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"abstract": "OBJECTIVE\nBone turnover suppression agents are widely used for prophylaxis of bone metastases from cancer and osteoporosis; the occurrence of their side effect, antiresorptive agent-related osteonecrosis of the jaw (ARONJ), has been increasing. We investigated the relationships between opacification in the nasal sinuses, rhinosinusitis, and ARONJ based on data obtained from oral surgeons.\n\n\nMETHODS\nWe examined 132 patients who had been clinically diagnosed with ARONJ based on clinical observations; all patients had undergone treatment at the Departments of Otorhinolaryngology and Oral Surgery. In 16 of the 132 patients, we confirmed a diagnosis of osteonecrosis of the upper jaw and the presence of ipsilateral opacification of the maxillary sinus. We analyzed the data of these 16 patients in detail.\n\n\nRESULTS\nFive of the 16 patients had some nasal symptoms and had been diagnosed with rhinosinusitis. The opacification of the rhinosinuses improved, partially improved, and remained unchanged after treatment in 10, three, and two patients, respectively; notably, imaging assessment could not be conducted after treatment in one case.\n\n\nCONCLUSIONS\nAlthough there is no consensus regarding the treatment of sinusitis accompanying ARONJ, attempts to improve the causal foci and conservative treatment may offer favorable results; thorough investigation is necessary in refractory cases before determining the use of surgery.",
"affiliations": "Department of Otolaryngology, Head and Neck Surgery, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, 181-8611 Tokyo, Japan.;Department of Otolaryngology, Head and Neck Surgery, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, 181-8611 Tokyo, Japan. Electronic address: h-yokoi@ks.kyorin-u.ac.jp.;Department of Oral Surgery, Kyorin University School of Medicine, Tokyo, Japan.;Department of Otolaryngology, Head and Neck Surgery, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, 181-8611 Tokyo, Japan.;Department of Otolaryngology, Head and Neck Surgery, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, 181-8611 Tokyo, Japan.",
"authors": "Matsumoto|Yuma|Y|;Yokoi|Hidenori|H|;Ikeda|Tetsuya|T|;Kawada|Michitsugu|M|;Saito|Koichiro|K|",
"chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D024841:Fluoroquinolones; D000069448:Denosumab; C076246:sitafloxacin",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.anl.2020.05.013",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-8146",
"issue": "47(6)",
"journal": "Auris, nasus, larynx",
"keywords": "Antiresorptive agent-related osteonecrosis of the jaw; Antiresorptive inhibitor; Odontogenic rhinosinusitis; Rhinosinusitis; Treatment",
"medline_ta": "Auris Nasus Larynx",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw; D050071:Bone Density Conservation Agents; D000069448:Denosumab; D004164:Diphosphonates; D005260:Female; D024841:Fluoroquinolones; D006801:Humans; D007571:Jaw Diseases; D008297:Male; D008875:Middle Aged; D010020:Osteonecrosis; D010256:Paranasal Sinuses; D012220:Rhinitis; D012852:Sinusitis; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "7708170",
"other_id": null,
"pages": "996-1002",
"pmc": null,
"pmid": "32591168",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Relationships of opacification in the nasal sinuses, rhinosinusitis, and antiresorptive agent-related osteonecrosis of the jaw.",
"title_normalized": "relationships of opacification in the nasal sinuses rhinosinusitis and antiresorptive agent related osteonecrosis of the jaw"
} | [
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"companynumb": "JP-TEVA-2021-JP-1898060",
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"activesubstancename": "ZOLEDRONIC ACID"
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{
"abstract": "BACKGROUND\nPneumonia caused by opportunistic fungi is a serious complication in immunocompromised patients. Hypercalcemia has been described in renal transplantation associated with Pneumocystis jirovecii (PJP) or Histoplasma capsulatum (HCP) pneumonia.\n\n\nMETHODS\nWe describe 5 patients who underwent kidney transplant between 2014 and 2019 and developed hypercalcemia before the diagnosis of pulmonary fungal infection: 4 patients with PJP and 1 with HCP. We assessed calcium metabolism and kidney function by total and ionized calcium, phosphorus, intact parathormone (iPTH), 25-OH vitamin D, 1,25(OH)2 vitamin D, and serum creatinine levels.\n\n\nRESULTS\nMean albumin-corrected calcium and ionized calcium were 12.56 mg/dL (range, 10.8-13.8 mg/dL) and 1.57 mmol/L (range, 1.43-1.69 mmol/L). Patients were normocalcemic, at 10.12 mg/dL (range, 9.6-10.5 mg/dL), before diagnosis and resolved hypercalcemia after antifungal treatment, at 8.86 mg/dL (range, 8.0-9.5 mg/dL). All patients had low or normal iPTH values, at 29.1 pg/mL (range, <3-44 pg/mL), with higher PTH levels 3 months before diagnosis and after treatment, at 147.3 pg/mL (range, 28.1-479 pg/mL) and 117.5 pg/mL (range, 18.2-245 pg/mL), respectively. The mean value for 25-OH vitamin D was 30.8 ng/mL (range, 14.6-62.8 ng/mL). This supports a PTH-independent mechanism, and we postulated an extrarenal production of 1,25(OH)2 vitamin D.\n\n\nCONCLUSIONS\nIn kidney transplant patients, hypercalcemia independent of PTH and refractory to treatment should alert for the possibility of opportunistic fungal pneumonia.",
"affiliations": "Department of Nephrology, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina. Electronic address: maria.giordani@hospitalitaliano.org.ar.;Department of Nephrology, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.;Department of Endocrinology, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.;Department of Infectology, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.;Department of Nephrology, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.;Department of Nephrology, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.;Department of Nephrology, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.;Department of Nephrology, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.;Department of Nephrology, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.",
"authors": "Giordani|María Cora|MC|;Villamil Cortez|Susana K|SK|;Diehl|María|M|;Barcan|Laura A|LA|;Rosa-Diez|Guillermo|G|;Groppa|S Rosana|SR|;Schreck|Carlos|C|;Mombelli|César|C|;Imperiali|Nora|N|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2020.03.031",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "52(4)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000328:Adult; D005260:Female; D006660:Histoplasmosis; D006801:Humans; D006934:Hypercalcemia; D016867:Immunocompromised Host; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009181:Mycoses; D009894:Opportunistic Infections; D011014:Pneumonia; D011020:Pneumonia, Pneumocystis; D055815:Young Adult",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "1178-1182",
"pmc": null,
"pmid": "32340747",
"pubdate": "2020-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Hypercalcemia as an Early Finding of Opportunistic Fungal Pneumonia in Renal Transplantation: A Case Series Report.",
"title_normalized": "hypercalcemia as an early finding of opportunistic fungal pneumonia in renal transplantation a case series report"
} | [
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"companynumb": "NVSC2020AR144536",
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"occurcountry": "AR",
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"abstract": "BACKGROUND The etiology of syndrome of inappropriate antidiuretic hormone secretion (SIADH) is highly variable. With little evidence, much of the guidance and recommendations available for management are based on clinical judgement. Although percutaneous balloon kyphoplasty can effectively relieve the severe pain associated with osteoporotic vertebral compression fractures that do not respond to conventional treatments, the effect of balloon kyphoplasty on SIADH associated with vertebral compression fracture remains unknown. CASE REPORT A 72-year-old woman was admitted to our hospital due to severe pain associated with lumbar compression fracture and pain-related SIADH. Since her pain could not be relieved by analgesics, she underwent percutaneous balloon kyphoplasty, a minimally invasive procedure intended to relieve pain. After the surgery, the patient's pain almost completely disappeared and her sodium level was gradually corrected within 3 days without any adverse events. CONCLUSIONS Percutaneous balloon kyphoplasty is a novel treatment option for SIADH associated with vertebral compression fracture. In the case presented here, it rapidly reduced pain and disability and also improved severe pain-associated SIADH without adverse effects. It may offer an alternative to pain regimens consisting of drugs, such as duloxetine, pregabalin, and opioids, that may exacerbate SIADH and hyponatremia. This case suggests treatment for new-onset or worsening hyponatremia in patients with vertebral compression fracture.",
"affiliations": "Division of Community Medicine, Kanazawa Medical University Himi Municipal Hospital, Himi, Toyama, Japan.;Division of Community Medicine, Kanazawa Medical University Himi Municipal Hospital, Himi, Toyama, Japan.;Division of Community Medicine, Kanazawa Medical University Himi Municipal Hospital, Himi, Toyama, Japan.;Division of Community Medicine, Kanazawa Medical University Himi Municipal Hospital, Himi, Toyama, Japan.",
"authors": "Izumida|Toshihide|T|;Sangen|Ryusho|R|;Usuda|Daisuke|D|;Kasamaki|Yuji|Y|",
"chemical_list": "D014667:Vasopressins",
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.928055",
"fulltext": "\n==== Front\nAm J Case Rep\nAm J Case Rep\namjcaserep\nThe American Journal of Case Reports\n1941-5923\nInternational Scientific Literature, Inc.\n\n33661857\n10.12659/AJCR.928055\n928055\nArticles\nSuccessful Treatment with Percutaneous Balloon Kyphoplasty for Syndrome of Inappropriate Secretion of Antidiuretic Hormone Associated with Vertebral Compression Fracture: A Case Report\nIzumida Toshihide ABCDEF\nSangen Ryusho A\nUsuda Daisuke AEF\nKasamaki Yuji DEF\nDivision of Community Medicine, Kanazawa Medical University Himi Municipal Hospital, Himi, Toyama, Japan\nCorresponding Author: Yuji Kasamaki, e-mail: kasamaki@kanazawa-med.ac.jp\nAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\n2021\n04 3 2021\n22 e928055-1e928055-5\n18 8 2020\n29 12 2020\n23 1 2021\n© Am J Case Rep, 2021\n2021\nThis work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)\nPatient: Female, 72-year-old\n\nFinal Diagnosis: Syndrome of inappropriate antidiuretic hormone secretion (SIADH)\n\nSymptoms: Agitation • nausea • pain\n\nMedication: —\n\nClinical Procedure: —\n\nSpecialty: Endocrinology and Metabolic\n\nObjective:\n\nUnusual or unexpected effect of treatment\n\nBackground:\n\nThe etiology of syndrome of inappropriate antidiuretic hormone secretion (SIADH) is highly variable. With little evidence, much of the guidance and recommendations available for management are based on clinical judgement. Although percutaneous balloon kyphoplasty can effectively relieve the severe pain associated with osteoporotic vertebral compression fractures that do not respond to conventional treatments, the effect of balloon kyphoplasty on SIADH associated with vertebral compression fracture remains unknown.\n\nCase Report:\n\nA 72-year-old woman was admitted to our hospital due to severe pain associated with lumbar compression fracture and pain-related SIADH. Since her pain could not be relieved by analgesics, she underwent percutaneous balloon kyphoplasty, a minimally invasive procedure intended to relieve pain. After the surgery, the patient’s pain almost completely disappeared and her sodium level was gradually corrected within 3 days without any adverse events.\n\nConclusions:\n\nPercutaneous balloon kyphoplasty is a novel treatment option for SIADH associated with vertebral compression fracture. In the case presented here, it rapidly reduced pain and disability and also improved severe pain-associated SIADH without adverse effects. It may offer an alternative to pain regimens consisting of drugs, such as duloxetine, pregabalin, and opioids, that may exacerbate SIADH and hyponatremia. This case suggests treatment for new-onset or worsening hyponatremia in patients with vertebral compression fracture.\n\nKeywords:\n\nFractures, Compression\nInappropriate ADH Syndrome\nPerioperative Care\n==== Body\nBackground\n\nHyponatremia is a common electrolyte disturbance in clinical practice, and syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the most frequent condition underlying hyponatremia [1]. SIADH is characterized by abnormal release of antidiuretic hormone (ADH) or enhanced action of ADH on the kidney. The causative factors of SIADH include a wide variety of symptoms, diseases, and drugs [2]. There are a variety of management approaches for SIADH in clinical practice, but the evidence supporting their use is limited [3]. Percutaneous balloon kyphoplasty can effectively relieve severe pain associated with osteoporotic vertebral compression fractures that do not respond to conventional treatments, and it may help decrease the physical consequences related to fracture [4,5]. However, the effect of balloon kyphoplasty on SIADH associated with vertebral compression fracture remains unknown.\n\nWe report a case of SIADH associated with lumbar compression fracture in a patient who subsequently underwent percutaneous balloon kyphoplasty. We discuss the pathogenesis of SIADH in our case, as well as the perioperative management and treatment strategy for hyponatremia in SIADH associated with lumbar compression fracture.\n\nCase Report\n\nA 72-year-old woman was transferred to our hospital for the evaluation and treatment of severe lower back pain and radiating pain in the left leg. Although no significant traumatic event occurred, she experienced severe and worsening back pain and leg pain for 1 week before her transfer. Upon arrival, the patient rated her pain as 10/10 on a visual analog scale (VAS), where 0 indicated “no pain” and 10 indicated “worst pain.” She described her pain as stabbing, and it was exacerbated by movement of the axial spine. She experienced pain radiating toward the left lower extremity, but she had no problems with bowel and bladder function. Magnetic resonance imaging of the spine showed low intensity in a T1-weighted image and high intensity in a T2-weighted image at L5 (Figure 1A). Computed tomography myelography did not show compressive lesions pressing against the nerve roots or spinal cord (Figure 1B). An L5 osteoporotic vertebral compression fracture was diagnosed. The patient’s medical history was significant for type 2 diabetes mellitus and hypertension, but otherwise, she had no remarkable history. Her medications included metformin, angiotensin II receptor blockers, and Ca-channel blocker, but not any diuretics. On the fourth day of admission, a preoperative evaluation was conducted to determine whether pain relief surgery could be safely performed. The patient’s vital signs were as follows: height, 155.0 cm; weight, 47.0 kg without recent changes; temperature, 36.7°C; blood pressure, 116/65 mmHg; and pulse, 80 beats/min, with a regular sinus rhythm. Physical examination was also performed, and the findings were as follows. Her skin was moist, the heart sounds were normal with no murmurs, the lungs were clear without rales, and the lower extremities showed no signs of edema. Neurological examination findings were normal. The patient rated her pain as 9–10/10 on VAS. Clinical chemistry showed moderate hyponatremia (Na 125 mEq/L), hypo-osmolality (262 mOsm/kg), and hyperglycemia (fasting glucose, 176 mg/dL). Endocrine studies showed elevated ADH (1.6 pg/mL) and normal thyroid and adrenal gland function. Urinary sodium concentration was increased (56 mEq/L), and urinary osmolality was 410 mOsm/kg. Chest X-ray, electrocardiogram, and chest computed tomography findings upon admission were normal. The patient exhibited hyponatremia, plasma hypo-osmolality, inappropriate urinary concentration at some level of plasma hypo-osmolality, elevated urinary sodium excretion, and absence of other potential causes of plasma hypo-osmolality, which indicated SIADH. Pregabalin for severe pain was initially suspected as the cause of SIADH. As the patient’s pain remained uncontrolled, pregabalin treatment was continued. Figure 2 shows the patient’s clinical course. The patient was initially instructed to restrict water intake (750 mL/d) and take salt tablets (54 mEq/d). However, the sodium level decreased after duloxetine was added to the patient’s treatment for severe pain. The patient’s pain was slightly relieved after addition of duloxetine, but she still rated it as 8–9/10 on VAS. As the patient refused opioids, duloxetine was continued. On the sixth day, she had nausea and mild agitation possibly due to increased intracranial pressure, and hypertonic saline infusion was started to treat her worsening hyponatremia. On the eighth day, she underwent percutaneous balloon kyphoplasty, a minimally invasive procedure intended to relieve pain. Postoperative rapid diuresis did not occur, and the sodium level was gradually corrected within 3 days. On the 10th day, the patient’s pain was rated as 0–2/10 on VAS. After pain relief surgery, hyponatremia and other findings improved spontaneously (Figure 2). On the 11th day, duloxetine was discontinued. The sodium level during a 6-month follow-up was within the normal range, although the patient continued to take only pregabalin.\n\nDiscussion\n\nSIADH is a clinical syndrome of euvolemic hyponatremia [6]. Our patient showed hyponatremia, plasma hypo-osmolality, inappropriate urinary concentration at some level of plasma hypo-osmolality, elevated urinary sodium excretion, and normal function of the thyroid and adrenal glands, which indicated SIADH [7].\n\nOur case encompasses 2 main concerns. The first involves the pathogenesis of SIADH. ADH plays an important part in the development of SIADH. Abnormal release of ADH or enhanced action of ADH on the kidney induces SIADH. In our case, plasma ADH concentrations were measured with a radioimmuno-assay kit (YAMASA Shoyu Corporation, Choshi, Japan) using a primary rabbit polyclonal antibody (interassay coefficient of variation [CV], 2.3–6.7%; intra-assay CV, 4.0–8.0%) and ADH was detectable in the setting of plasma hypo-osmolality, which suggested relative ADH elevation [8]. Given that hyponatremia in our patient worsened after treatment with duloxetine and pregabalin, yet it spontaneously resolved after pain relief surgery despite the patient continuing to take the medications, severe pain may stimulate ADH secretion. However, duloxetine and pregabalin may induce or worsen hyponatremia, more so in presence of predisposing factors like advanced age and pain. We cannot elucidate the mechanisms underlying the development of SIADH in the present case; however, the stimulation of hypothalamus, which is one of the pain modulation sites, might affect ADH secretion [9]. ADH secretion may also be increased by duloxetine through the stimulation of the serotonin and norepinephrine receptors in the hypothalamus [10,11]. Pregabalin-induced SIADH has rarely been reported, and the pathogenesis remains unknown [12]. However, measurement of ADH may be clinically of little value because plasma ADH is elevated in both hypovolemic and hypervolemic hyponatremia, and it might be difficult to measure accurately because of the difficult of handling, storing, and assaying samples [6].\n\nThe second concern is the treatment strategy for SIADH associated with vertebral compressive fractures. Various treatment approaches for SIADH have been recommended in different countries and organizations, yet they lack strong evidence in support of their use [13]. Common treatment options include fluid restriction, the management of the underlying disorder, and the discontinuation of the offending medication, but some patients with SIADH require other options. Percutaneous balloon kyphoplasty may be a novel treatment option for SIADH associated with vertebral compression fracture. It not only rapidly reduced pain and disability in the current case but also improved severe pain-associated SIADH without adverse effects [3,4]. Percutaneous balloon kyphoplasty may offer an alternative to pain regimens consisting of drugs that may further worsen SIADH and hyponatremia.\n\nOur experience centered on the perioperative management of a patient with SIADH-related hyponatremia who underwent pain relief surgery. A recent cohort study showed that preoperative hyponatremia was a prognostic marker for morbidity and mortality, but the effectiveness and safety of the intervention for preoperative hyponatremia have not yet been established [14]. However, a dynamic change in sodium level may increase the risk for several adverse outcomes such as postoperative pneumonia, renal failure, and central pontine myelinolysis [15]. Therefore, we carefully monitored the patient’s sodium level to avoid overcorrection after surgery. Postoperative rapid diuresis did not occur, and the sodium level was gradually corrected within 3 days. SIADH induced by severe pain slowly resolved after pain relief surgery. This phenomenon might reflect the pathogenesis of SIADH induced by pain, which can stimulate ADH secretion. This case could help clinicians treat new-onset or worsening hyponatremia in patients with a vertebral compression fracture.\n\nConclusions\n\nWe report a case of SIADH associated with lumbar compression fracture in a patient who underwent balloon kyphoplasty for pain relief. In case of SIADH associated with a vertebral compression fracture, percutaneous balloon kyphoplasty might offer an alternative to pain regimens consisting of drugs that may further worsen SIADH and hyponatremia.\n\nFigure 1. (A) Sagittal lumbar magnetic resonance image displaying a fracture with associated edema on L5. The arrow indicates the fracture. (B) Sagittal computed tomography myelography did not show compressive lesions pressing against the nerve roots and spinal cord.\n\nFigure 2. Clinical course of our patient. The image shows the change in serum sodium level in relation to the administration of pregabalin and duloxetine. Hyponatremia gradually resolved after pain relief surgery. VAS – visual analog scale.\n\nConflict of Interests\n\nNone.\n==== Refs\nReferences:\n\n1. Bartter FC Schwartz WB The syndrome of inappropriate secretion of antidiuretic hormone Am J Med 1967 42 790 806 5337379\n2. Ellison DH Berl T The syndrome of inappropriate antidiuresis N Engl J Med 2007 356 2064 72 17507705\n3. Lee JJ Kilonzo K Nistico A Yeates K Management of hyponatremia CMAJ 2014 186 E281 86 24344146\n4. Garfin SR Yuan HA Reiley MA New technologies in spine: Kyphoplasty and vertebroplasty for the treatment of painful osteoporotic compression fractures Spine (Phila Pa 1976) 2001 26 1511 15 11462078\n5. Zhao G Liu X Li F Balloon kyphoplasty versus percutaneous vertebroplasty for treatment of osteoporotic vertebral compression fractures (OVCFs) Osteoporos Int 2016 27 2823 34 27121344\n6. Cuesta M Thompson CJ The syndrome of inappropriate antidiuresis (SIAD) Best Pract Res Clin Endocrinol Metab 2016 30 175 87 27156757\n7. Verbalis JG Goldsmith SR Greenberg A Diagnosis, evaluation, and treatment of hyponatremia: Expert panel recommendations Am J Med 2013 126 10 Suppl. 1 S1 42\n8. Tanaka S Urakami M Mizuno H Togashi K [Development of a RIA kit “YAMASA” for measuring plasma ADH concentrations] Igaku To Yakugaku 2015 72 1379 88 [in Japanese]\n9. Dafny N Dong WQ Prieto-Gomez C Lateral hypothalamus: Site involved in pain modulation Neuroscience 1996 70 449 60 8848153\n10. Kirby D Harrigan S Ames D Hyponatraemia in elderly psychiatric patients treated with selective serotonin reuptake inhibitors and venlafaxine: A retrospective controlled study in an inpatient unit Int J Geriatr Psychiatry 2002 17 231 37 11921151\n11. Iovino M Steardo L Effect of substances influencing brain serotonergic transmission on plasma vasopressin levels in the rat Eur J Pharmacol 1985 113 99 103 2931284\n12. Jung YJ Lee DY Kim HW A case report of syndrome of inappropriate antidiuretic hormone induced by pregabalin Electrolyte Blood Press 2016 14 31 34 28275386\n13. Verbalis JG Grossman A Höybye C Runkle I Review and analysis of differing regulatory indications and expert panel guidelines for the treatment of hyponatremia Curr Med Res Opin 2014 30 1201 7 24809970\n14. Leung AA McAlister FA Rogers SO Jr Preoperative hyponatremia and perioperative complications Arch Intern Med 2012 172 1474 81 22965221\n15. Feinstein AJ Davis J Gonzalez L Hyponatremia and perioperative complications in patients with head and neck squamous cell carcinoma Head Neck 2016 38 E1370 74 26382762\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1941-5923",
"issue": "22()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D000368:Aged; D005260:Female; D050815:Fractures, Compression; D006801:Humans; D058498:Kyphoplasty; D058866:Osteoporotic Fractures; D016103:Spinal Fractures; D016896:Treatment Outcome; D014667:Vasopressins",
"nlm_unique_id": "101489566",
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"pages": "e928055",
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"pmid": "33661857",
"pubdate": "2021-03-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22965221;24074529;28275386;17507705;2931284;27121344;11462078;24344146;5337379;27156757;8848153;11921151;26382762;24809970",
"title": "Successful Treatment with Percutaneous Balloon Kyphoplasty for Syndrome of Inappropriate Secretion of Antidiuretic Hormone Associated with Vertebral Compression Fracture: A Case Report.",
"title_normalized": "successful treatment with percutaneous balloon kyphoplasty for syndrome of inappropriate secretion of antidiuretic hormone associated with vertebral compression fracture a case report"
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{
"abstract": "Acute flaccid quadriparesis secondary to hyperkalemia is a very rare and serious but reversible medical emergency. We present a case of a 73-year-old female who was admitted with rapidly progressive ascending paraparesis progressing to quadriparesis in about 10 h due to hyperkalemia. Patient was treated with antihyperkalemic measures. Her power improved dramatically as potassium levels normalized and she had an uneventful recovery.",
"affiliations": "Department of Critical Care Medicine, Max Super Speciality Hospital, Saket, New Delhi, India.;Department of Critical Care Medicine, Max Super Speciality Hospital, Saket, New Delhi, India.;Department of Critical Care Medicine, Max Super Speciality Hospital, Saket, New Delhi, India.;Department of Critical Care Medicine, Max Super Speciality Hospital, Saket, New Delhi, India.;Department of Neurology, Max Super Speciality Hospital, Saket, New Delhi, India.;Department of Neurology, Max Super Speciality Hospital, Saket, New Delhi, India.",
"authors": "Garg|Suneel Kumar|SK|;Saxena|Sanjay|S|;Juneja|Deven|D|;Singh|Omender|O|;Kumar|Mukesh|M|;Mukherji|Joy Dev|JD|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/0972-5229.125439",
"fulltext": "\n==== Front\nIndian J Crit Care MedIndian J Crit Care MedIJCCMIndian Journal of Critical Care Medicine : Peer-reviewed, Official Publication of Indian Society of Critical Care Medicine0972-52291998-359XMedknow Publications & Media Pvt Ltd India IJCCM-18-4610.4103/0972-5229.125439Case ReportHyperkalemia: A rare cause of acute flaccid quadriparesis Garg Suneel Kumar Saxena Sanjay Juneja Deven Singh Omender Kumar Mukesh 1Mukherji Joy Dev 1From: Department of Critical Care Medicine, Max Super Speciality Hospital, Saket, New Delhi, India1 Department of Neurology, Max Super Speciality Hospital, Saket, New Delhi, IndiaCorrespondence: Dr. Deven Juneja, Institute of Critical Care Medicine, Max Super Speciality Hospital, 1, Press Enclave Road, Saket, New Delhi - 110 017, India. E-mail: devenjuneja@gmail.com1 2014 18 1 46 48 Copyright: © Indian Journal of Critical Care Medicine2014This 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.Acute flaccid quadriparesis secondary to hyperkalemia is a very rare and serious but reversible medical emergency. We present a case of a 73-year-old female who was admitted with rapidly progressive ascending paraparesis progressing to quadriparesis in about 10 h due to hyperkalemia. Patient was treated with antihyperkalemic measures. Her power improved dramatically as potassium levels normalized and she had an uneventful recovery.\n\nAcute flaccid paralysishyperkalemiaquadriparesis\n==== Body\nIntroduction\nPrimary hyperkalemic paralysis occurs from genetic defects in sodium channels and secondary hyperkalemic paralysis from diverse causes including renal dysfunction, potassium retaining drugs, Addison's disease etc.[1] Acute flaccid quadriparesis (AFQ) induced by hyperkalemia has been described in only a few case reports. Here, we report a case of hyperkalemia -induced AFQ due to its rarity.\n\nCase Report\nA 73-year-old diabetic, hypertensive and hypothyroid female presented with the complaints of rapidly progressive ascending paraparesis, progressing to AFQ in about 10 h. She woke up with bilateral lower limb weakness with gradual inability to move upper limbs and had developed difficulty in breathing by the time she presented to the hospital. She was on glimipride, metformin, thyroxine, atenolol, ramipril and spironolactone. There was no other significant history.\n\nOn admission, she was conscious and oriented. Her pulse rate, blood pressure, respiratory rate and temperature were 72/min, 124/60 mmHg, 20/min and 98°F, respectively. Her oxygen saturation was 93% on room air. Neurological evaluation revealed normal pupils, symmetrical normal bulk and hypotonia in all limbs. Upper limbs had proximal and distal power of 4/5. In lower limbs, proximal and distal power was 2/5 with no sensory deficit. Deep tendon reflexes were absent. Bilaterally the plantar reflexes were mute. There were no lateralizing signs and the cranial nerves were normal. Other systemic examination was unremarkable. A clinical diagnosis of acute inflammatory demyelinating polyneuropathy was made. Arterial blood gas mixed primary metabolic and the respiratory acidosis and initial serum potassium level was 9.1 mmol/L. Other laboratory tests were normal. Electrocardiograph [Figure 1] showed tall T wave in anterior and lateral leads.\n\nFigure 1 Electrocardiogram on day 1 showing tall T wave in anterior and lateral leads\n\nRaised potassium levels raised the possibility of hyperkalemia induced AFQ. Urgent antihyperkalemic measures in the form of calcium gluconate, insulin dextrose solution, furosemide, beta-2 agonist nebulization and calcium polystyrene sulfonate (K-bind) with sorbitol, were instituted. Patient required non-invasive ventilation (NIV) support for type-2 respiratory failure. Hemodialysis was not required as she had a good urine output and serum potassium levels showed steady decline. Serial declining level of K+: 9.1, 8.6, 7.1, 6.1, 4.4 was accompanied by improving power and resulted in weaning of ventilatory support within 48 h.\n\nA nerve conduction velocity (NCV) study on day 1 was suggestive of demyelination. Subsequent NCV on day 4 was normal. She was shifted to the ward on day 4 by which time her biochemical parameters were normal. Electrocardiography on day 2 [Figure 2] showed normal T wave in anterior and lateral leads.\n\nFigure 2 Electrocardiogram on day 2 showing resolution of tall T wave in anterior and lateral leads\n\nDiscussion\nHyperkalemia is defined as measured serum potassium levels of >5.5 mEq/L. Clinical manifestations of hyperkalemia usually result from disordered membrane polarization. Cardiac manifestations are the most serious. Other symptoms include neuromuscular dysfunction, respiratory compromise and gastrointestinal signs. Our case was unique because she presented with AFQ and respiratory compromise requiring NIV support, which could be managed without hemodialysis.\n\nQuadriparesis induced by hyperkalemia has been described only in a few case reports.[123456] AFQ with no sensory deficit may mimic Guillain-Barré-syndrome (GBS).[7] Autonomic disturbance, a remarkable feature of GBS is not a recognized feature of hyperkalemic ascending quadriparesis, although it has been described in other situations associated with hyperkalemia.[8]\n\nThe exact mechanism of secondary hyperkalemic paralysis is not clear. It is thought to be due to direct action of potassium on the muscle fiber and cell membrane,[910] whereas some believe that a functional peripheral neuropathy induced by high serum potassium level is responsible.[911]\n\nThe most frequently reported causes of hyperkalemia-induced AFQ are renal insufficiency,[2356] use of potassium-sparing drugs[12] or a combination of both.[3] One case was due to tumor lysis syndrome.[3] Consistent with these reports, our patient was receiving an angiotensin converting enzyme inhibitor (Ramipril), Beta-blocker (Atenolol) and a potassium sparing diuretic (Aldactone). In these case reports, potassium levels ranged from 8 mEq/L to 9.69 mEq/L[356] comparable to ours (9.1 mEq/L).\n\nThe quadriparesis is usually ascending, with areflexia, normal sensory function and normal cranial nerves. In all case reports, quadriparesis reversed regardless of how the hyperkalemia was treated. As in our patient, reversal started almost immediately after treatment, with full strength returning over the next few hours.\n\nTo conclude, as hyperkalemia may be a potentially life-threatening but rapidly reversible cause of quadriparesis, a strong index of suspicion should be the key to early diagnosis in any patient presenting to the emergency room with features of AFQ especially in those who are on drugs with potential to cause hyperkalemia.\n\nSource of Support: Nil\n\nConflict of Interest: None declared.\n==== Refs\n1 Naik KR Saroja AO Khanpet MS Reversible electrophysiological abnormalities in acute secondary hyperkalemic paralysis Ann Indian Acad Neurol 2012 15 339 43 23349611 \n2 Kumar KS Ramakrishna C Padmanabhan S Kumar VS Hyperkalemic quadriparesis in a patient of ESRD Indian J Nephrol 2005 15 108 9 \n3 Desport E Leroy J Nanadoumgar H Chatellier D Robert R An unusual diagnostic of quadriparesia: Hyperkalemic paralysis. Report of four non-familial cases Rev Med Interne 2006 27 148 51 16364505 \n4 Berrebi R Orban JC Levraut J Grimaud D Ichai C Secondary hyperkalaemic acute flaccid tetraplegia Ann Fr Anesth Reanim 2009 28 381 3 19304442 \n5 Wahab A Panwar RB Ola V Alvi S Acute onset quadriparesis with sine wave: A rare presentation Am J Emerg Med 2011 29 575.e1 2 20716474 \n6 Panichpisal K Gandhi S Nugent K Anziska Y Acute quadriplegia from hyperkalemia: A case report and literature review Neurologist 2010 16 390 3 21150391 \n7 Evers S Engelien A Karsch V Hund M Secondary hyperkalaemic paralysis J Neurol Neurosurg Psychiatry 1998 64 249 52 9489541 \n8 Perez GO Oster JR Pelleya R Caralis PV Kem DC Hyperkalemia from single small oral doses of potassium chloride Nephron 1984 36 270 1 6709118 \n9 Livingstone IR Cumming WJ Hyperkalaemic paralysis resembling Guillain-Barré syndrome Lancet 1979 2 963 4 91060 \n10 Villabona C Rodriguez P Joven J Costa P Avila J Valdes M Potassium disturbances as a cause of metabolic neuromyopathy Intensive Care Med 1987 13 208 10 3495559 \n11 Shinotoh H Hattori T Kitano K Suzuki J Hyperkalaemic paralysis following traumatic rupture of the urinary bladder J Neurol Neurosurg Psychiatry 1985 48 484 5 3998756 \n12 Dutta D Fischler M McClung A Angiotensin converting enzyme inhibitor induced hyperkalaemic paralysis Postgrad Med J 2001 77 114 5 11161080\n\n",
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"keywords": "Acute flaccid paralysis; hyperkalemia; quadriparesis",
"medline_ta": "Indian J Crit Care Med",
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"title": "Hyperkalemia: A rare cause of acute flaccid quadriparesis.",
"title_normalized": "hyperkalemia a rare cause of acute flaccid quadriparesis"
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"abstract": "Although direct-acting oral anticoagulants (DOACs) decrease the bleeding risk compared with vitamin K antagonists (VKAs), DOACs might cause spontaneous hemothorax in very elderly patients, even at a very low dose. Interactions between drugs might increase the risk of bleeding. In this article, we report a case of a 95-year-old man who developed spontaneous hemothorax while taking rivaroxaban 2.5 mg twice daily, 3 days after concomitant use of itraconazole. Rivaroxaban was discontinued, and thoracentesis was performed to drain grossly bloody pleural effusion. To our knowledge, this is the first case report of spontaneous hemothorax that might have been caused by concomitant low-dose rivaroxaban and azole anti-fungal agents. This case highlights the potential risk of spontaneous hemothorax in very elderly patients while taking rivaroxaban and azole anti-fungal agents simultaneously. Special attention should be paid to interactions between drugs that might increase the risk of bleeding. Drugs that have competing metabolic pathways should be avoided. Closer monitoring, including testing for anti-Xa and additional reassessment, should be considered in high-risk patients.",
"affiliations": "Department of Geriatrics, 26447Peking University First Hospital, Peking University First Hospital, Beijing, China.;Department of Geriatrics, 26447Peking University First Hospital, Peking University First Hospital, Beijing, China.;Department of Geriatrics, 26447Peking University First Hospital, Peking University First Hospital, Beijing, China.",
"authors": "Liu|Mei|M|https://orcid.org/0000-0003-2114-7143;Liu|Wenwen|W|;Jiao|Hongmei|H|",
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"fulltext": "\n==== Front\nJ Int Med Res\nJ Int Med Res\nIMR\nspimr\nThe Journal of International Medical Research\n0300-0605\n1473-2300\nSAGE Publications Sage UK: London, England\n\n34586928\n10.1177/03000605211047712\n10.1177_03000605211047712\nCase Reports\nSpontaneous hemothorax caused by concomitant low-dose rivaroxaban and itraconazole in a 95-year-old patient: case report and literature review\nhttps://orcid.org/0000-0003-2114-7143\nLiu Mei\nLiu Wenwen\nJiao Hongmei\nDepartment of Geriatrics, 26447 Peking University First Hospital , Peking University First Hospital, Beijing, China\nHongmei Jiao, Department of Geriatrics, Peking University First Hospital, No. 8 Xishiku Street, Beijing 100034, China. Email: jiaohongmei@sina.com\n29 9 2021\n9 2021\n49 9 0300060521104771217 3 2021\n2 9 2021\n© The Author(s) 2021\n2021\nSAGE Publications\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).\nAlthough direct-acting oral anticoagulants (DOACs) decrease the bleeding risk compared with vitamin K antagonists (VKAs), DOACs might cause spontaneous hemothorax in very elderly patients, even at a very low dose. Interactions between drugs might increase the risk of bleeding. In this article, we report a case of a 95-year-old man who developed spontaneous hemothorax while taking rivaroxaban 2.5 mg twice daily, 3 days after concomitant use of itraconazole. Rivaroxaban was discontinued, and thoracentesis was performed to drain grossly bloody pleural effusion. To our knowledge, this is the first case report of spontaneous hemothorax that might have been caused by concomitant low-dose rivaroxaban and azole anti-fungal agents. This case highlights the potential risk of spontaneous hemothorax in very elderly patients while taking rivaroxaban and azole anti-fungal agents simultaneously. Special attention should be paid to interactions between drugs that might increase the risk of bleeding. Drugs that have competing metabolic pathways should be avoided. Closer monitoring, including testing for anti-Xa and additional reassessment, should be considered in high-risk patients.\n\nRivaroxaban\ndirect-acting oral anticoagulant\nspontaneous hemothorax\nconcomitant medication\nitraconazole\ndrug interaction\nInterdisciplinary clinical research project of Peking University First Hospital 2019CR40 Scientific Research Seed Fund of Peking University First Hospital 2020SF22 typesetterts2\n==== Body\npmcIntroduction\n\nAlthough the risk of major bleeding with direct-acting oral anticoagulants (DOACs) is low, spontaneous hemothorax might occur in very elderly patients with comorbidities, even at a very low dose.1 Interaction between rivaroxaban and other medications that share a similar metabolic pathway might increase the risk of bleeding.\n\nCase presentation\n\nA 95-year-old man who complained of fever, cough, and expectoration was admitted to our hospital. He had a history of pulmonary infection, chronic obstructive pulmonary disease, hypertension, and hiatal hernia. Rivaroxaban was prescribed for deep vein thrombosis (DVT) 1 year earlier. Because DVT recurred after discontinuation of rivaroxaban, and no bleeding events occurred, anticoagulant therapy was prolonged after the standard 3-month therapy. The maintenance dose was adjusted to 2.5 mg twice daily after considering his age and low body mass index (BMI) of 19 kg/m2, to reduce the risk of bleeding. He was treated with caspofungin for fungal pneumonia for 2 weeks, then with itraconazole 200 mg twice daily. Three days after beginning itraconazole, he complained of dyspnea. He spent most of the day in bed and denied any history of chest trauma. Medications upon the onset of dyspnea are listed in Table 1.\n\nTable 1. List of medications at the onset of dyspnea.\n\nClassification\tDrug\tDose\t\nCardiovascular disease\tRivaroxaban*\t2.5 mg BID\t\nBisoprolol fumarate\t1.25 mg QD\t\nIsosorbide mononitrate\t30 mg QD\t\nSpironolactone\t20 mg QD\t\nPulmonary disease\tItraconazole*\t200 mg BID\t\nTiotropium bromide\t18 µg QN\t\nSalmeterol fluticasone\t50 µg/250 µg Q12h\t\nAmbroxol hydrochloride\t30 mg TID\t\nOthers\tFerrous succinate\t100 mg TID\t\nVitamin C\t100 mg BID\t\nEsomeprazole\t20 mg BID\t\nNote: *indicates drugs that may cause drug interactions.\n\nBID, twice daily; QD, once daily; QN, once, at night; Q12h, every 12 hours; TID, three times daily.\n\nThe patient’s blood pressure was 105/60 mmHg, heart rate: 85 beats/minute, and respiratory rate: 25 breaths/minute with pulse oxygen saturation of 93% upon inhaling 1 L/minute oxygen through a nasal catheter. Pulmonary auscultation revealed reduced breath sounds over the left lower lung. Chest computed tomography (CT) revealed left encapsulated pleural effusion and interlobular effusion (Figure 1a). The average Hounsfield units (HU) of the pleural effusion was 25.0 Hu to 30.0 Hu. The patient’s hemoglobin (Hb) level was low, at 65 g/L (normal range: 130–175 g/L); platelet count: 78 × 109 cells/L (normal range: 125–350 × 103 cells/μL); prothrombin time (PT): 17.6 s (normal range: 10.1–12.6 s); international normalized ratio (INR): 1.52; activated partial thromboplastin time (aPTT): 30.5 s (normal range: 26.9–37.6 s); and trough concentration of anti-factor Xa (anti-Xa) activity: 0.80 IU/mL. The serum creatinine level was 132 μmol/L (normal range: 44–133 μmol/L), and the serum alanine transaminase level was 10 IU/L (normal range: 9–50 IU/L). In comparison, 5 days prior to the onset of dyspnea, the patient’s corresponding parameters were: Hb: 79 g/L, platelet count: 85 × 109 cells/L, PT: 12.7 s, INR: 1.10, aPTT: 28.1 s, and trough concentration of anti-Xa activity: 0.07 IU/mL.\n\nFigure 1. (a) Coronal reconstruction image of chest computed tomographic (CT) images showing left encapsulated pleural effusion and interlobular effusion (b) CT image showing that the pleural effusion resolved without new-onset pleural effusion 3 months after effusion drainage and discontinuation of rivaroxaban.\n\nRivaroxaban was discontinued, and 2 units of packed red blood cells and 200 mL fresh frozen plasma were transfused. Thoracentesis was performed with a 16-Fr catheter inserted after discontinuation of rivaroxaban for 24 hours. Approximately 600 mL of grossly bloody pleural effusion was drained on the first day. Dyspnea improved soon after the thoracentesis and drainage. Analysis of the pleural fluid showed a hematocrit (Hct) of 13.0% and a white blood count of 5290 × 106 cells/L. Bacterial Gram stain, acid-fast bacilli smear for tuberculosis, and bacterial culture, and cytology to detect malignant cells, were negative. Peripheral blood (PB) Hct was 24.6% on the same day, and the ratio of pleural to PB Hct was >0.5, confirming the diagnosis of hemothorax. The catheter was removed 7 days later when the daily drainage was <100 mL for 3 consecutive days. The total drainage volume was approximately 1705 mL.\n\nChest CT showed that the pleural effusion had resolved without new-onset effusion 3 months after effusion drainage and discontinuation of rivaroxaban (Figure 1b). When the patient was stable, the indication for anticoagulation was reassessed, and the net clinical benefit of anticoagulation was evaluated. Ultrasonography showed that there was no DVT in either lower extremity. The Padua score was 4, which indicated a high risk of venous thromboembolism. However, for this very elderly patient, the risk of bleeding outweighed the benefit of anticoagulation in the context of the recent major bleeding at an anatomically critical site. Therefore, anticoagulation was discontinued and was not reinstituted. The patient’s condition remained stable, and he was discharged shortly, thereafter. The medications upon discharge are listed in Table 2.\n\nTable 2. List of medications at discharge.\n\nClassification\tDrug\tDose\t\nCardiovascular disease\tBisoprolol fumarate\t1.25 mg QD\t\nIsosorbide mononitrate\t30 mg QD\t\nSpironolactone\t20 mg QD\t\nPulmonary disease\tTiotropium bromide\t18 µg QN\t\nSalmeterol fluticasone\t50 µg/250 µg Q12h\t\nAmbroxol hydrochloride\t30 mg TID\t\nOthers\tFerrous succinate\t100 mg TID\t\nVitamin C\t100 mg BID\t\nEsomeprazole\t20 mg BID\t\nQD, once daily; QN, once, at night; Q12h, every 12 hours; TID, three times daily; BID, twice daily.\n\nThis case report was prepared in accordance with the CARE guidelines. 2\n\nDiscussion\n\nSpontaneous hemothorax is defined as pleural fluid with a pleural to PB Hct ratio of >50%, without chest trauma or procedures affecting the lung or pleural space.3 This condition is rare in clinical practice. Anticoagulant-related spontaneous hemothorax has been reported in patients receiving heparin, warfarin, dabigatran, or enoxaparin, as a result of spontaneous rupture of small vessels.1,4\n\nCases of spontaneous hemothorax in patients receiving rivaroxaban have been reported in recent years. Four case reports were retrieved by inputting “spontaneous hemothorax” and “rivaroxaban” in PubMed (Table 3).5–8 The ages of the patients ranged from 24 to 81 years, and three were women older than 60 years of age. The onset of the spontaneous hemothorax varied from 10 days to 4 months after taking rivaroxaban regularly. All of the cases presented with significant degrees of decreased hemoglobin, and three had elevated INR (range: 1.21–2.1). Treatments included discontinuation of anticoagulation, red blood cell transfusion, and thoracentesis. The 81-year-old patient ultimately died from septic shock, while another three patients were discharged with no observation of pleural effusion on follow-up.\n\nTable 3. Clinical features and outcomes of the published cases of spontaneous hemothorax related to rivaroxaban.\n\nAge/sex\tIndication for anticoagulation\tDose of rivaroxaban (mg/day)\tOnset of symptoms\tConcomitant medications\tLocation of hemothorax\tBleeding in other locations\tComplications\tSerum creatinine (µmol/L)\tINR\tOutcome\t\n78 y/F[5]\tpulmonary embolism\t*\tdyspnea, chest pain\tamlodipine, atorvastatin, fluticasone/salmeterol\tleft\tnone\t*\t*\t1.71\tdischarge\t\n24 y/M[6]\tpulmonary embolism\t30\tdyspnea\t*\tleft\tnone\tshock\t*\t*\tdischarge\t\n63 y/F[7]\tatrial fibrillation\t15\tdyspnea, chest pain\t*\tright\tmediastinal hematoma\t*\t79.6\t1.21\tdischarge\t\n81 y/F[8]\tdeep vein thrombosis\t15\tsyncopal attack\tnon-steroidal anti-inflammatory drug\tbilateral\themopericardium\tpneumonia, acute renal failure, septic shock\t70.7\t2.1\tdeath\t\nNote: *Not mentioned.\n\nM, male; F, female; y, years; INR: international normalized ratio.\n\nOur case showed unique characteristics compared with previous published cases. First, this was a very elderly patient, with comorbidities and taking concomitant medications. Second, the patient received a very low dose of rivaroxaban (2.5 mg twice daily), which was a quarter of the recommended dose for DVT maintenance therapy. Moreover, the competing metabolic pathway between itraconazole and rivaroxaban might have increased the risk of bleeding in this case, even at such a low dose. This theory was supported by blood coagulation function test results. The trough anti-Xa activity increased significantly from 0.07 to 0.80 IU/mL, and PT increased from 12.7 s previously to 17.6 s on the day of the onset of dyspnea, 3 days after concomitant use of itraconazole. Itraconazole is a strong inhibitor of both cytochrome P450 enzyme (CYP3A4 isoform) and efflux transporter protein P-glycoprotein (P-gp).9 Because CYP3A4 accounts for approximately 18% of total rivaroxaban elimination, and rivaroxaban is a substrate of P-gp,10 the concomitant use of itraconazole and rivaroxaban increases rivaroxaban plasma concentrations, leading to an increased risk of bleeding. Finally, the etiology of our patient’s hemothorax was diagnosed by excluding tumors and tuberculosis, and appropriate treatment led to a favorable prognosis.\n\nHemothorax is considered major bleeding in patients taking oral anticoagulants, despite its rare occurrence. Patients and their physicians should be more aware of hemothorax as one complication of anticoagulants. Our case revealed the importance of paying careful attention to the interaction between rivaroxaban and other medications that might share similar metabolic pathways. Drugs that share competing metabolic pathways should be avoided. Anti-Xa activity is related to the concentration of oral direct factor Xa inhibitors. An anti-Xa assay is recommended in select clinical situations (e.g., renal insufficiency, assessment of compliance, periprocedural measurement of drug concentration, suspected overdose, advanced age, and extremes of body weight), and this assay is useful to prevent bleeding in high-risk patients. Closer monitoring of anti-Xa assay results and additional reassessment should be considered, especially in elderly patients with comorbidities.\n\nConclusion\n\nSpontaneous hemothorax is very rare and one of the major hemorrhagic complications of DOACs in very elderly patients with comorbidities. Special attention should be paid to interactions between drugs that might increase the risk of bleeding. Closer monitoring, including anti-Xa activity and additional reassessment, should be considered in high-risk patients.\n\nDeclaration of conflicting interest: The authors declare that there is no conflict of interest.\n\nEthics statement: Written informed consent was provided by the patient to have the case details and any accompanying images published. Approval by an ethics committee was not required because all data used in this study were obtained from previous medical records.\n\nFunding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by grants from the Scientific Research Seed Fund of Peking University First Hospital (2020SF22), and the Interdisciplinary Clinical Research Project of Peking University First Hospital (2019CR40).\n\nORCID iD: Mei Liu https://orcid.org/0000-0003-2114-7143\n==== Refs\nReferences\n\n1 Akgedik R Günaydin Z Bektas O , et al . Spontaneous hemothorax due to dabigatran use in a patient with atrial fibrillation. Clin Respir J 2017; 11 : 394–396.26083004\n2 Gagnier JJ Kienle G Altman DG , et al . The CARE guidelines: consensus-based clinical case reporting guideline development. Headache 2013; 53 : 1541–1547.24266334\n3 Azfar AH Lippmann M Mundathaje U , et al . Spontaneous hemothorax: a comprehensive review. Chest 2008; 134 : 1056–1065.18988781\n4 Mrug M Mishra PV Lusane HC , et al . Hemothorax and retroperitoneal hematoma after anticoagulation with enoxaparin. South Med J 2002; 95 : 936–938.12190238\n5 Lee HR Jeong YY Lee JD , et al . Spontaneous hemothorax as an adverse effect of rivaroxaban treatment. Turk Gogus Kalp Damar Cerrahisi Derg 2018; 26 : 309–311.32082753\n6 Yan DT RGK H Ng HJ. Massive spontaneous haemothorax after rivaroxaban therapy for acute pulmonary embolism. Eur J Case Rep Intern Med 2019; 6 : 001236.31742199\n7 Yıldız İ Aksu E Özmen YPÖ , et al . A case of rivaroxaban associated spontaneous hemothorax. Turk Gogus Kalp Damar Cerrahisi Derg 2019; 27 : 118–120.32082838\n8 Yu JH Liu HH Hsieh MJ , et al . Spontaneous bilateral haemothorax with haemopericardium secondary to rivaroxaban. J Clin Pharm Ther 2020; 45 : 1175–1178.32023350\n9 Piérard GE Arrese JE Piérard-Franchimont C. Itraconazole. Expert Opin Pharmacother 2000; 1 : 287–304.11249550\n10 Mueck W Stampfuss J Kubitza D , et al . Clinical pharmacokinetic and pharmacodynamic profile of rivaroxaban. Clin Pharmacokinet 2014; 53 : 1–16.23999929\n\n",
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"journal": "The Journal of international medical research",
"keywords": "Rivaroxaban; concomitant medication; direct-acting oral anticoagulant; drug interaction; itraconazole; spontaneous hemothorax",
"medline_ta": "J Int Med Res",
"mesh_terms": "D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants; D001281:Atrial Fibrillation; D065427:Factor Xa Inhibitors; D006470:Hemorrhage; D006491:Hemothorax; D006801:Humans; D017964:Itraconazole; D008297:Male; D000069552:Rivaroxaban",
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"title": "Spontaneous hemothorax caused by concomitant low-dose rivaroxaban and itraconazole in a 95-year-old patient: case report and literature review.",
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"abstract": "BACKGROUND\nRecipients of organ transplant who are immunosuppressed are at greatly increased risk of nonmelanoma skin cancers compared with the general population, but their risk of appendageal tumors is unknown.\n\n\nOBJECTIVE\nOur aim was to conduct a systematic examination of cutaneous appendageal tumors arising in recipients of organ transplants compared with individuals who were immunocompetent (ICP).\n\n\nMETHODS\nWe conducted a retrospective, clinicopathologic analysis of consecutive appendageal tumors arising in 650 recipients of organ transplants and in the general population of approximately 605,000 people served by our institution.\n\n\nRESULTS\nBetween 1993 and 1998, 231 appendageal tumors were identified in 211 individuals; 23 tumors were found in 21 of 650 patients undergoing transplant (3%), 10 in individuals with other immunosuppressive conditions, 3 in 2 patients with Muir-Torre syndrome, and 195 in 178 apparently ICP. In addition to the increased frequency of appendageal tumors among recipients of transplants, malignant tumors were overrepresented (43% of transplant tumors vs 4% in ICP; P <.0001) as were tumors of sebaceous origin (30% vs 6%; P <.0001).\n\n\nCONCLUSIONS\nRecipients of organ transplant who are immunosuppressed have a greatly increased risk of cutaneous appendageal tumors compared with apparently ICP. In addition, their tumors are more likely to be malignant and of sebaceous origin.",
"affiliations": "Department of Academic Dermatology and Cancer Research, London, UK. caharwood@doctors.org.uk",
"authors": "Harwood|Catherine A|CA|;McGregor|Jane M|JM|;Swale|Victoria J|VJ|;Proby|Charlotte M|CM|;Leigh|Irene M|IM|;Newton|Robert|R|;Khorshid|S Mohsen|SM|;Cerio|Rino|R|",
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"mesh_terms": "D000328:Adult; D017677:Age Distribution; D000368:Aged; D000369:Aged, 80 and over; D001707:Biopsy, Needle; D018280:Carcinoma, Skin Appendage; D016022:Case-Control Studies; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D016867:Immunocompromised Host; D007150:Immunohistochemistry; D015994:Incidence; D008297:Male; D008875:Middle Aged; D016377:Organ Transplantation; D012016:Reference Values; D012189:Retrospective Studies; D018570:Risk Assessment; D017678:Sex Distribution; D012878:Skin Neoplasms; D014181:Transplantation Immunology",
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"title": "High frequency and diversity of cutaneous appendageal tumors in organ transplant recipients.",
"title_normalized": "high frequency and diversity of cutaneous appendageal tumors in organ transplant recipients"
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"abstract": "An immune etiology for idiopathic recurrent miscarriage is an important issue because a fetus is allogenetically different from the mother. Type 1 T helper (Th1) and Type 2 (Th2) cells have important functions in immune responses and there is a general agreement that pregnancy is associated with Th2 cell dominance. The purpose of this case report is to establish the effectiveness of an immunosuppressive treatment for a patient who had 11 consecutive miscarriages despite several treatments, such as anticoagulation, that showed elevated Th1/Th2 cell ratios.\n\n\n\nThis patient visited our clinic following 11 consecutive miscarriages between 2009 and 2014 that occurred between 5 and 8 weeks' gestation. The Th1/Th2 cell ratio was evaluated after the 12th conception and she received an immunosuppressive treatment (tacrolimus; 1 mg/d).\n\n\n\nThe Th1/Th2 cell ratio was elevated after the 12th conception, but the patient miscarried, with a normal karyotype of chorionic villi despite the immunosuppressive treatment. After the 13th conception, she began receiving treatment with 2 mg/d of tacrolimus at 4 weeks' gestation, which was continued until delivery.\n\n\n\nFor recurrent miscarriage cases that show an elevated Th1/Th2 cell ratio after achieving pregnancy, immunosuppressive treatment with tacrolimus could be effective.",
"affiliations": "Division of Reproductive Medicine Sugiyama Clinic Tokyo Japan.;Department of Obstetrics and Gynecology Faculty of Medicine Juntendo University Tokyo Japan.;Division of Reproductive Medicine Sugiyama Clinic Tokyo Japan.;Department of Maternal-Fetal Biology National Center for Child Health and Development Tokyo Japan.",
"authors": "Nakagawa|Koji|K|0000-0003-0874-5894;Kuroda|Keiji|K|;Sugiyama|Rikikazu|R|;Yamaguchi|Koushi|K|",
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"fulltext": "\n==== Front\nReprod Med BiolReprod. Med. Biol10.1111/(ISSN)1447-0578RMB2Reproductive Medicine and Biology1445-57811447-0578John Wiley and Sons Inc. Hoboken 10.1002/rmb2.12040RMB212040Case ReportCase ReportAfter 12 consecutive miscarriages, a patient received immunosuppressive treatment and delivered an intact baby Nakagawa Koji http://orcid.org/0000-0003-0874-5894koji@sugiyama.or.jp \n1\nKuroda Keiji \n2\nSugiyama Rikikazu \n1\nYamaguchi Koushi \n3\n\n1 \nDivision of Reproductive Medicine\nSugiyama Clinic\nTokyo\nJapan\n\n2 \nDepartment of Obstetrics and Gynecology\nFaculty of Medicine\nJuntendo University\nTokyo\nJapan\n\n3 \nDepartment of Maternal–Fetal Biology\nNational Center for Child Health and Development\nTokyo\nJapan\n* Correspondence\n\nKoji Nakagawa, Division of Reproductive Medicine, Sugiyama Clinic, Tokyo, Japan.\n\nEmail: koji@sugiyama.or.jp\n21 6 2017 7 2017 16 3 10.1111/rmb2.2017.16.issue-3297 301 25 11 2016 07 5 2017 © 2017 The Authors. Reproductive Medicine and Biology published by John Wiley & Sons Australia, Ltd on behalf of Japan Society for Reproductive Medicine.This 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.Abstract\nAim\nAn immune etiology for idiopathic recurrent miscarriage is an important issue because a fetus is allogenetically different from the mother. Type 1 T helper (Th1) and Type 2 (Th2) cells have important functions in immune responses and there is a general agreement that pregnancy is associated with Th2 cell dominance. The purpose of this case report is to establish the effectiveness of an immunosuppressive treatment for a patient who had 11 consecutive miscarriages despite several treatments, such as anticoagulation, that showed elevated Th1/Th2 cell ratios.\n\nMethods\nThis patient visited our clinic following 11 consecutive miscarriages between 2009 and 2014 that occurred between 5 and 8 weeks’ gestation. The Th1/Th2 cell ratio was evaluated after the 12th conception and she received an immunosuppressive treatment (tacrolimus; 1 mg/d).\n\nResults\nThe Th1/Th2 cell ratio was elevated after the 12th conception, but the patient miscarried, with a normal karyotype of chorionic villi despite the immunosuppressive treatment. After the 13th conception, she began receiving treatment with 2 mg/d of tacrolimus at 4 weeks’ gestation, which was continued until delivery.\n\nConclusion\nFor recurrent miscarriage cases that show an elevated Th1/Th2 cell ratio after achieving pregnancy, immunosuppressive treatment with tacrolimus could be effective.\n\nimmunological rejectionimmunosuppressive agentrecurrent pregnancy lossT helper type 1:2 cell ratiotacrolimus source-schema-version-number2.0component-idrmb212040cover-dateJuly 2017details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.2.7 mode:remove_FC converted:04.12.2017\n\n\nNakagawa \nK \n, \nKuroda \nK \n, \nSugiyama \nR \n, \nYamaguchi \nK \n. After 12 consecutive miscarriages, a patient received immunosuppressive treatment and delivered an intact baby . Reprod Med Biol . 2017 ;16 :297 –301 . https://doi.org/10.1002/rmb2.12040\n==== Body\n1 INTRODUCTION\nType‐1 T helper (Th1) and type‐2 T helper (Th2) cells play important roles in immune responses, particularly in immune rejection and tolerance.1, 2 Hence, a method to achieve Th1/Th2 balance has been proposed to offset materno–fetal immune reactions during pregnancy. Pregnancy is generally associated with Th2 cell dominance except during instances of implantation and parturition. Over‐reactive Th1 cell immune responses at the time of implantation have been associated with implantation failure, early pregnancy losses and repeated pregnancy losses3, 4, 5, 6 and can be compared to an allograft rejection.7 Immunological rejection might be one of the causes of miscarriage8 and several immunomodulation therapies such as prednisolone, γ‐globulin therapy, and allogenic leukocyte immunization have been used for these types of patients. These therapies have their own demerits, which are disadvantages for both the patient and the fetus.\n\nThe patient described here was found to have an impaired Th2 dominance after the establishment of pregnancy. The administration of an immunosuppressive agent allowed the patient to continue her pregnancy, and she had a successful delivery.\n\n2 CASE REPORT\nThe histories of this patient's miscarriages are summarized in Table 1\n. She had received no treatment before her 1st and 2nd miscarriages. Because she had been diagnosed as a case of idiopathic recurrent miscarriage, she received empirical low‐dose aspirin, low‐molecular‐weight heparin, prednisolone (5 mg/d), or intravenous massive immunoglobulin therapy between 2009 and 2014. For three out of these 11 miscarriages the fetal karyotype was subsequently found to be normal. There was no past medical, surgical, obstetric or gynecological history of note. Investigative screenings for recurrent miscarriage were performed on March 24, 2008, and all results were negative (Table 1).\n\nTable 1 Characteristics of the treatment for the patient's 12 consecutive miscarriages\n\nNo.\tDate\thCGa\n\tGSb\n\tYolk sac\tEmbryo\tFHMc\n\tD&C\tCromd\n\tLDAe\n\tHeparin\tPSLf\n\tIVIGg\n\tIMh\n\tMiscarriage\t\n1\t2007/11\t+\tYes\tNo\tNo\tNo\tNo\tNo\tNo\tNo\tNo\tNo\tNo\tYes\t\n2\t2008/02\t+\tYes\tYes\tYes\tYes\tYes\tNo\tNo\tNo\tNo\tNo\tNo\tYes\t\n3\t2008/09\t+\tNo\tNo\tNo\tNo\tNo\tNo\tYes\tNo\tNo\tNo\tNo\tYes\t\n4\t2009/03\t+\tYes\tNo\tNo\tNo\tYes\tNo\tYes\tNo\tNo\tNo\tNo\tYes\t\n5\t2009/11\t+\tYes\tYes\tYes\tYes\tYes\t46, XX\tYes\tNo\tNo\tNo\tNo\tYes\t\n6\t2010/05\t+\tYes\tNo\tNo\tNo\tNo\tNo\tYes\tYesi\n\tNo\tNo\tNo\tYes\t\n7\t2011/06\t+\tYes\tNo\tNo\tNo\tNo\tNo\tYes\tYesj\n\tNo\tNo\tNo\tYes\t\n8\t2011/09\t+\tYes\tNo\tNo\tNo\tYes\t46, XY\tYes\tYesk\n\tNo\tNo\tNo\tYes\t\n9\t2012/05\t+\tNo\tNo\tNo\tNo\tNo\tNo\tYes\tNo\tNo\tNo\tNo\tYes\t\n10\t2012/09\t+\tYes\tYes\tCRL:16l\n\tYes\tYes\t46, XY\tYes\tYesk\n\t5 mg\tNo\tNo\tYes\t\n11\t2014/04\t+\tYes\tYes\tCRL:15l\n\tYes\tYes\t47, XX+22\tYes\tYesk\n\t5 mg\tYes\tNo\tYes\t\n12\t2014/09\t+\tYes\tYes\tYes\tYes\tYes\t46, XX\tYes\tYesk\n\tNo\tNo\t1 mg\tYes\t\n13\t2015/02\t+\tYes\tYes\tYes\tYes\tNo\tNo\tNo\tNo\tNo\tNo\t2 mg\tNo\t\n\nahCG, the confirmation of serum human chorionic gonadotropin; bThe presence of a gestational sac in the uterine cavity; cThe confirmation of fetal heart movement; dChromosomal analysis; eLow‐dose aspirin (81 mg/d); fPrednisolone administration; gi.v. immunoglobulin administration (1 g/kg/3 d); hAdministration of an immunosuppressive agent (tacrolimus, mg/d); iHeparin (2500 IU/d); jHeparin (5000 IU/day); kHeparin (10 000 IU/d); lCRL: crown rump length (mm).\n\nJohn Wiley & Sons, LtdThis patient visited our clinic following 11 consecutive miscarriages between 2009 and 2014 that occurred between 5 and 8 weeks’ gestation (Table 2). The peripheral blood Th1/Th2 cytokine producing cell ratio was measured at 8.9 (Th1=19.6, Th2=2.2). Th1 cells and Th2 cells were defined as CD4+ lymphocytes with intracellular IFN‐γ but without IL‐4 (CD4+IFN‐γ+) and CD4+ lymphocytes with intracellular IL‐4 but without IFN‐γ (CD4+IL‐4+), respectively, and the normal range of a Th1/Th2 cell ratio was set at less than 10.3 according to our previous report.3 This Th1/Th2 cell ratio was re‐checked just after confirmation of the 12th conception (14th day after a LH‐positive day) and an elevation at 15.2 was detected (Th1=18.2, Th2=1.2; Table 3). The patient began to receive immunosuppressive treatment (tacrolimus; 1 mg/d) after the 12th conception, combined with low‐dose aspirin and low‐molecular‐weight heparin. Unfortunately, she miscarried at 8 weeks gestation due to subchorionic hemorrhage, with a normotype of chorionic villi.\n\nTable 2 Result of investigating screening for recurrent pregnancy losses (checked on March 24, 2008)\n\nBasal hormonal profile\tValue\tAntiphospholipid syndrome screening\tValue\t\nLH (IU/L)\t3.7\tIgM anticardiolipin antibody titers (U/mL)\t<5000\t\nFSH (IU/L)\t10.2\tIgG anticardiolipin antibody titers (U/mL)\t1000\t\nProlactin (ng/mL)\t6.3\tLAC (dilute Russell viper venom time)\t0.800\t\nBlood coagulation testing\tAnti‐PE IgG (kininogen+)\t0.206\t\nPT (second)\t11.0\tAnti‐PE IgM\t0.370\t\nAPTT (second)\t25.6\tAnti‐PS IgG\t<0.500\t\nProtein S\t71.0\tAnti‐PS IgM\t0.600\t\nProtein C (%)\t104.0\tβ2GP1 antibody\t<0.200\t\nCoagulation factor XII (%)\t138.0\tAutoimmune screening\t\t\nFull blood count\tAnti‐DNA\t<80 000\t\nWhite blood cells (/μL)\t4700.0\tMitochondrial antibodies\t<20 000\t\nRed blood cells (million/μL)\t372.0\tThyroid antibodies (IU/mL)\t1200\t\nHemoglobin (g/dl)\t11.7\tViral screening\t\t\nPlatelets (/μL)\t267,000.0\tHepatitis B antigen\tNegative\t\nRandom blood sugar count (g/dl)\t98.0\tHepatitis C antibody\tNegative\t\nThyroid gland profile\t<20.0\tHuman immunosuppressive virus\tNegative\t\nTSH (μIU/mL)\t1.7\tKaryotype analysis of both parents\t\nFree T3 (pg/mL)\t3.6\tPatient\t46, XX\t\nFree T4 (ng/mL)\t1.5\tPartner\t46, XY\t\nAPTT, activated partial thromboplastin time; FSH, follicle‐stimulating hormone; GP, glycoprotein; Ig, immunoglobulin; LAC, lupus anticoagulant; LH, luteinizing hormone; PE, phosphatidylethanolamine; PS, phosphatidylserine; PT, prothrombin time; TSH, thyroid stimulating hormone.\n\nJohn Wiley & Sons, LtdTable 3 Changes in the T helper 1 (Th1) and T helper 2 (Th2) cells before and after pregnancy\n\nDate\tStatus\tTh1 (%)\tTh2 (%)\tTh1/Th2\tTacrolimus\t\n2012‐10‐01\t10th conception (6 weeks)\t18.8\t1.7\t11.1\tNone\t\n2013‐05‐10\tNon‐pregnancy\t19.6\t2.2\t8.9\tNone\t\n2014‐09‐08\t12th conception (8 weeks)\t18.2\t1.2\t15.2\t1 mg/d\t\n2015‐02‐13\t13th conception (4 weeks)\t14.6\t0.9\t16.2\t2 mg/d\t\nJohn Wiley & Sons, LtdOn her 13th conception, she received only immunosuppressive treatment (tacrolimus; 2 mg/d) that was started at 4 weeks’ gestation after a home pregnancy test was positive, and she continued this dose until the day of delivery. A fetal heartbeat was confirmed at 6 weeks’ gestation, but the fetal growth was small for gestational age. The pregnancy was monitored with serial ultrasonography and complicated by intrauterine growth restriction; therefore, the patient was moved from our clinic to the National Center for Child Health and Development. The patient's blood pressure was found to be elevated at around 24 weeks gestation, and she was treated with an antihypertensive drug. As a result of poor fetal growth velocity detected by serial ultrasonography and an inability to control her blood pressure, at 29 weeks a cesarean section was performed that resulted in the birth of a female infant weighting 748 g. Her physical condition improved rapidly after giving birth, and she was discharged 2 weeks after delivery. The baby girl was placed in the neonatal care unit (NICU), where her weight increased at a good rate, and she was discharged 3 months after birth without complications.\n\n3 DISCUSSION\nThis case report is interesting because it is a case of immunosuppressive treatment using tacrolimus for a patient who showed an elevated Th1/Th2 cell ratio after conception in recurrent miscarriages. In this case, the patient miscarried at 8 weeks’ gestation despite receiving intravenous massive immunoglobulin (IVIG) following the 11th conception, which marked her longest period without miscarriage. Locally, we believed that IVIG could be effective for this case, and suspected that a cause of her miscarriages might be an immunological rejection. Therefore, we checked the levels of Th1 and Th2 cells in the non‐pregnant period after the 11th miscarriage. However, she showed a normal Th1/th2 cell ratio, according to our criteria.3\n\n\nOn the 12th pregnancy, the patient received immunosuppressive treatment (tacrolimus 1 mg/d) with empirical low‐dose aspirin and low‐molecular‐weight heparin. As a result of this treatment, a subchorionic hemorrhage occurred and caused another miscarriage. Her Th1/Th2 ratio after the establishment of pregnancy was 15.2, which was due to a decrease in the Th2 cell level. She began a regimen of tacrolimus (1 mg/d) following a positive urinary pregnancy test (the 12th pregnancy). During the 12th pregnancy, her Th1 and Th2 levels were 18.2 and 1.2 with tacrolimus treatment (1 mg/d), respectively, and it was lower than that (Th2=2.2) before this pregnancy (non‐pregnant status). As a consequence, her Th1/Th2 ratio was elevated (Th1/Th2=15.2). Although the patient received 1 mg/d of tacrolimus during the 12th pregnancy, this resulted in miscarriage regardless of her demonstration of a euploid chromosome (46, XX) from the chorionic villi sampling. Based on this data, we speculated that the cause of this miscarriage was a weakening of immunological tolerance. The immunosuppressive treatment using tacrolimus had not strengthened her immunological tolerance, and, instead, it had seemed to have weakened her immunological rejection (Th1 level). In this case, the decrease in immunological rejection that caused a miscarriage of the 12th pregnancy might have been a case of immunological rejection due to the weakening of her immunological tolerance despite the administration of an immunosuppressive agent. It was concluded that the dose of tacrolimus might not have been sufficient. Moreover, we were convinced that anticoagulant therapy was unnecessary for this patient.\n\nThere were no data concerning the Th1/Th2 ratio between the 12th and 13th pregnancies. However, the Th1/Th2 ratio was checked on October 1, 2012, on the day the patient was diagnosed with her 10th miscarriage (Table 3). Seven months after the 10th miscarriage, her Th1/Th2 was checked again, and it was confirmed that the Th1/Th2 ratio was less than 10.3, and lower than that at the previous check. When this patient was not pregnant, her Th1/Th2 ratio was less than 10.3. Therefore, the Th1/Th2 ratio was thought to have decreased to less than ten after her 12th miscarriage.\n\nAfter the 13th conception, she began receiving treatment with tacrolimus of 2 mg/d at 4 weeks’ gestation until delivery with no further anticoagulant therapy. During the patient's 13th pregnancy, the combination of tacrolimus and massive IVIG was an option for immunomodulation, but the patient did not agree to the use of IVIG due to its cost (1 million JPY/one treatment), therefore, we abandoned the combination of massive IVIG and tacrolimus, and decided to simply increase the dose of tacrolimus.\n\nThe embryo expresses paternal antigens that are foreign to the mother and therefore may be viewed as an allograft; in a normal pregnancy, the embryo is not rejected by the mother's immune system.4 Antigens expressed on the surface of fetal or placental tissues possibly induce alloimmune responses by the mother, along with certain immunologic mechanisms that sustain the continuation of a normal pregnancy. Moreover, Th2 cell dominance is important for the maintenance of a normal pregnancy, and is a common phenomenon. With regard to immunological disorders as causative factors, it is assumed that recurrent pregnancy loss (RPL) could be caused by an increase in type 1 cytokines prior to implantation by essential immunological status in the whole body, while recurrent implantation failure would induce the production of type 1 cytokines in the uterus, which would then be reflected in the whole body. A relative increase in the population of Th2 cells in a normal pregnancy is observed as a result of the suppression of type 1 cytokines production. The Th1/Th2 cell ratio in RPL patients who may have immunological disorders shows an excessive response to the fetus and tends to be elevated in general.2, 5 Initially, fetus antigens are recognized in early pregnancy and extensive numbers of antigens are transferred to maternal circulation in the second trimester. Theoretically, two peaks of immune responses to the fetus would be observed in patients who have either a failure of immunological tolerance or a suppression of immunological rejection.\n\nIn a previous study, changes in the percentage of Th1 cells, Th2 cells, and the Th1/Th2 ratio were reported in patients with unexplained recurrent abortions before and after immunotherapy with the husband's mononuclear cells.8 In the present report, iimmunotherapy significantly increased the percentage of Th2 cells, while the Th1/Th2 ratio was significantly decreased in the total patient population, and the Th1/Th2 ratio was significantly decreased with immunotherapy in the total patient population. The present study demonstrated that Th2 cell dominance is important in order to avoid miscarriage. A worldwide meta‐analysis study has concluded that immunization may be highly effective, although this is indicated only for a small number of patients.8 Wegmann et al. proposed an immunotrophic theory,9 whereby some cytokines produced by maternal cells, which recognize fetal antigens, promote the proliferation of trophoblastic cells and sustain pregnancy continuation.\n\nThere are several immunotherapy methods for treatment of unexplained recurrent pregnancy losses, such as IVIG, immunotherapy with the husband's mononuclear cells, and the administration of prednisolone. IVIG therapy is expensive, requires infusion, and might cause unknown viral infections. Immunotherapy using a husband's mononuclear cells presents the risk of graft‐versus‐host disease (GVHD), and the preparation of a mononuclear cell is a cumbersome procedure. Prednisolone therapy requires a high dose (20 mg/d) for treatment of unexplained recurrent pregnancy losses. These three immunotherapies all possess disadvantageous aspects for patients. On the other hand, tacrolimus therapy is safe and simple, and is much more convenient for patients.\n\nTacrolimus has been utilized throughout pregnancy for women who have received an allogeneic organ transplant, and many female recipients have given birth while taking tacrolimus.10 Tacrolimus reduces peptidyl‐prolyl isomerase activity by binding to the immunophilin FKBP12 (FK506 binding protein) and creating a new complex. This FKBP12‐FK506 complex interacts and inhibits calcineurin, and further inhibits both T‐lymphocyte signal transduction and IL‐2 transcription.11 The values for short‐term immunosuppression and graft survival by patients are found to be similar between the two drugs. However, tacrolimus results in a more favorable lipid profile which may have important long‐term implications given the prognostic influence of rejection on graft survival.12\n\n\nIn the present case, the cause of the patient's miscarriages was difficult to determine, because her elevated Th1/Th2 cell ratio was detectable only when she became pregnant. Tacrolimus is a major immune‐suppressive agent for allogenic organ transplantation, but it has never been used for the treatment of recurrent miscarriages due to immunological rejection. This patient is an identical twin, and her sister had two children without a history of miscarriage. Based on the history of her sister, the cause of the patient's miscarriages was thought to be immunological rejection against the paternal antigen, which might have been acquired after birth.\n\nDISCLOSURES\n\nConflict of interest: The authors declare no conflict of interest. Human and Animal Rights: All the procedures that were followed were in accordance with the ethical standards of the responsible committee of Sugiyama Clinic and with the Helsinki Declaration of 1964 and its later amendments. Informed consent was obtained from this patient to be included in this case report. This article does not contain any study with animal participants that have been performed by any of the authors.\n\nACKNOWLEDGEMENTS\nThe authors appreciated the obstetrical and NICU staff members in the Tokyo Metropolitan Otuka Hospital, where the patient and her baby in this case report were managed and treated during the perinatal period.\n==== Refs\nREFERENCES\n1 \n\nKheshtchin \nN \n, \nGharagozloo \nM \n, \nAndalib \nA \n, \nGhahiri \nA \n, \nMaracy \nMR \n, \nRezaei \nA \n. The expression of Th1‐ and Th2‐related chemokine receptors in women with recurrent miscarriage: the impact of lymphocyte immunotherapy . Am J Reprod Immunol . 2010 ;64 :104 ‐112 .20331585 \n2 \n\nSaito \nS \n, \nNakashima \nA \n, \nShima \nT \n, \nIto \nM \n. Th1/Th2/Th17 and regulatory T‐cell paradigm in pregnancy . Am J Reprod Immunol . 2010 ;63 :601 ‐610 .20455873 \n3 \n\nNakagawa \nK \n, \nKwak‐Kim \nJ \n, \nOta \nK \n, et al. Immuno suppression with tacrolimus improved reproductive outcome of women with repeated implantation failure and elevated peripheral blood Th1/Th2 cell ratios . Am J Reprod Immunol . 2015 ;73 :353 ‐361 .25394810 \n4 \n\nWu \nL \n, \nLuo \nLH \n, \nZhang \nYX \n, et al. Alteration of Th17 and Treg cells in patients with unexplained recurrent spontaneous abortion before and after lymphocyte immunization therapy . Reprod Biol Endocrinol . 2014 ;12 :74 .25086467 \n5 \n\nKwak‐Kim \nJ \n, \nChung‐Bang \nHS \n, \nNg \nSC \n, et al. Increased T cell 1 cytokine responses by circulating T cells are present in women with recurrent pregnancy losses and in infertile women with multiple implantation failures after IVF . Hum Reprod . 2003 ;18 :767 ‐773 .12660269 \n6 \n\nNg \nSC \n, \nGilman‐Sachs \nA \n, \nThakar \nP \n, \nBeaman \nKD \n, \nBeer \nAE \n, \nKwak‐Kim \nJ \n. Expression of intracellular Th1 and Th2 cytokines in women with recurrent spontaneous abortion, implantation failures after IVF–ET or normal pregnancy . Am J Reprod Immunol . 2002 ;48 :77 ‐86 .12389596 \n7 \n\nRiley \nJK \n. Trophoblast immune receptors in maternal–fetal tolerance . Immunol Invest . 2008 ;37 :395 ‐426 .18716931 \n8 \n\nYokoo \nT \n, \nTakakuwa \nK \n, \nOoki \nI \n, \nKikuchi \nA \n, \nTamura \nM \n, \nTanaka \nK \n. Alteration of TH1 and TH2 cells by intracellular cytokine detection in patients with unexplained recurrent abortion before and after immunotherapy with the husband's mononuclear cells . Fertil Steril . 2006 ;85 :1452 ‐1458 .16647376 \n9 \n\nWegmann \nTG \n. Placental immunotrophism: maternal T cells enhance placental growth and function . Am J Reprod Immunol Microbiol . 1987 ;156 :676 ‐679 .\n10 \n\nOstensen \nM \n, \nFörger \nF \n. How safe are anti‐rheumatic drugs during pregnancy? \nCurr Opin Pharmacol . 2013 ;13 :470 ‐475 .23522967 \n11 \n\nLiu \nJ \n, \nFarmer \nJD \nJr\n, \nLane \nWS \n, \nFriedman \nJ \n, \nWeissman \nI \n, \nSchreiber \nSL \n. Calcineurin is a common target of cyclophilin–cyclosporin A and FKBP‐FK506 complexes . Cell . 1991 ;66 :807 ‐815 .1715244 \n12 \n\nRath \nT \n. Tacrolimus in transplant rejection . Expert Opin Pharmacother . 2013 ;14 :115 ‐122 .23228138\n\n",
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"issue": "16(3)",
"journal": "Reproductive medicine and biology",
"keywords": "T helper type 1:2 cell ratio; immunological rejection; immunosuppressive agent; recurrent pregnancy loss; tacrolimus",
"medline_ta": "Reprod Med Biol",
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"pmid": "29259481",
"pubdate": "2017-07",
"publication_types": "D002363:Case Reports",
"references": "20331585;20455873;3501677;12660269;1715244;29259481;12389596;18716931;23522967;16647376;25086467;25394810;23228138",
"title": "After 12 consecutive miscarriages, a patient received immunosuppressive treatment and delivered an intact baby.",
"title_normalized": "after 12 consecutive miscarriages a patient received immunosuppressive treatment and delivered an intact baby"
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"abstract": "Many patients with autoimmune hepatitis (AIH) develop steroid-specific side effects or require doses of steroids that are unacceptable for long-term treatment. We investigated the efficacy of budesonide as an alternative steroid for patients previously treated with prednisolone who developed side effects or were unable to reduce their dose of prednisolone below acceptable levels. We also report the effects of more than 12 months of budesonide treatment in a large cohort of patients with AIH.\n\n\n\nWe performed a retrospective analysis of data from 60 patients (51 female) with AIH who were treated initially with prednisolone (mean time, 47 mo) but then switched to budesonide, managed at a single center in Germany from 2001 through June 2016. Patients were evaluated after 6 months, 12 months, 24 months, 36 months, and at the last follow-up evaluation; response to treatment with budesonide was assessed based on normal serum levels of aminotransferases and IgG (biochemical response).\n\n\n\nThirty patients were switched to budesonide therapy because of prednisolone-induced side effects and 30 patients switched because of prednisolone dependency. Overall, a biochemical response was detected in 55% of patients after 6 months of budesonide treatment, in 70% after 12 months, and in 67% after 24 months. At the last follow-up evaluation (mean time, 63 mo) 23 patients (38%) still were receiving budesonide treatment. Fifteen patients (25%) had switched back to prednisolone therapy because of insufficient response to budesonide or its side effects. Fifteen patients with osteopenia at the beginning of budesonide treatment were followed up and evaluated by dual-energy X-ray absorptiometry. After a median of 24 months of budesonide treatment, bone mineral density had improved in 6 patients, remained stable in 8 patients, and worsened in 1 patient.\n\n\n\nWe performed a retrospective analysis of patients with AIH that confirmed the therapeutic value of budesonide beyond 12 months of treatment in patients who are intolerant to or dependent on prednisolone. Although budesonide-induced side effects appear to be mild in real life, effectiveness was limited in a considerable proportion of patients; close monitoring is advised.",
"affiliations": "First Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.;First Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.;First Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.;First Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.;First Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.;First Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.;First Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.;First Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.;First Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.;First Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany. Electronic address: cschramm@uke.de.",
"authors": "Peiseler|Moritz|M|;Liebscher|Tina|T|;Sebode|Marcial|M|;Zenouzi|Roman|R|;Hartl|Johannes|J|;Ehlken|Hanno|H|;Pannicke|Nadine|N|;Weiler-Normann|Christina|C|;Lohse|Ansgar W|AW|;Schramm|Christoph|C|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D001323:Autoantibodies; D007074:Immunoglobulin G; D019819:Budesonide; D000637:Transaminases",
"country": "United States",
"delete": false,
"doi": "10.1016/j.cgh.2016.12.040",
"fulltext": null,
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"issn_linking": "1542-3565",
"issue": "16(2)",
"journal": "Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association",
"keywords": "Autoimmune Liver Diseases; Bone Density; Second-Line Treatment; Steroid-Induced Side Effects",
"medline_ta": "Clin Gastroenterol Hepatol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000893:Anti-Inflammatory Agents; D001323:Autoantibodies; D015519:Bone Density; D019819:Budesonide; D002648:Child; D002675:Child, Preschool; D005260:Female; D005858:Germany; D019693:Hepatitis, Autoimmune; D006801:Humans; D007074:Immunoglobulin G; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D000637:Transaminases; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101160775",
"other_id": null,
"pages": "260-267.e1",
"pmc": null,
"pmid": "28126427",
"pubdate": "2018-02",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Efficacy and Limitations of Budesonide as a Second-Line Treatment for Patients With Autoimmune Hepatitis.",
"title_normalized": "efficacy and limitations of budesonide as a second line treatment for patients with autoimmune hepatitis"
} | [
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"abstract": "Adenovirus (ADV) is a recognized cause of severe disease among immunocompromised patients. We report a previously healthy 39-year-old female, admitted with influenza pneumonia and evolving with lung hemorrhage and acute renal failure requiring mechanical ventilation and hemodialysis. She received high corticosteroid doses due to an initial suspicion of alveolar hemorrhage. Lymphopenia already present before steroid use (567/μL), was maintained during the whole hospital stay (mean 782/μL). From the second week of admission she presented a high-volume diarrhea (mean 2.5 L/day) associated to intermittent bloody stools. An ulcerative enterocolitis was confirmed by CT images and colonoscopy. ADV was detected in a colonic tissue sample by real time PCR but not by a commercial filmarray test. Cidofovir-probenecid and racecadotril therapy were indicated without changing the clinical course of diarrhea and the patient finally died.",
"affiliations": "Hospital Militar de Santiago, Santiago, Chile.;Sede Hospital Militar de Santiago, Facultad de Medicina, Universidad de Valparaíso, Valparaíso, Chile.;Escuela de Medicina, Universidad de los Andes, Santiago, Chile.;sede Hospital Militar de Santiago, Escuela de Medicina, Universidad de los Andes, Santiago, Chile.;Servicio de Anatomía Patológica, Hospital Militar de Santiago, Santiago, Chile.",
"authors": "Fica|Alberto|A|;Cataldo|Pabla|P|;Aceituno|Diana|D|;Villarroel|María Ignacia|MI|;Escalona|Arturo|A|",
"chemical_list": null,
"country": "Chile",
"delete": false,
"doi": "10.4067/s0034-98872019000200256",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0034-9887",
"issue": "147(2)",
"journal": "Revista medica de Chile",
"keywords": null,
"medline_ta": "Rev Med Chil",
"mesh_terms": "D000256:Adenoviridae; D000257:Adenoviridae Infections; D000328:Adult; D003428:Cross Infection; D003967:Diarrhea; D004760:Enterocolitis; D017809:Fatal Outcome; D005260:Female; D006471:Gastrointestinal Hemorrhage; D006801:Humans; D016867:Immunocompromised Host",
"nlm_unique_id": "0404312",
"other_id": null,
"pages": "256-260",
"pmc": null,
"pmid": "31095177",
"pubdate": "2019-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fatal nosocomial hemorrhagic enterocolitis probably caused by adenovirus. Report of one case.",
"title_normalized": "fatal nosocomial hemorrhagic enterocolitis probably caused by adenovirus report of one case"
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"activesubstancename": "CEFTRIAXONE"
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"abstract": "Citrobacter koseri is a gram-negative bacillius that belongs to the Enterobacteriaceae family. It is an uncommon pathogen that typically causes meningitis and brain abscesses in children, however central nervous system (CNS) infections are rarely found in adults. We present a case of C. koseri meningitis in an immunocompetent adult secondary to intestinal micro-perforation caused by Strongyloides A 76-year-old man admitted for asthma exacerbation developed septic shock. A lumbar puncture revealed bacterial meningitis. Blood and CSF cultures grew Citrobacter koseri with identical susceptibilities, suggesting infection by one strain. Despite broad-spectrum antibiotics, the patient expired of multi-organ failure. Autopsy identified diffuse alveolar hemorrhage as the immedi ate cause of death with a heavy burden of Strongyloides stercoralis in his gastrointestinal system, lungs, and meninges. Citrobacter koseri is a gram-negative bacillus of the Enterobacteriaceae family. It is an uncommon pathogen that typically causes meningitis and brain abscesses in children. Infections in adults occur in immunocompromised hosts or instances where an insult creates a port of entry. This is the first documented case of C.koseri sepsis in an immunocompetent host associated with Strongyloides Hyperinfection Syndrome (SHS), where massive parasitic intestinal invasion reaches pulmonary circulation and perforates the alveolar membrane. This case highlights that presence of rare enterobacterial infections should prompt consideration of differentials including SHS.",
"affiliations": "Department of Medicine, SUNY Downstate Medical Center, Brooklyn, NY, USA.;Department of Medicine, SUNY Downstate Medical Center, Brooklyn, NY, USA.;Department of Pathology, SUNY Downstate Medical Center, Brooklyn, NY, USA.;Department of Medicine, SUNY Downstate Medical Center, Brooklyn, NY, USA.;Department of Pulmonary and Critical Care Medicine, SUNY Downstate Medical Center, Brooklyn, NY, USA.",
"authors": "Reyes|Felix|F|;Singh|Navneet|N|;Anjuman-Khurram|Nigar|N|;Lee|Jihae|J|;Chow|Lillian|L|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.idcr.2017.09.005",
"fulltext": "\n==== Front\nIDCasesIDCasesIDCases2214-2509Elsevier S2214-2509(17)30162-210.1016/j.idcr.2017.09.005ArticleStrongyloides Hyperinfection Syndrome causing fatal meningitis and septicemia by Citrobacter koseri Reyes Felix abcSingh Navneet Navneet.singh@downstate.edua⁎Anjuman-Khurram Nigar bLee Jihae aChow Lillian ca Department of Medicine, SUNY Downstate Medical Center, Brooklyn, NY, USAb Department of Pathology, SUNY Downstate Medical Center, Brooklyn, NY, USAc Department of Pulmonary and Critical Care Medicine, SUNY Downstate Medical Center, Brooklyn, NY, USA⁎ Corresponding author at: 450 Clarkson Ave, Box 1262, Brooklyn, NY, 11203, USA. Navneet.singh@downstate.edu20 9 2017 2017 20 9 2017 10 102 104 29 8 2017 14 9 2017 14 9 2017 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Citrobacter koseri is a gram-negative bacillius that belongs to the Enterobacteriaceae family. It is an uncommon pathogen that typically causes meningitis and brain abscesses in children, however central nervous system (CNS) infections are rarely found in adults. We present a case of C. koseri meningitis in an immunocompetent adult secondary to intestinal micro-perforation caused by Strongyloides A 76-year-old man admitted for asthma exacerbation developed septic shock. A lumbar puncture revealed bacterial meningitis. Blood and CSF cultures grew Citrobacter koseri with identical susceptibilities, suggesting infection by one strain. Despite broad-spectrum antibiotics, the patient expired of multi-organ failure. Autopsy identified diffuse alveolar hemorrhage as the immedi ate cause of death with a heavy burden of Strongyloides stercoralis in his gastrointestinal system, lungs, and meninges.\n\nCitrobacter koseri is a gram-negative bacillus of the Enterobacteriaceae family. It is an uncommon pathogen that typically causes meningitis and brain abscesses in children. Infections in adults occur in immunocompromised hosts or instances where an insult creates a port of entry. This is the first documented case of C.koseri sepsis in an immunocompetent host associated with Strongyloides Hyperinfection Syndrome (SHS), where massive parasitic intestinal invasion reaches pulmonary circulation and perforates the alveolar membrane. This case highlights that presence of rare enterobacterial infections should prompt consideration of differentials including SHS.\n\nKeywords\nCitrobacter koseristronglyoides hyperinfection syndromemeningitis\n==== Body\nIntroduction\nCitrobacter koseri is a gram-negative bacillus that belongs to the Enterobacteriaceae family. It is an uncommon pathogen that typically causes meningitis and brain abscesses in children. Central nervous system (CNS) infections caused by Citrobacter koseri are rarely found in adults with thirteen cases reported. Most cases have been related to head trauma, facial fractures, post neurosurgical procedures, or found in immunocompromised patients. We present a case of Citrobacter koseri meningitis in an immunocompetent adult secondary to intestinal micro-perforation caused by Strongyloides.\n\nCase Presentation\nA 76-year-old man with history of diabetes mellitus, hypertension, hyperlipidemia, multiple myeloma in remission, hypothyroidism, ischemic stroke, asthma, benign prostatic hyperplasia, and recent deep vein thrombosis on warfarin presented with shortness of breath. He reported failure of his nebulizers in achieving symptomatic relief. On admission, vitals were stable and the patient was in no distress with a baseline neurological exam. Labs were significant for baseline anemia and supratherapeutic INR >8 with no signs of bleeding. Chest X-Ray showed no airway opacity. He was treated with nebulizers, oral corticosteroids, and admitted for an exacerbation of asthma. By day 5, the patient was noted with progressively worsening altered mental status, fever with hypotension, tachycardia, and progressive tachypnea causing hypoxic respiratory failure. Despite noninvasive positive pressure ventilation and fluid resuscitation, the patient progressively declined, requiring intubation and admission to the ICU where vasopressor and ventilator support was initiated.\n\nThe patient was treated with standard therapy for septic shock, including vancomycin with piperacillin/tazobactam for empiric broad-spectrum coverage of sepsis. Labs were significant for WBC 6,060 cell/mm3 with 34% band forms, acidemia with bicarbonate of 15 mmol/L and acute kidney injury with creatinine 3.28 mg/dL from 1.35 mg/dL on admission. Arterial blood gas prior to intubation showed metabolic acidosis with respiratory compensation. A lumbar puncture was performed with results consistent with bacterial meningitis (Table 1). Gram stain showed gram-negative rods. Given clinical suspicion for bacterial meningitis, ceftriaxone, metronidazole, ampicillin, and acyclovir were started after dexamethasone. Blood cultures grew gram-negative rods and ceftriaxone was changed to cefepime.Table 1 Comparison of lumbar punctures.\n\nTable 1\tInitial Lumbar Puncture\tRepeat Lumbar Puncture\t\nGram Stain\tGram Negative Rod\tGram Negative Rod\t\nOrganism\tCitrobacter koserii\t\t\nAppearance\tCloudy\tCloudy\t\nColor\tXanthochromic\tColorless\t\nWBC\t4289\t19325\t\nRBC\t2733\t611\t\nSegs\t85\t89\t\nBands\t8\t2\t\nLymphs\t3\t5\t\nMonos\t4\t4\t\nBacteria Extracellular\tPresent\tPresent\t\nBacteria Intracellular\tPresent\tPresent\t\nSmudge Cells\tPresent\tPresent\t\n\n\nOn ICU day 3, the blood and CSF cultures grew Citrobacter koseri with pansensitivity except for ciprofloxacin and tetracycline. All antimicrobials except for cefepime were discontinued. The next day, the patient’s vasopressor requirement increased and he was noted to have increasing leukocytosis. Chest X-ray showed worsening bilateral opacities. A bronchoscopy with bronchoalveolar lavage (BAL) was performed with no significant findings on visual inspection and preliminary BAL resulting negative. A repeat LP showed downtrending glucose and protein with uptrending WBC. CSF culture grew the same initial organism and antimicrobials were escalated to meropenem and levofloxacin. On ICU day 6, the patient suffered a cardiac arrest and expired despite several attempts at resuscitation. Autopsy revealed diffuse alveolar hemorrhage as the immediate cause of death with Enterobacteriaceae in pulmonary cultures. Further analysis revealed a heavy burden of Strongyloides throughout the gastrointestinal tract. Strongyloides was also evidenced in the respiratory tract with parasites visualized in the meninges and choroid plexus (Fig. 1). This corresponded to the post-mortem result of Strongyloides in the sputum from BAL.Fig. 1 Autopsy slides showing extensive pulmonary hemorrhage, diffuse alveolar damage, and Strongyloides larvae.\n\nFig. 1\n\nDiscussion\nCitrobacter, a member of the Enterobacteriaceae family, comprises a group of aerobic, gram-negative bacilli that are frequently found in water, soil, food, and animal and human intestines. C.koseri infection has been reported to cause lung abscess and brain abscesses in neonates [1], [2], acute rhinosinusitis, intraorbital abscesses [3], retroperitoneal abscesses [4], [5], brain abscesses [1]. Immunocompromised hosts, such as diabetics, transplant recipients, and cirrhotics, are known to be at increased risk of C.koseri infection [4]. In immunocompetent hosts, a port of entry is typically described.\n\nIn our case, post-mortem analysis of the bronchoalveolar lavage (BAL) revealed Strongyloides in the sputum and provided a clue towards the unifying diagnosis [6]. Autopsy revealed the port of entry of C. koseri was intestinal microperforation by Strongyloides. Strongyloides Hyperinfection Syndrome (SHS) is caused by massive intestinal invasion by parasites, which reach the pulmonary circulation and perforate the alveolar membrane6. SHS carries a high mortality which increases with bacterial superinfection. The overwhelming majority of cases of SHS are in immunocompromised patients, including those with HIV/AIDS (13%), active hematological malignancies (27%), and autoimmune disease (33%) [6]. While cases of strongyloidiasis have been documented in immunocompetent patients such as ours, this patient population typically has lower parasite burden and develops a chronic or asymptomatic infection [6], [7], [8]. Our patient had a history of multiple myeloma treated with levalidomide, however on presentation he was in remission and on no therapy. To our knowledge, our patient had no evidence of being immunocompromised prior to admission.\n\nOne notable risk factor for SHS in the immunocompetent patient is systemic corticosteroid therapy [6], [9], however our patient was not taking steroids on admission. Another well accepted notion is that co-infection with HTLV in an otherwise immunocompetent patients plays an important role to dampen T-cell response to the parasite and allows for higher parasite burdens and more widespread infection [7], [8], [10], [11]. Given that HTLV infection often remains subacute, one could speculate that while we believed our patient was immunocompetent he may have had a deficiency in his cellular immunity caused by a prior HTLV infection that predisposed him to the development of SHS.\n\nIn a case series of 133 patients with SHS, 38% of patients presented with bacterial infections, with bacteremia as the most frequent manifestation and meningitis the least frequent [6]. The culprit organisms of bacteremia in SHS commonly belong to the Enterobacteriaceae family but no cases of Citrobacter koseri infection have been documented. Bacterial seeding of the meninges through hematological spread was confirmed in our case by the repeated blood cultures and CSF cultures showing C.koseri. Corresponding with our case, Citrobacter is reported to be resistant to ampicillin and susceptible to ciprofloxacin and gentamicin [3], [4].\n\nThis case underscores the severity of SHS associated with a bacterial superinfection and the urgency of considering less common causes of intestinal bacterial translocation into the blood and other organs. Another important point is the consideration of unusual infections in patients who are thought to be immunocompetent. Considering factors interfering with cellular immunity such as co-infection with HTLV in this case may prompt more timely consideration of alternative diagnoses and therapies.\n==== Refs\nReferences\n1 Ariza-Prota M.A. Pando-Sandoval A. Garcia-Clemente M. Fernandez R. Casan P. Community-Acquired Pneumonia and Empyema Caused by Citrobacter koseri in an Immunocompetent Patient Case Rep Pulmonol. 2015 2015 670373 26634165 \n2 Vaz Marecos C. Ferreira M. Ferreira M.M. Barroso M.R. Sepsis, meningitis and cerebral abscesses caused by Citrobacter koseri BMJ Case Rep. 2012 2012 \n3 Lovato A. DEF C. Acute rhinosinusitis and intraorbital abscess caused by Citrobacter koseri infection Epidemiol Infect 144 12 2016 2670 2671 27245934 \n4 Lin S.Y. Ho M.W. Yang Y.F. Abscess caused by Citrobacter koseri infection: three case reports and a literature review Intern Med. 50 12 2011 1333 1337 21673472 \n5 Cai T. Giubilei G. Vichi F. Farina U. Costanzi A. Bartoletti R. A rare case of lethal retroperitoneal abscess caused by Citrobacter koseri Urol Int. 79 4 2007 364 366 18025858 \n6 Geri G. Rabbat A. Mayaux J. Strongyloides stercoralis hyperinfection syndrome: a case series and a review of the literature Infection. 43 6 2015 691 698 26008854 \n7 Montes M. Sanchez C. Verdonck K. Regulatory T cell expansion in HTLV-1 and strongyloidiasis co-infection is associated with reduced IL-5 responses to Strongyloides stercoralis antigen PLoS Negl Trop Dis. 3 6 2009 e456 19513105 \n8 Porto M.A. Muniz A. Oliveira Junior J. Carvalho E.M. [Clinical and immunological consequences of the association between HTLV-1 and strongyloidiasis] Rev Soc Bras Med Trop. 35 6 2002 641 649 12612748 \n9 Ramanathan R. Nutman T. Strongyloides stercoralis infection in the immunocompromised host Curr Infect Dis Rep. 10 2 2008 105 110 18462583 \n10 Porto A.F. Neva F.A. Bittencourt H. HTLV-1 decreases Th2 type of immune response in patients with strongyloidiasis Parasite Immunol. 23 9 2001 503 507 11589779 \n11 Carvalho E.M. Da Fonseca Porto A. Epidemiological and clinical interaction between HTLV-1 and Strongyloides stercoralis Parasite Immunol 26 11–12 2004 487 497 15771684\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-2509",
"issue": "10()",
"journal": "IDCases",
"keywords": "Citrobacter koseri; meningitis; stronglyoides hyperinfection syndrome",
"medline_ta": "IDCases",
"mesh_terms": null,
"nlm_unique_id": "101634540",
"other_id": null,
"pages": "102-104",
"pmc": null,
"pmid": "29062711",
"pubdate": "2017",
"publication_types": "D016428:Journal Article; D002363:Case Reports",
"references": "11589779;22665908;19513105;12612748;26008854;27245934;26634165;21673472;18025858;15771684;18462583",
"title": "Strongyloides Hyperinfection Syndrome causing fatal meningitis and septicemia by Citrobacter koseri.",
"title_normalized": "strongyloides hyperinfection syndrome causing fatal meningitis and septicemia by citrobacter koseri"
} | [
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"activesubstancename": "LEVOFLOXACIN"
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"abstract": "Ruptured iliac artery may initially clinically mimic an isolated inferior limb venous involvement. It was indeed an acute iliac artery dissection complicated by contained rupture and misdiagnosed as inferior limb venous thrombosis that led to the death of Thomas Mann in 1955. The details of the complex case are analyzed. Considerations of medical interest and on actuality of his work are also added.",
"affiliations": "General and Speciality Surgical Department Paride Stefanini, University of Rome La Sapienza, Rome, Italy. Electronic address: valeria.silvestri@uniroma1.it.",
"authors": "Silvestri|Valeria|V|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.avsg.2017.08.005",
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"issue": "46()",
"journal": "Annals of vascular surgery",
"keywords": null,
"medline_ta": "Ann Vasc Surg",
"mesh_terms": "D000784:Aneurysm, Dissecting; D002423:Cause of Death; D003951:Diagnostic Errors; D005197:Famous Persons; D049673:History, 20th Century; D017543:Iliac Aneurysm; D009613:Nobel Prize; D011237:Predictive Value of Tests; D014956:Writing",
"nlm_unique_id": "8703941",
"other_id": null,
"pages": "407-409",
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"pubdate": "2018-01",
"publication_types": "D019215:Biography; D016456:Historical Article; D016428:Journal Article",
"references": null,
"title": "Thomas Mann: Vascular Fatal Illness of the Writer Who Mastered Disease Through Literary Fiction.",
"title_normalized": "thomas mann vascular fatal illness of the writer who mastered disease through literary fiction"
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"companynumb": "IT-MYLANLABS-2018M1028628",
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"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
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"abstract": "BACKGROUND\nA 45-year-old woman with small-cell lung cancer presented to a hospital emergency department in an acute confusional state, with blurred vision and mild headache. Following progressively increasing lethargy, she subsequently became unresponsive to tactile and verbal stimuli. She had recently been started on chemotherapy with carboplatin and gemcitabine.\n\n\nMETHODS\nPhysical examination, imaging studies including brain MRI, noncontrast brain CT scans and magnetic resonance angiography, continuous EEG monitoring, and cerebrospinal fluid analysis.\n\n\nMETHODS\nPosterior reversible leukoencephalopathy syndrome (PRES) related to chemotherapy, and nonconvulsive status epilepticus related to PRES.\n\n\nRESULTS\nWithholding of chemotherapeutic agents, and antiseizure therapy for the status epilepticus.",
"affiliations": "Department of Neurology and Ophthalmology, Michigan State University, East Lansing, MI 48823, USA. archit.bhatt@ht.msu.edu",
"authors": "Bhatt|Archit|A|;Farooq|Muhammad U|MU|;Majid|Arshad|A|;Kassab|Mounzer|M|",
"chemical_list": "D000927:Anticonvulsants; D000970:Antineoplastic Agents; D003841:Deoxycytidine; C056507:gemcitabine; D016190:Carboplatin",
"country": "England",
"delete": false,
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"issn_linking": "1745-834X",
"issue": "5(3)",
"journal": "Nature clinical practice. Neurology",
"keywords": null,
"medline_ta": "Nat Clin Pract Neurol",
"mesh_terms": "D000927:Anticonvulsants; D000970:Antineoplastic Agents; D001921:Brain; D016190:Carboplatin; D003841:Deoxycytidine; D003937:Diagnosis, Differential; D004569:Electroencephalography; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D054038:Posterior Leukoencephalopathy Syndrome; D055752:Small Cell Lung Carcinoma; D013226:Status Epilepticus; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101261799",
"other_id": null,
"pages": "163-9",
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"pmid": "19262592",
"pubdate": "2009-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17538177;8625249;10715035;12552054;18290326;17316891;17698535;18854444;18403560;8799875;18356474;18055853;2830955;8275420;16449142;18079186;8608526;17164233;17724292;18365964;1279431;18024699;17933863;8559202;9158653",
"title": "Chemotherapy-related posterior reversible leukoencephalopathy syndrome.",
"title_normalized": "chemotherapy related posterior reversible leukoencephalopathy syndrome"
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... |
{
"abstract": "OBJECTIVE\nCarotid intervention shortly after an acute neurologic ischemic event is being performed more frequently in stroke centers to reduce the risk of recurrent stroke. Thrombolysis with recombinant tissue plasminogen activator (tPA) is offered to select patients with ischemic stroke symptoms who present within 4.5 hours. However, there is a paucity of data as to whether tPA followed by urgent carotid endarterectomy (CEA) or carotid artery stenting (CAS) has an increased risk of complications, particularly intracerebral hemorrhage (ICH). We sought to determine the periprocedural complications of urgently performed CEA or CAS following tPA.\n\n\nMETHODS\nFrom January 2009 to January 2015, 762 patients underwent carotid interventions (CEA, n = 440; CAS, n = 322) at a tertiary referral center and 165 patients (21.6%) underwent an urgent CEA or CAS during the index hospitalization for an acute transient ischemic attack or stroke. We compared the effect of intravenous tPA on 30-day complications, including ICH. The χ(2) and Fisher exact tests were used to determine significance between groups.\n\n\nRESULTS\nDuring the 6-year period, 165 patients underwent urgent carotid interventions (CEA, n = 135; CAS, n = 30) for acute neurologic symptoms. Of these, 19% (31 patients [CEA, n = 25; CAS, n = 6]) had tPA for an acute stroke; the remaining (134 patients [CEA, n = 110; CAS, n = 24]) fell outside of the tPA time window. Most strokes were minor or moderate with a mean National Institutes of Health Stroke Scale (NIHSS) score of 6.6 (range, 0-19). The mean time to intervention for both groups was 2.4 days (0-15 days). The 30-day stroke, death, and myocardial infarction rates were 9.7% (3 of 31) for the tPA group compared with 4.5% (6 of 134) for the no-tPA group (P = .37). Including bleeding complications in these 30-day outcomes, there was no difference between the tPA (3 of 31) and the no-tPA cohorts (8 of 134; P = .43). In the tPA group, there were one ICH, one neck hematoma/death, and an additional death; in the no-tPA group, there were one ICH, two neck hematomas, one stroke, two myocardial infarctions, one ICH/death, and one additional death. No significant increased rates of bleeding were noted within the tPA group (2 of 31) compared with the no-tPA group (4 of 134; P = .32). Moreover, in the tPA cohort, more than half of the patients (17 of 31) underwent revascularization within 72 hours (CEA = 13; CAS = 4) with outcomes similar to those who underwent revascularization after 72 hours.\n\n\nCONCLUSIONS\nThrombolysis followed by urgent CEA or CAS is not associated with an increased risk of complications in select patients who present with acute neurologic symptoms. Selection of patients is important; there was no ICH and only one death in each group for patients with minor to moderate ischemic stroke (NIHSS score <10).",
"affiliations": "Section of Vascular/Endovascular Surgery, Department of Surgery, Ochsner Clinic, New Orleans, La. Electronic address: hbazan@ochsner.org.;Section of Vascular/Endovascular Surgery, Department of Surgery, Ochsner Clinic, New Orleans, La.;Stroke/Vascular Neurology, Department of Neurology, Ochsner Clinic, New Orleans, La.;Section of Vascular/Endovascular Surgery, Department of Surgery, Ochsner Clinic, New Orleans, La.;Stroke/Vascular Neurology, Department of Neurology, Ochsner Clinic, New Orleans, La.;Section of Vascular/Endovascular Surgery, Department of Surgery, Ochsner Clinic, New Orleans, La.",
"authors": "Bazan|Hernan A|HA|;Zea|Nicolas|N|;Jennings|Bethany|B|;Smith|Taylor A|TA|;Vidal|Gabriel|G|;Sternbergh|W Charles|WC|",
"chemical_list": "D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0741-5214",
"issue": "62(6)",
"journal": "Journal of vascular surgery",
"keywords": null,
"medline_ta": "J Vasc Surg",
"mesh_terms": "D000208:Acute Disease; D000368:Aged; D000369:Aged, 80 and over; D002545:Brain Ischemia; D004632:Emergency Medical Services; D016894:Endarterectomy, Carotid; D005260:Female; D005343:Fibrinolytic Agents; D006801:Humans; D020300:Intracranial Hemorrhages; D008297:Male; D008875:Middle Aged; D012720:Severity of Illness Index; D015607:Stents; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator",
"nlm_unique_id": "8407742",
"other_id": null,
"pages": "1529-38",
"pmc": null,
"pmid": "26412434",
"pubdate": "2015-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Urgent carotid intervention is safe after thrombolysis for minor to moderate acute ischemic stroke.",
"title_normalized": "urgent carotid intervention is safe after thrombolysis for minor to moderate acute ischemic stroke"
} | [
{
"companynumb": "US-ROCHE-1681158",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ALTEPLASE"
},
"drugadditional": null,
"drug... |
{
"abstract": "OBJECTIVE\nAlthough the mortality among previously healthy children with acute encephalopathy (AE) is approximately 5%, their detailed clinical course has not been clarified. The objective of the present study was to describe the detailed clinical course, in minutes, of fatal AE.\n\n\nMETHODS\nWe retrospectively reviewed the medical records of five patients (from 6 months to 14 years of age) who previously had no neurological disorders and were diagnosed with brain death due to AE between 2002 and 2018 at Kobe Children's Hospital.\n\n\nRESULTS\nThe initial clinical symptoms were convulsion in three cases and impaired consciousness in two. The earliest noted brain imaging abnormality was 7.5 h after neurological symptom detection. Liver enzymes and creatinine levels increased at initial examination, and sodium elevated gradually. All patients met the criteria of systemic inflammatory response syndrome, disseminated intravascular coagulation, and shock within 14 h of symptom detection. High dose steroids and targeted temperature management were initiated 3.5-14 h after onset. Despite these therapies, patients were diagnosed with brain death from 16 h to 4 days after initial neurological symptoms. AE diagnoses were made between 4 h 29 min and 4 days after initial neurological symptoms and included hemorrhagic shock and encephalopathy syndromes, Reye-like syndrome, and acute necrotizing encephalopathy in two, two, and one patient(s), respectively.\n\n\nCONCLUSIONS\nWe revealed the time series' of clinical events (e.g. SIRS, shock, DIC, AE diagnosis, brain death, and treatments) and laboratory findings relative to initial neurological symptom in fatal AE.",
"affiliations": "Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan. Electronic address: toimoka@med.kobe-u.ac.jp.;Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.;Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.;Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.;Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.;Department of Neurology, Hyogo Prefectural Kobe Children's Hospital, Kobe, Japan.;Department of Neurology, Hyogo Prefectural Kobe Children's Hospital, Kobe, Japan.;Department of Neurology, Hyogo Prefectural Kobe Children's Hospital, Kobe, Japan.;Department of Neurology, Hyogo Prefectural Kobe Children's Hospital, Kobe, Japan.;Department of Emergency and General Medicine, Hyogo Prefectural Kobe Children's Hospital, Kobe, Japan.;Department of Pediatric Critical Care Medicine, Hyogo Prefectural Kobe Children's Hospital, Kobe, Japan.;Department of Pediatric Critical Care Medicine, Hyogo Prefectural Kobe Children's Hospital, Kobe, Japan.;Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.;Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.;Department of Pediatric Critical Care Medicine, Hyogo Prefectural Kobe Children's Hospital, Kobe, Japan.;Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.",
"authors": "Tomioka|Kazumi|K|;Nishiyama|Masahiro|M|;Nagase|Hiroaki|H|;Ishida|Yusuke|Y|;Tanaka|Tsukasa|T|;Tokumoto|Shoichi|S|;Yamaguchi|Hiroshi|H|;Toyoshima|Daisaku|D|;Maruyama|Azusa|A|;Fujita|Kyoko|K|;Aoki|Kazunori|K|;Seino|Yusuke|Y|;Nozu|Kandai|K|;Nishimura|Noriyuki|N|;Kurosawa|Hiroshi|H|;Iijima|Kazumoto|K|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.braindev.2019.04.012",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0387-7604",
"issue": "41(8)",
"journal": "Brain & development",
"keywords": "Acute encephalopathy; Brain death; Pediatrics",
"medline_ta": "Brain Dev",
"mesh_terms": "D000208:Acute Disease; D000071072:Acute Febrile Encephalopathy; D000293:Adolescent; D001926:Brain Death; D001927:Brain Diseases; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D012189:Retrospective Studies; D012640:Seizures; D013997:Time Factors",
"nlm_unique_id": "7909235",
"other_id": null,
"pages": "691-698",
"pmc": null,
"pmid": "31337523",
"pubdate": "2019-09",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Detailed clinical course of fatal acute encephalopathy in children.",
"title_normalized": "detailed clinical course of fatal acute encephalopathy in children"
} | [
{
"companynumb": "JP-PFIZER INC-2019382901",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE SODIUM SUCCINATE"
},
"druga... |
{
"abstract": "Bronchial thermoplasty has been found to be a safe and effective therapy for severe asthma. We report the case of a mediastinal hematoma and hemothorax developing in a 66-year-old woman several days after an uneventful bronchial thermoplasty of the right lower lobe. Evaluation revealed a bleeding right bronchial artery pseudoaneurysm. Pseudoaneuryms have been reported in association with other procedures involving the therapeutic application of thermal energy, and a single case of hemoptysis requiring bronchial artery embolization occurred in a clinical trial of bronchial thermoplasty. However, bronchial artery pseudoaneurysm with hemomediastinum and hemothorax has not previously been reported after bronchial thermoplasty.",
"affiliations": "Division of Pulmonary, Critical Care, and Sleep Medicine, UC Davis Medical Center, Sacramento, CA; Sacramento Veterans Affairs Medical Center, Mather, CA.;Division of Pulmonary, Critical Care, and Sleep Medicine, UC Davis Medical Center, Sacramento, CA; Sacramento Veterans Affairs Medical Center, Mather, CA. Electronic address: sxmurin@ucdavis.edu.",
"authors": "Nguyen|Dan-Vinh|DV|;Murin|Susan|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0012-3692",
"issue": "149(4)",
"journal": "Chest",
"keywords": "asthma; bronchial artery embolization; case report; fiber optic bronchoscopy; pseudoaneurysm; thermoplasty",
"medline_ta": "Chest",
"mesh_terms": "D000368:Aged; D017541:Aneurysm, False; D000792:Angiography; D001249:Asthma; D001980:Bronchi; D001981:Bronchial Arteries; D001999:Bronchoscopy; D017115:Catheter Ablation; D004621:Embolization, Therapeutic; D005260:Female; D006470:Hemorrhage; D006491:Hemothorax; D006801:Humans; D008477:Mediastinal Diseases; D011183:Postoperative Complications; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "0231335",
"other_id": null,
"pages": "e95-7",
"pmc": null,
"pmid": "27055718",
"pubdate": "2016-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bronchial Artery Pseudoaneurysm With Major Hemorrhage After Bronchial Thermoplasty.",
"title_normalized": "bronchial artery pseudoaneurysm with major hemorrhage after bronchial thermoplasty"
} | [
{
"companynumb": "US-WEST-WARD PHARMACEUTICALS CORP.-US-H14001-16-00898",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
... |
{
"abstract": "The clinical presentation and outcome of hepatitis E virus (HEV) infection in inflammatory rheumatic diseases are unknown. We aimed to investigate the severity of acute HEV infection and the risk of chronic viral replication in patients with inflammatory arthritides treated with immunosuppressive drugs. All rheumatology and internal medicine practitioners belonging to the Club Rhumatismes et Inflammation in France were sent newsletters asking for reports of HEV infection and inflammatory arthritides. Baseline characteristics of patients and the course of HEV infection were retrospectively assessed by use of a standardized questionnaire. From January 2010 to August 2013, we obtained reports of 23 cases of HEV infection in patients with rheumatoid arthritis (n = 11), axial spondyloarthritis (n = 5), psoriatic arthritis (n = 4), other types of arthritides (n = 3). Patients received methotrexate (n = 16), antitumor necrosis factor α agents (n = 10), rituximab (n = 4), abatacept (n = 2), tocilizumab (n = 2), and corticosteroids (n = 10, median dose 6 mg/d, range 2-20). All had acute hepatitis: median aspartate and alanine aminotransferase levels were 679 and 1300 U/L, respectively. Eleven patients were asymptomatic, 4 had jaundice. The HEV infection diagnosis relied on positive PCR results for HEV RNA (n = 14 patients) or anti-HEV IgM positivity (n = 9). Median follow-up was 29 months (range 3-55). Treatment included discontinuation of immunosuppressants for 20 patients and ribavirin treatment for 5. Liver enzyme levels normalized and immunosuppressant therapy could be reinitiated in all patients. No chronic infection was observed. Acute HEV infection should be considered in patients with inflammatory rheumatism and elevated liver enzyme values. The outcome of HEV infection seems favorable, with no evolution to chronic hepatitis or fulminant liver failure.",
"affiliations": "From the Service de Rhumatologie (HB, J-EG, EC, CS, JS), Centre de Référence des Maladies Auto-Immunes Systémiques Rares, C.H.U. de Hautepierre, Strasbourg; Service de Rhumatologie (CL, AC); Service d'Hépato-gastro-entérologie (SF, J-MP); Laboratoire de Virologie (FA, JI), C.H.U. Purpan, Toulouse; Service de Rhumatologie (PC), C.H.U. Henri Mondor, Créteil; Service de Rhumatologie (CH, AM), C.H.U Cochin, Paris; Service d'Immunologie Clinique et Thérapeutique Ostéo-Articulaire (SF, Y-MP), C.H.U. Lapeyronie, Montpellier; Service de Médecine Interne (GL), C.H.R.U. de Lille; Service de Rhumatologie (LM), Institut Calot, Berck-s-Mer; Service de Rhumatologie (AM), C.H. de Saint Brieuc; Service de Médecine Interne et de Rhumatologie (LM), C.H. Pasteur, Colmar; Service de Rhumatologie (BP-P), C.H.U. Bellevue, Saint Etienne; Laboratoire de Virologie (AM-RA), Hôpital Paul Brousse, Villejuif; Service de Rhumatologie (CR), Hôpital de l'Archet 1, Nice; Service de Rhumatologie (MS), C.H.U. de Clermont-Ferrand; Service de Rhumatologie (CV), C.H.U. Pellegrin, Bordeaux; and Service de Rhumatologie (DW), C.H.U. Minjoz, Besançon, France.",
"authors": "Bauer|Hélène|H|;Luxembourger|Cécile|C|;Gottenberg|Jacques-Eric|JE|;Fournier|Sophie|S|;Abravanel|Florence|F|;Cantagrel|Alain|A|;Chatelus|Emmanuel|E|;Claudepierre|Pascal|P|;Hudry|Christophe|C|;Izopet|Jacques|J|;Fabre|Sylvie|S|;Lefevre|Guillaume|G|;Marguerie|Laurent|L|;Martin|Antoine|A|;Messer|Laurent|L|;Molto|Anna|A|;Pallot-Prades|Béatrice|B|;Pers|Yves-Marie|YM|;Roque-Afonso|Anne-Marie|AM|;Roux|Christian|C|;Sordet|Christelle|C|;Soubrier|Martin|M|;Veissier|Claire|C|;Wendling|Daniel|D|;Péron|Jean-Marie|JM|;Sibilia|Jean|J|;|||",
