article dict | reports listlengths 1 3.97k |
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{
"abstract": "To report a case of a woman in whom alopecia appeared after several months of treatment with anidulafungin.\n\n\nMETHODS\nA 34-year-old woman with chronic femoral osteomyelitis with the presence of persistent suppuration, developed a Candida albicans infection, isolated in the fistula exudate cultures. After initial failures of single therapy with azoles, it was decided to administer fluconazole and anidulafungin 100 mg/d. One month after starting the treatment, the patient mentioned a greater hair loss than usual. At 3 months, the patient stopped taking the drug on noting the loss and easy falling out of her hair, with alopecia plaques 1 to 2 cm in size. At 2 months after stopping the anidulafungin, it was decided to restart combined antifungal treatment using micafungin and fluconazole; there was no mention of new or greater loss of hair. It was decided to change micafungin to anidulafungin again 90 days after starting treatment. In the first month of treatment, there appeared to be a reactivation in hair loss that later stabilized and improved.\n\n\nCONCLUSIONS\nDrug-induced hair loss is an adverse reaction that has been identified during different hair growth phases. It has been described for the azoles group and has not been associated with candins until now. Results of the causality analysis, using the probability scale established by Naranjo, found the relationship as probable.\n\n\nCONCLUSIONS\nAnidulafungin could be associated with hair loss. Physicians must be aware of this adverse effect in order to approach it properly and to detect possible nonadherence to treatment.",
"affiliations": "Hospital Universitari i Politècnic La Fe, Valencia, Spain.",
"authors": "Ruiz-Ramos|J|J|;Salavert-Lleti|M|M|;Monte-Boquet|E|E|;Lorente-Fernández|L|L|;Gil-Gómez|I|I|;Poveda-Andrés|J L|JL|",
"chemical_list": "D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D015725:Fluconazole; D000077612:Anidulafungin; D000077551:Micafungin",
"country": "United States",
"delete": false,
"doi": "10.1177/1060028014524534",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1060-0280",
"issue": "48(5)",
"journal": "The Annals of pharmacotherapy",
"keywords": "adverse drug reactions; alopecia; anidulafungin; hair loss",
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D000328:Adult; D000505:Alopecia; D000077612:Anidulafungin; D000935:Antifungal Agents; D002177:Candidiasis; D004359:Drug Therapy, Combination; D054714:Echinocandins; D005260:Female; D015725:Fluconazole; D006801:Humans; D055666:Lipopeptides; D000077551:Micafungin",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "660-2",
"pmc": null,
"pmid": "24604921",
"pubdate": "2014-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Anidulafungin-induced alopecia.",
"title_normalized": "anidulafungin induced alopecia"
} | [
{
"companynumb": "ES-CUBIST PHARMACEUTICAL, INC.-2014CBST000709",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ANIDULAFUNGIN"
},
"druga... |
{
"abstract": "Placenta accreta (PA) is a life-threatening disorder associated with decidual maldevelopment and a thin endometrium. Few cases of systemic lupus erythematosus (SLE) pregnancy complicated by PA have been reported, and the background pathophysiology remains elusive. Here, we report a case of PA in SLE pregnancy treated with hydroxychloroquine. A nulligravida woman with SLE, aged 41 years, visited our hospital because of infertility problems. Her SLE was treated with prednisolone and tacrolimus. We conducted assisted reproductive technology and gained several embryos. An artificial cycle successfully prepared the endometrium for embryo transfer with sufficient thickness. Over time, her SLE exacerbated, and we started hydroxychloroquine administration. Consequently, the endometrium did not respond to hormonal supplementation and remained thin, but we transferred the embryo and managed to achieve pregnancy. On the 38th week of gestation, we conducted labor induction because of elevated blood pressure. Induction was not effective, so we performed cesarean section; PA was observed. We performed compression suturing and were able to stop the hemorrhage. Postoperative uterine infarction and pelvic infection were successfully managed with conservative treatment. The present case highlights the use of hydroxychloroquine during endometrial development and contributes evidence regarding the pathogenesis of PA in pregnancy complicated by SLE.",
"affiliations": "Department of Pediatrics, Perinatal and Maternal Medicine, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.;Department of Comprehensive Reproductive Medicine, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.;Department of Pediatrics, Perinatal and Maternal Medicine, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.;Department of Pediatrics, Perinatal and Maternal Medicine, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.;Department of Comprehensive Reproductive Medicine, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.;Department of Comprehensive Reproductive Medicine, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.;Department of Comprehensive Reproductive Medicine, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.;Department of Comprehensive Reproductive Medicine, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.",
"authors": "Saito|Kazuki|K|;Mano|Chihiro|C|;Tatsumi|Takayuki|T|;Ishikawa|Tomonori|T|;Sekiguchi|Masaki|M|;Iwahara|Yuki|Y|;Hiramitsu|Shiro|S|;Miyasaka|Naoyuki|N|",
"chemical_list": "D006886:Hydroxychloroquine",
"country": "England",
"delete": false,
"doi": "10.1080/09513590.2020.1743652",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0951-3590",
"issue": "36(9)",
"journal": "Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology",
"keywords": "Artificial cycle; endometrium; frozen-thawed embryo transfer; hydroxychloroquine; placenta accreta",
"medline_ta": "Gynecol Endocrinol",
"mesh_terms": "D000328:Adult; D001755:Blastocyst; D002585:Cesarean Section; D015925:Cryopreservation; D004624:Embryo Transfer; D005260:Female; D005615:Freezing; D006801:Humans; D006886:Hydroxychloroquine; D007231:Infant, Newborn; D007247:Infertility, Female; D007564:Japan; D008180:Lupus Erythematosus, Systemic; D010921:Placenta Accreta; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D027724:Reproductive Techniques, Assisted; D016896:Treatment Outcome",
"nlm_unique_id": "8807913",
"other_id": null,
"pages": "843-846",
"pmc": null,
"pmid": "32268819",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Placenta accrete after a frozen-thawed embryo transfer in a systemic lupus erythematosus patient treated with hydroxychloroquine.",
"title_normalized": "placenta accrete after a frozen thawed embryo transfer in a systemic lupus erythematosus patient treated with hydroxychloroquine"
} | [
{
"companynumb": "JP-PBT-000287",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
"drugadmi... |
{
"abstract": "Interstitial Cystitis or Bladder Pain Syndrome (IC/BPS) is a heterogeneous condition characterized by elevated levels of inflammatory cytokines, IL-1β, IL-6, IL-8, IL-10, TNF-α, and is associated with debilitating symptoms of pelvic pain and frequent urination. A standard of care for IC/BPS has not been established, and most patients must undergo a series of different treatment options, with potential for severe adverse events. Here, we report a patient with a 26-year history of IC/BPS following treatment with multiple therapies, including low doses of etodolac, amitriptyline and gabapentin, which she was unable to tolerate because of adverse effects, including headaches, blurred vision and cognitive impairment. The patient achieved a complete clinical remission with minimal adverse events after 16 cycles of N-acetylcysteine (NAC) intravenous (IV) infusions over a period of 5 months, and pro-inflammatory cytokine levels were reduced when compared to measurements taken at presentation. Personalized low dose NAC IV infusion therapy represents an effective, safe, anti-inflammatory therapy administered in the outpatient setting for IC/BPS, and warrants further investigation.",
"affiliations": "Department of Medicine, The Maharaj Institute of Immune Regenerative Medicine, Boynton Beach, FL 33437, USA.;Department of Medicine, The Maharaj Institute of Immune Regenerative Medicine, Boynton Beach, FL 33437, USA.;Department of Medicine, The Maharaj Institute of Immune Regenerative Medicine, Boynton Beach, FL 33437, USA.;Palm Beach Atlantic University, West Palm Beach, FL 33401, USA.;Department of Medicine, The Maharaj Institute of Immune Regenerative Medicine, Boynton Beach, FL 33437, USA.",
"authors": "Maharaj|Dipnarine|D|0000-0001-9825-1905;Srinivasan|Gayathri|G|;Makepeace|Sarah|S|;Hickey|Christopher J|CJ|;Gouvea|Jacqueline|J|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/jpm11050342",
