019520:Living Donors; D008297:Male; D008875:Middle Aged; D009392:Nephrectomy; D020127:Recovery of Function; D012086:Reoperation; D016896:Treatment Outcome; D014662:Vasoconstrictor Agents",
"nlm_unique_id": "101207333",
"other_id": null,
"pages": "96-98",
"pmc": null,
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"pubdate": "2018-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Management of a Resistant Hypotension Developing After Reperfusion of a Living-Donor Kidney Transplant.",
"title_normalized": "management of a resistant hypotension developing after reperfusion of a living donor kidney transplant"
} | [
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"companynumb": "TR-ASTELLAS-2018US015121",
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"activesubstancename": "METHYLPREDNISOLONE"
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"abstract": "OBJECTIVE\nIncidence of caesarean scar pregnancy (CSP) is increasing due to rising caesarean section rate and advanced imaging modalities. At present, there is no consensus to recommend any specific intervention. In our centre, we have adopted the high dose intravenous methotrexate therapy followed by folinic acid for the management of CSP. In this retrospective study, we report the success rate and safety of this regimen.\n\n\nMETHODS\nThis was a 10-year retrospective study of women with CSP who received high dose methotrexate therapy with folinic acid at a tertiary centre from 1 st January 2008 to 31 st December 2017. Treatment regimen consisted of a bolus dose of intravenous methotrexate followed by methotrexate infusion over 12 h. Oral folinic acid rescues were given post treatment. Successful treatment was confirmed with either resolution of serum beta-human chorionic gonadotropin or subsequent intrauterine pregnancy.\n\n\nRESULTS\nOf 28 women with CSP who were treated with the regimen, 24 women (85.7%) were treated successfully with methotrexate alone. 3 women (10.7%) required suction evacuation following initial treatment with methotrexate and folinic acid. There was no serious side effect from methotrexate. Advanced gestational age, higher serum β-hCG, larger gestational sac diameter and crown-rump length, and the presence of embryonic cardiac activity were associated with methotrexate failure or need for additional therapy.\n\n\nCONCLUSIONS\nOur high dose intravenous methotrexate infusion therapy with folinic acid is effective and well tolerated. Caution is needed with factors associated with failure. Ensuring follow up ultrasound for live CSP and follow up β-hCG for all women with CSP is essential.",
"affiliations": "Women's and Newborn Services, Royal Brisbane and Women's Hospital, Herston, Australia; Faculty of Medicine, The University of Queensland, Herston, Australia. Electronic address: k.tanaka@uq.edu.au.;Obstetrics and Gynaecology, Townsville Hospital, Townsville, Australia.;MNHHS Statistics Unit, QIMR Berghofer Medical Research Institute, Herston, Australia.;Women's and Newborn Services, Royal Brisbane and Women's Hospital, Herston, Australia.;Women's and Newborn Services, Royal Brisbane and Women's Hospital, Herston, Australia; Faculty of Medicine, The University of Queensland, Herston, Australia.;Women's and Newborn Services, Royal Brisbane and Women's Hospital, Herston, Australia.;Women's and Newborn Services, Royal Brisbane and Women's Hospital, Herston, Australia.",
"authors": "Tanaka|Keisuke|K|;Coghill|Elise|E|;Ballard|Emma|E|;Sekar|Renuka|R|;Amoako|Akwasi|A|;Khalil|Akram|A|;Baartz|David|D|",
"chemical_list": "D000020:Abortifacient Agents, Nonsteroidal; D008727:Methotrexate",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.ejogrb.2019.04.008",
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"issn_linking": "0301-2115",
"issue": "237()",
"journal": "European journal of obstetrics, gynecology, and reproductive biology",
"keywords": "Caesarean scar pregnancy; Ectopic pregnancy; Medical management; Methotrexate",
"medline_ta": "Eur J Obstet Gynecol Reprod Biol",
"mesh_terms": "D000020:Abortifacient Agents, Nonsteroidal; D000328:Adult; D002585:Cesarean Section; D002921:Cicatrix; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008727:Methotrexate; D011247:Pregnancy; D011271:Pregnancy, Ectopic; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "0375672",
"other_id": null,
"pages": "28-32",
"pmc": null,
"pmid": "30999082",
"pubdate": "2019-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Management of caesarean scar pregnancy with high dose intravenous methotrexate infusion therapy: 10-year experience at a single tertiary centre.",
"title_normalized": "management of caesarean scar pregnancy with high dose intravenous methotrexate infusion therapy 10 year experience at a single tertiary centre"
} | [
{
"companynumb": "AU-ACCORD-125762",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "LEUCOVORIN"
},
"drugadditional": null,
"dru... |
{
"abstract": "Second primary malignancies (SPMs) are issues for patients with multiple myeloma (MM). There may have been some limitations in prior studies, such as difficulties in a longer follow-up and absence of established screening methods. Therefore, we studied autopsied cases to overcome these limitations. This study aimed to examine SPMs using autopsy reports. Ninety-one cases of MM autopsied at our institution from 1979 to 2013 were analyzed. Median age of autopsied patients was 64.1 years, and proportion of male/female was 59/32. Autopsy was performed in 35.3% of patients died of MM. There were five cases of SPMs with a median confirmation time of 38 (12-132) months from the diagnosis of MM. In three of the five patients, the diagnosis of SPMs was established at autopsy. One case was of myelodysplastic syndrome, and the others were of non-hematological malignancies. The annual risk of SPM estimated using the Kaplan-Meier method was approximately 1%. Three of five SPM cases were detected at autopsy. Analysis of autopsy may contribute to estimate the actual risk of SPMs in MM.",
"affiliations": "Division of Hematology, Department of Internal Medicine, National Center for Global Health and Medicine , Tokyo, Japan.;Division of Hematology, Department of Internal Medicine, National Center for Global Health and Medicine , Tokyo, Japan.;Division of Hematology, Department of Internal Medicine, National Center for Global Health and Medicine , Tokyo, Japan.",
"authors": "Takano|Junichiro|J|;Hagiwara|Shotaro|S|;Miwa|Akiyoshi|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.4081/rt.2015.5949",
"fulltext": "\n==== Front\nRare TumorsRare TumorsRTRare Tumors2036-36052036-3613PAGEPress Publications, Pavia, Italy 10.4081/rt.2015.5949ArticleAutopsy Analysis may Contribute to Establish Actual Incidence of Second Primary Malignancies in Myeloma Takano Junichiro Hagiwara Shotaro Miwa Akiyoshi Division of Hematology, Department of Internal Medicine, National Center for Global Health and Medicine, Tokyo, JapanDivision of Hematology, Department of Internal Medicine, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku, Tokyo, 162-8655, Japan. +81.3.3202.7181 - +81.3207.1038. shagiwar@hosp.ncgm.go.jpContributions: the authors contributed equally.\n\nConflict of interest: the authors declare no potential conflict of interest.\n\n29 12 2015 29 12 2015 7 4 594911 4 2015 12 4 2015 ©Copyright J. Takano et al.2015Licensee PAGEPress, ItalyThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Second primary malignancies (SPMs) are issues for patients with multiple myeloma (MM). There may have been some limitations in prior studies, such as difficulties in a longer follow-up and absence of established screening methods. Therefore, we studied autopsied cases to overcome these limitations. This study aimed to examine SPMs using autopsy reports. Ninety-one cases of MM autopsied at our institution from 1979 to 2013 were analyzed. Median age of autopsied patients was 64.1 years, and proportion of male/female was 59/32. Autopsy was performed in 35.3% of patients died of MM. There were five cases of SPMs with a median confirmation time of 38 (12-132) months from the diagnosis of MM. In three of the five patients, the diagnosis of SPMs was established at autopsy. One case was of myelodysplastic syndrome, and the others were of non-hematological malignancies. The annual risk of SPM estimated using the Kaplan-Meier method was approximately 1%. Three of five SPM cases were detected at autopsy. Analysis of autopsy may contribute to estimate the actual risk of SPMs in MM.\n\nKey words\nMultiple myelomasecond primary malignancyautopsymelphalanimmunomodu-lating agents\n==== Body\nIntroduction\nIn the recent decades, the treatment of multiple myeloma (MM) has markedly improved, however second primary malignancies (SPMs) have become problematic for long-term sur-vivors.1 The development of SPM in MM may reflect a combination of several causes such as host-related, disease-related, treatment-related, and environmental or behavioral factors. For host factors, MM develops in older popula-tions.2 A gene expression microarray analysis revealed that germline polymorphisms may play a role in the development of MM and might have some role in the development of SPMs.3,4 Among the disease-related factors, epigenetic changes and alterations in signaling pathways may occur with the progression of MM.5,6 Furthermore, MM may influence immune cells including macrophages, T cells, or NK cells and disturb tumor immunity.7,8 Treatment-related factors have been intensively studied.1 The tumorigenicity of nitrosourea is a well-known phenomenon.9 Since Bergsagel et al. observed an increased the incidence of acute leukemia with the use of alkylating agents,10 their role in the development of SPM has been widely assessed.1 Cuzick et al. reported a positive association between the duration of L-PAM therapy and the subsequent risk of developing leukemia. In addition, they showed the cumulative doses of L-PAM given up to 3 years before the diagnosis of leukemia was the most important risk factor.11 Although the Finnish Leukemia Group showed no significant correlation between the development of SPM and the use of L-PAM,12 LPAM is widely viewed as a risk factor.13 The risk of SPM after the use of high-dose L-PAM, as a preconditioning regimen for autologous stem cell transplantation, is not considered to increase the risk of SPM compared with lower doses of L-PAM.14 However, the results of the Intergroupe Fraccophone du Myeloma (IFM) study suggested that the risk may be higher after double transplantation.15 Recently immunomodulating agents (IMids) including thalidomide (Thal) and lenalidomide (Len) were identified as agents that may increase the risk of SPMs;16-18 however, this is controversial. For example, a meta-analysis by Palumbo et al. showed that SPMs were linked to Len and L-PAM combination therapy rather than Len monotherapy.19\n\nThe exact mechanism by which SPMs develop remains elusive.1 Although SPMs in patients with MM have been intensely studied since the 1960s, previous studies have some limitations. For example, they did not follow patients throughout life and the method used to screen for SPMs was not established in earlier studies.20 Therefore, some SPMs may have been missed. Thus, we studied autopsied cases because an autopsy allows systemic pathological diagnosis and follow-up throughout the entire lifespan of a patient. The aim of this study was to examine SPMs using autopsy reports from patients with MM, although we are aware that focusing only on autopsies may yield some selection bias.\n\nMaterials and Methods\nAs shown in Table 1, this study included 91 consecutive cases of MM autopsied at National Center for Global Health and Medicine, Tokyo, Japan, from 1979 to 2013 (median patient age, 64.1 years; male/female ratio, 59/32). Autopsy was performed in 35.3% of patients died of MM. Most cases were Durie-Salmon stage III (M-proteins IgG/IgA/IgD/BJP/uncertain = 46/12/7/18/8). All patients had undergone conventional treatments. Twenty-one patients also underwent autologous stem cell transplantation (ASCT) during their treatment course. Thal and Len were used in six and three patients, respectively (the duration of Len use was 3-6 months; all three patients underwent ASCT before the administration of Len).\n\nStatistical analysis\nThe cumulative incidence of SPMs was estimated using the Kaplan-Meier method. Statistical analyses were performed using SPSS (version 17.0).\n\nResults\nAs shown in the Table 2, there were five cases of SPM (5.5% of all cases), with a median confirmation time of 38 (12-132) months since the diagnosis of MM. Prostate (n=2), lungs (n=1), and thyroid (n=1) were the sites of SPMs; there was also one case of myelodys-plastic syndrome (MDS). The diagnosis of SPM was established at autopsy in three of the five patients. SPMs tended to develop in older patients with median ages of 68.6 and 62.4 years in patients with or without SPMs, respectively (P=0.300; Table 3).\n\nAll five patients with SPMs were administered L-PAM, with a median cumulative dose of 784 mg. Three patients also received nitrosourea. Three and none of the five had used Thal and Len previously, respectively. One patient had previously undergone ASCT (Table 4). The estimated annual risk of SPM is shown in Figure 1.\n\nDiscussion\nSPMs are a potential risk in long-term MM survivors.1 There have been challenges associated with studies of SPMs in MM, such as insufficient long-term follow-up and absence of an established screening method.20 The aim of this study was to overcome these limitations using autopsies, which allows the systemic pathological diagnosis and the follow-up of patients’ whole life. We found three cases of SPM that were diagnosed at autopsy. This suggests that studying SPMs using autopsy is feasible. The 5.5% incidence of SPM and the median time of 38 months since the diagnosis of MM observed in the current study are consistent with previous reports.14,21,22 In addition, the annual risk of SPM estimated using the Kaplan-Meier method was similar to data based on 33,229 patients with MM between 1973 and 2008 in the United States, reported by Thomas et al.1\n\nAmong the five cases of SPM, two were prostate cancer. In contrast, Razavi et al. reported a significantly lower overall risk of prostate cancer in patients with MM.23 The incidence of hematological malignancies in the current study was similar to a recently published report from the Mayo clinic, which reported the long-term follow-up data of newly diagnosed patients with MM treated with Len and dexamethasone.24 They found that 12 (4.2%) patients had an SPM and only two patients developed hematological malignancies.\n\nThree of the five patients with SPMs were treated with nitrosourea in the current study. All five patients received L-PAM with a median cumulative dose of 784 mg, which is compatible with prior reports.25 Because of the small number of patients with SPM in the current study, it is difficult to discuss a causal link between the use of IMids or ASCT and the development of SPMs. However, no SPM developed in the three patients who received Len, three of six patients who received Thal developed SPMs, and only one of the 21 patients treated with ASCT later developed an SPM.\n\nThe current study has some limitations that must be discussed. First, we could not avoid selection bias because we studied only autopsied cases. Second, the sample size was small. Nevertheless, our data provide several unique insights; especially 3 SPMs were found at autopsy and this may suggest the availability of studying SPMs based on autopsied cases. Because few similar approaches have been previously undertaken, therefore, we recommend that the current results should be explored in a larger cohort of patients.\n\nFigure 1. Cumulative incidence of second primary malignancies estimated using the Kaplan–Meier method.\n\nTable 1. Characteristics of patients.\n\nCharacteristic\tN.\t\nAutopsies in MM patients, %\t35.3\t\nMale/female\t59/32\t\nMedian age at death, years\t64.1 (38-85)\t\nTime from diagnosis, months\t49 (1-156)\t\nM-protein IgG\t46\t\n IgA\t12\t\n IgD\t7\t\n BJP\t18\t\n Unknown\t8\t\nDurie-Salmon stage\talmost all cases are 3\t\nConventional chemotherapy\t91\t\n ASCT\t21\t\n Thal\t6\t\n Len\t3\t\nMM, multiple myeloma; IG, immunoglobulin; BJP, Bence Jones protein; ASCT, autologous stem cell transplantation; Thal, thalidomide; Len, lenalidomide.\n\nTable 2. Characteristics of 5 second primary malignancies (SPMs) cases.\n\n\tAge\tSex\tTime to diagnosis, months\tOverall survival, months\tSPMs\t\n1\t58\tM\t38\t38\tProstate\t\n2\t71\tM\t12\t14\tLung\t\n3\t75\tM\t30\t30\tThyroid\t\n4\t64\tM\t56\t56\tProstate\t\n5\t75\tF\t21\t156\tMDS\t\nMDS, myelodysplastic syndrome. Median confirmation time form multiple myeloma diagnosis: 38 (12-132) months. Three SPMs cases are diagnosed at autopsy.\n\nTable 3. Comparison of age and overall survival (OS) between second primary malignancies (SPMs) positive and negative patients.\n\n\tSPMs positive\tSPMs negative\tP-value\t\nAge\t68.6 years old\t62.7 years old\t0.300\t\nOS\t58.4 months\t39 months\t0.117\t\nTable 4. Treatment history of 5 second primary malignancies (SPMs) cases.\n\n\tSPMs\tMCNU\tL-PAM, mg\tLen\tThal\tASCT\tCPM\tOther\t\n1\tProstate\tNo\t370\tNo\tNo\tNo\tNo\t\t\n2\tLung\tYes\t48\tNo\tNo\tNo\tNo\t\t\n3\tThyroid\tYes\tunknown\tNo\tNo\tNo\tNo\tVP-16\t\n4\tProstate\tYes\t1440\tNo\tYes\tYes\t1000 mg\tRx, VAD, BTZ\t\n5\tMDS\tNo\t1168\tNo\tYes\tNo\tNo\t\t\nMedian cumulative dose of L-PAM: 784 mg. Thal, thalidomide; Len, lenalidomide; ASCT, Autologous stem cell transplant.\n==== Refs\nReferences\n1. Landgren O Thomas A Mailankody S \nMyeloma and second primary cancers . N Engl J Med \n2011 ;365 :2241 -2 .22150057 \n2. Palumbo A Anderson K \nMultiple myeloma . N Engl J Med \n2011 ;364 :1046 -60 .21410373 \n3. Knight JA Skol AD Shinde A \nGenome-wide association study to identify novel loci associated with therapy-related myeloid leukemia susceptibility . Blood \n2008 ;113 :5575 -82 .19299336 \n4. Ellis NA Huo D Yildiz O \nMDM2 SNP309 and TP53 Arg72Pro interact to alter therapy-related acute myeloid leukemia susceptibility . Blood \n2008 ;112 : 741 -9 .18426989 \n5. Hideshima T Mitsiades C Tonon G \nUnderstanding multiple myeloma patho-genesis in the bone marrow to identify new therapeutic targets . Nat Rev Cancer \n2007 ;7 :585 -58 .17646864 \n6. Zhan F Sawyer J Tricot G \nThe role of cytogenetics in myeloma . Leukemia \n2006 ;20 : 1484 -6 .16926848 \n7. Asimakopoulos F Jaehyup K Ryan A \nMacrophages in multiple myeloma: emerging concepts and therapeutic implications . Leuk Lymphoma . 2013 ;54 \n2112 -21 .23432691 \n8. Borrello I \nCan we change the disease biology of multiple myeloma? \nLeuk Res \n2012 ;36 :S3 -12 .23176722 \n9. Zeller WJ Schmähl D \nDevelopment of second malignancies in rats after cure of acute leukemia L 5222 by single doses of 2-chloroethylnitrosoureas . J Cancer Res Clin Oncol \n1979 ;95 :83 -6 .227910 \n10. Bergsagel DE Bailey AJ Langley GR \nThe chemotherapy on plasma-cell myeloma and the incidence of acute leukemia . N Engl J Med \n1979 ;301 :743 -8 .481481 \n11. Cuzick J Erskine S Edelman D Galton DA \nA comparison of the incidence of the myelodysplastic syndrome and acute myeloid leukemia following melphalan and cyclophosphamide treatment for myelomatosis: a report to the Medical Research Council’s working party on leukemia in adults . Br J Cancer \n1987 ;55 :523 -9 .3300761 \n12. Finnish Leukaemia Group \nAcute leukemia and other secondary neoplasms in patients treated with conventional chemotherapy for multiple myeloma . Eur J Haematol \n2000 ;65 :123 -7 .10966173 \n13. Langdren O Maliankoby S \nUpdate on second primary malignancies in multiple myeloma: a focused review . Leuksemia \n2014 ;28 :1423 -6 .\n14. Mailankody S Pfeiffer RM Kristinsson SY \nRisk of acute myeloid leukemia and myelodysplastic syndromes following multiple myeloma and its precursor disease (MGUS) . Blood \n2011 ;118 :4086 -92 .21795746 \n15. Attal M Lauwers-Cances V Marit G \nContinuous lenalidomide treatment for newly diagnosed multiple myeloma . N Engl J Med \n2012 ;366 :1782 -91 .22571202 \n16. Dimopoulos MA Richardson PG Brandenburg N \nA review of second primary malignancy in patients with relapsed or refractory multiple myeloma treated with lenalidomide . Blood \n2012 ;119 :2764 -67 .22323483 \n17. Palumbo A Hajek R Delforge M \nContinuous lenalidomide treatment for newly diagnosed multiple myeloma . N Engl J Med \n2012 ;336 :1759 -69 .22571200 \n18. McCarthy PL Owzer K Hofmeister CC \nLenalidomide after stem-cell transplantation for multiple myeloma . N Engl J Med \n2012 ;366 :1770 -81 .22571201 \n19. Palumbo A Bringhen S Kumar SK \nSecond primary malignancies with lenalidomide therapy for newly diagnosed myeloma: a meta-analysis of individual patient data . Lancet Oncol \n2014 ;15 :333 -42 .24525202 \n20. Guy P \nLenalidomide and second malignancies in myeloma patients . Lancet Oncol \n2014 ;15 :253 -4 .24525201 \n21. Dong C Hemminki K \nSecond primary neoplasms among 53 159 haematolympho-proliferative malignancy patients in Sweden, 1958-1996: a search for common mechanisms . Br J Cancer \n2011 ;85 :9971005 .\n22. Hasakarl J Ihorst G De pasquale D \nAssociation of multiple myeloma with different neoplasms; systemic analysis in consecutive patients with myeloma . Leuk Lymphoma \n2011 ;52 :247 -59 .21054148 \n23. Razavi P Rand KA Cozen W \nPatterns of second primary malignancy risk in multiple myeloma patients before and after the introduction of novel therapeutics . Blood Cancer J \n2013 ;3 :e121 .23811785 \n24. Srivastava G Rana V Lacy MQ \nLong-term outcome with lenalidomide and dex-amethasone therapy for newly diagnosed multiple myeloma . Leukemia \n2013 ;27 :2062 -6 .23648667 \n25. Greene MH Boice JD Greer BE \nAcute nonlymphocytic leukemia after therapy with alkylating agents for ovarian cancer . N Engl J Med \n1982 :1416 -21 .6752720\n\n",
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"title": "Autopsy Analysis may Contribute to Establish Actual Incidence of Second Primary Malignancies in Myeloma.",
"title_normalized": "autopsy analysis may contribute to establish actual incidence of second primary malignancies in myeloma"
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"abstract": "We report a case of a child with severe psoriasis vulgaris that developed neutralizing anti-drug antibodies against the biologic agent adalimumab 3 months after the first administration of the drug during Streptococcus pyogenes infection of the throat. After replacement of biologic agent, she was unsuccessfully treated with etanercept. Treatment with ustekinumab was the last option and initially it also appeared ineffective, but as we shortened the interval and doubled the dosage our patient's skin condition finally improved.",
"affiliations": "Department of Dermatovenerology, Ljubljana University Medical Center, Ljubljana, Slovenia.;Department of Dermatovenerology, Ljubljana University Medical Center, Ljubljana, Slovenia.",
"authors": "Starbek Zorko|Mateja|M|;Selan|Maruša|M|",
"chemical_list": "D000906:Antibodies; D001685:Biological Factors; D000069549:Ustekinumab; D000068879:Adalimumab",
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"mesh_terms": "D000068879:Adalimumab; D000906:Antibodies; D001685:Biological Factors; D002648:Child; D006801:Humans; D011565:Psoriasis; D016896:Treatment Outcome; D000069549:Ustekinumab",
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"title": "Hard-to-treat psoriasis in a child developing neutralizing anti-drug antibodies against adalimumab during Streptococcus pyogenes throat infection: a case report.",
"title_normalized": "hard to treat psoriasis in a child developing neutralizing anti drug antibodies against adalimumab during streptococcus pyogenes throat infection a case report"
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"abstract": "In recent years, one of the most successful advances in treating acute myeloid leukaemia (AML) has been the combination of the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax with hypomethylating agents (decitabine or azacytidine). This combination treatment has an accelerated approval by the Food and Drug Administration for newly diagnosed AML adults who are 75 years of age or older or who have comorbidities and are not eligible to receive intensive induction chemotherapy. AML is the most common form of acute leukaemia in adults, with a median age at diagnosis of 68 years. Consequently, most of the patients included in the studies are elderly. Traditionally, young patients achieve higher remission rates compared with the elderly AML population. Although venetoclax combination therapy could become a treatment option for treating young patients with relapsed/refractory AML, this regimen has not been systematically tested in this setting. In this study, we summarize the currently available evidence on the treatment of venetoclax in combination with hypomethylating agents for the treatment of young relapsed/refractory AML patients, in addition to our experience in clinical practice with two case reports. Venetoclax, combined with hypomethylating agents, seems to be an effective option for young relapsed/refractory AML patients. However, due to the poor quality of the evidence, additional well-designed studies with greater numbers of patients are needed to confirm the effectiveness and safety of venetoclax combination regimens for this population.",
"affiliations": "Hospital Pharmacy Department, Virgen del Rocio University Hospital, Seville, Spain.;Hospital Pharmacy Department, Virgen del Rocio University Hospital, Avda. Manuel Siurot s/n, 41013 Seville, Spain.;Hospital Pharmacy Department, Virgen del Rocio University Hospital, Seville, Spain.;Department of Hematology, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS/CSIC/CIBERONC), University of Seville, Seville, Spain.;Hospital Pharmacy Department, Virgen del Rocio University Hospital, Seville, Spain.",
"authors": "Báez-Gutiérrez|Nerea|N|https://orcid.org/0000-0002-9419-7742;Rodríguez-Ramallo|Héctor|H|;Moreno|María Antonia-Pérez|MA|;Arboli|Eduardo-Rodriguez|ER|;Abdel-Kader Martín|Laila|L|",
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"fulltext": "\n==== Front\nTher Adv Hematol\nTher Adv Hematol\nTAH\nsptah\nTherapeutic Advances in Hematology\n2040-6207\n2040-6215\nSAGE Publications Sage UK: London, England\n\n10.1177/20406207211040335\n10.1177_20406207211040335\nCase Series\nVenetoclax combination therapy with hypomethylating agents in young adults with relapsed/refractory acute myeloid leukaemia\nhttps://orcid.org/0000-0002-9419-7742\nBáez-Gutiérrez Nerea Hospital Pharmacy Department, Virgen del Rocio University Hospital, Seville, Spain\n\nRodríguez-Ramallo Héctor Hospital Pharmacy Department, Virgen del Rocio University Hospital, Avda. Manuel Siurot s/n, 41013 Seville, Spain\n\nMoreno María Antonia-Pérez Hospital Pharmacy Department, Virgen del Rocio University Hospital, Seville, Spain\n\nArboli Eduardo-Rodriguez *Department of Hematology, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS/CSIC/CIBERONC), University of Seville, Seville, Spain\n\nAbdel-kader Martín Laila *Hospital Pharmacy Department, Virgen del Rocio University Hospital, Seville, Spain\n\nhectorodra@gmail.com\n* These authors contributed equally to this work.\n\n28 8 2021\n2021\n12 2040620721104033515 4 2021\n27 7 2021\n© The Author(s), 2021\n2021\nSAGE Publications\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).\nIn recent years, one of the most successful advances in treating acute myeloid leukaemia (AML) has been the combination of the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax with hypomethylating agents (decitabine or azacytidine). This combination treatment has an accelerated approval by the Food and Drug Administration for newly diagnosed AML adults who are 75 years of age or older or who have comorbidities and are not eligible to receive intensive induction chemotherapy. AML is the most common form of acute leukaemia in adults, with a median age at diagnosis of 68 years. Consequently, most of the patients included in the studies are elderly. Traditionally, young patients achieve higher remission rates compared with the elderly AML population. Although venetoclax combination therapy could become a treatment option for treating young patients with relapsed/refractory AML, this regimen has not been systematically tested in this setting. In this study, we summarize the currently available evidence on the treatment of venetoclax in combination with hypomethylating agents for the treatment of young relapsed/refractory AML patients, in addition to our experience in clinical practice with two case reports. Venetoclax, combined with hypomethylating agents, seems to be an effective option for young relapsed/refractory AML patients. However, due to the poor quality of the evidence, additional well-designed studies with greater numbers of patients are needed to confirm the effectiveness and safety of venetoclax combination regimens for this population.\n\nacute myeloid leukaemia\nhypomethylating agent\nrefractory\nrelapsed\nvenetoclax\nyoung patients\ncover-dateJanuary-December 2021\ntypesetterts1\n==== Body\nIntroduction\n\nAcute myeloid leukaemia (AML) is the most common form of acute leukaemia in adults, with an incidence ranging from 5 to 8 per 100,000 in Europe1 and with a current 5-year survival rate of 28.7%.2\n\nThe treatment of relapsed/refractory (R/R) AML represents a formidable challenge for treating clinicians. Intensive chemotherapy is usually recommended for fit patients to achieve a second complete remission (CR) to proceed to haematopoietic stem cell transplantation (HSCT). However, this approach commonly fails due to the patient’s complexity.3 In those patients who are not eligible for induction chemotherapy, hypomethylating agents (HMAs), that is, decitabine (DEC) or azacytidine (AZA), have been shown to be beneficial4,5 but, in the salvage setting, are mainly used as palliative treatment. Novel noncytotoxic approaches have been recently developed due to a better understanding of the molecular complexity and biology of AML. Targeted agents such as ivosidenib (IDH1 mutation),6 enasidenib (IDH2 mutation)7 and gilteritinib (FLT3 mutation)8 have been shown to be effective in treating R/R patients with specific mutations.\n\nVenetoclax (VEN) is a selective, orally bioavailable inhibitor of the antiapoptotic protein B-cell lymphoma 2 (BCL-2) with activity in a variety of haematologic malignancies.9–11 As BCL-2 overexpression is associated with AML cell survival and treatment resistance,12 BCL-2 inhibitors have the potential to sensitize AML cells to HMA,13 thereby providing the rationale for combining VEN with HMA.\n\nThe US Food and Drug Administration has accelerated the approval of VEN in combination with HMA for adults who are 75 years of age or older or who have comorbidities and cannot use intensive induction chemotherapy. The clinical trial that motivated this approval was a phase I/II clinical trial of VEN + AZA or DEC in previously untreated AML patients older than 65 years who are not candidates for intensive therapy that showed CR + complete remission with incomplete haematologic recovery (CRi) rate of 73% with a median overall survival (mOS) of 17.5 months.14 Subsequently, the phase III trial (VIALE-A) results were published, in which an OS of 14.7 months in the AZA–VEN group and an overall response rate (ORR) of 66.4% were obtained.15\n\nThe combination of VEN and HMA has not been systematically tested in R/R AML. Furthermore, AML is the most common form of acute leukaemia in adults, with a median age at diagnosis of 68 years.16 Therefore, the vast majority of evidence published related to R/R AML is based on results obtained from the elderly population. Nevertheless, data concerning young patients have not been clearly defined and documented.\n\nThis study aims to review the available evidence in refractory AML patients treated with the VEN + HMA combination, specifically in young adult patients. In addition, we report two cases of young patients successfully treated in our centre with VEN + HMA.\n\nThe search was performed in the MEDLINE database using the following key terms: ‘acute myeloblastic leukaemia’, ‘azacytidine’, ‘decitabine’, ‘venetoclax’, ‘relapse’ and ‘refractory’.\n\nVEN combination therapy in R/R AML patients\n\nIn the R/R setting, VEN combination therapy with HMA is an option for unfit patients and those who are unlikely to benefit from standard salvage treatment due to recurrence after heterogeneous HSCT and high-risk genetic factors as complex cytogenetics, mononuclear karyotype, TP53 mutations and so on.\n\nData on VEN combination therapy are mainly limited to retrospective studies and one clinical trial (Table 1). A total of 16 observational studies of VEN + HMA combination therapy for R/R AML patients were identified (15 retrospective and 1 prospective) and 1 phase 1 clinical trial.17–33 Of them, 16 included adults,17–31,33 the majority being elderly patients, and only one study focused on paediatric patients and young adults.32\n\nTable 1. Clinical studies with VEN combination therapy in relapsed/refractory AML.\n\nStudy\tDesign\tN\tR/R AML\tDosage, n (%)\tEfficacy, n (%)\tToxicity, n (%)\tPost-VEN combination HSCT\t\nAldoss and colleagues17\tRETRO\t33\t33\tVEN + AZA, 2 (6.1%)\nVEN + DEC, 16 (48.5%)\tORR: 21 (64%)\nCR: 10 (30%)\nCRi: 7 (21%)\nMLFS: 4 (12%)\n1-year OS: 53%\tSepsis 11 (33.3%)\nPneumonia 5 (15.2%)\nColitis and diarrhoea 3 (9%)\nAtrial fibrillation 2 (6%)\nAcute renal failure 2 (6%)\t3 (9.1%)\t\nDiNardo and colleagues18\tRETRO\t43\t39\tVEN + AZA, 8 (18.6%)\nVEN + DEC, 23 (53.5%)\nVEN + LDAC, 8 (18.6%)\nVEN + Other, 4 (9.3%)\tORR: 9 (21%)\nCR: 2 (4.7%)\nCRi: 3 (6.5%)\nMLFS: 4 (9.3%)\nmOS: 3 (0.5–8) months\tG ⩾ 3 neutropenia 43 (100%)\nG ⩾ 3 infection 31 (72%)\t2 (5%)\t\nAldoss and colleagues19\tRETRO\t90\t90\tVEN + AZA, 9 (10%)\nVEN + DEC, 81 (90%)\tCR/CRi: 41 (46%)\nCR: 23 (26%)\nCRi: 18 (20%)\nmOS: 7.8 months\tN/A\t14 (1.5%)\t\nAldoss and colleagues20\tRETRO\t31\t16\tVEN + AZA, 3 (9.7%)\nVEN + DEC, 28 (90.3%)\tCR/CRi: 16 (51.6%)\nCR: 7 (22.6%)\nCRi: 9 (29.0%)\nmOS: 11 months\tN/A\t5 (16.1%)\t\nAsghari and colleagues21\tRETRO\t31\t31\tVEN, 1 (3.2%)\nVEN + AZA, 13 (41.9%)\nVEN + DEC, 17 (54.8%)\tORR: 10 (34.5%)\nCR: 0 (0%)\nCRi: 8 (27.6%)\nMLFS: 2 (6.9%)\nmOS: 4.9 months\tN/A\t2 (6.5%)\t\nMittal and colleagues22\tRETRO\t11\t11\tVEN + AZA, 8 (72.7%)\nVEN + DEC, 3 (27.3%)\tCR/CRi: 4 (36%)\nPR/SD: 5 (45%)\nmOS: 11 months\tN/A\tN/A\t\nRam and colleagues23\tPROSP\t23\t23\tVEN + AZA, 16 (69.6%)\nVEN + DEC, 4 (17.4%)\nVEN + LDAC, 3 (13%)\tCR/CRi: 10 (43%)\nCR: 5 (21.7%)\nCRi: 5 (21.7%)\n6-month mOS: 74%\nmOS: 5.6 months\tFebrile neutropenia 18 (78%)\t1 (4.35%)\t\nAldoss and colleagues24\tRETRO\t50\t33\tVEN + AZA, 2 (6%)\nVEN + DEC, 31 (94%)\tCR/CRi: 14 (42%)\nmOS: 8.33 months\tN/A\t8 (24.24%)\t\nByrne and colleagues25\tRETRO\t21\t21\tVEN + AZA, 12 (57.1%)\nVEN + DEC, 4 (19%)\nVEN + LDAC, 5 (23.8%)\tORR: 8 (42.1%)\nCR: 5 (26.3%)\nCRi: 3 (15.8%)\nPR: 0 (0%)\nMLFS: 4 (21.1%)\nmOS: 7.8 months\tInfectious complications 13 (61.9%)\t4 (19.1%)\t\nDiNardo and colleagues26\tPhase 2b RCT\t168\t55\tVEN + DEC, 55 (100%)\tCR/CRi: 23 (42%)\nCR: 13 (24%)\nCRi: 10 (18%)\nmOS: 7.8 (5.4–13.3) months\tG3 infections 79 (47%)\nG4 neutropenia 79 (47%)\nFebrile neutropenia 49 (29%)\t10 (18.2%)\t\nGaut and colleagues27\tRETRO\t14\t14\tVEN + AZA, 8 (57.1%)\nVEN + DEC, 5 (35.7%)\nVEN + LDAC, 1 (7.1%)\tORR: 35.7%\nCR: 3 (60%)\nPR: (2 (40%)\nmOS: 4.7 months\tGrade 3/4:\nInfection 7 (50%)\nIntracranial haemorrhage 3 (21.4%)\t3 (21.4%)\t\nLou and colleagues28\tRETRO\t48\t48\tVEN + AZA, 48 (100%)\tORR: 23 (47.9%)\nCR: 14 (29.2%)\nCRi: 9 (18.8%)\tGrade 3/4:\nNeutropenia 44 (92%)\nThrombocytopenia 43 (90%)\t6 (12.5%)\t\nMorsia and colleagues29\tRETRO\t86\t42\tVEN + AZA, 8 (19%)\nVEN + DEC, 35 (83.3%)\tCR/CRi: 14 (33.3%)\nCR: 8 (19.1%)\nCRi: 6 (14.3%)\nmOS: 5 (3–9) months\tN/A\tN/A\t\nTiong and colleagues30\tRETRO\t12\t12\tVEN + AZA, 3 (25%)\nVEN + LDAC, 9 (75%)\tCR: 11 (92%)\tG3 nonhaematological toxicities 2 (17%)\t3 (25%)\t\nWang and colleagues31\tRETRO\t40\t40\tVEN, 8 (20%)\nVEN + AZA, 21 (52.5%)\nVEN + LDAC, 10 (25%)\nVEN + FLAG, 1 (2.5%)\tORR: 20 (50%)\nCR: 5 (12.5%)\nCRi: 4 (10%)\nMLFS: 5 (12.5%)\nPR: 6 (15%)\nmOS: 6.6 months\tFebrile neutropenia 27 (75%)\nInfections 18 (45%)\t6 (15%)\t\nWinters and colleagues32\tRETRO\t8\t8\tVEN + AZA, 8 (100%)\tORR: 6 (75%)\nCR: 3 (37.5%)\nMLFS: 1 (12.5%)\n<5% blasts: 2 (25%)\tG4 neutropenia 8 (100%)\nG4 thrombocytopenia 8 (100%)\t4 (50%)\t\nJoshi and colleagues33\tRETRO\t29\t29\tVEN, 1 (3.4%)\nVEN + AZA, 8 (27.6%)\nVEN + DEC, 18 (62%)\nVEN + LDAC, 1 (3.4%)\nVEN + gilteritinib, 1 (3.4%)\tORR: 11 (38%)\nCR/CRi: 8 (28%)\nPR: 3 (10%)\nmOS: 2.6 (0.1–13.4) months\tG3/4:\nNeutropenia 20 (69%)\nThrombocytopenia 19 (65.5%)\nInfections 16 (55.2%)\nAnaemia 15 (51.7%)\tN/A\t\nAML, acute myeloid leukaemia; AZA, azacytidine; CR, complete remission; CRi, CR with incomplete haematologic recovery; DEC, decitabine; FLAG, Fludarabine-Arabinofuranosyl cytidine- Granulocite colony-stimulating factor; HSCT, haematopoietic stem cell transplantation; LDAC, low-dose cytarabine; MLFS, morphologic leukaemia-free state; mOS, median overall survival; N/A, not available; ORR, overall rate response; PR, partial remission; PROSP, prospective study; RCT, randomized controlled trial; RETRO, retrospective study; R/R, relapse/refractory; SD, stationary disease; VEN, venetoclax.\n\nFive hundred sixty-four patients were treated in 17 studies, 177 (31.38%) patients received VEN + AZA and 320 (56.73%) received VEN + DEC. In the different studies, the ORR was mainly evaluated in the population as a whole.\n\nThe efficacy results obtained in these studies ranged from an ORR between 21.0%18 and 92.0%.30 mOS ranged from 318 to 11 months.22 12.59% (n = 71) of the patients received an allogeneic HSCT after treatment with VEN in combination. These results should be interpreted with caution because the number of patients included in these studies was small (median: 32, range: 8–90 patients), and treatment regimens, patient population and clinical response were heterogeneous (Table 2).\n\nTable 2. Patients’ baseline characteristics.