"chemical_list": "D000998:Antiviral Agents; D007166:Immunosuppressive Agents; D012254:Ribavirin",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000000675",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 2586021210.1097/MD.0000000000000675006756900ArticleObservational StudyOutcome of Hepatitis E Virus Infection in Patients With Inflammatory Arthritides Treated With Immunosuppressants A French Retrospective Multicenter StudyBauer Hélène Luxembourger Cécile Gottenberg Jacques-Eric MD, PhDFournier Sophie Abravanel Florence MDCantagrel Alain MD, PhDChatelus Emmanuel MDClaudepierre Pascal MD, PhDHudry Christophe MDIzopet Jacques MD, PhDFabre Sylvie MDLefevre Guillaume MDMarguerie Laurent MDMartin Antoine MDMesser Laurent MDMolto Anna MDPallot-Prades Béatrice MDPers Yves-Marie MDRoque-Afonso Anne-Marie MD, PhDRoux Christian MDSordet Christelle MDSoubrier Martin MD, PhDVeissier Claire Wendling Daniel MD, PhDPéron Jean-Marie MD, PhDSibilia Jean MD, PhDon behalf of the Club Rhumatismes et Inflammation, a section of the French Society of RheumatologyAstete. Carlos Antonio Guillen From the Service de Rhumatologie (HB, J-EG, EC, CS, JS), Centre de Référence des Maladies Auto-Immunes Systémiques Rares, C.H.U. de Hautepierre, Strasbourg; Service de Rhumatologie (CL, AC); Service d’Hépato-gastro-entérologie (SF, J-MP); Laboratoire de Virologie (FA, JI), C.H.U. Purpan, Toulouse; Service de Rhumatologie (PC), C.H.U. Henri Mondor, Créteil; Service de Rhumatologie (CH, AM), C.H.U Cochin, Paris; Service d’Immunologie Clinique et Thérapeutique Ostéo-Articulaire (SF, Y-MP), C.H.U. Lapeyronie, Montpellier; Service de Médecine Interne (GL), C.H.R.U. de Lille; Service de Rhumatologie (LM), Institut Calot, Berck-s-Mer; Service de Rhumatologie (AM), C.H. de Saint Brieuc; Service de Médecine Interne et de Rhumatologie (LM), C.H. Pasteur, Colmar; Service de Rhumatologie (BP-P), C.H.U. Bellevue, Saint Etienne; Laboratoire de Virologie (AM-RA), Hôpital Paul Brousse, Villejuif; Service de Rhumatologie (CR), Hôpital de l’Archet 1, Nice; Service de Rhumatologie (MS), C.H.U. de Clermont-Ferrand; Service de Rhumatologie (CV), C.H.U. Pellegrin, Bordeaux; and Service de Rhumatologie (DW), C.H.U. Minjoz, Besançon, France.Correspondence: Hélène Bauer and Jacques-Eric Gottenberg, service de rhumatologie, Hôpital de Hautepierre, 1 avenue Molière, 67098 Strasbourg, France (e-mail: lnbauer@gmail.com; jacques-eric.gottenberg@chru-strasbourg.fr).4 2015 10 4 2015 94 14 e67512 12 2014 25 2 2015 27 2 2015 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.2015This is an open access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0, where it is permissible to download, share and reproduce the work in any medium, provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0Abstract\nThe clinical presentation and outcome of hepatitis E virus (HEV) infection in inflammatory rheumatic diseases are unknown. We aimed to investigate the severity of acute HEV infection and the risk of chronic viral replication in patients with inflammatory arthritides treated with immunosuppressive drugs.\n\nAll rheumatology and internal medicine practitioners belonging to the Club Rhumatismes et Inflammation in France were sent newsletters asking for reports of HEV infection and inflammatory arthritides. Baseline characteristics of patients and the course of HEV infection were retrospectively assessed by use of a standardized questionnaire.\n\nFrom January 2010 to August 2013, we obtained reports of 23 cases of HEV infection in patients with rheumatoid arthritis (n = 11), axial spondyloarthritis (n = 5), psoriatic arthritis (n = 4), other types of arthritides (n = 3). Patients received methotrexate (n = 16), antitumor necrosis factor α agents (n = 10), rituximab (n = 4), abatacept (n = 2), tocilizumab (n = 2), and corticosteroids (n = 10, median dose 6 mg/d, range 2–20). All had acute hepatitis: median aspartate and alanine aminotransferase levels were 679 and 1300 U/L, respectively. Eleven patients were asymptomatic, 4 had jaundice. The HEV infection diagnosis relied on positive PCR results for HEV RNA (n = 14 patients) or anti-HEV IgM positivity (n = 9). Median follow-up was 29 months (range 3–55). Treatment included discontinuation of immunosuppressants for 20 patients and ribavirin treatment for 5. Liver enzyme levels normalized and immunosuppressant therapy could be reinitiated in all patients. No chronic infection was observed.\n\nAcute HEV infection should be considered in patients with inflammatory rheumatism and elevated liver enzyme values. The outcome of HEV infection seems favorable, with no evolution to chronic hepatitis or fulminant liver failure.\n\nOPEN-ACCESSTRUE\n==== Body\nHepatitis E virus (HEV) infection is ubiquitous and is due to a small nonenveloped virus with a positive-sense, single-stranded RNA genome. The virus was discovered in the 1980s. Four major genotypes representing a single serotype have been recognized: HEV1 and HEV2 are restricted to humans and transmitted via contaminated water in developing countries; HEV3 and HEV4 infect humans, pigs, and other mammalian species and are responsible for sporadic cases of autochthonous HEV infection in Western countries. In this setting, HEV infection causes acute disease, mainly in middle-aged and older men. Such an infection might be mistaken for drug-induced liver injury.1 Acute HEV infection might range in severity from subclinical to fulminant, in particular in the risk group of pregnant women, whose death rate in the course of HEV infection could approach 15% to 20%.2,3 However, in the rest of the population and in immunosuppressed patients,4 acute HEV infection is usually asymptomatic. Thus, in a French study of kidney transplant recipients, acute HEV infection was asymptomatic in 14 of 16 patients (87.5%).5 Some extrahepatic manifestations of HEV infection were reported. Kamar et al6 reported neurologic disorders among 126 patients with HEV infection: inflammatory polyradiculopathy (n = 3), Guillain-Barre syndrome (n = 1), bilateral brachial neuritis (n = 1), encephalitis (n = 1), and ataxia/proximal myopathy (n = 1). Hematological disorders, notably acute immune thrombocytopenia,7 were also reported.\n\nRecent efforts to develop and standardize the HEV serology led to data showing increasingly recognized cases of HEV infection. HEV infection might correspond to about 10% of cases of non-A–D acute viral hepatitis in Western countries among nontravelers.8\n\nAnother feature of HEV is its ability to cause chronic infection, defined as a persistent infection lasting >6 months, usually in severely immunocompromised patients.9 In 3 well-known circumstances of immunodeficiency—AIDS, kidney or liver transplantation, and haematological malignancies—HEV infection can develop into chronic infection.10,11 In liver transplant recipients,12 chronic infection with HEV can result in HEV-related cirrhosis.13 However, little is known about the incidence and severity of acute and chronic HEV infection in patients with inflammatory rheumatic diseases. We therefore addressed this issue of HEV infection in patients receiving treatment for inflammatory arthritides.\n\nPATIENTS AND METHODS\nThis retrospective multicenter study was initiated by the Club Rhumatismes et Inflammation, a section of the Society of Rheumatology in France. All rheumatology and internal medicine practitioners belonging to the club (nearly 2400 physicians) were sent 3 newsletters over 12 months asking for reports of HEV infection and inflammatory rheumatism. Informed consent was given by all enrolled patients. No ethical approval was requested, since it is not required for noninterventional retrospective studies in France. Practitioners were sent a standardized and anonymized questionnaire to collect information on baseline characteristics of patients and the course of HEV infection. Inclusion criteria in the study were (1) diagnosis of inflammatory rheumatism according to international criteria, (2) treatment with an immunosuppressive drug, and (3) detection of specific IgM antibodies against HEV or HEV RNA in serum and/or stools with tests performed in 2 national reference centers in Paris and Toulouse, as previously described.14–16 Patients with positive IgG antibodies and negative IgM antibodies and negative PCR results for HEV RNA were excluded because the presence of IgG antibodies indicated only that HEV was seroprevalent in those patients. Chronic HEV infection was defined by continued PCR detection of HEV RNA in serum or stools for >6 months.\n\nRESULTS\nPatient Characteristics\nThe main characteristics of patients are provided in Table 1. Cases for 23 patients (10 men; median age at diagnosis 51 years [range 26–79 years]) were reported between January 2010 and August 2013. Most patients did not have any other comorbidity; only 1 patient showed excessive consumption of alcohol and none had chronic liver disease. Three patients had type II diabetes, 2 had arterial hypertension, and 10 were overweight.\n\nTABLE 1 Patient Characteristics\n\nIn total, 11 patients had rheumatoid arthritis (RA), 5 axial spondyloarthritis, 4 psoriatic arthritis, and 1 each juvenile idiopathic arthritis, discoid lupus with Jaccoud arthropathy and undifferentiated arthritis. Median disease duration was 15 years (range 1.5–34 years). Overall, 18 patients received a biologic drug, including an antitumor necrosis factor α agent (n = 10), rituximab (n = 4), abatacept (n = 2), and tocilizumab (n = 2); 16 received methotrexate, 4 leflunomide, and 1 cyclosporine. In all, 15 patients received both a biologic drug and a conventional immunosuppressive drug; 10 received corticosteroids (median dose 6 mg/d, range 2–20 mg/d).\n\nClinical Presentation of HEV\nOverall, 21 cases were autochthonous. Two patients had traveled out of France in the 3 months preceding infection, 1 to Spain (patient 9) and the other to Morocco (patient 17). The patient who had traveled to Spain, along with 3 family members had become infected with HEV by eating contaminated chorizo. Seven patients lived in the northern part of France and 16 in the southern part.\n\nIn total, 11 of the 23 cases were clinically asymptomatic and HEV infection was suspected because of liver enzyme elevation; 8 patients reported asthenia, which was the only symptom in 2 of them. The other symptoms were jaundice (n = 4), pain in the right hypochondriac region (n = 4), fever (n = 3), skin eruption (n = 3, including a bullous eruption [patient 3] and purpura [patient 11]), pruritus (n = 2), and arthralgia (n = 1). In 1 patient (patient 9), concomitant to HEV infection, a bilateral Parsonage–Turner syndrome developed (also called bilateral brachial neuritis or neuralgic amyotrophy), and was proven by electroneuromyography.\n\nLaboratory Presentation of HEV\nLiver biology tests and virology tests at diagnosis of HEV infection are provided in Table 2. All patients had acute elevated aspartate and alanine aminotransferase (ALT) levels, and 11 also had moderate cholestasis. Median aspartate and ALT levels were 679 and 1300 U/L, respectively. The diagnosis of acute HEV infection relied on positive PCR results for HEV RNA in blood (n = 13 patients) and/or stools (n = 3 patients), positive IgM antibodies without PCR assessment (n = 4), or positive IgM antibodies with negative PCR results for HEV RNA (n = 5). The viral genotype for 8 patients was 3c for 3 and 3f for 5. No other etiology for the hepatitis could be found, specially no coinfection with hepatitis A, B, or C.\n\nTABLE 2 Liver Biochemical and Virological Tests\n\nTwo patients had a liver failure with decreased prothrombin time (PT). A 49-year-old woman (patient 11) with RA for 10 years received tocilizumab, methotrexate (15 mg/week), and corticosteroids (3 mg/day). The PT was 46% with ALT level 79-fold the upper limit of normal (ULN) and associated with cholestasis (bilirubin level up to 400 μmol/L). For the other patient (patient 17), a 61-year-old man with RA for 12 years and receiving rituximab and corticosteroids (3 mg/day), the PT was 57% with an ALT level 8-fold the ULN.\n\nOutcome of HEV Infection\nAll patients had a follow-up of at least 3 months, and all recovered. The median reported follow-up was 29 months (range 3–55 months). Liver enzyme levels normalized within 1 month for 12 patients, 3 months for 9 patients (including the 2 patients with liver failure), and 4 months for 2 patients.\n\nPCR tests were repeated for 14 patients who previously had positive results, and all were negative within 3 months after HEV infection. Among the 9 patients with a diagnosis based on positivity for IgM antibodies, 4 were not retested, 3 were IgM negative, and 2 remained IgM positive (1 month and 7 months after diagnosis, both with a negative PCR result 1 month after diagnosis). The time of active infection was estimated as the time from the first day of increased liver enzyme level and the day of the first negative PCR result for HEV RNA in blood and/or stools. Median time of active infection, estimated for 13 patients, was 6 weeks (range 19 days–11 weeks). After a first negative PCR result for HEV RNA, 7 patients had at least 1 other PCR test. No viral reactivation was observed, with a minimal follow-up of 3 months.\n\nTreatment With Ribavirin\nTreatment for HEV infection included an antiviral treatment with ribavirin for only 5 patients, which lasted 1 to 24 weeks.\n\nPatient 9 had psoriatic arthritis previously treated with cyclosporine. The discontinuation of the immunosuppressive treatment triggered a major clinical flare-up, with synovitis and pustular psoriasis. That patient was the one who developed the bilateral Parsonage–Turner syndrome. Because a new immunosuppressive treatment had to be initiated and to counter this severe HEV infection, the physician decided to treat with ribavirin for 26 weeks. The viremia was undetectable within 7.5 weeks.\n\nPatient 4 had axial spondyloarthritis treated with infliximab. At diagnosis of HEV, ribavirin treatment was introduced. However, the antiviral drug was stopped after 1 week, when the first PCR test for HEV RNA was negative, showing a short period of viremia.\n\nPatient 16 was a 68-year-old man with RA for 20 years who received methotrexate and rituximab. The elevated liver enzyme levels (19-fold ULN aspartate aminotransferase and 24-fold ULN ALT) occurred 5 months after the last rituximab infusion. The patient received ribavirin for 3 months. The HEV load disappeared within 8 weeks.\n\nIn patients 1 and 3, who were followed by the same hepatologist, PCR testing for HEV RNA was performed weekly, and ribavirin was stopped when results were negative.\n\nOutcome and Therapeutic Management of Inflammatory Rheumatic Disease\nTherapeutic management is summarized in Table 3. Treatment of HEV infection included the discontinuation of immunosuppressants in 20 of 23 patients. Biologic therapy was discontinued in all but 3 patients: adalimumab was maintained in 1 patient (without ribavirin treatment), infliximab was maintained in 1 patient receiving ribavirin for 1 week, and the third patient had a new cycle of rituximab 3 months after HEV infection when HEV RNA became undetectable. Methotrexate was maintained in 2 patients, both receiving ribavirin (3 months and 1 week) and was introduced simultaneously with ribavirin (6 months) in 1 patient previously receiving cyclosporine. Corticosteroids were discontinued in 2 of 10 patients. In 2 other patients, corticosteroids were introduced because of flare of the rheumatic disease after discontinuation of biologic therapy (doses of 20 and 40 mg/day).\n\nTABLE 3 Therapeutic Management\n\nInformation on rheumatic disease activity after discontinuation of immunosuppressants was available in 22 patients. Eleven of them experienced a flare of the rheumatic disease after discontinuation of their treatment. The median time between the treatment discontinuation and the flare-up was 4 weeks (range 1 day–10 weeks).\n\nAmong the 20 patients who discontinued immunosuppressants, an immunosuppressant could be reinitiated in all of them. The median time to biologic and methotrexate discontinuation was 12 (range 4–20) and 11.5 weeks (1–16), respectively. For all the patients, the rheumatic disease was controlled after resumption of their immunosuppressive treatment.\n\nDISCUSSION\nWe report 23 cases of HEV infection in patients with inflammatory arthritides treated with immunosuppressants. All had acute hepatitis. The HEV infection diagnosis was based on positive PCR detection for HEV RNA in the serum and/or stools or anti-HEV IgM antibodies. Treatment included discontinuation of immunosuppressants for 20 patients and ribavirin treatment for 5. Some patients underwent a flare of their arthritides after discontinuation of immunosuppressants. In all patients, liver enzyme levels normalized and immunosuppressant therapy could be reinitiated. No chronic infection was observed. Even in patients whose immunosuppressive therapy was continued and in those under immunosuppressive treatment with a long half-life (as rituximab), no complication of HEV infection was observed. Acute HEV infection should be considered in patients with inflammatory rheumatism and elevated liver enzyme levels. The outcome of HEV infection seems favorable, with no evolution to chronic hepatitis or fulminant liver failure.\n\nIn the present study, 2 patients with RA and HEV infection were previously reported as case reports.17–18\n\nOur epidemiological and biological characteristics of HEV infection are consistent with current knowledge of this infection. The course of acute HEV was found to be cytolytic rather than cholestatic, and liver cytolysis predominantly concerned ALT. The duration of liver cytolysis was most frequently <3 months.\n\nNearly half of the patients reported in the present study were totally asymptomatic, emphasizing the need to specifically look for HEV in the checkup of elevated liver enzymes in patients with inflammatory arthritides, regardless of the symptoms.\n\nOne patient had a neurologic manifestation of HEV infection. Neurologic symptoms associated with HEV have been reported in up to 5.5% of HEV infection in immunocompetent and immunocompromised patients. Recently a study found HEV infection in 10% of group of 47 patients with neuralgic amyotrophy,19 making HEV one of the most common etiology of brachial neuritis.\n\nFor all reported cases of HEV, the outcome was favorable within 3 months, with or without antiviral treatment with ribavirin. No fulminant hepatic failure was reported.\n\nTreatment of HEV infection in patients receiving treatment for inflammatory arthritides is not codified. The present study gives some indication of how to manage this infection. Immunosuppressive treatment was discontinued in most of our patients. The evolution of viral infection was monitored with PCR tests of HEV RNA in blood and/or stools. Immunosuppressive therapy could be resumed after a negative PCR result for HEV RNA in blood and/or stools. Only a few patients received antiviral treatment with ribavirin, by analogy with HCV infection.20 Ribavirin was prescribed when liver enzyme levels were particularly elevated and/or when the activity of the inflammatory arthritides required immunosuppressive drugs.\n\nAnother feature of HEV is its ability to cause chronic infection, defined as a persistent infection lasting >6 months, usually in severely immunocompromised patients.9 In liver transplant recipients,12 chronic infection with HEV can result in HEV-related cirrhosis.13 In patients with inflammatory arthritides, no chronic infection was observed in the present study. The duration of the patient follow-up was sufficient to establish the resolution of the HEV infection, but the absence of reactivation of HEV infection must be confirmed in the longer term.\n\nThe main limitations of this study are its retrospective nature and the various procedures used to perform the diagnosis and monitoring of HEV infection. Diagnosis of acute HEV infection was based on positive PCR results or IgM positivity. Some patients were IgM positive, but the first PCR result for HEV RNA was negative. In these patients with elevated liver enzyme levels, the diagnosis of acute HEV is completely reliable because of the high specificity of IgM detection.21 A short period of viremia explains the negative PCR result, often performed after serology findings.\n\nIn conclusion, given the increasingly diagnosed autochthonous HEV infection in some countries, HEV infection could be suspected in patients with inflammatory arthritides and elevated liver enzyme levels. The present study of a limited number of patients with acute HEV infection does not suggest a particular severity or risk of chronicity of this infection in patients with inflammatory arthritis treated with immunosuppressants. Further larger studies are needed to evaluate longer-term outcomes.\n\nAbbreviations: μmol/L = micromoles per day, AIDS = Acquired Immune Deficiency Syndrome, ALT = alanine aminotransferase, C.H. = centre hospitalier, C.H.R.U. = centre hospitalier régional universitaire, C.H.U. = centre hospitalo-universitaire, HCV = hepatitis C virus, HEV = hepatitis E virus, IgG = immunoglobulin G, IgM = immunoglobulin M, mg/d = milligrams per day, PCR = polymerase chain reaction, PT = prothrombin time, RA = rheumatoid arthritis, RNA = ribonucleic acid, U/L = units per liter, ULN = upper limit of normal.\n\nHB, CL, J-M P, and JS equally contributed to this study.\n\nThe authors have no funding and conflicts of interest to disclose.\n==== Refs\nREFERENCES\n1. Dalton HR Fellows HJ Stableforth W \nThe role of hepatitis E virus testing in drug-induced liver injury . Aliment Pharmacol Ther \n2007 ; 26 :1429 –1435 .17850420 \n2. Rayis DA Jumaa AM Gasim GI \nAn outbreak of hepatitis E and high maternal mortality at Port Sudan . Eastern Sudan Pathog Glob Health \n2013 ; 107 :66 –68 .23683332 \n3. Jilani N Das BC Husain SA \nHepatitis E virus infection and fulminant hepatic failure during pregnancy . Gastroenterol Hepatol \n2007 ; 22 :676 –682 .\n4. Kamar N Selves J Mansuy JM \nHepatitis E virus and chronic hepatitis in organ-transplant recipients . N Engl J Med \n2008 ; 358 :811 –817 .18287603 \n5. Moal V Legris T Burtey S \nInfection with hepatitis E virus in kidney transplant recipients in southeastern France . J Med Virol \n2013 ; 85 :462 –471 .23239466 \n6. Kamar N Bendall RP Peron JM \nHepatitis E virus and neurologic disorders . Emerg Infect Dis \n2011 ; 17 :173 –179 .21291585 \n7. Singh NK Gangappa M \nAcute immune thrombocytopenia associated with hepatitis E in an adult . Am J Hematol \n2007 ; 82 :942 –943 .17616970 \n8. Echevarria JM \nLight and darkness: prevalence of hepatitis E virus infection among the general population . Scientifica \n2014 ; 2014 : Article ID 481016, 14 p, doi:10.1155/2014/481016. .\n9. Parvez MK \nChronic hepatitis E infection: risks and controls . Intervirology \n2013 ; 56 :213 –216 .23689166 \n10. Kamar N Bendall R Legrand-Abravanel F \nHepatitis E . Lancet \n2012 ; 379 :2477 –2488 .22549046 \n11. Tavitian S Péron JM Huynh A \nHepatitis E virus excretion can be prolonged in patients with hematological malignancies . Clin Virol \n2010 ; 49 :141 –144 .\n12. Pischke S Wedemeyer H \nChronic hepatitis E in liver transplant recipients: a significant clinical problem? \nMinerva Gastroenterol Dietol \n2010 ; 56 :121 –128 .20485250 \n13. Dalton HR Bendall RP Keane FE \nPersistent carriage of hepatitis E virus in patients with HIV infection . N Engl J Med \n2009 ; 361 :1025 –1027 .19726781 \n14. Abravanel F Sandres-Saune K Lhomme S \nGenotype 3 diversity and quantification of hepatitis E virus RNA . J Clin Microbiol \n2012 ; 50 :897 –902 .22205792 \n15. Legrand-Abravanel F Mansuy JM Dubois M \nHepatitis E virus genotype 3 diversity . France Emerg Infect Dis \n2009 ; 15 :110 –114 .19116067 \n16. Cooper K Huang FF Batista L \nIdentification of genotype 3 hepatitis E virus (HEV) in serum and fecal samples from pigs in Thailand and Mexico, where genotype 1 and 2 HEV strains are prevalent in the respective human populations . J Clin Microbiol \n2005 ; 43 :1684 –1688 .15814985 \n17. Roux CH Anty R Patouraux S \nHepatitis E: are rheumatic patients at risk? \nJ Rheumatol \n2013 ; 40 :99 .23280171 \n18. Bauer H Sibilia J Moreau P \nAcute hepatitis E during biotherapy . Joint Bone Spine \n2013 ; 80 :91 –92 .22999908 \n19. Van Eijk JJ Madden RG van der Eijk AA \nNeuralgic amyotrophy and hepatitis E virus infection . Neurology \n2014 ; 82 :498 –503 .24401685 \n20. Pischke S Hardtke S Bode U \nRibavirin treatment of acute and chronic hepatitis E: a single-centre experience . Liver Int \n2013 ; 33 :722 –726 .23489973 \n21. Abravanel F Chapuy-Regaud S Lhomme S \nPerformance of two commercial assays for detecting hepatitis E virus RNA in acute or chronic infections . J Clin Microbiol \n2013 ; 51 :1913 –1916 .23515544\n\n",
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"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000328:Adult; D000368:Aged; D000998:Antiviral Agents; D001168:Arthritis; D005260:Female; D005602:France; D016751:Hepatitis E; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012254:Ribavirin; D016896:Treatment Outcome",
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"title": "Outcome of hepatitis E virus infection in patients with inflammatory arthritides treated with immunosuppressants: a French retrospective multicenter study.",
"title_normalized": "outcome of hepatitis e virus infection in patients with inflammatory arthritides treated with immunosuppressants a french retrospective multicenter study"
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"abstract": "BACKGROUND\nSubcutaneous phaeohyphomycosis usually results from traumatic inoculation with the fungus and generally occurs in immunosuppressed men. Cladosporium, Exophiala, and Alternaria spp. are commonly implicated pathogens.\n\n\nOBJECTIVE\nWe present a case of subcutaneous phaeohyphomycosis caused by Rhytidhysteron sp. that was refractory to conventional antifungal therapy.\n\n\nMETHODS\nA 72-year-old man with hypertension and diabetes presented with a multiloculated, large cystic swelling over the right dorsal foot. Laboratory findings and x-rays of the chest and left foot were normal.\n\n\nRESULTS\nAdequate control of the patient's diabetes was achieved, and the swelling was excised under itraconazole/terbinafine coverage. Histology showed multiple areas of neutrophilic abscess, epithelioid cells, foreign body giant cells, and multiple septate hyphae and yeast-like cells. Dematiaceous fungus was cultured but failed to produce spores. Sequencing of the isolate showed a match of > 99% with Rhytidhysteron rufulum. The patient demonstrated no response after one year of therapy with itraconazole/terbinafine. Weekly infiltration of the lesion with liposomal amphotericin B resulted in its complete resolution within 15 weeks.\n\n\nCONCLUSIONS\nLesions of phaeohyphomycosis appear morphologically similar regardless of the organism implicated. Hence, their diagnosis rests entirely on the clinicopathological and microbiological presentation. Molecular studies may be required to identify a fungus if attempts to grow it in artificial culture media fail. Rhytidhysteron spp. are not known as pathogens in humans, and no treatment protocol exists. Intralesional amphotericin was highly effective in our patient and caused no systemic adverse effects. Voriconazole and posaconazole are effective against disseminated/visceral phaeohyphomycotic infections, but their efficacy against Rhytidhysteron spp. remains unstudied.",
"affiliations": "Department of Dermatology, Venereology and Leprosy, Dr Rajendra Prasad Government Medical College, Kangra at Tanda, Himachal Pradesh, India.",
"authors": "Mahajan|Vikram K|VK|;Sharma|Vikas|V|;Prabha|Neel|N|;Thakur|Kamlesh|K|;Sharma|Nand Lal|NL|;Rudramurthy|Shivaprakash M|SM|;Chauhan|Pushpinder S|PS|;Mehta|Karaninder S|KS|;Abhinav|C|C|",
"chemical_list": "D000935:Antifungal Agents; D008081:Liposomes; D009281:Naphthalenes; D017964:Itraconazole; D000666:Amphotericin B; D000077291:Terbinafine",
"country": "England",
"delete": false,
"doi": "10.1111/ijd.12529",
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"issn_linking": "0011-9059",
"issue": "53(12)",
"journal": "International journal of dermatology",
"keywords": null,
"medline_ta": "Int J Dermatol",
"mesh_terms": "D000368:Aged; D000666:Amphotericin B; D000935:Antifungal Agents; D001203:Ascomycota; D006801:Humans; D017964:Itraconazole; D008081:Liposomes; D008297:Male; D009181:Mycoses; D009281:Naphthalenes; D060446:Phaeohyphomycosis; D000077291:Terbinafine",
"nlm_unique_id": "0243704",
"other_id": null,
"pages": "1485-9",
"pmc": null,
"pmid": "24898242",
"pubdate": "2014-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A rare case of subcutaneous phaeohyphomycosis caused by a Rhytidhysteron species: a clinico-therapeutic experience.",
"title_normalized": "a rare case of subcutaneous phaeohyphomycosis caused by a rhytidhysteron species a clinico therapeutic experience"
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"companynumb": "IN-MYLANLABS-2015M1021647",
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"activesubstancename": "ITRACONAZOLE"
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... |
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"abstract": "OBJECTIVE\nSignificant controversy still exists about ritonavir-boosted protease inhibitor monotherapy (mtPI/rtv) as a simplification strategy that is used up to now to treat patients that have not experienced previous virological failure (VF) while on protease inhibitor (PI) -based regimens. We have evaluated the effectiveness of two mtPI/rtv regimens in an actual clinical practice setting, including patients that had experienced previous VF with PI-based regimens.\n\n\nMETHODS\nThis retrospective study analyzed 1060 HIV-infected patients with undetectable viremia that were switched to lopinavir/ritonavir or darunavir/ritonavir monotherapy. In cases in which the patient had previously experienced VF while on a PI-based regimen, the lack of major HIV protease resistance mutations to lopinavir or darunavir, respectively, was mandatory. The primary endpoint of this study was the percentage of participants with virological suppression after 96 weeks according to intention-to-treat analysis (non-complete/missing = failure).\n\n\nRESULTS\nA total of 1060 patients were analyzed, including 205 with previous VF while on PI-based regimens, 90 of whom were on complex therapies due to extensive resistance. The rates of treatment effectiveness (intention-to-treat analysis) and virological efficacy (on-treatment analysis) at week 96 were 79.3% (CI95, 76.8-81.8) and 91.5% (CI95, 89.6-93.4), respectively. No relationships were found between VF and earlier VF while on PI-based regimens, the presence of major or minor protease resistance mutations, the previous time on viral suppression, CD4+ T-cell nadir, and HCV-coinfection. Genotypic resistance tests were available in 49 out of the 74 patients with VFs and only four patients presented new major protease resistance mutations.\n\n\nCONCLUSIONS\nSwitching to mtPI/rtv achieves sustained virological control in most patients, even in those with previous VF on PI-based regimens as long as no major resistance mutations are present for the administered drug.",
"affiliations": "Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.;Hospital Universitario Carlos Haya, Málaga, Spain.;Hospital Universitario Virgen de las Nieves, Granada, Spain.;Hospital Universitario Virgen Macarena, Sevilla, Spain.;Hospital Universitario San Cecilio, Granada, Spain.;Complejo Hospitalario Juan Ramón Jiménez, Huelva, Spain.;Hospital Universitario de Puerto Real, Cádiz, Spain.;Hospital Universitario Virgen de la Victoria, Málaga, Spain.;Hospital Jerez de la Frontera, Cádiz, Spain.;Hospital La Línea, Cádiz, Spain.;Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.;Hospital Universitario Carlos Haya, Málaga, Spain.;Hospital Universitario Virgen Macarena, Sevilla, Spain.;Hospital Universitario San Cecilio, Granada, Spain.;Complejo Hospitalario Juan Ramón Jiménez, Huelva, Spain.;Hospital Universitario de Puerto Real, Cádiz, Spain.;Hospital Universitario Virgen de la Victoria, Málaga, Spain.;Hospital Universitario Virgen de las Nieves, Granada, Spain.",
"authors": "López-Cortés|Luis F|LF|;Castaño|Manuel A|MA|;López-Ruz|Miguel A|MA|;Rios-Villegas|María J|MJ|;Hernández-Quero|José|J|;Merino|Dolores|D|;Jiménez-Aguilar|Patricia|P|;Marquez-Solero|Manuel|M|;Terrón-Pernía|Alberto|A|;Tellez-Pérez|Francisco|F|;Viciana|Pompeyo|P|;Orihuela-Cañadas|Francisco|F|;Palacios-Baena|Zaira|Z|;Vinuesa-Garcia|David|D|;Fajardo-Pico|Jose M|JM|;Romero-Palacios|Alberto|A|;Ojeda-Burgos|Guillermo|G|;Pasquau-Liaño|Juan|J|",
"chemical_list": "D017320:HIV Protease Inhibitors; D016333:HIV Protease; D019438:Ritonavir",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0148924",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 2687233110.1371/journal.pone.0148924PONE-D-15-22177Research ArticleBiology and Life SciencesBiochemistryEnzymologyEnzymesProteasesBiology and Life SciencesBiochemistryProteinsEnzymesProteasesBiology and Life SciencesBiochemistryEnzymologyEnzyme InhibitorsProtease InhibitorsBiology and Life SciencesImmunologyVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyMedicine and Health SciencesImmunologyVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyMedicine and Health SciencesPublic and Occupational HealthPreventive MedicineVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyBiology and Life SciencesMicrobiologyMedical MicrobiologyMicrobial PathogensViral PathogensImmunodeficiency VirusesHIVMedicine and Health SciencesPathology and Laboratory MedicinePathogensMicrobial PathogensViral PathogensImmunodeficiency VirusesHIVBiology and Life SciencesOrganismsVirusesViral PathogensImmunodeficiency VirusesHIVBiology and Life SciencesOrganismsVirusesImmunodeficiency VirusesHIVBiology and life sciencesOrganismsVirusesRNA virusesRetrovirusesLentivirusHIVBiology and Life SciencesMicrobiologyMedical MicrobiologyMicrobial PathogensViral PathogensRetrovirusesLentivirusHIVMedicine and Health SciencesPathology and Laboratory MedicinePathogensMicrobial PathogensViral PathogensRetrovirusesLentivirusHIVBiology and Life SciencesOrganismsVirusesViral PathogensRetrovirusesLentivirusHIVBiology and Life SciencesImmunologyVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyProtease Inhibitor TherapyMedicine and Health SciencesImmunologyVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyProtease Inhibitor TherapyMedicine and Health SciencesPublic and Occupational HealthPreventive MedicineVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyProtease Inhibitor TherapyMedicine and Health SciencesPharmacologyDrugsAntimicrobialsAntiviralsAntiretroviralsBiology and Life SciencesMicrobiologyMicrobial ControlAntimicrobialsAntiviralsAntiretroviralsBiology and Life SciencesMicrobiologyVirologyAntiviralsAntiretroviralsBiology and Life SciencesMicrobiologyVirologyViral Transmission and InfectionViral LoadMedicine and Health SciencesInfectious DiseasesViral DiseasesViremiaEffectiveness of Ritonavir-Boosted Protease Inhibitor Monotherapy in Clinical Practice Even with Previous Virological Failures to Protease Inhibitor-Based Regimens Protease Inhibitor MonotherapyLópez-Cortés Luis F. 1*Castaño Manuel A. 2López-Ruz Miguel A. 3Rios-Villegas María J. 4Hernández-Quero José 5Merino Dolores 6Jiménez-Aguilar Patricia 7Marquez-Solero Manuel 8Terrón-Pernía Alberto 9Tellez-Pérez Francisco 10Viciana Pompeyo 1Orihuela-Cañadas Francisco 2Palacios-Baena Zaira 4Vinuesa-Garcia David 5Fajardo-Pico Jose M. 6Romero-Palacios Alberto 7Ojeda-Burgos Guillermo 8Pasquau-Liaño Juan 31 \nInstituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain2 \nHospital Universitario Carlos Haya, Málaga, Spain3 \nHospital Universitario Virgen de las Nieves, Granada, Spain4 \nHospital Universitario Virgen Macarena, Sevilla, Spain5 \nHospital Universitario San Cecilio, Granada, Spain6 \nComplejo Hospitalario Juan Ramón Jiménez, Huelva, Spain7 \nHospital Universitario de Puerto Real, Cádiz, Spain8 \nHospital Universitario Virgen de la Victoria, Málaga, Spain9 \nHospital Jerez de la Frontera, Cádiz, Spain10 \nHospital La Línea, Cádiz, SpainApetrei Cristian EditorUniversity of Pittsburgh Center for Vaccine Research, UNITED STATESCompeting Interests: FL and PV have received unrestricted grants for research and personal fees for speaking at symposia on behalf of Abbvie laboratories (Spain), Bristol-Myers Squibb, Glaxo Smithkline, Gilead Sciences, Janssen España, Merck Sharp & Dohme España, Roche Pharma SA, and ViiV Healthcare. MAL and MM have received unrestricted research grants and personal fees for speaking at symposia on behalf of Abbott laboratories (Spain), Janssen España, Merck Sharp & Dohme España, and ViiV Healthcare. JP has received unrestricted grants for research and speaker honoraria from Bristol-Myers Squibb, Janssen, Abbvie laboratories, Merck Sharp & Dohme, ViiV Healthcare, Gilead Sciences and Roche Pharma. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials. All other authors have no competing interests to declare.\n\nConceived and designed the experiments: LFL. Performed the experiments: LFL MAC MAL MJR JH DM PJ MM AT FT PV FO ZP DV JMF AR GO JP. Analyzed the data: LFL. Contributed reagents/materials/analysis tools: LFL MAC MAL MJR JH DM PJ MM AT FT PV FO ZP DV JMF AR GO JP. Wrote the paper: LFL. Critical revision of the article for important intellectual content: JH DM JP.\n\n* E-mail: lflopez@us.es12 2 2016 2016 11 2 e014892421 5 2015 19 1 2016 © 2016 López-Cortés et al2016López-Cortés 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 credited.Background and Objective\nSignificant controversy still exists about ritonavir-boosted protease inhibitor monotherapy (mtPI/rtv) as a simplification strategy that is used up to now to treat patients that have not experienced previous virological failure (VF) while on protease inhibitor (PI) -based regimens. We have evaluated the effectiveness of two mtPI/rtv regimens in an actual clinical practice setting, including patients that had experienced previous VF with PI-based regimens.\n\nMethods\nThis retrospective study analyzed 1060 HIV-infected patients with undetectable viremia that were switched to lopinavir/ritonavir or darunavir/ritonavir monotherapy. In cases in which the patient had previously experienced VF while on a PI-based regimen, the lack of major HIV protease resistance mutations to lopinavir or darunavir, respectively, was mandatory. The primary endpoint of this study was the percentage of participants with virological suppression after 96 weeks according to intention-to-treat analysis (non-complete/missing = failure).\n\nResults\nA total of 1060 patients were analyzed, including 205 with previous VF while on PI-based regimens, 90 of whom were on complex therapies due to extensive resistance. The rates of treatment effectiveness (intention-to-treat analysis) and virological efficacy (on-treatment analysis) at week 96 were 79.3% (CI95, 76.8−81.8) and 91.5% (CI95, 89.6–93.4), respectively. No relationships were found between VF and earlier VF while on PI-based regimens, the presence of major or minor protease resistance mutations, the previous time on viral suppression, CD4+ T-cell nadir, and HCV-coinfection. Genotypic resistance tests were available in 49 out of the 74 patients with VFs and only four patients presented new major protease resistance mutations.\n\nConclusion\nSwitching to mtPI/rtv achieves sustained virological control in most patients, even in those with previous VF on PI-based regimens as long as no major resistance mutations are present for the administered drug.\n\nThe authors received no specific funding for this work. Data AvailabilityAll relevant data are available via Dryad (http://dx.doi.org/10.5061/dryad.hf040).Data Availability\nAll relevant data are available via Dryad (http://dx.doi.org/10.5061/dryad.hf040).\n==== Body\nIntroduction\nThe idea of simplifying the HIV-1 antiretroviral treatment (ART) once achieved virological suppression arose after the initial enthusiasm that the efficacy of the first highly active antiretroviral therapies was tempered by their short- and long-term toxicity and the frequent occurrence of resistance-associated mutations. Nevertheless, this strategy failed to sustain viral suppression when compared with maintaining triple-drug therapy in the earlier studies, probably due to the low genetic barrier and/or the low antiviral potency of the drugs used at that time [1–3].\n\nYears later, the idea re-emerged after researchers became aware of the potent antiviral activity and the high genetic barrier of the ritonavir-boosted protease inhibitors [4]. Since then, a considerable amount of data have been accumulated on ritonavir-boosted protease inhibitor monotherapy (mtPI/rtv), particularly for lopinavir/ritonavir (mtLPV/rtv) and darunavir/ritonavir (mtDRV/rtv), from several clinical trials in which a high proportion of the patients maintained undetectable viremia with these simplified regimens [4–12]. However, significant controversy still exists regarding mtPI/rtv as a maintenance strategy [13–17]. Moreover, until now, at most, mtPI/rtv has only been administered to patients without a history of virological failure (VF) while on prior protease inhibitor-based therapy regimens.\n\nBoth the encouraging results of the above-mentioned clinical trials and the benefits of simpler regimens lacking the toxicity of nucleoside analogs or other antiretroviral drugs and cost-effectiveness [18,19] have made the use of mtPI/rtv a frequent practice in Spain, particularly in Andalusia. In fact, this treatment strategy is considered as a simplification option in both the Spanish and European guidelines for the use of antiretroviral agents in HIV-1-infected adults from 2009 onwards, although applying only to patients without history of failure on prior PI-based therapy and who have had viral load < 50 copies/mL in at least the past 6 months [14,15,20,21]\n\nIn this study, we evaluated the treatment effectiveness of two mtPI/rtv regimens in an actual clinical practice in the largest cohort reported to date, including patients that experienced previous virological failures while on protease inhibitors (PIs).\n\nPatients, Material and Methods\nStudy population and design\nIn this retrospective study, all of the HIV-infected adults at the participating centers who were switched from a triple antiretroviral regimen to either mtLPV/rtv (400/100 mg twice daily) or mtDRV/rtv (800/100 mg once daily) for the first time, from January 2010 to September 2012, were consecutively included. The participating centers (sorted by number of cases included) were Hospital Universitario Virgen del Rocío (Sevilla), Hospital Universitario Carlos Haya (Málaga), Hospital Universitario Virgen de las Nieves (Granada), Hospital Universitario Virgen Macarena (Sevilla), Hospital Universitario San Cecilio (Granada), Complejo Hospitalario Juan Ramón Jiménez (Huelva), Hospital Universitario de Puerto Real (Cádiz), Hospital Universitario Virgen de la Victoria (Málaga), Hospital Jerez de la Frontera (Cádiz), Hospital La Línea(Cádiz). The authors were the attendant physicians involved in making treatment decisions for patients. In most of these centers, clinical data of HIV-infected patients are recorded prospectively using the same software application (ACyH®, Betek 43 SL, Spain). The criteria for switching from a triple antiretroviral regimen to mtPI/rtv were fairly uniform across the participating centers. As a rule, patients were switched to mtPI/rtv after ≥6 months of plasma HIV-RNA determinations of <50 copies/mL and a treatment history of no previous virological failure (VF) while on PI-based regimens. In cases in which the patient had an earlier VF while on PI-based regimens, lack of major HIV resistance mutations to LPV/rtv (V32I, I47V/A, L76V, and V82A/F/T/S) or DRV/rtv (I47V, I50V, I54M/L, L76V, and I84V), respectively, in the genotypic resistance tests was mandatory according to the 2010 International AIDS Society [22]. Patients were switched from a triple regimen to boosted monotherapy because of adverse events (AEs) from the previous regimen or to simplify the treatment approach. However, not all patients who met the inclusion criteria at the participating centers were switched from triple therapy to mtPI/rtv. It largely depended on the decision of the responsible physicians, which was influenced by their confidence in mtPI/rtv and the acceptance by the patient after receiving verbal information. MtLPV/rtv was used more frequently in the first part of the study, while mtDRV/rtv was used more recently as data of clinical trials on that drug were reported.\n\nNo entry restrictions were made regarding plasma HIV-RNA, CD4 T cell count, illegal drug or methadone use, HCV-coinfection, or alterations in laboratory parameters. MtPI/rtv was not prescribed in cases of pregnancy, hepatitis B coinfection, or concomitant use of drugs with potential interactions with lopinavir/ritonavir or darunavir/ritonavir, respectively. The assembling of data was approved by the Ethics Committee in Biomedical Research of Andalucía and the Spanish Agency for Medicines and it was conducted according to the rules of the Declaration of Helsinki. The ethics committee specifically waived the need for patient consent since, according to Spanish law, the study did not require informed consent due to its retrospective nature and the fact that only completely anonymous information from existing records was collected, thereby ensuring the protection of personal data in accordance with the Personal Data Protection Organic Law15/199 enacted on December 13, 1999.\n\nEndpoints, follow-up, and assessments\nThe primary clinical endpoint was treatment effectiveness, which was measured as the percentage of patients with virological suppression after 96 weeks according to intention-to-treat analysis (non-complete/missing = failure). VF was defined as a confirmed plasma HIV-RNA of >200 copies/mL, considering the time of the first assessment meeting the failure criteria as the time of failure, or a single HIV-RNA level >200 copies/mL, if followed by loss of follow-up. A cut-off level of 200 copies/mL was chosen because it is a more accurate measurement of VF than a lower cut-off value [12,23,24]. As a secondary outcome, virological efficacy was assessed using on-treatment (OT) analysis. Additionally, patients were classified into four non-overlapping groups based on their virological outcome during the follow-up: i) continuous viral load of <50 copies/mL (cUV); ii) blips: transitory episodes of HIV-RNA viral loads of >50 copies/mL, preceded and followed by a plasma viral load of <50 copies/mL without changes in the antiretroviral treatment; iii) intermittent viremia (IV): episodes of detectable plasma HIV-RNA viral loads of >50 copies/mL during the follow-up without meeting blip or VF criteria; and iv) VF as defined above. AEs were categorized via the standardized toxicity-grade scale used by the AIDS Clinical Trials Group [25]. However, in patients with chronic viral hepatitis C or cirrhosis, toxicity was classified according to changes relative to the baseline values rather than the ULN: grade 0, <1.25 x baseline; grade 1, (1.25 to 2.5) x baseline; grade 2, (2.6 to 3.5) x baseline; grade 3, (3.6 to 5) x baseline; and grade 4, >5 x baseline.\n\nPatient assessment was performed at baseline and every three months thereafter, and included AEs, biochemical profiles, hematologic counts, flow cytometric counts of CD4+ T cells, and plasma HIV-RNA levels measured by polymerase chain reaction (PCR) (Amplicor HIV-1 Monitor test v. 1.0 with a lower detection limit of 50 copies/ml or COBAS AmpliPrep/COBAS TaqMan HIV-1 Test, v. 2.0 with a lower detection limit of 15 copies/ml, more recently). Patients missing two consecutive scheduled visits were considered lost to follow-up.\n\nStatistical analysis\nDescriptive statistics were used for demographic, epidemiological, and clinical data, prior ART, CD4 T cell count, and plasma HIV-RNA levels. Quantitative and qualitative variables are expressed as median, interquartile range (IQR), or range and number (%), respectively. Categorical variables were compared by using Student’s t-test or the Mann-Whitney non-parametric test, according to their distribution. The relationships between VF and the different variables were assessed by the χ2 test or Fisher's exact test and Spearman's rank correlation coefficients. Time-to-event analyses were performed using Kaplan-Meier survival curves and the log-rank test.\n\nResults\nBaseline patient characteristics\nA total of 1096 patients were initially included in the study, 36 of them were excluded from the analysis due to an HIV-RNA of >50 copies/ml at the time of the mtPI/rtv switching (n = 32) and four because the presence of one major protease resistance mutation for lopinavir/ritonavir (V82A/T) in previous genotypic resistance tests. Out of the remaining 1060 patients, 88.2% were switched to mtPI/rtv for simplification and 11.8% were switched due to AEs from the previous regimen. The main baseline characteristics of the patients are shown in Table 1, categorized according to the type of PI used (LPV/rtv or DRV/rtv). Before switching to mtLPV/rtv, almost 90% of the patients were on ART with two nucleos(t)ide reverse transcriptase inhibitors (NRTIs) plus one ritonavir-boosted protease inhibitor, mostly LPV/rtv (76.0%). In contrast, the previous ART regimens were more heterogeneous in the mtDRV/rtv group, in which only 101 patients (25.4%) were on a DRV/rtv-based treatment before switching to mtDRV/rtv. It is important to note that 90 patients were on complex combinations, including one NRTI or one non-nucleoside reverse transcriptase inhibitor (NNRTI) plus raltegravir plus one PI/rtv or even enfuvirtide plus PI/rtv ± maraviroc, due to extensive resistance to NRTIs and/or NNRTIs (Table 1).\n\n10.1371/journal.pone.0148924.t001Table 1 Baseline patients’ characteristics.\n\tmtDRV/rtv\tmtLPV/rtv\t\t\n\tn = 596\tn = 464\tp\t\nMale, no. (%)\t446 (74.8)\t344 (74.1)\t0.832\t\nAge, years. M (range)\t46 (18–88)\t46 (18–77)\t0.189\t\nWeight, kg. M (range)\t70 (39–115)\t68 (40–123)\t0.210\t\nRisk factor for HIV, no. (%)\t\t\t0.024\t\n Heterosexual\t161 (27.0)\t118 (25.4)\t\t\n Homosexual\t171 (28.7)\t96 (20.7)\t\t\n Other\t24 (4.0)\t16 (3.4)\t\t\nDrug addiction or methadone treatment\t61 (10.2)\t57 (12.3)\t0.617\t\nPrevious C stage (CDC), no. (%)\t164 (27.5)\t158 (34.1)\t0.027\t\nNadir CD4+ T cells count/μL. M (range)\t174 (1–861)\t155 (1–880)\t0.517\t\nCD4+ T cells count/μL. M (range)\t585 (46–1346)\t585 (76–1638)\t0.431\t\nChronic hepatitis, no. (%)\t198 (33.2)\t214 (46.1)\t0.001\t\n Cirrhosis\t27 (5.3)\t33 (7.1)\t0.106\t\nNo. of previous antiretroviral regimens\t4 (1–10)\t4 (1–10)\t0.170\t\nMonths on antiviral therapy. M (range)\t96 (9–288)\t78 (9–238)\t0.051\t\nPrevious failure on PI, no. (%)\t123 (20.6)\t82 (17.6)\t0.393\t\nPrevious failure on NNRTIs, no. (%)\t123 (21.2)\t90 (19.4)\t0.825\t\nMonths with HIV-RNA <50 copies/mL, M (range)\t34 (6–173)\t30 (6–184)\t0.451\t\nBlips in the previous 12 months, no. (%)\t141 (23.6)\t70 (15.0)\t0.001\t\nLast ART combinations, no. (%)\t\t\t\t\n 2 NRTIs + PI/rtv\t397 (66.6)\t410 (8.3)\t0.001\t\n LPV/rtv\t81 (20.4)\t312 (76.0)\t\t\n SQV/rtv\t91 (22.9)\t78 (19.0)\t\t\n DRV/rtv\t101 (25.4)\t2 (0.5)\t\t\n fAPV/rtv\t65 (16.3)\t9 (2.2)\t\t\n ATV/rtv\t59 (14.8)\t9 (2.1)\t\t\n 2 NRTIs + NNRTIs\t136 (22.8)\t21 (4.5)\t0.001\t\n 2 NRTIs + RAL or MRV\t6 (1.0)\t‒\t\t\n Last 2 NRTIs used\t\t\t\t\n TDF + FTC\t298 (55.3)\t232 (53.8)\t0.540\t\n ABV + 3TC\t134 (24.9)\t78 (18.1)\t\t\n Other 2 NRTIs\t107 (19.9)\t121 (28.1)\t\t\n Other combinations\t57 (9.5)\t33 (7.1)\t0.155\t\n NRTI + NNRTI + PI/rtv\t9\t5\t\t\n NRTI + RAL + PI/rtv\t17\t18\t\t\n NNRTI + RAL + PI/rtv\t7\t2\t\t\n NNRTI + MRV + PI/rtv\t2\t‒\t\t\n NNRTI + PI/rtv\t6\t2\t\t\n RAL + PI/rtv\t13\t5\t\t\n MRV + PI/rtv\t2\t‒\t\t\n T20 + PI/rtv\t1\t‒\t\t\n T20 + RAL + PI/rtv\t‒\t1\t\t\nmtDRV/rtv, darunavir/ritonavir monotherapy. mtLPV/rtv, lopinavir/ritonavir monotherapy. M, median; ART, antiretroviral therapy; NRTIs, nucleos(t)ide reverse transcriptase inhibitors; PI, protease inhibitors; PI/rtv, ritonavir-boosted protease inhibitors; NNRTIs, non-nucleoside reverse transcriptase inhibitors; LPV/rtv, lopinavir/ritonavir; SQV/rtv, saquinavir/rtv; DRV/rtv, darunavir/ritonavir; fAPV/rtv, fosamprenavir/ritonavir; ATV/rtv, atazanavir/ritonavir; NNRTIs, non-nucleoside reverse transcriptase inhibitors; RAL, raltegravir; MRV, maraviroc; T20, enfuvirtide.\n\nTwo hundred and five patients (19.3%) had a previous VF on either a non-ritonavir-boosted protease inhibitor-based regimen (41.9%), a PI/rtv-based regimen, or both (58.1%). One hundred and fifty eight (77.1%) of these 205 patients had available genotypic resistance tests just after these VFs; in 107 of those patients, the HIV protease gene showed a wild-type virus or only minor protease mutations while in 54 of them one or two major protease mutations plus minor mutations were observed. Although no patients had major resistance mutations for lopinavir or darunavir, 37 of the patients receiving mtLPV/rtv had minor mutations for that drug (median, 2; range, 1–3) and eight patients receiving mtDRV/rtv had minor mutations for darunavir/ritonavir (median, 2; range, 1–4) (Table 2).\n\n10.1371/journal.pone.0148924.t002Table 2 Mutations in HIV protease gene after previous virological failure (VF) on protease inhibitor-based regimen.\nProtease mutations after previous VF on PI-based regimen (n = 158/205)\tn (%)\t\nWild type\t59 (37.3)\t\nOnly mm (M, 2; range, 1–7)\t48 (30.3)\t\n1 MM (L90M, 25; D30N, 11; V82A, 2; N88S, 2; I50L/V, 2) + mm (M, 3; range, 0–8)\t42 (26.6)\t\n2 MM (V82A + L90M, 5; I84V + L90M, 2; N88S + L90M, 2; V82A + I84V, 1; D30N\t\t\n+ N88S, 1; I54L + L90M, 1;) + mm (M, 6; range, 4–10)\t12 (8.6)\t\nPI, protease inhibitor. mm, protease minor mutations. MM, HIV protease major mutations; M, median. Specific major protease mutations in brackets.\n\nTreatment effectiveness and safety\nGiven that the effectiveness rates were similar in the two groups, the data from all of the patients were analyzed together. The Kaplan-Meier estimations of treatment effectiveness by intention to treat analysis were 88.3% (CI95, 86.4‒89.4) and 79.3% (CI95, 76.8–81.8) at week 48 and 96, respectively.\n\nIn addition to VF episodes, other treatment failures were due to: (1) AEs (n = 35; diarrhea, 17; hyperlipidemia, 9; abdominal discomfort or vomiting, 5; increased aminotransferase levels, 2; hyperglycemia, 1; lipohypertrophy, 1); (2) loss to follow-up or treatment dropout (n = 33); (3) death not related to treatment (n = 7); (4) moved to another city or imprisonment (n = 10); and (5) medical decision without VF criteria or AEs (50 patients).\n\nOnly four out of the 85 patients with treatment failures due to AEs, loss to follow-up or dropout, deaths, and moving, had detectable viral load at the time of the last available HIV-RNA assessment (59–189 copies/mL). Among the 50 patients changing treatment for medical reasons, 16 had an undetectable viral load at the time of switching. The remaining 34 patients had median HIV-RNA levels of 131 copies/mL (range, 63–491).\n\nThe median increase in CD4+ T-cell counts from baseline to week 48 and 96 was 32 cells/μL (IQR, -71 to 143) and 49 (IQR, -70 to 170), respectively, as this was inversely proportional to the baseline CD4 counts (r = -0.302 and -0.286; p <0.001). Aminotransferase level increases throughout the follow-up period occurred in 107 (16.5%) out of 648 patients with no previous history of chronic hepatitis [grade 1, 78 patients (12.0%); grade 2, 19 patients (2.9%); grade 3, 8 patients (1.2%), and grade 4, 2 patients (0.3%)], and in 194 (47.0%) out of 412 patients with chronic hepatitis or cirrhosis [(grade 1, 161 patients (39.0%), grade 2, 22 patients (5.3%), grade 3, 7 patients (1.7%), and grade 4, 8 patients (1.9%)]. These alterations were transient and improved without treatment modification in most cases, but it motivated a treatment change in three patients. Regarding the lipid profile, the median (IQR) changes in total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides (mg/DL) for 928 patients at 48 weeks on mtPI/rtv were 11 (-13 to 34), 1 (-5 to 9), 9 (-11 to 29), and 5 (-36 to 55) respectively. After 96 weeks, these values were 12 (-17 to 37), 3 (-3 to 11), 11 (-14 to 30), and 5 (-51 to 48), respectively.\n\nVirological efficacy and genotypic resistance tests at failure\nThe Kaplan-Meier estimations of virological efficacy determined by on-treatment analysis were 95.6% (CI95, 94.5–96.7) and 91.5% (CI95, 89.6–93.4) at 48 and 96 weeks, respectively (Fig 1A). After 96 weeks there were 39 (6.5%) and 35 (7.5%) VF episodes in the mtDRV/rtv and mtLPV/rtv groups, respectively (p = 0.545). The VF rates were observed to be similar among those patients with and without a previous VF while on a protease inhibitor-based regimen (7.3% vs. 5.9%; p = 0.544) (Fig 1B). No relationships were observed between VF and either the presence of major or minor protease resistance mutations or the total number of both types of mutations. The time period with undetectable viral load before switching to mtPI/rtv was similar between the patients presenting with VF (median, 29 months; range, 6–146) and those who did not present with VP (median, 32 months; range, 6–184), p = 0.961). Likewise, there were no differences between both groups regarding the CD4+ T-cell nadir levels (median, 136 cells/μL; IQR, 35–227; range, 1–633 vs. 168 cells/μL; IQR, 64–265; range, 1–880), (p = 0.195). Only one of the 90 patients receiving previous complex therapy due to extensive resistance had a VF. Table 3 and Fig 1C show the estimated VF rates using tighter criteria for VF to compare this study’s results with the findings from other studies with different VF criteria.\n\n10.1371/journal.pone.0148924.g001Fig 1 Efficaccy rates.\nA) Efficacy rates according to the ritonavir-boosted protease inhibitor used by intention-to-treat and by on-treatment analyses. B) Virological efficacy rates according to virological failure (VF) defined as >200 copies/mL or C) >50 copies/mL or treatment change due to a single positive viremia, according to the presence or absence of previous VF on a non-boosted protease inhibitor- and/or ritonavir-boosted protease inhibitor-based regimen (PI/rtv). DRV/rtv, darunavir/ritonavir; LPV/rtv, lopinavir/ritonavir.\n\n10.1371/journal.pone.0148924.t003Table 3 Kaplan-Meier estimations of the efficacy as determined by on-treatment analysis applying different criteria for virological failure.\n\tVirological efficacy\t\nVirological failure definition\tweek 48\tweek 96\t\nHIV-RNA >200 copies/mL x2 or >200 x1 followed by loss to follow-up.\t95.6% (CI95, 94.5–96.7)\t91.5% (CI95, 89.6–93.4)\t\nHIV-RNA >50 copies/mL x2 or >50 x1 followed by loss to follow-up.\t94.4% (CI95, 93.1–97.7)\t85.2% (CI95, 82.9–87.5)\t\nHIV-RNA >50 copies/mL x2 or >50 x1 followed by loss to follow-up + treatment change due to a single detectable viremia.\t93.5% (CI95, 92.0–95.0)\t83.5% (CI95, 81.0–86.0)\t\nAmong the 74 patients experiencing VF, the median plasma HIV-RNA was 752 copies/mL (range, 205–50,775). In 49 (66.2%) of those patients, the HIV protease could be amplified and results are shown in Table 4.\n\n10.1371/journal.pone.0148924.t004Table 4 New mutations in the HIV protease gene after VF on ritonavir-boosted protease inhibitors monotherapy (mtPI/rtv).\nHIV protease gene after VF on mtPI/rtv (n = 49/74)\tn (%)\t\nWild type\t31 (63.3)\t\nOnly mm (M, 1; range, 1–3)\t14 (28.5)\t\n ▪ 1mm (L10V, 1; I62V, 2; L63P, 3; I64V, 1; A71T, 1)\t8 (16.3)\t\n ▪ 2 mm (L63P plus I62V or I64V or A71V or V77I or V82I)\t5 (10.2)\t\n ▪ 3 mm (L63P, M46I, I62V)\t1 (2.0)\t\n1 MM + mm\t3 (6.1)\t\n ▪ V32I\t1 (2.0)\t\n ▪ I50V, L10I, K20R, M36I, M46I, G48V\t1 (2.0)\t\n ▪ V82A, L10V, M36I, M46I, M54V\t1 (2.0)\t\n2 MM + mm\t\t\n ▪ V32I, T74P, L76V\t1 (2.0)\t\nM: median; MM: major protease resistance mutations; mm: minor protease resistance mutations.\n\nHIV-RNA evolution during the monotherapy and the outcome after virological failure\nThe median HIV-RNA determinations per subject was 5 (IQR, 4–7; range, 1–12), which adds up to a total of 5,793 HIV-RNA determinations. In addition to the 74 patients who experienced VF (7%), 693 patients (65.4%) maintained viral suppression during the follow-up, 225 (21.2%) experienced blip episodes (1, 190 patients; 2, 33 patients; and 3, 2 patients), and 68 (6.4%) showed intermittent viremia with a median of 40.0% of detectable HIV-RNA determinations (range, 14.0–100%) (Fig 2).\n\n10.1371/journal.pone.0148924.g002Fig 2 Percentages of detectable HIV-RNA determinations (red) according to virological behavior during the follow-up for ritonavir-boosted protease inhibitor monotherapy.\nUndetectable viremia (green).\n\nOne to three months after VF, only two out of 74 patients who presented a VF maintained a VL >50 copies/mL (1170 and 139 copies/mL, respectively). Sixty-four patients (86.4%) regained virological control either by continuing on mtPI/rtv and improving adherence (n = 22; 29.7%) or by adding one or two NRTIs (n = 36; 48.6%) or maraviroc (n = 6; 8.1%) to the protease inhibitor. Additionally, eight patients were lost to follow-up (10.8%).\n\nDiscussion\nThe ART simplification to mtPI/rtv has raised great concern from the beginning. Indeed, these regimens have largely been called into question much more than triple therapy. Whereas the efficacy of the latter is assessed in terms of achieving good control of the viremia, in the case of mtPI/rtv its reliability to either control HIV reservoirs or penetrate \"sanctuaries\", such as the genitourinary tract or the CNS, has been extensively questioned, as has the potential higher incidence of neurocognitive impairment. However, currently most of these events have been favorably clarified [26–34].\n\nThe results in this large cohort are similar to or slightly inferior to those observed in the main clinical trials on mtPI/rtv [5–10], as they reflect the results obtained in usual clinical practice more than the results from selected patients inherent to clinical trials. Moreover, the majority of the patients in this cohort were not checked for tolerance to LPV/rtv or DRV/rtv before starting monotherapy and some of the patients with VF in our cohort might actually be dropouts, as suggested by the high viral load they presented at failure.\n\nUntil now, mtPI/rtv was only allowed for patients with no previous VF while on protease inhibitor-based regimens. We believed that the absence of major protease resistance mutations to LPV/rtv or DRV/rtv, respectively, would not affect the virological efficacy of mtPI/rtv in cases of an earlier VF on PI-based regimens. Indeed, our results show that neither a history of VF on PI-based regimens nor the presence of protease mayor resistance mutations not reducing susceptibility to the PIs used or minor resistance mutations, including those specific for LPV/rtv or DRV/rtv, negatively affected the efficacy of mtPI/rtv as a maintenance treatment. In fact, the latest European guidelines admits the possibility of using it whenever there are no resistance to the PI used [14].\n\nMoreover, mtPI/rtv allowed for the simplification even of complex therapy due to extensive resistance, with a VF rate of only 1% in these patients. Other results of our series are also worth highlighting, such as the low incidence and grade of the AEs causing a treatment change, the favorable liver safety profile in a population in which more than 40% of patients are affected by chronic hepatitis C or cirrhosis, and the very low rate of new major and/or minor resistance mutations at VF, which barely compromised the activity of LPV/rtv or DRV/rtv, making it possible to regain virological control switching back to dual or triple therapy or even only improving adherence. Although some studies have shown that a CD4+ T-cell count nadir below 100–200 cells/μL and hepatitis C virus co-infection are factors associated with FV [9,35], but our findings do not support these observations nor a relationship with the previous time on virological suppression.\n\nNevertheless, our study has several limitations due to its retrospective nature and the lack of both a triple therapy comparator arm and a proper adherence assessment, particularly when adherence has been extensively associated with VF on mtPI/rtv (6,34,35). In contrast, the fact that all of the adult HIV-infected patients in our cohort switched from a triple antiretroviral regimen to mtPI/rtv at the participant centers minimized the selection biases, thereby reflecting what this simplification regimen can potentially offer in a real-world, clinical practice.\n\nIn summary, switching to mtPI/rtv is a feasible simplification option for virologically suppressed patients, even those with previous VF while on protease inhibitor-based regimens and with complex antiretroviral regimens, as long as no major resistance mutations are present for the administered drugs. A large proportion of patients maintained sustained viral suppression, and there was minimal risk of resistance development in those who failed.\n\nWe are indebted to A. Marín-Niebla (MD, PhD) for her assistance with the English version of this manuscript. All of the authors are members of the Sociedad Andaluza de Enfermedades Infecciosas (Andalusian Society of Infectious Diseases. http://www.saei.org/), which is the sponsor of this study.\n==== Refs\nReferences\n1 Havlir DV , Marschner IC , Hirsch MS , Collier AC , Tebas P , Bassett RL , et al\nMaintenance antiretroviral therapies in HIV infected patients with undetectable plasma HIV RNA after triple-drug therapy . N Engl J Med . 1998 \n10 \n29 ;339 (18 ): 1261 –1268 . 9791141 \n2 Pialoux G , Raffi F , Brun-Vezinet F , et al\nA randomized trial of three maintenance regimens given after three months of induction therapy with zidovudine, lamivudine, and indinavir in previously untreated HIV-1-infected patients . N Engl J Med \n1998 ; 339 : 1269 –1276 . 9791142 \n3 Reijers MH , Weverling GJ , Jurriaans S , Wit FW , Weigel HM , Ten Kate RW ,et al\nMaintenance therapy after quadruple induction therapy in HIV-1 infected individuals: Amsterdam Duration of Antiretroviral Medication (ADAM) study . Lancet . 1998 \n7 \n18 ;352 (9123 ): 185 –190 . 9683207 \n4 Arribas JR , Pulido F , Delgado R , Lorenzo A , Miralles P , Arranz A , et al\nLopinavir/ritonavir as single-drug therapy for maintenance of HIV-1 viral suppression: 48-week results of a randomized, controlled, open-label, proof-of-concept pilot clinical trial (OK Study) . J Acquir Immune Defic Syndr . 2005 \n11 \n1 ;40 (3 ): 280 –287 . 16249701 \n5 Pulido F , Delgado R , Pérez-Valero I , González-García J , Miralles P , Arranz A , et al\nLong-term (4 years) efficacy of lopinavir/ritonavir monotherapy for maintenance of HIV suppression . J Antimicrob Chemother . 2008 \n6 ;61 (6 ): 1359 –1361 . 10.1093/jac/dkn103 \n18343802 \n6 Arribas JR , Delgado R , Arranz A , Muñoz R , Portilla J , Pasquau J , et al\nLopinavir-ritonavir monotherapy versus lopinavir-ritonavir and 2 nucleosides for maintenance therapy of HIV: 96-week analysis . J Acquir Immune Defic Syndr . 2009 \n6 \n1 ;51 (2 ): 147 –152 . 10.1097/QAI.0b013e3181a56de5 \n19349870 \n7 Meynard JL , Bouteloup V , Landman R , Bonnard P , Baillat V , Cabie A , et al\nLopinavir/ritonavir monotherapy versus current treatment continuation for maintenance therapy of HIV-1 infection: the KALESOLO trial . J Antimicrob Chemother . 2010 \n11 ;65 (11 ): 2436 –2444 . 10.1093/jac/dkq327 \n20843990 \n8 Valantin MA , Lambert-Niclot S , Flandre P , Morand-Joubert L , Cabiè A , Meynard JL , et al\nLong-term efficacy of darunavir/ritonavir monotherapy in patients with HIV-1 viral suppression: week 96 results from the MONOI ANRS 136 study . J Antimicrob Chemother . 2012 \n3 ;67 (3 ): 691 –695 \n10.1093/jac/dkr504 \n22160145 \n9 Clumeck N , Rieger A , Banhegyi D , Schmidt W , Hill A , Van Delft Y , et al\n96 week results from the MONET trial: a randomized comparison of darunavir/ritonavir with versus without nucleoside analogues, for patients with HIV RNA <50 copies/mL at baseline . J Antimicrob Chemother . 2011 \n8 ;66 (8 ): 1878 –1885 . 10.1093/jac/dkr199 \n21652619 \n10 Mathis S , Khanlari B , Pulido F , Schechter M , Negredo E , Nelson M , et al\nEffectiveness of protease inhibitor monotherapy versus combination antiretroviral maintenance therapy: a meta-analysis . PLoS One \n2011 ;6 : e22003 \n10.1371/journal.pone.0022003 \n21811554 \n11 Arribas JR , Doroana M , Turner D , Vandekerckhove L , Streinu-Cercel A . Boosted protease inhibitor monotherapy in HIV-infected adults: outputs from a pan-European expert panel meeting . AIDS Res Ther . 2013 \n1 \n24 ;10 (1 ): 3 \n10.1186/1742-6405-10-3 \n23347595 \n12 Panel on Antiretroviral Guidelines for Adults and Adolescents . Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents\nDepartment of Health and Human Services \n2015 Available: http://aidsinfo.nih.gov/guidelines/. Accessed 1 July 2015.\n13 Günthard HF , Aberg JA , Eron JJ , Hoy JF , Telenti A , Benson CA , et al\nAntiretroviral treatment of adult HIV infection: 2014 recommendations of the International Antiviral Society-USA Panel . JAMA . 2014 \n7 \n23–30 ;312 (4 ):410 –425 \n10.1001/jama.2014.8722 \n25038359 \n14 European AIDS Clinical Society. European Guidelines for treatment of HIV infected adults in Europe. October 2015. Version 8. Available: http://eacsociety.org/Guidelines.aspx. Accessed 1 December 2015.\n15 Panel de expertos de GeSIDA y Plan Nacional sobre el Sida. Documento de consenso de GeSIDA/Plan Nacional sobre el Sida respecto al tratamiento antirretroviral en adultos infectados por el virus de la inmunodeficiencia humana (January 2015). Available: http://www.gesida-seimc.org/index.php. Accessed 1 March 2015.\n16 Williams I , Churchill D , Anderson J , Anderson J , Boffito M , Bower M , et al\nBritish HIV Association guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy 2012 (2013 update) . HIV Med . 2014 \n1 ;15 \nSuppl 1 : 1 –85 . 10.1111/hiv.12119 \n24330011 \n17 Hoen B , Bonnet F , Delaugerre C , Delobel P , Goujard C , L'Hénaff M , et al\nFrench 2013 guidelines for antiretroviral therapy of HIV-1 infection in adults . J Int AIDS Soc . 2014 \n6 \n17 ;17 : 19034 \n10.7448/IAS.17.1.19034 \n24942364 \n18 Pasquau J , Gostkorzewicz J , Ledesma F , Anceau A , Hill A , Moecklinghoff C . Budget impact analysis of switching to darunavir/ritonavir monotherapy for HIV-infected people in Spain . Appl Health Econ Health Policy . 2012 \n3 \n1 ;10 (2 ): 139 –141 . 10.2165/11598380-000000000-00000 \n22293019 \n19 Brogan AJ , Mrus J , Hill A , Sawyer AW , Smets E . Comparative cost-efficacy analysis of darunavir/ritonavir and other ritonavir-boosted protease inhibitors for first-line treatment of HIV-1 infection in the United States . HIV Clin Trials . 2010 \nMay-Jun ;11 (3 ): 133 –144 . 10.1310/hct1103-133 \n20736150 \n20 Panel de expertos de Gesida y Plan Nacional sobre el Sida . [Recommendations from the GESIDA/Spanish AIDS Plan regarding antiretroviral treatment in adults with human immunodeficiency virus infection (update February 2009) ]. Enferm Infecc Microbiol Clin . 2009 \n4 ;27 (4 ):222 –35 . 10.1016/j.eimc.2008.11.002 \n19246124 \n21 European AIDS Clinical Society (EACS) guidelines for the clinical management and treatment of HIV‐infected adults. Version 5. 2009. Available: http://www.eacsociety.org/files/2009_eacsguidelines-v5-english.pdf. Accessed 1 March 2014.\n22 Johnson VA , Brun-Vézinet F , Clotet B , Günthard HF , Kuritzkes DR , Pillay D , et al\nUpdate of the drug resistance mutations in HIV-1: December 2010 . Top HIV Med . 2010 \n12 ;18 (5 ):156 –63 .Verhofstede C, Van Wanzeele F, Reynaerts J, Mangelschots M, Plum J, Fransen K. Viral load assay sensitivity and low level viremia in HAART treated HIV patients. J Clin Virol. 2010 Apr;47(4): 335–339. 21245516 \n23 Ruelle J , Debaisieux L , Vancutsem E , De Bel A , Delforge ML , Piérard D , et al\nHIV-1 low-level viraemia assessed with 3 commercial real-time PCR assays show high variability . BMC Infect Dis . 2012 \n4 \n24 ;12 : 100 \n22530816 \n24 AIDS Clinical Trials Group . 1996 \nTable of grading severity of adult adverse experiences\nDivision of AIDS, National Institute of Allergy and Infectious Diseases , Rockville, MD .\n25 Lambert-Niclot S , Flandre P , Valantin MA , Soulie C , Fourati S , Wirden M , et al\nSimilar evolution of cellular HIV-1 DNA level in darunavir/ritonavir monotherapy versus triple therapy in MONOI-ANRS136 trial over 96 weeks . PLoS One \n2012 ;7 : e41390 \n10.1371/journal.pone.0041390 \n22848481 \n26 Torres-Cornejo A , Benmarzouk-Hidalgo OJ , Gutiérrez-Valencia A , Pérez-Romero P , Martín-Peña R , Ruiz-Valderas R , et al\nCellular HIV reservoir replenishment is not affected by blip or intermittent viremia episodes during darunavir/ritonavir monotherapy . AIDS . 2014 \n1 \n14 ;28 (2 ): 201 –208 . 10.1097/QAD.0000000000000060 \n24361681 \n27 Benmarzouk-Hidalgo OJ , Torres-Cornejo A , Gutiérrez-Valencia A , Ruiz-Valderas R , Viciana P , López-Cortés LF . Immune activation throughout a boosted darunavir monotherapy simplification strategy . Clin Microbiol Infect . 2014 \n12 ;20 (12 ): 1297 –1303 . 10.1111/1469-0691.12521 \n24372830 \n28 Vinuesa D , Parra-Ruiz J , Chueca N , Alvarez M , Muñoz-Medina L , Garcia F , et al\nProtease inhibitor monotherapy is not associated with increased viral replication in lymph nodes . AIDS . 2014 \n7 \n31 ;28 (12 ): 1835 –1837 . 10.1097/QAD.0000000000000312 \n24835357 \n29 Lambert-Niclot S , Peytavin G , Duvivier C , Poirot C , Algarte-Genin M , Pakianather S , et al\nLow frequency of intermittent HIV-1 semen excretion in patients treated with darunavir-ritonavir at 600/100 milligrams twice a day plus two nucleoside reverse transcriptase inhibitors or monotherapy . Antimicrob Agents Chemother . 2010 \n11 ;54 (11 ): 4910 –4913 . 10.1128/AAC.00725-10 \n20713677 \n30 Yeh RF, Hammill HA, Fiscus SA, et al: Single Agent Therapy (SAT) with lopinavir/ritonavir (LPV/r) controls HIV-1 viral replication in the female genital tract. [Abstract P7.7/02]. In: Program and abstracts of the 11th European AIDS Clinical Society Conference. Madrid. Spain. 2007.\n31 Yeh RF, Letendre S, Novak I, et al. Single-agent therapy with lopinavir/ritonavir controls HIV-1 viral replication in the central nervous system. [Abstract E-177]. In: Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections. Los Angeles, California. 2007.\n32 Pérez-Valero I , González-Baeza A , Estébanez M , Montes-Ramírez ML , Bayón C , Pulido F , et al\nNeurocognitive impairment in patients treated with protease inhibitor monotherapy or triple drug antiretroviral therapy . PLoS One . 2013 \n7 \n25 ;8 (7 ): e69493 \n10.1371/journal.pone.0069493 \n23936029 \n33 Estébanez M , Stella-Ascariz N , Mingorance J , Pérez-Valero I , González-Baeza A , Bayón C , et al\nA Comparative Study of Neurocognitively Impaired Patients Receiving Protease Inhibitor Monotherapy or Triple Drug Antiretroviral Therapy . J Acquir Immune Defic Syndr . 2014 \n12 \n1 ;67 (4 ): 419 –423 . 10.1097/QAI.0000000000000337 \n25197825 \n34 Pulido F , Pérez-Valero I , Delgado R , Arranz A , Pasquau J , Portilla J , et al\nRisk factors for loss of virological suppression in patients receiving lopinavir/ritonavir monotherapy for maintenance of HIV suppression . Antivir Ther . 2009 ;14 (2 ): 195 –201 . 19430094 \n35 Lambert-Niclot S , Flandre P , Peytavin G , Duvivier C , Haim-Boukobza S , Algarte-Genin M , et al\nFactors associated with virological failure in HIV-1-infected patients receiving darunavir/ritonavir monotherapy . J Infect Dis . 2011 \n10 \n15 ;204 (8 ): 1211 –1216 . 10.1093/infdis/jir518 \n21917894\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1932-6203",
"issue": "11(2)",
"journal": "PloS one",
"keywords": null,
"medline_ta": "PLoS One",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004252:DNA Mutational Analysis; D024882:Drug Resistance, Viral; D005260:Female; D015658:HIV Infections; D016333:HIV Protease; D017320:HIV Protease Inhibitors; D015497:HIV-1; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D012189:Retrospective Studies; D019438:Ritonavir; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101285081",
"other_id": null,
"pages": "e0148924",
"pmc": null,
"pmid": "26872331",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": "20843990;19246124;25197825;24330011;22293019;9791142;20713677;16249701;18343802;21917894;21811554;22530816;24361681;9683207;23936029;21652619;20736150;19430094;24372830;24942364;22848481;24835357;9791141;25038359;23347595;22160145;19349870;21388714",
"title": "Effectiveness of Ritonavir-Boosted Protease Inhibitor Monotherapy in Clinical Practice Even with Previous Virological Failures to Protease Inhibitor-Based Regimens.",
"title_normalized": "effectiveness of ritonavir boosted protease inhibitor monotherapy in clinical practice even with previous virological failures to protease inhibitor based regimens"
} | [
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"activesubstancename": "LOPINAVIR\\RITONAVIR"
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"abstract": "A fatal case of hyperphosphatemia secondary to enteral administration of Fleet Phospo-Soda is presented. A 64-yr-old male admitted for theophylline toxicity was treated with activated charcoal and sorbitol, but subsequently developed colonic ileus. Two sequential doses of Phospo-Soda were administered to facilitate clearance of the charcoal; however, this resulted in marked hyperphosphatemia, hypocalcemia, acidemia, and other electrolyte abnormalities, followed by the patient's demise. This case is added to several other reports about the risks of injudicious use of sodium phosphate cathartics.",
"affiliations": "Department of Medicine, University of Arizona Health Sciences Center, Tucson.",
"authors": "Fass|R|R|;Do|S|S|;Hixson|L J|LJ|",
"chemical_list": "D010710:Phosphates; D002606:Charcoal; D013012:Sorbitol; D013806:Theophylline; C018279:sodium phosphate",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9270",
"issue": "88(6)",
"journal": "The American journal of gastroenterology",
"keywords": null,
"medline_ta": "Am J Gastroenterol",
"mesh_terms": "D002606:Charcoal; D003108:Colonic Diseases; D004733:Enema; D006801:Humans; D007415:Intestinal Obstruction; D008297:Male; D008875:Middle Aged; D010710:Phosphates; D013012:Sorbitol; D013806:Theophylline; D014883:Water-Electrolyte Imbalance",
"nlm_unique_id": "0421030",
"other_id": null,
"pages": "929-32",
"pmc": null,
"pmid": "8503390",
"pubdate": "1993-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Fatal hyperphosphatemia following Fleet Phospo-Soda in a patient with colonic ileus.",
"title_normalized": "fatal hyperphosphatemia following fleet phospo soda in a patient with colonic ileus"
} | [
{
"companynumb": "US-PFIZER INC-2017156314",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"activesubstancename": "THEOPHYLLINE ANHYDROUS"
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"drugadditional": "... |
{
"abstract": "OBJECTIVE\nThe aim of this study was to carry out a safety evaluation of biologic agents in patients with JIA and associated uveitis.\n\n\nMETHODS\nIn three tertiary centres in Finland, all adverse events (AEs) in 348 consecutive patients were collected. AEs were classified according to the Common Terminology Criteria for AEs.\n\n\nRESULTS\nA total of 1516 patient-years (py) were included: 710 on etanercept, 591 on infliximab, 188 on adalimumab, 8 on rituximab, 5 on anakinra, 6 on tocilizumab, 6 on abatacept and 1 on golimumab. The median follow-up of an individual patient was 51 months (range 1-155). The most common of the 2902 AEs (191/100 py) observed were mild infections, infusion or injection site reactions and alanine aminotransferase elevations. At least one AE occurred in 319 (92%) patients and 121 (35%) had at least one serious AE (SAE). The rate of SAEs was 11.4/100 py on etanercept, 11.8 on infliximab, 10.1 on adalimumab, 15.7 on abatacept, 31.2 on tocilizumab and 87.5 on rituximab, higher than with most anti-TNF agents (P = 0.005). No cases of malignant neoplasms or tuberculosis were detected. New-onset uveitis occurred in 9 patients, psoriasis or psoriasiform lesions in 13 and IBD in 6.\n\n\nCONCLUSIONS\nMild and moderate AEs in patients with JIA treated with biologics were more frequent than previously reported. SAEs were observed in one-third of the patients, but SAEs seldom led to drug discontinuation.",
"affiliations": "Children's Hospital, Helsinki University Central Hospital, Institute of Clinical Medicine, University of Helsinki, Poison Information Center, Helsinki University Central Hospital, Helsinki, Finland, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland Children's Hospital, Helsinki University Central Hospital, Institute of Clinical Medicine, University of Helsinki, Poison Information Center, Helsinki University Central Hospital, Helsinki, Finland, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland maarit.tarkiainen@helsinki.fi.;Children's Hospital, Helsinki University Central Hospital, Institute of Clinical Medicine, University of Helsinki, Poison Information Center, Helsinki University Central Hospital, Helsinki, Finland, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland Children's Hospital, Helsinki University Central Hospital, Institute of Clinical Medicine, University of Helsinki, Poison Information Center, Helsinki University Central Hospital, Helsinki, Finland, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.;Children's Hospital, Helsinki University Central Hospital, Institute of Clinical Medicine, University of Helsinki, Poison Information Center, Helsinki University Central Hospital, Helsinki, Finland, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland Children's Hospital, Helsinki University Central Hospital, Institute of Clinical Medicine, University of Helsinki, Poison Information Center, Helsinki University Central Hospital, Helsinki, Finland, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland Children's Hospital, Helsinki University Central Hospital, Institute of Clinical Medicine, University of Helsinki, Poison Information Center, Helsinki University Central Hospital, Helsinki, Finland, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.;Children's Hospital, Helsinki University Central Hospital, Institute of Clinical Medicine, University of Helsinki, Poison Information Center, Helsinki University Central Hospital, Helsinki, Finland, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.",
"authors": "Tarkiainen|Maarit|M|;Tynjälä|Pirjo|P|;Vähäsalo|Paula|P|;Lahdenne|Pekka|P|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D001685:Biological Factors; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000410:Alanine Transaminase; D000068879:Adalimumab; D000068800:Etanercept",
"country": "England",
"delete": false,
"doi": "10.1093/rheumatology/keu457",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1462-0324",
"issue": "54(7)",
"journal": "Rheumatology (Oxford, England)",
"keywords": "adverse drug event; anti-TNF; anti-rheumatic agent; biologic therapy; disease-modifying anti-rheumatic drug; juvenile idiopathic arthritis",
"medline_ta": "Rheumatology (Oxford)",
"mesh_terms": "D000068879:Adalimumab; D000293:Adolescent; D000410:Alanine Transaminase; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D001171:Arthritis, Juvenile; D001685:Biological Factors; D002648:Child; D002675:Child, Preschool; D000068800:Etanercept; D005260:Female; D005500:Follow-Up Studies; D006261:Headache; D006801:Humans; D007074:Immunoglobulin G; D015994:Incidence; D007223:Infant; D000069285:Infliximab; D008137:Longitudinal Studies; D008297:Male; D009894:Opportunistic Infections; D010349:Patient Compliance; D011565:Psoriasis; D018124:Receptors, Tumor Necrosis Factor; D012189:Retrospective Studies; D014409:Tumor Necrosis Factor-alpha; D014605:Uveitis; D055815:Young Adult",
"nlm_unique_id": "100883501",
"other_id": null,
"pages": "1170-6",
"pmc": null,
"pmid": "25504896",
"pubdate": "2015-07",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Occurrence of adverse events in patients with JIA receiving biologic agents: long-term follow-up in a real-life setting.",
"title_normalized": "occurrence of adverse events in patients with jia receiving biologic agents long term follow up in a real life setting"
} | [
{
"companynumb": "FI-JNJFOC-20150621891",
"fulfillexpeditecriteria": "1",
"occurcountry": "FI",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "Cases of coronary artery spasm secondary to contrast agent use are rarely reported. Herein, we report the case of a 53-year-old woman who developed chest pain, dyspnea, and bradycardia and quickly become unresponsive after magnetic resonance imaging of the brain. A heart monitor showed ST elevation, and an electrocardiogram showed ST elevations in leads II, III, aVF, V3, and V4 and ST segment depression in lead I. Urgent left heart catheterization revealed no evidence of obstructive coronary artery disease or pulmonary embolism. A few days later, she was discharged from the hospital with no symptoms. A type I variant of Kounis syndrome was diagnosed.",
"affiliations": "Department of Internal Medicine, Joan C. Edwards School of Medicine, Marshall UniversityHuntingtonWest Virginia.;Department of Internal Medicine, Joan C. Edwards School of Medicine, Marshall UniversityHuntingtonWest Virginia.;Department of Internal Medicine, Joan C. Edwards School of Medicine, Marshall UniversityHuntingtonWest Virginia.;Department of Family Medicine, Joan C. Edwards School of Medicine, Marshall UniversityHuntingtonWest Virginia.;Department of Pulmonary Medicine, Joan C. Edwards School of Medicine, Marshall UniversityHuntingtonWest Virginia.",
"authors": "Abusnina|Waiel|W|0000-0003-2617-8483;Shehata|Mena|M|0000-0002-6358-1573;Abouzid|Mahmoud|M|0000-0001-8078-4199;Price|Malesa|M|;Zeid|Fuad|F|0000-0001-5287-5691",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1080/08998280.2019.1581319",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0899-8280",
"issue": "32(2)",
"journal": "Proceedings (Baylor University. Medical Center)",
"keywords": "Acute coronary syndrome; Kounis syndrome; allergy; contrast medium–induced coronary vasospasm; coronary hypersensitivity disorder",
"medline_ta": "Proc (Bayl Univ Med Cent)",
"mesh_terms": null,
"nlm_unique_id": "9302033",
"other_id": null,
"pages": "253-255",
"pmc": null,
"pmid": "31191145",
"pubdate": "2019-04",
"publication_types": "D002363:Case Reports",
"references": "10604922;14789736;14987309;1793697;18721322;20461972;25547529;26130889;26421155;27914212;29486712;30146563",
"title": "Kounis syndrome secondary to gadolinium contrast agent.",
"title_normalized": "kounis syndrome secondary to gadolinium contrast agent"
} | [
{
"companynumb": "US-GE HEALTHCARE-2021CSU006613",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "GADOLINIUM"
},
"drugadditional": "4",
... |
{
"abstract": "OBJECTIVE\nThe blood concentration of tacrolimus can be affected by co-administrated drugs. The objective is to draw more attention to herb-drug interactions in China, where herbal medicines are commonly used.\n\n\nMETHODS\nThe blood concentration of tacrolimus in a girl with refractory nephrotic syndrome decreased nearly a half despite no change in dose. Nebulizer therapy, cyclophosphamide and a compound Chinese herbal medicine were the only additional treatments than usual.\n\n\nCONCLUSIONS\nThe most possible cause of the decrease in tacrolimus concentration was the administration of Radix Astragali among compound Chinese herbal medicine granules.",
"affiliations": "Department of Pharmacy, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.;Department of Pharmacy, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.;Department of Nephrology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.;Department of Nephrology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.;Department of Nephrology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.;Department of Nephrology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.;Department of Nephrology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.;Department of Pharmacy, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.",
"authors": "Yang|Peipei|P|;He|Fan|F|;Tan|Mei|M|;Zhong|Fazhan|F|;Liao|Xin|X|;Li|Yingjie|Y|;Deng|Hui|H|;Mo|Xiaolan|X|https://orcid.org/0000-0003-3623-3474",
"chemical_list": "D004365:Drugs, Chinese Herbal; D007166:Immunosuppressive Agents; C027492:Huang Qi; D016559:Tacrolimus",
"country": "England",
"delete": false,
"doi": "10.1111/jcpt.13256",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-4727",
"issue": "46(1)",
"journal": "Journal of clinical pharmacy and therapeutics",
"keywords": "\nRadix Astragali\n; blood concentration; herb-drug interaction; nephrotic syndrome; tacrolimus",
"medline_ta": "J Clin Pharm Ther",
"mesh_terms": "D027885:Astragalus propinquus; D002648:Child; D004365:Drugs, Chinese Herbal; D005260:Female; D041743:Herb-Drug Interactions; D006801:Humans; D007166:Immunosuppressive Agents; D009404:Nephrotic Syndrome; D016559:Tacrolimus",
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"title": "Marked decrease of tacrolimus blood concentration caused by compound Chinese herbal granules in a patient with refractory nephrotic syndrome.",
"title_normalized": "marked decrease of tacrolimus blood concentration caused by compound chinese herbal granules in a patient with refractory nephrotic syndrome"
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"abstract": "Prevention and rehabilitation of hearing loss and tinnitus, the two most commonly awarded service-connected disabilities, are high priority initiatives in the Department of Veterans Affairs (VA). At least 4,000 Veterans, most with significant hearing loss, will receive cisplatin this year, with more than half sustaining permanent hearing shift and nearly 40% developing new tinnitus. With improved survivability following cancer treatment, Veterans treated with cisplatin are approached with the dual goals of effective treatment and preserved quality of life. This article describes COMP-VA, a comprehensive ototoxicity monitoring program developed for VA patients receiving cisplatin. The program includes an individualized pretreatment prediction model that identifies the likelihood of hearing shift given cisplatin dose and patient factors. It supports both manual and automated hearing testing with a newly developed portable audiometer capable of performing the recommended procedures on the chemotherapy unit during treatment. It also includes objective methods for identifying outer hair cell changes and predicting audiogram changes using distortion-product otoacoustic emissions. We describe this program of evidence-based ototoxicity monitoring protocols using a case example to give the reader an understanding of how this program would be applied, along with a plan for future work to accomplish the final stages of program development.",
"affiliations": "Portland VA Medical Center, National Center for Rehabilitative Auditory Research, 3710 SW US Veterans Hosp Rd, P5-NCRAR, Portland, OR 97239. dawn.martin@va.gov.",
"authors": "Konrad-Martin|Dawn|D|;Reavis|Kelly M|KM|;McMillan|Garnett|G|;Helt|Wendy J|WJ|;Dille|Marilyn|M|",
"chemical_list": "D002945:Cisplatin",
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"keywords": "COMP-VA; DPOAE; OtoID; aural rehabilitation; chemotherapy; cisplatin; distortion-product otoacoustic emissions; hearing; ototoxicity monitoring; sensitive range for \nototoxicity",
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"mesh_terms": "D019540:Area Under Curve; D001301:Audiometry, Pure-Tone; D001309:Auditory Threshold; D002294:Carcinoma, Squamous Cell; D002945:Cisplatin; D019317:Evidence-Based Medicine; D034381:Hearing Loss; D006320:Hearing Tests; D006801:Humans; D008297:Male; D008875:Middle Aged; D018670:Monitoring, Ambulatory; D017084:Otoacoustic Emissions, Spontaneous; D016730:Program Development; D011788:Quality of Life; D012372:ROC Curve; D018570:Risk Assessment; D014012:Tinnitus; D014062:Tongue Neoplasms; D014067:Tonsillar Neoplasms; D014481:United States; D014728:Veterans",
"nlm_unique_id": "8410047",
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"references": "22992258;11132710;19749461;12637478;16187247;20815453;10052832;14655957;18753950;1486202;22264063;1547792;1768872;24301436;19116379;9215367;23563060;17823555;19893928;8464301;21787192;17457342;14570962;10615688;12002864;7556513;9579846;10580222;22801480;15077641;19217931;17642021;22122961;20625302;10613387;12782811;10037289;20569665;9300767",
"title": "Proposed comprehensive ototoxicity monitoring program for VA healthcare (COMP-VA).",
"title_normalized": "proposed comprehensive ototoxicity monitoring program for va healthcare comp va"
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"abstract": "A 41-year-old woman presented with burning and erythema in her extremities triggered by warmth and activity, which was relieved by applying ice. Extensive workup was consistent with adult-onset primary erythromelalgia (EM). Several pharmacological treatments were tried including local anesthetics, capsaicin, ziconotide, and dantrolene, all providing 24-48 hours of relief followed by symptom flare. Interventional therapies, including peripheral and sympathetic ganglion blocks, also failed. Thus far, clonidine and ketamine have been the only effective agents for our patient. Genetic testing was negative for an EM-associated mutation in the SCN9A gene, encoding the NaV1.7 sodium channel, suggesting a mutation in an alternate gene.",
"affiliations": "Department of Internal Medicine, Banner University Medical Center, University of Arizona College of Medicine, Tucson, AZ.;Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University, Palo Alto.;Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University, Palo Alto.",
"authors": "Low|Sarah A|SA|;Robbins|Wendye|W|;Tawfik|Vivianne L|VL|",
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"fulltext": "\n==== Front\nJ Pain ResJ Pain ResJournal of Pain ResearchJournal of Pain Research1178-7090Dove Medical Press 10.2147/JPR.S129661jpr-10-973Case ReportComplex management of a patient with refractory primary erythromelalgia lacking a SCN9A mutation Low Sarah A 1Robbins Wendye 23Tawfik Vivianne L 21 Department of Internal Medicine, Banner University Medical Center, University of Arizona College of Medicine, Tucson, AZ2 Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University, Palo Alto3 Blade Therapeutics, South San Francisco, CA, USACorrespondence: Vivianne L Tawfik, Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University, 450 Broadway Street, Pavilion A, 1st Floor, Redwood City, CA 94063, USA, Tel +1 650 723 6238, Fax +1 650 721 3417, Email vivianne@stanford.edu2017 27 4 2017 10 973 977 © 2017 Low et al. This work is published and licensed by Dove Medical Press Limited2017The 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.A 41-year-old woman presented with burning and erythema in her extremities triggered by warmth and activity, which was relieved by applying ice. Extensive workup was consistent with adult-onset primary erythromelalgia (EM). Several pharmacological treatments were tried including local anesthetics, capsaicin, ziconotide, and dantrolene, all providing 24–48 hours of relief followed by symptom flare. Interventional therapies, including peripheral and sympathetic ganglion blocks, also failed. Thus far, clonidine and ketamine have been the only effective agents for our patient. Genetic testing was negative for an EM-associated mutation in the SCN9A gene, encoding the NaV1.7 sodium channel, suggesting a mutation in an alternate gene.\n\nKeywords\nerythromelalgiachronic paingenetic testingsodium channelsketamine\n==== Body\nIntroduction\nErythromelalgia (EM) is a rare neurovascular disorder characterized by swelling, erythema, and burning in the extremities in a stocking-glove distribution, which is relieved by exposure to cold but worsened by heat stimuli. Based on its etiology, EM is classified into two types: primary and secondary EM. Primary EM may be either hereditary with mutations in SCN9A resulting in defective NaV1.7 sodium channels or idiopathic with spontaneous gain-of-function mutations in SCN9A or other genes. Secondary EM is associated with hematological disorders involving thrombocytosis, certain immunological disorders, and some vasoactive medications.1 Despite the discovery of underlying NaV1.7 channel dysfunction in inherited EM,2 these patients often course through many different treatment modalities with inconsistent therapeutic responses.3 This report describes a case of refractory late-onset primary EM and raises key questions about its diagnosis, treatment, and the utility of genetic testing.\n\nConsent for publication\nWe obtained written permission from the patient to publish this case report and the accompanying images.\n\nCase description\nA 41-year-old woman presented to our clinic with late-onset EM, diagnosed 9 years prior at another institution following prolonged casting for a left metatarsal stress fracture. Her clinical presentation included burning, erythema, and swelling throughout her left foot. Over the course of next 3–4 months, her symptoms progressed to involve all extremities in a stocking-glove distribution. Her pain grew more intense with the addition of “throbbing, stabbing, and jerking” sensations. The frequency of her symptoms also escalated over time. Initially, she suffered from monthly flares lasting up to 24–48 hours, but within 5 years, she was essentially confined to her home maintained at an ambient temperature of 15°C. Her past medical history was significant for Raynaud’s disease, focal alopecia, hirsutism, premature ovarian failure, and severe melanosis coli secondary to long-term laxative use for chronic constipation. Her family history was negative for EM.\n\nDuring her initial visit to our clinic in 2012, her symptoms were nearly constant and had spread to involve her nose and ears. Her extremities were swollen, erythematous, and mottled (Figure 1A and B), and she episodically developed purple patches on her digits with a characteristic evolution (Figure 1C and D). Over the course of approximately 4 weeks, hard immobile papules would appear, whiten, and then ulcerate. Her symptoms were exacerbated by warmth, stress, physical activity, certain foods, and alcohol. She also had allodynia and arthralgias that persisted between flares.\n\nHaving failed several treatments at other institutions, she had stopped taking any medications when she presented to us but was chronically icing her limbs and receiving intermittent herbal body wraps that briefly mitigated her symptoms. Laboratory studies including complete blood count, comprehensive autoimmune panel (rheumatoid factor, erythrocyte sedimentation rate, C-reactive protein, anti-nuclear antibody, anti-dsDNA, anti-cyclic citrullinated peptide, anti-Ro, anti-La, anti-Sm, anti-ribonucleoprotein, anti-Scl70, anti-centromere), cold agglutinin screen, serum protein electrophoresis, and serum concentrations of IgG and heavy metals were all negative, ruling out secondary causes of EM. Autonomic reflex screen showed cardiovagal impairment consistent with limited neuropathy, as cardiovascular adrenergic and postganglionic sympathetic sudomotor function was preserved. There was evidence of length-dependent large-fiber peripheral neuropathy per nerve conduction studies, and transcutaneous oximetry (tcpO2) showed abnormal peripheral hemodynamic regulation with increased tcpO2 at the distal extremities, which decreased more proximally. Plain radiographs of the hands showed resorptive changes involving distal tufts of her distal phalanges, but there were normal degenerative changes in the feet where her symptoms were the most severe. Quantitative sensory testing revealed changes consistent with peripheral neuropathy, with the most significant changes noted with vibration and temperature sense. Thermography was positive, and her skin biopsy showed pernio, microvascular inflammation from repeated exposure to cold, which likely reflected her icing habits. Other special testing including hemodynamic responses to valsalva and tilt table testing as well as quantitative axon reflex sweat tests were negative.\n\nMedical treatment over the past 4 years included trials of an array of oral, intravenous (IV), and topical medications including opioids, sodium and calcium channel blockers, antidepressants, antiepileptics, dantrolene, immunoglobulin infusions, compounded creams, and other adjuvants (Table 1 presents a summary of medical and interventional therapies). Medical management with these agents was either ineffective or amplified her symptoms. These flares involved 1 week of pain intensification followed by 2–4 weeks of swelling with fulminant development of ulcerating lesions on her digits. Sequential rounds of IV nitroglycerin and high-dose capsaicin patches were also tried but were discontinued secondary to desquamation. An initial improvement with IV dantrolene infusion was encouraging; however, the therapy was discontinued due to side effects. Transdermal clonidine improved her erythema and swelling; however, the associated vasodilation worsened her pain, which was controlled by the addition of IV ketamine. Clonidine and ketamine were the only agents that transiently dampened her symptoms without provocation of flares; however, she required monthly week-long hospitalizations for these treatments, which provided only minimal relief (Figure 1E and F).\n\nInterventional therapies included sympathetic ganglion and perivascular blocks as well as intrathecal and epidural infusions of fentanyl, local anesthetics, clonidine, and ziconotide, which all resulted in brief symptom mitigation (up to 48 hours) followed by her characteristic flare lasting up to 4 weeks. Epidural catheter placement resulted several times in insertion-site erythema, pain, and sterile drainage in the absence of systemic signs of infection. In one instance, 48 hours after the initiation of an epidural infusion of 0.25% bupivacaine, she developed sudden onset complete lower extremity motor weakness and saddle anesthesia that resolved 3 hours after terminating the infusion.\n\nGiven the intractability of her symptoms, she was enrolled in a clinical trial testing of a topical small-molecule NaV1.7 inhibitor, XEN402, a novel compound that exhibits potent, voltage-dependent block of Na V1.7.4 She was prematurely discontinued from this trial due to dramatic desquamation that developed days after initial application of the inhibitor. With the goal of formulating our therapeutic strategy, we sought the results of her SCN9A exon sequencing, which was performed during the clinical trial. Surprisingly, it revealed a wild-type sequence for the SCN9A gene encoding the NaV1.7 α-subunit. This ruled out all known coding region genetic defects linked to inherited EM as well as any novel mutations.\n\nDiscussion\nIn this case report, we describe the condition of a patient severely affected by erythema, swelling, and pain in her hands and feet that progressed in spite of multiple therapeutic trials. Complex regional pain syndrome (CRPS) is a disease affecting the extremities that often develops after fracture or minor injury,5 as was the case with this patient. However, while she does meet the criteria for CRPS (including vasomotor, sudomotor, motor, and sensory signs),6 the triggering of her symptoms by even mild increases in ambient temperature or activity, the use of cooling behaviors to achieve symptom relief, and predominance of erythema and burning are highly suggestive of EM as the primary diagnosis.\n\nIn 2004, the SCN9A gene was implicated in the pathogenesis of inherited EM,2 and since then, an impressive amount of research has been performed to produce targeted inhibitors of the NaV1.7 channel.4,7 Interestingly, however, the heterogeneous clinical presentation of patients with EM explains the phenotype–genotype discrepancy of this disease,7,8 as even patients with the same mutation can exhibit a range of phenotypes.3,9 Nevertheless, genetic testing may still help develop targeted treatment strategies, as certain NaV1.7 mutations have been shown to be exquisitely responsive to specific agents such as mexiletine8,10 and carbamazepine.11,12\n\nThis case report highlights the challenge in managing symptoms of primary EM in patients for whom genetic testing rules out an SCN9A exonic mutation. Interestingly, one recent study of 48 patients meeting clinical criteria for EM found that only seven of the 48 patients carried protein-modifying mutations of NaV1.7, whereas 20 patients had rare protein-modifying mutations in genes encoding other sodium channel α- or β-subunits, transient receptor potential channels, or other pain-related targets.13 This suggests that screening our patient for mutations beyond the SCN9A gene may identify additional targets and clarify the genetic basis of her condition.\n\nTreatment for our patient began with local anesthetics (LAs) in an effort to directly dampen aberrant sodium channel activity. Sodium channel-binding sites of LAs are highly dynamic, as LAs’ binding affinity is voltage-dependent and the charges within binding sites fluctuate as the channel cycles change between four different conformational states. Thus, several different LAs were tried given their varied state-dependent binding preferences, with lidocaine having greater affinity to the open state, for example, and flecainide to the closed state.14 Antiepileptics were then tried as their sodium channel antagonism is produced via a different mechanism allowing them to preferentially inhibit the high-frequency repetitive firing of hyperexcitable neurons.15 Even at high doses, however, antiepileptics, such as carbamazepine, oxcarbazepine, lamotrigine, and topiramate, were not effective. Consequently, our patient was enrolled in a clinical trial testing of topical application of a novel NaV1.7 small molecule inhibitor. Unfortunately, however, it was negligibly therapeutic for her, and she was discontinued from the trial due to severe desquamation.\n\nWe then extended our approach to target the vasculature using agents such as calcium channel blockers, TrpV1 antagonists, phosphodiesterase inhibitors, and nitrates. These vasoactive drugs notably increased our patient’s swelling, pain, and lesion/ulcer formation independent of the delivery method. Then, we hypothesized that dantrolene, a ryanodine receptor antagonist that blocks intracellular calcium release from the sarcoplasmic reticulum, may be beneficial. Dantrolene is effective in malignant hyperthermia, a pathological state involving build-up of available intracellular calcium leading to cellular hypermetabolism, and notably, increased autonomic activity. In our patient, IV dantrolene did not impart symptom relief. Instead, she experienced multiple side effects including eye pain, myalgias, slurred speech, and vomiting that continued for 2 weeks after cessation of the drug.\n\nThe characteristic symptoms of EM are both sensory and autonomic in nature, reflecting the known distribution of sodium channels in sensory and sympathetic ganglia.16 In our patient, clonidine and ketamine effectively mitigated her symptoms but only when administered systemically, suggesting that a central site of action was necessary for efficacy. As an adrenergic α2-receptor agonist, clonidine may address sympathetic overdrive in EM by blunting excess central outflow via medullary α2-receptors and peripherally counteracting aberrant vasoconstriction. Ketamine, an N-methyl-D-aspartate (NMDA)-receptor antagonist, has been effective in treating CRPS, a pain disorder marked by local sympathetic dysfunction.17 The mechanism by which ketamine blunts the apparent sympathetically mediated pain in these patients is unclear; however, inhibition of pathological synaptic changes has been suggested by a study which shows that NMDA-receptor antagonism impedes synaptic plasticity.18 The fact that EM symptoms typically affect the extremities in sequence suggests that synaptic plasticity may contribute to the progression of the disease.\n\nWe therefore suggest that successful management of patients with EM can be achieved when three major goals are simultaneously addressed: primary analgesic management, dampening sympathetic outflow, and reversing excessive vasoconstriction. Genetic testing may be informative if an SCN9A mutation is identified that may be responsive to specific agents. As our understanding of the pathophysiology and diverse genetic basis of primary EM continues to expand, the development of directed definitive treatments for this debilitating disease will continue to evolve. Until then, cases like this emphasize the need for multimodal approaches to achieving symptomatic relief for our patients.\n\nAcknowledgments\nDr Tawfik is funded by the Foundation for Anesthesia Education and Research (FAER).\n\nAuthor contributions\n\nAll authors contributed toward data analysis, drafting and critically revising the paper and agree to be accountable for all aspects of the work.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 Erythematous feet (A) and hands (B) at baseline with firm, nodular lesions in the beginning stages of development. An example of extremities (C and D) during a symptom flare with progression of lesions to blisters and ulceration. Demonstration of feet (E) and hands (F) after successful treatment with clonidine and ketamine, and lesions in the process of healing.\n\nTable 1 Classes of medications and interventions tried with varying efficacy\n\nMedications\t\n NSAIDs\t\n Opioids (full and partial agonists)\t\n Antidepressants (tricyclics and serotonin–norepinephrine reuptake inhibitors)\t\n Antiepileptics\t\n GABA analogs\t\n Sodium channel blockers (oral, epidural, IV, IT)\t\n Sodium channel blockers (small molecule, topical)\t\n Calcium channel blockers\t\n Alpha-2-agonists\t\n Dissociative anesthetics (ketamine)\t\n TrpV1 agonists (cream, patch)\t\n Glucocorticoids (oral, epidural)\t\n Quinolines (hydroxychloroquine)\t\n Biologics (IVIG)\t\n Nitrates and phosphodiesterase inhibitors\t\n Microtubule polymerization inhibitors\t\n Antihyperglycemics (rosiglitazone)\t\n Xanthine derivatives (pentoxyfylline)\t\n Ryanodine receptor antagonists (dantrolene)\t\nInterventions\t\n Thoracolumbar spinal cord stimulator, T11-L3 (trial only)\t\n Epidural steroid injections\t\n Epidural and intrathecal infusions\t\n Local anesthetics (lidocaine, bupivacaine)\t\n Opioids (fentanyl, dilaudid)\t\n Clonidine\t\n Sympathetic ganglion blocks\t\n Peripheral nerve blocks\t\n Perivascular blocks\t\nAbbreviations: NSAIDs, nonsteroidal anti-inflammatory drugs; GABA, gamma aminobutyric acid; IV, intravenous; IT, intrathecal; IVIG, intravenous immunoglobulin.\n==== Refs\nReferences\n1 Drenth JP Michiels JJ Erythromelalgia and erythermalgia: diagnostic differentiation Int J Dermatol 1994 33 6 393 397 8056469 \n2 Yang Y Wang Y Li S Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia J Med Genet 2004 41 3 171 174 14985375 \n3 Davis MD O’Fallon WM Rogers RS 3rd Rooke TW Natural history of erythromelalgia: presentation and outcome in 168 patients Arch Dermatol 2000 136 3 330 336 10724194 \n4 Emery EC Luiz A Wood JN Nav1.7 and other voltage-gated sodium channels as drug targets for pain relief Expert Opin Ther Targets 2016 20 8 1 9 26420565 \n5 de Mos M de Bruijn AG Huygen FJ Dieleman JP Stricker BH Sturkenboom MC The incidence of complex regional pain syndrome: a population-based study Pain 2007 129 1–2 12 20 17084977 \n6 Harden N Bruehl S Perez RS Validation of proposed diagnostic criteria (the ‘Budapest Criteria’) for Complex Regional Pain Syndrome Pain 2010 150 2 268 274 20493633 \n7 Cao L McDonnell A Nitzsche A Pharmacological reversal of a pain phenotype in iPSC-derived sensory neurons and patients with inherited erythromelalgia Sci Transl Med 2016 8 335 335ra56 \n8 Waxman S Merkies IS Gerrits MM Sodium channel genes in pain-related disorders: phenotype–genotype associations and recommendations for clinical use Lancet Neurol 2014 13 11 1152 1160 25316021 \n9 Estacion M Han C Choi JS Intra- and interfamily phenotypic diversity in pain syndromes associated with a gain-of-function variant of NaV 1.7 Mol Pain 2011 7 92 22136189 \n10 Choi JS Zhang L Dib-Hajj SD Mexiletine-responsive erythromelalgia due to a new Nav1.7 mutation showing use-dependent current fall-off Exp Neurol 2009 216 2 383 389 19162012 \n11 Fischer TZ Gilmore ES Estacion M A novel Nav1.7 mutation producing carbamazepine-responsive erythromelalgia Ann Neurol 2009 65 6 733 741 19557861 \n12 Geha P Yang Y Estacion M Pharmacotherapy for pain in a family with inherited erythromelalgia guided by genomic analysis and functional profiling JAMA Neurol 2016 73 6 659 667 27088781 \n13 Zhang Z Schmelz M Segerdahl M Exonic mutations in SCN9A (NaV1.7) are found in a minority of patients with erythromelalgia Scand J Pain 2014 5 4 217 225 \n14 Sheets MF Fozzard HA Lipkind GM Hanck DA Sodium channel molecular conformations and antiarrhythmic drug affinity Trends Cardiovasc Med 2010 20 1 16 21 20685573 \n15 Lipkind GM Fozzard HA Molecular model of anticonvulsant drug binding to the voltage-gated sodium channel inner pore Mol Pharmacol 2010 78 4 631 638 20643904 \n16 Dib-Hajj S Yang Y Black JA Waxman SG The Na(V)1.7 sodium channel: from molecule to man Nat Rev Neurosci 2012 14 1 49 62 23232607 \n17 Schwartzman RJ Alexander GM Grothusen JR Paylor T Reichenberger E Perreault M Outpatient intravenous ketamine for the treatment of complex regional pain syndrome: a double-blind placebo controlled study Pain 2009 147 1–3 107 115 19783371 \n18 Woolf CJ Thompson SW The induction and maintenance of central sensitization is dependent on N-methyl-D-aspartic acid receptor activation; implications for the treatment of post-injury pain hypersensitivity states Pain 1991 44 3 293 299 1828878\n\n",
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"title": "Complex management of a patient with refractory primary erythromelalgia lacking a SCN9A mutation.",
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"abstract": "Depression is an accepted risk factor for dementia, but it is unclear if this relationship is causal. This study investigated whether dementia associated with depression decreases with antidepressant use and is independent of the time between exposure to depression and the onset of dementia. We completed a 14-year longitudinal study of 4922 cognitively healthy men aged 71-89 years, and collected information about history of past depression, current depression and severity of depressive symptoms. Other measures included use of antidepressants, age, education, smoking and history of diabetes, hypertension, coronary heart disease, and stroke. The onset of dementia and death during follow-up was ascertained via the Western Australian Data Linkage System. A total of 682 men had past (n=388) or current (n=294) depression. During 8.9 years follow-up, 903 (18.3%) developed dementia and 1884 (38.3%) died free of dementia. The sub-hazard ratios (SHRs) of dementia for men with past and current depression were 1.3 (95% confidence interval (CI)=1.0, 1.6) and 1.5 (95% CI=1.2, 2.0). The use of antidepressants did not decrease this risk. Compared to men with no symptoms, the SHRs of dementia associated with questionable, mild-to-moderate and severe depressive symptoms were 1.2 (95% CI=1.0, 1.4), 1.7 (95% CI=1.4, 2.2) and 2.1 (95% CI=1.4, 3.2), respectively. The association between depression and dementia was only apparent during the initial 5 years of follow-up. Older men with history of depression are at increased risk of developing dementia, but depression is more likely to be a marker of incipient dementia than a truly modifiable risk factor.",
"affiliations": "School of Psychiatry and Clinical Neurosciences, University of Western Australia, Perth, WA, Australia.;School of Medicine and Pharmacology, University of Western Australia, Perth, WA, Australia.;School of Medicine and Pharmacology, University of Western Australia, Perth, WA, Australia.;Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, QLD, Australia.;WA Centre for Health & Ageing of Centre for Medical Research, Harry Perkins Institute of Medical Research, Perth, WA, Australia.",
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"fulltext": "\n==== Front\nTransl PsychiatryTransl PsychiatryTranslational Psychiatry2158-3188Nature Publishing Group tp20179010.1038/tp.2017.9028463236Original ArticleDepression as a modifiable factor to decrease the risk of dementia Depression and dementiaAlmeida O P 123*Hankey G J 45Yeap B B 46Golledge J 78Flicker L 2491 School of Psychiatry and Clinical Neurosciences, University of Western Australia, Perth, WA, Australia2 WA Centre for Health & Ageing of Centre for Medical Research, Harry Perkins Institute of Medical Research, Perth, WA, Australia3 Department of Psychiatry, Royal Perth Hospital and Bentley Hospital, Perth, WA, Australia4 School of Medicine and Pharmacology, University of Western Australia, Perth, WA, Australia5 Department of Neurology, Sir Charles Gairdner Hospital, Perth, WA, Australia6 Department of Endocrinology, Fiona Stanley Hospital, Perth, WA, Australia7 Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, QLD, Australia8 Department of Vascular and Endovascular Surgery, The Townsville Hospital, Townsville, QLD, Australia9 Department of Geriatric Medicine, Royal Perth Hospital, Perth, WA, Australia* School of Psychiatry and Clinical Neurosciences (M573), University of Western Australia, 35 Stirling Highway, Crawley, Perth, WA 6009, Australia. E-mail: osvaldo.almeida@uwa.edu.au05 2017 02 05 2017 1 5 2017 7 5 e1117 21 12 2016 13 02 2017 16 03 2017 Copyright © 2017 The Author(s)2017The Author(s)This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 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-nc-sa/4.0/Depression is an accepted risk factor for dementia, but it is unclear if this relationship is causal. This study investigated whether dementia associated with depression decreases with antidepressant use and is independent of the time between exposure to depression and the onset of dementia. We completed a 14-year longitudinal study of 4922 cognitively healthy men aged 71–89 years, and collected information about history of past depression, current depression and severity of depressive symptoms. Other measures included use of antidepressants, age, education, smoking and history of diabetes, hypertension, coronary heart disease, and stroke. The onset of dementia and death during follow-up was ascertained via the Western Australian Data Linkage System. A total of 682 men had past (n=388) or current (n=294) depression. During 8.9 years follow-up, 903 (18.3%) developed dementia and 1884 (38.3%) died free of dementia. The sub-hazard ratios (SHRs) of dementia for men with past and current depression were 1.3 (95% confidence interval (CI)=1.0, 1.6) and 1.5 (95% CI=1.2, 2.0). The use of antidepressants did not decrease this risk. Compared to men with no symptoms, the SHRs of dementia associated with questionable, mild-to-moderate and severe depressive symptoms were 1.2 (95% CI=1.0, 1.4), 1.7 (95% CI=1.4, 2.2) and 2.1 (95% CI=1.4, 3.2), respectively. The association between depression and dementia was only apparent during the initial 5 years of follow-up. Older men with history of depression are at increased risk of developing dementia, but depression is more likely to be a marker of incipient dementia than a truly modifiable risk factor.\n==== Body\nIntroduction\nSymptomatic treatments for dementia remain limited in scope and efficacy,1 and despite significant financial investment, there is no cure in sight.2 However, accumulating epidemiological data has revealed several potentially modifiable risk factors, offering hope that prevention is possible. Education, diabetes, hypertension, obesity, physical inactivity, smoking and depression account for ~30% of Alzheimer’s disease cases so that risk-modifying interventions could potentially reduce its prevalence worldwide.3 Emerging trial data indicate that this may be a strategy worth pursuing.4, 5, 6\n\nNorton et al.3 estimated that 5–11% of Alzheimer’s disease cases could be attributed to depression. It means that the prevalence of dementia in the population would be reduced by the same amount if depression could be prevented or adequately treated. The personal and socioeconomic benefits of such a reduction would be substantial.7 This assumes, of course, that depression causes dementia. The most compelling way of demonstrating causality would be by means of a randomised controlled trial, but such a trial would not be ethical or feasible. Observational data consistently show that depression increases the risk of incident dementia,8 and there is tentative evidence for a dose-effect modulating this relationship,9, 10 particularly when the severity of symptoms increases over time.11, 12 In addition, older adults with depression show improved cognitive performance after successful treatment,13, 14 and there is some evidence that depression may lead to loss of hippocampal volume, particularly when symptoms are persistent.15 Finally, new observational data suggest that severe depression may contribute to accelerate cellular ageing, as measured by telomere length.16 Taken together, these findings imply that the association between depression and cognitive impairment is both consistent and plausible.\n\nWe used data from the Health In Men Study to investigate whether depression is likely to be causally related to incident dementia. On the basis of existing evidence, we hypothesised that the risk of incident dementia would be associated with: (1) past and current depression, (2) increasing severity of depressive symptoms and (3) lower exposure to antidepressant treatment. Finally, we hypothesised that the risk of dementia associated with depression would be independent of the duration of the follow-up period. This latter hypothesis is based on the premise that depression is not simply an early prodromal manifestation of dementia.\n\nMaterials and methods\nStudy design and setting\nHealth In Men Study is a community-based cohort study based in Western Australia.\n\nParticipants\nWe used the Australian Electoral Roll to recruit a sample of 12 203 men aged 65–84 years living in Perth in 1996—voting is compulsory in Australia.17 During a second wave of assessments between 2001 and 2004, 5514 participants provided information about depressive symptoms and past history of depression (details below)—592 of them had documented history of dementia (details below) or cognitive impairment (Mini-Mental State Examination score<24).18 Hence, the study sample consisted of 4922 men aged 71–89 years who were free of dementia/cognitive impairment. They were followed until the onset of dementia, death or up to 30 June 2015, whichever occurred first.\n\nThe study was conducted in accordance with the principles expressed in the Declaration of Helsinki and was approved by the Ethics Committees of the University of Western Australia and of the Department of Health of Western Australia. All men offered written informed consent.\n\nOutcome of interest\nDementia was the primary endpoint of the study, and its onset was established through the Western Australian Data Linkage System. Western Australian Data Linkage System brings together data for all health contacts with the hospital system of Western Australia, including emergency departments, elective and non-elective admissions, mental health outpatient services, community aged care services, as well as cancer and death registries.19 Each occasion of service triggers the recording of the respective date and associated primary and up to 20 secondary diagnoses, which are coded according to the International Classification of Diseases 10th edition. The following codes indicated the diagnosis of dementia: F00, F01, F02, F03, G30, G31.0, G31.1 and G31.83. We did not examine individual types of dementia because ‘unspecified dementia’ was the most frequently recorded diagnosis. We used Western Australian Data Linkage System to exclude following up of men with a recorded diagnosis of dementia before 2001–2004, as described above. From 1 January 1979 to the 30 June 1999, the following International Classification of Diseases 9th edition codes were used for the diagnosis of dementia: 290, 294.1, 294.2, 331.0, 331.1, 331.2 and 331.82.\n\nOther study measures\nAt the 2001–2004 assessment, we asked participants whether they had ‘ever been treated for an emotional or nervous illness such as depression’ (possible answers: yes/no), and considered that past depression was present when men answered in the affirmative. Participants also completed the short version of the Geriatric Depression Scale (GDS-15), and we considered that clinically significant symptoms of depression were present when the total score was 7 or greater.20 As previously described,21 participants were also grouped according to the severity of depressive symptoms: none (GDS-15=0), questionable (GDS-15 between 1 and 4), mild to moderate (GDS-15 between 5 and 9) and severe (GDS-15⩾10).\n\nAt this same point in time, participants were asked to provide a complete list of the medications they had been using on a regular basis. All medications were coded according to the Anatomical Therapeutic Chemical Classification System.22 Code N06A indicates the use of antidepressants. The codes N06AA, N06AB, N06AF and N06AX are the codes used for tricyclic, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors (non-selective) and other antidepressants, respectively.\n\nParticipants provided information about their age (in years), date of birth, educational achievement (completed high school vs incomplete high school), smoking (never, past or current) and medical history. In addition, we asked them whether a doctor had ever told them that they had diabetes, hypertension, coronary heart disease or a stroke (yes/no).\n\nStatistical analyses\nWe used the statistical package Stata 14.2 (StataCorp, College Station, TX, USA) to manage and analyse the data. We stratified the study population according to the history of depression (never, past only and current). We examined the distribution of study measures (counts and proportions) for the population and for depression groups, and calculated the odds ratio and respective 95% confidence interval (95% CI) relative to men who had never been depressed. As death was a competing risk of dementia, we used competing risk Cox regression models. The risk estimates are expressed as sub-hazard ratios (SHRs) and 95% CI. We repeated these same analyses by subsequently taking into account the interaction between the depression group and use of antidepressants. We then completed a series of planned analyses to investigate the effect of time of follow-up on the risk of dementia. We did this by limiting the analyses described above to a short (<5 years), medium (5 to up 10 years) and long (⩾10 years) duration of follow-up. We also investigated the SHR of dementia associated with individual groups of antidepressants: selective serotonin reuptake inhibitor, tricyclic, monoamine oxidase inhibitors (non-selective) and others. We calculated crude and adjusted associations—for the latter, we included in the models study measures associated with P<0.1. Finally, we calculated the annual rate of dementia per 1000 person-years for men with and without history of past or current depression. Alpha was set at 5% and all tests reported were two-tailed.\n\nComputational codes used in the analysis of the data are available from the corresponding author upon request.\n\nSample size\nThe annual incidence proportion of dementia is about 53 new cases per 1000 persons.23 Using the Schoenfeld method, we estimated that the study would have 80% power to detect a hazard ratio of 1.3 or greater for a sample of 180 men with current depression and 180 men with past depression. As 38% of the sample died during follow-up, the number of participants with current and past depression would have to be at least 250 each to allow for censoring. The study included 294 men with current depression and 388 with past depression.\n\nResults\nThis study included 4922 men free of dementia or clinically significant cognitive impairment. Their mean age was 77.2 years (s.d.=3.7), and their characteristics at the start of follow-up are summarised in Table 1.\n\nParticipants were followed, on average, for 8.9 years (range: 0.02–14.3 years). During this time, 903 men received the diagnosis of dementia (18.3%) and 1884 died free of dementia (38.3%). The adjusted SHR of dementia among men who had ever been depressed (past or current) was 1.3 (95% CI=1.2, 1.7), and for men with a past history of depression only was 1.3 (95% CI=1.0, 1.6) and for men with current depression (with or without past depression) was 1.5 (95% CI=1.2, 2.0; Figure 1). 302 men (6.1%) were using antidepressants at the time of the assessment. Figure 2 shows the SHR of dementia (and respective 95% CI) according to history of depression and antidepressant use. The use of antidepressants did not decrease the risk of dementia (Figure 2). The interaction term between antidepressant use and history of depression did not reach statistical significance (P=0.120). All analyses were adjusted for age, and history of diabetes and stroke (other variables made no significant contribution to the model).\n\nWe found that 1081 (22.0%) men had no depressive symptoms, 3171 (64.4%) had questionable symptoms, 509 (10.3%) had mild-to-moderate symptoms and 106 (2.1%) had severe symptoms. Fifty-five (1.1%) participants returned missing data for at least one GDS-15 item. Compared with men with no symptoms, the SHRs of dementia were 1.2 (95% CI=1.0, 1.4), 1.7 (95% CI=1.4, 2.2) and 2.1 (95% CI=1.4, 3.2) for participants with questionable, mild-to-moderate and severe depressive symptoms. Similarly, the respective adjusted SHRs were 0.2 (95% CI=0.0, 1.6) for men with no depressive symptoms on antidepressants, 1.1 (95% CI=0.9, 1.4) for men with questionable depressive symptoms not on antidepressants, 1.4 (95% CI=0.9, 2.0) for men with questionable depressive symptoms on antidepressants, 1.6 (95% CI=1.2, 2.1) for men with mild-to-moderate depressive symptoms who were not on antidepressants, 2.5 (95% CI=1.6, 3.8) for men with mild-to-moderate depressive symptoms on antidepressants, 1.5 (95% CI=0.9, 2.5) for men with severe depressive symptoms not on antidepressants and 4.8 (95% CI=2.3, 9.8) for men with severe depressive symptoms on antidepressants. The interaction between the severity of depressive symptoms and the use of antidepressants on dementia risk was statistically significant (P<0.05). All analyses were adjusted for age, and history of diabetes and stroke (all other measures made no obvious contribution to the model).\n\nThe number of men who developed dementia during the initial 5 years of follow-up was 234, from 5 to 10 years 516 and after 10 years 153. We stratified the data according to time of follow-up to investigate whether the risk of dementia associated with depression varied according to the duration of the follow-up period (Figure 3). All analyses were adjusted for age, and history of diabetes and stroke.\n\nWe then completed a series of post hoc analyses to investigate the contribution of individual antidepressant classes to dementia risk. The independent SHR of dementia associated with antidepressant use was 1.3 (95% CI=1.0, 1.7). The use of selective serotonin reuptake inhibitors, tricyclics, monoamine oxidase inhibitors (non-selective) and other antidepressants was reported by 127 (2.6%), 132 (2.7%), 8 (0.2%) and 50 (1.0%) men. The SHRs of dementia associated with the use of selective serotonin reuptake inhibitors, tricyclics, monoamine oxidase inhibitors (non-selective) and other antidepressants were 1.4 (95% CI=0.8, 2.1), 1.0 (95% CI=0.7, 1.5), 1.2 (95% CI=0.3, 5.0) and 2.2 (95% CI=1.3, 3.8). These analyses were adjusted for age, history of diabetes and stroke, and history of depression (past or current).\n\nThe annual rates of dementia per 1000 person-years for men without depression were 3.0 (95% CI=1.3, 6.5), 5.6 (95% CI=4.4, 7.2), 17.8 (95% CI=15.8, 20.1) and 41.1 (95% CI=37.3, 45.4) for ages 70–75, 75–80, 80–85 and >85 years. Similarly, for men with history of past or current depression, the respective rates were 3.1 (95% CI=0.4, 22.3), 19.2 (95% CI=13.5, 27.3), 34.2 (95% CI=27.0, 43.4) and 47.0 (95% CI=36.8, 60.1). There were 234 incidence cases of dementia during the first 5 years of follow-up (169 never depressed, 26 with history of past depression and 39 with current depression), 516 between 5 and 10 years (436 never depressed, 48 with history of past depression and 32 with current depression) and 153 after 10 years (133 never depressed, 12 with history of past depression and 8 with current depression).\n\nDiscussion\nThe results of this 14-year longitudinal study of older men confirmed that history of depression is associated with increased risk of incident dementia, and that this risk is particularly high among men with clinically significant symptoms of depression at the start of the follow-up period. We also found that there was a graded association between the severity of depressive symptoms and the risk of dementia, with the risk being more pronounced for men with severe depression. Contrary to our expectations, the use of antidepressants did not decrease the risk of dementia associated with depression. Finally, we found that the association between depression and incident dementia was largely due to cases of dementia accrued during the first 5 years of follow-up, after which the association between depression and incident dementia disappeared.\n\nThis project has the merit of having had access to a large and well-characterised cohort of older men and a suitably long follow-up period to ascertain the onset of dementia. Another important feature of a longitudinal study such as this is that follow-up data were available through Western Australian Data Linkage System for all participants, as the internal and external migratory movement of older Western Australians is negligible.24 The diagnosis of dementia itself, although not derived from structured clinical, neuropsychological and imaging investigations, included the best available information retrieved from hospital and community services. As the rates of dementia that we observed in our sample were largely consistent with those reported by others using different methods,25 we trust that our approach was appropriate to identify most cases of dementia. Nonetheless, we accept that some cases of dementia may have not been detected. If the distribution of these cases was random, some loss of power would have ensued, but not bias. It is conceivable, however, that the detection of cases may have occurred more frequently among men with depression because they come to medical attention more frequently than men without depression26—this would have increased the opportunity for the diagnosis of dementia to be established. Such bias could have inflated the number of cases of dementia associated with depression, so that the real association between depression and dementia could be less pronounced than our numbers suggest.\n\nWe also acknowledge that our assessment of depression was not based on a gold standard structured clinical interview, but on self-report and a depression scale. However, both approaches have good face-validity.20, 27 Perhaps, the most obvious limitation of our study design was the lack of information about the onset and recurrence of depressive symptoms and the use of antidepressants during follow-up. A considerable number of depression cases in later life are due to recurrence, but incident cases do occur particularly in people aged in their 80s.28 Such new false-negative cases of depression would have increased the chance of type II error and, potentially, would have led to an underestimation of the effect size of the association between depression and incident dementia. In addition, the lack of information about the use of medications during follow-up and their use as maintenance therapy creates uncertainty about the potential effect of antidepressants in modifying dementia risk. Confounding by indication is another issue that should be considered, as antidepressants may have been prescribed preferentially to the more severe cases of depression. However, it is helpful to note that only ~30% of antidepressant users suffer from depression (past or current),29 which together with our finding that the use of antidepressants by men without depression had no observable beneficial effect on the risk of dementia, suggest that the overall results of our study are likely to offer an acceptable, although tentative, estimate of risk associated with depression and antidepressant use.\n\nAnother potential caveat of the study is the lack of information about the timeline associated with history of past depression. It is conceivable that depression with onset in early or mid-life could contribute to modulate the risk of dementia later in life, whereas depression arising in older age may be more frequently an early manifestation of an underlying neurodegenerative process. As we did not have access to information about the age of onset of symptoms, we cannot be entirely certain that depression with early and late onset do not differ in their relationship with dementia risk.\n\nIt is also important to consider the issue of bias associated with competing risks. When assessing an event that occurs late in life (such as dementia),25 premature death will remove from the sample people who could have developed dementia later, if they had survived. This may be particularly important in this case, as people with depression die earlier than those without.21 The early censoring of older men with depression could have led to a biased lower risk of dementia among older men with history of depression. For this reason, and in contrast with previous studies,8 we used a competing risk Cox regression model that took into account the competing risk of death and the potential confounding associated with the overlapping risk factors for depression and dementia.3, 30 This approach to the analysis of the data enhances our confidence that our findings are most likely valid, although they are limited to men and cannot be generalised to women. Furthermore, we concede that some unmeasured factors, such as apolipoprotein E genotype and lipids, were not taken into account in our analyses, although findings from other relevant studies are consistent with ours.11, 12, 31\n\nLike previous studies,8 we found that history of past or current depression increased the risk of dementia, but this relationship is unlikely to be causal. Treatment with antidepressants, despite less than ideal efficacy,32, 33 would have been expected to reduce the risk of dementia associated with depression—that did not occur. Moreover, the association between depression and dementia was limited to the first few years of follow-up, suggesting that depression may represent a prodromal manifestation of dementia rather than one of its causes. Data from the Rotterdam Study are consistent with this interpretation: 4393 older adults (mean age 73 years) were followed for up to 13.7 years for incident dementia, which was diagnosed according to the Diagnostic and Statistical Manual for Mental Disorders 3rd edition revised criteria.34 They found that 13% of them developed dementia and that depression increased the hazard of dementia by ~20% by 2 and 5 years, but not beyond that time point.34 In fact, depressive symptoms are common antecedents of several neurodegenerative disorders35, 36 and could be seen as an early non-specific behavioural manifestation of a brain under physiological stress. If that is the case, depression in later life may be better understood, at least in some cases, as an early sign of dementia rather than a factor that can be potentially modified to decrease future risk. There is evidence from longitudinal studies of depression that this may indeed be the case.13, 14 However, our data cannot dismiss the possibility that depressive disorder with onset in earlier life may be a potentially modifiable risk factor for dementia.\n\nIn conclusion, our findings indicate that older men with the history of depression are at increased risk of developing dementia, although depression in later life is more likely to be a marker of incipient dementia than a truly modifiable risk factor. Older people with depression may be better viewed as potential targets of indicated prevention strategies,37 rather like people with mild cognitive impairment.\n\nWe thank study participants for their generous contribution. The Health In Men Study has been funded by the following competitive project grants from the National Health and Medical Research Council of Australia: 279408, 379600, 403963, 513823, 540403, 540504, 540405, 634492, 1021416, 1045710 and 1060557.\n\nAuthor contributions\n\nOPA conceived and designed the experiments, which were performed by all authors. All authors contributed to obtain funding for this project. OPA analysed the data and drafted the manuscript. All authors edited the manuscript for important intellectual content and approved its submission to the journal. OPA acts as the guarantor of the data reported in this manuscript.\n\nDisclaimer\n\nThe sponsors had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; or preparation, review or approval of the manuscript.\n\nThe authors declare no conflict of interest.\n\nFigure 1 The figure shows the proportion of men remaining free of dementia over 14 years according to history of depression at the start of the follow-up period. The sub-hazard ratios of dementia associated with past and with current depression were 1.4 (95% confidence interval (CI)=1.1, 1.7) and 1.8 (95% CI=1.4, 2.3).\n\nFigure 2 The figure shows the risk ratio of dementia over a follow-up period of up to 14 years according to history of depression and exposure to antidepressants at study entry (reference: men with no history of depression who were not using antidepressants). The diamonds show the sub-hazard ratio (SHR) of dementia and the whiskers the 95% confidence interval of the SHR. Blue and red diamonds show ratios for men not using and using antidepressants, respectively. The presentation was stratified into no, past and current depression.\n\nFigure 3 The figure shows the risk ratio of dementia according to time of follow-up (⩽5, 5–10 and ⩾10). The diamonds show the sub-hazard ratio of dementia and the whiskers show the 95% confidence interval of the sub-hazard ratio. The blue and red diamonds depict men with past and current depression at study entry, respectively.\n\nTable 1 Sociodemographic and clinical characteristics of older men free of cognitive impairment at the start of the follow-up period according to their history of depression\n \tPopulation (N=4922), n (%)\tEver depressed (N=682), n (%)\tEver depressed, OR (95% CI)\tPast depression (N=388), n (%)\tPast depression, OR (95% CI)\tCurrent depression (N=294), n (%)\tCurrent depression, OR (95% CI)\t\nAge group (years)\t\n 70–74\t1738 (35.3)\t222 (32.6)\t1 (Reference)\t148 (38.2)\t1 (Reference)\t74 (25.2)\t1 (Reference)\t\n 75–79\t2120 (43.1)\t292 (42.8)\t1.1 (0.9, 1.3)\t160 (41.3)\t0.9 (0.7, 1.1)\t132 (44.9)\t1.5 (1.1, 2.0)\t\n 80–84\t860 (17.5)\t131 (19.2)\t1.2 (1.0, 1.5)\t64 (16.3)\t0.9 (0.7, 1.2)\t67 (22.8)\t1.9 (1.3, 2.7)\t\n ≥ 85\t204 (4.1)\t37 (5.4)\t1.5 (1.0, 2.2)\t16 (4.1)\t1.0 (0.6, 1.7)\t21 (7.1)\t2.6 (1.5, 4.3)\t\n \t\nHigh-school education\t2328 (47.3)\t306 (44.9)\t0.9 (0.8, 1.0)\t202 (52.1)\t1.2 (1.0, 1.5)\t104 (35.4)\t0.6 (0.5, 0.8)\t\n \t \t \t \t \t \t \t \t\nSmoking\t\n Never\t1605 (32.6)\t168 (24.6)\t1 (Reference)\t109 (28.1)\t1 (Reference)\t59 (20.1)\t1 (Reference)\t\n Past\t3055 (62.1)\t467 (68.5)\t1.5 (1.3, 1.9)\t258 (66.5)\t1.3 (1.0, 1.7)\t209 (71.1)\t2.0 (1.5, 2.6)\t\n Current\t258 (5.3)\t47 (7.0)\t1.9 (1.3, 2.7)\t21 (5.4)\t1.3 (0.8, 2.1)\t26 (8.8)\t3.0 (1.9, 4.9)\t\n \t\nDiabetes\t740 (15.0)\t137 (20.1)\t1.5 (1.2, 1.9)\t65 (16.7)\t1.2 (0.9, 1.6)\t72 (24.5)\t2.0 (1.5, 2.6)\t\nHypertension\t2378 (48.3)\t379 (55.6)\t1.4 (1.2, 1.6)\t216 (55.7)\t1.4 (1.1, 1.7)\t163 (55.4)\t1.4 (1.1, 1.8)\t\nCoronary heart disease\t1527 (31.0)\t255 (37.4)\t1.4 (1.2, 1.6)\t132 (34.0)\t1.2 (1.0, 1.5)\t123 (41.8)\t1.7 (1.3, 2.1)\t\nStroke\t636 (12.9)\t150 (22.0)\t2.2 (1.8, 2.7)\t67 (17.3)\t1.6 (1.2, 2.1)\t83 (28.2)\t3.0 (2.3, 4.0)\t\nUsing an antidepressant\t302 (6.1)\t201 (29.5)\t17.1 (13.2, 22.1)\t148 (38.1)\t25.3 (19.0, 33.6)\t53 (18.0)\t9.0 (6.3, 12.9)\t\nAbbreviations: 95% CI: 95% confidence interval of the odds ratio; OR, odds ratio.\n\nBold print used to highlight statistically significant associations.\n==== Refs\nTan CC, Yu JT, Wang HF, Tan MS, Meng XF, Wang C et al. 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Int J Epidemiol \n2009 ; 38 : 48 –52.18316347 \nCrum RM, Anthony JC, Bassett SS, Folstein MF. Population-based norms for the Mini-Mental State Examination by age and educational level . JAMA \n1993 ; 269 : 2386 –2391.8479064 \nHolman CD, Bass AJ, Rosman DL, Smith MB, Semmens JB, Glasson EJ et al. A decade of data linkage in Western Australia: strategic design, applications and benefits of the WA data linkage system . Aust Health Rev \n2008 ; 32 : 766 –777.18980573 \nAlmeida OP, Almeida SA. Short versions of the geriatric depression scale: a study of their validity for the diagnosis of a major depressive episode according to ICD-10 and DSM-IV . Int J Geriatr Psychiatry \n1999 ; 14 : 858 –865.10521885 \nAlmeida OP, Alfonso H, Hankey GJ, Flicker L. Depression, antidepressant use and mortality in later life: the Health In Men Study . PLoS ONE \n2010 ; 5 : e11266 .20585644 \nWHO Collaborating Centre for Drug Statistics MethodologyGuidelines for ATC Classification and DDD Assignment 2013 . WHO Collaborating Centre for Drug Statistics Methodology: Oslo, Norway, 2012 .\nFiest KM, Jette N, Roberts JI, Maxwell CJ, Smith EE, Black SE et al. The Prevalence and Incidence of Dementia: a Systematic Review and Meta-analysis . Can J Neurol Sci \n2016 ; 43 Suppl 1: S3 –S50.\nABS3412.0 - Migration, Australia, 2013-14 . Australian Bureau of Statistics: Canberra, 2015 .\nMatthews FE, Stephan BC, Robinson L, Jagger C, Barnes LE, Arthur A et al. A two decade dementia incidence comparison from the Cognitive Function and Ageing Studies I and II . Nat Commun \n2016 ; 7 : 11398 .27092707 \nPrina AM, Huisman M, Yeap BB, Hankey GJ, Flicker L, Brayne C et al. Association between depression and hospital outcomes among older men . CMAJ \n2013 ; 185 : 117 –123.23228999 \nStuart AL, Pasco JA, Jacka FN, Brennan SL, Berk M, Williams LJ. Comparison of self-report and structured clinical interview in the identification of depression . Compr Psychiatry \n2014 ; 55 : 866 –869.24467941 \nBlazer DG. Depression in late life: review and commentary . J Gerontol A Biol Sci Med Sci \n2003 ; 58 : 249 –265.12634292 \nTakayanagi Y, Spira AP, Bienvenu OJ, Hock RS, Carras MC, Eaton WW et al. Antidepressant use and lifetime history of mental disorders in a community sample: results from the Baltimore Epidemiologic Catchment Area Study . J Clin Psychiatry \n2015 ; 76 : 40 –44.25188822 \nAlmeida OP, Alfonso H, Pirkis J, Kerse N, Sim M, Flicker L et al. A practical approach to assess depression risk and to guide risk reduction strategies in later life . Int Psychogeriatr \n2011 ; 23 : 280 –291.20880427 \nDal Forno G, Palermo MT, Donohue JE, Karagiozis H, Zonderman AB, Kawas CH. Depressive symptoms, sex, and risk for Alzheimer’s disease . Ann Neurol \n2005 ; 57 : 381 –387.15732103 \nAlmeida OP, Ford AH, Hirani V, Singh V, vanBockxmeer FM, McCaul K et al. B vitamins to enhance treatment response to antidepressants in middle-aged and older adults: results from the B-VITAGE randomised, double-blind, placebo-controlled trial . Br J Psychiatry \n2014 ; 205 : 450 –457.25257064 \nKirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, Johnson BT. Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration . PLoS Med \n2008 ; 5 : e45 .18303940 \nMirza SS, de Bruijn RF, Direk N, Hofman A, Koudstaal PJ, Ikram MA et al. Depressive symptoms predict incident dementia during short- but not long-term follow-up period . Alzheimers Dement \n2014 ; 10 : S323 –S329, e321.24530024 \nvan Duijn E, Craufurd D, Hubers AA, Giltay EJ, Bonelli R, Rickards H et al. Neuropsychiatric symptoms in a European Huntington’s disease cohort (REGISTRY) . J Neurol Neurosurg Psychiatry \n2014 ; 85 : 1411 –1418.24828898 \nLeentjens AF, Van den Akker M, Metsemakers JF, Lousberg R, Verhey FR. Higher incidence of depression preceding the onset of Parkinson’s disease: a register study . Mov Disord \n2003 ; 18 : 414 –418.12671948 \nAlmeida OP. Prevention of depression in older age . Maturitas \n2014 ; 79 : 136 –141.24713453\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "2158-3188",