"fulltext": "\n==== Front\nJ Pers Med\nJ Pers Med\njpm\nJournal of Personalized Medicine\n2075-4426\nMDPI\n\n33923265\n10.3390/jpm11050342\njpm-11-00342\nCase Report\nClinical Remission Using Personalized Low-Dose Intravenous Infusions of N-acetylcysteine with Minimal Toxicities for Interstitial Cystitis/Bladder Pain Syndrome\nhttps://orcid.org/0000-0001-9825-1905\nMaharaj Dipnarine 1*\nSrinivasan Gayathri 1\nMakepeace Sarah 12\nHickey Christopher J. 2\nGouvea Jacqueline 1\nFalzarano Sara M. Academic Editor\n1 Department of Medicine, The Maharaj Institute of Immune Regenerative Medicine, Boynton Beach, FL 33437, USA; education@miirm.org (G.S.); sjmakepeace9@gmail.com (S.M.); jgouvea@bmscti.org (J.G.)\n2 Palm Beach Atlantic University, West Palm Beach, FL 33401, USA; chris_hickey@pba.edu\n* Correspondence: dmaharaj@bmscti.org\n24 4 2021\n5 2021\n11 5 34202 4 2021\n22 4 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nInterstitial Cystitis or Bladder Pain Syndrome (IC/BPS) is a heterogeneous condition characterized by elevated levels of inflammatory cytokines, IL-1β, IL-6, IL-8, IL-10, TNF-α, and is associated with debilitating symptoms of pelvic pain and frequent urination. A standard of care for IC/BPS has not been established, and most patients must undergo a series of different treatment options, with potential for severe adverse events. Here, we report a patient with a 26-year history of IC/BPS following treatment with multiple therapies, including low doses of etodolac, amitriptyline and gabapentin, which she was unable to tolerate because of adverse effects, including headaches, blurred vision and cognitive impairment. The patient achieved a complete clinical remission with minimal adverse events after 16 cycles of N-acetylcysteine (NAC) intravenous (IV) infusions over a period of 5 months, and pro-inflammatory cytokine levels were reduced when compared to measurements taken at presentation. Personalized low dose NAC IV infusion therapy represents an effective, safe, anti-inflammatory therapy administered in the outpatient setting for IC/BPS, and warrants further investigation.\n\ninterstitial cystitis\nbladder pain syndrome\nN-acetylcysteine\npersonalized medicine\npro-inflammatory cytokines\ninflammation\nTNF-α\nIL-1β\nanti-inflammatory therapy\n==== Body\n1. Introduction\n\nInterstitial Cystitis (IC), or Bladder Pain Syndrome (BPS), is a heterogeneous condition involving inflammation of the urinary bladder wall that produces debilitating symptoms of pelvic pain and frequent urination in affected patients. Since the etiology of IC/BPS is yet unknown, it is clinically diagnosed by exclusion in patients exhibiting bladder or pelvic pain, urinary frequency, urgency, and nocturia [1,2,3,4]. Another consequence of the imprecise diagnostic criteria is a lack of certainty in IC/BPS occurrence. It has been established that the condition is disproportionately seen among women [5,6], comprising up to 90% of cases in the United States [6]. A 2016 report estimated that between 2.7% and 6.5% of American women experience IC/BPS symptoms, but prevalence in both men and women is likely underreported [6]. The heterogeneous nature of symptoms may be explained by the increasingly widespread theory that IC/BPS is likely caused by multiple diseases which produce chronic inflammation, manifesting as various lower urinary tract symptoms [1].\n\nA standard of care for interstitial cystitis has not yet been established and, as a consequence, most patients must undergo a series of different treatment options to elucidate what is effective for their individual situation. Current treatments for IC/BPS include drug therapy such as dimethyl sulfoxide, amitriptyline, pentosane polysulfate, cyclosporine A, or nonsteroidal anti-inflammatory compounds, as well as alternative medicine treatments involving the modification of lifestyle factors [2,7,8]. Although pharmacological therapies have shown some benefit in control of IC/BPS symptoms, they may have a negative impact on the patient due to the inherent potential of adverse events [9]. In vivo studies using mouse models have shown that pentosan polysulfate may cause uncontrolled activation of immune function, which may lead to chronic inflammation, hypersensitivity, or autoimmunity [10]. As IC/BPS therapies continue to evolve, triple-targeted therapy using gabapentin, amitriptyline, and a nonsteroidal anti-inflammatory drug (NSAID) have demonstrated improved clinical outcomes [11,12]. Gabapentin is an effective anticonvulsant which addresses the chronic pain, including neuropathic pain, associated with IC/BPS [12]. Serving as an extension of pain management, amitriptyline, a tricyclic antidepressant, has been found to act as an effective analgesic in many patients [12,13]. Using these two drugs in combination with NSAIDs is a strategy for treatment of IC/BPS that attempts to target pain and overactive bladder symptoms, including voiding frequency and urgency [11], in a more effective way than using one medication alone.\n\nDespite promising results, triple-targeted therapies are not without potential for severe adverse events. Gabapentin carries the risks of psychedelic properties, dizziness, and respiratory failure [14], while amitriptyline can cause serious side effects such as blurred vision, tachycardia, and hypotension [15]. In combination, studies show that these drugs may cause side effects such as dizziness and sedation in up to half of participants [16]. Very few studies have examined the effects of this triple-therapy for IC/BPS treatment, and those that have been conducted focused on small cohorts with limited follow-up periods [11,12]. Additionally, these studies show that, although alleviation of symptoms was reported early in treatment with triple-therapy, the initial decrease in symptoms levels off after weeks or months of treatment [11,12].\n\nN-acetylcysteine (NAC) is a potential alternative novel therapy to reduce the inflammation associated with IC/BPS. NAC works directly by scavenging free radicals, and indirectly by increasing intracellular levels of glutathione, the most prevalent cellular antioxidant [17]. NAC has been shown to reduce oxidative stress in cells [18], as well as exert systemic anti-inflammatory effects in the body, with little to no harmful effects reported [17]. Clinically, NAC is used to treat a wide variety of diseases and conditions, including several inflammation-related diseases such as asthma, ulcerative colitis, and chronic bronchitis [17]. Taken together, the dualistic antioxidant and anti-inflammatory functions of NAC can be utilized to treat patients with IC/BPS by modifying the immune microenvironment to augment anti-inflammatory responses.\n\nAlthough outcome measurements of IC/BPS treatments are largely symptom-based, multiple studies have reported the value of tracking cytokines in monitoring the disease course [19,20]. Expressions of IL-1β, IL-6, IL-8, and TNF-α are all significantly elevated in animals [21], as well as human patients with IC/BPS, in comparison to individuals without the disease [19,20]. These persistently increased pro-inflammatory cytokines indicate a chronic inflammatory immune response, which is a likely contributor to IC/BPS pathology and symptoms [19,20,21].\n\nWe use a novel personalized treatment approach of NAC intravenous (IV) infusion dosing and frequency based upon serial plasma cytokine measurements to monitor the efficacy of treatment by reduction of symptoms and cytokine levels, while minimizing adverse events. In this case report, we describe a female patient presenting with IC/BPS for over 26 years following multiple therapies, including low-dose triple therapy of amitriptyline, gabapentin, and NSAID, which were terminated due to adverse events. At our clinic, the patient achieved a complete clinical remission with minimal adverse events after 16 cycles of NAC IV infusions over a period of 5 months, and pro-inflammatory cytokine levels were reduced when compared to measurements taken at presentation.\n\n2. Results\n\nCase Report\n\nA 70-year-old woman with a history of IC/BPS first attended our clinic in September 2019 (timeline of the key information is summarized in Figure 1). In 1961, the patient had frequent urination with recurrent urinary tract infections (UTI). In 1968, the patient was involved in a motor vehicle accident and she had fractures of L3-L5 and injury to her bladder. She subsequently developed chronic bladder and pelvic pain, urinary frequency, urgency and nocturia, and she was diagnosed with IC/BPS in 1994. The patient opted not to take prescribed medications and she adopted a holistic lifestyle consisting of a vegan diet, acupuncture, and massage therapy. In 2012 the patient was enrolled in an IC/BPS medical trial which included low doses of etodolac, amitriptyline and gabapentin for 3 months. After experiencing adverse effects including headaches, blurred vision and cognitive impairment, the patient ended her participation in the clinical trial and she resumed her holistic program.