\n\nStudy\tN\tmAge (range)\tMale, n (%)\tDiagnosis/AML type\tRefractory, n (%)\tRelapsed, n (%)\tCytogenetics, n (%)\tELN risk stratification, n (%)\tPrior ASCT, n (%)\tPrior lines\nMedian (range)\t\nAldoss and colleagues17\t33\t62 (19–81)\t15 (45.5%)\tDe novo 23 (69.7%)\nSecondary 5 (15.2%)\nt-AML 5 (15.2%)\t11 (33.3%)\tFR: 14 (42.4%)\nSR: 8 (24.2%)\tGood 3 (9%)\nIntermediate 11 (33%)\nHigh 18 (55%)\nUnknown 1 (3%)\tN/A\t13 (39.4%)\t2 (1–8)\t\nDinardo and colleagues18\t43\t68 (25–83)\t28 (65%)\tAML 39 (91%)\nMDS/MPN 2 (5%)\nBPDCN 2 (5%)\t43 (100%)\tFirst: 7 (16%)\nSecond: 36 (84%)\tAdverse 20 (47%)\nDiploid 12 (28%)\nInvasive (16) 2 (5%) Intermediate 9 (21%)\tN/A\t5 (12%)\t3 (1–6)\t\nAldoss and colleagues19\t90\t59 (18–81)\t46 (51%)\tDe novo 58 (64%)\nt-AML 10 (11%)\nSecondary 22 (24%)\tN/A\tN/A\tN/A\tFav/Interm 31 (34%)\nAdverse 59 (66%)\t26 (29%)\t2 (1–8)\t\nAldoss and colleagues20\t31\t68 (22–85)\t14 (45%)\tDe novo 13 (42%) Secondary/t-AML 18 (58%)\t16 (52%)\tN/A\tComplex 24 (77%)\nNormal 2 (6%)\nOthers 5 (16%)\tN/A\t5 (16%)\tN/A\t\nAsghari and colleagues21\t31\t63 (25–77)\t13 (41.9%)\tAML-MRC 19 (61.3%)\nt-AML 3 (9.7%)\nOther AML 9 (29%)\tN/A\tN/A\tN/A\tFav/Interm 8 (26%)\nAdverse 14 (45%)\nN/A 9 (29%)\tN/A\t2 (1–6)\t\nMittal and colleagues22\t11\t66 (25–75)\tN/A\tR/R de novo or secondary AML or progressive MDS following ASCT\tN/A\tN/A\tN/A\tN/A\t11 (100%)\tN/A\t\nRam and colleagues23\t23\t76 (41–92)\t14 (60.9%)\tAML-RGA 3 (13%)\nAML-MRC 10 (44%)\nt-AML 5 (22%)\nAML NOS 5 (22%)\t23 (100%)\tFR: 6 (26.1%)\tNormal 11 (48%)\nComplex 6 (26%)\tFavourable 2 (9%)\nIntermediate 11 (48%)\nHigh risk 10 (43%)\t6 (26%)\t2 (1–5)\t\nAldoss and colleagues24\t50\t58 (18–77)\t16 (48%)\tDe novo 25 (76%) Secondary/t-AML 8 (24%)\tN/A\tN/A\tN/A\tFavourable 1 (3%)\nIntermediate 23 (70%)\nHigh 9 (27%)\t9 (27%)\t2 (1–7)\t\nByrne and colleagues25\t21\t64.5 (35–74)\t13 (61.9%)\tCMML 1 (4.8%)\nMDS 3 (14.3%)\nPMF 1 (4.76%)\nAML 16 (76.19%)\tN/A\tFR: 21 (100%)\tNormal 2 (9.5%)\nComplex 2 (9.5%)\nNot complex 1 (5%)\nAdverse 4 (19%)\nIntermediate 11 (52%)\nFavourable 1 (5%)\tN/A\t21 (100%)\tN/A\t\nDiNardo and colleagues26\t168\t62 (43–73)\t31 (56%)\tDe novo 51 (93%)\nt-AML 4 (7%)\t55 (32.7%)\tN/A\tFavourable 0\nIntermediate 32 (58%)\nAdverse 23 (42%)\tFavourable 8 (15%)\nIntermediate 12 (22%)\nAdverse 35 (64%)\t18 (33%)\t2 (1–3)\t\nGaut and colleagues27\t14\t58 (41–79)\t11 (78.6%)\tDe novo 9 (64.3%)\nSecondary 5 (35.7%)\t7 (50%)\tFR: 5 (35.7%)\nSR: 2 (14.3%)\tIntermediate 4 (28.6%)\nAdverse 10 (71.4%)\tN/A\t3 (21.4%)\t3 (1–8)\t\nLou and colleagues28\t48\t61 (19–73)\t28 (58.3%)\tR/R AML 48 (100%)\t16 (33.3%)\tFR: 21 (43.8%)\nSR: 27 (56.2%)\tN/A\tFavourable 7 (14%)\nIntermediate 21 (44%)\nAdverse 20 (42%)\tN/A\tN/A\t\nMorsia and colleagues29\t86\t73.5 (37–91)\t27 (61.4%)\tDe novo 20 (47.6%)\nSecondary 15 (35.7%)\nt-AML 7 (16.7%)\t25 (59.5%)\tFR: 13 (31%)\nSR: 4 (9.5%)\tN/A\tGood 5 (11%)\nIntermediate 12 (27%)\nPoor 27 (62%)\tN/A\t2 (1–5)\t\nTiong and colleagues30\t12\t60.5 (29–81)\t7 (58.3%)\tR/R AML 12 (100%)\t5 (41.7%)\tFR: 6 (50%)\nSR: 1 (8.3%)\tNormal (91.6%)\nComplex (8.33%)\tN/A\t1 (8.3%)\t3 (1–6)\t\nWang and colleagues31\t40\t63 (20–88)\t26 (65%)\tDe novo 25 (62.5%)\nSecondary 13 (32.5%)\nt-AML 2 (5%)\tN/A\tN/A\tFavourable 1 (2.5%)\nIntermediate 25 (62.5%)\nUnfavourable 11 (27.5%)\nUnknown 3 (7.5%)\tFavourable 5 (12%)\nIntermediate 7 (18%)\nUnfavourable 28 (70%)\t13 (32.5%)\t3 (1–9)\t\nWinters and colleagues32\t8\t11 (2–20)\t4 (50%)\tAML 5 (62.5%)\nMDS/AML 1 (12.5%)\nMDS 2 (25%)\t2 (25%)\tFR: 3 (37.5%)\tNormal 3 (37.5%)\nComplex 2 (25%)\tN/A\tN/A\tN/A\t\nJoshi and colleagues33\t29\t58 (20–72)\t14 (48%)\tDe novo 11 (38%) Secondary 5 (17%)\nt-AML 3 (10%)\nHigh-risk MDS 10 (35%)\t4 (14%)\tFR: 21 (72%)\nSR: 4 (14%)\tFavourable 1 (3%)\nIntermediate 10 (35%)\nAdverse 18 (62%)\tN/A\t29 (100%)\t2 (1–4)\t\nAML, acute myeloid leukaemia; AML-MRC, acute myeloid leukaemia with myelodysplasia-related changes; AML-RGA, acute myeloid leukaemia with recurrent genetic abnormalities; ASCT, autologous stem cell transplant; BPDCN, blastic plasmacytoid dendritic cell neoplasm; CMML, chronic myelomonocytic leukaemia; ELN, European LeukemiaNet; Fav/Interm, favourable/intermediate; FR, first relapsed; mAge, median age expressed in years; MDS, myelodysplastic syndrome; MPN, myeloproliferative neoplasm; N/A, not available; NOS, not otherwise specified; PMF, primary myelofibrosis; R/R, relapse/refractory; t-AML, therapy-related AML; SR, second relapsed.\n\nRegarding safety data, the most common adverse events (AEs) reported were haematologic or infectious AEs. These AEs were also the most commonly reported severe AEs (Table 1).\n\nVEN combination therapy for young R/R AML patients\n\nTraditionally, young AML patients achieve higher remission rates after chemotherapy compared with elderly patients. The most common definition of a young patient in the AML population is younger than 60 years, with slight differences between the studies. However, there is a wide age range from 18 to 60 years, between which there may be differences that explain the different responses obtained to the same drug.\n\nA group of young AML patients which are usually studied separately is the group of adolescents and young adults, which encompass a group of the population that arbitrarily combines paediatric and adult patients with an age range of 15–39 years34\n\nThe currently available evidence of VEN combination therapy for young R/R AML patients is scarce. Of the 17 studies we have identified, only 1 focuses on paediatric and young adult patients. Of the remaining studies, 12 (70.6%) included a population with a median age more than 60 years.\n\nWinters and colleagues32 is the only study identified on the VEN + AZA combination that includes paediatric patients (n = 6) and young adults (n = 2). Of the two young adult patients identified, the first (18-year-old woman) achieved a morphologic leukaemia-free state. This patient presented FLT3-ITD, WT1 and NUP98/NSD1 mutations. The other patient (30-year-old man) with the following cytogenetic alterations 3 46, XY, t (2; 14) (q22; q32) and the following mutations FLT3-TKD, WT1, BCORL1, GATA2 reached complete response, with negative molecular measurable residual disease (MRD) subsequently being able to receive an allogeneic transplant.\n\nHere, we report two cases of AML refractory young patients treated with VEN + HMA.\n\nCase 1\n\nWe report the case of a 26-year-old woman. In August 2018, she was diagnosed with monocytic AML [t (6; 11), mixed-lineage leukaemia (MLL) positive, FLT3-ITD negative]. She was treated with conventional chemotherapy following the ‘3 + 7’ scheme and ‘2 + 5’ scheme. She achieved complete haematological and molecular remission with negative MRD.\n\nIn February 2019, she received an allogeneic HSCT from a matched related donor with a myeloablative conditioning regimen with busulfan and cytarabine (BuCy). The patient was in a CR situation with a positive molecular MRD post-HSCT. She suffered hepatic graft-versus-host disease (GvHD) as a complication associated with the HSCT.\n\nIn December 2019, she was hospitalized with a non-neutropenic febrile syndrome of amygdalar focus, diagnosed with a medullary relapse of her AML. She was treated with reinduction chemotherapy following the FLAGQUIDA scheme (FLAGIDA + quizartinib 40 mg) within a clinical trial. Postinduction CR with complete chimerism and negative molecular MRD was reached. As complications of reinduction treatment, she presented invasive pulmonary aspergillosis and cutaneous GvHD. She received consolidation chemotherapy with high-dose cytarabine and maintenance chemotherapy with quizartinib.\n\nIn March 2020, an MRD positivization was detected, and she was treated with two donor lymphocyte infusions (DLIs) in June and July. After the first dose, in June 2020, a medullary control was performed and revealed an overt relapse.\n\nIn July 2020, she started treatment with AZA (75 mg/m2, days 1–7 of each 28-day cycle) for two cycles without response. Antifungal prophylaxis with posaconazole was also started. Three months later (October 2020), she started combination treatment with AZA + VEN (uptitrated from 100 mg daily to a maximum dose of 400 mg). Antifungal prophylaxis with posaconazole was withdrawn due to potential interaction with VEN treatment. She presented asthenia as the main adverse effect associated with the treatment.\n\nA third DLI was administered in September 2020. After two cycles (November 2020), she was hospitalized due to an episode of febrile neutropenia with a probable rectal-perianal focus, and VEN treatment was withheld. She was treated with broad-spectrum antibiotics. During admission, antifungal prophylaxis with posaconazole was reinstated. At the beginning of December, treatment response was evaluated by a bone marrow biopsy, obtaining a result of CRi.\n\nIn January 2021, another bone marrow biopsy was performed, revealing 57% of the myeloblast. After this result, it was decided to restart AZA + VEN treatment (third cycle). VEN dose was uptitrated from 50 mg to a maximum dosage of 70 mg due to concomitant use of posaconazole and previous myelosuppression.\n\nAfter this treatment cycle, she was admitted for intravenous antibiotic therapy administration due to a persistent superinfected whitlow in the first toe of both feet, despite oral antibiotic therapy. Treatment with VEN was withheld until recovery from infection. After recovery, the patient restarted with VEN in combination with AZA at a dose of 100 mg/day and completed another cycle of treatment.\n\nIn March 2021, a bone marrow biopsy was performed, revealing disease progression with 57% of the myeloblast. A month later, she was hospitalized due to febrile syndrome. Due to the underlying disease development, a multiple organ failure caused her death 12 days later.\n\nCase 2\n\nWe report the case of a 47-year-old woman. In April 2018, she was diagnosed with AML with myelodysplasia-related changes with complex karyotype including del5q, delTP53, trisomy 8 and three copies of MLL, nonmutated FLT3, TP53 and PTPN11 mutations.\n\nShe was treated with induction chemotherapy following the ‘3 + 7’ scheme without treatment response. Then, she received rescue treatment with guadecitabine within a clinical trial (SGI-110-06). After three cycles of chemotherapy, CR with negative MDR was reached. During these admissions, she presented notable complications such as gangrenous appendicitis that required appendectomy in May 2018 and a paracolic abscess with inflammatory changes in the cecum and right colon with colic and ileal fistulization that required a right hemicolectomy in September 2018.\n\nIn December 2018, she received an allogeneic HSCT from a matched related donor with a reduced-intensity conditioning regimen with fludarabine and busulfan and GvHD prophylaxis with tacrolimus and rapamycin. As posttransplant complications, she presented grade 2 cutaneous GvHD and pasty stools with irregular bowel habits. The results of endoscopy with biopsy were not suggestive of intestinal GvHD.\n\nApproximately 3 months later, she presented positive MRD in the marrow (0.5% of blasts). Treatment with AZA (75 mg/m2, days 1–7 of each 28-day cycle) and decreased immunosuppression were indicated.\n\nIn June 2019, a medullar study revealed an overt relapse. Combination treatment with VEN (uptitrated from 100 mg daily to a maximum dose of 400 mg) and DEC (20 mg/m2 × days 1–5 of each 28-day cycle) and rapid immunosuppression withdrawal were initiated. After the first cycle of VEN + DEC, she reached CRi with positive MRD. As treatment complications, she presented myelosuppression and required admission due to febrile neutropenia. Treatment with VEN was withheld during hospitalization and was subsequently restarted at a dose of 100 mg per day due to cytotoxicity and possible interaction with antifungal prophylaxis with posaconazole.\n\nDuring treatment with VEN + DEC, she presented primary Escherichia coli bacteremia with possible secondary splenic abscess and possible disseminated candidiasis, initially treated with caspofungin administered via outpatient parenteral antimicrobial therapy followed by oral voriconazole. During treatment with voriconazole, the VEN dose was reduced to 70 mg due to possible interaction.\n\nAfter five cycles of combination therapy, it was decided to suspend the combination treatment due to myelosuppression and the associated risk of infectious complications after reaching CR and negative MRD. A second related donor transplant was considered, although it was finally decided to prophylactically perform a DLI to maintain CR with negative MRD and complete chimerism.\n\nThe patient remained without treatment until August 2020, when the level of myeloblast reached 40%. Then, it was decided to restart treatment with DEC + VEN (100 mg per day due to risk of interaction with posaconazole treatment) before performing a second HSCT. In September, she was admitted, with diarrhoea and fever being diagnosed with community-acquired pneumonia with Klebsiella pneumoniae isolation. After 8 days of hospitalization in the intensive care unit, the patient died of septic shock due to pneumonia.\n\nDiscussion\n\nTreatment of R/R AML remains a formidable challenge for treating clinicians because of the high failure rate of reinduction treatment characterized by a short survival period with OS estimated not more than 10% at 3 years and progressive complications.35,36\n\nAs a result of this review, VEN combination treatment with HMAs appears to be a therapeutic option for R/R AML. Nevertheless, ORR described in the literature is very heterogeneous, ranging from 21.0% to 92.0% and mOS between 3 and 11 months among adult patients. Regarding the efficacy of this treatment for young patients, it is difficult to draw conclusions because most of the patients included in the studies were elderly patients, and the results were not expressed by age subgroups. Usually, the elderly AML population achieves lower remission rates (40–50%) after chemotherapy compared with young patients (60–70%).37,38 Thus, the efficacy of VEN combination therapy is expected to be similar or superior to that obtained in elderly patients, as in the case of Winters and colleagues,32 which obtained an ORR of 75%. However, there is no solid evidence to make a firm conclusion for VEN combination therapy for young AML patients at present. In fact, our patients obtained limited success with this combination regimen. Concerning safety, haematologic or infectious adverse reactions were the most frequently reported. The incidence of adverse reactions reported for VEN combination therapy was higher than that reported for HMA monotherapy.15\n\nVEN + HMA regimen has been used in naïve15 and R/R patients,17–31,33 being a therapeutic alternative in patients who are not candidates for HSCT. This review showed that most patients were treated with VEN + HMA as a salvage approach previous to an HSCT; however, we found several studies that included previously transplanted patients. Focusing on those studies, we observed response rates of 36%,22 38%33 and 42.1%25 and mOS of up to 11 months.22 Although the results in this group of patients may be discrete compared with those obtained in patients who have not previously received an HSCT, this scheme may be an option for patients with few therapeutic alternatives. Moreover, at our centre, this treatment combination was used on patients who were refractory to a first HSCT. Thus, the VEN + HMA combination could be a salvage approach for refractory patients before and after receiving an HSCT or when this procedure is not feasible.\n\nHowever, these approaches should be tested on well-designed randomized controlled trials that compare VEN + HMA and conventional chemotherapy. Therefore, in the absence of quality evidence, the clinician should assess this combination therapy’s benefit/risk balance with AML patients.\n\nA significant aspect of this combination is its high response rate across various cytogenetics and almost all molecular subtypes of AML. Among the studies included in this review, an excellent clinical activity for this combination has been obtained even for patients with high-risk cytogenetics or poor prognosis. Mutations with increased sensitivity to VEN + HMA therapy have been identified, such as IDH1, IDH2, NPM1, RUNX1 and SRSF2.14,17,18,31,32\n\nAs bridging therapy before HSCT, VEN + HMA combination is not associated with significant toxic effects beyond cytopenias, so a considerable increase in adverse effects associated with pretransplant conditioning regimens or prophylaxis regimens for GvHD management is not initially expected. Compared with patients receiving intensive salvage chemotherapy, it is expected that patients undergoing HSCT after HMA + VEN treatment, especially in the case of R/R AML, will have a better performance status and reduced morbidity.39\n\nGiven that the primary toxicity of the VEN + HMA combination treatment is peripheral blood cytopenias, the potential for accumulated risk of infections after HSCT may be a concern. This can be notably true for invasive fungal infections (IFIs) because affected patients might be undergoing HSCT with occult or evident IFIs. The risk of IFIs seems to be low in patients receiving VEN + HMA treatment for first-line AML treatment; however, patients with R/R AML might be at higher risk.40\n\nOne of the uncertain areas in the treatment of AML with VEN is the routine use of antifungal prophylaxis. VEN is a CYP3A4 substrate, so there is a risk of potential interaction with drugs used in antifungal prophylaxis in patients with haematologic malignancies such as azoles which are CYP3A4 inhibitors. Patients receiving antifungal prophylaxis usually require dosing modification for safe VEN use. Both of our patients receive antifungal treatment with posaconazole (patients 1 and 2) and voriconazole (patient 2) with a consequent reduction of VEN doses to reduce AE risk. For both patients, a 75% reduction on VEN dose was applied when they started posaconazole treatment. For patient 2, an additional reduction of 82.5% of the initial dose was applied. Both patients benefitted from the dose adjustments, reducing the adverse effects associated with the treatment. Clinical trials usually exclude patients treated with CYP3A4 inhibitors due to potential interactions. However, a phase 1b trial included an arm receiving posaconazole prophylaxis to evaluate the pharmacokinetics interaction. The recommendation was to perform a 75% dose reduction of VEN when given simultaneously with posaconazole.41 Mei and colleagues42 recommend reducing VEN dose by 50% for patients receiving treatment with moderate CYP3A4 inhibitors, such as isavuconazole, and 75% for patients receiving potent CYP3A4 inhibitors, such as posaconazole or voriconazole. At the moment, we routinely use posaconazole as antifungal prophylaxis, even when isavuconazole is usually better tolerated and has fewer interactions than other azoles.43 Isavuconazole, however, may also worsen myelosuppression due to increased levels of VEN, despite being a moderate CYP3A4 inhibitor. So far, there is no evidence that the use of isavuconazole is preferable to posaconazole concomitantly with VEN. Rauch and colleagues study showed that the concomitant use of azoles with the VEN + HMA regimen resulted in similar absolute neutrophil count and platelet recovery times, suggesting that the azole used is indifferent as long as the appropriate VEN dose reduction is applied.44 Unfortunately, there are no techniques to monitor VEN serum levels at present in clinical practice.43\n\nIn our centre, generally, for treating young AML patients, we use the FLAGIDA scheme as the first rescue option, as was done in the case of patient 1. With the FLAGIDA scheme, a CR/CRi of 51% in patients younger than 60 years and an mOS of 0.8 years (0.6–1.4) have been obtained.45 In patients with TP53 mutations with elevated variant allele frequency (VAF), the use of conventional chemotherapy versus VEN + HMA may be more debatable. There are conflicting results in the literature for patients with this mutation; in the study by Short and colleagues,46 the VEN + HMA scheme was ineffective in de novo patients. However, in the VIALE-A trial,15 patients with the TP53 mutation appeared to benefit from the combined treatment.\n\nWe report two young patients with R/R AML who achieved CR and negative MRD after treatment with a VEN + HMA regimen. Both patients achieved CR after the first two cycles of treatment which was consistent with other retrospective studies of VEN combination therapy for R/R AML, where the best response was found after a median of two cycles (range 1–3) and one cycle at the earliest.9,15,17,18,41 Knowing this average response time can help stop treatment prematurely if no response is found. In turn, this may help reduce some of the AEs caused by long-term VEN combination therapy. Mei and colleagues42 recommend a bone marrow biopsy to assess response only after two cycles of therapy, as at this point, the majority of CR is recorded.\n\nAs the main adverse reactions associated with combination treatment, both patients suffered myelosuppression, asthenia and infections which are consistent with those reported in previous studies.17,18,23,25–28,30–32 In both cases, treatment withhold was required due to cytopenia and the associated high risk of infections. For patient 1, VEN treatment was interrupted after two cycles due to a febrile neutropenia episode. The patient was in CRi when the treatment was interrupted. After almost 3 months without treatment, her blast increased to 57%. Mei and colleagues42 recommend not interrupting therapy, delaying cycles or reducing dose based on peripheral blood cytopenia, marrow hypocellularity or aplasia before achieving maximal response because this may reduce the depth and speed of response. This may explain why patient 1 took so long to achieve CR, as she was required to suspend treatment several times due to toxicity. For patient 2, it was decided to suspend treatment for a while after reaching CR due to the high associated risk of infections.\n\nIn our centre, we make dose adjustments once the patient has obtained a remission, or at least, we confirm aplasia without blasts. However, these patients often already have baseline G3-4 cytopenias due to the disease’s nature, so the impact of dose adjustment in these cases may be limited.14 Despite the promising efficacy results obtained with VEN combination treatment, its toxicity and potential interactions are limiting factors. Furthermore, the degree of cytopenias reported in refractory AML patients is higher than that reported in naïve-treatment patients, possibly due to higher rates and degrees of cytopenias before VEN combination treatment administration.14,18\n\nThe results presented in this brief review should be interpreted cautiously due to the heterogeneity of patients and regimens used, the relatively low quality of the available evidence, based essentially on retrospective observational studies, and the lack of results expressed by age subgroups. Further controlled clinical trials are needed to prove whether VEN + HMAs combination is an adequate alternative to conventional regimens for young R/R AML patients.\n\nAs limitations of the study, we highlight that a systematic review method was not followed to review the available literature; however, an exhaustive search of the literature was conducted in MEDLINE and Embase databases. However, the synthesis of the evidence performed was qualitative, given the heterogeneity of the available studies. Given the heterogeneity between studies, quantitative synthesis of the evidence could not be developed currently.\n\nIn summary, we provide a review of the available evidence on the treatment of VEN in combination with HMA for the treatment of young R/R AML patients, in addition to our experience in clinical practice. VEN + HMA seems to be a therapeutic option for treating young adult R/R AML patients. Notwithstanding, due to the limited quality of the available evidence, well-designed studies with greater numbers of patients are needed to confirm the efficacy and safety of VEN combination regimens for young patients with R/R AML.\n\nEduardo Rodriguez Arboli and Laila Abdel-kader Martín contributed equally to this work.\n\nConflict of interest statement: The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.\n\nFunding: The authors received no financial support for the research, authorship and/or publication of this article.\n\nConsent for publication: Due to the fact that both patients died, it was not possible to request their consent for the publication of the cases.\n\nEthical approval statement: According to the local regulations, approval by the local ethical committee is not required for publication of case reports because all patient-related data were collected retrospectively and anonymously.\n\nORCID iD: Nerea Báez-Gutiérrez https://orcid.org/0000-0002-9419-7742\n==== Refs\nReferences\n\n1 Fey MF Buske C ESMO Guidelines Working Group. Acute myeloblastic leukaemias in adult patients: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013; 24 (Suppl. 6 ): vi138–vi143.23970018\n2 SEER stat fact sheets: acute myeloid leukemia (AML). National Cancer Institute, https://seer.cancer.gov/statfacts/index.html (accessed 6 February 2021).\n3 Forman SJ Rowe JM. The myth of the second remission of acute leukemia in the adult. Blood 2013; 121 : 1077–1082.23243288\n4 Ram R Gatt M Merkel D , et al . Second line azacitidine for elderly or infirmed patients with acute myeloid leukemia (AML) not eligible for allogeneic hematopoietic cell transplantation – a retrospective national multicenter study. Ann Hematol 2017; 96 : 575–579.28058490\n5 Seymour JF Dohner H Butrym A , et al . Azacitidine improves clinical outcomes in older patients with acute myeloid leukaemia with myelodysplasia-related changes compared with conventional care regimens. BMC Cancer 2017; 17 : 852.29241450\n6 DiNardo CD Stein EM de Botton S , et al . Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med 2018; 378 : 2386–2398.29860938\n7 Stein EM DiNardo CD Fathi AT , et al . Molecular remission and response patterns in patients with mutant-IDH2 acute myeloid leukemia treated with enasidenib. Blood 2019; 133 : 676–687.30510081\n8 Pratz KW Cherry M Altman JK , et al . Updated results from a phase 1 study of gilteritinib in combination with induction and consolidation chemotherapy in subjects with newly diagnosed acute myeloid leukemia (AML). Blood 2018; 132 (Suppl. 1 ): 564–564.\n9 Konopleva M Pollyea DA Potluri J , et al . Efficacy and biological correlates of response in a phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discov 2016; 6 : 1106–1117.27520294\n10 Kumar S Kaufman JL Gasparetto C , et al . Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma. Blood 2017; 130 : 2401–2409.29018077\n11 Roberts AW Davids MS Pagel JM , et al . Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med 2016; 374 : 311–322.26639348\n12 Konopleva M Contractor R Tsao T , et al . Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell 2006; 10 : 375–388.17097560\n13 Bogenberger JM Kornblau SM Pierceall WE , et al . BCL-2 family proteins as 5-azacytidine-sensitizing targets and determinants of response in myeloid malignancies. Leukemia 2014; 28 : 1657–1665.24451410\n14 DiNardo CD Pratz K Pullarkat V , et al . Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood 2019; 133 : 7–17.30361262\n15 DiNardo CD Jonas BA Pullarkat V , et al . Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med 2020; 383 : 617–629.32786187\n16 Cancer stat facts: acute myeloid leukemia. Surveillance, Epidemiology, and End Results Program, https://seer.cancer.gov/statfacts/html/amyl.html (accessed 2 December 2020).\n17 Aldoss I Yang D Aribi A , et al . Efficacy of the combination of venetoclax and hypomethylating agents in relapsed/refractory acute myeloid leukemia. Haematologica 2018; 103 : e404–e407.\n18 DiNardo CD Rausch CR Benton C , et al . Clinical experience with the BCL2-inhibitor venetoclax in combination therapy for relapsed and refractory acute myeloid leukemia and related myeloid malignancies. Am J Hematol 2018; 93 : 401–407.29218851\n19 Aldoss I Yang D Pillai R , et al . Association of leukemia genetics with response to venetoclax and hypomethylating agents in relapsed/refractory acute myeloid leukemia. Am J Hematol 2019; 94 : E253–E255.\n20 Aldoss I Zhang J Pillai R , et al . Venetoclax and hypomethylating agents in TP53-mutated acute myeloid leukaemia. Br J Haematol 2019; 187 : e45–e48.\n21 Asghari H Lee D Deutsch YE , et al . Outcomes of patients with relapsed or refractory acute myeloid leukemia receiving hypomethylating agent and venetoclax. Blood 2019; 134 (Suppl. 1 ): 1357–1357.\n22 Mittal V Lo M Damon LE , et al . Efficacy of venetoclax combination therapy with hypomethylating agents in patients with relapsed acute myeloid leukemia after allogeneic hematopoietic cell transplantation. Blood 2019; 134 (Suppl. 1 ): 5089–5089.\n23 Ram R Amit O Zuckerman T , et al . Venetoclax in patients with acute myeloid leukemia refractory to hypomethylating agents-a multicenter historical prospective study. Ann Hematol 2019; 98 : 1927–1932.31187237\n24 Aldoss I Zhang J Mei M , et al . Venetoclax and hypomethylating agents in FLT3-mutated acute myeloid leukemia. Am J Hematol. Epub ahead of print 6 July 2020. DOI: 10.1002/ajh.25929.\n25 Byrne M Danielson N Sengsayadeth S , et al . The use of venetoclax-based salvage therapy for post-hematopoietic cell transplantation relapse of acute myeloid leukemia. Am J Hematol 2020; 95 : 1006–1014.32390196\n26 DiNardo CD Maiti A Rausch CR , et al . 10-day decitabine with venetoclax for newly diagnosed intensive chemotherapy ineligible, and relapsed or refractory acute myeloid leukaemia: a single-centre, phase 2 trial. Lancet Haematol 2020; 7 : e724–e736.32896301\n27 Gaut D Burkenroad A Duong T , et al . Venetoclax combination therapy in relapsed/refractory acute myeloid leukemia: a single institution experience. Leuk Res 2020; 90 : 106314.32035355\n28 Lou Y Shao L Mao L , et al . Efficacy and predictive factors of venetoclax combined with azacitidine as salvage therapy in advanced acute myeloid leukemia patients: a multicenter retrospective study. Leuk Res 2020; 91 : 106317.32092584\n29 Morsia E McCullough K Joshi M , et al . Venetoclax and hypomethylating agents in acute myeloid leukemia: Mayo Clinic series on 86 patients. Am J Hematol 2020; 95 : 1511–1521.32833294\n30 Tiong IS Dillon R Ivey A , et al . Venetoclax induces rapid elimination of NPM1 mutant measurable residual disease in combination with low-intensity chemotherapy in acute myeloid leukaemia. Br J Haematol 2021; 192 : 1026–1030.32458446\n31 Wang YW Tsai CH Lin CC , et al . Cytogenetics and mutations could predict outcome in relapsed and refractory acute myeloid leukemia patients receiving BCL-2 inhibitor venetoclax. Ann Hematol 2020; 99 : 501–511.31965269\n32 Winters AC Maloney KW Treece AL , et al . Single-center pediatric experience with venetoclax and azacitidine as treatment for myelodysplastic syndrome and acute myeloid leukemia. Pediatr Blood Cancer 2020; 67 : e28398.\n33 Joshi M Cook J McCullough K , et al . Salvage use of venetoclax-based therapy for relapsed AML post allogeneic hematopoietic cell transplantation. Blood Cancer J 2021; 11 : 49.33664234\n34 Coccia PF Altman J Bhatia S , et al . Adolescent and young adult oncology. Clinical practice guidelines in oncology. J Natl Compr Canc Netw 2012; 10 : 1112–1150.22956810\n35 Dohner H Weisdorf DJ Bloomfield CD. Acute myeloid leukemia. N Engl J Med 2015; 373 : 1136–1152.26376137\n36 Rowe JM Tallman MS. How I treat acute myeloid leukemia. Blood 2010; 116 : 3147–3156.20558611\n37 Menzin J Lang K Earle CC , et al . The outcomes and costs of acute myeloid leukemia among the elderly. Arch Intern Med 2002; 162 : 1597–1603.12123403\n38 Mohammadi M Cao Y Glimelius I , et al . The impact of comorbid disease history on all-cause and cancer-specific mortality in myeloid leukemia and myeloma – a Swedish population based study. BMC Cancer 2015; 15 : 850.26537111\n39 Sandhu KS Dadwal S Yang D , et al . Outcome of allogeneic hematopoietic cell transplantation after venetoclax and hypomethylating agent therapy for acute myelogenous leukemia. Biol Blood Marrow Transplant 2020; 26 : e322–e327.32866594\n40 Aldoss I Dadwal S Zhang J , et al . Invasive fungal infections in acute myeloid leukemia treated with venetoclax and hypomethylating agents. Blood Adv 2019; 3 : 4043–4049.31816059\n41 DiNardo CD Pratz KW Letai A , et al . Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study. Lancet Oncol 2018; 19 : 216–228.29339097\n42 Mei M Aldoss I Marcucci G , et al . Hypomethylating agents in combination with venetoclax for acute myeloid leukemia: update on clinical trial data and practical considerations for use. Am J Hematol 2019; 94 : 358–362.30499168\n43 Bose P McCue D Wurster S , et al . Isavuconazole as primary antifungal prophylaxis in patients with acute myeloid leukemia or myelodysplastic syndrome: an open-label, prospective, phase 2 study. Clin Infect Dis 2021; 72 : 1755–1763.32236406\n44 Rausch CR DiNardo CD Maiti A , et al . Duration of cytopenias with concomitant venetoclax and azole antifungals in acute myeloid leukemia. Cancer 2021; 127 : 2489–2499.33793970\n45 Bergua JM Montesinos P Martinez-Cuadrón D , et al . A prognostic model for survival after salvage treatment with FLAG-Ida +/- gemtuzumab-ozogamicine in adult patients with refractory/relapsed acute myeloid leukaemia. Br J Haematol 2016; 174 : 700–710.27118319\n46 Short NJ Montalban-Bravo G Hwang H , et al . Prognostic and therapeutic impacts of mutant TP53 variant allelic frequency in newly diagnosed acute myeloid leukemia. Blood Adv 2020; 4 : 5681–5689.33211826\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2040-6207",
"issue": "12()",
"journal": "Therapeutic advances in hematology",
"keywords": "acute myeloid leukaemia; hypomethylating agent; refractory; relapsed; venetoclax; young patients",
"medline_ta": "Ther Adv Hematol",
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"pages": "20406207211040335",
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"pmid": "34471510",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "24451410;32458446;23243288;29018077;31259427;23970018;26537111;32092584;29545346;30510081;32236406;32035355;29218851;31816059;29860938;32786187;32628327;26639348;29339097;29241450;32735397;22956810;32896301;27520294;31187237;32866594;30361262;26376137;33211826;20558611;30499168;27118319;17097560;32833294;31965269;31441045;33664234;33793970;32390196;28058490;12123403",
"title": "Venetoclax combination therapy with hypomethylating agents in young adults with relapsed/refractory acute myeloid leukaemia.",
"title_normalized": "venetoclax combination therapy with hypomethylating agents in young adults with relapsed refractory acute myeloid leukaemia"
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"abstract": "Safety and efficacy data on pegylated asparaginase (PEG-ASP) in adult acute lymphoblastic leukaemia (ALL) induction regimens are limited. The UK National Cancer Research Institute UKALL14 trial NCT01085617 prospectively evaluated the tolerability of 1000 IU/m2 PEG-ASP administered on days 4 and 18 as part of a five-drug induction regimen in adults aged 25-65 years with de novo ALL. Median age was 46.5 years. Sixteen of the 90 patients (median age 56 years) suffered treatment-related mortality during initial induction therapy. Eight of the 16 died of sepsis in combination with hepatotoxicity. Age and Philadelphia (Ph) status were independent variables predicting induction death >40 versus ⩽40 years, odds ratio (OR) 18.5 (2.02-169.0), P=0.01; Ph- versus Ph+ disease, OR 13.60 (3.52-52.36), P<0.001. Of the 74 patients who did not die, 37 (50.0%) experienced at least one grade 3/4 PEG-ASP-related adverse event, most commonly hepatotoxicity (36.5%, n=27). A single dose of PEG-ASP achieved trough therapeutic enzyme levels in 42/49 (86%) of the patients tested. Although PEG-ASP delivered prolonged asparaginase activity in adults, it was difficult to administer safely as part of the UKALL14 intensive multiagent regimen to those aged >40 years. It proved extremely toxic in patients with Ph+ ALL, possibly owing to interaction with imatinib.",
"affiliations": "Barts Cancer Institute, The London School of Medicine, Queen Mary University of London, London, UK.;CR UK and UCL Cancer Trials Centre, London, UK.;Cancer Institute, University College London, London, UK.;Centre for Clinical Haematology, Nottingham City Hospital, Nottingham, UK.;United Bristol Healthcare Trust, Bristol, UK.;Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK.;CR UK and UCL Cancer Trials Centre, London, UK.;CR UK and UCL Cancer Trials Centre, London, UK.;CR UK and UCL Cancer Trials Centre, London, UK.;Cardiff and Vale UHB, London, UK.;CR UK and UCL Cancer Trials Centre, London, UK.;Cancer Institute, University College London, London, UK.",
"authors": "Patel|B|B|;Kirkwood|A A|AA|;Dey|A|A|;Marks|D I|DI|;McMillan|A K|AK|;Menne|T F|TF|;Micklewright|L|L|;Patrick|P|P|;Purnell|S|S|;Rowntree|C J|CJ|;Smith|P|P|;Fielding|A K|AK|",
"chemical_list": "D000970:Antineoplastic Agents; D011092:Polyethylene Glycols; C042705:pegaspargase; D001215:Asparaginase",