"issue": "7(5)",
"journal": "Translational psychiatry",
"keywords": null,
"medline_ta": "Transl Psychiatry",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000928:Antidepressive Agents; D001315:Australia; D015897:Comorbidity; D003704:Dementia; D003863:Depression; D005500:Follow-Up Studies; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D017063:Outcome Assessment, Health Care; D012307:Risk Factors; D012720:Severity of Illness Index",
"nlm_unique_id": "101562664",
"other_id": null,
"pages": "e1117",
"pmc": null,
"pmid": "28463236",
"pubdate": "2017-05-02",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": "24378256;8733217;23228999;27138970;24467941;26982217;24097423;27307127;20880427;24530024;22035455;25030513;23637108;25188822;25771249;11097959;10521885;27474376;8479064;12634292;12671948;18316347;18303940;18980573;25257064;24828898;20585644;24662102;23791538;15732103;27092707;24713453;18768414;24217256",
"title": "Depression as a modifiable factor to decrease the risk of dementia.",
"title_normalized": "depression as a modifiable factor to decrease the risk of dementia"
} | [
{
"companynumb": "GB-TAKEDA-2019TUS055766",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN\\CODEINE PHOSPHATE"
},
"drugaddi... |
{
"abstract": "BACKGROUND\nAlthough survival of children with acute lymphoblastic leukaemia has improved greatly in the past two decades, the outcome of those who relapse has remained static. We investigated the outcome of children with acute lymphoblastic leukaemia who relapsed on present therapeutic regimens.\n\n\nMETHODS\nThis open-label randomised trial was undertaken in 22 centres in the UK and Ireland and nine in Australia and New Zealand. Patients aged 1-18 years with first relapse of acute lymphoblastic leukaemia were stratified into high-risk, intermediate-risk, and standard-risk groups on the basis of duration of first complete remission, site of relapse, and immunophenotype. All patients were allocated to receive either idarubicin or mitoxantrone in induction by stratified concealed randomisation. Neither patients nor those giving interventions were masked. After three blocks of therapy, all high-risk group patients and those from the intermediate group with postinduction high minimal residual disease (≥10(-4) cells) received an allogenic stem-cell transplant. Standard-risk and intermediate-risk patients with postinduction low minimal residual disease (<10(-4) cells) continued chemotherapy. The primary outcome was progression-free survival and the method of analysis was intention-to-treat. Randomisation was stopped in December, 2007 because of differences in progression-free and overall survival between the two groups. This trial is registered, reference number ISCRTN45724312.\n\n\nRESULTS\nOf 239 registered patients, 216 were randomly assigned to either idarubicin (109 analysed) or mitoxantrone (103 analysed). Estimated 3-year progression-free survival was 35·9% (95% CI 25·9-45·9) in the idarubicin group versus 64·6% (54·2-73·2) in the mitoxantrone group (p=0·0004), and 3-year overall survival was 45·2% (34·5-55·3) versus 69·0% (58·5-77·3; p=0·004). Differences in progression-free survival between groups were mainly related to a decrease in disease events (progression, second relapse, disease-related deaths; HR 0·56, 0·34-0·92, p=0·007) rather than an increase in adverse treatment effects (treatment death, second malignancy; HR 0·52, 0·24-1·11, p=0·11).\n\n\nCONCLUSIONS\nAs compared with idarubicin, mitoxantrone conferred a significant benefit in progression-free and overall survival in children with relapsed acute lymphobastic leukaemia, a potentially useful clinical finding that warrants further investigation.\n\n\nBACKGROUND\nCancer Research UK, Leukaemia and Lymphoma Research, Cancer Council NSW, and Sporting Chance Cancer Foundation.",
"affiliations": "Cancer Research UK Children's Cancer Group, School of Cancer and Enabling Sciences, University of Manchester, Manchester Academic Health Science Centre, Central Manchester University Hospitals Foundation Trust, Manchester, UK.",
"authors": "Parker|Catriona|C|;Waters|Rachel|R|;Leighton|Carly|C|;Hancock|Jeremy|J|;Sutton|Rosemary|R|;Moorman|Anthony V|AV|;Ancliff|Philip|P|;Morgan|Mary|M|;Masurekar|Ashish|A|;Goulden|Nicholas|N|;Green|Nina|N|;Révész|Tamas|T|;Darbyshire|Philip|P|;Love|Sharon|S|;Saha|Vaskar|V|",
"chemical_list": "D000903:Antibiotics, Antineoplastic; D003561:Cytarabine; D011092:Polyethylene Glycols; D014750:Vincristine; D005047:Etoposide; C042705:pegaspargase; D003907:Dexamethasone; D003520:Cyclophosphamide; D008942:Mitoxantrone; D015122:Mercaptopurine; D001215:Asparaginase; D014740:Vidarabine; C024352:fludarabine; D008727:Methotrexate; D015255:Idarubicin",
"country": "England",
"delete": false,
"doi": "10.1016/S0140-6736(10)62002-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0140-6736",
"issue": "376(9757)",
"journal": "Lancet (London, England)",
"keywords": null,
"medline_ta": "Lancet",
"mesh_terms": "D000293:Adolescent; D000903:Antibiotics, Antineoplastic; D000971:Antineoplastic Combined Chemotherapy Protocols; D001215:Asparaginase; D002648:Child; D002675:Child, Preschool; D003520:Cyclophosphamide; D003561:Cytarabine; D003907:Dexamethasone; D018572:Disease-Free Survival; D005047:Etoposide; D005260:Female; D006801:Humans; D015255:Idarubicin; D007223:Infant; D053208:Kaplan-Meier Estimate; D007958:Leukocyte Count; D008297:Male; D015122:Mercaptopurine; D008727:Methotrexate; D008942:Mitoxantrone; D011092:Polyethylene Glycols; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D012008:Recurrence; D018570:Risk Assessment; D016896:Treatment Outcome; D006113:United Kingdom; D014740:Vidarabine; D014750:Vincristine",
"nlm_unique_id": "2985213R",
"other_id": null,
"pages": "2009-17",
"pmc": null,
"pmid": "21131038",
"pubdate": "2010-12-11",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "18089878;9499665;15982346;15647217;14963025;12764363;9614257;19841326;15606626;16258094;12406912;15494596;10759711;12181040;20385996;16304572;3860629;1878583;14504921;18039957;20145664;18089849;18928659;20016529;20003823;2208112;19725919;12903007;18711187;1747457",
"title": "Effect of mitoxantrone on outcome of children with first relapse of acute lymphoblastic leukaemia (ALL R3): an open-label randomised trial.",
"title_normalized": "effect of mitoxantrone on outcome of children with first relapse of acute lymphoblastic leukaemia all r3 an open label randomised trial"
} | [
{
"companynumb": "GB-PFIZER INC-2020198054",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PEGASPARGASE"
},
"drugadditional": "3",
... |
{
"abstract": "A 67-year-old male patient presented with an irregular mass involving the pancreatic body and tail with multiple liver/lymph node metastases. A biopsy indicated the presence of a poorly differentiated adenocarcinoma. Fever and increased white blood cell count, C-reactive protein levels, and granulocyte-colony stimulating factor (G-CSF) levels led to the diagnose of G-CSF-producing pancreatic cancer. The patient did not respond to FOLFIRINOX therapy (leucovorin, fluorouracil, irinotecan, and oxaliplatin), but nab-paclitaxel plus gemcitabine treatment was effective, resulting in tumor shrinkage and reduced G-CSF levels. After the fifth course of this therapy, exacerbation was noted, and the patient died of primary cancer 6 months after initiating the therapy. Here we report the case of this patient with G-CSF-producing pancreatic cancer who responded to chemotherapy.",
"affiliations": "Department of Gastroenterology, Tokai Central Hospital.;Department of Gastroenterology, Tokai Central Hospital.;Department of Gastroenterology, Toyohashi Municipal Hospital.;Department of Gastroenterology, Toyohashi Municipal Hospital.;Department of Gastroenterology, Toyohashi Municipal Hospital.;Department of Gastroenterology, Toyohashi Municipal Hospital.;Department of Gastroenterology, Toyohashi Municipal Hospital.;Department of Gastroenterology, Toyohashi Municipal Hospital.;Department of Gastroenterology, Toyohashi Municipal Hospital.",
"authors": "Kataoka|Kunio|K|;Achiwa|Koichi|K|;Minami|Yoshiyuki|Y|;Fujita|Motokazu|M|;Naitoh|Takehito|T|;Yamada|Masahiro|M|;Yamamoto|Hideko|H|;Matsubara|Hiroshi|H|;Urano|Fumihiro|F|",
"chemical_list": "C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D003841:Deoxycytidine; D016179:Granulocyte Colony-Stimulating Factor; C056507:gemcitabine; D017239:Paclitaxel",
"country": "Japan",
"delete": false,
"doi": "10.11405/nisshoshi.114.1277",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0446-6586",
"issue": "114(7)",
"journal": "Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology",
"keywords": null,
"medline_ta": "Nihon Shokakibyo Gakkai Zasshi",
"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D000418:Albumins; D000971:Antineoplastic Combined Chemotherapy Protocols; D003841:Deoxycytidine; D017809:Fatal Outcome; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D008297:Male; D017239:Paclitaxel; D010190:Pancreatic Neoplasms",
"nlm_unique_id": "2984683R",
"other_id": null,
"pages": "1277-1284",
"pmc": null,
"pmid": "28679984",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "A case of a patient with granulocyte-colony stimulating factor-producing pancreatic cancer who responded to nab-paclitaxel plus gemcitabine.",
"title_normalized": "a case of a patient with granulocyte colony stimulating factor producing pancreatic cancer who responded to nab paclitaxel plus gemcitabine"
} | [
{
"companynumb": "JP-ACCORD-056457",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": null,
"drug... |
{
"abstract": "We conducted a randomized exploratory study to assess safety and the probability of a favorable outcome with adjunctive argatroban, a direct thrombin-inhibitor, administered to recombinant tissue-type plasminogen activator (r-tPA)-treated ischemic stroke patients.\n\n\n\nPatients treated with standard-dose r-tPA, not receiving endovascular therapy, were randomized to receive no argatroban or argatroban (100 μg/kg bolus) followed by infusion of either 1 (low dose) or 3 μg/kg per minute (high dose) for 48 hours. Safety was incidence of symptomatic intracerebral hemorrhage. Probability of clinical benefit (modified Rankin Scale score 0-1 at 90 days) was estimated using a conservative Bayesian Poisson model (neutral prior probability centered at relative risk, 1.0 and 95% prior intervals, 0.33-3.0).\n\n\n\nNinety patients were randomized: 29 to r-tPA alone, 30 to r-tPA+low-dose argatroban, and 31 to r-tPA+high-dose argatroban. Rates of symptomatic intracerebral hemorrhage were similar among control, low-dose, and high-dose arms: 3/29 (10%), 4/30 (13%), and 2/31 (7%), respectively. At 90 days, 6 (21%) r-tPA alone, 9 (30%) low-dose, and 10 (32%) high-dose patients were with modified Rankin Scale score 0 to 1. The relative risks (95% credible interval) for modified Rankin Scale score 0 to 1 with low, high, and either low or high dose argatroban were 1.17 (0.57-2.37), 1.27 (0.63-2.53), and 1.34 (0.68-2.76), respectively. The probability that adjunctive argatroban was superior to r-tPA alone was 67%, 74%, and 79% for low, high, and low or high dose, respectively.\n\n\n\nIn patients treated with r-tPA, adjunctive argatroban was not associated with increased risk of symptomatic intracerebral hemorrhage and provides evidence that a definitive effectiveness trial is indicated.\n\n\n\nURL: http://www.clinicaltrials.gov. Unique Identifier: NCT01464788.",
"affiliations": "From the Department of Neurology (A.D.B., L.S.), Center for Clinical Research and Evidence-Based Medicine (A.D.B., C.P., J.T.), and Division of Clinical and Translational Sciences (DCTS), Department of Internal Medicine (C.C., M.H.R.), McGovern Medical School at The University of Texas Health Science Center at Houston; Newcastle Clinical Trials Unit (NCTU), Newcastle University, United Kingdom (G.A.F.); Division of Medical Sciences, Oxford University, and Oxford University Hospitals NHS Foundation Trust, Headley Way, United Kingdom (G.A.F.); and Clinical Innovation and Research Institute, Memorial Hermann Hospital, Texas Medical Center, Houston (J.C.G.). andrew.d.barreto@uth.tmc.edu.;From the Department of Neurology (A.D.B., L.S.), Center for Clinical Research and Evidence-Based Medicine (A.D.B., C.P., J.T.), and Division of Clinical and Translational Sciences (DCTS), Department of Internal Medicine (C.C., M.H.R.), McGovern Medical School at The University of Texas Health Science Center at Houston; Newcastle Clinical Trials Unit (NCTU), Newcastle University, United Kingdom (G.A.F.); Division of Medical Sciences, Oxford University, and Oxford University Hospitals NHS Foundation Trust, Headley Way, United Kingdom (G.A.F.); and Clinical Innovation and Research Institute, Memorial Hermann Hospital, Texas Medical Center, Houston (J.C.G.).;From the Department of Neurology (A.D.B., L.S.), Center for Clinical Research and Evidence-Based Medicine (A.D.B., C.P., J.T.), and Division of Clinical and Translational Sciences (DCTS), Department of Internal Medicine (C.C., M.H.R.), McGovern Medical School at The University of Texas Health Science Center at Houston; Newcastle Clinical Trials Unit (NCTU), Newcastle University, United Kingdom (G.A.F.); Division of Medical Sciences, Oxford University, and Oxford University Hospitals NHS Foundation Trust, Headley Way, United Kingdom (G.A.F.); and Clinical Innovation and Research Institute, Memorial Hermann Hospital, Texas Medical Center, Houston (J.C.G.).;From the Department of Neurology (A.D.B., L.S.), Center for Clinical Research and Evidence-Based Medicine (A.D.B., C.P., J.T.), and Division of Clinical and Translational Sciences (DCTS), Department of Internal Medicine (C.C., M.H.R.), McGovern Medical School at The University of Texas Health Science Center at Houston; Newcastle Clinical Trials Unit (NCTU), Newcastle University, United Kingdom (G.A.F.); Division of Medical Sciences, Oxford University, and Oxford University Hospitals NHS Foundation Trust, Headley Way, United Kingdom (G.A.F.); and Clinical Innovation and Research Institute, Memorial Hermann Hospital, Texas Medical Center, Houston (J.C.G.).;From the Department of Neurology (A.D.B., L.S.), Center for Clinical Research and Evidence-Based Medicine (A.D.B., C.P., J.T.), and Division of Clinical and Translational Sciences (DCTS), Department of Internal Medicine (C.C., M.H.R.), McGovern Medical School at The University of Texas Health Science Center at Houston; Newcastle Clinical Trials Unit (NCTU), Newcastle University, United Kingdom (G.A.F.); Division of Medical Sciences, Oxford University, and Oxford University Hospitals NHS Foundation Trust, Headley Way, United Kingdom (G.A.F.); and Clinical Innovation and Research Institute, Memorial Hermann Hospital, Texas Medical Center, Houston (J.C.G.).;From the Department of Neurology (A.D.B., L.S.), Center for Clinical Research and Evidence-Based Medicine (A.D.B., C.P., J.T.), and Division of Clinical and Translational Sciences (DCTS), Department of Internal Medicine (C.C., M.H.R.), McGovern Medical School at The University of Texas Health Science Center at Houston; Newcastle Clinical Trials Unit (NCTU), Newcastle University, United Kingdom (G.A.F.); Division of Medical Sciences, Oxford University, and Oxford University Hospitals NHS Foundation Trust, Headley Way, United Kingdom (G.A.F.); and Clinical Innovation and Research Institute, Memorial Hermann Hospital, Texas Medical Center, Houston (J.C.G.).;From the Department of Neurology (A.D.B., L.S.), Center for Clinical Research and Evidence-Based Medicine (A.D.B., C.P., J.T.), and Division of Clinical and Translational Sciences (DCTS), Department of Internal Medicine (C.C., M.H.R.), McGovern Medical School at The University of Texas Health Science Center at Houston; Newcastle Clinical Trials Unit (NCTU), Newcastle University, United Kingdom (G.A.F.); Division of Medical Sciences, Oxford University, and Oxford University Hospitals NHS Foundation Trust, Headley Way, United Kingdom (G.A.F.); and Clinical Innovation and Research Institute, Memorial Hermann Hospital, Texas Medical Center, Houston (J.C.G.).;From the Department of Neurology (A.D.B., L.S.), Center for Clinical Research and Evidence-Based Medicine (A.D.B., C.P., J.T.), and Division of Clinical and Translational Sciences (DCTS), Department of Internal Medicine (C.C., M.H.R.), McGovern Medical School at The University of Texas Health Science Center at Houston; Newcastle Clinical Trials Unit (NCTU), Newcastle University, United Kingdom (G.A.F.); Division of Medical Sciences, Oxford University, and Oxford University Hospitals NHS Foundation Trust, Headley Way, United Kingdom (G.A.F.); and Clinical Innovation and Research Institute, Memorial Hermann Hospital, Texas Medical Center, Houston (J.C.G.).",
"authors": "Barreto|Andrew D|AD|;Ford|Gary A|GA|;Shen|Loren|L|;Pedroza|Claudia|C|;Tyson|Jon|J|;Cai|Chunyan|C|;Rahbar|Mohammad H|MH|;Grotta|James C|JC|;|||",
"chemical_list": "D000991:Antithrombins; D005343:Fibrinolytic Agents; D010875:Pipecolic Acids; D013449:Sulfonamides; D001120:Arginine; D010959:Tissue Plasminogen Activator; C031942:argatroban",
"country": "United States",
"delete": false,
"doi": "10.1161/STROKEAHA.117.016720",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0039-2499",
"issue": "48(6)",
"journal": "Stroke",
"keywords": "acute stroke; adjunctive therapy; anticoagulation; argatroban; randomized controlled trial; thrombin inhibitor; thrombolysis",
"medline_ta": "Stroke",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000991:Antithrombins; D001120:Arginine; D002545:Brain Ischemia; D002543:Cerebral Hemorrhage; D004359:Drug Therapy, Combination; D005260:Female; D005343:Fibrinolytic Agents; D006801:Humans; D008297:Male; D008875:Middle Aged; D017063:Outcome Assessment, Health Care; D010875:Pipecolic Acids; D012720:Severity of Illness Index; D020521:Stroke; D013449:Sulfonamides; D010959:Tissue Plasminogen Activator",
"nlm_unique_id": "0235266",
"other_id": null,
"pages": "1608-1616",
"pmc": null,
"pmid": "28507269",
"pubdate": "2017-06",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": "8555809;26668090;10454409;9469624;27834743;26278031;27289487;17258667;18955684;22711340;21830924;24001084;17290031;27165260;24473182;26243231;1100130;27507856;18947971;25096731;10622312;22223235;12297567",
"title": "Randomized, Multicenter Trial of ARTSS-2 (Argatroban With Recombinant Tissue Plasminogen Activator for Acute Stroke).",
"title_normalized": "randomized multicenter trial of artss 2 argatroban with recombinant tissue plasminogen activator for acute stroke"
} | [
{
"companynumb": "US-ROCHE-1952177",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALTEPLASE"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "Statins are useful in the armamentarium of the clinician dealing with dyslipidemia, which increases cardiovascular morbi-mortality in hypertensive and diabetic patients among others. Dyslipidemia commonly exists as a comorbidity factor in the development of atherosclerotic cardiovascular disease. Use of statins is however associated with side effects which at times are so disabling as to interfere with activities of daily living. There are various ways of dealing with this, including use of more water-soluble varieties, intermittent dosing, or use of statin alternatives. Of late, use of co-enzyme Q10 has become acceptable for the muscle side effects. Only one report of any benefit on the rarely reported memory side effect was encountered by the author in the search of English medical literature. This is a report of a documented case of a Nigerian woman with history of statin intolerance in this case, memory dysfunction despite persisting dyslipidemia comorbidity. Her memory dysfunction side effect which interfered with activities of daily living and background muscle pain cleared when coenzyme Q10 was administered alongside low dose statin. Her lipid profile normalized and has remained normal. It is being recommended for use when statin side effects (muscle- and memory-related) impair quality of life and leave patient at dyslipidemia-induced cardiovascular morbi-mortality.",
"affiliations": "Cardiology Sub-Unit 1, Department of Medicine, Jos University Teaching Hospital, Jos, Nigeria.",
"authors": "Okeahialam|Basil N|BN|",
"chemical_list": "D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D014451:Ubiquinone; C024989:coenzyme Q10",
"country": "New Zealand",
"delete": false,
"doi": "10.2147/VHRM.S90551",
"fulltext": "\n==== Front\nVasc Health Risk ManagVasc Health Risk ManagVascular Health and Risk ManagementVascular Health and Risk Management1176-63441178-2048Dove Medical Press 10.2147/VHRM.S90551vhrm-11-579Case ReportReversal of statin-induced memory dysfunction by co-enzyme Q10: a case report Okeahialam Basil N Cardiology Sub-Unit 1, Department of Medicine, Jos University Teaching Hospital, Jos, NigeriaCorrespondence: Basil N Okeahialam, Jos University Teaching Hospital, PMB 2076 (3 Murtala Muhammed Way) Jos, 930001, Plateau State, Nigeria, Tel +234 80 5149 9271, Email basokeam@yahoo.com2015 06 11 2015 11 579 581 © 2015 Okeahialam. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License2015The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Statins are useful in the armamentarium of the clinician dealing with dyslipidemia, which increases cardiovascular morbi-mortality in hypertensive and diabetic patients among others. Dyslipidemia commonly exists as a comorbidity factor in the development of atherosclerotic cardiovascular disease. Use of statins is however associated with side effects which at times are so disabling as to interfere with activities of daily living. There are various ways of dealing with this, including use of more water-soluble varieties, intermittent dosing, or use of statin alternatives. Of late, use of co-enzyme Q10 has become acceptable for the muscle side effects. Only one report of any benefit on the rarely reported memory side effect was encountered by the author in the search of English medical literature. This is a report of a documented case of a Nigerian woman with history of statin intolerance in this case, memory dysfunction despite persisting dyslipidemia comorbidity. Her memory dysfunction side effect which interfered with activities of daily living and background muscle pain cleared when coenzyme Q10 was administered alongside low dose statin. Her lipid profile normalized and has remained normal. It is being recommended for use when statin side effects (muscle- and memory-related) impair quality of life and leave patient at dyslipidemia-induced cardiovascular morbi-mortality.\n\nVideo abstract\n\n\n\nKeywords\nstatinmemory dysfunctionco-enzyme Q10improvement\n==== Body\nIntroduction\nMemory dysfunction, though said to be a rare occurrence,1 is a recognized side effect of statin therapy.2 Only one case has been reported in the medical literature from Nigeria.3 It tends to greatly limit normal functioning in an individual so afflicted, hence its potential for impairing quality of life. This side effect like others usually results in discontinuation of the culprit drug.4 In dyslipidemia, this results in persistence of cardiovascular morbidity in the individual(s) in question.\n\nIn the case of skeletal muscle side effect, co-enzyme Q10 (CoE Q10) has been reported to have an ameliorating effect,5 as well as vitamin D replacement.6 Only one report of such amelioration on the part of CoE Q10 for statin-induced memory dysfunction was encountered in a wide search of medical literature.7 No such report was encountered from sub-Saharan Africa. CoE Q10 has been used with statins in situations where the disease impairs mitochondrial bioenergetics with increased oxidative stress; as in some neurological diseases, with benefit.8 It has been shown to reverse age-related impairment in spatial learning while lowering protein oxidation, leading to the conclusion that it stands to ameliorate age-associated symptoms of cognitive deficit.9 Recently, one was compelled to try CoE Q10 supplementation in a patient previously reported3 for intolerance of statin manifesting with muscle and memory side effects – as her lipid profile worsened despite substitution with statin substitutes and adjuvants.10 The response was impressive. She experienced no muscle or memory side effect while on CoE Q10 supplementation and her lipid profile improved.\n\nThis case is being reported to suggest to clinicians who may encounter memory issues with statin that CoE Q10 supplementation may be worth the try.\n\nCase report\nPatient AA had been reported previously with memory dysfunction while on different statins.3 For the current report, ethical approval was not sought because the case did not meet institutional requirements and the Declaration of Helsinki was duly observed. As she remained dyslipidemic with a history of statin discontinuation, she was given fish oil in the form of Omega-3 1,000 mg daily in September 2011. This did not necessarily improve her memory. With her lipid profile standing at total cholesterol (TC) – 5.2 mmol/L, high density lipoprotein cholesterol (HDL-C) – 1.0 mmol/L, low density lipoprotein cholesterol (LDL-C) – 3.0 mmol/L, and triglyceride (TG) – 0.9 mmol/L in December 2011, she was given fenofibrate 160 mg daily. She reported to cause her muscle cramps like the statins prompting self-discontinuation and a repeat lipid profile. We could not assay for creatinine kinase, but her liver and kidneys were normal in structure and function. With lipid profile standing at TC – 5.7 mmol/L, HDL-C – 1.0 mmol/L, LDL-C – 3.2 mmol/L, and TG – 1.1 mmol/L in January 2012, she was advised to persevere on fenofibrate, because the symptom of muscle cramp was mild. Attempting to do this brought in addition vertigo and unsteady gait. Reporting this, she was asked to stop the drug and put on Stugeron brand of cinnarizine (15 mg twice daily) which controlled the symptoms.\n\nWhen her lipid profile was repeated late in June 2012, it stood at TC – 6.0 mmol/L, HDL-C – 1.4 mmol/L, LDL-C – 3.1 mmol/L, and TG – 1.3 mmol/L. She was consequently put on niacin 100 mg daily. With this, there was no complaint, but the lipid profile worsened over time to levels of TC – 6.1 mmol/L, HDL-C – 0.9 mmol/L, and TG – 1.3 mmol/L when repeated in February 2013. This prompted the addition of Lipitor brand of atorvastatin to the 100 mg daily of niacin. No sooner had she started this combination did disabling and unsettling memory lapses recur. Lipitor was dropped as a result. She was then asked to take a combination of low dose statin and CoE Q10 when she came in September 2013. Out of fear and frustration, she did not but returned in November 2013 with a lipid profile of TC – 6.1 mmol/L, HDL-C – 1.2 mmol/L, LDL-C – 4.2 mmol/L, and TG – 0.9 mmol/L. She was counseled and her fears dispelled. She then accepted to use rosuvastatin 5 mg at night and CoE Q10 capsules 100 mg daily. She returned in February 2014 to report that she had neither memory dysfunction nor muscle cramp, and her lipid profile now stood at TC – 3.7 mmol/L, HDL-C – 1.0 mmol/L, LDL-C – 1.7 mmol/L, and TG – 1.4 mmol/L. By her last appointment in May 2014 while still on the last treatment, she still remained well regarding her memory with a lipid profile of TC – 3.8 mmol/L, HDL-C – 1.0 mmol/L, LDL-C – 2.0 mmol/L, and TG – 0.7 mmol/L (Table 1).\n\nComments\nThe most common side effect reported with statins is myalgia.11 This is said to largely result from depletion of CoE Q10 caused by statins.12 Statins being HMG-CoA reductase inhibitors do this by blocking the mevalonate pathway.12 CoE Q10 is an antioxidant that stabilizes the cell membrane, and as a critical cofactor in the mitochondrial energy metabolism is responsible for regenerating ATP.13 Because it is found in every single cell in the body, its level could also fall in the brain cells as statins have been shown to target several tissues.14\n\nSupplementation of CoE Q10 in statin-treated patients with myopathy has been shown to ameliorate such pains.5 This patient suffered myopathy with several statins as reported earlier.3 She eventually developed memory dysfunction which led to their discontinuation. She did not even tolerate fenofibrate, a statin alternative recommended in the face of persisting dyslipidemia for patients intolerant of statins.10 Interestingly, on another recommended alternative niacin, she had no side effect but the lipid parameters worsened. With the morbidity consequence of mixed dyslipidemia remaining and even worsening, she was put on low dose rosuvastatin 5 mg with 100 mg of CoE Q10. The choice of rosuvastatin was because of its water solubility and utilization of non-CYP3A4 metabolic pathways, which as posited in an earlier paper is a reasonable approach when statin intolerance is experienced.15 Her frustration with statins and the persisting dyslipidemia made us not give her any chance with only stains irrespective of the type. With CoE Q10 supplementation, she experienced no muscle discomfort and her memory remained unaffected.\n\nCoE Q10 has been reported to improve cognitive function in depressed patients,16 and in both Alzheimer’s and Parkinson patients.17 It has been reported to improve statin-induced myopathy,5 as well as memory dysfunction.7 The nonappearance of both muscle and memory side effects in this patient when CoE Q10 was given with rosuvastatin albeit in low dose would tend to suggest that in her the possible depletion of CoE Q10 was affecting both muscle and brain energy metabolism. A limitation of this report is that a mini-mental state examination which would have objectively strengthened the link was not obtained.\n\nConclusion\nJust as it is becoming acceptable to add CoE Q10 to reverse myopathy in patients on statins12 rather than on discontinuation, it may not be out of place to suggest considering CoE Q10 supplementation in other statin-induced side effects particularly and generally for cardiovascular diseases. As posited in a paper,18 mitochondrial oxidative defense integrity has a place in onset and severity of cardiovascular diseases. When in equilibrium such diseases are checked, but any disequilibrium results in disease manifestation. Further studies in this regard are called for, before it can become the standard of care.\n\nDisclosure\n\nThe author reports no conflicts of interest in this work.\n\nTable 1 Lipid profiles with time on various treatments\n\nDate\tTC\tHDL-C\tLDL-C\tTG\tRemarks\t\nDecember 2011\t5.2\t1.0\t3.0\t0.9\tGiven fenofibrate 160 mg daily\t\nJanuary 2012\t5.7\t1.0\t3.2\t1.1\tRemained on above\t\nJune 2012\t6.0\t1.4\t3.1\t1.3\tGiven niacin 100 mg daily\t\nFebruary 2013\t6.1\t0.9\t–\t1.3\tRemained on above\t\nNovember\t6.1\t1.2\t4.2\t0.9\tGiven rosuvastatin\t\n2013\t\t\t\t\tand CoE Q10\t\nFebruary 2014\t3.7\t1.0\t1.7\t1.4\tRemained on above\t\nMay 2014\t3.8\t1.0\t2.0\t0.7\tOn above, no muscle/memory issue\t\nNotes: All values are in units of mmol/L. Fenofibrate gave mild muscle discomfort that was later followed by vertigo and ataxia. Niacin gave no side effects but did not improve lipid profile. Rosuvastatin and CoE Q10 normalized lipid profile and did not cause any side effects.\n\nAbbreviations: TC, total cholesterol; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; TG, triglyceride; CoE Q10, co-enzyme Q10.\n==== Refs\nReferences\n1 Rojas-Fernandez CH Cameron JF Is statin associated cognitive impairment clinically relevant? A narrative review and clinical recommendations Ann Pharmacother 2012 46 4 549 557 22474137 \n2 Padala KP Padala PR Potter JF Simvastatin induced decline in cognition Ann Pharmacother 2006 40 10 1880 1883 16940411 \n3 Okeahialam BN Isiguzoro IO Statin related memory dysfunction in a Nigerian woman. A case report Curr Drug Saf 2012 7 33 34 22663955 \n4 Brucket C Haygen G Dejager S Yau C Begand M Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients – the PRIMO study Cardiovasc Drugs Ther 2005 19 6 403 414 16453090 \n5 Caso G Kelly P McNurlan MA Lawson WE Effect of co-enzyme Q10 on myopathic symptoms in patients treated with statins Am J Cardiol 2007 99 10 1409 1412 17493470 \n6 Morley JE The cholesterol conundrum J Am Geriatr Soc 2011 59 10 1955 1956 22091506 \n7 Langsjoen PH Langsjoen JO Langsjoen AM Lucas LA Treatment of statin adverse effects with supplemental co-enzyme Q10 and statin discontinuation Biofactors 2005 25 1–4 147 152 16873939 \n8 Littarru GP Tiano L Clinical aspects of coenzyme Q10: an update Curr Opin Clin Nutr Metab Care 2005 8 6 641 646 16205466 \n9 Shetty RA Forster MJ Sumien N Co-enzyme Q10 supplementation reverses age-related impairment in spatial learning and lowers protein oxidation Age (Dordo) 2013 35 5 1821 1834 \n10 Sorrentino MJ An update on statin alternatives and adjuncts Clin Lipidol 2012 7 6 721 730 \n11 Nawarskas JJ HMG-CoA reductase inhibitors and co-enzyme Q 10 Cardiol Rev 2005 13 2 76 79 15705257 \n12 Marcoff L Thompson PD The role of co-enzyme Q 10 in statin associated myopathy: a systematic review J Am Col Cardiol 2007 49 23 2231 2237 \n13 Wyman M Leonard M Morledge T Co-enzyme Q10: a therapy for hypertension and statin induced myalgia Clin J Med 2010 77 7 435 442 \n14 Hargreaves IP Duncan AJ Heales SJ Lend JM The effect of HMG CoA reductase inhibitors on co-enzyme Q10: possible biochemical/clinical implication Drug Saf 2005 28 8 659 676 16048353 \n15 DiNicolantonio JJ Co-Q10 and L-carnitine for statin myalgia? Expert Rev Cardiovasc Ther 2012 10 10 1325 1333 \n16 Bragin V Chemodanova M Dzanofarova N Bragin I Czerniawski JL Aliev G Integrated treatment approach improves cognitive function in demented and critically depressed patients Am J Alzheimers Dis Other Demen 2005 20 1 21 26 15751450 \n17 DiMauro S Mancuso M Mitochondrial diseases: therapeutic approaches Biosci Rep 2007 27 125 137 17486439 \n18 Babato JC Have no fear, MitoQ10 is here Hypertension 2009 54 222 223 19581501\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1176-6344",
"issue": "11()",
"journal": "Vascular health and risk management",
"keywords": "co-enzyme Q10; improvement; memory dysfunction; statin",
"medline_ta": "Vasc Health Risk Manag",
"mesh_terms": "D050171:Dyslipidemias; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008568:Memory; D008569:Memory Disorders; D009135:Muscular Diseases; D020127:Recovery of Function; D016896:Treatment Outcome; D014451:Ubiquinone",
"nlm_unique_id": "101273479",
"other_id": null,
"pages": "579-81",
"pmc": null,
"pmid": "26604775",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D059040:Video-Audio Media",
"references": "16048353;15751450;15705257;17560286;17493470;16940411;16873939;17486439;16453090;16205466;23190071;22663955;22474137;22091506;20601617;19581501;23138632",
"title": "Reversal of statin-induced memory dysfunction by co-enzyme Q10: a case report.",
"title_normalized": "reversal of statin induced memory dysfunction by co enzyme q10 a case report"
} | [
{
"companynumb": "NG-PFIZER INC-2015418057",
"fulfillexpeditecriteria": "1",
"occurcountry": "NG",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NIACIN"
},
"drugadditional": null,
"... |
{
"abstract": "The desire for enhancement is a common motive for non-medical use of prescription drugs in Western countries. Little is known about the factors that motivate use in non-Western contexts.\n\n\n\nThe study explores access to prescription drugs and the motivations for using them among educated young adults in a city located in Anambra State, South-Eastern Nigeria. Semi-structured interviews were conducted with 23 participants aged 23-29 years. Data were thematically analysed using NVivo 12 Software.\n\n\n\nThe data indicate that prescription drugs are widely available and easy to access without a prescription in the unregistered 'pharmacies' and medicine shops that form part of Nigeria's informal healthcare system. Social networks are also a source of drugs. Participants shared detailed perspectives on their use of prescription drugs, revealing that codeine, Rohypnol, and high doses of tramadol are used to enhance performance in several social life domains. These drugs were described as enhancing performance and productivity in the workplace, and were taken by participants working as labourers and sales representatives. Male participants also shared accounts of using high doses of tramadol to improve stamina and skill in sports. Some participants took Rohypnol to enhance their creative and academic performance. Participants stated that drug use enabled them to meet the pressures associated with work, academia, and parental expectations.\n\n\n\nThe findings suggest that prescription drugs are being strategically and instrumentally deployed by users to enhance different domains of social life. This is driven by users' experiences of the drugs' bodily effects, and it is supported by a context in which self-medication and informal healthcare are common. Participants' reasons for seeking drug-induced enhancement reflect sociocultural factors within Nigeria and some West African countries, such as employment scarcity and the championing of sporting prowess. The findings can be used to inform the design of tailored approaches to reduce the harms presented by the non-medical use of pharmaceuticals among young adults.",
"affiliations": "Institute for Therapy and Health Research, Harmsstrasse 2, 24114, Kiel, Germany; Department of Sociology and Anthropology, Nnamdi Azikiwe University, Enugu-Onitsha Express Way, Awka, Anambra State, Nigeria; Department of Social and Political Sciences, Brunel University London, Uxbridge, London, United Kingdom, UB8 3PW. Electronic address: ew.dumbili@unizik.edu.ng.;School of Social Sciences, Monash University, Wellington Rd, Clayton VIC 3800, Australia.;Coventry University, Scarborough, YO11 2JW, United Kingdom.;Institute for Therapy and Health Research, Harmsstrasse 2, 24114, Kiel, Germany.",
"authors": "Dumbili|Emeka W|EW|;Gardner|John|J|;Degge|Hannah M|HM|;Hanewinkel|Reiner|R|",
"chemical_list": "D058573:Performance-Enhancing Substances; D055553:Prescription Drugs",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.drugpo.2020.102995",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0955-3959",
"issue": "95()",
"journal": "The International journal on drug policy",
"keywords": "Enhancement motives; Human enhancement drugs; Performance-enhancing drugs tramadol; Prescription drug use; Young adults",
"medline_ta": "Int J Drug Policy",
"mesh_terms": "D000328:Adult; D006801:Humans; D008297:Male; D009042:Motivation; D009549:Nigeria; D058573:Performance-Enhancing Substances; D063487:Prescription Drug Misuse; D055553:Prescription Drugs; D055815:Young Adult",
"nlm_unique_id": "9014759",
"other_id": null,
"pages": "102995",
"pmc": null,
"pmid": "33707065",
"pubdate": "2021-09",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Enhancement motivations for using prescription drugs among young adults in Nigeria.",
"title_normalized": "enhancement motivations for using prescription drugs among young adults in nigeria"
} | [
{
"companynumb": "DE-MYLANLABS-2020M1099653",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TRAMADOL"
},
"drugadditional": null,
... |
{
"abstract": "Central giant cell granuloma (CGCG) is a benign but locally aggressive intraosseous lesion of the mandible. Historically, it is treated by curettage or resection. Medical therapy is indicated when surgery is associated with increased morbidity or in adjuvant setting to decrease recurrence. Treatment of CGCG with denosumab, a receptor activator of nuclear factor kappa-beta (RANK) ligand inhibitor, is not well studied, especially in children. Here, we describe our experience with the use of denosumab in the treatment of six children with CGCG. All patients had a favorable response with manageable side effects, which suggests that denosumab is an effective treatment option without increased morbidity.",
"affiliations": "Cancer and Hematology Center, Texas Children's Hospital, Houston, Texas.;Cancer and Hematology Center, Texas Children's Hospital, Houston, Texas.;Cancer and Hematology Center, Texas Children's Hospital, Houston, Texas.;Cancer and Hematology Center, Texas Children's Hospital, Houston, Texas.;Cancer and Hematology Center, Texas Children's Hospital, Houston, Texas.;Edward B. Singleton Department of Radiology, Texas Children's Hospital, Houston, Texas.;Cancer and Hematology Center, Texas Children's Hospital, Houston, Texas.",
"authors": "Choe|Michelle|M|0000-0001-9850-9435;Smith|Valeria|V|;Okcu|M Fatih|MF|;Wulff|Jade|J|;Gruner|Stephanie|S|;Huisman|Thierry A G M|TAGM|;Venkatramani|Rajkumar|R|0000-0002-4785-106X",
"chemical_list": "D050071:Bone Density Conservation Agents; D000069448:Denosumab",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.28778",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "68(3)",
"journal": "Pediatric blood & cancer",
"keywords": "central giant cell granuloma; denosumab; hypercalcemia; hypocalcemia; pediatric",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D050071:Bone Density Conservation Agents; D002648:Child; D002675:Child, Preschool; D000069448:Denosumab; D005260:Female; D005500:Follow-Up Studies; D006101:Granuloma, Giant Cell; D006801:Humans; D008297:Male; D011379:Prognosis",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "e28778",
"pmc": null,
"pmid": "33089644",
"pubdate": "2021-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Treatment of central giant cell granuloma in children with denosumab.",
"title_normalized": "treatment of central giant cell granuloma in children with denosumab"
} | [
{
"companynumb": "US-AMGEN-USASP2020176053",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CALCIUM"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nNon-small cell lung cancer (NSCLC)-patients with an epidermal growth factor receptor (EGFR)-mutation have median progression-free survival (PFS) of 12 months on tyrosine kinase inhibitors (TKIs). Resistance is mediated by the EGFR T790M-mutation in the majority of patients. Longitudinal follow-up data are lacking. We retrospectively evaluated EGFR-mutated NSCLC-patients who were rebiopsied after TKI-treatment. A subgroup was sequentially rebiopsied along the course of the disease.\n\n\nMETHODS\nAdvanced EGFR-mutated NSCLC-patients who had both a pre-TKI biopsy and post-TKI biopsy available were included. Information on treatments and (re)biopsies was collected chronologically. Primary endpoint was the incidence of the T790M-mutation.\n\n\nRESULTS\nSixty-six patients fulfilled the inclusion criteria. In first post-TKI biopsies, T790M-mutation was detected in 34 patients (52%) of patients. Twenty-seven patients had subsequent post-TKI rebiopsies with mutation analysis available; in 10 patients (37%) the T790M-status in subsequent post-TKI rebiopsies was not consistent with the T790M-status of the first post-TKI biopsy. Progression free survival (PFS) on TKI-treatment was 12.0 months. Objective response rate on TKI-treatment was 81%. Patients developing T790M-mutation at post-TKI biopsy had longer median PFS compared to T790M-negative patients (14.2 versus 11.1 months respectively (P=0.034)) and longer overall survival (45.9 months versus 29.8 months respectively (P=0.213)). Transformation to SCLC was detected in 1 patient (2%).\n\n\nCONCLUSIONS\nIncidence of T790M-mutation at first post-TKI biopsy in this cohort of EGFR-mutated NSCLC-patients was 52%. Detection of T790M-mutation was not consistent over time; some patients who were T790M-positive at first post-TKI biopsy became T790M-negative in later post-TKI rebiopsies and vice versa. T790M-positive patients showed longer PFS than T790M-negative patients. Whether the low incidence of transformation to SCLC is justifying post-TKI rebiopsy in EGFR-mutated NSCLC-patients with acquired TKI-resistance in regular clinical practice is debatable.",
"affiliations": "Department of Pulmonary Diseases, VU University Medical Center, Amsterdam, The Netherlands. Electronic address: jl.kuiper@vumc.nl.;Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.;Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.;Department of Cardiothoracic Surgery, VU University Medical Center, Amsterdam, The Netherlands.;Department of Pulmonary Diseases, VU University Medical Center, Amsterdam, The Netherlands.;Department of Pulmonary Diseases, VU University Medical Center, Amsterdam, The Netherlands.;Department of Pulmonary Diseases, VU University Medical Center, Amsterdam, The Netherlands.",
"authors": "Kuiper|J L|JL|;Heideman|D A M|DA|;Thunnissen|E|E|;Paul|M A|MA|;van Wijk|A W|AW|;Postmus|P E|PE|;Smit|E F|EF|",
"chemical_list": "D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; C512478:EGFR protein, human; D066246:ErbB Receptors",
"country": "Ireland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0169-5002",
"issue": "85(1)",
"journal": "Lung cancer (Amsterdam, Netherlands)",
"keywords": "EGFR mutation; NSCLC; Rebiopsy; T790M-mutation; TKI-resistance; Targeted therapy",
"medline_ta": "Lung Cancer",
"mesh_terms": "D000230:Adenocarcinoma; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D001706:Biopsy; D002289:Carcinoma, Non-Small-Cell Lung; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors; D005260:Female; D006801:Humans; D015994:Incidence; D053208:Kaplan-Meier Estimate; D008168:Lung; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D020125:Mutation, Missense; D047428:Protein Kinase Inhibitors; D012189:Retrospective Studies",
"nlm_unique_id": "8800805",
"other_id": null,
"pages": "19-24",
"pmc": null,
"pmid": "24768581",
"pubdate": "2014-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Incidence of T790M mutation in (sequential) rebiopsies in EGFR-mutated NSCLC-patients.",
"title_normalized": "incidence of t790m mutation in sequential rebiopsies in egfr mutated nsclc patients"
} | [
{
"companynumb": "NL-MYLANLABS-2015M1005880",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ERLOTINIB"
},
"drugadditional": null,
... |
{
"abstract": "Transversus abdominis plane blocks are increasingly used to achieve opioid-sparing analgesia after colorectal surgery. Traditionally, bupivacaine was the long-acting analgesic of choice, but the addition of dexamethasone and/or epinephrine to bupivacaine may extend block duration. Liposomal bupivacaine has also been suggested to achieve an extended analgesia duration of 72 hours but is significantly more expensive.\n\n\n\nThe purpose of this study was to compare pain control between laparoscopic transversus abdominis plane blocks using liposomal bupivacaine versus bupivacaine with epinephrine and dexamethasone.\n\n\n\nThis was a parallel-group, single-institution, randomized clinical trial.\n\n\n\nThe study was conducted at a single tertiary medical center.\n\n\n\nConsecutive patients between October 2018 to October 2019, ages 18 to 90 years, undergoing minimally invasive colorectal surgery with multimodal analgesia were included.\n\n\n\nPatients were randomly assigned 1:1 to receive a laparoscopic transversus abdominis plane block with liposomal bupivacaine or bupivacaine with epinephrine and dexamethasone.\n\n\n\nThe primary outcome was total oral morphine equivalents administered in the first 48 hours postoperatively. Secondary outcomes included pain scores, time to ambulation and solid diet, hospital length of stay, and complications.\n\n\n\nA total of 102 patients (50 men) with a median age of 42 years (interquartile range, 29-60 y) consented and were randomly assigned. The primary end point, total oral morphine equivalents administered in the first 48 hours, was not significantly different between the liposomal bupivacaine group (median = 69 mg) and the bupivacaine with epinephrine and dexamethasone group (median = 47 mg; difference in medians = 22 mg, (95% CI, -17 to 49 mg); p = 0.60). There were no significant differences in pain scores, time to ambulation, time to diet tolerance, time to bowel movement, length of stay, overall complications, or readmission rate between groups. There were no treatment-related adverse outcomes.\n\n\n\nThis study was not placebo controlled or blinded.\n\n\n\nThis first randomized trial comparing laparoscopic transversus abdominis plane block with liposomal bupivacaine or bupivacaine with epinephrine and dexamethasone showed that a liposomal bupivacaine block does not provide superior or extended analgesia in the era of standardized multimodal analgesia protocols.See Video Abstract at http://links.lww.com/DCR/B533.\n\n\n\nANTECEDENTES:El bloqueo anestésico del plano muscular transverso del abdomen se utiliza cada vez más para lograr una analgesia con menos consumo de opioides después de cirugía colorrectal. Tradicionalmente, la Bupivacaína era el analgésico de acción prolongada de elección, pero al agregarse Dexametasona y/o Adrenalina a la Bupivacaína se puede prolongar la duración del bloqueo. También se ha propuesto que la Bupivacaína liposomal logra una duración prolongada de la analgesia de 72 horas, pero es significativamente más cara.OBJETIVO:Comparar el control del dolor entre bloqueo laparoscópico del plano de los transversos del abdomen usando Bupivacaína liposomal versus Bupivacaína con Adrenalina y Dexametasona.DISEÑO:Estudio clínico prospectivo y randomizado de una sola institución en grupos paralelos.AJUSTE:Centro médico terciario único.PACIENTES:Todos aquellos pacientes entre 18 y 90 años sometidos a cirugía colorrectal mínimamente invasiva con analgesia multimodal, entre octubre de 2018 a octubre de 2019 incluidos de manera consecutiva.INTERVENCIONES:Los pacientes fueron seleccionados aleatoriamente 1:1 para recibir un bloqueo laparoscópico del plano de los transversos del abdomen con Bupivacaína liposomal o Bupivacaína con Adrenalina y Dexametasona.PRINCIPALES MEDIDAS DE RESULTADO:El resultado primario fue el total de equivalentes de morfina oral administradas en las primeras 48 horas después de la operación. Los resultados secundarios incluyeron puntuaciones de dolor, inicio de dieta sólida, tiempo de inicio a la deambulación, la estadía hospitalaria y las complicaciones.RESULTADOS:Un total de 102 pacientes (50 hombres) con una mediana de edad de 42 años (IQR 29-60) fueron incluidos aleatoriamente. El criterio de valoración principal, equivalentes de morfina oral total administrada en las primeras 48 horas, no fue significativamente diferente entre el grupo de Bupivacaína liposomal (mediana = 69 mg) y el grupo de Bupivacaína con Adrenalina y Dexametasona (mediana = 47 mg; diferencia en medianas = 22 mg, IC del 95% [-17] - 49 mg, p = 0,60). No hubo diferencias significativas en las puntuaciones de dolor, tiempo de inicio a la deambulación, el tiempo de tolerancia a la dieta sólida, el tiempo hasta el primer evacuado intestinal, la duración de la estadía hospitalaria, las complicaciones generales o la tasa de readmisión entre los grupos. No hubo resultados adversos relacionados con el tratamiento.LIMITACIONES:Este estudio no fue controlado con placebo ni de manera cegada.CONCLUSIONES:Este primer estudio prospectivo y randomizado que comparó el bloqueo del plano de los músculos transversos del abdomen por vía laparoscópica, utilizando Bupivacaína liposomal o Bupivacaína con Adrenalina y Dexametasona, demostró que el bloqueo de Bupivacaína liposomal no proporciona ni mejor analgesia ni un efecto mas prolongado.Consulte Video Resumen en http://links.lww.com/DCR/B533.",
"affiliations": "Division of Colorectal Surgery, Cedars-Sinai Medical Center, Los Angeles, California.;Division of Colorectal Surgery, Cedars-Sinai Medical Center, Los Angeles, California.;Department of Biostatistics, Cedars-Sinai Medical Center, Los Angeles, California.;Department of Pharmacy, Cedars-Sinai Medical Center, Los Angeles, California.;Department of Pharmacy, Cedars-Sinai Medical Center, Los Angeles, California.;Division of Colorectal Surgery, Cedars-Sinai Medical Center, Los Angeles, California.",
"authors": "Truong|Adam|A|;Fleshner|Phillip R|PR|;Mirocha|James M|JM|;Tran|Hai P|HP|;Shane|Rita|R|;Zaghiyan|Karen N|KN|",
"chemical_list": "D000701:Analgesics, Opioid; D000779:Anesthetics, Local; D008081:Liposomes; D009020:Morphine; D003907:Dexamethasone; D002045:Bupivacaine; D004837:Epinephrine",
"country": "United States",
"delete": false,
"doi": "10.1097/DCR.0000000000002008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0012-3706",
"issue": "64(7)",
"journal": "Diseases of the colon and rectum",
"keywords": null,
"medline_ta": "Dis Colon Rectum",
"mesh_terms": "D000009:Abdominal Muscles; D000284:Administration, Oral; D000328:Adult; D000701:Analgesics, Opioid; D000779:Anesthetics, Local; D002045:Bupivacaine; D003107:Colorectal Surgery; D003131:Combined Modality Therapy; D003907:Dexamethasone; D000080482:Enhanced Recovery After Surgery; D004837:Epinephrine; D005260:Female; D006801:Humans; D007430:Intraoperative Care; D010535:Laparoscopy; D007902:Length of Stay; D008081:Liposomes; D008297:Male; D008875:Middle Aged; D009020:Morphine; D009407:Nerve Block; D059408:Pain Management; D011446:Prospective Studies; D066231:Surgeons",
"nlm_unique_id": "0372764",
"other_id": null,
"pages": "888-898",
"pmc": null,
"pmid": "34086002",
"pubdate": "2021-07-01",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial; D059040:Video-Audio Media",
"references": null,
"title": "A Prospective Randomized Trial of Surgeon-Administered Intraoperative Transversus Abdominis Plane Block With Bupivacaine Against Liposomal Bupivacaine: The TINGLE Trial.",
"title_normalized": "a prospective randomized trial of surgeon administered intraoperative transversus abdominis plane block with bupivacaine against liposomal bupivacaine the tingle trial"
} | [
{
"companynumb": "US-PACIRA-2021000272",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TRAMADOL"
},
"drugadditional": null,
"d... |
{
"abstract": "BACKGROUND\nOvarian cancer is usually diagnosed at an advanced stage, most often co-occurring with malignant bowel obstruction. Affected patients are generally in poor physical condition, and it is important to manage the bowel obstruction to improve quality of life.\n\n\nMETHODS\nWe present the case of a 75-year-old woman who underwent a left hemicolectomy for an ovarian carcinoma with bowel obstruction. 3 years after hemicolectomy, the patient presented with an extrinsic anastomotic substenosis. A self-expanding metal stent was placed which remained in place for 7 years, rendering other invasive surgical treatments unnecessary.\n\n\nCONCLUSIONS\nThe placement of a long-lasting stent is an important option in patients with bowel obstruction subsequent to recurrent ovarian cancer, since this provides a viable alternative to surgery and increases patients' quality of life.",
"affiliations": "Department of Gynecology, Obstetrics and Urology, Sapienza University, Rome, Italy.",
"authors": "Corvino|Raffaella|R|;De Iuliis|Francesca|F|;D'Aniello|Debora|D|;Cefalì|Katia|K|;Ferraro|Emanuela|E|;Lamazza|Antonietta|A|;Lanza|Rosina|R|;Scarpa|Susanna|S|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1159/000444273",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2296-5270",
"issue": "39(3)",
"journal": "Oncology research and treatment",
"keywords": null,
"medline_ta": "Oncol Res Treat",
"mesh_terms": "D005260:Female; D006801:Humans; D007415:Intestinal Obstruction; D008137:Longitudinal Studies; D010051:Ovarian Neoplasms; D010166:Palliative Care; D019919:Prosthesis Implantation; D015607:Stents; D016896:Treatment Outcome",
"nlm_unique_id": "101627692",
"other_id": null,
"pages": "146-8",
"pmc": null,
"pmid": "27031123",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Long-Lasting Stent Placement in an Elderly Advanced Ovarian Cancer Patient.",
"title_normalized": "long lasting stent placement in an elderly advanced ovarian cancer patient"
} | [
{
"companynumb": "IT-ACTAVIS-2016-10102",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "EPIRUBICIN"
},
"drugadditional": null,
... |
{
"abstract": "This case report describes a paediatric patient diagnosed with otitis externa and treated with topical ciprofloxacin/dexamethasone. The patient completed the course of therapy and then developed precipitate formation from the pharmacological treatment. Laboratory testing of the precipitate confirmed the presence of a large quantity of ciprofloxacin. Removal of the precipitate required the use of an elephant ear washer system and removal with surgical tweezers. This case report investigated a probable topical ciprofloxacin/dexamethasone-induced ear precipitate formation in the ear canal, which, subsequently, was successfully removed from the patient's ear canal.",
"affiliations": "Department of Pharmacotherapy and Translational Research, University of Florida, Gainesville, Florida, USA scurtis@cop.ufl.edu.;Department of Pharmacotherapy and Translational Research, University of Florida, Jacksonville, Florida, USA.;Department of Clinical Sciences, High Point University Fred Wilson School of Pharmacy, High Point, North Carolina, USA.",
"authors": "Curtis|Stacey D|SD|http://orcid.org/0000-0002-4335-1471;Egelund|Eric F|EF|;Ebied|Alex M|AM|http://orcid.org/0000-0003-1133-413X",
"chemical_list": "D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D004338:Drug Combinations; D019999:Pharmaceutical Solutions; D002939:Ciprofloxacin; D003907:Dexamethasone",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-234290",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "13(7)",
"journal": "BMJ case reports",
"keywords": "ear, nose and throat; paediatrics; unwanted effects / adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000287:Administration, Topical; D000293:Adolescent; D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D002939:Ciprofloxacin; D003907:Dexamethasone; D004338:Drug Combinations; D004424:Ear Canal; D005260:Female; D006801:Humans; D010032:Otitis Externa; D019999:Pharmaceutical Solutions; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32616534",
"pubdate": "2020-07-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Ciprofloxacin/dexamethasone precipitate formation in the ear canal of a paediatric patient.",
"title_normalized": "ciprofloxacin dexamethasone precipitate formation in the ear canal of a paediatric patient"
} | [
{
"companynumb": "US-OTONOMY INC.-2020OTO00002",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CIPROFLOXACIN\\DEXAMETHASONE"
},
"drugaddi... |
{
"abstract": "OBJECTIVE\nTo describe the use of high doses of intravitreal ganciclovir combined with highly active antiretroviral therapy (HAART) for the treatment of cytomegalovirus (CMV) retinitis in human immunodeficiency virus (HIV)-infected patients.\n\n\nMETHODS\nThirteen HIV-infected patients (18 eyes) with active CMV retinitis (83.3% in zone 1 and 38.4% resistant) participated in this prospective interventional case series. Patients were treated with high dose intravitreal ganciclovir (5.0 mg/0.1 mL once a week) in combination with HAART therapy. Intravitreal injections were discontinued once CMV retinitis healed if there was a significant increase in CD4+ count (any increase of > or 50 cells/microL to levels over 100 cells/microL sustained for at least 3 months). Mean follow-up was 15.6 months. Main outcome measures included assessment of visual acuity and retinal inflammation (CMV retinitis activity). A matched historical control group of 20 eyes (15 patients) with CMV retinitis treated with systemic ganciclovir (intravenous [induction] and oral [maintenance]) was included.\n\n\nRESULTS\nComplete regression of the retinitis was obtained with high doses of intravitreal ganciclovir in 88.8% of eyes (two patients died during follow-up) at a mean of 4.5 weeks (2 to 8 weeks). Visual acuity improved two or more lines in 61.1% of eyes. No ganciclovir retinal toxicity was identified. Three eyes presented CMV retinitis reactivation at a mean of 25.6 days after their last injection. Complications (33.3%) included retinal detachment (RD; 3 eyes), immune recovery uveitis (IRU; 2 eyes), and endophthalmitis (1 eye). In our control group complete regression of the retinitis was obtained in 100% of eyes at a mean of 4 weeks (3 to 7 weeks). However, 12 eyes (60%) presented with CMV retinitis relapse at a mean of 29 days (21 to 32 days) after initiating oral ganciclovir (maintenance). Complications included RD (7 eyes, 35%) and IRU (3 eyes, 15%). Severe neutropenia occurred in 2 patients (13%).\n\n\nCONCLUSIONS\nHigh doses of intravitreal ganciclovir (5.0 mg) once a week in combination with HAART therapy is effective to control CMV retinitis, and may be discontinued after CMV retinitis has healed if immune reconstitution with a significant increase in CD4+ count has occurred.",
"affiliations": "Retina and Vitreous Service, Clinica Oftalmologica Centro Caracas, Caracas, Venezuela. areval1@telcel.net.ve",
"authors": "Arevalo|J F|JF|;Garcia|R A|RA|;Mendoza|A J|AJ|",
"chemical_list": "D019380:Anti-HIV Agents; D000998:Antiviral Agents; D015774:Ganciclovir",
"country": "United States",
"delete": false,
"doi": "10.1177/112067210501500512",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1120-6721",
"issue": "15(5)",
"journal": "European journal of ophthalmology",
"keywords": null,
"medline_ta": "Eur J Ophthalmol",
"mesh_terms": "D017088:AIDS-Related Opportunistic Infections; D000328:Adult; D019380:Anti-HIV Agents; D023241:Antiretroviral Therapy, Highly Active; D000998:Antiviral Agents; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes; D017726:Cytomegalovirus Retinitis; D005260:Female; D015774:Ganciclovir; D006801:Humans; D007267:Injections; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D016896:Treatment Outcome; D014687:Venezuela; D014792:Visual Acuity; D014822:Vitreous Body",
"nlm_unique_id": "9110772",
"other_id": null,
"pages": "610-8",
"pmc": null,
"pmid": "16167292",
"pubdate": "2005",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "High-dose (5000-microg) intravitreal ganciclovir combined with highly active antiretroviral therapy for cytomegalovirus retinitis in HIV-infected patients in Venezuela.",
"title_normalized": "high dose 5000 microg intravitreal ganciclovir combined with highly active antiretroviral therapy for cytomegalovirus retinitis in hiv infected patients in venezuela"
} | [
{
"companynumb": "VE-ROCHE-2040756",
"fulfillexpeditecriteria": "1",
"occurcountry": "VE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LAMIVUDINE"
},
"drugadditional": "3",
"druga... |
{
"abstract": "\"Real life\" data are needed to complement published trials on the efficacy of lenalidomide in patients with myelodysplastic syndrome (MDS) and del(5q) and on the risk of inducing acute myeloid leukemia (AML) progression. Here, we present results of lenalidomide treatment in a consecutive, population-based series of 21 red blood cell (RBC) transfusion-dependent elderly patients with multiple comorbidities. Of 18 evaluable patients (median follow-up: 22 months), 17 achieved an erythroid hematologic response (HI-E) and 16 an RBC transfusion independence. Cytogenetic response (CyR) rate was 80%, median overall survival was 48 months (range 3-164), and 5-year leukemia-free survival was 84%. Three patients progressed to AML; one, with baseline TP53 mutation, achieved HI-E, partial CyR, and did not progress to AML. Eighteen patients experienced hematological adverse events. Overall, lenalidomide was very effective and well tolerated even in unselected elderly patients with multiple comorbidities and did not appear to increase the risk of AML.",
"affiliations": "a Department of Hematology , A.O. Spedali Civili , Brescia , Italy.;a Department of Hematology , A.O. Spedali Civili , Brescia , Italy.;a Department of Hematology , A.O. Spedali Civili , Brescia , Italy.;a Department of Hematology , A.O. Spedali Civili , Brescia , Italy.;a Department of Hematology , A.O. Spedali Civili , Brescia , Italy.;b Cytogenetics and Genetics Laboratory, Department of Genetic and Molecular Medicine , University of Brescia , Brescia , Italy.;a Department of Hematology , A.O. Spedali Civili , Brescia , Italy.;c Pathology Section, Department of Molecular and Translational Medicine , University of Brescia , Brescia , Italy.;d Centro Ricerca Emato-oncologica AIL (CREA), Diagnostics Department, A.O. Spedali Civili , Brescia , Italy.;d Centro Ricerca Emato-oncologica AIL (CREA), Diagnostics Department, A.O. Spedali Civili , Brescia , Italy.;a Department of Hematology , A.O. Spedali Civili , Brescia , Italy.",
"authors": "Cerqui|Elisa|E|;Pelizzari|Annamaria|A|;Schieppati|Francesca|F|;Borlenghi|Erika|E|;Pagani|Chiara|C|;Bellotti|Daniela|D|;Lamorgese|Cinzia|C|;Boiocchi|Leonardo|L|;Sottini|Alessandra|A|;Imberti|Luisa|L|;Rossi|Giuseppe|G|",
"chemical_list": "D000970:Antineoplastic Agents; D016159:Tumor Suppressor Protein p53; D013792:Thalidomide; D000077269:Lenalidomide",
"country": "United States",
"delete": false,
"doi": "10.3109/10428194.2015.1034703",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1026-8022",
"issue": "56(11)",
"journal": "Leukemia & lymphoma",
"keywords": "Cytogenetic response; del(5q) MDS; elderly; erythroid response; lenalidomide; transfusion independence",
"medline_ta": "Leuk Lymphoma",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D001853:Bone Marrow; D002872:Chromosome Deletion; D002895:Chromosomes, Human, Pair 5; D015897:Comorbidity; D018450:Disease Progression; D017707:Erythrocyte Transfusion; D005260:Female; D005500:Follow-Up Studies; D015870:Gene Expression; D006801:Humans; D000077269:Lenalidomide; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes; D011379:Prognosis; D013792:Thalidomide; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53",
"nlm_unique_id": "9007422",
"other_id": null,
"pages": "3129-34",
"pmc": null,
"pmid": "25811676",
"pubdate": "2015",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Lenalidomide in patients with red blood cell transfusion-dependent myelodysplastic syndrome and del(5q): a single-centre \"real-world\" experience.",
"title_normalized": "lenalidomide in patients with red blood cell transfusion dependent myelodysplastic syndrome and del 5q a single centre real world experience"
} | [
{
"companynumb": "IT-CELGENE-083-21880-13073920",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LENALIDOMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Hematopoietic stem cell transplantation (HSCT) is currently the only curative treatment for thalassemia majorTM. Graft rejection (GR) and graft-versus-host disease (GVHD) are the primary obstacles to a successful outcome.\n\n\n\nWe conducted a retrospective study of HSCT in 29 children (median age at transplantation: 6 years) with Beta-thalassemia (β-TM) after the combined infusion of granulocyte colony-stimulating factor-primed bone marrow (G-BM) and cord blood (CB) from the human leukocyte antigen (HLA)-identical sibling donors. We also compared the outcomes of the co-transplanted children with those of children with β-TM who received G-BM alone from an HLA-identical sibling donor (n = 26).\n\n\n\nCompared to the G-BM transplant (G-BMT) recipients, those who received a co-transplant had a lower incidence of grade ≥II acute (17.24 vs. 30.7%, p = 0.047) and limited chronic (0 vs.15.4%, p = 0.022) GVHD as well as a lower incidence of GR (0 vs. 7.7%, p = 0.132). Neutrophil recovery time was faster in the co-transplant group (18.5 vs. 21 days, p = 0.04). All the patients were monitored until December 31, 2016; the median follow-up time was 74 months<unterline>,</unterline> and the 5-year thalassemia-free survival rate was 89.7% in the co-transplant group and 84.6% in the G-BMT-alone group (p = 0.590).\n\n\n\nA combined CB and G-BM graft from an HLA-identical sibling donor is an effective treatment option for TM in children, with less acute and chronic GVHD.",
"affiliations": null,
"authors": "Wen|Jianyun|J|;Haque|Qareen|Q|;Pei|Fuyu|F|;Chen|Libai|L|;Ruan|Yongsheng|Y|;Liu|Xuan|X|;He|Yuelin|Y|;Feng|Xiaoqin|X|;Li|Chunfu|C|;Wu|Xuedong|X|",
"chemical_list": "D006680:HLA Antigens; D007166:Immunosuppressive Agents; D016179:Granulocyte Colony-Stimulating Factor",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000490407",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0001-5792",
"issue": "140(1)",
"journal": "Acta haematologica",
"keywords": "Beta-thalassemia major; Bone marrow; Cord blood; Hematopoietic stem cell transplant",
"medline_ta": "Acta Haematol",
"mesh_terms": "D000293:Adolescent; D001854:Bone Marrow Cells; D002454:Cell Differentiation; D002648:Child; D002675:Child, Preschool; D003587:Cytomegalovirus; D018572:Disease-Free Survival; D005312:Fetal Blood; D006086:Graft vs Host Disease; D016179:Granulocyte Colony-Stimulating Factor; D006680:HLA Antigens; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells; D006801:Humans; D007166:Immunosuppressive Agents; D007223:Infant; D012189:Retrospective Studies; D012720:Severity of Illness Index; D014775:Virus Activation; D017086:beta-Thalassemia",
"nlm_unique_id": "0141053",
"other_id": null,
"pages": "20-29",
"pmc": null,
"pmid": "30071526",
"pubdate": "2018",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Transplant Outcomes in Beta-Thalassemia Major Patients Receiving Combined Granulocyte Colony-Stimulating Factor-Primed Bone Marrow and Cord Blood Graft Compared to Granulocyte Colony-Stimulating Factor-Primed Bone Marrow Alone.",
"title_normalized": "transplant outcomes in beta thalassemia major patients receiving combined granulocyte colony stimulating factor primed bone marrow and cord blood graft compared to granulocyte colony stimulating factor primed bone marrow alone"
} | [
{
"companynumb": "CN-STRIDES ARCOLAB LIMITED-2018SP009125",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"drugaddition... |
{
"abstract": "Malignant prolactinoma is a rare entity and only a few cases have been published. The diagnostic criteria and the clinical course remain unclear. We present a case of malignant prolactinoma in a woman with a 30-year duration of the disease. In the terminal stage of the disease the prolactinoma metastasized to the left eye, the prolactin level reaching 196000 mU/l. Bromocriptine in high doses was not effective. The response to pergolide was good in the first two years of treatment; thereafter an escape effect was observed. The patient died in a comatose state. A review of previously published cases follows.",
"affiliations": "Institute of Endocrinology, Chaim Sheba Medical Center, Tel Hashomer, Israel.",
"authors": "Berezin|M|M|;Gutman|I|I|;Tadmor|R|R|;Horowitz|A|A|;Findler|G|G|",
"chemical_list": "D010479:Pergolide; D001971:Bromocriptine; D011388:Prolactin",
"country": "Denmark",
"delete": false,
"doi": "10.1530/acta.0.1270476",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0001-5598",
"issue": "127(5)",
"journal": "Acta endocrinologica",
"keywords": null,
"medline_ta": "Acta Endocrinol (Copenh)",
"mesh_terms": "D001971:Bromocriptine; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D008875:Middle Aged; D009918:Orbital Neoplasms; D010479:Pergolide; D010911:Pituitary Neoplasms; D011388:Prolactin; D015175:Prolactinoma",
"nlm_unique_id": "0370312",
"other_id": null,
"pages": "476-80",
"pmc": null,
"pmid": "1471460",
"pubdate": "1992-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Malignant prolactinoma.",
"title_normalized": "malignant prolactinoma"
} | [
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"fulfillexpeditecriteria": "1",
"occurcountry": "CZ",
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"abstract": "Agitation is a common and serious symptom of bipolar mania and schizophrenia, and can be defined as excessive motor and verbal activity. If left unrecognized and untreated, agitation can evolve into aggression, resulting in potential patient and staff injury. An ideal treatment for agitation would have a rapid onset, cause calmness without sedation, and be tolerable, efficacious, and non-coercive, while managing the underlying condition. A novel approach for the treatment of agitation is inhaled loxapine. Inhaled loxapine is rapidly absorbed into the systemic circulation through the alveoli, resulting in a near immediate onset of action. The efficacy of inhaled loxapine was established in an extensive clinical development program that included persons with schizophrenia and bipolar mania. Additionally, inhaled loxapine has comparable efficacy to intramuscular ziprasidone, olanzapine, haloperidol, aripiprazole, and lorazepam, with the added benefit of being non-painful and non-traumatizing. Inhaled loxapine carries a bolded black box warning for bronchospasm, and as a result, in the US, requires enrollment in a Risk Evaluation and Mitigation Strategy program, and is contraindicated in those with pulmonary disease. Additionally, the use of inhaled loxapine can be associated with dysgeusia and throat irritation. Inhaled loxapine requires some degree of patient cooperation, and therefore may not be appropriate for all agitated patients.",
"affiliations": "Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19125, USA.;Psychiatry & Behavioral Sciences, New York Medical College, Valhalla, NY 10595, USA.",
"authors": "Faden|Justin|J|;Citrome|Leslie|L|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/NDT.S173567",
"fulltext": "\n==== Front\nNeuropsychiatr Dis TreatNeuropsychiatr Dis TreatNDTneurodistNeuropsychiatric Disease and Treatment1176-63281178-2021Dove 17356710.2147/NDT.S173567ReviewExamining the safety, efficacy, and patient acceptability of inhaled loxapine for the acute treatment of agitation associated with schizophrenia or bipolar I disorder in adults Faden and CitromeFaden and CitromeFaden Justin 1Citrome Leslie 2\n1 \nLewis Katz School of Medicine, Temple University, Philadelphia, PA\n19125, USA\n2 \nPsychiatry & Behavioral Sciences, New York Medical College, Valhalla, NY\n10595, USA\nCorrespondence: Leslie Citrome11 Medical Park Drive, Suite 106, Pomona, NY10970, USATel +1 845 362 2081Email citrome@cnsconsultant.com07 8 2019 2019 15 2273 2283 08 4 2019 24 6 2019 © 2019 Faden and Citrome.2019Faden and Citrome.This work is published and licensed by Dove Medical Press Limited. The 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. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).Abstract\nAgitation is a common and serious symptom of bipolar mania and schizophrenia, and can be defined as excessive motor and verbal activity. If left unrecognized and untreated, agitation can evolve into aggression, resulting in potential patient and staff injury. An ideal treatment for agitation would have a rapid onset, cause calmness without sedation, and be tolerable, efficacious, and non-coercive, while managing the underlying condition. A novel approach for the treatment of agitation is inhaled loxapine. Inhaled loxapine is rapidly absorbed into the systemic circulation through the alveoli, resulting in a near immediate onset of action. The efficacy of inhaled loxapine was established in an extensive clinical development program that included persons with schizophrenia and bipolar mania. Additionally, inhaled loxapine has comparable efficacy to intramuscular ziprasidone, olanzapine, haloperidol, aripiprazole, and lorazepam, with the added benefit of being non-painful and non-traumatizing. Inhaled loxapine carries a bolded black box warning for bronchospasm, and as a result, in the US, requires enrollment in a Risk Evaluation and Mitigation Strategy program, and is contraindicated in those with pulmonary disease. Additionally, the use of inhaled loxapine can be associated with dysgeusia and throat irritation. Inhaled loxapine requires some degree of patient cooperation, and therefore may not be appropriate for all agitated patients.\n\nKeywords\ninhaled loxapineagitationschizophreniabipolar disordermaniaantipsychotic\n==== Body\nIntroduction\nAgitation is a heterogeneous and multifactorial syndrome with varying causations, definitions, and displays, and accounts for nearly 1.7 million annual visits to the emergency department in the United States.1 Agitation can be seen in persons with acute bipolar mania and acute exacerbations of schizophrenia, particularly in emergency department settings as well as during acute hospitalizations.2\n\nBroadly, agitation can be defined as abnormal and excessive motor and verbal activity.3 When agitation evolves into aggression, it can result in patient and staff injury, and should be considered a medical and psychiatric emergency.4\n\nThis review will focus on one option for the treatment of agitation: inhaled loxapine. After a brief overview of pharmacotherapeutic principles, including that concerning oral and parenteral formulations, inhaled loxapine is discussed in detail. A literature search was conducted 8 October 2018 using the US National Library of Medicine’s PubMed.gov resource (https://www.ncbi.nlm.nih.gov/pubmed/) using the words “inhaled loxapine”, “staccato loxapine”, and “agitation AND loxapine”. Only full text articles were considered and there were no other filters. The search yielded a total of 144 results, and after eliminating duplicates, 89 citations were identified and reviewed by the authors for applicability.\n\nPharmacotherapeutic principles\n\nPharmacologic guidelines and algorithms for the treatment of agitation are numerous and constantly evolving.5 Pharmacologic treatment options are classically broken down into three options: oral and sublingual, intramuscular, and intravenous medications (Table 1).6 A fourth more recent option consists of inhaled medications. Pharmacologic options primarily consist of two different classes of medications; benzodiazepines and antipsychotics. For a medication to be utilized for the treatment of agitation, it needs to have a rapid onset of action, induce calmness without excessive sedation, be safe and tolerable, and be predictably efficacious in reducing agitation.Table 1 Characteristics of selected oral, intramuscular, and intravenous medications used for agitation\n\nMedication\tDosage, mg\tTmaxa\tAdvantages\tDisadvantages\t\nOrally administered\t\t\tNon-invasive. Easily administered. Potentially higher patient satisfaction than intramuscular administration.\tErratic absorption through GI system and slow onset of action. Risk of medication being diverted (ie, “cheeked”). Requires active patient cooperation.\t\nLorazepam\t0.5–2\t20–30\tNo active metabolites. Can treat comorbid alcohol/benzodiazepine withdrawal. Can be combined with antipsychotic for synergistic effects.\tNo antipsychotic effect. Can cause respiratory depression. Can be misused by persons with addictive disorders. In the presence of physiological tolerance, diminished efficacy may be observed. Paradoxical behavioral disinhibition risk.\t\nHaloperidol\t5–10\t2–6 hrs\tReduces and treats psychosis. Can be given with benzodiazepines. Inexpensive.\tRisk of akathisia and dystonic reactions.\t\nRisperidone\t2\t60\tReduces and treats psychosis. Also available as an ODT and liquid formulation. Low risk of EPS compared to FGAs. Can be given with benzodiazepines.\tHigher rate of dystonic reactions than other SGAs.\t\nOlanzapine\t5–10\t5–8 hrs\tReduces and treats psychosis. Also available as an ODT. Low risk of EPS compared to FGAs.\tCan cause excess sedation and adverse effects when given concurrently with benzodiazepines – combination should be avoided.\t\nAsenapine\t10\t30–90\tSublingual administration. Absorbed in the oral mucosa. Low risk of diversion. Low risk of EPS compared to FGAs.\tLow bioavailability if swallowed. Side effects of oral hypoesthesia and dysgeusia. No food or fluids for 2–10 mins after administration.\t\nIntramuscularly administered\t\t\tReliably absorbed into systemic circulation. Bypasses GI system. Can be administered over the patient's objections. \tInvasive, coercive, painful. Can alienate patient and damage rapport.\t\nLorazepam\t0.5–2\t20–30\tNo active metabolites. Can treat comorbid alcohol/benzodiazepine withdrawal. Can be combined with antipsychotic for synergistic effects.\tNo antipsychotic effect. Can cause respiratory depression. Can be abused in addiction. Paradoxical behavioral disinhibition risk.\t\nHaloperidol\t2–10\t20–60\tReduces and treats psychosis. Can be given with benzodiazepines. Inexpensive.\tRisk of akathisia and dystonic reactions.\t\nZiprasidone\t10–20\t15–60\tReduces and treats psychosis. Low risk of EPS compared to FGAs. Can be given with benzodiazepines.\tQTc prolongation. Caution in patients with impaired renal function because the excipient is cleared by renal filtration\t\nOlanzapine\t10\t15–45\tReduces and treats psychosis. Low risk of EPS compared to FGAs.\tConcomitant administration with a benzodiazepine can result in excessive sedation and cardiorespiratory depression.\t\nAripiprazole\t9.75\t1–3 hrs\tReduces and treats psychosis. Low risk of EPS compared to FGAs.\tRates of sedation and orthostatic hypotension are greater when administered with benzodiazepines. No longer available in the US.\t\nIntravenously administered\t\t\t\t\t\nHaloperidol\t2–5 or higher\tImmediate\tNear immediate onset of action\tRequires venous access. Increases risk of QT prolongation and Torsades de pointes. Requires cardiac monitoring.\t\nNote:\naTime to maximum concentration in minutes unless stated otherwise.\n\nAbbreviations: EPS, extra-pyramidal symptoms; FGA, first-generation antipsychotic; GI, gastro-intestinal; ODT, orally disintegrating tablet; SGA, second-generation antipsychotic.\n\n\n\n\nOral medications\nOral medications have the benefit of being non-invasive and can be easily administered. However, oral administration by swallowing has the slowest onset of action and providers need to be cognizant of patients “cheeking” (taking but not swallowing) or otherwise diverting the medications.7,8 Liquid and oral disintegrating formulations of several antipsychotics and benzodiazepines have been developed, although not all remain commercially available. These options do not improve time to onset of action as these medications disintegrate in the saliva and must still be swallowed.9 An option that circumvents this is sublingual asenapine, which is absorbed in the oral mucosa and appears efficacious in reducing agitation as evidenced in a randomized placebo-controlled clinical trial.10\n\nIntramuscular treatment options\nBy entering the systemic circulation through the muscle’s vasculature, intramuscular formulations provide faster absorption, bioavailability, and a more rapid onset of action when compared with oral medications.8,11,12 However, intramuscular administration of medications can lead to a higher incidence of adverse events with enduring consequences; for example, acute dystonia with haloperidol can negatively affect a patient’s willingness to take antipsychotic medications in the future.8 Intramuscular benzodiazepines, such as lorazepam and diazepam, can also cause respiratory depression, especially in those with lung disease or sleep apnea. Injections of medications can be considered by some as coercive and invasive, reducing patient autonomy and damaging the doctor–patient therapeutic relationship.5 On a practical standpoint, the process of administering an injection in a person refusing medication places health care providers at increased risk of being assaulted as well as experiencing needlestick injuries.8\n\nInhaled medications: loxapine\nInhalation of medications allows for the potential of rapid absorption and thus the rapid onset of action. Inhaled loxapine was approved in 2012 by the US Food and Drug Administration (FDA) for the treatment of agitation associated with schizophrenia or bipolar mania.13,14 Its use in the US is limited to a single dose of 10 mg in a 24-hr period. The clinical development program for inhaled loxapine included three randomized placebo-controlled clinical trials in adults: a Phase II trial in patients with schizophrenia, a Phase III trial in patients with schizophrenia, and a Phase III trial in patients with bipolar mania.15–17 Loxapine itself is a first-generation antipsychotic and has been commercially available for decades.14\n\nThis is a novel approach to the management of agitation. No other antipsychotic is currently available as an inhaled formulation.\n\nInhaled loxapine delivery system\nInhaled loxapine is delivered through a handheld, single-use, breath-activated device. The delivery system is designed to quickly administer the aerosolized drug into the alveoli, leading to a rapid systemic effect.18 A breath sensor on the device detects a single inhalation, triggering a thermally generated condensation aerosol of a thin layer of the drug, free of excipients, or propellants.18 Purity of the emitted medication is greater than 99.5%, and no special breathing or hand/breath coordination is required.18 The vaporization process takes 0.1 s, and the drug then rapidly cools and condenses into aerosol particles 1–3.5 microns in diameter, allowing for deep lung penetration and fast systemic absorption in less than a second.19 Inhaled loxapine is rapidly absorbed and reaches peak plasma concentration in approximately 2 mins (Tmax), with a maximum concentration of 312 ng/mL (Cmax), and a half-life of 8 hrs.20,21 Deposition of particles into the oropharyngeal region is estimated to be only 11% of the emitted dose.22 Some degree of patient cooperation is necessary, potentially making inhaled loxapine unsuitable for patients with severe agitation.\n\nInhaled loxapine pharmacology, mechanism of action (MOA), and pharmacokinetics\nLoxapine is a medium potency dibenzoxazepine antipsychotic medication that is structurally similar to clozapine.23 It is a post-synaptic antagonist at the D2 receptor, dissociating at an intermediate rate, as well as an antagonist at the serotonin 5-HT2A receptor.24,25 Based on human and animal studies, loxapine has a negligible affinity to glutamate N-methyl-D-aspartate (NMDA) receptors, unlike clozapine which may function as an NMDA receptor modulator.26,27 Other pharmacologic effects include antagonism at histaminergic H1, cholinergic M1, and adrenergic α1 receptors, which may be responsible for side effects including somnolence, anticholinergic effects, and orthostatic hypotension.3,28 Loxapine binds to the D4 receptor with higher affinity than to other dopaminergic receptors in human and animal models.26,29 Although it has a ratio of D2/D3 binding affinity that is similar to that of some atypical antipsychotic medications, a systematic Cochrane review assessing all randomized controlled trials comparing loxapine (in dosages up to 300 mg/day) to other treatments for schizophrenia found the adverse effect profile of loxapine to be similar to that of other typical antipsychotic agents, and may cause a greater risk of extrapyramidal side effects than atypical antipsychotics.30 This may be attributed to the equipotent 5-HT/D2 affinity ratio.24,31 Although in vitro studies show loxapine affinity to 5HT2 receptors to be higher than its affinity to D2 receptors, in vivo human and animal studies have not supported this.24,32,33 Loxapine is metabolized to its primary N-demethylated metabolite amoxapine, a tricyclic antidepressant, and via hydroxylation to 7-OH loxapine.34 In animal studies, the 7-OH loxapine metabolite has a five-fold higher affinity for the D2 receptor compared with loxapine, and thus it may contribute to the clinical effect of the drug as well as altering the 5-HT/D2 affinity ratio.20 However, inhaled loxapine has been shown to have a lower incidence of extrapyramidal symptoms (EPS) than oral loxapine due to lower levels of 7-OH reaching the striatum in rat brains, as well as possibly due to a lower dose exposure than in patients receiving ongoing oral treatment.35\n\nEfficacy\nThe efficacy of inhaled loxapine for the treatment of agitation associated with bipolar disorder and schizophrenia has been established in a Phase II study and two Phase III Studies (Table 2). Patients ≥65 years of age were excluded from the studies. The study designs for each study were similar, with a primary efficacy endpoint being change from baseline on the Positive and Negative Syndrome Scale–Excited Component (PANSS–EC) after 2 hrs. Secondary endpoints included: (1) Clinical Global Impressions-Improvement Scale (CGI-I) score 2 hrs after receiving study medication, (2) time to rescue medication (intramuscular lorazepam), (3) changes in PANSS-EC measured 10, 20, 30, 45, 90, and 120 mins, as well as 4 and 24 hrs, after receiving study medication. For safety purposes, the Agitation–Calmness Evaluation Scale (Phase III studies) or Behavioral Agitation Rating Scale (Phase II study) was administered. In the Phase II study, participants were restricted to receiving only one dose of inhaled loxapine, however, in both Phase III trials, participants could receive up to three doses in the case of persistent or recurrent agitation over a 24-hr period. In the Phase III studies, rescue lorazepam could be used after dose 2 and patients who received lorazepam rescue medication did not receive additional loxapine.Table 2 Efficacy of inhaled loxapine as reported from one Phase II study15 and two Phase III studies16,17 (all are randomized. double-blind, multi-site, placebo-controlled, parallel group, clinical trials)\n\nAuthors, year\tPatient population\t% CGI-I Responders and NNT vs. placebo (95% CI)*\t% PANSS-EC Responders and NNT vs. placebo (95% CI)**\tMain findings\t\nAllen et al, 201115\t129 patients agitated patients with schizophrenia or schizoaffective disorder\tPlacebo, 21%\nLoxapine 5 mg, 49%, 4(3–12)\nLoxapine 10 mg, 63%, 3 (2–5)\tData not available\tLoxapine 5 and 10 mg demonstrated a greater reduction in in the PANSS-EC compared to placebo, though only the 10 mg dose was statistically significantly different from placebo. Loxapine 10 mg separated from placebo 20 mins after administration, whereas inhaled loxapine 5 mg failed to statistically diverge. After 2 hrs, there was a statistically significant improvement in CGI-I for both loxapine 5 and 10 mg. Time to rescue medication demonstrated advantages for both dosages of loxapine.\t\nLesem et al, 201116\t344 agitated patients with schizophrenia\tPlacebo, 36%\nLoxapine 5 mg, 57%, 5 (3–11)\nLoxapine 10 mg, 67%, 4 (3–6)\tPlacebo, 38%\nLoxapine 5 mg, 63%, 5 (3–9)\nLoxapine 10 mg, 70%, 4 (3–6)\tLoxapine 5 and 10 mg demonstrated a statistically significant reduction in agitation compared to placebo at 2 hrs based on the PANSS-EC and demonstrated an overall advantage using the CGI-I. A statistically significant reduction in the PANSS-EC compared to placebo was evident 10 mins after administration with both 5 and 10 mg of inhaled loxapine. Participants that received placebo received a second dose for persistent or recurrent agitation sooner than those taking inhaled loxapine (Kaplan–Meier overall comparison), and also required rescue medication more frequently than those randomized to either dose of loxapine.\t\nKwentus et al, 201217\t314 agitated patients with bipolar I disorder (manic or mixed state)\tPlacebo, 28%\nLoxapine 5 mg, 66%, 3 (2–4)\nLoxapine 10 mg, 74%, 3 (2–3)\tPlacebo, 28%\nLoxapine 5 mg, 63%, 3 (3–5)\nLoxapine 10 mg, 73%, 3 (2–3)\tAt the 2hrs end point, inhaled loxapine 5 and 10 mg resulted in a statistically significant reduction of agitation when compared to placebo based on the PANSS-EC. Overall advantages for loxapine were also demonstrated by improvements in the CGI-I score. Both dosages of loxapine demonstrated superiority over placebo as early as 10 mins post-administration. A Kaplan–Meier survival analysis of the time to a second dose of medication demonstrated statistical superiority for both loxapine groups over placebo.\t\nNotes: *CGI-I response is defined as a CGI-I scale score of 1 (very much improved) or 2 (much improved) at 2 hrs post-initial dose administration. **PANSS-EC response is defined as a PANSS-EC score change from baseline ≥40% at 2 hrs post-initial dose administration.\n\nAbbreviations: CI, confidence interval; CGI-I, clinical global impressions-improvement; NNT, number needed to treat; NS, not significant; PANSS-EC, positive and negative syndrome scale – excited component.\n\n\n\n\nIn the randomized, double-blind, placebo-controlled Phase II study, investigators randomized 129 agitated patients with schizophrenia or schizoaffective disorder to receive either inhaled loxapine 5 mg, 10 mg, or placebo.15 Both inhaled loxapine 5 and 10 mg resulted in a greater reduction in PANSS-EC scores compared to placebo, though only the 10 mg dosage achieved statistical significance (p-values 0.088 and 0.002, respectively). Secondary endpoints revealed that inhaled loxapine 10 mg statistically separated from placebo 20 mins after drug administration (p≤0.05), whereas inhaled loxapine 5 mg failed to statistically diverge, suggesting a dose–response relationship. After 2 hrs, there was a statistically significant improvement in CGI-I for both inhaled loxapine 10 (p=0.0003) and 5 mg (p=0.0067) compared to placebo. Time to rescue medication demonstrated advantages for both inhaled loxapine 5 and 10 mg vs placebo.\n\nTwo Phase III studies were completed; one included agitated patients with schizophrenia,16 and another agitated patients with bipolar mania.17 Both studies were randomized, double-blind, multi-site, placebo-controlled, parallel-group trials. In the schizophrenia trial, a total of 344 patients were randomized to receive inhaled loxapine 5 mg, 10 mg, or placebo.16 Both loxapine 5 and 10 mg were superior to placebo in reducing agitation as measured by change in the PANSS-EC score at 2 hrs (p=0.0004 and p<0.0001, respectively). Reduced PANSS-EC scores relative to placebo were evident 10 mins after dosage (the first time point after administration where this assessment took place) with both 5 and 10 mg of loxapine (p=0.0003 and p<0.0001, respectively). The CGI-I score 2 hrs after dosage demonstrated a statistically significant improvement for both loxapine 5 mg (p=0.0015) and 10 mg (p<0.0001) dosages compared with inhaled placebo. Additionally, participants that received placebo required an additional dose for persistent or recurrent agitation sooner than those taking inhaled loxapine. A Kaplan–Meier survival analysis of the time to a second dose showed statistical superiority for loxapine 10 mg over placebo (p=0.0076), whereas loxapine 5 mg showed a numerical superiority that was not significant (p=0.115). Participants receiving intramuscular lorazepam were 5%, 6%, and 16% for those randomized to loxapine 10 mg, loxapine 5 mg, and placebo, respectively.3 The second Phase III study involved 314 agitated patients with bipolar disorder.17 Patients were randomized to receive inhaled loxapine 5 mg, 10 mg, or placebo. At the 2-hr end point, inhaled loxapine 10 and 5 mg resulted in a significant reduction of agitation when compared to placebo (p<0.0001) based on the PANSS-EC score. Both dosage strengths of loxapine demonstrated superiority over placebo as early as 10 mins post-inhalation. The CGI-I score for both loxapine groups statistically separated from placebo at the 2-hr endpoint (p<0.0001). A Kaplan–Meier survival analysis of the time to the second dose of inhaled study drug showed statistical superiority for both loxapine groups over placebo (10 mg, p<0.0001, 5 mg, p=0.0058). Proportions of patients receiving intramuscular lorazepam were 9%, 9%, and 21% for those randomized to loxapine 10 mg, loxapine 5 mg, and placebo, respectively.\n\nAn additional set of analyses of the data from the Phase III studies examined the percentage of patients achieving clinical response (defined as a reduction of ≥40% in PANSS-EC score) and also assessed changes in the five individual items of the PANSS-EC.36 Response was observed in approximately 20% of the patients with schizophrenia and bipolar disorder 10 mins after receiving inhaled loxapine in both 5 and 10 mg doses. Response rate continued to improve over time until 90–120 mins post-inhalation where approximately 70% in the 10 mg loxapine group for both schizophrenia and bipolar disorder were categorized as responders. Additionally, in both studies, there were statistically significant reductions in all five PANSS-EC items at the 2-hr post-administration time point (p<0.05).\n\nThe number needed to treat (NNT) to achieve ≥40% reduction from baseline on the PANSS-EC at 2 hrs for inhaled loxapine 10 and 5 mg vs placebo for agitation associated with bipolar disorder is 3 and 3, respectively, and for agitation associated with schizophrenia, 4 and 5, respectively. Pooling the results, the NNT vs placebo for loxapine 5 mg was 4 (95% CI 3–5) and the NNT for the 10 mg dose was 3 (95% CI 3–4).19 This compares well to NNT values for response for intramuscular ziprasidone (10 or 20 mg vs 2 mg, NNT 3), olanzapine (10 mg vs placebo, NNT 3), haloperidol (6.5–7.5 mg vs placebo, NNT 4), lorazepam (2 mg vs placebo, NNT 4), and aripiprazole (9.75 mg vs placebo, NNT 5).37\n\nIn a head-to-head, multi-site, open-label, assessor-blind, randomized, active-controlled, parallel-group clinical trial, inhaled loxapine 10 mg was compared with intramuscular aripiprazole (9.75 mg) in acutely agitated patients with schizophrenia or bipolar I disorder.38 Three hundred and fifty-seven acutely agitated (CGI-Severity [CGI-S] score ≥4) patients aged 18–65 years were randomized (1:1) to receive inhaled loxapine or intramuscular aripiprazole. Patients received a maximum of two doses of study drug, with the second dose given at least 2 hrs after the first for persistent or recurrent agitation. Rescue medication consisting of intramuscular lorazepam 2 mg could be administered ≥20 mins after the second dose of study medication if warranted. The primary efficacy endpoint was time to response, defined as a CGI-I score of 1 (very much improved) or 2 (much improved). Secondary endpoints included: (1) proportion of patients achieving CGI-I treatment response at 10, 20, 30, 40, 50, 60, 90, and 120 mins after dose one; (2) the number of patients who received one or two doses of study drug; (3) time to second dose of study medication; (4) the number of patients receiving rescue medication; (5) and satisfaction with treatment (evaluated with Treatment Satisfaction Questionnaire for Medication [TSQM]). Of the 357 patients, 297 were diagnosed with schizophrenia and 60 with bipolar disorder. In patients with schizophrenia, there was a statistically significant difference (p=0.0028) in median time to respond for loxapine vs aripiprazole (50 mins [95% CI 50.0–60.0 mins] vs 60 mins [95% CI 50.0–90.0 mins]). A similar trend was noted in patients with bipolar disorder, however, it did not reach statistical significance (30 mins [95%CI 20.0–60.0 mins] vs 50 mins [95% CI 50.0–120.0 mins]) (p=0.06). Patients receiving inhaled loxapine responded more rapidly than those receiving intramuscular aripiprazole; at the 10-min time point, 14% of the patients receiving loxapine achieved response compared to 3.9% of the patients receiving aripiprazole (p=0.0009). This trend continued up to the 60-min time point, and at 120-mins, 84.4% of the patients receiving loxapine showed response compared to 82.6% of the patients receiving aripiprazole. Few patients in each treatment group received dose two, and only one patient in the study received a rescue medication. Of note, short-acting injectable aripiprazole is no longer commercially available in the US.\n\nIn a retrospective chart review, pragmatic outcome measures, including the need for rescue medications, use of restraints, and time until achieving medical clearance after receiving medication, were assessed for patients in an emergency department.39 Subjects were patients that received antipsychotic medication for agitation associated with psychosis. Medications administered included inhaled loxapine, haloperidol, and ziprasidone. A total of 406 patients were identified and included in the study. Inhaled loxapine was compared to the combined results of ziprasidone and haloperidol (Table 3). After receiving inhaled loxapine or intramuscular haloperidol/ziprasidone, patients having received loxapine were medically cleared faster than those receiving other antipsychotics (p<0.01), received fewer dosages of rescue medication consisting of benzodiazepines (p<0.01), and were placed in physical restraints less frequently (p<0.01).Table 3 Efficacy of inhaled loxapine compared to other antipsychotics administered in an emergency department for agitation associated with psychosis, as measured by pragmatic outcomes48\n\nMedication, Total N=406 (%)\tNeeding restraints, Total N=70 n (%)\tMedian time (IQR) until medical clearance after receiving first medication (hours)\tRescue medication (benzodiazepine), Total N=248 n (%)\t\nMode of administration, n (%)\t\nLoxapine, N=54 (13)\n Inhaled, N=54\t1 (1.8)*\t4.8 (2.0–8.8)*\t19 (35.2)*\t\nAll other antipsychotics, N=352\t69 (19.8)*\t7.2 (3.8–13.3)*\t229 (65.1)*\t\n Haloperidol, N=127 (31)\t\t\t\t\n Oral 9 (7.1)\t\t\t\t\n IM 85 (66.9)\t\t\t\t\n IV 6 (4.7)\t\t\t\t\n Missing 27 (21.3)\t\t\t\t\n Ziprasidone, N=225 (55)\t\t\t\t\n Oral 37 (16.4)\t\t\t\t\n IM 146 (64.9)\t\t\t\t\n Missing 42 (18.7)\t\t\t\t\nNote: *p<0.01, demonstrating significant difference between loxapine and other pooled antipsychotics.\n\nAbbreviations: IM, intramuscular; IQR, interquartile range; IV, intravenous.\n\n\n\n\nSafety\nAdverse effects\n\nTables 4 and 5 include a list of adverse events of interest that may be associated with inhaled loxapine. The adverse event occurring at a rate of ≥5% and ≥2-times that observed with placebo is dysgeusia (14.3%, 11.3%, and 4.9% for loxapine 10 mg, 5 mg, and placebo, respectively). The number needed to harm (NNH) for dysgeusia for inhaled loxapine vs placebo was 11 (95% CI 7–23) for the 10 mg dose and 16 (95% CI 10–58) for the 5 mg dose.3Table 4 Adverse events as reported in Phase II and III trials comparing inhaled loxapine to placebo5\n\nAdverse event\tPlacebo (N=263)\tLoxapine 5 mg (N=265)\tLoxapine 10 mg (N=259)\t\nN (%)\tN (%)\tN (%)\t\nDysgeusia\t13 (4.9)\t30 (11.3)\t37 (14.3)\t\nSomnolence\t25 (9.5)\t32 (12.1)\t31 (12)\t\nDizziness\t23 (8.7)\t17 (6.4)\t19 (7.3)\t\nThroat irritation\t1 (0.4)\t2 (0.8)\t7 (2.7)\t\nAny EPS\t1 (0.4)\t5 (1.9)\t4 (1.5)\t\nBronchospasm\t0 (0)\t0 (0)\t2 (0.8)\t\nAbbreviation: EPS, extrapyramidal symptoms.\n\n\nTable 5 Adverse events as reported in a head-to-head trial comparing inhaled loxapine to intramuscular aripiprazole47\n\nAdverse event\tLoxapine 10 mg (N=179)\tAripiprazole 9.75 mg (N=178)\t\nN (%)\tN (%)\t\nDysgeusia\t22 (12.3)\t0 (0)\t\nSomnolence\t26 (14.5)\t25 (14.1)\t\nDizziness\t4 (2.2)\t11 (6.2)\t\nThroat irritation\t4 (2.2)\t0 (0)\t\nAny EPS\tNot reported\tNot reported\t\nBronchospasm\t0 (0)\t0 (0)\t\nAbbreviation: EPS, extrapyramidal symptoms.\n\n\n\n\nEPS, including akathisia, were uncommon and statistically non-significant when compared to placebo, unlike what can be seen with intramuscular haloperidol.37 Inhaled loxapine does not prolong the QTc interval.21,28,40\n\nDoes inhaled loxapine affect pulmonary function?\nInhaled loxapine carries a black box warning for bronchospasm, and as a result, in the US, requires enrollment in a Risk Evaluation and Mitigation Strategy (REMS) program.28 As a consequence of the REMS program, administration of inhaled loxapine is restricted to health care facilities with access to supplies and personnel trained to manage acute bronchospasm, and have access to a short-acting bronchodilator (ie, albuterol). Similarly, patients with a diagnosis of asthma, chronic obstructive pulmonary disease (COPD), any other lung disease associated with bronchospasm, or current acute respiratory symptoms (ie, wheezing), are contraindicated from receiving inhaled loxapine.\n\nIn the clinical trial program, including Phase II/III trials, one participant (0.09%) out of 1095 study subjects without active airway disease required treatment with albuterol for bronchospasm. Cough was the most common airway adverse event (19/1095 subjects; 1.7%). In the Phase II/III clinical trials, approximately 87% of the patients were current or ex-smokers, yet bronchospasm was rare, occurring in 0% (0/263) of the placebo group and 0.8% (2/259) of the inhaled loxapine 10 mg group, for a NNH of 130 (not significant).3 An important caveat is that severe asthmatics and very severe COPD patients were excluded from these studies, and thus the results may not reflect those in patients with more severe airway diseases.\n\nTo more fully appraise the potential of inhaled loxapine to adversely affect pulmonary function in persons with airway/lung disease, two distinct randomized, double-blind, parallel-arm, placebo-controlled trials were conducted comparing inhaled loxapine 10 mg vs placebo in 52 patients with asthma and 53 patients with COPD.41 The primary outcome measure was spirometry results. The results showed that in subjects with asthma and COPD, inhaled loxapine causes a decrease in forced expiratory volume in 1 s. In patients with asthma, there was also an increased risk of bronchospasm (NNH=5 [3–23]).13 All airway adverse events in patients with asthma and COPD were mild or moderate in severity. Nonetheless, the “single digit” NNH results reinforce the need to avoid the use of inhaled loxapine in persons with active airway/lung disease.\n\nPatient acceptability\nApproximately two-thirds of patients recognize when they are becoming agitated and are also able to categorize and identify their triggers.42 Symptom recognition allows for intervention before agitation has time to escalate and intensify, resulting in better outcomes. As patients can often identify when they are becoming agitated, they can also often identify what best ameliorates agitation. To enhance the therapeutic alliance, patient’s individual preferences and values should be taken into consideration. In a survey of 583 outpatients with schizophrenia or bipolar disorder who experienced episodes of agitation, the most commonly employed strategy for agitation was taking “as needed” medication, with high overall satisfaction for lessening agitation.42 A workgroup of 20 clinicians with experience in the clinical management of agitated patients met to identify a consensus statement for the ideal pharmacologic treatment of agitation.5 The group found inhaled loxapine to be the closest to an ideal treatment, with similar positive attributes to both intramuscular/intravenous medications (rapid onset of action), and oral/sublingual medications (non-invasive/non-coercive, advantageous tolerability, and high patient preference).\n\nThese patient satisfaction findings were assessed in the head-to-head comparison of inhaled loxapine vs intramuscular aripiprazole for the treatment of agitation described earlier.38 Study participants completed the TSQM 2 and 24 hrs after medication administration.43 Significantly more (p=0.0012) patients in the inhaled loxapine group (53.8%) than in the intramuscular aripiprazole group (36.4%) were “very satisfied” or “extremely satisfied” with the treatment received.\n\nIn 168 patients with schizophrenia or bipolar disorder, health-related quality of life was surveyed using a time trade-off approach.44 Patients were asked about the impact of medication administration method for acute agitation, comparing oral, injection, and inhalation methods. Respondents considered treatment with inhaled medication to be preferable to receiving treatment with tablets or injections. Inhalation was the most valuable treatment and injection was the least valuable. The utility value, a measure of health status and quality of life, where 1 is perfect health and 0 is death, was 0.762 for inhalable treatment, 0.707 for injection, and 0.734 for tablet treatment, further reinforcing the potential advantage of inhaled formulations in the treatment of agitation.\n\nCost\nInhaled loxapine has a higher acquisition cost than the oral and intramuscular medications commonly used to treat agitation in psychiatric conditions. Based on a survey of five independent health care organizations in New York, New Jersey, and Pennsylvania conducted in 2019 March, the acquisition cost of inhaled loxapine 10 mg is $140/dose in the US, compared to much lower costs for alternative intramuscular medications (Table 6).Table 6 Acquisition cost of inhaled loxapine compared to other frequently used medications for the treatment of agitation based on a survey of five independent health care organizations in Pennsylvania, New Jersey, and New York (by the authors, March 2019)\n\nMedication a\tMean cost in US dollars (range if applicable)\t\nInhaled Loxapine 10 mg\t$140\t\nZiprasidone 20 mg\t$38.97 ($21.22–$46.99)\t\nOlanzapine 10 mg\t$33.68 ($19.85–$42.20)\t\nHaloperidol 5 mg\t$0.83 ($0.57–$1.18)\t\nHaloperidol 10 mg\t$1.67 ($1.14–$2.35)\t\nLorazepam 2 mg\t$0.90 ($0.46–$1.79)\t\nNote:\naIntramuscular unless otherwise specified.\n\n\n\n\nDiscussion\nAn ideal medication for the treatment of agitation would be efficacious, tolerable, non-painful, and have a rapid onset of action. Inhaled loxapine plays a unique role due to its novel delivery system. Because of its administration through the deep lung, inhaled loxapine is rapidly absorbed into the systemic circulation, resulting in a near immediate onset of action, with comparable efficacy to the intramuscular formulations of ziprasidone, olanzapine, haloperidol, aripiprazole, and lorazepam. The stigma and pain associated with the emergency use of short-acting intramuscular medication can be avoided with the use of inhaled loxapine. Thus, inhaled loxapine is a promising treatment for acute agitation secondary to schizophrenia and bipolar mania. Inhaled loxapine has also been utilized “off-label” in agitated patients with a borderline personality disorder, dual diagnosis (defined as concomitant psychiatric and substance use disorders), weaning from ventilation, electroconvulsive therapy pretreatment, and child and adolescent psychiatric conditions.45–49\n\nHowever, like any treatment, there are drawbacks to inhaled loxapine. Loxapine has higher rates of dysgeusia and throat irritation when compared to placebo. As it is absorbed through the respiratory system, it is more likely to cause pulmonary adverse effects. Inhaled loxapine carries a black box warning for bronchospasm, and is contraindicated in those with pulmonary disease. The rate of bronchospasm (includes wheezing, cough, shortness of breath) is 37% (19/52) in patients with COPD or asthma, but only 0.8% (2/259) in patients without pulmonary disease receiving 10 mg loxapine.3,41 Of note, all airway adverse events in persons with schizophrenia or bipolar disorder were considered mild or moderate in severity, and smoking did not increase the risk of bronchospasm.\n\nInhaled loxapine may not be appropriate for some patients with severe levels of agitation because administering loxapine is a collaborative process, requiring patient cooperation. In persons already aggressive, or severely agitated and unable or unwilling to cooperate with an inhaled medication, intramuscular medication remains the first-line treatment.\n\nConclusion\nAgitation is a clinical condition of paramount importance, and inhaled loxapine represents a new treatment option with a novel delivery system, resulting in the rapid onset of action without the need for injection. Patient satisfaction scores are high with comparable efficacy to existing treatment options. Inhaled loxapine has a prominent warning for bronchospasm and in the US requires a REMS program for use. In the US, inhaled loxapine is restricted to health care facilities with access to interventions and personnel trained to manage acute bronchospasm. Inhaled loxapine is not appropriate for all patients and is contraindicated in patients with a diagnosis of asthma, COPD, any other lung disease associated with bronchospasm, or any current acute respiratory symptoms. Additionally, as it requires patient cooperation to administer, it may not be appropriate for persons exhibiting severe levels of agitation. In considering the advantages and disadvantages, inhaled loxapine is a welcome addition to the armamentarium of pharmacologic options for patients with agitation secondary to schizophrenia or bipolar mania, and may be an ideal option for a subgroup of agitated patients.\n\nDisclosure\nLeslie Citrome was a consultant for and received personal fees from: Acadia, Alkermes, Allergan, Indivior, Intra-Cellular Therapeutics, Janssen, Lundbeck, Merck, Neurocrine, Noven, Osmotica, Otsuka, Pfizer, Shire, Sunovion, Takeda, Teva, and Vanda in the past 12 months. He was also a speaker for and received personal fees from: Acadia, Alkermes, Allergan, Janssen, Lundbeck, Merck, Neurocrine, Otsuka, Pfizer, Shire, Sunovion, Takeda, and Teva. He owns small number of shares of common stock from Bristol-Myers Squibb, Eli Lilly, J & J, Merck, Pfizer and received royalties from Wiley as the Editor-in-Chief, International Journal of Clinical Practice, UpToDate as the reviewer, and Springer Healthcare (published a book), outside the submitted work. The authors report no other conflicts of interest in this work.\n==== Refs\nReferences\n1. Allen \nMH , Currier \nGW . Use of restraints and pharmacotherapy in academic psychiatric emergency services . Gen Hosp Psychiatry . 2004 ;26 (1 ):42 –49 . doi:10.1016/j.genhosppsych.2003.08.002 14757302 \n2. Garriga \nM , Pacchiarotti \nI , Kasper \nS , et al. Assessment and management of agitation in psychiatry: expert consensus . World J Biol Psychiatry . 2016 ;17 (2 ):86 –128 . doi:10.3109/15622975.2015.1132007 26912127 \n3. Citrome \nL . 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Jorgensen \nTR , Emborg \nC , Dahlen \nK , Bogelund \nM , Carlborg \nA . The effect of the medicine administration route on health-related quality of life: results from a time trade-off survey in patients with bipolar disorder or schizophrenia in 2 Nordic countries . BMC Psychiatry . 2016 ;16 :244-016-0930-6 . doi:10.1186/s12888-016-0930-6 \n45. Kahl \nKG , Negt \nP , Wollmer \nA , Jung \nS , Kruger \nTH . Inhaled loxapine for acute treatment of agitation in patients with borderline personality disorder: a case series . J Clin Psychopharmacol . 2015 ;35 (6 ):741 –743 . doi:10.1097/JCP.0000000000000402 26448403 \n46. Roncero \nC , Ros-Cucurull \nE , Grau-Lopez \nL , Fadeuilhe \nC , Casas \nM . Effectiveness of Inhaled Loxapine in dual-diagnosis patients: a case series . Clin Neuropharmacol . 2016 ;39 (4 ):206 –209 . doi:10.1097/WNF.0000000000000153 27015036 \n47. Sztrymf \nB , Chevrel \nG , Bertrand \nF , et al. 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"issue": "15()",
"journal": "Neuropsychiatric disease and treatment",
"keywords": "agitation; antipsychotic; bipolar disorder; inhaled loxapine; mania; schizophrenia",
"medline_ta": "Neuropsychiatr Dis Treat",
"mesh_terms": null,
"nlm_unique_id": "101240304",
"other_id": null,
"pages": "2273-2283",
"pmc": null,
"pmid": "31496709",
"pubdate": "2019",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "10623971;14757302;14987333;15278098;16432443;16848689;17414241;17943763;18162018;19915181;20459867;20528148;21199198;21200077;21294997;22226343;22329470;22461918;23538290;23723707;23739987;24375070;24606117;24745666;2576319;25859275;26439438;26448403;26501204;26912127;26973742;27015036;27421880;28208695;28510296;29163985;29535649;29661160;29724638;30747748;8103793;8500919;8524985;8580115;9356559",
"title": "Examining the safety, efficacy, and patient acceptability of inhaled loxapine for the acute treatment of agitation associated with schizophrenia or bipolar I disorder in adults.",
"title_normalized": "examining the safety efficacy and patient acceptability of inhaled loxapine for the acute treatment of agitation associated with schizophrenia or bipolar i disorder in adults"
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{
"companynumb": "US-OTSUKA-2019_032213",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
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"activesubstancename": "ARIPIPRAZOLE"
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{
"abstract": "Pustulosis acuta generalisata is an uncommon condition characterized by scattered symmetrical eruption of sterile pustules associated with elevated inflammatory markers, leukocytosis, fever and arthropathy caused by previous infection by group A streptococci (GAS). We reported here a case of pustulosis acuta generalisata in an HIV-positive patient recently treated with chemotherapy for a seminoma.",
"affiliations": "San Raffaele Scientific Institute, Department of Infectious Diseases, Milano, Italy.",
"authors": "Ripa|Marco|M|;Chiappetta|Stefania|S|;Nozza|Silvia|S|",
"chemical_list": "D000900:Anti-Bacterial Agents; D019980:Amoxicillin-Potassium Clavulanate Combination",
"country": "England",
"delete": false,
"doi": "10.1177/0956462413491080",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0956-4624",
"issue": "24(12)",
"journal": "International journal of STD & AIDS",
"keywords": "AIDS; Europe; HIV; Human immunodeficiency virus; Pustulosis acuta generalisata; antiretroviral therapy; diagnosis; toxicity",
"medline_ta": "Int J STD AIDS",
"mesh_terms": "D056150:Acute Generalized Exanthematous Pustulosis; D000328:Adult; D019980:Amoxicillin-Potassium Clavulanate Combination; D000900:Anti-Bacterial Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D015658:HIV Infections; D006801:Humans; D008297:Male; D018239:Seminoma; D013290:Streptococcal Infections; D013297:Streptococcus pyogenes; D013736:Testicular Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "9007917",
"other_id": null,
"pages": "980-2",
"pmc": null,
"pmid": "23970624",
"pubdate": "2013-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pustulosis acuta generalisata following chemotherapy in an HIV-positive patient.",
"title_normalized": "pustulosis acuta generalisata following chemotherapy in an hiv positive patient"
} | [
{
"companynumb": "IT-PFIZER INC-2014030913",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FLUCONAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nHeparin is widely used to prevent clotting of the extracorporeal circuit during haemodialysis (HD). Heparin-induced thrombocytopenia (HIT) is a potentially devastating immune mediated adverse drug reaction caused by the emergence of antibodies that activate platelets in the presence of heparin, leading to a pro-thrombotic state. Danaparoid is an alternative anticoagulant used in patients on HD with HIT but its dosing recommendations in obese patients on HD are relatively scarce.\n\n\nMETHODS\nWe report a case of a 48-year-old morbidly obese patient who received weight-based dosing of danaparoid for HD with monitoring of anti-Xa activity. However, despite the patient's anti-Xa level being within the therapeutic range at various time points, the circuit lines kept clotting during HD.\n\n\nCONCLUSIONS\nThe report provides evidence that the manufacturer's recommendations on dosing danaparoid based on body weight may lead to sub-optimal therapeutic benefit and highlight the need for higher than recommended weight-based dosing in obese individuals on dialysis.",
"affiliations": "Faculty of Medicine and Health, University of Sydney, NSW 2006, Australia; Blacktown Hospital, Western Sydney Local Health District (WSLHD), NSW 2148, Australia. Electronic address: ronald.castelino@sydney.edu.au.;Blacktown Hospital, Western Sydney Local Health District (WSLHD), NSW 2148, Australia.;Blacktown Hospital, Western Sydney Local Health District (WSLHD), NSW 2148, Australia; Western Sydney University Medical School, Australia.;Faculty of Medicine and Health, University of Sydney, NSW 2006, Australia; Blacktown Hospital, Western Sydney Local Health District (WSLHD), NSW 2148, Australia; Nepean Blue Mountains Local Health District, Australia.;Blacktown Hospital, Western Sydney Local Health District (WSLHD), NSW 2148, Australia; Western Sydney University Medical School, Australia.",
"authors": "Castelino|Ronald L|RL|;Maddula|Meghana|M|;Tarafdar|Surjit|S|;Sud|Kamal|K|;Kairaitis|Lukas|L|",
"chemical_list": "D000925:Anticoagulants; D003871:Dermatan Sulfate; D006493:Heparin; D002809:Chondroitin Sulfates; D006497:Heparitin Sulfate; C035838:danaparoid",
"country": "United States",
"delete": false,
"doi": "10.1016/j.thromres.2019.06.008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0049-3848",
"issue": "180()",
"journal": "Thrombosis research",
"keywords": "Danaparoid; Haemodialysis; Heparin-induced thrombocytopenia; Obesity",
"medline_ta": "Thromb Res",
"mesh_terms": "D000925:Anticoagulants; D002809:Chondroitin Sulfates; D003871:Dermatan Sulfate; D004305:Dose-Response Relationship, Drug; D005260:Female; D006493:Heparin; D006497:Heparitin Sulfate; D006801:Humans; D009767:Obesity, Morbid; D006435:Renal Dialysis; D013921:Thrombocytopenia; D013927:Thrombosis",
"nlm_unique_id": "0326377",
"other_id": null,
"pages": "70-73",
"pmc": null,
"pmid": "31229923",
"pubdate": "2019-08",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "Danaparoid use for haemodialysis in a morbidly obese patient with heparin-induced thrombocytopenia - Need for a higher than recommended weight-based dosing.",
"title_normalized": "danaparoid use for haemodialysis in a morbidly obese patient with heparin induced thrombocytopenia need for a higher than recommended weight based dosing"
} | [
{
"companynumb": "AU-PFIZER INC-2019276196",
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"activesubstancename": "WARFARIN"
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... |
{
"abstract": "Abiraterone is an agent effective for castration-resistant prostate cancer, but there have been no reports of cardiotoxic effects inducing cardiomyopathy, to our knowledge. We present a case of an 86-year-old man with castration-resistant prostate cancer treated with abiraterone. He had received an androgen receptor antagonist (bicalutamide) and a gonadotropin-releasing hormone antagonist (degarelix) for 3 years. These agents were changed to enzalutamide due to elevation of plasma prostate-specific antigen level of 129 ng/mL. One year later, the oral androgen receptor inhibitor (enzalutamide) caused drug-induced lung injury and was changed to abiraterone. Transthoracic echocardiography (TTE) revealed normal left ventricular systolic function, and left ventricular ejection fraction (LVEF) was 67%. Four weeks after administration of abiraterone, he complained of dyspnea on effort and bilateral leg edema, and he was diagnosed with heart failure. TTE showed hypokinesis of the diffuse LV, and LVEF decreased to 45%. The various causes of heart failure were excluded. Since a cardiotoxic effect of abiraterone was suspected, administration of abiraterone was discontinued. Two weeks after cessation of abiraterone, LVEF ameliorated to 57%, and then 5 months after cessation of abiraterone, LVEF further improved to 65%. To our knowledge, this is the first report of definite cancer therapeutics-related cardiac dysfunction due to a hormonal agent such as abiraterone diagnosed according to the American Society of Echocardiography and European Association of Cardiovascular Imaging criteria.",
"affiliations": "Department of Cardiology, Federation of National Public Service Personnel Mutual Aid Association Tachikawa Hospital, 4-2-22, Nishiki, Tachikawa, Tokyo, 190-8531, Japan. tsugu.z7@keio.jp.;Department of Cardiology, National Defense Medical College Hospital, Tokorozawa, 359-8513, Japan.;Department of Cardiology, Federation of National Public Service Personnel Mutual Aid Association Tachikawa Hospital, 4-2-22, Nishiki, Tachikawa, Tokyo, 190-8531, Japan.;Department of Cardiology, Federation of National Public Service Personnel Mutual Aid Association Tachikawa Hospital, 4-2-22, Nishiki, Tachikawa, Tokyo, 190-8531, Japan.;Department of Urology, Federation of National Public Service Personnel Mutual Aid Association Tachikawa Hospital, Tachikawa, 190-8531, Japan.;Department of Cardiology, School of Medicine, Keio University, Tokyo, 160-8582, Japan.;Department of Cardiology, School of Medicine, Keio University, Tokyo, 160-8582, Japan.;Center for Preventive Medicine, School of Medicine, Keio University, Tokyo, 160-8582, Japan.;Department of Cardiology, Federation of National Public Service Personnel Mutual Aid Association Tachikawa Hospital, 4-2-22, Nishiki, Tachikawa, Tokyo, 190-8531, Japan.",
"authors": "Tsugu|Toshimitsu|T|http://orcid.org/0000-0002-3399-8757;Nagatomo|Yuji|Y|;Nakajima|Yuki|Y|;Kageyama|Toshimi|T|;Akise|Yushi|Y|;Endo|Jin|J|;Itabashi|Yuji|Y|;Murata|Mitsushige|M|;Mitamura|Hideo|H|",
"chemical_list": "D000736:Androstenes; D000970:Antineoplastic Agents; D017430:Prostate-Specific Antigen; C089740:abiraterone",
"country": "Japan",
"delete": false,
"doi": "10.1007/s10396-018-0897-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1346-4523",
"issue": "46(2)",
"journal": "Journal of medical ultrasonics (2001)",
"keywords": "Cardiac toxicity; Cardio-oncology; Chemotherapy; Echocardiography; Hormonal therapy",
"medline_ta": "J Med Ultrason (2001)",
"mesh_terms": "D000369:Aged, 80 and over; D000736:Androstenes; D000970:Antineoplastic Agents; D018450:Disease Progression; D057915:Drug Substitution; D006333:Heart Failure; D006801:Humans; D008297:Male; D017430:Prostate-Specific Antigen; D064129:Prostatic Neoplasms, Castration-Resistant; D016896:Treatment Outcome",
"nlm_unique_id": "101128385",
"other_id": null,
"pages": "239-243",
"pmc": null,
"pmid": "30151629",
"pubdate": "2019-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19375626;22995653;23084528;25172399;25239940;25601341;9761805",
"title": "Cancer therapeutics-related cardiac dysfunction in a patient treated with abiraterone for castration-resistant prostate cancer.",
"title_normalized": "cancer therapeutics related cardiac dysfunction in a patient treated with abiraterone for castration resistant prostate cancer"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-206440",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ABIRATERONE ACETATE"
},
... |
{
"abstract": "Cervical cancer is the most common gynecological cancer occurring in pregnancy, creating a complex situation both for patient and physician. Neoadjuvant chemotherapy is an innovative way of managing cervical cancer in pregnancy.\n\n\n\nIn our paper, we report a retrospective case series of 4 women treated with chemotherapy for invasive cervical cancer during pregnancy in our center over the last 5 years, and we summarize the available literature and guidelines.\n\n\n\nAll the cases were locally advanced cervical cancers that received chemotherapy with platinum and/or taxanes. All patients showed a good response to chemotherapy and a radical surgery was performed with no additional morbidities at the cesarean delivery time in 3 of 4 cases. Three of 4 patients are alive and have a good outcome with no recurrence of disease up to date. One patient died because of recurrent disease 2 years after the first-line treatment during pregnancy. All babies are alive and well up to date (maximum follow-up, 63 months).\n\n\n\nEven if there are no standardized practices in the treatment of cervical cancer in pregnancy, in our opinion, neoadjuvant chemotherapy can be a very useful strategy for patients and physicians facing the challenge.",
"affiliations": "Polo Salute della Donna e del Bambino, Fondazione Policlinico Universitario \"A. Gemelli,\" Division of Gynecologic Oncology, Catholic University of the Sacred Heart, Rome, Italy.",
"authors": "Ricci|Caterina|C|;Scambia|Giovanni|G|;De Vincenzo|Rosa|R|",
"chemical_list": "D017239:Paclitaxel; D002945:Cisplatin",
"country": "England",
"delete": false,
"doi": "10.1097/IGC.0000000000000795",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1048-891X",
"issue": "26(8)",
"journal": "International journal of gynecological cancer : official journal of the International Gynecological Cancer Society",
"keywords": null,
"medline_ta": "Int J Gynecol Cancer",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin; D005260:Female; D006801:Humans; D020360:Neoadjuvant Therapy; D017239:Paclitaxel; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic; D011256:Pregnancy Outcome; D012189:Retrospective Studies; D002583:Uterine Cervical Neoplasms",
"nlm_unique_id": "9111626",
"other_id": null,
"pages": "1490-6",
"pmc": null,
"pmid": "27575627",
"pubdate": "2016-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Locally Advanced Cervical Cancer in Pregnancy: Overcoming the Challenge. A Case Series and Review of the Literature.",
"title_normalized": "locally advanced cervical cancer in pregnancy overcoming the challenge a case series and review of the literature"
} | [
{
"companynumb": "IT-ACCORD-064310",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
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{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
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"drugadditional": null,
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{
"abstract": "Gynecomastia is a common finding in males, with an incidence that varies widely globally. In 10-25% of cases, it is caused by drugs. Its pathophysiologic mechanism includes exposure to exogenous estrogens and medications that cause hypogonadism, antiandrogenic effects and hyperprolactinemia. Gynecomastia is associated with exposure to antiretroviral therapy (ART), particularly efavirenz. Sometimes surgery may be required as treatment. We report a case of a 46-year-old man receiving ART presenting with a marked bilateral breast enlargement who underwent bilateral mastectomy as the only successful treatment in a low-income setting.",
"affiliations": "Department of Surgery, Central Hospital of Beira, Beira, Mozambique.;Department of Emergency and Organ Transplantation, Section of Thoracic Surgery, University of Bari \"Aldo Moro\", Bari, Italy.;Operational Research Unit, Doctors with Africa CUAMM, Rua Fernao Mendes Pinto 165, Ponta Gea, 1363, Beira, Mozambique. d.pizzol@cuamm.org.;Clinic of Infection Diseases, University of Bari \"Aldo Moro\", Bari, Italy.;Plastic Surgery Consultant Emergency Department, Mater Dei Hospital, Bari, Italy.;Department of Emergency and Organ Transplantation, Section of Thoracic Surgery, University of Bari \"Aldo Moro\", Bari, Italy.",
"authors": "Antunes|Mario|M|;Schiavone|Marcella|M|;Pizzol|Damiano|D|http://orcid.org/0000-0003-4122-0774;Di Gennaro|Francesco|F|;Ludovico|Rossana|R|;De Palma|Angela|A|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1007/s40800-018-0085-0",