\n\nIn September 2019, the patient attended our clinic for evaluation of her disease and immune status. The patient reported mild urinary incontinence, difficulty starting and frequent, painful urination. A Pelvic Pain and Urgency/Frequency (PUF) questionnaire was administered to rule out other probable causes of painful urination such as endometriosis, or UTI. The PUF questionnaire was chosen over other IC/BPS questionnaires due to its comprehensive nature and its demonstrated ability to distinguish IC/BPS more efficiently [22,23]. The PUF scale showed a score of 28. Scores greater than 10 are associated with 90% sensitivity for IC/BPS [24]. Plasma cytokines showed levels of IL-1β at 19.49 pg/mL (elevated at 50th–75th percentile), TNF-α at 10.54 pg/mL (elevated at 75th–90th percentile), IL-10 at 7.72 (elevated at 50th–75th percentile), IL-8 at 2.24 pg/mL (at 25th–50th percentile), and IL-6 at 3.02 pg/mL (elevated at 50th–75th percentile) (Figure 2). Reference ranges by percentile were determined by calculating the mean and standard deviation from a cohort of healthy men and women. Treatment options discussed included responses and side effects of pentosane polysulfate, amitriptyline, cimetidine, cyclosporin A, hydroxyzine, self-care practices and behavior modification techniques, or no therapy. The patient refused treatments with potentially severe side effects and continued her holistic program.\n\nIn February 2020, the patient reported persistent urinary incontinence and worsening frequent/painful urination. The patient gave informed consent for treatment using personalized low dose N-acetylcysteine (NAC) IV infusions, including publication of results. The objective was to treat the chronic inflammation associated with IC/BPS using weekly low dose NAC IV infusions. Variation of the duration, dosing and frequency of administration of NAC was based on the patient’s symptoms and plasma cytokine levels.\n\nOn 5 May 2020, the patient started her weekly NAC IV infusions at a low dose of 6000 mg per IV infusion cycle. Plasma cytokines levels were elevated, with IL-1β at 18.27 pg/mL (elevated at 50th–75th percentile), TNF-α at 6.22 pg/mL (elevated at 50th–75th percentile), IL-10 24.72 pg/mL (elevated above 90th percentile), IL-8 at 1.79 pg/mL (at 25th–50th percentile), and IL-6 at 3.37 pg/mL (elevated at 50th–75th percentile) (Figure 2). On 26 May 2020, the patient complained of bladder discomfort and urinary frequency, and urinalysis confirmed an Escherichia coli infection for which the patient was treated with 500 mg of levofloxacin once a day for three days, along with her weekly NAC IV infusions. By 1 June 2020, the patient denied any urinary frequency, urgency, or bladder discomfort.\n\nOn 10 June 2020, the patient had successfully completed 5 NAC IV infusions with no complications. The patient was asymptomatic of all pain and urinary symptoms, and she chose to suspend NAC treatment. On 17 July 2020, the patient reported urinary urgency and she resumed weekly NAC IV infusions. After three more IV infusions the patient reported that her urinary urgency, incontinence, pains and spasms had completely resolved, and the patient remarked that this was the first time that she was completely pain free.\n\nThe patient experienced no associated side effects of the treatment. Plasma cytokine evaluation showed reductions in IL1-β at 10.75 pg/mL (at 25th–50th percentile), TNF-α at 3.56 pg/mL (at 25th–50th percentile), IL-10 8.00 pg/mL (elevated at 50th–75th percentile), IL-8 at 1.02 pg/mL (below 10th percentile), and IL-6 at 2.58 pg/mL (at 25th–50th percentile) (Figure 2). The patient was recommended to continue weekly NAC IV infusions to further reduce chronic inflammation.\n\nIn October 2020, the patient completed her 16th and final NAC IV infusion cycle, with no associated side effects. The patient continued to report no recurrence of urinary pains, spasms, urgency, or incontinence. Plasma cytokines showed continued improvements, with IL1-β at 7.88 pg/mL (at 25th–50th percentile), TNF-α at 1.45 pg/mL (below 10th percentile), IL-10 at 3.25 pg/mL (at 10th–25th percentile), IL-8 at 1.09 pg/mL (below 10th percentile), and IL-6 at 4.22 pg/mL (elevated at 50th–75th percentile) (Figure 2). The PUF questionnaire given at this time yielded a score of 11, which was an improvement from the baseline of 28. Five months following completion of the NAC IV infusion cycles, the patient remains in complete clinical remission. This is the longest duration of time that the patient has remained completely symptom-free.\n\n3. Discussion\n\nWe report a case of complete clinical remission of IC/BPS with personalized NAC IV infusions in a patient who had suffered for at least 26 years with debilitating symptoms, despite undergoing a series of commonly used treatments. The patient did not experience any therapy-related adverse events throughout the course of personalized NAC treatment. Symptom relief occurred after 4 NAC IV infusions, and the patient achieved complete clinical remission after completing 16 NAC IV infusions, with marked improvements in levels of plasma cytokines.\n\nNAC as a treatment for interstitial cystitis is a novel approach. Based on experimental data and successful treatment of several chronic inflammation-related diseases [17], we personalized the dose and schedule of low-dose NAC by monitoring symptoms and plasma cytokines before and after infusions. Recent studies using NAC to treat liposaccharide-induced interstitial cystitis in rats demonstrated positive results [25,26]. Intraperitoneal NAC injections in rat subjects reduced inflammation, reversed the progression of fibrosis, and restored the integrity of the urothelium, resulting in improvement of abnormal voiding symptoms [25]. Although it is generally well-tolerated with minimal adverse effects [18], NAC may act like a pro-oxidant at high doses, increasing oxidative stress and stimulating inflammation and abnormal cell proliferation [25,27,28]. Because of this potential risk, appropriate dosing is crucial in clinical application of NAC. In our treatment plan, variation of duration, dosage, and frequency of administration of NAC was based on plasma cytokine levels, and the patient was monitored frequently, with symptom tracking using the Pelvic Pain and Urgency/Frequency (PUF) questionnaire. The patient received low doses of 6000 mg per IV infusion cycle and showed no adverse reactions to the treatment. Although there is not a universal standard for NAC dosage, one meta-analysis showed ranges from 500–1200 mg once or twice per day, to 14,000 mg in multiple IV infusions over the course of a day [29]. A recent study using NAC to treat the cytokine storm of COVID-19 used a dosing regimen of 30,000 mg in three separate doses over 24 h, with favorable results [30].\n\nChronic inflammation manifesting as various lower urinary tract symptoms is characteristic of IC [1,3,4]. Elevated levels of cytokines such as IL1-β, TNF-α, IL-8, and IL-6 in patients with IC/BPS can serve as a guide for the dosing of NAC. IL-1β is a pro-inflammatory cytokine that is primarily increased in patients with IC/BPS, and animal model studies have shown that NAC inhibits the pro-inflammatory expression of IL-1β [19,20,21]. Immediately prior to beginning treatment in May 2020, the patient exhibited elevated levels of IL-1β at 18.27 pg/mL (Figure 2a), when the patient’s symptoms of urinary pain, incontinence and urgency were severe, and accompanied by a high PUF score of 28. With continuous treatments of NAC, IL-1β was reduced to 7.88 pg/mL, which was consistent with the resolution of symptoms and a decrease of the PUF score to 10.\n\nTNF-α is a pleiotropic, pro-inflammatory cytokine released by mast cells in the bladder urothelium of patients with IC, and this overexpression has been shown to participate in IC/BPS pathology [31]. In a study using transgenic mice, TNF-α was shown to promote urothelial apoptosis and cause the characteristic symptoms of pelvic pain, voiding abnormalities and urothelial lesions [31]. Our patient showed elevated TNF-α levels prior to treatment, at 6.22 pg/mL (Figure 2b), higher than the average value reported in IC/BPS patients of 2.63 pg/mL [19,20]. After completing the full 16 cycles of NAC IV infusions, the patient’s levels decreased to 1.45 pg/mL and correlated with symptom resolution. This value is much closer to the average TNF-α expression observed in control patients of 0.91 pg/mL [19,20].