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"fulltext": "\n==== Front\nLeukemiaLeukemiaLeukemia0887-69241476-5551Nature Publishing Group leu201621910.1038/leu.2016.21927480385Original ArticlePegylated-asparaginase during induction therapy for adult acute lymphoblastic leukaemia: toxicity data from the UKALL14 trial Toxicity during UKALL14 induction therapy for ALLPatel B 1Kirkwood A A 2Dey A 3Marks D I 4McMillan A K 5Menne T F 6Micklewright L 2Patrick P 2Purnell S 2Rowntree C J 7Smith P 2Fielding A K 3*1 Barts Cancer Institute, The London School of Medicine, Queen Mary University of London, London, UK2 CR UK and UCL Cancer Trials Centre, London, UK3 Cancer Institute, University College London, London, UK4 Centre for Clinical Haematology, Nottingham City Hospital, Nottingham, UK5 United Bristol Healthcare Trust, Bristol, UK6 Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK7 Cardiff and Vale UHB, London, UK* Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK. E-mail a.fielding@ucl.ac.uk01 2017 02 08 2016 09 09 2016 31 1 58 64 22 04 2016 06 07 2016 08 07 2016 Copyright © 2017 The Author(s)2017The Author(s)This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/Safety and efficacy data on pegylated asparaginase (PEG-ASP) in adult acute lymphoblastic leukaemia (ALL) induction regimens are limited. The UK National Cancer Research Institute UKALL14 trial NCT01085617 prospectively evaluated the tolerability of 1000 IU/m2 PEG-ASP administered on days 4 and 18 as part of a five-drug induction regimen in adults aged 25–65 years with de novo ALL. Median age was 46.5 years. Sixteen of the 90 patients (median age 56 years) suffered treatment-related mortality during initial induction therapy. Eight of the 16 died of sepsis in combination with hepatotoxicity. Age and Philadelphia (Ph) status were independent variables predicting induction death >40 versus ⩽40 years, odds ratio (OR) 18.5 (2.02–169.0), P=0.01; Ph− versus Ph+ disease, OR 13.60 (3.52–52.36), P<0.001. Of the 74 patients who did not die, 37 (50.0%) experienced at least one grade 3/4 PEG-ASP-related adverse event, most commonly hepatotoxicity (36.5%, n=27). A single dose of PEG-ASP achieved trough therapeutic enzyme levels in 42/49 (86%) of the patients tested. Although PEG-ASP delivered prolonged asparaginase activity in adults, it was difficult to administer safely as part of the UKALL14 intensive multiagent regimen to those aged >40 years. It proved extremely toxic in patients with Ph+ ALL, possibly owing to interaction with imatinib.\n==== Body\nIntroduction\nDepletion of extracellular asparagine by parenteral administration of the enzyme L-asparaginase is a key component of most current therapeutic strategies in acute lymphoblastic leukaemia (ALL). In children, intensive L-asparaginase treatment, typically delivered by pegylated Escherichia coli-derived L-asparaginase (PEG-ASP), improves clinical outcome,1, 2, 3, 4, 5, 6 offering a longer half-life7 and a lower risk of antiasparaginase antibody formation. Safety and efficacy is less well established in older adults,8, 9 and toxicity can be substantial10—in a phase 2 trial, failure to deliver the intended doses was closely correlated with advancing age.11\n\nUKALL14 (NCT01085617) is an on-going, multicentre, phase 3 study that addresses several questions in the treatment of newly diagnosed adult ALL. A major study aim is to evaluate the addition of two doses of 1000 IU/m2 PEG-ASP to the standard induction regimen that had been evaluated in our previous study, UKALL12,12 in which non-pegylated E. coli L-asparaginase was given at 10 000 IU daily on days 17–28 of phase 1 induction. The only other change to the ‘backbone' induction regimen between the two consecutive national trials was the addition of a steroid prephase and the substitution of pulsed dexamethasone for prednisolone. The aim of these changes was to make our regimen more compatible with a 'paediatric-inspired' intensive approach.\n\nThe overall end point of the trial is event-free survival. However, a specific end point of the PEG-ASP evaluation is toxicity related to PEG-ASP. Secondary end points include rate of complete remission (CR), overall survival, minimal residual disease (MRD) quantitation at the end of the first phase of induction and antiasparaginase antibody formation. Here we report on the outcome of PEG-ASP administered during induction in the first consecutive 91 trial subjects. At this point, it was judged by the trial management group that a toxicity end point had been reached and a change was made to the PEG-ASP trial therapy.\n\nMATERIALS AND Methods\nUKALL14 induction phase 1 treatment\nEligible patients were aged ⩾25 and ⩽65 years with newly diagnosed ALL, irrespective of Philadelphia (Ph) chromosome status. There was no exclusion for poor organ function or performance status at diagnosis. Ethical approval was obtained from the UK National Research Ethics Committee. All patients gave written, informed consent, according to the Declaration of Helsinki. Patients received a 5–7-day prephase of dexamethasone 6 mg/m2/day followed by two sequential courses of induction therapy, termed induction phase 1 and induction phase 2, respectively. Patients with precursor B lineage ALL were randomised to receive chemotherapy alone or chemotherapy plus four doses of rituximab given on day (D) 3, D10, D17 and D24, PEG-ASP 1000 IU/m2 on D4 and D18, daunorubicin 60 mg/m2 and vincristine 1.4 mg/m2 (2 mg max.) on D1, D8, D15 and D21, dexamethasone 10 mg/m2 D1, −D4, D8–D11 and D15–D18 and a single 12.5 mg intrathecal methotrexate dose on D14. Patients with Ph chromosome-positive (Ph+) disease received continuous oral imatinib from D1, starting at 400 mg and escalating to 600 mg given daily throughout induction. Antibacterial, antiviral and antifungal prophylaxis was mandated, but centres used local policy for choice of agents. Granulocyte colony-stimulating factor support was strongly recommended. Routine antithrombotic prophylaxis was suggested but not mandated for all patients with platelet counts >50 × 109/l. Anticoagulation with antithrombin replacement was recommended in the case of thrombosis. Routine coagulation factor replacement for laboratory-detected coagulopathy was specifically discouraged.\n\nAll patients had an initial assessment of response—including MRD response by BCR-ABL transcript monitoring or clonal immunoglobulin (Ig)/T-cell receptor gene rearrangement quantification—at the end of induction phase 1, which did not affect treatment decision. Formal assessment of response to induction therapy (outside the scope of this report) was documented after phase 2 induction.\n\nA simplified schema of the remainder of UKALL14 treatment is provided in Figure 1.\n\nCausality assessment for toxicity and death\nThe standard Common Terminology Criteria for Adverse Events (CTCAE) reporting system (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm) was used. Causality of events was attributed, as is standard practice, by both the local site Principal Investigator and the central study clinical team. Additional detailed questionnaires and Principal Investigator's narratives were received for all induction deaths allowing a more detailed analysis of individual events.\n\nPEG-ASP antibody assays\nAntibodies against PEG-ASP (IgG and IgE) were measured by two indirect enzyme-linked immunosorbent assays, which detected anti-PEG-ASP and non-pegylated anti-E. coli (non-pegylated asparaginase). Seroconversion was reported with positivity in at least one assay with a clearly negative predose sample. Anti-asparaginase antibody ratio over negative control >1.1 was used to define positivity.\n\nSerum asparaginase activity by MAAT testing\nPEG-ASP enzyme activity was quantified in sera using the MAAT7 assay. Therapeutic enzyme levels were defined as >100 IU/l.\n\nStatistical analysis\nInduction phase 1 treatment-related death was defined as any death occurring before the start of phase 2 induction where the cause of death was not primarily attributable to progressive ALL. Logistic regression was used to examine risk potential factors for induction death and grade 3/4 adverse events (AEs). Factors with a conservative P<0.2 in the univariate analysis were included in the multivariable analyses. All analyses were conducted using Stata 14.0 (Stata Corporation, College Station, TX, USA). Non-fatal grade III–IV AEs causally related to PEG-ASP were those classified as probably or definitely related. All AEs were graded according to CTCAE version 4.0.\n\nResults\nPatient characteristics\nNinety-one eligible patients (from 37 centres) were enrolled onto UKALL14 between 30 December 2010 and 19 April 2012. One patient died before starting any treatment and has been excluded from all analyses. Patient characteristics at diagnosis are summarised in Table 1. The majority (59 of 90, 66%) of patients were aged >40 years and nearly a third (26/90, 29%) had Ph+ ALL. Most patients (92%) had performance scores of 0–1 at diagnosis. Median follow-up was 36.0 months (12 days–50.4 months).\n\nInduction deaths\nProgress through the induction therapy blocks is shown in Figure 2. Among those commencing phase 1 induction therapy (n=90), there were 18 early deaths. Two patients died of progressive ALL and the other 16 (16/90, 18%) deaths were related to induction treatment, occurring at a median time from start to induction of 23 days (range 10–53).\n\nThe causes of induction deaths are summarised in Table 2. In 12 of the 16 (75%), the causes of death were most often multifactorial; sepsis together with hepatotoxicity occurred in 8 of 16, 50.0%. Neutropenic sepsis alone occurred in 3 of the 16 patients, (18.8%). A causative organism was identified in 11 of the cases of sepsis, with a Gram-negative bacterial infection being responsible in 8 of those. Additional causes of death were: hepatotoxicity plus bowel ischaemia (n=2), acute coronary syndrome plus neutropenic sepsis (n=1), hepatotoxicity plus pancreatitis (n=1), and pulmonary haemorrhage (n=1). Nine of the 11 hepatotoxicity-related induction deaths were associated with grade 3–4 hyperbilirubinaemia. In total, half of the induction deaths were accompanied by recognised PEG-ASP toxicities (namely, those already listed in the Summary of Product Characteristics as occurring in 1:⩾1000 patients, or less common but clearly recognised as being related to PEG-ASP). There was no obvious association between baseline comorbidities and induction death.\n\nAll patients received D4 PEG-ASP. Sixty-four, including 5 of the 16 who suffered induction deaths, received the second dose on D18. For patients who died during induction, the median time from last dose of PEG-ASP to death was 13 days (range 6–50).\n\nRisk factors for induction death\nTable 3 shows a univariate analysis of factors predictive of induction death. Age, Ph positivity and high-risk cytogenetics were all risk factors. Patients aged over 40 years had a more than 10-fold increase in risk of death during induction with Ph+ disease conferring a more than 8-fold increase compared with Ph−disease (odds ratio (OR): 8.65 (2.61–28.71), P<0.001). There was no relationship to baseline albumin levels or body mass index (BMI). The data monitoring committee also confirmed that there was no relationship to rituximab randomisation arm. The multivariable analysis is also shown in Table 3. Although high-risk cytogenetics appeared to be associated with induction death, this was driven by the presence of t(9;22), so this factor alone was included in the multivariable analysis. Age and Ph status remained significantly associated with induction death; in patients who were Ph−, there were no deaths in the 21 patients aged ⩽40 years and 5 in the 43 patients aged >40 years. In patients with Ph+ ALL, 1 of the 10 patients aged ⩽40 years died compared with 10 of the 16 who were aged >40 years.\n\nAEs during phase 1 induction therapy\nIncluding the patients discussed above who subsequently died, 87 of the 91 patients (97%) experienced a grade 3–5 AE during induction phase 1; among these 46 (51%) suffered one or more recognised PEG-ASP toxicities; 34 had grade 3–5 AEs indicating liver dysfunction, including 22 with raised bilirubin. Other PEG-ASP toxicities included pancreatitis (n=3), intracranial haemorrhage (n=1), allergic reaction (n=3), coagulation disorder (n=4) and vascular events (n=6). Thirty-seven of the 74 surviving patients (50.0%) experienced at least one recognised grade 3–4 PEG-ASP-related, non-fatal toxicity summarised in Table 4. Hepatotoxicity—including biochemical markers of liver dysfunction—was the most frequent PEG-ASP-related toxicity (36.5%, n=27). Venous thromboembolism (4.1%, n=3), allergic reaction (4.1%, n=3) and pancreatitis (2.7%, n=2) were all reported but were relatively uncommon. A complete line-listing of all AE/serious AE as well as the subset known to be recognised toxicities of PEG-ASP from which Table 4 is derived is given in Supplementary Supplementary Table S1. As liver toxicity was so prominent and can be a key determinant of subsequent on-time therapy delivery, an analysis of any pretreatment factors associated with grade 3–4 hepatotoxicity was carried out. This is shown in Table 5. Older age and BMI were the only factors that showed a significant association (OR: 2.88 (1.62–15.44), P=0.005, for patients aged >40 years compared with those ⩽40 years and OR: 1.58 (1.02–2.44), P=0.041, for a 5 unit increase in BMI).\n\nAsparaginase activity, antiasparaginase antibody formation and correlation with MRD response\nA trough level of asparaginase activity by MAAT testing7, 13 was assessed 14 days after the first (D4) PEG-ASP dose in 49 patients in whom serum was available (n=49). Therapeutic activity (enzyme level >100IU/l) was achieved in 42 of 49 (86%). The median enzyme level in those achieving therapeutic enzyme levels was 234 IU/l (range 101.5–602.8) as compared with 44.8IU/l (0–97.5) in those with subtherapeutic levels. There was no evidence of an association between age and achievement of therapeutic enzyme level. Molecular MRD at the end of phase 1 induction was documented in 27 patients. Molecular remission rates did not significantly differ between those achieving therapeutic enzyme levels of PEG-ASP and those who did not (14/26 compared with 3/4), suggesting that an early complete molecular response in this setting is not contingent upon therapeutic asparaginase enzyme activity. Anti-PEG-ASP antibody formation at D18 was assessed in 59 patients, and at that time point, there were no instances of seroconversion.\n\nDiscussion\nSuccessful achievement of CR during induction therapy for ALL is an absolute prerequisite for long-term disease-free survival. Numerous previous studies have suggested that induction regimens typically used in children give a better outcome for teenagers and younger adults than typical ‘adult' regimens.14, 15, 16, 17, 18 As a consequence, there is general acceptance of testing the outcome of increasing the intensity of non-myelosuppressive agents such as PEG-ASP in regimens used for older adults.\n\nWithin the first 91 patients enrolled, we noted significantly greater induction mortality in UKALL14 than in our previous trial, UKALL12. Induction death occurred in 16 of the first 90 (17.8%) treated patients, and 15 of the first 59 (25%) participants being aged >40 years (10/29 (33%) being aged >55 years). The median age of the patient population enrolled in this period was 46.5 years, with 29% of patients being aged >55 years. By comparison, the induction death rate in our previous trial, UKALL12/ECOG2993, was 6% overall (ages 15–60 years, median age 36 years)12 and 15% in the 55–65-year range (median age 56 years).19 UKALL14 did not exclude any patient with poor organ function or comorbidity at diagnosis, but we did not find any evidence of these factors having a causal contribution to PEG-ASP-related mortality.\n\nAnalysis of the cause of each death in UKALL14 included a complete written narrative from the treating physician as well as the standard case report forms for serious AE collection. Bacterial sepsis was revealed as a major contributor to the deaths. However, concomitant grade 3–4 PEG-ASP toxicities were very common among those suffering induction death, such that a recognised PEG-ASP toxicity was associated with half of the 16 induction deaths. It is impossible to disentangle the role of the investigational medicinal product (IMP) PEG-ASP from that of concomitant non-IMP induction agents. However, the introduction of dexamethasone instead of prednisolone was the only change that had been made to the standard backbone regimen between UKALL12 and UKALL14.\n\nIt is noteworthy that most of the induction deaths reported here occurred after an early, single (D4) dose of PEG-ASP, any toxicity of which would overlap with the myelosuppressive toxicity of anthracycline administered on D1, D8, D15 and D22. The 60 mg/m2 dose of anthracycline given in the UKALL12 regimen was well tolerated, but asparaginase was not started until D17. The earlier addition of PEG-ASP-associated liver dysfunction to subsequent myelosuppression-related sepsis may have been responsible for the overlapping toxicity. The fact that sepsis was a major contributor to the mortality supports that contention.\n\nTo date, only two other studies reporting the use of PEG-ASP specifically in adults have been published, both of which report a lower dose and/or different schedule of anthracycline. A phase 2 trial CALGB 9511(ref. 11) reported on 102 adults treated with PEG-ASP at 2000 U/m2 subcutaneously, capped at 3750 U/m2, starting on D5 of the five-drug induction regimen. Although the regimen was reported to be 'tolerable', bilirubin >51.3 μm (3 mg/dl) occurred in 54% of patients. CR rate was only 77% but induction deaths are not separated from induction failures within the report. There was a statistically significant difference in median age of those achieving full dose delivery and asparagine depletion—32 years versus 48 years. In a more recent study from Douer et al.20 in 51 adults median age 32 years, upper age limit 57 years reported no deaths directly as a result of PEG-ASP in regimen, which included 2000 IU/m2 PEG-ASP given on D15. However, 3 of the 51 (6%) patients died of neutropenic sepsis during consolidation. In this case, daunorubicin was given at 60 mg/m2 intravenously on D1–D3. Grade 3–4 hyperbilirubinaemia (1/3 patients) or transaminitis (2/3 of patients) was very common. Douer et al.20 also reported long median intervals from PEG-ASP to bilirubin recovery, which affected subsequent chemotherapy delivery. The younger median age of patients in that study, the small number receiving concurrent imatinib (N=5), a more modest anthracycline dose and different scheduling of PEG-ASP administration so as not to coincide with the maximal myelosuppression may all have contributed to the difference in toxicity.\n\nThe German Multicentre Adult ALL Group have reported in abstract form21 on 1000 adult patients aged 15–55 years, treated on the German 07/2003 study in which a single dose of 1000–2000 U/m2 PEG-ASP was administered on D3 during induction with a reported rate of induction death rate of <5% and a grade IV hyperbilirubinaemia incidence of 16%. As with the study by Douer et al.,20 the younger median age (35 years) of the cohort in addition to the lower dose of anthracycline (45 versus the 60 mg/m2 used in the current study) may underpin the differences in toxicity.\n\nIt should be noted that the French GRAAALL group also reported that advancing age resulted in a higher cumulative incidence of chemotherapy-related deaths (23% versus 5%, respectively; P<0.001) and deaths in first CR (22% versus 5%, respectively; P<0.001) during 'paediatric-style' therapy, even when non-pegylated asparaginsae was used. In the study reported by Huguet et al.,22 ⩾45 years of age was the strongest predictor of severe toxicity,\n\nAs a consequence of the toxicity reported here, the UKALL14 protocol was amended to omit D4 PEG-ASP for those aged >40 years. Furthermore, PEG-ASP was completely removed from induction treatment for all patients with Ph+ ALL. In addition, owing to the high level of sepsis related to profound myelosuppression, the daunorubicin dose was halved to 30 mg/m2 on D1, D8, D15 and D22. One year following this amendment, when an additional 302 further patients had been recruited with 244 patients assessable for induction death, a repeat analysis showed only 6 (2.5%) phase 1 induction deaths (data not shown).\n\nUnivariate analysis demonstrated that older age and poor-risk cytogenetics—including t(9;22)—were significantly associated with induction death. On multivariable analysis, age and Ph positivity remained as independent risk factors for induction death, suggesting that the concomitant imatinib therapy only received by those with Ph+ ALL may have compounded the potential for PEG-ASP toxicity. The precise mechanism by which this might occur is not known. However, from the Summary of Product Characteristics for imatinib, ‘increased hepatic enzymes' is reported as common (1:10 to 1:100), hyperbilirubinaemia occurs in between 1:100 and 1:1000 patients and, finally, hepatic failure is noted as ‘rare', namely, occurring between 1:1000 and 1:10 000 cases. Hence, the potential for overlapping hepatotoxicity of PEG-ASP and imatinib is clearly present.\n\nHalf of the patients who did not experience an induction death experienced one or more grade 3–4 PEG-ASP toxicities from which they eventually recovered—most commonly, hepatotoxicity. Twenty-three percent of patients in this study experienced grade ⩾3 hyperbilirubinaemia; by definition, a limitation or exclusion to further dosing with many commonly used ALL therapeutics. On analysis of treatment delays in our previous trial, UKALL12/E2993 study showed that delays of >4 weeks were associated with poorer overall survival and event-free survival in patients undergoing allogeneic hematopoietic stem cell transplantation but not in patients undergoing postremission chemotherapy.22 Any long-term impact of any delays engendered by toxicity during initial induction therapy in this study will become clear when the trial is completed and we can evaluate any delays in relation to our primary end point, event-free survival.\n\nOur pharmacokinetic studies indicate that a single dose of 1000 IU/m2 PEG-ASP generates therapeutic enzyme levels in most patients—86% of assessable patients had therapeutic levels of PEG-ASP activity 14 days after administration. A recent longitudinal analysis of PEG-ASP pharmacokinetics during a ‘paediatric' regimen in adult ALL demonstrated therapeutic enzyme activity in a similar proportion of adult patients for up to 21 days.20 In our study, antiasparaginase antibodies were not seen at the early time point documented.\n\nIn conclusion, we have shown that PEG-ASP achieves very effective asparagine depletion without antiasparaginase antibody formation in the majority of adult patients. However, toxicity can be substantial in older patients, making a 'paediatric-inspired' regimen of the type commonly used used in paediatric and young adult therapy difficult to deliver safely to those aged >40 years. Avoidance of overlapping toxicities and careful timing of administration will be of key importance to the more widespread use of this type of regimen in older adults.\n\nAs remission can be induced with minimal mortality in patients with Ph+ ALL,23, 24 we suggest that PEG-ASP is never coadministered with imatinib during induction therapy.\n\nUKALL14 was funded by Cancer Research UK grant CRUK/09/006 to AKF. The MAAT testing and antiasparaginase antibody testing was funded by a 2-year, unrestricted educational grant from Medac GMBH to AKF between 2010 and 2012. BP was funded by Bloodwise grant 07062. We thank all centres and patients who contributed to this study.\n\nAuthor contributions\n\nBP, AK and AKF wrote the paper. AKF designed the study, contributed data and was Chief Investigator of the trial. AK analysed data. PS, LM, SP and PP co-ordinated the study, collected data and contributed to the analysis. AD carried out the MAAT testing. CJR, TM, AKMcM and DM contributed data and managed the trial. All authors contributed to writing the manuscript and approved the final version.\n\nSupplementary Information accompanies this paper on the Leukemia website (http://www.nature.com/leu)\n\nFielding received lab funding from Medac GmBH to carry out part of this work and that company were the supplier of PEG-ASP at the time of this work. The remaining authors declare no conflict of interest.\n\nSupplementary Material\nSupplementary Information Click here for additional data file.\n\n Figure 1 Schematic of UKALL14 treatment protocol. High risk features: karyotypes: t(9;22) t(4;11), low hypodiploidy near triploidy or complex, age >40 years, WBC ⩾30 × 109/l (precursor B lineage ALL), ⩾100 × 109/l (T-cell-ALL), molecular minimal residual disease positivity (>1 × 10−4) after induction phase 2.\n\nFigure 2 Flow chart of progress of the 91 patients enrolled. Grade 4 sepsis n=4, grade IV organ toxicity n=4 (hepatotoxicity n=1, pancreatitis n=1, hepatotoxicity plus neurological event n=1, hepatotoxicity plus thromboembolism together with sepsis n=1 and wrong diagnosis n=1, withdrawal of consent, n=1.\n\nTable 1 Patient characteristics at diagnosis\nCharacteristic\tN (%)\t\nLineage\t\n B-precursor\t77 (86)\t\n T-cell\t13 (14)\t\n \t \t\nSex\t\n Male\t48 (53)\t\n Female\t42 (47)\t\n \t \t\nAge at entry (years)\t\n Median (range)\t46.50 (25–65)\t\n ⩾55\t29 (32)\t\n ⩾41\t59 (66)\t\n \t \t\nPresenting WBC ( × 109/l)\t\n Median (range)\t9.26 (0.52–297.4)\t\n <30\t62 (69)\t\n 30–99.9\t15 (17)\t\n 100+\t13 (14)\t\n \t \t\nCytogenetic risk status\t\n High riska\t28 (31)\t\n Low risk\t42 (47)\t\n Unknownb\t20 (22)\t\n \t \t\nt(9;22)\t\n Absent\t64 (71)\t\n Present\t26 (29)\t\n \t \t\nLow hypodiploidy/near triploidy\t\n Absent\t65 (72)\t\n Present\t4 (4)\t\n Failed/missing\t21 (23)\t\n \t \t\nt(4;11)\t\n Absent\t75 (83)\t\n Present\t7 ( 8)\t\n Failed/missing\t8 (9)\t\n \t \t\nComplex karyotype\t\n Absent\t64 (71)\t\n Present\t5 (6)\t\n Failed/missing\t21 (23)\t\n \t \t\nPerformance status\t\n 0\t55 (61)\t\n 1\t28 (31)\t\n 2\t5 ( 6)\t\n 3\t1 (1)\t\n Missing\t1 (1)\t\n \t \t\nBMI\t\n Normal/underweightc\t31 (34)\t\n Overweight\t25 (28)\t\n Obese\t34 (38)\t\nAbbreviations: BMI, body mass index; WBC, white blood cell.\n\na High risk: t(9;22), t(4;11) low hypodiploidy/near triploidy or complex karyotypes.\n\nb No high-risk factors and at least one risk factor is missing or failed.\n\nc 30 in the normal range and 1 patient with a BMI of 17.\n\nTable 2 Summary of deaths during induction\nID\tPatient details\tComorbidities\tHepatotoxicity (grade)\tNeutropenic sepsis (organism)\tHaemorrhage (site)\tThrombosis/visceral ischaemia (site)\tPancreatitis\tOther\tPEG-ASP doses\tDays from last PEG-ASP dose\t\n1003\tAge 54 years PH−\tLiver cirrhosis\t4\tNot known\t \t \t \t \tD4 and 18\t19\t\n1004\tAge 46 years PH+\tNone\t \tPseudomonas aeruginosa\t \tAcute coronary syndrome\t \t \tD4\t16\t\n1011\tAge 43 years PH+\tNone\t4\tEscherichia coli\t \t \t \tRenal failure\tD4 & 18\t8\t\n1021\tAge 65 years PH−\tNone\t4\tPseudomonas aeruginosa\t \tGastrointestinal\t \t \tD4\t50\t\n1026\tAge 64 years PH+\tDepression\t4\tPseudomonas aeruginosa\t \t \t \t \tD4\t20\t\n1028\tAge 38 years PH+\tNone\t \tEnterococcus faecium\t \t \t \t \tD4\t15\t\n1029\tAge 60 years PH+\tIHD\t4\tEscherichia coli\t \t \t \t \tD4\t14\t\n1030\tAge 49 years PH+\tNone\t \t \tPulmonary\t \t \t \tD4\t6\t\n1039\tAge 62 years PH+\tNone\t2\t \t \tSmall bowel\t \t \tD4\t10\t\n1043\tAge 63 years PH−\tGrade 4 renal failure\t4\tKlebsiella pneumoniae\tCarotid artery puncture site\t \t \t \tD4 and D18\t43\t\n1049\tAge 56 years PH+\tNone\t4\tPseudomonas aeruginosa\t \t \t \t \tD4\t11\t\n1057\tAge 57 years PH−\tNone\t4\t \t \tSmall bowel\t \t \tD4\t20\t\n1061\tAge 54 years PH+\tParoxysmal atrial fibrillation\t3\t \t \t \tYes\tGI perforation\tD4\t10\t\n1063\tAge 62 years PH+\tNone\t \tCoagulase-negative staph/Enterococcus faecium\t \t \t \t \tD4 and D18\t12\t\n1068\tAge 64 years PH+\tNone\t4\tRespiratory syncytial virus\t \t \t \tRenal failure\tD4\t21\t\n2007\tAge 55 years PH−\tNone\t \tPseudomonas aeruginosa\t \t \t \t \tD4 and D18\t8\t\nAbbreviations: IHD, ischaemic heart disease; PEG-ASP, pegylated asparaginase.\n\nTable 3 Univariate and multivariate analysis of risk factors for induction death\nRisk factor\tEvents/n\tUnivariable\tMultivariable\t\n \t \tOdds ratio (95% CI)\tP-value\tOdds ratio (95% CI)\tP-value\t\nAge, years\t\n ⩽40\t1/31\t1.00\t0.03\t18.50 (2.02–169.0)\t0.01\t\n >40\t15/59\t10.23 (1.28–81.59)\t \t \t \t\n \t \t \t \t \t \t\nGender\t\n Male\t8/48\t1.00\t0.77\t—\t—\t\n Female\t8/42\t1.18 (0.40–3.47)\t \t \t \t\n \t \t \t \t \t \t\nBaseline WBC per × 109/l increment\t16/90\t1.00 (0.99–1.01)\t0.56\t—\t \t\n \t \t \t \t \t \t\nCytogeneticsa\t\n Standard risk\t2/28\t1.00\t0.0029\t—\t—\t\n High risk\t13/42\t5.83 (1.20–28.29)\t \t \t \t\n \t \t \t \t \t \t\nPh\t \t \t \t \t \t\n Absent\t5/64\t1.00\t<0.001\t13.60 (3.53–52.36)\t<0.001\t\n Present\t11/26\t8.65 (2.61–28.71)\t \t \t \t\n \t \t \t \t \t \t\nBase albumin (g/l) (10 unit increment)\t16/90\t1.03 (0.40–2.64)\t0.95\t—\t—\t\nBase bilirubin (μmol/l) (10 unit increment)\t16/90\t0.91 (0.59–1.42)\t0.69\t—\t—\t\nBMI (5 unit increment)\t16/90\t1.29 (0.82–2.02)\t0.27\t—\t—\t\nAbbreviations: BMI, body mass index; CI, confidence interval; WBC, white blood cell.\n\na Analysed as no high-risk factors versus high-risk Ph and high-risk Ph+ gives HRs of 1.86 (0.24–14.64) and 9.53 (1.86–49.91), respectively.\n\nTable 4 Patients who did not die during induction: summary of the grade 3/4 AEs recognised in SPC as being related to PEG-ASPa\nSOC/event term\tGrade 3+ PEG-ASP known AEs, N (%)\t\nGastrointestinal disorders\t2 (3)\t\n Pancreatitis\t2 (3)\t\n \t \t\nHepatobiliary disorders\t3 (4)\t\n Liver failure\t1 (1)\t\n Liver dysfunction\t2 (3)\t\n \t \t\nImmune system disorders\t3 (4)\t\n Allergic reaction\t3 (4)\t\n \t \t\nInvestigations\t29 (39)\t\n Lipase increased\t1 (1)\t\n Serum amylase increased\t3 (4)\t\n Alkaline phosphatase increased\t15 (20)\t\n Aspartate aminotransferase increased\t4 (5)\t\n Blood bilirubin increased\t17 (23)\t\n Alanine aminotransferase increased\t10 (14)\t\n GGT increased\t5 (7)\t\n \t \t\nMetabolism and nutrition disorders\t3 (4)\t\n Increased triglycerides\t1 (1)\t\n Hypoalbuminaemia\t2 (3)\t\n \t \t\nNervous system disorders\t1 (1)\t\n Intracranial haemorrhage\t1 (1)\t\n \t \t\nVascular disorders\t4 (5)\t\n Pulmonary embolism\t1 (1)\t\n Thromboembolic event\t3 (4)\t\n \t \t\nNon-CTCAE terms\t \t\n Coagulation disorder\t3 (4)\t\n \t \t\nAny liver event\t27 (36)\t\nAny toxicity\t37 (50)\t\nAbbreviations: AE, adverse event; CTCAE, Common Terminology Criteria; GGT, gamma glutamyl transpeptidase; PEG-ASP, pegylated asparaginase; SPC, Summary of Product Characteristics; SOC, System Organ Class.\n\na A complete line listing of grade 3+ AE/serious AE according to CTCAE criteria with assignment of causality by both site and by trial management group is provided in Supplementary Table S1.\n\nTable 5 Analysis of risk factors for liver-related grade 3/4 adverse events during phase 1 induction in patients who did not have an induction death\nRisk factor\tGrade 3/4 liver AEs\t\n \tEvents/n\tOdds ratio (95% CI)\tP-value\t\nAge\t\n ⩽40\t5/30\t1.00\t0.005\t\n >40\t22/44\t2.9 (1.62–15.44)\t \t\n \t \t \t \t\nSex\t\n Male\t16/40\t1.00\t0.50\t\n Female\t11/34\t0.72 (0.28–1.87)\t \t\n \t \t \t \t\nBaseline WBC per × 109/l increment\t27/74\t1.00 (0.99–1.01)\t0.71\t\n \t \t \t \t\nCytogenetics\t\n Standard risk\t10/26\t1.00\t0.97\t\n High risk\t11/29\t0.98 (0.33–2.91)\t \t\n \t \t \t \t\nPh\t\n Absent\t20/59\t1.00\t0.36\t\n Present\t7/15\t1.71 (0.54–5.38)\t \t\n \t \t \t \t\nBase albumin (g/l) (10 unit increment)\t27/74\t0.89 (0.41–1.92)\t0.77\t\nBase bilirubin (μmol/l) (10 unit increment)\t27/74\t1.02 (0.81–1.30)\t0.86\t\nBMI (5 unit increment)\t27/74\t1.58 (1.02–2.44)\t0.041\t\nAbbreviations: AE, adverse event; BMI, body mass index; CI, confidence interval; WBC, white blood cell.\n==== Refs\nSallan SE, Hitchcock-Bryan S, Gelber R, Cassady JR, Frei E 3rd, Nathan DG. Influence of intensive asparaginase in the treatment of childhood non-T-cell acute lymphoblastic leukemia . Cancer Res \n1983 ; 43 : 5601 –5607.6352020 \nAvramis VI, Sencer S, Periclou AP, Sather H, Bostrom BC, Cohen LJ et al. A randomized comparison of native Escherichia coli asparaginase and polyethylene glycol conjugated asparaginase for treatment of children with newly diagnosed standard-risk acute lymphoblastic leukemia: a Children's Cancer Group study . Blood \n2002 ; 99 : 1986 –1994.11877270 \nSeibel NL. Treatment of acute lymphoblastic leukemia in children and adolescents: peaks and pitfalls . Hematology Am Soc Hematol Educ Program \n2008 , 374 –380.19074113 \nAvramis VI, Spence SA. Clinical pharmacology of asparaginases in the United States: asparaginase population pharmacokinetic and pharmacodynamic (PK-PD) models (NONMEM) in adult and pediatric ALL patients . J Pediatr Hematol Oncol \n2007 ; 29 : 239 –247.17414566 \nKurtzberg J, Asselin B, Bernstein M, Buchanan GR, Pollock BH, Camitta BM. Polyethylene glycol-conjugated L-asparaginase versus native L-asparaginase in combination with standard agents for children with acute lymphoblastic leukemia in second bone marrow relapse: a Children's Oncology Group Study (POG 8866) . J Pediatr Hematol Oncol \n2011 ; 33 : 610 –616.22042277 \nPession A, Valsecchi MG, Masera G, Kamps WA, Magyarosy E, Rizzari C et al. Long-term results of a randomized trial on extended use of high dose L-asparaginase for standard risk childhood acute lymphoblastic leukemia . J Clin Oncol \n2005 ; 23 : 7161 –7167.16192600 \nAsselin BL, Whitin JC, Coppola DJ, Rupp IP, Sallan SE, Cohen HJ. Comparative pharmacokinetic studies of three asparaginase preparations . J Clin Oncol \n1993 ; 11 : 1780 –1786.8355045 \nDouer D. Is asparaginase a critical component in the treatment of acute lymphoblastic leukemia ? Best Pract Res Clin Haematol \n2008 ; 21 : 647 –658.19041604 \nDouer D, Yampolsky H, Cohen LJ, Watkins K, Levine AM, Periclou AP et al. Pharmacodynamics and safety of intravenous pegaspargase during remission induction in adults aged 55 years or younger with newly diagnosed acute lymphoblastic leukemia . Blood \n2007 ; 109 : 2744 –2750.17132721 \nStock W, Douer D, Deangelo DJ, Arellano M, Advani A, Damon L et al. Prevention and management of asparaginase/pegasparaginase-associated toxicities in adults and older adolescents: recommendations of an expert panel . Leuk Lymphoma \n2011 ; 52 : 2237 –2253.21827361 \nWetzler M, Sanford BL, Kurtzberg J, Deoliveira D, Frankel SR, Powell BL et al. Effective asparagine depletion with pegylated asparaginase results in improved outcomes in adult acute lymphoblastic leukemia — Cancer and Leukemia Group B Study 9511 . Blood \n2007 ; 109 : 4164 –4167.17264295 \nRowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM et al. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993 . Blood \n2005 ; 106 : 3760 –3767.16105981 \nFabry U, Korholz D, Jurgens H, Gobel U, Wahn V. Anaphylaxis to L-asparaginase during treatment for acute lymphoblastic leukemia in children—evidence of a complement-mediated mechanism . Pediatr Res \n1985 ; 19 : 400 –408.3858789 \nDeAngelo DJ, Stevenson KE, Dahlberg SE, Silverman LB, Couban S, Supko JG et al. Long-term outcome of a pediatric-inspired regimen used for adults aged 18-50 years with newly diagnosed acute lymphoblastic leukemia . Leukemia \n2015 ; 29 : 526 –534.25079173 \nBoissel N, Auclerc MF, Lheritier V, Perel Y, Thomas X, Leblanc T et al. Should adolescents with acute lymphoblastic leukemia be treated as old children or young adults? Comparison of the French FRALLE-93 and LALA-94 trials . J Clin Oncol \n2003 ; 21 : 774 –780.12610173 \nde Bont JM, Holt B, Dekker AW, van der Does-van den Berg A, Sonneveld P, Pieters R. Significant difference in outcome for adolescents with acute lymphoblastic leukemia treated on pediatric vs adult protocols in the Netherlands . Leukemia \n2004 ; 18 : 2032 –2035.15483674 \nRamanujachar R, Richards S, Hann I, Goldstone A, Mitchell C, Vora A et al. Adolescents with acute lymphoblastic leukaemia: outcome on UK national paediatric (ALL97) and adult (UKALLXII/E2993) trials . Pediatr Blood Cancer \n2007 ; 48 : 254 –261.16421910 \nStock W, La M, Sanford B, Bloomfield C, Vardiman J, Gaynon P et al. What determines the outcomes for adolescents and young adults with acute lymphoblastic leukemia treated on cooperative group protocols? A comparison of Children's Cancer Group and Cancer and Leukemia Group B studies . Blood \n2008 ; 112 : 1646 –1654.18502832 \nSive JI, Buck G, Fielding A, Lazarus HM, Litzow MR, Luger S et al. Outcomes in older adults with acute lymphoblastic leukaemia (ALL): results from the international MRC UKALL XII/ECOG2993 trial . Br J Haematol \n2012 ; 157 : 463 –471.22409379 \nDouer D, Aldoss I, Lunning MA, Burke PW, Ramezani L, Mark L et al. Pharmacokinetics-based integration of multiple doses of intravenous pegaspargase in a pediatric regimen for adults with newly diagnosed acute lymphoblastic leukemia . J Clin Oncol \n2014 ; 32 : 905 –911.24516026 \nGoekbuget N. PEG-asparaginase intensification in adult acute lymphoblastic leukemia (ALL): significant improvement of outcome with moderate increase of liver toxicity in the German Multicenter Study Group for Adult ALL (GMALL) Study 07/2003 . ASH Annu Meeting Abstr \n2010 ; 116 : 494 .\nHuguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E et al. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study . J Clin Oncol \n2009 ; 27 : 911 –918.19124805 \nVignetti M, Fazi P, Cimino G, Martinelli G, Di Raimondo F, Ferrara F et al. Imatinib plus steroids induces complete remissions and prolonged survival in elderly Philadelphia chromosome-positive patients with acute lymphoblastic leukemia without additional chemotherapy: results of the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) LAL0201-B protocol . Blood \n2007 ; 109 : 3676 –3678.17213285 \nFoa R, Vitale A, Vignetti M, Meloni G, Guarini A, De Propris MS et al. Dasatinib as first-line treatment for adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia . Blood \n2011 ; 118 : 6521 –6528.21931113\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0887-6924",
"issue": "31(1)",
"journal": "Leukemia",
"keywords": null,
"medline_ta": "Leukemia",
"mesh_terms": "D000328:Adult; D000367:Age Factors; D000368:Aged; D000970:Antineoplastic Agents; D001215:Asparaginase; D056486:Chemical and Drug Induced Liver Injury; D006801:Humans; D060828:Induction Chemotherapy; D008875:Middle Aged; D010677:Philadelphia Chromosome; D011092:Polyethylene Glycols; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D018805:Sepsis",
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"references": "24516026;17213285;17132721;22042277;6352020;17264295;15483674;19124805;3858789;21931113;16192600;17414566;25079173;16421910;19041604;21827361;19074113;22409379;8355045;18502832;12610173;16105981;11877270",
"title": "Pegylated-asparaginase during induction therapy for adult acute lymphoblastic leukaemia: toxicity data from the UKALL14 trial.",
"title_normalized": "pegylated asparaginase during induction therapy for adult acute lymphoblastic leukaemia toxicity data from the ukall14 trial"