"fulltext": "\n==== Front\nDrug Saf Case RepDrug Saf Case RepDrug Safety - Case Reports2199-11622198-977XSpringer International Publishing Cham 297526348510.1007/s40800-018-0085-0Case ReportBilateral Mastectomy as Radical Treatment of Gynecomastia Secondary to Antiretroviral Therapy in a Low-Income Setting: A Case Report Antunes Mario 1Schiavone Marcella 23http://orcid.org/0000-0003-4122-0774Pizzol Damiano d.pizzol@cuamm.org 3Di Gennaro Francesco 4Ludovico Rossana 5De Palma Angela 21 Department of Surgery, Central Hospital of Beira, Beira, Mozambique 2 0000 0001 0120 3326grid.7644.1Department of Emergency and Organ Transplantation, Section of Thoracic Surgery, University of Bari “Aldo Moro”, Bari, Italy 3 Operational Research Unit, Doctors with Africa CUAMM, Rua Fernao Mendes Pinto 165, Ponta Gea, 1363 Beira, Mozambique 4 0000 0001 0120 3326grid.7644.1Clinic of Infection Diseases, University of Bari “Aldo Moro”, Bari, Italy 5 Plastic Surgery Consultant Emergency Department, Mater Dei Hospital, Bari, Italy 11 5 2018 11 5 2018 12 2018 5 21© The Author(s) 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial 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.Gynecomastia is a common finding in males, with an incidence that varies widely globally. In 10–25% of cases, it is caused by drugs. Its pathophysiologic mechanism includes exposure to exogenous estrogens and medications that cause hypogonadism, antiandrogenic effects and hyperprolactinemia. Gynecomastia is associated with exposure to antiretroviral therapy (ART), particularly efavirenz. Sometimes surgery may be required as treatment. We report a case of a 46-year-old man receiving ART presenting with a marked bilateral breast enlargement who underwent bilateral mastectomy as the only successful treatment in a low-income setting.\n\nissue-copyright-statement© The Author(s) 2018\n==== Body\nKey Points\n\nOne possible adverse drug effect of antiretroviral treatments, especially efavirenz, is male gynecomastia.\t\nThe development of prevention and early diagnosis strategies is crucial to improve treatment and patient health and to reduce health costs, especially in low-income countries given the large number of patients with HIV in these countries.\t\nSurgery can be a solution, especially in low-income countries facing late-stage disease and a lack of specialized health professionals and equipment.\t\n\n\n\nIntroduction\nGynecomastia is the enlargement of male breast tissue in men and is frequently observed in newborns, adolescents, and older men [1].\n\nIt should be differentiated from breast carcinoma and pseudogynecomastia, which is characterized by fat deposition without glandular proliferation.\n\nPhysiological gynecomastia, occurring in almost 25% of cases, is benign and self-limiting; this type is observed especially in young men, up to 65% of adolescents [2].\n\nHowever, several conditions, such as the use of narcotic substances and drugs may induce proliferation of male breast tissue. Moreover, true gynecomastia is a common feature often related to estrogen excess, androgen deficiency, and a high elevation of sex hormone-binding globuline (SHBG) as a consequence of different endocrine disorders [3]. Non-endocrine illnesses, including liver failure, chronic kidney disease, and drug side effects [1], may also cause gynecomastia.\n\nDrug-induced gynecomastia particularly merits deep consideration as it may account for as many as 25% of all cases of gynecomastia in adults. Although the mechanism is not fully clear, it may include estrogen-like activities, stimulation of testicular production of estrogens, inhibition of testosterone synthesis or blockade of androgen action. Anabolic steroids, particularly when used during the pubertal stage, may cause significant irreversible gynecomastia [4]. The pathophysiologic mechanism includes exposure to exogenous estrogens and medications that cause hypogonadism, antiandrogenic effects, and hyperprolactinemia [5].\n\nDrugs definitely associated with the onset of gynecomastia are spironolactone, cimetidine, ketoconazole, human growth hormone (hGH), estrogens, human chorionic gonadotropin (hCG), antiandrogens, gonadotropin-releasing hormone (GnRH) analogs, and 5-α reductase inhibitors. Other drug classes seem to be protease inhibitors, and nucleoside reverse transcriptase inhibitors, although their association with gynecomastia is based on poor-quality evidence [6]. Finally, drugs probably associated with gynecomastia include risperidone, verapamil, nifedipine, omeprazole, alkylating agents, HIV therapies, anabolic steroids, alcohol, and opioids [7].\n\nEfavirenz is the antiretroviral treatment (ART) most clearly associated with gynecomastia as a possible adverse drug reaction, especially with prolonged exposure [8].\n\nWe report a case of advanced-stage ART-related gynecomastia, treated with surgery and managed with satisfying results in a low-income setting.\n\nCase Report\nA 46-year-old man was admitted to Beira Central Hospital (Mozambique) with marked bilateral breast enlargement (Fig. 1). He was HIV positive, had been receiving ART (tenofivir/lamivudine/efavirenz 300 mg) for the past 5 years and reported gradual breast growth over the last year. Previous diseases were unremarkable, he was in good general condition, and his vital parameters were normal. Although he had lived for many months with the discomfort of this condition, he decided to treat the disease only after consultation with a traditional healer, and after it caused marked stigmata. He had no other signs and symptoms such as nipple discharge, bleeding, or breast pain.Fig. 1 46-year-old HIV-positive man with gynecomastia due to antiretroviral (ART) with tenofivir/lamivudine/efavirenz admitted to Beira Central Hospital (Mozambique) and successfully treated with bilateral mastectomy\n\n\n\nWe were unable to perform specific laboratory tests such as those for sex hormones and tumor markers, so, after clinical examination and excluding other main causes, such as seminoma, liver diseases, and malnutrition, we clinically hypothesized the diagnosis of gynecomastia associated with ART.\n\nDiscontinuation of HIV therapy was not feasible, and the risk of recurrence with surgical undercorrection had to be avoided. Thus, a mastectomy, with double incision approach and nipple–areola complex (NAC) free transplantation, was proposed to the patient as radical treatment of his severe bilateral gynecomastia.\n\nPre-operative routine laboratory tests were normal: CD4 count 440/mm3.\n\nThe patient’s chest characteristics and proportions were considered preoperatively, and the breasts were marked in a standing position: any side of lipodystrophy was noted in the patient’s slim chest, no atypical thoracic conformation was detected, and severe bilateral hypertrophy with little asymmetry was noted in the context of a Simon III gynecomastia.\n\nThe NAC was removed as a full-thickness graft, trimmed to 2.5 cm and preserved in wet gauze until the end of the mastectomy. The mammary pocket was cleaned, and hemostasis was checked. The excess skin was removed, and the inframammary fold was closed in layers over a drain. Finally, the NAC was placed and fixed onto a de-epithelialized bed previously marked symmetrically on the chest so the new nipple–sternal notch distance was 15 cm bilaterally.\n\nThe removed specimens weighed 1.5 kg (right) and 1.7 kg (left).\n\nPostoperative antibiotics and analgesics (amoxicillin and clavulanic acid 1000 mg every 8 h and ibuprofen 600 mg every 8 h) were administered, and a moulage compressive dressing with non-stick gauze was maintained on the wounds for 3 days. The drain was then removed, and the patient was discharged on the fifth postoperative day without any complication. Compressive dressing of the wounds for 2 weeks was recommended. The patient continued with the same ART drugs and dosage. Although all instructions were given to the patient with a recommendation to return for follow-up, he never did so.\n\nHistopathological examination confirmed the clinical diagnosis of gynecomastia, reporting epithelial and ductal cells and myxoid stroma.\n\nDiscussion\nIn low-income settings, it is common to be faced with extreme and late-stage diseases, with consequent management difficulties and negative outcomes. In fact, in these contexts, healthcare must deal with many sociocultural aspects such as superstitions and (often misinformed) traditional healers turning patients away from conventional medicine. Moreover, people are often reluctant to refer to conventional doctors because of the risk of stigma and marginalization in doing so.\n\nWe reported a case of gynecomastia in a patient receiving ART for HIV. The weak healthcare system, poor-quality infrastructure and equipment, and limited tests and diagnostic procedures available to us meant an accurate diagnosis was impossible. However, given the clinical features and histopathological examination, we excluded other causes and, based on the literature, we concluded this case was ART related.\n\nThe management of this patient represented a challenge, most of all due to the delay before treatment, which led to physical, social, and psychological disability, reducing the chance of optimal results. For our patient, surgery represented the only therapeutic possibility, so we performed a bilateral mastectomy. We did not perform a reductive mastoplasty, even though it would have been aesthetically more suitable, because of the risk of glandular residue that with therapy would have again hypertrophied. The procedure we performed has already been reported in the literature as treatment for gynecomastia, with satisfactory results [9]. In this case, the mastectomy procedure was not difficult because of the well-delineated surgical plans and well-defined glandular tissue, which did not trespass into the pectoral regions or beyond the anterior axillary line.\n\nThe other big challenge in this case was the follow-up. In fact, the patient did not return for regular follow-up, which is common behavior in low-income settings, particularly when there are no complications. On the other hand, it was not possible to perform appropriate biochemical evaluation, including sex hormones, for adequate post-operative follow-up from an endocrine point of view.\n\nConclusion\nOur approach to this case of gynecomastia was successful and effective, resulting in a satisfied patient, despite the extreme condition of the disease presentation. However, in low-income settings, it is crucial that the health system be strengthened in terms of both healthcare and prevention. In fact, if further studies confirm the frequent association between ART and gynecomastia, given the high prevalence of patients with HIV worldwide, it is crucial that prevention and early diagnosis strategies are developed to improve treatment and patient health and reduce health costs.\n\nFunding\nNo financial support was received for the conduct of this study or preparation of this manuscript.\n\nAcknowledgements\nThe authors are very grateful to Dr. Pelizzon Alessandro of the School of Law and Justice, Southern Cross University, East Lismore, NSW 2480, Australia, for his kind and careful editing.\n\nConflict of interest\nMario Antunes, Marcella Schiavone, Damiano Pizzol, Francesco Di Gennaro, Rossana Ludovico, and Angela De Palma have no conflicts of interest.\n\nInformed consent\nThe patient provided written informed consent to publish this case report and any accompanying images. A copy of the written consent may be requested for review from the corresponding author.\n==== Refs\nReferences\n1. Sansone A Romanelli F Sansone M Lenzi A Di Luigi L Gynecomastia and hormones Endocrine 2017 55 1 37 44 10.1007/s12020-016-0975-9 27145756 \n2. Paris F Gaspari L Mbou F Philibert P Audran F Morel Y Biason-Lauber A Sultan C Endocrine and molecular investigations in a cohort of 25 adolescent males with prominent/persistent pubertal gynecomastia Andrology 2016 4 2 263 269 10.1111/andr.12145 26845730 \n3. Czajka-Oraniec I Zgliczyński W Phenotype of patients with gynecomastia Endokrynol Pol 2008 59 2 131 139 18465688 \n4. Lo TE Andal ZC Lantion-Ang FL Fluoxymesterone-induced gynaecomastia in a patient with childhood aplastic anaemia BMJ Case Rep 2015 6 2015 \n5. Eckman A Dobs A Drug-induced gynecomastia Expert Opin Drug Saf 2008 7 6 691 702 10.1517/14740330802442382 18983216 \n6. Bowman JD Kim H Bustamante JJ Drug-induced gynecomastia Pharmacotherapy 2012 32 12 1123 1140 10.1002/phar.1138 23165798 \n7. Deepinder F Braunstein GD Drug-induced gynecomastia: an evidence-based review Expert Opin Drug Saf 2012 11 5 779 795 10.1517/14740338.2012.712109 22862307 \n8. Njuguna C Swart A Blockman M Maartens G Chisholm B Stewart A Uys A Cohen K Cases of antiretroviral-associated gynaecomastia reported to the National HIV & Tuberculosis Health Care Worker Hotline in South Africa AIDS Res Ther 2016 13 40 10.1186/s12981-016-0121-z 27891161 \n9. Muneer A Laghari ZH Shaikh AR Laghari QA Gynaecomastia: management in a developing country J Ayub Med Coll Abbottabad 2009 21 3 7 11 20929002\n\n",
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"issue": "5(1)",
"journal": "Drug safety - case reports",
"keywords": null,
"medline_ta": "Drug Saf Case Rep",
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"nlm_unique_id": "101674544",
"other_id": null,
"pages": "21",
"pmc": null,
"pmid": "29752634",
"pubdate": "2018-05-11",
"publication_types": "D016428:Journal Article",
"references": "23165798;27891161;18983216;22862307;25948845;26845730;20929002;27145756;18465688",
"title": "Bilateral Mastectomy as Radical Treatment of Gynecomastia Secondary to Antiretroviral Therapy in a Low-Income Setting: A Case Report.",
"title_normalized": "bilateral mastectomy as radical treatment of gynecomastia secondary to antiretroviral therapy in a low income setting a case report"
} | [
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"companynumb": "MZ-LANNETT COMPANY, INC.-MZ-2018LAN000892",
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"abstract": "Autoimmune cytopenias (AC) after allogeneic hematopoietic stem cell transplantation (HSCT) are associated with a dismal prognosis. We describe a 1-year-old female with multi-lineage AC occurring on day +43 after HSCT. Multi-agent treatment with high-dose prednisolone, intravenous immunoglobulins, cyclosporine A, mycophenolate mofetil, sirolimus, and rituximab was unsuccessful. Combined treatment with bortezomib and vincristine in addition to ongoing immunosuppressive therapy was started on day +414 with transfusion-independence after day +444. Immunosuppressants were tapered until day +638. On day +1,121 the patient remained in remission. Bortezomib with vincristine may be a promising treatment modality for refractory AC after HSCT that requires further study.",
"affiliations": "Division of Stem Cell Transplantation (SCT), University Children's Hospital, Zurich, Switzerland.",
"authors": "Waespe|Nicolas|N|;Zeilhofer|Ulrike|U|;Güngör|Tayfun|T|",
"chemical_list": "D001897:Boronic Acids; D007166:Immunosuppressive Agents; D011719:Pyrazines; D014750:Vincristine; D000069286:Bortezomib",
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"issue": "61(11)",
"journal": "Pediatric blood & cancer",
"keywords": "Evans syndrome; bortezomib; cord blood; pediatric hematology/oncology; stem cell transplantation; vincristine",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D001897:Boronic Acids; D000069286:Bortezomib; D036101:Cord Blood Stem Cell Transplantation; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D007223:Infant; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D016553:Purpura, Thrombocytopenic, Idiopathic; D011719:Pyrazines; D014750:Vincristine",
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"title": "Treatment-refractory multi-lineage autoimmune cytopenia after unrelated cord blood transplantation: remission after combined bortezomib and vincristine treatment.",
"title_normalized": "treatment refractory multi lineage autoimmune cytopenia after unrelated cord blood transplantation remission after combined bortezomib and vincristine treatment"
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"abstract": "We report the first case of Acrophialophora levis causing cerebral phaeohyphomycosis in a solid organ transplantation recipient. A. levis is a rare cause of invasive dematiaceous fungal infection among immunocompromised persons. We describe the clinical course of a kidney transplant patient who presented with acute hemiplegia due to a brain abscess from which A. levis was isolated. We review published clinical cases attributed to Acrophialophora species infection and discuss current limitations in its identification, diagnosis and management.",
"affiliations": "Department of Medicine, Emory University School of Medicine, Atlanta, GA, 30322, United States.;Department of Medicine, Emory University School of Medicine, Atlanta, GA, 30322, United States.;Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, United States.;Mycotic Diseases Branch, Centers for Disease Control and Prevention, Atlanta, GA, 30333, United States.;Department of Medicine, Emory University School of Medicine, Atlanta, GA, 30322, United States.",
"authors": "Modlin|Chelsea E|CE|;Collins|Lauren F|LF|;Burd|Eileen M|EM|;Lockhart|Shawn R|SR|;Marshall Lyon|G|G|",
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"fulltext": "\n==== Front\nMed Mycol Case Rep\nMed Mycol Case Rep\nMedical Mycology Case Reports\n2211-7539 Elsevier \n\nS2211-7539(20)30016-6\n10.1016/j.mmcr.2020.03.002\nCase Report\nAcrophialophora levis brain abscess in a kidney transplant patient: A case report and review of the literature\nModlin Chelsea E. a Collins Lauren F. a Burd Eileen M. b Lockhart Shawn R. c Marshall Lyon G. gmlyon@emory.edua* a Department of Medicine, Emory University School of Medicine, Atlanta, GA, 30322, United States\nb Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, United States\nc Mycotic Diseases Branch, Centers for Disease Control and Prevention, Atlanta, GA, 30333, United States\n* Corresponding author. gmlyon@emory.edu\n10 3 2020 \n6 2020 \n10 3 2020 \n28 12 15\n26 1 2020 2 3 2020 5 3 2020 © 2020 The Authors2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).We report the first case of Acrophialophora levis causing cerebral phaeohyphomycosis in a solid organ transplantation recipient. A. levis is a rare cause of invasive dematiaceous fungal infection among immunocompromised persons. We describe the clinical course of a kidney transplant patient who presented with acute hemiplegia due to a brain abscess from which A. levis was isolated. We review published clinical cases attributed to Acrophialophora species infection and discuss current limitations in its identification, diagnosis and management.\n\nKeywords\nAcrophialophora levisPhaeohyphomycosisBrain abscessImmunocompromised hostKidney transplantation\n==== Body\n1 Introduction\nThe Acrophialophora genus are thermotolerant fungi found in the soil of temperate and tropical regions [1]. There are now three recognized species: A. fusispora, A. levis, A. nainiana. Earlier reports of Acrophialophora classified all as A. fusispora based on morphology [2]. However, a recent sequencing analysis of Acrophialophora isolates found that while the three species are 99.9% homologous in large subunit ribosomal DNA, differences in internal transcribed spacer (ITS) and β-tubulin allow for species-level discrimination [3]. Acrophialophora form white colonies on culture media that age to grey/brown with a “black reverse.” This distinguishing feature of dematiaceous, or pigmented, molds is attributed to melanin-laden cell walls [1].\n\nDematiaceous molds are considered opportunistic pathogens and therefore rare entities of clinical disease. However, their epidemiology is evolving in the era of transplantation medicine and use of immunosuppressants for autoimmune and other conditions. Among a growing population of chronically immunocompromised patients, the prevalence of dematiaceous fungal infections, globally termed “phaeohyphomycosis,” is increasing [4]. Clinical illness ranges from mild superficial to life-threatening disseminated infection depending on host immunocompetency.\n\nCerebral phaeohyphomycosis is particularly devastating with mortality rates as high as 70–80% [5]. The route of intracranial infection is presumed to be either direct extension from the paranasal sinuses or hematogenous with an initial, usually subclinical, pulmonary focus. Previous reports speculate that some dematiaceous molds, including Acrophialophora, exhibit neurotropism [2] facilitated by melanin in the cell wall as a selective virulence factor [6]. The classic constellation of symptoms (i.e. fever, headache, focal neurologic deficits) is often absent among immunocompromised hosts, possibly leading to delayed diagnosis. Other potential contributors to poor clinical outcomes in patients with cerebral phaeohyphomycosis include: (1) difficulty in intracranial sampling to arrive at a tissue diagnosis, (2) limited diagnostics for mold identification, and (3) lack of adequate antifungal susceptibility data to guide appropriate treatment plans.\n\n2 Case\nA 54-year-old female with hypertension and type 2 diabetes complicated by end-stage renal disease prompting deceased-donor kidney transplantation on day −269 was admitted for acute right hemiparesis on hospital day 0.\n\nThe patient's immediate post-transplant course was complicated by acute cellular rejection on day −263 requiring thymoglobulin with return of graft function. On day −24 she was hospitalized for significant proteinuria due to de novo collapsing focal segmental glomerulosclerosis for which she received high-dose steroids and plasmapheresis. She was treated for Candida esophagitis with fluconazole loading dose 400mg PO followed by renally-dosed 100mg PO daily for 14 days and cytomegalovirus viremia with valganciclovir 450mg PO daily. She was maintained on immunosuppressive therapy with mycophenolate 500mg PO BID, tacrolimus 1mg PO qAM and 2mg PO qPM and prednisone 5mg PO daily.\n\nThis admission she presented with 8 h of right-sided weakness and was found to have right facial droop and 2/5 strength in her right upper and lower extremities. The remainder of her neurologic exam was intact, including mentation, speech, reflexes, sensation and proprioception. The patient lived with her two adult children in an urban setting. She did not smoke tobacco, drink alcohol or use illicit drugs. She did not spend significant time outdoors and had no recent travel or sick contacts.\n\nLaboratory studies were notable for neutropenia (absolute neutrophil count 540 cells/mcL) and post-transplant renal insufficiency unchanged from her recent baseline (creatinine 2.0 mg/dL). Chest radiograph did not show evidence of cardiopulmonary disease. A non-contrasted computerized tomography scan of the head revealed a left thalamic hypodensity (1.9 × 2.2 cm) with local mass effect. Brain magnetic resonance imaging further characterized the lesion as ring-enhancing on T2 sequencing, highly concerning for early abscess formation (Fig. 1). She was started empirically on vancomycin and meropenem, and underwent lumbar puncture (opening pressure normal at 10 cm H2O) on day +1. Cerebrospinal fluid (CSF) assessment revealed one nucleated cell with elevated glucose (116 mg/dL) and protein (141 mg/dL). Additional CSF evaluation was unrevealing, including bacterial, acid-fast bacilli and fungal cultures; Cryptococcal antigen; polymerase chain reaction testing for Toxoplasma gondii, Epstein-Barr virus, cytomegalovirus, Mycobacterium tuberculosis complex.Fig. 1 Magnetic resonance imaging of the brain revealing a ring-enhancing lesion in the left thalamus [1.9 × 2.2 cm], consistent with early abscess formation, accompanied by peripherally scattered infarcts in the left cerebral hemisphere and cerebellum on T2 sequencing.\n\nFig. 1\n\nStereotactic biopsy of the thalamic brain lesion on day +3 aspirated frank purulence. This specimen grew downy, white colonies on blood agar and Sabouraud dextrose media within 48 hours of being plated (Fig. 2). Subsequently, antibacterials were discontinued and voriconazole 6mg/kg IV BID for two doses followed by 4 mg/kg IV BID was initiated on day +5 given concern for an invasive mold infection. Microscopy showed pigmented hyphae with short phialides with swollen bases and cylindrical conidia in short chains (Fig. 3). Multiple attempts at identifying the organism by matrix-assisted laser desorption ionization time-of-flight mass spectroscopy (MALDI-ToF MS) were unsuccessful. The isolate was sent to the Centers for Disease Control and Prevention (CDC) whereby DNA sequencing of the ITS and β-tubulin identified Acrophialophora levis on day +14. Antifungal susceptibility testing of the isolate by the CDC were available on day +21 and revealed the following minimum inhibitory concentration (MIC) values: voriconazole 0.25 μg/mL, fluconazole 8 μg/mL, itraconazole 0.06 μg/mL, posaconazole 0.06 μg/mL, isavuconazole 0.25 μg/mL, anidulafungin 0.5 μg/mL, caspofungin 1 μg/mL, micafungin 1 μg/mL (by broth microdilution read at 48 hours) and amphotericin 1.5 μg/mL (determined using Etest following 48 hours of growth). MIC values for quality control isolates were in range.Fig. 2 Left thalamic brain tissue plated on Sabouraud dextrose media demonstrating the progression of colony growth from day +6 (A) to day +16 (B) to day +23 (C obverse, D reverse); the latter depicting the characteristic “black reverse” of dematiaceous fungi. The isolate was identified as Acrophialophora levis by internal transcribed spacer and β-tubulin DNA sequencing performed by the Centers for Disease Control and Prevention (CDC).\n\nFig. 2Fig. 3 Biopsy of left thalamic brain tissue stained with lactophenol cotton blue shown under microscopy 40x power revealing unbranched pigmented hyphae with short phialides with swollen bases and cylindrical conidia in short chains (inset) suggestive of cerebral phaeohyphomycosis. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)\n\nFig. 3\n\nThe patient experienced encephalopathy following the brain biopsy which prolonged her clinical recovery. With continued therapy that was transitioned to voriconazole 300mg PO BID, her mental status returned to baseline, however, her right-sided weakness persisted. She was transferred to a subacute rehabilitation facility for continued care on hospital day +32. Serum voriconazole level was checked on day +121 and returned therapeutic at 5.6 mcg/mL (range 1.0–6.0 mcg/mL).\n\n3 Discussion\nOur patient experience is the first to our knowledge reporting isolation of A. levis from a clinical specimen. There have been nine previously published clinical cases of Acrophialophora species infection, all attributed to A. fusispora (Table 1). Cases included keratitis [[7], [8], [9], [10]], pulmonary infection (two of which occurred in lung transplantation recipients) [11], and brain abscesses [2,12]. It is likely that A. levis as an etiologic agent of clinical disease has been previously underrecognized and underreported. A sequencing analysis of 39 Acrophialophora isolates (32 from human clinical specimens; 7 from environmental/animal sources) identified 73% of isolates initially considered A. fusispora as A. levis [3]. All isolates reclassified as A. levis, except one, were derived from human specimens, suggesting this species may be the most common Acrophialophora causing clinical disease. Only 16% (5/32) of the clinical isolates were linked to accession numbers published in case reports, implying the incidence of human disease secondary to Acrophialophora far exceeds the number of reported cases and that the majority may be due to A. levis.Table 1 Summary of nine clinical cases of Acrophialophora species published to date in the literature.\n\nTable 1Case\tYear\tLocation\tAge\tSex\tRisk Factor\tSite of Positive Culture\tSpecies Identified\tAntifungals\tOutcome\tReference\t\n1\t2000\tSaudi Arabia\t12\tF\tacute lymphoblastic leukemia\tbrain\tA. fusispora\tamphotericin B + itraconazole\tsurvived\t[2]\t\n2\t2001\tUnited States\t76\tF\tkeratitis (contact lens)\teye\tA. fusispora\titraconazole\tsurvived\t[11]\t\n3\t2001\tTaiwan\t60\tM\tHIV/AIDS\tbrain\tA. fusispora\tvoriconazole\tdied\t[15]\t\n4\t2004\tFrance\t13\tM\tcystic fibrosis\tBAL\tA. fusispora\titraconazole\tsurvived\t[14]\t\n5\t2004\tFrance\t26\tF\tcystic fibrosis\tBAL\tA. fusispora\titraconazole\tsurvived\t[14]\t\n6\t2007\tIndia\t55\tF\ttraumatic keratitis\teye\tA. fusispora\tfluconazole\tLTFU\t[10]\t\n7\t2007\tPortugal\t33\tM\tbilateral lung transplant\tBAL\tA. fusispora\tvoriconazole\tsurvived\t[10]\t\n8\t2007\tSpain\t67\tM\tsingle lung transplant\tsputum\tA. fusispora\tamphotericin B + itraconazole\tdied\t[10]\t\n9\t2017\tJapan\t77\tM\tneutropenia, prostate cancer\teye\tAcrophialophora sp.\tvoriconazole\tsurvived\t[12]\t\nAbbreviations: BAL = bronchoalveolar lavage; HIV/AIDS = human immunodeficiency virus/acquired immunodeficiency syndrome; LTFU = lost to follow-up.\n\n\n\nChallenges with accurate mold identification likely also contributes to limited reports of Acrophialophora as an agent of clinically relevant disease. Acrophialophora has been misidentified as Scopulariopsis chartarum [13] and Scedosporium prolificans [9], the latter being the most common cause of disseminated phaeohyphomycosis [14]. Further, a case of Acrophialophora cultured from bronchial secretions of a lung transplantation recipient highlights underappreciation of this organism as a true pathogen [7]. The result was assumed to represent contamination, antifungal therapy was discontinued, and unfortunately, the patient died 50 days later. On autopsy, Acrophialophora was isolated from lung tissue with evidence of pulmonary dissemination. Taken together, Acrophialophora may be more commonly implicated as an opportunistic infection than previously acknowledged, and under-recognition can lead to poor clinical outcomes.\n\nGiven morphologic similarity between Acrophialophora species by microscopy, more sensitive methods of identification are needed for species differentiation. While use of MALDI-ToF MS has been widely adopted in microbiology laboratories in the U.S. and Europe for rapid bacterial and yeast biotyping, its utility for mold identification is less well-established. Several genera commonly implicated in human disease (including Aspergillus, Fusarium, Penicillium, and Trichoderma) have been successfully identified by MALDI-ToF MS [15], however, an identification will not be returned when there is no reference spectrum available in the database, as was the case for our patient. Ten days lapsed between initial colony growth on culture media to identification of A. levis by DNA sequencing of the isolate performed by the CDC. Given that fungal sequencing is not routinely available in clinical microbiology laboratories, expansion of the MALDI-ToF MS reference library to include a wider array of dematiaceous molds would facilitate more rapid and accurate detection of these emerging clinical pathogens.\n\nOptimal treatment for Acrophialophora and other neurotropic molds is not clearly established. Further, susceptibility testing of dematiaceous fungi has not been standardized. A consensus approach to managing cerebral phaeohyphomycosis (based on published cases) is surgical resection of the abscess and combination antifungal therapy, typically with liposomal amphotericin B and an azole. For example, a case of acute lymphoblastic leukemia complicated by brain and pulmonary abscesses secondary to Acrophialophora did not improve clinically after 26 days of amphotericin B until itraconazole was added [2]. While itraconazole has sufficient brain tissue penetration, its low activity in the CSF may risk inadequate treatment of phaeohyphomycotic meningitis. Therefore, voriconazole is a particularly good candidate for empiric coverage given its excellent penetration into both brain tissue and CSF [5]. Successful treatment of Acrophialophora is challenging, with several reported fatalities despite receipt of appropriate azole therapy [7,12]. Further investigation of optimal management is needed.\n\n4 Conclusions\nWe report the first case of Acrophialophora levis causing cerebral phaeohyphomycosis in a kidney transplantation recipient. Identification by ITS and β-tubulin DNA sequencing after failing to identify on MALDI-ToF MS allowed for accurate discrimination between closely-related Acrophialophora species and rapid initiation of appropriate therapy with voriconazole. With the increasing use of immunosuppressive agents, especially in the context of transplantation medicine, dedicated surveillance of this pathogen is needed to better characterize its evolving epidemiology. Finally, a high level of clinical suspicion for neurotropic dematiaceous fungi, including Acrophialophora, must be employed when considering the different etiologies of a brain abscess in an immunocompromised host, as delayed diagnosis and treatment initiation is likely to be fatal.\n\nDisclaimer\nThe findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.\n\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\nThere are no conflicts of interest among any of the authors.\n\nAcknowledgements\nThe authors are grateful to Natalie Nunnally at the Centers for Disease Control and Prevention Mycotic Diseases Branch for performing antifungal susceptibility testing. We also thank Ahmed Babiker, MD and Jessica Hambrick, MD for their assistance in the Emory University Department of Pathology and Laboratory Medicine.\n==== Refs\nReferences\n1 Kidd S. Halliday C. Alexiou H. Ellis D. Acrophialophora fusispora Descriptions of Medical Fungi third ed. 2007 University of Adelaide Adelaide 2 \n2 Al-Mohsen I.Z. Sutton D.A. Sigler L. Almodovar E. Mahgoub N. Frayha H. Al-Hajjar S. Rinaldi M.G. Walsh T.J. Acrophialophora fusispora brain abscess in a child with acute lymphoblastic leukemia: review of cases and taxonomy J. Clin. Microbiol. 2000 \n3 Sandoval-Denis M. Gené J. Sutton D.A. Wiederhold N.P. Guarro J. Acrophialophora, a poorly known fungus with clinical significance J. Clin. Microbiol. 2015 \n4 Revankar S.G. Baddley J.W. Chen S.C.-A. Kauffman C.A. Slavin M. Vazquez J.A. Seas C. Morris M.I. Nguyen M.H. Shoham S. Thompson G.R. Alexander B.D. Simkins J. Ostrosky-Zeichner L. Mullane K. Alangaden G. Andes D.R. Cornely O.A. Wahlers K. Lockhart S.R. Pappas P.G. A mycoses study group international prospective study of phaeohyphomycosis: an analysis of 99 proven/probable cases Open Forum Infect. Dis. 2017 \n5 Revankar S.G. Sutton D.A. Rinaldi M.G. Primary central nervous system phaeohyphomycosis: a review of 101 cases Clin. Infect. Dis. 2004 \n6 Kwon-Chung K.J. Polacheck I. Popkin T.J. Melanin-lacking mutants of Cryptococcus neoformans and their virulence for mice J. Bacteriol. 1982 \n7 Guarro J. Kumar Mendiratta D. De Sequeira H. Rodríguez V. Thamke D. Gomes A.M. Kumar Shukla A. Menezes F. Narang P. Roldão Vieira J. Gené J. Acrophialophora fusispora: an emerging agent of human mycoses. A report of 3 new clinical cases Diagn. Microbiol. Infect. Dis. 2007 \n8 Guarro J. Gené J. Sigler L. Sutton D.A. Arthur S. Steed L.L. Acrophialophora fusispora misidentified as Scedosporium prolificans J. Clin. Microbiol. 2002 \n9 Watanabe Y. Kobayashi T. Nakamura I. Fujita H. Shimoinaba M. Fukushima S. Miyazaki Y. Matsumoto T. A case of conjunctival ulcer and uveitis caused by acrophialophora sp. in an immunocompromised patient: a case report and literature review Jpn. J. Infect. Dis. 2018 \n10 Shukla P.K. Khan Z.A. Lal B. Agrawal P.K. Srivastava O.P. Clinical and experimental keratitis caused by the colletotrichum state of glomerella cingulata and acrophialophora fusispora Med. Mycol. 1983 \n11 Cimon B. Challier S. Béguin H. Carrère J. Chabasse D. Bouchara J.P. Airway colonization by Acrophialophora fusispora in patients with cystic fibrosis J. Clin. Microbiol. 2005 \n12 Li C.W. Lee H.C. Chang T.C. Wan J.Y. Chen H.M. Wu C.J. Lee N.Y. Chang C.M. Lee C.C. Ko W.C. Acrophialophora fusispora brain abscess in a patient with acquired immunodeficiency syndrome: a case report and review of the literature Diagn. Microbiol. Infect. Dis. 2013 \n13 Welsh R.D. Ely R.W. Scopulariopsis chartatum systemic mycosis in a dog J. Clin. Microbiol. 1999 \n14 Chalupová J. Raus M. Sedlářová M. Šebela M. Identification of fungal microorganisms by MALDI-TOF mass spectrometry Biotechnol. Adv. 2014 \n15 González-Escalada A. Del Palacio A. Calvo M.T. Gené J. Guarro J. Two cases of scalp wound colonization and respiratory tract by mycelial fungi Rev. Iberoam. De. Micol. 2000\n\n",
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"journal": "Medical mycology case reports",
"keywords": "Acrophialophora levis; Brain abscess; Immunocompromised host; Kidney transplantation; Phaeohyphomycosis",
"medline_ta": "Med Mycol Case Rep",
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"title": "Acrophialophora levis brain abscess in a kidney transplant patient: A case report and review of the literature.",
"title_normalized": "acrophialophora levis brain abscess in a kidney transplant patient a case report and review of the literature"
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"abstract": "We report the successful use of ceftolozane/tazobactam (C/T) to treat a pulmonary exacerbation in a 35 year old female, post lung transplant, with cystic fibrosis (CF), malnutrition, chronic kidney disease, and multi-drug resistant Pseudomonas aeruginosa infection (MDR PSA). Given the complexity of the clinical profile, we measured drug levels of C/T during treatment of her current exacerbation to determine pharmacokinetics. The patient achieved an estimated ceftolozane peak of 174.1 μg/mL and trough of 9.2 μg/mL. Serum half-life was found to be slightly shorter than previously reported in normal subjects, (2.3 hr. vs. 2.6 hr.) despite the presence of renal insufficiency. Treatment resulted in improvement in serum inflammatory markers and symptoms and was well-tolerated.",
"affiliations": "Maine Medical Center, Division of Pulmonary and Critical Care Medicine, Portland, ME 04102, USA.;Maine Medical Center, Division of Pulmonary and Critical Care Medicine, Portland, ME 04102, USA.;Hartford Hospital, Center for Anti-Infective Research and Development, 80 Seymour Street, P O Box 5037, Hartford, CT 06102, USA.;Maine Medical Center, Department of Pharmacy, Portland, ME 04102, USA.;Maine Medical Center, Division of Pulmonary and Critical Care Medicine, Portland, ME 04102, USA.",
"authors": "Stokem|Katie|K|;Zuckerman|Jonathan B|JB|;Nicolau|David P|DP|;Wungwattana|Minkey|M|;Sears|Edmund H|EH|",
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"fulltext": "\n==== Front\nRespir Med Case RepRespir Med Case RepRespiratory Medicine Case Reports2213-0071Elsevier S2213-0071(17)30302-710.1016/j.rmcr.2017.10.012Case ReportUse of ceftolozane-tazobactam in a cystic fibrosis patient with multidrug-resistant pseudomonas infection and renal insufficiency Stokem Katie stokek1@mmc.orga∗Zuckerman Jonathan B. JZuckerman@cmamaine.comaNicolau David P. David.Nicolau@hhchealth.orgbWungwattana Minkey MWungwatta@mmc.orgcSears Edmund H. tsears@cmamaine.comaa Maine Medical Center, Division of Pulmonary and Critical Care Medicine, Portland, ME 04102, USAb Hartford Hospital, Center for Anti-Infective Research and Development, 80 Seymour Street, P O Box 5037, Hartford, CT 06102, USAc Maine Medical Center, Department of Pharmacy, Portland, ME 04102, USA∗ Corresponding author. stokek1@mmc.org28 10 2017 2018 28 10 2017 23 8 9 14 9 2017 26 10 2017 27 10 2017 © 2017 The Authors2017This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).We report the successful use of ceftolozane/tazobactam (C/T) to treat a pulmonary exacerbation in a 35 year old female, post lung transplant, with cystic fibrosis (CF), malnutrition, chronic kidney disease, and multi-drug resistant Pseudomonas aeruginosa infection (MDR PSA). Given the complexity of the clinical profile, we measured drug levels of C/T during treatment of her current exacerbation to determine pharmacokinetics. The patient achieved an estimated ceftolozane peak of 174.1 μg/mL and trough of 9.2 μg/mL. Serum half-life was found to be slightly shorter than previously reported in normal subjects, (2.3 hr. vs. 2.6 hr.) despite the presence of renal insufficiency. Treatment resulted in improvement in serum inflammatory markers and symptoms and was well-tolerated.\n\nKeywords\nCeftolozaneTazobactamCystic fibrosisRenal insufficiency\n==== Body\n1 Introduction\nCystic fibrosis (CF) is a genetic lung disease that is typically characterized by chronic lower airway infection and development of progressive bronchiectasis. In the 2015 United States CF Patient Registry, 9.2% of adult CF patients in 2015 were infected with MDR PSA [1]. Treatment of pulmonary exacerbations in affected individuals is currently problematic due to limited antimicrobial choices.\n\nCeftolozane/tazobactam (C/T) is a novel second-generation β-lactam/β-lactamase inhibitor that was recently approved by the Food and Drug Administration for treatment of complicated intra-abdominal and urinary tract infections. Ceftolozane contains a pyrazole side chain, increasing stability to AmpC β-lactamase, an inducible enzyme that confers drug resistance in PSA [2]; as a result of this enhanced activity, C/T is an important new therapeutic option for MDR PSA infections [3]. However, information about C/T use in CF is limited [4]. We report the successful employment of this agent in a CF patient with multiple comorbid conditions and characterize the pharmacokinetics of C/T during treatment.\n\n2 Case presentation\nA 35 year-old female with CF (homozygous for the F508del mutation) and chronic MDR PSA infection presented with a pulmonary exacerbation. She had a history of living donor lung transplant 17 years prior, CF related diabetes, calcineurin-related chronic kidney disease (estimated creatinine clearance of 40–50 mL/min calculated using the Cockroft-Gault equation), and hypertension. She previously received 9 days of intravenous ciprofloxacin 400 mg every 8 hours and piperacillin-tazobactam 4.5 g every 8 hours infused over 4 hours without clinical improvement and was subsequently transitioned to 14 days of meropenem 2 g every 8 hours via 3 hour infusion. While symptoms improved briefly on meropenem, measured pulmonary function was unchanged with FEV1 of 0.77 L (27% of predicted), and she returned four weeks later with increased dyspnea, productive cough, and fatigue. Akron pulmonary exacerbation score was 13 on current admission, after having been 9 at last admission, and 6-min walk distance was lower at 1020 feet, after having been 1400 feet prior to discharge from her last hospitalization [5]. CRP on current admission was 62 mg/L, increased from 3.0 mg/L prior to discharge from her previous admission.\n\nAfter reviewing the medication list for agents that may affect the clearance of C/T, we administered C/T 2000 mg/1000 mg intravenously every 12 hours. The selected dose was adopted from a clinical trial (NCT02070757) involving C/T for nosocomial pneumonia in mechanically ventilated patients. We obtained blood samples to assess the steady state concentrations of C/T. Serum concentrations were determined utilizing a validated high-performance liquid chromatography assay [6]. The steady state 1-h post infusion peak concentration (Cmax,ss) was 174.1 μg/mL for ceftolozane (Fig. 1). The ceftolozane steady-state volume of distribution (Vss), half-life (t1/2), and minimum concentration (Cmin,ss) were 11.5 L, 2.3 hours, and 9.2 μg/mL, respectively. Tazobactam concentrations could only be measured at two time points due to interference from other substances in the samples. However, tazobactam t1/2, calculated from available samples, was 2.1 hours.Fig. 1 Pharmacokinetics of ceftolozane. Dotted line represents the distribution phase following drug administration (blood samples were not collected during this period). The solid line represents the elimination phase.\n\nFig. 1\n\nThe patient completed 14 days of total therapy with C/T without any significant side effects or complications. She reported significant improvement in sputum production, fatigue and dyspnea. The forced expiratory volume in the first second improved from 25% to 30% of predicted, and serum C-reactive protein declined from 62 to <1.0 mg/L. She did not experience side effects or complications attributable to C/T.\n\n3 Discussion\nTo our knowledge, this is the second report of successful treatment of a CF pulmonary exacerbation with C/T [7] and the first to describe the pharmacokinetics of the compound in a CF patient with renal insufficiency. Selecting the optimal dose and frequency of administration of C/T in this case was challenging in several respects. It is well recognized that many medications exhibit altered pharmacokinetic-pharmacodynamic (PKPD) profiles in CF [8]. Published C/T PKPD data are currently sparse, and it was unclear how this limited information would apply to a patient with a body mass of only 47 kg, chronic kidney disease, and concomitant use of immunosuppressive medications.\n\nInitial studies of C/T in healthy volunteers displayed dose proportional and linear kinetics. Our patient exhibited a slightly higher Cmax than non-CF patients who have received ceftolozane and C/T [9]. This may be attributable to her lower body mass and Vss. Monogue et al. [8] reported lower central compartment volume in CF patients compared to non-CF adults. Chandorkar et al. [10] characterized pharmacokinetics of C/T in patients with varying degrees of renal dysfunction and found decreased ceftolozane clearance in those with reduced creatinine clearance. Interestingly, despite having impaired renal function, our patient displayed a shorter half-life compared to healthy subjects (∼2.3 vs. 2.6 hours, respectively). Furthermore, our patient displayed a shorter half-life in comparison to the mean half-life reported by Monogue et al. (2.87 hours) [8].\n\nWe later performed susceptibility testing on two PSA isolates from a sputum sample collected prior to C/T initiation (research use ETEST® strips, bioMériuex, Inc). The resulting minimum inhibitory concentrations (MICs) were 2/4 and 0.5/0.25 μg/mL. Given the penetration ratios of 0.59 of ceftolozane and tazobactam of 0.38 [11], we estimated the trough tissue concentrations of ceftolozane and tazobactam to be approximately 5.4 and 0.8 μg/mL, respectively. Therefore, optimal time above MIC (estimated 100% time above MIC of ceftolozane achieved against both isolates) was likely attained at the dose and frequency provided in this case.\n\nGiven her excellent clinical response to this dosing, as well as the appropriate pharmacokinetic levels obtained we would plan similar dosing for patients with these comorbidities in the future. Indeed, in the past year, this patient has been treated a second time with ceftolozane/tazobactam with the same dosing for another pulmonary exacerbation with similar improvement, though we did not repeat drug levels.\n\nThe serum concentrations of ceftolozane obtained from our patient may provide a basis for estimating appropriate dosing regimens for CF patients with similar characteristics. We hope these results stimulate further studies of C/T for treating pulmonary exacerbations in CF patients especially those with complex co-morbidities.\n\nConflicts of interest\nDr. Nicolau has acted as a consultant, speaker bureau member and research investigator for Merck; however, no funds were received in support of any aspect of this current report. All other authors declare that they have no conflicts of interest regarding the publication of this paper.\n\nAcknowledgements\nNone.\n==== Refs\nReferences\n1 Registry C.F.F.P. 2015 Patient Registry Annual Data Report 2015 \n2 Murano K. Structural requirements for the stability of novel cephalosporins to AmpC beta-lactamase based on 3D-structure Bioorg. Med. Chem. 16 5 2008 2261 2275 18082409 \n3 Sutherland C.A. Nicolau D.P. Susceptibility profile of ceftolozane/tazobactam and other parenteral antimicrobials against Escherichia coli , Klebsiella pneumoniae , and Pseudomonas aeruginosa from US hospitals Clin. Ther. 37 7 2015 1564 1571 26088525 \n4 Kuti J.L. Microbiological activity of ceftolozane/tazobactam, ceftazidime, meropenem, and piperacillin/tazobactam against Pseudomonas aeruginosa isolated from children with cystic fibrosis Diagn. Microbiol. Infect. Dis. 83 1 2015 53 55 26003469 \n5 Kraynack N.C. McBride J.T. Improving care at cystic fibrosis centers through quality improvement Semin. Respir. Crit. Care Med. 30 5 2009 547 558 19760542 \n6 Sutherland C.A. Nicolau D.P. Development of an HPLC method for the determination of ceftolozane/tazobactam in biological and aqueous matrixes J. Chromatogr. Sci. 54 6 2016 1037 1040 27048639 \n7 Vickery S.B. McClain D. Wargo K.A. Successful use of ceftolozane-tazobactam to treat a pulmonary exacerbation of cystic fibrosis caused by multidrug-resistant Pseudomonas aeruginosa Pharmacotherapy 36 10 2016 e154 e159 27522066 \n8 Monogue M.L. Population pharmacokinetics and safety of ceftolozane-tazobactam in adult cystic fibrosis patients admitted with acute pulmonary exacerbation Antimicrob. Agents Chemother. 60 11 2016 6578 6584 27550351 \n9 Miller B. Pharmacokinetics and safety of intravenous ceftolozane-tazobactam in healthy adult subjects following single and multiple ascending doses Antimicrob. Agents Chemother. 56 6 2012 3086 3091 22450972 \n10 Chandorkar G. Population pharmacokinetics of ceftolozane/tazobactam in healthy volunteers, subjects with varying degrees of renal function and patients with bacterial infections J. Clin. Pharmacol. 55 2 2014 230 239 25196976 \n11 Chandorkar G. Intrapulmonary penetration of ceftolozane/tazobactam and piperacillin/tazobactam in healthy adult subjects J. Antimicrob. Chemother. 67 10 2012 2463 2469 22773741\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2213-0071",
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"journal": "Respiratory medicine case reports",
"keywords": "Ceftolozane; Cystic fibrosis; Renal insufficiency; Tazobactam",
"medline_ta": "Respir Med Case Rep",
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"title": "Use of ceftolozane-tazobactam in a cystic fibrosis patient with multidrug-resistant pseudomonas infection and renal insufficiency.",
"title_normalized": "use of ceftolozane tazobactam in a cystic fibrosis patient with multidrug resistant pseudomonas infection and renal insufficiency"
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"abstract": "BACKGROUND\nAcute ischemic stroke (AIS) is a time-dependent treatable cause of morbidity and mortality. Despite the increasing stroke incidence in developing countries, parallel increasing stroke thrombolysis rates have not been documented.\n\n\nOBJECTIVE\nThis study aims to determine trends in patient characteristics and rates of recombinant tissue plasminogen activator (rtPA) use in AIS patients in a tertiary care center in northern India.\n\n\nMETHODS\nAll AIS patients presenting within 8 hours of symptoms onset from January 2011 to December 2015 were enrolled and analyzed.\n\n\nRESULTS\nA total of 867 AIS patients presented within 8 hours of symptoms onset. Out of 593 eligible patients, 189 (31.87%) underwent intravenous thrombolysis (IVT) with rtPA within 4.5 hours of the window period. Patients (undergoing) IVT had onset-to-door times of 2 hours or less (23.81%), 2-3 hours (33.86%), and 3.0-4.5 hours (42.33%). IVT rates in 2 hours or less of symptom onset increased from 22% to 25% and IVT rates in 2-3 hours increased from 38.9% to 43.8%. Door-to-computerized tomographic time (median 27 versus 11 minutes, P = .0001) and door-to-needle time (median 83 versus 67 minutes, P = .011) improved, with a significant improvement of computerized tomography imaging time within 25 minutes of arrival (from 50% to 78.4%, P = .014). Post-IVT symptomatic hemorrhage was noted in 5 patients (2.65%). The median National Institutes of Health Stroke Scale score at presentation was 11, whereas a favorable modified Rankin Scale score (0-1) at 3 months was seen in 39.68%.\n\n\nCONCLUSIONS\nEncouraging trends in IVT over the years may be indicative of increasing community awareness of stroke and improving quality of stroke care in developing countries such as India.",
"affiliations": "Department of Neurology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India. Electronic address: dherajk@yahoo.com.;Department of Neurology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.;Department of Neurology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.;Department of Neurology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.;Department of Radiology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.;Department of Neurology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.;Department of Neurology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.",
"authors": "Khurana|Dheeraj|D|;Das|Biplab|B|;Kumar|Ashok|A|;Kumar S|Amith|A|;Khandelwal|Niranjan|N|;Lal|Vivek|V|;Prabhakar|Sudesh|S|",
"chemical_list": "D005343:Fibrinolytic Agents; D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator",
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"doi": "10.1016/j.jstrokecerebrovasdis.2017.01.019",
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"issue": "26(6)",
"journal": "Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association",
"keywords": "Stroke; developing countries; intravenous thrombolysis; rtPA; trends",
"medline_ta": "J Stroke Cerebrovasc Dis",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002545:Brain Ischemia; D002533:Cerebral Angiography; D000072226:Computed Tomography Angiography; D004185:Disability Evaluation; D004334:Drug Administration Schedule; D005260:Female; D005343:Fibrinolytic Agents; D006801:Humans; D007194:India; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D010818:Practice Patterns, Physicians'; D017064:Process Assessment, Health Care; D058996:Quality Improvement; D019984:Quality Indicators, Health Care; D011994:Recombinant Proteins; D020521:Stroke; D062606:Tertiary Care Centers; D015912:Thrombolytic Therapy; D013997:Time Factors; D061665:Time-to-Treatment; D010959:Tissue Plasminogen Activator; D016896:Treatment Outcome",
"nlm_unique_id": "9111633",
"other_id": null,
"pages": "1266-1273",
"pmc": null,
"pmid": "28237123",
"pubdate": "2017-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Temporal Trends in Intravenous Thrombolysis in Acute Ischemic Stroke: Experience from a Tertiary Care Center in India.",
"title_normalized": "temporal trends in intravenous thrombolysis in acute ischemic stroke experience from a tertiary care center in india"
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"abstract": "Subtype C HIV-1 is responsible for the largest proportion of people living with HIV-1 infection. However, there is limited information about the roles of the brain and its cell types as a potential sanctuary for this subtype and how the sanctuary may be affected by the administration of anti-retroviral therapy (ART). To address this issue, we collected postmortem brain tissues from ART treated HIV-1 infected Zambian individuals who experienced complete viral suppression and those who did not. Tissues from various brain compartments were collected from each individual as frozen and formalin-fixed paraffin embedded brain specimens, for detection and quantification of HIV-1 genomes and identification of the infected cell type. Genomic DNA and RNA were extracted from frozen brain tissues. The extracted DNA and RNA were then subjected to droplet digital PCR for HIV-1 quantification. RNA/DNAscope in situ hybridization (ISH) for HIV-1 was performed on formalin-fixed paraffin embedded brain tissues in conjugation with immunohistochemistry to identify the infected cell types. Droplet digital PCR revealed that HIV-1 gag DNA and RNA were detectable in half of the cases studied regardless of ART success or failure. The presence of HIV-1 lacked specific tissue compartmentalization since detection was random among various brain tissues. When combined with immunohistochemistry, RNA/DNAscope ISH demonstrated co-localization of HIV-1 DNA with CD68 expressing cells indicative of microglia or peripheral macrophage. Our study showed that brain is a potential sanctuary for subtype C HIV-1, as HIV-1 can be detected in the brain of infected individuals irrespective of ART treatment outcome and no compartmentalization of HIV-1 to specific brain compartments was evident.",
"affiliations": "Nebraska Center for Virology and the School of Biological Sciences, University of Nebraska-Lincoln, Nebraska, United States of America.;Nebraska Center for Virology and the School of Biological Sciences, University of Nebraska-Lincoln, Nebraska, United States of America.;Nebraska Center for Virology and the School of Biological Sciences, University of Nebraska-Lincoln, Nebraska, United States of America.;Department of Pathology and Microbiology, University Teaching Hospital, Nationalist Road, Lusaka, Zambia.;Nebraska Center for Virology and the School of Biological Sciences, University of Nebraska-Lincoln, Nebraska, United States of America.;Nebraska Center for Virology and the School of Biological Sciences, University of Nebraska-Lincoln, Nebraska, United States of America.;Nebraska Center for Virology and the School of Biological Sciences, University of Nebraska-Lincoln, Nebraska, United States of America.",
"authors": "Tso|For Yue|FY|;Kang|Guobin|G|;Kwon|Eun Hee|EH|;Julius|Peter|P|;Li|Qingsheng|Q|;West|John T|JT|;Wood|Charles|C|0000-0002-4256-1530",
"chemical_list": "D044966:Anti-Retroviral Agents; D012367:RNA, Viral; D054301:gag Gene Products, Human Immunodeficiency Virus",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0201325",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 10.1371/journal.pone.0201325PONE-D-18-17606Research ArticleBiology and Life SciencesMicrobiologyMedical MicrobiologyMicrobial PathogensViral PathogensImmunodeficiency VirusesHIVHIV-1Medicine and Health SciencesPathology and Laboratory MedicinePathogensMicrobial PathogensViral PathogensImmunodeficiency VirusesHIVHIV-1Biology and Life SciencesOrganismsVirusesViral PathogensImmunodeficiency VirusesHIVHIV-1Biology and Life SciencesOrganismsVirusesImmunodeficiency VirusesHIVHIV-1Biology and life sciencesOrganismsVirusesRNA virusesRetrovirusesLentivirusHIVHIV-1Biology and Life SciencesMicrobiologyMedical MicrobiologyMicrobial PathogensViral PathogensRetrovirusesLentivirusHIVHIV-1Medicine and Health SciencesPathology and Laboratory MedicinePathogensMicrobial PathogensViral PathogensRetrovirusesLentivirusHIVHIV-1Biology and Life SciencesOrganismsVirusesViral PathogensRetrovirusesLentivirusHIVHIV-1Research and analysis methodsExtraction techniquesRNA extractionBiology and Life SciencesAnatomyBrainBasal GangliaMedicine and Health SciencesAnatomyBrainBasal GangliaBiology and life sciencesMolecular biologyMolecular biology techniquesMolecular probe techniquesProbe hybridizationDNA-RNA hybridizationResearch and analysis methodsMolecular biology techniquesMolecular probe techniquesProbe hybridizationDNA-RNA hybridizationBiology and Life SciencesAnatomyNervous SystemCentral Nervous SystemMedicine and Health SciencesAnatomyNervous SystemCentral Nervous SystemResearch and analysis methodsExtraction techniquesDNA extractionBiology and Life SciencesMolecular BiologyMolecular Biology TechniquesArtificial Gene Amplification and ExtensionPolymerase Chain ReactionResearch and Analysis MethodsMolecular Biology TechniquesArtificial Gene Amplification and ExtensionPolymerase Chain ReactionBiology and Life SciencesAnatomyBrainCerebral CortexOccipital LobeMedicine and Health SciencesAnatomyBrainCerebral CortexOccipital LobeBrain is a potential sanctuary for subtype C HIV-1 irrespective of ART treatment outcome Brain sanctuary for subtype C HIV-1Tso For Yue Data curationFormal analysisInvestigationMethodologyVisualizationWriting – original draftWriting – review & editing1Kang Guobin Data curationMethodologyVisualization1Kwon Eun Hee Methodology1Julius Peter Resources2Li Qingsheng MethodologyVisualizationWriting – review & editing1West John T. Formal analysisWriting – review & editing1http://orcid.org/0000-0002-4256-1530Wood Charles ConceptualizationFunding acquisitionInvestigationProject administrationResourcesSupervisionWriting – review & editing1*1 \nNebraska Center for Virology and the School of Biological Sciences, University of Nebraska-Lincoln, Nebraska, United States of America2 \nDepartment of Pathology and Microbiology, University Teaching Hospital, Nationalist Road, Lusaka, ZambiaSluis-Cremer Nicolas EditorUniversity of Pittsburgh, UNITED STATESCompeting Interests: The authors have declared that no competing interests exist.\n\n* E-mail: cwood1@unl.edu24 7 2018 2018 13 7 e020132512 6 2018 12 7 2018 © 2018 Tso et al2018Tso 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 credited.Subtype C HIV-1 is responsible for the largest proportion of people living with HIV-1 infection. However, there is limited information about the roles of the brain and its cell types as a potential sanctuary for this subtype and how the sanctuary may be affected by the administration of anti-retroviral therapy (ART). To address this issue, we collected postmortem brain tissues from ART treated HIV-1 infected Zambian individuals who experienced complete viral suppression and those who did not. Tissues from various brain compartments were collected from each individual as frozen and formalin-fixed paraffin embedded brain specimens, for detection and quantification of HIV-1 genomes and identification of the infected cell type. Genomic DNA and RNA were extracted from frozen brain tissues. The extracted DNA and RNA were then subjected to droplet digital PCR for HIV-1 quantification. RNA/DNAscope in situ hybridization (ISH) for HIV-1 was performed on formalin-fixed paraffin embedded brain tissues in conjugation with immunohistochemistry to identify the infected cell types. Droplet digital PCR revealed that HIV-1 gag DNA and RNA were detectable in half of the cases studied regardless of ART success or failure. The presence of HIV-1 lacked specific tissue compartmentalization since detection was random among various brain tissues. When combined with immunohistochemistry, RNA/DNAscope ISH demonstrated co-localization of HIV-1 DNA with CD68 expressing cells indicative of microglia or peripheral macrophage. Our study showed that brain is a potential sanctuary for subtype C HIV-1, as HIV-1 can be detected in the brain of infected individuals irrespective of ART treatment outcome and no compartmentalization of HIV-1 to specific brain compartments was evident.\n\nAmerican foundation for AIDS research109123-57-RGRhttp://orcid.org/0000-0002-4256-1530Wood Charles http://dx.doi.org/10.13039/100000002National Institutes of HealthNS074903http://orcid.org/0000-0002-4256-1530Wood Charles http://dx.doi.org/10.13039/100000002National Institutes of HealthCA75903http://orcid.org/0000-0002-4256-1530Wood Charles http://dx.doi.org/10.13039/100000002National Institutes of HealthP30 GM103509http://orcid.org/0000-0002-4256-1530Wood Charles http://dx.doi.org/10.13039/100000061Fogarty International CenterD43 TW01492http://orcid.org/0000-0002-4256-1530Wood Charles http://dx.doi.org/10.13039/100000061Fogarty International CenterTW010354http://orcid.org/0000-0002-4256-1530Wood Charles http://dx.doi.org/10.13039/100000060National Institute of Allergy and Infectious DiseasesUM1AI126620 BEAT-HIVLi Qingsheng http://dx.doi.org/10.13039/100000061Fogarty International CenterFellowJulius Peter This work is supported in part by American Foundation for AIDS Research (109123-57-RGR), and the National Institutes of Health (NIH) Grants (NS074903, CA75903, P30 GM103509 and Fogarty D43 TW01492 and TW010354) to C.W; NIAID UM1AI126620 BEAT-HIV: Delaney Collaboratory to Cure HIV-1 Infection by Combination Immunotherapy to Q.L.; P.J. is a Fogarty Fellow. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data AvailabilityAll relevant data are within the paper.Data Availability\nAll relevant data are within the paper.\n==== Body\nIntroduction\nThe introduction of combined anti-retroviral therapy (ART) has been an important milestone in curtaining the HIV-1 AIDS epidemic and has led to drastic improvement in the prognosis of HIV-1 infected individuals. Although the ART regimens have extended the life expectancy of many individuals, prolonged treatment comes with an increased probability of adverse effects [1]. Emergence of ART resistant HIV-1 variants and other non-AIDS associated complications such as HIV-1 associated neurocognitive disorders (HAND) and cancers continue to be problematic despite the effective use of ART [2]. Additionally, the high cost of ART has placed a heavy financial burden on resource-limited countries, such as those in sub-Saharan Africa, and such burden potentially limit the universal access and sustainability of ART implementation in these countries [3].\n\nThe ability of HIV-1 to persist in the infected host under suppressive ART has proven to be a formidable obstacle to the eradication of HIV-1. Despite its capacity to reduce productive infectious HIV-1 in the peripheral circulation to undetectable levels, ART does not eradicate latent HIV-1, and therefore treatment has to be lifelong without discontinuation. This may prove financially difficult to sustain in perpetuity. Hence, there has been an emphasis on the development of latency-reversing agents (LRAs) with the goal to reactivate latent HIV-1, followed by therapeutic intervention in the “shock and kill” strategy [4]. However, for such latency reversal strategies to be most effective, it requires a better understanding of where latent HIV-1 sanctuaries exist in infected individuals, whether those sanctuaries are modulated by treatment outcomes and vary with different HIV-1 subtypes.\n\nThe central nervous system (CNS) has been documented as a potential sanctuary for HIV-1 and the virus can readily be detected in the cerebrospinal fluid (CSF) early after HIV-1 infection [5, 6]. The CNS is protected by the blood-brain barrier (BBB) and is considered an immunological and pharmacological privileged site to which ART has limited access [7–10]. Thus, the CNS presents a favorable environment for HIV-1 persistence. The presence of HIV-1 in the CNS has been associated with increased risk of developing HAND in HIV-1 infected individuals who are ART naïve or have experienced therapy failure [11]. Additionally, a substantial proportion of ~18% HIV-1 infected individuals achieving viral suppression also experienced neuropsychological impairment [12].\n\nHIV-1 infection of the CNS has primarily been studied in subtype B HIV-1 infected individuals [5, 13, 14]. Despite the fact that subtype C HIV-1 is responsible for the largest proportion of people living with HIV-1 infection, there is limited information about the roles of the brain as a potential sanctuary for this subtype and how the sanctuary may be affected by the administration of ART [15, 16]. The inaccessibility of brain tissues from HIV-1 infected individuals makes sampling difficult and any longitudinal study impossible. In this study, we were able to collect postmortem brain tissues from ART treated, subtype C HIV-1 infected, individuals from Zambia. We performed a cross-sectional examination for the presence of HIV-1 in the brain tissues of those who were virally suppressed versus those who had experienced ART failures. We utilized ultra-sensitive detection methods such as droplet digital-PCR (ddPCR) and RNA/DNAscope in situ hybridization (ISH) in conjugation with traditional immunohistochemistry (IHC) to detect low HIV-1 copy in the frozen and formalin-fixed paraffin embedded brain tissues respectively [17–19]. Our study is significant as it addresses important knowledge gaps as to whether the CNS can serve as a potential sanctuary for subtype C HIV-1 in infected individuals and how the sanctuary is impacted by ART treatment.\n\nMaterials and methods\nPostmortem brain sample\nPermission to conduct this study was obtained from the University of Zambia Biomedical Research Ethics Committee and the Institutional Review Board of the University of Nebraska-Lincoln. Upon notification of a death in the adult medical wards at the University Teaching Hospital (UTH) in Zambia, family members of the deceased were approached by an experienced team member. Grief counseling was offered to the family members present regardless of their decision to consent or not. The goals of the study were then explained as well as the procedures to be conducted for tissue collection during autopsy. For those that provided written consent, postmortem samples were collected at 24 hours after death from the following brain compartments: frontal lobe, cerebellum, hippocampus, basal ganglia, temporal lobe, parietal lobe and occipital lobe. Representative tissue slice (at least 3 mm) for each brain compartment was dissected and divided for snap freezing in liquid nitrogen and fixation in 4% paraformaldehyde for paraffin-embedding. Venous blood was also collected if possible.\n\nRT-PCR for plasma HIV-1 RNA load\nHIV-1 RNA was extracted from plasma with QIAamp Viral RNA Mini Kit (Qiagen, Hilden, Germany) according to the manufacturer’s protocol with on-column DNase I treatment. HIV-1 plasma viral load was quantified with RNA UltraSense One-Step Quantitative RT-PCR System (Invitrogen, Waltham, MA) using the following conditions: 50°C for 15 min; 95°C for 2 min; 40 cycles at 95°C for 15 sec and 60°C for 1 min. The primers and probe target the HIV-1 gag as previously described [17]. AcroMetrix HIV-1 panel (ThermoFisher Scientific, Fremont, CA) was used for standard curve.\n\nExtraction of genomic DNA and RNA from postmortem brain tissues\n250 to 300 mg of each fresh-frozen brain tissue were pulverized by cryo-cracking in liquid nitrogen. Cryo-cracked tissues were incubated overnight at 55°C with cell lysis solution and proteinase K (Qiagen, Hilden, Germany). The sample was then chilled on ice for 5 mins before the addition of protein precipitation solution, mix and spun twice at 2000 x g for 10 mins at 4°C to pellet the protein precipitates. The supernatant was transferred to a new tube with glycogen and isopropanol to precipitate both genomic DNA and RNA simultaneously. The mixture was then spun at 2000 x g for 5 mins at 4°C to pellet the genomic DNA and RNA. The DNA/RNA pellet was washed twice with 70% ethanol, air-dried, resuspended in hydration solution (Qiagen, Hilden, Germany) and incubated at 65°C for 30 mins to dissolve the pellet.\n\nTo separate the genomic RNA from DNA, Ambion TRIzol LS reagent (Invitrogen, Waltham, MA) was added to the genomic DNA/RNA solution according to the manufacturer’s protocol. After phase separation, genomic RNA from the aqueous layer was extracted using QIAgen miRNeasy mini kit (Qiagen, Hilden, Germany) according to manufacturer’s protocol with additional on-column DNase I treatment.\n\nTo extract the genomic DNA, the aqueous layer after phase separation was mixed with glycogen and 100% ethanol for 5 mins before spun at 15000 x g for 5 mins at 4°C. After the supernatant was discarded, the genomic DNA pellet was washed twice with 0.1M sodium citrate in 10% ethanol for 30 mins at room temperature and spun at 15000 x g for 5 mins at 4°C. The genomic DNA pellet was then washed with 75% ethanol for 10 mins at room temperature, spun at 15000 x g for 5 mins at 4°C. The genomic DNA pellet was air-dried, resuspended in hydration solution (Qiagen, Hilden, Germany) and incubated at 65°C for 1 hr before overnight incubation at room temperature to ensure the DNA pellet was completely solubilized. The genomic DNA was then further purified through standard ethanol precipitation.\n\nConcentration of the extracted genomic DNA and RNA was determined using Qubit double-stranded DNA and RNA broad-range kits (Invitrogen, Waltham, MA), and measured by Qubit fluorometer (Invitrogen, Waltham, MA).\n\nddPCR for HIV-1 DNA and RNA\nHIV-1 copy numbers from the extracted genomic DNA and RNA were determined by ddPCR, as previously described [17]. Briefly, for detection of HIV-1 DNA, the extracted genomic DNA was first digested with restriction enzyme Msc I to reduce sample viscosity and increase template accessibility. The target sequences does not contain Msc I recognition sites. Each DNA ddPCR reaction consisted of 1X ddPCR supermix for probes (Biorad, Hercules, CA), 900 nM each of HIV-1 gag forward and reverse primers, 250 nM FAM-labeled HIV-1 gag probe, template DNA and top up to 20 μl with molecular grade water [17]. The reaction mixture was then loaded into QX100 droplet generator (Biorad, Hercules, CA) for droplet emulsion generation and PCR was performed with C1000 Touch Thermal Cycler (Biorad, Hercules, CA). Fluorescence signal was quantified and analyzed by the QX100 droplet reader (Biorad, Hercules, CA) and QuantaSoft version 1.3.2.0 (Biorad, Hercules, CA) respectively. To determine the total number of analyzed cells, a separate ddPCR reactions were performed against the beta-globin gene. The cut-off value for ddPCR positivity was determined using the genomic DNA extracted from a total of 6.74 x 107 cells from various brain tissues of an HIV-1 negative individual (44 years old, male, cause of death as cardiac arrest), and was consistently found to be at an average of ~1 HIV-1 copy/106 cells. Brain tissue from a HIV-1 positive (30 years old, male, cause of death as toxoplasmosis) ART naïve individual was used as positive control.\n\nDetection of HIV-1 RNA was similar to the DNA method, except that the reaction mix consisted of 1X One-Step RT-ddPCR supermix (Biorad, Hercules, CA) and an additional 1 mM of manganese acetate solution. A total of 120 ng of genomic RNA from each brain compartment was analyzed for HIV-1 gag RNA. The cut-off value for ddPCR positivity was determined using genomic RNA extracted from the various brain tissues of an HIV-1 negative individual, and signals above ~2 HIV-1 copies/μg of RNA input were determined to be true signals. The mean viral copies and statistical analysis (Unpaired T test) were performed using GraphPad Prism 5 (GraphPad Software, La Jolla, CA).\n\nRNA/DNAscope ISH and IHC\nHIV-1 DNA and RNA in brain tissues were detected using DNAscope ISH sense and antisense riboprobes in combination with RNAscope 2.0 HD red reagent kit (Advanced Cell Diagnostics, CA), respectively. The experiment was conducted according to kit’s instruction and previously reported protocol [20]. The ISH stained sections were then digitized using Aperio CS2 Scanscope (Leica Aperio, CA). For determining the cell types of HIV-1 RNA and DNA positive cells, the coverslip of viral RNA or viral DNA positive tissue sections were removed and tissue sections were rehydrated and received antigen retrieval as previously reported [21]. CD68+ cells or CD4+ T cells were immunohistochemically stained with mouse anti-human CD68 monoclonal antibody (KP1, 1:200, Abcam) or rabbit anti-human CD4 monoclonal antibody (EPR6855, 1:200, Abcam) and the signal was developed with the Dako Envision and Peroxidase kit using diaminobenzidine (DAB) as substrate. Stained sections were digitized and CD68+ cells or CD4+ T cells were analyzed by Aperio’s Spectrum Plus analysis program (version 9.1; Aperio ePathology Solutions) as described previously [22].\n\nResults\nA total of 8 HIV-1 positive individuals were studied. These subjects had been on ART for >6 months (range 9–108 months) prior to death (Table 1). The ART regimens of these subjects were similar, consisting primarily of a protease inhibitor, nucleoside reverse transcriptase inhibitors and non- nucleoside reverse transcriptase inhibitors. Despite the administration of ART over extended period of time, half of the cohort were considered to be ART failures given the detectable plasma HIV-1 RNA ranging from 4 x 102 to 1 x 105 copies/ml (Table 1) despite treatment for >6 months. The remainder were virally suppressed with undetectable plasma HIV-1 RNA by RT-PCR. There was no correlation between the duration of ART and the outcome of ART therapy. The frontal lobe, cerebellum, hippocampus, basal ganglia, temporal lobe, parietal lobe and occipital lobe of the brain from each subject were used for subsequent analyses.\n\n10.1371/journal.pone.0201325.t001Table 1 Subject demographic information.\nSubject\tAge\tSex\tLast known CD4 count (cells/μl)\tPlasma HIV-1 RNA load (copies/ml)\tART duration (months)\tART regiment\t\nClinical diagnosis\t\n245\t40\tMale\tUndetermined\tUndetectable\t48\tTenofovir, Emtricitabine, Efavirenz\tCor pulmonale with cardiogenic shock\t\n328\t37\tMale\tUndetermined\tUndetectable\t10\tTenofovir, Emtricitabine, Efavirenz\tMeningo-encephalitis\t\n332\t37\tFemale\tUndetermined\tUndetectable\t24\tTenofovir, Emtricitabine, Efavirenz\tRetroviral disease, upper gastrointestinal tract bleeding, gastric ulcer\t\n408\t17\tMale\t900\tUndetectable\t108\tTenofovir, Emtricitabine, Nevirapine\tRetroviral disease, chronic meningitis\t\n257\t40\tMale\tUndetermined\t3 x 104\t9\tTenofovir, Emtricitabine, Efavirenz\tRetroviral disease, anaemia\t\n283\t34\tFemale\t300\t4 x 102\t36\tTenofovir, Emtricitabine, Nevirapine\tRetroviral disease, tuberculosis\t\n309\t34\tFemale\t318\t2 x 104\t96\tTenofovir, Emtricitabine, Efavirenz\tRetroviral disease, cerebrovascular accident\t\n319\t44\tFemale\t70\t1 x 105\t24\tLopinavir, Abacavir, Lamivudine\tRetroviral disease, anaemia\t\nAmong the virally suppressed aviremic subjects, three out of four cases have detectable viral DNA or RNA or both. One case (subject 245) has no statistical significant copies of either viral DNA or RNA (Fig 1A and 1B). For subject 408, both viral DNA and RNA were detected in some tissues. Low but statistical significance copies of HIV-1 gag DNA, at 3 copies/106 cells (P = 0.0375) were detected in the basal ganglia (Fig 1A). The frontal lobe from this subject also contained HIV-1 gag RNA at 27 copies/μg of genomic RNA input (P = 0.0013) (Fig 1B). For subject 332 statistically significant HIV-1 gag RNA level was distinctly detected in the basal ganglia and occipital lobe at 26 copies/μg of genomic RNA input (P = 0.0014) and 25 copies/μg of genomic RNA input (P = 0.002), respectively (Fig 1B). However, even though some viral DNA was only detected in occipital lobe but the copy number is too low to be significant. Interestingly, for subject 328, low but consistent and statistically significant copies of viral DNA were detected by ddPCR in the occipital lobe at 5 copies/106 cells (P < 0.0001). No significant copy number of viral RNA was detected in any tissue tested for this subject.\n\n10.1371/journal.pone.0201325.g001Fig 1 Droplet digital PCR detection of HIV-1 DNA and RNA in brain tissues of viral suppressed individuals.\n(A) HIV-1 gag DNA copies per million cells in various brain tissues (B) HIV-1 gag RNA copies per million cells in various brain tissues. Basal Ganglia was not available for subject 245. P-value indicate statistically significant from background/negative control. Dash lines indicate cut-off value for ddPCR positivity based on the negative control. Negative control derived from brain tissue of a HIV-1 negative individual. Positive control derived from brain tissue of a HIV-1 positive but ART naïve individual.\n\nSurprisingly, among the individuals failing to control viral load while on ART, only one of four cases has detectable viral DNA and RNA. HIV-1 gag DNA that was statistically distinct from the background was only detected in the basal ganglia of subject 319 that had the highest level of HIV-1 gag DNA in the entire cohort, at 56 copies/106 cells (P < 0.0001) (Fig 2A). This subject also had significant amount of HIV-1 gag RNA in the basal ganglia, temporal lobe and occipital lobe at 52, 27 and 50 copies/μg of input genomic RNA respectively (Fig 2B). No significant gag RNA was detected among the three ART failure individuals in their tested brain tissues.\n\n10.1371/journal.pone.0201325.g002Fig 2 Droplet digital PCR detection of HIV-1 DNA and RNA in brain tissues of ART failure individuals.\n(A) HIV-1 gag DNA copies per million cells in various brain tissues (B) HIV-1 gag RNA copies per million cells in various brain tissues. P-value indicate statistically significant from background/negative control. Dash lines indicate cut-off value for ddPCR positivity based on the negative control. Negative control derived from brain tissue of a HIV-1 negative individual. Positive control derived from brain tissue of a HIV-1 positive but ART naïve individual.\n\nThe lack of detection for both the HIV-1 gag DNA and RNA in some of the brain samples was not likely due to insufficient number of cells analyzed. On average, about 5 x 106 cellular equivalents were used for ddPCR analysis for both the virally suppressed and ART failure cases (Fig 3A and 3B respectively). Furthermore, the basal ganglia from subject 408 had the least number of cells analyzed with only 2.6 x 106 cells (Fig 3A), but the HIV-1 gag DNA was still detectable. The ddPCR detection of HIV-1 DNA and RNA from the brain tissues was confirmed with RNA/DNAscope ISH on selected tissues. For example, the presence of HIV-1 RNA and DNA were evident in the basal ganglia of ART failure subject 319, where both viral RNA and DNA expressing cells were detected (Fig 4A and 4B, respectively). Likewise, RNA/DNAscope ISH results from a viral suppressed subject 408, whose basal ganglia had ddPCR detectable viral DNA, but not viral RNA, showed only viral DNA positive cells (Fig 4C).\n\n10.1371/journal.pone.0201325.g003Fig 3 Number of cells analyzed by droplet digital PCR for HIV-1 DNA and RNA in brain tissues.\n(A) Viral suppressed subjects (B) ART failure subjects.\n\n10.1371/journal.pone.0201325.g004Fig 4 RNA/DNAscope in situ hybridization for HIV-1 RNA and DNA detection.\n(A) HIV-1 RNA in basal ganglia of subject 319. (B) HIV-1 DNA in basal ganglia of subject 319. (C) HIV-1 DNA in basal ganglia of subject 408. (D) CD68 expression in basal ganglia of subject 408 (E) Merged of HIV-1 DNA and CD68 expression in basal ganglia of subject 408. HIV-1 RNA/DNA positive signals are shown as red color. Nucleus are shown as blue color. CD68 expression are shown as brown color. Green circles highlight representative cells positive for HIV-1 RNA or DNA and/or CD68 expression.\n\nWe then proceeded to determine the identity of the viral DNA positive infected cells in the basal ganglia of subject 408 by performing IHC for CD4+ T cells or CD68+ expressing cells that are indicative of microglia or peripheral macrophage, in conjunction with DNAscope ISH against HIV-1 DNA. Although we only detected very few CD4+ T cells in the brain tissues (data not shown), cells expressing CD68+ were readily detected in the brain tissues and, more importantly, overlapped with HIV-1 DNA signal from DNAscope ISH (Fig 4C, 4D and 4E). This result suggests that microglia or peripheral macrophage that infiltrated the brain are the major cell types infected by subtype C HIV-1 in the brain, at least based on the cases that we have analyzed.\n\nDiscussion\nThe existence of a brain sanctuary in HIV-1 infected individuals on suppressive ART is still controversial and has not been studied extensively due to difficulties in obtaining tissues for such analysis. In addition, most studies on HIV-1 infection of the central nervous system to date have focused on subtype B strains [23, 24]. A previous study reported subtype C HIV-1 compartmentalization in the central nervous system in HIV-1 infected children [25]. However, that study only examined the cerebrospinal fluid without access to parenchymal brain tissues. Although another study had explored the presence of subtype C HIV-1 in brain tissues from autopsy, it only examined proviral DNA in ART naïve cases [26]. It had no ART treated cases for comparison and did not address the question of viral reactivation. Our postmortem study design directly addresses the question of whether the brain can serve as a sanctuary for subtype C HIV-1 by examining parenchymal tissues from sub-Saharan African ART treated individuals. Subtype C HIV-1 is the dominant strain in Zambia and the subtype C classification for our sample was also confirmed by sequencing for the viral envelope from subject 328 [27]. Our findings are particularly relevant since subtype C HIV-1 is the most prevalent strain present in >50% of individuals living with HIV-1 worldwide.\n\nHIV-1 infection is known to cause chronic inflammation, which could lead to dysregulation of the tight junction between the brain microvascular endothelial cells and permeabilization of the blood-brain barrier, thereby potentially increase HIV-1 infiltration into the brain [28–30]. Additionally, the failure of ART to suppress the HIV-1 viral load in the peripheral blood would have been predicted to increase the chances for HIV-1 to infect the CNS. Several groups have previously reported that subtype B HIV-1 can be detected from the brain tissues in about 50–55% of HIV-1 infected and ART treated patients [23, 31]. Similar to these reports, our data also showed a 50% HIV-1 detection rate, with 4 out of the 8 subtype C HIV-1 infected and ART treated subjects having detectable HIV-1 DNA or RNA in brain tissues. Despite the lack of HIV-1 in most cases, we cannot rule out the presence of virus in these ‘negative’ samples since we can only analyzed a small section of each brain tissue, or the virus could be present at a frequency below our detection limit. Nevertheless the detection of viral DNA in the absence of viral RNA is of important even though we cannot determine whether the provial DNA detected represent defective or intact viral genome. Surprisingly, our data did not show differential HIV-1 infection frequency in the brains of ART failure cases compared to those with fully suppressed peripheral viral load. One possible explanation is that, in addition to our analyses were from a limited section of the brain tissues, subtype C HIV-1 might be less neurotropic than subtype B. This notion may be supported by previous reports suggesting that subtype C HIV-1 causes less pathological changes in the brain than subtype B in both human patients and experimentally infected animals [32, 33].\n\nPrevious studies have also suggested that certain brain compartments, such as the basal ganglia, temporal lobe and hippocampus, have an increased tendency to harbor HIV-1 [34, 35]. Although HIV-1 DNA or RNA was detected in the basal ganglia and temporal lobe from several individuals in our study, we did not observe any obvious pattern in the distribution of detectable events among the various brain compartments. Since our data revealed no specific brain compartment as being more susceptible to subtype C HIV-1 infection than others, we conclude that infection of the various brain compartments likely results from random events.\n\nThe distribution of detectable HIV-1 RNA was also not compartment-specific and moreover did not correlate with the outcome of ART. Since we employed a primer set that targeted the HIV-1 gag gene, which is typically encoded by genome length unspliced transcripts, we eliminated the possibility of detecting prematurely terminated short viral transcripts derived solely from the long-terminal repeat [36]. Detection of HIV-1 gag RNA in brain tissue, strongly suggests that there could be persistent low-level viral replication or reactivation in the brain tissues despite administration of ART. A recent non-human primate study with simian immunodeficiency virus followed by comparative phylogenetic analysis of the viral sequences in the cerebrospinal fluid versus plasma also suggested that HIV-1 can indeed be reactivated in the brain [37, 38]. In contrast, some of our samples had detectable HIV-1 gag RNA but no viral DNA. The detected virus, presumably in the vasculature, might therefore have originated from an unsampled region within the same tissue, from other brain compartments, or even from another peripheral tissue reservoir. It is also possible that viral DNA was present but simply below our detection limit, or we have missed the sections that were positive.\n\nThe precise mechanism that HIV-1 utilizes to enter the brain has not been absolutely defined, but is thought to involve both infected T-cells and cell-free virions infiltrating past the blood-brain barrier. Once in the brain parenchyma, HIV-1 cannot infect neurons, but is known to infect CD68+ microglia [39, 40]. To identify the infected cell type in our cohort, we performed IHC in conjunction with DNAscope ISH for HIV-1 DNA on selected brain tissues. Our data showed that the HIV-1 DNA detected in the brain resides within CD68 expressing microglia cells or brain-infiltrating peripheral macrophages. However, there are several limitations to our present study. First is the small number of cases studied mainly due to the difficulties in obtaining these postmortem cases especially in the African setting, a future study with a much larger cohort will be needed to support our preliminary findings. Furthermore, at this juncture, it is not possible to determine whether the viral genomes detected are from intact and therefore reactivable viral genomes or not since viral outgrowth assays have not yet been successfully performed with postmortem brain tissues. Nevertheless, the presence of HIV-1 DNA in the absence of viral RNA at least in one of our cases suggests the possibility of functional latent sanctuary in the brain that could repopulate the periphery upon treatment cessation.\n\nIn conclusion, our study has shown that brain from subtype C HIV-1 infected individuals can harbor viral genomes and can be a potential sanctuary, regardless of the peripheral success or failure of ART. The virus appears to be randomly distributed among the various brain compartments with evidence of low copies of viral RNA in some cases, indicative of ongoing persistent viral replication. Such a sanctuary may present a major challenge for HIV-1 treatments as the capacity to penetrate the blood-brain barrier will need to be taken into consideration.\n\nWe thank the families of all tissue donors for their participation in this study. This work is supported in part by American Foundation for AIDS Research (109123-57-RGR), and the National Institutes of Health (NIH) Grants (NS074903, CA75903, P30 GM103509 and Fogarty D43 TW01492 and TW010354) to C.W; NIAID UM1AI126620 BEAT-HIV: Delaney Collaboratory to Cure HIV-1 Infection by Combination Immunotherapy to Q.L.; P.J. is a Fogarty Fellow.\n==== Refs\nReferences\n1 Mouton JP , Cohen K , Maartens G . Key toxicity issues with the WHO-recommended first-line antiretroviral therapy regimen . Expert Rev Clin Pharmacol . 2016 :1 –11 . 10.1080/17512433.2016.1221760 .27498720 \n2 Neuhaus J , Angus B , Kowalska JD , La Rosa A , Sampson J , Wentworth D , et al\nRisk of all-cause mortality associated with nonfatal AIDS and serious non-AIDS events among adults infected with HIV . 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"pmid": "30040863",
"pubdate": "2018",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "27466426;23072749;9546286;9390565;18971501;12052920;24516154;10696506;22551810;24113395;23300446;26167617;16036796;15308706;27430032;15078175;19887401;25750071;21297424;27498720;22156215;15546130;27898590;21871429;20177360;22122760;17805010;24862332;24338353;3016903;21135382;19641870;15793562;22007152;21416169;18829958;12379911;20015984;25011654;22166544",
"title": "Brain is a potential sanctuary for subtype C HIV-1 irrespective of ART treatment outcome.",
"title_normalized": "brain is a potential sanctuary for subtype c hiv 1 irrespective of art treatment outcome"
} | [
{
"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2018-BI-040525",
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"occurcountry": "US",
"patient": {
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{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "NEVIRAPINE"
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{
"abstract": "Repeated asparaginase treatment has been associated with hypersensitivity reactions against the bacterial macromolecule in a considerable number of patients. Immunological reactions may range from anaphylaxis without impairment of serum asparaginase activity to a very fast decline in enzyme activity without any clinical symptoms. Previous investigations on a limited number of patients have shown high interindividual variability of asparaginase activity time courses and hypersensitivity reactions in about 30% of patients during reinduction treatment. Therefore, monitoring of reinduction treatment was performed prospectively in 76 children with newly diagnosed acute lymphoblastic leukaemia (ALL). According to the ALL-Berlin-Frankfurt-Münster (BFM) 95 protocol, 10 000 U/m2 body surface area of native Escherichia coli asparaginase (Asparaginase medac) was given on d 8, 11, 15 and 18. In 45/76 children, trough and peak activities were determined with every dose, and also on d 4 and d 11 after the last administration. Data on asparaginase activity were not available from the remaining 31 patients, but information with regard to hypersensitivity reactions only was given. Eighteen out of 76 patients (24%) suffered a clinical hypersensitivity reaction; however, no silent inactivation was observed. Activity in the therapeutic range of greater than 100 U/l for at least 14 d was determined in 43 of the 45 patients who were analysed for enzyme activity.",
"affiliations": "Department of Paediatric Haematology/Oncology, University of Münster, Germany. hmuller@uni-muenster.de",
"authors": "Müller|H J|HJ|;Beier|R|R|;Löning|L|L|;Blütters-Sawatzki|R|R|;Dörffel|W|W|;Maass|E|E|;Müller-Weihrich|S|S|;Scheel-Walter|H G|HG|;Scherer|F|F|;Stahnke|K|K|;Schrappe|M|M|;Horn|A|A|;Lümkemann|K|K|;Boos|J|J|",
"chemical_list": "D001215:Asparaginase",
"country": "England",
"delete": false,
"doi": "10.1046/j.1365-2141.2001.03009.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-1048",
"issue": "114(4)",
"journal": "British journal of haematology",
"keywords": null,
"medline_ta": "Br J Haematol",
"mesh_terms": "D000293:Adolescent; D000707:Anaphylaxis; D000971:Antineoplastic Combined Chemotherapy Protocols; D001215:Asparaginase; D002648:Child; D002675:Child, Preschool; D004342:Drug Hypersensitivity; D016903:Drug Monitoring; D004789:Enzyme Activation; D004926:Escherichia coli; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011446:Prospective Studies",
"nlm_unique_id": "0372544",
"other_id": null,
"pages": "794-9",
"pmc": null,
"pmid": "11564065",
"pubdate": "2001-09",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Pharmacokinetics of native Escherichia coli asparaginase (Asparaginase medac) and hypersensitivity reactions in ALL-BFM 95 reinduction treatment.",
"title_normalized": "pharmacokinetics of native escherichia coli asparaginase asparaginase medac and hypersensitivity reactions in all bfm 95 reinduction treatment"
} | [
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"companynumb": "DE-JAZZ-2016-DE-006722",
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"activesubstancename": "ASPARAGINASE ERWINIA CHRYSANTHEMI"
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{
"abstract": "OBJECTIVE\nLong-term hormonal ablation in prostate cancer is associated with decreased overall health and quality of life. Few reports emphasized the role of chemotherapy in the management of early stage prostate cancer. This study analyzed the safety and efficacy of androgen deprivation therapy (ADT) plus chemotherapy as initial treatment for patients identified as local failures or not eligible for prostatectomy or radiation therapy due to advanced disease presentation.\n\n\nMETHODS\nEnrolled patients received ADT in the form of leuprolide every 12 weeks for 24 months with bicalutamide initiating after the completion of chemotherapy. Chemotherapy consisted of ketoconazole and doxorubicin for weeks 1, 3, and 5 and estramustine and docetaxel and for weeks 2, 4 and 6. During weeks 7 and 8, no treatment was received.\n\n\nRESULTS\nForty-six patients were enrolled, and forty-five patients were evaluable. Median progression-free survival (PFS) was 23.4 months. Median overall survival (OS) was 53.7 months. Out of 45 patients with measurable disease, 22 patients had an objective response: 9 patients achieved a complete response; 2 patients achieved a partial response; 10 patients achieved stable disease. Frequent grade 3 adverse events included elevated ALT (17 %), hypokalemia (13 %), and hypophosphatemia (13 %). Grade 4 adverse events were rare and included low bicarbonate (2 %), hypokalemia (2 %), leukocytopenia (2 %), and neutropenia (2 %).\n\n\nCONCLUSIONS\nThe treatment demonstrated clinical benefit in all patient subsets with minimal reversible treatment-related adverse events. Subgroup analysis suggests that having prior local therapy resulted in greater PFS and OS.",
"affiliations": "Division of Oncology, Department of Internal Medicine, University of Texas Health Science Center at Houston (Medical School)/Memorial Hermann Cancer Center, 6410 Fannin St., Suite 830, Houston, TX 77030, USA. robert.amato@uth.tmc.edu",
"authors": "Amato|Robert|R|;Stepankiw|Mika|M|;Gonzales|Patricia|P|",
"chemical_list": "D000726:Androgen Antagonists; D000813:Anilides; D018931:Antineoplastic Agents, Hormonal; D009570:Nitriles; D014105:Tosyl Compounds; C053541:bicalutamide; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen; D016729:Leuprolide",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00280-013-2163-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0344-5704",
"issue": "71(6)",
"journal": "Cancer chemotherapy and pharmacology",
"keywords": null,
"medline_ta": "Cancer Chemother Pharmacol",
"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D000369:Aged, 80 and over; D000726:Androgen Antagonists; D000813:Anilides; D018931:Antineoplastic Agents, Hormonal; D000971:Antineoplastic Combined Chemotherapy Protocols; D018572:Disease-Free Survival; D006801:Humans; D007610:Kallikreins; D016729:Leuprolide; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009570:Nitriles; D017430:Prostate-Specific Antigen; D011468:Prostatectomy; D011471:Prostatic Neoplasms; D011878:Radiotherapy; D014105:Tosyl Compounds; D017211:Treatment Failure",
"nlm_unique_id": "7806519",
"other_id": null,
"pages": "1629-34",
"pmc": null,
"pmid": "23604530",
"pubdate": "2013-06",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article",
"references": null,
"title": "A phase II trial of androgen deprivation therapy (ADT) plus chemotherapy as initial treatment for local failures or advanced prostate cancer.",
"title_normalized": "a phase ii trial of androgen deprivation therapy adt plus chemotherapy as initial treatment for local failures or advanced prostate cancer"
} | [
{
"companynumb": "US-JNJFOC-20130602788",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"drugadditional": null,
... |
{
"abstract": "Electronic Nicotine Delivery Systems (ENDS), commonly referred to as \"e-cigs,\" were first introduced in the United States in 2007. Since then, their use has grown substantially, with the largest market among adolescents and young adults. ENDS are often perceived by the public as safe alternatives to traditional cigarettes and as aids in smoking cessation. Little is known about inhalational hazards of e-cigs. We describe the case of a 45-year-old man who developed acute respiratory symptoms associated with onset of severe fixed airways obstruction 9 months after he quit traditional cigarettes and began high-dose vaping. Lung biopsy showed respiratory bronchiolitis. Analysis of his heated e-cigarette solution identified a mixture containing vanillin, aldehydes, alcohols and other chemicals, the inhalation effects of which have not been well-studied. This case report adds to the growing literature describing potentially severe lung health effects of vaping and provides a framework for taking a clinical vaping history so that the health consequences of e-cigarettes may be better understood.",
"affiliations": "University of Colorado School of Medicine Anschutz Medical Campus, Aurora, CO, USA.;Division of Environmental and Occupational Health Sciences , National Jewish Health, Denver, CO, USA.;Division of Environmental and Occupational Health Sciences , National Jewish Health, Denver, CO, USA. rosec@njhealth.org.",
"authors": "Macedonia|Tony V|TV|;Krefft|Silpa D|SD|;Rose|Cecile S|CS|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1007/s11606-019-05462-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0884-8734",
"issue": "35(1)",
"journal": "Journal of general internal medicine",
"keywords": null,
"medline_ta": "J Gen Intern Med",
"mesh_terms": "D066300:Electronic Nicotine Delivery Systems; D006801:Humans; D008297:Male; D008875:Middle Aged; D016540:Smoking Cessation; D062789:Tobacco Products; D014481:United States; D000072137:Vaping",
"nlm_unique_id": "8605834",
"other_id": null,
"pages": "345-349",
"pmc": null,
"pmid": "31705470",
"pubdate": "2020-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24436327;28337465;15828073;28617771;28392919;25607446;28983782;27787495;25658421;24832759;22194587;25180080;27184162;24462024;26642857;7952649;29392888;15332401;29053025;25930009;29065196;28877023;23778060;28248584;28522559;11979095;12151470;29059377;28884423;24935895",
"title": "Persistent Severe Fixed Airways Obstruction in a High-Dosing E-cigarette User.",
"title_normalized": "persistent severe fixed airways obstruction in a high dosing e cigarette user"
} | [
{
"companynumb": "NVSC2020US039732",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
"druga... |
{
"abstract": "BACKGROUND Diffuse alveolar hemorrhage (DAH) represents a life-threatening complication for many respiratory infections. We present a case of a patient with influenza A pneumonia associated with DAH. CASE REPORT An 80-year-old female patient was admitted with lethargy, dyspnea, and chest pain. On examination, she was afebrile with bilateral basal inspiratory crackles. Her chest x-ray revealed retro-cardiac infiltrate. Her hospital course was complicated by respiratory failure and septic shock requiring intubation. Nasopharyngeal swabs, rapid testing was positive for influenza A. Bronchoscopy showed diffuse bleeding and bronchoalveolar lavage (BAL) of the left lower lobe showed progressively bloody returns, consistent with DAH. Methylprednisolone 250 mg daily was started, with improvement in oxygenation. Repeat bronchoscopy 2 days later revealed normal mucosa and no further bleeding. The patient's respiratory status and infiltrates improved, but her overall status continued to deteriorate, and she died 2 weeks after admission. CONCLUSIONS High fatality rates have been reported in patients with influenza A viral pneumonia complicated by DAH. Advanced age and the presence of significant co-morbidities might predispose a patient to the development of a more aggressive clinical manifestation of influenza A and also increases the risk of developing DAH. Therefore, clinicians managing patients with influenza A viral pneumonia with this predisposing history should also maintain a high suspicion for DAH. We suggest early BAL for diagnosis and for the evaluation of other infections etiologies. Aggressive supportive care and the use of antiviral agents is recommended. The role of steroids is unclear and can be considered in patients with fulminant disease but might have no outcome benefit.",
"affiliations": "Division of Pulmonary and Critical Care Medicine, BronxCare Health System, Bronx, NY, USA.;Icahn School of Medicine at Mount Sinai, New York City, NY, USA.;Division of Pulmonary and Critical Care Medicine, BronxCare Health System, Bronx, NY, USA.",
"authors": "Toolsie|Omesh|O|;Tehreem|Aniqa|A|;Diaz-Fuentes|Gilda|G|",
"chemical_list": "D000914:Antibodies, Viral",
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.913801",
"fulltext": "\n==== Front\nAm J Case RepAm J Case RepamjcaserepThe American Journal of Case Reports1941-5923International Scientific Literature, Inc. 3101918910.12659/AJCR.913801913801ArticlesInfluenza A Pneumonia Associated with Diffuse Alveolar Hemorrhage. A Case Report and Literature Review Toolsie Omesh EF12Tehreem Aniqa DE23Diaz-Fuentes Gilda EF12\n1 Division of Pulmonary and Critical Care Medicine, BronxCare Health System, Bronx, NY, U.S.A.\n2 Icahn School of Medicine at Mount Sinai, New York City, NY, U.S.A.\n3 Department of Medicine, BronxCare Health System, Bronx, NY, U.S.A.Authors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\nCorresponding Author: Omesh Toolsie, e-mail: otoolsie@bronxleb.org2019 25 4 2019 20 592 596 25 10 2018 22 2 2019 © Am J Case Rep, 20192019This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Female, 80\n\nFinal Diagnosis: Diffuse alveolar hemorrhage in influenza A viral pneumonia\n\nSymptoms: Generalized fatigue • shortness of breath\n\nMedication: —\n\nClinical Procedure: —\n\nSpecialty: Critical Care Medicine\n\nObjective:\nRare co-existance of disease or pathology\n\nBackground:\nDiffuse alveolar hemorrhage (DAH) represents a life-threatening complication for many respiratory infections. We present a case of a patient with influenza A pneumonia associated with DAH.\n\nCase Report:\nAn 80-year-old female patient was admitted with lethargy, dyspnea, and chest pain. On examination, she was afebrile with bilateral basal inspiratory crackles. Her chest x-ray revealed retro-cardiac infiltrate. Her hospital course was complicated by respiratory failure and septic shock requiring intubation. Nasopharyngeal swabs, rapid testing was positive for influenza A. Bronchoscopy showed diffuse bleeding and bronchoalveolar lavage (BAL) of the left lower lobe showed progressively bloody returns, consistent with DAH. Methylprednisolone 250 mg daily was started, with improvement in oxygenation. Repeat bronchoscopy 2 days later revealed normal mucosa and no further bleeding. The patient’s respiratory status and infiltrates improved, but her overall status continued to deteriorate, and she died 2 weeks after admission.\n\nConclusions:\nHigh fatality rates have been reported in patients with influenza A viral pneumonia complicated by DAH. Advanced age and the presence of significant co-morbidities might predispose a patient to the development of a more aggressive clinical manifestation of influenza A and also increases the risk of developing DAH. Therefore, clinicians managing patients with influenza A viral pneumonia with this predisposing history should also maintain a high suspicion for DAH. We suggest early BAL for diagnosis and for the evaluation of other infections etiologies. Aggressive supportive care and the use of antiviral agents is recommended. The role of steroids is unclear and can be considered in patients with fulminant disease but might have no outcome benefit.\n\nMeSH Keywords:\nHemorrhageInfluenza A virusPneumonia\n==== Body\nBackground\nDiffuse alveolar hemorrhage (DAH) is considered a life-threatening medical emergency with nonspecific signs, symptoms, and chest imaging that can lead to respiratory failure and death. Hemoptysis, anemia, and new lung infiltrates are the most common presentation; however, in one-third of cases, hemoptysis is absent. Hemorrhagic bronchoscopic bronchoalveolar lavage (BAL) on serial samples is confirmatory for DAH. Treatment is based on the etiology of the hemorrhage. Causes of DAH include vasculitis, which is the most common etiology, followed by thrombocytopenia, post-autologous stem cell transplantation, autoimmune disorders, coagulation disorders, drugs, and infections [1]. We present a case of an elderly immuno-competent patient with influenza A (H1N1) complicated with DAH presenting without hemoptysis and who was stabilized with antibiotics and steroids.\n\nCase Report\nAn 80-year-old female was admitted to the intensive care unit during the winter season with a 4-day history of dyspnea, lethargy, and chest tightness. The patient denied cough, hemoptysis, fever, gastrointestinal symptoms, recent sick contacts, or traveling. Her medical history was significant for end-stage renal disease (ESRD) from long-standing hypertension on hemodialysis, severe pulmonary hypertension, and chronic obstructive pulmonary disease (COPD). She was a former smoker with 15-pack year history of cigarette use with no other toxic habits. The patient was not on any anti-coagulants, amiodarone, or chemotherapeutic agents, and had no recent nitrofurantoin use.\n\nOn examination, she was in acute respiratory distress with tachypnea and hypoxemia, oxygen saturation of 89% on room air which improved to 95% on 2 liters of oxygen via nasal cannula. She was afebrile with a temperature of 36.7°C (98°F), a blood pressure of 89/55 mmHg, and a heart rate of 89 beats per minute. Lungs examination was normal. The patient was awake and alert, and the rest of her examination, including cardiac and abdomen examinations was normal. Her skin demonstrated no petechiae or bruising with no gingival bleeding on oral examination or oozing from sites of intravenous access. Laboratory investigations showed anemia with a hemoglobin level of 9.9 g/dL (noted to be 13.3 g/dL at 1 month prior), (leukocytosis (white blood cell count was 13.0×103 cells/μL) with a left shift (neutrophil count was 10.8×103 cells/μL), a serum lactate of 3.7 mmol/L, and an arterial blood gas done on room air with a pH of 7.317, pCO2 of 57.7 mmHg, and pO2 of 40.2 mmHg. Coagulation profile reported an international normalized ratio (INR) of 1.1 with a prothrombin time (PT) of 13.5 seconds and a partial thromboplastin time (PTT) of 30.6 seconds. Urine and serum toxicology were negative. Chest x-ray showed retrocardiac infiltrates (Figure 1A). Nasopharyngeal swabs, rapid testing was positive for influenza A. The clinical status of the patient deteriorated rapidly with development of shock, for which she was intubated, and the patient was placed on mechanical ventilation and pressors. She was started on vancomycin, piperacillin-tazobactam, azithromycin, and oseltamivir for severe pneumonia. A chest computed tomography (CT) showed left lower and right upper lobe infiltrates, a right lower lobe nodule and no evidence of a pulmonary embolus (Figure 1B, 1C).\n\nFiberoptic bronchoscopy performed on day 2 of admission revealed airway erythema of the left and right bronchial trees and BAL performed in the left lower lobe showed progressive bloody returns consistent with DAH. BAL done in the right lower lobe also produced similar findings. Bronchoscopy and blood and urine cultures were negative. BAL cytology 4 1513 cells/mm3 for WBCs of which 54% were segmented neutrophils and 44% were lymphocytes. There were 111 250 million cells/mm3 of red blood cells. Autoimmune workup including antinuclear antibody, cytoplasmic and perinuclear antineutrophilic cytoplasmic autoantibodies, and rheumatoid factor were negative. Echocardiogram showed severe pulmonary hypertension with a pulmonary artery systolic pressure of 78 mmHg. The patient was hypoxic, with an arterial to inspired oxygen (PaO2/FiO2) ratio of 102 mmHg on a positive end expiratory pressure of 8 mmHg. On day 2 of admission in view of no improvement, intravenous methylprednisolone 250 mg/day was started with improvement in oxygenation by day 3 with an arterial to inspired PaO2/FiO2 ratio of 317 mmHg.\n\nA repeated fiberoptic bronchoscopy done 3 days following the first revealed normal mucosa and progressively clear returns on BAL performed in the left lower lobe (Figure 2A, 2B). The patient’s respiratory conditions improved with decreased oxygen requirement. She remained in septic shock and she died 2 weeks after admission.\n\nDiscussion\nDiffuse alveolar hemorrhage (DAH) is a distinct syndrome of pulmonary hemorrhage resulting from disruption of the alveolar-capillary basement membrane from injury to the pulmonary microcirculation including the alveolar capillaries, arterioles, and venules [2]. It is considered a life-threatening condition with reported hospital mortality ranging from 20% to 100% [3]. A high degree of suspicion is necessary for early recognition and diagnosis, as prompt initiation of treatment is necessary for survival. DAH can present at any age, either associated with an already established diagnosis or represent the initial presentation of a pre-existing or new systemic disease [1].\n\nDAH is defined pathologically by the accumulation of red blood cells, fibrin, and/or hemosiderin-laden macrophages in the alveolar space on biopsy [4]. The etiology is typically divided into 3 main histologic patterns reflecting the nature of the underlying disease process. The 3 main histologic subtypes include pulmonary capillaritis, bland pulmonary hemorrhage, and diffuse alveolar damage (DAD). The causes of DAH can also be divided into infectious and non-infectious, with the later affecting immunocompetent or immunocompromised patients. In immunocompromised patients, the main infectious etiologies associated with DAH include cytomegalovirus, adenovirus, invasive aspergillosis, Mycoplasma, Legionella, and Strongyloides. In immunocompetent individuals, influenza A (H1N1), dengue, leptospirosis, malaria, and Staphylococcus aureus infection have been reported [5]. In general, pulmonary infections are rarely associated with DAH but should always be considered in the initial diagnostic workup due to high mortality associated with this condition if left untreated.\n\nThe diagnosis of DAH requires bronchoscopy with BAL showing progressively hemorrhagic returns; in addition, hemosiderin-laden macrophages can be found in the lavage [6]. Respiratory cultures provided from BAL can also be evaluated for potential infectious etiologies. Routine laboratory studies and serologic analysis for connective tissue diseases and systemic vasculitis is an essential part of the initial workup in patients diagnosed with DAH. Rarely, an open lung or surgical biopsy might be necessary if the history and laboratory investigations do not reveal a diagnosis [1]. In our case, we were presented with an immunocompetent patient with acute hypoxic respiratory failure due to influenza A and associated DAH.\n\nThere are several diagnostic modalities that can be used for influenza A (H1N1), with real-time reverse-transcriptase polymerase chain reaction (rRT-PCR) having the highest sensitivity and specificity [7]. Our patient was diagnosed with a Food and Drug Administration approved influenza A and B Rapid Influenza Diagnostic Test (RIDT). RIDTs are antigen-based tests used for the rapid diagnosis of influenza virus infections. These tests use monoclonal antibodies that target the viral nucleo-protein and employ either enzyme immunoassay or immunochromatographic (lateral flow) techniques. RIDTs have shown variable assay performance with sensitivities ranging between 10% to 70%, with up to 90% specificity compared to standard RT-PCR-based assays [8].\n\nPresentations of influenza A virus infection vary from a mild upper respiratory illness to a fulminant pneumonia as was the case for our patient [9]. Clinical presentation includes an acute or subacute onset of cough, hemoptysis, and dyspnea, bilateral diffuse infiltrates of the lung, anemia, and acute respiratory failure. While hemoptysis is considered a hallmark presentation, it can be absent in up to one-third of the patients, as was the case for our patient described here. Extra-pulmonary manifestations are usually related to the underlying systemic disease. In the epidemiological data from the H1NI 2009 pandemic in the United Kingdom, several factors were associated with fulminant disease progression. These factors included age over 65 years, morbid obesity, cardiovascular disease, diabetes, chronic lung disease, metabolic disorders including diabetes mellitus, chronic renal or hepatic disease, immunosuppression, hemoglobinopathy, and a long history of smoking [10]. Our patient was 80 years old with ESRD and COPD with a 15-pack year history of smoking.\n\nDAH represents a complication that has high mortality in patients developing influenza A viral pneumonia. In 2010, Gilbert et al. described a case of novel H1N1 influenza A viral infection associated with DAH in a patient who presented with fever and developed hemoptysis, with bilateral alveolar infiltrates on chest-x-ray [11]. As in our patient’s case, this was a fatal case of influenza A (H1N1) infection despite aggressive management with mechanical ventilation, broad-spectrum antibiotics, and oseltamivir therapy. Mauad et al. reviewed the autopsy findings of 21 patients with confirmed novel human influenza A (H1N1) infection and found the presence of exu-dative DAD with intense alveolar hemorrhage in 5 patients of the 21 patients. They also described an influenza virus-induced “cytokine storm” within the lungs and high circulating levels of tumor necrosis factor-alpha and interform-gamma with viral overload leading to altered innate immune responses with a sustained increase in inflammation [12]. Another retrospective autopsy analysis of 15 fatal cases of influenza A (H1N1) infection also revealed DAD and DAD with hemorrhage [13].\n\nManagement of DAH involves aggressive supportive care and addressing the underlying systemic disease if any. In those patients with pulmonary capillaritis, the mainstay of treatment includes a combination of systemic glucocorticoids and immunosuppressive therapy, such as cyclophosphamide, rituximab, or plasmapheresis [2]. For patients with infection related DAD, treating the underlying infection is paramount. The role of steroids in the management of severe influenza A (H1N1) is less clearly defined. A meta-analysis conducted by Zhang et al. investigating the effect of steroids on hospital mortality in patients with severe influenza A (H1N1) infection suggested that corticosteroids has no beneficial effects in those patients [14]. In view of progressive respiratory deterioration, we decided to give systemic steroids to our patient with improvement in oxygenation and resolution of DAH following bronchoscopy. Several factors might have contributed to our patient’s partial recovery including early administration of oseltamivir with aggressive supportive care and possibly the addition of steroids. This partial recovery was short-lived, however, as the patient succumbed to the significant burden of disease.\n\nConclusions\nInfluenza usually affects the elderly and those patients with significant co-morbidities; the same group of patients where the risk for DAH is increased. Influenza associated with DAH is a rare condition, and clinicians should maintain a high index of suspicion especially in patients with rapidly fulminant disease. We suggest early bronchoscopy with BAL as this will allow for diagnosis of DAH, as well as diagnosis of associated infections. Antiviral therapy with aggressive supportive care is paramount and could decrease mortality. The role for steroids in treating this condition is not well established, and likely has no impact on outcomes.\n\nConflict of interest\n\nNone.\n\nAbbreviations:\nDAHdiffuse alveolar hemorrhage;\n\nBALbronchoalveolar lavage;\n\nESRDend-stage renal disease;\n\nCOPDchronic obstructive pulmonary disease;\n\nDADdiffuse alveolar damage\n\nFigure 1. (A) Chest x-ray on admission demonstrating a retrocardiac infiltrate. (B) Computed tomography (CT) chest, sagittal plane demonstrating left lower lobe infiltrate. (C) CT chest, coronal plane demonstrating right upper lobe infiltrate.\n\nFigure 2. (A) Bronchoalveolar lavage (BAL) done with progressively bloody returns on day 2 of admission. (B) Repeat BAL done on day 5 of admission.\n==== Refs\nReferences:\n1. Lara AR Schwarz MI Diffuse alveolar hemorrhage Chest 2010 137 5 1164 71 20442117 \n2. Park MS Diffuse alveolar hemorrhage Tuberc Respir Dis (Seoul) 2013 74 4 151 62 23678356 \n3. de Prost N Parrot A Picard C Diffuse alveolar haemorrhage: Factors associated with in-hospital and long-term mortality Eur Respir J 2010 35 1303 11 19840965 \n4. Collard HR Schwarz MI Diffuse alveolar hemorrhage Clin Chest Med 2004 25 583 92 15331194 \n5. von Ranke FM Zanetti G Hochhegger B Marchiori E Infectious diseases causing diffuse alveolar hemorrhage in immunocompetent patients: A state-of-the-art review Lung 2013 191 1 9 18 23128913 \n6. Zamora MR Warner ML Tuder R Schwarz MI Diffuse alveolar hemorrhage and systemic lupus erythematosus. Clinical presentation, histology, survival, and outcome Medicine (Baltimore) 1997 76 3 192 202 9193454 \n7. Centers for disease control, information on rapid molecular assays, RTPCR, and other molecular assays for diagnosis of influenza virus infection . Available at https://www.cdc.gov/flu/professionals/diagnosis/molecular-as-says.htm \n8. Vemula SV Zhao J Liu J Current approaches for diagnosis of influenza virus infections in humans Viruses 2016 8 4 96 27077877 \n9. Cao B Li XW Mao Y A national influenza pandemic (H1N1) 2009 Clinical Investigation Group of China (2009) Clinical features of the initial cases of 2009 pandemic influenza A (H1N1) virus infection in China N Engl J Med 2009 361 2507 17 20007555 \n10. London Health Protection Agency (HPA) Pandemic (H1N1) 2009 in England: An overview of initial epidemiological findings and implications for the second wave 2009 \n11. Gilbert CR Vipul K Baram M Novel H1N1 influenza A viral infection complicated by alveolar hemorrhage Respir Care 2010 55 5 623 25 20420734 \n12. Mauad T Hajjar LA Callegari GD Lung pathology in fatal novel human influenza A (H1N1) infection Am J Respir Crit Care Med 2010 181 72 79 19875682 \n13. Prasad HB Puranik SC Kadam DB Sangle SA Retrospective analysis of necropsy findings in patients of H1N1 and their correlation to the clinical features J Assoc Physicians India 2011 59 498 500 21887906 \n14. Soto-Abraham MV Soriano-Rosas J Díaz-Quiñónez A Pathological changes associated with the 2009 H1N1 virus N Engl J Med 2009 361 20 2001 3 19907053\n\n",
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"title": "Influenza A Pneumonia Associated with Diffuse Alveolar Hemorrhage. A Case Report and Literature Review.",
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"abstract": "Mid-esophageal diverticulum is a rare disease, formed by the traction caused by inflamed bronchial lymph nodes or by pulsion induced by motility disorder. We herein report a case of mid-esophageal diverticular bleeding in a patient with kyphosis who was taking an anti-platelet drug. She was successfully treated with endoscopic hemostasis. An 80-year-old woman presented to our emergency department with hematemesis. She had kyphosis and was taking dipyridamole for her chest pain. Emergent upper endoscopy revealed bleeding from a mid-esophageal diverticulum; hemostasis was achieved via clipping. Mid-esophageal diverticula can cause upper gastrointestinal bleeding. An endoscopic examination and hemostasis are effective treatments.",
"affiliations": "Department of Gastroenterology, Shimane Prefectural Central Hospital, Japan.;Department of Gastroenterology, Shimane Prefectural Central Hospital, Japan.;Department of Gastroenterology, Shimane Prefectural Central Hospital, Japan.;Department of Gastroenterology, Shimane Prefectural Central Hospital, Japan.;Department of Gastroenterology, Shimane Prefectural Central Hospital, Japan.;Department of Gastroenterology, Shimane Prefectural Central Hospital, Japan.;Department of Gastroenterology, Shimane Prefectural Central Hospital, Japan.;Department of Gastroenterology, Shimane Prefectural Central Hospital, Japan.;Department of Gastroenterology, Shimane Prefectural Central Hospital, Japan.;Department of Gastroenterology, Shimane Prefectural Central Hospital, Japan.;Department of Endoscopy, Shimane Prefectural Central Hospital, Japan.;Department of Endoscopy, Shimane Prefectural Central Hospital, Japan.;Department of Hepatology, Shimane Prefectural Central Hospital, Japan.;Department of Gastroenterology, Shimane Prefectural Central Hospital, Japan.;Department of Gastroenterology, Shimane Prefectural Central Hospital, Japan.;Department of Gastroenterology and Hepatology, Shimane University School of Medicine, Japan.;Department of Gastroenterology and Hepatology, Shimane University School of Medicine, Japan.",
"authors": "Kishi|Kanako|K|;Kusunoki|Ryusaku|R|;Fujishiro|Hirofumi|H|;Suemitsu|Shinsuke|S|;Kataoka|Masatoshi|M|;Fujiwara|Aya|A|;Tsukano|Kosuke|K|;Kotani|Satoshi|S|;Yamanouchi|Satoshi|S|;Aimi|Masahito|M|;Tanaka|Masaki|M|;Miyaoka|Youichi|Y|;Miyake|Tatsuya|T|;Kohge|Naruaki|N|;Imaoka|Tomonori|T|;Ishihara|Shunji|S|;Kinoshita|Yoshikazu|Y|",
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"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 3132783110.2169/internalmedicine.2951-19Case ReportMid-esophageal Diverticular Bleeding in a Patient with Kyphosis Kishi Kanako 1Kusunoki Ryusaku 1Fujishiro Hirofumi 1Suemitsu Shinsuke 1Kataoka Masatoshi 1Fujiwara Aya 1Tsukano Kosuke 1Kotani Satoshi 1Yamanouchi Satoshi 1Aimi Masahito 1Tanaka Masaki 2Miyaoka Youichi 2Miyake Tatsuya 3Kohge Naruaki 1Imaoka Tomonori 1Ishihara Shunji 4Kinoshita Yoshikazu 4\n1 Department of Gastroenterology, Shimane Prefectural Central Hospital, Japan\n2 Department of Endoscopy, Shimane Prefectural Central Hospital, Japan\n3 Department of Hepatology, Shimane Prefectural Central Hospital, Japan\n4 Department of Gastroenterology and Hepatology, Shimane University School of Medicine, JapanCorrespondence to Dr. Ryusaku Kusunoki, ryusakukusunoki@yahoo.co.jp\n\n22 7 2019 15 11 2019 58 22 3239 3242 4 3 2019 5 6 2019 Copyright © 2019 by The Japanese Society of Internal MedicineThe 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/).Mid-esophageal diverticulum is a rare disease, formed by the traction caused by inflamed bronchial lymph nodes or by pulsion induced by motility disorder. We herein report a case of mid-esophageal diverticular bleeding in a patient with kyphosis who was taking an anti-platelet drug. She was successfully treated with endoscopic hemostasis. An 80-year-old woman presented to our emergency department with hematemesis. She had kyphosis and was taking dipyridamole for her chest pain. Emergent upper endoscopy revealed bleeding from a mid-esophageal diverticulum; hemostasis was achieved via clipping. Mid-esophageal diverticula can cause upper gastrointestinal bleeding. An endoscopic examination and hemostasis are effective treatments. \n\nmid-esophageal diverticuladiverticular bleeding\n==== Body\nIntroduction\nGastrointestinal diverticula are usually asymptomatic and need no treatment. Mid-esophageal diverticula, which are true diverticula, develop as a result of traction from inflamed bronchial lymph nodes or pulsion by motility disorder (1).\n\nWe herein report a rare case of bleeding from a mid-esophageal diverticulum in a patient with kyphosis who was taking an anti-platelet drug. An endoscopic examination and hemostasis with clipping were effective.\n\nCase Report\nAn 80-year-old woman presented to our emergency department with hematemesis. She had a medical history of chest pain and had been taking dipyridamole after a diagnosis of angina pectoris. On arrival, her blood pressure was 135/74 mmHg, heart rate 89 beats per minute, and body temperature 36.7℃. She complained of nausea but no abdominal pain, melena, or diarrhea. Her laboratory test results were as follows: hemoglobin, 8.4 g/dL; hematocrit, 27.1%. Leukocyte and platelet counts were within normal ranges.\n\nAn emergency upper endoscopic examination revealed active esophageal bleeding from a small diverticulum at the anterior wall, 25 cm from the incisors (Fig. 1a). A small ulcer at the bottom of the diverticulum was revealed after endoscopic suctioning and inverting the diverticulum into the cap attachment. A hemostatic clip was immediately applied directly to the point of bleeding, the small ulcer at the bottom of the diverticulum. In addition, two hemostatic clips were applied, and the diverticulum opening was sutured (Fig. 1b). Bleeding was stopped with clipping, after which thrombin was sprayed around the diverticulum. A large hiatal hernia was observed. Reflex esophagitis was not observed. The stomach and duodenum appeared normal. Gastric atrophy was not observed on an endoscopic examination, and serum anti Helicobacter pylori IgG antibody was negative. Following the endoscopic hemostasis, the patient was treated with fasting and administered the proton pump inhibitor omeprazole 20 mg by injection 2 times a day.\n\nFigure 1. (a) An endoscopic examination revealed bleeding from the mid-esophageal diverticulum in the anterior wall. (b) Inverted diverticula during endoscopic hemostasis. (c) A clipping procedure at the bottom and opening of the diverticulum resulted in hemostasis.\n\nContrast-enhanced computed tomography (CT) showed a mid-esophageal diverticulum close to the tracheal bifurcation. Adjacent to the diverticulum, a lymph node with a small calcification was seen, suggesting a cicatrix of tuberculous lymphadenitis (Fig. 2). Diverticula usually develop due to traction from the lymph node. An esophagogram revealed retention of the contrast medium in the diverticulum of the anterior wall (Fig. 3). Because of significant kyphosis in the patient, her esophagus was approximately parallel to the ground in a standing position. There was a large hiatal hernia, and a large quantity of backflow from the stomach was seen. Eight days after admission, upper endoscopy showed three hemoclips on the diverticulum with no bleeding or blood clots.\n\nFigure 2. Computed tomography (CT) revealed the mid-esophageal diverticulum (arrows) close to the tracheal bifurcation. Adjacent the diverticulum, a lymph node with small calcification (arrowheads) was revealed. (a) Horizontal sectional view, (b) sagittal sectional view.\n\nFigure 3. An esophagogram, left lateral view, revealed retention of the contrast medium in the diverticulum of the anterior wall (arrows). (a) A large quantity of backflow from the stomach (asterisk) to the esophagus (double asterisk) was shown because of kyphosis and a large hiatal hernia. Vertebrae (dots) and diaphragm (arrowheads) are also shown. (b) Magnifying view of the mid-esophageal diverticulum. A hemoclip remained at the opening of the diverticulum.\n\nAfter endoscopic hemostasis, the patient remained well with no hematemesis or nausea, and anemia gradually improved without the need for blood transfusion. The administration of dipyridamole was stopped, and omeprazole 20 mg orally once a day was continued. Medical guidance was provided to prevent gastroesophageal reflux. The patient was discharged and continues to be well three years after treatment with no recurrence of gastrointestinal bleeding.\n\nDiscussion\nWe describe two important clinical findings in this case. First, mid-esophageal diverticular bleeding can occur in a patient with kyphosis on an anti-platelet drug; and second, emergent endoscopic hemostasis is effective.\n\nEsophageal diverticulum is classified according to its location into three categories: pharyngoesophageal (Zenker), mid-esophageal (Rokitansky), and epiphrenic. Mid-esophageal diverticulum is a true diverticulum, as it comprises all of the layers of the esophageal wall. Mid-esophageal diverticulum develops due to traction from inflamed bronchial lymph nodes. A recent study that reported the high coexistence ratio of motor disorder and mid-esophageal diverticulum suggested that the increase in intraluminal pressure by motility disorder secondarily induces the pulsion mechanism by which the diverticulum develops (1). We did not evaluate the esophageal function in this case. Based on the CT findings, we speculated that the diverticulum of this patient developed due to traction from inflamed bronchial lymph nodes. Esophageal diverticula are usually asymptomatic and rarely come to medical attention. If large or inflammatory diverticula occur associated with dysphagia or odynophagia, surgical resection may be required. Esophageal diverticular bleeding is very rare, and only six cases have been reported to date (2-7).\n\nKyphosis increases the risk of gastroesophageal reflex disease (GERD). GERD is induced by a decrease in the lesser esophageal sphincter (LES) pressure and regurgitation of gastric contents into the esophagus. Hiatal hernia is a major cause of decreased LES pressure and has a positive correlation with the severity of kyphosis (8,9). In this case, as represented by a contrast X-ray examination, the reflux and retention of gastric acid or dietary constituents stimulated mucosal injury in the diverticulum. In a study of seven cases of mid-esophageal diverticular bleeding, four cases, including our own, had coexisting hiatal hernia (Table). Furthermore, in the present case, acid secreted from non-atrophic gastric mucosa might have induced mucosal injury in the diverticulum. Therefore, the administration of a proton-pump inhibitor helped keep the patient well-maintained without recurrence of bleeding for three years.\n\nTable. Clinical Features of Mid-esophageal Bleeding.\n\nNo.\tReference\tAge/sex\tHiatal hernia\tNSAIDs\tSize\tNumber\tHemostatic therapy\t\n1\t2\t55/F\tYes\tNo\tNA\t2\tNo (spontaneous hemostasis)\t\n2\t3\t56/F\tYes\tNo\tsmall\t1\tSurgery\t\n3\t4\t82/F\tYes\tYes\tlarge\t1\tEndoscopic (epinephrine injection)\t\n4\t5\t56/F\tNo\tNo\tsmall\tmultiple\tNo (spontaneous hemostasis)\t\n5\t6\t63/M\tNo\tNo\tgiant\t1\tEndoscopic (injection therapy + clipping) S-B tube\t\n6\t7\t61/M\tNo\tYes\tlarge\t1\tPEG\t\n7\tThis case\t83/F\tYes\tYes\tsmall\t1\tEndoscopic (clipping)\t\nNA: not available, S-B: Sengstaken-Blakemore, PEG: percutaneous endoscopic gastrostomy\n\nUse of aspirin, other non-steroidal anti-inflammatory drugs (NSAIDs), or anti-platelet drugs increases the risk of diverticular bleeding in the colon (10). NSAIDs, including aspirin, are thought to damage the colonic mucosa via a direct topical effect and/or impaired prostaglandin synthesis, thus compromising the mucosal integrity, increasing the permeability, and enabling the influx of bacteria and other toxins (10). Although the risk factors for esophageal diverticular bleeding are not known, the use of dipyridamole might have induced mucosal injury and bleeding in our patient. In the study mentioned earlier, two patients had been on anti-platelet drugs (Table).\n\nA hemostatic approach for mid-esophageal diverticular bleeding has not yet been established. Three cases, including our own, were treated with an endoscopic approach, one was treated with injection therapy, and one was treated with injection therapy and clipping and subsequently with the Sengstaken-Blakemore double (S-B) tube (Table). Endoscopic hemostatic procedures for diverticular bleeding are mostly practiced in the colon. Colonic diverticula are usually small pseudo-diverticula, and colonic diverticular bleeding is the main cause of lower gastrointestinal bleeding. Endoscopic clipping provides a high hemostatic rate, relatively few complications, and a low re-bleeding rate for colonic diverticular bleeding. Endoscopic clipping is divided into two procedures: direct placement, which involves clipping to the bleeding vessel; and indirect placement, which involves clipping and suturing of the opening of the diverticulum. Direct placement reduces the re-bleeding rate from the colonic diverticulum more than indirect placement (11).\n\nThis is the first case of mid-esophageal diverticular bleeding that was successfully treated with the endoscopic clipping procedure. In our case, kyphosis and the administration of antiplatelet drugs may have induced the mid-esophageal diverticular bleeding, which was effectively treated using the endoscopic hemoclip procedure by direct placement.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. do Nascimento FA , Lemme EM , Costa MM \nEsophageal diverticula: pathogenesis, clinical aspects, and natural history . Dysphagia \n21 : 198 -205 , 2006 .16900308 \n2. Jonasson OM , Gunn LC \nMidesophageal diverticulum with hemorrhage: report of a case . Arch Surg \n90 : 713 -715 , 1965 .14280232 \n3. Tucker LE , Aquino T , Sasser W \nMid-esophageal traction diverticulum: rare cause of massive upper gastrointestinal bleeding . Mo Med \n91 : 140 -142 , 1994 .8170460 \n4. Helft S , Sideridis K , Greenberg RE , Bank S \nMid esophageal diverticulum with a bleeding ulcer: case report and review . Gastrointest Endosc \n61 : 759 -762 , 2005 .15855989 \n5. Al-Haddad M , Raimondo M \nUpper gastrointestinal bleed from esophageal diverticula in a patient with dermatomyositis . Dig Dis Sci \n52 : 137 -139 , 2007 .17160717 \n6. Turan I , Ozturk A , Akarca U , Ozutemiz O \nAn usual cause of massive upper gastrointestinal bleeding: Dieulafoy's lesion within a giant mid-esophageal diverticulum . Endoscopy \n40 (Suppl ): E177 , 2008 .18668464 \n7. Ballehaninna UK , Shaw JP , Brichkov I \nTraction esophageal diverticulum: a rare cause of gastro-intestinal bleeding . Springerplus \n1 : 50 , 2012 .23626926 \n8. Imagama S , Hasegawa Y , Wakao N , Hirano K , Hamajima N , Ishiguro N \nInfluence of lumbar kyphosis and back muscle strength on the symptoms of gastroesophageal reflux disease in middle-aged and elderly people . Eur Spine J \n21 : 2149 -2157 , 2012 .22370926 \n9. Yoshimura M , Nagahara A , Ohtaka K , et al \nPresence of vertebral fractures is highly associated with hiatal hernia and reflux esophagitis in Japanese elderly people . Intern Med \n47 : 1451 -1455 , 2008 .18703854 \n10. Strate LL , Liu YL , Huang ES , Giovannucci EL , Chan AT \nUse of aspirin or nonsteroidal anti-inflammatory drugs increases risk for diverticulitis and diverticular bleeding . Gastroenterology \n140 : 1427 -1433 , 2011 .21320500 \n11. Ishii N , Hirata N , Omata F , et al \nLocation in the ascending colon is a predictor of refractory colonic diverticular hemorrhage after endoscopic clipping . Gastrointest Endosc \n76 : 1175 -1181 , 2012 .23021162\n\n",
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"keywords": "diverticular bleeding; mid-esophageal diverticula",
"medline_ta": "Intern Med",
"mesh_terms": "D000369:Aged, 80 and over; D004238:Diverticulitis; D004936:Diverticulum, Esophageal; D005260:Female; D006471:Gastrointestinal Hemorrhage; D006396:Hematemesis; D016558:Hemostasis, Endoscopic; D006801:Humans; D007738:Kyphosis; D010975:Platelet Aggregation Inhibitors",
"nlm_unique_id": "9204241",
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"title": "Mid-esophageal Diverticular Bleeding in a Patient with Kyphosis.",
"title_normalized": "mid esophageal diverticular bleeding in a patient with kyphosis"
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"abstract": "►This case is an unusual presentation of a rare disease entity. ►The diagnosis of epithelioid trophoblastic tumor can be challenging resulting in delay in diagnosis. ►Epithelioid trophoblastic tumor can have a very aggressive course, especially in metastatic disease.",
"affiliations": "Department of Obstetrics and Gynecology, Henry Ford Health System, 2799 W.Grand Blvd., K-9 Detroit, MI-48202, United States.;Department of Pathology, Henry Ford Health System, 2799 W.Grand Blvd., K-9 Detroit, MI-48202, United States.;Gynecologic Oncology, Henry Ford Health System, 2799 W.Grand Blvd., K-9 Detroit, MI-48202, United States.",
"authors": "Madhu|Bagaria|B|;Gerbi|Rada|R|;Nabila|Rasool|R|",
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"title": "Epithelioid trophoblastic tumor and its diagnostic dilemmas: A rare case report.",
"title_normalized": "epithelioid trophoblastic tumor and its diagnostic dilemmas a rare case report"
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"abstract": "BACKGROUND\nChimeric antigen receptor T-cell therapies (CAR-T) are transforming the treatment of B-cell leukemias and lymphomas. Cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome represent common, potentially life-threatening toxicities from chimeric antigen receptor T-cell therapy treatment.\n\n\nMETHODS\nWe present a 53-year-old patient with primary refractory high-grade B-cell lymphoma who developed severe, refractory neurotoxicity following chimeric antigen receptor T-cell therapy but exhibited complete recovery after extracorporeal blood purification with CytoSorb (CytoSorbents, Monmouth Junction, NJ).Six days after chimeric antigen receptor T-cell therapy infusion, the patient developed cytokine release syndrome grade 3, prompting administration of dexamethasone and tocilizumab, a monoclonal antibody against the interleukin-6 receptor. His C-reactive protein levels started to decrease with tocilizumab and dexamethasone treatments. However, his ferritin levels continued to rise, and his interleukin-6 levels were above the upper detection threshold. Thirty-six hours later, the patient showed improved cytokine release syndrome but developed severe immune effector cell-associated neurotoxicity syndrome with predominant encephalopathy (grade 3) despite treatment with dexamethasone/methylprednisolone, tocilizumab, and anakinra. We therefore sought a rescue strategy to remove inflammatory mediators. Following emergency use authorization, we initiated extracorporeal blood purification with CytoSorb (CytoSorbents).Four-day extracorporeal blood purification resulted in complete resolution of immune effector cell-associated neurotoxicity syndrome and greater than 95% reduction in interleukin-6 levels without side effects. The patient was discharged home 10 days later with no signs of neurotoxicity or other secondary end-organ dysfunction.\n\n\nCONCLUSIONS\nOur case represents the first reported, successful application of extracorporeal blood purification with CytoSorb (CytoSorbents) to treat severe, refractory neurotoxicity following chimeric antigen receptor T-cell therapy.",