\n\nFollowing completion of the 16 IV infusions of NAC in November, 2020, the patient’s IL-8 levels decreased, indicating improvement (1.09 pg/mL vs. 1.79 pg/mL) (Figure 2d), and IL-10 levels also decreased (3.25 pg/mL vs. 24.72 pg/mL) (Figure 2c). While IL-10’s anti-inflammatory properties are well documented, studies from recent years have shown its potential pro-inflammatory characteristics [32]. Patients treated with IL-10 displayed increased levels of inflammatory markers CRP, IL-6, and lipopolysaccharide binding protein (LBP) [33]. Other studies showed that IL-10 administration was associated with increases in levels of IL-6, IL-8 and TNF-α, although these did not show statistical significance [34]. This is consistent with the findings in our patient who demonstrated increased levels of IL-10, which correlated with increased levels of IL-8 and TNF-α; these levels decreased when IL-10 expression decreased. Additional studies have revealed that IL-10 is significantly elevated in patients with UTIs [35,36]. Our findings are consistent, since, at the time of our patient’s UTI at the beginning of treatment (Figure 1), she had the highest levels of IL-10 (Figure 2c). Once her UTI symptoms were resolved, IL-10 expression showed a dramatic decrease (Figure 2c). Collectively, these studies and our findings support the pro-inflammatory characteristics and increased expression of IL-10 in inflammatory environments [32,33,34,35,36].\n\nInterestingly, IL-6 levels initially decreased, from 3.37 pg/mL to lowest levels of 2.58 pg/mL in July after 5 NAC IV infusions, but then increased to 4.22 pg/mL in October 2020. The reason for the subsequent increase in IL-6 levels while on NAC is unclear, since all other pro-inflammatory cytokines were reduced and she displayed no symptoms. Our patient’s older age may be a factor, since younger patients with IC/BPS treated with cyclosporin A or pentosane polysulfate sodium did not exhibit significant changes to IL-6 levels; however, in older patients (patients older than 53 years), IL-6 levels were reduced after cyclosporin A treatment [37]. Further serum immune testing performed to monitor IL-6 in December 2020 showed a decreased level of 2.90 pg/mL, which was consistent with the decreases seen in her other pro-inflammatory cytokines. We are continuing to monitor our patient’s IL-6 levels after completion of treatment. Overall, our patient’s course of symptom relief correlated with an improvement of plasma cytokines levels. In July 2020, the patient reported a complete absence of urinary pains and spasms, as well as urinary urgency and incontinence. The patient has remained in clinical remission for five months following the completion of the IV infusion cycles in October 2020, and she has remained off all treatment.\n\nThis report describes a previously unreported approach for treating IC/BPS by measuring inflammatory biomarkers IL-1β, TNF-α, IL-8, IL-10 and IL-6, and tailoring the dose and frequency of NAC IV infusions in response to the reduced expression of these biomarkers, combined with symptom monitoring using the PUF score. Our report serves as a basis for a precise and personalized low toxicity anti-inflammatory therapeutic option in patients with debilitating IC/BPS symptoms who have been unresponsive to commonly used treatments.\n\n4. Conclusions\n\nIC/BPS is associated with debilitating symptoms which often show short-lived responses or lack of response to commonly used treatments. Our data showed that personalized treatment with low-dose IV infusions of NAC was associated with reduced expression of pro-inflammatory cytokines of IC/BPS, and resulted in the desired outcome of complete remission with no adverse events.\n\n5. Future Perspective\n\nThis case report shows that personalized anti-inflammatory treatment with NAC IV infusions resulted in complete clinical remission, with no adverse events, in a patient with IC/BPS who had suffered with chronic debilitating symptoms for over 26 years and who had a poor response and adverse events to commonly used treatments. This unique approach is an important contribution and it supports the need for future research concerning this therapeutic option to improve outcomes and minimize side effects in patients with IC/BPS.\n\nAcknowledgments\n\nThe authors wish to thank the patient for giving consent to publish our findings.\n\nAuthor Contributions\n\nConcept and design, D.M.; data collection, analysis, and interpretation, D.M., G.S. and S.M.; drafting the manuscript for important intellectual content, D.M., G.S., S.M., C.J.H., and J.G. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research received no external funding.\n\nInstitutional Review Board Statement\n\nEthical review and approval were waived for this manuscript due to the Department of Health and Human Services (DHHS) research guidelines for case reports.\n\nInformed Consent Statement\n\nWritten informed consent has been obtained from the patient to publish this paper.\n\nConflicts of Interest\n\nThe authors declare no conflict of interest.\n\nFigure 1 Key timeline information. Green arrows indicate treatment initiation. Blue arrows indicate the duration of treatment. Red octagons indicate when the patient stopped treatment. Beginning in 1994 after IC/BPS diagnosis, holistic treatment was used. In 2012, patient underwent a 3-month IC/BPS clinical trial using low-dose triple therapy. In May 2020, patient began weekly 6000 mg NAC IV infusions. Patient suspended IV infusions in June 2020. Patient resumed NAC IV infusion treatment in July 2020. NAC treatment was completed in October 2020.\n\nFigure 2 Changes in plasma cytokine secretion in response to NAC IV infusions. (a) IL-1β expression (ELISA) in peripheral blood. (b) TNF-α expression (ELISA) in peripheral blood. (c) IL-10 expression (ELISA) in peripheral blood. (d) IL-8 expression (ELISA) in peripheral blood.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Wesselmann U. Interstitial cystitis: A chronic visceral pain syndrome Urology 2001 57 Suppl. 1 32 39 10.1016/S0090-4295(01)01123-2 11378048\n2. Dasgupta J. Tincello D.G. Interstitial cystitis/bladder pain syndrome: An update Maturitas 2009 64 212 217 10.1016/j.maturitas.2009.09.016 19837525\n3. Hanno P.M. Burks D.A. Clemens J.Q. Dmochowski R.R. Erickson D. Fitzgerald M.P. Forrest J.B. Gordon B. Gray M. Mayer R.D. Interstitial cystitis guidelines panel of the American Urological Association Education and Research, Inc. AUA guideline for the diagnosis and treatment of interstitial cystitis/bladder pain syndrome J. Urol. 2011 185 2162 2170 10.1016/j.juro.2011.03.064 21497847\n4. Hanno P.M. Erickson D. Moldwin R. Faraday M.M. American Urological Association Diagnosis and treatment of interstitial cystitis/bladder pain syndrome: AUA guideline amendment J. Urol. 2015 193 1545 1553 10.1016/j.juro.2015.01.086 25623737\n5. Rovner E. Propert K.J. Brensinger C. Wein A.J. Foy M. Kirkemo A. Landis J.R. Kusek J.W. Nyberg L.M. Treatments used in women with interstitial cystitis: The Interstitial Cystitis Data Base (ICDB) study experience Urology 2000 56 940 945 10.1016/S0090-4295(00)00845-1 11113737\n6. Cox A. Golda N. Nadeau G. Curtis Nickel J. Carr L. Corcos J. Teichman J. CUA guideline: Diagnosis and treatment of interstitial cystitis/bladder pain syndrome Can. Urol. Assoc. J. 2016 10 E136 E155 10.5489/cuaj.3786 27790294\n7. Hanno P.M. Sant G.R. Clinical highlights of the National Institute of Diabetes and Digestive and Kidney Diseases/Interstitial Cystitis Association scientific conference on interstitial cystitis Urology 2001 57 Suppl. 1 2 6 10.1016/S0090-4295(01)01112-8 11378041\n8. Whitmore K.E. Complementary and alternative therapies as treatment approaches for interstitial cystitis Rev. Urol. 2002 4 Suppl. 1 S28 S35\n9. Greiman A. Cox L. Pharmacotherapy for interstitial cystitis/bladder pain syndrome Curr. Bladder Dysfunct. Rep. 2019 14 365 376 10.1007/s11884-019-00540-9\n10. Thakur S.A. Nyska A. White K.L. Jr. Smith M.J. Auttachoat W. Germolec D.R. Immunomodulatory activity of orphan drug Elmiron® in female B6C3F1/N mice Food Chem. Toxicol. 2014 68 196 203 10.1016/j.fct.2014.03.015 24657363\n11. Kwon W.-A. Ahn S.H. Oh T.H. Lee J.W. Han D.Y. Jeong H.J. Effect of low-dose triple therapy using gabapentin, amitriptyline, and a nonsteroidal anti-inflammatory drug for overactive bladder symptoms in patients with bladder pain syndrome Int. Neurourol. J. 2013 17 78 82 10.5213/inj.2013.17.2.78 23869272\n12. Lee J.W. Han D.Y. Jeong H.J. Bladder pain syndrome treated with triple therapy with gabapentin, amitriptyline, and a nonsteroidal anti-inflammatory drug Int. Neurourol. J. 2010 14 256 260 10.5213/inj.2010.14.4.256 21253338\n13. Chen W. Xie D. Liu G. Chen Y. Cai Z. Effect of low-dose amitriptyline treatment for interstitial cystitis/bladder pain syndrome Clin. Res. Urol. 2018 1 1 5\n14. Quintero G.C. Review about gabapentin misuse, interactions, contraindications and side effects J. Exp. Pharmacol. 