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"abstract": "OBJECTIVE\nThe objective of this study was to evaluate the efficacy and safety of the sequential use of bedaquiline (Bdq) and delamanid (Dlm) in patients with multidrug-resistant tuberculosis (MDR-TB) and limited treatment options.\n\n\nMETHODS\nThis study evaluated 74 MDR-TB patients treated between March 2016 and December 2018 with Bdq followed by Dlm (n = 22), or vice versa (n= 52), combined with optimized background regimens.\n\n\nRESULTS\nThe mean age of the participants was 49.0 ± 15.8 years. Fifty-one (68.9%) of the participants were male. Fluoroquinolone resistance was identified in 54 (72.9%) patients, including 20 (27.0%) with extensively drug-resistant TB. Of the 47 (63.5%) patients with positive cultures at the commencement of the first new drug, culture conversion occurred in 44 (93.6%). The interim treatment outcome after 12 months was favourable in 68/74 patients (91.9%). Twenty-four weeks of treatment were completed in 137 of 148 episodes of new drug use (92.3%). Regarding the 11 early discontinuation events, six patients stopped using a new drug due to adverse drug reactions that were not life-threatening, including one (1.4%) who stopped Bdq due to QT-prolongation.\n\n\nCONCLUSIONS\nSequential use of the two new drugs appears to be an effective and safe option for MDR-TB patients with few treatment options.",
"affiliations": "Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea.;Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea.;Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea.;Department of Internal Medicine, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan, South Korea.;Department of Chest Medicine, Masan National Tuberculosis Hospital, Changwon, South Korea.;Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea. Electronic address: shimts@amc.seoul.kr.",
"authors": "Lee|Hoon Hee|HH|;Jo|Kyung-Wook|KW|;Yim|Jae-Joon|JJ|;Jeon|Doosoo|D|;Kang|Hyungseok|H|;Shim|Tae Sun|TS|",
"chemical_list": "D000995:Antitubercular Agents; D064687:Diarylquinolines; D009593:Nitroimidazoles; C516022:OPC-67683; D010080:Oxazoles; C493870:bedaquiline",
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"keywords": "Bedaquiline; Delamanid; MDR; Treatment outcome; Tuberculosis",
"medline_ta": "Int J Infect Dis",
"mesh_terms": "D000328:Adult; D000368:Aged; D000995:Antitubercular Agents; D064687:Diarylquinolines; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009593:Nitroimidazoles; D010080:Oxazoles; D012189:Retrospective Studies; D016896:Treatment Outcome; D018088:Tuberculosis, Multidrug-Resistant; D055815:Young Adult",
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"title": "Interim treatment outcomes in multidrug-resistant tuberculosis patients treated sequentially with bedaquiline and delamanid.",
"title_normalized": "interim treatment outcomes in multidrug resistant tuberculosis patients treated sequentially with bedaquiline and delamanid"
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"abstract": "Nocardiosis is an uncommon opportunistic Gram-positive bacterial infection caused by aerobic actinomycetes in the genus Nocardia. Nocardia can cause localized or systemic suppurative diseases involving eyes, kidneys, skin, lungs, bone, and central nervous system. Disseminated nocardiosis is a rare condition, seen among immunocompromised patients. We report the case of a 55-year-old African American, kidney transplant male recipient on maintenance immunosuppression, who was diagnosed with cutaneous and pulmonary nocardiosis. Presenting symptoms were shortness of breath, and bilateral lower extremities pain and swelling. Tissue culture grew Gram-positive bacilli specified as Nocardia farcinica from thigh and gluteal abscesses. CT thorax showed bilateral reticulonodular opacities. The patient was managed with immunosuppression reduction and specific treatment with high-dose trimethoprim-sulfamethoxazole (TMP-SMX) in conjunction with linezolid. Combination antibiotics were continued for four weeks, and thereafter, TMP-SMX alone was continued for 12 months, at which point all lesions had healed. Nocardiosis with systemic involvement carries a poor prognosis. However, early diagnosis and appropriate antibiotic coverage had a favorable outcome in a renal transplant recipient. Recommended treatment duration is 6 to 12 months.",
"affiliations": "Internal Medicine/Nephrology, Wayne State University Detroit Medical Center, Detroit, USA.;Internal Medicine, Beaumont Health, Dearborn, USA.;Internal Medicine, Advocate Aurora Health Care, Detroit, USA.;Infectious Diseases, Wayne State University Detroit Medical Center, Detroit, USA.;Nephrology, Wayne State University School of Medicine, Detroit, USA.",
"authors": "Ghandour|Mohamedanwar|M|;Shereef|Hammam|H|;Homida|Hassan|H|;Revankar|Sanjay|S|;Zachariah|Mareena S|MS|",
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"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.12497\nInfectious Disease\nNephrology\nDisseminated Nocardiosis in a Renal Transplant Recipient\nMuacevic Alexander Adler John R Ghandour Mohamedanwar 1 Shereef Hammam 2 Homida Hassan 3 Revankar Sanjay 4 Zachariah Mareena S 5 \n1 \nInternal Medicine/Nephrology, Wayne State University Detroit Medical Center, Detroit, USA \n\n2 \nInternal Medicine, Beaumont Health, Dearborn, USA \n\n3 \nInternal Medicine, Advocate Aurora Health Care, Detroit, USA \n\n4 \nInfectious Diseases, Wayne State University Detroit Medical Center, Detroit, USA \n\n5 \nNephrology, Wayne State University School of Medicine, Detroit, USA \n\nMohamedanwar Ghandour mr.anwar90@yahoo.com\n5 1 2021 \n1 2021 \n13 1 e124975 1 2021 Copyright © 2021, Ghandour et al.2021Ghandour et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/42490-disseminated-nocardiosis-in-a-renal-transplant-recipientNocardiosis is an uncommon opportunistic Gram-positive bacterial infection caused by aerobic actinomycetes in the genus Nocardia. Nocardia can cause localized or systemic suppurative diseases involving eyes, kidneys, skin, lungs, bone, and central nervous system. Disseminated nocardiosis is a rare condition, seen among immunocompromised patients. We report the case of a 55-year-old African American, kidney transplant male recipient on maintenance immunosuppression, who was diagnosed with cutaneous and pulmonary nocardiosis. Presenting symptoms were shortness of breath, and bilateral lower extremities pain and swelling. Tissue culture grew Gram-positive bacilli specified as Nocardia farcinica from thigh and gluteal abscesses. CT thorax showed bilateral reticulonodular opacities. The patient was managed with immunosuppression reduction and specific treatment with high-dose trimethoprim-sulfamethoxazole (TMP-SMX) in conjunction with linezolid. Combination antibiotics were continued for four weeks, and thereafter, TMP-SMX alone was continued for 12 months, at which point all lesions had healed. Nocardiosis with systemic involvement carries a poor prognosis. However, early diagnosis and appropriate antibiotic coverage had a favorable outcome in a renal transplant recipient. Recommended treatment duration is 6 to 12 months.\n\ndisseminated nocardiosisrenal transplantThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nNocardiosis is an uncommon opportunistic Gram-positive bacterial infection caused by aerobic actinomycetes in the genus Nocardia. It can cause localized or systemic suppurative diseases in humans, involving eyes, kidneys, skin, pulmonary, brain as well as disseminated infection. Inhalation of the organism is the most common mode of entry; that is why the majority of infections involve lungs. Herein, we report a case of a renal transplant recipient who presented with disseminated nocardiosis with pulmonary and cutaneous involvement and was successfully treated with combined antibiotic therapy and surgical drainage.\n\nCase presentation\nWe report the case of a 55-year-old male with a past medical history of end-stage kidney disease secondary to medical renal disease of hypertension. After a dialysis vintage of six years, he received a deceased donor renal transplant in 2018. Post-transplant, his allograft function remained stable with a baseline serum creatinine level at 1.6-1.8 mg/dL. After induction with basiliximab, the patient was maintained on triple immunosuppressive therapy consisting of mycophenolic acid 720 mg twice daily per oral (PO), tacrolimus 2 mg twice daily PO, and prednisone 5 mg daily PO.\n\nSix months following the renal transplant, the patient presented to the hospital with a chief complaint of progressive bilateral lower extremities pain with swelling, which started 10 days before presentation. Associated symptoms included shortness of breath. Workup included an ultrasound of the right lower leg, which showed a heterogeneous mass in the right posterior thigh; nevertheless, the patient received hydrocodone/acetaminophen and was instructed to follow up with his primary care physician in a week. However, one week later, the patient presented again due to the worsening of symptoms; physical exam revealed a palpable, fluctuant, and tender fullness involving the left gluteal and the right posterior thigh region with associated left knee swelling.\n\nLaboratory workup revealed the following: C-reactive protein 149 mg/L, creatinine 1.65 mg/dL (baseline creatinine 1.6-1.8 mg/dL), and white blood cell count 9,500/mm3. CT pelvis and bilateral lower extremities without contrast showed a 3.5-cm fluid collection in the right posterior thigh and the left buttock (Figure 1). Chest CT showed multi-focal irregular airspace opacities with new scattered sub-centimeter pulmonary nodules (Figure 2). The two-dimensional echo was negative for valve vegetations. MRI brain was negative for masses or abscesses; blood cultures were negative and tissue culture grew Gram-positive bacilli identified as Nocardia farcinica. The patient underwent incision and drainage of the thigh and gluteal abscesses with the placement of Penrose drain and surgical site cultures obtained. Tacrolimus and myfortic acid were held for two weeks due to the presumed infectious process; prednisone 20 mg daily PO was initiated along with high-dose trimethoprim-sulfamethoxazole (TMP-SMX) in conjunction with linezolid. The patient’s condition subsequently improved and he was discharged on oral linezolid and TMP-SMX. He was treated with the combination for four weeks, and then continued with TMP-SMX alone for a total of 12 months at which point all lesions had resolved without allograft dysfunction.\n\nFigure 1 CT pelvis and bilateral lower extremities without contrast showed a 3.5-cm fluid collection (arrow) in the right posterior thigh\nFigure 2 CT thorax showing pulmonary nodule (arrow)\nDiscussion\nRenal transplant patients are at an increased risk of certain infections, particularly following the initiation of immunosuppressive drugs after the transplant [1]. Nocardia infection is commonly seen among patients with T-cell and macrophage function disorders, such as patients who are taking immunosuppressive agents [2]. The risk of nocardiosis is increased in the first year following renal transplantation, presumably due to using immunosuppression to prevent rejection [3]. Patients treated with steroid-sparing regimens, such as cyclosporine, have found significantly reduced rates of nocardial infections, to 0.7%, in renal transplant recipients [4]. The patient was diagnosed with nocardiosis six months following the renal transplant.\n\nNocardia species are not ordinarily seen in the respiratory tract, yet pulmonary involvement is the primary site of nocardial infection in more than two-thirds of cases [3,5]. Therefore, a sputum culture is mostly indicative of Nocardia infection. Rarely, respiratory nocardial isolate has been considered a non-pathogen (i.e., colonizer) [6]. Most pulmonary infections are primary, but Nocardia can spread to the lung from other sites, such as the skin [7]. On the other hand, cutaneous lesions are reported in kidney transplant recipients with a Nocardia infection [2]. Manifestations of primary cutaneous nocardiosis include ulcerations, pyoderma, cellulitis, nodules, and subcutaneous abscesses [8,9]. The reported patient had disseminated nocardiosis involving lungs and skin, though lungs were thought to be the primary source of infection. Also, imaging findings in pulmonary nocardiosis are different, including lung nodules, lung masses (with or without cavitation), reticulonodular infiltrates, interstitial infiltrates, lobar consolidation, subpleural plaques, and pleural effusions [10]. Our patient’s CT thorax showed irregular airspace opacities in the left upper lobe.\n\nTMP-SMX is considered first-line therapy for nocardiosis. However, some Nocardia species are resistant to TMP-SMX, including N. farcinica, while Nocardia asteroides and Nocardia nova remain sensitive primarily to TMP-SMX, with susceptibility rates of >95% and 89%, respectively [11,12]. Moreover, there is no consensus for the role of TMP-SMX as prophylaxis for Nocardia. Although one study proposed that TMP-SMX prophylaxis is effective in heart transplant recipients, nocardiosis has been documented in one-third of the renal transplant recipients who received TMP-SMX as Pneumocystis carinii prophylaxis [13]. Deaths related to Nocardia infection in transplant recipients have been rare. In one study, the nocardial infection has been neither found to be associated with mortality nor overall survival. Also, in the same study, early diagnosis suggests a favorable therapeutic outcome [14].\n\nConclusions\nOverall, disseminated nocardiosis with systemic involvement carries a grave prognosis. However, early diagnosis of the case, with proper antibiotic coverage, leads to a favorable outcome, even in a post-renal transplant patient.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 Central nervous system infections in the compromised host: a diagnostic approach Infect Dis Clin North Am Cunha BA 567 590 15 2001 11447710 \n2 Nocardial infections in renal transplant recipients Medicine Wilson JP Turner HR Kirchner KA Chapman SW 38 57 68 1989 2642586 \n3 A case series and focused review of nocardiosis: clinical and microbiologic aspects Medicine Lederman ER Crum NF 300 313 83 2004 15342974 \n4 Nocardiosis in renal transplant recipients undergoing immunosuppression with cyclosporine Clin Infect Dis Arduino RC Johnson PC Miranda AG 505 512 16 1993 8513056 \n5 Nocardiosis: 7‐year experience at an Australian tertiary hospital Intern Med J Paige EK Spelman D 373 379 49 2019 30091232 \n6 Clinical spectrum and outcome of Nocardia infection: experience of 15-year period from a single tertiary medical center Am J Med Sci Hardak E Yigla M Berger G Sprecher H Oren I 286 290 343 2012 21825961 \n7 Primary cutaneous Nocardia asteroides infection with dissemination Am J Med Kahn FW Gornick CC Tofte RW 859 863 70 1981 7011025 \n8 Primary cutaneous nocardiosis JAMA Satterwhite TK Wallace RJ Jr Jr 333 336 242 1979 376887 \n9 Disseminated subcutaneous Nocardia farcinica abscesses in a nephrotic syndrome patient J Am Acad Dermatol Shimizu T Furumoto H Asagami C Kanaya K Mikami Y Muto M 874 876 38 1998 9591807 \n10 Pulmonary nocardiosis with multiple cavitary nodules in a HIV-negative immunocompromised patient Intern Med Hwang JH Koh WJ Suh GY 852 854 43 2004 15497524 \n11 Evaluation of therapy for Nocardia asteroides complex infections Infect Dis Clin Pract McNeil MM Brown JM Hutwagner LC Schiff TA 287 4 1995 https://journals.lww.com/infectdis/Citation/1995/07000/Evaluation_of_Therapy_for_Nocardia_asteroides.11.aspx \n12 Sulfonamide resistance in isolates of Nocardia spp. from a US multicenter survey J Clin Microbiol Brown-Elliott BA Biehle J Conville PS 670 672 50 2012 22170936 \n13 Pneumocystis carinii infection in heart transplant recipients. Efficacy of a weekend prophylaxis schedule Medicine Muñoz P Muñoz RM Palomo J Rodríguez-Creixéms M Muñoz R Bouza E 415 422 76 1997 9413427 \n14 Nocardial infections in the immunocompromised host: a detailed study in a defined population Rev Infect Dis Simpson GL Stinson EB Egger MJ Remington JS 492 507 3 1981 7025149\n\n",
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"pages": "e12497",
"pmc": null,
"pmid": "33564506",
"pubdate": "2021-01-05",
"publication_types": "D002363:Case Reports",
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"title": "Disseminated Nocardiosis in a Renal Transplant Recipient.",
"title_normalized": "disseminated nocardiosis in a renal transplant recipient"
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"abstract": "A 65-year-old woman was diagnosed with low-grade non-Hodgkin lymphoma (Figure 1). She was treated with six cycles of cyclophosphamide, hydroxydaunorubicin, oncovin (vincristine), and prednisolone (CHOP) and three cycles of fludarabine and mitoxantrone. Ten months later she received radiotherapy to the left groin (total dose of 50 Gy in 25 fractions over 5 weeks) without complications.",
"affiliations": "Departments of Dermatology, Sir Paul Boffa Hospital, Floriana, Malta; jclark@maltanet.net.;Departments of Dermatology, Sir Paul Boffa Hospital, Floriana, Malta.;Oncology, Sir Paul Boffa Hospital, Floriana, Malta.;Oncology, Sir Paul Boffa Hospital, Floriana, Malta.",
"authors": "Clark|Eileen|E|;Boffa|Michael|M|;Magri|Claude|C|;Muscat|Victor|V|",
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"abstract": "We investigated the association between early recanalization degree after intravenous thrombolysis (IVT), occurrence of hemorrhagic transformation, and functional outcome. We also evaluated whether recombinant tissue plasminogen activator (rTPA) dosing error could influence the outcome. Patients with ischemic stroke with major vessel occlusion (n=256) who underwent IVT were included. Recanalization status (no recanalization, partial recanalization, and complete recanalization) was confirmed by subsequent magnetic resonance or conventional angiography. Association between early recanalization degree and favorable outcome (modified Rankin Scale score ≤2) was evaluated using logistic regression analysis. Early partial recanalization was achieved in 33 (12.9%), and complete recanalization in 7 (2.7%) patients. Patients with the highest quintile of rTPA dosage achieved complete recanalization more frequently than the lower four quintiles (8.0% vs 2.0%, P=0.03). Hemorrhagic transformation tended to occur more frequently in patients with complete recanalization as compared with patients with partial recanalization (57.1% vs 21.2%, P=0.15). The proportion of favorable outcome was significantly lower in patients with the highest quintile of rTPA dosage used as compared with the patients with lower four quintiles (40.8%, 57.0%, P=0.04). In multivariable analysis, partial recanalization was significantly associated with favorable outcome (adjusted odds ratio, 3.15; 95% CI, 1.06-9.35), but complete recanalization was not. Early partial recanalization after IVT may be an indicator of favorable outcome with low occurrence of any hemorrhagic transformation.",
"affiliations": "Department of Neurology, Gyeongsang National University Changwon Hospital, Changwon, Republic of Korea.;Department of Neurosurgery, Gyeongsang National University Changwon Hospital, Changwon, Republic of Korea.;Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Republic of Korea.;Department of Neurology, Gyeongsang National University Changwon Hospital, Changwon, Republic of Korea.;Department of Neurology, Seoul National University Bun-Dang Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.;Department of Neurosurgery, Seoul National University Bun-Dang Hospital, Seongnam, Republic of Korea.;Department of Neurology, Seoul National University Bun-Dang Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea. Electronic address: mkhan@snu.ac.kr.",
"authors": "Chang|Jun Young|JY|;Park|Hyun|H|;Jang|Se Young|SY|;Jung|Seunguk|S|;Bae|Hee-Joon|HJ|;Kwon|O-Ki|OK|;Han|Moon-Ku|MK|",
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"journal": "Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia",
"keywords": "Clinical outcome; Intravenous thrombolysis; Ischemic stroke; Revascularization",
"medline_ta": "J Clin Neurosci",
"mesh_terms": "D000368:Aged; D002545:Brain Ischemia; D005260:Female; D005343:Fibrinolytic Agents; D006801:Humans; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D020521:Stroke; D015912:Thrombolytic Therapy; D013997:Time Factors; D010959:Tissue Plasminogen Activator; D016896:Treatment Outcome",
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"pubdate": "2017-12",
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"title": "Early partial recanalization after intravenous thrombolysis leads to prediction of favorable outcome in cases of acute ischemic stroke with major vessel occlusion.",
"title_normalized": "early partial recanalization after intravenous thrombolysis leads to prediction of favorable outcome in cases of acute ischemic stroke with major vessel occlusion"
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"abstract": "BACKGROUND\nThe application of mycophenolate mofetil (MMF) in treating patients with immunoglobulin A nephropathy (IgAN) remains uncertain. This update meta-analysis was performed to re-evaluate the therapeutic potential of MMF in IgAN.\n\n\nMETHODS\nArticles were obtained by searching the electronic databases without language restriction. Randomized controlled trials studying the role of MMF in treating IgAN were collected. The quality of included studies was critically evaluated. Data analyses were performed by using RevMan 5.3 software.\n\n\nRESULTS\nA total of 297 articles were screened and eight articles were finally included. Among the eight randomized controlled trials, five and three were high quality and low quality, respectively. Both fixed-effect and random-effect model were used. Pooled results by combining all the eight studies suggested that IgAN patients in MMF group had a higher remission rate than that in control group. Compared to placebo or corticosteroid monotherapy, MMF monotherapy exerted a higher remission rate and side effect rate in both main analysis and subgroup analysis by human race. Compared to corticosteroid plus other immunosuppressive agent therapy, corticosteroid plus MMF therapy had a higher remission rate, lower serum creatinine doubling rate, progression to end-stage renal disease rate and side effects rate. Subgroup analysis by therapeutic regimen further confirmed these results between corticosteroid plus MMF therapy and corticosteroid plus cyclophosphamide therapy. Funnel-plot displayed a symmetrical figure, indicating no publication bias existed.\n\n\nCONCLUSIONS\nMMF has the potential in treatment of IgAN, especially for Asians. The evidence currently available shows that MMF monotherapy has a more efficacy but higher side effects when compared to placebo or corticosteroid monotherapy in treatment of Asians with IgAN. While MMF combined with corticosteroid regimen has a more efficacy and lower side effects when compared with corticosteroid plus cyclophosphamide regimen.",
"affiliations": "Department of Cardiology, the Second Part of First Hospital, Jilin University, Changchun, 130031, China.;Department of Nephrology, Second Hospital, Jilin University, 218 Ziqiang Street, Changchun, Jilin, 130041, China.;Department of Nephrology, Second Hospital, Jilin University, 218 Ziqiang Street, Changchun, Jilin, 130041, China.;Department of Nephrology, Second Hospital, Jilin University, 218 Ziqiang Street, Changchun, Jilin, 130041, China.;Department of Nephrology, Second Hospital, Jilin University, 218 Ziqiang Street, Changchun, Jilin, 130041, China.;Department of Nephrology, Second Hospital, Jilin University, 218 Ziqiang Street, Changchun, Jilin, 130041, China. wenpengcui@163.com.",
"authors": "Du|Bing|B|;Jia|Ye|Y|;Zhou|Wenhua|W|;Min|Xu|X|;Miao|Lining|L|;Cui|Wenpeng|W|",
"chemical_list": "D000904:Antibiotics, Antitubercular; D009173:Mycophenolic Acid",
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"doi": "10.1186/s12882-017-0647-x",
"fulltext": "\n==== Front\nBMC NephrolBMC NephrolBMC Nephrology1471-2369BioMed Central London 64710.1186/s12882-017-0647-xResearch ArticleEfficacy and safety of mycophenolate mofetil in patients with IgA nephropathy: an update meta-analysis Du Bing dbdavina@126.com 1Jia Ye jiay382@hotmail.com 2Zhou Wenhua 153762368@qq.com 2Min Xu 1262159195@qq.com 2Miao Lining miaolining55@163.com 2Cui Wenpeng wenpengcui@163.com 21 0000 0004 1760 5735grid.64924.3dDepartment of Cardiology, the Second Part of First Hospital, Jilin University, Changchun, 130031 China 2 0000 0004 1760 5735grid.64924.3dDepartment of Nephrology, Second Hospital, Jilin University, 218 Ziqiang Street, Changchun, Jilin, 130041 China 19 7 2017 19 7 2017 2017 18 2451 6 2016 28 6 2017 © 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\nThe application of mycophenolate mofetil (MMF) in treating patients with immunoglobulin A nephropathy (IgAN) remains uncertain. This update meta-analysis was performed to re-evaluate the therapeutic potential of MMF in IgAN.\n\nMethods\nArticles were obtained by searching the electronic databases without language restriction. Randomized controlled trials studying the role of MMF in treating IgAN were collected. The quality of included studies was critically evaluated. Data analyses were performed by using RevMan 5.3 software.\n\nResults\nA total of 297 articles were screened and eight articles were finally included. Among the eight randomized controlled trials, five and three were high quality and low quality, respectively. Both fixed-effect and random-effect model were used. Pooled results by combining all the eight studies suggested that IgAN patients in MMF group had a higher remission rate than that in control group. Compared to placebo or corticosteroid monotherapy, MMF monotherapy exerted a higher remission rate and side effect rate in both main analysis and subgroup analysis by human race. Compared to corticosteroid plus other immunosuppressive agent therapy, corticosteroid plus MMF therapy had a higher remission rate, lower serum creatinine doubling rate, progression to end-stage renal disease rate and side effects rate. Subgroup analysis by therapeutic regimen further confirmed these results between corticosteroid plus MMF therapy and corticosteroid plus cyclophosphamide therapy. Funnel-plot displayed a symmetrical figure, indicating no publication bias existed.\n\nConclusions\nMMF has the potential in treatment of IgAN, especially for Asians. The evidence currently available shows that MMF monotherapy has a more efficacy but higher side effects when compared to placebo or corticosteroid monotherapy in treatment of Asians with IgAN. While MMF combined with corticosteroid regimen has a more efficacy and lower side effects when compared with corticosteroid plus cyclophosphamide regimen.\n\nKeywords\nImmunoglobulin a nephropathyMeta-analysisMycophenolate mofetilChinese Society of Nephrology14050440581Cui Wenpeng Jilin Province Science and Technology Development Program funded project20150520034JHCui Wenpeng Jilin Province Science and Technology Development Program funded project 20160414014GHCui Wenpeng Norman Bethune Program of Jilin University2015214Cui Wenpeng issue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nImmunoglobulin A nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide and is the leading cause of end-stage renal disease (ESRD) [1, 2]. According to Kidney Disease Improving Global outcomes (KDIGO) guideline, renin-angiotensin system inhibitor for IgAN patients with persistent proteinuria ≥0.5 g/d, and renin-angiotensin system inhibitor plus corticosteroid for IgAN patients with persistent proteinuria ≥1 g/d are recommended [3]. However, up to 30% of the treated patients fail to respond to these therapies [4, 5]. Therefore the lack of satisfactory therapeutic approach for IgAN still confuses physicians and researchers working in nephrology. The predominant character of IgAN is abnormal IgA1 deposition in mesangial area. Moreover, molecular and cellular interaction studies [6], as well as genome-wide association studies [7] revealed the autoimmune nature of this disease. These knowledges provide nephrologists a theoretical basis for the treatment of IgAN with immunosuppressive therapy.\n\nMycophenolate mofetil (MMF), a highly effective immunosuppressive agent, acts by releasing mycophenolic acid which leads to apoptosis of cytotoxic T-lymphocytes and reduction of antibody synthesis via selectively inhibits T- and B-lymphocyte proliferation [8, 9]. In addition, growing clinical evidences have demonstrated that oral MMF is beneficial for IgAN secondary to systemic diseases, such as lupus nephritis [10] and Henoch-Schonlein purpura nephritis [11]. However, the application of MMF in treatment patients with primary IgAN is still uncertain. So far, few randomized controlled trails (RCTs) have studied the therapeutic effects of MMF on IgAN. The first RCT investigating the role of MMF in patients with IgAN was carried out by Chen et al. in 2002 [12]. This study demonstrated that compared to prednisone, MMF was more effective in reducing proteinuria in patients with severe IgAN [12]. Another RCT from China also claimed that corticosteroid-free MMF monotherapy was effective in decreasing proteinuria and ameliorating some of the abnormalities in IgAN [13]. Moreover, a six-year follow-up of the same cohort also suggested a kidney survival benefit in patients treated with MMF monotherapy [14]. In contrast to studies from Asians [12–14], in a prospective placebo-controlled randomized study carried out in Belgium, patients were treated with restriction of salt intake, angiotensin converting enzyme inhibitors and either MMF or placebo [15]. After 36 months of follow-up, however, no beneficial effects of MMF treatment could be demonstrated on renal function or proteinuria [15]. One year later, similar result was reported in another double-blind, randomized, placebo-controlled trial from USA [16]. Because of the inconsistency between these RCTs mentioned above, MMF was not recommended in treating IgAN by KDIGO guideline in 2012 [3].\n\nSo far, more RCTs have provided the evidence for the effectiveness of MMF therapy in IgAN [17–19]. Therefore re-evaluating the usage of MMF in treating patients with IgAN seems to be necessary. In a recent meta-analysis, both efficacy and safety of MMF regimen in treating IgAN were estimated [20]. However, there were some limitations in this study. First, one trial included in this meta-analysis contained obviously incorrect data [21]. Second, subgroup analysis by human race was not taken.\n\nConsidering these limitations may lead to unreliable conclusion, we carried out this update meta-analysis to comprehensively re-evaluate the efficacy and safety of MMF therapy in treating IgAN. In current meta-analysis, we added one new published RCT [19], and removed one study with obviously incorrect data [21].\n\nMethods\nSearch strategy\nOur study protocol and analysis were planned in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [22]. Eligible studies were obtained by systematically searching the electronic databases of EMBASE, MEDLINE, the Cochrane Library, and China National Knowledge Infrastructure without language restriction. In addition, the following key words and subject terms were used in the search strategy: Berger’s disease, immunoglobulin A nephropathy, IgA nephropathy, IgAN, IgA nephritis, IgA glomerulonephritis, mycophenolate mofetil, MMF, mycophenolic acid, and their derivative words. All studies, published up to December 2015, focusing on the efficacy and safety of MMF in IgAN were considered to be included in our meta-analysis. Moreover, we also took out a manual search of abstracts from selected conferences. No ethical approval and patient consent are required, because the current study is based on previous published studies.\n\nInclusion and exclusion criteria\nTwo authors (Du B and Min X) conducted the literature search and selection independently. Discrepancies were resolved by consultation and discussion with the third authors (Cui W). The title and abstract of potential studies were screened for appropriateness before full article intensive reading. Inclusion criteria: (a) all cases were renal biopsy-proven IgAN, (b) the study design was RCT, and (c) the efficacy in treating IgAN was compared between MMF monotherapy and placebo or between MMF monotherapy and corticosteroid monotherapy or between MMF and other immunosuppressive agents on the basis of corticosteroid. Exclusion criteria: (a) the quality of study was too low, (b) the study was just a trial protocol, and (c) the study did not clearly report the primary outcome (remission rate).\n\nData extraction\nFor each included study, the following information was extracted separately by two authors (Du B and Min X): first author, year of publication, study design, human race of the participants, simple size, treatment proposal, time of follow-up, primary outcome (remission rate), secondary outcomes (urinary protein reduction, serum creatinine doubling rate and progression to ESRD rate) and adverse events.\n\nStudy quality assessment\nJadad score was used to assess the methodologic quality of the included trials by two authors (Jia Y and Zhou W). Studies gained 1–2 points were regarded as low quality, while the ones gained 3–5 points were regards as high quality [23].\n\nStatistical methods\nThe primary outcome was remission rate and secondary outcomes included reduction of proteinuria, serum creatinine doubling rate and progression to ESRD rate. For dichotomous data, such as remission rate, serum creatinine doubling rate, progression to ESRD rate and side effect rate, pooled odds ratio (OR) with the corresponding 95% confidence interval (CI) was used. For continuous data, such as urinary protein reduction, weighted mean difference (WMD) was used. ORs or WMD of different RCTs were combined by using the random-effects model if true between-study heterogeneity existed or else using the fixed-effects model instead.\n\nBoth I2 and Q statistics were considered for testing heterogeneity between studies [24]. The I2 takes values between 0 and 100%, with higher values denoting greater degree of heterogeneity (I2 = 0–25%, 25%–50%, 50%–75% and 75%–100% represents no, moderate, large and extreme heterogeneity, respectively). What’s more, we also performed subgroup analysis to explore underlying sources of heterogeneity. Visual analysis of the funnel plot was made to assess the publication bias. The statistical software packages for managing and analyzing all aspects of a Cochrane Collaboration systematic review, Review Manager 5.3, was used in current study.\n\nResults\nCharacteristics of trials\nThere were 297 articles relevant to the search term and eight articles [12, 13, 15–19, 25] involving 347 patients with IgAN (MMF group: 178 patients, control group: 169 patients) were included in this meta-analysis finally. Of the eight studies, there were five and three studies using corticosteroid-free, MMF monotherapy [12, 13, 15, 16, 19] and corticosteroid plus MMF therapy [17, 18, 25], respectively. Moreover, there were five, two and one RCTs investigating Asians [12, 13, 17, 18, 25], Caucasians [15, 16] and mixed races [19], respectively. The flow chart for the selection of RCTs to be included in our analysis was shown in Fig. 1. The characteristics of these trials were showed in Table 1.Fig. 1 Flow diagram of study selection. The number of citations retrieved by individual searches, the final number of RCTs included in the meta-analysis, and reasons for exclusions are provided. RCT, randomized controlled trial\n\n\nTable 1 Basic characteristics of included studies\n\nStudies\tRacial decent (country)\tStudy design\tTherapeutic regimen\tSample size\tTime of follow-up (months)\tRandom method\tWithdraw & lost to follow-up\tBlinding\tJadad Score\t\nHogg 2015 [19]\tMixed (Canada)\tRCT\tMMF (25–36 mg/kg, max 2.0 g/day)\t22\t6\t1\t1\t1\t3\t\nPlacebo\t22\t\nLiu 2014 [18]\tAsians (China)\tRCT\tMMF (1.5 g/day) + prednisone\t42\t12\t2\t1\t0\t3\t\nCTX + prednisone\t42\t\nLiu 2010 [17]\tAsians (China)\tRCT\tMMF (1.5 g/day) + prednisone\t20\t6\t1\t1\t0\t2\t\nLEF + prednisone\t20\t\nBao 2007\tAsians (China)\tRCT\tMMF (2.0 g/day) + prednisone\t18\t12\t1\t1\t0\t2\t\nCTX + prednisone\t16\t\nFrich 2005\tCaucasians (America)\tRCT\tMMF (2.0 g/day)\t17\t24\t2\t1\t2\t5\t\nPlacebo\t15\t\nTang 2005 [13]\tAsians (China)\tRCT\tMMF (2.0 g/day)\t20\t18\t1\t1\t1\t3\t\nPlacebo\t20\t\nBaes 2004\tCaucasians (Belgium)\tRCT\tMMF (2.0 g/day)\t21\t36\t1\t1\t1\t3\t\nPlacebo\t13\t\nChen 2002 [12]\tAsians (China)\tRCT\tMMF (1.5 g/day)\t18\t18\t1\t1\t0\t2\t\nprednisone\t21\t\n\n\n\nMethodologic quality assessment\nAll the trials included in this meta-analysis mentioned the term “random”, but the detail method was illuminated in two articles only [16, 18]. There were four trials mentioned the term “double blind” [13, 16, 19, 25], but only one article explained the detail method [16]. All the eight trials described the data of the patients who withdrew during the treatment period. According to the Jadad score, five and three articles were regarded as high quality literatures [13, 15, 16, 18, 19] and low quality literatures [12, 17, 25], respectively (Table 1).