"affiliations": "Department of Critical Care Medicine, Mayo Clinic, Phoenix, AZ.;Division of Hematology/Oncology, Department of Medicine, Mayo Clinic, Phoenix, AZ.;Division of Hematology/Oncology, Department of Medicine, Mayo Clinic, Phoenix, AZ.;Department of Critical Care Medicine, Mayo Clinic, Phoenix, AZ.;Department of Critical Care Medicine, Mayo Clinic, Phoenix, AZ.",
"authors": "Singbartl|Kai|K|;Rosenthal|Allison|A|;Leis|Jose|J|;Patel|Bhavesh|B|;Sen|Ayan|A|",
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"fulltext": "\n==== Front\nCrit Care Explor\nCrit Care Explor\nCC9\nCritical Care Explorations\n2639-8028\nLippincott Williams & Wilkins Hagerstown, MD\n\n34235458\n00006\n10.1097/CCE.0000000000000472\nCase Report\nNovel Use of Extracorporeal Blood Purification for Treatment of Severe, Refractory Neurotoxicity After Chimeric Antigen Receptor T-Cell Therapy—A Case Report\nSingbartl Kai MD, MPH 1\nRosenthal Allison DO 2\nLeis Jose MD, PhD 2\nPatel Bhavesh MD 1\nSen Ayan MD, MSc 1\n1 Department of Critical Care Medicine, Mayo Clinic, Phoenix, AZ.\n2 Division of Hematology/Oncology, Department of Medicine, Mayo Clinic, Phoenix, AZ.\nFor information regarding this article, E-mail: ks.ms@posteo.de\n29 6 2021\n7 2021\n3 7 e0472Copyright © 2021 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.\n\nBACKGROUND:\n\nChimeric antigen receptor T-cell therapies (CAR-T) are transforming the treatment of B-cell leukemias and lymphomas. Cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome represent common, potentially life-threatening toxicities from chimeric antigen receptor T-cell therapy treatment.\n\nCASE SUMMARY:\n\nWe present a 53-year-old patient with primary refractory high-grade B-cell lymphoma who developed severe, refractory neurotoxicity following chimeric antigen receptor T-cell therapy but exhibited complete recovery after extracorporeal blood purification with CytoSorb (CytoSorbents, Monmouth Junction, NJ).\n\nSix days after chimeric antigen receptor T-cell therapy infusion, the patient developed cytokine release syndrome grade 3, prompting administration of dexamethasone and tocilizumab, a monoclonal antibody against the interleukin-6 receptor. His C-reactive protein levels started to decrease with tocilizumab and dexamethasone treatments. However, his ferritin levels continued to rise, and his interleukin-6 levels were above the upper detection threshold. Thirty-six hours later, the patient showed improved cytokine release syndrome but developed severe immune effector cell-associated neurotoxicity syndrome with predominant encephalopathy (grade 3) despite treatment with dexamethasone/methylprednisolone, tocilizumab, and anakinra. We therefore sought a rescue strategy to remove inflammatory mediators. Following emergency use authorization, we initiated extracorporeal blood purification with CytoSorb (CytoSorbents).\n\nFour-day extracorporeal blood purification resulted in complete resolution of immune effector cell-associated neurotoxicity syndrome and greater than 95% reduction in interleukin-6 levels without side effects. The patient was discharged home 10 days later with no signs of neurotoxicity or other secondary end-organ dysfunction.\n\nCONCLUSIONS:\n\nOur case represents the first reported, successful application of extracorporeal blood purification with CytoSorb (CytoSorbents) to treat severe, refractory neurotoxicity following chimeric antigen receptor T-cell therapy.\n\nchimeric antigen receptor T-cell therapies\nextracorporeal blood purification\nneurotoxicity\nOPEN-ACCESSTRUE\n==== Body\nAnti-CD19 chimeric antigen receptor T-cell therapies (CAR-T) represent a promising approach for treatment of refractory CD19+ B-cell malignancies, for example, acute and chronic B-cell leukemias and B-cell non-Hodgkin lymphomas (1). CAR-T, however, carry unique, potentially life-threatening toxicities that require specialized monitoring and management.\n\nCAR-T encompass autologous or allogeneic T cells that are genetically engineered to express chimeric antigen receptors, redirecting the cytotoxic effects toward tumor cells. Recognition of tumor-associated antigens initiates immune proliferation and release of cytokines by effector CAR-T cells. Interleukin (IL)-6, interferon gamma (IFNγ), and granulocyte-macrophage colony-stimulating factor as well as IL-8, IL-10, monocyte chemoattractant protein-1, and macrophage inflammatory protein-1b all are considered crucial mediators in this response (2, 3).\n\nOverwhelming and widespread immune activation after CAR-T can lead to two potentially life-threatening adverse reactions: cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) (4). CRS typically manifests with general symptoms, such as fever, weakness, and myalgias, but it can involve any organ system and lead to hemodynamic instability, respiratory distress, and acute kidney or liver injury. Cases of fulminant hemophagocytic lymphohistiocytosis (HLH), a severe immune activation with lymphohistiocytic tissue infiltration and immune-mediated multiple organ failure, have also occurred after CAR-T (4). CRS grading includes presence and severity of fever, hypotension, and hypoxemia but not laboratory markers of inflammation (5). ICANS frequently manifests as encephalopathy but also delirium, dizziness, aphasia, motor dysfunction, tremor, ataxia, seizure, dyscalculia, or myoclonus. ICANS grading involves screening for encephalopathy via the Immune Effector Cell-Associated Encephalopathy (ICE) score as well as evaluating for level of consciousness, motor symptoms, seizures, and elevated intracranial pressure/cerebral edema (Tables 1 and 2) (5). ICANS often accompanies CRS, but its clinical course does not always parallel that of CRS (6).\n\nTABLE 1. Immune Effector Cell-Associated Encephalopathy Score\n\nPoints\tOrientation (Year, Month, City, Hospital)\tNaming (Name Three Objects)\tFollowing Simple Commands\tWriting a Standard Sentence\tAttention (e.g., Count Backward From 100 by 10)\t\n4\t4 (of 4)\t\t\t\t\t\n3\t3 (of 4)\t3 (of 3)\t\t\t\t\n2\t2 (of 4)\t2 (of 3)\t\t\t\t\n1\t1 (of 4)\t1 (of 3)\tYes\tYes\tYes\t\n0\t0 (of 4)\t0 (of 3)\tNo\tNo\tNo\t\nMaximum score is 10.\n\nCompiled after American Society for Transplantation and Cellular Therapy consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells (5).\n\nTABLE 2. Immune Effector Cell-Associated Neurotoxicity Syndrome\n\nGrade\tNeurotoxicity Domain\t\nImmune Effector Cell-Associated Encephalopathy Score\tDepressed Level of Consciousness\tSeizure\tMotor Findings\tElevated ICP/Cerebral Edema\t\n1\t7–9\tAwakens spontaneously\t\t\t\t\n2\t3–6\tAwakens to voice\t\t\t\t\n3\t0–2\tAwakens only to tactile stimulus\tClinical seizure with rapid resolution or nonconvulsive seizures on electroencephalography with resolution after intervention\t\tFocal/local edema on neuroimaging\t\n4\t0 (patient is unable to perform)\tUnarousable or requires vigorous or repetitive stimuli to arouse\tProlonged seizure (> 5 min) or repetitive seizures without return to baseline in between\tDeep focal motor weakness (e.g., hemiparesis or paraparesis)\tDiffuse cerebral edema on neuroimaging; decerebrate or decorticate posturing; or cranial nerve VI palsy; or papilledema; or Cushing triad\t\nCompiled after American Society for Transplantation and Cellular Therapy consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells (5).\n\nCurrent management of CAR-T toxicities entails supportive care, corticosteroids, and anti-IL-6 therapy (4). Tocilizumab is a humanized monoclonal antibody against the IL-6 receptor and thereby blocks binding of IL-6 to its receptor. Tocilizumab is U.S. Food and Drug Administration (FDA)-approved for treatment of CRS after CAR-T.\n\nHemoadsorption is an extracorporeal blood purification technique intended to remove various molecules, for example, cytokines, from the bloodstream. During hemoadsorption, blood flows through adsorbent columns, which are made of porous polymer beads that vary in size, side chains, and chemical properties to target molecules of interest (7). With the exception of emergency use authorization for severe coronavirus disease 2019, hemoadsorbtion devices have not received FDA approval. Some devices, including CytoSorb (CytoSorbents, Monmouth Junction, NJ), have been approved within the European Union for over 10 years and used in over 130,000 treatments with severe inflammatory syndromes (8).\n\nCASE PRESENTATION\n\nWith written informed consent, we present a 53-year-old male patient with primary refractory high-grade B-cell lymphoma and rearrangements of MYC/BCL2 and BCL6, who had failed rituximab, etoposide, prednisone, vincristine, Cytoxan, and doxorubicin and rituximab, oxaliplatin, cytarabine, and dexamethasone treatments. He received lymphocyte-depleting chemotherapy with fludarabine and Cytoxan 5 days prior to hospital admission. CAR-T infusion (axicabtagene ciloleucel) on the day of hospital admission (day 0) (Fig. 1) commenced without immediate side effects.\n\nFigure 1. Patient's hospital course. A, Course of Immune Effector Cell-Associated Encephalopathy (ICE) in relationship to inflammatory markers and treatments throughout hospitalization (days 0–25) for chimeric antigen receptor T-cell therapy (CAR-T) infusion. IL-6 plasma concentrations above the upper detection limit (greater than 400 µg/L) are displayed as equaling 400 µg/L and marked with “*”. B, Course of hematological parameters and treatments throughout hospitalization (days 0–25) for CAR-T infusion. CRP = C-reactive protein, CRRT = continuous renal replacement therapy.\n\nC-reactive protein (CRP) rose on day 3, whereas his ferritin levels remained normal until day 5 (Fig. 1A). Clinical assessments for CRS and ICANS were negative at that time. On day 4, he developed a fever of 39.1°C (grade 1 CRS) (Fig. 1B). His examination was negative for ICANS (ICE score 10/10), whereas his CRP continued to rise. In the evening of day 5, he became mildly disoriented and demonstrated altered handwriting.\n\nOngoing fevers and new hypotension on day 6 prompted the first administration of tocilizumab (grade 2 CRS, ICE 9/10) (Fig. 1, A and B), followed by two additional doses later. He also required intermittent fluid resuscitation and treatment with dexamethasone. His CRP levels started to decrease, whereas his ferritin levels increased further.\n\nWorsening renal function, evolving hyperactive delirium, and need for vasopressors mandated a transfer to the ICU on hospital day 8. A bone marrow biopsy at that time showed no evidence of lymphoma but prominent hemophagocytosis, consistent with HLH/macrophage activation syndrome due to CRS.\n\nDespite ongoing supportive care, including continuous renal replacement therapy (CRRT), and treatment with (escalating doses of) dexamethasone, the patient’s clinical status did not improve. Workup for underlying infections remained negative, except for positive Clostridium difficile surveillance (polymerase chain reaction for toxin) with ongoing diarrhea. The patient had tested positive for C. difficile toxin approximately 1 month prior to admission. Neuroimaging and electroencephalography studies were also unremarkable. A lumbar puncture was deferred because of refractory low platelet counts (Fig. 1B) and fibrinogen levels (less than 110 mg/dL). He became increasingly encephalopathic (ICE 7/10). His ferritin levels were still rising, and IL-6 levels were above the upper detection limit (greater than 400 pg/mL). Additional doses of tocilizumab and one dose of anakinra (IL-1 receptor antagonist) were given, followed by methylprednisolone.\n\nDrastically worsening encephalopathy (ICE 2/10, protected airway, and hospital day 9) together with persistently elevated inflammatory markers led us to explore novel rescue options. After careful consideration of risks and benefits, we obtained emergency use authorization for extracorporeal blood purification with CytoSorb (CytoSorbents) from our local Institutional Review Board. Continuous hemoadsorption with CytoSorb (CytoSorbents) was initiated on hospital day 11. Six CytoSorb (CytoSorbents) cartridges, for 12–24 hours each, were used over 4 days in conjunction (predialyzer) with standard CRRT (continuous veno-venous hemodiafiltration, Prismaflex M150 with AN69 membrane hemofilter, Baxter Healthcare Corporation, Deerfield, IL, blood flow 250 mL/min, fluid removal rate 0–250 mL/hr, and total effluent flow rate 25–30 mL/kg/hr). Because of persistent thrombocytopenia and low fibrinogen levels, we refrained from systemic anticoagulation. The treatment was well tolerated without any obvious side effects.\n\nInflammatory markers, in particular IL-6, started to decline rapidly within 48 hours of hemoadsorption and continued to do so throughout the treatment course (Fig. 1A). This was followed by complete neurologic and renal recovery over the next 3 days (ICE score 10/10) (Fig. 1A). The patient was transferred out of the ICU the next day (hospital day 16) and continued to recover throughout the remainder of his hospital stay. He was discharged home on hospital day 25 without any signs of secondary end-organ dysfunction and is currently undergoing CAR-T follow-up care.\n\nDISCUSSION\n\nFollowing CAR-T infusion, our patient developed CRS followed by ICANS 4 days later. Both CRS and ICANS are well-known adverse effects after CAR-T and the result of an overwhelming immune response. Treatment with repetitive doses of tocilizumab and dexamethasone together with supportive care appeared to resolve the clinical symptoms of CRS. On the contrary, ICANS progressed rapidly and was refractory to currently accepted treatment options, including blockade of individual cytokines with tocilizumab and anakinra. Similarly, available data suggest that most patients with neurotoxicity do not respond to tocilizumab treatment (3, 6).\n\nSelective blockade of individual cytokines also poses risks that might have contributed to the observed treatment failure. Administration of tocilizumab can lead to an increase in IL-6 and soluble IL-6 receptor levels, reflecting states of increased production or decreased clearance of IL-6 (9, 10). IL-6 can cross the blood-brain barrier and exert neurotoxic effects. Tocilizumab is not expected to cross over, largely because of its size (11). Published observations that tocilizumab administration is associated with precipitation or worsening of ICANS further support this concept and make a delayed response in our case unlikely (11–13). Here, our patient did not develop ICANS until after initiation of tocilizumab treatment and drastically deteriorated after the fourth dose.\n\nIL-6 is not the only cytokine involved. Selective blockade of single mediators might not be sufficient to attenuate the overall response. We therefore sought a rescue strategy that allowed for broad-spectrum, continuous cytokine elimination rather than selectively blocking individual cytokines. We selected hemoadsorption with CytoSorb (CytoSorbents), an extracorporeal blood purification technique. Previous case reports and smaller studies of various systemic inflammatory conditions, for example, septic shock, and pancreatitis, have indicated clinical improvement after treatment with CytoSorb (CytoSorbents). Sepsis, like CRS or ICANS, is characterized by the circulation of inflammatory cytokines. Extracorporeal blood purification techniques to remove cytokines during sepsis have been of great interest for a long time (8). Various techniques, including hemofiltration, hemoperfusion, intermittent or continuous high-volume hemofiltration, plasmapheresis, or hemoadsorption, have been studied to remove cytokines. Only plasma exchange or hemoadsorption seem to be effective extracorporeal blood purification techniques during sepsis (8, 14, 15). Standard CRRT protocols and equipment, as in our case, do not remove cytokines in a relevant manner (16–18).\n\nCytoSorb (CytoSorbents) unselectively removes substances from blood by means of hemoadsorption to biocompatible porous polymer beads, packed into cartridges (7). CytoSorb (CytoSorbents) can remove substances, ranging from 5 to 60 kDa in size, including IL-6 and other cytokines (7). Although exact clinical data are not available, it is unlikely that it removes tocilizumab or other antibodies from the circulation. However, CytoSorb (CytoSorbents) will likely remove low-molecular-weight substances like dexamethasone or methylprednisolone.\n\nTwo case reports have shown hemodynamic and respiratory improvement during CytoSorb (CytoSorbents) treatment in patients with CRS after CAR-T infusions (17, 18). A current randomized controlled trial focuses on changes in plasma IL-6 in patients with severe CRS or ICANS after CAR-T (clinicaltrials.gov; NCT0404843).\n\nConclusion\n\nTo this end, we present the first successful treatment of severe, refractory CAR-T-induced neurotoxicity employing extracorporeal blood purification with CytoSorb (CytoSorbents). Considering the inherent limitations of a case report, we cannot truly assess the impact of this treatment on our patient’s recovery. Nonetheless, the results of our novel approach to treat an otherwise potentially fatal complication from CAR-T deserve future research efforts.\n\nThe authors have disclosed that they do not have any potential conflicts of interest.\n==== Refs\nREFERENCES\n\n1. June CH Sadelain M . Chimeric antigen receptor therapy. N Engl J Med. 2018; 379 :64–73 29972754\n2. Schmidts A Wehrli M Maus MV . Toward better understanding and management of CAR-T cell-associated toxicity. Annu Rev Med. 2021; 72 :365–382 32776808\n3. Freyer CW Porter DL . Cytokine release syndrome and neurotoxicity following CAR T-cell therapy for hematologic malignancies. J Allergy Clin Immunol. 2020; 146 :940–948 32771558\n4. Neelapu SS Tummala S Kebriaei P . Chimeric antigen receptor T-cell therapy—assessment and management of toxicities. Nat Rev Clin Oncol. 2018; 15 :47–62 28925994\n5. Lee DW Santomasso BD Locke FL . ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant. 2019; 25 :625–638 30592986\n6. Santomasso BD Park JH Salloum D . Clinical and biological correlates of neurotoxicity associated with CAR T-cell therapy in patients with B-cell acute lymphoblastic leukemia. Cancer Discov. 2018; 8 :958–971 29880584\n7. Bonavia A Groff A Karamchandani K . Clinical utility of extracorporeal cytokine hemoadsorption therapy: A literature review. Blood Purif. 2018; 46 :337–349 30176653\n8. Honore PM Hoste E Molnár Z . Cytokine removal in human septic shock: Where are we and where are we going? Ann Intensive Care. 2019; 9 :56 31089920\n9. Uchiyama Y Yoshida H Koike N . Anti-IL-6 receptor antibody increases blood IL-6 level via the blockade of IL-6 clearance, but not via the induction of IL-6 production. Int Immunopharmacol. 2008; 8 :1595–1601 18664393\n10. Nishimoto N Terao K Mima T . Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease. Blood. 2008; 112 :3959–3964 18784373\n11. Gust J Hay KA Hanafi LA . Endothelial activation and blood-brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T cells. Cancer Discov. 2017; 7 :1404–1419 29025771\n12. Nellan A McCully CML Cruz Garcia R . Improved CNS exposure to tocilizumab after cerebrospinal fluid compared to intravenous administration in rhesus macaques. Blood. 2018; 132 :662–666 29954750\n13. Lee DW Gardner R Porter DL . Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014; 124 :188–195 24876563\n14. Rimmer E Houston BL Kumar A . The efficacy and safety of plasma exchange in patients with sepsis and septic shock: A systematic review and meta-analysis. Crit Care. 2014; 18 :699 25527094\n15. Chang T Tu YK Lee CT . Effects of polymyxin B hemoperfusion on mortality in patients with severe sepsis and septic shock: A systemic review, meta-analysis update, and disease severity subgroup meta-analysis. Crit Care Med. 2017; 45 :e858–e864 28445237\n16. Hattori N Oda S . Cytokine-adsorbing hemofilter: Old but new modality for septic acute kidney injury. Ren Replacement Ther. 2016; 2 :41\n17. Stahl K Schmidt BMW Hoeper MM . Extracorporeal cytokine removal in severe CAR-T cell associated cytokine release syndrome. J Crit Care. 2020; 57 :124–129 32113143\n18. Bottari G Merli P Guzzo I . Multimodal therapeutic approach of cytokine release syndrome developing in a child given chimeric antigen receptor-modified T cell infusion. Crit Care Explor. 2020; 2 :e0071 32166291\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2639-8028",
"issue": "3(7)",
"journal": "Critical care explorations",
"keywords": "chimeric antigen receptor T-cell therapies; extracorporeal blood purification; neurotoxicity",
"medline_ta": "Crit Care Explor",
"mesh_terms": null,
"nlm_unique_id": "101746347",
"other_id": null,
"pages": "e0472",
"pmc": null,
"pmid": "34235458",
"pubdate": "2021-07",
"publication_types": "D002363:Case Reports",
"references": "28445237;18664393;32771558;30176653;29954750;32776808;18784373;30592986;28925994;29025771;32166291;31089920;24876563;29972754;32113143;25527094;29880584",
"title": "Novel Use of Extracorporeal Blood Purification for Treatment of Severe, Refractory Neurotoxicity After Chimeric Antigen Receptor T-Cell Therapy-A Case Report.",
"title_normalized": "novel use of extracorporeal blood purification for treatment of severe refractory neurotoxicity after chimeric antigen receptor t cell therapy a case report"
} | [
{
"companynumb": "US-PRA-000117",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
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"drugadditional": "3",
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{
"abstract": "BACKGROUND\nOptimal management of posttransplant lymphoproliferative disease (PTLD) remains to be defined due to heterogeneity of this condition and lack of predictors of the outcome. Here we report our experience with pediatric PTLD nonresponsive to immunosuppression (IS) withdrawal, managed after stratification into high and low risk according to the presenting features.\n\n\nMETHODS\nThis is a single-center retrospective review of prospectively enrolled patients. From 2001 to 2011, 17 children were diagnosed with severe B-lineage, CD20+, PTLD after a median of 37 months (range, 5-93) from liver (12), heart (4), or multiorgan (1) transplantation. Treatment was tailored on 2 risk groups: (1) standard-risk (SR) patients received IS reduction and rituximab; (2) high-risk (HR) patients received IS discontinuation, rituximab and polychemotherapy.\n\n\nRESULTS\nThe cumulative incidence of rejection at 1 and 5 years after the diagnosis of PTLD was 35% (95% confidence interval [95% CI], 18-69%) and 53% (33-85%), respectively, whereas the disease-free survival at 1 and 5 years was 94% (95% CI, 65-99%) and 75% (45-90%), respectively. Three children died, PTLD-free, from different transplant-related complications: primary nonfunction after retransplantation (liver), cytomegalovirus disease 21 months after PTLD treatment (liver), graft dysfunction 25 months after PTLD (heart).\n\n\nCONCLUSIONS\nSevere B-lineage PTLD after solid organ transplantation may be classified as SR or HR and treated accordingly with a tailored protocol obtaining a satisfactory long-term outcome. This approach accomplishes the control of lymphoproliferation in severe forms as well as the minimization of toxicity in milder PTLDs.",
"affiliations": "1 Department of Pediatrics, Hospital Papa Giovanni XXIII, Bergamo, Italy. 2 Department of Transplant Surgery, Hospital Papa Giovanni XXIII, Bergamo, Italy. 3 Department of Cardiac Surgery, Hospital Papa Giovanni XXIII, Bergamo, Italy. 4 Department of Pathology, Hospital Papa Giovanni XXIII, Bergamo, Italy. 5 Department of Hematology, Hospital Papa Giovanni XXIII, Bergamo, Italy.",
"authors": "Giraldi|Eugenia|E|;Provenzi|Massimo|M|;Conter|Valentino|V|;Colledan|Michele|M|;Bolognini|Stefania|S|;Foglia|Carlo|C|;Sebastiani|Roberta|R|;Fiocchi|Roberto|R|;Gianatti|Andrea|A|;DʼAntiga|Lorenzo|L|;Rambaldi|Alessandro|A|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "United States",
"delete": false,
"doi": "10.1097/TP.0000000000000845",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1337",
"issue": "100(2)",
"journal": "Transplantation",
"keywords": null,
"medline_ta": "Transplantation",
"mesh_terms": "D000293:Adolescent; D000367:Age Factors; D001402:B-Lymphocytes; D019070:Cell Lineage; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D005260:Female; D006084:Graft Rejection; D006801:Humans; D007166:Immunosuppressive Agents; D007223:Infant; D007558:Italy; D053208:Kaplan-Meier Estimate; D008232:Lymphoproliferative Disorders; D008297:Male; D016377:Organ Transplantation; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D012720:Severity of Illness Index; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "0132144",
"other_id": null,
"pages": "437-45",
"pmc": null,
"pmid": "26270449",
"pubdate": "2016-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Risk-adapted Treatment for Severe B-Lineage Posttransplant Lymphoproliferative Disease After Solid Organ Transplantation in Children.",
"title_normalized": "risk adapted treatment for severe b lineage posttransplant lymphoproliferative disease after solid organ transplantation in children"
} | [
{
"companynumb": "IT-BAXTER-2011BH029729",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nRenin-angiotensin system inhibitors (ACEI/ARB-II), diuretics and NSAIDs, a combination known as \"Triple Whammy\", can result in decreased glomerular filtration rate (GFR) and acute kidney injury (AKI). Objectives: To describe the incidence of AKI for each drug type and their combinations. To define the profile of patients admitted for drug-related AKI secondary to Triple Whammy drugs (AKITW), with an assessment of costs and mortality.\n\n\nMETHODS\nA retrospective observational 15-month study developed in three stages: - First: a cross-sectional stage to identify and describe hospitalizations due to AKITW. - Second: a follow-up stage of an outpatient cohort consuming these drugs (15,307 subjects). - Third: a cohort stage to assess costs and mortality, which compared 62 hospitalized patients with AKITW and 62 without AKI, paired by medical specialty, sex, age and comorbidity according to their Clinical Risk Groups.\n\n\nRESULTS\nThere were 85 hospitalization episodes due to AKITW, and 78% of patients were over the age of 70. The incidence of AKITW in the population was 3.40 cases/1000 users/year (95% CI: 2.59-4.45). By categories, these were: NSAIDs + diuretics 8.99 (95% CI: 3.16-25.3); Triple Whammy 8.82 (95% CI: 4.4-17.3); ACEI/ARB-II + diuretics 6.87 (95% CI: 4.81-9.82); and monotherapy with diuretics 3.31 (95% CI: 1.39-7.85). Mean hospital stay was 7.6 days (SD 6.4), and mean avoidable costs were estimated at €214,604/100,000 inhabitants/year. Mortality during hospitalization and at 12 months was 11.3% and 38.7% respectively, and there were no significant differences when compared with the control group.\n\n\nCONCLUSIONS\nTreatment with ACEI, ARB-II, diuretics and/or NSAIDs shows a high incidence of hospitalization episodes due to AKI; diuretics as monotherapy or dual and triple combination therapy cause the highest incidence. AKITW involves high health care costs and avoidable mortality.",
"affiliations": "Servicio de Nefrología. Hospital de Palamós. Palamos, Girona (España). Electronic address: rmgarcia@ssibe.cat.;Servicio de Farmacia, Serveis de Salut Integrats Baix Emporda (SSIBE). Palamós, Girona (España).;Servicio de Nefrología. Hospital de Palamós. Palamos, Girona (España).;Servicio de Nefrología. Hospital de Palamós. Palamos, Girona (España).;Grup de recerca en Serveis Sanitaris i Resultats en Salut (GRESSIRES). Serveis de Salut Integrats Baix Emporda (SSIBE). Palamós, Girona (España).;Unidad de información asistencial. Serveis de Salut Integrats Baix Emporda (SSIBE). Palamós, Girona (España).;Grup de recerca en Serveis Sanitaris i Resultats en Salut (GRESSIRES). Serveis de Salut Integrats Baix Emporda (SSIBE). Palamós, Girona (España).",
"authors": "Camin|Rosa Maria Garcia|RM|;Cols|Montse|M|;Chevarria|Julio Leonel|JL|;Osuna|Rosa García|RG|;Carreras|Marc|M|;Lisbona|Josep Maria|JM|;Coderch|Jordi|J|",
"chemical_list": "D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004232:Diuretics",
"country": "Spain",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0211-6995",
"issue": "35(2)",
"journal": "Nefrologia : publicacion oficial de la Sociedad Espanola Nefrologia",
"keywords": "Acute kidney injury; Agentes antihipertensivos; Agentes antiinflamatorios; Anti-inflammatory agents; Antihypertensive agents; Diuretics; Diuréticos; Drug interactions; Interacciones farmacológicas; Lesión renal aguda",
"medline_ta": "Nefrologia",
"mesh_terms": "D058186:Acute Kidney Injury; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D000894:Anti-Inflammatory Agents, Non-Steroidal; D003430:Cross-Sectional Studies; D004232:Diuretics; D004357:Drug Synergism; D005260:Female; D017721:Hospital Costs; D006760:Hospitalization; D006801:Humans; D008297:Male; D008875:Middle Aged; D012084:Renin-Angiotensin System; D012189:Retrospective Studies; D013030:Spain",
"nlm_unique_id": "8301215",
"other_id": null,
"pages": "197-206",
"pmc": null,
"pmid": "26300514",
"pubdate": "2015",
"publication_types": "D016428:Journal Article; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Acute kidney injury secondary to a combination of renin-angiotensin system inhibitors, diuretics and NSAIDS: \"The Triple Whammy\".",
"title_normalized": "acute kidney injury secondary to a combination of renin angiotensin system inhibitors diuretics and nsaids the triple whammy"
} | [
{
"companynumb": "ES-JNJFOC-20180423923",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional": "3",
"d... |
{
"abstract": "BACKGROUND\nThe purpose of this study was to evaluate the superficial lymph drainage patterns of primary skin cancers of the head arising from the occipital or parietal region.\n\n\nMETHODS\nThe dominant patterns of lymph drainage were retrospectively reviewed in eight patients aged 36-85 years with skin cancers in the occipital or parietal region in whom sentinel lymph node biopsy or lymph node dissection had been performed at Hokkaido University Hospital between January 1981 and December 2015.\n\n\nRESULTS\nLymph drainage was mainly to the occipital (6/8, 75%), level II (5/8, 63%), and level V lymph nodes (5/8, 63%). Of the six patients with drainage to the occipital lymph nodes, four (67%) also had drainage to level V nodes.\n\n\nCONCLUSIONS\nThe dominant lymph drainage pattern in patients with skin cancer arising from the occipital or parietal region was to the occipital, level II, and level V lymph nodes. Further, lymph tended to drain directly from the occipital region to the level V lymph nodes.",
"affiliations": "Department of Plastic and Reconstructive Surgery, Graduate School of Medicine, Hokkaido University, Kita-15 Nishi-7, Kita-ku, Sapporo City, Hokkaido, 060-8638, Japan.;Department of Plastic and Reconstructive Surgery, Graduate School of Medicine, Hokkaido University, Kita-15 Nishi-7, Kita-ku, Sapporo City, Hokkaido, 060-8638, Japan.;Department of Plastic and Reconstructive Surgery, Graduate School of Medicine, Hokkaido University, Kita-15 Nishi-7, Kita-ku, Sapporo City, Hokkaido, 060-8638, Japan.;Department of Plastic and Reconstructive Surgery, Graduate School of Medicine, Hokkaido University, Kita-15 Nishi-7, Kita-ku, Sapporo City, Hokkaido, 060-8638, Japan.;Department of Plastic and Reconstructive Surgery, Graduate School of Medicine, Hokkaido University, Kita-15 Nishi-7, Kita-ku, Sapporo City, Hokkaido, 060-8638, Japan.;Department of Plastic and Reconstructive Surgery, Graduate School of Medicine, Hokkaido University, Kita-15 Nishi-7, Kita-ku, Sapporo City, Hokkaido, 060-8638, Japan.;Department of Plastic and Reconstructive Surgery, Graduate School of Medicine, Hokkaido University, Kita-15 Nishi-7, Kita-ku, Sapporo City, Hokkaido, 060-8638, Japan. toshi-116@nifty.com.",
"authors": "Maeda|Taku|T|;Yamamoto|Yuhei|Y|;Furukawa|Hiroshi|H|;Oyama|Akihiko|A|;Funayama|Emi|E|;Murao|Naoki|N|;Hayashi|Toshihiko|T|http://orcid.org/0000-0002-1180-1685",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1007/s10147-017-1121-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-9625",
"issue": "22(4)",
"journal": "International journal of clinical oncology",
"keywords": "Lymph node dissection; Lymphatic flow; Parieto-occipital region; Sentinel lymph node; Skin cancer",
"medline_ta": "Int J Clin Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006258:Head and Neck Neoplasms; D006801:Humans; D008197:Lymph Node Excision; D008198:Lymph Nodes; D008207:Lymphatic Metastasis; D008297:Male; D008545:Melanoma; D008875:Middle Aged; D009778:Occipital Lobe; D010296:Parietal Lobe; D012189:Retrospective Studies; D021701:Sentinel Lymph Node Biopsy; D012878:Skin Neoplasms",
"nlm_unique_id": "9616295",
"other_id": null,
"pages": "774-779",
"pmc": null,
"pmid": "28364313",
"pubdate": "2017-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "8402110;24521106;18453984;21246639;15923849;21814882;8615963;23606459;19917835;21285766;10877250",
"title": "Dominant lymph drainage patterns in the occipital and parietal regions: evaluation of lymph nodes in patients with skin cancer of the head.",
"title_normalized": "dominant lymph drainage patterns in the occipital and parietal regions evaluation of lymph nodes in patients with skin cancer of the head"
} | [
{
"companynumb": "JP-BIOGEN-2017BI00448432",
"fulfillexpeditecriteria": "1",
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "INTERFERON BETA-1A"
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{
"abstract": "Toxic epidermal necrolysis and Staphylococcal scalded skin syndrome (SSSS) are potentially life-threatening dermatological emergencies that present in a similar clinical fashion. Toxic epidermal necrolysis is typically triggered by anticonvulsant and other neurological medications and reports clindamycin inducing the disease is exceedingly rare. SSSS seldomly occurs in adult patients. We present the case of a 60-year-old male presenting with dermatological rash covering >80% his body surface. Diagnosis and therapy involved multidisciplinary contribution from medical physicians, dermatologists, microbiologists and histopathologists to provide a favourable outcome.",
"affiliations": "Department of Respiratory Medicine, Galway University Hospital, Galway, Ireland.;Department of Respiratory Medicine, Galway University Hospital, Galway, Ireland.;Department of Respiratory Medicine, Galway University Hospital, Galway, Ireland.;Department of Respiratory Medicine, Galway University Hospital, Galway, Ireland.;National University of Ireland, Galway, Ireland.",
"authors": "Davey|Matthew G|MG|;Birrane|John|J|;Brennan|Michelle|M|;Breen|David P|DP|;Laing|Mary E|ME|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/omcr/omaa020",
"fulltext": "\n==== Front\nOxf Med Case Reports\nOxf Med Case Reports\nomcr\nOxford Medical Case Reports\n2053-8855 Oxford University Press \n\n10.1093/omcr/omaa020\nomaa020\nCase Report\nClindamycin induced toxic epidermal necrolysis versus Staphylococcal scalded skin syndrome: a case report\nDavey Matthew G 12 Birrane John 12 Brennan Michelle 1 Breen David P 12 Laing Mary E 23 1 \nDepartment of Respiratory Medicine, Galway University Hospital, Galway, Ireland\n2 \nNational University of Ireland, Galway, Ireland\n3 \nDepartment of Dermatology, Galway University Hospital, Galway, Ireland\nCorrespondence address. Department of Respiratory Medicine, Galway University Hospital, Newcastle Rd, Galway, H91 YR71, Ireland. Tel: +353860732042; Fax: +353860732042; E-mail: m.davey7@nuigalway.iematthew.davey@hse.ie\n3 2020 \n06 5 2020 \n06 5 2020 \n2020 3 omaa02023 1 2020 22 2 2020 18 3 2020 © The Author(s) 2020. Published by Oxford University Press.2020This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nToxic epidermal necrolysis and Staphylococcal scalded skin syndrome (SSSS) are potentially life-threatening dermatological emergencies that present in a similar clinical fashion. Toxic epidermal necrolysis is typically triggered by anticonvulsant and other neurological medications and reports clindamycin inducing the disease is exceedingly rare. SSSS seldomly occurs in adult patients. We present the case of a 60-year-old male presenting with dermatological rash covering >80% his body surface. Diagnosis and therapy involved multidisciplinary contribution from medical physicians, dermatologists, microbiologists and histopathologists to provide a favourable outcome.\n==== Body\nINTRODUCTION\nToxic epidermal necrolysis (TEN) and Staphylococcal scalded skin syndrome (SSSS) have the tendency to mimic one another on clinical presentation in the form of a widespread, blistering Nikolosky positive rash. Differentiation and accurate diagnosis of both diseases depend upon thorough clinical examination with subsequent comprehensive histological reporting. Lincosamide antibiotics such as clindamycin have rarely been associated with TEN in medical literature and medications such as anticonvulsant and antipsychotics being recognised as the major pharmacological triggers of the disease [1]. Similar to TEN, adult SSSS is a disease known to carry a high mortality rate with poor predictability of outcome when compared to the paediatric population who suffer from the disease [2, 3]. The purpose of this case report is to report a diagnostic conundrum of clindamycin induced TEN vs SSSS in a 63-year-old male patient who presented to the emergency department of a University Teaching Hospital in the West of Ireland late in August 2019. This report outlines factors in differentiating these two dermatological emergencies and the difficulties faced in treating such a case on presentation to the emergency department.\n\nCASE PRESENTATION\nA 63-year-old male presented with a 2-day history of a widespread, erythematous rash covering all surfaces of his body. The rash appeared 2 days prior to admission with associated prodromal malaise and anorexia. His medical history was significant for a cellulitis of his left lower limb for which he was prescribed oral clindamycin 5 days prior. Two days before admission, the patient noted a pruritic rash on his abdomen which subsequently became erythematous. The rash then migrated to his face and the rest of his torso. Within the next 48 h, it spread to involve his back and upper and lower limbs. The patient then began experiencing subjective fever and presented to his general practitioner before being referred to hospital. On hospital presentation he was apyrexic, tachycardic (irregularly irregular pulse rate of 170 beats per min) and was tachypneoic (respiratory rate of 28). He was normotensive (126/84 mmHg) and remained alert and interactive clinical examination was remarkable for an oatmeal dermatitis of the face and perioral area (Figs 1 and 2) and an erythematous, blistering rash covering 80% of his total body surface area. Nikolosky sign was positive. Oral involvement was noted. The palms of his hands and the soles of his feet were spared.\n\nFigure 1 Image demonstrating the oatmeal dermatitis affecting the patients oral and nasal facial mucosa.\n\nFigure 2 Sparing of the mucosal membranes of the oatmeal dermatologicalrash.\n\nPotentially causative medications (including clindamycin) were stopped. Electrocardiogram confirmed atrial fibrillation. The patient was immediately isolated from other patients and increased contact precautions were taken. Fluid resuscitation was commenced as per local hospital sepsis guidelines and urinary output monitored. Paraffin gel was applied liberally two hourly and potent topical corticosteroids twice daily. Intravenous hydrocortisone (100 mg) was given four times daily. Laboratory investigations on admission were significant for a moderate leucocytosis of 15.5 × 109/l and a neutrophilia of 14.5 × 109/l. C-reactive protein levels were 123 mg/l and venous lactate was markedly elevated at 6.5 mg/dl. Blood, urine and wound site cultures were sent for culture and sensitivity. Autoimmune and viral screens were taken. Skin biopsies were performed on two occasions: A 4 mm punch biopsy of affected skin was taken from the anterolateral left forearm and a repeat punch biopsy was taken from the sacral area on Day 2 of admission. The patient’s chest X-ray revealed no abnormality.\n\nA marked improvement in the patient’s rash was seen on admission Days 3 and 4, and his clinical condition gradually improved. The patient remained apyrexic. A switch from intravenous hydrocortisone to 30 mg of oral prednisolone was made on Day 7. The patient evidenced impressive regeneration of the affected skin and corticosteroids were tapered prior to discharge 21 days after admission.\n\nDISCUSSION\nTEN and SSSS may provide diagnostic dilemma for clinicians on the basis of their similar clinical manifestations. Table 1 illustrates the important clinical and histopathological considerations for accurate diagnosis of these potentially life-threatening diseases at presentation and during workup.\n\nTable 1 Clinical, pathophysiological and diagnostic differences between TEN andSSSS\n\n\tToxic epidermal necrolysis\tSSSS\t\nClinical presentation\tWidespread blistering, positive Nikolosky sign, erythematous, tender skin\tWidespread blistering, positive Nikolosky sign, erythematous, tender skin\t\nDifferences in clinical presentation\tBase of blistering tends to be pink or white (the colour of dermis), while surrounding skin is brown, tan or black due to melanin pigment at and above the basal layer of the epidermis, no mucosal involvement, typically occurs after pharmacological trigger\tBase of blistering tends to be the same colour as the surrounding adjacent skin, mucosal involvement, typically paediatric patients and atypically in adults, adult patients usually have renal impairment\t\nMortality\t26% [4]\t4–11% in children, 40–63% in adult population [3, 9]\t\nPathophysiology\tPathophysiological mechanism is largely unknown; usually a pharmacological or infectious trigger are thought to drive a CD8+ cytotoxic lymphocyte delayed hypersensitivity response against an individual’s own keratinocytes. A protein called granulysin is released by cytotoxic CD+ lymphocytes and natural killer cells has been identified in in vitro and animal studies as a key molecule underlying development of the characteristic lesions of SJS–TEN\tHistologically, epidermal layer is detached, blisters affect subcorneal layer. Epidermal detachment occurs in sheets due to Staphylococcal exotoxin producing a serine protease that destroys desmoglein 1 in the epidermis (handler). Adult patients with renal impairment tend to be affected by SSSS as they fail to excrete exotoxins produced by Staphyococcal bacteria [9]\t\nHistological diagnostic features\tDermal-epidermal blister with focal dyskeratosis and areas of full thickness epidermal necrosis\tSubcorneal bullae with scant inflammation\t\nTEN is a potentially life-threatening dermatological emergency carrying a mortality rate of ~26% [4]. Antibiotics, anticonvulsant drugs, and non-steroid antiinflammatory drugs are described in medical literature as common inducers of the Steven–Johnson syndrome–toxic epidermal necrolysis disease spectrum (SJS-TEN) [1, 5]. Lincosamide antibiotics such as clindamycin are poorly recorded as being causative: formal literature review of the PUBMED, SCOPUS and MEDLINE databases results provided only five recorded cases of clindamycin as a putative trigger of SJS/TEN syndromes. These cases typically involved acute onset rash developing over a number of hours post clindamycin administration. All of these cases involved corticosteroid as a primary therapeutic agent and consequential settling of symptoms. Our patient reported a history of clindamycin treatment for leg cellulitis 5 days prior to presentation which raised suspicion for a drug-induced hypersensitivity reaction. Initial histological reporting during patient workup described: ‘fragments of detached necrotic epidermis and stratum corneum with parakeratotic changes with no bacterial colonies’. When considering this patients history and clinical picture in combination with epidermal tissue necrosis as the main histopathological diagnostic feature in TEN, this was considered the working diagnosis for thiscase.\n\nSSSS is a superficial epidermolyic skin disorder triggered by exfoliative toxins A and B produced by 5% of Staphylococcus [6]. This condition, first described by Ritter von Rittershain in 1878, is well described in paediatric patients and carries a mortality of up to 50% [7]. Diagnosis is exceedingly rare in the adult population [2, 8]. Formal diagnosis of SSSS is made when histopathological evaluation demonstrates a subcorneal split along the granular cell layer which contain acantholytic cells, whilst inflammatory cell infiltrate and cell necrosis are characteristically absent [9]. Our patients epidermal biopsies taken 2 days after his initial biopsy yielded results favouring SSSS as a histopathological diagnosis: ‘…skin showing a thick surface crust composed of mixed neutrophils and parakeratotic material with possible bacterial colonies present, no evidence of vasculitis, no evidence of bullous change. Provisional conclusion: There is no evidence of vasculitis or the histological features of TEN. The histological differential diagnosis would include staphylococcus scalded skin syndrome although no subcorneal bulla is seen’. Patients with SSSS have the classic tendency to have scant inflammatory response on histological tissue biopsy, yet our patient’s second biopsy manifested the presence of mixed neutrophils. Despite this, patients may develop leucocytosis on blood film and our patient displayed only moderate leucocytosis despite the severe nature of his rash encompassing 80% of his total body surface area. Clinically, pyrexia would be typically be expected in SSSS; however, our patient remained apyrexic throughout his hospital admission. Interestingly, our patient was prescribed clindamycin as a measure to treat cellulitis. It is plausible this cellulitic tissue harboured a Staphylococcus infection, which may have possessed the endotoxins necessary to potentiate SSSS. This theory further complicates this diagnostic conundrum. However, repetitive swab cultures from blister sites and blood cultures were negative for Staphylococcus infection rendering SSSS diagnosis less likely. These clinical inconsistencies for textbook knowledge of these conditions added complexity diagnosis.\n\nThis case demonstrates a favourable outcome despite ambiguity in suspected dermatological disease processes and disparate histology. Staphylococcal scalded skin and toxic epidermal necrolysis are known to clinically present in an almost analogous manner despite disparate disease processes and can pose diagnostic difficulty as clearly outlined in this case where a patient does not clearly fit into either disease process.\n\nAcknowledgments\nNone.\n\nConflict of interest statement\nNone declared.\n\nFunding\nNone Received.\n\nEthical Approval\nNot applicable.\n\nConsent\nVerbal and written consent was obtained from this patient.\n\nGuarantor\nNot applicable.\n==== Refs\nReferences\n1. \nWang YH , Chen CB , Tassaneeyakul W , Saito Y , Aihara M , Choon SE et al. \nThe medication risk of Stevens-Johnson syndrome and toxic epidermal Necrolysis in Asians: the major drug causality and comparison with the US FDA label\n. Clin Pharmacol Ther 2019 ;105 :112 –20\n.29569740 \n2. \nPatel GK , Finlay AY \nStaphylococcal scalded skin syndrome: diagnosis and management\n. Am J Clin Dermatol 2003 ;4 :165 –75\n.12627992 \n3. \nJeyakumari D , Gopal R , Eswaran M , Kumar CM \nStaphylococcal scalded skin syndrome in a newborn\n. J Glob Infect 2009 ;1 :45 –7\n.\n4. \nBettuzzi T , Penso L , de Prost N , Hemery F , Hua C , Colin A et al. \nTrends in mortality rates for Stevens-Johnson syndrome and toxic epidermal necrolysis: experience of a single Centre in France between 1997 and 2017\n. Br J Dermatol 2020 ;182 :247 –8\n.31323695 \n5. \nDodiuk-Gad RP , Chung WH , Valeyrie-Allanore L , Shear NH \nStevens-Johnson syndrome and toxic epidermal necrolysis: an update\n. Am J Clin Dermatol 2015 ;16 :475 –93\n.26481651 \n6. \nFarroha A , Frew Q , Jabir S , Dziewulski P \nStaphylococcal scalded skin syndrome due to burn wound infection\n. Ann Burns Fire Disasters 2012 ;25 :140 –2\n.23467312 \n7. \nMockenhaupt M , Idzko M , Grosber M , Schöpf E , Norgauer J \nEpidemiology of Staphylococcal scalded skin syndrome in Germany\n. J Invest Dermatol 2005 ;124 :700 –3\n.15816826 \n8. \nStaiman A , Hsu DY , Silverberg JI \nEpidemiology of Staphylococcal scalded skin syndrome in U.S. children\n. Br J Dermatol 2018 ;178 :704 –8\n.29077993 \n9. \nHandler MZ , Schwartz RA \nStaphylococcal scalded skin syndrome: diagnosis and management in children and adults\n. J Eur Acad Dermatol Venereol 2014 ;28 :1418 –23\n.24841497\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2053-8855",
"issue": "2020(3)",
"journal": "Oxford medical case reports",
"keywords": null,
"medline_ta": "Oxf Med Case Reports",
"mesh_terms": null,
"nlm_unique_id": "101642070",
"other_id": null,
"pages": "omaa020",
"pmc": null,
"pmid": "32395254",
"pubdate": "2020-03",
"publication_types": "D016428:Journal Article",
"references": "15816826;24841497;26481651;12627992;29077993;31323695;20300386;23467312;29569740",
"title": "Clindamycin induced toxic epidermal necrolysis versus Staphylococcal scalded skin syndrome: a case report.",
"title_normalized": "clindamycin induced toxic epidermal necrolysis versus staphylococcal scalded skin syndrome a case report"
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{
"companynumb": "IE-GLASSHOUSE PHARMACEUTICALS LIMITED CA-2021GLH00001",
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"activesubstancename": "CLINDAMYCIN"
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"abstract": "OBJECTIVE Minimally invasive lateral lumbar interbody fusion (LLIF) via the retroperitoneal transpsoas approach is a technically demanding procedure with a multitude of potential complications. A relatively unknown complication is the contralateral psoas hematoma. The authors speculate that injury occurs from segmental vessel injury at the time of contralateral annulus release; however, this is not fully understood. In this multicenter retrospective review, the authors report the incidence of this contralateral complication and its neurological sequelae. METHODS This study was a retrospective chart review of all minimally invasive LLIF performed at participating institutions from 2008 to 2014. Exclusion criteria included an underlying diagnosis of trauma or neoplasia as well as lateral corpectomies or anterior column releases. Single-level, multilevel, and stand-alone constructs were included. All patients underwent preoperative MRI. Follow-up was at least 12 months. All complications and clinical outcomes were self-reported by each surgeon. RESULTS There were 3950 lumbar interbody cages placed via the retroperitoneal transpsoas approach, with 7 cases (0.18% incidence) of symptomatic contralateral psoas hematoma, 3 of which required reoperation for hematoma evacuation. Neurological outcome did not improve after reoperation. Reoperation occurred an average of 1 month after the initial operation due to a delay in diagnosis. In 1 case, segmental artery injury was confirmed at the time of surgery; in the others, segmental vessel injury was suspected, although it could not be confirmed. Neurological deficits persisted in 3 patients while the others remained neurologically intact. Two patients were receiving antiplatelet therapy prior to the procedure. CONCLUSIONS The contralateral psoas hematoma is a rare complication suspected to occur from segmental vessel injury during contralateral annulus release. Detailed review of preoperative imaging for aberrant vessel anatomy may prevent injury and subsequent neurological deficit.",
"affiliations": "Department of Neurosurgery & Brain Repair, Morsani College of Medicine, University of South Florida, Tampa.;Department of Neurosurgery & Brain Repair, Morsani College of Medicine, University of South Florida, Tampa.;Department of Neurosurgery & Brain Repair, Morsani College of Medicine, University of South Florida, Tampa.;Center for Spinal Disorders, Florida Orthopaedic Institute, Tampa, Florida.;Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina; and.;Instituto de Patologia da Coluna, São Paulo, Brazil.;Department of Neurosurgery & Brain Repair, Morsani College of Medicine, University of South Florida, Tampa.",
"authors": "Beckman|Joshua M|JM|;Vincent|Berney|B|;Park|Michael S|MS|;Billys|James B|JB|;Isaacs|Robert E|RE|;Pimenta|Luiz|L|;Uribe|Juan S|JS|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.3171/2016.4.SPINE151040",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1547-5646",
"issue": "26(1)",
"journal": "Journal of neurosurgery. Spine",
"keywords": "LLIF = lateral lumbar interbody fusion; complication; lateral lumbar interbody fusion; psoas hematoma; segmental vessel; transpsoas",
"medline_ta": "J Neurosurg Spine",
"mesh_terms": "D000368:Aged; D005260:Female; D005500:Follow-Up Studies; D006406:Hematoma; D006801:Humans; D015994:Incidence; D008159:Lumbar Vertebrae; D008297:Male; D008875:Middle Aged; D019060:Minimally Invasive Surgical Procedures; D011183:Postoperative Complications; D016658:Psoas Muscles; D012189:Retrospective Studies; D013123:Spinal Fusion",
"nlm_unique_id": "101223545",
"other_id": null,
"pages": "50-54",
"pmc": null,
"pmid": "27494784",
"pubdate": "2017-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Contralateral psoas hematoma after minimally invasive, lateral retroperitoneal transpsoas lumbar interbody fusion: a multicenter review of 3950 lumbar levels.",
"title_normalized": "contralateral psoas hematoma after minimally invasive lateral retroperitoneal transpsoas lumbar interbody fusion a multicenter review of 3950 lumbar levels"
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"companynumb": "US-BAYER-2017-155801",
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"abstract": "Gestational diabetes is on the rise and demographics are changing in many countries due to increased migration. Simultaneously, the treatment of gestational diabetes in our clinic has shifted towards metformin with substantially less insulin treatment. The aim was to study the impact of these changes on metabolic control and pregnancy outcome by comparing women diagnosed with gestational diabetes during 2012-2013 and 2016-2017.\n\n\n\nOur universal Oral Glucose Tolerance Test screening program for gestational diabetes diagnosed 199 women with singleton pregnancies during 2012-2013 and 203 during 2016-2017. Treatment and achieved metabolic control in the two different time periods were compared. Pregnancy outcome data related to gestational diabetes were retrieved from case notes and compared between the different time periods.\n\n\n\nWhen comparing results from 2016-2017 with 2012-2013 there was no difference in maternal weight or weight gain. There was a higher frequency of heredity (52.6 vs 35.4%; P = 0.001) and non-Scandinavian ethnicity (46.5 vs 33.8%; P = 0.011).The frequency of smoking during pregnancy was significantly lower (2.6 vs 7.7%; P = 0.023) There was an improved metabolic control as measured by median glucose in 2016-2017 compared with 2012-2013 (5.8 vs 6.2 mmol/L; P < 0.001). Insulin was less frequently used in 2016-2017 than in 2012-2013 (32.5 vs 44.7%; P = 0.012). There was a significant increase in the use of metformin (14.8 vs 0%; P < 0.001). There were no differences regarding the frequency of large-for-gestational-age infants (8.2% vs 7.3%; P = 0.762) or macrosomia (16.3 vs 15.1%; P = 0.745), median birthweight (3510 vs 3521; P = 0.879), frequency of cesarean section (28.1 vs 27.8%; P = 0.951) or Apgar scores at 10 minutes (10 [3-10] vs 10 [7-10]; P = 0.290).\n\n\n\nIn an increasing but changing population of gestational diabetes women in our region, with more hereditary and non-Scandinavian origins, but with fewer smokers, metabolic control has improved with maintained favorable pregnancy outcomes, with more frequent use of metformin and substantially less use of insulin treatment.",
"affiliations": "Department of Endocrinology, Skåne University Hospital, Lund, Sweden.;Department of Endocrinology, Skåne University Hospital, Lund, Sweden.;Institution of Clinical Sciences, Lund University, Lund, Sweden.;Department of Endocrinology, Skåne University Hospital, Lund, Sweden.;Institution of Clinical Sciences, Lund University, Lund, Sweden.",
"authors": "Moll|Ulrika|U|0000-0002-7038-9475;Landin-Olsson|Mona|M|;Nilsson|Charlotta|C|0000-0002-0561-8526;Ursing|Dag|D|;Strevens|Helena|H|",
"chemical_list": "D007004:Hypoglycemic Agents",
"country": "United States",
"delete": false,
"doi": "10.1111/aogs.13758",
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"issue": "99(3)",
"journal": "Acta obstetricia et gynecologica Scandinavica",
"keywords": "blood glucose; cesarean section; gestational diabetes; glucose tolerance test; large for gestational age; macrosomia; pregnancy outcome",
"medline_ta": "Acta Obstet Gynecol Scand",
"mesh_terms": "D000328:Adult; D003710:Demography; D016640:Diabetes, Gestational; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents; D007231:Infant, Newborn; D008137:Longitudinal Studies; D011247:Pregnancy; D011256:Pregnancy Outcome; D011295:Prenatal Care; D013548:Sweden",
"nlm_unique_id": "0370343",
"other_id": null,
"pages": "333-340",
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"pubdate": "2020-03",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Pregnancy outcome in women with gestational diabetes - A longitudinal study of changes in demography and treatment modalities.",
"title_normalized": "pregnancy outcome in women with gestational diabetes a longitudinal study of changes in demography and treatment modalities"
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"companynumb": "SE-ALKEM LABORATORIES LIMITED-SE-ALKEM-2019-09848",
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"activesubstancename": "INSULIN NOS"
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{
"abstract": "BACKGROUND\nAcute myeloid leukemia (AML) is an aggressive malignancy only cured by intensive therapy. However, many elderly and unfit patients cannot receive such treatment due to an unacceptable risk of treatment-related morbidity and mortality. Disease-stabilizing therapy is then the only possible strategy, one alternative being treatment based on all-trans retinoic acid (ATRA) combined with the histone deacetylase inhibitor valproic acid and possibly low-toxicity conventional chemotherapy.\n\n\nMETHODS\nPrimary AML cells were derived from 43 patients included in two clinical studies of treatment based on ATRA, valproic acid and theophyllamine; low toxicity chemotherapy (low-dose cytarabine, hydroxyurea, 6-mercaptopurin) was also allowed. Pretreatment leukemic cells were analyzed by mutation profiling of 54 genes frequently mutated in myeloid malignancies and by global gene expression profiling before and during in vivo treatment.\n\n\nRESULTS\nPatients were classified as responders and non-responders to the treatment, however response to treatment showed no significant associations with karyotype or mutational profiles. Significance analysis of microarray (SAM) showed that responders and non-responders significantly differed with regard to the expression of 179 different genes. The differentially expressed genes encoding proteins with a known function were further classified based on the PANTHER (protein annotation through evolutionary relationship) classification system. The identified genes encoded proteins that are involved in several important biological functions, but a main subset of the genes were important for transcriptional regulation. These pretherapy differences in gene expression were largely maintained during treatment. Our analyses of primary AML cells during in vivo treatment suggest that ATRA modulates HOX activity (i.e. decreased expression of HOXA3, HOXA4 and HOXA5 and their regulator PBX3), but altered function of DNA methyl transferase 3A (DNMT3A) and G-protein coupled receptor signaling may also contribute to the effect of the overall treatment.\n\n\nCONCLUSIONS\nResponders and non-responders to AML stabilizing treatment based on ATRA and valproic acid differ in the pretreatment transcriptional regulation of their leukemic cells, and these differences may be important for the clinical effect of this treatment.\n\n\nBACKGROUND\nClinicalTrials.gov no. NCT00175812 ; EudraCT no. 2004-001663-22, registered September 9, 2005 and ClinicalTrials.gov no. NCT00995332 ; EudraCT no. 2007-2007-001995-36, registered October 14, 2009.",
"affiliations": "Department of Medicine, Haukeland University Hospital, N-5021, Bergen, Norway. Hakon.Reikvam@med.uib.no.;Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.;Section for Hematology, Institute of Clinical Science, University of Bergen, Bergen, Norway.;Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.;Section for Hematology, Institute of Clinical Science, University of Bergen, Bergen, Norway.;Section for Hematology, Institute of Clinical Science, University of Bergen, Bergen, Norway.;Section for Hematology, Institute of Clinical Science, University of Bergen, Bergen, Norway.",
"authors": "Reikvam|Håkon|H|http://orcid.org/0000-0001-5439-8411;Hovland|Randi|R|;Forthun|Rakel Brendsdal|RB|;Erdal|Sigrid|S|;Gjertsen|Bjørn Tore|BT|;Fredly|Hanne|H|;Bruserud|Øystein|Ø|",
"chemical_list": "D014212:Tretinoin; D014635:Valproic Acid",
"country": "England",
"delete": false,
"doi": "10.1186/s12885-017-3620-y",
"fulltext": "\n==== Front\nBMC CancerBMC CancerBMC Cancer1471-2407BioMed Central London 362010.1186/s12885-017-3620-yResearch ArticleDisease-stabilizing treatment based on all-trans retinoic acid and valproic acid in acute myeloid leukemia – identification of responders by gene expression profiling of pretreatment leukemic cells http://orcid.org/0000-0001-5439-8411Reikvam Håkon +47 55975000Hakon.Reikvam@med.uib.nohakon.reikvam@uib.no 1Hovland Randi Randi.Hovaland@helse-bergen.no 2Forthun Rakel Brendsdal Rakel.Forthun@uib.no 3Erdal Sigrid Sigrid.Erdal@helse-bergen.no 2Gjertsen Bjørn Tore Bjorn.Gjertsen@med.uib.no 3Fredly Hanne Hanne.Fredly@med.uib.no 3Bruserud Øystein Oystein.Bruserud@helse-bergen.no 31 0000 0000 9753 1393grid.412008.fDepartment of Medicine, Haukeland University Hospital, N-5021 Bergen, Norway 2 0000 0000 9753 1393grid.412008.fCenter for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway 3 0000 0004 1936 7443grid.7914.bSection for Hematology, Institute of Clinical Science, University of Bergen, Bergen, Norway 6 9 2017 6 9 2017 2017 17 63018 7 2016 28 8 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\nAcute myeloid leukemia (AML) is an aggressive malignancy only cured by intensive therapy. However, many elderly and unfit patients cannot receive such treatment due to an unacceptable risk of treatment-related morbidity and mortality. Disease-stabilizing therapy is then the only possible strategy, one alternative being treatment based on all-trans retinoic acid (ATRA) combined with the histone deacetylase inhibitor valproic acid and possibly low-toxicity conventional chemotherapy.\n\nMethods\nPrimary AML cells were derived from 43 patients included in two clinical studies of treatment based on ATRA, valproic acid and theophyllamine; low toxicity chemotherapy (low-dose cytarabine, hydroxyurea, 6-mercaptopurin) was also allowed. Pretreatment leukemic cells were analyzed by mutation profiling of 54 genes frequently mutated in myeloid malignancies and by global gene expression profiling before and during in vivo treatment.\n\nResults\nPatients were classified as responders and non-responders to the treatment, however response to treatment showed no significant associations with karyotype or mutational profiles. Significance analysis of microarray (SAM) showed that responders and non-responders significantly differed with regard to the expression of 179 different genes. The differentially expressed genes encoding proteins with a known function were further classified based on the PANTHER (protein annotation through evolutionary relationship) classification system. The identified genes encoded proteins that are involved in several important biological functions, but a main subset of the genes were important for transcriptional regulation. These pretherapy differences in gene expression were largely maintained during treatment. Our analyses of primary AML cells during in vivo treatment suggest that ATRA modulates HOX activity (i.e. decreased expression of HOXA3, HOXA4 and HOXA5 and their regulator PBX3), but altered function of DNA methyl transferase 3A (DNMT3A) and G-protein coupled receptor signaling may also contribute to the effect of the overall treatment.\n\nConclusions\nResponders and non-responders to AML stabilizing treatment based on ATRA and valproic acid differ in the pretreatment transcriptional regulation of their leukemic cells, and these differences may be important for the clinical effect of this treatment.\n\nTrial registrations\n\nClinicalTrials.gov no. NCT00175812; EudraCT no. 2004–001663-22, registered September 9, 2005 and ClinicalTrials.gov no. NCT00995332; EudraCT no. 2007–2007–001995-36, registered October 14, 2009.\n\nElectronic supplementary material\nThe online version of this article (10.1186/s12885-017-3620-y) contains supplementary material, which is available to authorized users.\n\nKeywords\nAcute myeloid leukemiaAll-trans retinoic acidValproic acidGene expression profilinghttp://dx.doi.org/10.13039/501100004257Helse Vesthttp://dx.doi.org/10.13039/100008730Kreftforeningenissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nAcute myelogenous leukemia (AML) is an aggressive malignant disease of the bone marrow in which hematopoietic precursors are arrested in an early stage of development. AML are distinguished from other related blood disorders by the presence of >20% blasts in the bone marrow [1]. The only possibility for cure is intensive induction chemotherapy followed by consolidation treatment with intensive chemotherapy or stem cell transplantation, although for various reasons this treatment is not possible for several elderly or unfit patients [2–4]. Firstly, elderly patients have a higher and often unacceptable risk of severe treatment-related complications compared with younger patients [2–4]. The median age at the time of diagnosis of AML is 65–70 years and elderly patients thus represent the largest group of AML patients [1]. Secondly, unfit patients with severe comorbidity also have an unacceptable risk of severe complications and treatment-related mortality. Thirdly, several patients with relapsed or resistant disease will not receive further intensive treatment [5]. All these groups constitute a relatively large patient population that should be considered for AML-stabilizing treatment, e.g. treatment based on all-trans retinoic acid (ATRA) + valproic acid and low-toxicity cytotoxic treatment with hydroxyurea, 6-mercaptopurin or low-dose cytarabine [6–11].\n\nNew treatment approaches are currently considered for AML patients unfit for intensive chemotherapy. A promising concept is modulation of protein lysine acetylation through inhibition of histone deacetylases (HDACs) [12]. These enzymes alter acetylation of histones as well as transcription factors and other proteins involved in the regulation of cellular proliferation and survival. Valproic acid has features as a HDAC inhibitor, and are currently investigated in clinical studies of elderly or unfit AML patients, often in combination with ATRA [13, 14]. The toxicity of this treatment is low. Complete hematological remission lasting for several months has been reported for a minority (<5–10%) of patients but increased peripheral blood platelet counts are seen for 30–40% of patients and may last for up to 1–2 years [13, 14]. Valproic acid and ATRA may also be combined with conventional low-toxicity chemotherapy [7, 13, 14].\n\nATRA is a vitamin A metabolite that binds to retinoid-responsive nuclear receptors and thereby exerts effects on cell growth, differentiation and apoptosis [15]. It is used in the treatment of acute promyelocytic leukemia (APL) [16], although may also have antileukemic effects in non-APL variants of AML [17–19]. HDAC-inhibitors can reduce proliferation and induce differentiation in malignant hematopoietic cells [20], and these effects seem to be enhanced in combination with ATRA [21, 22]. The combination of valproic acid, ATRA and possibly low-toxicity chemotherapy has been examined in several clinical studies of AML patients with non-APL disease [14]. In this context we compared genetic abnormalities and gene expression patterns for responders and non-responder patients to low-toxicity treatment based on the combination of ATRA and valproic acid.\n\nMethods\nPatient characterization and classification\nPatients included\nA large group of consecutive AML patients unfit for intensive chemotherapy was included in two different phase 1/2 studies [9, 13]. Both the first study, including 24 patients, and the second study, including 36 patients were approved, by the Regional Ethics committee (REK Vest 215.03 and 231.06, respectively) and registered in a public database (for the first study ClinicalTrials.gov number NCT00175812 and EudraCT number 2004–001663-22; for the second study ClinicalTrials.gov number NCT00995332 and EudraCT number 2007–2007–001995-36 respectively). All patients were included after written informed consent.\n\nA total of 60 patients unfit for more intensive therapy were included in the two studies; their characteristics are summarized in Additional file 1: Table S1. A majority of them were elderly patients with high-risk disease (i.e. leukemia relapse, secondary AML or high-risk cytogenetic abnormalities). Detailed information of all patients included in our present study are given in Additional file 1: Table S2.\n\nDuring the time periods for the two clinical studies 9 additional patients unfit for intensive treatment were also diagnosed at our department; these patients were not included in the clinical studies because they (i) did not accept inclusion (1 patient); (ii) informed consent (6 patients) or (iii) adequate follow-up was not possible (1 patient); and (iv) hydroxyurea treatment was already started (1 patient).\n\nThe antileukemic treatments in the two clinical studies are summarized in Additional file 1: Table S3. Both protocols were based on intermittent ATRA therapy for 2 weeks at 12 weeks intervals, continuous oral valproic acid treatment and additional low-dose chemotherapy given either as (i) hydroxyurea (daily)/6-mercaptopurine (daily)/low-dose cytarabine (at least 4 weeks intervals) to maintain peripheral blood blast counts below 50 × 109/L (the 24 patient in study 1) [9]; or (ii) low-dose cytarabine at 12 weeks intervals as long as peripheral blood blast counts were below 50 × 109/L, this being replaced by oral hydroxyurea/6-mercaptopurin if blast counts increased (the 36 patients in study 2) [13]. A total of 28 patients were included in the global gene expression studies of pretreatment primary AML cells (see Table 1; 17 from the first and 11 from the second study; 14 males and 14 females; median age 76 years with range 48–87 years). Only 16 of the 28 patients had de novo AML, the others had either AML secondary to chronic myeloproliferative neoplasia (3 patients), previous chemotherapy (1 patient) or myelodysplastic syndrome (MDS, 5 patients); 3 additional patients had AML relapse. Seventeen patients had normal karyotype and 7 had adverse karyotype; 10 patients had FLT3-ITD. Twenty-three patients could be classified as having unfavorable prognosis having at least one of the following criteria: High-risk karyotype (7 patients), AML relapse (3 patients) or secondary AML (9 patients).Table 1 Comparison of global gene expression profiles for responders and non-responders to AML stabilizing treatment based on ATRA and valproic acid – a summary of the results from the Gene Set Enrichment Analysis (GSEA)\n\nGENE SET\tSIZE\tES\tNES\tNOM P-VALUE\t\nSignal sequence binding\t21\t−0.62\t−1.85\t<0.01\t\nOlfactory bulb interneuron development\t10\t−0.72\t−1.77\t<0.01\t\nNegative regulation of MAPK cascade\t38\t−0.5\t−1.76\t<0.01\t\nResponse to ionizing radiation\t85\t−0.45\t−1.69\t<0.01\t\nZinc ion transport\t16\t−0.67\t−1.76\t0.01\t\nPre-mRNA binding\t13\t−0.7\t−1.73\t0.01\t\nPositive regulation of oxidoreductase activity\t14\t−0.65\t−1.73\t0.01\t\nInactivation of MAPK activity\t27\t−0.48\t−1.62\t0.01\t\nRegulation of interferon-gamma biosynthetic process\t16\t−0.6\t−1.61\t0.01\t\nCarboxylic acid catabolic process\t34\t−0.45\t−1.61\t0.01\t\nResponse to radiation\t189\t−0.37\t−1.56\t0.01\t\nNegative regulation of reactive oxygen species metabolic process\t11\t−0.64\t−1.68\t0.02\t\nRegulation of bone resorption\t10\t−0.7\t−1.66\t0.02\t\nRNA polymerase II transcription factor binding transcription factor activity involved in negative regulation of transcription\t11\t−0.62\t−1.65\t0.02\t\nBiotin metabolic process\t10\t−0.73\t−1.65\t0.02\t\nRegulation of isotype switching\t20\t−0.55\t−1.64\t0.02\t\nFucosyltransferase activity\t14\t−0.64\t−1.65\t0.03\t\nMicrotubule bundle formation\t24\t−0.52\t−1.6\t0.03\t\nNegative regulation of JNK cascade\t22\t−0.59\t−1.59\t0.03\t\nUV protection\t11\t−0.6\t−1.56\t0.03\t\nMutSalpha complex binding\t11\t−0.72\t−1.59\t0.04\t\nAminopeptidase activity\t34\t−0.47\t−1.58\t0.04\t\nMismatch repair complex\t10\t−0.74\t−1.57\t0.04\t\nNegative regulation of transcription by competitive promoter binding\t10\t−0.61\t−1.56\t0.04\t\nCholesterol efflux\t25\t−0.51\t−1.55\t0.04\t\nNegative regulation of cytoskeleton organization\t51\t−0.41\t−1.51\t0.04\t\nRegulation of protein localization to cell surface\t17\t−0.53\t−1.51\t0.04\t\nResponse to gamma radiation\t32\t−0.44\t−1.47\t0.04\t\n\nAbbreviations: ES enrichment score JNK c-Jun N-terminal kinases, MAPK mitogen-activated protein kinase, NES normalized enrichment score\n\n\n\n\nTreatment\nPatients included in the Study 1 were treated with oral ATRA 22.5 mg/m2 twice daily days 1–14, and valproic acid together with theophyllamine from day 3 until disease progression [9]. The treatment with valproic acid and theophyllamine started with an initial intravenous loading dose followed by 48 h of intravenous infusion guided by the serum levels before the oral treatment. For valproic acid the loading dose of 5 mg/kg was administered during 30 min and continued as an intravenous infusion of 28 mg/kg/24 h. For theophyllamine the loading dose of 5 mg/kg was administered over 30 min and continued as an intravenous infusion of 0.65 mg/kg/h. Samples were collected before treatment (day 1), after 2 days of treatment with ATRA alone (day 3) and after 5 additional days of treatment with the triple combination (day 8). ATRA was repeated with 12 weeks intervals (Study registration: ClinicalTrials.gov no. NCT00175812 and EudraCT no.2004–001663-22).\n\nPatients included in study 2 were treated with valproic acid from day 1 and until disease progression, oral ATRA 22.5 mg/m2 twice daily days 8–22 and subcutaneous cytarabine 10 mg/m2 administered once daily on days 15–24 [13]. The treatment with ATRA/cytarabine was repeated with 12 weeks intervals. Treatment with valproic acid started with an intravenous loading dose and thereafter an intravenous infusion for 24 h before the treatment was continued as oral administration guided by the serum level. Samples were collected before treatment (day 1) (Study registration: ClinicalTrials.gov no. NCT00995332 and EudraCT no. 2007–2007–001995-36).\n\nResponse criteria\nThe international working group in AML [23, 24] defined complete remission (CR) of AML as (i) less than 5% blast in the bone marrow, no Auer rods and no persistence of extra-medullary disease, and (ii) neutrophil counts above 1.0 × 109/L, platelet levels above 100 × 109/L and erythrocyte transfusion independence. There is no requirement in terms of duration of this response. The MDS response criteria [24, 25] generally require a duration of 8 weeks for the response. The requirements for CR in MDS are (i) less than 5% blasts in the bone marrow and no dysplasia, (ii) hemoglobin level > 11 g/100 ml, neutrophils counts >1.5 × 109/L, platelets counts >100 × 109/L and (iii) no circulating blasts. The MDS criteria also define stable disease as no evidence of progression for at least 8 weeks. Patients referred to as responders in our present study corresponded to patients achieving either (i) complete remission as defined by the AML criteria lasting for at least 8 weeks or (ii) fulfilling the MDS criteria for at least stable disease or hematological improvement with increased normal peripheral blood cell counts.\n\nCell preparation\nThe 28 patients included in the microarray studies represent the subset of patients with high enough peripheral blood blast counts to allow sampling from the peripheral blood of sufficient cells for microarray studies. Leukemic peripheral blood mononuclear cells (PBMCs) were isolated by density gradient separation (Ficoll-Hypaque; NycoMed, Oslo, Norway; specific density 1.077) from peripheral blood of patients with at least 80% of the leukocytes being AML cells. Cells were stored frozen in liquid nitrogen. The percentage of AML blasts among leukemia PBMC exceeded 95% [26].\n\nMutation profiling\nSubmicroscopic mutation profiling of 54 genes frequently mutated in myeloid leukemias was done by the Illuminas TruSight Myeloid Gene Panel and sequenced using the MiSeq system and reagent kit v3 (all from Illumina, San Diego, CA, USA) (Additional file 1: Table S4). Amplicon sequencing library was prepared from 50 ng DNA according to the manufacturer’s instructions with the exception of normalization being done manually. 8–16 samples were sequenced each time and the total DNA input on the flow cell was 15 picomolar. Secondary analysis was performed using MiSeqReporter version 2.4.60.8 (Illumina) mapping to the human genome reference hg19. Sequence alignment of selected variants was manually examined with the Integrative Genomics Viewer (IGV) [27]. Annotation was done by snpSIFT og snpEFF v 4.1. As no matching normal DNA was available variants with >1% minor allele frequency in the 1000 genomes data were presumed to be germline and removed from further interpretations. Synonymous substitutions, intronic variants not in the splice site and variant interpreted as benign or most likely benign are not included. The variant allele frequency (VAF) was calculated for each mutation as number of variant reads divided by total reads. Cut-off for reported variants for VAF was 8% and read depth 100. Only variants interpreted as pathogenic, probably pathogenic and variants of unknown significance are reported. The nomenclature is according to Human Genome Structural Variation consortium.\n\nFragment analysis of FLT3 exon 14–15 and NPM1 exon 12 were done as described in [28] and CEBPA mutation analysis as described previously [28].\n\nRNA preparation, labelling and microarray hybridization\nAll microarray experiments were performed using the Illumina iScan Reader, which is based upon fluorescence detection of biotin-labelled cRNA. Three hundred ng of total RNA from each sample was reversely transcribed, amplified and Biotin-16-UTP-labelled using the Illumina TotalPrep RNA Amplification Kit (Applied Biosystems/Ambion, USA). The amount and quality of the Biotin-labelled cRNA was controlled both by the NanoDrop spectrophotometer and Agilent 2100 Bioanalyzer. Biotin- labelled cRNA (750 ng) was hybridized to the HumanHT-12 V4 Expression BeadChip according to the manufacturer’s instructions. The HumanHT-12 V4 BeadChip targets 47,231 probes that are mainly derived from genes in the NCBI RefSeq database (Release 38).\n\nPreprocessing, normalization and annotations of microarray data\nData from the array scanning were investigated in GenomeStudio and J-Express 2012 for quality control measures [29]. All arrays within each experiment were quantile normalized to be comparable before being compiled into an expression profile data matrix. The probe with the highest fluorescence was used in the analyses if the expression of the same gene was examined by different probes. In all our analyses of gene expression profiles we used significant analyses of microarray (SAM) [30], and gene set enrichment analysis (GSEA) [31], to compare different patient subsets or samples. The genes encoding proteins with a known function were classified by using the PANTHER (protein annotation through evolutionary relationship) classification system [32].\n\nResults\nClassification of patients as responders and non-responders to ATRA/valproic acid\nAll patients in the present study were included in two previous clinical studies. These studies included 60 patients (20 responders); the characteristics of all patients are summarized in Additional file 1: Table S1 and the characteristics of individual patients included in the present study are presented in Additional file 1: Table S2. Additional analysis of the mutational profiles was possible for 12 responders and 29 non-responders to the treatment (Additional file 1: Table S3; patients 1–12 and 15–43). The effects of antileukemic treatment on gene expression profile were analyzed for eight patients from the study by Ryningen et al. [13]. A high frequency of patients with high-risk disease according to conventional prognostic criteria (i.e. AML relapse, secondary AML, high-risk cytogenetic abnormalities) was seen both for the whole group of 60 patients, the 41 patients included in the study of mutational profiles (Additional file 1: Table S2; patients 7, 8, 17, 23, 26, 31, 38 and 42). None of the patients had low-risk cytogenetic abnormalities.\n\nResponsiveness to AML-stabilizing therapy was not significantly associated with karyotype or the mutational profile\nA detailed submicroscopic mutational profile was examined for 41 patients (Additional file 1: Table S2; 12 responders and 29 non-responders); the profile included genes frequently mutated in myeloid malignancies (Additional file 1: Table S4, Fig. 1). Thirty-two of these genes were mutated in at least one of the patients, and according to previous studies [33, 34] these mutations were classified as (i) NPM1 mutations, (ii) mutations causing activation of intracellular signaling; (iii) mutated tumor suppressor genes; (iv) mutations in genes involved in DNA methylation or (v) chromatin modification; (vi) mutations in genes encoding myeloid transcription factors; (vii) mutated genes important for the spliceosome or (viii) encoding cohesion protein; and (ix) others.Fig. 1 Mutational profiling of responders and non-responders to AML-stabilizing treatment based on ATRA plus valproic acid. Primary AML cells derived from 41 patients (Additional file 1: Table S2, patients 1–2 and 15–43) were analyzed for AML-associated mutations (see Additional file 1: Table S4). The 41 patients included 12 responders and 29 non-responders to the treatment. The patient numbers at the top of the figure refer to the numbers given in Additional file 1: Table S2, and the figure presents the results only for those mutations that were detected for at least one of these patients. The classification of the mutations can be seen in the left part of the figure. The karyotype classification is given at the bottom of the figure, whereas more detailed information about the cytogenetic abnormalities are included in Additional file 1: Table S2\n\n\n\n\nThe number of detected mutations differed between patients, the median number being three mutations (range 0–7). Responders and non-responders did not differ with regard to the number of mutations. FLT3 mutations were most frequent (15 out of 41 patients, 37%) followed by NPM1 mutations (14/41, 34%). Most patients had at least one mutation causing activation of intracellular signaling (25/41, 61%), and all six patients with TP53 mutations had an adverse karyotype. Even though NPM1, FLT3, TP53 and DNMT3A mutations showed higher frequencies for non-responders than for responders, these differences did not reach statistical significance.\n\nThe gene expression profiles of responders and non-responders to AML-stabilizing treatment differ especially for genes important in nucleic acid binding, intracellular transport, function of hydrolases and modulation of enzyme activity\nWe compared the global gene expression profiles for pretreatment AML cell samples derived from 28 patients who later could be classified as responders or non-responders to the leukemia-stabilizing treatment. All these AML cell samples were derived from patients with high peripheral blood blast counts, and highly enriched AML cell populations could thereby be prepared by a simple and highly standardized method based on gradient separation. Nineteen of these patients were classified as non-responders and nine as responders according to the criteria previously described in detail by Fredly et al. [13]. We used SAM to compare the global gene expression profiles for responders and non-responders. When setting the d-score to ±2.5 we identified 243 probes that differed significantly between the two groups, and these probes represent 179 different genes (Additional file 1: Table S5). We then used the Panther database to classify the encoded proteins (Fig. 2), and 159 of these genes encoded proteins that could be classified. Genes encoding for proteins that belonged to the “nucleic acid binding” class were overrepresented (38 out of 159 genes), and these genes encoded both DNA binding protein (16 proteins), RNA binding proteins (20 proteins) and nucleases (2 proteins).Fig. 2 Comparison of the global gene expression profiles for responders and non-responders to the AML-stabilizing treatment based on ATRA and valproic acid – an analysis of the differentially expressed genes based on the function of their encoded proteins. Differentially expressed genes were identified by SAM, and the functional analysis of the encoded proteins was based on the Panther database. Only genes encoding annotated proteins were included in this analysis. The figure thus presents the representative distribution of the genes with known functions that showed differential expression according to the Panther protein class (PS) category. The name of each of the identified classes is given in the figure along with number of genes in each category. Only classes containing ≥ 5 genes are named in the figure. The genes included in each of the five major classes nucleic acid binding, transcription factor, enzyme modulator, hydrolase and receptor are listed in Table 2, and important biological functions of individual genes are described in Additional file 1: Table S6\n\n\n\n\nAll the genes showing at least a 2-fold difference between responders and non-responders are listed in Additional file 1: Table S6. The proteins encoded by these genes included oncogenes (RGL4, LMO4) as well as regulators of protein degradation/activation/modulation (QPCT, ELANE), transcription (HOXA3, HOXA5, PBX3; the only three with decreased expression), iron metabolism (HP, LTF), energy metabolism (MOSC1, CYP4F3, OLR1, SNCA), apoptosis/proliferation (OLFM4, PGLYRP1) and communication (COL17A1, TACSTD2). The Hox genes may be of particular importance, and HOXA4 expression was also significantly lower although the difference was less than two-fold.\n\nWe also performed a GSEA. This alternative analysis also showed that the differentially expressed genes are important for a wide range of cellular function, but several of the identified GO-terms with p-value <0.05 describe binding/function/regulation of nucleic acids and showed increased expression for the responders (Table 1).\n\nThe effect of in vivo ATRA therapy on the global gene expression profile of primary human AML cells\nTranscriptomic profiling of primary AML cells during in vivo ATRA treatment was only possible for eight patients included in the first study [9]. We first compared AML cell samples derived (i) before start of treatment on day 1, and (ii) after two days of oral ATRA monotherapy (day 3). These eight patients were two responders and six non-responders, and due to this low number of available patients it was not possible to compare the effects of ATRA in responders and non-responders. Thus, by this comparison we identified alterations in global gene expression profiles that are common for responders and non-responders. By this approach we could not identify quantitative differences in the expression of these identified genes and probably not effects of ATRA that are specific for responders/non-responders either. However, differences between responders and non-responders to ATRA may be caused by different downstream responses to common ATRA-induced alterations, and only such mechanisms are likely to be identified by our strategy for analysis.\n\nWe performed a SAM analysis that identified the top rankled differently expressed genes with d-score of ±2.0 (400 permutations) when comparing AML cells sampled on day 1 before ATRA treatment and after two days of treatment on day 3. All differentially expressed genes are listed in Additional file 1: Table S5. The Panther classification analysis based on the function of the encoded proteins (Fig. 3); for these analyses we only included the 70 genes (36 upregulated and 34 downregulated on day 3) that were annotated; these genes can be identified from Additional file 1: Table S5). ATRA altered the expression of genes with a wide range of functions, but a major effect of this in vivo therapy was altered expression of genes encoding proteins that show nucleic acid binding and/or being involved in transcriptional regulation. Additional effects were altered expression of receptor-associated genes, whereas the pretreatment differences between responders and non-responders with regard to hydrolases and enzyme modulation (see above) seem to be maintained during ATRA. However, relatively few genes were altered during ATRA therapy for the 5 terms Nucleic acid binding/transcription factors/enzyme modulation/hydrolases/receptors (see Tables 2 and 3), but the genes encode proteins that are involved both in regulation of DNMT3A (SALL3) and retinol metabolism (RBP1). Finally, there was only a small overlap between those genes showing differential expression when comparing responders and non-responders and those genes being altered by ATRA (Tables 2 and 3). This last observation suggests that the pretreatment differences between responders and non-responders with regard to these 5 terms are maintained during treatment.Fig. 3 Comparison of the global gene expression profiles – a comparison of primary AML cells sampled before treatment (day 1), after treatment with ATRA alone (day 3) and after triple therapy with ATRA, valproic acid and theophyllamine (day 8). Each part of the figure shows the results for one analysis. The upper part presents the comparison of pretreatment samples and cells collected after 2 days of ATRA therapy (day 3 versus pretreatment samples), the middle figure show the effect of adding valproic acid plus theophyllamine to the ATRA therapy (day 8 versus day 3 samples) and the lower figure shows the effect of the triple combination (pretreatment samples versus AML cells sampled on day 8). The same strategies were used for all three analyses. Differentially expressed genes were first identified by SAM, and the functional analyses of the encoded proteins were based on the Panther database. Only genes encoding annotated proteins were included in these analyses. The figures thus present the representative distribution of the genes with known functions that showed differential expression according to the Panther protein class (PS) category..The name of each of the identified classes is given in the figure along with number of genes in each category. Only classes containing ≥ 2 genes are named. The genes included in each of the five major classes nucleic acid binding, transcription factor, enzyme modulator, hydrolase and receptor are listed in Table 2, and important biological functions of individual genes are described in Additional file 1: Table S6\n\n\nTable 2 An overview of individual genes that belong to the 5 the GO-terms Nucleic acid binding/transcription factor/hydrolases/enzyme modulation/receptors and their expression in primary human AML cells – differences in gene expression between responders and non-responders\n\nNucleic acid binding transcription factor\tHydrolases\tEnzyme modulation\tReceptors\t\nIncreased*\tDecreased\t\tIncreased\tDecreased\tIncreased\tDecreased\tIncreased\tDecreased\t\n\nAGAP3\n\t\nAARSD1\n\t\nMBTD1\n\t\nACP22\n\t\nAPOBEC3H\n\t\nAGAP3\n\t\nARL16\n\t\nOLFM4*\n\t\nADRA2C\n\t\n\nARAP3\n\t\nAPOBEC3H\n\t\nMCART1\n\t\nAFMID\n\t\nATP2A2\n\t\nARAP3\n\t\nBIRC3\n\t\nST7\n\t\nHP*\n\t\n\nLMO4\n\t\nARAP3\n\t\nMRPS15\n\t\nLTF*\n\t\nCDC14A\n\t\nFBXO8\n\t\nGNB4\n\t\nTACSTD2*\n\t\nMCHR2\n\t\n\nNLRX1\n\t\nDDX5I\n\t\nMYCBP2\n\t\nRNASE4\n\t\nELANE\n\t\nMCF2L2\n\t\nHP*\n\t\t\nQRFPR\n\t\n\nPCBP2\n\t\nCDKN2AIP\n\t\nPBX3\n\t\t\nGNB4\n\t\nPCBP2\n\t\nMCYBP2\n\t\t\nTHADA\n\t\n\nRBMI5\n\t\nDDX51\n\t\nPHAX\n\t\t\nHP*\n\t\nPI3\n\t\nMYO3B\n\t\t\nXPO1\n\t\n\nRNASE4\n\t\nFOXP1\n\t\nSMC4\n\t\t\nLRAP\n\t\nRGL4*\n\t\nPHKB\n\t\t\t\n\nRPL30\n\t\nHIST2H2AC\n\t\nSNRNP70\n\t\t\nSMC4\n\t\nRNASE4\n\t\t\t\t\n\nSNRPB\n\t\nHOXA3*\n\t\nTDRD1\n\t\t\nTDP1\n\t\nTP53BP2\n\t\t\t\t\n\nTAF8\n\t\nHOXA4\n\t\nTHOC\n\t\t\nXRCC2\n\t\t\t\t\t\n\nUBL4A\n\t\nHOXA5*\n\t\nXRCC2\n\t\t\t\t\t\t\t\n\nWRN\n\t\nLCOR\n\t\nZMAT3\n\t\t\t\t\t\t\t\n\t\nLRRF1P1\n\t\nZNF394\n\t\t\t\t\t\t\t\n\nMBD2\n\t\t\nThe classification of the genes refer to increased/decreased levels in responders compared with non-responders. Only those genes/probes with an annotation were included in the Panther analysis (and thereby also in this table) that is the basis for this classification\n\nIncreased or decreased levels means increased expression in responder patients\n\n*Genes with significantly different expression also when comparing responders versus nonresponders (see Additional file 1: Table S5) \n\n\nTable 3 An overview of individual genes that belong to the 5 the GO-terms Nucleic acid binding/transcription factor/hydrolases/enzyme modulation/receptors and their expression in primary human AML cells – effects of in vivo treatment with the triple combination on the gene expression profile\n\nComparison\n(Number of genes included in the comparison)\tNucleic acid binding transcription factor\tHydrolases\tEnzyme Modulation\tReceptors\t\nIncreased\tDecreased\tIncreased\tDecreased\tIncreased\tDecreased\tIncreased\tDecreased\t\nDay 1 versus day 3a\n\t\nFOXB1\n\n\nJRKL\n\t\nSALL3\n\t\nETHE1\n\t\t\t\nRBP1\n\n\nKIAA244\n\t\t\nGRM1\n\n\nIGFALS\n\n\nPTCHD1\n\t\nDay 3 versus day 8b\n\t\nRSPH9\n\n\nSIRT6\n\n\nONECUT\n\t\t\nSIRT6\n\t\nKLK1\n\t\nITI4\n\n\nANGBL3\n\t\nKLK1\n\n\nGNG12\n\t\nAVPR1B\n\t\nHS.344170\n\n\nKLK1\n\n\nAVPR1B\n\n\nGALR2\n\t\nDay 1 versus day 8c\n\t\nNR2F1\n\n\nPRDM13\n\t\nZBTB7C\n\t\t\t\nCCNE2\n\t\nSIPA1L1\n\n\nDYNLL2\n\n\nITIH3\n\t\nMRGPRX4\n\n\nHCRTR1\n\n\nUNC5B\n\n\nGPR151\n\t\nGRM1\n\n\nAVPR1A\n\n\nLRRC55\n\t\nThese five terms included a major part of the genes that showed differential expression when comparing responders and non-responders. Only genes with known annotations were included in the Panther analysis (and thereby in this table) that forms the basis for the table. The table presents those genes belonging to these five terms altered during treatment. The terms Increased/decreased expression means that the indicated genes showed increased/decreased expression during the investigated therapeutic intervention, i.e. during ATRA treatment day 3, following addition of valproic acid plus theophyllamine day8 and following triple therapy day 8\n\n\naIncreased or decreased on day 3 after ATRA therapy\n\n\nbIncreased or decreased on day 8 after addition of valproic acid plus theophyllamine\n\n\ncIncreased or decreased on day 8 after triple therapy\n\n\n\n\nThe effect of in vivo treatment with valproic acid plus theophyllamine on the global gene expression profile of primary human AML cells\nWe compared the gene expression profiles for AML cells derived from the same 8 patients before addition of valproic acid and theophyllamine to the ATRA therapy (days 3) and during treatment with the triple combination (day 8). We then did a SAM analyses identifying the top ranked differently expressed genes with d-score of ±2.0 (400 permutations), and thereafter a Panther protein classification only based on those 81 genes (42 upregulated and 39 downregulated on day 8) that were annotated. The identity of these genes can be seen from Additional file 1: Table S5. The showed that addition of valproic acid/theophyllamine altered the expression of genes that are involved in a wide range of cellular functions, again including altered transcriptional regulation (Fig. 3, Table 3, Additional file 1: Table S7). Altered expression after addition of valproic acid/theophyllamine was observed for relatively few genes, but including genes encoding proteins important for epigenetic regulation (SIRT6) and for the kallikrein system (ITIH4, KLK) (Additional file 1: Table S7). Very few of these genes differed significantly when comparing pretreatment levels for responders and non-responders (see Tables 2 and 3), i.e. this is similar to the ATRA treatment and suggests that the pretreatment differences between these two patient subsets are maintained during this treatment.\n\nThe overall effect of in vivo treatment with ATRA, valproic acid and theophyllamine on the global gene expression profile of primary human AML cells\nWe finally compared the effects of the triple drug combination by comparing the global gene expression profiles for primary AML cells derived from the 8 patients before start of treatment and after triple therapy on day 8. The therapeutic serum level for theophyllamine was 55–110 μmol/L. The daily valproic acid dose was increased to the maximal tolerated dose. The therapeutic serum level of valproic acid was 300–600 μmol/L, but the mean valproic acid level during the 5 days of triple treatment varied for individual patients between 178 and 717 μmol/L (median value 407 μmol/L) and did not reach the lower therapeutic limit for 2 of the patients.\n\nWe did a SAM analysis identifying the top ranked differentially expressed genes with d-score of ±2.0 (400 permutations), and thereafter we did a Panther protein classification only based on the 76 annotated genes (39 upregulated and 37 downregulated in day 8 samples). The genes included in the terms transcriptional regulation/nucleic acid binding represent only a minority among the genes with altered expression during the triple drug therapy, and the same was true for the term hydrolases (Figure 3, Table 3, Additional file 1: Table S7). Thus, a major part of the pre-therapy differences between responders and non-responders seem to be maintained during the triple treatment and this was also seen for the separate analyses of ATRA and valproic acid/theophyllamine treatment (see above). The triple therapy altered the expression of genes included in several annotations, but major effects seem to be altered receptor expression/function (especially G-protein coupled receptors for neuromediators, i.e. AVPR1B, GALR2, HCRTR1, GPR151) together with altered expression of transcriptional regulators (Additional file 1: Table S7). Finally, altered expression after valproic acid/theophyllaminee was observed for relatively few genes (Table 2) and very few of these genes differed significantly when comparing pre-treatment levels for responders and non-responders (Additional file 1: Table S5), i.e. pre-treatment differences are maintained during treatment.\n\nDiscussion\nMost AML patients are elderly and many of these elderly patients as well as younger unfit patients will not benefit from intensive chemotherapy because remission induction is less likely [3, 4] and/or (ii) they have a high risk of severe treatment-related complications and early death due to age, comorbidity or poor performance status [14, 17, 35]. Treatment based on ATRA plus the HDAC inhibitor valproic acid may be an alternative for such patients. However, the in vivo effects of this treatment on the leukemic cells are largely unknown [36, 37].\n\nThe treatment of elderly and unfit AML patients often needs to be individualized, and this was also true for the patients included in our present study [9, 13]. Even though our patients were treated according to two different protocols, they all received similar AML-stabilizing treatment (Additional file 1: Table S3) based on ATRA, valproic acid and low-toxicity chemotherapy. Patients with high peripheral blood blast counts at the time of diagnosis received chemotherapy from the start of treatment, otherwise patients in the second protocol received chemotherapy from day 14 and patients in the first protocol received chemotherapy if the peripheral blood blast count increased during treatment. Finally, patients in the first study received theophyllaminee, but this was probably less important with regard to clinical efficiency because the frequency of responders in this study was similar to other previous studies of ATRA + valproic acid alone [14].\n\nATRA was given at the same daily dose as used in APL therapy and in previous studies of non-APL variants of AML treated with ATRA + valproic acid [9, 14, 17]. The tolerated dose of valproic acid varied between patients [9, 13], but previous studies have demonstrated that clinically relevant effects with improvement of platelet counts can be observed even for patients having concentrations below the therapeutic serum level [14]. Our patients should be regarded as representative for elderly/unfit patients with regard to systemic valproic acid levels [9, 14, 17].\n\nThe responses to ATRA + valproic acid based treatment are usually detected after 2–3 weeks [13, 14]. On the other hand, many patients (especially elderly patients) have a short expected survival [13, 14], and if they do not respond to the first AML-stabilizing treatment there may not be sufficient time left to try an alternative treatment. Our present results suggest that gene expression profiling can be used for early identification of patients who are likely to respond to treatment based on ATRA + valproic acid, whereas conventional prognostic criteria (relapse versus first diagnosis, karyotype, molecular genetics) could not be used for prediction of treatment responses.\n\nSeveral randomized studies have failed to show an effect of ATRA on survival for AML patients receiving intensive and potentially curative chemotherapy (for detailed information and additional references see [38, 39], although a recent study suggests that ATRA improves survival for the subset of patients having NPM1 mutations or having genetic low risk disease [38]. Thus, the effect of ATRA may be observed only for a subset of patients identified by their genetic abnormalities. For this reason we compared the frequencies of various genetic abnormalities for responders and non-responders to our AML-stabilizing treatment, but we could not detect any significant differences between the two groups. This was also true for DNMT3, even though the effect of its regulator SALL3 (see Additional file 1: Table S7) is altered by ATRA. However, these observations have to be interpreted with great care because we investigated only a limited number of molecular abnormalities and compared relatively small groups of patients. Furthermore, our observation that the responders included several patients with high-risk disease according to conventional prognostic criteria also support the conclusion that conventional prognostic parameters (including cytogenetic and molecular-genetic analysis) have a limited value with regard to predicting responsiveness to AML-stabilizing treatment based on ATRA and valproic acid.\n\nSeveral studies have described effects of ATRA and valproic acid on gene expression in human AML cells [40–44], and we investigated whether the treatment-induced differences in gene expression or differences between our responders and non-responders included genes that had also been identified in these studies (Additional file 1: Table S5). We first compared our results with 241 genes regulated by retinoic acid [40], but only a minority of these genes were altered by ATRA/valproic acid/theophyllamine (NR2F1, PCDH12, SFTPA1B, RBP1) or differed significantly between responders and non-responders (ABCB1, BIRC3, OLR1). Secondly, Zheng et al. [41] identified 108 ATRA responsive genes in the NB4 AML cell line, but only CGREF1 was altered during treatment and only NCOA3 differed significantly between responders and non-responders. Similarly, Park et al. [42] identified 15 genes altered by in vitro exposure of primary AML cells to ATRA; none of them differed between our responders and non-responders or were altered during treatment. Finally, Bullinger et al. [43] analyzed effects of ATRA on the HL60 AML cell line and detected 427 ATRA-responsive genes; none of their 39 genes with FDR < 0.05 were altered during treatment and only two of these genes (ARAP3, HOXA3) differed between our responders and non-responders. However, the decreased levels of HOXA3, HOXA4 and HOXA5 together with their modulator PBX3 suggest that HOX genes are important for the response to treatment.\n\nRücker et al. investigated the in vivo effect of valproic acid for AML patients receiving intensive induction treatment [44]. Neither the expression of their 50 top-ranked genes, the 20 genes in their valproic acid-associated miRNA profile nor their 9 response-predicting genes were altered during treatment of our patients or showed differential expression in responders/non-responders.\n\nExpression a stem cell-like mRNA signature seems to be associated with an adverse prognosis in AML; this has been shown both for a leukemic stem cell related profile (34 genes), hematopoietic stem cell related profile (32 genes) and recently by using a 17-gene stemness scoring system [45, 46]. However, only two of these genes (ABCB1 and HOXA5) differed between responders and non-responders, and none of the genes were altered during treatment (Additional file 1: Table S4).\n\nThus, our present results confirm that both ATRA and valproic acid can alter the expression of a large number of genes involved in a wide range of important cellular processes in primary human AML cells, but only a small number of genes previously shown to be responsive to ATRA or valproic acid were associated with response to treatment or were altered during in vivo treatment of our patients. This lack of overlap suggests that the effects of ATRA/valproic acid on gene expression in human AML cells depend on the biological context during drug exposure.\n\nRecent studies have demonstrated that the mRNA expression of the oncogene EVI1, that is important in myeloid malignancies, is induced by ATRA and act as a modulator of ATRA responses [47–49].\n\nFurthermore a substantial part of AML patients with enhanced expression of EVI1 seem to respond to ATRA by induction of differentiation and decreased clonogenic capacity of myeloid blasts [50]. However, EV11 was not associated with ATRA responsiveness and was not induced during ATRA treatment in our patients. These observations are also consistent with the observation that the effects of ATRA depends on the biological context; the EVI1 observations described above were based on in vitro studies of various cells lines and these effects of EVI1/ATRA may then be different from primary AML cells exposed to ATRA in vivo.\n\nOnly eight patients were available for global gene expression analyses during in vivo treatment. When analyzing pre-therapy samples in responders and non-responders we conclude that these two groups differ mainly in their expression of genes included in the terms nucleic acid binding, transcription factors, hydrolase and enzyme modulators. These pre-therapy differences were maintained during the triple treatment both when comparing pre-therapy expression with the expression after ATRA alone (day 3 samples) and triple therapy (day 8 samples). The most important differences observed on day 8 compared with pre-therapy samples was altered expression by several receptors. Thus, the final effect of the triple in vivo treatment is maintenance of pretreatment differences between responders and non-responders and the most striking treatment-induced difference being increased expression of several receptors.\n\nSeveral receptors were upregulated during treatment, and many of them were G-protein coupled receptors and/or receptors for neuromediators. The functions of these receptors in leukemogenesis are largely unknown, although a previous study also suggested that they are expressed by malignant hematopoietic cells and are then involved in growth regulation [51]. Thus, the altered expression of these receptors may thus contribute to the final effect of our AML-stabilizing treatment.\n\nConclusions\nA subset of AML patients responds to disease-stabilizing therapy based on ATRA + valproic acid; the responders include several patients with relapsed/chemoresistant disease and patients with high-risk disease based on their genetic abnormalities. We could not detect any significant differences between responders and non-responders when comparing the frequencies of their genetic abnormalities. Responders and non-responders could be identified by differences in their global gene expression profiles, especially differences in the expression of genes encoding proteins that are important for transcriptional regulation. These differences are maintained during treatment; the triple therapy has only minor effects on the expression of transcriptional regulators but they altered the expression of several receptors.\n\nAdditional file 1\n\nAdditional file 1: Table S1. The characteristics of the 60 patients included in the two clinical studies. Table S2. Clinical and biological characteristics of the patients included in the study. Table S3. AML-stabilizing treatment based on ATRA plus valproic acid; a summary and comparison of the two treatment regimen. Table S4. Analysis of 54 submikrocopic mutations in primary human AML cells. Table S5. Differences in global gene expression profiles by primary human AML cells derived from responders and non-responders to AML-stabilizing treatment. Table S6. Differences in global gene expression profiles by primary human AML cells derived during AML-stabilizing treatment. Table S7. Differentially expressed genes identified from comparison of primary AML cells before and after treatment. (DOCX 55 kb)\n\n\n\n\nAbbreviations\nAMLAcute myelogenous leukemia\n\nAPLAcute promyelocytic leukemia\n\nATRAAll-trans retinoic acid\n\nCRComplete remission\n\nGOGene-ontology\n\nGSEAGene set enrichment analysis\n\nHDACHistone deacetylase\n\nMDSMyelodysplastic syndrome\n\nPBMCPeripheral blood mononuclear cells\n\nSAMSignificant analyses of microarray\n\nTGFBTransforming growth factor beta\n\nVAFVariant allele frequency\n\nElectronic supplementary material\n\nThe online version of this article (10.1186/s12885-017-3620-y) contains supplementary material, which is available to authorized users.\n\nThe technical assistance of support from Karen Marie Hagen, Kristin Paulsen Rye, Atle Brendehaug, Hans Petter Brodal, Stian Knappskog and Laura Minsaas are greatly appreciated.\n\nAvailability of data materials\nMicroarray data are available data at Gene Expression Omnibus.\n\nFunding\nThe study was supported by the Norwegian Cancer Society and Helse-Vest. None of the funding sources had any role in the study design, data collection/analyses, interpretation of data, or writing of the manuscript.\n\nAuthors’ contributions\nHR collected the data, performed the analyses and prepared the figures; RH, RBF and SE performed the genetic analyses, BTG and ØB initiated both clinical studies, ØB was responsible for the first clinical study and for collection of all samples in both studies, HF and ØB were responsible for the second clinical study, HR and ØB designed and coordinated the present study and wrote the manuscript. We confirm that all authors fulfill the criteria for authorship as given by the Vancouver Recommendations. All authors have read and approved the final version of this manuscript.\n\nEthics approval and consent to participate\nAll studies were approved by the local Ethics Committee (Region III, University of Bergen, Norway) and samples collected after written informed consent.\n\nStudy registrations: ClinicalTrials.gov no. NCT00175812; EudraCT no. 2004–001663-22; ClinicalTrials.gov no. NCT00995332 and EudraCT no. 2007–2007–001995-36.\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. Döhner H Weisdorf DJ Bloomfield CD Acute Myeloid Leukemia New Eng J Med 2015 373 12 1136 1152 10.1056/NEJMra1406184 26376137 \n2. Latagliata R Bongarzoni V Carmosino I Mengarelli A Breccia M Borza PA D'Andrea M D'Elia GM Mecarocci S Morano SG Acute myelogenous leukemia in elderly patients not eligible for intensive chemotherapy: the dark side of the moon Ann Oncol 2006 17 2 281 285 10.1093/annonc/mdj112 16373393 \n3. Pollyea DA Kohrt HE Medeiros BC Acute myeloid leukaemia in the elderly: a review Br J Haematol 2011 152 5 524 542 10.1111/j.1365-2141.2010.08470.x 21314823 \n4. 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Cheson BD Bennett JM Kantarjian H Pinto A Schiffer CA Nimer SD Lowenberg B Beran M de Witte TM Stone RM Report of an international working group to standardize response criteria for myelodysplastic syndromes Blood 2000 96 12 3671 3674 11090046 \n25. Cheson BD Greenberg PL Bennett JM Lowenberg B Wijermans PW Nimer SD Pinto A Beran M de Witte TM Stone RM Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia Blood 2006 108 2 419 425 10.1182/blood-2005-10-4149 16609072 \n26. Bruserud O Hovland R Wergeland L Huang TS Gjertsen BT Flt 3-mediated signaling in human acute myelogenous leukemia (AML) blasts: a functional characterization of Flt 3-ligand effects in AML cell populations with and without genetic Flt 3 abnormalities Haematologica 2003 88 4 416 428 12681969 \n27. Robinson JT Thorvaldsdottir H Winckler W Guttman M Lander ES Getz G Mesirov JP Integrative genomics viewer Nat Biotechnol 2011 29 1 24 26 10.1038/nbt.1754 21221095 \n28. Staffas A Kanduri M Hovland R Rosenquist R Ommen HB Abrahamsson J Forestier E Jahnukainen K Jonsson OG Zeller B Presence of FLT3-ITD and high BAALC expression are independent prognostic markers in childhood acute myeloid leukemia Blood 2011 118 22 5905 5913 10.1182/blood-2011-05-353185 21967978 \n29. Stavrum AK, Petersen K, Jonassen I, Dysvik B. Analysis of gene-expression data using J-Express. Curr Protoc Bioinforma. 2008, Chapter 7:Unit 7.3; doi:10.1002/0471250953.bi0703s21.\n30. Tusher VG Tibshirani R Chu G Significance analysis of microarrays applied to the ionizing radiation response Proc Natl Acad Sci U S A 2001 98 9 5116 5121 10.1073/pnas.091062498 11309499 \n31. Subramanian A Tamayo P Mootha VK Mukherjee S Ebert BL Gillette MA Paulovich A Pomeroy SL Golub TR Lander ES Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles Proc Natl Acad Sci U S A 2005 102 43 15545 15550 10.1073/pnas.0506580102 16199517 \n32. Mi H Muruganujan A Casagrande JT Thomas PD Large-scale gene function analysis with the PANTHER classification system Nat Protoc 2013 8 8 1551 1566 10.1038/nprot.2013.092 23868073 \n33. Network CGAR Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia New Eng J Med 2013 368 22 2059 2074 10.1056/NEJMoa1301689 23634996 \n34. Papaemmanuil E Gerstung M Bullinger L Gaidzik VI Paschka P Roberts ND Potter NE Heuser M Thol F Bolli N Genomic Classification and Prognosis in Acute Myeloid Leukemia New Eng J Med 2016 374 23 2209 2221 10.1056/NEJMoa1516192 27276561 \n35. Kantarjian H Ravandi F O'Brien S Cortes J Faderl S Garcia-Manero G Jabbour E Wierda W Kadia T Pierce S Intensive chemotherapy does not benefit most older patients (age 70 years or older) with acute myeloid leukemia Blood 2010 116 22 4422 4429 10.1182/blood-2010-03-276485 20668231 \n36. Zhang XZ Yin AH Lin DJ Zhu XY Ding Q Wang CH Chen YX Analyzing gene expression profile in K562 cells exposed to sodium valproate using microarray combined with the connectivity map database J Biomed Biotechnol 2012 2012 654291 22701306 \n37. Wang J Fong CC Tzang CH Xiao P Han R Yang M Gene expression analysis of human promyelocytic leukemia HL-60 cell differentiation and cytotoxicity induced by natural and synthetic retinoids Life Sci 2009 84 17–18 576 583 10.1016/j.lfs.2009.02.001 \n38. Schlenk RF Lubbert M Benner A Lamparter A Krauter J Herr W Martin H Salih HR Kundgen A Horst HA All-trans retinoic acid as adjunct to intensive treatment in younger adult patients with acute myeloid leukemia: results of the randomized AMLSG 07–04 study Ann Hematol 2016 95 12 1931 1942 10.1007/s00277-016-2810-z 27696203 \n39. Ryningen A Stapnes C Paulsen K Lassalle P Gjertsen BT Bruserud O In vivo biological effects of ATRA in the treatment of AML Expert Opin Investig Drugs 2008 17 11 1623 1633 10.1517/13543784.17.11.1623 18922099 \n40. Balmer JE Blomhoff R Gene expression regulation by retinoic acid J Lipid Res 2002 43 11 1773 1808 10.1194/jlr.R100015-JLR200 12401878 \n41. Zheng PZ Wang KK Zhang QY Huang QH Du YZ Zhang QH Xiao DK Shen SH Imbeaud S Eveno E Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia Proc Natl Acad Sci U S A 2005 102 21 7653 7658 10.1073/pnas.0502825102 15894607 \n42. Park MH Cho SA Yoo KH Yang MH Ahn JY Lee HS Lee KE Mun YC Cho DH Seong CM Gene expression profile related to prognosis of acute myeloid leukemia Oncol Rep 2007 18 6 1395 1402 17982622 \n43. Bullinger L Schlenk RF Gotz M Botzenhardt U Hofmann S Russ AC Babiak A Zhang L Schneider V Dohner K PRAME-induced inhibition of retinoic acid receptor signaling-mediated differentiation--a possible target for ATRA response in AML without t(15; 17) Clin Cancer Res 2013 19 9 2562 2571 10.1158/1078-0432.CCR-11-2524 23444226 \n44. Rucker FG Lang KM Futterer M Komarica V Schmid M Dohner H Schlenk RF Dohner K Knudsen S Bullinger L Molecular dissection of valproic acid effects in acute myeloid leukemia identifies predictive networks Epigenetics 2016 11 7 517 525 10.1080/15592294.2016.1187350 27309669 \n45. Eppert K Takenaka K Lechman ER Waldron L Nilsson B van Galen P Metzeler KH Poeppl A Ling V Beyene J Stem cell gene expression programs influence clinical outcome in human leukemia Nat Med 2011 17 9 1086 1093 10.1038/nm.2415 21873988 \n46. Ng SW Mitchell A Kennedy JA Chen WC McLeod J Ibrahimova N Arruda A Popescu A Gupta V Schimmer AD A 17-gene stemness score for rapid determination of risk in acute leukaemia Nature 2016 540 7633 433 437 10.1038/nature20598 27926740 \n47. Steinmetz B Hackl H Slabakova E Schwarzinger I Smejova M Spittler A Arbesu I Shehata M Soucek K Wieser R The oncogene EVI1 enhances transcriptional and biological responses of human myeloid cells to all-trans retinoic acid Cell Cycle 2014 13 18 2931 2943 10.4161/15384101.2014.946869 25486480 \n48. Rommer A Steinmetz B Herbst F Hackl H Heffeter P Heilos D Filipits M Steinleitner K Hemmati S Herbacek I EVI1 inhibits apoptosis induced by antileukemic drugs via upregulation of CDKN1A/p 21/WAF in human myeloid cells PLoS One 2013 8 2 e56308 10.1371/journal.pone.0056308 23457546 \n49. Wieser R New functions for ecotropic viral integration site 1 (EVI1), an oncogene causing aggressive malignant disease Cell Cycle 2012 11 21 3915 10.4161/cc.22392 23032258 \n50. Verhagen HJMP Smit MA Rutten A Denkers F Poddighe PJ Merle PA Ossenkoppele GJ Smit L Primary acute myeloid leukemia cells with overexpression of EVI-1 are sensitive to all-trans retinoic acid Blood 2016 127 4 458 463 10.1182/blood-2015-07-653840 26582376 \n51. Kronenwett R Butterweck U Steidl U Kliszewski S Neumann F Bork S Blanco ED Roes N Graf T Brors B Distinct molecular phenotype of malignant CD34(+) hematopoietic stem and progenitor cells in chronic myelogenous leukemia Oncogene 2005 24 34 5313 5324 10.1038/sj.onc.1208596 15806158\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2407",
"issue": "17(1)",
"journal": "BMC cancer",
"keywords": "Acute myeloid leukemia; All-trans retinoic acid; Gene expression profiling; Valproic acid",
"medline_ta": "BMC Cancer",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D019295:Computational Biology; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D059785:Karyotype; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D009154:Mutation; D000071185:Pharmacogenomic Testing; D059467:Transcriptome; D016896:Treatment Outcome; D014212:Tretinoin; D014635:Valproic Acid",
"nlm_unique_id": "100967800",
"other_id": null,
"pages": "630",
"pmc": null,
"pmid": "28877686",
"pubdate": "2017-09-06",
"publication_types": "D016428:Journal Article",
"references": "23915396;27309669;16199517;20668231;26376137;16609072;12401878;16294345;23457546;18922099;22701306;23032258;25515963;20863429;25486480;18299451;25852056;15894607;21314823;27276561;21967978;23898968;22374841;11090046;21873988;21474179;20929432;18428687;15806158;15902297;11877298;26582376;25631637;22829110;19335274;21221095;23634996;19302803;23868073;14673054;19007987;12681969;11309499;27926740;27696203;17982680;16373393;23444226;17982622;25336205",
"title": "Disease-stabilizing treatment based on all-trans retinoic acid and valproic acid in acute myeloid leukemia - identification of responders by gene expression profiling of pretreatment leukemic cells.",
"title_normalized": "disease stabilizing treatment based on all trans retinoic acid and valproic acid in acute myeloid leukemia identification of responders by gene expression profiling of pretreatment leukemic cells"
} | [
{
"companynumb": "NO-CHEPLA-C20170626_23",
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"occurcountry": "NO",
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"activesubstancename": "VALPROIC ACID"
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"abstract": "BACKGROUND\nAlthough delusional jealousy accounts for merely 10% of delusional disorders, it is associated to risk of serious violence and suicide. With this clinical case, we intend to explore the difficulties in the pharmacological approach of delusional jealousy disorder and to summarise the most recent findings in the treatment of this condition.\n\n\nMETHODS\nCase report.\n\n\nMETHODS\nA 76-year-old man involuntarily admitted to a psychiatric ward due to threats of physical aggression to his wife in the context of irreducible ideas of her infidelity. Initially, we observed an improvement of symptomatology with risperidone and its long-acting injectable formulation, but the emergence of hypotensive side effects required the off-label use of paliperidone palmitate 50 mg/ml.\n\n\nCONCLUSIONS\nFew studies, mainly case reports, look at the specific treatment of delusional jealousy. Given the negative consequences for patients and for their spouses, better scientific evidence to treat this condition is needed.",
"affiliations": "Servicio de Psiquiatría, Hospital Magalhães Lemos, Porto, Portugal. Electronic address: carolinaarmachado@gmail.com.;Servicio de Psiquiatría, Hospital Magalhães Lemos, Porto, Portugal.;Servicio de Psiquiatría, Hospital Magalhães Lemos, Porto, Portugal.",
"authors": "Machado|Carolina R|CR|;Fragoeiro|Cristina|C|;Passos|Margarida|M|",
"chemical_list": null,
"country": "Spain",
"delete": false,
"doi": "10.1016/j.rcp.2020.12.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2530-3120",
"issue": null,
"journal": "Revista Colombiana de psiquiatria (English ed.)",
"keywords": "Antipsicótico inyectable de acción prolongada; Delirio celotípico; Delusional jealousy; Long-acting injectable antipsychotic; Tratamiento; Treatment",
"medline_ta": "Rev Colomb Psiquiatr (Engl Ed)",
"mesh_terms": null,
"nlm_unique_id": "101778593",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33735050",
"pubdate": "2021-03-17",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Delusional Jealousy: How Can Treatment be Improved? A Case Report.",
"title_normalized": "delusional jealousy how can treatment be improved a case report"
} | [
{
"companynumb": "PT-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-295985",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"dru... |
{
"abstract": "BACKGROUND\nConcerns exist that clozapine is underutilized in the management of treatment-resistant schizophrenia. Although a 2015 change in the US Food and Drug Administration (FDA) monitoring recommendations lowered the threshold of the absolute neutrophil count for treatment interruption from 1,500/μL to 1,000/μL and removed white blood cell count thresholds from the monitoring algorithm, the implications of this policy change on clozapine interruptions remain unknown.\n\n\nMETHODS\nWe analyzed outpatient prescribing records for antipsychotic medications in the Veterans Integrated Service Network 7 (VISN 7) database between 1999 and 2012 to assess the potential impact of the recent changes in FDA neutropenia monitoring recommendations on clozapine treatment discontinuation. We evaluated results of complete blood count monitoring to compare percentages of patients who developed or would have developed ≥ 1 hematologic event under the previous and current FDA guidelines in the first year following initiation of clozapine.\n\n\nRESULTS\nFrom a cohort of 14,620 patients with schizophrenia (ICD-9-295.x), 246 patients received clozapine treatment (1.7%). No agranulocytosis was observed during the study period. Under the former recommendations, 5 patients in the clozapine initiation cohort (n = 160, 3.1%; 95% CI, 0.43-5.83) qualified for treatment interruption during the first year of clozapine treatment, while only 1 patient (0.6%) qualified under the current recommendations. Under the former recommendations, hematologic events occurred at a similar rate for individuals taking and not taking clozapine.\n\n\nCONCLUSIONS\nWhile clozapine remains an underused medication, the new FDA monitoring guidelines are likely to substantially reduce the percentage of patients who meet criteria for clozapine-associated hematologic events requiring treatment interruption. This decrease may reduce the clinical burden of managing patients on clozapine and therefore increase the number of individuals treated with this uniquely effective medication. However, prospective studies of individuals treated under the new guidelines are needed to fully assess safety of the FDA's change.",
"affiliations": "New York State Psychiatric Institute/Department of Psychiatry, College of Physicians and Surgeons of Columbia University, 1051 Riverside Dr, New York, NY 10032. rs3511@cumc.columbia.edu.;Department of Psychiatry, College of Physicians and Surgeons, Columbia University; and the New York State Psychiatric Institute, New York, New York, USA.;Department of Psychiatry, The Zucker Hillside Hospital, Northwell Health, Glenn Oaks; Hofstra Northwell School of Medicine, Hempstead; and The Feinstein Institute for Medical Research, Manhasset, New York, USA.;Atlanta Veterans Affairs Medical Center, and Department of Psychiatry and Behavioral Sciences, Emory School of Medicine, Atlanta, Georgia, USA.",
"authors": "Sultan|Ryan S|RS|;Olfson|Mark|M|;Correll|Christoph U|CU|;Duncan|Erica J|EJ|",
"chemical_list": "D014150:Antipsychotic Agents; D003024:Clozapine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0160-6689",
"issue": "78(8)",
"journal": "The Journal of clinical psychiatry",
"keywords": null,
"medline_ta": "J Clin Psychiatry",
"mesh_terms": "D000328:Adult; D016907:Adverse Drug Reaction Reporting Systems; D014150:Antipsychotic Agents; D003024:Clozapine; D016903:Drug Monitoring; D011307:Drug Prescriptions; D005260:Female; D006801:Humans; D007958:Leukocyte Count; D008297:Male; D054539:Medication Therapy Management; D008875:Middle Aged; D009503:Neutropenia; D060735:Pharmacovigilance; D017410:Practice Guidelines as Topic; D011569:Psychiatric Status Rating Scales; D058996:Quality Improvement; D012559:Schizophrenia; D014481:United States; D014486:United States Food and Drug Administration",
"nlm_unique_id": "7801243",
"other_id": null,
"pages": "e933-e939",
"pmc": null,
"pmid": "28742291",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": "3046553;26841681;26884144;8894200;24233347;24004162;17170061;19153164;20639387;12777341;8515788;20868635;14646004;10789357;23842012;11743944;23338869;26842482;26522679;20175050;26541815;8425137;17470834;10385477;23810019;25187353;27400856;12511175;22113154;24869938;15746507",
"title": "Evaluating the Effect of the Changes in FDA Guidelines for Clozapine Monitoring.",
"title_normalized": "evaluating the effect of the changes in fda guidelines for clozapine monitoring"
} | [
{
"companynumb": "US-TEVA-2017-US-832139",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CLOZAPINE"
},
"drugadditional": null,
... |
{
"abstract": "Primary central nervous system lymphoma (PCNSL) remains a therapeutic challenge due to impaired drugs diffusion as a result of the blood-brain barrier and high risk of relapse. Patients with good performance status, chemo-sensitive disease, and eligible for autologous stem cell transplant (ASCT) may benefit from salvage therapy and therapeutic intensification that may allow long-term remission.",
"affiliations": "Department of Hematology Centre Henri Becquerel Rouen France.;Department of Hematology Centre Henri Becquerel Rouen France.;Department of Hematology Centre Henri Becquerel Rouen France.;Department of Hematology Centre Henri Becquerel Rouen France.;Department of Hematology Centre Henri Becquerel Rouen France.",
"authors": "Camus|Vincent|V|0000-0002-1559-007X;Dubois|Sydney|S|;Lepretre|Stéphane|S|;Jardin|Fabrice|F|;Tilly|Hervé|H|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.1630",