2017 9 13 21 10.2147/JEP.S124391 28223849\n15. Thour A. Marwaha R. Amitriptyline StatPearls StatPearls Publishing Treasure Island, FL, USA 2020\n16. Kamble S.V. Motlekar S.A. D’souza L.L. Kudrigikar V.N. Rao S.E. Low doses of amitriptyline, pregabalin, and gabapentin are preferred for management of neuropathic pain in India: Is there a need for revisiting dosing recommendations? Korean J. Pain 2017 30 183 191 10.3344/kjp.2017.30.3.183 28757918\n17. Mokhtari V. Afsharian P. Shahhoseini M. Kalantar S.M. Moini A. A review on various uses of N-acetyl cysteine Cell J. 2017 19 11 17 28367412\n18. Bavarsad Shahripour R. Harrigan M.R. Alexandrov A.V. N-acetylcysteine (NAC) in neurological disorders: Mechanisms of action and therapeutic opportunities Brain Behav. 2014 4 108 122 10.1002/brb3.208 24683506\n19. Jiang Y.-H. Peng C.-H. Liu H.-T. Kuo H.-C. Increased pro-inflammatory cytokines, C-reactive protein and nerve growth factor expressions in serum of patients with interstitial cystitis/bladder pain syndrome PLoS ONE 2013 8 e76779 10.1371/journal.pone.0076779 24146927\n20. Liu H.-T. Kuo H.-C. Biomarkers for patients with interstitial cystitis/bladder pain syndrome Urol. Sci. 2015 26 225 229 10.1016/j.urols.2015.02.002\n21. Mohamaden W.I. Alterations of pro-inflammatory cytokines and tissue protein expressions in cats with interstitial cystitis Pak. Vet. J. 2019 39 151 156 10.29261/pakvetj/2019.026\n22. Carr L.K. Corcos J. Nickel J.C. Teichman J. Diagnosis of interstitial cystitis June 2007 Can. Urol. Assoc. J. 2009 3 81 86 10.5489/cuaj.1030 19293986\n23. Kushner L. Moldwin R.M. Efficiency of questionnaires used to screen for interstitial cystitis J. Urol. 2006 176 587 592 10.1016/j.juro.2006.03.035 16813894\n24. Parsons C.L. Dell J. Stanford E.J. Bullen M. Kahn B.S. Waxell T. Koziol J.A. Increased prevalence of interstitial cystitis: Previously unrecognized urologic and gynecologic cases identified using a new symptom questionnaire and intravesical potassium sensitivity Urology 2002 60 573 578 12385909\n25. Ryu C.-M. Shin J.H. Yu H.Y. Ju H. Kim S. Lim J. Heo J. Lee S. Shin D.-M. Choo M.-S. N-acetylcysteine prevents bladder tissue fibrosis in a lipopolysaccharide-induced cystitis rat model Sci. Rep. 2019 9 8134 10.1038/s41598-019-44631-3 31148586\n26. Shin J.H. Ryu C.-M. Ju H. Yu H.Y. Song S. Shin D.-M. Choo M.-S. Synergistic effects of N-acetylcysteine and mesenchymal stem cell in a lipopolysaccharide-induced interstitial cystitis rat model Cells 2019 9 86 10.3390/cells9010086\n27. Sprong R.C. Winkelhuyzen-Janssen A.M. Aarsman C.J. van Oirschot J.F. van der Bruggen T. van Asbeck B.S. Low-dose N-acetylcysteine protects rats against endotoxin-mediated oxidative stress, but high-dose increases mortality Am. J. Respir. Crit. Care Med. 1998 157 Pt 1 1283 1293 10.1164/ajrccm.157.4.9508063 9563752\n28. Szkudlarek U. Zdziechowski A. Witkowski K. Kasielski M. Luczyńska M. Luczyński R. Sarniak A. Nowak D. Effect of inhaled N-acetylcysteine on hydrogen peroxide exhalation in healthy subjects Pulm. Pharmacol. Ther. 2004 17 155 162 10.1016/j.pupt.2004.01.007 15123225\n29. Sun Z. Fu Q. Cao L. Jin W. Cheng L. Li Z. Intravenous N-acetylcysteine for prevention of contrast-induced nephropathy: A meta-analysis of randomized, controlled trials PLoS ONE 2013 8 e55124 23383076\n30. Ibrahim H. Perl A. Smith D. Lewis T. Kon Z. Goldenberg R. Yarta K. Staniloae C. Williams M. Therapeutic blockade of inflammation in severe COVID-19 infection with intravenous N-acetylcysteine Clin. Immunol. 2020 219 108544 10.1016/j.clim.2020.108544 32707089\n31. Yang W. Searl T.J. Yaggie R. Schaeffer A.J. Klumpp D.J. A MAPP network study: Overexpression of tumor necrosis factor-α in mouse urothelium mimics interstitial cystitis Am. J. Physiol. Renal Physiol. 2018 315 F36 F44 10.1152/ajprenal.00075.2017 29465304\n32. Mühl H. Pro-inflammatory signaling by IL-10 and IL-22: Bad habit stirred up by interferons? Front. Immunol. 2013 4 18 10.3389/fimmu.2013.00018 23382730\n33. Döcke W.-D. Asadullah K. Belbe G. Ebeling M. Höflich C. Friedrich M. Sterry W. Volk H.-D. Comprehensive biomarker monitoring in cytokine therapy: Heterogeneous, time-dependent, and persisting immune effects of interleukin-10 application in psoriasis J. Leukoc. Biol. 2009 85 582 593 10.1189/jlb.0408249 19038787\n34. Cooper P.J. Fekade D. Remick D.G. Grint P. Wherry J. Griffin G.E. Recombinant human interleukin-10 fails to alter proinflammatory cytokine production or physiologic changes Associated with the Jarisch-Herxheimer reaction J. Infect. Dis. 2000 181 203 209 10.1086/315183 10608768\n35. Duell B.L. Carey A.J. Tan C.K. Cui X. Webb R.I. Totsika M. Schembri M.A. Derrington P. Irving-Rodgers H. Brooks A.J. Innate transcriptional networks activated in bladder in response to uropathogenic Escherichia coli drive diverse biological pathways and rapid synthesis of IL-10 for defense against bacterial urinary tract infection J. Immunol. 2012 188 781 792 10.4049/jimmunol.1101231 22184725\n36. Drage L.K.L. Robson W. Mowbray C. Ali A. Perry J.D. Walton K.E. Harding C. Pickard R. Hall J. Aldridge P.D. Elevated urine IL-10 concentrations associate with Escherichia coli persistence in older patients susceptible to recurrent urinary tract infections Immun. Ageing 2019 16 16 10.1186/s12979-019-0156-9 31338112\n37. Sairanen J. Hotakainen K. Tammela T.L.J. Stenman U.-H. Ruutu M. Urinary epidermal growth factor and interleukin-6 levels in patients with painful bladder syndrome/interstitial cystitis treated with cyclosporine or pentosan polysulfate sodium Urology 2008 71 630 633 10.1016/j.urology.2007.11.055 18387391\n\n",
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"keywords": "IL-1β; N-acetylcysteine; TNF-α; anti-inflammatory therapy; bladder pain syndrome; inflammation; interstitial cystitis; personalized medicine; pro-inflammatory cytokines",
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"title": "Clinical Remission Using Personalized Low-Dose Intravenous Infusions of N-acetylcysteine with Minimal Toxicities for Interstitial Cystitis/Bladder Pain Syndrome.",
"title_normalized": "clinical remission using personalized low dose intravenous infusions of n acetylcysteine with minimal toxicities for interstitial cystitis bladder pain syndrome"
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"abstract": "Neoadjuvant imatinib may prevent tumor rupture and the need for extended surgery by reducing the tumor size by approximately 35%, especially for large gastric gastrointestinal stromal tumors(GISTs), as shown in a previous phase Ⅱ study (Kurokawa et al. BJC 2017); however, the use ofneoadjuvant imatinib is not prevalent in clinical practice. Herein, we report a large gastric GIST that was successfully treated with neoadjuvant imatinib. A 74-year-old woman complained ofabdominal pain, and abdominal computed tomography(CT)revealed a 14 cm oval tumor in the left upper abdominal cavity. Gastric biopsy revealed that the tumor was a GIST. The patient also had a small lung tumor that was diagnosed as a primary lung carcinoma in the right upper lobe. We performed neoadjuvant imatinib for 6 months as the primary treatment. After 7 months ofimatinib administration, CT revealed that the GIST decreased in size but the lung cancer was slightly enlarged. Therefore, we performed right upper lung lobectomy and continued imatinib therapy for an additional 3 months. After a total of9 months ofneoadjuvant imatinib treatment, we performed partial gastrectomy combined with splenectomy without tumor rupture. The patient is scheduled to continue imatinib therapy for a total of 3 years.",
"affiliations": "Dept. of Surgery, Tokyo Metropolitan Cancer and Infectious Disease Center Komagome Hospital.",
"authors": "Oguri|Yohei|Y|;Cho|Haruhiko|H|;Oohinata|Ryouki|R|;Onoyama|Haruna|H|;Horiguchi|Shinichiro|S|",
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"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D005260:Female; D046152:Gastrointestinal Stromal Tumors; D006801:Humans; D000068877:Imatinib Mesylate; D020360:Neoadjuvant Therapy; D013274:Stomach Neoplasms",
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"title": "A Large Gastric Gastrointestinal Stromal Tumor Successfully Treated with Neoadjuvant Imatinib Followed by Surgery-A Case Report.",
"title_normalized": "a large gastric gastrointestinal stromal tumor successfully treated with neoadjuvant imatinib followed by surgery a case report"