\n\nHeterogeneity test\nFor all including studies, fixed-effect model was chosen to combine the results because no significant heterogeneities between studies in analyses for remission rate (Fig. 2).Fig. 2 Forest plot of remission rate of IgAN patients treated with MMF or other therapy. IgAN, immunoglobulin A nephropathy; MMF, mycophenolate mofetil\n\n\n\n\nFor studies using MMF monotherapy, random-effect model was chosen to combine the results because there were significant heterogeneities between studies in analyses for urinary protein reduction rate. Fixed-effect model was chosen to combine the results because no significant heterogeneities between studies in analyses for remission rate, serum creatinine doubling rate, progression to ESRD rate and side effect rate were found (Fig. 3).Fig. 3 Forest plot of outcomes of IgAN patients treated with MMF monotherapy or corticosteroid monotherapy or placebo. Main analysis and subgroup analysis by human race of remission rate (a), urinary protein reduction (b), serum creatinine doubling rate (c), progression to ESRD rate (d) and side effect rate (e) are provided. ESRD, end-stage renal disease; IgAN, immunoglobulin A nephropathy; MMF, mycophenolate mofetil\n\n\n\n\nFor studies using corticosteroid plus MMF therapy, random-effect model was chosen to combine the results because there were significant heterogeneities between studies in analyses for urinary protein reduction rate. Fixed-effect model was chosen to combine the results because no significant heterogeneities between studies in analyses for remission rate, serum creatinine doubling rate and side effect rate were found (Fig. 4).Fig. 4 Forest plot of outcomes of IgAN patients treated with corticosteroid plus MMF therapy or corticosteroid plus other immunosuppressive agents. Main analysis and subgroup analysis by therapeutic regimen of remission rate (a), urinary protein reduction (b), serum creatinine doubling rate (c) and side effect rate (d) are provided. CTX, cyclophosphamide; IgAN, immunoglobulin A nephropathy; LEF, leflunomide; MMF, mycophenolate mofetil\n\n\n\n\nPooled results of all including studies\nRemission rate was recorded in all these eight trials. The main analysis revealed that the remission rate in MMF group was significant higher than that in control group (Z = 3.51, P = 0.0004) (Fig. 2).\n\nPooled results of studies using MMF monotherapy\nFive studies evaluated the role of MMF monotherapy in treatment of IgAN patients [12, 13, 15, 16, 19]. Remission rate was recorded in all these five trials. The remission rate in MMF group was significantly higher than that in control group (Z = 2.48, P = 0.01) (Fig. 3a). When subgroup analysis for human race was taken, similar result was found in Asians but not in Caucasians or mixed races (Fig. 3a).\n\nReduction of urinary protein was also recorded in all the five trials. Of these five studies, four studies used 24 h urinary protein [12, 13, 15, 16] and one used urinary albumin to creatinine ratio [19]. Therefore, only four trials [12, 13, 15, 16] were included for analysis. The main analysis confessed that there were no significant differences in urinary protein reduction between the two groups (Fig. 3b). However, subgroup analysis for human race suggested that MMF monotherapy had a better efficacy on proteinuria alleviation compared to control in Asians (Z = 3.61, P = 0.0003) (Fig. 3b). There were three trials [13, 15, 16] reported serum creatinine doubling rate and progression to ESRD rate. The main analysis showed that there were no significant differences in serum creatinine doubling rate or progression to ESRD rate between the two groups (Fig. 3c-d). Moreover, similar results were found in subgroup analysis for human race (Fig. 3c-d).\n\nOf these five studies, four studies [13, 15, 16, 19] reported adverse events, including infection, gastrointestinal symptoms, elevated liver enzymes, blood system changes, hair loss and irregular menstruation. Detail information was shown in Table 2. The main analysis showed that there were marginal differences in side effect rate between MMF group and placebo group in treating patients with IgAN (Z = 2.19, P = 0.03) (Fig. 3e). Additionally, subgroup analysis for human race suggested that similar results were found in Asians (Z = 2.08, P = 0.04) but not in Caucasians or mixed races (Fig. 3e).Table 2 Adverse events reported in the included studies\n\nStudies\tTherapeutic regimen\tSample size\tInfection\tGastrointestinal symptoms\tElevated liver enzymes\tBlood system changes\tHair loss\tIrregular menstruation\tTotal\t\nHogg 2015 [19]\tMMF\t23\t0\t2\t0\t0\t0\t0\t2\t\nPlacebo\t27\t0\t1\t0\t0\t0\t0\t1\t\nLiu 2014 [18]\tMMF + prednisone\t42\t2\t0\t0\t0\t0\t0\t2\t\nCTX + prednisone\t42\t2\t3\t1\t1\t1\t3\t11\t\nLiu 2010 [17]\tMMF + prednisone\t20\t0\t0\t1\t0\t0\t0\t1\t\nLEF + prednisone\t20\t0\t1\t1\t0\t0\t0\t2\t\nBao 2007\tMMF + prednisone\t19\t2\t2\t0\t1\t0\t0\t5\t\nCTX + prednisone\t18\t3\t4\t1\t2\t2\t2\t13\t\nFrich 2005\tMMF\t17\t0\t2\t0\t0\t0\t0\t2\t\nPlacebo\t15\t0\t2\t0\t1\t0\t0\t3\t\nTang 2005 [13]\tMMF\t20\t3\t2\t0\t2\t0\t0\t7\t\nPlacebo\t20\t0\t0\t0\t0\t0\t0\t0\t\nBaes 2004\tMMF\t21\t1\t2\t0\t1\t0\t0\t4\t\nPlacebo\t13\t0\t0\t0\t0\t0\t0\t0\t\n\n\n\nPooled results of studies using corticosteroid plus MMF therapy\nThree studies evaluated the role of corticosteroid plus MMF therapy in treatment of IgAN patients [17, 18, 25] and all of these studies were from Asian. Remission rate was recorded in all the three trials. The pooled results of meta-analysis confessed that there were significant differences in remission rate between corticosteroid plus MMF regimen and other immunosuppressive agents plus corticosteroid regimen in treating patients with IgAN (Z = 2.49, P = 0.01) (Fig. 4a). Additionally, subgroup analysis for regimen suggested that compared to cyclophosphamide (CTX), MMF had a higher remission rate (Z = 3.14, P = 0.002) (Fig. 4a).\n\nReduction of urinary protein was also recorded in all the three trials. The pooled results of meta-analysis confessed that there were no significant differences in urinary protein reduction between corticosteroid plus MMF regimen and other immunosuppressive agents plus corticosteroid regimen in treating patients with IgAN (Fig. 4b). However, subgroup analysis for regimen suggested that MMF had a higher efficacy in urinary protein alleviation compared to CTX (Z = 5.42, P < 0.00001) (Fig. 4b). Two trials reported serum creatinine doubling rate [18, 25]. The pooled results of meta-analysis showed that compared to CTX, MMF had a lower serum creatinine doubling rate in treating patients with IgAN (Z = 2.01, P = 0.04) (Fig. 4c).\n\nAll the three studies reported adverse reactions, including infection, gastrointestinal symptoms, elevated liver enzymes, blood system changes, hair loss and irregular menstruation, detail information was shown in Table 2. The pooled result of meta-analysis showed on the basis of corticosteroid, MMF had a lower side effect rate than other immunosuppressive agents (Z = 3.72, P = 0.0002) (Fig. 4d). What’s more, in subgroup analysis for regimen, corticosteroid plus MMF regimen had a lower side effect rate than corticosteroid plus CTX regimen (Z = 3.74, P = 0.0002) (Fig. 4d).\n\nPublication bias\nAnalysis of publication bias was conducted. No evidence of publication bias was found since the funnel plots was symmetrical based on a visual analysis (Fig. 5).Fig. 5 Funnel plot of included studies in this meta-analysis\n\n\n\n\nDiscussion\nIn a recent meta-analysis, the authors declared a relatively short course of MMF monotherapy might have favorable therapeutic effects such as remission rate and urinary protein reduction in IgAN [20]. In fact, it is indeed hard to explain why the outcomes from long course of MMF monotherapy are not better than that from short course of MMF monotherapy. In present study, we performed an update meta-analysis by adding one new RCT [19], and removing one RCT with unreliable data (in method part 19 and 14 participants were mentioned in MMF group and CTX group, respectively, but in result part 21 and 10 participants were mentioned in MMF group and CTX group, respectively) [21]. We made main analysis by including all the eight studies at first, and then we divided the studies into two categories, corticosteroid-free, MMF monotherapy [12, 13, 15, 16, 19] and corticosteroid plus MMF therapy [17, 18, 25].\n\nFor all the eight studies, our main analysis found higher remission rates in MMF group compared to control group. However, these results were not consistence with the previous meta-analysis [20]. Accumulating evidences have emerged and claimed that genetic factor contributes to the pathogeneses of IgAN [26, 27]. Furthermore, the genetic risk score is highest in Asians, intermediate in Caucasians, and lowest in Africans [28]. These genetic inconsistencies may explain why different human races have different responses to the same therapeutic regimen. Therefore, subgroup analysis by human race, which was not considered in previous meta-analysis [20], were performed in our study. Despite moderate to extreme heterogeneities were found in all comparisons, the heterogeneities were reduced or even disappeared in subgroup analysis, suggesting different human races may be one of the sources of heterogeneities in present meta-analysis.\n\nIn subgroup analysis by human race, two RCTs from Asians [12, 13] demonstrated obviously favorable outcomes, but two RCTs from Caucasians [15, 16] and one RCT from mixed races [19] failed to find significant differences between the two groups. Considering disease pathogenesis and the pharmacological effect of MMF, MMF is expected to play an important role in the treatment of IgAN. However, it was disappointed to see the negative results in Caucasians and mixed races from our present study. To be noticed, besides steroids and MMF, omega-3 fatty acid which was proven to be effective in treating IgAN [29] was also used in the RCT from mixed races [19]. Although all participants were administrated with omega-3 fatty acid during the entire trial, MMF treatment still could not significantly reduce proteinuria in patients with IgAN. The following reasons may explain the unexpected results. First, baseline proteinuria was severer in MMF monotherapy group than placebo group in one Caucasian RCT [15]. As both a major outcome and a positive predictor, the non-comparative baseline urinary protein might lead to a negative result. Second, a study design of 2:1 randomization was used in above Caucasian RCT to maximize the sample size [15]. Thus, the statistical power of this RCT was limited and we should interpret the result with caution. Third, in the other Caucasian RCT, baseline serum creatinine ranged from 2.2 mg/dl to 2.6 mg/dl [16]. Since patient selection, in other words baseline renal function directly influences the therapeutic effects of MMF [30], the advanced renal damage before MMF treating may cause non-favorable outcome. Fourth, all included five RCTs were single-center clinical trials, so the small sample size was another factor affecting the statistic power. Last but not least, corticosteroid recognized as the elementary medicine in treating IgAN [31] was used in only one of the five trials [12]. Maybe corticosteroid is basic and necessary for MMF to exert a therapeutic effect.\n\nImmunosuppressive therapy like corticosteroid monotherapy and corticosteroid plus immunosuppressive agent therapy were well accepted in progressive IgAN treatment [32, 33]. However, which immunosuppressive agent is more effective is still unclear. Corticosteroid plus CTX therapy has been reported to obtain favorable outcome as a classic regimen in treating patients with IgAN [34, 35], while the adverse events caused by CTX can’t be ignored. Therefore, more safety immunosuppressive agents are needed. For corticosteroid plus MMF therapy studies, main analyses revealed better therapeutic effects in corticosteroid plus MMF group compared to corticosteroid plus other immunosuppressive agent group (CTX and LEF), including the remission rate and stable renal function. Our data were supported by previous studies [14, 36]. All the three RCTs were from Asians, so we made subgroup analysis by therapy regimen instead of human race. Despite high to extreme heterogeneities were found in some comparisons, the heterogeneities disappeared in subgroup analysis, suggesting different therapy regimens may be another source of heterogeneities in our meta-analysis.\n\nIn subgroup analysis by therapy regimen, compared to corticosteroid plus CTX but not LEF therapy, corticosteroid plus MMF therapy had a more superior effect on IgAN outcomes, such as remission rate, reduction of urinary protein and stable renal function. Compared to CTX, the better efficacy of MMF on the basis of corticosteroid was found not only in mild IgAN [25] but also in severe IgAN patients [18]. Our result was consistent with another retrospective study from China. In this study, the effects of MMF and CTX were compared in treating proliferative pathological IgAN. Data showed that combination of MMF and prednisone therapy lead to a beret renal survival compared to that of prednisone with CTX [37]. These results provided us evidence from evidence-based medicine. By removing one RCT with unreliable data [21], our new results were similar with the previous meta-analysis [20], suggesting the stability of this result. Both the efficacy and safety were comparative between corticosteroid plus MMF therapy and corticosteroid plus LEF therapy [17]. However, this conclusion was based on only one RCT, therefore, more RCTs evaluating corticosteroid plus LEF therapy are needed.\n\nBesides human race and therapy regimen, renal histopathology was also an important factor affecting the efficacy of immunosuppressive therapy. For all the eight included studies, five studies had renal histologic assessment [13, 16, 18, 19, 25]. Although the degree of histologic damage at baseline between MMF group and control group was comparable, no study discussed the impact of renal pathology on therapeutic effects. In an observed study conducted by a Chinese group, the efficacy of MMF plus prednisone in treating Children with steroid-resistant IgAN was investigated. All biopsy samples were scored according to the Oxford classification. It was suggested that MMF plus prednisone therapy was effective in steroid-resistant children. However, unsatisfactory outcome was found in children with tubular atrophy/interstitial fibrosis [38].\n\nOur main analysis of adverse events revealed that MMF monotherapy seemed to have a higher side effect rate because of the marginal difference between the two groups (P = 0.03). By restudying the included RCTs, we found only one RCT from Asians reported a significant higher side effect rate in MMF monotherapy group [13]. The main adverse events in MMF monotherapy group were gastrointestinal symptoms (8/81), infection (4/81) and blood system changes (3/81). Considering the marginal differences and small number of participants in this meta-analysis, to convince our result, more RCTs with big sample size are requested. In contrast to the above results, main analysis of adverse events showed that side effect rate in corticosteroid plus MMF group was much lower than that in corticosteroid plus other immunosuppressive agent group. And subgroup analysis by therapeutic regimen confirms the main analysis results. Except for infection, gastrointestinal symptoms and blood system changes, irregular menstruation (5/80), liver damage (3/80), blood system damages (3/80) and hair loss (3/80) in corticosteroid plus CTX regimen group were reported.\n\nOur present meta-analysis has some limitations. First, not all included studies were high quality RCTs. Second, it will takes 15–30 years to progress to ESRD from IgAN onset [39]. Thus, with the follow-up period ranged from six to thirty-six months in these RCTs, it is difficult to observe obvious changes in kidney survival situation. Third, the majority of studies were from Asian patients, studies from other human races are needed.\n\nConclusion\nIn summary, the evidences currently available show that IgAN patients in MMF group have a higher remission rate than that in control group, especially for Asians. In addition, MMF monotherapy offers benefits over placebo or corticosteroid monotherapy in treatment of patients with IgAN, but exerts more side effects. While MMF combined with corticosteroid regimen has a more efficacy and lower side effects compared with corticosteroid plus CTX regimen. Moreover, due to the methodological insufficiency more high quality RCTs with big sample size and from different human races are desired to obtain more rigorous and objective clinical evidence.\n\nAbbreviations\nCIConfidence interval\n\nCTXCyclophosphamide\n\nESRDEnd-stage renal disease\n\nIgANImmunoglobulin A nephropathy\n\nKDIGOKidney Disease Improving Global outcomes\n\nMMFMycophenolate mofetil\n\nORPooled odds ratio\n\nRCTsRandomized controlled trails\n\nWMDWeighted mean difference\n\nWe would like to express our gratitude to the doctors participating in this study.\n\nFunding\nThis work was supported by Chinese Society of Nephrology (No.14050440581), Jilin Province Science and Technology Development Program funded project (No.20150520034JH) and (No. 20160414014GH) and Norman Bethune Program of Jilin University (No.2015214).\n\nAvailability of data and materials\nOur datasets are available as additional supporting files.\n\nAuthors’ contributions\nWC conceived and designed the experiment. WC and BD wrote this manuscript. WC, BD and XM searched the articles. WC and XM analyzed the data. YJ, WZ and LM reviewed this manuscript. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nNot applicable.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Donadio JV Grande JP IgA nephropathy N Engl J Med 2002 347 10 738 748 10.1056/NEJMra020109 12213946 \n2. Moresco RN Speeckaert MM Delanghe JR Diagnosis and monitoring of IgA nephropathy: the role of biomarkers as an alternative to renal biopsy Autoimmun Rev 2015 14 10 847 853 10.1016/j.autrev.2015.05.009 26026694 \n3. Chapter 10: Immunoglobulin A nephropathy. Kidney international supplements 2012, 2(2):209–217.\n4. Li PK Leung CB Chow KM Cheng YL Fung SK Mak SK Tang AW Wong TY Yung CY Yung JC Hong Kong study using valsartan in IgA nephropathy (HKVIN): a double-blind, randomized, placebo-controlled study American journal of kidney diseases : the official journal of the National Kidney Foundation 2006 47 5 751 760 10.1053/j.ajkd.2006.01.017 16632013 \n5. Manno C Torres DD Rossini M Pesce F Schena FP Randomized controlled clinical trial of corticosteroids plus ACE-inhibitors with long-term follow-up in proteinuric IgA nephropathy Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 2009 24 12 3694 3701 10.1093/ndt/gfp356 \n6. Mestecky J Raska M Julian BA Gharavi AG Renfrow MB Moldoveanu Z Novak L Matousovic K Novak J IgA nephropathy: molecular mechanisms of the disease Annu Rev Pathol 2013 8 217 240 10.1146/annurev-pathol-011110-130216 23092188 \n7. Kiryluk K Li Y Scolari F Sanna-Cherchi S Choi M Verbitsky M Fasel D Lata S Prakash S Shapiro S Discovery of new risk loci for IgA nephropathy implicates genes involved in immunity against intestinal pathogens Nat Genet 2014 46 11 1187 1196 10.1038/ng.3118 25305756 \n8. Allison AC Eugui EM Mycophenolate mofetil and its mechanisms of action Immunopharmacology 2000 47 2–3 85 118 10.1016/S0162-3109(00)00188-0 10878285 \n9. Allison AC Eugui EM Purine metabolism and immunosuppressive effects of mycophenolate mofetil (MMF) Clin Transpl 1996 10 1 Pt 2 77 84 \n10. Rathi M, Goyal A, Jaryal A, Sharma A, Gupta PK, Ramachandran R, Kumar V, Kohli HS, Sakhuja V, Jha V, et al. Comparison of low-dose intravenous cyclophosphamide with oral mycophenolate mofetil in the treatment of lupus nephritis. Kidney Int. 2015;\n11. Ren P Han F Chen L Xu Y Wang Y Chen J The combination of mycophenolate mofetil with corticosteroids induces remission of Henoch-Schonlein purpura nephritis Am J Nephrol 2012 36 3 271 277 10.1159/000341914 22965140 \n12. Chen X Chen P Cai G Wu J Cui Y Zhang Y Liu S Tang L: [a randomized control trial of mycophenolate mofeil treatment in severe IgA nephropathy] Zhonghua Yi Xue Za Zhi 2002 82 12 796 801 12126522 \n13. Tang S Leung JC Chan LY Lui YH Tang CS Kan CH Ho YW Lai KN Mycophenolate mofetil alleviates persistent proteinuria in IgA nephropathy Kidney Int 2005 68 2 802 812 10.1111/j.1523-1755.2005.00460.x 16014059 \n14. Tang SC Tang AW Wong SS Leung JC Ho YW Lai KN Long-term study of mycophenolate mofetil treatment in IgA nephropathy Kidney Int 2010 77 6 543 549 10.1038/ki.2009.499 20032964 \n15. Maes BD Oyen R Claes K Evenepoel P Kuypers D Vanwalleghem J Van Damme B Vanrenterghem YF Mycophenolate mofetil in IgA nephropathy: results of a 3-year prospective placebo-controlled randomized study Kidney Int 2004 65 5 1842 1849 10.1111/j.1523-1755.2004.00588.x 15086925 \n16. Frisch G Lin J Rosenstock J Markowitz G D'Agati V Radhakrishnan J Preddie D Crew J Valeri A Appel G Mycophenolate mofetil (MMF) vs placebo in patients with moderately advanced IgA nephropathy: a double-blind randomized controlled trial Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 2005 20 10 2139 2145 10.1093/ndt/gfh974 \n17. Liu XW Li DM Xu GS Sun SR Comparison of the therapeutic effects of leflunomide and mycophenolate mofetil in the treatment of immunoglobulin a nephropathy manifesting with nephrotic syndrome Int J Clin Pharmacol Ther 2010 48 8 509 513 10.5414/CPP48509 20650041 \n18. Liu X Dewei D Sun S Xu G Liu H He L Zhang P Treatment of severe IgA nephropathy: mycophenolate mofetil/prednisone compared to cyclophosphamide/prednisone Int J Clin Pharmacol Ther 2014 52 2 95 102 10.5414/CP201887 24161158 \n19. Hogg RJ Bay RC Jennette JC Sibley R Kumar S Fervenza FC Appel G Cattran D Fischer D Hurley RM Randomized controlled trial of mycophenolate mofetil in children, adolescents, and adults with IgA nephropathy American journal of kidney diseases : the official journal of the National Kidney Foundation 2015 66 5 783 791 10.1053/j.ajkd.2015.06.013 26209543 \n20. Chen Y Li Y Yang S Li Y Liang M Efficacy and safety of mycophenolate mofetil treatment in IgA nephropathy: a systematic review BMC Nephrol 2014 15 193 10.1186/1471-2369-15-193 25475967 \n21. Macchini F De Carli A Testa S Arnoldi R Ghirardello S Ardissino G Mosca F Torricelli M Leva E Feasibility of peritoneal dialysis in extremely low birth weight infants Journal of neonatal surgery 2012 1 4 52 26023411 \n22. Moher D Liberati A Tetzlaff J Altman DG Group P Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement PLoS Med 2009 6 7 10.1371/journal.pmed.1000097 19621072 \n23. Jadad AR Moore RA Carroll D Jenkinson C Reynolds DJ Gavaghan DJ McQuay HJ Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996 17 1 1 12 10.1016/0197-2456(95)00134-4 8721797 \n24. Higgins JP Thompson SG Quantifying heterogeneity in a meta-analysis Stat Med 2002 21 11 1539 1558 10.1002/sim.1186 12111919 \n25. Harshman LA Muff-Luett M Neuberger ML Dagle JM Shilyansky J Nester CM Brophy PD Jetton JG Peritoneal dialysis in an extremely low-birth-weight infant with acute kidney injury Clin Kidney J 2014 7 6 582 585 10.1093/ckj/sfu095 25859376 \n26. Liu R Hu B Li Q Jing X Zhong C Chang Y Liao Q Lam MF Leung JC Lai KN Novel genes and variants associated with IgA nephropathy by co-segregating with the disease phenotypes in 10 IgAN families Gene 2015 571 1 43 51 10.1016/j.gene.2015.06.041 26095808 \n27. Magistroni R, D'Agati VD, Appel GB, Kiryluk K. New developments in the genetics, pathogenesis, and therapy of IgA nephropathy. Kidney Int. 2015;\n28. Kiryluk K Novak J Gharavi AG Pathogenesis of immunoglobulin a nephropathy: recent insight from genetic studies Annu Rev Med 2013 64 339 356 10.1146/annurev-med-041811-142014 23072577 \n29. Donadio JV Jr Bergstralh EJ Offord KP Spencer DC Holley KE A controlled trial of fish oil in IgA nephropathy. Mayo nephrology collaborative group N Engl J Med 1994 331 18 1194 1199 10.1056/NEJM199411033311804 7935657 \n30. Fang J Li W Li D Tan Z Baseline proteinuria, urinary osmotic pressure, and renal function as positive predictors of corticosteroids plus cyclophosphamide treatment efficacy in IgA nephropathy Chin Med J 2014 127 9 1710 1714 24791879 \n31. Lv J Xu D Perkovic V Ma X Johnson DW Woodward M Levin A Zhang H Wang H Group TS Corticosteroid therapy in IgA nephropathy Journal of the American Society of Nephrology : JASN 2012 23 6 1108 1116 10.1681/ASN.2011111112 22539830 \n32. Yeo SC Liew A Barratt J Emerging therapies in immunoglobulin a nephropathy Nephrology 2015 20 11 788 800 10.1111/nep.12527 26032537 \n33. Rasche FM, Keller F, Rasche WG, Schiekofer S, Kahn T, Fahnert J. Sequential therapy with cyclophosphamide and mycophenolic acid in patients with progressive IgA nephropathy - a long-term follow-up. Clin Exp Immunol. 2015;\n34. Ramachandran R Doddi P Nandakrishna B Nada R Kumar V Rathi M Kohli HS Jha V Sakhuja V Gupta KL Combination of pulse cyclophosphamide and steroids in crescentic IgA nephropathy Int Urol Nephrol 2015 47 11 1917 1918 10.1007/s11255-015-1076-z 26411427 \n35. Ballardie FW Roberts IS Controlled prospective trial of prednisolone and cytotoxics in progressive IgA nephropathy Journal of the American Society of Nephrology : JASN 2002 13 1 142 148 11752031 \n36. Roccatello D Rossi D Marletto F Naretto C Sciascia S Baldovino S Piras D Giachino O Long-term effects of methylprednisolone pulses and mycophenolate mofetil in IgA nephropathy patients at risk of progression Journal of nephrology 2012 25 2 198 203 10.5301/JN.2011.8452 21725921 \n37. Liang Y Zhang J Liu D Quan S Xing G Liu Z Retrospective study of mycophenolate mofetil treatment in IgA nephropathy with proliferative pathological phenotype Chin Med J 2014 127 1 102 108 24384432 \n38. Kang Z Li Z Duan C Wu T Xun M Ding Y Zhang Y Zhang L Yin Y Mycophenolate mofetil therapy for steroid-resistant IgA nephropathy with the nephrotic syndrome in children Pediatr Nephrol 2015 30 7 1121 1129 10.1007/s00467-014-3041-y 25773534 \n39. Pettersson E IgA nephropathy: 30 years on J Intern Med 1997 242 5 349 353 10.1046/j.1365-2796.1997.00194.x 9408061\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2369",
"issue": "18(1)",
"journal": "BMC nephrology",
"keywords": "Immunoglobulin a nephropathy; Meta-analysis; Mycophenolate mofetil",
"medline_ta": "BMC Nephrol",
"mesh_terms": "D000904:Antibiotics, Antitubercular; D044466:Asians; D005767:Gastrointestinal Diseases; D005922:Glomerulonephritis, IGA; D006801:Humans; D009173:Mycophenolic Acid; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome",
"nlm_unique_id": "100967793",
"other_id": null,
"pages": "245",
"pmc": null,
"pmid": "28724421",
"pubdate": "2017-07-19",
"publication_types": "D016428:Journal Article; D017418:Meta-Analysis",
"references": "8680053;23072577;12126522;10878285;26209543;12111919;26376134;20650041;16632013;26026694;25859376;24384432;22539830;26439797;22965140;20032964;11752031;25475967;19628647;16030050;26411427;21725921;25773534;7935657;25018935;24791879;8721797;26032537;25305756;26095808;24161158;9408061;26489028;23092188;15086925;16014059;12213946;26023411;19621072",
"title": "Efficacy and safety of mycophenolate mofetil in patients with IgA nephropathy: an update meta-analysis.",
"title_normalized": "efficacy and safety of mycophenolate mofetil in patients with iga nephropathy an update meta analysis"
} | [
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"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2018-05503",
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"activesubstancename": "OMEGA-3-ACID ETHYL ESTERS"
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"abstract": "OBJECTIVE\nThe aim of the study was to assess pregnancy complications in HIV-positive women and changes in the rates of such complications over 11 years in the Frankfurt HIV Cohort.\n\n\nMETHODS\nThere were 330 pregnancies in HIV-positive women between 1 January 2002 and 31 December 2012. The rate of pregnancy-related complications, such as gestational diabetes mellitus (GDM), pre-eclampsia and preterm delivery, the mode of delivery and obstetric history were analysed. Maternal and neonatal morbidity/mortality as well as HIV mother-to-child transmission (MTCT) were evaluated.\n\n\nRESULTS\nIn our cohort, GDM was diagnosed in 38 of 330 women (11.4%). Five women (1.5%) developed pre-eclamspia or hypertension. In 16 women (4.8%), premature rupture of membranes (PROM) occurred and 46 women (13.7%) were admitted with preterm contractions. The preterm delivery rate was 36.5% (n = 122), and 26.9% of deliveries (n = 90) were between 34+0 and 36+6 weeks of gestation. Over the observation period, the percentage of women with undetectable HIV viral load (VL) increased significantly (P < 0.001), from 26.1% to 75%, leading to obstetric changes, including an increase in the rate of vaginal deliveries (P < 0.001), from no vaginal births to 50%. The preterm delivery rate decreased significantly (P < 0.001), from 79.2% to 8.3%. There were no significant changes in the rate of GDM, pre-eclampsia, PROM or preterm contractions.\n\n\nCONCLUSIONS\nIn the 11 years of our analysis, there was a significant reduction in the rate of preterm deliveries and an increase in the vaginal delivery rate, possibly reflecting changes in treatment policies in the same period and the availability of more effective antiretroviral therapy options. The rates of complications such as GDM, pre-eclampsia, preterm contractions, PROM and postnatal complications were stable over the 11 years, but were still increased compared with the general population.",
"affiliations": "Department of Obstetrics and Gynaecology, University Hospital Frankfurt, Goethe University, Frankfurt, Germany.",
"authors": "Reitter|A|A|;Stücker|A U|AU|;Linde|R|R|;Königs|C|C|;Knecht|G|G|;Herrmann|E|E|;Schlößer|R|R|;Louwen|F|F|;Haberl|A|A|",
"chemical_list": "D019380:Anti-HIV Agents",
"country": "England",
"delete": false,
"doi": "10.1111/hiv.12142",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1464-2662",
"issue": "15(9)",
"journal": "HIV medicine",
"keywords": "HIV; gestational diabetes mellitus (GDM); high-risk pregnancy; highly active antiretroviral therapy (HAART); mother-to-child transmission (MTCT); preterm delivery",
"medline_ta": "HIV Med",
"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D002585:Cesarean Section; D015331:Cohort Studies; D060085:Coinfection; D036861:Delivery, Obstetric; D017558:Elective Surgical Procedures; D005260:Female; D005858:Germany; D015658:HIV Infections; D006801:Humans; D007231:Infant, Newborn; D018445:Infectious Disease Transmission, Vertical; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D047928:Premature Birth; D012017:Referral and Consultation; D019966:Substance-Related Disorders; D019562:Viral Load",
"nlm_unique_id": "100897392",
"other_id": null,
"pages": "525-36",
"pmc": null,
"pmid": "24602285",
"pubdate": "2014-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Pregnancy complications in HIV-positive women: 11-year data from the Frankfurt HIV Cohort.",
"title_normalized": "pregnancy complications in hiv positive women 11 year data from the frankfurt hiv cohort"
} | [
{
"companynumb": "DE-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2017-BI-006503",
"fulfillexpeditecriteria": "1",
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"activesubstancename": "NEVIRAPINE"
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"... |
{
"abstract": "Infections due to Enterococcus hirae have rarely been reported in humans but are not uncommon in mammals and birds. We describe a case of E. hirae bacteremia and pneumonia in a bird breeder and its potential relationship with regorafenib, a tirosin kinase inhibitor (TKI).\n\n\n\nDescriptive study and review of the literature through a PubMed search of the cases described previously to date.\n\n\n\nOnly seventeen cases have been described, mainly endocarditis, pyelonephritis, and intraabdominal infections. No cases of pneumonia have been reported so far. The recent increase in TKI use opens a new field to explore in infectious diseases due to both the exposure to these immunosuppressive drugs and the increased survival of subjects with severe underlying comorbidities.\n\n\n\nIn patients in contact with birds, immunosuppressed by their underlying morbidities and treated with regorafenib, clinicians should be aware of an increased risk of unusual potentially severe infections.",
"affiliations": "Infectious Diseases Dept, University Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain. Electronic address: javier.merlo.g@hotmail.com.;Infectious Diseases Dept, University Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain.;Infectious Diseases Dept, University Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain.",
"authors": "Merlo|Javier|J|;Bustamante|Gloria|G|;Llibre|Josep M|JM|",
"chemical_list": "D010671:Phenylurea Compounds; D011725:Pyridines; C559147:regorafenib",
"country": "Spain",
"delete": false,
"doi": "10.1016/j.eimc.2019.06.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2529-993X",
"issue": "38(5)",
"journal": "Enfermedades infecciosas y microbiologia clinica (English ed.)",
"keywords": "Enterococcus hirae; Inhibidor de la tirosina quinasa; Regorafenib; Tyrosin kinase inhibitors",
"medline_ta": "Enferm Infecc Microbiol Clin (Engl Ed)",
"mesh_terms": "D000818:Animals; D016470:Bacteremia; D000070076:Enterococcus hirae; D006801:Humans; D010671:Phenylurea Compounds; D018410:Pneumonia, Bacterial; D011725:Pyridines",
"nlm_unique_id": "101777541",
"other_id": null,
"pages": "226-229",
"pmc": null,
"pmid": "31492453",
"pubdate": "2020-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bacteremic pneumonia caused by Enterococcus hirae in a subject receiving regorafenib.",
"title_normalized": "bacteremic pneumonia caused by enterococcus hirae in a subject receiving regorafenib"
} | [
{
"companynumb": "ES-BAYER-2019-173204",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "REGORAFENIB"
},
"drugadditional": null,
... |
{
"abstract": "We present a case of a 60-year-old Caucasian woman, with no prior history of swellings, who was admitted to a hospital due to life-threatening angio-oedema. She had, the previous day, been prescribed an ACE inhibitor for her essential hypertension. She had taken one tablet at night-time, and awoke in the morning with a swollen face progressing to involve the tongue and throat within a few hours. On arrival at her doctor's office, her voice had altered. Corticosteroids and antihistamine were administered while awaiting an ambulance. Arriving at the emergency department, she had dyspnoea due to increasingly severe angio-oedema of the upper airways. Neither adrenaline inhalations, intravenously administrated corticosteroids, atropine nor furosemide were effective and the patient soon become bradycardic. A tracheotomy was performed and the patient was placed on a ventilator. She eventually made a full recovery. It was concluded that she had suffered from life-threatening angio-oedema due to her new medication.",
"affiliations": "Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, Rigshospitalet, University Hospital of Copenhagen, Denmark.;Dermatology and Allergy Center, University Hospital of Odense, Odense, Denmark.;Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, Rigshospitalet, University Hospital of Copenhagen, Denmark.",
"authors": "Krogh Nielsen|Troels|T|;Bygum|Anette|A|;Rye Rasmussen|Eva|E|",
"chemical_list": "D000806:Angiotensin-Converting Enzyme Inhibitors; D001920:Bradykinin",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2016()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000402:Airway Obstruction; D000799:Angioedema; D000806:Angiotensin-Converting Enzyme Inhibitors; D001920:Bradykinin; D005260:Female; D006801:Humans; D008875:Middle Aged; D014140:Tracheotomy",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "27229746",
"pubdate": "2016-05-26",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18680700;25629740;23178416;20625347;25583256;25059449;25182544;9734886;23838604;16451161;24285044;24673465;21250556;17085287;16907654;17446944;18025295",
"title": "Life-threatening angio-oedema after the first dose of an ACE inhibitor-not an anaphylactic reaction.",
"title_normalized": "life threatening angio oedema after the first dose of an ace inhibitor not an anaphylactic reaction"
} | [
{
"companynumb": "DK-VALIDUS PHARMACEUTICALS LLC-DK-2016VAL002269",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ATROPINE"
},
"drugaddit... |
{
"abstract": "BACKGROUND\nReal-world evidence on later line treatment of relapsed/refractory multiple myeloma (RRMM) is sparse. We evaluated clinical outcomes among RRMM patients in the 1-year following treatment with pomalidomide or daratumumab and compared economic outcomes between RRMM patients and non-MM patients.\n\n\nMETHODS\nAdult patients with ≥1 claim of pomalidomide or daratumumab were identified between January 2012 and February 2018 using IQVIA PharMetrics® Plus US claims database. Patients were required to have a diagnosis or treatment for MM and a claim of any immunomodulatory drugs and proteasome inhibitors before the index date. Mean time to new therapy, overall survival (OS) using Kaplan-Meier curve and adverse events (AEs) were reported over the 1-year post-index period. RRMM patients were also matched to a non-MM comparator cohort and economic outcomes were compared between the two cohorts.\n\n\nRESULTS\n289 RRMM patients were matched to 1,445 patients without MM. Most prevalent hematological AE was anemia (72.0%) and non-hematological AE was infections (75.4%). Mean (SD) time to a new treatment was 4.7 (5.3) months and median OS was 14.6 months. RRMM patients had significantly higher hospitalizations and physician office visits (Both P < .0001) compared to non-MM patients. Adjusting for baseline characteristics, patients with RRMM had 4.9 times (95% CI 3.8-6.4, P < .0001) the total healthcare costs compared with patients without MM. The major driver of total costs among RRMM patients was pharmacy costs (67.3%).\n\n\nCONCLUSIONS\nRRMM patients showed a high frequency of AEs, low OS, and a substantial economic burden suggesting need for effective treatment options.",
"affiliations": "Tisch Cancer institute at Mount Sinai Medical Center, New York, NY, USA.;IQVIA, Falls Church, VA, USA.;IQVIA, Falls Church, VA, USA.;Oncopeptides Inc, Waltham, MA, USA.;Oncopeptides AB, Stockholm, Sweden.;IQVIA, Falls Church, VA, USA.",
"authors": "Richter|Joshua|J|https://orcid.org/0000-0002-0274-0585;Anupindi|Vamshi Ruthwik|VR|;Yeaw|Jason|J|;Kudaravalli|Suneel|S|;Zavisic|Stojan|S|;Shah|Drishti|D|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/1078155221995532",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": null,
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Myeloma; chemotherapy; daratumumab; pomalidomide; real-world",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": null,
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "1078155221995532",
"pmc": null,
"pmid": "33611973",
"pubdate": "2021-02-20",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Real-world treatment patterns in relapsed/refractory multiple myeloma: Clinical and economic outcomes in patients treated with pomalidomide or daratumumab.",
"title_normalized": "real world treatment patterns in relapsed refractory multiple myeloma clinical and economic outcomes in patients treated with pomalidomide or daratumumab"
} | [
{