"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.1630CCR31630Case ReportCase ReportsProlonged third complete remission after busulfan, thiotepa, and autologous stem cell transplant in a primary central nervous system lymphoma patient CAMUS et al.Camus Vincent http://orcid.org/0000-0002-1559-007Xvincent.camus@chb.unicancer.fr \n1\nDubois Sydney \n1\nLepretre Stéphane \n1\nJardin Fabrice \n1\nTilly Hervé \n1\n\n1 \nDepartment of Hematology\nCentre Henri Becquerel\nRouen\nFrance\n* Correspondence\n\nVincent Camus, Department of Hematology, Centre Henri Becquerel, Rouen, France.\n\nEmail: vincent.camus@chb.unicancer.fr\n04 6 2018 8 2018 6 8 10.1002/ccr3.2018.6.issue-81418 1421 27 2 2018 19 4 2018 11 5 2018 © 2018 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Key clinical message\nPrimary central nervous system lymphoma (PCNSL) remains a therapeutic challenge due to impaired drugs diffusion as a result of the blood‐brain barrier and high risk of relapse. Patients with good performance status, chemo‐sensitive disease, and eligible for autologous stem cell transplant (ASCT) may benefit from salvage therapy and therapeutic intensification that may allow long‐term remission.\n\nautologous stem cell transplantbusulfancomplete remissionprimary central nervous system lymphomathiotepa source-schema-version-number2.0component-idccr31630cover-dateAugust 2018details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.4 mode:remove_FC converted:19.08.2018\n\n\nCamus \nV \n, \nDubois \nS \n, \nLepretre \nS \n, \nJardin \nF \n, \nTilly \nH \n. Prolonged third complete remission after busulfan, thiotepa, and autologous stem cell transplant in a primary central nervous system lymphoma patient . Clin Case Rep . 2018 ;6 :1418 –1421 . 10.1002/ccr3.1630\n==== Body\n1 INTRODUCTION\nWe present a rare case of primary central nervous system lymphoma (PCNSL) that relapsed twice with a prolonged third complete remission after therapeutic intensification and autologous stem cell transplant. This case opens up the potential beneficial role of busulfan or thiotepa for discussion.\n\nPrimary central nervous system lymphoma is a rare but well‐described extranodal high‐grade non‐Hodgkin B‐cell malignancy, accounting for 6.6% of primary brain neoplasms,1 with most PCNSLs (>90%) that are diffuse large B‐cell lymphomas (DLBCL). Diagnosis is difficult, based on clusters of clinical, computed tomography (CT), magnetic resonance imaging (MRI), and cerebrospinal fluid (CSF)‐positive cytology arguments. Histological brain biopsy, sometimes very difficult to achieve because of the inaccessibility of the tumor, must always be performed before the implementation of a specific treatment.\n\nPrimary central nervous system lymphoma remains a therapeutic challenge because drugs diffusion is down by the blood‐brain barrier, and drugs toxicities reduce the relevance of applicable treatment procedures. We describe here an exceptional case of young PCNSL patient who underwent two relapses and successful salvage chemotherapies with therapeutic intensifications followed by autologous stem cell transplant (ASCT).\n\n2 CASE REPORT\nA 38‐year‐old male patient, with no relevant medical history, was admitted to the hematology department of the Henri Becquerel Center in Rouen in May 1999 for diplopia with clinical signs of intracranial hypertension. A cerebral CT scan shows left frontal, left parietal, right occipital, and right lateral lesions strongly enhanced after injection of contrast medium with perilesional edema and mass effect on the lateral ventricles. An encephalic MRI is performed which confirms the visible lesions on the initial CT scan. A stereotaxic biopsy is performed and histological samples indicate a large B‐cell lymphoma with a centroblastic phenotype. The initial assessment therefore concludes with the diagnosis of multiple‐site PNCSL of the brain.\n\nThe patient presented with a Karnofksy Performance status (KPS) of 70% (ECOG PS = 2), LDH were not elevated, cell blood count and standard chemical test revealed no abnormalities, CSF protein was mildly increased (0.47 g/L) with negative cytology and there were no deep brain lesions. CSF flow cytometry was not performed. The patient’s IELSG prognostic index2 was considered “intermediate” and the patient was treated with debulking chemotherapy (cyclophosphamide, vincristine, prednisone) followed by 2 cycles of COPADEM induction (Vincristine 1.4 mg/m² day (D) 1, methotrexate 3000 mg/m² D1, doxorubicin 60 mg/m² D2, cyclophosphamide 250 mg/m²/12 h D2 to D4, methylprednisolone 60 mg/m² D1 to D6 with intrathecal cytarabine injection on D3) followed by 2 cycles of CYM consolidation (methotrexate 3000 mg/m² D1, cytarabine 100 mg/m² D2 to D6, methylprednisolone 60 mg/m² D1 to D6, with intrathecal injection of cytarabine on D3) and whole‐brain radiotherapy with 40 Grays in 16 fractions enabling a first complete remission (CR) lasting 2 years.\n\nFirst relapse occurred in February 2001 with appearance of gait disorder and micrographia; KPS was still at 70%; the cerebral CT was in favor of a recurrence, with multiple localizations, notably in the basal ganglia (data not shown). These lesions were too deep to biopsy; salvage chemotherapy was decided and the patient was treated with 3 cycles of DIAM, 21 days apart (cytarabine 1500 mg/m² × 2/d on D1‐D2, ifosfamide 1500 mg/m² D1 to D5, dexamethasone 40 mg D1 to D4, methotrexate 3000 mg/m² on D3, with intrathecal injection of methotrexate 15 mg), then therapeutic intensification was conditioned by BEAM‐ARAC high dose (VP 16: 200 mg/m² from D‐7 to D‐4, Cytarabine: 2000 mg/m² infused over 1 hour, ie 3900 mg from D‐7 to D‐4, melphalan: 140 mg/m² or 270 mg at D‐3, dexametasone: 20 mg/day from D‐7 to D‐4) and autologous stem cell transplant (ASCT). Peripheral blood progenitor cells were obtained after 2 cycles of DIAM with 14 × 106/kg CD34(+) cells in the graft with one apheresis collection. No complications occurred during the ASCT and a second CR was obtained.\n\nSecond relapse was diagnosed in October 2007 with the appearance of a decrease in left visual acuity with uveitis and left‐sided hemiparesis, with KPS at 80%. A brain MRI was performed showing a gadolinium‐enhanced tissue lesion, measured at 23 × 19 × 15 mm, of the right front‐parietal supracentricular white matter with significant perilesional edema, and discreet mass effect on the roof of the right lateral ventricle (Figure 1). The patient initially benefited from a left vitrectomy, which identified a very high concentration of interleukin‐10 (500 IU/L vs normal <10 IU/L). A cerebral stereotactic biopsy of a right prerolandic lesion was performed, confirming the presence of PCNSL. There was no extra‐cerebral involvement. The patient benefited from 4 courses of R‐DIAM (rituximab 375 mg/m² IV at D1 combined with the DIAM chemotherapy previously described), was mobilized by the use of Granulocyte colony‐stimulating factor (GCSF, lenograstim) 34 MUI/d, starting at D12 after the 2nd cycle of R‐DIAM, with apheresis performed at D17 (quantification of hematopoietic progenitors in blood at D17: CD34(+) = 145/μL,) with 9.5 × 106/kg CD34(+) cells in the graft with one apheresis collection. The patient received then a second therapeutic intensification conditioned by thiotepa, busulfan, and cyclophosphamide (thiotepa 250 mg/² on D‐9, D‐8, and D‐7, intravenous busulfan 0.8 mg/kg × 4/on day D‐6, D‐5, and D‐4, cyclophosphamide 60 mg/kg on D‐3 and D‐2) and ASCT. The second ASCT was marked by Grade IV mucositis and Enterobacter asburiae and Pseudomonas aeruginosa septicemia, which improved over the course of antibiotic therapy. Absolute neutrophil count (ANC) recovery above 0.5 × 109/L and white blood cell (WBC) recovery above 4 × 109/L for 3 consecutive days was achieved at D14 with filgrastim administration from D5 to D14. Platelet count exceeding 20 G/L without transfusion support was obtained at D50.\n\nFigure 1 A and B, FLAIR cerebral MRI sequence of October 2007, in favor of a pre‐rolandic right frontal lymphomatous recurrence of 23 × 19 × 15 mm of the supra‐ventricular right white matter with perilesional edema and discrete mass effect on the roof of the right lateral ventricle. C and D, cerebral computed tomography of January 2008, displaying an annular enhancement measuring approximately 19 mm (antero posterior axis) by 17 mm (height) of the right semioval center. A discrete perilesional hypodensity is associated, no mass effect on the adjacent structures is observed, notably there is no abnormality of the ventricular system, which is symmetrical. No evolution is detected after comparison with the MRI of October 2007. The patient did not receive an MRI for cerebral evaluation in 2008 because of the development of claustrophobia contraindicating this procedure\n\nA third CR was achieved (Figure 2), and is clinically persisting 9 years after the end of treatment. After this third line treatment, no cognitive disorder was observed, and the patient’s medical follow‐up was marked by:\n\nFigure 2 A and B, Cerebral computed tomography of September 2009 identifying the persistence of a discreetly dilated aspect of the lateral ventricles. Persistence of superior right parietal calcification and persistence of right parieto‐occipital cortico‐subcortical hypodensity is also observed, with a sequellar aspect. The aspect is in favor of the persistence of complete remission\n\n\nEar, nose, and throat infectious complications with mastoiditis, right rock lysis, and chronic otitis.\n\nImmunological deficiency with compensated hypogammaglobulinemia.\n\nRenal failure related to chronic tubulointerstitial nephropathy post‐antibiotherapy, relatively stable since 2010.\n\n\n\n\n3 DISCUSSION\nThis case of PNCSL having relapsed twice with a prolonged third CR is very rare and showcases the potential beneficial role of high‐dose chemotherapy, busulfan, or thiotepa. In the case of our patient, the beneficial role of rituximab could also be suggested, although the patient was able to achieve complete remission with both the DIAM and R‐DIAM regimens. Furthermore, the benefit of the addition of rituximab to high‐dose methotrexate‐based chemotherapy is still unclear, and did not improve PFS in the HOVON study which included 200 patients with newly diagnosed PCNSL.2\n\n\nIn addition, our patient also benefited from the strategy of two therapeutic intensifications with ASCT. At the time of first relapse in 2001, thiothepa was not available and BEAM‐adapted conditioning regimen with high‐dose cytarabine followed by ASCT appeared as an interesting therapeutic option that may explain partially the good outcome of the patient, with prolonged second progression‐free survival (PFS2).3, 4 We also note that our patient has very long time intervals between relapses, well over 1 year, which possibly explains the favorable evolution in the long term. This is consistent with the prognostic factors identified in the cohort of 256 PCNSL published in 2016 by the LOC network6: KPS ≥ 70%, sensitivity to first‐line therapy, duration of first CR (>1 year), management at relapse/progression with salvage therapy (vs palliative therapy).\n\nNevertheless, the results obtained with the second therapeutic intensification with ASCT in terms of better PFS bring the question of the choice of conditioning. The announced central nervous system (CNS) diffusion of busulfan is >80%, while that of cyclophosphamide is 20%‐30%.7 Thiotepa is a cytotoxic alkylating agent close to nitrogen mustards, passing the blood‐brain barrier with a ratio of 100% in the CSF, whose efficacy in myeloablative conditioning followed by ASCT in relapsing PNCSL has been well demonstrated since 1990.5, 8 The excellent CNS entrance of the thiothepa‐busulfan combination contrasts with that of agents in the BEAM‐ARAC high‐dose regimen, where CNS diffusion of BCNU is 15%‐70%, etoposide is <5%, and melphalan is 10%.7 It should be noted that the regimen of the second therapeutic intensification of the patient, with thiothepa and busulfan, was quite toxic and marked by numerous infectious complications, which must be taken into account before prescribing this type of conditioning regimen.\n\nFinally, the hypothesis of a combined beneficial effect of thiotepa and busulfan is very likely9, 10 in the case of this patient.\n\n4 CONCLUSION\nPrimary central nervous system lymphoma is a hematological malignancy that remains chemo‐sensitive at relapse; combinations with molecules such as thiotepa can potentially bring hope for a prolonged CR.\n\nCONFLICT OF INTEREST\nNone declared.\n\nAUTHORS’ CONTRIBUTION\nConception and design: all authors. Administrative support: all authors. Provision of study materials or patients: all authors. Collection and assembly of data: all authors. Data analysis and interpretation: all authors. Manuscript writing: All authors. Final approval of manuscript: All authors.\n==== Refs\nREFERENCES\n1 \n\nMiller \nDC \n, \nHochberg \nFH \n, \nHarris \nNL \n, \nGruber \nML \n, \nLouis \nDN \n, \nCohen \nH \n. Pathology with clinical correlations of primary central nervous system non‐Hodgkin’s lymphoma. The Massachusetts General Hospital experience 1958‐1989 . Cancer . 1994 ;74 :1383 ‐1397 .8055462 \n2 \n\nFerreri \nAJM \n, \nBatchelor \nT \n, \nZucca \nE \n, \nCavalli \nF \n, \nArmitage \nJ \n. International Collaborative Group against Primary CNS Lymphomas . J Clin Oncol . 2003 ;21 :1649 ‐1650 .12697892 \n3 \n\nBromberg \nJ \n, \nIssa \nS \n, \nBukanina \nK \n, et al. Effect of rituximab in primary central nervous system lymphoma – results of the randomized phase III HOVON 105/ALLG NHL 24 Study . N°582, ASH;\n2017 .\n4 \n\nSoussain \nC \n, \nSuzan \nF \n, \nHoang‐Xuan \nK \n, et al. Results of intensive chemotherapy followed by hematopoietic stem‐cell rescue in 22 patients with refractory or recurrent primary CNS lymphoma or intraocular lymphoma . J Clin Oncol . 2001 ;19 :742 ‐749 .11157026 \n5 \n\nSoussain \nC \n, \nChoquet \nS \n, \nFourme \nE \n, et al. Intensive chemotherapy with thiotepa, busulfan and cyclophosphamide and hematopoietic stem cell rescue in relapsed or refractory primary central nervous system lymphoma and intraocular lymphoma: a retrospective study of 79 cases . Haematologica . 2012 ;97 :1751 ‐1756 .22581000 \n6 \n\nLangner‐Lemercier \nS \n, \nHouillier \nC \n, \nSoussain \nC \n, et al. Primary CNS lymphoma at first relapse/progression: characteristics, management, and outcome of 256 patients from the French LOC network . Neuro‐Oncol . 2016 ;18 :1297 ‐1303 .26951382 \n7 \n\nWiebe \nVJ \n, \nSmith \nBR \n, \nDeGregorio \nMW \n, \nRappeport \nJM \n. Pharmacology of agents used in bone marrow transplant conditioning regimens . Crit Rev Oncol Hematol . 1992 ;13 :241 ‐270 .1476655 \n8 \n\nKasenda \nB \n, \nIhorst \nG \n, \nSchroers \nR \n, et al. High‐dose chemotherapy with autologous haematopoietic stem cell support for relapsed or refractory primary CNS lymphoma: a prospective multicentre trial by the German Cooperative PCNSL study group . Leukemia . 2017 ;31 :2623 ‐2629 .28559537 \n9 \n\nFerreri \nAJ \n, \nCwynarski \nK \n, \nPulczynski \nE \n, et al. Chemoimmunotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix regimen) in patients with primary CNS lymphoma: results of the first randomisation of the International Extranodal Lymphoma Study Group‐32 (IELSG32) phase 2 trial . Lancet Haematol . 2016 ;3 :e217 ‐e227 .27132696 \n10 \n\nChen \nYB \n, \nBatchelor \nT \n, \nLi \nS \n, et al. Phase 2 trial of high‐dose rituximab with high‐dose cytarabine mobilization therapy and high‐dose thiotepa, busulfan, and cyclophosphamide autologous stem cell transplantation in patients with central nervous system involvement by non‐Hodgkin lymphoma . Cancer . 2015 ;121 :226 ‐233 .25204639\n\n",
"fulltext_license": "CC BY",
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"keywords": "autologous stem cell transplant; busulfan; complete remission; primary central nervous system lymphoma; thiotepa",
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"title": "Prolonged third complete remission after busulfan, thiotepa, and autologous stem cell transplant in a primary central nervous system lymphoma patient.",
"title_normalized": "prolonged third complete remission after busulfan thiotepa and autologous stem cell transplant in a primary central nervous system lymphoma patient"
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"abstract": "Herein, we describe our experience with a recurrent ovarian cancer patient who was treated safely with bevacizumab and who achieved a complete response despite receiving nine prior chemotherapy regimens. The patient was a 54-year-old woman with stage IIIC recurrent ovarian serous adenocarcinoma (grade 3). Computed tomography (CT) revealed that no evidence of ascites, multiple intraperitoneal dissemination, or intrapelvic lymph node metastases was present. The absence of bowel obstruction and disseminated lesions involving the intestinal tract was confirmed by CT. Performance status was 0, and a blood test also indicated preservation of major organ function. In our hospital, weekly paclitaxel plus bevacizumab therapy (paclitaxel at 80 mg/m(2) on days 1, 8, and 15; bevacizumab at 15/mg/kg on day 1 and every 21 days thereafter) was started. Eight cycles were administered, with no signs of gastrointestinal perforation, and the antitumor effect was evaluated as a complete response. The observed adverse events included grade 1 hyponatremia and grade 1 hypochloremia, and there was one grade 1 sensory peripheral neuropathy. These adverse events neither delayed treatment nor necessitated any dosage reductions. This case suggests that bevacizumab can be safely administered even to patients with recurrent ovarian cancer who have received three or more prior chemotherapy regimens if there are neither symptoms of bowel obstruction nor lesions suggestive of intestinal invasion on diagnostic imaging.",
"affiliations": "Department of Obstetrics and Gynecology, School of Medicine, Iwate Medical University, Morioka, Japan.;Department of Obstetrics and Gynecology, School of Medicine, Iwate Medical University, Morioka, Japan.;Department of Obstetrics and Gynecology, School of Medicine, Iwate Medical University, Morioka, Japan.;Department of Obstetrics and Gynecology, School of Medicine, Iwate Medical University, Morioka, Japan.;Department of Obstetrics and Gynecology, Iwate Prefectural Miyako Hospital, Miyako, Japan.;Department of Obstetrics and Gynecology, School of Medicine, Iwate Medical University, Morioka, Japan.",
"authors": "Takatori|Eriko|E|;Shoji|Tadahiro|T|;Nagasawa|Takayuki|T|;Takeuchi|Satoshi|S|;Hosoyachi|Akira|A|;Sugiyama|Toru|T|",
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"fulltext": "\n==== Front\nOnco Targets TherOnco Targets TherOncoTargets and TherapyOncoTargets and therapy1178-6930Dove Medical Press 10.2147/OTT.S80143ott-8-2097Case ReportA recurrent ovarian cancer patient with a history of nine prior chemotherapy regimens who was safely treated with weekly paclitaxel plus bevacizumab and achieved a complete response: a case report Takatori Eriko 1Shoji Tadahiro 1Nagasawa Takayuki 1Takeuchi Satoshi 1Hosoyachi Akira 2Sugiyama Toru 11 Department of Obstetrics and Gynecology, School of Medicine, Iwate Medical University, Morioka, Japan2 Department of Obstetrics and Gynecology, Iwate Prefectural Miyako Hospital, Miyako, JapanCorrespondence: Eriko Takatori, School of Medicine, Iwate Medical University, 19-1 Uchimaru, Morioka, Iwate 020-8505, Japan, Tel +81 19 651 5111, Fax +81 19 622 1900, Email sppe8459@yahoo.co.jp2015 11 8 2015 8 2097 2100 © 2015 Takatori et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License2015The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Herein, we describe our experience with a recurrent ovarian cancer patient who was treated safely with bevacizumab and who achieved a complete response despite receiving nine prior chemotherapy regimens. The patient was a 54-year-old woman with stage IIIC recurrent ovarian serous adenocarcinoma (grade 3). Computed tomography (CT) revealed that no evidence of ascites, multiple intraperitoneal dissemination, or intrapelvic lymph node metastases was present. The absence of bowel obstruction and disseminated lesions involving the intestinal tract was confirmed by CT. Performance status was 0, and a blood test also indicated preservation of major organ function. In our hospital, weekly paclitaxel plus bevacizumab therapy (paclitaxel at 80 mg/m2 on days 1, 8, and 15; bevacizumab at 15/mg/kg on day 1 and every 21 days thereafter) was started. Eight cycles were administered, with no signs of gastrointestinal perforation, and the antitumor effect was evaluated as a complete response. The observed adverse events included grade 1 hyponatremia and grade 1 hypochloremia, and there was one grade 1 sensory peripheral neuropathy. These adverse events neither delayed treatment nor necessitated any dosage reductions. This case suggests that bevacizumab can be safely administered even to patients with recurrent ovarian cancer who have received three or more prior chemotherapy regimens if there are neither symptoms of bowel obstruction nor lesions suggestive of intestinal invasion on diagnostic imaging.\n\nKeywords\nrecurrent ovarian cancergastrointestinal perforation\n==== Body\nIntroduction\nRecently, overseas, four randomized Phase III trials have reported the addition of bevacizumab to either first-line chemotherapy (GOG-0218 and ICON7) or to second-line chemotherapy in platinum-sensitive (OCEANS Trial) and platinum-resistant (AURELIA Trial) recurrent ovarian cancer. Relative to progression-free survival (PFS), the absolute median PFS advantage of bevacizumab added to chemotherapy followed by maintenance compared with chemotherapy alone (and placebo, in GOG-0218) as first-line treatment was 3.8 months (14.1 vs 10.3 months, respectively) in the GOG-0218 trial1 and 1.5 months (21.8 vs 20.3 months, respectively) in ICON7.2 The median PFS benefit as measured in months associated with adding bevacizumab to chemotherapy seems to be similar in recurrent ovarian cancer, being 4 months in platinum-sensitive relapse (lengthening PFS from 8.4 to 12.4 months in the OCEANS Trial)3 and 3.3 months in platinum-resistant disease (from 3.4 to 6.7 months in the AURELIA Trial).4 In Japan, bevacizumab was approved for health insurance coverage in November 2013 for the treatment of ovarian cancer, which allows administration of this drug at 15 mg/kg every 3 weeks for the cancer. Gastrointestinal (GI) perforation is among the serious adverse events of bevacizumab. In recurrent cases especially, sufficient caution is required when administering bevacizumab. One of the eligibility criteria for the AURELIA trial was that patients had received no more than two prior chemotherapy regimens, ie, those who had received three or more regimens were excluded.4 We herein report our experience with a case in which weekly paclitaxel plus bevacizumab therapy was safely administered to a patient with recurrent ovarian cancer who had received nine prior chemotherapy regimens.\n\nCase report\nThe patient was a 54-year-old woman, gravida 2, para 2, with stage IIIC ovarian cancer (histology: serous cystadenocarcinoma grade 3). She was referred for the treatment of recurrent cancer to the Department of Obstetrics and Gynecology at our hospital in April 2014.\n\nIn June 2004, the patient had undergone simple total hysterectomy, bilateral uterine adnexectomy, and pelvic lymphadenectomy at the previous hospital. However, a tumor remained on the surface of the rectal serosa. After surgery, three cycles of paclitaxel plus carboplatin (TC) therapy (paclitaxel at 175 mg/m2 on day 1; carboplatin [area under the curve [AUC] 6 mg/mL per min] on day 1 and every 21 days thereafter) were administered, followed by interval debulking surgery consisting of omentectomy and para-aortic lymphadenectomy. Because the tumor on the surface of the rectal serosa had macroscopically disappeared, the rectum was not resected. However, because rapid cytology of ascites provided a diagnosis of adenocarcinoma, cisplatin was intraperitoneally injected at 50 mg/m2 during surgery. After interval debulking surgery, six cycles of TC therapy were added. Remission was achieved, and the patient was followed up. In August 2007, secondary debulking surgery (SDS) was performed, with a diagnosis of pelvic recurrence, and recurrent tumors over the entire rectum were removed. During the SDS, cisplatin was again intraperitoneally injected at 50 mg/m2. After SDS, six cycles of TC therapy were administered. Remission was again achieved, and the patient was followed up. In September 2010, with a diagnosis of liver and para-aortic lymph node metastases, six cycles of TC therapy were administered again. The metastatic lesions disappeared, and she was again followed up. In May 2011, because new multiple intraperitoneal dissemination and intrapelvic lymph node metastases were detected, two cycles of pegylated liposomal doxorubicin monotherapy (50 mg/m2 every 28 days) were administered, but there was no clinical response. Starting in September 2011, 20 cycles of gemcitabine monotherapy (1,500 mg/m2 on day 1 and every 14 days thereafter) were given. Tumor reduction was not achieved, and the metastatic lesions grew. Thus, starting in July 2013, she received eight cycles of irinotecan hydrochloride (CPT-11) plus etoposide (VP-16) therapy (irinotecan at 60 mg/m2 on days 1 and 15; oral etoposide at 50 mg/body on days 1 to 21 and every 28 days thereafter). However, further growth of the metastatic lesions was observed. At the previous hospital, the patient and her family were informed that there was no further treatment available at that hospital. The patient and her family had then requested treatment with bevacizumab, and she was thus referred to our hospital. The prior chemotherapy regimens is shown in Table 1.\n\nComputed tomography (CT) at our hospital revealed that no evidence of ascites, multiple intraperitoneal dissemination, or intrapelvic lymph node metastases was present (Figure 1). In addition, the absence of bowel obstruction and disseminated lesions involving the intestinal tract was confirmed by CT. Performance status was 0, and a blood test also indicated preservation of major organ functions. After the patient and her family had received a detailed explanation of the possible serious adverse reactions to bevacizumab, such as GI perforation and thrombosis, weekly paclitaxel plus bevacizumab therapy (paclitaxel at 80 mg/m2 on days 1, 8, and 15; bevacizumab at 15 mg/kg on day 1 and every 21 days thereafter) was started in May 2014. To date, eight cycles have been administered. The antitumor effect was evaluated as a complete response (Figure 1). Moreover, the level of carcinoma antigen (CA)125 decreased from 940 U/mL to 49 U/mL. PFS is 7 months, to date, and she remains alive with disease. Regarding adverse events, the observed metabolic/laboratory events were grade 1 hyponatremia and grade 1 hypochloremia, and the only nonmetabolic/laboratory events was grade 1 sensory peripheral neuropathy. These adverse events did not necessitate delay of starting the subsequent treatment cycle or any dosage reductions.\n\nDiscussion\nThe AVF 2949g trial was a clinical study on platinum-resistant recurrent ovarian cancer. Because GI perforation was observed in five (23.8%) of the 21 patients who had received three prior chemotherapy regimens and in 11.4% of patients overall, this trial was terminated early.5 However, the incidence of GI perforation was reevaluated as part of the retrospective analysis of the AVF 2949g trial results in 25 patients, with the following unique exclusion criteria: (a) clinical symptoms of bowel obstruction; (b) evidence of rectosigmoid involvement on pelvic examination; and (c) bowel involvement on CT scan. This subset analysis revealed that although the median number of prior chemotherapy regimens was five (range 2–12), the incidence of GI perforation was zero.6 In the AVF 2949g trial, patients with a high risk of GI perforation, as described above, had not been excluded. It is thus assumed that GI perforation had occurred at a high rate in the high-risk subset. GI perforation caused by administration of bevacizumab appears to occur in patients with intestinal complications rather than in those receiving a certain number of prior chemotherapy regimens. On the other hand, Takano et al reported that GI perforation occurred in the ninth week of weekly paclitaxel plus bevacizumab therapy, which was administered as the fourth-line regimen to patients without these risk factors.7 The GOG-0218 study found the incidence of GI perforation to be significantly increased in patients with a history of inflammatory bowel treatment, large-bowel surgery, and primary small-bowel surgery.8 Meta-analyses have shown the incidence to be significantly increased in patients with a history of bowel surgery, those with symptoms of bowel obstruction, and those with invasive tumors in the area from the rectum to the vagina, indicating that there is no association between the number of prior regimens and GI perforation.9,10 Moreover, in the GOG-0218 study, GI perforation occurred during the sixth cycle or earlier in the majority of the patients, whereas there was only one patient in whom GI perforation occurred during maintenance therapy with bevacizumab during or after the sixth cycle.8 Based on these observations, it is reasonable to assume that in our patient, for whom 7 months have passed to date since the start of treatment, the possibility of developing GI perforation might be low in the absence of a relapse.\n\nAt present, there are two ongoing clinical studies on combination bevacizumab therapy for recurrent ovarian cancer: the GOG-0213 study and the Study of Clinical and Biological Prognostic Factors in Patients with Ovarian Cancer Receiving Carboplatin + Paclitaxel with Bevacizumab (MITO16/ManGO), which target patients with platinum-sensitive tumors. According to the eligibility criteria for these studies, the maximum allowable number of prior chemotherapy regimens is one. In the AURELIA trial, which was conducted in patients with platinum-resistant tumors, the maximum allowable number was two regimens.4 With regards to administration of bevacizumab, further studies on the association between the number of prior chemotherapy regimens and GI perforation are needed.\n\nIn the AURELIA trial, which was a clinical study targeting patients with platinum-resistant recurrent ovarian cancer, the subanalysis showed that those receiving weekly paclitaxel plus bevacizumab therapy had favorable treatment outcomes, as evidenced by a response rate of 51.3% and the median PFS of 6 months.4 For our patient, weekly paclitaxel plus bevacizumab therapy was selected for the following reasons: pegylated liposomal doxorubicin had been used previously, and topotecan is the recommended drug in Japan when the number of prior chemotherapy regimens is three or less.\n\nIn the AURELIA trial, paclitaxel was administered at 80 mg/m2 on days 1, 8, 15, and 22, and bevacizumab at 10 mg/kg on days 1 and 15, with one cycle being defined as 28 days. However, in Japan, administration of bevacizumab at 10 mg/kg every 2 weeks is not approved by the national health insurance scheme. Thus, our patient received a regimen consisting of paclitaxel at 80 mg/m2 on days 1, 8, and 15 and bevacizumab at 15 mg/kg on day 1, with one cycle consisting of 21 days.\n\nIn our patient, the possible reasons for responding to this regimen were that 3 years and 3 months had passed since the last dose of paclitaxel, and that weekly administration of paclitaxel at 80 mg/m2 increases the dose intensity. While treatment is ongoing, PFS is 7 months at present, and longer survival is anticipated.\n\nOur patient, who had received nine prior chemotherapy regimens, was safely administered bevacizumab in combination with paclitaxel. Even in patients who have received three or more prior chemotherapy regimens, bevacizumab can be safely administered for recurrent ovarian cancer if neither symptoms of bowel obstruction nor lesions suggestive of intestinal invasion are present on diagnostic imaging. This is the first report in Japan showing that bevacizumab can be concomitantly used for patients with recurrent ovarian cancer regardless of the number of prior chemotherapy regimens. We consider this report to be significant in that the regimen employed herein has potential to contribute to an improved prognosis for such patients.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 Multiple intraperitoneal dissemination (A and B) and intrapelvic lymph node metastases (C) were observed before treatment (arrows). After eight cycles of weekly paclitaxel plus bevacizumab therapy, the antitumor effect was evaluated as a complete response (D–F).\n\nTable 1 Prior chemotherapy regimens\n\nRegimen\tCycle(s)\tBest response\t\n1. TC\t3\tCR\t\n2. CDDP\t1\tNE\t\n3. TC\t6\tNE\t\n4. CDDP\t1\tNE\t\n5. TC\t6\tNE\t\n6. TC\t6\tCR\t\n7. PLD\t2\tPD\t\n8. GEM\t20\tSD\t\n9. CPT-11/VP-16\t8\tSD\t\nNotes: CDDP = cisplatin 50 mg/m2 (intraperitoneal injection). CPT-11/VP-16 = irinotecan hydrochloride 60 mg/m2 days 1 and 15, and oral etoposide 50 mg/body on days 1 and 21 and every 28 days. GEM = gemcitabine 1,500 mg/m2 and every 14 days. PLD = pegylated liposomal doxorubicin 50 mg/m2 on day 1 and every 28 days. TC = paclitaxel 175 mg/m2 on day 1, and carboplatin AUC 6 mg/ml per min on day 1 and every 21 days.\n\nAbbreviations: AUC, area under the curve; CR, complete response; NE, not evaluable; PD, progressive disease; SD, stable disease.\n==== Refs\nReferences\n1 Burger RA Brady MF Bookman MA Incorporation of bevacizumab in the primary treatment of ovarian cancer N Engl J Med 2011 365 26 2473 2483 22204724 \n2 Perren TJ Swart AM Pfisterer J ICON7 Investigators A phase 3 trial of bevacizumab in ovarian cancer N Engl J Med 2011 365 26 2484 2496 22204725 \n3 Aghajanian C Blank SV Goff BA OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer J Clin Oncol 2012 30 17 2039 2045 22529265 \n4 Pujade-Lauraine E Hilpert F Weber B Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial J Clin Oncol 2014 32 13 1302 1308 24637997 \n5 Cannistra SA Matulonis UA Penson RT Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer J Clin Oncol 2007 25 33 5180 5186 18024865 \n6 Simpkins F Belinson JL Rose PG Avoiding bevacizumab related gastrointestinal toxicity for recurrent ovarian cancer by careful patient screening Gynecol Oncol 2007 107 1 118 123 17658587 \n7 Takano M Kikuchi Y Kato M Yoshikawa T Kita T Bowel perforation associated with bevacizumab therapy in recurrent ovarian cancers without bowel obstruction or bowel involvement Gan To Kagaku Ryoho 2008 35 11 1981 1984 Japanese 19011357 \n8 Burger RA Brady MF Bookman MA Risk factors for GI adverse events in a phase III randomized trial of bevacizumab in first-line therapy of advanced ovarian cancer: A Gynecologic Oncology Group Study J Clin Oncol 2014 32 12 1210 1217 24637999 \n9 Richardson DL Backes FJ Hurt JD Which factors predict bowel complications in patients with recurrent epithelial ovarian cancer being treated with bevacizumab? Gynecol Oncol 2010 118 1 47 51 20382413 \n10 Tanyi JL McCann G Hagemann AR Clinical predictors of bevacizumab-associated gastrointestinal perforation Gynecol Oncol 2011 120 3 464 469 21168199\n\n",
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"keywords": "gastrointestinal perforation; recurrent ovarian cancer",
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"title": "A recurrent ovarian cancer patient with a history of nine prior chemotherapy regimens who was safely treated with weekly paclitaxel plus bevacizumab and achieved a complete response: a case report.",
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"abstract": "BACKGROUND\nWe conducted a study to determine whether dutasteride reduces the risk of incident prostate cancer, as detected on biopsy, among men who are at increased risk for the disease.\n\n\nMETHODS\nIn this 4-year, multicenter, randomized, double-blind, placebo-controlled, parallel-group study, we compared dutasteride, at a dose of 0.5 mg daily, with placebo. Men were eligible for inclusion in the study if they were 50 to 75 years of age, had a prostate-specific antigen (PSA) level of 2.5 to 10.0 ng per milliliter, and had had one negative prostate biopsy (6 to 12 cores) within 6 months before enrollment. Subjects underwent a 10-core transrectal ultrasound-guided biopsy at 2 and 4 years.\n\n\nRESULTS\nAmong 6729 men who underwent a biopsy or prostate surgery, cancer was detected in 659 of the 3305 men in the dutasteride group, as compared with 858 of the 3424 men in the placebo group, representing a relative risk reduction with dutasteride of 22.8% (95% confidence interval, 15.2 to 29.8) over the 4-year study period (P<0.001). Overall, in years 1 through 4, among the 6706 men who underwent a needle biopsy, there were 220 tumors with a Gleason score of 7 to 10 among 3299 men in the dutasteride group and 233 among 3407 men in the placebo group (P=0.81). During years 3 and 4, there were 12 tumors with a Gleason score of 8 to 10 in the dutasteride group, as compared with only 1 in the placebo group (P=0.003). Dutasteride therapy, as compared with placebo, resulted in a reduction in the rate of acute urinary retention (1.6% vs. 6.7%, a 77.3% relative reduction). The incidence of adverse events was similar to that in studies of dutasteride therapy for benign prostatic hyperplasia, except that in our study, as compared with previous studies, the relative incidence of the composite category of cardiac failure was higher in the dutasteride group than in the placebo group (0.7% [30 men] vs. 0.4% [16 men], P=0.03).\n\n\nCONCLUSIONS\nOver the course of the 4-year study period, dutasteride reduced the risk of incident prostate cancer detected on biopsy and improved the outcomes related to benign prostatic hyperplasia. (ClinicalTrials.gov number, NCT00056407.)",
"affiliations": "Division of Urology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA. andrioleg@wustl.edu",
"authors": "Andriole|Gerald L|GL|;Bostwick|David G|DG|;Brawley|Otis W|OW|;Gomella|Leonard G|LG|;Marberger|Michael|M|;Montorsi|Francesco|F|;Pettaway|Curtis A|CA|;Tammela|Teuvo L|TL|;Teloken|Claudio|C|;Tindall|Donald J|DJ|;Somerville|Matthew C|MC|;Wilson|Timothy H|TH|;Fowler|Ivy L|IL|;Rittmaster|Roger S|RS|;|||",
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"abstract": "Opioid substitution treatment (OST) with methadone or buprenorphine is the most effective means of treating opioid dependence. If these substances are used by people who are not undergoing OST, they can however carry serious risks. This article examines the lifetime prevalence, motives, and drug sources for such use, as well as geographical differences in these variables.\n\n\n\nStructured interviews were conducted with 411 patients from 11 OST clinics in five Swedish cities. The researchers carried out 280 interviews on-site, while 131 interviews were conducted by specially trained patients through privileged access interviewing. Data were analyzed by frequency and average calculations, cross-tabulations, and χ2 tests.\n\n\n\nThe lifetime prevalence of non-prescribed use was 87.8% for methadone, 80.5% for buprenorphine, and 50.6% for buprenorphine/naloxone. Pseudo-therapeutic motives-avoiding withdrawal symptoms, staying clean from heroin, detoxification, or taking care of one's own OST-were commonly cited as driving the use, while using the drugs for euphoric purposes was a less common motive. Most respondents had bought or received the substances from patients in OST, but dealers were also a significant source of non-prescribed methadone and buprenorphine. Geographical differences of use, motives, and sources suggest that prescription practices in OST have a great impact on which substances are used outside of the treatment.\n\n\n\nExperiences of non-prescribed use of methadone and buprenorphine are extremely common among those in OST in southern Sweden. As the use is typically driven by pseudo-therapeutic motives, increased access to OST might decrease the illicit demand for these substances. Buprenorphine/naloxone has a lower abuse potential than buprenorphine and should therefore be prioritized as the prescribed drug. Supervised dosage and other control measures are important provisions in the prevention of drug diversion and non-prescribed use among people not undergoing OST.",
"affiliations": "Department of Social Work, Malmö University, Malmö, Sweden. bjorn.johnson@mau.se.;Department of Social Work, Malmö University, Malmö, Sweden.",
"authors": "Johnson|Björn|B|0000-0002-1601-2706;Richert|Torkel|T|",
"chemical_list": "D000701:Analgesics, Opioid; D000069479:Buprenorphine, Naloxone Drug Combination; D002047:Buprenorphine; D008691:Methadone",
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"doi": "10.1186/s12954-019-0301-y",
"fulltext": "\n==== Front\nHarm Reduct JHarm Reduct JHarm Reduction Journal1477-7517BioMed Central London 30110.1186/s12954-019-0301-yResearchNon-prescribed use of methadone and buprenorphine prior to opioid substitution treatment: lifetime prevalence, motives, and drug sources among people with opioid dependence in five Swedish cities http://orcid.org/0000-0002-1601-2706Johnson Björn +46 40 665 76 90bjorn.johnson@mau.se Richert Torkel +46 40 665 79 63torkel.richert@mau.se 0000 0000 9961 9487grid.32995.34Department of Social Work, Malmö University, Malmö, Sweden 2 5 2019 2 5 2019 2019 16 314 3 2019 15 4 2019 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 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\nOpioid substitution treatment (OST) with methadone or buprenorphine is the most effective means of treating opioid dependence. If these substances are used by people who are not undergoing OST, they can however carry serious risks. This article examines the lifetime prevalence, motives, and drug sources for such use, as well as geographical differences in these variables.\n\nMethods\nStructured interviews were conducted with 411 patients from 11 OST clinics in five Swedish cities. The researchers carried out 280 interviews on-site, while 131 interviews were conducted by specially trained patients through privileged access interviewing. Data were analyzed by frequency and average calculations, cross-tabulations, and χ2 tests.\n\nResults\nThe lifetime prevalence of non-prescribed use was 87.8% for methadone, 80.5% for buprenorphine, and 50.6% for buprenorphine/naloxone. Pseudo-therapeutic motives—avoiding withdrawal symptoms, staying clean from heroin, detoxification, or taking care of one’s own OST—were commonly cited as driving the use, while using the drugs for euphoric purposes was a less common motive. Most respondents had bought or received the substances from patients in OST, but dealers were also a significant source of non-prescribed methadone and buprenorphine. Geographical differences of use, motives, and sources suggest that prescription practices in OST have a great impact on which substances are used outside of the treatment.\n\nConclusions\nExperiences of non-prescribed use of methadone and buprenorphine are extremely common among those in OST in southern Sweden. As the use is typically driven by pseudo-therapeutic motives, increased access to OST might decrease the illicit demand for these substances. Buprenorphine/naloxone has a lower abuse potential than buprenorphine and should therefore be prioritized as the prescribed drug. Supervised dosage and other control measures are important provisions in the prevention of drug diversion and non-prescribed use among people not undergoing OST.\n\nKeywords\nOpioid substitution treatmentMethadoneBuprenorphineBuprenorphine/naloxoneNon-prescribed usePseudo-therapeutic useDiversionOpioid dependenceSwedish Research Council for Health, Working Life and Welfare2010–1144Johnson Björn issue-copyright-statement© The Author(s) 2019\n==== Body\nBackground and aims\nOpioid substitution treatment (OST) with methadone or buprenorphine (including buprenorphine/naloxone) is considered the most effective means of treating opioid dependence. There is ample research evidence of positive outcomes in terms of reduced mortality, morbidity, illicit drug use, and criminality [1–4].\n\nMethadone and buprenorphine are safe and effective when used according to the prescription [5, 6]. However, if they are used improperly (in a way contravening the prescription) or by people who are not undergoing OST, these substances can carry serious risks. There is a high risk of developing dependence, and overdosing may lead to death as a result of depressed ventilation. If the substances are injected, the risks are similar to those of injected heroin, including overdose, life-threatening infections, and transmission of blood-borne diseases [7, 8].\n\nMethadone-related deaths have been highlighted as a problem in many countries [5, 9–12]. Buprenorphine, too, has been involved in many deaths, mainly in polydrug poisonings with sedative substances and alcohol [13–15]. Those who have died with these substances found in their body have mainly acquired the substances illicitly, that is, they have not themselves been in OST [12, 16–18].\n\nAnd yet, the non-prescribed use of methadone and buprenorphine can also bring benefits. According to Harris and Rhodes, who have studied the non-prescribed use of methadone, such use can serve as a “protective strategy” and can enable opioid-dependent persons to control their drug use, improve their social relations, and reduce the transmission of blood-borne viruses as a result of decreased injecting [19]. Non-prescribed use of buprenorphine has also shown to carry fewer health risks and lead to a better quality of life than the use of heroin [6, 20].\n\nThis article examines experiences of previous, non-prescribed use of methadone and buprenorphine in a group of 411 persons in OST in 5 cities in southern Sweden. The data was collected in 2012 from structured interviews in conjunction with a research project focusing on drug diversion and non-prescribed use of methadone and buprenorphine.1\n\nWe will discuss (1) how commonly the interviewees engaged in non-prescribed use of methadone and buprenorphine before entering treatment, (2) the various motives for use and whether there are differences between the cities, and (3) which sources the interviewees have used to get hold of the drugs and whether there are differences between the cities. The results are analyzed against an extensive review of previous research on non-prescribed use.\n\nFor many years, the access to OST in Sweden was severely restricted, but availability increased significantly following the launch of buprenorphine (Subutex®) in January 2000, from under 600 patients nationwide to almost 4000 patients in 2013 [21, 22]. This coincided with a sizeable increase in the number of methadone- and buprenorphine-related cases of death. While there were 9 deaths in 1998 where a forensic autopsy found traces of methadone or buprenorphine in the deceased’s body, the number increased to 201 in 2013 (the number of cases where a narcotic substance of some kind was detected rose from 286 to 748 during the same period) [23]. A study of methadone- and buprenorphine-related deaths found that only 20% of the deceased had had a prescription for these substances. It is therefore important to examine the non-prescribed use of these substances.\n\nWe focus on the geographical aspect because there is a lack of research that compares similarities and differences of non-prescribed use in different contexts. The drug situation and the availability of OST differ somewhat between the studied cities. This is discussed in greater detail in the “Methods” section.\n\nThe combination drug buprenorphine/naloxone (Suboxone®) was introduced in Sweden in November 2006 and has been used to varying degrees as complementing or replacing buprenorphine in the five cities that this study was conducted in. We distinguish between buprenorphine and buprenorphine/naloxone where this is relevant.\n\nPrevious research\nNon-prescribed use of methadone and buprenorphine is not a large international research area, but there is a growing body of research—especially in the US, Australia, and several western European countries—where the prevalence of non-prescribed use has been examined in different contexts and in different groups of drug users. The motives for this use have also been explored in several studies, while there has been less research on the sources that these drugs come from. Non-prescribed use of methadone and buprenorphine has received little research attention in Sweden or the other Nordic countries.\n\nPrevalence of non-prescribed use\nNon-prescribed use of methadone began to gain attention at the beginning of the 1970s after the treatment had spread throughout the country [24, 25]. Ethnographic studies described how methadone had become integrated into the drug scenes, serving as a street drug among heroin users [26–28]. Similar experiences have emerged in many countries where methadone-based OST has been widely used [29–32].\n\nBuprenorphine appeared on the illegal drug market in the 1980s in the form of Temgesic® painkillers [33], but it was only in the 1990s when it was launched as a medication (Subutex) in OST that buprenorphine became more established among users of illicit drugs [6]. During the first decade of the 2000s, it became increasingly common in many countries among injecting drug users and those with heroin dependence [6, 34, 35]. Finland has been one of the most conspicuous examples in this respect, as buprenorphine has been the predominant opioid on the Finnish illegal drug market. Two studies showed in 2007 that buprenorphine was the most common drug among injecting drug users in Helsinki and that 97% of those who sought OST had buprenorphine as their main drug [36, 37].\n\nStudies on different groups of drug users show variation in the use of methadone and buprenorphine. The lifetime prevalence of non-prescribed use of methadone has varied between 17 and 95% [29, 30, 38–42], while the lifetime prevalence of non-prescribed use of buprenorphine has varied between 8 and 76% [37, 43–48]. The higher prevalence rates are found in studies focusing on individuals whose drug use is dominated by opioids [6, 34, 45]. The highest prevalence numbers—in terms of both lifetime and current use—is found in studies on those who inject heroin or other opioids and in studies on individuals who have sought treatment for opioid dependence [30, 37, 40, 41, 49]. A case in point is a Swedish study of non-prescribed use of buprenorphine conducted with 350 interviewees at a needle exchange program in Malmö in 2004. Almost half of the respondents had heroin as their main drug, and as many as 89% of these said that they had used buprenorphine during the past year. Among those whose main drug was amphetamine, the figure was 24% [44].\n\nThat the non-prescribed use varies from one place and time to another may depend on shifting availability and price of heroin and other opioids but also on the availability and setup of OST [6, 35, 50]. Greater access to OST can increase the supply of methadone and buprenorphine on the illegal market as a result of drug diversion (“leakage”) by the patients. However, greater availability can also decrease the illicit demand for these substances, when more people turn toward treatment [6, 51, 52]. Prior to this study, there are no comparative studies on differences in use between different locations.\n\nMuch of the research has focused on experienced drug users, most of all on individuals who have a long-term opioid dependence and/or who inject drugs. The results suggest that methadone and buprenorphine tend to come in late in a person’s drug use trajectory and that they are rarely the users’ primary choice within the opioid group [48, 53]. Some results go against these findings, however, at least regarding buprenorphine. The Finnish experiences should be mentioned here (see above), as well as some studies from other countries. In a survey among injecting drug users in the country of Georgia, 11.5% of the respondents said that buprenorphine was the drug that they first developed a dependence of [54], while a study from India suggested that drug users who had turned to injecting were more prone to using buprenorphine than heroin [55]. These studies, too, focus on experienced drug users.\n\nFew studies have examined the use of methadone and buprenorphine among younger and/or recreational drug users. A study of ours in Sweden, drawing on register data and interviews with professionals, shows that these substances are very rare among adolescents and young adults who do not already have severe drug problems. We compared three different populations in the study: a general group of grade two high school students (16–17 years of age), a group that had sought help or had been referred to clinics for adolescents and young adults with problems related to alcohol or other drugs, and a group of young adults in care for severe drug problems. Both the register data and the interviews showed that methadone and buprenorphine were generally unknown among high school students and extremely uncommon among clients at outpatient clinics for adolescents. The substances were relatively common among young adults with serious drug problems and were often part of polydrug use [56].\n\nMotives for non-prescribed use\nThe fact that non-prescribed methadone and buprenorphine are mainly used by experienced drug users and by those with an established opioid dependence also shows in the motives driving the use. These are often related to the so-called pseudo-therapeutic reasons, which correlate with the intended medical use of these substances. Pseudo-therapeutic use can aim to mitigate or avoid withdrawal symptoms (“to stay straight”), to take care of one’s own detoxification, to stay clean from heroin, or to alleviate pain [6, 30, 34, 49, 50, 56–58]. In the study referred to above at the needle exchange program in Malmö, 87% of those whose main drug was heroin said that they had use non-prescribed buprenorphine for withdrawal symptoms or detoxification [44].\n\nAnother common motive for using non-prescribed methadone or buprenorphine is taking care of one’s own OST. The substances are here used as in regular treatment; roughly equal amounts are taken daily for an extended period, with the primary aim of staying away from other opioids. This kind of use has been documented in several studies [49, 51, 59–61].\n\nBarriers to OST have been pointed out as crucially contributing to pseudo-therapeutic use [59, 60]. In a previous study, we interviewed 27 people who had treated themselves with methadone or buprenorphine for at least 3 months. They had started self-medicating because they wished to change their lives or to cut back on heroin but also because they felt there were barriers to OST. The barriers had to do with difficulties accessing treatment (because of strict admission criteria, limited availability, or a bureaucratic and demanding assessment process), difficulties remaining in treatment (as a result of being involuntarily discharged for relapsing), and ambivalence toward or reluctance to seek treatment (most of all as a result of a fear of stigmatization or disciplinary action) [51].\n\nNon-prescribed methadone and buprenorphine are also used for euphoric purposes (“to get high”), either on their own or combined with other substances. This is a less common motive, at least in studies with experienced drug users whose main drug is heroin or other opioids [6, 30, 42]. However, getting high on buprenorphine is common in countries where it has become the predominant illicit opioid [62, 63].\n\nEconomic motives are also claimed to play a role in the non-prescribed use of methadone and buprenorphine, which are often available at an attractive price on the illegal market compared to heroin [7, 35, 42, 49]. Methadone and buprenorphine also have a demand among patients undergoing OST, when they have failed to pick up their doses or are unhappy with their prescribed dose [64, 65].\n\nThe route of administration of non-prescribed use varies. There are many who take the substances as intended medically, that is, orally in the case of methadone and sublingually (to dissolve under the tongue) with buprenorphine. Injecting methadone carries high risks but is done both within and outside of treatment [66, 67]. In an Australian study with 312 heroin users, 52% had at some point injected methadone, and 29% had done so during the past 6 months [68]. Buprenorphine is both injected and snorted relatively commonly [6, 30, 34, 44]. Buprenorphine is generally much less typically injected than heroin [34], but there are exceptions. In a Finnish study, 81% of those seeking treatment who had buprenorphine as their primary drug said that they mainly injected this drug. Among those who primarily used heroin and sought treatment, the corresponding figure was 70% [63].\n\nTo reduce the risk of improper use, buprenorphine is often prescribed in a buprenorphine/naloxone combination. Naloxone has been added to make injecting and snorting less appealing.2 Many studies have shown that buprenorphine/naloxone is injected and snorted to a much lesser extent than plain buprenorphine [6, 34, 62, 69, 70] and that it is less sought after on the illegal market [71, 72].\n\nDifferent routes of administration can relate to different motives for use, as well as the availability of different formulations. Oral administration of methadone and sublingual use of buprenorphine are more common in pseudo-therapeutic use, while the users more commonly resort to injecting when they wish to get high [19, 46, 47]. There can also be other reasons for injecting: for example, withdrawal symptoms are alleviated more quickly if the drugs are injected. Injecting is also the most economic route of administration, because the bioavailability is at its greatest at injecting (the substances are absorbed more effectively by the body) [47]. In addition, for some people who have injected for a long time, the very ritual of injecting can be closely associated with pleasure and make the habit extremely hard to break. This is known as the needle fixation [73, 74].\n\nSources of non-prescribed substances\nWhere do users of non-prescribed methadone or buprenorphine get hold of the substances? There is not much research on this, but the issue has been examined in several studies since the 1970s. The substances are typically said to come from friends, acquaintances, or family members, who share the drugs among themselves or sell them out of their own legal prescription [6, 32, 45, 64, 71, 75]. These persons are most often undergoing OST [32, 50, 64, 71], but there are also those who have been prescribed methadone or buprenorphine to relieve pain [76, 77]. The drugs are handed over after payment or as a gift in a relationship that builds on favors or friendship [32, 48, 71, 77]. Bourgois argues that a “moral economy of sharing” often emerges among drug users; in this norm system, it is considered morally wrong not to share among friends suffering from withdrawal symptoms [78].\n\nResearch on the diversion of methadone and buprenorphine by patients in OST is contradictory about the extent of the phenomenon [32, 64, 67, 79, 80]. While many studies speak for a low prevalence of such drug diversion, this is at odds with the often extremely high prevalence rate reported in studies of non-prescribed use. A previous study of ours suggests in fact that drug diversion may be considerably more common than has been assumed.3 In this study, 68% of the patients said that they had at some point sold or shared their drugs, and 24% declared having done so during the past month [72]. For a clear majority, diversion takes place to a limited extent and only sporadically. Only a small group does it more systematically [64, 81].\n\nDealers are another major source of non-prescribed substances [77]. Dealers in this context refer to people who sell pharmaceuticals that they do not have a prescription for (they may of course have got hold of the substances via patients who have acquired them on prescription). Dealers have been declared as the most common source of buprenorphine in a few studies [48, 61], but existing research has overall found dealers to be a less common source than friends, acquaintances, and family members [32, 45, 50, 64, 71, 75].\n\nInternational smuggling of buprenorphine has been documented, especially between European countries. France and the Baltic countries have often been identified as countries of origin for buprenorphine sold at the illegal drug markets in Finland and Sweden [82, 83]. A study conducted by The National Board of Health and Welfare in Sweden on the buprenorphine seized by the Swedish police found that the countries of origin could be traced in more than half of the seizures. Over 90% of the traced tablets came from abroad, mainly from France [84]. However, we need to be very cautious in drawing conclusions based on data on seizures, because this data totally depends on the data collection, that is, police efforts [85]. There is a reason to assume that the police do not prioritize measures against OST patients’ dealing and sharing their medication with friends and acquaintances. Based on the study by The National Board of Health and Welfare, it is reasonable to conclude that illegal trafficking represents a not insignificant share of the illegal supply of buprenorphine in Sweden.\n\nFrivolous or dubious prescriptions by doctors are another source identified in previous research. Such prescribing partly reflects how prescriptions are regulated in different countries [77]. For example, some research suggests that private clinics prescribe larger methadone doses and keep a poorer control than do dependence clinics in the public sector [86]. “Doctor-shopping,” the practice of patients visiting multiple doctors to obtain multiple prescriptions, has been relatively common in countries which lack centrally regulated OST. In France, where buprenorphine is prescribed by general practitioners, 15–20% of the prescriptions have been calculated to be the result of doctor-shopping [87]. Buprenorphine was prescribed more liberally in Sweden in 2000–2005, before the rules were tightened by The National Board of Health and Welfare [21].4\n\nOther sources, such as online purchases and thefts from healthcare facilities, have seldom been mentioned in the research on non-prescribed use of methadone and buprenorphine. Their role has been marginal in the few inquiries which have specifically studied these sources [48, 88]. This accords with a systematic overview and meta-analysis of sources of non-prescribed pharmaceuticals in general, where theft and online purchases are recognized as uncommon sources [77].\n\nMethods\nSampling, participants, and recruitment\nThis study involves 411 patients recruited from 9 public and 2 private OST clinics in 5 cities in southern Sweden. Structured interviews were conducted between May and December 2012. The participants were required to have undergone OST for at least four weeks to be included. Table 1 shows the distribution of the data between the five cities.Table 1 Number of interviews in the five cities\n\nCity\tNumber\tProportion (%)\t\nMalmö\t196\t47.7\t\nGöteborg\t118\t28.7\t\nLund\t54\t13.1\t\nNorrköping\t22\t5.4\t\nJönköping\t21\t5.1\t\nTotal\t411\t100.0\t\n\n\nThe five cities were chosen for their varied drug scenes and availability of OST. In the neighboring cities of Lund and Malmö, heroin appeared on the illegal drug market in the 1970s, while Göteborg and Norrköping are more recent heroin cities (1990s). Opioid pharmaceuticals have dominated the drug scene in Jönköping (and later also in Norrköping), but heroin has been uncommon. OST with methadone was introduced in Lund and Malmö in the early 1990s, and methadone continues to be the predominant prescribed drug in these cities. In Göteborg, Jönköping, and Norrköping, OST with buprenorphine began at the beginning of the 2000s, whereas methadone began to be used later (as a result of new national guidelines). Buprenorphine has been the dominant OST drug in these cities but has been replaced by buprenorphine/naloxone in Jönköping and Norrköping after this substance was launched in Sweden in 2007. We have merged these two cities in the analyses to avoid creating groups which are too small. All five cities have had a relatively low availability of OST.\n\nWe used two different data collection methods: (1) on-site interviews conducted by the two researchers (Johnson and Richert) and three project assistants and (2) peer-to-peer interviews conducted by patients.\n\nThe on-site interviews (n = 280) were made in all five cities. Announcements were posted on the clinic walls a week or two before our arrival. Written information and booking sheets were left with a secretary. We then spent 2–10 working days at the clinics, conducting appointed interviews and recruiting more participants among the visitors. The interviews were conducted in private rooms.\n\nThe peer-to-peer-interviews (n = 131) were conducted in the two largest cities—Göteborg and Malmö—through “privileged access interviewing” [89–91] by nine specially trained patients. The interviewers, five women and four men, had a stable lifestyle and had large contact networks in different patient groups. They recruited interviewees from among their circles and conducted the interviews at various sites outside of the clinics—in homes, cafés, parks, etc. Before the data collection began, both the peer interviewers and the project assistants were trained on the contents of the interview itself and on the interviewing technique. We have discussed in detail the method of privileged access interviewing and the process of recruiting interviewers in a previous article [91].\n\nDue to the nature of the recruitment procedure, a sophisticated non-response analysis is not possible, but on the group level, we have received information on patient numbers, gender, age, type of medication, average dose, and pick-up routines from the 11 clinics. The clinics had in all 1006 patients, which means that the 411 interviews represented 40.8% of the total population (minimum 24.3%, maximum 64.3%). Table 2 shows a comparison between the study population and the clinics’ total population. There are significant differences only in pick-up routines; our material has an overrepresentation of patients who pick up their medication on 5–7 days of the week (34.5% vs. 21.2% in the total population) and an underrepresentation of patients who come and get their medication once a week or more seldom (29.2% vs. 42.3%). This difference was to be expected, as most of the interviewees were recruited at the clinics.Table 2 Non-response analysis\n\nVariable\tStudy group (411)\tAll patients (1006)\tP value (χ2 test)\t\nGender (man)\t74.7% (307)\t75.2% (757)\t0.736\t\nAge (mean)\t39.36 (411)\t39.85 (1006)\t\t\nMedication\t\n Methadone\t53.3% (219)\t51.6% (519)\t0.628\t\n Buprenorphine\t27.3% (112)\t28.7% (289)\t\t\n Buprenorphine/naloxone\t19.5% (80)\t19.7% (198)\t\t\nDose (mg)\t\n Methadone\t99.32 (219)\t98.55 (517)\t\t\n Mono-buprenorphine\t19.02 (112)\t19.44 (289)\t\t\n Buprenorphine/naloxone\t18.78 (80)\t18.88 (198)\t\t\nPick-up routines\t\n 5–7 days/week\t34.5% (142)\t21.4% (215)\t0.000\t\n 2–4 days/week\t36.3% (149)\t35.8% (360)\t\t\n More seldom\t29.2% (120)\t42.8% (431)\t\t\n\n\nInterviewing\nThe interview procedure was the same irrespective of who did the interviewing. The participants were first told about the project and its aims orally and in writing. They were told that the study was confidential, that it would not have an impact on their treatment, and that they could at any point stop the interview. The participants could subsequently choose between a gift voucher for SEK 200 (about € 19) or a book, regardless of whether they completed the interview or not.\n\nThe interviews were conducted with a standardized questionnaire. The questionnaire had 106 closed-ended and 5 open-ended questions covering the following areas: demographic information, health, social situation, drug use (past and current), experiences of own non-prescribed use of substitution drugs, treatment experiences, current OST and ideas about this treatment, and views on and own experiences of diversion. The interviews lasted on average about 1 h.\n\nVariables and statistical analysis\nThe variables examined in this article build on the following questions:Medication: “What is your prescribed OST medication?” Response options: (a) methadone, (b) buprenorphine (Subutex, Buprenotex), and (c) buprenorphine-naloxone (Suboxone).\n\nLength of treatment: “How long have you been in OST this treatment episode?” Response options: number of months.\n\nExperience of involuntary discharge: “Have you ever been discharged from OST against your will?” Response options: yes/no.\n\nUse of methadone outside treatment: “Have you used methadone outside treatment?” Response options: (a) no, (b) yes, only drinkable methadone, (c) yes, only methadone tablets, and (d) yes, both drinkable methadone and tablets. The answers have been dichotomized for the analyses in this article (yes/no).\n\nUse of buprenorphine outside treatment: “Have you used buprenorphine (Subutex, Buprenotex) outside treatment?” Response options: yes/no.\n\nUse of buprenorphine/naloxone outside treatment: “Have you used buprenorphine/naloxone (Suboxone) outside treatment?” Response options: yes/no.\n\nInjecting methadone: “Have you injected methadone outside treatment?” Response options: yes/no.\n\nRoute of administration for buprenorphine or buprenorphine/naloxone: “When you were using buprenorphine or buprenorphine/naloxone, how did you usually take it?” Response options: (a) under the tongue, (b) injecting, (c) snorting, (d) smoking, and (e) other (specify).\n\nMotives for use outside treatment: “Why did you use methadone, buprenorphine, or buprenorphine/naloxone?” Response options: (a) own detoxification, (b) to avoid withdrawal, (c) own OST, (d) to get high, (e) hard to get hold of heroin, (f) wanted to stay clean from heroin, and (g) other reason (specify).\n\nSources of drugs outside treatment: “Where did you usually get hold of methadone or buprenorphine?” Response options: (a) purchased from someone undergoing OST, (b) purchased from a dealer, (c) purchased from a patient in treatment other than OST, (d) from a doctor, from within health care, (e) online trade, and (f) another source (specify).\n\nStreet price: “Do you know the current street price for methadone, buprenorphine, or buprenorphine/naloxone?” The price was cited as per bottle (90 mg) of methadone and tablet (8 mg) of buprenorphine and buprenorphine/naloxone.\n\n\n\nThe data have been analyzed by frequency and average calculations and cross-tabulations. Chi-squared tests and variance analysis (ANOVA) were performed to establish a level of significance of group differences. All analyses were done in SPSS version 24 for Windows.\n\nResults\nPrevalence of non-prescribed use in the study population\nTable 3 shows the prevalence of non-prescribed use for the three substances in the study population according to demographic variables, treatment variables, geographical location, and type of interviewer. The use of methadone (87.8%) and buprenorphine (80.5%) is very common in the population, while the use of buprenorphine/naloxone (50.6%) is not quite as common. This is probably because buprenorphine/naloxone had only been used for a few years in Sweden at the time of the interviews and that it was not prescribed at the clinics to a similar extent as methadone and buprenorphine. There are no clear differences in the use according to the demographic variables (gender, country of birth, and education).Table 3 Non-prescribed use of methadone, buprenorphine, and buprenorphine/naloxone in the study population\n\n\tNon-prescribed use of methadone\tNon-prescribed use of buprenorphine\tNon-prescribed use of buprenorphine/naloxone\t\nTotal\t\n Whole population (411)\t87.8%\t80.5%\t50.6%\t\nGender\t\n Woman (104)\t85.6%\t75.0%\t54.1%\t\n Man (307)\t88.6%\t82.4%\t43.0%\t\n Chi-2 (P value)\t0.415\t0.099\t0.054\t\nCountry of birth\t\n Sweden (333)\t88.9%\t82.6%\t53.5%\t\n Other country (78)\t83.3%\t71.8%\t42.1%\t\n Chi-2 (P value)\t0.177\t0.030\t0.073\t\nEducation\t\n Comprehensive school (195)\t86.7%\t82.6%\t52.9%\t\n High school or more (216)\t88.9%\t78.7%\t50.0%\t\n Chi-2 (P value)\t0.491\t0.324\t0.563\t\nDrug\t\n Methadone (219)\t92.7%\t74.0%\t45.1%\t\n Buprenorphine (112)\t81.3%\t87.5%\t49.5%\t\n Buprenorphine/naloxone (80)\t83.8%\t88.8%\t70.9%\t\n Chi-2 (P value)\t0.005\t0.002\t0.000\t\nTreatment period, length of\t\n Up to 1 year (138)\t90.6%\t88.4%\t65.9%\t\n 1–3 years (140)\t90.7%\t85.7%\t58.6%\t\n More than 3 years (130)\t82.3%\t66.2%\t25.8%\t\n Chi-2 (P value)\t0.054\t0.000\t0.000\t\nExperience of involuntary discharge\t\n No (262)\t85.9%\t80.2%\t52.3%\t\n Yes (149)\t91.3%\t81.2%\t49.7%\t\n Chi-2 (P value)\t0.108\t0.795\t0.606\t\nCity\t\n Malmö (196)\t92.9%\t75.5%\t51.5%\t\n Göteborg (118)\t81.4%\t88.1%\t49.1%\t\n Lund (54)\t88.9%\t77.8%\t46.3%\t\n Jönköping/Norrköping (43)\t81.4%\t86.0%\t63.4%\t\n Chi-2 (P value)\t0.012\t0.035\t0.366\t\nInterviewers\t\n Researchers (280)\t88.2%\t78.6%\t49.1%\t\n Privileged access interviewers (131)\t87.0%\t84.7%\t56.2%\t\n Chi-2 (P value)\t0.731\t0.142\t0.184\t\n\n\nRegarding the treatment variables, a greater share of patients had used those substances that they were later prescribed in OST. This is especially clear in the use of buprenorphine/naloxone. The differences may be down to the patients’ positive experiences of non-prescribed use of a certain substance; they may have asked to be given this substance at the beginning of the treatment. It might also be that patients who had been involuntarily discharged from a treatment program had continued to use the substance that they used to be prescribed and were now waiting to be readmitted into treatment.5 There are significant differences also in terms of the treatment period; patients who had been in ongoing treatment for longer than 3 years have less experience of buprenorphine and considerably less experience of buprenorphine/naloxone. The most likely explanation is that some patients in this group have not had the opportunity to use these substances outside treatment, because they were not available before the patients began their OST. As regards the experience of involuntary discharge, there are no differences. This suggests that the decision to seek OST is generally preceded by the non-prescribed use of methadone, buprenorphine, and buprenorphine/naloxone.\n\nThe use of methadone and buprenorphine varies between the cities, while the use of buprenorphine/naloxone seems to be more stable. In Malmö and Lund, methadone was the drug most commonly used without prescription, whereas buprenorphine was the most common drug in Göteborg and Jönköping/Norrköping. In a previous article, we showed that privileged access interviewing may produce different results than traditional researcher interviews, especially when it comes to sensitive topics. Since researchers conducted interviews in all cities, and privileged access interviewers only in Göteborg and Malmö, we have included the type of interviewer as a variable in Table 3. The analysis indicates that the differences between cities cannot be explained by the differing data collection methods. However, the differences correlate with the predominant drug prescribed in OST in the cities under study—methadone in Malmö and Lund, buprenorphine in Göteborg, and buprenorphine and later buprenorphine/naloxone in Jönköping/Norrköping.\n\nMotives for non-prescribed use in the five cities, and routes of administration\nThe interviewees’ declared motives for use are shown in Table 4, presented in relation to substance and city (many interviewees stated more than one motive). A general pattern is that many interviewees cited several different motives for their use. A clear majority said that they had used the drugs to avoid withdrawal symptoms; this was the most common response for all three substances (and many expressed it as having used the drugs to “stay straight”). Other pseudo-therapeutic motives were similarly common, such as using the drugs for own OST or to stay clean from heroin. Lack of heroin was a common motive for using methadone, but slightly less common for using buprenorphine and buprenorphine/naloxone. Using these substances for euphoric purposes (to “get high”) was the least common motive. Around a third had used methadone and buprenorphine in order to get high, but the proportion was lower for buprenorphine/naloxone (17.8%).6Table 4 Motives for non-prescribed use in different cities\n\n\tMalmö\tGöteborg\tLund\tJönköping/Norrköping\tAll cities\tChi-2 (P value)\t\nMotives for use of methadone\t(182)\t(96)\t(48)\t(35)\t(361)\t\t\n Avoid withdrawal symptoms\t92.9\t89.6\t79.2\t85.7\t89.5\t0.043\t\n Lack of heroin\t57.1\t54.2\t43.8\t51.4\t54.0\t0.416\t\n Own detoxification\t64.3\t40.6\t43.8\t45.7\t53.5\t0.001\t\n Wanted to stay clean from heroin\t56.6\t50.0\t58.3\t28.6\t52.4\t0.017\t\n Own substitution treatment\t42.3\t21.9\t54.2\t34.3\t37.7\t0.001\t\n Get high\t24.7\t32.3\t18.8\t60.0\t29.4\t0.000\t\nMotives for use of buprenorphine\t(148)\t(104)\t(41)\t(37)\t(330)\t\t\n Avoid withdrawal\t83.8\t83.7\t85.4\t89.2\t84.5\t0.859\t\n Lack of heroin\t44.9\t45.2\t36.6\t48.6\t44.4\t0.723\t\n Own detoxification\t53.4\t45.2\t61.0\t54.1\t51.8\t0.331\t\n Wanted to stay clean from heroin\t43.9\t52.9\t61.0\t54.1\t50.0\t0.191\t\n Own substitution treatment\t25.7\t44.2\t61.0\t75.7\t41.5\t0.000\t\n Get high\t35.1\t26.0\t17.1\t45.9\t31.2\t0.019\t\nMotives for use of buprenorphine/naloxone\t(100)\t(57)\t(25)\t(26)\t(208)\t\t\n Avoid withdrawal\t77.0\t82.5\t76.0\t69.2\t77.4\t0.601\t\n Lack of heroin\t39.0\t45.6\t36.0\t26.9\t38.9\t0.434\t\n Own detoxification\t49.0\t41.1\t40.0\t34.6\t44.0\t0.512\t\n Wanted to stay clean from heroin\t40.0\t38.6\t48.0\t34.6\t39.9\t0.795\t\n Own substitution treatment\t25.0\t31.6\t40.0\t50.0\t31.7\t0.076\t\n Get high\t17.0\t14.0\t20.0\t26.9\t17.8\t0.540\t\n\n\nAnother pattern is that the various motives are cited to a lesser degree for buprenorphine/naloxone than for methadone and buprenorphine. This indicates that buprenorphine/naloxone is a less popular substance for non-prescribed use. Many interviewees declared spontaneously that they had used buprenorphine/naloxone when they had failed to get hold of buprenorphine (this response option was missing from the questionnaire).\n\nThere are significant differences between the cities in certain purposes of use, but the differences vary between the substances and are therefore hard to explain. In the case of own OST, different drugs (methadone or buprenorphine) seem to have been prioritized in different cities, but it is difficult to say why. The motive of getting high was cited more often by interviewees in Jönköping/Norrköping. This might be because synthetic opioids have had a more prominent role on the drug markets in these cities, while heroin has been available more sporadically. The general impression is however that there are no great differences in the declared motives in the different cities.\n\nThe interviewees’ routes of administration are shown in Table 5 for the whole population (some respondents had several routes of administration). The prescribed routes of administration were the most common for all three substances. Just under half of methadone users said that they had at some point injected the drug. It was more common to snort buprenorphine and buprenorphine/naloxone than to inject them. Buprenorphine/naloxone was most often administered sublingually, while injecting was uncommon. Many of those who had injected buprenorphine/naloxone said that the effect of the naloxone had made it a negative experience.Table 5 Route of administration for non-prescribed use\n\nRoute of administration\tMethadone (361)\tBuprenorphine (330)\tBuprenorphine/naloxone (208)\t\nSublingually\tNV\t79.7%\t85.6%\t\nSnorted\tNV\t70.6%%\t51.0%\t\nInjected\t47.4%\t40.9%\t15.4%\t\nOrally\t100.0%\tNA\tNA\t\nNA not asked, NV non-viable means of consumption\n\n\n\nSourcing non-prescribed drugs in different cities\nThe sources given by the interviewees for methadone and buprenorphine (which here also includes buprenorphine/naloxone) are presented in Table 6. The results show clearly that patients undergoing OST were the most commonly cited source. This applies to both methadone and buprenorphine and to all cities, except for buprenorphine among interviewees in Göteborg (where dealers were the most common source).Table 6 Sources for non-prescribed drugs in different cities\n\n\tMalmö\tGöteborg\tLund\tJönköping/Norrköping\tAll cities\tChi-2 (P value)\t\nSources: methadone\t(182)\t(93)\t(48)\t(35)\t(358)\t\t\n Patient in substitution treatment\t74.2\t71.0\t66.7\t65.7\t71.5\t0.620\t\n Dealer\t47.3\t65.6\t25.0\t51.4\t49.4\t0.000\t\n Other healthcare patient\t12.1\t10.8\t6.3\t34.3\t13.1\t0.001\t\n From doctor/health care\t6.0\t0.0\t4.2\t2.9\t3.9\t0.107\t\n Online\t0.0\t2.2\t0.0\t2.9\t0.8\t0.133\t\n Other source\t56.4\t30.1\t52.1\t17.1\t44.6\t0.000\t\nSources: buprenorphine and buprenorphine/naloxone\t(143)\t(95)\t(39)\t(36)\t(313)\t\t\n Patient in substitution treatment\t75.5\t56.8\t76.9\t72.2\t69.6\t0.013\t\n Dealer\t48.3\t71.6\t66.7\t66.7\t59.7\t0.002\t\n Other healthcare patient\t6.3\t0.0\t0.0\t5.6\t3.5\t0.036\t\n From doctor/health care\t3.5\t3.2\t2.6\t0.0\t2.9\t0.728\t\n Online\t0.0\t1.1\t10.3\t11.1\t2.9\t0.000\t\n Other source\t4.2\t14.1\t5.1\t16.7\t8.7\t0.015\t\nStreet price\t\t\t\t\t\t(ANOVA)\t\n Methadone 90 mg\t227\t319\t242\t344\t262\t0.000\t\n Buprenorphine 8 mg\t103\t155\t108\t271\t137\t0.000\t\n Buprenorphine/naloxone 8 mg\t84\t127\t93\t215\t112\t0.000\t\n\n\nOverall, dealers were the second most cited source for both methadone and buprenorphine, with interesting and significant differences between the cities. Dealers were the declared source of methadone to a much higher degree in Göteborg than in Lund, while in Malmö, the dealers were declared to be a source for buprenorphine less often than in the other cities. Such differences suggest considerable variation between the local drug markets in terms of the availability of illicit drugs and pharmaceuticals.\n\n“Other sources” were cited by almost half of the interviewees in the case of methadone. This category consisted almost exclusively of people who said that they had purchased methadone from Danish patients and/or dealers in Denmark, smuggling small amounts for personal use. Denmark also appears as a source among a great many respondents in Göteborg but to a much smaller extent in Jönköping/Norrköping.7 There was no corresponding cross-border trade for buprenorphine, which has traditionally not been much used in Danish OST [92]. It also turned out that some users had bought buprenorphine in Stockholm and that this was more common among interviewees in Göteborg and Jönköping/Norrköping, which are geographically closer to Stockholm.\n\nOther sources—other healthcare patients, doctors/health care, and online trade—were generally uncommon. Certain significant differences emerge between the cities, but the proportion of yes/no responses is so small that the differences are hard to explain. However, the proportion of those who said that they had acquired methadone from another healthcare patient was considerably bigger in Jönköping/Norrköping than in the other cities. This may be linked to what has already been referred to that synthetic opioids have cornered the drug markets in these cities.8\n\nTable 6 also lists the average price for illegal purchases of methadone, buprenorphine, and buprenorphine/naloxone in the different cities. The prices varied greatly for all substances but were generally lowest in Malmö and Lund and highest in Jönköping/Norrköping. Buprenorphine had a higher street price in all cities than buprenorphine/naloxone.\n\nDiscussion\nOur study confirms many of the findings of previous research on the non-prescribed use of methadone and buprenorphine. Such use is very common among those whose drug use is dominated by opioids and especially among those who have sought treatment for opioid dependence. The prevalence rates of non-prescribed use in our study—87.8% for methadone, 80.5% for buprenorphine, and 50.6% for buprenorphine/naloxone—are high but correspond to those presented by previous studies among those who have sought OST [30, 38, 42, 43, 45].\n\nSimilarly, the motives given by the interviewees for non-prescribed use correspond to those named in previous research. The dominant motives pertain to what we have labeled as pseudo-therapeutic reasons, that is, those that align with the intended medical use of these substances [6, 30, 34, 44, 49, 50, 56–61]. It is often the case that the users want to avoid withdrawal symptoms, stay clean from heroin, detox themselves, or take care of their own OST by illicitly obtained drugs. The least common motive was non-prescribed use for euphoric purposes (to get high), but this too was reported by a sizeable minority of about 30% of those who had used non-prescribed methadone or buprenorphine.\n\nNon-prescribed use of methadone and buprenorphine can carry considerable health risks, as we pointed out at the outset. Whether such use should be seen as a serious problem or not depends on how widespread the phenomenon is, but is also connected to which groups use these drugs and for which purposes. Pseudo-therapeutic use among people with an established opioid dependence can also lead to health benefits, which has been raised by many researchers [6, 19, 20, 51, 93]. Such use can therefore be seen as less serious than if the substances are used for euphoric purposes, by adolescents and young adults early in their drug-using trajectory [56]. Still, the positive aspects of non-prescribed use must not be read as reducing the problems and risks involved in such use.\n\nOur study also by and large confirms the results of previous research as regards the sources for non-prescribed drugs. The methadone and buprenorphine markets have a structure which differs from that dealing with such illegal drugs as heroin, cocaine, or cannabis. The latter markets often draw on several bigger players who organize networks of dealers on different levels. The methadone and buprenorphine markets are based on substances originating from pharmaceutical companies. These markets are more decentralized, with many players selling smaller quantities of drugs that they have themselves been prescribed [28, 64, 76, 94, 95]. These are comparatively closed systems of current opioid users and patients undergoing OST [39, 64, 96]—a reasonable description also for the small-scale cross-border smuggling of methadone that takes place in southern Sweden. At the same time, however, a parallel and a more traditional illegal trade goes on with smuggled buprenorphine [82, 84].\n\nThe diversion of prescription drugs has been referred to as a “disorganized for-profit industry” with many kinds of actors [97]. This description is only partially applicable to the methadone and buprenorphine market. As we have shown previously, many of the drugs are handed over free of charge between family members, friends, and acquaintances with similar drug experiences [81, 96]. In the drug scenes that these people know and spend their time in, it is often considered morally right to share one’s drugs with those who do not have them at that point and thus risk getting “sick” (with withdrawal symptoms). Drugs may also be sold of course, but it is more often the case that there is an expectation that the person will do a similar favor later, if needed. It is this norm system that Bourgois calls a “moral economy of sharing” [78].\n\nOur study is the first to examine geographical variations in non-prescribed use. Even if there are some significant disparities between the studied cities, the similarities outweigh the differences. The prevalence of non-prescribed use is very high in all cities, and the predominant motives are pseudo-therapeutic by their nature. This may be because all five cities have a history of insufficient availability of OST. The Swedish model for OST has been called restrictive and oriented toward rehabilitation, placing heavy demands on the patients and exercising heavy control [21, 98, 99].9 There has been a policy in all studied cities of discharging patients for repeated relapse, which is likely to be an important reason why many interviewees said that they had used the drugs for their own OST and detoxification and to stay clean from heroin. The fact that a low availability of OST can lead to a high illicit demand for methadone and buprenorphine has also been stressed in previous research [51, 61, 65, 100].\n\nThe Swedish model has gradually changed during the past decade. More treatment is now available, and it has become more oriented toward harm reduction [101]. These developments had begun at the time when the interviews were conducted, but much of the non-prescribed use examined here has taken place during the previous, more restrictive treatment model.\n\nThe geographical comparisons suggest that the drugs prescribed in OST have a great impact on which substances are used outside the treatment. This is not surprising. In Malmö and Lund, where methadone has long been the most common drug in OST, it is also the drug which is the most common substance in non-prescribed use. In Göteborg, Jönköping, and Norrköping, that drug is buprenorphine.\n\nThere are also big similarities between the cities in terms of the sources for the drugs. In all cities, patients undergoing OST were the source most often named by the interviewees—with one exception, there were more respondents in Göteborg for whom dealers were the most common source for buprenorphine. Dealers are relatively common sources in all cities. The main difference pertains to the proximity of the interviewees in Malmö and Lund to the Danish illegal market. Many respondents in the two cities said that they had purchased methadone from Danish dealers and patients, which we listed under “other source.”\n\nAs we pointed out in the research review, many previous studies have found that buprenorphine/naloxone has a lower abuse potential and a lower street price than drugs solely containing buprenorphine [6, 34, 62, 69–72, 102]. These results are also confirmed by our study. Many interviewees did say that they had used non-prescribed buprenorphine/naloxone, but it was less in demand and was available at a lower average price in all cities. The proportion of who said that they had injected or taken buprenorphine/naloxone intranasally was considerably lower than for buprenorphine. This indicates that buprenorphine/naloxone should be prioritized over buprenorphine when possible. Both the Swedish Medical Products Agency and The National Board of Health and Welfare have recommended buprenorphine/naloxone and have advised doctors against prescribing buprenorphine except in special cases, but these recommendations have been implemented in a checkered manner nationwide. In our study, it was only in Jönköping and Norrköping that the doctors clearly prioritized buprenorphine/naloxone over buprenorphine.\n\nAnother important implication that emerges from our study is that OST should be more readily available. Those who have an opioid dependence and request to be given these drugs should be able to obtain them as a part of a controlled medical treatment program [48, 61]. Even if Swedish OST has in recent years grown to be more inclusive, there are still many with an opioid dependence who involuntarily remain outside the treatment system. There are regional differences in this respect, and in some parts of the country, the queues are exceedingly long. Measures to shorten these queues, to lower the threshold, and to increase retention in OST can curb the illicit demand for methadone and buprenorphine.\n\nControls are still needed in OST to reduce the risk of drug diversion. Well thought-out pick-up routines and supervised dosage are important features in this control [11, 81, 103]. As such controls entail intrusion and restrictions on patients’ lives, the control measures need to be carefully balanced. Misguided or altogether too strict measures mean worse treatment, can lead to lower retention, and may thus increase rather than decrease the diversion problems.\n\nLimitations\nThe data was collected 7 years ago. Since then, the access to OST has increased significantly in Malmö, but not in other cities included in the study. Increased access to OST may have an impact on the non-prescribed use of methadone and buprenorphine, for instance regarding pseudo-therapeutic motives.\n\nOur study group consists of individuals undergoing OST, and the majority has a long history of heroin or other opioid use. As regards the prevalence of non-prescribed use of methadone and buprenorphine, the motives driving the use, and the sources for getting hold of the drugs, the results correspond to those attained in previous research on similar samples, but cannot be generalized to other groups.\n\nAnother limitation is that the interviews dealt with historical data and lifetime prevalence of drug use. In order to study the prevalence and frequency of current use, a different kind of sample is called for, consisting of current opioid users not undergoing OST.\n\nConclusions\nExperiences of non-prescribed use of methadone and buprenorphine are extremely common among individuals who have an opioid dependence and are undergoing OST in southern Sweden. Such use typically has pseudo-therapeutic motives but is less common for euphoric purposes. This means that insufficient access to OST is likely to be a major factor behind the illicit demand for these substances. At the same time, patients in OST are the most common source for illicit methadone and buprenorphine, although other sources are also named, such as dealers and international cross-border trade.\n\nIncreased access to OST might well reduce the illicit demand for methadone and buprenorphine. Supervised dosage and other control measures are however an important part of the treatment regime to prevent the diversion of drugs to persons not in treatment. Also, buprenorphine/naloxone should be prescribed rather than buprenorphine, because buprenorphine/naloxone has a lower abuse potential.\n\n1 Alternative concepts that appear in the research are illicit (or illegal) use and non-medical use, but these are less suited to our context. While non-prescribed use is illegal in Sweden, it is unnecessary here to emphasize this aspect, as it is not the focus of our analysis. The concept of non-medical use runs the risk of being misleading, as the non-prescribed use is often driven by medically related (pseudo-therapeutic) motives. We will return to this question later in this article.\n\n2 If the drug is injected or snorted, naloxone has a high bioavailability and thus counteracts the effects of buprenorphine, which leads to an unpleasant sensation. Taken sublingually, naloxone has a very low bioavailability, and the combination drug works like regular buprenorphine. Buprenorphine/naloxone is available both as tablets and sublingual film. The film sticks onto the palate, which further makes inappropriate use more difficult.\n\n3 Our previous study builds on the same data set as this article. To say that one has used methadone and buprenorphine outside treatment seems unproblematic for most drug users. The low figures on drug diversion however suggest a problem with such self-reported information. To tell a researcher that they have sold or shared their drugs with others may be sensitive, even if the interviewees trust the researcher’s promises of confidentiality. We dealt with this problem by two different data collection techniques, using interviews conducted by researchers and interviews conducted by trained patients through “privileged access interviewing,” and then comparing the results. The idea was that the likelihood would grow of the interviewees reporting sensitive information if they were interviewed by an insider with own experience of substitution treatment. The data collection techniques are described in more detail in the methods section.\n\n4 In 2000–2005, all Swedish doctors with a prescriptive authority were entitled to prescribe high-dose buprenorphine (Subutex). The prescribing of methadone for substitution treatment was however strictly regulated by directives from The National Board of Health and Welfare and was only allowed for psychiatric specialists. As of 2005, the two substances have been regulated by the same directives, and buprenorphine has been regulated similarly to methadone. This was done to prevent overprescribing and drug diversion onto the illegal market.\n\n5 Patients who had been involuntarily discharged were issued an obligatory ban preventing them from seeking substitution treatment again for a fixed period. This period, set by The National Board of Health and Welfare, was 6 months as of 2005, was reduced to 3 months in 2010, and was abolished in 2016.\n\n6 We also asked the interviewees what their most common motives had been to use the different substances. “Avoiding withdrawal symptoms” was by far the most common motive with all substances (54.0% for methadone, 48.0% for buprenorphine, and 48.7% for buprenorphine/naloxone), “own substitution treatment” was the second most common motive (14.8% for methadone, 26.8% for buprenorphine, and 20.3% for buprenorphine/naloxone), and “own detoxification” was the third most common motive (9.8% for methadone, 7.9% for buprenorphine, and 8.6% for buprenorphine/naloxone). The ranking order for the most common motives was the same in all cities.\n\n7 Copenhagen, the capital of Denmark, is close to both Lund and Malmö. A train ride from Malmö to Copenhagen via the Öresund Bridge takes about 30 min.\n\n8 We also asked the interviewees about their most common source for the drugs. As regards methadone, patients undergoing substitution treatment were clearly the most common source (49.1%), followed by “other source” (that is, Denmark, 25.3%), and dealers (21.3%). Patients in substitution treatment were the most common source also for buprenorphine (56.4%), followed by dealers (35.5%), and “other source” (5.1%). Sources other than these were only marginally important.\n\n9 From a European perspective, the Swedish model has been marked by strict admission criteria, government rules which have led to discharging patients for repeated relapse, and by a ban which has prevented the discharged patients from seeking admission into new treatment for a certain period.\n\nAcknowledgements\nWe wish to thank Lisa Andersson, Johan Nordgren, and two anonymous reviewers for their close readings and suggestions for this article.\n\nFunding\nThe research was supported by a grant from the Swedish Research Council for Health, Working Life and Welfare (grant no. 2010–1144).\n\nAvailability of data and materials\nThe datasets generated and/or analysed during the current study are not publicly available due to requirements from the Regional Ethical Review Board but are available from the corresponding author upon reasonable request.\n\nAuthors’ contributions\nBJ planned the original project. BJ and TR designed the study and did most of the researcher interviews. BJ conducted the analysis and wrote the first draft. Final revisions were made jointly by BJ and TR. Both authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nThe project has been carried out in accordance with the Swedish Act concerning the Ethical Review of Research Involving Humans (SFS 2004:460). The design and implementation of the project, including the interview questionnaire, has been reviewed and approved by the Regional Ethical Review Board at the Lund University.\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. Mattick, R. P, Breen, C, Kimber, J. & Davoli, M.. 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"fulltext_license": "CC BY",
"issn_linking": "1477-7517",
"issue": "16(1)",
"journal": "Harm reduction journal",
"keywords": "Buprenorphine; Buprenorphine/naloxone; Diversion; Methadone; Non-prescribed use; Opioid dependence; Opioid substitution treatment; Pseudo-therapeutic use",
"medline_ta": "Harm Reduct J",
"mesh_terms": "D000328:Adult; D000701:Analgesics, Opioid; D002047:Buprenorphine; D000069479:Buprenorphine, Naloxone Drug Combination; D002947:Cities; D064423:Drug Trafficking; D005260:Female; D006801:Humans; D008297:Male; D008691:Methadone; D009042:Motivation; D058850:Opiate Substitution Treatment; D009293:Opioid-Related Disorders; D064226:Prescription Drug Diversion; D015995:Prevalence; D012651:Self Medication; D013375:Substance Withdrawal Syndrome; D013548:Sweden",
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"pages": "31",
"pmc": null,
"pmid": "31046774",
"pubdate": "2019-05-02",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "15679749;9219394;17613961;20403021;24131626;25934054;18264882;21030851;10823123;23726899;22704124;17506154;18679031;17055191;27692193;22216993;17077102;8130701;18805686;21975742;20141452;3265643;730402;30514306;18359216;25889208;16958555;30359928;21466501;26426530;25747920;22036303;23952511;24984689;22565115;25060839;17298648;23841864;24139199;25543167;19040199;17305688;7869467;20847018;22835477;19588333;25744650;20155607;11300960;12189001;9023075;29626777;25221984;12738352;19874152;17913395;23246070;23199896;21844833;29291766;19887803;15204673;24183330;18957116;22243982;24735085;21565452;24500948;5071145;12814505;28132698;20975276;15657321;10795360;17851242;20434868;11440615;30095563;25496247;1187897;9758016;25465344;26818083",
"title": "Non-prescribed use of methadone and buprenorphine prior to opioid substitution treatment: lifetime prevalence, motives, and drug sources among people with opioid dependence in five Swedish cities.",
"title_normalized": "non prescribed use of methadone and buprenorphine prior to opioid substitution treatment lifetime prevalence motives and drug sources among people with opioid dependence in five swedish cities"
} | [
{
"companynumb": "GB-ALKEM LABORATORIES LIMITED-GB-ALKEM-2019-04511",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHADONE HYDROCHLORIDE"
},
... |
{
"abstract": "Nivolumab was approved as a new agent for advanced renal cell carcinoma (RCC) in Japan on September 2016. Nivolumab is an immune checkpoint inhibitor that activates the cytotoxic immune response and has exerted antitumor effects in a mechanism different from other available molecular targeted agents. Therefore, its response pattern, efficacy and adverse events are different from those of the molecular targeted agents for RCC. Here, we report our initial clinical experience with nivolumab. From December 2016 to September 2017, we applied nivolumab to 7 patients with metastatic RCC. The most common metastatic site was the lungs, followed by lymph nodes, bones and brain. According to the immune-related response criteria, the efficacy was stable disease in 2 patients and progressive disease in 5 patients. In 5 cases with multiple metastases, responses differed with the site of metastasis. The response was best in lung metastasis and worst in brain metastasis. Six cases had minor adverse events. In two cases, we discontinued administration of nivolumab temporarily. The patients recovered completely and we considered nivolumab effective and safe for treatment of metastatic RCC.",
"affiliations": "The Department of Urology, Kyoto University Hospital.;The Department of Urology, Kyoto University Hospital.;The Department of Urology, Kyoto University Hospital.;The Department of Urology, Kyoto University Hospital.;The Department of Urology, Kyoto University Hospital.;The Department of Urology, Kyoto University Hospital.;The Department of Urology, Kyoto University Hospital.;The Department of Urology, Kyoto University Hospital.;The Department of Urology, Kyoto University Hospital.;The Department of Urology, Kyoto University Hospital.;The Department of Urology, Kyoto University Hospital.;The Department of Urology, Kyoto University Hospital.;The Department of Urology, Kyoto University Hospital.;The Department of Urology, Kyoto University Hospital.",
"authors": "Fukunaga|Arinobu|A|;Yamasaki|Toshinari|T|;Okuno|Tomoya|T|;Imai|Kazuto|K|;Ikeuchi|Ryosuke|R|;Hishiki|Kosuke|K|;Goto|Takayuki|T|;Sawada|Atsuro|A|;Negoro|Hiromitsu|H|;Akamatsu|Syusuke|S|;Saito|Ryoichi|R|;Kobayashi|Takashi|T|;Inoue|Takahiro|T|;Ogawa|Osamu|O|",
"chemical_list": "D000970:Antineoplastic Agents; D000077594:Nivolumab",
"country": "Japan",
"delete": false,
"doi": "10.14989/ActaUrolJap_64_10_383",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0018-1994",
"issue": "64(10)",
"journal": "Hinyokika kiyo. Acta urologica Japonica",
"keywords": null,
"medline_ta": "Hinyokika Kiyo",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D002292:Carcinoma, Renal Cell; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D000077594:Nivolumab; D016896:Treatment Outcome",
"nlm_unique_id": "0421145",
"other_id": null,
"pages": "383-389",
"pmc": null,
"pmid": "30543735",
"pubdate": "2018-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Initial Clinical Experience of Nivolumab for Metastatic Renal Cell Carcinoma.",
"title_normalized": "initial clinical experience of nivolumab for metastatic renal cell carcinoma"
} | [
{
"companynumb": "JP-PFIZER INC-2019023855",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NIVOLUMAB"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nWe measured birth prevalence of major congenital malformations (MCMs) after topiramate use during pregnancy to screen for a possible signal of increased risk.\n\n\nMETHODS\nUsing four healthcare databases, we identified three cohorts of pregnant women: cohort 1, used topiramate during the first trimester; cohort 2, used topiramate or another antiepileptic drug previously but not during pregnancy; and cohort 3, were pregnant and did not use topiramate but had indications for use individually matched to those of users. Cohort 1 was compared with cohorts 2 and 3. MCMs were a code for any major congenital malformation dated within 30 days of the delivery date on the mother's claims or within 365 days after infant birth date, excluding a genetic or syndromic basis, and with procedure or healthcare usage consistent with the MCM diagnosis code in the 365 days after infant birth.\n\n\nRESULTS\nOf the 10 specific common MCMs evaluated, 1 (conotruncal heart defects) had a prevalence ratio greater than 1.5 for both primary comparisons, and 4 (ventricular septal defect, atrial septal defect, hypospadias, coarctation of the aorta) had a prevalence ratio greater than 1.5 for one of the two comparisons. Following screening of organ systems with elevated MCMs, the prevalence ratio was greater than 1.5 for patent ductus arteriosus in both comparisons and for obstructive genitourinary defects in one comparison.\n\n\nCONCLUSIONS\nTo evaluate a large number of MCMs across many pregnancies, we used crude methods for detecting potential signals. Therefore, these results should be seen as potential signals, not causal.",
"affiliations": "Pharmacoepidemiology and Risk Management, RTI Health Solutions, RTI International, Research Triangle Park, North Carolina.",
"authors": "Tennis|Patricia|P|;Chan|K Arnold|KA|;Curkendall|Suellen M|SM|;Li|De-Kun|DK|;Mines|Daniel|D|;Peterson|Craig|C|;Andrews|Elizabeth B|EB|;Calingaert|Brian|B|;Chen|Hong Y|HY|;Deshpande|Gaurav|G|;Everage|Nicholas|N|;Holick|Crystal N|CN|;Meyer|Nicole M|NM|;Nkhoma|Ella T|ET|;Quinn|Sherry|S|;Rothman|Kenneth J|KJ|;Esposito|Daina B|DB|",
"chemical_list": "D000077236:Topiramate; D005632:Fructose",
"country": "United States",
"delete": false,
"doi": "10.1002/bdra.23357",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1542-0752",
"issue": "103(4)",
"journal": "Birth defects research. Part A, Clinical and molecular teratology",
"keywords": "FORTRESS; cardiac malformations; epidemiology; major malformations; topiramate",
"medline_ta": "Birth Defects Res A Clin Mol Teratol",
"mesh_terms": "D000014:Abnormalities, Drug-Induced; D015331:Cohort Studies; D005260:Female; D005632:Fructose; D006801:Humans; D011247:Pregnancy; D015995:Prevalence; D018570:Risk Assessment; D000077236:Topiramate; D014481:United States",
"nlm_unique_id": "101155107",
"other_id": null,
"pages": "269-75",
"pmc": null,
"pmid": "25776342",
"pubdate": "2015-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Topiramate use during pregnancy and major congenital malformations in multiple populations.",
"title_normalized": "topiramate use during pregnancy and major congenital malformations in multiple populations"
} | [
{
"companynumb": "US-CIPLA LTD.-2015US02537",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TOPIRAMATE"
},
"drugadditional": null,
... |
{
"abstract": "Pemphigus vulgaris is an autoimmune blistering disorder treated with systemic steroids and immunosuppressive agents. Treatment of this disorder in young women of childbearing age must take into consideration the patient's desire for pregnancy and effects of the treatment on both mother and child. We report two young women with pemphigus, initially treated with standard immunosuppressive medications, who expressed their wishes for pregnancy. The immunosuppressive agents were tapered and both patients were treated with Rituximab and IVIG, permitting discontinuation of other medications, conception and pregnancy without any oral steroids or immunosuppressive agents. Both patients maintained normal pregnancies and delivered healthy babies, supporting the use of this treatment early in the disease course of this population.",
"affiliations": "a Department of Dermatology , University of Illinois at Chicago , Chicago , IL , USA.;a Department of Dermatology , University of Illinois at Chicago , Chicago , IL , USA.;a Department of Dermatology , University of Illinois at Chicago , Chicago , IL , USA.",
"authors": "Lake|Eden P|EP|;Huang|Yu-Hui|YH|;Aronson|Iris K|IK|",
"chemical_list": "D016756:Immunoglobulins, Intravenous; D007166:Immunosuppressive Agents; D000069283:Rituximab",
"country": "England",
"delete": false,
"doi": "10.1080/09546634.2016.1255302",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0954-6634",
"issue": "28(8)",
"journal": "The Journal of dermatological treatment",
"keywords": "Rituximab; pemphigus; pregnancy",
"medline_ta": "J Dermatolog Treat",
"mesh_terms": "D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007166:Immunosuppressive Agents; D010392:Pemphigus; D011247:Pregnancy; D000069283:Rituximab; D055815:Young Adult",
"nlm_unique_id": "8918133",
"other_id": null,
"pages": "751-752",
"pmc": null,
"pmid": "27796136",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Rituximab treatment of pemphigus in women of childbearing age: experience with two patients.",
"title_normalized": "rituximab treatment of pemphigus in women of childbearing age experience with two patients"
} | [
{
"companynumb": "US-ACCORD-062561",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MYCOPHENOLIC ACID"
},
"drugadditional": "1",
... |
{
"abstract": "Patients with cirrhosis and coronary artery disease (CAD) are at high risk for morbidity during surgical revascularization so they are often referred for complex percutaneous coronary intervention (PCI). Percutaneous coronary intervention in the cirrhotic population also has inherent risks; however, quantifiable data on long-term outcomes are lacking.\nPatients with angiographically significant CAD and cirrhosis were identified from the catheterization lab databases of the University of Pennsylvania Health System between 2007 and 2015. Outcomes were obtained from the medical record and telephonic contact with patients/families.\nPercutaneous coronary intervention was successfully performed in 42 patients (51 PCIs). Twenty-nine patients with significant CAD were managed medically (36 angiograms). The primary outcome (a composite of mortality, subsequent revascularization, and myocardial infarction) was not significantly different between the 2 groups during a follow-up period at 1 year (PCI: 50%, Control: 40%, P = .383). In the PCI group, a composite adverse outcome rate that included acute kidney injury (AKI), severe bleed, and peri-procedural stroke was elevated (40%), with severe bleeding occurring after 23% of PCI events and post-procedural AKI occurring after 26% of events. The medical management group had significantly fewer total matched adverse outcomes (17% vs 40% in the PCI group, P = .03), with severe bleeding occurring after 11% of events and AKI occurring after 6% of events. Increased risk of adverse events following PCI was associated with severity of liver disease by Child-Pugh class.\nPercutaneous coronary intervention in patients with cirrhosis is associated with an elevated risk of adverse events, including severe bleeding and AKI.",
"affiliations": "New York Presbyterian Hospital - Weill Cornell Medical Center, New York, NY, USA.;Hackensack Meridian Health Jersey Shore University Medical Center, Neptune, NJ, USA.;Hackensack Meridian Health Jersey Shore University Medical Center, Neptune, NJ, USA.;Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.;Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.;Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.;Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.",
"authors": "Lu|Daniel Y|DY|https://orcid.org/0000-0001-9824-3956;Saybolt|Matthew D|MD|;Kiss|Daniel H|DH|;Matthai|William H|WH|;Forde|Kimberly A|KA|;Giri|Jay|J|;Wilensky|Robert L|RL|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/1179546820901491",
"fulltext": "\n==== Front\nClin Med Insights CardiolClin Med Insights CardiolCICspcicClinical Medicine Insights. Cardiology1179-5468SAGE Publications Sage UK: London, England 10.1177/117954682090149110.1177_1179546820901491CIC-19-0025.R1Original ResearchOne-Year Outcomes of Percutaneous Coronary Intervention in Patients\nwith End-Stage Liver Disease https://orcid.org/0000-0001-9824-3956Lu Daniel Y 1Saybolt Matthew D 2Kiss Daniel H 2Matthai William H 34Forde Kimberly A 356Giri Jay 37Wilensky Robert L 371 New York Presbyterian Hospital – Weill\nCornell Medical Center, New York, NY, USA2 Hackensack Meridian Health Jersey Shore\nUniversity Medical Center, Neptune, NJ, USA3 Perelman School of Medicine, University\nof Pennsylvania, Philadelphia, PA, USA4 Division of Cardiovascular Medicine,\nPenn Presbyterian Medical Center, Philadelphia, PA, USA5 Division of Gastroenterology, Hospital\nof the University of Pennsylvania, Philadelphia, PA, USA6 Center for Clinical Epidemiology and\nBiostatistics, Perelman School of Medicine, University of Pennsylvania,\nPhiladelphia, PA, USA7 Division of Cardiovascular Medicine,\nHospital of the University of Pennsylvania, Philadelphia, PA, USARobert L Wilensky, Division of\nCardiovascular Medicine, Hospital of the University of Pennsylvania, Perelman\nCenter for Advanced Medicine, 11th floor South Pavilion, 3400 Civic Center Blvd,\nPhiladelphia, PA 19104, USA. Email:\nRobert.Wilensky@pennmedicine.upenn.edu22 1 2020 2020 14 11795468209014918 8 2019 1 1 2020 © The Author(s) 20202020SAGE Publications Ltd unless otherwise noted.\nManuscript content on this site is licensed under Creative Commons\nLicensesThis article is distributed under the terms of the Creative Commons\nAttribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which\npermits non-commercial use, reproduction and distribution of the work\nwithout further permission provided the original work is attributed as\nspecified on the SAGE and Open Access pages(https://us.sagepub.com/en-us/nam/open-access-at-sage).Background:\nPatients with cirrhosis and coronary artery disease (CAD) are at high risk\nfor morbidity during surgical revascularization so they are often referred\nfor complex percutaneous coronary intervention (PCI). Percutaneous coronary\nintervention in the cirrhotic population also has inherent risks; however,\nquantifiable data on long-term outcomes are lacking.\n\nMethods:\nPatients with angiographically significant CAD and cirrhosis were identified\nfrom the catheterization lab databases of the University of Pennsylvania\nHealth System between 2007 and 2015. Outcomes were obtained from the medical\nrecord and telephonic contact with patients/families.\n\nResults:\nPercutaneous coronary intervention was successfully performed in 42 patients\n(51 PCIs). Twenty-nine patients with significant CAD were managed medically\n(36 angiograms). The primary outcome (a composite of mortality, subsequent\nrevascularization, and myocardial infarction) was not significantly\ndifferent between the 2 groups during a follow-up period at 1 year (PCI:\n50%, Control: 40%, P = .383). In the PCI group, a composite\nadverse outcome rate that included acute kidney injury (AKI), severe bleed,\nand peri-procedural stroke was elevated (40%), with severe bleeding\noccurring after 23% of PCI events and post-procedural AKI occurring after\n26% of events. The medical management group had significantly fewer total\nmatched adverse outcomes (17% vs 40% in the PCI group,\nP = .03), with severe bleeding occurring after 11% of\nevents and AKI occurring after 6% of events. Increased risk of adverse\nevents following PCI was associated with severity of liver disease by\nChild-Pugh class.\n\nConclusions:\nPercutaneous coronary intervention in patients with cirrhosis is associated\nwith an elevated risk of adverse events, including severe bleeding and\nAKI.\n\nPCIcirrhosisdual antiplatelet therapycover-dateJanuary-December 2020typesetterts1\n==== Body\nIntroduction\nPatients with cirrhosis or end-stage liver disease often have co-existing coronary\nartery disease (CAD) with a similar or higher prevalence than the general\npopulation.1-7 Individuals with pre-cirrhotic\npathology, particularly nonalcoholic steatohepatitis (NASH) or nonalcoholic fatty\nliver disease (NAFLD), also have an elevated risk of developing CAD.8,9 When an indication for coronary\nrevascularization arises, patients with advanced liver disease are often deemed poor\nsurgical revascularization candidates given their risk of death, post-operative\nliver failure, and/or bleeding, and thus they are often referred for high-risk\npercutaneous coronary intervention (PCI).5,10-13 However, PCI in the cirrhotic\npopulation has its own inherent risks, including but not limited to: acute kidney\ninjury (AKI) secondary to dynamic renal perfusion, and increased bleeding while on\ndual antiplatelet therapy (DAPT) due to coagulopathies, cytopenias, and consequences\nof portal hypertension such as varices and gastritis.\n\nIn addition, there exists a cohort of patients with advanced liver disease who may be\ncandidates for orthotopic liver transplantation. The evaluation and battery of\ntesting necessary to assess a patient’s candidacy for solid organ transplantation is\nextensive and includes screening for occult cardiovascular conditions.14,15 In many\ncenters, patients with CAD may be denied listing for liver transplantation unless\nthey first undergo coronary revascularization. This common uninvestigated strategy\nis based on the intention of mitigating the risk of perioperative ischemia or\ninfarction as well as treating a comorbid condition that may shorten life expectancy\nindependent of cirrhosis.5,7,16,17\n\nThe safety and efficacy of PCI in the cirrhotic population are not well known, and\nthere are currently no clear hepatology or transplant practice guidelines addressing\nrevascularization. While a few retrospective studies investigating the safety and\nshort-term/in-hospital outcomes of PCI in cirrhotics have been reported,1,4,18-20 long-term outcome data are\nscant. Furthermore, the incidence of bleeding attributable to PCI and antiplatelet\ntherapy, acute renal failure, and outcomes of patients who receive transplant\nfollowing PCI remain poorly characterized. We sought to undertake an exploratory\nanalysis of single-center patient-level outcome data to evaluate the short- and\nlong-term outcomes and adverse events related to PCI in patients with cirrhosis.\n\nMethods\nPatients with liver disease who underwent coronary angiography at the Hospital of the\nUniversity of Pennsylvania and Penn Presbyterian Medical Center between January 2007\nand December 2015 were identified. Corroborating patient-level electronic medical\nrecord data were obtained using proprietary natural language search software. Liver\ndisease was identified using the search terms “cirrhosis,” “liver,” “hepatic,” or\n“MELD” (Model for End-Stage Liver Disease). From the populated list, patient charts\nwere individually abstracted by authors DYL and MDS to confirm the combined\ndiagnosis of cirrhosis/end-stage liver disease and angiographically significant CAD\ndiagnosed during coronary angiography (Figure 1). Patients with other pathologies\nincluding acute liver injury or hepatic tumors without specific mention of cirrhosis\nwere excluded, as were patients with previous liver transplantation unless they had\ndocumented end-stage allograft dysfunction. Angiographically significant obstructive\nCAD was defined as a greater than or equal to 50% stenosis in the left main coronary\nartery or greater than or equal to 70% stenosis in any other major epicardial\ncoronary artery or major branch, as determined by visual estimation of the\nperforming board-certified interventional cardiologist.\n\nFigure 1. Identification of patients with angiographically significant CAD and\ncirrhosis (time interval: 2007-2015).\n\nCAD indicates coronary artery disease; LHC, left heart catheterization; PCI,\npercutaneous coronary intervention. *Seven patients were at some point\nmembers of both these groups during the specified time interval. See text\nfor details.\n\nPatient medical records were individually reviewed in their entirety. If the medical\nrecord was incomplete or if patients were lost to follow-up, patients or next-of-kin\nwere contacted directly by phone. Follow-up chart review was also performed at the\nPhiladelphia Veterans Affairs (VA) Medical Center for a small subset of patients.\nBased on treatment strategy, 2 cohorts of cirrhotic patients were examined: Cohort\nA—patients with obstructive CAD treated with PCI, and Cohort B—patients with\nobstructive CAD managed medically without PCI. Given that some patients had multiple\nangiograms at discreet and often distant time points, comparisons of adverse events\nand cardiovascular outcomes were based on individual PCI or diagnostic angiography\nepisodes; as such, a small subset of patients may be included in both groups at\ndistinct distant time points. Staged PCI or repeat PCI/catheterization performed for\nthe same indication within the same hospitalization was considered part of 1 single\nepisode.\n\nPatients were further stratified based on the severity of their liver disease\n(Child-Pugh classification).11,12 Acute kidney injury was defined as a documented increase in\nserum creatinine by 0.3 mg/dL or a 50% increase over baseline. Bleeding events were\ndefined as the Bleeding Academic Research Consortium (BARC) definition type 2 or above.21 Severe bleeding events were defined as BARC type 3B or above. Significant\nprocedural site hematomas were defined as any hematoma meeting BARC type 2 or above\ncriteria. Events involving transfusions or hospitalizations for anemia without a\ndocumented overt bleed were not counted as significant bleeding events. For staged\nprocedures, contrast load was averaged across the interventions, and radial/femoral\naccess was defined as the access used during the initial intervention.\n\nThe primary outcome was a composite of major adverse cardiovascular events (MACE)\nincluding death, myocardial infarction, or need for repeat revascularization.\nSecondary outcomes included a composite adverse event rate that included AKI, severe\nbleeding events (BARC 3B or above), and post-procedural stroke, as well as\nindividual components of the composite outcome. Short-term peri-procedural outcomes\nincluded peri-procedural AKI, stroke, and site complications, whereas long-term\noutcomes were MACE and major bleeding events. Follow-up was obtained for up to\n1 year, or until death or last contact with the patient. Transplant status was\nfollowed for more than 1 year until either death, listing for transplant, or\ntransplantation.\n\nResults are reported as un-adjusted outcome data with statistical comparisons on\nbaseline demographics, cardiovascular outcomes, and adverse event rates using the\n2-sided Fisher’s exact testing for categorical variables or 2-sided t-test for\ncontinuous variables. The study protocol was approved by the institutional review\nboard (IRB) of the University of Pennsylvania (#818083) and the Philadelphia VA\n(#01626). Informed consent was waived per the IRB protocol for the electronic\nmedical data review, and verbal informed consent was obtained for telephonic contact\nas per IRB protocol.\n\nResults\nWe identified 613 patients with liver pathology, 64 of whom carried diagnosis of\ncirrhosis and angiographically significant CAD (Figure 1). Forty-two patients underwent 51\ndiscreet PCI episodes (Cohort A). Twenty-nine patients had at least 1 coronary\nangiogram with significant CAD subsequently managed medically, resulting in 36 such\nevents (Cohort B).\n\nPatient demographics are listed in Table 1. No significant differences were\nobserved in the baseline characteristics between the groups, although there was a\nnumerically higher rate of insulin-dependent diabetes in those treated with PCI.\nAverage contrast use was higher in the PCI group (PCI: 178.97 mL, medical\nmanagement: 94.03 mL, P < .01), and average SYNTAX scores were\nslightly higher in the medical management group (PCI: 17.73, medical management:\n23.97, P = .04). Groups were also stratified based on CAD\ncomplexity and Child-Pugh class (Table 2). Left main or multivessel CAD were\nfound with similar frequency in both groups (PCI: 68.6%, medical management: 75.0%,\nP = .52). Coronary intervention (N = 51) used bare metal stents\nin 55% of cases, drug-eluting stents in 39%, and balloon angioplasty alone in 8%. A\nnumerically higher proportion of Child-Pugh class A patients received drug-eluting\nstents (56%, 9/16) compared with Child-Pugh class B and C patients (31%, 10/32,\nP = .12). Of those undergoing PCI, 51% were performed on an\nurgent or emergent basis while 25% were performed during evaluation for liver\ntransplant candidacy (Table\n3). In the medical management cohort, 33% of angiograms were performed on\nan urgent or emergent basis, and 33% were performed for liver transplant\nevaluation.\n\nTable 1. Baseline characteristics.\n\n\tPCI events\nn = 51 discrete events\tSignificant CAD without PCI\nn = 36 discrete\nevents\tP-value\t\nDemographics\t\n Age (years)\t62.25 ± 1.05\t62.69 ± 1.16\t.78\t\n Gender\t40 M, 11 F\t33 M, 3 F\t.14\t\n Body mass index\t29.1 ± 0.84\t29.80 ± 0.80\t.55\t\nMedical history\t\n Systolic heart failure (EF ⩽ 45%)\t15 (29%)\t11 (31%)\t1.00\t\n Peripheral vascular disease\t15 (29%)\t12 (34%)\t.64\t\n Stroke/TIA\t5 (10%)\t1 (3%)\t.39\t\n COPD\t8 (16%)\t5 (14%)\t1.00\t\n Hypertension\t44 (86%)\t29 (83%)\t.76\t\n Hyperlipidemia\t37 (73%)\t20 (63%)\t.36\t\n Insulin-dependent diabetes\t27 (53%)\t10 (31%)\t.07\t\n Chronic kidney disease\t18 (38%)\t8 (24%)\t.23\t\n Anticoagulation\t2 (4%)\t3 (9%)\t.64\t\n Current/former smoker\t44 (86%)\t30 (88%)\t1.00\t\nCirrhosis etiology\t\n Hepatitis B\t4 (8%)\t0 (0%)\t.14\t\n Hepatitis C\t24 (47%)\t17 (50%)\t.83\t\n Alcohol\t2 (4%)\t4 (12%)\t.23\t\n NASH\t14 (27%)\t6 (19%)\t.45\t\n Multifactorial\t4 (8%)\t1 (3%)\t.40\t\n Unknown/Other\t3 (6%)\t6 (17%)\t.15\t\nHistory of decompensations\t\n Ascites\t27 (54%)\t16 (49%)\t.66\t\n Bleeding varices\t8 (16%)\t4 (11%)\t.75\t\n Hepatic encephalopathy\t19 (38%)\t12 (36%)\t1.00\t\nHepatocellular carcinoma\t11 (22%)\t12 (33%)\t.23\t\nLab data\t\n Thrombocytopenia\t33 (65%)\t25 (74%)\t.48\t\nPlatelet counts ( 1000/µL)\t129.20 ± 9.76\t114.44 ± 11.22\t.32\t\n Albumin (g/dL)\t3.05 ± 0.09\t3.18 ± 0.12\t.39\t\n Creatinine (mg/dL)\t1.79 ± 0.27\t1.36 ± 0.17\t.19\t\n Total bilirubin (mg/dL)\t1.56 ± 0.19\t1.72 ± 0.22\t.58\t\n INR\t1.27 ± 0.03\t1.28 ± 0.05\t.99\t\n MELD\t13.70 ± 0.71\t13.18 ± 0.92\t.66\t\n MELD-Na\t15.22 ± 0.79\t13.91 ± 0.96\t.29\t\nProcedural characteristics\t\n Contrast use\t178.97 ± 11.34\t94.03 ± 7.90\t<.01\t\n SYNTAX score\t17.73 ± 1.65\t23.97 ± 2.75\t.04\t\n Access\t45 femoral, 6 radial\t27 femoral, 9 radial\t.15\t\nChild-Pugh class\t\n A\t16 (31%)\t13 (36%)\t.98\t\n B\t26 (51%)\t17 (47%)\t\t\n C\t6 (12%)\t4 (11%)\t\t\n Unknown\t3 (6%)\t2 (6%)\t\t\nData are presented as percentages for categorical variables or as\nmean ± standard error of the mean (SEM) for continuous variables. Total\nn for each row may be 1 to 3 less than 51 or 36 if variables were\nunobtainable or missing for certain patients—percentages, means, and SEM\nwere adjusted for such.\n\nAbbreviations: CAD, coronary artery disease; COPD, chronic obstructive\npulmonary disease; EF, ejection fraction; INR, international normalized\nratio; MELD, Model for End-Stage Liver Disease score; NASH, nonalcoholic\nsteatohepatitis; PCI, percutaneous coronary intervention; TIA, transient\nischemic attack.\n\nTable 2. Anatomic characteristics of coronary lesions.\n\nChild-Pugh class\t1-Vessel disease\t2-Vessel disease\t3-Vessel disease\tLeft main with or without multivessel disease\t\nPCI events (n = 51)\t16\t10\t17\t8\t\n A\t5\t4\t7\t0\t\n B\t6\t5\t8\t7\t\n C\t3\t1\t1\t1\t\n Unknown\t2\t0\t1\t0\t\nSignificant CAD without PCI (n = 36)\t9\t11\t11\t5\t\n A\t5\t4\t4\t0\t\n B\t3\t4\t6\t4\t\n C\t1\t3\t0\t0\t\n Unknown\t0\t0\t1\t1\t\nAbbreviations: CAD, coronary artery disease; PCI, percutaneous coronary\nintervention.\n\nTable 3. PCI and transplant outcomes.\n\n\tPCI\tSignificant CAD without PCI\t\nNo. of patients\tn = 42\tn = 29\t\n Urgent/emergent procedure\t26/51 (51%)\t12/36 (33%)\t\n Elective procedure\t25/51 (49%)\t24/36 (67%)\t\n Elective procedure for transplant evaluation\t13/51 (25%)\t12/36 (33%)\t\n Staged PCI\t15/51 (29%)\t\t\n Failed PCI\t\t2\t\n CABG\t\t2\t\n Listed for liver transplant\t11\t9\t\n Complete revascularization of listed patients\t7 (64%)\t0 (0%)\t\n Transplanted\t4\t6\t\n Complete revascularization of transplanted patients\t3 (75%)\t0 (0%)\t\n Peri-transplant cardiovascular events\t1 (25%)\t0\t\nAbbreviations: CABG, coronary artery bypass graft; CAD, coronary artery\ndisease; PCI, percutaneous coronary intervention.\n\nThree-month and 1-year mortality were associated with severity of liver disease\n(Table 4). Mortality\nin the PCI group, compared with the medical therapy group, was greater at 3 months\n(27% vs 8%, P = .048) and at 1 year (42% vs 14%,\nP = .008). The rates of subsequent revascularization (13% vs 20%,\nP = .377) and myocardial infarction (23% vs 17%,\nP = .591) did not differ statistically. The composite outcome\nrate of mortality, need for repeat revascularization, and myocardial infarction were\nsimilar (50% vs 40%, P = .383).\n\nTable 4. Mortality and composite major adverse cardiac events.\n\n\t3-month mortality\t1-year mortality\tRevascularization\tMyocardial infarction\tComposite\t\nPCI\t13/48 (27%)\t20/48 (42%)\t6/48 (13%)\t11/48 (23%)\t24/48 (50%)\t\n Child-Pugh class A\t3/15 (20%)\t4/15 (27%)\t3/15 (20%)\t2/15 (13%)\t5/15 (33%)\t\n Child-Pugh class B\t6/26 (23%)\t11/26 (42%)\t3/26 (12%)\t6/26 (23%)\t14/26 (54%)\t\n Child-Pugh class C\t3/5 (60%)\t4/5 (80%)\t0/5 (0%)\t2/5 (40%)\t4/5 (80%)\t\n Unknown\t1/2 (50%)\t1/2 (50%)\t0/2 (0%)\t1/2 (50%)\t1/2 (50%)\t\nSignificant CAD without PCI\t3/36 (8%)\t5/35 (14%)\t7/35 (20%)\t6/35 (17%)\t14/35 (40%)\t\n Child-Pugh class A\t0/13 (0%)\t0/12 (0%)\t3/13 (23%)\t0/13 (0%)\t3/13 (23%)\t\n Child-Pugh class B\t3/17 (18%)\t5/17 (29%)\t3/17 (18%)\t6/17 (35%)\t10/17 (59%)\t\n Child-Pugh class C\t0/4 (0%)\t0/4 (0%)\t0/4 (0%)\t0/4 (0%)\t0/4 (0%)\t\n Unknown\t0/2 (0%)\t0/2 (0%)\t1/1 (100%)\t0/1 (0%)\t1/1 (100%)\t\nP-value\t.048\t.008\t.377\t.591\t.383\t\nDiscrepancies in total numbers between 3-month and 1-year survivals are\ndue to loss to follow-up. Composite score is the combined rate of\nmortality, myocardial infarction, and need for revascularization in the\nfollow-up period.\n\nAbbreviations: CAD, coronary artery disease; PCI, percutaneous coronary\nintervention.\n\nIn the PCI group, the composite adverse event rate of stroke, AKI, and severe\nbleeding episodes at 1-year follow-up was high at 40%. Severe bleeding (BARC 3B and\nabove) while on DAPT was observed after 23% of the PCI events and post-procedural\nAKI was observed after 26%. Total bleeding events (BARC 2 and higher) approached\n46%, including a 10% rate of access site complications under the same definition\n(Table 5). Four PCI\npatients, all with pre-existing renal dysfunction (glomerular filtration rate\n[GFR] < 60), developed AKI requiring renal replacement therapy. The medical\nmanagement group had a significantly lower composite adverse event rate of\nperi-procedural stroke, AKI, and severe bleeding (17% vs 40%,\nP = .032) and a lower rate of AKI (6% vs 26%,\nP = .02). While the overall rate of total major and minor bleeding\nevents was similar between the PCI and the medical management groups (46% vs 40%,\nP = .658), the rate of severe bleeding events was numerically\ntwice as high in the PCI group (23% vs 11%, P = .25). Adverse event\nrates in the PCI group were associated with Child-Pugh class (class A: 2/15 or 13%,\nclasses B and C: 16/31 or 52%, P = .02) but not MELD score\n(MELD < 15: 10/32 or 31%, MELD ⩾ 15: 9/16 or 56%, P = .12).\n\nTable 5. Adverse events related to PCI.\n\nChild-Pugh class\tPost-procedural AKIa\tPost-procedural stroke\tBleeding events (BARC 2+)\tSevere bleeding events (BARC 3B+)\tSite complications\tComposite adverse events of stroke, AKI, severe\nbleed\t\nPCI\t12/47 (26%)\t0/51 (0%)\t22/48 (46%)\t11/48 (23%)\t5/51 (10%)\t19/48 (40%)\t\n A\t1/15 (7%)\t0\t6/15 (40%)\t1/15 (7%)\t2/16 (13%)\t2/15 (13%)\t\n B\t9/24 (38%)\t0\t13/26 (50%)\t8/26 (31%)\t1/26 (4%)\t14/26 (54%)\t\n C\t1/6 (17%)\t0\t3/5 (60%)\t2/5 (40%)\t2/6 (33%)\t2/5 (40%)\t\n Unknown\t1/2 (50%)\t0\t0/2 (0%)\t0/2 (0%)\t0/3 (0%)\t1/2 (50%)\t\nSignificant CAD without PCI\t2/35 (6%)\t0/36 (0%)\t14/35 (40%)\t4/35 (11%)\t0/36 (0%)\t6/35 (17%)\t\n A\t0/13 (0%)\t0\t3/13 (23%)\t0/13 (0%)\t0/13 (0%)\t0/13 (0%)\t\n B\t2/17 (12%)\t0\t7/17 (41%)\t1/17 (6%)\t0/17 (0%)\t3/17 (18%)\t\n C\t0/4 (0%)\t0\t4/4 (100%)\t3/4 (75%)\t0/4 (0%)\t3/4 (75%)\t\n Unknown\t0/1 (0%)\t0\t0/1 (0%)\t0/1 (0%)\t0/2 (0%)\t0/1 (0%)\t\nP-value\t.020\t\t.658\t.251\t.074\t.032\t\nFollow-up interval for adverse events was until death, loss to follow-up,\n1 year, or crossover to PCI. Patients who were lost to follow-up were\nremoved from the analysis of adverse events unless the events occurred\nduring follow-up availability. Other adverse events not listed in the\ntable include aspiration pneumonia and toe gangrene.\n\na Patients who already had end-stage renal disease on dialysis were\nexcluded from the analysis of AKI.\n\nb Total bleeding events—PCI group: 41 total (14 BARC 2, 14 BARC 3a, 10 BARC\n3b, 2 BARC 3c, 1 BARC 5b); Significant CAD without PCI group—22 total\n(11 BARC 2, 7 BARC 3a, 3 BARC 3b, 1 BARC 3c).21\n\nAbbreviations: AKI, acute kidney injury; BARC, Bleeding Academic Research\nConsortium; CAD, coronary artery disease; PCI, percutaneous coronary\nintervention.\n\nWhen stratified by procedural indication (Table 6 and Supplemental Table I), procedures done for acute coronary syndrome\n(ACS) generally had poorer outcomes compared with procedures done for elective\nreasons (stable angina, pre-operative evaluation, transplant evaluation), with the\nprimary outcome occurring after 59% of ACS procedures and 31% of elective procedures\n(P = .015). The composite adverse event outcome was also\nnumerically higher, occurring after 39% of ACS procedures and 21% of elective\nprocedures (P = .095). However, stratification by procedure\nindication did not change the composite and adverse outcome findings presented in\nTables 4 and 5, as there was no\ndifference in the primary outcome between the PCI and no-PCI groups for both ACS and\nelective procedures (Table\n6) and a numerically higher adverse event rate in the PCI group for both\nACS and elective procedures (Supplemental Table I).\n\nTable 6. Major adverse cardiac events stratified by procedural indication.\n\n\t3-month mortality\t1-year mortality\tRevascularization\tMyocardial infarction\tComposite\t\nACS\t13/44 (30%)\t19/44 (43%)\t8/44 (18%)\t13/44 (30%)\t26/44 (59%)*\t\n PCI\t11/30 (37%)\t16/30 (53%)\t5/30 (17%)\t8/30 (27%)\t18/30 (60%)\t\n Significant CAD without PCI\t2/14 (14%)\t3/14 (21%)\t3/14 (21%)\t5/14 (36%)\t8/14 (57%)\t\nP-value\t.170\t.058\t.695\t.724\t1.000\t\nElective\t3/40 (8%)\t6/39 (15%)\t5/39 (13%)\t4/39 (10%)\t12/39 (31%)*\t\n PCI\t2/18 (11%)\t4/18 (22%)\t1/18 (6%)\t3/18 (17%)\t6/18 (33%)\t\n Significant CAD without PCI\t1/22 (5%)\t2/21 (10%)\t4/21 (19%)\t1/21 (5%)\t6/21 (29%)\t\nP-value\t.579\t.387\t.349\t.318\t1.000\t\nDiscrepancies in total numbers are due to loss of follow-up. Composite\nscore is the combined rate of mortality, myocardial infarction, and need\nfor revascularization in the follow-up period.\n\nAbbreviations: ACS, acute coronary syndrome; CAD, coronary artery\ndisease; PCI, percutaneous coronary intervention.\n\n* P = .015 for comparison of composite outcome between ACS\nand elective intervention.\n\nOverall, 11 patients in the PCI group were candidates for liver transplant, of which\nonly 7 underwent pre-operative complete percutaneous revascularization; 4 ultimately\nreceived orthotopic liver transplantation (Table 3). In the medical management group,\n9 patients were candidates for transplant, of which 6 received liver\ntransplantation. While all transplanted patients were free of unrevascularized left\nmain or proximal left anterior descending CAD at the time of surgery, most of the\npatients with CAD were successfully operated on despite incomplete\nrevascularization. An isolated and minor type 2 non-ST elevation myocardial\ninfarction occurred in the PCI group, managed expectantly (Table 3).\n\nDiscussion\nTo our knowledge, this is the first study to evaluate long-term PCI outcomes of\npatients with cirrhosis in the United States using event-level data. The total\ncomposite outcome (myocardial infarction, repeat revascularization, and mortality)\nwas not statistically different between patients treated with PCI and those without\nPCI (despite a higher complexity of CAD as measured by SYNTAX score within the\nnon-PCI cohort). Importantly, however, there was an increased adverse event rate\nincluding AKI and severe bleeding in those treated with PCI and subsequent long-term\nDAPT therapy, with the rate correlated to cirrhosis severity as defined by\nChild-Pugh class.\n\nIn the context of cirrhosis, patients with pre-existing CAD generally have poorer\noutcomes with liver transplantation,5,16,17 with multivessel CAD\npredicting increased mortality and length of stay after transplantation.22 The 2013 American Association for the Study of Liver Diseases (AASLD) and the\nAmerican Society of Transplantation guidelines recommended cardiac evaluation with\nstress echocardiography in all adult liver transplant candidates, with cardiac\ncatheterization and revascularization as clinically indicated if significant CAD was detected.14 The scientific statement from the American Heart Association (AHA) and the\nAmerican College of Cardiology (ACC) suggests that noninvasive stress testing may be\nconsidered for transplant candidates who have multiple risk factors for CAD.15 Cirrhotics found to have comorbid multivessel CAD have limited options,\nunable to undergo transplant due to cardiac risk while simultaneously having\nprohibitive risk for surgical revascularization.11,12 Many are referred for\nhigh-risk multivessel PCI. Such patients frequently are asymptomatic or have stable\nangina; a population which, in the absence of liver disease, does not derive a\nsurvival benefit from PCI.23\n\nStudies of PCI in this patient population have mostly been retrospective, focusing on\nshort-term outcomes, with little data on the completeness of revascularization or\nlong-term outcomes.1,4,18-20,24 Our data support and extend\nthe findings of a recent retrospective study evaluating the in-hospital and\nshort-term outcomes of PCI in patients with end-stage liver disease, which concluded\nthat although PCI remains relatively safe, it is riskier than for the general population.1 The largest long-term study to date was a retrospective study of 233 Japanese\npatients, which suggested that complete revascularization was not associated with\nbetter survival outcomes given a high rate of non-cardiovascular mortality in cirrhotics.24 Our findings in an American population are similar and provide unique\ninsights into the long-term risk of adverse events while also suggesting that\nsuccessful transplantation is possible in selected patients, both following\nsuccessful PCI and also when PCI is not performed.\n\nAdverse event rates of PCI were high, with occurrence of the composite event rate in\nup to 40% and occurrence of AKI and severe bleeding in 26% and 23% of PCIs,\nrespectively, and greater than that observed in patients who were medically managed.\nThis difference was mostly driven by the rate of AKI, and notably, 4 patients\nrequired initiation of renal replacement therapy after their PCI. The cirrhotic\npatient population, characterized by dynamic renal perfusion and a high prevalence\nof baseline chronic kidney disease, may be exquisitely sensitive to the higher\nquantities of iodinated contrast exposure during PCI. Furthermore, many patients\nhave complex multivessel disease resulting in staged and/or long multivessel PCI\nprocedures compared with the general population, further increasing their contrast\nexposure.\n\nPrior studies assessing in-hospital and short-term outcomes of PCI in cirrhotics show\nincreased hemorrhagic and transfusion rates of 7% to 15%.1,18 In our study, long-term\nbleeding rates during up to 1-year follow-up were greater, with a 46% rate of\ncombined major and minor bleeding events. Moreover, bleeding risk increased (40%)\neven without PCI in patients with cirrhosis given their coagulopathy and portal\nhypertension. However, despite the similarity in total bleeding rate, the rate of\nsevere bleeding rate was numerically doubled after PCI, suggesting that PCI and\nsubsequent use of DAPT convert minor bleeding events into major bleeding events.\n\nOur results, while only hypothesis-generating, showed an increased mortality rate and\nan overall equivalence in composite cardiovascular outcomes in cirrhotic patients\ntreated with PCI compared with medical therapy. The increased mortality may be\nattributable to the revascularization procedure itself, the untoward and cumulative\nrisks that come thereafter, or from unmeasured confounders. Finally, despite the\nlack of complete revascularization in most of the patients receiving transplant,\nthere was only 1 minor peri-procedural cardiovascular event, managed conservatively.\nFurther large-scale studies will be needed to truly address this issue, especially\ngiven the increase in major adverse events related to PCI.\n\nPrior studies have noted a correlation between the severity and complexity of CAD as\nmeasured by the SYNTAX score and the severity of liver disease as measured by the\nNAFLD fibrosis score.25 However, we did not find a convincing correlation between the SYNTAX score\nand the severity of liver disease as measured by Child-Pugh class within the overall\npopulation of our study (Supplemental Table II), potentially due to the low number of\npatients with NASH cirrhosis and high number with hepatitis C (Table 1).\n\nFinally, despite the lack of complete revascularization in most of the patients\nreceiving transplant, there was only 1 minor peri-procedural cardiovascular event\nrequiring no intervention. Although only hypothesis-forming, it suggests that\ncomplete revascularization may not be absolutely necessary prior to clearance for\ntransplant, and that a multidisciplinary team of cardiologists, hepatologists, and\ntransplant surgeons were effective at risk stratifying patients based on their\nindividualized coronary anatomy and cardiac, bleeding, hepatic, and renal risks. For\nexample, it is possible that left main or proximal left anterior descending coronary\nartery may be the only vessels necessarily requiring pre-operative\nrevascularization. A prior multicenter retrospective review demonstrated that the\npresence of obstructive CAD did not affect post-liver transplant survival when\ncurrent CAD treatment strategies were employed, although that study was not designed\nto detect adverse events while awaiting transplant.26 Further large-scale multicenter studies will be needed to address this issue,\ngiven the high rate of major adverse events related to PCI.\n\nLimitations of our study include the limitations of a retrospective analysis at a\nsingle institution. Comparisons between mortality and transplant outcomes between\nthe PCI and the medical management groups are limited given the small sample size\nand heterogeneity of the patient population. Furthermore, a small subset of patients\nwas lost to follow-up despite efforts to contact them directly. Finally, our\nexploratory analysis resulted in sample sizes too small for propensity matching.\nStrengths of our study include a comprehensive review of patient-level data and up\nto 1-year follow-up. Furthermore, the ability to identify and manually classify\nindividual events rather than using registry data and diagnosis codes led to a more\naccurate assessment of these events and their severity.\n\nConclusions\nIn conclusion, PCI in patients with cirrhosis is associated with an increased 1-year\nadverse event rate including severe bleeding and renal injury related to the\nunderlying severity of liver disease without a corresponding decrease in the rate of\ncomposite major adverse cardiovascular outcomes. Large-scale, multi-institutional,\nprospective studies or registry analysis of long-term outcomes of PCI in patients\nwith cirrhosis are needed to provide additional guidance to practice.\n\nSupplemental Material\ncic_901491 – Supplemental material for One-Year Outcomes of Percutaneous\nCoronary Intervention in Patients with End-Stage Liver Disease\nClick here for additional data file.\n\nSupplemental material, cic_901491 for One-Year Outcomes of Percutaneous Coronary\nIntervention in Patients with End-Stage Liver Disease by Daniel Y Lu, Matthew D\nSaybolt, Daniel H Kiss, William H Matthai, Kimberly A Forde, Jay Giri and Robert\nL Wilensky in Clinical Medicine Insights: Cardiology\n\n Funding:The author(s) received no financial support for the research, authorship, and/or\npublication of this article.\n\nDeclaration of conflicting interests:The author(s) declared no potential conflicts of interest with respect to the\nresearch, authorship, and/or publication of this article.\n\nAuthor Contributions: Conception, design, data analysis, and drafting of the manuscript were performed\nby DYL, MDS, and RLW. Chart review was performed by DYL and MDS. Critical\nrevision of the manuscript and final approval were performed by all listed\nauthors.\n\nORCID iD: Daniel Y Lu \nhttps://orcid.org/0000-0001-9824-3956\n\nSupplemental Material: Supplemental material for this article is available online.\n==== Refs\nReferences\n1 \nSingh V Patel NJ Rodriguez AP , et al\nPercutaneous coronary\nintervention in patients with end-stage liver disease .\nAm J Cardiol .\n2016 ;117 :1729 -1734 .27103158 \n2 \nTiukinhoy-Laing SD Rossi JS Bayram M , et al\nCardiac hemodynamic and\ncoronary angiographic characteristics of patients being evaluated for liver\ntransplantation . 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Liver Int .\n2009 ;29 :1141 -1151 .19515218 \n14 \nMartin P DiMartini A Feng S Brown R JrFallon M \nEvaluation for liver transplantation in adults:\n2013 practice guideline by the American Association for the Study of Liver\nDiseases and the American Society of Transplantation .\nHepatology .\n2014 ;59 :1144 -1165 .24716201 \n15 \nLentine KL Costa SP Weir MR , et al\nCardiac disease evaluation\nand management among kidney and liver transplantation candidates: a\nscientific statement from the American Heart Association and the American\nCollege of Cardiology Foundation . J Am Coll\nCardiol .\n2012 ;60 :434 -480 .22763103 \n16 \nDiedrich DA Findlay JY Harrison BA Rosen CB \nInfluence of coronary artery disease on outcomes\nafter liver transplantation . Transplant\nProc .\n2008 ;40 :3554 -3557 .19100436 \n17 \nPlotkin JS Scott VL Pinna A Dobsch BP De Wolf AM Kang Y \nMorbidity and mortality in patients with\ncoronary artery disease undergoing orthotopic liver\ntransplantation . Liver Transpl Surg .\n1996 ;2 :426 -430 .9346688 \n18 \nSharma M Yong C Majure D , et al\nSafety of cardiac\ncatheterization in patients with end-stage liver disease awaiting liver\ntransplantation . Am J Cardiol .\n2009 ;103 :742 -746 .19231345 \n19 \nJacobs E Singh V Damluji A , et al\nSafety of transradial\ncardiac catheterization in patients with end-stage liver\ndisease . Catheter Cardiovasc Interv .\n2014 ;83 :360 -366 .23723127 \n20 \nPillarisetti J Patel P Duthuluru S , et al\nCardiac catheterization in\npatients with end-stage liver disease: safety and outcomes .\nCatheter Cardiovasc Interv .\n2011 ;77 :45 -48 .20506280 \n21 \nMehran R Rao SV Bhatt DL , et al\nStandardized bleeding\ndefinitions for cardiovascular clinical trials: a consensus report from the\nBleeding Academic Research Consortium .\nCirculation .\n2011 ;123 :2736 -2747 .21670242 \n22 \nYong CM Sharma M Ochoa V , et al\nMultivessel coronary artery\ndisease predicts mortality, length of stay, and pressor requirements after\nliver transplantation . Liver Transpl .\n2010 ;16 :1242 -1248 .21031539 \n23 \nBoden WE O’Rourke RA Teo KK , et al\nOptimal medical therapy with\nor without PCI for stable coronary disease . N Engl J\nMed .\n2007 ;356 :1503 -1516 .17387127 \n24 \nMarui A Kimura T Tanaka S , et al\nCoronary revascularization\nin patients with liver cirrhosis . Ann Thorac\nSurg .\n2011 ;91 :1393 -1399 .21396626 \n25 \nTuran Y \nThe nonalcoholic fatty liver disease fibrosis\nscore is related to epicardial fat thickness and complexity of coronary\nartery disease . Angiology .\n2020 ;71 :77 -82 .31018673 \n26 \nWray C Scovotti JC Tobis J , et al\nLiver transplantation\noutcome in patients with angiographically proven coronary artery disease: a\nmulti-institutional study . Am J Transplant .\n2013 ;13 :184 -191 .23126562\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1179-5468",