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"abstract": "The antagonists of tumour necrosis factor (anti-TNF) have been successfully used in several chronic inflammatory diseases such as Rheumatoid Arthritis (RA), but some studies have observed the development of infections by intracellular pathogens in patients using anti-TNF. We report a case of a female patient with previous diagnosis of RA for 16 years that used several disease-modifying anti-rheumatic drugs (DMARDs) that resulted in treatment failure, and then was treated with infliximab. After fifteen days of the second dose, the patient developed ventilatory-dependent chest pain, dry cough and dyspnea. She was hospitalized, and the diagnosis of pneumonia by Legionella pneumophila was confirmed by the presence of Legionella antigen in an urine test. TNF is an inflammatory cytokine that also acts inhibiting the bacterial growth of intracellular pathogens, and its inhibition seems to increase susceptibility to these infections in some patients.",
"affiliations": "Universidade Federal de Santa Catarina, Florianópolis, SC, Brasil.;Universidade Federal de Santa Catarina, Florianópolis, SC, Brasil.;Núcleo de Reumatologia, Hospital Universitário Polydoro Ernani de São Thiago, Florianópolis, SC, Brasil.;Núcleo de Reumatologia, Hospital Universitário Polydoro Ernani de São Thiago, Florianópolis, SC, Brasil.;Núcleo de Reumatologia, Hospital Universitário Polydoro Ernani de São Thiago, Florianópolis, SC, Brasil. Electronic address: ivaniop@matrix.com.br.",
"authors": "Giassi|Karina de Souza|Kde S|;Furlanetto|Vilson|V|;Fialho|Sonia|S|;Gomes Ribeiro|Giovana|G|;Pereira|Ivânio Alves|IA|",
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"mesh_terms": "D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D005260:Female; D006801:Humans; D000069285:Infliximab; D007877:Legionnaires' Disease; D008875:Middle Aged; D014409:Tumor Necrosis Factor-alpha",
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"abstract": "Survival rates of children with acute lymphoblastic leukemia have improved since the incorporation of asparaginase in the treatment protocol, but the medication has potential serious complications, including vascular thrombosis. Here, we describe the case of a 13-year-old boy with pre-T-cell acute lymphoblastic leukemia whose treatment course was complicated by perforated jejunitis requiring resection of a portion of his small bowel. Pathologic assessment showed transmural ischemia, mesenteric venous and arterial thrombi, and scattered cytomegalovirus inclusion bodies. Pediatric mesenteric ischemia is rare, and its consideration in patients treated with asparaginase is discussed.",
"affiliations": "Department of Radiology, Seattle Children's Hospital, University of Washington School of Medicine, 4800 Sand Point Way NE, Seattle, WA 98105, USA.;Department of Radiology, Seattle Children's Hospital, University of Washington School of Medicine, 4800 Sand Point Way NE, Seattle, WA 98105, USA.;Department of Pathology, Seattle Children's Hospital, University of Washington School of Medicine, Seattle, WA, USA.;Department of Pediatrics, Division of Hematology-Oncology, Seattle Children's Hospital, University of Washington School of Medicine, Seattle, WA, USA.",
"authors": "Tang|Elizabeth R|ER|;Chapman|Teresa|T|;Finn|Laura S|LS|;Leger|Kasey J|KJ|",
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"fulltext": "\n==== Front\nRadiol Case RepRadiol Case RepRadiology Case Reports1930-0433Elsevier S1930-0433(18)30070-010.1016/j.radcr.2018.02.017PediatricPerforated jejunitis in a child with acute lymphoblastic leukemia treated with pegaspargase Tang Elizabeth R. MDaChapman Teresa MD, MAteresa.chapman@seattlechildrens.orga*Finn Laura S. MDbLeger Kasey J. MD, MScca Department of Radiology, Seattle Children's Hospital, University of Washington School of Medicine, 4800 Sand Point Way NE, Seattle, WA 98105, USAb Department of Pathology, Seattle Children's Hospital, University of Washington School of Medicine, Seattle, WA, USAc Department of Pediatrics, Division of Hematology-Oncology, Seattle Children's Hospital, University of Washington School of Medicine, Seattle, WA, USA* Corresponding author. teresa.chapman@seattlechildrens.org08 3 2018 6 2018 08 3 2018 13 3 568 572 2 2 2018 7 2 2018 © 2018 The Authors2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Survival rates of children with acute lymphoblastic leukemia have improved since the incorporation of asparaginase in the treatment protocol, but the medication has potential serious complications, including vascular thrombosis. Here, we describe the case of a 13-year-old boy with pre-T-cell acute lymphoblastic leukemia whose treatment course was complicated by perforated jejunitis requiring resection of a portion of his small bowel. Pathologic assessment showed transmural ischemia, mesenteric venous and arterial thrombi, and scattered cytomegalovirus inclusion bodies. Pediatric mesenteric ischemia is rare, and its consideration in patients treated with asparaginase is discussed.\n\nKeywords\nAcute lymphoblastic leukemiaPediatricAsparaginaseComplicationsAcute mesenteric ischemiaComputed tomography\n==== Body\nIntroduction\nAcute lymphoblastic leukemia (ALL) is the most common cancer diagnosed in children, with an incidence of approximately 3.9% among individuals younger than 19 years and a mortality rate of 0.3 per 100,000 in the United States [1]. Reported toxicities in patients undergoing chemotherapy for ALL are high [2], and gastrointestinal (GI) complications such as diarrhea and neutropenic colitis are particularly common [3]. The long-term survival of patients with ALL has improved substantially since the introduction of asparaginase therapy [4]. However, this therapy can be associated with many serious toxicities, including an increased propensity for thrombosis [5]. We present a case of an adolescent with pre-T-cell ALL who was found to have perforated jejunitis during induction chemotherapy. Pathologic assessment of the resected bowel demonstrated changes associated with transmural ischemia, as well as focal mesenteric venous and arterial thrombi and scattered cytomegalovirus (CMV) inclusion bodies. This case illustrates the complex pathophysiology of jejunitis in a child undergoing induction chemotherapy for ALL and allows for a discussion about both mesenteric ischemia and CMV enteritis in children.\n\nCase report\nA 13-year-old boy with a recent diagnosis of pre-T-cell ALL presented with severe worsening abdominal pain that began 2 weeks after initiation of chemotherapy. The boy was undergoing induction chemotherapy per the standard arm of Children's Oncology Group study AALL1231 that includes dexamethasone, daunorubicin, vincristine, and intensified pegaspargase (given on days 4 and 18). On day 14 of induction, the patient developed epigastric abdominal pain and was found to have lost 5 kg since his initial ALL diagnosis. Abdominal pain and nutritional status initially improved with optimization of proton pump inhibition and initiation of nasogastric feeds. However, on day 25 of induction, the patient presented to the emergency department with increasing epigastric pain and multiple episodes of nonbilious, nonbloody emesis.\n\nOn examination, the patient was afebrile and normotensive. He had left periumbilical tenderness, without peritoneal signs. Significant laboratory results included an absolute neutrophil count of 3100 cells/µL, elevated serum lactate, and worsening metabolic acidosis. Abdominal radiograph (Fig. 1A) revealed multiple air-fluid levels, suggestive of ileus or early bowel obstruction, as well as probable pneumatosis in the left midabdomen. Contrast-enhanced computed tomography (CT) performed in standard portal venous phase confirmed ileus and pneumatosis intestinalis in the jejunum, with associated bowel wall thickening and segments of mucosal hypoenhancement and hyperenhancement (Fig. 1B). Simple-appearing ascites was seen. There was portal venous gas, along with small amounts of ectopic air dissecting along the mesenteric root into the esophageal or periesophageal region of the lower posterior mediastinum (Fig. 1C). Mesenteric vasculature was normal, without obvious CT evidence of arterial or venous thrombosis, although CT angiography was not performed.Fig. 1 Abdominal imaging acquired on day 14 of induction chemotherapy after onset of abdominal pain showing jejunal pneumatosis and dissection of gas through the mesentery into the retroperitoneum and the portal venous system. (A) The upright anterior-posterior abdominal radiograph shows pneumatosis in the left upper quadrant (white arrows), as well as air-fluid levels in mildly dilated loops of bowel (white arrowheads). Contrast-enhanced computed tomography images in (B) the coronal plane with soft tissue algorithm and in (C) the axial plane with lung algorithm shows pneumatosis involving an abnormally dilated segment of jejunum (white arrows in B) and abnormally enhancing mucosa in the jejunum (white arrowheads in B). Abnormal retroperitoneal air is present at the diaphragmatic hiatus (black arrows in C), and portal venous gas is also observed (black arrow in B, black arrowheads in C).