"companynumb": "US-JNJFOC-20200807829",
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"activesubstancename": "BORTEZOMIB"
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{
"abstract": "Providing effective pain management to acutely intoxicated trauma patients represents a challenge of balancing appropriate pain management with the risk of potential respiratory depression from opioid administration. The objective of this study was to quantify the incidence of respiratory depression in trauma patients acutely intoxicated with ethanol who received opioids as compared with those who did not and identify potential risk factors for respiratory depression in this population. Retrospective medical record review was conducted for subjects identified via the trauma registry who were admitted as a trauma activation and had a detectable serum ethanol level upon admission. Risk factors and characteristics compared included demographics, Injury Severity Score, Glasgow Coma Score, serum ethanol level upon arrival, urine drug screen results, incidence of respiratory depression, and opioid and other sedative medication use. A total of 233 patients were included (78.5% male). Patients who received opioids were more likely to have a higher Injury Severity Score and initial pain score on admission as compared with those who did not receive opioids. Blood ethanol content was higher in patients who did not receive opioids (0.205 vs 0.237 mg/dL, P = .015). Patients who did not receive opioids were more likely to be intubated within 4 hours of admission (1.7% vs 12.1%, P = .02). Opioid administration was not associated with increased risk of respiratory depression (19.7% vs 22.4%, P = .606). Increased cumulative fentanyl dose was associated with increased risk of respiratory depression. Increased cumulative fentanyl dose, but not opioid administration alone, was found to be a risk factor for respiratory depression.",
"affiliations": "Department of Pharmacy, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR, 97239. Electronic address: elenikin@gmail.coma.;Department of Pharmacy, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR, 97239. Electronic address: bartonc@ohsu.edu.;Department of Pharmacy, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR, 97239. Electronic address: mahn@ohsu.edu.;Department of Emergency Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR, 97239. Electronic address: ran@ohsu.edu.;Department of Emergency Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR, 97239. Electronic address: hendriro@ohsu.edu.;Department of Trauma, Critical Care and Acute Care Surgery, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR, 97239. Electronic address: wattersj@ohsu.edu.",
"authors": "Shenk|Eleni|E|;Barton|Cassie A|CA|;Mah|Nathan D|ND|;Ran|Ran|R|;Hendrickson|Robert G|RG|;Watters|Jennifer|J|",
"chemical_list": "D000701:Analgesics, Opioid; D006993:Hypnotics and Sedatives; D000431:Ethanol",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-6757",
"issue": "34(2)",
"journal": "The American journal of emergency medicine",
"keywords": null,
"medline_ta": "Am J Emerg Med",
"mesh_terms": "D000328:Adult; D000701:Analgesics, Opioid; D000431:Ethanol; D005260:Female; D015600:Glasgow Coma Scale; D006801:Humans; D006993:Hypnotics and Sedatives; D015994:Incidence; D015601:Injury Severity Score; D008297:Male; D059408:Pain Management; D012131:Respiratory Insufficiency; D012189:Retrospective Studies; D012307:Risk Factors; D014193:Trauma Centers; D014947:Wounds and Injuries",
"nlm_unique_id": "8309942",
"other_id": null,
"pages": "250-3",
"pmc": null,
"pmid": "26614581",
"pubdate": "2016-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Respiratory depression in the intoxicated trauma patient: are opioids to blame?",
"title_normalized": "respiratory depression in the intoxicated trauma patient are opioids to blame"
} | [
{
"companynumb": "US-JNJFOC-20151214751",
"fulfillexpeditecriteria": "2",
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"patient": {
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"activesubstance": {
"activesubstancename": "FENTANYL"
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"d... |
{
"abstract": "OBJECTIVE\nTo explore antipsychotic (AP) medications and physical restraint use and their effects on physical function and cognition in older nursing home residents.\n\n\nMETHODS\nThis retrospective cohort studied involved 532 residents with dementia from 57 nursing homes participating in the Services and Health for Elderly in Long-Term Care study. Poisson log regression models explored the effect of physical restraint and/or AP medication use on cognitive or functional decline at 6 months.\n\n\nRESULTS\nPhysical restraint use was associated with a higher risk of both functional and cognitive decline compared with AP medication use alone. These risks were highest among residents receiving both AP medications and physical restraints, suggesting additive effects.\n\n\nCONCLUSIONS\nPhysical restraint use, and even more strongly, concurrent physical restraint and AP medication use, is related to function and cognitive decline in nursing home residents with dementia. Antipsychotic use is cautioned, but these results suggest physical restraint use is potentially more risky.",
"affiliations": "Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Centro Medicina dell'Invecchiamento, Università Cattolica del Sacro Cuore, Rome, Italy. Electronic address: andrea.foebel@ki.se.;Centro Medicina dell'Invecchiamento, Università Cattolica del Sacro Cuore, Rome, Italy.;Aging and Services Unit, National Institute for Health and Welfare, Helsinki, Finland.;AGAPLESION Bethesda Clinic, Geriatric Center, Ulm University, Ulm, Germany.;AGAPLESION Bethesda Clinic, Geriatric Center, Ulm University, Ulm, Germany.;Centro Medicina dell'Invecchiamento, Università Cattolica del Sacro Cuore, Rome, Italy.;Centro Medicina dell'Invecchiamento, Università Cattolica del Sacro Cuore, Rome, Italy.;Centro Medicina dell'Invecchiamento, Università Cattolica del Sacro Cuore, Rome, Italy.;Centro Medicina dell'Invecchiamento, Università Cattolica del Sacro Cuore, Rome, Italy.;Centro Medicina dell'Invecchiamento, Università Cattolica del Sacro Cuore, Rome, Italy.",
"authors": "Foebel|Andrea D|AD|;Onder|Graziano|G|;Finne-Soveri|Harriet|H|;Lukas|Albert|A|;Denkinger|Michael D|MD|;Carfi|Angelo|A|;Vetrano|Davide L|DL|;Brandi|Vincenzo|V|;Bernabei|Roberto|R|;Liperoti|Rosa|R|",
"chemical_list": "D014150:Antipsychotic Agents",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1525-8610",
"issue": "17(2)",
"journal": "Journal of the American Medical Directors Association",
"keywords": "Physical restraint; activities of daily living; antipsychotics; cognition; dementia; nursing homes",
"medline_ta": "J Am Med Dir Assoc",
"mesh_terms": "D000203:Activities of Daily Living; D000368:Aged; D000369:Aged, 80 and over; D014150:Antipsychotic Agents; D003704:Dementia; D005260:Female; D006801:Humans; D008297:Male; D009735:Nursing Homes; D012149:Restraint, Physical; D012189:Retrospective Studies",
"nlm_unique_id": "100893243",
"other_id": null,
"pages": "184.e9-14",
"pmc": null,
"pmid": "26778491",
"pubdate": "2016-02",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Physical Restraint and Antipsychotic Medication Use Among Nursing Home Residents With Dementia.",
"title_normalized": "physical restraint and antipsychotic medication use among nursing home residents with dementia"
} | [
{
"companynumb": "SE-JNJFOC-20160315443",
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"occurcountry": "SE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"drugadditional": null,
... |
{
"abstract": "Acquired haemophilia (AH) is a rare bleeding disorder characterized by the presence of acquired inhibitors against Factor VIII causing disruption of coagulation cascade. It has no known genetic inheritance, and diagnosis remains a challenge. The peculiar presentations are later age of onset as acute pain in weight-bearing joints and spontaneous muscle haematoma with isolated prolonged activated partial thrombin time (APTT). Prevalence is 1 per million per year affecting both genders equally where blood product transfusion is seen in almost 87% of cases. The direct cause of AH is still unknown, and autoimmune dysregulation has been postulated, which predisposes to the development of the factor inhibitors. Being extremely rare, we are reporting two consecutive patients diagnosed by unusual bleeding episodes with isolated prolonged APTT due to Factor VIII inhibitors. AH deserves a special mention as high index of suspicion is required. More studies are required to provide better guidance in diagnosis and management of this condition.",
"affiliations": "Department of Medicine , Hospital Serdang , Kajang, Selangor Darul Ehsan , Malaysia.;Department of Medicine, Faculty of Medicine and Health Sciences , Universiti Putra Malaysia , Serdang, Selangor Darul Ehsan , Malaysia.",
"authors": "Lee|Chiou Perng|CP|;Khalid|Bahariah Bt|BB|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/omcr/omv055",
"fulltext": "\n==== Front\nOxf Med Case ReportsOxf Med Case ReportsomcromcrOxford Medical Case Reports2053-8855Oxford University Press 2656883710.1093/omcr/omv055omv0551000600Case ReportsA case series of acquired haemophilia in a Malaysian hospital: unpredictably rare medical emergency Lee Chiou Perng 1*Khalid Bahariah Bt 21 Department of Medicine, Hospital Serdang, Kajang, Selangor Darul Ehsan, Malaysia2 Department of Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor Darul Ehsan, Malaysia* Correspondence address. Department of Medicine, Hospital Serdang, JalanPuchong, Kajang, Selangor Darul Ehsan 43400, Malaysia. Tel: +603-89475555; Fax: +603-89475050; E-mail: leeperng@gmail.com10 2015 06 10 2015 2015 10 330 332 9 7 2015 26 8 2015 5 9 2015 © The Author 2015. Published by Oxford University Press.2015This 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.comAcquired haemophilia (AH) is a rare bleeding disorder characterized by the presence of acquired inhibitors against Factor VIII causing disruption of coagulation cascade. It has no known genetic inheritance, and diagnosis remains a challenge. The peculiar presentations are later age of onset as acute pain in weight-bearing joints and spontaneous muscle haematoma with isolated prolonged activated partial thrombin time (APTT). Prevalence is 1 per million per year affecting both genders equally where blood product transfusion is seen in almost 87% of cases. The direct cause of AH is still unknown, and autoimmune dysregulation has been postulated, which predisposes to the development of the factor inhibitors. Being extremely rare, we are reporting two consecutive patients diagnosed by unusual bleeding episodes with isolated prolonged APTT due to Factor VIII inhibitors. AH deserves a special mention as high index of suspicion is required. More studies are required to provide better guidance in diagnosis and management of this condition.\n==== Body\nINTRODUCTION\nAcquired haemophilia (AH) is a rare disorder when compared with its congenital counterpart. There is neither any hereditary pattern nor gender preponderance. Incidence is 1.5 cases/million/year [1]. Mortality is 8–22% [2]. Majority of the cases affect the adult population unlike congenital haemophilia. Median age at presentation is 60–67 years [2]. AH is characterized by the presence of non-complement fixing autoantibodies against Factor VIII [3]. The severity of AH depends on the inhibitors' level measured in Bethesda Units (BU). In 50% of the cases, there is an association with other underlying medical conditions such as pregnancy (also post-partum state), solid tumours, autoimmune diseases (systemic lupus erythematosus, rheumatoid arthritis, Sjogren's syndrome), lymphoproliferative malignancies, skin disorders and drugs-induced or even graft-versus-host disease [2]. We are reporting two patients who spontaneously developed Factor VIII inhibitors with one of the abovementioned underlying medical conditions.\n\nCASE REPORTS\nThe first case was a 61-year-old male smoker with underlying diabetes mellitus, hypertension and hyperlipidaemia taking aspirin 75 mg daily, clopidogrel 75 mg daily, perindopril 4 mg daily, simvastatin 20 mg daily, metoprolol 25 mgBid, metformin 500 mgBid and nitroglycerine 1 tablet as required. He was electively admitted for angiogram, during which he developed spontaneous bruising and swelling over the left calf (Fig. 1) and the right buttock (Fig. 2). Initial blood investigations, haemoglobin (Hb) 13.5 g/dl, platelet 256 × 109/l, white blood cells (WBC) 8.0 × 109/l, international normalized ratio (INR) 0.82 and normal prothrombin time (PT) with prolonged activated partial thrombin time (APTT) at 72 s. He then developed per rectum bleeding with Hb dropped to 6.7 g/dl. Hence, antiplatelets were stopped, and packed red cells were transfused. However, repeated blood investigation shows worsening coagulation profile; INR becomes 1.12 and APTT 120 s. A mixing study was immediately performed, which did not show correction of the APTT. His fibrinogen level was normal. Factor VIII activity was reported at 1.2% (normal >25%), and Factor VIII inhibitors were reported to be 60 BU using Bethesda method. Therefore, intravenous (IV) methylprednisolone 500 mg OD was started, and multiple transfusions were given before his transfer to another haematology centre for commencement of immuno-suppressive therapy.\nFigure 1: Haematoma over the left calf region.\n\n\nFigure 2: Ecchymoses over the right buttock.\n\n\n\nThe second case was a 40-year-old post-partum lady with underlying pustular psoriasis who was on methotrexate for 4 years. She also has hypertension and gestational diabetes mellitus not on any treatment. She was admitted for relapsed pustular psoriasis after stopping her methotrexate during her pregnancy and intrauterine growth retardation at 38 weeks of gestation. She then underwent an emergency caesarean section following foetal distress. The procedure was uneventful, and estimated blood loss was only 200 ml. Her blood investigations 2 months before delivery showed Hb 12.8 g/dl, platelet 305 × 109/l, PT 12.1 s, INR 0.89 and APTT 36.1 s. However, during the post-partum period, the Hb dropped to 9.6 g/dl, platelet 496 × 109/l, PT 12.5 s, INR 0.93 and APTT 88.9 s. The coagulation profile was not corrected in the mixing study and the presence of Inhibitor Factor VIII 2BU. Her serum fibrinogen and von Willebrand factors were normal. She was started on prednisolone and cyclophosphamide; however, the inhibitors remain at 2 BU. She was then given rituximab. Three months later, her APTT increased to 110 s suggesting a relapse. Hence, she was reinduced with IV cyclophosphamide and T. prednisolone 40 mg OD, and at the same time, she developed retroperitoneal haematoma as seen on computed tomography scan with a drastic drop in Hb to 6.4 g/dl (baseline was 12.6 g/dl); therefore, blood products were given, and she was transferred to another tertiary facility for commencement of Recombinant Factor VIIa (rFVIIa). (Normal laboratory values: Hb 11.5–16 g/dl, WBC 4–11 × 109/l, platelet 150–450 × 109/l, PT 10–13 s, APTT 28–38 s and INR 0.9–1.2.)\n\nDISCUSSION\nThese cases presented with typical clinical scenario of isolated prolonged APTT and major bleeding. Prevalence rate in Malaysia is unknown; however, there are two reports found in the literature describing the same disease from 1995 till 2013 [5, 6]. The exact aetiology is unknown but believed to be related to the development of autoantibodies against Factor VIII and hampering the coagulation cascade. Frequently, the isolated prolonged APTT could present long before any major bleeding. It is worth mentioning that inhibitor could develop during post-partum period either during labour or after parturition [2]. Transplacental transfer of inhibitor has been reported, which could lead to neonatal bleeding [7]. Fortunately, there was no neonatal bleeding noted in our case. The investigations include mixing study, which is done by mixing incubated patient's plasma with normal plasma; inhibitor is said to be present if APTT fails to normalize; and the level of inhibitor is then determined by the Bethasda method, which is measured in BU [8]. BU can also be used in monitoring disease activity. Treatment of AH is divided into two major parts [2, 4]. Firstly, securing haemostasis. rFVIIa is recommended as the first-line treatment regardless of inhibitor titre or residual Factor VIII activity. rFVIIa acts as Factor VIII bypassing agent to activate the coagulation cascade hence securing haemostasis, suggested dose is 90 µg/kg every 2–3 h until haemostasis is secured [4]. Other recommended agents are DDAVP (desmopressin), Factor VIII concentrates and activated prothrombin complex concentrates [2]. None of them is said to be superior to another.\n\nSecondly, inhibitor elimination. The recommended first line is corticosteroid with or without cyclophosphamide [4]. The recommended dosage is prednisolone 1 mg/kg/day orally for 4–6 weeks [2, 4]. Elimination of inhibitors can be achieved in ∼30% of patients [2]. The addition of cyclophosphamide 50–100 mg per day (or 1.5–2 mg/kg/day for up to 6 weeks) [4] could increase the inhibitor elimination rate to 60–70% [2]. Suggested second-line agent is Rituximab, which was used in our second case. Rituximab was used when failure of corticosteroid + cyclophosphamide to achieve a stable disease. Other suggested agents are azathioprine, vincristine, mycophenolate and cyclosporine [4]. The response rate of IV immunoglobulin is quoted differently. Alice et al. quotes 30% response rate over 2 or 5 days of usage [2]. Another author quotes only 10–12% in patients with low inhibitor titre (<5 BU); thus, its usage is not recommended [4]. In conclusion, coagulation profile derangement may occur before bleeding event; hence, isolated prolonged APTT should not be ignored especially for patient with bleeding tendency in post-partum period. Randomized controlled trials are needed to conclude a better standard of care.\n\nCONFLICT OF INTEREST STATEMENT\nNone declared.\n==== Refs\nREFERENCES\n1 Collins PW Hirsch S Baglin TP Dolan G Hanley J Makris \nAcquired hemophilia A in the United Kingdom: a 2-year national surveillance study by the United Kingdom Haemophilia Centre Doctors’ organisation . Blood \n2007 ;109 :1870 –1877 .17047148 \n2 Ma AD Carrizosa D \nAcquired factor VIII inhibitors: pathophysiology and treatment . Hematology Am Soc Hematol Educ Program \n2006 ;1 :432 –437 .17124095 \n3 Cohen AJ Kessler CM \nAcquired inhibitors . Bailliere Clin Haem \n1996 ;2 :331 –354 .\n4 Huth-Kühne A Baudo F Collins P Ingerslev J Kessler CM Lévesque H \nInternational recommendations on the diagnosis and treatment of patients with acquired hemophilia A . Haematologica \n2009 ;94 :566 –575 .19336751 \n5 Teh A Leong KW Bosco JJ Koong PL Jayaranee S \nAcquired haemophilia—a therapeutic challenge . Med J Malaysia \n1995 ;50 :166 –170 .7565188 \n6 Kyaw TZ Jayaranee S Bee PC Chin EFM \nAcquired factor VIII inhibitors: three cases . Turk J Haem \n2013 ;30 :76 –80 .\n7 Ries M Wölfel D Maier-Brandt B \nSevere intracranial hemorrhage in a newborn infant with transplacental transfer of an acquired factor VII:C inhibitor . J Pediatr \n1995 ;127 :649 –650 .7562294 \n8 Kasper CK Aledort L Aronson D Counts R Edson JR J van Eys \nProceedings: a more uniform measurement of factor VIII inhibitors . Thromb Diath Haemorrh \n1975 ;34 :612 .1198543\n\n",
"fulltext_license": "CC BY-NC",
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"issue": "2015(10)",
"journal": "Oxford medical case reports",
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"other_id": null,
"pages": "330-2",
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"pmid": "26568837",
"pubdate": "2015-10",
"publication_types": "D002363:Case Reports",
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"title": "A case series of acquired haemophilia in a Malaysian hospital: unpredictably rare medical emergency.",
"title_normalized": "a case series of acquired haemophilia in a malaysian hospital unpredictably rare medical emergency"
} | [
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"activesubstancename": "METHOTREXATE"
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"dr... |
{
"abstract": "Silicone/mineral oil-induced granulomas have been described as an inflammatory granulomatous response when silicone/mineral oil is injected for cosmetic purposes. These sclerosing granulomas can lead to hypercalcemia. Here we present a 33-year-old man with hypercalcemia, hypophosphatemia, progressively worsening fatigue, severe proximal muscle weakness, and depression. He had an athletic build with increased muscle bulk and several areas of indurated, nontender, firm, well-circumscribed lesions in the subcutaneous tissue of his anterior pectoralis, triceps, and biceps bilaterally because of injecting himself with silicone/mineral oil-based product into his muscles. Sclerosing granulomas were diagnosed on the MRI. He had extremely low or undetectable serum levels of 25-hydroxyvitamin D [25(OH)D], and persistently elevated serum levels of 1,25-dihydroxyvitamin D [1,25(OH)2D] and calcium. He developed hypophosphatemia associated with elevated levels of fibroblast growth factor 23 (FGF-23) and severe proximal muscle weakness. Treatment with systemic steroids, furosemide, calcitonin, ketoconazole, and denosumab resulted in a significant decrease in his serum calcium, but with minimal impact on his hypophosphatemia and fatigue.Correcting his severe vitamin D deficiency with small doses of vitamin D and raising his blood level of 25(OH)D from undetectable to 10 ng/mL without significantly affecting his serum calcium or phosphate was effective in reversing his severe proximal muscle weakness, permitting him to lift his head and to be free of his wheelchair. Although measurement of the 1,25(OH)2D level is not mandatory in all cases of hypercalcemia, it is indicated in a patient who has low serum PTH levels. Clinicians need to be aware that vitamin D deficiency can cause severe proximal muscle weakness such that the patient is unable to lift his head from his chest or ambulate. This may lead to a psychiatric disorder misdiagnosis. © 2019 The Authors. JBMR Plus is published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.",
"affiliations": "Section of Endocrinology, Diabetes & Nutrition, Department of Medicine, Vitamin D, Skin, and Bone Research Laboratory Boston University School of Medicine (BUSM) Boston MA USA.;Division of Endocrinology Diabetes and Hypertension, Brigham and Women's Hospital, Harvard Medical School Boston MA USA.;Section of Endocrinology, Diabetes & Nutrition, Department of Medicine, Vitamin D, Skin, and Bone Research Laboratory Boston University School of Medicine (BUSM) Boston MA USA.",
"authors": "Shirvani|Arash|A|https://orcid.org/0000-0003-2847-4737;Palermo|Nadine E|NE|;Holick|Michael F|MF|https://orcid.org/0000-0001-6023-9062",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/jbm4.10208",
"fulltext": "\n==== Front\nJBMR PlusJBMR Plus10.1002/(ISSN)2473-4039JBM4JBMR Plus2473-4039John Wiley and Sons Inc. Hoboken 10.1002/jbm4.10208JBM410208Clinical VignetteClinical VignetteMan of Steel Syndrome: Silicone and Mineral Oil Injections With Associated Hypercalcemia, Hypophosphatemia, and Proximal Muscle Weakness SILICONE AND MINERAL OIL INJECTIONS WITH ASSOCIATED COMPLICATIONSSHIRVANI ET AL.Shirvani Arash https://orcid.org/0000-0003-2847-4737\n1\nPalermo Nadine E \n2\nHolick Michael F https://orcid.org/0000-0001-6023-9062\n1\nmfholick@bu.edu \n1 \nSection of Endocrinology, Diabetes & Nutrition, Department of Medicine, Vitamin D, Skin, and Bone Research Laboratory\nBoston University School of Medicine (BUSM)\nBoston\nMA\nUSA\n\n2 \nDivision of Endocrinology\nDiabetes and Hypertension, Brigham and Women's Hospital, Harvard Medical School\nBoston\nMA\nUSA\n* Address correspondence to: Michael F Holick, 85 East Newton Street, M‐1013, Boston, MA 02118. E‐mail address: mfholick@bu.edu\n29 7 2019 10 2019 3 10 10.1002/jbm4.v3.10e1020815 1 2019 02 5 2019 25 5 2019 © 2019 The Authors. JBMR Plus is published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.ABSTRACT\nSilicone/mineral oil‐induced granulomas have been described as an inflammatory granulomatous response when silicone/mineral oil is injected for cosmetic purposes. These sclerosing granulomas can lead to hypercalcemia. Here we present a 33‐year‐old man with hypercalcemia, hypophosphatemia, progressively worsening fatigue, severe proximal muscle weakness, and depression. He had an athletic build with increased muscle bulk and several areas of indurated, nontender, firm, well‐circumscribed lesions in the subcutaneous tissue of his anterior pectoralis, triceps, and biceps bilaterally because of injecting himself with silicone/mineral oil‐based product into his muscles. Sclerosing granulomas were diagnosed on the MRI. He had extremely low or undetectable serum levels of 25‐hydroxyvitamin D [25(OH)D], and persistently elevated serum levels of 1,25‐dihydroxyvitamin D [1,25(OH)2D] and calcium. He developed hypophosphatemia associated with elevated levels of fibroblast growth factor 23 (FGF‐23) and severe proximal muscle weakness. Treatment with systemic steroids, furosemide, calcitonin, ketoconazole, and denosumab resulted in a significant decrease in his serum calcium, but with minimal impact on his hypophosphatemia and fatigue.Correcting his severe vitamin D deficiency with small doses of vitamin D and raising his blood level of 25(OH)D from undetectable to 10 ng/mL without significantly affecting his serum calcium or phosphate was effective in reversing his severe proximal muscle weakness, permitting him to lift his head and to be free of his wheelchair. Although measurement of the 1,25(OH)2D level is not mandatory in all cases of hypercalcemia, it is indicated in a patient who has low serum PTH levels. Clinicians need to be aware that vitamin D deficiency can cause severe proximal muscle weakness such that the patient is unable to lift his head from his chest or ambulate. This may lead to a psychiatric disorder misdiagnosis. © 2019 The Authors. JBMR Plus is published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.\n\nPTH/ VITAMIN D /FGF‐23SILICONE/GRANULOMAHYPERCALCEMIAHYPOPHOPHATEMIA1,25‐DIHYDROXYVITAMIN‐D source-schema-version-number2.0component-idjbm410208cover-dateOctober 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.7.0 mode:remove_FC converted:30.10.2019\n==== Body\nIntroduction\nSilicone/mineral oil injected for cosmetic purposes can stimulate an inflammatory granulomatous response. The sclerosing granulomas resulting from mineral oil or silicone injections have been associated with severe and recurrent hypercalcemia.1, 2, 3 The mechanism for the silicone/mineral oil granuloma‐induced hypercalcemia has been demonstrated to be based on increased serum 1,25‐dihydroxyvitamin D [1,25(OH)2D] because of macrophage synthesis of and release of 1,25(OH)2D.1, 4 We describe a case of severe recurrent hypercalcemia and hypophosphatemia associated with extrarenal production of 1,25(OH)2D from sclerosing granulomas after injections of silicone/mineral oil for cosmetic reasons.\n\nClinical Vignette\nA 33‐year‐old white male presented to our endocrine clinic with an 11‐month history of progressively worsening fatigue, nausea, and polyuria. He had been hospitalized approximately 10 times for severe hypercalcemia with hypophosphatemia.\n\nHis past medical history was significant for depression, bipolar disorder, seizure disorder with change for personality, and a benign thyroid nodule. In recent months, he expressed suicidal ideation and was undergoing active treatment for depression. He had no history of fractures, but had several small kidney stones. He was not currently taking any vitamins, supplements, or antacids. He had no current use or previous history of tobacco or alcohol abuse. He had no pets and reported no exposure to other animals.\n\nHe denied weight loss, fever, chills, cough, or recent travel. He lived at home with his wife and two children. Prior to hospitalizations for hypercalcemia, he was very active, an avid runner, and involved in competitive weightlifting. His chronic medications included venlafaxine, omeprazole, divalproex sodium, and dexamphetamine. He had been on prednisone for the last 6 months and was started on alendronate approximately 3 weeks prior to this clinic visit for his persistent hypercalcemia. He admitted to injecting himself with silicone/mineral oil‐based product that he purchased on the Internet (the product was advertised as a nonandrogen steroid that could improve muscle size) into his pectoralis majors, biceps, and triceps to enlarge these muscles volumetrically during bodybuilding. Family history was notable for nephrolithiasis in his mother. His mother did not have hypercalciuria. He had no known family history of calcium, bone, thyroid, or other endocrinopathies.\n\nOn physical examination, he was an ambulatory male with an athletic build in no apparent distress. He was mentally oriented ×3. He oriented as to who he is, where he is, and when it is. He had increased muscle bulk that was rock hard and several areas of firm, indurated, nontender areas in the subcutaneous tissue of his anterior pectoralis, triceps, and biceps bilaterally, as well as inflammatory acne over his anterior chest (Fig. 1\nA and B). He did not complain of bone pain, and on physical examination he had no periosteal tenderness of his sternum, anterior tibia radius, or ulna. Cardiopulmonary, abdominal, neurologic, and lymph node examinations were normal.\n\nFigure 1 Severe proximal muscle weakness in silicone/mineral oil‐induced granulomas. The male patient had impressive man‐of‐steel‐like firm muscle bulk and several indurated, nontender firm areas in the subcutaneous tissue of his anterior pectoralis major, triceps, and biceps as well as inflammatory acne over his anterior chest (red arrows) in the first visit (A) and after 4 years (B). Patient presented with severe fatigue that progressed to severe proximal muscle weakness, resulting in him being unable to lift his head or stand from a sitting position without assistance (C). His extreme fatigue and severe proximal muscle weakness markedly improved so that he was able to ambulate after receiving small doses of vitamin D3 (400 IUs daily) and raising his blood level of 25(OH)D from <4 ng/mL (lowest detection limit for the assay) to 10 ng/mL.\n\nHis laboratory testing revealed his serum calcium level was 15.2 mg/dL (normal range 8.4 to 10.2 mg/dL), his ionized calcium level was >7.8 mg/dL, and his phosphorus level was 2.3 mg/dL (normal range 2.7 to 4.5 mg/dL). Several months previously his serum calcium level had exceeded 18 mg/dL and his phosphorus level had been 0.9 mg/dL. His levels of hemoglobin, glucose, albumin, total protein, chloride, potassium, sodium, magnesium, bilirubin, liver function tests, and alkaline phosphatase, as well as blood cell and platelet counts were normal. The 24‐hour urine collection period was preceded by 3 days with the patient on a hypophosphoric diet. The urine calcium level was 17.3 mg/dL, the urine phosphorus was 31.1 mg/dL, and the urine creatinine was 675 mg/dL. The calculated tubular reabsorption of phosphate (TRP) was 0.97 (normal range 0.85 to 1.00) and the tubular threshold maximum for phosphorus per glomerular filtration rate (TMP/GFR) was 1.36 mmol/L (normal range 2.5 to 4.2 mg/dL). His PTH level was 11 pg/mL (normal range 15 to 90 pg/mL), and the PTHrP was 22 pg/mL (normal range 15 to 65 pg/mL), and the thyroid‐stimulating hormone level was 1.9 mIU/L (normal range 0.3 to 5.0 mIU/L). The creatinine level was 2.25 mg/dL, and the GFR was 34 mm3/min/1.73 m3. Additional biochemical evaluation was notable for 25(OH)D of 17 ng/mL (normal range 20 to 100 ng/mL) and 1,25(OH)2D of 101 pg/mL (normal range 15 to 80 pg/mL); his levels of serum protein electrophoresis (SPEP) and urine protein electrophoresis (UPEP) were normal.\n\nOver subsequent months he received denosumab, prednisone, ketoconazole, furosemide, calcitonin, and hydration, but continued to have a persistently elevated serum calcium level (corrected calcium 12.2 mg/dL), an ionized calcium level of 7 mg/dL, a normal phosphorus level (3.2 mg/dL), with a creatinine level of 2.3 mg/dL. The GFR was 32 mm3/min/1.73 m3, and urea nitrogen was 33 mg/dL. The serum levels of albumin, total protein, chloride, potassium, sodium, magnesium, bilirubin, alanine aminotransferase, aspartate aminotransferase, osteocalcin, and alkaline phosphatase, as well as the random urine N‐telopeptide level were normal. A follow‐up PTH level was 9 pg/mL (normal range 11 to 90 pg/mL); 25(OH)D was <4 ng/mL (detection limit for the assay); 1,25(OH)2D was 35 pg/mL. FGF‐23 levels were markedly elevated with values ranging from 665 to 3227 RU/mL (normal <180 RU/mL). The results of his lab tests are shown in Fig. 2. Four months later he presented with a new symptom of extreme fatigue. He was unable to lift his head from his chest, to ambulate, or to get from a sitting to standing position without the assistance of a cane (Fig. 1\nC). An initial evaluation by a psychiatric consult at an outside hospital concluded that this was caused by his depression and was intentional. Further psychiatric evaluation was recommended.\n\nFigure 2 Laboratory results. The elevated serum levels of 1,25‐dihydroxyvitamin D [1,25(OH)2D] with a low serum level of 25‐hydroxyvitamin D [25(OH)D] and suppressed PTH were consistent with ectopic production of 1,25(OH)2D. His extreme fatigue and proximal muscle weakness were associated with undetectable serum levels of 25(OH)D (red arrow). Treatment with 400 IUs of vitamin D3 daily raised his blood level of 25(OH)D from undetectable (<4 ng/mL) to 10 ng/mL. This resulted in a dramatic improvement in his proximal muscle function and fatigue (green arrow).\n\nChest radiography showed multiple peripheral ground glass opacities scattered throughout the visualized portions of the lungs (Fig. 3\nA and B). CT of his upper extremity and chest showed subcutaneous fatty stranding of the visualized portions of the upper extremities and anterior chest wall with multiple associated punctate calcifications. There is marked heterogeneity and numerous foci of fluid attenuation and fat throughout the majority of the musculature of the upper extremities and anterior chest wall, particularly involving the biceps, triceps, deltoids, and pectoralis majors (Fig. 3\nC and D).\n\nFigure 3 Radiologic findings in the patient. Chest radiography showed multiple peripheral ground glass opacities scattered throughout the visualized portions of the lungs. There were tiny scattered subcentimeter punctate hyperdensities seen within the lung bases that possibly represent calcified granulomas (panel A and B). MRI of the chest revealed enlargement and heterogeneity with scattered foci of hyperintensity through the sternal head of the pectoralis major and visualized deltoid and bicep brachii muscles bilaterally and marked dermal thickening and heterogeneity of the subcutaneous tissue of the anterior chest wall (C, D). MRI of his upper extremity showed subcutaneous fatty stranding of the visualized portions of the upper extremities with multiple associated punctate calcifications. There is marked heterogeneity and numerous foci of fluid attenuation and fat throughout the majority of the musculature of the upper extremities, particularly involving the biceps, triceps, and deltoids (E–G). MRI of his brain did not detect any mass, hemorrhage, cortical dysplasia or heterotopia, recent infarct, or enhancing parenchymal lesion. No abnormal meningeal enhancement noted. A 1.2‐cm area isointense to CSF related to the left transverse sinus may be a prominent arachnoid granulation. Very mild nonenhancing white matter hyper‐intensities had been reported (H, I).\n\nMRI of the chest revealed extensive inflammatory changes and enlargement and heterogeneity with scattered foci of hyperintensity through the sternal head of the pectoralis major, visualized deltoid, and biceps brachii muscles, as well as marked dermal thickening and heterogeneity of the subcutaneous tissue of the anterior chest wall (Fig. 3\nE–G).\n\nNoncontrast CT of the pelvis confirmed a stone within the left ureter with associated periureteral stranding, proximal hydroureter, and left‐sided nephrolithiasis, but no hydronephrosis or other abnormalities were seen. Brain MRI was without evidence of masses, hemorrhage, cortical dysplasia or heterotopia, recent infarct, abnormal meningeal enhancement, or enhancing parenchymal lesions. Very mild, nonenhancing, white matter hyperintensities had been reported (Fig. 3\nH and I). Bone mineral densitometry was performed of the hip and spine; the results were normal. The results of a gallium‐68 neuroendocrine PET/CT whole‐body scan indicated there was no definite evidence of suspected oncogenic osteomalacia.\n\nDiscussion\nThe combination of hypercalcemia with suppressed PTH is suspicious of malignancy. Primary hyperparathyroidism and malignant neoplasms are responsible for more than 90% of all cases of hypercalcemia.5, 6 Primary hyperparathyroidism was ruled out because of the suppressed PTH level in this patient; therefore, this was a PTH‐independent process. His phosphorus levels were very low and he had a normal PTHrP, ruling out a PTHrP‐mediated malignancy such as non‐Hodgkin lymphoma and solid squamous cell tumors, particularly of the lung and kidney. Also, his SPEP and UPEP were normal. SPEP has a sensitivity ofapproximately 80% for multiple myeloma, and sensitivity is increased to >95% with the addition of serum immunofixation and UPEP/urine immunofixation, which was found to be normal, ruling out multiple myeloma. The results of the whole‐body neuroendocrine PET/CT scan indicated there was no definite evidence of tumor‐induced osteomalacia.\n\nOther causes of hypercalcemia that were ruled out included milk–alkali syndrome caused by anexcessive use of absorbable alkali and calcium, vitamin D intoxication, vitamin A intoxication, sarcoidosis, tuberculosis, familial forms of primary hyperparathyroidism, Addison disease, some fungal infections, prolonged immobilization in patients with high skeletal turnover including Paget disease patients, the recovery phase of rhabdomyolysis‐associated acute renal failure, and certain medications including long‐term lithium use resulting in tertiary hyperparathyroidismand hydrochlorothiazide.