"issue": "14()",
"journal": "Clinical Medicine Insights. Cardiology",
"keywords": "PCI; cirrhosis; dual antiplatelet therapy",
"medline_ta": "Clin Med Insights Cardiol",
"mesh_terms": null,
"nlm_unique_id": "101525768",
"other_id": null,
"pages": "1179546820901491",
"pmc": null,
"pmid": "32030068",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": "19100436;23495716;19231345;18662837;23126562;19228510;17387127;15290666;16828588;21670242;19515218;22763103;21396626;17427174;23723127;21031539;20440764;31018673;7701580;9346688;20506280;21425429;11552207;27103158;19413701;24716201",
"title": "One-Year Outcomes of Percutaneous Coronary Intervention in Patients with End-Stage Liver Disease.",
"title_normalized": "one year outcomes of percutaneous coronary intervention in patients with end stage liver disease"
} | [
{
"companynumb": "US-BAYER-2020-025239",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "Background: Tafamidis is approved in over 40 countries to delay neurologic progression in patients with transthyretin amyloid polyneuropathy (ATTR-PN). A comprehensive, integrated analysis of safety data from interventional, observational and surveillance studies of tafamidis in ATTR-PN patients was conducted. Methods: Safety data from all sponsored, completed, or ongoing, Phase 2/3 studies of tafamidis in ATTR-PN patients as of 3 January 2017 were pooled. Also assessed were safety data from the ongoing Transthyretin Amyloidosis Outcomes Survey (THAOS) as of 3 January 2017 and post-marketing surveillance reports as of 31 March 2017. Results: There were 137 patients in Phase 2/3 studies (mean duration of tafamidis exposure, 44.2 months), with 134 (97.8%) experiencing ≥1 treatment-emergent adverse event (TEAE) and 46 (33.6%) ≥1 treatment-emergent serious adverse event (TESAE). The most common TEAEs were diarrhoea (26.3%), urinary tract infection (UTI; 25.5%) and influenza (21.2%). In THAOS, 661 subjects had tafamidis exposure (mean duration, 27.6 months), with 250 (37.8%) experiencing ≥1 TEAE and 96 (14.5%) ≥1 TESAE. The most common TEAE was UTI (6.1%). Post-marketing surveillance reports generally reflected the known safety profile of tafamidis. Conclusions: This analysis did not reveal any significant new safety findings; tafamidis was generally safe and well tolerated in ATTR-PN patients. ClinicalTrials.gov: NCT00409175, NCT00791492, NCT00630864, NCT01435655, NCT00925002, and NCT00628745.",
"affiliations": "Pfizer Inc. , Collegeville , PA , USA.;Pfizer Inc. , Collegeville , PA , USA.;Pfizer Inc. , New York , NY , USA.;Pfizer Inc. , Collegeville , PA , USA.;Pfizer Inc. , Collegeville , PA , USA.;Pfizer Inc. , Collegeville , PA , USA.;Pfizer Inc. , Groton , CT , USA.;Pfizer Inc. , New York , NY , USA.",
"authors": "Huber|Peter|P|;Flynn|Alison|A|;Sultan|Marla B|MB|;Li|Huihua|H|;Rill|Denise|D|;Ebede|Ben|B|;Gundapaneni|Balarama|B|;Schwartz|Jeffrey H|JH|",
"chemical_list": "D001583:Benzoxazoles; C547076:tafamidis",
"country": "England",
"delete": false,
"doi": "10.1080/13506129.2019.1643714",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1350-6129",
"issue": "26(4)",
"journal": "Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis",
"keywords": "Transthyretin amyloidosis; adverse events; clinical trials; post-marketing surveillance; safety; tafamidis",
"medline_ta": "Amyloid",
"mesh_terms": "D000328:Adult; D028227:Amyloid Neuropathies, Familial; D001583:Benzoxazoles; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D064887:Observational Studies as Topic; D011115:Polyneuropathies; D011358:Product Surveillance, Postmarketing",
"nlm_unique_id": "9433802",
"other_id": null,
"pages": "203-209",
"pmc": null,
"pmid": "31353964",
"pubdate": "2019-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A comprehensive safety profile of tafamidis in patients with transthyretin amyloid polyneuropathy.",
"title_normalized": "a comprehensive safety profile of tafamidis in patients with transthyretin amyloid polyneuropathy"
} | [
{
"companynumb": "SE-PFIZER INC-FX-006-SWE-007/09",
"fulfillexpeditecriteria": "1",
"occurcountry": "SE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TAFAMIDIS MEGLUMINE"
},
"drugadditional... |
{
"abstract": "Recently, four SCN5A mutations have been associated with Multifocal Ectopic Purkinje-related Premature Contractions (MEPPC), a rare cardiac syndrome combining polymorphic ventricular arrhythmia with dilated cardiomyopathy (DCM). Here, we identified a novel heterozygous mutation in SCN5A (c.611C>A, pAla204Glu) in a young woman presenting with polymorphic premature ventricular contractions (PVCs) and DCM. After failure of antiarrhythmic drugs and an attempt of radiofrequency catheter ablation showing three exit-sites of PVCs, all with presystolic Purkinje potentials, a treatment by hydroquinidine was tried, leading to an immediate and spectacular disappearance of all PVCs and normalization of cardiac function. Electrophysiological studies showed that Nav 1.5-A204E mutant channels exhibited a significant leftward shift of 8 mV of the activation curve, leading to a larger hyperpolarized window current when compared to wild-type. Action potential modeling using Purkinje fiber and ventricular cell models predicted an arrhythmogenic effect predominant in Purkinje fibers for the A204E mutation. Comparison with other MEPPC-associated Nav 1.5 mutations revealed a common electrophysiological pattern of abnormal voltage-dependence of activation leading to a larger hyperpolarized window current as a shared biophysical mechanism of this syndrome. These features of the mutant sodium channels are likely to be responsible for the hyperexcitability of the fascicular-Purkinje system observed in patients with MEPPC.",
"affiliations": "Faculté de Médecine, Sorbonne Université, Paris, France.;Département de Cardiologie, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.;Faculté de Médecine, Sorbonne Université, Paris, France.;ICAN, Institute of Cardiometabolism and Nutrition, Paris, France.;Faculté de Médecine, Sorbonne Université, Paris, France.;Faculté de Médecine, Sorbonne Université, Paris, France.;Faculté de Médecine, Sorbonne Université, Paris, France.;ICAN, Institute of Cardiometabolism and Nutrition, Paris, France.;Faculté de Médecine, Sorbonne Université, Paris, France.;Faculté de Médecine, Sorbonne Université, Paris, France.",
"authors": "Doisne|Nicolas|N|0000-0002-2790-3897;Waldmann|Victor|V|0000-0001-8057-1900;Redheuil|Alban|A|;Waintraub|Xavier|X|;Fressart|Véronique|V|;Ader|Flavie|F|0000-0001-7891-3385;Fossé|Lucie|L|;Hidden-Lucet|Françoise|F|0000-0003-1257-5357;Gandjbakhch|Estelle|E|0000-0002-4846-5021;Neyroud|Nathalie|N|0000-0003-3382-7680",
"chemical_list": "D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human",
"country": "United States",
"delete": false,
"doi": "10.1002/humu.23981",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1059-7794",
"issue": "41(4)",
"journal": "Human mutation",
"keywords": "Purkinje; SCN5A; dilated cardiomyopathy; electrophysiology; gain-of-function mutation; polymorphic premature ventricular complexes",
"medline_ta": "Hum Mutat",
"mesh_terms": "D000293:Adolescent; D000483:Alleles; D001483:Base Sequence; D004252:DNA Mutational Analysis; D004562:Electrocardiography; D005260:Female; D000073659:Gain of Function Mutation; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D008279:Magnetic Resonance Imaging; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010641:Phenotype; D011690:Purkinje Fibers; D018879:Ventricular Premature Complexes",
"nlm_unique_id": "9215429",
"other_id": null,
"pages": "850-859",
"pmc": null,
"pmid": "31930659",
"pubdate": "2020-04",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A novel gain-of-function mutation in SCN5A responsible for multifocal ectopic Purkinje-related premature contractions.",
"title_normalized": "a novel gain of function mutation in scn5a responsible for multifocal ectopic purkinje related premature contractions"
} | [
{
"companynumb": "FR-MYLANLABS-2020M1035630",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FLECAINIDE"
},
"drugadditional": null,
... |
{
"abstract": "Outcomes of extremely low gestational age neonates (ELGANs) may be adversely impacted by packed red blood cell (pRBC) transfusions. We investigated the impact of transfusions on neurodevelopmental outcome in the Preterm Erythropoietin (Epo) Neuroprotection (PENUT) Trial population.\n\n\n\nThis is a post hoc analysis of 936 infants 24-0/6 to 27-6/7 weeks' gestation enrolled in the PENUT Trial. Epo 1000 U/kg or placebo was given every 48 h × 6 doses, followed by 400 U/kg or sham injections 3 times a week through 32 weeks postmenstrual age. Six hundred and twenty-eight (315 placebo, 313 Epo) survived and were assessed at 2 years of age. We evaluated associations between BSID-III scores and the number and volume of pRBC transfusions.\n\n\n\nEach transfusion was associated with a decrease in mean cognitive score of 0.96 (95% CI of [-1.34, -0.57]), a decrease in mean motor score of 1.51 (-1.91, -1.12), and a decrease in mean language score of 1.10 (-1.54, -0.66). Significant negative associations between BSID-III score and transfusion volume and donor exposure were observed in the placebo group but not in the Epo group.\n\n\n\nTransfusions in ELGANs were associated with worse outcomes. We speculate that strategies to minimize the need for transfusions may improve outcomes.\n\n\n\nTransfusion number, volume, and donor exposure in the neonatal period are associated with worse neurodevelopmental (ND) outcome at 2 years of age, as assessed by the Bayley Infant Scales of Development, Third Edition (BSID-III). The impact of neonatal packed red blood cell transfusions on the neurodevelopmental outcome of preterm infants is unknown. We speculate that strategies to minimize the need for transfusions may improve neurodevelopmental outcomes.",
"affiliations": "Department of Biostatistics, University of Washington, Seattle, WA, USA.;Department of Pediatrics, University of Utah, Salt Lake City, UT, USA.;Department of Pediatrics, University of Washington, Seattle, WA, USA.;Department of Pediatrics, University of Washington, Seattle, WA, USA.;Department of Biostatistics, University of Washington, Seattle, WA, USA.;Department of Biostatistics, University of Washington, Seattle, WA, USA.;Department of Pediatrics, University of Washington, Seattle, WA, USA. sjuul@uw.edu.",
"authors": "Vu|Phuong T|PT|;Ohls|Robin K|RK|;Mayock|Dennis E|DE|;German|Kendell R|KR|;Comstock|Bryan A|BA|;Heagerty|Patrick J|PJ|;Juul|Sandra E|SE|http://orcid.org/0000-0002-6861-6229;|||",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1038/s41390-020-01273-w",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-3998",
"issue": "90(1)",
"journal": "Pediatric research",
"keywords": null,
"medline_ta": "Pediatr Res",
"mesh_terms": null,
"nlm_unique_id": "0100714",
"other_id": null,
"pages": "109-116",
"pmc": null,
"pmid": "33432157",
"pubdate": "2021-07",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "21473518;27731885;30897226",
"title": "Transfusions and neurodevelopmental outcomes in extremely low gestation neonates enrolled in the PENUT Trial: a randomized clinical trial.",
"title_normalized": "transfusions and neurodevelopmental outcomes in extremely low gestation neonates enrolled in the penut trial a randomized clinical trial"
} | [
{
"companynumb": "US-AMGEN-USASP2021001122",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ERYTHROPOIETIN"
},
"drugadditional": null,
... |
{
"abstract": "A 59-year old man with idiopathic CD4 lymphopenia presented with extensive disseminated Cryptococcus neoformans infection including a large rib cryptoccocoma, vertebral spondylitis and pleural empyema. Complete resection of the affected part of the rib was necessary after failure of initial antifungal treatment. The vertebral spondylitis has been successfully managed at 3 years of follow-up by continuous itraconazole treatment and regular MRI combined with leucocyte scintigraphy assessment.",
"affiliations": "Department of Infectious Diseases, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen O, Denmark.;Department of Thoracic Surgery, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen O, Denmark.;Department of Microbiology, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen O, Denmark.;Department of Infectious Diseases, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen O, Denmark.;Department of Infectious Diseases, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen O, Denmark.",
"authors": "Legarth|Rebecca A|RA|;Christensen|Merete|M|;Calum|Henrik|H|;Katzenstein|Terese L|TL|;Helweg-Larsen|Jannik|J|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.mmcr.2014.02.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2211-7539",
"issue": "4()",
"journal": "Medical mycology case reports",
"keywords": "C. neoformans; Cryptococcoma; Idiopathic CD4 penia; Spondylitis",
"medline_ta": "Med Mycol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101598259",
"other_id": null,
"pages": "16-8",
"pmc": null,
"pmid": "24624326",
"pubdate": "2014-04",
"publication_types": "D016428:Journal Article",
"references": "8093633;12627365;21985306;18456875;22143898;2184491;20876624;8093638;7578756;9488829;22081285;19049641;16984867;10879590;10853888;22971990;20463247;11477526;20047480;18442854",
"title": "Cryptococcal rib osteomyelitis as primary and only symptom of idiopathic CD4 penia.",
"title_normalized": "cryptococcal rib osteomyelitis as primary and only symptom of idiopathic cd4 penia"
} | [
{
"companynumb": "DK-RANBAXY-2014R1-87635",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FLUCONAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "Thrombocytopenia and thromboembolism are common complications in coronavirus disease 2019 (COVID-19) patients. The fact that COVID-19 patients develop both thrombocytopenia and thromboembolism has been observed, and multiple studies have investigated the underlying pathophysiology. Extracorporeal membrane oxygenation (ECMO) is reserved for COVID-19 patients who develop respiratory failure and not respond to conventional mechanical ventilation. ECMO induces thromboembolism and raises the incidence of developing thromboembolic events in COVID-19 patients. Here, we report the hospital courses and outcomes of three COVID-19 patients who were treated with ECMO, then developed both thrombocytopenia and thromboembolism. The coexistence of thrombocytopenia and thromboembolism challenges the clinical treatment strategy, including the decision of initiating anticoagulation. Based on current data, anticoagulation is recommended to all hospitalized COVID-19 patients unless there is active bleeding, previous bleeding history within 3 days, or platelet count is lower than 30,000 cells/μl. Further investigation into the mechanisms and implications of thrombocytopenia and thromboembolism in patients with COVID-19 pneumonia will lead to significantly improved outcomes and prognosis for the patients.",
"affiliations": "John Fitzgerald Kennedy Medical Center Palm Beach Regional Graduate Medical Education Consortium, Atlantis, University of Miami, Miami, FL, United States.;John Fitzgerald Kennedy Medical Center Palm Beach Regional Graduate Medical Education Consortium, Atlantis, University of Miami, Miami, FL, United States.;John Fitzgerald Kennedy Medical Center, Atlantis, Miami, FL, United States.",
"authors": "Jones|Can|C|;Chen|Kai|K|;Narendran|Vijay|V|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fmed.2021.731352",
"fulltext": "\n==== Front\nFront Med (Lausanne)\nFront Med (Lausanne)\nFront. Med.\nFrontiers in Medicine\n2296-858X\nFrontiers Media S.A.\n\n10.3389/fmed.2021.731352\nMedicine\nCase Report\nCase Series: The Coexistence of Thrombocytopenia and Thromboembolism in COVID-19 Patients on ECMO: A Case Series and Literature Review\nJones Can 1 *\n\nChen Kai 1\nNarendran Vijay 2\n1John Fitzgerald Kennedy Medical Center Palm Beach Regional Graduate Medical Education Consortium, Atlantis, University of Miami, Miami, FL, United States\n2John Fitzgerald Kennedy Medical Center, Atlantis, Miami, FL, United States\nEdited by: Robert Campbell, The University of Utah, United States\n\nReviewed by: Maria Gavriilaki, University General Hospital of Thessaloniki AHEPA, Greece; Angela Ugwu, University of Nigeria, Nigeria\n\n*Correspondence: Can Jones cxj470@med.miami.edu\nThis article was submitted to Hematology, a section of the journal Frontiers in Medicine\n\n08 9 2021\n2021\n08 9 2021\n8 73135226 6 2021\n06 8 2021\nCopyright © 2021 Jones, Chen and Narendran.\n2021\nJones, Chen and Narendran\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.\nThrombocytopenia and thromboembolism are common complications in coronavirus disease 2019 (COVID-19) patients. The fact that COVID-19 patients develop both thrombocytopenia and thromboembolism has been observed, and multiple studies have investigated the underlying pathophysiology. Extracorporeal membrane oxygenation (ECMO) is reserved for COVID-19 patients who develop respiratory failure and not respond to conventional mechanical ventilation. ECMO induces thromboembolism and raises the incidence of developing thromboembolic events in COVID-19 patients. Here, we report the hospital courses and outcomes of three COVID-19 patients who were treated with ECMO, then developed both thrombocytopenia and thromboembolism. The coexistence of thrombocytopenia and thromboembolism challenges the clinical treatment strategy, including the decision of initiating anticoagulation. Based on current data, anticoagulation is recommended to all hospitalized COVID-19 patients unless there is active bleeding, previous bleeding history within 3 days, or platelet count is lower than 30,000 cells/μl. Further investigation into the mechanisms and implications of thrombocytopenia and thromboembolism in patients with COVID-19 pneumonia will lead to significantly improved outcomes and prognosis for the patients.\n\nthrombocytopenia\nthromboembolism\nCOVID-19\nECMO\nanticoagulation\n==== Body\npmcIntroduction\n\nThrombocytopenia and thromboembolism are common complications in coronavirus disease 2019 (COVID-19) patients.\n\nThe possible mechanisms (1) of thrombocytopenia in COVID-19 patients include decreased platelet production and increased platelet destruction and consumption. COVID-19-induced cytokine storm leads to the destruction of bone marrow progenitor cells and causes decreased platelet production; direct infection of hematopoietic and bone marrow stromal cells also has a consequence of bone marrow suppression. Immune thrombocytopenia has been frequently reported in COVID-19 patients. Increased of autoantibodies and immune complexes lead to platelet destruction (2). Pulmonary endothelial injury from COVID-19 infection triggers platelet activation, aggregation, and formation of microthrombi, which causes increased platelet consumption. Meanwhile, acute respiratory distress syndrome (ARDS) secondary to COVID-19 pneumonia contributes to dysfunction of megakaryopoiesis, since the lungs are important sites to release platelets from mature megakaryopoiesis, which leads to delayed phase thrombocytopenia (3). According to current studies, thrombocytopenia indicates poor prognosis (4) and high mortality of hospitalized COVID-19 patients (5).\n\nInterestingly, COVID-19 patients tend to develop thromboembolism, which often leads to sudden deterioration and death. D-dimer is an excellent marker to monitor hypercoagulability and predict outcome (6). Evidence suggests that there are multiple mechanisms involved in the development of thromboembolism. Endothelial dysfunction plays a critical role in the pathogenesis (7). Endothelial injury precipitates platelet activation and adhesion, leukocyte aggregation, cytokine storm, and complement activation. The expression of pro-inflammatory cytokines are significantly elevated in COVID-19 patients, and cytokine storm triggers coagulation activation and thrombin generation (8). Interleukin 6 (IL-6) is considered a dominant inflammatory cytokine by activating coagulation pathway, stimulating megakaryopoiesis, and facilitating the production of coagulation factors. IL-6 has been investigated as a promising immunotherapy target for COVID-19 infection (9). Complement activation is also thought to trigger the formation of systemic thrombus through recruiting inflammatory cytokines and possible complement-mediated thrombotic microangiopathy (7, 8). Recent study revealed that spike surface glycoprotein expressed by the virus could bind to angiotensin-converting enzyme 2 (ACE2), decrease its expression, and stimulate renin-angiotensin system (RAS). This process mediates platelet activation and adhesion, eventually promoting systemic thromboembolism (9).\n\nPatients on extracorporeal membrane oxygenation (ECMO) are at risk of developing thromboembolism. Thrombus formation within the extracorporeal circuit is the main reason that leads to systemic thromboembolism, including formation of pulmonary embolism (PE). The mechanism is possibly that by contacting blood and non-endothelial surfaces, ECMO triggers activation of coagulation pathway and inflammatory response (10). Thrombocytopenia is often complicated in ECMO as well due to shearing force in circuit and heparin-induced thrombocytopenia (HIT). However, there is no valid screening score which could be used specifically in ECMO patients for HIT prior to thromboembolic events (11).\n\nThe balance between bleeding prevention and thromboembolic prophylaxis in the setting of coexistence of thrombocytopenia and thromboembolism in COVID-19 patients is critical. Here, we report three COVID-19 patients who were treated with ECMO-developed thromboembolism and thrombocytopenia. HIT was excluded from all of the cases.\n\nMethods\n\nThe study was approved by the local institutional review board. Data of three patients who were diagnosed with COVID-19 pneumonia by polymerase chain reaction (PCR) and managed with ECMO were collected (Tables 1, 2). Anticoagulation protocol was initiated on hospital day one. All these three patients developed thrombocytopenia and thromboembolism while on ECMO support (Figures 1, 2). CARE guideline was followed throughout the study.\n\nTable 1 Clinical characteristics of three patients on admission.\n\nPatient\t1\t2\t3\t\nAge (years)\t35\t51\t52\t\nGender\tMale\tMale\tMale\t\nRace\tBlack\tBlack\tHispanic\t\nBody mass index (BMI)\t20.9\t22.1\t27.6\t\nHypertension\tYes\tYes\tNo\t\nDiabetes\tYes\tYes\tNo\t\nHyperlipidemia\tNo\tNo\tNo\t\nChronic lung disease\tNo\tNo\tNo\t\nChronic kidney disease\tNo\tNo\tNo\t\nMalignancy\tNo\tNo\tNo\t\nActive smoker\tNo\tNo\tNo\t\nUsing ACEI/ARB\tNo\tNo\tNo\t\n\nTable 2 Clinical presentations and baseline laboratory studies on admission.\n\n\tPatient 1\tPatient 2\tPatient 3\t\nCOVID-19 symptoms\tFatigue, fever, cough, and abdominal pain\tFever and dyspnea\tFever and dyspnea\t\nVital signs on admission\t\t\t\t\nHeart rate (bpm)\t133\t110\t58\t\nRespiratory rate (bpm)\t28\t21\t28\t\nBlood pressure (mmHg)\t185/110\t110/72\t114/61\t\nTemperature (degrees Celsius)\t37.2\t37.8\t36.4\t\nPhysical examination findings on admission\tIntubated, rhonchi at bilateral lungs\tTachypnea; oxygen saturation 88% on room air\tIntubated, rhonchi at bilateral lungs\t\nCOVID-19 PCR test\tPositive\tPositive\tPositive\t\nWBC count (×109)\t15.9\t19.8\t12.5\t\nPLT count (×1,000 cells/μl)\t567\t239\t218\t\nALT (U/L)\t65\t72\t29\t\nAST (U/L)\t55\t79\t36\t\nCreatinine (mg/dl)\t0.63\t1\t4.33\t\nTroponin (pg/ml)\t<0.012\t<0.012\t<0.012\t\nLactic acid (mmol/L)\t1.2\t1.5\t1.4\t\nFerritin (ng/ml)\t695\t710\t1,160\t\nC reactive protein (mg/dl)\t4.9\t26.7\t7.5\t\nLDH (Units/L)\t461\t475\t824\t\nD-dimer (ng/ml)\t5,250\t722\t4,065\t\nPartial thromboplastin time (s)\t28.3\t27.7\t54.3\t\nProthrombin time (s)\t10.5\t18.8\t17.3\t\nTotal bilirubin (mg/dl)\t0.8\t1.1\t0.7\t\nAlkaline phosphatase (Units/L)\t257\t136\t61\t\n\nFigure 1 Anticoagulation course of thromboprophylaxis and thromboembolism treatment.\n\nFigure 2 The course of platelet counts of the three ECMO-managed COVID-19 patients.\n\nHospital Course\n\nPatient 1 was a 35-year-old African American male with past medical history (PMH) of hypertension and type 2 diabetes presented to a local emergency department (ED) with 3 days of fatigue, fever, abdominal pain, and cough. He was initially diagnosed with diabetic ketoacidosis after missing his medications for several days in the setting of bilateral pneumonia. He was eventually diagnosed with COVID-19 by polymerase chain reaction (PCR) test and received treatment with convalescent plasma, remdesivir, and dexamethasone. The patient continued to clinically decline with progressive hypoxia and was intubated and placed on mechanical ventilation due to severe ARDS. Patient was transferred to current facility after intubation. On admission, patient was intubated, and the auscultation of lungs revealed bilateral rhonchi. Soon after, ECMO was initiated, and he was started on continuous heparin infusion to prevent thromboembolic events. The patient's platelet level was above normal (567,000 cells/μl) range and gradually decreased to 253,000 cells/μl on the second day of heparin treatment. Venous ultrasound identified upper and lower extremity deep venous thrombosis (DVT) on hospital day 3, involving the right axillary, brachial veins, left subclavian veins, and axillary veins. Clots were not noticed in the ECMO circuit. Given a decreasing platelet count and slightly elevated heparin antibody level, the medical team suspected HIT with thrombosis. Heparin infusion was stopped and argatroban infusion was initiated. Despite this change, the platelet level did not improve, and the serotonin release assay eventually was found to be negative, indicating that HIT was unlikely. Argatroban was switched to bivalirudin. The patient did not develop active bleeding. In this case, the patient's thromboembolism was likely related to COVID-19-induced hypercoagulability, combined with the known risk of thromboembolism in patients receiving ECMO. The patient had been on ECMO for 52 days and expired due to asystole during hospitalization on hospital day 53 (Table 3).\n\nTable 3 Thrombocytopenia and thromboembolic events on ECMO support.\n\nPlatelet on admission (cells/μl)\t567,000\t239,000\t218,000\t\nECMO type\tV-V\tV-V\tV-V\t\nTime of ECMO initiation since admission\tDay 2\tDay 5\tDay 2\t\nPlatelet level on first day of ECMO (cells/μl)\t462,000\t153,000\t177,000\t\nInitiation of anticoagulation\tDay 1\tDay 1\tDay 1\t\nTime of development of thrombocytopenia since admission\tDay 30\tDay 7\tDay 34\t\nPlatelet nadir (cells/μl)\t52,000\t61,000\t30,000\t\nTime of thromboembolism development since admission\tDay 3\tDay 5\tDay 3\t\nType of thromboembolism\tMultiple DVT, diagnoses by venous ultrasound\tPE, diagnosed by chest CTA\tMultiple DVT, diagnosed by venous ultrasound\t\nHemorrhage requiring transfusion\tYes (day 26)\tYes (day 44)\tNo\t\nSite of bleeding\tGastrointestinal tract\tHemothorax\tNone\t\nECMO circuit thrombosis\tNo\tNo\tNo\t\nHIT\tNo\tNo\tNo\t\nStroke\tNo\tNo\tNo\t\nTotal ECMO days\t52\t23\t22\t\nHospital days of stay\t53\t58\t38\t\nOutcome\tDeceased\tDischarged\tDischarged\t\nCause of death\tAsystole\tNone\tNone\t\n\nPatient 2 was a 51-year-old African American male with a history of hypertension and type 2 diabetes presented to the ED for dyspnea and fever and was diagnosed with COVID-19 pneumonia by PCR test. Physical examination on admission revealed tachypnea with clear lung auscultation. Patient's oxygen saturation was 88% on room air. His hospitalization course was complicated by acute hypoxemic respiratory failure and septic shock. ECMO was initiated on hospital day 4 along with continuous heparin infusion for thromboprophylaxis. The patient's platelet level was within normal range on admission then decreased to 129,000 cells/μl on hospital day 6 at which time he was found to have a PE by chest computed tomography angiography (CTA). No clots were found in the ECMO circuit. Considering possibility of HIT, heparin was switched to argatroban on day 8. Heparin antibody was mildly elevated with negative serotonin release assay result making the diagnosis of HIT unlikely. He continued on argatroban, and with time, his clinical symptoms improved and his platelet level rose to normal range. He was managed on ECMO for 23 days and discharged to long-term care facility on hospital day 58.\n\nPatient 3 was a 52-year-old Hispanic male with no significant PMH presented at a local ED for dyspnea and fever. He was diagnosed as having COVID-19 pneumonia by PCR test. The patient was transferred to current facility because of acute hypoxemic respiratory failure. On admission, patient was intubated, and physical examination revealed bilateral pulmonary rhonchi. ECMO was initiated on hospital day 2. Heparin was started for thromboprophylaxis. His platelet level was normal on admission. He suffered progressive thrombocytopenia on ECMO, and on hospital day 3, venous ultrasound revealed partially occlusive DVT in the distal left femoral vein, left popliteal vein, and left posterior tibial vein and occlusive DVT in the right subclavian vein, axillary vein, and brachial vein. Given concern for HIT, bivalirudin was used for anticoagulation to treat DVT and for thromboprophylaxis on ECMO. Serotonin release assay was negative, indicating that HIT was unlikely. Clots were not identified in the ECMO circuit. Heparin was reinitiated after ECMO decannulation on hospital day 24. His course was complicated by thrombocytopenia again (36,000 cells/μl) in the setting of sepsis secondary to intra-abdominal infection due to malpositioned percutaneous endoscopic gastrostomy (PEG) tube and delivery of tube feedings to peritoneum. Given at least intermediate risk for HIT at the time of re-exposure, heparin was again switched to bivalirudin. Heparin antibody level was borderline positive, and serotonin release assay result was again negative. His infection was well-controlled with antibiotics, and his COVID testing returned persistently negative results. However, the patient's platelet level did not improve, and he developed chronic respiratory failure. No active bleeding was identified during the hospitalization course. Warfarin was recommended as a long-term anticoagulant, considering his renal function and the patient was discharged to long-term care facility.\n\nDiscussion\n\nAs we know, ECMO increases the incidence of thrombotic events (10), and COVID-19 patients are at high risk to develop thromboembolism. A recent study discussed the hemorrhagic and thrombotic events on eight COVID-19 patients who were managed with ECMO (12). Incidences of oxygenator thrombus, trachea hemorrhage, and oronasal hemorrhage were high among the eight patients. Similar findings were not observed in our retrospective study. However, there were several limitations of our study. Our study emphasized on the hematological complications including thrombocytopenia, thromboembolism, and anticoagulation management on ECMO-treated COVID-19 patients. The sample size of our study was small and may not represent the general population. Biases may present in the retrospective, single-center observational study. ECMO initiation criteria and anticoagulation management guidelines may vary among the different hospital facilities.\n\nThe coexistence of thrombocytopenia and thromboembolism in COVID-19 patients should raise physicians' concern. Studies suggest that thrombocytopenia is caused by COVID-19-induced bone marrow suppression and platelet consumption and destruction (1, 2). Cytokine storm and IL-6 production triggered by COVID-19 infection play a prominent role in the development of thromboembolism by activating coagulation pathway and promoting synthesis of coagulating factors. The specific virus mechanism is also involved in the process of thromboembolism. COVID-19 induces activation of renin-angiotensin system and amplifies the production of angiotensin. Through its prothrombotic and pro-inflammatory effects, angiotensin contributes to thromboembolic events including DVT and PE (13).\n\nVenous thromboembolism prophylaxis is indicated in all hospitalized COVID-19 patients unless the risks of bleeding outweigh the benefit of prophylaxis (14), especially those who are treated with ECMO. Early identification and initiation of therapeutic anticoagulation treatment play an essential role in improving the outcome. Dynamic monitoring of D-dimer and platelet level provides valuable assessment of thrombotic events. Thrombocytopenia has been reported in both ECMO-treated patients and COVID-19 patients. It is associated with high mortality among hospitalized COVID-19 patients (15). Although thrombocytopenia increases the risk of active bleeding, incidence of bleeding in COVID-19 infection was lower compared with other viruses such as Ebola virus (16). The possible rationale is that COVID-19 coagulopathy leads more toward a hypercoagulable inflammatory state overcoming bleeding risk due to thrombocytopenia (16). Recent studies suggest that steroids, intravenous immune globulin (IVIG), thrombopoietin receptor agonists (TPO-RA), and platelet transfusion are all options to treat severe thrombocytopenia with active bleeding (17). Steroids seem to be a good initial choice if there are no contraindications. One concern considering the use of TPO-RA in patients with COVID-19 pneumonia is increased medication-induced thrombotic potential in patients who already have a prothrombotic state due to COVID-19 infection. IVIG may be initiated to immediately elevate platelet level and is reserved as the second-line treatment. Platelet transfusion can be used in those refractory to IVIG and especially for those with life-threatening bleeding (18). All choices should be carefully considered, and treatment plans individualized for each patient.\n\nIn conclusion, in the setting of coexistence of thrombocytopenia and thromboembolism, all hospitalized COVID-19 patients should be on thromboembolic prophylaxis, especially those who are treated with ECMO. Although those patients are at higher risk of bleeding due to low platelet level, treatment of thrombocytopenia should not be initiated unless there is active bleeding or platelet level is lower than 30,000 cells/μl. Anticoagulants should be held if platelet level is <30,000 cells/μl (18). Further investigation into the implications and mechanisms of thrombocytopenia and venous thromboembolism in patients with COVID-19 pneumonia will lead to better outcomes for our patients.\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.\n\nEthics Statement\n\nThe studies involving human participants were reviewed and approved by HCA Health Care. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\n\nAll authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.\n\nAuthor Disclaimer\n\nThe views expressed in this publication represent those of the author(s) and do not necessarily represent the official views of HCA Healthcare or any of its affiliated entities.\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\nAbbreviations\n\nARDS acute respiratory distress syndrome\n\nCOVID-19 coronavirus disease 2019\n\nCTA computed tomography angiography\n\nDVT deep venous thrombosis\n\nECMO extracorporeal membrane oxygenation\n\nED emergency department\n\nHIT heparin induced thrombocytopenia\n\nIL-6 interleukin 6\n\nIVIG intravenous immune globulin\n\nPE pulmonary embolism\n\nPCR polymerase chain reaction\n\nPEG percutaneous endoscopic gastrostomy\n\nPMH past medical history\n\nTPO-RA thrombopoietin receptor agonists.\n==== Refs\nReferences\n\n1. Xu P Zhou Q Xu J . Mechanism of thrombocytopenia in COVID-19 patients. Ann Hematol. (2020) 99 :1205–8. 10.1007/s00277-020-04019-0 32296910\n2. Zhang Y Zeng X Jiao Y Li Z Liu Q Ye J . Mechanisms involved in the development of thrombocytopenia in patients with COVID-19. Thromb Res. (2020) 193 :110–5. 10.1016/j.thromres.2020.06.008 32535232\n3. Chen W Li Z Yang B Wang P Zhou Q Zhu J . Delayed-phase thrombocytopenia in patients of Coronavirus disease 2019 (COVID-19). Br J Haematol. (2020) 190 :179–84. 10.1111/bjh.16885 32453877\n4. Maquet J Lafaurie M Sommet A Moulis G . Thrombocytopenia is independently associated with poor outcome in patients hospitalized for COVID-19. Br J Haematol. (2020) 190 :e276–9. 10.1111/bjh.16950 32557535\n5. Yang X Yang Q Wang Y Wu Y Xu J Yu Y . Thrombocytopenia and its association with mortality in patients with COVID-19. J Thromb Haemost. (2020) 18 :1469–72. 10.1111/jth.14848 32302435\n6. Dobesh PP Trujillo TC . Coagulopathy, venous thromboembolism, and anticoagulation in patients with COVID-19. Pharmacotherapy. (2020) 40 :1130–51. 10.1002/phar.2465 33006163\n7. Gavriilaki E Anyfanti P Gavriilaki M Lazaridis A Douma S Gkaliagkousi E . Endothelial dysfunction in COVID-19: lessons learned from coronaviruses. Curr Hypertens Rep. (2020) 22 :63. 10.1007/s11906-020-01078-6 32852642\n8. Hanff TC Mohareb AM Giri J Cohen JB Chirinos JA . Thrombosis in COVID-19. Am J Hematol. (2020) 95 :1578–89. 10.1002/ajh.25982 32857878\n9. Lazzaroni MG Piantoni S Masneri S Garrafa E Martini G Tincani A . Coagulation dysfunction in COVID-19: the interplay between inflammation, viral infection and the coagulation system. Blood Rev. (2021) 46 :100745. 10.1016/j.blre.2020.100745 32868115\n10. Murphy DA Hockings LE Andrews RK Aubron C Gardiner EE Pellegrino VA . Extracorporeal membrane oxygenation-hemostatic complications. Transfus Med Rev. (2015) 29 :90–101. 10.1016/j.tmrv.2014.12.001 25595476\n11. Brown MA Najam F Pocock ES Munoz PF Farrar KA Yamane DP . A comparison of bivalirudin and heparin for patients on extracorporeal membrane oxygenation. Thromb Res. (2020) 190 :76–8. 10.1016/j.thromres.2020.04.009 32315870\n12. Guo Z Sun L Li B Tian R Zhang X Zhang Z . Anticoagulation management in severe Coronavirus disease 2019 patients on extracorporeal membrane oxygenation. J Cardiothorac Vasc Anesth. (2021) 35 :389–97. 10.1053/j.jvca.2020.08.067 32994131\n13. Ali MAM Spinler SA . COVID-19 and thrombosis: from bench to bedside. Trends Cardiovasc Med. (2021) 31 :143–60. 10.1016/j.tcm.2020.12.004 33338635\n14. Levi M Thachil J Iba T Levy JH . Coagulation abnormalities and thrombosis in patients with COVID-19. Lancet Haematol. (2020) 7 :e438–40. 10.1016/S2352-3026(20)30145-9 32407672\n15. Lippi G Plebani M Henry BM . Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: a meta-analysis. Clin Chim Acta. (2020) 506 :145–8. 10.1016/j.cca.2020.03.022 32178975\n16. Mei H Luo L Hu Y . Thrombocytopenia and thrombosis in hospitalized patients with COVID-19. J Hematol Oncol. (2020) 13 :161. 10.1186/s13045-020-01003-z 33261634\n17. Lorenzo-Villalba N Zulfiqar A-A Auburtin M Schuhmacher MH Meyer A Maouche Y . Thrombocytopenia in the course of COVID-19 infection. Eur J Case Rep Intern Med. (2020) 7 :001702. 10.12890/2020_001702 32523922\n18. Pavord S Thachil J Hunt BJ Murphy M Lowe G Laffan M . Practical guidance for the management of adults with immune thrombocytopenia during the COVID-19 pandemic. Br J Haematol. (2020) 189 :1038–43. 10.1111/bjh.16775 32374026\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2296-858X",
"issue": "8()",
"journal": "Frontiers in medicine",
"keywords": "COVID-19; ECMO; anticoagulation; thrombocytopenia; thromboembolism",
"medline_ta": "Front Med (Lausanne)",
"mesh_terms": null,
"nlm_unique_id": "101648047",
"other_id": null,
"pages": "731352",
"pmc": null,
"pmid": "34568388",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "32296910;32178975;33338635;32868115;33006163;32302435;32535232;32857878;32453877;32852642;32523922;32557535;32315870;25595476;32407672;32994131;32374026;33261634",
"title": "Case Series: The Coexistence of Thrombocytopenia and Thromboembolism in COVID-19 Patients on ECMO: A Case Series and Literature Review.",
"title_normalized": "case series the coexistence of thrombocytopenia and thromboembolism in covid 19 patients on ecmo a case series and literature review"
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"abstract": "BACKGROUND\nChimeric antigen receptor (CAR) T-cell therapy is effective in treating relapsed and refractory B-cell non-Hodgkin lymphoma. However, because of the mortality risk associated with immune effector cell-associated neurotoxicity syndrome and pseudoprogression, patients with central nervous system (CNS) involvement are less likely to receive CAR T-cell therapy.\nWe report a case of a 61-year-old, male patient with intravascular large B-cell lymphoma who suffered a CNS relapse after standard chemotherapy.\n\n\nMETHODS\nA diagnosis of intravascular large B-cell lymphoma with CNS involvement was made.\n\n\nMETHODS\nWe treated the patient using CAR T-cell therapy following a conditioning regimen consisting of thiotepa and busulfan and autologous stem cell transplantation. Although he experienced grade 1 cytokine release syndrome, no other serious adverse events, such as immune effector cell-associated neurotoxicity syndrome or pseudoprogression, were observed.\n\n\nRESULTS\nThe patient achieved complete remission after the CAR T-cell infusion.\n\n\nCONCLUSIONS\nCAR T-cell therapy following autologous stem cell transplantation is a viable option for relapsed/refractory lymphoma with CNS infiltration. Further clinical studies are warranted to verify its safety and efficacy.",
"affiliations": "Department of Medical Oncology, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.;Department of Medical Oncology, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.;Department of Medical Oncology, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.;Department of Medical Oncology, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.;Department of Medical Oncology, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.;Department of Medical Oncology, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.;Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.;Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.;Department of Medical Oncology, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.;Department of Radiation Oncology, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.;Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.;Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.;Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.;Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.;Division of Transfusion and Cell Therapy, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.;Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.;Division of Transfusion and Cell Therapy, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.;Department of Medical Oncology, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.;Department of Medical Oncology, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.",
"authors": "Yagi|Yu|Y|;Kanemasa|Yusuke|Y|0000-0002-9809-2008;Ohigashi|An|A|;Morita|Yuka|Y|;Tamura|Taichi|T|;Nakamura|Shohei|S|;Otsuka|Yuki|Y|;Kishida|Yuya|Y|;Kageyama|Akihiko|A|;Shimizuguchi|Takuya|T|;Toya|Takashi|T|;Shimizu|Hiroaki|H|;Najima|Yuho|Y|;Kobayashi|Takeshi|T|;Haraguchi|Kyoko|K|;Doki|Noriko|N|;Okuyama|Yoshiki|Y|;Omuro|Yasushi|Y|;Shimoyama|Tatsu|T|",
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"country": "United States",
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"doi": "10.1097/MD.0000000000027733",
"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974\n1536-5964\nLippincott Williams & Wilkins Hagerstown, MD\n\nMD-D-21-06330\n10.1097/MD.0000000000027733\n27733\n4800\nResearch Article\nClinical Case Report\nChimeric antigen receptor T-cell therapy following autologous transplantation for secondary central nervous system lymphoma\nA case report\nYagi Yu MD a\nhttp://orcid.org/0000-0002-9809-2008\nKanemasa Yusuke MD a ∗\nOhigashi An MD a\nMorita Yuka MD a\nTamura Taichi MD a\nNakamura Shohei MD a\nOtsuka Yuki MD b\nKishida Yuya MD b\nKageyama Akihiko MD a\nShimizuguchi Takuya MD c\nToya Takashi MD, PhD b\nShimizu Hiroaki MD, PhD b\nNajima Yuho MD, PhD b\nKobayashi Takeshi MD b\nHaraguchi Kyoko MD, PhD d\nDoki Noriko MD, PhD b\nOkuyama Yoshiki MD, PhD d\nOmuro Yasushi MD a\nShimoyama Tatsu MD a\nSaranathan. Maya\na Department of Medical Oncology, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan\nb Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan\nc Department of Radiation Oncology, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan\nd Division of Transfusion and Cell Therapy, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.\n∗ Correspondence: Yusuke Kanemasa, Department of Medical Oncology, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, 3-18-22 Hon-komagome, Bunkyo-ku, Tokyo 113-8677, Japan (e-mail: y-kanemasa@cick.jp).\n05 11 2021\n05 11 2021\n100 44 e2773311 9 2021\n13 10 2021\n22 10 2021\nCopyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0\n\nAbstract\n\nRationale:\n\nChimeric antigen receptor (CAR) T-cell therapy is effective in treating relapsed and refractory B-cell non-Hodgkin lymphoma. However, because of the mortality risk associated with immune effector cell-associated neurotoxicity syndrome and pseudoprogression, patients with central nervous system (CNS) involvement are less likely to receive CAR T-cell therapy.\n\nPatients concerns:\n\nWe report a case of a 61-year-old, male patient with intravascular large B-cell lymphoma who suffered a CNS relapse after standard chemotherapy.\n\nDiagnosis:\n\nA diagnosis of intravascular large B-cell lymphoma with CNS involvement was made.\n\nInterventions:\n\nWe treated the patient using CAR T-cell therapy following a conditioning regimen consisting of thiotepa and busulfan and autologous stem cell transplantation. Although he experienced grade 1 cytokine release syndrome, no other serious adverse events, such as immune effector cell-associated neurotoxicity syndrome or pseudoprogression, were observed.\n\nOutcomes:\n\nThe patient achieved complete remission after the CAR T-cell infusion.\n\nLessons:\n\nCAR T-cell therapy following autologous stem cell transplantation is a viable option for relapsed/refractory lymphoma with CNS infiltration. Further clinical studies are warranted to verify its safety and efficacy.\n\nKeywords\n\nautologous stem cell transplantation\ncase report\ncentral nervous system relapse\nchimeric antigen receptor T-cell therapy\nintravascular large B-cell lymphoma\nOPEN-ACCESSTRUE\n==== Body\npmc1 Introduction\n\nThe therapeutic efficacy of chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma.[1] However, CAR T-cell therapy can have potentially severe side effects, such as cytokine release syndrome (CRS) and CAR T-cell therapy-related immune effector cell-associated neurotoxicity syndrome (ICANS).[2] The incidence of CRS and ICANS in patients with hematological malignancies is significantly higher than in those with other solid malignancies.[3] Due to the mortality risk associated with ICANS, patients with central nervous system (CNS) involvement are excluded from almost all clinical trials of CAR T-cell therapy. Although there are some reports of the application of CD19-targeted CAR T-cells in CNS lymphoma treatment,[4–6] there are no reports of an increased incidence of ICANS in patients with CNS lymphoma so far. The efficacy and safety of CAR T-cell therapy in patients with CNS involvement have not been established yet due to the rarity of these patients.\n\nHerein, we reported a case of a CNS relapse of intravascular large B-cell lymphoma (IVLBCL) successfully treated with autologous stem cell transplantation (ASCT) followed by CAR T-cell therapy. This study was approved by the Ethics Committee of Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital. Written informed consent was obtained from the patient for publication of this case report.\n\n2 Case report\n\nA previously healthy, 61-year-old, male patient presented with fever and dyspnea. On admission, a blood test revealed a marked elevation of lactate dehydrogenase (1450 U/L normal: 106–211 U/L) and interleukin 2 receptor (8800 U/mL normal: 122–496 U/mL). Computed tomography revealed consolidation in the upper lobe. IVLBCL was diagnosed based on an analysis of bone marrow, lung biopsy, and skin biopsy specimens. Brain magnetic resonance imaging (MRI) revealed no abnormalities, and the patient was not considered to have lymphoma with CNS involvement. He achieved complete remission (CR) after 6 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone and 8 cycles of rituximab plus 2 cycles of high-dose methotrexate (HD-MTX). One month later, he experienced a CNS relapse with brain lesions detected by positron emission tomography and computed tomography. MRI revealed a 25 mm × 20 mm × 34 mm mass in the right basal ganglia and other smaller lesions in the brain (Fig. 1). No lymphoma cells were found in cerebrospinal fluid, nor were any lesions detected outside the CNS. Owing to the difficulty of curing a CNS relapse by salvage chemotherapy even with ASCT, the addition of CAR T-cell therapy after ASCT was planned. He underwent 3 cycles of HD-MTX and rituximab followed by 3 cycles of HD-MTX/cytarabine. Lymphocyte apheresis for CAR T-cell manufacturing was performed during the salvage chemotherapy. Subsequent MRI showed a partial response. A peripheral blood stem cell harvest was performed, and the patient received a conditioning regimen consisting of BuTT (thiotepa 5 mg/kg on days -7 to -6, busulfan 3.2 mg/kg on days -5 to -4) and ASCT on day 0. Although MRI after the ASCT was unable to detect the residual lesions, the patient was still considered to have residual CNS disease. He received lymphodepleting chemotherapy consisting of fludarabine 25 mg/m2/day and cyclophosphamide 250 mg/m2/day on days -7 to -5 and an infusion of anti-CD19 CAR T-cells (tisagenlecleucel) on day 0. Four hours after the CAR T-cell infusion, a fever, which failed to respond to broad-spectrum antibiotics or supportive treatment, developed without hypotension or hypoxia, leading to the diagnosis of grade 1 CRS. Although the patient was treated with tocilizumab 8 mg/kg/day on days 2 and 3, the symptoms continued. Finally, he was given methylprednisolone 2 mg/kg/day from day 3, and his temperature normalized by day 5. Thereafter the methylprednisolone was tapered, then stopped on day 8. No neurotoxic events were observed during the follow-up period. Grade 4 neutropenia developed from day 23 and improved by day 78. No serious infections were observed. Grade 4 thrombocytopenia developed from day 36 and improved by day 47 (Fig. 2). One month after the CAR T-cell infusion, brain MRI showed a complete absence of brain lesions, indicating a CR (Fig. 1). Eight months after the CAR T-cell infusion, the patient remains in CR.\n\nFigure 1 Clinical course: The patient received R-MTX (rituximab and methotrexate) and R-MA (rituximab, methotrexate, and cytarabine) after a central nervous system (CNS) relapse. He received BuTT (busulfan and thiotepa) as the conditioning regimen followed by ASCT (autologous stem cell transplantation). Posttransplantation, he received lymphodepleting chemotherapy consisting of FLU/CY (fludarabine and cyclophosphamide) and an infusion of anti-CD19 CAR (chimeric antigen receptor) T-cells. Brain MRI after the CAR-T cell infusion demonstrated resolution of the CNS lesions, indicating a complete response. The arrowheads show the presence of lymphoma lesions in the brain. MRI = magnetic resonance imaging.\n\nFigure 2 Clinical course after CAR T-cell infusion: Fever ≥ 38°C without hypotension or hypoxia developed after CAR (chimeric antigen receptor) T-cell infusion, corresponding to grade 1 cytokine release syndrome. The patient was treated with tocilizumab and methylprednisolone (mPSL) (A). Grade 4 neutropenia and thrombocytopenia developed after CAR T-cell infusion (B).\n\n3 Discussion\n\nThe patient in the present study had R/R B-cell non-Hodgkin lymphoma with a CNS relapse and failed to achieve a CR with salvage chemotherapy, high-dose chemotherapy (HDC) or ASCT. After CAR T-cell therapy, he finally achieved durable CR without any severe adverse events, such as ICANS. To the best of our knowledge, the present report is the first to demonstrate the safety and efficacy of CAR T-cell therapy following ASCT in patients with CNS involvement.\n\nPrevious studies reported the risk of CNS relapse in diffuse large B-cell lymphoma (DLBCL) to be approximately 5%.[7–9] IVLBCL is characterized by clinically aggressive behavior and a high rate of CNS involvement at diagnosis. Several, previous studies have examined IVLBCL patients with a CNS relapse, and a retrospective study reported that the risk of CNS recurrence at 3 years was 25% among 82 patients without CNS involvement at the initial diagnosis.[10–13]\n\nThe incidence of CNS involvement secondary to DLBCL is considerably higher in patients with certain, high-risk, clinical features at diagnosis. Multivariate risk models, such as CNS-IPI, are effective in predicting the risk of CNS recurrence.[14] Identifying patients with a high risk of CNS relapse allows us to offer appropriate prophylaxis during the first line therapy. Intravenous and intrathecal prophylaxis is most frequently used, but the evidence is equivocal as to its effectiveness.[15] Intravenous HD-MTX can be safely administered in combination with standard chemoimmunotherapy and decreases the risk of CNS recurrence in patients with high-risk DLBCL. However, there is currently no standard form of CNS-prophylaxis.[15]\n\nThe prognosis of patients with a CNS relapse is still poor, and there is as of yet no consensus on the optimal salvage treatment. The median overall survival after CNS relapse is reportedly about 7 months.[16,17] The data supporting the efficacy of HDC and ASCT in patients with DLBCL with secondary CNS lymphoma are limited although some studies have shown favorable survival outcomes (the median DFS and overall survival for patients with CR at ASCT was 36 and 33 months, respectively).[18–21] The optimal HDC regimen for secondary CNS lymphoma is also unknown. Conditioning regimens containing agents that can effectively penetrate the blood-brain barrier, such as BuTT, are reportedly associated with promising disease control for relapsed CNS lymphoma. Some retrospective analyses reported an association between the thiotepa/busulfan-based conditioning therapy with ASCT for secondary CNS lymphoma and progression-free survival at years 2 and 3 of 76.1% to 93%, respectively.[18,19] Despite the use of the HDC regimen and ASCT in the treatment of CNS lesions, a complete cure for secondary CNS lymphoma is still elusive. CAR T-cell therapy may therefore augment these therapies to improve the possibility of CR.\n\nThe occurrence of lethal neurotoxicity after CAR T-cell therapy prevents most patients with a CNS lesion from receiving this treatment. Abramson et al[4] reported the first case of CNS lymphoma treated with CAR T-cell therapy, which induced CR without ICANS. A retrospective analysis of tisagenlecleucel for the treatment of R/R B-cell non-Hodgkin lymphoma with secondary CNS involvement showed that none of the patients experienced CAR T-cell-related neurotoxicity.[5] In addition, the rate of ICNAS did not increase in 5 patients treated with axicabtagene ciloleucel for R/R NHL with secondary CNS involvement.[22]\n\nThe pathogenesis of ICANS is not completely understood but may be related to cytokine-mediated toxicity resulting from endothelial dysfunction, increased blood-brain barrier permeability, and failure to protect cerebrospinal fluid from high concentrations of systemic cytokines.[23] The most significant risk factor of ICANS is a history of severe CRS. A high tumor burden is also associated with ICANS development.[24,25] In the present case, ICNAS did not occur after CAR T-cell therapy partly because the ASCT after BuTT was able to reduce the tumor burden sufficiently.\n\nPseudoprogression, a well-defined phenomenon in other immunotherapies for solid tumors, is characterized by a temporary enlargement of the tumors due to immune cell infiltration and is also observed during CAR T-cell therapy. However, this enlargement can cause local compression,[26] and CAR T-cell therapy in the presence of substantial residual disease can be fatal in cases of CNS invasion. Combined with the fact that a durable response to CAR T-cell therapy is associated with a low baseline tumor burden,[27] reducing the tumor burden as much as possible before CAR T-cell therapy, especially in cases of CNS involvement, is crucial.\n\nHDC and ASCT are the current standard of care for R/R DLBCL. However, relapse rates are still high. Some reports demonstrated the feasibility of CAR T-cell therapy a couple of days after ASCT for R/R B-cell non-Hodgkin lymphoma,[28–30] unlike the present case, in which CAR T-cell therapy was performed about 1 month after ASCT. The tumor burden decreases as a result of myeloablative conditioning, and the immunosuppressive microenvironment is attenuated after ASCT. Consecutive administration of ASCT and CAR-T cells eradicates the residual disease and reduces the recurrence rate. In fact, CAR T-cell therapy following ASCT exhibited a higher rate of CR in patients with R/R large B-cell lymphoma than CAR T-cell therapy alone.[28] However, the therapy was associated with a high incidence of reversible neurotoxicity, with 10 of 15 patients in a phase I clinical study experiencing grade 3 to 4 neurotoxicity, which may have been caused by the high-dose conditioning and pegfilgrastim administered immediately before the CAR T-cell infusion.[29] We believe that CAR T-cell therapy after an interval following ASCT can increase the response rate by reducing the tumor volume with less neurotoxicity.\n\nWhole brain radiotherapy (WBRT) for CNS lymphoma prolongs progression-free survival.[31] However, the major impediment to using WBRT is the high risk of late-delayed neurotoxicity, which manifests as progressive leukoencephalopathy with cognitive deterioration often leading to severe dementia and death. In an attempt to minimize neurotoxicity, WBRT is often avoided altogether in the treatment of patients with lymphoma with CNS involvement.[32] CAR T-cell therapy following ASCT may be a viable alternative to WBRT in the treatment of CNS lymphoma.\n\n4 Conclusion\n\nCAR T-cell therapy was safely administered after ASCT to a patient with secondary CNS lymphoma. CAR T-cell therapy following ASCT is a promising treatment for patients with lymphoma with CNS involvement. Vigilant follow-up of the present patient and further studies are needed to determine whether CAR T-cell cell therapy following ASCT is indeed a viable therapeutic option for R/R B-cell non-Hodgkin lymphoma with CNS infiltration.\n\nAcknowledgments\n\nThe authors would like to thank the nursing staff at Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital for their excellent patient care.\n\nAuthor contributions\n\nConceptualization: Tatsu Shimoyama.\n\nInvestigation: Yu Yagi, Yusuke Kanemasa, An Ohigashi, Yuka Morita, Taichi Tamura, Shohei Nakamura, Yuki Otsuka, Yuya Kishida, Akihiko Kageyama, Takuya Shimizuguchi, Takashi Toya, Hiroaki Shimizu, Yuho Najima, Takeshi Kobayashi, Kyoko Haraguchi, Noriko Doki, Yoshiki Okuyama, Yasushi Omuro.\n\nSupervision: Yasushi Omuro, Tatsu Shimoyama.\n\nWriting – original draft: Yu Yagi.\n\nWriting – review & editing: Yusuke Kanemasa.\n\nAbbreviations: ASCT = autologous stem cell transplantation, BuTT = thiotepa and busulfan, CAR = chimeric antigen receptor, CNS = central nervous system, CR = complete remission, CRS = cytokine release syndrome, DLBCL = diffuse large B-cell lymphoma, HDC = high-dose chemotherapy, HD-MTX = high-dose methotrexate, ICANS = immune effector cell-associated neurotoxicity syndrome, IVLBCL = intravascular large B-cell lymphoma, MRI = magnetic resonance imaging, R/R = relapsed/refractory, WBRT = whole brain radiotherapy.\n\nHow to cite this article: Yagi Y, Kanemasa Y, Ohigashi A, Morita Y, Tamura T, Nakamura S, Otsuka Y, Kishida Y, Kageyama A, Shimizuguchi T, Toya T, Shimizu H, Najima Y, Kobayashi T, Haraguchi K, Doki N, Okuyama Y, Omuro Y, Shimoyama T. Chimeric antigen receptor T-cell therapy following autologous transplantation for secondary central nervous system lymphoma: a case report. Medicine. 2021;100:44(e27733).\n\nThe authors have no funding and conflicts of interest to disclose.\n\nAll data generated or analyzed during this study are included in this published article [and its supplementary information files].\n==== Refs\nReferences\n\n[1] Neelapu SS Locke FL Bartlett NL . Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med 2017;377 :2531–44.29226797\n[2] Schuster SJ Bishop MR Tam CS . Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med 2019;380 :45–56.30501490\n[3] Yu WL Hua ZC . Chimeric antigen receptor T-cell (CAR T) therapy for hematologic and solid malignancies: efficacy and safety-a systematic review with meta-analysis. Cancers (Basel) 2019;11 :47 doi:10.3390/cancers11010047.\n[4] Abramson JS McGree B Noyes S . Anti-CD19 CAR T cells in CNS diffuse large-B-cell lymphoma. N Engl J Med 2017;377 :783–4.28834486\n[5] Frigault MJ Dietrich J Martinez-Lage M . Tisagenlecleucel CAR T-cell therapy in secondary CNS lymphoma. Blood 2019;134 :860–6.31320380\n[6] Tu S Zhou X Guo Z . CD19 and CD70 dual-target chimeric antigen receptor T-cell therapy for the treatment of relapsed and refractory primary central nervous system diffuse large B-cell lymphoma. Front Oncol 2019;9 :1350 doi: 10.3389/fonc.2019.01350.31867275\n[7] Hollender A Kvaloy S Nome O Skovlund E Lote K Holte H . Central nervous system involvement following diagnosis of non-Hodgkin's lymphoma: a risk model. Ann Oncol 2002;13 :1099–107.12176790\n[8] Kanemasa Y Shimoyama T Sasaki Y . Central nervous system relapse in patients with diffuse large B cell lymphoma: analysis of the risk factors and proposal of a new prognostic model. Ann Hematol 2016;95 :1661–9.27370993\n[9] Shimazu Y Notohara K Ueda Y . Diffuse large B-cell lymphoma with central nervous system relapse: prognosis and risk factors according to retrospective analysis from a single-center experience. Int J Hematol 2009;89 :577–83.19353238\n[10] Anghel G Petrinato G Severino A . Intravascular B-cell lymphoma: report of two cases with different clinical presentation but rapid central nervous system involvement. Leuk Lymphoma 2003;44 :1353–9.12952229\n[11] Imai H Kajimoto K Taniwaki M . Intravascular large B-cell lymphoma presenting with mass lesions in the central nervous system: a report of five cases. Pathol Int 2004;54 :231–6.15028023\n[12] Ohno T Sakamoto T Mizumoto C . Leukemic and meningeal relapse of CD5+ intravascular large B-cell lymphoma with down-modulation of CD20 after rituximab therapy. Int J Hematol 2006;84 :74–8.16867907\n[13] Shimada K Murase T Matsue K . Central nervous system involvement in intravascular large B-cell lymphoma: a retrospective analysis of 109 patients. Cancer Sci 2010;101 :1480–6.20412122\n[14] Schmitz N Zeynalova S Nickelsen M . CNS international prognostic index: a risk model for CNS relapse in patients with diffuse large B-cell lymphoma treated with R-CHOP. J Clin Oncol 2016;34 :3150–6.27382100\n[15] Abramson JS Hellmann M Barnes JA . Intravenous methotrexate as central nervous system (CNS) prophylaxis is associated with a low risk of CNS recurrence in high-risk patients with diffuse large B-cell lymphoma. Cancer 2010;116 :4283–90.20564149\n[16] Bromberg JE Doorduijn JK Illerhaus G . Central nervous system recurrence of systemic lymphoma in the era of stem cell transplantation--an International Primary Central Nervous System Lymphoma Study Group project. Haematologica 2013;98 :808–13.23144196\n[17] Lee MY Kim HS Lee JY . Efficacy and feasibility of autologous stem cell transplantation in patients with diffuse large B-cell lymphoma with secondary central nervous system involvement. Int J Hematol 2015;102 :678–88.26493833\n[18] Oh DH Chua N Street L Stewart DA . Treatment of patients with secondary central nervous system lymphoma with high-dose busulfan/thiotepa-based conditioning and autologous stem cell transplant. Leuk Lymphoma 2016;57 :28–33.25747968\n[19] Qualls D Sullivan A Li S . High-dose thiotepa, busulfan, cyclophosphamide, and autologous stem cell transplantation as upfront consolidation for systemic non-Hodgkin lymphoma with synchronous central nervous system involvement. Clin Lymphoma Myeloma Leuk 2017;17 :884–8.28870642\n[20] Welch MR Sauter CS Matasar MJ . Autologous stem cell transplant in recurrent or refractory primary or secondary central nervous system lymphoma using thiotepa, busulfan and cyclophosphamide. Leuk Lymphoma 2015;56 :361–7.24745937\n[21] Patil S Spencer A Schwarer A . Disease status at autologous stem cell transplantation and the cell of origin phenotype are important predictors of outcome in patients with neurologic (central nervous system) relapse of diffuse large B-cell lymphoma undergoing autologous stem cell transplantation. Leuk Lymphoma 2009;50 :1964–8.19860614\n[22] Ghafouri S Timmerman J Larson S Mead MD . Axicabtagene Ciloleucel CAR T-cell therapy for relapsed/refractory secondary CNS non-Hodgkin lymphoma: comparable outcomes and toxicities, but shorter remissions may warrant alternative consolidative strategies? Bone Marrow Transplant 2020;56 :974–7.33168933\n[23] Gust J Hay KA Hanafi LA . Endothelial activation and blood-brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T cells. Cancer Discov 2017;7 :1404–19.29025771\n[24] Freyer CW Porter DL . Cytokine release syndrome and neurotoxicity following CAR T-cell therapy for hematologic malignancies. J Allergy Clin Immunol 2020;146 :940–8.32771558\n[25] Rice J Nagle S Randall J Hinson HE . Chimeric antigen receptor T cell-related neurotoxicity: mechanisms, clinical presentation, and approach to treatment. Curr Treat Options Neurol 2019;21 :40 doi: 10.1007/s11940-019-0580-3.31327064\n[26] Wang J Hu Y Yang S . Role of fluorodeoxyglucose positron emission tomography/computed tomography in predicting the adverse effects of chimeric antigen receptor T cell therapy in patients with non-Hodgkin lymphoma. Biol Blood Marrow Transplant 2019;25 :1092–8.30769193\n[27] Locke FL Rossi JM Neelapu SS . Tumor burden, inflammation, and product attributes determine outcomes of axicabtagene ciloleucel in large B-cell lymphoma. Blood Adv 2020;4 :4898–911.33035333\n[28] Liu W Huang W Lv R . Anti-CD19 CAR T therapy following autologous HSCT may be safe and effective in patients with refractory large B-cell lymphoma. Blood 2019;134 : (Suppl 1) : 784–1784.\n[29] Sauter CS Senechal B Rivière I . CD19 CAR T cells following autologous transplantation in poor-risk relapsed and refractory B-cell non-Hodgkin lymphoma. Blood 2019;134 :626–35.31262783\n[30] Wang X Popplewell LL Wagner JR . Phase 1 studies of central memory-derived CD19 CAR T-cell therapy following autologous HSCT in patients with B-cell NHL. Blood 2016;127 :2980–90.27118452\n[31] Omuro A Taillandier L Chinot O . Primary CNS lymphoma in patients younger than 60: can whole-brain radiotherapy be deferred? J Neurooncol 2011;104 :323–30.21170569\n[32] Omuro AM Ben-Porat LS Panageas KS . Delayed neurotoxicity in primary central nervous system lymphoma. Arch Neurol 2005;62 :1595–600.16216945\n\n",
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"title": "Chimeric antigen receptor T-cell therapy following autologous transplantation for secondary central nervous system lymphoma: A case report.",
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"abstract": "A previously healthy 11-month-old infant presented to the emergency department in status epilepticus. There was no clear trigger of her seizure activity which resolved with benzodiazepines and fosphenytoin. On further review, her parents disclosed that she had been prescribed topical 4% lidocaine cream for a groin rash and was ultimately diagnosed with lidocaine toxicity in the emergency department. She was monitored in the intensive care unit without cardiovascular abnormalities or recurrence of seizure activity. Emergency medicine providers must maintain a broader differential of status epileptics and be able to recognise and manage potential complications from systemic lidocaine toxicity.",
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"title": "Infant with status epilepticus secondary to systemic lidocaine toxicity from topical application.",
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"abstract": "Cryptococcal infections are classically associated to HIV/AIDS patients without therapy, but its presence among other immunosuppressed patients is less recognized. We report 3 lethal cases in non HIV-patients. Two of them presented with meningitis associated to renal transplant or corticosteroid use and, the third, with a necrotic skin infection in the context of progressive liver cirrhosis. In the former two patients, meningeal infection was suspected late, and in the latter, the diagnosis was established postmortem. Cryptococcal infections in non-HIV immunosupressed patients can affect different sites, are suspected late and have a high case-fatality ratio.",
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"title": "Cryptococcal infections in non-HIV infected patients: a new clinical problem in Chile.",
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"abstract": "Targeted kinase inhibitors and camptothecins have shown preclinical and clinical activity in several cancers. This trial evaluated the maximum tolerated dose (MTD) and dose-limiting toxicities of sorafenib and topotecan administered orally in pediatric patients with relapsed solid tumors. Sorafenib was administered twice daily and topotecan once daily on days 1-5 and 8-12 of each 28-day course. The study utilized a standard 3 + 3 dose escalation design. Three dose levels (DL) were evaluated: (1) sorafenib 150 mg/m(2) and topotecan 1 mg/m(2) ; (2) sorafenib 150 mg/m(2) and topotecan 1.4 mg/m(2) ; and (3) sorafenib 200 mg/m(2) and topotecan 1.4 mg/m(2) . Pharmacokinetics were ascertained and treatment response assessed. Thirteen patients were enrolled. DL2 was the determined MTD. Grade 4 thrombocytopenia delaying therapy for >7 days was observed in one of six patients on DL2, and grade 4 neutropenia that delayed therapy in two of three patients on DL3. A patient with preexisting cardiac failure controlled with medication developed a transient drop in the left ventricular ejection fraction that improved when sorafenib was withheld. Sorafenib exposure with or without topotecan was comparable, and the concentration-time profiles for topotecan alone and in combination with sorafenib were similar. One objective response was noted in a patient with fibromatosis. We determined MTD to be sorafenib 150 mg/m(2) twice daily orally on days 1-28 combined with topotecan 1.4 mg/m(2) once daily on days 1-5 and 8-12. While these doses are 1 DL below the MTD of the agents individually, pharmacokinetic studies suggested adequate drug exposure without drug interactions. The combination had limited activity in the population studied.",
"affiliations": "Sarcoma Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.;Division of Hematology, Oncology, Blood and Marrow Transplantation, Department of Pediatrics, Children's Hospital of Los Angeles and Keck School of Medicine, University of Southern California, Los Angeles, California.;Sarcoma Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.;All Children's Hospital, Johns Hopkins Medicine, St. Petersburg, Florida.;University of Miami, Miami, Florida.;Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, New York.;Nemours Children's Cancer Center, Jacksonville, Florida.;Connecticut Children's Medical Center, Hartford, Connecticut.;Sarcoma Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.;Department of Diagnostic Imaging, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.;Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.;Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.;Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.;Translational Research Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.;Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.",
"authors": "Reed|Damon R|DR|http://orcid.org/0000-0002-8238-2465;Mascarenhas|Leo|L|;Manning|Kathleen|K|;Hale|Gregory A|GA|;Goldberg|John|J|;Gill|Jonathan|J|;Sandler|Eric|E|;Isakoff|Michael S|MS|;Smith|Tiffany|T|;Caracciolo|Jamie|J|;Lush|Richard M|RM|;Juan|Tzu-Hua|TH|;Lee|Jae K|JK|;Neuger|Anthony M|AM|;Sullivan|Daniel M|DM|",
"chemical_list": "D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D000077157:Sorafenib",
"country": "United States",
"delete": false,
"doi": "10.1002/cam4.598",
"fulltext": "\n==== Front\nCancer MedCancer Med10.1002/(ISSN)2045-7634CAM4Cancer Medicine2045-7634John Wiley and Sons Inc. Hoboken 10.1002/cam4.598CAM4598Original ResearchClinical Cancer ResearchOriginal ResearchPediatric phase I trial of oral sorafenib and topotecan in refractory or recurrent pediatric solid malignancies Reed Damon R. http://orcid.org/0000-0002-8238-2465\n1\n\n2\n\n3\n\n5\nMascarenhas Leo \n4\nManning Kathleen \n1\nHale Gregory A. \n5\nGoldberg John \n6\nGill Jonathan \n7\nSandler Eric \n8\nIsakoff Michael S. \n9\nSmith Tiffany \n1\nCaracciolo Jamie \n10\nLush Richard M. \n2\nJuan Tzu‐Hua \n11\nLee Jae K. \n2\n\n11\nNeuger Anthony M. \n12\nSullivan Daniel M. \n2\n\n13\n1 Sarcoma DepartmentH. Lee Moffitt Cancer Center and Research InstituteTampaFlorida2 Chemical Biology and Molecular Medicine ProgramH. Lee Moffitt Cancer Center and Research InstituteTampaFlorida3 Adolescent and Young Adult ProgramH. Lee Moffitt Cancer Center and Research InstituteTampaFlorida4 Division of Hematology, Oncology, Blood and Marrow TransplantationDepartment of Pediatrics, Children's Hospital of Los Angeles and Keck School of MedicineUniversity of Southern CaliforniaLos AngelesCalifornia5 All Children's HospitalJohns Hopkins MedicineSt. PetersburgFlorida6 University of MiamiMiamiFlorida7 Children's Hospital at MontefioreAlbert Einstein College of MedicineBronxNew York8 Nemours Children's Cancer CenterJacksonvilleFlorida9 Connecticut Children's Medical CenterHartfordConnecticut10 Department of Diagnostic ImagingH. Lee Moffitt Cancer Center and Research InstituteTampaFlorida11 Department of Biostatistics and BioinformaticsH. Lee Moffitt Cancer Center and Research InstituteTampaFlorida12 Translational Research CoreH. Lee Moffitt Cancer Center and Research InstituteTampaFlorida13 Department of Blood and Marrow TransplantationH. Lee Moffitt Cancer Center and Research InstituteTampaFlorida* Correspondence\n\nDamon Reed, Chemical Biology and Molecular Medicine Program, Adolescent and Young Adult Oncology Program and Sarcoma Department, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, Florida 33612. Tel: 813‐745‐3242, Fax: 813‐745‐8337, E‐mail: damon.reed@moffitt.org\n29 12 2015 2 2016 5 2 10.1002/cam4.2016.5.issue-2294 303 20 8 2015 02 11 2015 05 11 2015 © 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nTargeted kinase inhibitors and camptothecins have shown preclinical and clinical activity in several cancers. This trial evaluated the maximum tolerated dose (MTD) and dose‐limiting toxicities of sorafenib and topotecan administered orally in pediatric patients with relapsed solid tumors. Sorafenib was administered twice daily and topotecan once daily on days 1–5 and 8–12 of each 28‐day course. The study utilized a standard 3 + 3 dose escalation design. Three dose levels (DL) were evaluated: (1) sorafenib 150 mg/m2 and topotecan 1 mg/m2; (2) sorafenib 150 mg/m2 and topotecan 1.4 mg/m2; and (3) sorafenib 200 mg/m2 and topotecan 1.4 mg/m2. Pharmacokinetics were ascertained and treatment response assessed. Thirteen patients were enrolled. DL2 was the determined MTD. Grade 4 thrombocytopenia delaying therapy for >7 days was observed in one of six patients on DL2, and grade 4 neutropenia that delayed therapy in two of three patients on DL3. A patient with preexisting cardiac failure controlled with medication developed a transient drop in the left ventricular ejection fraction that improved when sorafenib was withheld. Sorafenib exposure with or without topotecan was comparable, and the concentration‐time profiles for topotecan alone and in combination with sorafenib were similar. One objective response was noted in a patient with fibromatosis. We determined MTD to be sorafenib 150 mg/m2 twice daily orally on days 1–28 combined with topotecan 1.4 mg/m2 once daily on days 1–5 and 8–12. While these doses are 1 DL below the MTD of the agents individually, pharmacokinetic studies suggested adequate drug exposure without drug interactions. The combination had limited activity in the population studied.\n\nCombinationpediatric cancerphase IsarcomasorafenibtopotecanPediatric Cancer FoundationTranslational Research Core at the H. Lee Moffitt Cancer Center & Research InstituteP30‐CA076292 source-schema-version-number2.0component-idcam4598cover-dateFebruary 2016details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:4.7.6 mode:remove_FC converted:02.02.2016\n\nCancer Medicine \n2016 ; 5 (2 ): 294 –303\n==== Body\nIntroduction\nAlthough outcomes for pediatric cancer patients have steadily improved with the introduction of systemic chemotherapy and through carefully conducted clinical trials in the 1960s through 1990s, cure rates for advanced‐stage, solid tumors have unfortunately plateaued over the past decade. Many single‐agent phase I trials have demonstrated safety and defined a dose for further study in pediatrics, but incorporating these agents in front‐line protocols has often remained a challenge 1. Osteosarcoma, Ewing sarcoma, neuroblastoma, rhabdomyosarcoma, and Wilms tumor are treated with combinations of 2–10 chemotherapeutic agents in the front‐line setting 2, 3, 4, 5. We had previously explored emerging targeted therapies along with selected cytotoxic agents across 2 osteosarcoma, 2 Ewing sarcoma, and a single rhabdoid tumor cell line to help develop early‐phase clinical trials 6. Among the combinations with additive or synergistic effects were topotecan and sorafenib.\n\nSorafenib, a broad multikinase inhibitor affecting the serine/threonine kinases c‐Raf and B‐Raf and the receptor tyrosine kinases RET, Flt‐3, and c‐Kit at nanomolar concentrations 7, has demonstrated efficacy in pediatric preclinical cell models with a median IC50 of 4.3 μmol/L 8 and has been studied in hundreds of clinical trials 9. Sorafenib is currently approved by the Food and Drug Administration for hepatocellular carcinoma, renal cell carcinoma, and dedifferentiated thyroid cancer. Pediatric investigations of sorafenib alone and in combination have been reported since the current trial's inception, including combination trials in leukemia and solid tumors, which demonstrated tolerability and promising activity 10, 11. In a phase I single‐agent pediatric trial, sorafenib demonstrated good tolerability with doses similar to adult dosing by body‐surface area and dose‐limiting toxicities (DLTs) of rash and hypertension 12. Sorafenib has been studied in plexiform neurofibromas without clear efficacy and induced a response in a ventilation‐dependent patient with papillary thyroid cancer, leading to maintained disease remission after further therapy 13, 14.\n\nTopotecan has established efficacy as a single agent and in combination in a variety of pediatric malignancies, including germ cell tumors, Wilms tumor, neuroblastoma, acute lymphoblastic leukemia, central nervous system malignancies, and sarcomas 15, 16, 17, 18, 19, 20, 21, 22, 23. Topotecan is currently being investigated in a randomized phase III Ewing sarcoma trial (NCT01231906) and as part of standard induction therapy for higher‐risk neuroblastoma patients. Topotecan is also commonly used alone and in combination with other cytotoxic chemotherapies such as cyclophosphamide for a broad spectrum of malignancies 23, 24. Recently, topotecan was combined with targeted agents in ovarian cancer, although with toxicity limiting maximal therapy delivery and modest activity 25. The broad potential and anecdotal reported activities of both agents in a variety of pediatric malignancies, together with our preclinical data in sarcoma cell lines, provided the rationale to investigate this combination in a clinical trial.\n\nOur primary objective was to establish the maximum tolerated dose (MTD) for this combination. We started based on previously tested dose levels (DLs) at 2 levels below the topotecan MTD and 1 DL below the sorafenib single agent MTD. Secondary objectives were to describe toxicities, characterize pharmacokinetics (PK) of topotecan and sorafenib, apply Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 to measure response after even‐numbered cycles, and determine time to progression (TTP) for all patients and compare TTP on study and TTP on previous regimen. Additionally, all therapy was delivered orally, allowing for minimal time spent in clinics and hospitals.\n\nMethods\nThe sunshine project consortium\nThe Sunshine Project is multi‐institutional consortium funded by The Pediatric Cancer Foundation, with Moffitt Cancer Center as the coordinating center responsible for statistics, initial scientific review and Institutional Review Board approval, and regulatory aspects of the trial. Patients were enrolled at member sites only with 6 sites enrolling patients.\n\nPatient eligibility\nPatients aged 3–18 years with relapsed or refractory solid tumor malignancies; including central nervous system malignancies and fibromatosis and previously treated with chemotherapy were eligible. Patients needed to have radiologic evidence of disease and were preferred, but not required, to have measurable disease using RECIST 1.1, a life expectancy of at least 12 weeks, no known curative therapy, a Karnofsky or Lansky score ≥50, recovered from prior therapy, no previous sorafenib therapy, >6 months since prior topotecan, >3 weeks since last myelosuppressive therapy, >7 days since filgrastim and >14 days since pegfilgrastim, >21 days or 4 half‐lives (whichever is greater) since biologic agent, ≥4 weeks since completion of local palliative irradiation, ≥3 months from prior Total Body Irradiation, craniospinal irradiation, or ≥50 Gy radiation of pelvis, ≥6 weeks for substantial bone marrow radiation, ≥3 months since Stem Cell Transplant and no evidence of active graft versus host disease along with transfusion and growth factor independence, adequate bone marrow function (absolute neutrophil count ≥1500/μL, platelet count ≥100,000/μL, and hemoglobin ≥10 gm/dL), normal serum creatinine for age or a glomerular filtration rate ≥60 mL/min/1.73 m2, bilirubin ≤ upper limit of normal (ULN), alanine transaminase ≤ULN, and all clinically significant chemistries grade 1 or less with the exclusion of alkaline phosphatase, uric acid, aspartate transaminase, and lactate dehydrogenase, prothrombin time and partial thromboplastin time ≤1.5 X ULN, 12‐lead electrocardiogram with corrected QTc <450 msec, either shortening fraction ≥28% or left ventricular ejection fraction ≥50%, systolic and diastolic blood pressure ≤95% for age and gender (antihypertensive management allowed), no ongoing cardiac dysrhythmias ≥grade 2, atrial fibrillation of any grade, unstable angina, symptomatic congestive heart failure, or myocardial infarction, resting pulse oximetry of ≥92% and no dyspnea at rest. Patients with known bone marrow metastatic disease were eligible but could not be refractory to red blood cell or platelet transfusion. Women who were pregnant or lactating, patients with nonhealing wounds/ulcers or bone fractures, and patients with a history of organ allograft were excluded. The Internal Review Board for each participating institution approved the protocol, and written informed consent and assent were obtained according to local institutional guidelines.\n\nDrug administration\nThe starting dose of sorafenib was 150 mg/m2 twice daily on DLs 1 and 2 on days 1–28, except in cycle 1 when it was given on days 2–28. Dose escalation for sorafenib occurred at DL 3 to the maximum planned dose of 200 mg/m2 (Table 1). Intra‐patient dose escalation was not allowed on this study. Sorafenib was supplied by Bayer Pharmaceuticals (Bayer HealthCare Pharmaceuticals, Wayne, NJ) as 50 mg tablets. Total daily dose for patients was rounded to the nearest 50 mg tablet size based on patient BSA (a dosing nomogram was used to minimize inter‐patient dosing variability). Patients ingested tablets with clear liquids (2–4 ounces for children <12 and 4 ounces for ≥12 years) and while dispersion in liquid was allowed, all patients swallowed tablets.\n\nTable 1 Dose escalation schema and dose‐limiting toxicities\n\nDose level\tNumber of patients entered\tNumber of evaluable patients\tNumber of patients with dose‐limiting toxicity\tType of toxicity (n)\t\nTopotecan 1.0 mg/m2 per day + Sorafenib 150 mg/m2 per twice daily\t3\t3\t0\tNA\t\nTopotecan 1.4 mg/m2 per day + Sorafenib 150 mg/m2 per twice daily\t6\t6\t1\tPlatelet count decreased (1)\t\nTopotecan 1.4 mg/m2 per day + Sorafenib 200 mg/m2 per twice daily\t3\t3\t2\tNeutrophil count decreased (2)\t\nJohn Wiley & Sons, LtdThe starting dose of topotecan at DL 1 was 1.0 mg/m2 on days 1–5 and 8–12 of each cycle. Dose escalation for topotecan started with DL 2–1.4 mg/m2 and continued on DL 3 (Table 1). Topotecan was commercially available from multiple suppliers in either a capsule (0.25 mg or 1 mg) form or reconstituted liquid formulation, with dose rounding to the nearest 0.25 mg. The capsules could not be chewed, crushed, or divided and were swallowed whole. The reconstituted liquid formation of topotecan was supplied as a lyophilized, light‐yellow powder in vials containing 4 mg of topotecan (as the base), which were reconstituted with 4 mL bacteriostatic water yielding 1 mg/mL solution of topotecan. Vials were dispensed in light protective bags and kept refrigerated. The reconstituted formulation was drawn up in oral syringes to the prescribed volume and administered to the patient immediately after reconstitution. The process was observed by the clinic staff on day 1 of the first cycle and then allowed unsupervised once the family demonstrated a clear understanding of the dosing. Eight ounces of water were used to rinse and swallow after the topotecan was administered.\n\nStudy design\nThis dose‐escalation study used a standard 3 + 3 design, with up to six patients being enrolled on a DL. Enrollment to subsequent DLs was determined by the number of enrolled patients, the number with DLTs, and the number at risk for DLTs.\n\nToxicity was graded according to the Common Terminology Criteria for Adverse Events version 4.0 (http://ctep.cancer.gov). Hematologic DLTs were defined during cycle 1 only as grade 4 thrombocytopenia (platelet count <25,000/μL) or grade 4 neutropenia (<500/μL) lasting >7 days that was attributable to sorafenib or topotecan. Non‐hematologic DLTs were defined as any grade 4 nonhematological toxicity or grade 3 nonhematological toxicity with the following exceptions: grade 3 nausea/vomiting of <5 consecutive days with appropriate anti‐emetic therapy, grade 3 transaminase levels that returned to baseline levels within 7 days of study drug cessation, grade 3 fever/infection lasting <7 days, grade 3 hypocalcemia, hypokalemia, hypophosphatemia, and/or hypomagnesemia unresponsive to oral supplementation (defined as return to ≤grade 1), and asymptomatic chemical pancreatitis with elevations of amylase or lipase that returned to ≤grade 1 before meeting off‐study criteria. Non‐hematologic DLTs were also defined as any adverse event considered intolerable by the patient/family and requiring treatment interruption >14 days and any adverse event requiring interruption of study drug for >7 days and that recurred upon drug reintroduction. Dose‐limiting hypertension was defined as systolic or diastolic blood pressure >25 mmHg above the 95th percentile for age, height, and gender confirmed by repeated measurement for >14 consecutive days, as well as any grade 4 hypertension. The MTD was the DL immediately below the DL at which 2 or more patients in a DL experienced a DLT.\n\nTreatment response was assessed per RECIST 1.1. Central review occurred at the end of study, but decisions regarding patient therapy were made in real time by treating physicians.\n\nPatients were evaluated within 28 days before the start of study, at the completion of cycle 2, and at the end of each even‐numbered cycle if presenting with stable disease or better.\n\nPharmacokinetic studies\nSample collection\nBlood samples for sorafenib PK studies were collected on cycle 1, day 28 and cycle 2, day 1 at hours 0 (pre‐dose) and 1, 3, 5, and 8 h following the first dose of sorafenib, centrifuged at 1250g for 5 min, and frozen at −20°C until analysis. Blood samples for topotecan PK were collected on cycle 1, day 1 and cycle 2, day 1 at hours 0 (pre‐dose) and 1, 3, 5, and 8 h post‐dose and centrifuged at 1250g for 4 min. Exactly 400 μL of the upper plasma layer was transferred into prelabeled cryovials, with one set containing reagents specific for assaying for total topotecan and another for assaying for lactone topotecan, and frozen at −20°C until analysis.\n\nAnalytical methodology\nA liquid chromatography‐tandem mass spectrometry method validated under ICH/Food and Drug Administration guidelines was used to determine levels of sorafenib and was adapted from a previously published method 26. Plasma samples were analyzed by protein precipitation. Calibration curves, linear from 5 to 2500 ng/mL with an R\n2 of >0.99, were generated for each run, with patient sample concentrations back‐calculated from the corresponding regression line.\n\nTopotecan was measured by high‐performance liquid chromatography with fluorescence detection 27, validated under the same guidance, after protein precipitation, as previously described. The calibration curve was linear from 0.125 to 50 ng/mL, with the regression meeting acceptable criteria, with patient samples calculated as described above.\n\nPharmacokinetic analysis\nPlasma concentration‐time data for both drugs were analyzed by noncompartmental methods using Phoenix WinNonlin 6.3 (Pharsight Corp., Mountain View, CA). The following steady‐state characteristics for sorafenib were determined: AUC0‐8 h, C\nmax, T\nmax, C\nmin, T\nmin, and C\navg. For topotecan, when available, half‐life was determined along with AUC0‐inf, C\nmax, T\nmax, clearance, and volume of distribution.\n\nResults\nThirteen patients were enrolled between October 2013 and December 2014 across six sites. One patient withdrew consent before starting therapy, with the remaining 12 patients evaluable for toxicity. Patients had a median of two prior lines of therapy with a range of 1–4 prior lines of therapy (Table 2).\n\nTable 2 Characteristics of evaluable patients (n = 12)\n\n\tNumber (%)\t\nAge, median (range)\t13 years (8–18 years)\t\nSex\t\nMale\t8 (66.7)\t\nFemale\t4 (33.3)\t\nDiagnosis\t\nEmbryonal rhabdomyosarcoma\t1 (8.3)\t\nEwing sarcoma\t3 (25)\t\nFibromatosis\t2 (16.7)\t\nNeuroblastoma\t1 (8.3)\t\nNeuroendocrine carcinoma\t1 (8.3)\t\nOsteosarcoma\t4 (33.3)\t\nPrior therapy\t\nChemotherapy regimens, median (range)\t2 (1–4)\t\nRadiotherapy (number of patients)\t7\t\nBone marrow transplant (number of patients)\t2\t\nRace\t\nWhite\t7 (58.3)\t\nAsian\t0 (0)\t\nAmerican Indian or Alaska Native\t0 (0)\t\nBlack or African American\t2 (16.7)\t\nUnknown\t3 (25)\t\nEthnicity\t\nNon‐Hispanic\t7 (58.3)\t\nHispanic\t5 (41.7)\t\nJohn Wiley & Sons, LtdToxicity\nThree DLs were evaluated without a need for de‐escalation (Table 1). There were no deaths related to toxicity. DLTs were hematologic, including thrombocytopenia and neutropenia of defined duration over 7 days (Table 1). The MTD was reached at DL 2 with 2 of 3 patients experiencing DLTs at DL 3. Table 3 shows additional toxicities of at least grade 3 and possibly attributed to either sorafenib or topotecan and the maximal grade across all cycles for an individual patient is listed once. An osteosarcoma patient had a change in cardiac function that occurred during cycle 2, which was thus not considered a DLT. This patient had prior doxorubicin therapy to a cumulative dose of 450 mg/m2 and was on digoxin and lisinopril with the study entry ejection fraction meeting criteria for inclusion at 50.6% by echocardiogram. Due to poor cardiac medication compliance, it dropped to 37% during cycle 1 and rebounded to over 50% when digoxin and lisinopril were restarted. Sorafenib was also withheld during this time. When sorafenib was restarted during cycle 2, the ejection fraction again fell to grade 3 and the investigator, after consulting with cardiology, felt that the risk of continuing therapy outweighed the potential benefit and patient was taken off study. A single patient experienced grade 2 radiation recall, attributed to either topotecan or sorafenib and responded to topical therapy and withholding sorafenib and/or topotecan for 7 days during all cycles. During some of the cycles, the radiation recall occurred in mid‐cycle, requiring holding just sorafenib; in the other cycles, the radiation recall occurred at the end of the cycle, requiring delay in initiating the next cycle by 7 days 28. Severe treatment‐related adverse events included 3 instances of febrile neutropenia admissions and 2 admissions for blood product transfusion when outpatient facilities were not available.\n\nTable 3 Toxicities (grade 3 or greater) observed in evaluable patients and attributed to at least possibly related to sorafenib or topotecan\n\nToxicity type\tGrade 3\tDose level (n)\tGrade 4\tDose level (n)\t\nAlanine aminotransferase increased\t2\t2, 3\t0\t\t\nAnemia\t5\t1, 2(4)\t0\t\t\nEjection fraction decreased\t1\t1\t0\t\t\nFebrile neutropenia\t3\t2, 3(2)\t0\t\t\nHypertension\t1\t3\t0\t\t\nHypokalemia\t1\t2\t0\t\t\nNausea\t1\t2\t0\t\t\nNeutrophil count decreased\t3\t1, 2, 3\t7\t1, 2(4), 3(2)\t\nPlatelet count decreased\t1\t2\t10\t1(2), 2(5), 3(3)\t\nRadiation recall reaction (dermatologic)\t1\t3\t0\t\t\nVomiting\t1\t2\t0\t\t\nWeight loss\t1\t1\t0\t\t\nJohn Wiley & Sons, LtdResponses\nTwo patients with DLTs came off study before completing cycle 2, and both had clinical progression during the follow‐up period. Two patients had bone‐only disease and thus were not evaluable by RECIST 1.1, and another patient came off study before the first disease evaluation during cycle 2 due to physician choice. Thus, seven patients were evaluable for disease response. Of the 7 patients who could be evaluated for RECIST 1.1 response, 1 patient with fibromatosis showed radiologic partial response; this patient continues on the 8th cycle of therapy as of the data cut‐off. The other 6 patients with evaluable disease received 1–4 cycles of therapy with 5 of them receiving 2 cycles and with progressive disease at this first evaluation. The 2 patients with bone‐only disease had Ewing sarcoma and received 1 and 4 cycles before progression. TTP ranged from 11 to 111 days on study in the nonresponders (Table S1). Refractory disease, defined as <3 months between completion of prior therapy and enrollment was present in 6 of 7 evaluable patients. In the 7 evaluable patients, only the patient with fibromatosis had a TTP that was longer than the prior regimen.\n\nPharmacokinetics\nNine patients were evaluable for sorafenib PK on cycle 1, day 28 and 7 patients on cycle 2, day 1. As shown in Table 4, steady‐state kinetics varied widely for both groups, independent of dose or in combination with topotecan. Overall, when AUC is dose normalized, there are comparable amounts of exposure to sorafenib with and without exposure to topotecan (Fig. 1A).\n\nTable 4 Sorafenib and topotecan pharmacokinetic parameter estimates\n\n\tSorafenib\t\n\t\nT\nmax (h)\t\nC\nmax (μg/mL)\t\nT\nmin (h)\t\nC\nmin (μg/mL)\t\nC\navg (μg/mL)\tAUC(0‐8 h) (h × μg/mL)\t\nCycle 1, day 28, 150 mg/m2 (n = 8)\t4.0 ± 3.3\t6.8 ± 3.5\t4.6 ± 3.4\t2.9 ± 2.5\t5.4 ± 2.6\t43.1 ± 21.0\t\nCycle 2, day 1, 150 mg/m2 (n = 6)\t3.3 ± 2.9\t6.4 ± 5.4\t4.3 ± 2.7\t3.1 ± 2.8\t4.5 ± 3.8\t36.3 ± 30.2\t\nCycle 1, day 28, 200 mg/m2 (n = 1)\t3\t12.2\t8\t4.9\t7.6\t61.2\t\nCycle 2, day 1, 200 mg/m2 (n = 1)\t1\t14.4\t5\t6.7\t9.8\t78.4\t\n\tTotal topotecan\t\n\t\nT\nmax (h)\t\nC\nmax (μg/mL)\t\nT\nmin (h)\t\nC\nmin (μg/mL)\t\nC\navg (μg/mL)\tAUC(0‐8 h) (h × μg/mL)\t\nCycle 1 Day 1 – 1.0 mg/m2 (n = 3)\t5.3 (±3.7)\t2.4 (±1.2)\t4.7 (±1.1)\t50.3 (±38.0)\t214.5 (±42.2)\t35.9 (±17.7)\t\nCycle 2 Day 1 – 1.0 mg/m2 (n = 3)\t3.5 (±0.4)\t3.0 (±0.0)\t9.2 (±3.6)\t64.6 (±13.0)\t106.0 (±21.0)\t20.9 (±1.7)\t\nCycle 1 Day 1 – 1.4 mg/m2 (n = 9)\t2.6 (±0.6)\t2.3 (±1.0)\t5.7 (±2.1)\t30.6 (±9.3)\t291.2 (±164.9)\t75.7 (±29.8)\t\nCycle 2 Day 1 – 1.4 mg/m2 (n = 5)\t3.0 (±0.6)\t2.6 (±1.7)\t11.6 (±7.2)\t75.5 (±45.0)\t152.7 (±87.1)\t33.6 (±14.3)\t\n\tLactone\t\n\t\nt\n1/2 (h)\t\nT\nmax (h)\t\nC\nmax (ng/mL)\tAUC(0‐INF) (h × ng/mL)\tVolume of distribution (L)\tClearance (L/h)\t\nCycle 1, day 1, 1.0 mg/m2 (n = 3)\t4.8 ± 4.4\t1.7 ± 1.2\t0.6 ± 0.1\t5.8 ± 5.1\t1564.8 ± 211.5\t341.4 ± 186.5\t\nCycle 2, day 1, 1.0 mg/m2 (n = 3)\t3.5 ± 1.1\t1.7 ± 1.2\t1.6 ± 1.1\t10.2 ± 8.0\t951.3 ± 731.7\t195.6 ± 129.0\t\nCycle 1, day 1, 1.4 mg/m2 (n = 9)\t3.1 ± 1.4\t2.3 ± 1.4\t2.8 ± 1.6\t14.5 ± 7.5\t834.3 ± 533.4\t199.4 ± 133.1\t\nCycle 2, day 1, 1.4 mg/m2 (n = 5)\t2.0 ± 0.6\t2.6 ± 1.7\t6.5 ± 4.9\t32.7 ± 15.1\t195.2 ± 53.5\t72.6 ± 23.6\t\nFor sorafenib data, 9 patients were evaluable for pharmacokinetic parameter estimate determination on cycle 1, day 28 and only 7 on cycle 2, day 1. For topotecan data, 2 patients on cycle 2, day 1 were nonevaluable for t\n1/2, AUC, volume of distribution, and clearance. Additionally, 4 patients did not reach cycle 2, day 1 and therefore were nonevaluable for determining all pharmacokinetic parameter estimates.\n\nJohn Wiley & Sons, LtdFigure 1 (A) Dose‐normalized sorafenib area under the curve across all dose levels (DLs) on cycle1, day 28 (administered alone) and cycle 2, day 1 (administered with topotecan). (B) Cycle 1, day 1 topotecan mean concentration (±SD) versus time by DL given without sorafenib. (C) cycle 2, day 1 topotecan mean concentration (±SD) versus time by DL, administered while sorafenib at steady state.\n\nFor topotecan, we evaluated 12 patients on cycle 1, day 1 and 8 patients who remained on study through cycle 2, day 1 for PK studies. The concentration‐time profiles for topotecan when dosed alone and then in combination with sorafenib were very similar (Fig. 1B and C and Table 4). We also examined PK interactions between the 2 agents to determine whether there was any increase or decrease in exposure to the substrate in the presence of the interacting drug. We assessed such interactions by AUC with its 90% confidence intervals, compared to those of their reported single agent PK values 12, 28. The 90% confidence intervals for the geometric mean ratio of the AUC for both topotecan and sorafenib throughout this study were significantly higher or at least equivalent to those of each of the two agents when given alone previously.\n\nDiscussion\nWe describe the toxicity and a recommended phase 2 dose of a combination of a tyrosine kinase inhibitor and a topoisomerase I inhibitor delivered orally in children. Overall, the sorafenib and topotecan combination was tolerated with sorafenib dosed continuously at 150 mg/m2 by mouth twice per day and topotecan 1.4 mg/m2 by mouth daily. Both of these doses are 1 level below the single‐agent recommended phase II dose from prior studies 12, 28.\n\nAlthough there were no unexpected side effects, we were not able to deliver either the maximum single‐agent dose for either agent, mainly due to hematologic toxicity, which precluded further dose escalation. This finding is similar to an adult ovarian tumor study 25. However, in an irinotecan and sorafenib study in metastatic colorectal carcinoma, promising clinical activity was shown with the combination even though neither medication could be delivered at the maximum single‐agent dose 29. A trial in leukemia patients concluded that sorafenib combination therapy was tolerable with efficacy when combined with nucleoside analogs 11. A goal of our trial, with oral dosing, was to keep patients at home; however, we had 3 patients admitted to the hospital for fever and neutropenia. Additionally, angiogenesis targeting tyrosine kinase inhibitors in pediatric patients with pre‐existing cardiomyopathy is challenging. Careful consideration of inclusion and exclusion criteria should be made for patients at high risk for or with known cardiomyopathy or patients on cardiac medications.\n\nWe were able to assess the majority of patients for PK. The most common reason to not have matching sets of PK parameter estimates was due to sorafenib drug interruption toward the end of cycle 1 largely due to hematologic toxicity. Our PK findings indicate large inter‐patient variability for sorafenib when dosed alone or in combination with topotecan, as shown in other studies 12, 28. Our PK results for sorafenib when used in combination were similar to a previous sorafenib single‐agent phase I study 12. For topotecan, PK profiles determined in the presence of and in the absence of sorafenib indicated no apparent drug–drug interaction. Because all outside imaging examinations were reviewed centrally, we achieved 100% concordance of determination of response per RECIST 1.1.\n\nAlthough our study patients had a diversity of diagnoses, most had advanced sarcomas. Most patients entered this trial within 2 months of their most recent chemotherapy, suggesting progressive disease through the previous treatment regimen. This combination was not particularly effective in this context of chemotherapy refractory disease. In particular, in our small set of osteosarcoma patients, the activity was inferior to the recently reported sorafenib and everolimus study conducted in unresectable osteosarcoma patients 30. The therapy did offer the benefit of completely oral administration and was well tolerated.\n\nThe 2 fibromatosis patients on our trial both had been heavily pretreated and had potentially life‐threatening disease with further progression. Phase I therapy for fibromatosis has led to a promising therapy currently being evaluated in the phase II setting with PF‐03084014 31. Additionally, a single‐institution study reported promising activity of single‐agent sorafenib in fibromatosis, which provided the basis for an ongoing phase III study (NCT02066181) 32. Others have proposed that tolerability and acceptable toxicity for benign conditions be reconsidered for sorafenib 14. We report an ongoing response in a single patient and another patient with stable disease followed by radiographic progression after cycle 4.\n\nThe concept of combining tyrosine kinase inhibition with a topoisomerase inhibitor, or in more general terms targeted therapy along with cytotoxic chemotherapy, continues to be an attractive model and would likely be improved by matching to populations likely to benefit from both therapies. A more focused histology‐specific or biomarker‐specific approach could be coupled to trials to improve efficacy. A recently published model of cancer predicted more durable responses to targeted therapy when combined with a more broad inhibitor of cellular proliferation 33.\n\nBased on the lack of a clinical signal in our study population, future development for sorafenib and topotecan may be limited unless basic and translational research yield additional insight to study the combination in a particular histology. Sorafenib has not demonstrated enough single‐agent activity in pediatric tumors or sarcomas in general and will likely need to be combined with other therapies to extend its indications 34, 35, 36. Biomarkers, or matching increasingly available mutational panels, could potentially improve patient selection for future trials with these agents. Subcellular localization of topoisomerase could also be used to predict topotecan resistance. Based on the achievable serum levels and the associated toxicities, it is unlikely that this combination at the MTD could be combined with additional hematologic toxic agents going forward.\n\nConflict of Interest\nNone declared.\n\nSupporting information\n\nTable S1. Time to progression (TTP) on study and TTP on prior therapy for all enrolled patients.\n\nClick here for additional data file.\n\n Acknowledgments\nThis study was generously supported by the Pediatric Cancer Foundation (www.fastercure.org). We thank the patients, families, and staff at our institutions who helped with all aspects of trial conduct. This work has been supported in part by the Translational Research Core at the H. Lee Moffitt Cancer Center & Research Institute, an NCI‐designated Comprehensive Cancer Center (P30‐CA076292). The authors thank Rasa Hamilton (Moffitt Cancer Center) for her editorial review.\n==== Refs\nReferences\n1 \n\nJaneway , K. A. \n, \nA. E. \nPlace \n, \nM. W. \nKieran \n, and \nM. H. 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"fulltext_license": "CC BY",
"issn_linking": "2045-7634",
"issue": "5(2)",
"journal": "Cancer medicine",
"keywords": "Combination; pediatric cancer; phase I; sarcoma; sorafenib; topotecan",
"medline_ta": "Cancer Med",
"mesh_terms": "D000284:Administration, Oral; D000293:Adolescent; D000970:Antineoplastic Agents; D002648:Child; D004334:Drug Administration Schedule; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D009369:Neoplasms; D009536:Niacinamide; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D000077157:Sorafenib; D016896:Treatment Outcome",
"nlm_unique_id": "101595310",
"other_id": null,
"pages": "294-303",
"pmc": null,
"pmid": "26714427",
"pubdate": "2016-02",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "23255438;21955480;9703003;15007087;18309574;25231399;26714427;25421877;8738036;21447727;22961690;21527590;12902911;24282374;23589558;14990638;14635085;24667659;18852116;23434734;25498219;20672370;25407411;11481351;11896112;15310781;23091096;23580781;24407191;18318429;17355956;22962440;21768474;24487412;23544852;20879881;17634492",
"title": "Pediatric phase I trial of oral sorafenib and topotecan in refractory or recurrent pediatric solid malignancies.",
"title_normalized": "pediatric phase i trial of oral sorafenib and topotecan in refractory or recurrent pediatric solid malignancies"
} | [
{
"companynumb": "US-CIPLA LTD.-2016US00280",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SORAFENIB"
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"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nWide-necked anterior communicating artery aneurysms represent a subset of lesions with challenging endovascular treatment despite new endoluminal and intrasaccular devices.\n\n\nOBJECTIVE\nTo assess the long-term clinical and angiographic outcomes of stent-assisted embolization for wide-necked anterior communicating artery aneurysms.\n\n\nMETHODS\nBetween March 2008 and March 2014, 32 patients with unruptured wide-necked AComm aneurysms were treated using stent-assisted embolization. The Glasgow Outcome Scale was reviewed at the time of discharge and at latest follow-up. Ischemic and hemorrhagic events were also recorded and analyzed. Aneurysm occlusion was evaluated post-intervention and on subsequent follow-up evaluations.\n\n\nRESULTS\nSuccessful stent deployment was achieved in all cases, but in 1 patient the coils could not be contained inside the aneurysm, and the procedure was aborted without complications. The distal segment of the stent was positioned in the ipsilateral A2 in 16 patients, in the contralateral A2 in 15 patients, and in the contralateral A1 in 1 patient. There were no periprocedural thromboembolic or hemorrhagic complications. The rate of major complications was 6%. One patient developed intracranial hemorrhage related to antiplatelet therapy and another had ischemic events due to in-stent stenosis. Angiographic follow-up was available for 26 aneurysms and during a mean follow-up of 22 months, 81% of the lesions were completely occluded and 8% had a small residual neck. The retreatment rate for residual aneurysms was 3%.\n\n\nCONCLUSIONS\nOur long-term results suggest that stent-assisted embolization for anterior communicating artery aneurysms may be considered an excellent treatment option with an adequate combination of safety profile and effectiveness.",
"affiliations": "Departments of *Neurologic Surgery and ‡Radiology at Mayo Clinic, Jacksonville, Florida; §Lyerly Neurosurgery, Baptist Health, Jacksonville, Florida.",
"authors": "Brasiliense|Leonardo B C|LB|;Yoon|Jang W|JW|;Orina|Josiah N|JN|;Miller|David A|DA|;Tawk|Rabih G|RG|;Hanel|Ricardo A|RA|",
"chemical_list": "D010975:Platelet Aggregation Inhibitors",
"country": "United States",
"delete": false,
"doi": "10.1227/NEU.0000000000001161",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0148-396X",
"issue": "78(2)",
"journal": "Neurosurgery",
"keywords": null,
"medline_ta": "Neurosurgery",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002533:Cerebral Angiography; D004621:Embolization, Therapeutic; D005260:Female; D005500:Follow-Up Studies; D023261:Glasgow Outcome Scale; D006801:Humans; D002532:Intracranial Aneurysm; D008297:Male; D008875:Middle Aged; D010351:Patient Discharge; D010975:Platelet Aggregation Inhibitors; D019233:Retreatment; D012189:Retrospective Studies; D015607:Stents; D016896:Treatment Outcome",
"nlm_unique_id": "7802914",
"other_id": null,
"pages": "200-7",
"pmc": null,
"pmid": "26645968",
"pubdate": "2016-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A Reappraisal of Anterior Communicating Artery Aneurysms: A Case for Stent-Assisted Embolization.",
"title_normalized": "a reappraisal of anterior communicating artery aneurysms a case for stent assisted embolization"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/16/0078167",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": nu... |
{
"abstract": "Antiangiogenic drugs are currently standard of care in adults with renal cell carcinoma (RCC), including translocation RCC. Although antitumor activity and toxicity profile are well known in adults, few data have been reported in children. Here we present the case of a patient diagnosed at 2 years old with a metastatic translocation RCC, consecutively treated with 5 tyrosine kinase inhibitors during 6 years. The antitumor activity and toxic effects are described, and a brief review of the literature is presented.",
"affiliations": "Departments of *Pediatric Oncology, Adolescents and Young Adults †Translational Research ‡Radiology §Pathology ¶Somatic Genetics ††INSERM U830 Research Center, Institut Curie ∥Department of Pediatric Surgery, Necker Enfants-Malades Hospital, Assistance Publique #Department of Pediatrics, University of Paris-Descartes, Sorbonne Paris Cité, Paris **Department of Cancer Medicine, Gustave Roussy, Cancer Campus, Grand Paris, University of Paris-Sud, Villejuif, France.",
"authors": "Jiménez|Irene|I|;Brisse|Hervé J|HJ|;Fréneaux|Paul|P|;Sarnacki|Sabine|S|;Michon|Jean|J|;Orbach|Daniel|D|;Pierron|Gaelle|G|;Clément|Nathalie|N|;Doz|François|F|;Escudier|Bernard|B|;Schleiermacher|Gudrun|G|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases",
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000000774",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "39(5)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D020533:Angiogenesis Inhibitors; D002292:Carcinoma, Renal Cell; D002675:Child, Preschool; D005260:Female; D006801:Humans; D009362:Neoplasm Metastasis; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "e279-e284",
"pmc": null,
"pmid": "28338568",
"pubdate": "2017-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Pediatric Patient With Renal Cell Carcinoma Treated by Successive Antiangiogenics Drugs: A Case Report and Review of the Literature.",
"title_normalized": "pediatric patient with renal cell carcinoma treated by successive antiangiogenics drugs a case report and review of the literature"
} | [
{
"companynumb": "FR-BAYER-2017-137745",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "SORAFENIB"
},
"drugadditional": null,
"d... |
{
"abstract": "Purpose: To report two cases of Vogt-Koyanagi-Harada disease (VKH) resistant to systemic corticosteroid therapy, effectively treated with systemic cyclosporine.\nCase 1: A 52-year-old man diagnosed as VKH was administered oral corticosteroids (40 mg/day), following steroid pulse therapy. Since there was no significant improvement, he underwent a second course of steroid pulse therapy and oral corticosteroid administration (40 mg/day). However, there was still no improvement, and a combination therapy of both oral corticosteroids (40 mg/day) and cyclosporine 200 mg (3 mg/kg) was administered. As a result, the inflammation subsided and the dosage of the drugs was tapered successfully.\nCase 2: A 50-year-old man diagnosed as VKH underwent two courses of steroid pulse therapy, which did not improve significantly. We performed combination therapy of both corticosteroids and cyclosporine, similar to the case described above and obtained good results.\nConclusion: Our experience of these two cases indicates that systemic cyclosporine treatment was effective in the management of VKH patients resistant to conventional systemic corticosteroid therapy.",
"affiliations": null,
"authors": "Fukutomi|Akira|A|;Mashimo|Hisashi|H|;Yoshioka|Maiko|M|;Haruta|Mami|M|;Minami|Takamasa|T|;Shimojo|Hiroshi|H|;Ohguro|Nobuyuki||",
"chemical_list": "D013256:Steroids; D016572:Cyclosporine",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0029-0203",
"issue": "121(6)",
"journal": "Nippon Ganka Gakkai zasshi",
"keywords": null,
"medline_ta": "Nippon Ganka Gakkai Zasshi",
"mesh_terms": "D016572:Cyclosporine; D004361:Drug Tolerance; D006801:Humans; D008297:Male; D008875:Middle Aged; D013256:Steroids; D014607:Uveomeningoencephalitic Syndrome",
"nlm_unique_id": "7505716",
"other_id": null,
"pages": "480-6",
"pmc": null,
"pmid": "30088715",
"pubdate": "2017-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Steroid Resistant Vogt-Koyanagi-Harada Disease Treated Effectively with Cyclosporine.",
"title_normalized": "steroid resistant vogt koyanagi harada disease treated effectively with cyclosporine"
} | [
{
"companynumb": "JP-TEVA-2019-JP-1000862",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "Cutaneous squamous cell carcinoma (cSCC) is the second most common non-melanoma skin cancer worldwide, with ever increasing incidence and mortality. While most patients can be treated successfully with surgical excision, cryotherapy, or radiation therapy, there exist a subset of patients with aggressive cSCC who lack adequate therapies. Among these patients are solid organ transplant recipients who due to their immunosuppression, develop cSCC at a dramatically increased rate compared to the normal population. The enhanced ability of the tumor to effectively undergo immune escape in these patients leads to more aggressive tumors with a propensity to recur and metastasize. Herein, we present a case of aggressive, multi-focal cSCC in a double organ transplant recipient to frame our discussion and current understanding of the immunobiology of cSCC. We consider factors that contribute to the significantly increased incidence of cSCC in the context of immunosuppression in this patient population. Finally, we briefly review current literature describing experience with localized therapies for cSCC and present a strong argument and rationale for consideration of an IL-2 based intra-lesional treatment strategy for cSCC, particularly in this immunosuppressed patient population.",
"affiliations": "Department of Surgery, Faculty of Medicine, Dalhousie University, Halifax Regional Municipality, NS, Canada.;Faculty of Medicine, Dalhousie University, Halifax Regional Municipality, NS, Canada.;Department of Pathology and Laboratory Medicine, Faculty of Medicine, Dalhousie University, Halifax Regional Municipality, NS, Canada.;Department of Surgery, Faculty of Medicine, Dalhousie University, Halifax Regional Municipality, NS, Canada.;Department of Medicine, Faculty of Medicine, Dalhousie University, Halifax Regional Municipality, NS, Canada.;Department of Surgery, Faculty of Medicine, Dalhousie University, Halifax Regional Municipality, NS, Canada.;Department of Surgery, Faculty of Medicine, Dalhousie University, Halifax Regional Municipality, NS, Canada.;Department of Surgery, Faculty of Medicine, Dalhousie University, Halifax Regional Municipality, NS, Canada.",
"authors": "Vidovic|Dejan|D|;Simms|Gordon A|GA|;Pasternak|Sylvia|S|;Walsh|Mark|M|;Peltekian|Kevork|K|;Stein|John|J|;Helyer|Lucy K|LK|;Giacomantonio|Carman A|CA|",
"chemical_list": "D000970:Antineoplastic Agents; D007376:Interleukin-2; D000077271:Imiquimod",
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fimmu.2021.678028",