\n\nFig. 1\n\nTwo days after admission (day 26 of induction), the patient developed rebound tenderness, and the abdominal radiographs revealed pneumoperitoneum. A jejunal perforation was found during emergent and exploratory laparotomy. Two separate 30- to 35-cm segments of jejunum with gangrenous necrosis were resected, and the abdomen was left open. Re-exploration and washout of the abdomen were performed 2 days later, along with end-to-end anastomoses of 2 of the 3 jejunal segments and creation of mucus fistulae.\n\nThe resected bowel segments (Fig. 2) showed multiple foci of geographic transmural or mucosal necrosis with bile-stained bacteria-rich fibrinopurulent exudates borne between areas of residual mucosa. Several submucosal vessels near the ulcers were thrombosed. Few scattered CMV inclusions were identified in mucosal and submucosal endothelial and stromal cells. Occasional partially occlusive fibrin thrombi were seen within few mesenteric vessels; large feeding arteries were patent.Fig. 2 Cytomegalovirus inclusions (arrowheads) were identified in the endothelial cells of the mucosa (A) and in the submucosal stromal cells (B) (hematoxylin and eosin, 200×). Mesenteric arteries (C, D, left) have fibrin thrombi at varying stages of organization, adherent to the walls, and are variably occluding the lumens. A strand of fibrin clings to the vein wall (C, right). Fibrin and red and white blood cells obstruct a mesenteric vein (D, right) (hematoxylin and eosin, 100×). Low-power images show a small segment of residual mucosa adjacent to an ulcer bed (arrow) that is covered by bile-stained fibrinous exudate, resembling a pseudomembrane (E). There is partial necrosis of the muscularis propria (*) and a fibrotic serosa that contains dilated lymphatic spaces (E). Diffuse ulceration is associated with full-thickness necrosis (*, F) (Masson trichrome, 40×).\n\nFig. 2\n\nThe patient was treated with postoperative broad-spectrum antibiotics for non-neutropenic enterocolitis and ganciclovir (6 weeks) for CMV colitis. Jejunostomy takedown was uncomplicated, and the patient was discharged from the hospital tolerating full enteral feeds. The end of induction assessment for minimal residual disease (<0.01%) was negative for residual leukemia in the bone marrow.\n\nDiscussion\nWe present a rare case of non-neutropenic jejunal necrosis and perforation, in the setting of immunosuppression by chemotherapy, including pegaspargase. We believe the etiology of this patient's intestinal issues was multifactorial with contributions from pegaspargase-related hypercoagulability resulting in mesenteric ischemia and concurrent CMV.\n\nThe overall survival rates of children with ALL have improved substantially since the incorporation of asparaginase therapy into treatment protocols [6], [7]. However, this therapy's known toxicities include altered coagulation and fibrinolysis, which increase a patient's risk of thrombosis and bleeding, especially during induction. The overall incidence of thrombotic complications in children with ALL is 5.2%, and usually, these complications are intracranial thrombotic events or catheter-related thrombi [5], [8]. To the best of our knowledge, mesenteric thrombotic events have not been ascribed to pegaspargase therapy in published literature. However, the temporal association of the medication with the small intestine ischemia and perforation in this case may implicate pegaspargase-induced hypercoagulability in its development.\n\nA hypercoagulable state can lead to mesenteric arterial thrombosis or thromboembolism or mesenteric venous thrombosis. The published descriptions of mesenteric ischemia in children are quite limited. In both adults and children, contrast-enhanced CT of the abdomen and pelvis is appropriate [9], [10], [11], [12], [13]. Although dual-phase (arterial and venous) scanning protocols are commonly used in adults, repeat CT scanning of pediatric patients is typically avoided to reduce exposure to ionizing radiation [14]. In a review of 24 adults with acute mesenteric ischemia (AMI) who underwent single venous-phase CT, sensitivity and specificity for detection of mesenteric ischemia were 0.79 and 0.98, respectively [10]. The contrast-enhanced CT findings of AMI can vary, depending on the stage of disease. If the etiology is thromboembolism or thrombosis, filling defects may be seen in mesenteric vessels, although these were not discretely seen in our patient's CT findings. Bowel wall enhancement can be present with vasodilatory effects or can be absent with vasoconstriction and does not reflect ischemic severity [13]. Bowel wall thickening and dilation of bowel loops are common with ileus, but are nonspecific findings, as with this patient. With mucosal necrosis, intraluminal gas dissects into the wall, causing pneumatosis and possibly subsequent pneumoperitoneum and ascites [9], [10], [12], [13]. Notably, the CT findings associated with inflammatory or infectious arteritis overlap with those of ischemic enteritis. In the absence of discernible thrombi or emboli, CT has a low diagnostic utility for distinguishing the cause of intestinal abnormalities. Likewise, the clinical presentation of AMI is also nonspecific, as are the associated laboratory findings, such as elevated lactate and metabolic acidosis [13], [15]. Therefore, diagnostic imaging serves as the most practical and most rapidly acquired means for diagnosis in these cases, with the greatest impact on outcome due to preinfarction diagnosis [16].\n\nThe likely contribution of CMV to this patient's disease cannot be overlooked. Primary CMV infection is rarely the cause of jejunal perforation [17], [18], [19]. Based on reported clinical experiences with adult patients, the colon and the upper GI tract are the typical sites of involvement [18], [20], [21]. However, primary CMV infection has been associated with small bowel perforation in both adults and children [17], [18], [19], [22]. Latent CMV reactivates locally at sites of inflammation [23] and has been associated with vascular angiogenesis and endothelial damage that triggers thrombosis [24], [25]. In the rare reports of jejunal perforation in the setting of CMV infection, mesenteric thrombi or ulcerations can be seen [17], [18], [19].\n\nThe presentation of CMV-related GI infection can vary. Although CMV manifests typically in immunosuppressed individuals, vascular damage and thrombosis have also been reported in immunocompetent patients with acute CMV [20], [21], [26], [27]. In a review of 38 pediatric patients with symptomatic and histologically confirmed active CMV GI disease (median age of 5 months, ranging from 3 days to 12 years), 18% of the patients presented with clinical signs of peritonitis from perforation [22]. All 38 patients had impaired immunity, and 63% were malnourished. Additionally, in 10 of the 38 patients, a preceding local inflammatory insult was documented, such as surgery or necrotizing enterocolitis. Inflammatory polyps, ulceration, and mucosal sloughing are typical, in addition to perforation in the small bowel. Although our patient was not neutropenic, he had recent diarrhea preceding his jejunal disease. It is conceivable that in our patient, a local inflammatory cascade resulting from asparaginase-related ischemia triggered reactivation of latent CMV in the jejunum.\n\nThe etiology of perforated jejunitis in our patient was most likely multifactorial. In retrospect, had the index of suspicion for mesenteric ischemia been high, given the recent use of asparaginase and the associated risk of thrombotic complications, a dedicated CT angiography might have been performed to search for filling defects in the peripheral mesenteric vessels. Additionally, consideration of mesenteric ischemia as a contributing factor to jejunitis may have lowered the threshold for exploratory laparotomy.