\n\nThe presence of hypercalcemia with suppressed PTH and inappropriately elevated 1,25(OH)2D suggests a diagnosis of granulomatous disease. Evaluation for tuberculosis and sarcoidosis at outside institutions was unrevealing.There was no evidence for lymphoma that could also be associated with elevated levels of 1,25(OH)2D.\n\nHis severe vitamin D deficiency was in part caused by a previous recommendation to eliminate all vitamin D intake because of his granulomas and hypercalcemia.However, his deficiency was exacerbated by the increased circulating levels of 1,25(OH)2D and FGF‐23.\n\n1,25(OH)2D, when interacting with target tissues, immediately promotes its own destruction by increasing the expression and production of the 25‐hydroxyvitamin D‐24‐hydroxylase (cyp24A1). The elevated blood levels of 1,25(OH)2D increase the renal cyp24A1 activity, which not only causes side‐chain cleavage of 1,25(OH)2D between carbons 23 and 24 to form the water‐soluble biologically inactive calcitroic acid, but also does the same to 25(OH)D. In addition, FGF‐23 induces the expression of cyp24A1. As a result, there is a marked increase in the catabolism of 25(OH)D, thereby decreasing the blood levels of this metabolite. Therefore, these two mechanisms, coupled with the patient's vitamin D abstinence, accelerated this patient's severe vitamin D deficiency, resulting in extremely low or undetectable circulating levels of 25(OH)D.7, 8\n\n\nDespite the improvement of his hypercalcemia, our patient developed extreme fatigue. An outside psychiatric evaluation concluded that, with the improvement in his serum calcium, his inability to get from a sitting to standing position without assistance and his inability to extend his neck to lift his chin from his chest were based on a psychiatric disorder, not a metabolic disorder. In our patient, his extremely low serum 25(OH)D and intermittent low phosphorus levels were contributing factors for his fatigue. Hypophosphatemia is defined as a serum phosphate level <2.5 mg/dL (<0.80 mmol/L) and can be further characterized as mild (approximately 2.0 to 2.5 mg/dL or approximately 0.64 to 0.80 mmol/L), moderate (approximately 1.0 to 2.0 mg/dL or approximately 0.32 to 0.64 mmol/L), or severe (<1.0 mg/dL or <0.32 mmol/L). No specific symptoms suggest hypophosphatemia; rather, symptoms are often nonspecific and depend largely on the cause, duration, and severity. Mild hypophosphatemia is usually asymptomatic regardless of whether it is acute or chronic. Patients may complain of fatigue and weakness; however, whether this is related to the cause or an effect of hypophosphatemia is unclear. Patients with chronic and/or moderate or severe hypophosphatemia are more likely to be symptomatic. Symptoms of severe hypophosphatemia include irritability, confusion, coma, and respiratory difficulty. Prolonged hypophosphatemia with a normal serum calcium or low serum calcium, resulting in an inadequate calcium phosphate product, can also cause osteomalacia, resulting in extended pains in the bones and muscles.\n\nSevere vitamin D deficiency causes proximal muscle weakness. In addition, generalized muscle weakness is the most common symptom of hypophosphatemia; weakness and fatigue are frequent symptoms with acquired hypophosphatemia.9 The proximal muscle weakness in our patient with mild hypophosphatemia at the time he presented with severe proximal muscle weakness is likely related to his severe vitamin D deficiency. His alkaline phosphatase was normal. In chronic hypophosphatemia, osteomalacia develops and the alkaline phosphatase is usually in the high or high‐to‐normal range. We could not find any evidence of osteomalacia in our patient from his medical history or physical examination. This is likely because he had severe hypercalcemia and relatively short‐term and intermittent hypophosphatemia. A normal TMP/GFR in our patient indicates renal conservation of phosphate, and hence a nonrenal cause of his hypophosphatemia.\n\nThe sclerosing granulomas (paraffinomas) were diagnosed based on the presence of granulomas (reported in the MRI report), increased muscle bulk, and several nontender indurated areas where silicone/mineral oil was injected based on his physical examination. There are several case reports of 1,25(OH)2D‐mediated hypercalcemia from sclerosing granulomas caused by cosmetic injection of silicone and/or mineral oil.1, 10, 11, 12 Patients with chronic kidney disease (CKD) and chronic hyperphosphatemia often have elevated circulating levels of FGF‐23. Ahigh level of FGF‐23 is an important predictor of the progression of CKD and a strong predictor of death.13 Our patient had mild‐to‐moderate renal failure and intermittent normal and low serum phosphorus levels, which could not explain his elevated FGF‐23 levels. The calculated TRP was normal and the tubular threshold maximum for phosphorus per GFR was low. The low TMP/GFR may be the result of his low serum phosphorus level. A normal TRP and low TMP/GFR in our patient indicate renal conservation of phosphate, and hence a nonrenal cause of hypophosphatemia. The three primary mechanisms of hypophosphatemia include increased renal excretion, decreased intestinal absorption, and shifts from the extracellular to intracellular compartments. The genetic forms of hypophosphatemia are shown in Table 1.\n\nTable 1 Genetic Forms of Hypophosphatemia\n\nAutosomal dominant hypophosphatemic rickets\t\nX‐linked hypophosphatemia\t\nAutosomal recessive hypophosphatemia\t\nMcCune‐Albright syndrome\t\nHypophosphatemia with hyperparathyroidism\t\nHypophosphatemia with renal lithiasis or bone demineralization\t\nHereditary hypophosphatemic rickets with hypercalciuria\t\nJohn Wiley & Sons, Ltd.Phosphate is freely filtered at the glomerulus and then reabsorbed, but proximal tubular reabsorption is inhibited by both PTH and FGF‐23, resulting in hypophosphatemia. In vitro studies in cultured rat calvaria demonstrated that 1,25(OH)2D increased FGF‐23.14 In addition, it was reported that that FGF‐23 synthesis in rat calvaria was upregulated by 1,25(OH)2D.14 Therefore, the likely explanation for the markedly elevated blood levels of FGF‐23 in our patient is his elevated 1,25(OH)2D level, which in turn was stimulating the osteocytes and osteoblasts to produce this phosphate‐regulating hormone, resulting in hypophosphatemia (Figs. 2, 4).\n\nFigure 4 Proposed mechanism of severe fatigue, proximal muscle weakness, hypophosphatemia, and hypercalcemia. The sclerosing granulomas (paraffinomas) were caused by previous self‐administered silicone/mineral oil injections purchased on the Internet. It was advertised as a product that enhances muscle bulk without the use of androgen steroids. His persistently elevated serum 1,25‐dihydroxyvitamin D [1,25(OH)2D] levels was from the extrarenal production by the macrophage 25‐hydroxyvitamin D‐1α‐hydroxylase. The elevated 1,25(OH)2D enhances the 25‐hydroxyvitamin D‐24‐hydroxylase (cyp24A1), which increases the destruction of not only 1,25(OH)2D, but also 25‐hydroxyvitamin D resulting in severe vitamin D deficiency. The elevated 1,25(OH)2D caused hypercalciuria, hypercalcemia, nephrolithiasis, and renal insufficiency. The unregulated production of 1,25(OH)2D resulted in an increase in the production of FGF‐23 by osteocytes and osteoblasts causing an increase in cyp24A1 activity and hypophosphatemia. Although the hypophosphatemia was likely a cause for his severe fatigue and muscle weakness, the loss of his proximal muscle function in his shoulders and hips was caused by his severe vitamin D deficiency because the serum phosphate level was normal. His extreme fatigue and severe proximal muscle weakness markedly improved after receiving small doses of vitamin D (400 IUs daily) and raising his blood level of 25(OH)D from undetectable (<4 ng/mL) to 10 ng/mL.\n\nA trial of corticosteroid therapy has been widely advocated in the acute management of hypercalcemia associated with high levels of 1,25(OH)2D, originating from an extrarenal source.15 Prior to using antiresorption drugs, all potential causes of osteomalacia had been excluded in this patient. Treatment with systemic steroids, furosemide, calcitonin, ketoconazole, and denosumab resulted in a decrease in serum calcium levels and symptoms associated with his hypercalcemia, but the effects of treatment for his hypophosphatemia and fatigue were limited. With his continued hypercalcemia, there was concern about giving him oral phosphate because this could result in an elevated calcium–phosphate product, producing soft tissue calcification and worsening of his renal failure.However, correcting his severe vitamin D deficiency with small doses of vitamin D3 (400 IUs daily) and raising his blood level of 25(OH)D to 10 ng/mL was effective in reversing his severe proximal muscle weakness, allowing him to lift his head, free himselfof his wheelchair, and regain ambulation. This improvement in his proximal muscle function was likely caused by a vitamin D‐dependent effect on skeletal muscle function because his serum phosphate level was normal at this time(Fig. 2). Several studies report an association between vitamin D deficiency and proximal myopathy.16, 17, 18, 19 In 30% of patients, it can present as proximal muscle weakness before the biochemical signs of vitamin D deficiency appear, leading to unnecessary investigative workup.16, 17\n\n\nA previous study found that proximal muscle strength strikingly improved when 25(OH)D levels increased from <4 ng/mL to 16 ng/mL and continued to improve as the levels increased to >40 ng/mL.20 These results are consistent with our observation that a small improvement in 25(OH)D levels from <4 ng/mL to 10 ng/mL dramatically improved proximal muscle strength. A 41‐year‐old male, who presented with hypophosphatemia‐associated osteomalacia caused by a lack of sunlight exposure and adequate vitamin D intake,21 had a dramatic improvement in muscle function after receiving vitamin D3 supplementation. He had low serum phosphorus (1.9 mg/dL), with a serum calcium level of 8.1 mg/dL and a 25(OH)D level of 8.1 ng/mL. The patient was thought to have concomitant vitamin D deficiency and possible tumor‐induced osteomalacia. He was given a trial of vitamin D supplementation pending further investigation; in the ensuing 6 weeks he experienced a dramatic improvement in muscle power and regained the ability to climb stairs after 2 months.\n\nClinicians need to be aware that severe vitamin D deficiency, defined as an extremely low/undetectable 25(OH)D level (ie, at the detection level of the assay, usually >4 ng/mL), can cause severe proximal muscle weakness independent of secondary hyperparathyroidism‐induced hypophosphatemia.18, 19, 21 Furthermore, the persistently elevated blood levels of I,25(OH)2D generated by granulomas can indirectly affect phosphate metabolism by increasing the production of FGF‐23, which results in hypophosphatemia.\n\nDisclosures\nAll the authors, with the exception of MFH, state that they have no conflicts of interest. MFH is a consultant for Quest Diagnostics, Inc., and Ontometrics, Inc. He is also on the Speakers Bureau for Abbott Laboratories.\n\nAcknowledgments\nAuthors’ roles: AS, NP and MH wrote the first draft of the manuscript. All authors critically revised the paper for important intellectual content and approved the final version.\n\n",
"fulltext_license": "CC BY",
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"issue": "3(10)",
"journal": "JBMR plus",
"keywords": "1,25‐DIHYDROXYVITAMIN‐D; HYPERCALCEMIA; HYPOPHOPHATEMIA; PTH/ VITAMIN D /FGF‐23; SILICONE/GRANULOMA",
"medline_ta": "JBMR Plus",
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"title": "Man of Steel Syndrome: Silicone and Mineral Oil Injections With Associated Hypercalcemia, Hypophosphatemia, and Proximal Muscle Weakness.",
"title_normalized": "man of steel syndrome silicone and mineral oil injections with associated hypercalcemia hypophosphatemia and proximal muscle weakness"
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"abstract": "BACKGROUND\nOlaparib (Lynparza) is an oral poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitor that induces synthetic lethality in cancers with homologous recombination defects.\n\n\nMETHODS\nIn this phase I, dose-escalation trial, patients with advanced solid tumours received olaparib (50-200 mg capsules b.i.d.) continuously or intermittently (days 1-14, per 28-day cycle) plus gemcitabine [i.v. 600-800 mg/m(2); days 1, 8, 15, and 22 (cycle 1), days 1, 8, and 15 (subsequent cycles)] to establish the maximum tolerated dose. A separate dose-escalation phase evaluated olaparib in tablet formulation (100 mg o.d./b.i.d.; days 1-14) plus gemcitabine (600 mg/m(2)). In an expansion phase, patients with genetically unselected locally advanced or metastatic pancreatic cancer were randomised 2 : 1 to the tolerated olaparib capsule combination dose or gemcitabine alone (1000 mg/m(2)).\n\n\nRESULTS\nSixty-six patients were treated [dose-escalation phase, n = 44 (tablet cohort, n = 12); dose-expansion phase, n = 22 (olaparib plus gemcitabine, n = 15; gemcitabine alone, n = 7)]. In the dose-escalation phase, four patients (6%) experienced dose-limiting toxicities (raised alanine aminotransferase, n = 2; neutropenia, n = 1; febrile neutropenia, n = 1). Grade ≥3 adverse events were reported in 38/47 patients (81%) treated with olaparib capsules plus gemcitabine; most common were haematological toxicities (55%). Tolerated combinations were olaparib 100 mg b.i.d. capsule (intermittently, days 1-14) plus gemcitabine 600 mg/m(2) and olaparib 100 mg o.d. tablet (intermittently, days 1-14) plus gemcitabine 600 mg/m(2). There were no differences in efficacy observed during the dose-expansion phase.\n\n\nCONCLUSIONS\nOlaparib 100 mg b.i.d. (intermittent dosing; capsules) plus gemcitabine 600 mg/m(2) is tolerated in advanced solid tumour patients, with no unmanageable/unexpected toxicities. Continuous dosing of olaparib or combination with gemcitabine at doses >600 mg/m(2) was not considered to have an acceptable tolerability profile for further study.\nNCT00515866.",
"affiliations": "Drug Development Unit, Sarah Cannon Research Institute/Tennessee Oncology, Nashville. Electronic address: jbendell@tnonc.com.;Memorial Sloan Kettering Cancer Center, New York, USA.;Department of Oncology, University of Oxford, Oxford.;Department of Medicine, Royal Marsden Hospital, Sutton, UK.;Yale Cancer Center, Yale School of Medicine, New Haven, USA.;Global Medicines Development, AstraZeneca.;Clinical Pharmacology, AstraZeneca, Macclesfield, UK.;Drug Development Unit, Sarah Cannon Research Institute/Tennessee Oncology, Nashville.",
"authors": "Bendell|J|J|;O'Reilly|E M|EM|;Middleton|M R|MR|;Chau|I|I|;Hochster|H|H|;Fielding|A|A|;Burke|W|W|;Burris|H|H|",
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"journal": "Annals of oncology : official journal of the European Society for Medical Oncology",
"keywords": "gemcitabine; olaparib; pancreatic cancer",
"medline_ta": "Ann Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D003841:Deoxycytidine; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms; D010190:Pancreatic Neoplasms; D010793:Phthalazines; D010879:Piperazines; D011379:Prognosis; D015996:Survival Rate",
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"pubdate": "2015-04",
"publication_types": "D017426:Clinical Trial, Phase I; D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Phase I study of olaparib plus gemcitabine in patients with advanced solid tumours and comparison with gemcitabine alone in patients with locally advanced/metastatic pancreatic cancer.",
"title_normalized": "phase i study of olaparib plus gemcitabine in patients with advanced solid tumours and comparison with gemcitabine alone in patients with locally advanced metastatic pancreatic cancer"
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"abstract": "We report an 86-year-old woman who was diagnosed with multiple myeloma (MM) and was receiving chemotherapy since the age of 82. A high echoic mass attached to the mitral valve was observed on transthoracic echocardiography 4 years after the treatment. The possibility of malignancy could not be ruled out, and hence, the mass was excised surgically. Pathologically, most of the mass consisted of calcified lesion without tumour tissue, and these findings were not inconsistent with calcified amorphous tumour (CAT). This case suggests that CAT may be associated with MM and has been reported after a thorough literature review.",
"affiliations": "Tokyo Teishin Hospital, Chiyoda-ku, Japan yamanaka_tetsuo@yahoo.co.jp.;Tokyo Teishin Hospital, Chiyoda-ku, Japan.;Kawasaki Saiwai Hospital, Kawasaki-shi, Japan.;Kawasaki Saiwai Hospital, Kawasaki-shi, Japan.",
"authors": "Yamanaka|Tetsuo|T|;Fukatsu|Toru|T|;Uchimuro|Tomoya|T|;Takanashi|Shuichiro|S|",
"chemical_list": null,
"country": "England",
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"doi": "10.1136/bcr-2019-233679",
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"issn_linking": "1757-790X",
"issue": "13(4)",
"journal": "BMJ case reports",
"keywords": "cardiovascular medicine; haematology (incl blood transfusion)",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000369:Aged, 80 and over; D002114:Calcinosis; D003937:Diagnosis, Differential; D017548:Echocardiography, Transesophageal; D005260:Female; D006338:Heart Neoplasms; D006801:Humans; D008943:Mitral Valve; D009101:Multiple Myeloma",
"nlm_unique_id": "101526291",
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"pmid": "32350053",
"pubdate": "2020-04-28",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D059040:Video-Audio Media",
"references": null,
"title": "Cardiac calcified amorphous tumour associated with multiple myeloma.",
"title_normalized": "cardiac calcified amorphous tumour associated with multiple myeloma"
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"abstract": "The first-line treatment for metastatic esophageal squamous cell cancer (ESCC) is a platinum- or fluorouracil-based agent, followed by later treatment with taxanes or irinotecan. However, there is still no standard third-line treatment for patients with metastatic ESCC. We present a 62-year-old man initially diagnosed with locally advanced ESCC. After esophagectomy, the patient was administrated with six cycles of docetaxel and cisplatin combined with radiotherapy. After 8.0 months, computed tomography showed the left cervical lymph node metastasis. However, the metastatic lymph node was not significantly shrunk after locally palliative radiotherapy and the patient was intolerant of irinotecan as second-line systemic therapy. Then, the patient was rechallenged with six cycles of docetaxel combined with apatinib (an oral tyrosine kinase inhibitor to vascular endothelial growth factor receptor 2 [VEGFR2]), followed by single dose of apatinib as maintenance therapy. According to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 standard, partial response was achieved in this case after treating with docetaxel combined with apatinib. Now, the progression-free survival of this patient has been 7.5 months. After administrating with apatinib for 2 weeks, hypertension (grade III) was observed. Thus, the dose of apatinib was decreased from 850 to 500 mg and then the adverse effects were controllable and tolerable. In conclusion, apatinib with concurrent docetaxel provided potential efficacy as a salvage treatment for patients with metastatic ESCC. To our knowledge, this is the first case of ESCC who responded to apatinib combined with docetaxel.",
"affiliations": "Department of Radiation Oncology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, People's Republic of China, jxdysy1970@163.com.;Department of Radiation Oncology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, People's Republic of China, jxdysy1970@163.com.;Department of Radiation Oncology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, People's Republic of China, jxdysy1970@163.com.;Department of Radiation Oncology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, People's Republic of China, jxdysy1970@163.com.;Department of Radiation Oncology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, People's Republic of China, jxdysy1970@163.com.;Department of Radiation Oncology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, People's Republic of China, jxdysy1970@163.com.",
"authors": "Liang|Li-Jun|LJ|;Wen|Yi-Xuan|YX|;Xia|You-You|YY|;Wang|Lei|L|;Fei|Jia-Yan|JY|;Jiang|Xiao-Dong|XD|",
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"fulltext": "\n==== Front\nOnco Targets TherOnco Targets TherOncoTargets and TherapyOncoTargets and therapy1178-6930Dove Medical Press 10.2147/OTT.S174429ott-11-5821Case ReportApatinib combined with docetaxel as a salvage treatment for metastatic esophageal squamous cancer: a case report Liang Li-Jun 12*Wen Yi-Xuan 12*Xia You-You 1*Wang Lei 1Fei Jia-Yan 12Jiang Xiao-Dong 12\n1 Department of Radiation Oncology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, People’s Republic of China, jxdysy1970@163.com\n2 Tumor Laboratory, The Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, People’s Republic of China, jxdysy1970@163.comCorrespondence: Xiao-Dong Jiang, Department of Radiation Oncology, Tumor Laboratory, The Affiliated Lianyungang Hospital of Xuzhou Medical University, NO 182 Tongguan North Road, Lianyungang 222002, Jiangsu Province, People’s Republic of China, Tel +86 518 8560 5722, Fax +86 518 8545 6700, Email jxdysy1970@163.com* These authors contributed equally to this work\n\n2018 13 9 2018 11 5821 5826 © 2018 Liang et al. This work is published and licensed by Dove Medical Press Limited2018The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.The first-line treatment for metastatic esophageal squamous cell cancer (ESCC) is a platinum- or fluorouracil-based agent, followed by later treatment with taxanes or irinotecan. However, there is still no standard third-line treatment for patients with metastatic ESCC. We present a 62-year-old man initially diagnosed with locally advanced ESCC. After esophagectomy, the patient was administrated with six cycles of docetaxel and cisplatin combined with radiotherapy. After 8.0 months, computed tomography showed the left cervical lymph node metastasis. However, the metastatic lymph node was not significantly shrunk after locally palliative radiotherapy and the patient was intolerant of irinotecan as second-line systemic therapy. Then, the patient was rechallenged with six cycles of docetaxel combined with apatinib (an oral tyrosine kinase inhibitor to vascular endothelial growth factor receptor 2 [VEGFR2]), followed by single dose of apatinib as maintenance therapy. According to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 standard, partial response was achieved in this case after treating with docetaxel combined with apatinib. Now, the progression-free survival of this patient has been 7.5 months. After administrating with apatinib for 2 weeks, hypertension (grade III) was observed. Thus, the dose of apatinib was decreased from 850 to 500 mg and then the adverse effects were controllable and tolerable. In conclusion, apatinib with concurrent docetaxel provided potential efficacy as a salvage treatment for patients with metastatic ESCC. To our knowledge, this is the first case of ESCC who responded to apatinib combined with docetaxel.\n\nKeywords\nmetastatic esophageal cancerapatinibdocetaxelvascular endothelial growth factor receptor-2anti-angiogenesis\n==== Body\nIntroduction\nEsophageal cancer is the world’s eighth most common cancer and the sixth leading cause of cancer-related deaths.1 Different from the situation in western countries, esophageal squamous cell carcinoma (ESCC) is still the dominant pathological type in China, which accounts for more than 95% of clinical cases.2 The annual incidence of ESCC in China was about 260,000 and approximately half of the patients diagnosed with ESCC presented with metastatic diseases.2 The first-line treatment for metastatic esophageal cancer is a platinum or fluorouracil-based agent,3–5 followed by later treatment with taxanes6,7 or irinotecan.8,9 No treatment strategy has been defined for patients who have been failed or intolerant to current standard therapies.\n\nAngiogenesis is a critical process for cell growth, especially for the tumor growth.10 The vascular epidermal growth factor (VEGF) could bind to vascular epidermal growth factor receptor (VEGFR) and activate the downstream pathway to stimulate the proliferation of vessel endothelium, then leading to the growth of tumor.11 Previous molecular pathology studies have revealed that VEGF overexpression could be detected in about 44.43% of esophageal cancer and the estimated mortality risk was 1.82-fold greater in patients with high VEGF expression,12,13 which indicated that antiangiogenic agents may have a therapeutic effect on esophageal cancer.\n\nApatinib, a novel small molecule tyrosine kinase inhibitor (TKI), exerts its anti-tumor effects by specifically acting on VEGFR-2.14 Phase II and III clinical trials suggested that apatinib could prolong overall survival (OS) of advanced gastric cancer patients who failed in the second-line treatment.15,16 In December 2014, China State Food and Drug Administration approved and launched apatinib as a treatment for patients with chemotherapy-refractory gastric cancer. Furthermore, many clinical studies have reported the satisfying efficacy of apatinib on various cancers including non-small-cell lung cancer,17 breast cancer,18,19 and pancreatic cancer.20 However, there is rare report to evaluate its efficacy and safety in patient with esophageal cancer. We herein report a unique case of ESCC receiving concurrent apatinib and docetaxel following failure of the second-line therapy. The progression-free survival (PFS) of this patient at least 7.5 months has been achieved now, demonstrating the potential of apatinib combined with chemotherapy in the treatment of ESCC. To our knowledge, this is the first case of ESCC who responded to apatinib combined with docetaxel.\n\nCase report\nA 62-year-old man suffered from dysphagia for almost 1 month was admitted to our hospital. Endoscopy biopsy suggested ESCC 28–35 cm away from incisors (Figure 1A and B) and computed tomography (CT) indicated that there was a space-occupying lesion at the lower esophagus (Figure 2). Physical examination did not show syndromes of hoarse voice and cough during drinking water, and no swelling superficial lymph node felt by touch. The patient had no history of hypertension, heart disease, diabetes, and kidney-related diseases.\n\nThe esophagectomy was performed on September 2, 2016; postoperative pathological examination indicated moderately differentiated ESCC. The full thickness of the esophageal wall was invaded, with dimensions of 5 × 2 × 1.3 cm, and metastasis was observed in esophageal lymph nodes (3/7; Figure 1B) but not observed in the resection margin. According to the eighth edition Staging Guidelines of American Joint Committee on Cancer, the surgical-pathological staging was T3N2M0, stage IIIB. Since September 2016, the patient received six cycles of chemotherapy of docetaxel (75 mg/m2, day 1) and cisplatin (70 mg/m2, day 1) combined with radiation therapy (total dose=50 Gy/25 fractions). In the follow-up after therapy, the gastroscopy and imaging examination showed no tumor recurrence. Until May 1, 2017, a lump could be touched in the patient’s left neck, shown as left cervical lymph node metastasis by CT (Figure 3A and B). Subsequently, locally radiotherapy (total dose=50 Gy/25 fractions) and three cycles of irinotecan (CPT-11, 250 mg/m2, 21 days as one cycle) monotherapy were performed; however, the patient suffered intolerable myelosuppression (grade IV) and severe gastrointestinal disturbances. Since CT revealed that the left cervical lymph node was not narrowed, the treatment was terminated (Figure 3C). After symptomatic treatment, the patient’s leucocytes returned to normal level, and the gastrointestinal adverse reactions disappeared.\n\nSince July 28, 2017, the patient received apatinib combined with six cycles of docetaxel (75 mg/m2, day 1, 21 days as one cycle) and then administrated apatinib as maintenance therapy. After treatment with apatinib for 1.4 months, CT examination showed cervical lymph node was decreased, without tumor recurrence or metastasis in other sites (Figure 3D). These results suggested that the patient achieved partial response (PR) according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 standard. There was no sign of progression in the patient’s conditions until we reported this case and now the PFS was 7.5 months (until March 10, 2018). The treatment schedule is given in Figure 4.\n\nAfter apatinib was administrated for two weeks, hypertension (grade III) appeared, so the dose of apatinib was adjusted from 850 to 500 mg. During the apatinib treatment cycles, the patient developed mild-to-moderate hypertension and hand-foot syndromes. After treating with appropriate agents, no other anti-angiogenesis-associated adverse event (AE) was reported. Toxicity was evaluated and graded according to the NCI-CTC for Adverse Events, version 4.0.\n\nThe study was approved by the Medical Ethics Committee of the Affiliated Lianyungang Hospital of Xuzhou Medical University and written informed consent was obtained from the patient. The patient also provided his written informed consent for the case details and accompanying images to be published in this case study.\n\nDiscussion\nTo date, there has been no effective therapy as standard third-line therapy for improving the survival of ESCC patients due to its aggressive nature. To the best of our knowledge, this is the first case report on apatinib combined with docetaxel for ESCC treatment achieving PFS of 7.5 months. In addition, the patient tolerated well to the treatment, and reported satisfactory quality of life.\n\nAs early as 1971, professor Folkman suggested that tumor growth relied on the formation of tumor blood vessels, thus “anti-tumor angiogenesis” would be a promising strategy for treating tumors.11 Based on previous researches, multiple antiangiogenic agents have been developed and studied in clinical trials. In the RAINBOW clinical trial, ramucirumab (a monoclonal antibody of VEGFR-2) combined with paclitaxel significantly increased OS compared with placebo combined with paclitaxel in advanced gastric or gastro-esophageal junction adenocarcinoma.21 This agent was also advocated in treatment guidelines for esophageal adenocarcinoma.22 Some clinical trials have demonstrated the effectiveness of bevacizumab as neoadjuvant therapy in ESCC.23,24 However, there are very few studies on anti-angiogenesis agents for metastatic ESCC.\n\nApatinib is a novel orally taken small molecular TKI, exerting its anti-angiogenesis function through highly and selectively competing with intracellular VEGFR-2’s adenosine triphosphate (ATP) binding sites. Thus, downstream signaling could be blocked to inhibit neovascularization in tumor tissue. The Phase II clinical trial of apatinib reported that median OS was increased to 4.83 months with apatinib 850 mg group, 4.27 months with apatinib 425 mg group, compared with 2.50 months with placebo group (P<0.001 and P=0.0017, respectively).15 Similar results were confirmed by the Phase III study (median OS was 6.5 months in the apatinib 850 mg vs 4.7 months in the placebo group, P=0.0149; HR=0.709, 95% CI 0.537–0.937, P=0.0156).16 The efficacy of apatinib on 62 advanced ESCC patients who failed the standard therapy was retrospectively analyzed,25 among which, 15 received PR, while 31 achieved stable disease, with a manageable safety profile. These results demonstrated the preliminary efficacy and safety of apatinib for advanced ESCC.\n\nAlthough antiangiogenic therapies show remarkable antitumor activity, their efficacy is limited as monotherapy. Hence, these agents have been integrated with conventional chemotherapy or radiotherapy to enhance antitumor activity.26,27 In our case, the patient received the docetaxel plus cisplatin regimen as first-line treatment and a PFS of 8.0 months was achieved. After the failure of standard chemotherapy and local radiation therapy of metastatic lesion, the patient still showed performance status score of 1, with strong willingness to continue the treatment. Thus, the docetaxel plus apatinib was administrated as salvage treatment strategy. Beyond our expectation, for this patient, the PFS of third-line treatment can be favorably comparable with the first-line treatment, indicating a potentially synergistic effect between apatinib and docetaxel chemotherapy. Moreover, recent research showed that the cytotoxicity of paclitaxel could be significantly enhanced by apatinib in vitro and in vivo by reversing chemotherapy-resistance through blocking the function of multiple ATP-binding cassette transporters.28 Furthermore, apatinib can markedly increase the intracellular accumulation of conventional chemotherapy agents in side population cells sorted from K562 cells,29 and cisplatin-resistant non-small-cell lung carcinoma A549 cell could be resensitized through suppressing extracellular signal-regulated kinase signaling pathway.30 Currently, there are also multiple ongoing clinical trials investigating on apatinib for molecular targeted therapy in ESCC (Table 1).\n\nThe common AEs of apatinib were hypertension and hand-foot syndrome.31 According to the instruction of apatinib, we first prescribed the patient with apatinib of 850 mg daily. Then, grade III hypertension was observed, leading to dosage adjustment to 500 mg. The AEs were controllable and tolerable. The bioavailability of apatinib in ESCC patients was noteworthily higher than those in patients with gastric cancer, which might be attributed to the fact that most gastric cancer patient had a subtotal gastrectomy surgery history.32\n\nIn conclusion, apatinib with concurrent docetaxel had potential efficacy for metastatic ESCC patients as a salvage treatment and the prospective clinical trials are ongoing (Table 1).\n\nAcknowledgments\nWe thank the patients and all investigators involved in this study. The first authors of this manuscript are Li-Jun Liang, Yi-Xuan Wen, and You-You Xia.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 Endoscopy biopsy (A) suggested esophageal squamous cell carcinoma; postoperative pathology (B) demonstrated moderately differentiated esophageal squamous cell carcinoma invading the full thickness of the esophageal wall.\n\nFigure 2 The initial thoracic CT indicated that the middle thickening esophageal wall was markedly enhanced. Plain scan (A); arterial phase (B); venous phase (C).\n\nNote: Red arrows represent the lymph node.\n\nAbbreviation: CT, Computed tomography.\n\nFigure 3 Cervical CT showed no lymphadenopathy before surgery (A); CT showed a significantly enlarged lymph node in the left neck which prompted PD after first-line chemotherapy (B); CT revealed the left cervical lymph node was not reduced after radiotherapy and irinotecan treatment (C); CT examination showed the swollen lymph nodes significantly narrowed and the border was not clear, suggesting that the patient achieved PR (D).\n\nNote: Red arrows represent the lymph node.\n\nAbbreviations: CT, Computed tomography; PD, disease progression; PR, partial response.\n\nFigure 4 The treatment schedule of the patient.\n\nAbbreviations: CT, computed tomography; RT, radiotherapy; CPT-11, irinotecan.\n\nTable 1 Selected ongoing trials with apatinib in metastatic ESCC\n\nClinical trial identifier\tPhase\tSetting\tTreatment regimen\tPrimary endpoint\tStatus\t\nNCT03224221\tII\tSecond line\tApatinib+chemotherapy\tOne-year survival rate\tRecruiting\t\nNCT02645864\tI\tSecond line\tApatinib+irinotecan\tDLT, MTD\tRecruiting\t\nNCT03251417\tII\tSecond line\tApatinib+irinotecan\tDCR\tRecruiting\t\nNCT03274011\tII\tThird line\tApatinib\tPFS\tRecruiting\t\nNCT02683655\tII\tSecond line\tApatinib\tPFS\tOngoing but not recruiting\t\nNCT02976896\tII\tSecond line\tApatinib\tDCR\tRecruiting\t\nNCT03193424\tII\tSecond line\tApatinib+docetaxel\tPFS\tRecruiting\t\nNCT03320629\tII\tFirst line\tApatinib+S-1+radiotherapy\tPFS\tRecruiting\t\nNCT03170310\tII\tSecond line\tApatinib\tPFS\tRecruiting\t\nAbbreviations: DLT, dose-limiting toxicity; MTD, maximum tolerance dose; DCR, disease control rate; PFS, progression free survival.\n==== Refs\nReferences\n1 Torre LA Bray F Siegel RL CA: a cancer journal for clinicians 2015 65 2 87 108 25651787 \n2 Chen W Zheng R Baade PD Cancer statistics in China, 2015 CA Cancer J Clin 2016 66 2 115 132 26808342 \n3 Hayashi K Ando N Watanabe H Phase II evaluation of protracted infusion of cisplatin and 5-fluorouracil in advanced squamous cell carcinoma of the esophagus: a Japan Esophageal Oncology Group (JEOG) Trial (JCOG9407) Jpn J Clin Oncol 2001 31 9 419 423 11689594 \n4 Bleiberg H Conroy T Paillot B Randomised phase II study of cisplatin and 5-fluorouracil (5-FU) versus cisplatin alone in advanced squamous cell oesophageal cancer Eur J Cancer 1997 33 8 1216 1220 9301445 \n5 Huang J Zhou Y Zhang H A phase II study of biweekly paclitaxel and cisplatin chemotherapy for recurrent or metastatic esophageal squamous cell carcinoma: ERCC1 expression predicts response to chemotherapy Med Oncol 2013 30 1 343 23263828 \n6 Kato K Tahara M Hironaka S A phase II study of paclitaxel by weekly 1-h infusion for advanced or recurrent esophageal cancer in patients who had previously received platinum-based chemotherapy Cancer Chemother Pharmacol 2011 67 6 1265 1272 20703479 \n7 Muro K Hamaguchi T Ohtsu A A phase II study of single-agent docetaxel in patients with metastatic esophageal cancer Ann Oncol 2004 15 6 955 959 15151954 \n8 Burkart C Bokemeyer C Klump B Pereira P Teichmann R Hartmann JT A phase II trial of weekly irinotecan in cisplatin-refractory esophageal cancer Anticancer Res 2007 27 4C 2845 2848 17695458 \n9 Mühr-Wilkenshoff F Hinkelbein W Ohnesorge I A pilot study of irinotecan (CPT-11) as single-agent therapy in patients with locally advanced or metastatic esophageal carcinoma Int J Colorectal Dis 2003 18 4 330 334 12774248 \n10 Hanahan D Weinberg RA Hallmarks of cancer: the next generation Cell 2011 144 5 646 674 21376230 \n11 Ferrara N Adamis AP Ten years of anti-vascular endothelial growth factor therapy Nat Rev Drug Discov 2016 15 6 385 403 26775688 \n12 Luz CCF Noguti J Araújo L Expression of VEGF and Cox-2 in Patients with Esophageal Squamous Cell Carcinoma Asian Pac J Cancer Prev 2018 19 1 171 177 29373910 \n13 Chen M Cai E Huang J Yu P Li K Prognostic value of vascular endothelial growth factor expression in patients with esophageal cancer: a systematic review and meta-analysis Cancer Epidemiol Biomarkers Prev 2012 21 7 1126 1134 22564870 \n14 Tian S Quan H Xie C YN968D1 is a novel and selective inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase with potent activity in vitro and in vivo Cancer Sci 2011 102 7 1374 1380 21443688 \n15 Li J Qin S Xu J Apatinib for chemotherapy-refractory advanced metastatic gastric cancer: results from a randomized, placebo-controlled, parallel-arm, phase II trial J Clin Oncol 2013 31 26 3219 3225 23918952 \n16 Li J Qin S Xu J Randomized, Double-Blind, Placebo-Controlled Phase III Trial of Apatinib in Patients With Chemotherapy-Refractory Advanced or Metastatic Adenocarcinoma of the Stomach or Gastroesophageal Junction J Clin Oncol 2016 34 13 1448 1454 26884585 \n17 Zhang L Shi M Huang C A phase II, multicenter, placebo-controlled trial of apatinib in patients with advanced nonsquamous non-small cell lung cancer (NSCLC) after two previous treatment regimens Journal of Clinical Oncology 2012 30 15_suppl 7548 \n18 Hu X Zhang J Xu B Multicenter phase II study of apatinib, a novel VEGFR inhibitor in heavily pretreated patients with metastatic triple-negative breast cancer Int J Cancer 2014 135 8 1961 1969 24604288 \n19 Hu X Cao J Hu W Multicenter phase II study of apatinib in non-triple-negative metastatic breast cancer BMC Cancer 2014 14 820 25376790 \n20 Li CM Liu ZC Bao YT Sun XD Wang LL Extraordinary response of metastatic pancreatic cancer to apatinib after failed chemotherapy: A case report and literature review World J Gastroenterol 2017 23 41 7478 7488 29151702 \n21 Wilke H Muro K RAINBOW Study Group Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial Lancet Oncol 2014 15 11 1224 1235 25240821 \n22 Ajani JA D’Amico TA National comprehensive cancer network Esophageal and esophagogastric junction cancers, version 1. 2015 J Natl Compr Canc Netw 2015 13 2 194 227 25691612 \n23 Idelevich E Kashtan H Klein Y Prospective phase II study of neoadjuvant therapy with cisplatin, 5-fluorouracil, and bevacizumab for locally advanced resectable esophageal cancer Onkologie 2012 35 7–8 427 431 22846974 \n24 Bendell JC Meluch A Peyton J A phase II trial of preoperative concurrent chemotherapy/radiation therapy plus bevacizumab/erlotinib in the treatment of localized esophageal cancer Clin Adv Hematol Oncol 2012 10 7 430 437 22895283 \n25 Li J Wang L Efficacy and safety of apatinib treatment for advanced esophageal squamous cell carcinoma Onco Targets Ther 2017 10 3965 3969 28860804 \n26 Cheng X Xu Z Chen J Apatinib to enhance chemosensitivity of gastric cancer to paciltaxel and 5-fluorouracil J Clin Oncol 2017 35 15_suppl e15545 \n27 Zhou F Feng S Zhang J Aa J Wang G Combined treatment of apatinib with docetaxel in non-small-cell lung cancer mice and its material basis of pharmacokinetics Journal of Clinical Oncology 2017 35 15_suppl e14069 \n28 Yj M Liang YJ Huang HB Apatinib (YN968D1) reverses multi-drug resistance by inhibiting the efflux function of multiple ATP-binding cassette transporters Cancer Res 2010 70 20 7981 7991 20876799 \n29 Tong XZ Wang F Liang S Apatinib (YN968D1) enhances the efficacy of conventional chemotherapeutical drugs in side population cells and ABCB1-overexpressing leukemia cells Biochem Pharmacol 2012 83 5 586 597 22212563 \n30 Liu ZL Jin BJ Cheng CG Apatinib resensitizes cisplatin-resistant non-small cell lung carcinoma A549 cell through reversing multidrug resistance and suppressing ERK signaling pathway Eur Rev Med Pharmacol Sci 2017 21 23 5370 5377 29243778 \n31 Li J Zhao X Chen L Safety and pharmacokinetics of novel selective vascular endothelial growth factor receptor-2 inhibitor YN968D1 in patients with advanced malignancies BMC Cancer 2010 10 529 20923544 \n32 Yu M Gao Z Dai X Population Pharmacokinetic and Covariate Analysis of Apatinib, an Oral Tyrosine Kinase Inhibitor, in Healthy Volunteers and Patients with Solid Tumors Clin Pharmacokinet 2017 56 1 65 76 27379402\n\n",