"fulltext": "\n==== Front\nFront Immunol\nFront Immunol\nFront. Immunol.\nFrontiers in Immunology\n1664-3224\nFrontiers Media S.A.\n\n10.3389/fimmu.2021.678028\nImmunology\nCase Report\nCase Report: Combined Intra-Lesional IL-2 and Topical Imiquimod Safely and Effectively Clears Multi-Focal, High Grade Cutaneous Squamous Cell Cancer in a Combined Liver and Kidney Transplant Patient\nVidovic Dejan 1\n\nSimms Gordon A. 2\nPasternak Sylvia 3\nWalsh Mark 1\nPeltekian Kevork 4\nStein John 1\nHelyer Lucy K. 1\nGiacomantonio Carman A. 1 *\n\n1 Department of Surgery, Faculty of Medicine, Dalhousie University, Halifax Regional Municipality, NS, Canada\n2 Faculty of Medicine, Dalhousie University, Halifax Regional Municipality, NS, Canada\n3 Department of Pathology and Laboratory Medicine, Faculty of Medicine, Dalhousie University, Halifax Regional Municipality, NS, Canada\n4 Department of Medicine, Faculty of Medicine, Dalhousie University, Halifax Regional Municipality, NS, Canada\nEdited by: Amanda Psyrri, University General Hospital Attikon, Greece\n\nReviewed by: Hongbin Wang, California Northstate University, United States; Graham Robert Leggatt, The University of Queensland, Australia\n\n*Correspondence: Carman A. Giacomantonio, Carman.Giacomantonio@Dal.Ca\nThis article was submitted to Cancer Immunity and Immunotherapy, a section of the journal Frontiers in Immunology\n\n27 5 2021\n2021\n12 67802808 3 2021\n07 5 2021\nCopyright © 2021 Vidovic, Simms, Pasternak, Walsh, Peltekian, Stein, Helyer and Giacomantonio\n2021\nVidovic, Simms, Pasternak, Walsh, Peltekian, Stein, Helyer and Giacomantonio\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.\nCutaneous squamous cell carcinoma (cSCC) is the second most common non-melanoma skin cancer worldwide, with ever increasing incidence and mortality. While most patients can be treated successfully with surgical excision, cryotherapy, or radiation therapy, there exist a subset of patients with aggressive cSCC who lack adequate therapies. Among these patients are solid organ transplant recipients who due to their immunosuppression, develop cSCC at a dramatically increased rate compared to the normal population. The enhanced ability of the tumor to effectively undergo immune escape in these patients leads to more aggressive tumors with a propensity to recur and metastasize. Herein, we present a case of aggressive, multi-focal cSCC in a double organ transplant recipient to frame our discussion and current understanding of the immunobiology of cSCC. We consider factors that contribute to the significantly increased incidence of cSCC in the context of immunosuppression in this patient population. Finally, we briefly review current literature describing experience with localized therapies for cSCC and present a strong argument and rationale for consideration of an IL-2 based intra-lesional treatment strategy for cSCC, particularly in this immunosuppressed patient population.\n\nintralesional immunotherapy\nintralesional IL-2\norgan transplant recipient\nimiquimod\ncutaneous squamous cell carcinoma (cSCC)\nintralesional\ninterleukin-2 (IL2)\naldara\n==== Body\nIntroduction\n\nCutaneous squamous cell carcinoma (cSCC) is the second most common non-melanoma skin cancer worldwide (1, 2), and its incidence is steadily increasing yearly (3). While the mortality rates for almost all other forms of cancer decline, the age-standardized mortality rate of cSCC continues to rise. Despite being vastly outnumbered in incidence by basal cell carcinoma (BCC) (4), cSCC is associated with a significantly higher mortality (5). Indeed, in the United States alone, mortality figures for cSCC are now comparable to those of melanoma; a less common disease which is far more lethal (5, 6). Of the nearly 1 million new cases of cSCC each year, there are an estimated 15,000 deaths, compared to 9730 in the case of melanoma (7, 8).\n\nInitial treatment strategies for cSCC include electrodessication and curettage, surgical excision, cryotherapy, or radiation treatment (9). Surgical excision is considered the standard treatment of cSCC, and is able to cure 90% of cSCC cases with a 5-year recurrence rate of 8% and 5-year metastasis rate of 5% (9). Surgery, however, is not always possible, as on occasion, a cSCC is unresectable or is confined to cosmetically or functionally sensitive area. In addition to inoperable cSCCs, a small percentage of cSCCs are aggressive and refractory to standard dermatologic therapies (5, 10, 11). This subset of cSCC, known as aggressive (or high-risk) SCC, has a substantially higher rate of metastasis and associated morbidity and mortality (12, 13). Features consistent with aggressive cSCC include tumor size ≥ 2cm, evidence of perineural invasion, bone invasion or erosion and invasion beyond subcutaneous fat (14). It is noteworthy that high grade histology is also still considered a feature of aggressive disease in the BWH cSCC classification system but no longer in the AJCC 8th edition of cSCC classification (15). High risk cSCC in the context of a history of local recurrence or immunosuppression predicts a significantly higher risk of disease recurrence, metastasis and disease specific mortality.\n\nHerein, we describe the novel utilization of two immunomodulatory local therapies, intralesional IL-2 and topical 5% imiquimod, used in conjunction to achieve complete remission in a double solid order transplant recipient with no evidence of inducing immune-mediated organ rejection.\n\nCase Description\n\nA Case of High Grade, Multi Focal, Rapidly Progressing Cutaneous Squamous Cell Carcinoma in a Double Solid Organ Transplant Recipient\n\nOur patient, a 72-year-old male with a past medical history of polycystic kidney disease, received a liver and kidney transplant from a single donor in January 2006; however, this first kidney immediately failed. He subsequently received a second living-related (i.e. from a living family member) donor kidney in January 2008. His initial anti-rejection medications included tacrolimus (4 mg daily), mycophenolate (2 g daily) and prednisone (10 mg daily). From a transplantation perspective, he tolerated this regimen well. In 2009, however, he developed a small area of cSCC just above his right eyebrow. This was locally excised with clear margins. Cutaneous squamous cell cancer recurred at the same site over the right eye in 2014 and again in 2015. His second recurrence was characterized as well-differentiated cSCC, resected with clear margins but associated with perineural invasion. He received targeted radiation of 5000cg to the surgical site. In Aug 2017, cSCC recurred in the skin along the supraorbital rim, again with perineural invasion. Due to the extent of this recurrence, he received a radical excision with right eye enucleation and radial forearm skin graft to repair the resulting facial skin defect. All margins were reported negative. By this point, the patient’s immunosuppression medications had been modified and included sirolimus (1 mg oral daily), tacrolimus (1 mg oral daily), and prednisone (5 mg oral daily). Following his surgery, the tacrolimus dose was reduced (to 0.5mg every two days), and the sirolimus dose increased (to 2 mg oral daily) in hopes of reducing the risk of developing further cSCC. However, he went on to develop a small cSCC on the right side of the nose; treated with excision and local radiation. He subsequently developed two new lesions in April and May of 2019, both excised with narrow margins. In January 2020 he developed a further two new lesions, one in the skin overlying the right zygoma and a second at the margin of the radial forearm skin graft on the right cheek. Margins were now involved. The area was treated with targeted radiation, taking care to avoid significant radiation field overlap from previous treatments. In February 2020 five new lesions were identified ( Figure 1A ). Pathology now demonstrated poorly differentiated cSCC with lymphovascular invasion and positive margins ( Figure 1B ). At least one of the lesions was felt to be metastatic. Consultation was made for consideration of systemic immunotherapy; however, being a liver and kidney transplant recipient, it was felt that systemic immunosuppression would confer significant risk to failure of both transplants. Intra-lesional immunotherapy was offered as a potentially safer experimental alternative. After careful consideration of the options and associated potential risks and benefits, weekly injections of intra-lesional IL-2 (8M IU total dose per session, divided among multiple lesions and sites of injection) was initiated. Initially, he experienced partial regression in some lesions but clinical progression in others, with developmental of a new submandibular nodule deep to the skin. This subcutaneous nodule was treated intra-lesional injections of IL-2 (bringing the total dose administered to 10M IU per session). Additionally, at this time imiquimod (a topical TLR-7 agonist) was added to all facial lesions, administered as a thin film once daily for five out of seven days per week, by the patient. This was done in the hopes of augmenting an IL-2-mediated anti-tumor immune response. Over the course of the following six weeks, all facial lesions completely clinically responded. In addition, the subcutaneous, submandibular nodule had significantly diminished in size ( Figure 2A ). For a number of reasons, including patient-reported severe pain with injections particularly at the site of the submandibular lesion, ongoing cost of medications, and costs associated with travelling back and forth for weekly treatment, we elected to proceed with excision of the residual submandibular lesion; at the same time, a representative biopsy of the right facial skin was taken as well. The submandibular lesion demonstrated residual high-grade cSCC with necrosis and a pronounced lymphocytic infiltrate but no evidence of nodal tissue ( Figure 2C ). Histological analysis of the right cheek skin revealed no evidence of any residual cSCC ( Figure 2D ). Margins were clear and no lymphovascular invasion or perineural invasion was identified. The area remains disease free 3 months post-treatment ( Figure 2B ). During the course of treatment, liver and kidney function was closely monitored and unaffected by the localized treatment strategy. Overall, he experienced no decline in either (kidney or liver) graft function and had no signs of rejection.\n\nFigure 1 Pre-treatment recurrence of facial cSCC. (A) Extent of disease on the right cheek prior to starting treatment with intra-lesional IL-2. (B) Histological profile of facial lesions prior to starting intra-lesional IL2 (top 40X, bottom 100X magnification), showing poorly differentiated cSCC.\n\nFigure 2 Post-treatment course with intra-lesional IL2 and imiquimod. (A) Complete response of facial lesions with resolving submandibular nodule. Arrows identify nodule and infraorbital area of healing (biopsied) skin. (B) Sustained complete resolution of facial cSCC three months following completion of treatment. (C) (left) Histological profile of excised submandibular nodule low magnification; (right) 20X magnification reveals residual high-grade cSCC with necrosis, a pronounced lymphocytic infiltrate, with no evidence of nodal tissue (D) (left) 40X magnification of biopsied, healing infraorbital skin showing ulceration and complete clearance of cSCC; (right) 100X magnification.\n\nDiscussion\n\nThe Immunopathological Basis of cSCC in Solid Organ Transplant Recipients\n\nThe immune system plays a vital role in the pathogenesis and progression of cSCC (16). Indeed, the major risk factors for cSCC development include genetically defined skin type, chronic UV exposure, chronic skin damage, and immunosuppression (17–21). The impact of immunosuppression on cSCC development has been studied most thoroughly in the context of solid organ transplant recipients. While immunosuppression is necessary to prevent transplant rejections, lifelong use of these agents has been shown to promote carcinogenesis, with cSCC being one of the most common in these patients (22).\n\nThe prominence of cSCC development in patients with iatrogenic immunosuppression strongly suggests that cSCC may have an inherent ability – that other cancers lack – to circumvent cancer immune surveillance. It has been shown in a large series of renal transplant patients that immunosuppression increases cSCC formation up to 250-fold in comparison to immunocompetent patients (23–25). The degree of immunosuppression may correspond to cSCC incidence, where reduction of immunosuppression reduces the total number, and rate of formation of cSCC (26). Numerous immunosuppressive drugs have been linked to cSCC development, namely calcineurin inhibitors (26, 27), glucocorticoids (28–30), and biologics (infliximab (31, 32), etanercept (32–34), adalimumab (32)). Furthermore, when solid organ transplant recipients do develop cSCC, their tumors tend to be more aggressive and carry a higher risk for metastasis (35). Indeed, iatrogenic immunosuppression via calcineurin inhibitors inhibit Langerhan’s cells (36, 37), dermal dendritic cells (38, 39), and T-cell signaling and proliferation, and cyclosporine directly promotes tumor development (40–42). Calcineurin inhibitors effectively disrupt IL-2 production, and as such are able to dampen immune response to allogenic antigens – a desired effect when trying to persevere tolerance towards solid organ transplants; however, this iatrogenic immunosuppression comes at a price, and significantly impairs cancer immunosurveillance (23–27). Unlike calcineurin inhibitors, the mammalian target of rapamycin (mTOR) inhibitors block IL-2 induced signal transduction, and does not abrogate IL-2 production completely, thereby allowing some functions of IL-2 to remain intact (43). As such, recently mTOR inhibitors, which include sirolimus (rapamycin), temsirolimus, and everolimus, have garnered favour because they have a lower association with de novo skin malignancies, and may in-and-of themselves have a direct anti-tumor effect. In retrospective analyses renal transplant recipients who received either sirolimus or everolimus without cyclosporine had a reduced number of de novo skin malignancies (44), and some patients experienced regression of skin cancers such as Kaposi’s sarcoma (KS) and SCC that were present prior to initiation of mTOR therapy (45–49). For these reasons, in our high-risk patient presented above, recurrent cSCC was the major factor in deciding to switch him from tacrolimus to sirolimus early on. However, he unfortunately continued to present with recurrent cSCC.\n\nThe substantially higher incidence of cSCC in immunosuppressed patients underscores the impact of the immune system in cSCC susceptibility and pathogenesis. Indeed, variations in immunological makeup may influence the ability of human hosts to recruit adaptive immune responses needed to prevent cSCC development (50). Class I and class II HLA genes encode major histocompatibility complex (MHC) proteins which allow for presentation of antigenic peptides such as tumor antigens to CD8+ and CD4+ T-cell lymphocytes, respectively. Variations in MHC proteins have been implicated in multiple cancers by influencing host defenses against tumorigenesis (50). Aberrant expression of both class I and class II HLA proteins on the surface of cSCC cancer cells is reported in both immunocompetent and immunosuppressed patients (51–55). Abnormalities in class I and class II HLA proteins are well documented in cSCC cells, reinforcing the notion that cSCC pathogenesis is inherently connected to faulty immune regulation. Several clinical studies have indicated that specific class I HLA germlines may predispose the development of cSCC in immunosuppressed patients (56–58). It has also been proposed that aberrant expression of class II HLA proteins on cSCC cancer cells may facilitate tumor escape from host defense mechanisms, as seen in other cancers including HNSCC and acute myeloid leukemia (59, 60). Furthermore, cSCC has the ability to downregulate the presentation of highly immunogenic neoantigens to TCRs (61). Thus, an important facet in the mechanism of cSCC immune escape is HLA and neoantigen dysregulation; targeting mechanisms that improve tumor-associated antigen presentation may thus be useful in the immunotherapy of cSCC.\n\nAnother avenue through which cSCC mediates immune escape is through local cytokine dysregulation. For example, cSCC significantly downregulates CCL27, a chemokine that promotes T cell homing to skin, throughout its progression from AK to malignant cSCC (62). cSCC tumors that tend to be deeper and more advanced also significantly upregulate CXCR7, which signals through CXCL12 to promote ERK signaling, thus prolonging tumor cell survival (63). Cytokine profiling of tumors reveals that in the progression to malignant cSCC, precancerous lesions dramatically upregulate production of IL-6 (64), a proinflammatory cytokine that has previously been shown to augment cSCC growth through modulation of pro-tumorigenic cytokines and angiogenic factors (65). Therefore, therapies that modulate the local cytokine and chemokine profile of cSCC may be of benefit.\n\nSystemic Treatment of cSCC\n\nAside from surgical methods, there is a paucity of treatment modalities for aggressive cSCC. Systemic therapies for cSCC have shown limited success, although rigorous assessment of systemic therapies has been limited (66). To date, a number of systemic therapies have been used to treat cSCC, including: chemotherapeutics (cisplatin (67–69), 5-fluorouracil [5-FU] (67, 68, 70, 71), bleomycin (67), and doxorubicin (69)), 13-cis-retinoic acid (13cRA (72)), immunotherapies (interferon-α2a [IFN-α] (72)), gefitinib (73) and cetuximab (74) (agents targeting epidermal growth factor [EGFR]), and more recently nivolumab (75) and cemiplimab (76) (PD-1 immune checkpoint inhibitors).\n\nAlthough chemotherapeutics have enjoyed modest success in treating surgically unresectable, and metastatic cSCC, they are accompanied by a wide range of – sometimes intolerable – gastrointestinal, hematologic, and metabolic side effects (67–69). Studies using 13cRA and IFN-α to treat SCC are conflicting; in the only trial using these compounds as adjuvant therapies in cSCC, they were ineffective (66, 72). In recent years targeting EGFR has shown some promise; indeed, EGFR is implicated in a variety of cancers including non-small cell lung cancer, colorectal cancer, pancreatic cancer, and head and neck squamous cell carcinoma (HNSCC) (77–81). Insofar as treating cSCC, two candidates have recently made it through phase II clinical trials: cetuximab, a humanized monoclonal antibody targeting EGFR, and gefitinib, which inhibits ATP-binding to EGFR (73, 74). Both compounds showed modest complete response rates, albeit with moderate toxicity.\n\nThe moderate to severe toxicities of systemic agents used to treat aggressive cSCC makes it challenging to use these drugs in the context of high-risk patients with significant comorbidities and chronic conditions, such as SOTRs. Additionally, the use of any systemic immune modifying agents may trigger immune-related adverse events (irAEs) (82) that could manifest as life-threatening (i.e. organ rejection) in patients who are iatrogenically immunosuppressed; thus, they are generally not recommended for use in this clinical context (83). Therefore, it is imperative that therapies that minimize systemic toxicities while maximizing the local tumor clearance be studied further.\n\nIntra-Lesional and Topical Therapies\n\nThe serious toxicity profile associated with systemic therapies may be altogether avoided by treating instead with intra-lesional injections. Prior studies have revealed lowered rates of toxicity associated with intra-lesional injections when compared with systemic administration. Furthermore, by delivering an increased concentration of the active agent at the site of action, increased rates of efficacy are observed (84, 85). To date, only a handful of intra-lesional agents have been used for treatment of cSCC, although this method of delivery has been extensively studied in melanoma wherein systemic adverse events are minimized and the local immune response is maximized (86).\n\nSeveral case reports and small trials have been reported where actinic keratosis (AK) has been treated successfully using intra-lesional therapies (87, 88). Furthermore, 5-FU (70), methotrexate (MTX) (89), several INFs (90–93), and bleomycin (94) have all shown some utility in treating both AK and cSCC, although the data for cSCC is somewhat limited. The vast majority of reports of intra-lesional treatments of cSCC’s are case reports; however, most show good response rates and limited side effects, with the majority of side effects reported including erythema, pain and swelling at the site of injection, and occasionally, mild fever and chills. Indeed, when reflecting on our patient presented above, he experienced no immune-related adverse events. Remarkably, in a patient who cannot tolerate T cell activation (due to risk of graft failure), local injection of the potent T cell activator IL-2 was sufficient to maximize the anti-tumor immune response and did not cause any further toxicities. The patients’ side effects were limited to pain and swelling at the injection site with a short period of chills following injection, further demonstrating the benefit of intra-lesional immune therapies compared to systemic therapies.\n\nTopical therapies that are applied locally can also mitigate the risk of systemic adverse events. A number have achieved moderate success in the treatment of AK, such as topical 5-FU, imiquimod, ingenol mebutate, and diclofenac, which are all FDA approved for this indication (95). With regards to cSCC, topical 5-FU is also commonly used (96). Additionally, early randomized controlled trials show a high degree of clinical benefit from topical imiquimod in the context of cSCC, with approximately a 70% complete response rate (97, 98). Of particular importance, imiquimod is a potent Toll-like receptor 7 (TLR7) agonist that induces local cytokine changes to cause a shift in the immunological balance intratumorally (99).\n\nThese therapies individually or in combination therefore represent a possible treatment modality in the context of high risk cSCC. In solid organ transplant recipient patients who cannot tolerate other therapies, or have failed standard local treatment with surgery and/or radiation, use of intra-lesional and/or local therapies may provide substantial clinical benefit. As iatrogenic immunosuppression plays a role in mediating immune escape of these patients’ tumors, identifying local therapies that can counteract that process is paramount.\n\nAugmenting the Anti-Tumor Immune Response in cSCC to Prevent Immune Escape\n\nAs briefly discussed above, one of the avenues through which cSCC mediates immune escape is by downregulation of cytotoxic T cells. Thus, local therapies that promote T cell proliferation and activity are of particular interest. Outside of case reports, there are very few studies examining the immunological response to intra-lesional therapies in cSCC. Neoadjuvant intra-lesional MTX is able to induce lymphocytic inflammatory infiltrate, although the cell types and their role within the infiltrate are unclear (100). IFNα-2β;, another immunological treatment that was used intra-lesionally in a number of early studies achieved moderate clinical success, with a 88.2% complete response rate, but the specific mechanism of action is still unclear (101). However, extrapolating from its function in other contexts, it is likely upregulating a T cell-mediated anti-tumor response through the JAK1/STAT1 pathway (102). Unfortunately, in the years since these early studies, IFNα-2β; has fallen out of clinical investigation.\n\nInterestingly, other potent T cell activating immunotherapies such as IL-2, have not yet been studied in the context of cSCC, to our knowledge. This is despite its extensive investigation as an intra-lesional agent in melanoma (86, 103–105) and HNSCC (106–109), where it mediates a shift to CD8+ T cell-mediated tumor clearance. The excellent response demonstrated by this case warrants further investigation into the possible role intra-lesional IL-2 may have in the treatment of cSCC.\n\nImiquimod, the other local agent used in this case, applied topically to cSCC is able to induce numerous changes targeted at augmenting T cell effector function. First, imiquimod causes dense CD8+ T cell infiltration into treated tumors, which produce significantly higher amounts of IFNγ, perforin, and granzyme compared to untreated tumors (99). In addition, treatment with imiquimod causes a shift to a polarized Th1 cytokine response (110). Production of IL-10 and TGF-β, which are known cytokines responsible for cSCC immune evasion (111), were significantly downregulated following imiquimod treatment. Imiquimod also antagonizes cSCC-mediated vascular remodeling, by upregulating E-selectin to promote cytotoxic T cell homing to the tumor (112). Furthermore, it significantly decreases FOXP3+ Treg cell levels in treated tumors, and also inhibits their function (112). Most importantly, imiquimod-treated tumors exhibit clonally expanded CD8+ T cell repertoires (112), suggesting a specific anti-tumor immune response and possibly adaptive immunity.\n\nConclusion\n\nThe case presented herein provides an excellent example of the complexity of the pathobiology and clinical behavior of cSCC in the immunosuppressed patient population. The primary objective of immunosuppressive regimens in solid organ transplantation is prevention of acute allograft rejection through IL-2 blockade. Calcineurin inhibitors such as tacrolimus prevent IL-2 production while sirolimus inhibits IL-2 receptor signal transduction via action on mTOR. These complementary mechanisms of action align to effectively preventing acute allograft rejection while at the same time compromising both innate and adaptive immune pathways.\n\nCarcinogenesis in cSCC may be associated with a number of cellular modifications that facilitate immune escape including aberrant HLA expression, downregulation of important chemokines associated with T-cell homing and production of other cytokines such as IL-6, a cytokine having a myriad of functions including promoting angiogenesis, tumor cell growth and an overall proinflammatory and pro-tumorigenic response. In the setting of an immunocompromised host, cSCC is therefore ‘facilitated’ to evade the body’s natural cancer immune surveillance mechanisms via the aforementioned mechanisms. Our patient began experiencing cSCC within a year of his second kidney transplant. His initial lesions were small, well differentiated cSCC’s. However, early on in his disease he developed a high-risk feature, that being perineural invasion. Despite achieving clear surgical margins and receiving adjuvant radiation to the field, the disease recurred. Over time, the recurrences became more frequent, with increasing numbers of high-grade features including lesions greater than 2cm, perineural invasion and eventually transformation to high grade histology. At this point, further surgery was deemed futile and with no further options for radiation an alternate treatment strategy needed to be considered.\n\nWith recent randomized evidence to support systemic immunotherapy in cSCC, the option of systemic treatment with a PD-1 inhibitor was initially discussed. Given that there is currently a paucity of evidence to support safe delivery of systemic immune therapy in the solid organ transplantation population, and with both a liver and a kidney allograft at risk of rejection, we decided against systemic immunotherapy. However, we have developed local experience and success with IL-2 based intra-lesional treatment of cSCC in some of our kidney transplant patients. Our rationale for an IL-2 based treatment strategy in this population is based on the knowledge that current immunosuppressive regimens target IL-2 production or its effects systemically. Our hypothesis is that local re-introduction of IL-2 into skin bearing cSCC and specifically into the tumor microenvironment will serve to restore both the innate immunity, and effector T-cell function lost through iatrogenic IL-2 suppression thereby re-establishing effective cytotoxic immunity against cSCC. The initial observed response to IL-2 monotherapy was mixed with some lesions regressing while others progressed. We were concerned that significantly increasing the local IL-2 dose beyond the 10M IU (total injected dose) might systemically impact immunity and potentially initiate allograft rejection. Therefore, we added topical imiquimod with the intention of potentiating the local cytokine response promoting T-cell and NK-cell homing and effector function. The combination proved highly effective with clearance of all facial lesions and marked regression of the subcutaneous, submandibular nodule making surgical excision much easier to achieve with a clear margin. To help reduce the development of further cSCC’s, the patient’s calcineurin inhibitor dose was further reduced.\n\nThe foundational concepts of cSCC tumorigenesis in the immunocompromised population are aberrant HLA expression, alteration of chemokine and cytokine profiles, and T cell dysfunction, as discussed prior. In our patient, we used two immunomodulatory agents in conjunction in an attempt to modulate some of the aforementioned pathways in the favor of an anti-tumor response, while mitigating systemic immune toxicity. We acknowledge that it is not fully clear how IL-2 and imiquimod may act in conjunction to mediate these anti-tumor immune responses; this merits further mechanistic study.\n\nHerein we demonstrate, for the first time to our knowledge, that an IL-2 based intra-lesional treatment strategy safely and effectively treated multiple high grade cSCC lesions in an immunocompromised, multi-organ transplant patient. It is arguable that given the biological propensity for cSCC to evade immune systems in the setting of iatrogenic immunosuppression, an IL-2 based intra-lesional immunotherapy treatment strategy should be first line consideration for all cSCC lesions. Furthermore, from a patients’ perspective, offering patients a minimally invasive, localized therapy gives them the opportunity to forego complex surgical management, which in some cases can be undesirable cosmetically or may carry major perioperative risks in this population.\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.\n\nEthics Statement\n\nEthical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study.\n\nAuthor Contributions\n\nDV and CG contributed to conception and design of this manuscript, and wrote sections of the manuscript. GS wrote sections of the manuscript. SP provided data for figures within the manuscript. 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Intralesional Agents in the Management of Cutaneous Malignancy: A Review. J Am Acad Dermatol (2011) 64 :413–22. 10.1016/j.jaad.2009.12.013\n88 Chitwood K Etzkorn J Cohen G . Topical and Intralesional Treatment of Nonmelanoma Skin Cancer: Efficacy and Cost Comparisons. Dermatol Surg (2013) 39 :1306–16. 10.1111/dsu.12300\n89 Annest NM VanBeek MJ Arpey CJ Whitaker DC . Intralesional Methotrexate Treatment for Keratoacanthoma Tumors: A Retrospective Study and??Review of the Literature. J Am Acad Dermatol (2007) 56 :989–93. 10.1016/j.jaad.2006.12.017\n90 Kim KH Yavel RM Gross VL Brody N . Intralesional Interferon alpha-2b in the Treatment of Basal Cell Carcinoma and Squamous Cell Carcinoma: Revisited. Dermatol Surg Off Publ Am Soc Dermatol Surg Al (2004) 30 :116–20. 10.1097/00042728-200401000-00032\n91 Oh CK Son HS Lee JB Jang HS Kwon KS . Intralesional Interferon Alfa-2b Treatment of Keratoacanthomas. J Am Acad Dermatol (2004) 51 :2–5. 10.1016/j.jaad.2004.05.009\n92 Grob J Suzini F Richard M Weiller M . Large Keratoacanthomas Treated With Intralesional Interferon Alfa-2a. J Am Acad Dermatol (1993) 29 :237–41. 10.1016/0190-9622(93)70174-R\n93 Wickramasinghe L Hindson T Wacks H . Treatment of Neoplastic Skin Lesions With Intralesional Interferon. J Am Acad Dermatol (1989) 20 :71–4. 10.1016/S0190-9622(89)70009-8\n94 Sayama Tagami H . Treatment of Keratoacanthoma With Intralesional Bleomycin. Br J Dermatol (1983) 109 :449–52. 10.1111/j.1365-2133.1983.tb04619.x\n95 Que SKT Zwald FO Schmults CD . Cutaneous Squamous Cell Carcinoma: Management of Advanced and High-Stage Tumors. J Am Acad Dermatol (2018) 78 :249–61. 10.1016/j.jaad.2017.08.058\n96 Prince GT Cameron MC Fathi R Alkousakis T . Topical 5-Fluorouracil in Dermatologic Disease. Int J Dermatol (2018) 57 :1259–64. 10.1111/ijd.14106\n97 Patel GK Goodwin R Chawla M Laidler P Price PE Finlay AY . Imiquimod 5% Cream Monotherapy for Cutaneous Squamous Cell Carcinoma in Situ (Bowen’s Disease): A Randomized, Double-Blind, Placebo-Controlled Trial. J Am Acad Dermatol (2006) 54 :1025–32. 10.1016/j.jaad.2006.01.055\n98 Love WE Bernhard JD Bordeaux JS . Topical Imiquimod or Fluorouracil Therapy for Basal and Squamous Cell Carcinoma: A Systematic Review. Arch Dermatol (2009) 145 :1431–8. 10.1001/archdermatol.2009.291\n99 Huang SJ Hijnen D Murphy GF Kupper TS Calarese AW Mollet IG . Imiquimod Enhances IFN-gamma Production and Effector Function of T Cells Infiltrating Human Squamous Cell Carcinomas of the Skin. J Invest Dermatol (2009) 129 :2676–85. 10.1038/jid.2009.151\n100 Bergón-Sendín M Parra-Blanco V Pulido-Pérez A Nieto-Benito LM Rosell-Díaz ÁM Suárez-Fernández R . Histological Findings After Intralesional Methotrexate Treatment in Cutaneous Squamous Cell Carcinoma. Dermatol Ther (2020) 33 (6 ):e14377. 10.1111/dth.14377 33030310\n101 Edwards L Berman B Rapini RP Whiting DA Tyring S Greenway HT . Treatment of Cutaneous Squamous Cell Carcinomas by Intralesional Interferon alfa-2b Therapy. Arch Dermatol (1992) 128 :1486–9. 10.1001/archderm.128.11.1486\n102 Borden EC . Interferons α and β in Cancer: Therapeutic Opportunities From New Insights. Nat Rev Drug Discovery (2019) 18 :219–34. 10.1038/s41573-018-0011-2\n103 Byers BA Temple-Oberle CF Hurdle V McKinnon JG . Treatment of in-Transit Melanoma With Intra-Lesional Interleukin-2: A Systematic Review. J Surg Oncol (2014) 110 :770–5. 10.1002/jso.23702\n104 Green DS Dalgleish AG Belonwu N Fischer MD Bodman-Smith MD . Topical Imiquimod and Intralesional Interleukin-2 Increase Activated Lymphocytes and Restore the Th1/Th2 Balance in Patients With Metastatic Melanoma. Br J Dermatol (2008) 159 :606–14. 10.1111/j.1365-2133.2008.08709.x\n105 Garcia MS Ono Y Martinez SR Chen SL Goodarzi H Phan T . Complete Regression of Subcutaneous and Cutaneous Metastatic Melanoma With High-Dose Intralesional Interleukin 2 in Combination With Topical Imiquimod and Retinoid Cream. Melanoma Res (2011) 21 :235–43. 10.1097/CMR.0b013e328345e95e\n106 Whiteside TL Letessier E Hirabayashi H Vitolo D Bryant J Barnes L . Evidence for Local and Systemic Activation of Immune Cells by Peritumoral Injections of Interleukin 2 in Patients With Advanced Squamous Cell Carcinoma of the Head and Neck. Cancer Res (1993) 53 :5654–62.\n107 Tímár J Ladányi A Forster-Horváth C Lukits J Döme B Remenár E . Neoadjuvant Immunotherapy of Oral Squamous Cell Carcinoma Modulates Intratumoral CD4/CD8 Ratio and Tumor Microenvironment: A Multicenter Phase II Clinical Trial. J Clin Oncol Off J Am Soc Clin Oncol (2005) 23 :3421–32. 10.1200/JCO.2005.06.005\n108 Mattijssen V De Mulder PH De Graeff A Hupperets PS Joosten F Ruiter DJ . Intratumoral PEG-interleukin-2 Therapy in Patients With Locoregionally Recurrent Head and Neck Squamous-Cell Carcinoma. Ann Oncol Off J Eur Soc Med Oncol (1994) 5 :957–60. 10.1093/oxfordjournals.annonc.a058739\n109 Feinmesser M Okon E Schwartz A Kaganovsky E Hardy B Aminov E . Histologic and Immunohistochemical Characterization of Tumor and Inflammatory Infiltrates in Oral Squamous Cell Carcinomas Treated With Local Multikine Immunotherapy: The Macrophage at the Front Line. Eur Arch Oto-Rhino-Laryngol Off J Eur Fed Oto-Rhino-Laryngol Soc EUFOS Affil Ger Soc Oto-Rhino-Laryngol - Head Neck Surg (2004) 261 :359–68. 10.1007/s00405-003-0615-x\n110 Smith KJ Hamza S Skelton H . Topical Imidazoquinoline Therapy of Cutaneous Squamous Cell Carcinoma Polarizes Lymphoid and Monocyte/Macrophage Populations to a Th1 and M1 Cytokine Pattern. Clin Exp Dermatol (2004) 29 :505–12. 10.1111/j.1365-2230.2004.01593.x\n111 Kim J Modlin RL Moy RL Dubinett SM McHugh T Nickoloff BJ . IL-10 Production in Cutaneous Basal and Squamous Cell Carcinomas. A Mechanism for Evading the Local T Cell Immune Response. J Immunol Baltim Md 1950 (1995) 155 :2240–7.\n112 Clark RA Huang SJ Murphy GF Mollet IG Hijnen D Muthukuru M . Human Squamous Cell Carcinomas Evade the Immune Response by Down-Regulation of Vascular E-Selectin and Recruitment of Regulatory T Cells. J Exp Med (2008) 205 :2221–34. 10.1084/jem.20071190\n\n",
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"journal": "Frontiers in immunology",
"keywords": "aldara; cutaneous squamous cell carcinoma (cSCC); imiquimod; interleukin-2 (IL2); intralesional; intralesional IL-2; intralesional immunotherapy; organ transplant recipient",
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"mesh_terms": "D000279:Administration, Cutaneous; D000368:Aged; D000970:Antineoplastic Agents; D002294:Carcinoma, Squamous Cell; D006084:Graft Rejection; D006801:Humans; D000077271:Imiquimod; D016867:Immunocompromised Host; D007165:Immunosuppression Therapy; D036502:Infusions, Intralesional; D007376:Interleukin-2; D016030:Kidney Transplantation; D016031:Liver Transplantation; D008297:Male; D009364:Neoplasm Recurrence, Local; D012878:Skin Neoplasms; D066027:Transplant Recipients; D016896:Treatment Outcome",
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"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
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"title": "Case Report: Combined Intra-Lesional IL-2 and Topical Imiquimod Safely and Effectively Clears Multi-Focal, High Grade Cutaneous Squamous Cell Cancer in a Combined Liver and Kidney Transplant Patient.",
"title_normalized": "case report combined intra lesional il 2 and topical imiquimod safely and effectively clears multi focal high grade cutaneous squamous cell cancer in a combined liver and kidney transplant patient"
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"abstract": "Aneurysmal bone cysts (ABCs) are rare benign pseudotumoral bone lesions with potential aggressive behavior due to the extensive destruction of surrounding bone. Traditionally, these tumors were treated with open surgery, but there is more and more a shift to less invasive procedures. In particular, treatment for spinal ABCs is generally unsatisfactory due to the risk of morbidity, neurological impairment and recurrence, and there is a need for innovative therapies. Denosumab has been reported as a useful treatment in giant cell tumors of bone (GCTB), so its efficacy has been tested also in other fibro-osseus lesions affecting children and adolescents, such as spinal aneurysmal bone cysts. The pediatric literature is limited to case reports and small series, all of which highlight the efficacy of this treatment on lesions growth and associated bone pain. Some of these reports have already reported well known side effects associated with denosumab, such as hypocalcemia at the beginning of the treatment, and rebound hypercalcemia at the discontinuation. The latter seems to be more frequent in children and adolescents than in adults, probably due to the higher baseline bone turnover in children. In addition, the use of denosumab in young patients could affect both bone modeling and remodeling, even if the consequences on the growing skeleton have not been reported in detail. Here we describe the case of a spinal ABC diagnosed in an 8-year old young boy which was not accessible to surgery but responded favorably to denosumab. Our aim is to describe the rapid changes in mineral and bone homeostasis in this patient, that required advice from the experts of the European Reference Network (ERN) for rare bone and endocrine diseases.",
"affiliations": "Endocrinology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, ERN BOND, Milan, Italy.;Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Center, Paris-Saclay University, Villejuif, France.;Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Center, Paris-Saclay University, Villejuif, France.;Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Center, Paris-Saclay University, Villejuif, France.;Endocrinology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, ERN BOND, Milan, Italy.;AP-HP, Centre de Référence des maladies rares du métabolisme du Calcium et du Phosphate, filière OSCAR, Paris, France.;AP-HP, Service d'endocrinologie et diabète de l'enfant, ERN BOND, ERN for rare endocrine disorders, et Plateforme d'expertise des maladies rares, Hôpital Bicêtre Paris Saclay, Le Kremlin-Bicêtre, France.",
"authors": "Del Sindaco|Giulia|G|;Berlanga|Pablo|P|;Brugières|Laurence|L|;Thebault|Eric|E|;Mantovani|Giovanna|G|;Wicart|Philippe|P|;Linglart|Agnès|A|",
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"doi": "10.3389/fendo.2021.698963",
"fulltext": "\n==== Front\nFront Endocrinol (Lausanne)\nFront Endocrinol (Lausanne)\nFront. Endocrinol.\nFrontiers in Endocrinology\n1664-2392\nFrontiers Media S.A.\n\n10.3389/fendo.2021.698963\nEndocrinology\nCase Report\nMineral and Bone Consequences of High Dose Denosumab Therapy to Treat an Aneurysmal Bone Cyst, a Child Case Report\nDel Sindaco Giulia 1 2 3\n\nBerlanga Pablo 4\nBrugières Laurence 4\n\nThebault Eric 4\nMantovani Giovanna 1 2\n\nWicart Philippe 5 6\nLinglart Agnès 3 5 7 *\n\n1 Endocrinology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, ERN BOND, Milan, Italy\n2 Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy\n3 AP-HP, Service d’endocrinologie et diabète de l’enfant, ERN BOND, ERN for rare endocrine disorders, et Plateforme d’expertise des maladies rares, Hôpital Bicêtre Paris Saclay, Le Kremlin-Bicêtre, France\n4 Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Center, Paris-Saclay University, Villejuif, France\n5 AP-HP, Centre de Référence des maladies rares du métabolisme du Calcium et du Phosphate, filière OSCAR, Paris, France\n6 AP-HP, Department of Pediatric Orthopedic Surgery, Necker - Enfants Malades University Hospital, Paris, France. Paris Descartes University, Paris, France\n7 Université de Paris Saclay, INSERM, U1185, Le Kremlin-Bicêtre, France\nEdited by: Zoe Paskins, Keele University, United Kingdom\n\nReviewed by: Panagiotis Tsagkozis, Karolinska University Hospital, Sweden; Riccardo Ghermandi, Rizzoli Orthopaedic Institute, Italy\n\n*Correspondence: Agnès Linglart, agnes.linglart@aphp.fr\nThis article was submitted to Bone Research, a section of the journal Frontiers in Endocrinology\n\n16 7 2021\n2021\n12 69896322 4 2021\n25 6 2021\nCopyright © 2021 Del Sindaco, Berlanga, Brugières, Thebault, Mantovani, Wicart and Linglart\n2021\nDel Sindaco, Berlanga, Brugières, Thebault, Mantovani, Wicart and Linglart\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.\nAneurysmal bone cysts (ABCs) are rare benign pseudotumoral bone lesions with potential aggressive behavior due to the extensive destruction of surrounding bone. Traditionally, these tumors were treated with open surgery, but there is more and more a shift to less invasive procedures. In particular, treatment for spinal ABCs is generally unsatisfactory due to the risk of morbidity, neurological impairment and recurrence, and there is a need for innovative therapies. Denosumab has been reported as a useful treatment in giant cell tumors of bone (GCTB), so its efficacy has been tested also in other fibro-osseus lesions affecting children and adolescents, such as spinal aneurysmal bone cysts. The pediatric literature is limited to case reports and small series, all of which highlight the efficacy of this treatment on lesions growth and associated bone pain. Some of these reports have already reported well known side effects associated with denosumab, such as hypocalcemia at the beginning of the treatment, and rebound hypercalcemia at the discontinuation. The latter seems to be more frequent in children and adolescents than in adults, probably due to the higher baseline bone turnover in children. In addition, the use of denosumab in young patients could affect both bone modeling and remodeling, even if the consequences on the growing skeleton have not been reported in detail. Here we describe the case of a spinal ABC diagnosed in an 8-year old young boy which was not accessible to surgery but responded favorably to denosumab. Our aim is to describe the rapid changes in mineral and bone homeostasis in this patient, that required advice from the experts of the European Reference Network (ERN) for rare bone and endocrine diseases.\n\ndenosumab\naneurysmal bone cyst\nhypercalcemia\nbisphosphonate\nbone modeling\nUniversité Paris-Saclay10.13039/501100007241\n==== Body\nIntroduction\n\nAneurysmal bone cysts (ABCs) are rare tumors accounting for 1-2% of the primary bone tumors and for 15% of primary spine tumors (1). ABCs arising from the mobile spine account for the 10-30% of all ABC cases and manifest with axial pain as the most common symptom (2).\n\nAlthough ABCs are benign pseudotumoral bone lesions, they may have potentially aggressive behavior due to the extensive destruction of surrounding bone (3). ABCs belong to a family of benign (myo) fibroblastic tumor subtypes characterized by USP6-genetic rearrangements. These rearrangements are detected in over 60% of ABCs leading to the transcriptional upregulation of USP6, a deubiquitinating enzyme family protein. The increased expression of USP6 leads to the activation of the receptor activator of nuclear factor kappa B (NF-κB) (RANK) signaling pathway and the increased production of matrix metalloproteinase (4, 5).\n\nABCs contain cell types usually found in bone, including osteoclast-like multinucleated cells that express high levels of RANK, and neoplastic stromal cells that express high levels of RANK ligand (RANKL). Bone resorption and osteolysis are accrued as consequences of the RANK-RANKL increased signaling (6).\n\nTraditionally, these tumors were treated with open surgery, but currently there is a shift to less invasive procedures mainly in specific sites with high surgical morbidity (such as spinal or vertebral tumors) or in case of tumor recurrence. In addition, treatment for spinal ABCs is still generally unsatisfactory in many cases due to the considerable risk of morbidity, neurological impairment and recurrence, and there is therefore a need for innovative and non-invasive therapies (7). Therapeutic alternatives have been reported with various efficacy and/or safety including percutaneous surgery, embolization, sclerotherapy and radiotherapy. Lastly, non-invasive treatment with denosumab or bisphosphonates has been reported to be effective in the management of the disease (8).\n\nDenosumab is a fully human monoclonal antibody of the IgG2 immunoglobulin isotype to the receptor activator of nuclear factor-κB ligand (RANKL). It binds with high affinity and specificity to RANKL, mimicking the inhibitory effects of osteoprotegerin (OPG) on the RANK-RANKL signaling cascade and resulting in rapid suppression of bone resorption (9). The immunohistochemical similarities with giant cell tumor of bone (GCTB), lesion that display a satisfactory response to denosumab when surgery is not possible, suggest that denosumab may have positive effects on ABCs (7).\n\nThe reports on the use of denosumab for ABCs in children are currently limited to case reports and small series, highlighting mainly the beneficial effects on lesion growth, associated bone pain and facilitation of subsequent surgeries (9, 10). Some of these reports have already described well known side effects associated with denosumab, such as hypocalcemia when treatment is initiated, and rebound hypercalcemia at the treatment discontinuation (11–14).\n\nHere we describe the mineral and bone effects of high doses of denosumab over a 5-year follow-up in a young boy who was diagnosed at the age of 8 years with a large ABC of the spine. Because of the size of the lesion and the encagement of vertebral artery, surgery was contraindicated. Medical approach was preferred in order to minimize the risk of bleeding and major complications. Therefore, denosumab was administered with optimal control of tumor size but on the other side, the onset of bone and mineral effects.\n\nCase Illustration\n\nAn 8-year-old male with a 6-months history of progressive growth of cervical lesion was referred to a tertiary center of Pediatric Neurosurgery complaining about progressive weakness on left arm and painful restriction of cervical movements. On admission, physical examination revealed a calcified lateral-cervical lesion of about 6 cm, not painful to the touch and mild amyotrophy of proximal left arm. Neurological examination showed a grade 2/5 muscle strength of the left triceps and a grade 4/5 muscle strength of the biceps bilaterally. No sensory deficits were detected, but biceps reflex was absent. Left deltoid paralysis was also observed, with limitation of abduction, external rotation and anteropulsion of left shoulder. Magnetic resonance imaging ( Figure 1A ) and computerized tomography ( Figure 1B ) of cervical and thoracic spine were performed and identified a bulky, cystic, calcified, lytic lesion originating from C4-C7 hemivertebrae. The lesion extended to the left epidural space and to the subclavicular region; vertebral artery was encaged. A C6 vertebral fracture was also identified. Histology confirmed then the diagnosis of aneurysmal bone cyst (ABC).\n\nFigure 1 Aneurysmal bone cyst at diagnosis. MRI with 3D reconstruction at diagnosis (A) showing the calcified lytic lesion originating from C4-C7 hemivertebrae and encaging the vertebral artery, preventing invasive surgery; CT at diagnosis (B) identified a bulky lesion originating from C4-C7 hemivertebrae. CT performed 6 months after the introduction of denosumab (C) showed a massive calcification of the lesion that remained stable in size.\n\nTaking account of the size of the tumor and the vascular involvement, the lesion was considered as non resectable and medical therapy with denosumab was considered after discussion in a multidisciplinary tumor board.\n\nDenosumab Administration and Anti-Tumoral Effect\n\nDenosumab 70 mg/m2 was administered subcutaneously weekly for 4 weeks, then the maintenance dose was fixed at 1 administration monthly for one year.\n\nAfter 5 doses of denosumab, neurological deficits improved with complete normalization after 4 months of treatment. CT was performed and showed a massive calcification of the lesion that remained stable in size ( Figure 1C ). Thus, denosumab was stopped, on the basis of the optimal clinical response and lack of accurate guidelines on treatment duration. The patient was then followed with tumor radiological evaluation every 3 months. Tumor evaluation performed 9 months after the end of denosumab showed tumor growth recurrence, while patient was this time asymptomatic, and denosumab was resumed. After one year of treatment, denosumab was progressively tapered firstly one administration every 2 months for 4 months, then once every 3 months during 12 months. The anti-tumoral effect was considered satisfactory as the lytic cervical lesion was stable on MRI. At physical examination the lesion was described as stable, polylobulate and calcified, measuring ~6 x 7 cm. Two and a half years after this second course of denosumab, i.e. 4.5 years after the diagnosis, denosumab treatment was stopped because of the long-term tumoral control. At last follow-up (Dec 2020), 15 months after the last injection of denosumab, the patient continues asymptomatic and tumor size is stable. The anti-tumoral efficacy of this treatment in this patient was extensively reported in a case series (15).\n\nMineral Homeostasis During Denosumab Therapy\n\nDenosumab therapy led to optimal control of symptoms and persistent radiological response yet flawed severely the mineral homeostasis.\n\nSix months after the discontinuation of the first course of denosumab, the patient developed severe rebound hypercalcemia (total serum calcium 3.7 mmol/l, normal range 2.2-2.7 mmol/l; PTH 1 ng/l, normal range 14-74 ng/l), that required administration of a loop diuretic (furosemide) and intravenous infusion of zoledronic acid to restore normal serum calcium values. During this episode of hypercalcemia, a hypertensive crisis occurred that required the transient administration of calcium channel blockers to restore normal blood pressure.\n\nA new episode of hypercalcemia occurred after denosumab reintroduction, this time while on denosumab tapering, 3 months after the last denosumab injection, when he was hospitalized for intense abdominal pain and loss of appetite. Blood exams revealed severe hypercalcemia (total serum calcium 3.51 mmol/l; ionized serum calcium 1.71 mmol/l), severe dehydration and acute kidney injury, but neither ECG abnormalities nor neurological complications were detected. The patient was treated with aggressive intravenous rehydration and a loop diuretic (furosemide) to progressively lower serum calcium levels; in addition, he received his dose of denosumab as initially planned. Serum calcium lowered to 2.13 mmol/l; the last dose of denosumab was administered two months after this episode. Nevertheless, 45 days after the last injection of denosumab, the patient developed another episode of severe hypercalcemia (total serum calcium 3.15 mmol/l), that was treated with intravenous zoledronic acid (see Table 1 ). Because of the rebound hypercalcemia and the abnormal bone modelling (see below), the case was presented at a European expert panel through the Clinical Patient Management System (CPMS), a web solution designed to support European Reference Networks (ERN) in improving the diagnosis and treatment of patients affected with rare diseases. Parents gave their consent and experts from the endoERN and from the rare bone disease ERN (BOND) provided their advice.\n\nTable 1 Blood exams results during denosumab treatment.\n\nAge\t10 Y 1 M\t10Y 7M\t10Y 9M\t11Y10M\t12Y 2M\t12Y 4M\t12Y 5M\t12Y 6M\t12Y 8M\t12Y 9M\t12Y10M\t12Y 11M\t13Y 1M\t13Y6M\t13Y7M\t13Y11M\t14Y\t\nUr Creatinine (mmol/L)\t\t\t7.5\t17.2\t\t\t3.9\t17.6\t\t6.62\t\t8.1\t7.2\t21.8\t6.9\t\t\t\nUr Calcium (mmol/L)\t\t\t<0.2\t0.58\t\t\t4.77\t2.4\t\t8.13\t\t6.11\t8.56\t1.85\t3.0\t\t\t\nUr Ca/Crea ratio\t\t\t<0.2\t0.03\t\t\t1.22\t0.13\t\t1.22\t\t0.75\t1.8\t0.09\t0.43\t\t\t\nUr Phosphate (mmol/L)\t\t\t\t38.8\t\t\t16.6\t60\t\t13\t\t7.4\t11.4\t34.8\t7.9\t\t\t\nUr DPD/Crea\t\t\t7\t\t\t\t\t12.4\t\t\t\t\t\t\t\t\t\t\nCreatinine (μmol/L)\t\t\t\t41\t\t\t65\t38\t\t\t36\t40\t\t\t41\t\t45\t\nCalcium (mmol/L)\t3.7\t2.23\t2.33\t2.49\t2.76\t2.98\t3.51\t2.26\t3.15\t2.74\t2.27\t2.59\t2.66\t2.51\t2.6\t2.5\t2.48\t\nPhosphate (mmol/L)\t\t0.93\t0.97\t1.34\t\t\t2.05\t1.07\t\t1.83\t0.94\t1.86\t1.58\t1.77\t1.7\t1.69\t1.59\t\nMagnesium (mmol/L)\t\t\t0.91\t0.94\t\t\t\t\t\t0.79\t0.86\t0.78\t0.77\t0.80\t0.9\t\t0.8\t\nALP (U/L)\t\t\t\t98\t\t\t\t85\t\t148\t\t145\t237\t270\t253\t\t235\t\nC-telopeptide (ng/mL)\n(10-14 yo: 0.70-3.10)\t\t\t0.09\t\t\t\t\t0.33\t\t\t\t\t\t2.060\t3.9\t\t2.5\t\nFGF23 (23.2-95.3)\t\t\t43.9\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\nOsteocalcin (ng/ml)\n(4.00-60.00)\t\t\t43\t\t\t\t\t46\t\t\t\t\t141\t\t299\t\t217\t\nPTH (ng/l)\t1\t236\t180\t57\t\t\t1\t66\t\t6.9\t102\t13\t11\t18.1\t21\t20\t32\t\n25OHvitD (ng/mL)\t\t17\t20\t30\t\t\t79.1\t46\t\t56\t26\t35\t38\t39\t36\t36\t28\t\n1,25OHvitD (ng/mL)\t\t\t\t\t\t\t\t\t\t21\t\t\t\t65.7\t\t\t\t\n\t\t\t\t\t\t\t▲\t\t\t▲\t\t\t\n\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\n\t6 months since discontinuation of first course of Dmab\tDmab 1/wk\tDmab 1/mo\tDmab\n/2mo\t\t\tDmab\n/3mo\tDmab\n/2mo\tZoled\n0.05\nmg/kg\tDmab\n/2mo\tDmab\n/2mo\tDmab\n/2mo\tZoled/\n6 mo\tZoled/\n6 mo\tZoled/\n6 mo\t5 mo since last zoled\tZoled/\n6 mo\t\nDmab, denosumab; Zoled, zoledronic acid (0,05 mg/kg); Y, year; M, months; mo, months; wk, week; reintroduction of denosumab for the second course of treatment, ▲ denosumab injection a few days before the serum calcium measurement, discontinuation of denosumab.\n\nAbnormal results are shown in bold.\n\nAt this point, the tumor was considered as stable, denosumab was stopped and 6 monthly IV zoledronic acid infusions were initiated in order to control the rebound hypercalcemia post-denosumab therapy. At this day, four infusions have been performed at the dose of 0.05 mg/kg (last infusion Jan 2021), the patient is asymptomatic, and the calcium levels remained below the upper limit of normal.\n\nIn the Table 1 we describe the mineral homeostasis during denosumab treatment, with particular focus on the second course of the treatment, while the Figure 2 shows the trend of serum calcium levels.\n\nFigure 2 Trend of serum calcium levels during denosumab therapy. Hypercalcemia occurring during wash-out period, progressive rise of serum calcium levels when the injections are spaced and calcium levels remained below the upper limit of normal with 6 monthly IV zoledronic acid infusions.\n\nBone Remodeling, Modeling and Growth During Denosumab Therapy\n\nIn parallel to the rapid changes of mineral homeostasis during denosumab treatment, we observed an amplified bone remodeling in response to denosumab therapy. After 1 year of treatment, the patient developed sclerotic metaphyseal bands visible on radiographs. Sclerotic lines partially vanished during wash-out periods or when the injections of denosumab were spaced ( Figures 3A–D and Figures 4B, C ). These bands were more pronounced on long bones, but diffuse osteocondensation of ribs, hips and shoulders was also detected ( Figure 5A ).\n\nFigure 3 Hand and knee radiographs during follow-up. Radiographs taken (A) after 1 year of denosumab (onset of sclerotic metaphyseal bands), (B) after 10 months of denosumab wash-out (reduction of sclerotic bands), (C) after 1.5 years of the 2nd course of denosumab (more pronounced sclerotic metaphyseal bands) and (D) after 2 years of the 2nd course of denosumab (severe and persistent sclerotic metaphyseal bands).\n\nFigure 4 Knees and lower limb radiographs. Lower limbs were imaged standing using EOS. (A, B) lower limb deformities at the age of 12.4 years. (C) deformities worsened after one additional year, (D) post-surgery radiographs of knees.\n\nFigure 5 Spine, thoracic and hip radiographic view done by EOS and growth chart. (A) The radiograph was done after 2 years of the 2nd course of denosumab showing sclerotic bands at ribs, hips and shoulders. (B) Evolution of growth.\n\nAs expected, the spine bone mineral density measured by DEXA and its relative z-score progressively increased between the age of 9.5 and 12.4 years from 0.841 g/cm2 to 1.066 g/cm2, and from 0.7 to 1.9, respectively, see Figure 6 .\n\nFigure 6 Chart of the patient follow-up.\n\nDuring the follow-up we continue monitoring patient’s growth, that was regular and linear until he was 11 years old and 4 months. Then we documented a diminished growth velocity during the period that preceded puberty ( Figure 5B ).\n\nMoreover, it is worth signaling that over the years the patient developed lower limb deformities, i.e. genu valgum with intermalleolar distance of about 11 cm ( Figure 4 ), which have become progressively more and more painful and eventually required bilateral epiphysiodesis.\n\nDiscussion\n\nA recent review on denosumab therapy for pediatric bone disorders collected reports on 45 children who received denosumab for various conditions (9). This includes children treated with denosumab to target the RANKL/RANK/OPG, signaling pathway involved in the development of ABCs and tumor growth (6).\n\nLange et al. firstly described the use of denosumab in two boys aged 8 and 11 years to treat recurrent ABCs localized at the C5 vertebrae, and in whom surgery and arterial embolization had failed. Patients received high doses of denosumab, similarly to our report, i.e., 70 mg/m2 monthly (Patient 1) 70 mg/m2 weekly for 4 weeks and then 70 mg/m2 monthly (Patient 2). Both patients recovered from pain and neurological symptoms and showed tumor regression respectively after 2 and 4 months of treatment. During the 2 and 4 months of follow-up, no adverse effects was reported apart from asymptomatic hypocalcemia in one of the patients (7).\n\nSeveral other cases have been subsequently reported. Doses of denosumab ranged from 1.6 mg/kg monthly to 70 mg/m2 monthly for a duration of 4 months to 2 years. One patient developed transient hypocalcemia during the course of treatment (6, 12, 16–18).\n\nHypercalcemia has been reported in children upon denosumab therapy on average 5 months after the discontinuation of their treatment (see Table 2 ). In those cases, denosumab was used as an adjuvant therapy in giant cell tumors of bone (19–21), juvenile Paget’s disease (22), fibrous dysplasia (23), and osteogenesis imperfecta type VI (24, 25) or ABCs. In ABCs, children who presented rebound hypercalcemia received doses similar to our current report (13, 14). Many reports did not contain information about serum calcium after or during denosumab treatment; follow-up after denosumab discontinuation was often short likely underestimating the occurrence of mild hypercalcemia. In our experience, severe hypercalcemia occurred after discontinuation of denosumab or when the doses were spaced. It becomes clear that longer follow-up is required to evaluate the real prevalence of this post-discontinuation effect. In adults treated with long-term denosumab therapy, only few cases have been described (26, 27).\n\nTable 2 Post-discontinuation hypercalcemia after high dose denosumab in pediatric series.\n\nReference\tTumor\tPatient\tDose\tDuration\tResponse\tPost-discontinuation side effects\tTiming of hypercalcemia\tTotal doses\t\nGossai et al. (19)\tMetastatic GCTB of the knee\tF 10 yo\t120 mg weekly (4 times), 120 mg monthly\t24 months\tClinical and radiological improvement\tSevere hypercalcemia, metaphyseal bands in long bones (osteopetrosis)\t5 months after last denosumab injection\t27\t\nUday et al. (20)\tGCTB sacrum\nsacrum scapula\tM 15 yo\nF 14 yo\nM 40 yo\t120 mg weekly (4 times), 120 mg monthly\t3.6 y\n1.3 y\n4.0 y\tClinical and radiological improvement\tSevere hypercalcemia\nSevere hypercalcemia/ONJ\nSevere hypercalcemia\t7 months after last inj.\n6 months after last inj.\n5.5 months after last inj.\t46\n18\n51\t\nSetsu et al. (21)\tSacral GCTB\tM 10 yo\t120 mg monthly\t14 months\tClinical and radiological improvement\tSevere hypercalcemia\t4 months after last denosumab injection\t12\t\nGrasemann et al. (22)\tJPD\tF 7 yo\t0.5 mg/kg x 2 dose spaced 6 weeks\t6 weeks\tClinical improvement (pain, mobility)\tSevere hypercalcemia\t7 weeks after second dose\t2\t\nBoyce et al. (23)\tFD\tM 9 yo\t1 mg/kg monthly for 3 months-1.25 mg/kg monthly for 3 months-then 1.5 mg/kg monthly\t7 months (interrupted for occurring fracture)\tReduction in pain, BMT, tumor growth rate\tSevere hypercalcemia\t2 months after last denosumab injection\t7\t\nTrejo et al. (24)\tOI type VI\tM 4.6 yo\nF 3.9 yo\t1 mg/kg every 3 months\t\tIncreased BMD\tHypercalcemia during the interval between denosumab injections\t7 and 12 weeks after the preceding injection\t9\n6\t\nHoyer-Kuhn et al. (25)\tOI type 1, 3 & 4\t10 children 5-11 yo\t1 mg/kg every 3 months\t12 months\tIncreased BMD\tMild hypercalcemia\tDocumented at the end of the trial\t4\t\nKurucu et al. (14)\tABC\t9 cases (5 M; 4 F); median age 12.5 yo\t70 mg/m2 weekly (4 times) then monthly\tMedian 12 months\tClinical and radiological improvement\tSevere hypercalcemia in 2 patients who had received 17 doses of Denosumab\t5 months after last inj.\t17\t\nDürr et al. (13)\tABC\t6 cases (4 F; 2 M) median age 17 yo\t120 mg weekly (4 times), 120 mg monthly / 60mg every 4 weeks with two additional doses on days 8 and 15 in pt 6 yo\tMedian 12 months\tClinical improvement and radiological stability\tSevere hypercalcemia in patient who received 50% of proposed dosage\t6 months after last inj.\t15\t\nSydlik et al. (11)\tGCTB\nGCTB\nABC\nABC\tF 12 yo\nM 13 yo\nM 12 yo\nM 6 yo\t60 mg on days 1, 8, 15, 28, and then monthly\t14 months\n14/7 months\n17 months\n9 months\tClinical and radiological improvement\tSevere hypercalcemia\t2 m after last inj.\n2-3 m after last inj.\n1 m after last inj.\n3 m after last inj.\t14\n17/10\n17\n9\t\nRaux et al. (15)\tABC\tM 8 yo\nM 8 yo (our case, see below)\t70 mg/m2 weekly (4 times) then monthly\t17 months\t17 months\t3 episodes of hypercalcemia\t3, 5, 6 m after last inj.\t20\t\nOur case\tABC\t8 yo\t70 mg/m2 weekly (4 times) then monthly\n70 mg/m2 weekly (4 times) then monthly, then every 2 mon, finally every 3 mon\t12 months\n30 months\tClinical improvement and radiological stability\tSevere hypercalcemia,\nmetaphyseal bands in long bones\nSevere hypercalcemia,\nmetaphyseal bands in long bones\t5 months after last inj.\n3 months after last inj.\t15\n22\t\nGCTB, giant cell tumor of bone; JPD, juvenile Paget's disease; FD, fibrous dysplasia; BMT, bone marker turnover; OI,osteogenesis imperfecta; ABC, aneurysmal bone cyst.\n\nTowards the end of denosumab activity, the rapid recovery of bone resorption and the release of inhibition of osteoclast maturation and action may lead to a rebound hypercalcemia. Children may be particularly at risk for this rebound osteoclastic activity due to their higher baseline bone turnover (9). Rebound may also be more frequent in children with high bone turnover disorders, which usually support the use of denosumab in children (9). Therefore, a gradual tapering of the denosumab injections has been proposed to prevent the development or recurrence of hypercalcemia (13, 14). As we have shown in this report, alternative, or even, additional strategies may be necessary to inhibit osteoclastogenesis and slow the calcium release from the bone. Bisphosphonates are commonly used in adults to prevent rebound hypercalcemia (27–29); they are incorporated into the bone matrix, tampering the osteoclasts activity when denosumab is interrupted. Bisphosphonates should as well be considered in children at high risk of hypercalcemia because of denosumab therapy (11). In our experience, zoledronic acid allowed the rapid decrease of serum calcium and the prevention of recurrent episodes of symptomatic hypercalcemia.\n\nIn addition, use of denosumab in young patients whose growth plate have not yet closed, could result in changes similar to osteopetrosis (30). It is reported that in children treated with bisphosphonates, histological analyses of growth plates revealed retention of calcified cartilage, which is hypothesized to represent horizontal trabeculae formed during the temporary inhibition of epiphyseal activity; dense sclerotic bands on radiographs are seen as a consequence (31). Because denosumab and bisphosphonates both inhibit osteoclast function, the same underlying mechanism may explain the observed skeletal effects with denosumab (32), as in our patient. Experience with bisphosphonates in children is more extensive than that of denosumab, and few complications related to the sclerotic lines have been reported. However, the consequences of long-term bone turnover suppression on the growing skeleton have not been determined. To date, there are no reports suggesting significant effects of denosumab on linear growth (32). However, we think that denosumab impacted bone modeling in our case report through the alternance of suppressed and active bone resorption when denosumab was stopped and resumed or when injections were spaced.\n\nOn the other hand, growth chart of our patient shows a linear and regular pattern until the period that preceded puberty. This is probably due to the physiological deceleration of growth velocity before puberty, but we can’t exclude that the repeated action of denosumab on growth plates also played a role. It is possible that the inhibition and subsequent rebound osteoclasts activity have damaged growth plates cartilage and impacted linear skeletal growth. Further studies may be useful in this field.\n\nBone mineral density measured by DEXA and its relative z-score progressively increased during follow-up, as expected with age, height, weight and during pubertal development. The factors that contribute to the pubertal increase in mineralization are not fully known, but a critical role belongs to the sex steroids (33). The concomitant denosumab therapy in our case probably also had a role in the increase of bone mass.\n\nIn conclusion, more and more studies revealed the efficacy of denosumab treatment not only in giant cell tumors and aneurysmatic bone cysts but also in several other osteolytic diseases. Recently Raux et al. (15) stressed the importance of multidisciplinary discussion on the role of neoadjuvant denosumab treatment in children harboring ABCs. It remains critical to establish the optimal duration of the treatment and at the same time to investigate long term control of tumor growth when surgery is not performed. Moreover, unlike adults, severe hypercalcemia at discontinuation of treatment seems rather frequent in children. It is therefore critical to be aware of strategies for treatment or prevention. In addition, experts’ panels may bring insight for the management of these rare situations and should be easily solicited, as we did for our patient.\n\nThis case report has some limitations, such as the lack of long-term follow-up. Even if previously reported in other studies and case series, our aim was to describe detailed perturbations of mineral metabolism during and after denosumab treatment in children and adolescents, and to stress the importance of monitoring systematically growth, limb deformities, serum calcium and mineral homeostasis in children and adolescents receiving denosumab.\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.\n\nEthics Statement\n\nWritten informed consent was obtained from the minor(s)’ legal guardian/next of kin for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\n\nLB, PB, ET, AL, and PW performed clinical diagnosis and conducted patient management and follow-up. GD and AL drafted the manuscript. LB, PB, ET, GM, PW, and AL performed the critical revision of the manuscript. 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\nAcknowledgments\n\nAL: AP-HP, Centre de Référence des maladies rares du métabolisme du Calcium et du Phosphate, filière OSCAR, Paris, France.\n==== Refs\nReferences\n\n1 Sayago LR Remondino RG Tello CA Piantoni L Francheri Wilson IA Galaretto E . Aneurysmal Bone Cysts of the Spine in Children: A Review of 18 Cases. Glob Spine J (2020) 10 (7 ):875−80. 10.1177/2192568219881166\n2 Zhao Y He S Sun H Cai X Gao X Wang P . Symptomatic Aneurysmal Bone Cysts of the Spine: Clinical Features, Surgical Outcomes, and Prognostic Factors. Eur Spine J (2019) 28 (6 ):1537−45. 10.1007/s00586-019-05920-7 30838451\n3 Rapp TB Ward JP Alaia MJ . Aneurysmal Bone Cyst. 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Safety and Efficacy of Denosumab in Children With Osteogenesis Imperfecta - a First Prospective Trial. J Musculoskelet Neuronal Interact (2016) 16 (1 ):24–32.26944820\n26 Koldkjær Sølling AS Harsløf T Kaal A Rejnmark L Langdahl B . Hypercalcemia After Discontinuation of Long-Term Denosumab Treatment. Osteoporos Int J Establ Result Coop Eur Found Osteoporos Natl Osteoporos Found USA (2016) 27 (7 ):2383−6. 10.1007/s00198-016-3535-5\n27 Roux S Massicotte M-H Huot Daneault A Brazeau-Lamontagne L Dufresne J . Acute Hypercalcemia and Excessive Bone Resorption Following Anti-RANKL Withdrawal: Case Report and Brief Literature Review. Bone (2019) 120 :482−6. 10.1016/j.bone.2018.12.012 30572144\n28 Tsourdi E Langdahl B Cohen-Solal M Aubry-Rozier B Eriksen EF Guañabens N . Discontinuation of Denosumab Therapy for Osteoporosis: A Systematic Review and Position Statement by ECTS. Bone (2017) 105 :11−7. 10.1016/j.bone.2017.08.003 28789921\n29 Bone HG Bolognese MA Yuen CK Kendler DL Miller PD Yang Y-C . Effects of Denosumab Treatment and Discontinuation on Bone Mineral Density and Bone Turnover Markers in Postmenopausal Women With Low Bone Mass. J Clin Endocrinol Metab (2011) 96 (4 ):972−80. 10.1210/jc.2010-1502 21289258\n30 Dunnion S Paterson A Johnston R . Dense Sclerotic Metaphyseal Bands Caused by Denosumab Therapy. Pediatr Radiol (2020) 50 (6 ):877−8. 10.1007/s00247-020-04651-y 32189019\n31 Rauch F Travers R Munns C Glorieux FH . Sclerotic Metaphyseal Lines in a Child Treated With Pamidronate: Histomorphometric Analysis. J Bone Miner Res (2004) 19 (7 ):1191−3. 10.1359/JBMR.040303 15177003\n32 Wang HD Boyce AM Tsai JY Gafni RI Farley FA Kasa-Vubu JZ . Effects of Denosumab Treatment and Discontinuation on Human Growth Plates. J Clin Endocrinol Metab (2014) 99 (3 ):891−7. 10.1210/jc.2013-3081 24423331\n33 Yilmaz D Ersoy B Bilgin E Gümüşer G Onur E Pinar ED . Bone Mineral Density in Girls and Boys at Different Pubertal Stages: Relation With Gonadal Steroids, Bone Formation Markers, and Growth Parameters. J Bone Miner Metab (2005) 23 (6 ):476−82. 10.1007/s00774-005-0631-6 16261455\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1664-2392",
"issue": "12()",
"journal": "Frontiers in endocrinology",
"keywords": "aneurysmal bone cyst; bisphosphonate; bone modeling; denosumab; hypercalcemia",
"medline_ta": "Front Endocrinol (Lausanne)",
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"nlm_unique_id": "101555782",
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"references": "30972268;30572144;26793296;16261455;26944820;22431375;15177003;31630689;24423331;30631617;29504582;28789921;22474093;21289258;32189019;31358461;29470716;30838451;20418905;16382110;32776272;26056018;23788687;24726460;23455951;29211870;27098536;28643220;32905733;30931897;25556556;29286564;29181213",
"title": "Mineral and Bone Consequences of High Dose Denosumab Therapy to Treat an Aneurysmal Bone Cyst, a Child Case Report.",
"title_normalized": "mineral and bone consequences of high dose denosumab therapy to treat an aneurysmal bone cyst a child case report"
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"abstract": "Enterococcus faecium is a commensal organism commonly colonizing the human gastrointestinal tract. Although it is generally a non-virulent organism, E. faecium can cause significant morbidity and mortality due to its inherent and acquired resistances to commonly used antimicrobials. Patients who are immunosuppressed are particularly vulnerable.\nA 65-75-year-old patient with a history of an orthotopic liver transplant for hepatitis C infection and diabetes was re-admitted to the hospital with abdominal pain and fever. The patient had several recent admissions related to the presentation reported here, which included treatment with a prolonged course of broad-spectrum antibiotics. The patient was found to have a recurrent liver abscess and blood cultures grew vancomycin-resistant E. faecium, non-susceptible to all tested agents: ampicillin, penicillin, vancomycin, daptomycin and linezolid. The patient was started initially on chloramphenicol intravenously while awaiting additional susceptibility testing, which ultimately revealed chloramphenicol non-susceptibility. Tigecycline was started but the patient ultimately decided to pursue hospice care.\nMulti-drug-resistant organisms are increasingly being recognized and are associated with poorer outcomes, particularly in immunosuppressed patients. We describe a particularly resistant organism and discuss potential therapeutic options.",
"affiliations": "Division of Infectious Diseases, Department of Medicine, Emory University, Atlanta, GA, USA.;Department of Global Health, Emory University, Atlanta, GA, USA.;Division of Infectious Diseases, Department of Medicine, Emory University, Atlanta, GA, USA.;Division of Infectious Diseases, Department of Medicine, Emory University, Atlanta, GA, USA.;Division of Infectious Diseases, Department of Medicine, Emory University, Atlanta, GA, USA.",
"authors": "Summers|Nathan A|NA|;Gharbin|John|J|;Friedman-Moraco|Rachel|R|;Lyon|G Marshall|GM|;Lutgring|Joseph|J|",
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"fulltext": "\n==== Front\nJMM Case RepJMM Case RepjmmcrjmmcrJMM Case Reports2053-3721Microbiology Society jmmcr00517210.1099/jmmcr.0.005172Case ReportBlood/heart and LymphaticsMulti-drug-resistant Enterococcus faecium bacteraemia in a liver transplant recipient http://jmmcr.microbiologyresearch.orgSummers Nathan A. 1*Gharbin John 2Friedman-Moraco Rachel 1Lyon G. Marshall 1Lutgring Joseph 11 Division of Infectious Diseases, Department of Medicine, Emory University, Atlanta, GA, USA2 Department of Global Health, Emory University, Atlanta, GA, USA*Correspondence: Nathan A. Summers, nate.summers@gmail.com1 2019 20 12 2018 20 12 2018 6 1 e00517212 9 2018 04 12 2018 © 2019 The Authors2019This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Introduction\nEnterococcus faecium is a commensal organism commonly colonizing the human gastrointestinal tract. Although it is generally a non-virulent organism, E. faecium can cause significant morbidity and mortality due to its inherent and acquired resistances to commonly used antimicrobials. Patients who are immunosuppressed are particularly vulnerable.\n\nCase presentation\nA 65–75-year-old patient with a history of an orthotopic liver transplant for hepatitis C infection and diabetes was re-admitted to the hospital with abdominal pain and fever. The patient had several recent admissions related to the presentation reported here, which included treatment with a prolonged course of broad-spectrum antibiotics. The patient was found to have a recurrent liver abscess and blood cultures grew vancomycin-resistant E. faecium, non-susceptible to all tested agents: ampicillin, penicillin, vancomycin, daptomycin and linezolid. The patient was started initially on chloramphenicol intravenously while awaiting additional susceptibility testing, which ultimately revealed chloramphenicol non-susceptibility. Tigecycline was started but the patient ultimately decided to pursue hospice care.\n\nConclusion\nMulti-drug-resistant organisms are increasingly being recognized and are associated with poorer outcomes, particularly in immunosuppressed patients. We describe a particularly resistant organism and discuss potential therapeutic options.\n\nbacteraemialiver abscesschloramphenicoltigecyclinesolid organ transplantNational Institutes of HealthUL1 TR002378, TL1 TR002382OpenAccessEmbargo0\n==== Body\nIntroduction\nEnterococcus species, including Enterococcus faecium, are frequent colonizers of the human gastrointestinal tract and are frequently viewed as commensal organisms [1]. Although not typically considered to be virulent organisms, Enterococcus species, particularly E. faecium, can have significant pathogenic potential due to both inherent and acquired resistances to many commonly used antibiotics used today [1, 2]. Despite advances in clinical care, including newer antimicrobials, outcomes for infections caused by Enterococcus species are poor, and are considerably worse for vancomycin-resistant E. faecium (VRE) compared to susceptible strains [2]. Multi-drug-resistant organisms are increasingly recognized as problems for immunocompromised patients, particularly VRE [3]. Having a deeper understanding of the antimicrobials available, as well as their potential toxicities and drug–drug interactions, is vitally important to improving patient outcomes.\n\nCase report\nOur patient was a 65–75-year-old with a history of orthotopic liver transplant in 2000 for hepatitis C infection, on chronic immunosuppression with cyclosporine, pancreatic adenocarcinoma status post-Whipple procedure in 2015, and diabetes mellitus, who was admitted for fever and worsening abdominal pain. The patient had several recent admissions in the preceding 3 months for perihepatic abscess and bacteraemia. Three months prior to the admission reported here, liver abscess cultures obtained during drain placement grew Rothia mucilaginosa and α-haemolytic Streptococcus species, with Streptococcus parasanguinis growing in two sets of blood cultures. The patient was sent home on ceftriaxone 2 grams (gm) intravenously (IV) every 24 h and metronidazole 500 milligrams (mg) by mouth (PO) every 8 h but was readmitted 1 month later with Candida parapsilosis fungaemia, felt to be related to the peripherally inserted central catheter (PICC). The PICC was removed and antimicrobials were changed to moxifloxacin 400 mg PO once daily and a 2 week course of fluconazole 400 mg PO every 24 h. The patient was readmitted 1 month before the admission reported here while still on the moxifloxacin, and was found to have worsening abdominal pain and an enlarging perihepatic abscess on a computerized tomography (CT) scan of the abdomen. A new drain was placed into the liver abscess, and cultures from this drain grew VRE. Antibiotics were then adjusted to daptomycin (dosed at 10 mg kg−1 every 24 h) and moxifloxacin 400 mg PO every 24 h for presumed polymicrobial infection, and the patient was discharged with a new PICC to complete a tentative 4–6-week course.\n\nAt the beginning of the patient’s admission reported here, approximately 2 weeks after the most recent discharge, the antibiotics were changed to daptomycin 10 mg/kg every 24 h and meropenem 500 mg every 8 h (adjusted for his renal impairment) for improved Gram-negative and anaerobic coverage. A CT scan of the patient’s abdomen and pelvis was obtained (Fig. 1). Blood cultures returned with VRE, non-susceptible to ampicillin, penicillin, vancomycin, daptomycin and linezolid on initial susceptibilities performed by the MicroScan WalkAway-96 plus system with the Pos Combo 33 panel (Beckman Coulter Diagnostics). The daptomycin MIC was confirmed to be 8 µg ml−1 with ETEST (bioMérieux).\n\nFig. 1. CT scan of the liver abscess with the drain in place.\n\nAdditional susceptibilities were requested for chloramphenicol and tigecycline by ETEST. Susceptibility testing for quinupristin/dalfopristin, telavancin, dalbavancin and oritavancin was not performed because these agents were not on formulary and access to these therapeutics was not possible at the time. Quinupristin/dalfopristin was not used because it interacts with calcineurin inhibitors leading to supratherapeutic drug levels of cyclosporine and tacrolimus. The patient’s PICC was removed and the patient was started on intravenous chloramphenicol while awaiting further workup. This decision was based on the patient’s resistance pattern, as well as greater serum concentrations of chloramphenicol compared to tigecycline. Additional testing revealed non-susceptibility to chloramphenicol (MIC=16 µg ml−1). The isolate was susceptible to tigecycline (MIC ≤ 0.25 µg ml−1), so the decision was made to transition to tigecycline monotherapy, as it was felt that adequate serum concentrations were achievable with such a low MIC. The patient initially tolerated this change well and was discharged home with a new PICC. Unfortunately, the patient was later admitted with persistent failure to thrive including nausea, diarrhoea and weakness 1 month later. Palliative care was considered and the patient decided to pursue hospice care, declining further antimicrobial treatment.\n\nDiscussion\nMulti-drug-resistant E. faecium treatment is an increasing challenge, confronting clinicians globally. Although current recommendations encourage the use of daptomycin or linezolid as the first-line treatment options for VRE [4, 5], data is lacking for solid organ transplant recipients on immunosuppressive agents or in cases where the first-line antimicrobials are ineffective. Alternative therapeutic agents for the treatment of VRE in the presence of resistance to ampicillin, penicillin, vancomycin, daptomycin and linezolid are limited. Quinupristin/dalfopristin is active against E. faecium but not Enterococcus faecalis, but it is poorly tolerated, requires central venous access for administration, and increases serum concentrations of calcineurin inhibitors and mTOR inhibitors, which are commonly used in solid organ transplant recipients [3]. Tigecycline also possesses activity against VRE, but achieves very low serum concentrations and there is concern for increased mortality compared to other agents [6]. Telavancin, a lipoglycopeptide, is active against VRE strains possessing van B but not van A. Oritavancin, a long-acting lipoglycopeptide, is active against VRE strains possessing both van A and van B [7, 8], but clinical data for VRE bacteraemia is sparse.\n\nChloramphenicol possesses activity against VRE, but its toxicities limit widespread use today. Chloramphenicol is associated with both a reversible, dose-dependent bone marrow suppression, as well as dose-independent, irreversible aplastic anaemia [9, 10]. Although the mechanisms are not fully clear, the irreversible aplastic anaemia is primarily seen with oral administration of the agent, but not with intravenous administration. It is felt that enteric bacteria may play a role by degrading chloramphenicol, releasing toxic metabolites that are then absorbed enterally. The p-nitrosulfathiazole group, which inhibits DNA synthesis, is believed to be the causative metabolite, supported by the fact that thiamphenicol, available in Europe but not currently in the USA, does not possess this group and is not associated with aplastic anaemia [9, 10].\n\nIt was surprising to find chloramphenicol resistance despite a lack of prior exposure to the agent. Chloramphenicol resistance has been described previously and appears to be related to recent exposure to fluoroquinolones, as was the case for our patient [11]. Resistance is typically mediated through a multi-drug efflux pump, conveying resistance to fluoroquinolones, tetracyclines and chloramphenicol [12]. It is likely that our patient’s recent prolonged exposure to moxifloxacin upregulated this efflux pump, conveying resistance to chloramphenicol despite the patient’s lack of prior exposure.\n\nMulti-drug resistant and extensively drug resistant organisms are becoming more common with the increased use of broad-spectrum antimicrobials, especially in the immunocompromised host [3]. As resistance develops to the preferred agents, it is imperative to understand the strengths and limitations of alternative agents, along with emerging resistance mechanisms.\n\nFunding information\nN. A. S. is supported in part by the National Center for Advancing Translational Sciences of the National Institutes of Health (grant numbers UL1 TR002378 and TL1 TR002382).\n\nConflicts of interest\nThe authors declare that there are no conflicts of interest.\n\nAbbreviations: CT, computerized tomography; PICC, peripherally inserted central catheter; VRE, vancomycin-resistant Enterococcus faecium.\n==== Refs\nReferences\n1 Arias CA Murray BE The rise of the Enterococcus : beyond vancomycin resistance Nat Rev Microbiol 2012 10 266 278 10.1038/nrmicro2761 22421879 \n2 Prematunge C MacDougall C Johnstone J Adomako K Lam F VRE and VSE bacteremia outcomes in the era of effective vre therapy: a systematic review and meta-analysis Infect Control Hosp Epidemiol 2016 37 26 35 10.1017/ice.2015.228 26434609 \n3 Patel G Snydman DR AST Infectious Diseases Community of Practice Vancomycin-resistant Enterococcus infections in solid organ transplantation Am J Transplant 2013 13 (Suppl. 4) 59 67 10.1111/ajt.12099 23464999 \n4 Arias CA Contreras GA Murray BE Management of multidrug-resistant enterococcal infections Clin Microbiol Infect 2010 16 555 562 10.1111/j.1469-0691.2010.03214.x 20569266 \n5 Mermel LA Allon M Bouza E Craven DE Flynn P Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009. Update by the Infectious Diseases Society of America Clin Infect Dis 2009 49 1 45 10.1086/599376 19489710 \n6 FDA. FDA Warns of Increased Risk of Death with IV Antibacterial Tygacil (Tigecycline) and Approves New Boxed Warning. Silver Spring, MD: U.S. Food and Drug Administration; 2013 \n7 Arias CA Mendes RE Stilwell MG Jones RN Murray BE Unmet needs and prospects for oritavancin in the management of vancomycin-resistant enterococcal infections Clin Infect Dis 2012 54 S233 S238 10.1093/cid/cir924 22431854 \n8 Stryjewski ME Graham DR Wilson SE O'Riordan W Young D Telavancin versus vancomycin for the treatment of complicated skin and skin-structure infections caused by gram-positive organisms Clin Infect Dis 2008 46 1683 1693 10.1086/587896 18444791 \n9 Barnhill AE Brewer MT Carlson SA Adverse effects of antimicrobials via predictable or idiosyncratic inhibition of host mitochondrial components Antimicrob Agents Chemother 2012 56 4046 4051 10.1128/AAC.00678-12 22615289 \n10 Yunis AA Chloramphenicol toxicity: 25 years of research Am J Med 1989 87 44n 48n 2486534 \n11 Gould CV Fishman NO Nachamkin I Lautenbach E Chloramphenicol resistance in vancomycin-resistant enterococcal bacteremia: impact of prior fluoroquinolone use? Infect Control Hosp Epidemiol 2004 25 138 145 10.1086/502365 14994940 \n12 Lynch C Courvalin P Nikaido H Active efflux of antimicrobial agents in wild-type strains of enterococci Antimicrob Agents Chemother 1997 41 869 871 10.1128/AAC.41.4.869 9087510\n\n",
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"keywords": "bacteraemia; chloramphenicol; liver abscess; solid organ transplant; tigecycline",
"medline_ta": "JMM Case Rep",
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"title": "Multi-drug-resistant Enterococcus faecium bacteraemia in a liver transplant recipient.",
"title_normalized": "multi drug resistant enterococcus faecium bacteraemia in a liver transplant recipient"
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"abstract": "5-Aminolevulinic acid dehydratase (ALAD) porphyria (ADP) is an ultrarare autosomal recessive disease, with only eight documented cases, all of whom were males. Although classified as an acute hepatic porphyria (AHP), induction of the rate limiting hepatic enzyme 5-aminolevulinic acid synthase-1 (ALAS1) has not been demonstrated, and the marrow may also contribute excess 5-aminolevulinic acid (ALA). Two patients have died and reported follow up for the others is limited, so the natural history of this disease is poorly understood and treatment experience limited.\n\n\n\nWe report new molecular findings and update the clinical course and treatment of the sixth reported ADP patient, now 31 years old and the only known case in the Americas, and review published data regarding genotype-phenotype correlation and treatment.\n\n\n\nCirculating hepatic 5-aminolevulinic acid synthase-1 (ALAS1) mRNA was elevated in this case, as in other AHPs. Gain of function mutation of erythroid specific ALAS2 - an X-linked modifying gene in some other porphyrias - was not found. Seven reported ADP cases had compound heterozygous ALAD mutations resulting in very low residual ALAD activity and symptoms early in life or adolescence. One adult with a germline ALAD mutant allele developed ADP in association with a clonal myeloproliferative disorder, polycythemia vera.\n\n\n\nElevation in circulating hepatic ALAS1 and response to treatment with hemin indicate that the liver is an important source of excess ALA in ADP, although the marrow may also contribute. Intravenous hemin was effective in most reported cases for treatment and prevention of acute attacks of neurological symptoms.",
"affiliations": "Departments of Preventive Medicine and Population Health, and Internal Medicine (Division of Gastroenterology and Hepatology), University of Texas Medical Branch, Galveston, Texas, USA.;Departments of Preventive Medicine and Population Health, and Internal Medicine (Division of Gastroenterology and Hepatology), University of Texas Medical Branch, Galveston, Texas, USA. Electronic address: kanderso@utmb.edu.;Alnylam Pharmaceuticals, Cambridge, MA, USA.;Alnylam Pharmaceuticals, Cambridge, MA, USA.;Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.;Departments of Preventive Medicine and Population Health, and Internal Medicine (Division of Gastroenterology and Hepatology), University of Texas Medical Branch, Galveston, Texas, USA.",
"authors": "Lahiji|Arian Pourmehdi|AP|;Anderson|Karl E|KE|;Chan|Amy|A|;Simon|Amy|A|;Desnick|Robert J|RJ|;Ramanujam|V M Sadagopa|VMS|",
"chemical_list": "D012333:RNA, Messenger; D006418:Heme; D006427:Hemin; D011162:Porphobilinogen; D000624:5-Aminolevulinate Synthetase; C000630117:ALAS1 protein, human; D000623:Porphobilinogen Synthase",
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"keywords": "5-aminolevulinic acid dehydratase; 5-aminolevulinic acid dehydratase deficiency porphyria; 5-aminolevulinic acid synthase; Acute porphyria; Human hemin; Porphyrins",
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"mesh_terms": "D000624:5-Aminolevulinate Synthetase; D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D005260:Female; D006418:Heme; D006427:Hemin; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008099:Liver; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011162:Porphobilinogen; D000623:Porphobilinogen Synthase; D017118:Porphyria, Acute Intermittent; D017094:Porphyrias, Hepatic; D012333:RNA, Messenger; D055815:Young Adult",
"nlm_unique_id": "9805456",
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"references": null,
"title": "5-Aminolevulinate dehydratase porphyria: Update on hepatic 5-aminolevulinic acid synthase induction and long-term response to hemin.",
"title_normalized": "5 aminolevulinate dehydratase porphyria update on hepatic 5 aminolevulinic acid synthase induction and long term response to hemin"
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"abstract": "Despite the widespread use of the pipeline embolization device (PED), no complete aneurysm regrowth after its placement has been reported in the literature. We report the first case of aneurysm regrowth after the initial follow-up angiography demonstrating near-complete occlusion of the aneurysm and remodeling of the vessel with on-label PED use for a large 20 mm × 24 mm × 22 mm (width × depth × height) cavernous segment internal carotid artery (ICA) aneurysm. The patient was treated with two overlapping PED (4.5 mm × 20 mm and 5 mm × 20 mm). Follow-up angiogram at 4 months after treatment demonstrated remodeling of the ICA with a small residual component measuring approximately 7 mm × 8 mm × 7 mm. However, at 10 months after treatment, there was a complete regrowth of the aneurysm with interval growth, now measuring 25 mm × 28 mm × 18 mm. Despite the high aneurysm occlusion rates reported with the PED, persistent aneurysm filling and aneurysm regrowth, although rare, should not be overlooked.",
"affiliations": "Department of Neurological Surgery, University of Virginia Health System, Charlottesville, Virginia, USA.;Department of Neurological Surgery, University of Virginia Health System, Charlottesville, Virginia, USA.;Department of Neurological Surgery, University of Virginia Health System, Charlottesville, Virginia, USA.;Department of Neurological Surgery, University of Virginia Health System, Charlottesville, Virginia, USA.",
"authors": "Chen|Ching-Jen|CJ|;Patibandla|M Rao|MR|;Park|Min S|MS|;Kalani|M Yashar|MY|",
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"fulltext": "\n==== Front\nJ Neurosci Rural PractJ Neurosci Rural PractJNRPJournal of Neurosciences in Rural Practice0976-31470976-3155Medknow Publications & Media Pvt Ltd India JNRP-10-14210.4103/jnrp.jnrp_273_18Case ReportRegrowth of a Large Intracranial Aneurysm after On-Label Use of the Pipeline Embolization Device Chen Ching-Jen Patibandla M. Rao Park Min S. Kalani M. Yashar Department of Neurological Surgery, University of Virginia Health System, Charlottesville, Virginia, USAAddress for correspondence: M. Yashar Kalani, Department of Neurological Surgery, University of Virginia Health System, Charlottesville, Virginia 22908, USA. E-mail: YK6Z@hscmail.mcc.virginia.eduJan-Mar 2019 10 1 142 144 Copyright: © 2019 Journal of Neurosciences in Rural Practice2019This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.Despite the widespread use of the pipeline embolization device (PED), no complete aneurysm regrowth after its placement has been reported in the literature. We report the first case of aneurysm regrowth after the initial follow-up angiography demonstrating near-complete occlusion of the aneurysm and remodeling of the vessel with on-label PED use for a large 20 mm × 24 mm × 22 mm (width × depth × height) cavernous segment internal carotid artery (ICA) aneurysm. The patient was treated with two overlapping PED (4.5 mm × 20 mm and 5 mm × 20 mm). Follow-up angiogram at 4 months after treatment demonstrated remodeling of the ICA with a small residual component measuring approximately 7 mm × 8 mm × 7 mm. However, at 10 months after treatment, there was a complete regrowth of the aneurysm with interval growth, now measuring 25 mm × 28 mm × 18 mm. Despite the high aneurysm occlusion rates reported with the PED, persistent aneurysm filling and aneurysm regrowth, although rare, should not be overlooked.\n\nKEYWORDS:\nAneurysmcomplicationendovascularpipelineregrowth\n==== Body\nINTRODUCTION\nApproval of the pipeline embolization device (PED; Medtronic Inc., Minneapolis, MN, USA) in 2011 by the US Food and Drug Administration has revolutionized not only the treatment paradigm of large or giant wide-necked intracranial aneurysms in the proximal internal carotid artery (ICA) but also the treatment options available for small, distal anterior circulation, and posterior circulation aneurysms.[1] Despite the widespread use of the PED, no aneurysm regrowth after its placement has been reported in the literature, although aneurysm persistence has been noted. We report the first case of complete aneurysm regrowth after on-label PED treatment of a large cavernous segment ICA aneurysm.\n\nCASE REPORT\nThis is a 76-year-old female with a medical history of hypertension, hyperlipidemia, and cardiac arrhythmia who was found to have a large 20 mm × 24 mm × 22 mm (width × depth × height) left cavernous carotid wide-necked aneurysm during a workup for gait instability in 2016. The patient was taking rivaroxaban for her cardiac arrhythmia and smoked one packet of cigarettes per day. Given the morphology and location of an aneurysm, the treatment of an aneurysm using the PED was recommended. Seven days before the procedure, the patient was started on aspirin (325 mg daily), and immediately before the procedure, her aspirin assay was therapeutic (462 aspirin reaction unit [ARU]; <551 ARU was considered therapeutic). Her rivaroxaban was withheld 48 h before her procedure.\n\nIn March 2017, the patient underwent placement of two overlapping PED (4.5 mm × 20 mm and 5 mm × 20 mm) through the Marksman microcatheter (Medtronic Inc., Minneapolis, MN, USA) and Sofia intermediate catheter (MicroVention, Aliso Viejo, CA) for the treatment of her large left cavernous carotid aneurysm [Figure 1a]. The first PED (4.5 mm × 20 mm) was deployed spanning from the supraclinoid ICA into the neck of the aneurysm. Then, the second PED (5 mm × 20 mm) spanning from the cavernous ICA, overlapping the distal PED, into the vertical segment of the petrous ICA was placed, covering the neck of an aneurysm. The entire flow-diverter stent construct spanned from the supraclinoid ICA to the vertical segment of the petrous ICA [Figure 1b]. Final postprocedural control angiogram demonstrated significant contrast stasis within the aneurysm sac [Figure 1c] while fully heparinized. The patient was continued on her aspirin and restarted on her rivaroxaban following the procedure.\n\nFigure 1 (a) Lateral angiogram demonstrating a large 20 mm × 24 mm × 22 mm (width × depth × height) left cavernous carotid wide-necked aneurysm. (b) Lateral skull X-ray demonstrating two overlapping pipeline embolization device (4.5 mm × 20 mm and 5 mm × 20 mm, Medtronic Inc., Minneapolis, MN, USA) spanning from the left supraclinoid internal carotid artery to the vertical segment of the petrous internal carotid artery. (c) Lateral angiogram demonstrating contrast stasis within the aneurysm sac following placement of the two overlapping pipeline embolization device. (d) Lateral angiogram demonstrating significant decrease aneurysm sac filling with a small residual component measuring 7 mm × 8 mm at the anterior genu of the cavernous segment of the internal carotid artery at 4 months after pipeline embolization device placement. (e) Lateral angiogram demonstrating a large regrowth of the aneurysm, measuring 25 mm × 28 mm × 18 mm, at 10 months after pipeline embolization device placement. (f) Axial computed tomography angiogram demonstrating complete coverage of the aneurysm neck by the pipeline embolization device at 10 months after treatment\n\nThe patient returned for a follow-up angiogram at 4 months following treatment, which demonstrated remodeling of the ICA with only minimal filling of the aneurysm measuring 7 mm × 8 mm × 7 mm at the anterior genu of the cavernous segment of the ICA [Figure 1d]. Despite counseling, the patient continued to smoke during the follow-up period. In a subsequent angiogram, at 10 months after treatment, the aneurysm had regrown with interval expansion now measuring 25 mm × 28 mm × 18 mm [Figure 1e]. Computed tomography (CT) angiogram demonstrated complete PED coverage of the aneurysm neck [Figure 1f]. This patient underwent placement of another PED (5 mm × 25 mm), and interval follow-up at 3 months demonstrated persistent filling of the aneurysm.\n\nDISCUSSION\nFlow diversion is a well-established treatment for intracranial aneurysms with higher occlusion rates and similar complication rates compared to traditional embolization techniques.[2] Occlusion rates of >85%–90% at 6–12 months after PED placement have been reported in major series in the literature with low retreatment rates.[1345] In a recent study, comparing retreatment rates between PED alone versus PED and coil embolization, Park et al. reported a retreatment rate of 12% after a mean follow-up length of 9.6 months in the PED alone cohort comprising two patients with inadequate aneurysm neck coverage and six patients with persistent aneurysm filling.[3] In an earlier study comprising 101 intracranial aneurysms or dissections using the PED, Fischer reported a retreatment rate of 9% for persistent or unchanged aneurysm filling on follow-up angiography.[5] Other studies have reported similar rates of retreatment for incomplete aneurysm occlusion.[46] Despite a recent report of recurrence of a large middle cerebral artery aneurysm after a 6-month angiogram demonstrating complete occlusion after PED placement, no study in the literature has reported growth of an aneurysm after on-label PED use.[7]\n\nDevice migrations/retraction, which may result in inadequate aneurysm neck coverage by the PED, is a well-described phenomenon.[38] However, device migration/retraction was not observed in our patient, as the CT angiogram demonstrated unchanged location and configuration of the overlapping PED construct at 10-month postprocedure. Rivaroxaban use and smoking may contribute to the aneurysm regrowth and recanalization after on-label PED use. Smoking is a known risk factor of aneurysm development and subarachnoid hemorrhage (SAH), with positive correlation between the quantity of cigarettes smoked and SAH risk. In addition, smoking may be associated with aneurysm regrowth following endovascular coil embolization.[9] Similar to its effects on coiled aneurysms, smoking may preclude vessel remodeling and aneurysm sac clotting in the setting of flow diversion through its effects on vascular flow and collagen synthesis. However, data from 694 aneurysms treated using the PED have also suggested that current and former smokers have similar odds of incomplete aneurysm occlusion compared to never smokers at a mean follow-up period of 29 months.[10] Given the rarity of aneurysm regrowth after flow diversion, its risk factors may be difficult to identify.\n\nThis case represents the first reported case of aneurysm regrowth with on-label PED use after initial follow-up angiography demonstrating remodeling of the ICA and near-complete occlusion at 4 months. Despite the high aneurysm occlusion rates reported with the PED, persistent aneurysm filling and aneurysm regrowth, although rare, should not be overlooked. Although no aneurysm recurrence following complete occlusion with the on-label PED placement has been reported thus far, long-term imaging follow-up for those aneurysms may be warranted. The contribution of the rivaroxaban to regrowth in this patient should be noted, but caution should be used when counseling patients about the possibility of regrowth with this technology.\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Becske T Kallmes DF Saatci I McDougall CG Szikora I Lanzino G Pipeline for uncoilable or failed aneurysms: Results from a multicenter clinical trial Radiology 2013 267 858 68 23418004 \n2 Chalouhi N Tjoumakaris S Starke RM Gonzalez LF Randazzo C Hasan D Comparison of flow diversion and coiling in large unruptured intracranial saccular aneurysms Stroke 2013 44 2150 4 23723311 \n3 Park MS Nanaszko M Sanborn MR Moon K Albuquerque FC McDougall CG Re-treatment rates after treatment with the pipeline embolization device alone versus pipeline and coil embolization of cerebral aneurysms: A single-center experience J Neurosurg 2016 125 137 44 26684772 \n4 Chalouhi N Tjoumakaris S Phillips JL Starke RM Hasan D Wu C A single pipeline embolization device is sufficient for treatment of intracranial aneurysms AJNR Am J Neuroradiol 2014 35 1562 6 24788125 \n5 Fischer S Vajda Z Aguilar Perez M Schmid E Hopf N Bäzner H Pipeline embolization device (PED) for neurovascular reconstruction: Initial experience in the treatment of 101 intracranial aneurysms and dissections Neuroradiology 2012 54 369 82 21881914 \n6 Adeeb N Griessenauer CJ Shallwani H Shakir H Foreman PM Moore JM Pipeline embolization device in treatment of 50 unruptured large and giant aneurysms World Neurosurg 2017 105 232 7 28578117 \n7 Trivelato FP Ulhôa AC Rezende MT Castro-Afonso LH Abud DG Recurrence of a totally occluded aneurysm after treatment with a pipeline embolization device J Neurointerv Surg 2018 pii: Neurintsurg-2018-013842 \n8 Chalouhi N Tjoumakaris SI Gonzalez LF Hasan D Pema PJ Gould G Spontaneous delayed migration/shortening of the pipeline embolization device: Report of 5 cases AJNR Am J Neuroradiol 2013 34 2326 30 23811979 \n9 Futchko J Starr J Lau D Leach MR Roark C Pandey AS Influence of smoking on aneurysm recurrence after endovascular treatment of cerebrovascular aneurysms J Neurosurg 2018 128 992 8 28644100 \n10 Rouchaud A Brinjikji W Cloft HJ Lanzino G Becske T Kallmes DF Smoking does not affect occlusion rates and morbidity-mortality after pipeline embolization for intracranial aneurysms AJNR Am J Neuroradiol 2016 37 1122 6 26797135\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0976-3155",
"issue": "10(1)",
"journal": "Journal of neurosciences in rural practice",
"keywords": "Aneurysm; complication; endovascular; pipeline; regrowth",
"medline_ta": "J Neurosci Rural Pract",
"mesh_terms": null,
"nlm_unique_id": "101533710",
"other_id": null,
"pages": "142-144",
"pmc": null,
"pmid": "30765991",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "21881914;23418004;23723311;23811979;24788125;26684772;26797135;28578117;28644100;29794160",
"title": "Regrowth of a Large Intracranial Aneurysm after On-Label Use of the Pipeline Embolization Device.",
"title_normalized": "regrowth of a large intracranial aneurysm after on label use of the pipeline embolization device"
} | [
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"companynumb": "US-JNJFOC-20190207880",
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"activesubstance": {
"activesubstancename": "ASPIRIN"
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"abstract": "Acneiform rash is a commonly reported side effect to certain types of medications, including antipsychotic agents. Its clinical presentation consists mainly of papulopustular lesions. Other types of lesions, such as nodular or cystic, can also be observed. Body distribution of the lesions follows a similar pattern to acne vulgaris. Depending on the severity of the case, drug-induced acne may be treated in different ways. In mild cases, the use of topical antibiotics and retinoids in combination is usually effective. With more severe forms, it may be necessary to add oral antibiotics, such as tetracyclines, but a good response is not always achieved. Identification of the drug responsible for the side-effect is mandatory in refractory eruptions. Herein, we present the case of an Aripiprazole-induced acneiform rash successfully treated with oral Isotretinoin. The treatment was effective and well tolerated and there was no need to discontinue the psychopharmacological medication. This is the first study to report this modality of treatment.",
"affiliations": "Unit of Dermatology and Venereology, Hospital Clínico Universitario San Cecilio, Av. De la Investigación s/n, Granada, Granada, Spain.;Departament of Psychiatry, Hospital Clínico Universitario San Cecilio, Granada, Spain.;Departament of Psychiatry, Hospital Clínico Universitario San Cecilio, Granada, Spain.;Departament of Dermatology, Hospital Santa Ana, Motril, Spain.",
"authors": "Navarro-Triviño|Francisco José|FJ|http://orcid.org/0000-0002-5454-3671;de Jaime Ruiz|Pilar|P|;Porras Segovia|Alejandro|A|;Garrido Torres-Puchol|Valeriano|V|",
"chemical_list": "D014150:Antipsychotic Agents; D003879:Dermatologic Agents; D000068180:Aripiprazole; D015474:Isotretinoin",
"country": "United States",
"delete": false,
"doi": "10.1111/dth.12637",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1396-0296",
"issue": "31(4)",
"journal": "Dermatologic therapy",
"keywords": "Aripiprazol; Isotretinoin; acneiform rash",
"medline_ta": "Dermatol Ther",
"mesh_terms": "D017486:Acneiform Eruptions; D000284:Administration, Oral; D000328:Adult; D014150:Antipsychotic Agents; D000068180:Aripiprazole; D003879:Dermatologic Agents; D003875:Drug Eruptions; D006801:Humans; D015474:Isotretinoin; D008297:Male; D012074:Remission Induction; D012563:Schizophrenia, Paranoid; D012867:Skin; D016896:Treatment Outcome",
"nlm_unique_id": "9700070",
"other_id": null,
"pages": "e12637",
"pmc": null,
"pmid": "30019366",
"pubdate": "2018-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Oral Isotretinoin for the treatment of Aripiprazol-induced acneiform rash.",
"title_normalized": "oral isotretinoin for the treatment of aripiprazol induced acneiform rash"
} | [
{
"companynumb": "ES-APOTEX-2018AP018202",
"fulfillexpeditecriteria": "1",
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"actiondrug": "4",
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"activesubstancename": "ARIPIPRAZOLE"
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{
"abstract": "The World Health Organization pulmonary hypertension classification scheme provides a framework for evaluation and management of patients with pulmonary vascular disease. Methamphetamine is a recreational stimulant which causes cardiac and pulmonary vascular toxicity. We discuss three cases of methamphetamine users who presented with left ventricular systolic failure but on heart failure therapy developed features more consistent with pulmonary arterial hypertension (PAH) or combined pre-capillary and post-capillary pulmonary hypertension. All three were started on PAH treatment and showed clinical improvement in symptoms. These cases illustrate the difficulty with treating methamphetamine users with pulmonary hypertension who have been left out of randomized controlled trials. Consideration should be given to creating a clinical registry for patients with methamphetamine associated pulmonary hypertension to assist with best treatment strategies.",
"affiliations": "Division of Pulmonary, 26 North 1900 East, Wintrobe Building, Room 701, Salt Lake City, UT, 84132, USA.;The Oregon Clinic, Division of Pulmonary, Sleep and Critical Care Medicine, 1111 NE 99th Avenue, Suite 200, Portland, OR, 97220, USA.",
"authors": "Hendrickson|Kathryn|K|;Strauss|Wayne|W|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.rmcr.2020.101275",
"fulltext": "\n==== Front\nRespir Med Case Rep\nRespir Med Case Rep\nRespiratory Medicine Case Reports\n2213-0071 Elsevier \n\nS2213-0071(20)30489-5\n10.1016/j.rmcr.2020.101275\n101275\nCase Report\nCharacterization and treatment challenges of pulmonary hypertension in methamphetamine users\nHendrickson Kathryn a Strauss Wayne wstrauss@orclinic.comb∗ a Division of Pulmonary, 26 North 1900 East, Wintrobe Building, Room 701, Salt Lake City, UT, 84132, USA\nb The Oregon Clinic, Division of Pulmonary, Sleep and Critical Care Medicine, 1111 NE 99th Avenue, Suite 200, Portland, OR, 97220, USA\n∗ Corresponding author. wstrauss@orclinic.com\n06 11 2020 \n2020 \n06 11 2020 \n31 10127513 6 2020 30 10 2020 2 11 2020 © 2020 The Authors2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).The World Health Organization pulmonary hypertension classification scheme provides a framework for evaluation and management of patients with pulmonary vascular disease. Methamphetamine is a recreational stimulant which causes cardiac and pulmonary vascular toxicity. We discuss three cases of methamphetamine users who presented with left ventricular systolic failure but on heart failure therapy developed features more consistent with pulmonary arterial hypertension (PAH) or combined pre-capillary and post-capillary pulmonary hypertension. All three were started on PAH treatment and showed clinical improvement in symptoms. These cases illustrate the difficulty with treating methamphetamine users with pulmonary hypertension who have been left out of randomized controlled trials. Consideration should be given to creating a clinical registry for patients with methamphetamine associated pulmonary hypertension to assist with best treatment strategies.\n\nKeywords\nPulmonary arterial hypertensionSystolic heart failureMethamphetamine\n==== Body\nThere has been tremendous progress in understanding the pathophysiology and classification of pulmonary hypertension (PH) [3,5]. Updated guidelines from the 6th World Symposium on Pulmonary Hypertension continue to utilize a 5-diagnostic group classification scheme [11]. However, some patients have risk factors for multiple types of PH presenting challenges for clinicians.\n\nPulmonary arterial hypertension (PAH), group 1 disease, is a chronic and incurable disease of scarring in the small arterioles and capillaries of the lung that leads to progressive loss of effective vascular bed and right ventricular failure. However, most people with PH are found to have predominantly left sided heart disease (group 2) or lung diseases (group 3). Some patients are best characterized as combined pre-capillary and post-capillary pulmonary hypertension (Cpc-PH) in which the pulmonary vasculature is felt to be injured from long standing left atrial hypertension. Typically, therapies targeted to the pulmonary vasculature are reserved for patients with group 1 disease. Methamphetamine is an illegal stimulant and a known risk factor for both acute and chronic left ventricular systolic and diastolic dysfunction as well as PAH [1,2,[7], [8], [9],12].\n\nWe present three cases of methamphetamine associated PH with features of both group 1 and 2 disease or Cpc-PH. The clinical course of each patient is outlined in Table 1. Each of the three patients presented with signs of heart failure and initial echocardiogram demonstrating reduced left ventricular ejection fraction. None of these patients had invasive hemodynamic measurements on presentation. However, on standard heart failure treatment, follow up echocardiogram showed normalized left systolic function but worsened right ventricular failure associated with ongoing clinical deterioration. Work up excluded parenchymal and obstructive lung disease and chronic thromboembolic disease. Right heart catheterization for each patient showed normal pulmonary capillary wedge pressure (PCWP) and severe PH with marked elevation of pulmonary vascular resistance more consistent with a PAH phenotype. Right heart catheterization was performed in each case within 6 months of initial diagnosis. Each patient was started on treatment for PAH with combination oral therapy and clinically improved by walk test and functional class [4,6], These three cases demonstrate the complexities of characterizing and treating PH patients with methamphetamine exposure.Table 1 Characteristics of each patient and clinical time course with treatment.\n\nTable 1\tPatient 1\tPatient 2\tPatient 3\t\nInitial Presentation\t\nChief complaint\tDyspnea\tDyspnea, chest pain\tDyspnea, syncope\t\nPhysical Exam\tBilateral LE edema\nCrackles at bilateral lung bases.\tTrace LE edema\nNormal lung sounds\nNo JVD\tNo LE edema\nCrackles at bases\nElevated JVD\t\nECHO:\tNormal LV size\tNormal LV size\tNormal LV size\t\n LVEF:\t35%\t40%\t25–30%\t\n RVSP:\t51–56 mmHg\t68–73 mmHg\t89 mmHg\t\n TAPSE:\t1.45cm\t1.1cm\t\t\nTreatment\tCarvediolol, Lisinopril, furosemide\tCarvedilol, Lisinopril, furosemide\tCarvedilol\nLisinopril furosemide\t\nFollow up #1\t\nChief complaint\tDyspnea\tDyspnea\tDyspnea, syncope\t\nPhysical Exam\tNo LE edema\nBilateral lung crackles\tNo LE edema\nClear lungs\tNo LE edema\nClear lungs\t\nECHO:\tNormal LV size\tNormal LV size\tNormal LV size\t\n LVEF:\t60%\t50%\t60%\t\n RVSP:\t64–70 mmHg\t61–66 mmHg\t65 mmHg\t\n TAPSE:\t1.2cm\t1.5cm\t\t\nRight/Left heart catheterization:\tNormal coronary artery anatomy.\tNormal coronary artery anatomy.\tNormal coronary artery anatomy.\t\n PAP:\t71/35 (45)mmHg\t60/19 (40)mmHg\t79/34 (54)mmHg\t\n PCWP:\t12 mmHg\t2mmHg\t4mmHg\t\n PVR:\t8.2 wood units\t10.8 wood units\t11 wood units\t\n6 minute walk test\t308m\t330m\t91m\t\nVentilation-perfusion scan\tNormal\tNormal\tNormal\t\nCT Chest\tNormal\tNormal\tNormal\t\nSpirometry\tNormal\tNormal\tNormal\t\nPolysomnography\tNormal\tNormal\tNormal\t\nTreatment\tSildenafil and ambrisentan\tTadalafil and macitentan\tSildenafil and macitentan\t\nFollow up #2\t\nChief complaint\tImproved dyspnea\tImproved dyspnea\tNo syncope\t\nPhysical exam\tNo LE edema\nImproved lung crackles\tNo LE edema\nClear lungs\tNo LE edema\nClear lungs\t\nECHO:\tNormal LV size\tNormal LV size\tNormal LV size\t\n LVEF:\t70%\t60%\t60%\t\n RVSP:\t82 mmHg\t69 mmHg\tIncreased\t\n TAPSE:\t1.1cm\t1.9cm\t\t\n6-min walk test\t360m\t368m\t219m\t\nCourse\tPeriods of improved symptoms and periods of worsening symptoms largely related to ongoing methamphetamine use.\tLV function has remained normal, additional hospitalizations for right heart failure in conjunction with ongoing methamphetamine use.\tHis intermittent methamphetamine use has led to multiple hospitalizations and incarceration making consistent treatment difficult.\t\n\n\n1 Discussion\nEvaluation of PH in patients with methamphetamine abuse presents unique challenges due to both acute and chronic toxicity of the left and right ventricle and the pulmonary vasculature causing features of both group 1 and 2 disease. It is possible that these patients experienced acute, transient systolic heart failure from methamphetamine exposure in the background of chronic methamphetamine induced pulmonary vascular injury [10]. Alternatively, these patients may best fit into Cpc-PH from long standing drug induced elevated left ventricular filling pressures but normal PCWP is atypical. For patients with suspected Cpc-PH and normal PCWP, fluid challenge during RHC can be helpful in determining the contribution of LV disease to PH. However, fluid challenge was contraindicated in these patients due to decompensated right heart failure and clinical instability. The degree of pulmonary vascular resistance elevation with normal PCW suggested these patients could benefit from medications typically used to treat group 1 disease. As many methamphetamine users have difficulty with access to health care, it is uncertain how frequently other patients have a similar course.\n\nOptimal treatment strategies are not known for patients with PH associated with methamphetamine exposure as they are excluded from randomized trials and most observational studies. As the number of people with methamphetamine exposure continues to grow it will be important to better understand how they fit in the diagnostic groups. There is substantial risk to this population with both under and over treatment of pulmonary vascular disease. In general, there is a lack of data and consensus on treatment strategies for patients with Cpc-PH and no specific data for patient with methamphetamine exposure. Consideration should be given towards a clinical registry of patients with methamphetamine associated PH to increase our knowledge base and experience with these challenging patients.\n\nDeclaration of competing interest\nNeither author has any competing interests or conflicts of interest.\n==== Refs\nReferences\n1 Ben-Yehuda O. Sieche N. Crystal methamphetamine: a drug and cardiovascular epidemic JACC Heart Failure 6 3 2018 219 221 29496023 \n2 Chin K. Channick R. Rubin L. Is methamphetamine use associated with idiopathic pulmonary arterial hypertension? Chest 130 6 2006 1657 1663 17166979 \n3 Farber H.W. Loscalzo J. Pulmonary arterial hypertension N. Engl. J. Med. 351 16 2004 1655 1665 15483284 \n4 Franco V. Management of pulmonary hypertension: associated with left heart disease Heart Fail. Clin. 14 4 2018 545 551 2018 30266363 \n5 Frost A. Diagnosis of pulmonary hypertension Eur. Respir. J. 53 1 2019 \n6 Galie N. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension N. Engl. J. Med. 373 2015 834 844 26308684 \n7 Paratz E. Cunningham N. MacIsaac A. The cardiac complications of methamphetamines Heart Lung Circ. 25 4 2016 325 332 26706652 \n8 Ramirez R. Perez V. Zamanian Methamphetamine and the risk of pulmonary arterial hypertension Curr. Opin. Pulm. Med. 26 4 2018 416 424 \n9 Richards J. Harms B. Kelly A. Turnipseed S. Methamphetamine use and heart failure: prevalence, risk factors, and predictors American Journal of Cardiovascular Medicine 8 2018 1423 1428 \n10 Schurer S. Klingel K. Sandri M. Majunke M. Besler C. Kandolf R. … Mangner N. Clinical Characteristics, histopathological features, and clinical outcome of methamphetamine-associated cardiomyopathy JACC Heart Failure 5 6 2017 435 445 2017 28571597 \n11 Simmoneau Haemodynamic definitisona nd updated clinical classifications of pulmonary hypertension Eur. Respir. J. 53 1 2019 \n12 Zamanian R. Features and outcomes of methamphetamine-associated pulmonary arterial hypertension Am. J. Respir. Crit. Care Med. 197 6 2018 788 800 28934596\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2213-0071",
"issue": "31()",
"journal": "Respiratory medicine case reports",
"keywords": "Methamphetamine; Pulmonary arterial hypertension; Systolic heart failure",
"medline_ta": "Respir Med Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101604463",
"other_id": null,
"pages": "101275",
"pmc": null,
"pmid": "33294354",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "15483284;28571597;28934596;26308684;30036313;30266363;26706652;29307766;30545972;17166979;29496023",
"title": "Characterization and treatment challenges of pulmonary hypertension in methamphetamine users.",
"title_normalized": "characterization and treatment challenges of pulmonary hypertension in methamphetamine users"
} | [
{
"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-17-05155",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "AMBRISENTAN"
},
"... |
{
"abstract": "We herein report the case of an 80-year-old man with malignant lymphoma who became persistently infected with influenza A virus. Although he was repeatedly treated with NA inhibitors, such as oseltamivir or peramivir, nasal cavity swab tests for influenza A antigen continued to be positive for more than 2 months. Virological analyses revealed that he was infected with the NA inhibitor-resistant A (H3N2) virus possessing an R292K substitution in the NA protein. These findings suggest that a drug-resistant influenza virus strain might selectively survive antiviral therapy in elderly patients with refractory malignant lymphoma undergoing multiple chemotherapies.",
"affiliations": "Division of Hematology, NHO Matsumoto Medical Center, Japan.",
"authors": "Kawakami|Toru|T|;Hirabayashi|Yukio|Y|;Kawakami|Fumihiro|F|;Isobe|Rei|R|;Kaneko|Naoto|N|;Mimura|Yuto|Y|;Ito|Toshiro|T|;Furuta|Kiyoshi|K|;Shimazaki|Mami|M|;Nakazawa|Hideyuki|H|;Kitano|Kiyoshi|K|",
"chemical_list": "D000146:Acids, Carbocyclic; D000998:Antiviral Agents; D003517:Cyclopentanes; D006146:Guanidines; D053139:Oseltamivir; D009439:Neuraminidase; C414210:peramivir",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.55.6327",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0918-2918",
"issue": "55(13)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": null,
"medline_ta": "Intern Med",
"mesh_terms": "D000146:Acids, Carbocyclic; D000369:Aged, 80 and over; D000998:Antiviral Agents; D003517:Cyclopentanes; D024882:Drug Resistance, Viral; D006146:Guanidines; D006801:Humans; D053122:Influenza A Virus, H3N2 Subtype; D007251:Influenza, Human; D008223:Lymphoma; D008297:Male; D009154:Mutation; D009439:Neuraminidase; D053139:Oseltamivir",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "1807-10",
"pmc": null,
"pmid": "27374689",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Persistent Infection of Drug-resistant Influenza A Virus during Chemotherapy for Malignant Lymphoma.",
"title_normalized": "persistent infection of drug resistant influenza a virus during chemotherapy for malignant lymphoma"
} | [
{
"companynumb": "JP-WATSON-2016-16730",
"fulfillexpeditecriteria": "1",
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"activesubstance": {
"activesubstancename": "ETOPOSIDE"
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{
"abstract": "Systemic medications categorized as diphenylhydantoin, calcineurin inhibitor and calcium channel blocker may have effects on the oral cavity by modifying the inflammatory and immune response and causing undesired tissue proliferative reactions. Calcineurin inhibitors are medications commonly used for long periods in patients undergoing allogeneic hematopoietic stem cell transplant (HSCT) and solid organ transplantation. Medication-related fibrovascular hyperplasia (MRFH) is an extra gingival hyperplastic nodular growth associated with medications use. This study reports five cases of pediatric patients (6 to 12-years-old) diagnosed with Fanconi anemia (FA) after HSCT who presented similar oral mucosal lesions associated with the use of cyclosporine, phenobarbital and amlodipine. After excision of the lesions, histopathological analysis described them as pyogenic granuloma (PG). As the aetiology of the lesions manifested by the patients was associated with the use of medications, the final diagnosis was MRFH. Despite the clinical and histopathological similarity between PG and MRFH, it is fundamental to know the aetiological agent for achieving definitive diagnosis and correct management. Considering the etiologic agent (medication) and histopathological findings, it is suggested that the most appropriate term for this manifestation should be \"medication-related fibrovascular hyperplasia\". The correct nomenclature related to extra gingival hyperplastic lesions identified in patients on medications with potential to induce hyperplastic reactions should be adopted to facilitate scientific communication and improve the treatment.",
"affiliations": "Multiprofessional Residency Program in Oncology and Hematology, Clinic Hospital Complex, Federal University of Parana, Curitiba, Brazil.;Post-Graduate Program in Dentistry, Department of Stomatology, Federal University of Parana, Curitiba, Brazil.;Health Department, Nove de Julho University, São Paulo, Brazil.;Service of Bone Marrow Transplant, Clinic Hospital Complex, Federal University of Parana, Curitiba, Brazil.;Service of Bone Marrow Transplant, Clinic Hospital Complex, Federal University of Parana, Curitiba, Brazil.;Multiprofessional Residency Program in Oncology and Hematology, Clinic Hospital Complex, Federal University of Parana, Curitiba, Brazil.;Multiprofessional Residency Program in Oncology and Hematology, Clinic Hospital Complex, Federal University of Parana, Curitiba, Brazil.",
"authors": "Ballardin|Bárbara Soldatelli|BS|https://orcid.org/0000-0003-4385-3348;Mobile|Rafael Zancan|RZ|https://orcid.org/0000-0002-8603-2614;Coracin|Fábio Luiz|FL|https://orcid.org/0000-0002-0108-6593;Ribeiro|Lisandro Lima|LL|https://orcid.org/0000-0003-2938-5146;Bonfim|Carmem Maria Sales|CMS|https://orcid.org/0000-0003-0343-2610;Schussel|Juliana Lucena|JL|https://orcid.org/0000-0001-5204-0782;Carvalho Torres-Pereira|Cassius|C|https://orcid.org/0000-0001-8049-7544",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.13947",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "25(6)",
"journal": "Pediatric transplantation",
"keywords": "drug-related side effects and adverse reactions; fanconi anemia; hematopoietic stem cell transplantation; hyperplasia",
"medline_ta": "Pediatr Transplant",
"mesh_terms": null,
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "e13947",
"pmc": null,
"pmid": "33350561",
"pubdate": "2021-09",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "A case series of medication-related fibrovascular hyperplasia following hematopoietic stem cell transplantation for Fanconi anemia.",
"title_normalized": "a case series of medication related fibrovascular hyperplasia following hematopoietic stem cell transplantation for fanconi anemia"
} | [
{
"companynumb": "BR-ACCORD-213436",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PHENOBARBITAL"
},
"drugadditional": null,
"d... |
{
"abstract": "A 47-year-old man who had been taking minocycline for palmoplantar pustulosis developed fever, myalgias, polyneuropathy, and testicular pain, with elevated C-reactive protein (CRP). Neither myeloperoxidase- nor proteinase-3-antineutrophil cytoplasmic antibody was positive. These manifestations met the American College of Rheumatology 1990 criteria for the classification of polyarteritis nodosa. Stopping minocycline led to amelioration of symptoms and normalization of CRP level. To our knowledge, this is the second case of minocycline-induced vasculitis satisfying the criteria. Differential diagnosis for drug-induced disease is invaluable even for patients with classical polyarteritis nodosa.",
"affiliations": "Division of Allergy and Clinical Immunology, National Hospital Organization, Osaka-Minami Medical Center, 2-1 Kido-higashi, Kawachinagano, 586-8521, Japan. kataday@omh.hosp.go.jp",
"authors": "Katada|Yoshinori|Y|;Harada|Yoshinori|Y|;Azuma|Naoto|N|;Matsumoto|Kengo|K|;Terada|Haruko|H|;Kudo|Eriko|E|;Ishii|Masaru|M|;Yamane|Hiroyuki|H|;Yamamoto|Suguru|S|;Ohshima|Shiro|S|;Mima|Toru|T|;Tanaka|Toshio|T|;Saeki|Yukihiko|Y|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002097:C-Reactive Protein; D008911:Minocycline",
"country": "England",
"delete": false,
"doi": "10.1007/s10165-006-0492-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1439-7595",
"issue": "16(4)",
"journal": "Modern rheumatology",
"keywords": null,
"medline_ta": "Mod Rheumatol",
"mesh_terms": "D000900:Anti-Bacterial Agents; D018771:Arthralgia; D002097:C-Reactive Protein; D006801:Humans; D008297:Male; D008875:Middle Aged; D008911:Minocycline; D010292:Paresthesia; D010488:Polyarteritis Nodosa; D011565:Psoriasis; D013737:Testis",
"nlm_unique_id": "100959226",
"other_id": null,
"pages": "256-9",
"pmc": null,
"pmid": "16906379",
"pubdate": "2006",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Minocycline-induced vasculitis fulfilling the criteria of polyarteritis nodosa.",
"title_normalized": "minocycline induced vasculitis fulfilling the criteria of polyarteritis nodosa"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2018-01028",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MINOCYCLINE\\MINOCYCLINE HYDROCHLORIDE"
... |
{
"abstract": "COVID-19 reported in pregnant women has occured in late pregnancy, while there are no reports of infection in the first and second trimester. We report two neonates born to mothers with COVID-19 during the second trimester.\n\n\n\nTwo pregnant women had symptomatic COVID-19 in the second trimester. Throat swabs at delivery for SARS-COV-2 RNA were negative for both women and their newborns. The first woman had positive serum IgM and IgG antibodies to SARS-COV-2 before delivery. Her newborn had negative IgM antibody to SARS-COV-2 but IgG was positive on the 7th day after birth. The second woman had negative serum IgM antibody to SARS-COV-2 but IgG was positive before delivery. Her newborn had negative serum IgM antibody to SARS-COV-2 but IgG was positive at 48 h after birth. None of the neonates developed clinical symptoms of COVID-19.\n\n\n\nSARS-COV-2 is unlikely to be vertically transmitted in utero as evidenced by the specific antibodies in the serum of the two women and their newborns. The two women with SARS-COV-2 infection in the second trimester did not develop serious complications at delivery and outcomes of the neonates were good.",
"affiliations": "Department of Pharmacy, Wuhan No.1 Hospital, Wuhan, China.;Department of Pediatrics, Wuhan No.1 Hospital, Wuhan, China.;Department of Pediatrics, Wuhan No.1 Hospital, Wuhan, China.;Department of Pediatrics, Wuhan No.1 Hospital, Wuhan, China.",
"authors": "Tang|Jing-Yi|JY|0000-0002-1791-834X;Song|Wen-Qi|WQ|;Xu|Hao|H|;Wang|Na|N|",
"chemical_list": "D007075:Immunoglobulin M",
"country": "England",
"delete": false,
"doi": "10.1080/23744235.2020.1798499",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2374-4243",
"issue": "52(12)",
"journal": "Infectious diseases (London, England)",
"keywords": "COVID-19; IgG; IgM; SARS-CoV-2; The second trimester",
"medline_ta": "Infect Dis (Lond)",
"mesh_terms": "D000328:Adult; D000073640:Betacoronavirus; D000086382:COVID-19; D018352:Coronavirus Infections; D005260:Female; D006801:Humans; D007075:Immunoglobulin M; D007231:Infant, Newborn; D018445:Infectious Disease Transmission, Vertical; D009035:Mothers; D058873:Pandemics; D011024:Pneumonia, Viral; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D011262:Pregnancy Trimester, Second; D000086402:SARS-CoV-2",
"nlm_unique_id": "101650235",
"other_id": null,
"pages": "913-916",
"pmc": null,
"pmid": "32721199",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "No evidence for vertical transmission of SARS-CoV-2 in two neonates with mothers infected in the second trimester.",
"title_normalized": "no evidence for vertical transmission of sars cov 2 in two neonates with mothers infected in the second trimester"
} | [
{
"companynumb": "CN-ROCHE-2698569",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "OSELTAMIVIR"
},
"drugadditional": null,
"dru... |
{
"abstract": "Codeine is widely prescribed in clinical practice with over the counter (OTC) preparations of codeine freely available for consumption typically as a component of remedies for the common cold/cough. We describe the first reported case of acute confusional state in a previously healthy 14-year-old girl ultimately attributed to inappropriate codeine use. The usage of codeine in the paediatric setting has been highlighted in recent years with many reported deaths--mostly due to respiratory depression. The risks associated with codeine usage may be particularly unnecessary with OTC cough suppressants as evidence of efficacy is absent. Finally, codeine dependence is a common problem among adults and has been reported locally and internationally among adolescents. The combination of lack of efficacy, risk of acute intoxication and dependence, suggests that the use of OTC codeine preparations may be unwarranted.",
"affiliations": "School of Medicine, National University of Ireland, Galway, HSE West, Galway, Connacht, Ireland Donegal Clinical Research Academy, Letterkenny General Hospital, HSE West, Letterkenny, Ulster, Ireland.;Department of Paediatrics, Letterkenny General Hospital, HSE West, Letterkenny, Ulster, Ireland.;Academic Department of Paediatrics, National University of Ireland, Galway, HSE West, Galway, Connacht, Ireland.",
"authors": "O Reilly|David|D|;Thomas|Mathew|M|;Moylett|Edina|E|",
"chemical_list": "D000996:Antitussive Agents; D004366:Nonprescription Drugs; D003061:Codeine",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2015()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000293:Adolescent; D000996:Antitussive Agents; D003061:Codeine; D003221:Confusion; D003371:Cough; D011307:Drug Prescriptions; D005260:Female; D006801:Humans; D007494:Ireland; D004366:Nonprescription Drugs; D009293:Opioid-Related Disorders; D011605:Psychoses, Substance-Induced; D012131:Respiratory Insufficiency",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "26701876",
"pubdate": "2015-12-23",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16856446;19239735;19380101;21477952;23248093;23688907;25420096;30199940",
"title": "Cough, codeine and confusion.",
"title_normalized": "cough codeine and confusion"
} | [
{
"companynumb": "IE-VERNALIS THERAPEUTICS, INC.-2016VRN00001",
"fulfillexpeditecriteria": "1",
"occurcountry": "IE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CODEINE"
},
"drugadditional... |
{
"abstract": "BACKGROUND\nThe emergence of carbapenemase-producing Klebsiella pneumonia (KPC-Kp) has become a significant problem in terms of public health and clinical outcome in many hospitals in Southern Europe. Treatment options are usually limited and effective treatment of infections caused by these pathogens is a considerable challenge for clinicians. Ceftazidime-avibactam has been recently approved for the treatment of difficult-to-treat infections due to aerobic Gram-negative organisms in patients with limited treatment options.\n\n\nMETHODS\nWe reported the first case of KPC-Kp septic thrombophlebitis and right atrial endocarditis associated with metastatic lung abscesses successfully treated with a prolonged ceftazidime/avibactam plus ertapenem treatment course, suggesting that this combination therapy could be safe and effective for serious Gram-negative infections. Interestingly, we also observed an apparent discrepancy between clinical and microbiological courses: the patient became rapidly afebrile; hemodynamically stable and his procalcitonin levels showed a prompt decreasing trend. Nevertheless, blood cultures remained persistently positive for a prolonged period.\n\n\nCONCLUSIONS\nIn conclusion, ceftazidime-avibactam plus ertapenem was a safe and effective therapy of serious endovascular infection due to KPC-Kp. Moreover, in this setting, follow-up blood cultures might represent an irreplaceable tool to guide the therapy.",
"affiliations": "Department of Public Health and Infectious Diseases, \"Sapienza\" University of Rome, Rome, Italy.;Department of Clinical Medicine, \"Sapienza\" University of Rome, Rome, Italy.;Department of Public Health and Infectious Diseases, \"Sapienza\" University of Rome, Rome, Italy.;Department of Public Health and Infectious Diseases, \"Sapienza\" University of Rome, Rome, Italy.;Department of Public Health and Infectious Diseases, \"Sapienza\" University of Rome, Rome, Italy.;Department of Public Health and Infectious Diseases, \"Sapienza\" University of Rome, Rome, Italy. mario.venditti@uniroma1.it.",
"authors": "Iacovelli|Alessandra|A|;Spaziante|Martina|M|;Al Moghazi|Samir|S|;Giordano|Alessandra|A|;Ceccarelli|Giancarlo|G|;Venditti|Mario|M|",
"chemical_list": "D053961:Azabicyclo Compounds; D001426:Bacterial Proteins; D015415:Biomarkers; D004338:Drug Combinations; C000595613:avibactam, ceftazidime drug combination; D002442:Ceftazidime; D001618:beta-Lactamases; C063912:carbapenemase",
"country": "Germany",
"delete": false,
"doi": "10.1007/s15010-018-1166-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-8126",
"issue": "46(5)",
"journal": "Infection",
"keywords": "Ceftazidime–avibactam; Endocarditis; Klebsiella pneumoniae; Procalcitonin; Thrombophlebitis",
"medline_ta": "Infection",
"mesh_terms": "D053961:Azabicyclo Compounds; D016470:Bacteremia; D001426:Bacterial Proteins; D015415:Biomarkers; D002442:Ceftazidime; D004338:Drug Combinations; D004697:Endocarditis, Bacterial; D006801:Humans; D007710:Klebsiella Infections; D007711:Klebsiella pneumoniae; D008297:Male; D008875:Middle Aged; D013924:Thrombophlebitis; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D001618:beta-Lactamases",
"nlm_unique_id": "0365307",
"other_id": null,
"pages": "721-724",
"pmc": null,
"pmid": "29926399",
"pubdate": "2018-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22711599;18087053;29378721;19273776;28856589;28185222;28559250;29221995;29893802;29099911;28685153;28951106;20085604;18070961;27979420;19324295;22000347;26386029;27432599;27866944",
"title": "A challenging case of carbapenemase-producing Klebsiella pneumoniae septic thrombophlebitis and right mural endocarditis successfully treated with ceftazidime/avibactam.",
"title_normalized": "a challenging case of carbapenemase producing klebsiella pneumoniae septic thrombophlebitis and right mural endocarditis successfully treated with ceftazidime avibactam"
} | [
{
"companynumb": "IT-MYLANLABS-2018M1085669",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional": null,
... |
{
"abstract": "Pharmacokinetic data show reduced mycophenolic acid levels in renal transplant recipients taking mycophenolate mofetil (MMF) and proton pump inhibitors (PPIs) concomitantly. This reduced exposure could increase rejection risk. The typical initial MMF dose post renal transplantation is 2 g/day, which often requires dose reduction secondary to side effects. Existing studies have not shown significant acute rejection differences for patients taking MMF-PPI versus patients taking MMF-ranitidine.\n\n\n\nThe purpose of this study was to evaluate clinical outcomes in renal transplant recipients receiving a lower MMF dose than previously studied (1.5 g/day) and either a PPI or histamine-2 receptor antagonist (H2RA).\n\n\n\nThis retrospective cohort study included adult subjects receiving a renal transplant between January 1, 2009, and June 30, 2013. Comparison groups were defined based on acid-suppressing therapy class prescribed at discharge from transplantation. The primary outcome was acute rejection incidence within 1 year posttransplantation.\n\n\n\nOf 728 renal transplant recipients screened, 522 were included: 183 taking a PPI and 339 taking an H2RA. There was no significant difference in acute rejection within 1 year (H2RA 19% versus PPI 14%, p=0.12) or 3 months (4% vs 5%, p=0.44, respectively) posttransplantation. Maintenance immunosuppression (MMF dose and tacrolimus troughs) was similar between groups at 3 months and 1 year. Graft and patient survivals were favorable (> 95%), and graft function at 1 year was stable and similar between groups.\n\n\n\nDespite taking lower MMF doses than previously studied, subjects on a PPI compared to an H2RA were not at increased risk of acute rejection within 1 year posttransplantation.",
"affiliations": "Department of Pharmacy, Cleveland Clinic, Cleveland, Ohio.;Department of Nephrology and Hypertension, Cleveland Clinic, Cleveland, Ohio.;Department of Pharmacy, Cleveland Clinic, Cleveland, Ohio.;Department of Pharmacy, Cleveland Clinic, Cleveland, Ohio.;Department of Pharmacy, Cleveland Clinic, Cleveland, Ohio.",
"authors": "Patel|Kajal S|KS|;Stephany|Brian R|BR|;Barnes|Julie F|JF|;Bauer|Seth R|SR|;Spinner|Michael L|ML|",
"chemical_list": "D006635:Histamine H2 Antagonists; D054328:Proton Pump Inhibitors; D009173:Mycophenolic Acid",
"country": "United States",
"delete": false,
"doi": "10.1002/phar.2037",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-0008",
"issue": "37(12)",
"journal": "Pharmacotherapy",
"keywords": "graft rejection; histamine H2 antagonists; mycophenolate mofetil; proton pump inhibitors; renal transplantation",
"medline_ta": "Pharmacotherapy",
"mesh_terms": "D000328:Adult; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D006084:Graft Rejection; D006635:Histamine H2 Antagonists; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D054328:Proton Pump Inhibitors; D012189:Retrospective Studies",
"nlm_unique_id": "8111305",
"other_id": null,
"pages": "1507-1515",
"pmc": null,
"pmid": "28976570",
"pubdate": "2017-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Renal Transplant Acute Rejection with Lower Mycophenolate Mofetil Dosing and Proton Pump Inhibitors or Histamine-2 Receptor Antagonists.",
"title_normalized": "renal transplant acute rejection with lower mycophenolate mofetil dosing and proton pump inhibitors or histamine 2 receptor antagonists"
} | [
{
"companynumb": "PHHY2018US081012",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "3",
... |
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