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"issue": "11()",
"journal": "OncoTargets and therapy",
"keywords": "anti-angiogenesis; apatinib; docetaxel; metastatic esophageal cancer; vascular endothelial growth factor receptor-2",
"medline_ta": "Onco Targets Ther",
"mesh_terms": null,
"nlm_unique_id": "101514322",
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"pages": "5821-5826",
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"pubdate": "2018",
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"references": "22564870;15151954;21443688;24604288;11689594;9301445;22212563;29373910;25240821;27379402;22895283;26884585;21376230;23263828;20876799;26808342;26775688;20703479;29151702;25651787;22846974;12774248;25691612;20923544;23918952;25376790;29243778;17695458;28860804",
"title": "Apatinib combined with docetaxel as a salvage treatment for metastatic esophageal squamous cancer: a case report.",
"title_normalized": "apatinib combined with docetaxel as a salvage treatment for metastatic esophageal squamous cancer a case report"
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"abstract": "METHODS\nFemale, 51.\n\n\nMETHODS\nEwing sarcoma.\n\n\nMETHODS\nVisual disturbances.\n\n\nMETHODS\n-.\n\n\nMETHODS\n-.\n\n\nMETHODS\nOncology.\n\n\nOBJECTIVE\nRare disease.\n\n\nBACKGROUND\nPrimitive neuroectodermal tumor/Ewing sarcoma (PNET/EWS) is a round blue cell sarcoma that shows varying degrees of neuroectodermal differentiation. PNET/EWS as a primary intracranial tumor is extremely uncommon.\n\n\nMETHODS\nWe report a unique case of peripheral PNET presenting as an intracranial mass in an adult following chemotherapy and radiotherapy for a solid tumor. A 51-year-old woman with previously treated left breast cancer was evaluated for a newly developed brain mass. She underwent craniotomy with resection. Surgical pathology was consistent with a peripheral PNET/EWS with Ewing sarcoma gene translocation. She was treated appropriately with vincristine, cyclophosphamide, and doxorubicin (later dactinomycin) alternating with ifosfamide and etoposide.\n\n\nCONCLUSIONS\nAlthough development of PNET/EWS presenting along the CNS is exceedingly rare in adults, establishing the proper diagnosis of this \"small blue cell tumor\" is critical. The further distinction between central PNET and peripheral PNET can greatly impact both prognosis and treatment. Our case also highlights the importance of considering the impact of prior intensive therapies, including radiation and chemotherapy, on predisposing to future PNET/EWS.",
"affiliations": "Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, U.S.A.;Department of Pathology and Laboratory Medicine, Temple University Hospital, Philadelphia, PA, U.S.A.;Department of Neurosurgery, Temple University School of Medicine, Philadelphia, PA, U.S.A.;Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, U.S.A.;Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, U.S.A.;Department of Pathology and Laboratory Medicine, Temple University Hospital, Philadelphia, PA, U.S.A.;Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, U.S.A.;Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, U.S.A.;Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, U.S.A.;Department of Pathology and Laboratory Medicine, Temple University Hospital, Philadelphia, PA, U.S.A.",
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"journal": "The American journal of case reports",
"keywords": "Central Nervous System; Neuroectodermal Tumors, Primitive, Peripheral; Sarcoma, Ewing",
"medline_ta": "Am J Case Rep",
"mesh_terms": "D001943:Breast Neoplasms; D003131:Combined Modality Therapy; D003399:Craniotomy; D003937:Diagnosis, Differential; D004388:Dura Mater; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008279:Magnetic Resonance Imaging; D008577:Meningeal Neoplasms; D008875:Middle Aged; D018241:Neuroectodermal Tumors, Primitive, Peripheral",
"nlm_unique_id": "101489566",
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"pages": "294-9",
"pmc": null,
"pmid": "25045413",
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"references": "21572359;22109315;22402423;16784984;22123553;16292490;22629492;12065782;19204208;22847990;4751919;20634481;23564674;19996729",
"title": "Peripheral primitive neuroectodermal tumor of the dura in a 51-year-old woman following intensive treatment for breast cancer.",
"title_normalized": "peripheral primitive neuroectodermal tumor of the dura in a 51 year old woman following intensive treatment for breast cancer"
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"abstract": "BACKGROUND\nThis study includes 28 patients with genetically proven 22q11.2 deletion syndrome referred for treatment-resistant psychoses and aims at the identification of a suitable pharmacological treatment strategy.\n\n\nMETHODS\nBased on standardized diagnostic procedures, key psychiatric symptoms and cognitive status were assessed. Also, data about previous diagnostic vignettes as well as the history of psychotropic medication and medical conditions were collected. Finally, the effect of the subsequent treatment regimen was periodically re-assessed.\n\n\nRESULTS\nSince psychotic symptoms had been shown to be non-responsive to conventional antipsychotics including risperidone, treatment with either clozapine or quetiapine was started. In 21 patients, a substantial reduction of psychotic symptoms was achieved with either one, and in 3-quarters of this group remission was attained over a longer follow-up period. In a significant number of patients, valproic acid was added either for mood stabilizing purposes or to avoid epileptic side effects of clozapine.\n\n\nCONCLUSIONS\nTreatment of psychotic symptoms in patients with 22q11DS with the atypical antipsychotic quetiapine or clozapine in combination with the mood-stabilizing anticonvulsant valproic acid, appears likely to be more effective than with other psychotropic compounds.",
"affiliations": "Vincent van Gogh Institute for Psychiatry, Centre of Excellence for Neuropsychiatry, Venray, The Netherlands.;Vincent van Gogh Institute for Psychiatry, Centre of Excellence for Neuropsychiatry, Venray, The Netherlands.",
"authors": "Verhoeven|W M A|WM|;Egger|J I M|JI|",
"chemical_list": "D014150:Antipsychotic Agents",
"country": "Germany",
"delete": false,
"doi": "10.1055/s-0034-1398612",
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"issn_linking": "0176-3679",
"issue": "48(3)",
"journal": "Pharmacopsychiatry",
"keywords": null,
"medline_ta": "Pharmacopsychiatry",
"mesh_terms": "D058165:22q11 Deletion Syndrome; D000328:Adult; D000368:Aged; D014150:Antipsychotic Agents; D003072:Cognition Disorders; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D011569:Psychiatric Status Rating Scales; D011618:Psychotic Disorders; D012008:Recurrence; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "8402938",
"other_id": null,
"pages": "104-10",
"pmc": null,
"pmid": "25654302",
"pubdate": "2015-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Atypical Antipsychotics and Relapsing Psychoses in 22q11.2 Deletion Syndrome: A Long-term Evaluation of 28 Patients.",
"title_normalized": "atypical antipsychotics and relapsing psychoses in 22q11 2 deletion syndrome a long term evaluation of 28 patients"
} | [
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"activesubstancename": "OLANZAPINE"
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... |
{
"abstract": "Guillain-Barre syndrome (GBS) is rarely reported in children with acute lymphoblastic leukemia (ALL) and may be difficult to differentiate from vincristine induced neuropathy. Only few case reports highlighted GBS with ALL. We report a 10-year-old male child who was a diagnosed case of ALL since 3 month on chemotherapy. At 3(rd) week of chemotherapy, he developed rapidly progressive ascending motor quadriparesis over 2 days. Clinical and electrophysiology revealed acute motor axonal neuropathy (AMAN) variant of GBS. He was treated with intravenous immunoglobulin (2 g/kg) without discontinuing chemotherapy. Complete recovery took 12 weeks despite immunotherapy, and it was corroborating to slow remission. We concluded that AMAN variant is usually present in B-cell type ALL, may be causal for GBS and it takes 6-16 weeks to complete recovery which may correspond to remission of ALL. However, it needs to be studied. We also present a meta-analysis of previously reported cases of GBS in ALL.",
"affiliations": "Department of Neurology, Dr. S.N. Medical College and M.G. Hospital, Jodhpur, Rajasthan, India.;Department of Neurology, Dr. S.N. Medical College and M.G. Hospital, Jodhpur, Rajasthan, India.;Department of Neurology, Dr. S.N. Medical College and M.G. Hospital, Jodhpur, Rajasthan, India.;Department of Neurology, Dr. S.N. Medical College and M.G. Hospital, Jodhpur, Rajasthan, India.;Department of Medicine, Dr. S.N. Medical College and M.G. Hospital, Jodhpur, Rajasthan, India.",
"authors": "Bhushan|Bharat|B|;Bhargava|Amita|A|;Kasundra|Gaurav M|GM|;Shubhakaran|Khichar|K|;Sood|Isha|I|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/1817-1745.154358",
"fulltext": "\n==== Front\nJ Pediatr NeurosciJ Pediatr NeurosciJPNJournal of Pediatric Neurosciences1817-17451998-3948Medknow Publications & Media Pvt Ltd India JPN-10-6410.4103/1817-1745.154358Case ReportGuillain–Barre syndrome in acute lymphoblastic leukemia: Causal or coincidental Bhushan Bharat Bhargava Amita Kasundra Gaurav M. Shubhakaran Khichar Sood Isha 1Department of Neurology, Dr. S.N. Medical College and M.G. Hospital, Jodhpur, Rajasthan, India1 Department of Medicine, Dr. S.N. Medical College and M.G. Hospital, Jodhpur, Rajasthan, IndiaAddress for correspondence: Dr. Bharat Bhushan, H. No. 21/267, Chopasani Housing Board, Jodhpur - 340 008, Rajasthan, India. E-mail: drbhushan90@yahoo.comJan-Mar 2015 10 1 64 66 Copyright: © Journal of Pediatric Neurosciences2015This 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.Guillain–Barre syndrome (GBS) is rarely reported in children with acute lymphoblastic leukemia (ALL) and may be difficult to differentiate from vincristine induced neuropathy. Only few case reports highlighted GBS with ALL. We report a 10-year-old male child who was a diagnosed case of ALL since 3 month on chemotherapy. At 3rd week of chemotherapy, he developed rapidly progressive ascending motor quadriparesis over 2 days. Clinical and electrophysiology revealed acute motor axonal neuropathy (AMAN) variant of GBS. He was treated with intravenous immunoglobulin (2 g/kg) without discontinuing chemotherapy. Complete recovery took 12 weeks despite immunotherapy, and it was corroborating to slow remission. We concluded that AMAN variant is usually present in B-cell type ALL, may be causal for GBS and it takes 6–16 weeks to complete recovery which may correspond to remission of ALL. However, it needs to be studied. We also present a meta-analysis of previously reported cases of GBS in ALL.\n\nAcute lymphoblastic leukemiachemotherapychildrenGuillain–Barre syndrome\n==== Body\nIntroduction\nThe fact that so many cases of Guillain–Barre syndrome (GBS) begin after a viral or bacterial infection suggests that certain characteristics of some viruses and bacteria may activate the immune system inappropriately. Evidence of GBS in children with acute lymphoblastic leukemia (ALL) is very rarely highlighted. Differentiation from other neuropathies is important from the therapeutic point of view. We report a case of GBS in children on induction chemotherapy for B-cell types ALL.\n\nCase Report\nA 10-year-old boy, was investigated and diagnosed as ALL just 3 months prior for his 4 months symptoms of easy fatigability, fever, anemia and cervical lymphadenopathy. His bone marrow flow cytometry revealed 95% precursor B ALL with CD10, co-expression of CD10 and CD19 and human leukocyte antigen–DR positive, but his cerebrospinal fluid (CSF) had no blasts cells. He was kept on induction chemotherapeutic regimen according to the Medical Research Council United Kingdom Acute Lymphoblastic Leukaemia-12 protocol (daunorubicin 50 mg and vincristine 1.5 mg given intravenously on days 1, 8, 15 and 22, prednisolone 50 mg, once daily on days 1–28, and L-asparaginase 5000 units intramuscularly on days 17–28).\n\nDuring 4th week of chemotherapy (3 days after 4th dose of vincristine) he developed rapidly progressive ascending weakness of all four limbs over 48 h without concurrent or antecedent history of infections. On examination, he had pure motor are flexic quadriplegia without involving the bladder, respiratory or bulbar muscles. Power was grade three in upper limbs and grade zero in lower limbs. Polyradiculoneuropathy was considered with differentials of GBS, vincristine induced neuropathy and precipitation of hereditary neuropathy by drugs (vincristine). Investigation revealed leukocytosis (14,300/mm3), thrombocytopenia (98,700/ml), CSF showed glucose - 53 mg/dL; protein - 128 mg/dL; cell count - 5 lymphocytes/mm3 and absent blasts cells. Contrast enhancing magnetic resonance imaging spine and brain, anti-nuclear antibody and rest were normal. Electrophysiological evaluation done on day 5 of illness revealed a pure motor axonal polyradiculoneuropathy pattern. The common peroneal and tibial nerves were bilaterally unexcitable. Bilateral median and ulnar nerves showed reduction in amplitude of compound muscle action potentials, prolonged latencies, and normal conduction velocities. F waves were absent in lower limbs with prolonged latency in nerves of upper limbs. The sensory nerve action potentials were normal in all the tested nerves. Needle electromyography showed the neurogenic pattern. Correlating the clinical and electrophysiological findings, acute motor axonal neuropathy (AMAN) – a subtype of GBS was kept.\n\nHe was treated with intravenous immunoglobulin (IVIG) (0.4 g/kg/day) for 5 days without discontinuing chemotherapy. The weakness began to improve on the 10th day following administration of IVIG. Six weeks later, he had complete improvement in upper limbs but require assistance for walking (power grade 2–3/5). After 6 weeks, he started to achieve remission (bone marrow blast 29%), simultaneously his motor deficit also started to improve. He took total 14 weeks to achieve complete remission (bone marrow blast 5%) and 12 weeks to get full recovery in motor deficit. Unexpectedly both were achieved simultaneously. He is presently on maintenance chemotherapy. During 12th week, nerve conduction study showed normal parameter. Neither was there any finding on examination nor any family history suggestive of a hereditary neuropathy.\n\nDiscussion\nGuillain–Barre syndrome is an acute, severe and fulminant, polyradiculoneuropathy that is autoimmune in nature. Electrodiagnostically they are described as demyelinating and axonal subtypes. The immunological vulnerability of the peripheral nervous system could be increased in lymphoproliferative disorders; known infective triggers could precipitate an immune neuropathy in this setting. The association between GBS and ALL could be coincidental or causal. The pathophysiologic basis for acute inflammatory demyelinating polyradiculoneuropathy (AIDP) in children with ALL remains unclear. Some evidence suggests immunosuppression secondary to intensive chemotherapy.[1] Immune system neoplasms may also act to trigger AIDP in a manner similar to some viral infections.[2]\n\nDifferentials of neuropathy in our case could be vincristine induced neuropathy, AIDP, carcinomatous infiltration, expression of hidden hereditary neuropathy during induction (vincristin) therapy. However, a high index of suspicion is needed for differentiation from other neuropathies. Vincristine induced neuropathy, is a toxic, “dying-back” neuropathy with prominent sensory involvement.[3] Vincristine may also cause a fulminant neuropathy with severe weakness in patients with hereditary neuropathy. In our case, the clinical and electrophysiological features were not supportive of vincristine induced and hereditary neuropathy.[456]\n\nImprovement of GBS with immunotherapy, in this case (before remission of ALL) is different from other cases of GBS in an autoimmune disorder, not directly related to the hematologic malignancy. The cases so far reported, three were in the B cell type ALL and had AMAN variant.[678] Except two cases, all were described during induction therapy and onset was in 3–5 weeks of therapy. Almost all cases had albuminocytological dissociation in CSF. All responded to IVIG. All cases had vincristine in induction therapy and were continued during treatment of neuropathy. Albeit, complete improvement time were different and usually longer but association with remissions of ALL were not emphasized clearly. Longest recovery time (16 weeks) was only in one case of a 32-year-old female who was on induction therapy for ALL and developed AMAN variant of GBS like our case, but was treated successfully with two course of IVIG [Table 1]. Similar to this, our patient remained on vincristine, took longer time (12 weeks) to recover completely, however he started to show minimal response by a single course of IVIG. Complete response was simultaneous with complete remission in our case.\n\nTable 1 Meta-analysis of reported cases of GBS in ALL\n\nUsually the recovery can be either complete or partial, depending on initiation of immunomodulatory therapy and axonal or demyelinating pattern in GBS setting. Although axonal degeneration takes longer time to recover, but odd aspect is unexpected temporal association of improvement with remission of ALL.\n\nConclusion\nThe differentiation between GBS and vincristine neuropathy is important to initiate timely immunomodulatory therapies for GBS and avoid unnecessary withdrawal of vincristine, which could worsen the outcome of ALL. Electrophysiological studies guide to the correct diagnosis. Recovery can take more than 6–16 weeks and corroborates to complete remission in ALL. However it needs to be studied further.\n\nAcknowledgments\nDr. Guruprasad S Pujar, Dr. Banakar Basavaraj, Registrar, D.M. Neurology, Dr. S.N. Medical College and M.G. Hospital, Jodhpur, Rajasthan, India.\n\nSource of Support: Nil.\n\nConflict of Interest: None declared.\n==== Refs\n1 Aral YZ Gursel T Ozturk G Serdaroglu A Guillain-Barré syndrome in a child with acute lymphoblastic leukemia Pediatr Hematol Oncol 2001 18 343 6 11452406 \n2 Brigo F Balter R Marradi P Ferlisi M Zaccaron A Fiaschi A Vincristine-related neuropathy versus acute inflammatory demyelinating polyradiculoneuropathy in children with acute lymphoblastic leukemia J Child Neurol 2012 27 867 74 22241706 \n3 Guiheneuc P Ginet J Groleau JY Rojouan J Early phase of vincristine neuropathy in man. Electrophysiological evidence for a dying-back phenomenon, with transitory enhancement of spinal transmission of the monosynaptic reflex J Neurol Sci 1980 45 355 66 6245189 \n4 Moudgil SS Riggs JE Fulminant peripheral neuropathy with severe quadriparesis associated with vincristine therapy Ann Pharmacother 2000 34 1136 8 11054980 \n5 Pal PK Clinical and electrophysiological studies in vincristine induced neuropathy Electromyogr Clin Neurophysiol 1999 39 323 30 10499201 \n6 Norman M Elinder G Finkel Y Vincristine neuropathy and a Guillain-Barré syndrome: A case with acute lymphatic leukemia and quadriparesis Eur J Haematol 1987 39 75 6 3477471 \n7 Rajeswari B Krishnan S Sarada C Kusumakumary P Guillain-Barre syndrome with acute lymphoblastic leukemia Indian Pediatr 2013 50 791 2 24036643 \n8 Vembu P Al-Shubaili A Al-Khuraibet A Kreze O Pandita R Guillain-Barré syndrome in a case of acute lymphoblastic leukaemia. A case report Med Princ Pract 2003 12 272 5 12966204\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "1817-1745",
"issue": "10(1)",
"journal": "Journal of pediatric neurosciences",
"keywords": "Acute lymphoblastic leukemia; Guillain–Barre syndrome; chemotherapy; children",
"medline_ta": "J Pediatr Neurosci",
"mesh_terms": null,
"nlm_unique_id": "101273794",
"other_id": null,
"pages": "64-6",
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"pubdate": "2015",
"publication_types": "D002363:Case Reports",
"references": "24036643;11452406;10499201;11054980;3477471;6245189;12966204;22241706",
"title": "Guillain-Barre syndrome in acute lymphoblastic leukemia: Causal or coincidental.",
"title_normalized": "guillain barre syndrome in acute lymphoblastic leukemia causal or coincidental"
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"abstract": "Individuals with gender dysphoria can receive gender-affirming hormone therapy. Different guidelines mention a severe risk of liver injury within the first months after the start of treatment with anabolic androgenic steroids, anti-androgens, and oral contraceptives, which is potentially fatal.\nThe incidence of liver injury in a transgender population using gender-affirming hormone therapy.\nMulticentre prospective study with 1933 transgender individuals, who started with hormone therapy between 2010 and 2020.\nThe following parameters were analysed before hormone therapy, after 3 months, and after 12 months of hormone therapy: alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and gamma-glutamyltransferase (GGT). Both male and female reference values were considered. Liver injury was defined as either an elevation of 2× upper limit of normal (ULN) of ALP, 3× ULN of ALT, or 3× ULN of AST.\n889 transgender women and 1044 transgender men were included in the analysis. The incidence of liver injury within 12 months after the start of hormone therapy, without attribution to alcohol abuse, medical history, or comedication was 0.1 and 0.0%. in transgender women according to female and male reference intervals respectively, and 0.6 and 0.4% in transgender men (female and male reference intervals).\nThe incidence of liver injury is found to be very low. We, therefore, conclude that liver enzyme monitoring within the frame of the risk of liver injury due to hormone therapy is not necessary for a transgender population.",
"affiliations": "Department of Internal Medicine, Division of Endocrinology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.;Department of Internal Medicine, Division of Endocrinology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.;Department of Endocrinology, Centre for Sexology and Gender, Ghent University Hospital, Ghent, Belgium.;Department of Internal Medicine, Division of Endocrinology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.;Department of Experimental, Clinical and Biomedical Sciences, Sexual Medicine and Andrology Unit, University of Florence, Florence, Italy.;Department of Endocrinology, Oslo University Hospital, Oslo, Norway.;Department of Endocrinology, Centre for Sexology and Gender, Ghent University Hospital, Ghent, Belgium.;Department of Internal Medicine, Division of Endocrinology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.",
"authors": "A Stangl|Theresa|T|0000-0001-7856-5085;M Wiepjes|Chantal|C|0000-0002-8280-0065;Defreyne|Justine|J|;Conemans|Elfi|E|;D Fisher|Alessandra|A|;Schreiner|Thomas|T|;T'Sjoen|Guy|G|;den Heijer|Martin|M|0000-0003-3620-5617",
"chemical_list": "D000726:Androgen Antagonists; D012739:Gonadal Steroid Hormones; D013739:Testosterone; D004958:Estradiol",
"country": "England",
"delete": false,
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"mesh_terms": "D000328:Adult; D000726:Androgen Antagonists; D001530:Belgium; D056486:Chemical and Drug Induced Liver Injury; D015331:Cohort Studies; D004958:Estradiol; D005260:Female; D000068116:Gender Dysphoria; D012739:Gonadal Steroid Hormones; D006801:Humans; D007558:Italy; D008099:Liver; D008297:Male; D009426:Netherlands; D009664:Norway; D011446:Prospective Studies; D013739:Testosterone; D063106:Transgender Persons",
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"references": null,
"title": "Is there a need for liver enzyme monitoring in people using gender-affirming hormone therapy?",
"title_normalized": "is there a need for liver enzyme monitoring in people using gender affirming hormone therapy"
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{
"companynumb": "NL-ENDO PHARMACEUTICALS INC-2021-010015",
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{
"abstract": "Drug reaction with eosinophilia and systemic symptoms (DRESS) is a hypersensitivity syndrome most commonly associated with antiepileptic agents, allopurinol, and sulfonamides. It is a severe adverse reaction associated with fever, rash, eosinophilia, lymphadenopathy, and internal organ involvement. We present the case of a 17-year-old Caucasian female with bipolar disorder type II and posttraumatic stress disorder treated with lamotrigine for a non-Food and Drug Administration-approved indication that developed DRESS syndrome at an initial dose higher than that recommended. Her symptoms were atypical in that she developed a rash with influenza-like symptoms that resolved after discontinuation of lamotrigine and returned 8 days later. She was hospitalized because of elevated liver enzymes and treated with corticosteroids. In patients presenting with rash and systemic symptoms, DRESS syndrome should be considered and treated appropriately to reduce mortality, which can be as high as 10%. Treatment includes withdrawal of the offending agent and corticosteroids.",
"affiliations": "Department of Psychiatry, University of Florida, Gainesville, Florida.",
"authors": "Ginory|Almari|A|;Chaney-Catchpole|Michelle|M|;Demetree|Julie M|JM|;Mayol Sabatier|Laura M|LM|;Nguyen|Mathew|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.5863/1551-6776-18.3.236",
"fulltext": null,
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"issn_linking": "1551-6776",
"issue": "18(3)",
"journal": "The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG",
"keywords": "anticonvulsants; bipolar disorder; drug eruptions",
"medline_ta": "J Pediatr Pharmacol Ther",
"mesh_terms": null,
"nlm_unique_id": "101089851",
"other_id": null,
"pages": "236-40",
"pmc": null,
"pmid": "24052787",
"pubdate": "2013-07",
"publication_types": "D002363:Case Reports",
"references": "9069593;18627428;23691411;19221540;21359537;9276112;17300272;22714760;21098750;9781550;21361742;21592453;9371937",
"title": "Drug Reaction With Eosinophilia and Systemic Symptoms (DRESS) in an Adolescent Treated With Lamotrigine.",
"title_normalized": "drug reaction with eosinophilia and systemic symptoms dress in an adolescent treated with lamotrigine"
} | [
{
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"abstract": "This cohort study of the International Network on Cancer, Infertility and Pregnancy (INCIP) reports the maternal and neonatal outcomes of 80 pregnant patients diagnosed with non-Hodgkin lymphoma (NHL) between 1986 and 2019, focussing on 57 (71%) patients with diffuse large B-cell lymphoma (DLBCL). Of all 80 patients, 54 (68%) pregnant patients received chemotherapy; mostly (89%) CHOP-like (cyclophosphamide, doxorubicin, vincristine, and prednisone) regimens. Four early pregnancies were terminated. Among 76 ongoing pregnancies, there was one stillbirth (1·3%). Overall, there was a high incidence of small for gestational age neonates (39%), preterm delivery (52%), obstetric (41%) and neonatal complications (12·5%), and this could not exclusively be explained by the receipt of antenatal chemotherapy. Half of preterm deliveries (46%) were planned in order to tailor oncological treatment. The 3-year progression-free and overall survival for patients with DLBCL treated with rituximab-CHOP was 83·4% and 95·7% for limited stage (n = 29) and 60·6% and 73·3% for advanced stage (n = 15). Of 36 pregnant patients who received rituximab, five (13%) cases with neonatal complications and three (8%) with maternal infections were reported. In conclusion, standard treatment for DLBCL can be offered to pregnant patients in obstetric centres that cater for high-risk patients.",
"affiliations": "Department of Oncology, KU Leuven, Leuven, Belgium.;Department of Oncology, KU Leuven, Leuven, Belgium.;Department of Obstetrics and Gynaecology, Cooper, University Health Care, Camden, NJ, USA.;Department of Obstetrics, Cliniques Universitaires St Luc, UCL, Sint-Lambrechts-Woluwe, Belgium.;Hospital Regional de Alta Especialidad de Ixtapaluca (HRAEI) \"Reference clinic for haemato-oncological diseases during pregnancy CREHER\", Estado de México, México.;National Medical Research Centre for Obstetrics, Gynaecology and Perinatology named after Academician V.I. Kulakov of the Ministry of Healthcare of Russian Federation, Moscow, Russia.;Tel Aviv Sourasky Medical Centre, Tel Aviv, Israel.;Department Surgical Sciences, University of Torino, Torino, Italy.;Department of Obstetrics and Gynaecology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.;Department of Medical Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands.;Cooper Medical School, Rowan University, Camden, NJ, USA.;National Medical Research Centre for Obstetrics, Gynaecology and Perinatology named after Academician V.I. Kulakov of the Ministry of Healthcare of Russian Federation, Moscow, Russia.;Department of Obstetrics and Gynaecology, University Hospitals Leuven, Leuven, Belgium.;Department of Oncology, KU Leuven, Leuven, Belgium.;Department of Oncology, KU Leuven, Leuven, Belgium.",
"authors": "Maggen|Charlotte|C|0000-0002-7485-0839;Dierickx|Daan|D|0000-0002-8917-022X;Cardonick|Elyce|E|;Mhallem Gziri|Mina|M|;Cabrera-Garcia|Alvaro|A|;Shmakov|Roman G|RG|;Avivi|Irit|I|;Masturzo|Bianca|B|;Duvekot|Johannes J|JJ|;Ottevanger|Petronella B|PB|;O'Laughlin|Andie|A|;Polushkina|Evgeniya|E|;Van Calsteren|Kristel|K|0000-0002-2438-6783;Woei-A-Jin|F J Sherida H|FJSH|0000-0001-7840-6156;Amant|Frédéric|F|0000-0002-5452-4905;|||",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D000074322:Antineoplastic Agents, Immunological; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011239:Prednisolone",
"country": "England",
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"journal": "British journal of haematology",
"keywords": "R-CHOP; diffuse large B-cell lymphoma; maternal outcome; non-Hodgkin lymphoma; pregnancy",
"medline_ta": "Br J Haematol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D058846:Antibodies, Monoclonal, Murine-Derived; D000074322:Antineoplastic Agents, Immunological; D000971:Antineoplastic Combined Chemotherapy Protocols; D000013:Congenital Abnormalities; D003520:Cyclophosphamide; D004317:Doxorubicin; D005260:Female; D005317:Fetal Growth Retardation; D005865:Gestational Age; D006801:Humans; D015994:Incidence; D007231:Infant, Newborn; D007246:Infertility; D016403:Lymphoma, Large B-Cell, Diffuse; D008228:Lymphoma, Non-Hodgkin; D011239:Prednisolone; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D047928:Premature Birth; D000077982:Progression-Free Survival; D012189:Retrospective Studies; D000069283:Rituximab; D050497:Stillbirth; D014750:Vincristine",
"nlm_unique_id": "0372544",
"other_id": null,
"pages": "52-62",
"pmc": null,
"pmid": "32945547",
"pubdate": "2021-04",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Maternal and neonatal outcomes in 80 patients diagnosed with non-Hodgkin lymphoma during pregnancy: results from the International Network of Cancer, Infertility and Pregnancy.",
"title_normalized": "maternal and neonatal outcomes in 80 patients diagnosed with non hodgkin lymphoma during pregnancy results from the international network of cancer infertility and pregnancy"
} | [
{
"companynumb": "NL-MYLANLABS-2021M1031944",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nImmunoglobulin G4 (IgG4) related disease is a systemic inflammatory disease characterized by tumor-like tissue infiltration with IgG4 positive (IgG4+) plasma cells. Aspirin-exacerbated respiratory disease (AERD) is defined as asthma, chronic rhinosinusitis with nasal polyposis, and hypersensitivity to cyclooxygenase-1 inhibitors.\n\n\nOBJECTIVE\nWe described a case of a non-smoking 61-year-old male with prior NSAID sensitivity who presented with a 1-year history of left eye proptosis associated with chronic nasal symptoms, ultimately identified as concurrent AERD and IgG4 sinusitis.\n\n\nMETHODS\nThe patient was evaluated in the clinic and diagnosed by using clinical, radiographic, and surgical biopsy findings.\n\n\nRESULTS\nAlthough initial concern was greatest for malignancy, a biopsy specimen confirmed the presence of a dense lymphoplasmacytic infiltrate and storiform fibrosis, associated with increased IgG4+ plasma cells. Therefore, IgG4-related disease (RD) was identified in this patient with AERD.\n\n\nCONCLUSIONS\nShared type II inflammation may be responsible for the coexistence of IgG4-RD and AERD as observed in our patient. Health care workers must be cognizant of the simultaneous presentation of both IgG4-RD and AERD.",
"affiliations": "Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.",
"authors": "Johal|Kirti|K|;Welch|Kevin|K|;Peters|Anju|A|",
"chemical_list": "D007074:Immunoglobulin G; D001241:Aspirin",
"country": "United States",
"delete": false,
"doi": "10.2500/ajra.2017.31.4455",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1945-8932",
"issue": "31(5)",
"journal": "American journal of rhinology & allergy",
"keywords": null,
"medline_ta": "Am J Rhinol Allergy",
"mesh_terms": "D001241:Aspirin; D055963:Asthma, Aspirin-Induced; D006801:Humans; D007074:Immunoglobulin G; D008297:Male; D008875:Middle Aged; D009298:Nasal Polyps; D012130:Respiratory Hypersensitivity; D012852:Sinusitis",
"nlm_unique_id": "101490775",
"other_id": null,
"pages": "302-304",
"pmc": null,
"pmid": "28859705",
"pubdate": "2017-09-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Immunoglobulin G4 sinusitis in association with aspirin-exacerbated respiratory disease.",
"title_normalized": "immunoglobulin g4 sinusitis in association with aspirin exacerbated respiratory disease"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/17/0093780",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional": "3",
... |
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