\n==== Refs\nReferences\n1 Howlader N. Noone A.M. Krapcho M. Miller D. Bishop K. Kosary C.L. SEER cancer statistics review editors 1975-2014 National Cancer Institute Bethesda, MD https://seer.cancer.gov/csr/1975_2014/ based on November 2016 SEER data submission, posted to the SEER web site, April 2017 \n2 Schmiegelow K. Müller K. Mogensen S.S. Mogensen P.R. Wolthers B.O. Stoltze U.K. Non-infectious chemotherapy-associated acute toxicities during childhood acute lymphoblastic leukemia therapy F1000Res 6 2017 444 28413626 \n3 Board PS and PCE Gastrointestinal Complications (PDQ®)–Health Professional Version http://www.cancer.gov/about-cancer/treatment/side-effects/constipation/GI-complications-hp-pdq 2018 [accessed 03.18] \n4 Egler R.A. Ahuja S.P. Matloub Y. L-Asparaginase in the treatment of patients with acute lymphoblastic leukemia J Pharmacol Pharmacother 7 2 2016 62 71 27440950 \n5 Hijiya N. Van Der Sluis I.M. Asparaginase-associated toxicity in children with acute lymphoblastic leukemia Leuk Lymphoma 57 4 2016 748 757 26457414 \n6 Muller H. Boos J. Use of L-asparaginase in childhood ALL Crit Rev Oncol Hematol 28 1998 97 113 9768345 \n7 Riccardi R. Holcenberg J. Glaubiger D. Wood J. Poplack D. L-asparaginase pharmacokinetics and asparagine levels in cerebrospinal fluid of rhesus monkeys and humans Cancer Res 41 1981 4554 4558 6895481 \n8 Caruso V. Iacoviello L. Di Castelnuovo A. Storti S. Mariani G. de Gaetano G. Thrombotic complications in childhood acute lymphoblastic leukemia: a meta-analysis of 17 prospective studies comprising 1752 pediatric patients Blood 108 7 2006 2216 2222 16804111 \n9 Wiesner W. Khurana B. Ji H. Rox P. CT of acute bowel ischemia Radiology 226 2003 635 650 12601205 \n10 Wiesner W. Hauser A. Steinbrich W. Accuracy of multidetector row computed tomography for the diagnosis of acute bowel ischemia in a non-selected study population Eur Radiol 14 12 2004 2347 2356 15378337 \n11 Blachar A. Barnes S. Adam S.Z. Levy G. Weinstein I. Precel R. Radiologists' performance in the diagnosis of acute intestinal ischemia, using MDCT and specific CT findings, using a variety of CT protocols Emerg Radiol 18 5 2011 385 394 21655965 \n12 Angelelli G. Scardapane A. Memeo M. Stabile Ianora A.A. Rotondo A. Acute bowel ischemia: CT findings Eur J Radiol 50 1 2004 37 47 15093234 \n13 Sandstrom C.K. Ingraham C.R. Monroe E.J. Johnson G.E. Beyond decreased bowel enhancement: acute abnormalities of the mesenteric and portal vasculature Abdom Imaging 40 8 2015 2977 2992 26156618 \n14 Miglioretti D.L. Johnson E. Williams A. Greenlee R.T. Weinmann S. Solberg L.I. The use of computed tomography in pediatrics and the associated radiation exposure and estimated cancer risk JAMA Pediatr 167 8 2013 700 707 23754213 \n15 Evennett N. Petrov M. Mittal A. Windsor J. Systematic review and pooled estimates for the diagnostic accuracy of serological markers for intestinal ischemia World J Surg 33 7 2009 1374 1383 19424744 \n16 Brandt L. Boley S. AGA technical review on intestinal ischemia Gastroenterology 118 2000 954 968 10784596 \n17 Nabeshima K. Sakaguchi E. Inoue S. Eizuru Y. Minamishima Y. Koono M. Jejunal perforation associated with cytomegalovirus infection in a patient with adult T-cell leukemia-lymphoma Acta Pathol Jpn 42 4 1992 267 271 1319102 \n18 Jun Y.J. Sim J. Ahn H.I. Han H. Kim H. Yi K. Cytomegalovirus enteritis with jejunal perforation in a patient with endometrial adenocarcinoma World J Clin Cases 1 7 2013 220 223 24340271 \n19 DeRiso A.J. Kemeny M. Torres R. Oliver J. Multiple jejunal perforations secondary to cytomegalovirus in a patient with acquired immune deficiency syndrome Dig Dis Sci 34 4 1989 623 629 2539285 \n20 Hinnant K. Rotterdam H. Bell E. Tapper M. Cytomegalovirus infection of the alimentary tract: a clinicopathological correlation Am J Gastroenterol 81 10 1986 944 950 3020973 \n21 Goodgame R. Gastrointestinal cytomegalovirus disease Ann Intern Med 119 9 1993 924 935 8215005 \n22 Arnold M. Itzikowitz R. Young B. Machoki S.M. Hsiao N.Y. Pillay K. Surgical manifestations of gastrointestinal cytomegalovirus infection in children: clinical audit and literature review J Pediatr Surg 50 11 2015 1874 1879 26265193 \n23 Soderberg-Naucler C. Fish K. Nelson J. Reactivation of latent human cytomegalovirus by allogeneic stimulation of blood cells from healthy donors Cell 91 1 1997 119 126 9335340 \n24 Rahbar A. Soderberg-Naucler C. Human cytomegalovirus infection of endothelial cells triggers platelet adhesion and aggregation J Virol 79 4 2005 2211 2220 15681423 \n25 Caposio P. Orloff S.L. Streblow D.N. The role of cytomegalovirus in angiogenesis Virus Res 157 2 2011 204 211 20869406 \n26 Drew W.L. Laboratory diagnosis of cytomegalovirus infection and disease in immunocompromised patients Curr Opin Infect Dis 20 4 2007 408 411 17609601 \n27 Bang S. Park Y. Kang B. Park M.C. Hwang M.H. Kim H.K. CMV enteritis causing ileal perforation in underlying lupus enteritis Clin Rheumatol 23 1 2004 69 72 14749990\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1930-0433",
"issue": "13(3)",
"journal": "Radiology case reports",
"keywords": "Acute lymphoblastic leukemia; Acute mesenteric ischemia; Asparaginase; Complications; Computed tomography; Pediatric",
"medline_ta": "Radiol Case Rep",
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"pages": "568-572",
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"pmid": "29988797",
"pubdate": "2018-06",
"publication_types": "D002363:Case Reports",
"references": "19424744;15378337;9335340;8215005;20869406;17609601;21655965;27440950;26457414;9768345;3020973;16804111;23754213;28413626;2539285;26156618;12601205;6895481;24340271;26265193;1319102;15093234;14749990;10784596;15681423",
"title": "Perforated jejunitis in a child with acute lymphoblastic leukemia treated with pegaspargase.",
"title_normalized": "perforated jejunitis in a child with acute lymphoblastic leukemia treated with pegaspargase"
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"abstract": "There are few reports on the effectiveness of corticosteroids for immune checkpoint inhibitor-induced interstitial pneumonia in patients with a history of interstitial pneumonia. We report on 10 non-small cell lung cancer patients with a history of interstitial pneumonia who experienced immune checkpoint inhibitor-induced interstitial pneumonia. The immune checkpoint inhibitor-induced interstitial pneumonia lasted for a median duration of 41.5 days (range = 22-127 days). Eight of the ten patients responded to corticosteroid monotherapy; one patient responded to corticosteroids and the immunosuppressant, tacrolimus; and one patient did not improve after corticosteroid treatment. In non-small cell lung cancer patients with a history of interstitial pneumonia, immune checkpoint inhibitor-induced interstitial pneumonia was generally responds to corticosteroids.",
"affiliations": "Department of Hospital Pharmaceutics, School of Pharmacy, Showa University, Tokyo, Japan.;Department of Hospital Pharmaceutics, School of Pharmacy, Showa University, Tokyo, Japan.;Department of Hospital Pharmaceutics, School of Pharmacy, Showa University, Tokyo, Japan.;Department of Hospital Pharmaceutics, School of Pharmacy, Showa University, Tokyo, Japan.",
"authors": "Ichimura|Takenori|T|https://orcid.org/0000-0002-4731-6032;Hinata|Miwa|M|;Ichikura|Daisuke|D|;Suzuki|Shinya|S|",
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"fulltext": "\n==== Front\nSAGE Open Med Case Rep\nSAGE Open Med Case Rep\nSCO\nspsco\nSAGE Open Medical Case Reports\n2050-313X\nSAGE Publications Sage UK: London, England\n\n10.1177/2050313X211031313\n10.1177_2050313X211031313\nCase Report\nEffectiveness of corticosteroids on immune checkpoint inhibitor-induced interstitial pneumonia among patients with a history of interstitial pneumonia: A case series\nhttps://orcid.org/0000-0002-4731-6032\nIchimura Takenori 12\nHinata Miwa 12\nIchikura Daisuke 12\nSuzuki Shinya 1\n1 Department of Hospital Pharmaceutics, School of Pharmacy, Showa University, Tokyo, Japan\n2 Department of Pharmacy Services, Showa University Northern Yokohama Hospital, Kanagawa, Japan\nTakenori Ichimura, Department of Hospital Pharmaceutics, School of Pharmacy, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555666, Japan. Email: ichimura@cmed.showa-u.ac.jp\n9 7 2021\n2021\n9 2050313X21103131325 2 2021\n17 6 2021\n© The Author(s) 2021\n2021\nSAGE Publications\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).\nThere are few reports on the effectiveness of corticosteroids for immune checkpoint inhibitor-induced interstitial pneumonia in patients with a history of interstitial pneumonia. We report on 10 non-small cell lung cancer patients with a history of interstitial pneumonia who experienced immune checkpoint inhibitor-induced interstitial pneumonia. The immune checkpoint inhibitor-induced interstitial pneumonia lasted for a median duration of 41.5 days (range = 22–127 days). Eight of the ten patients responded to corticosteroid monotherapy; one patient responded to corticosteroids and the immunosuppressant, tacrolimus; and one patient did not improve after corticosteroid treatment. In non-small cell lung cancer patients with a history of interstitial pneumonia, immune checkpoint inhibitor-induced interstitial pneumonia was generally responds to corticosteroids.\n\nInterstitial pneumonia\nimmune checkpoint inhibitors\ncorticosteroids\ncover-dateJanuary-December 2021\ntypesetterts1\n==== Body\nIntroduction\n\nImmune checkpoint inhibitors can cause immune-related adverse events, including interstitial pneumonia. 1 In phase III trials, the incidence of interstitial pneumonia in non-small cell lung cancer patients was 3.8% (n = 287) with nivolumab, 2 5.8% (n = 154) with pembrolizumab, 3 and 2.3% (n = 609) with atezolizumab. 4 However, patients with a history of interstitial pneumonia were excluded from these clinical trials. Immune checkpoint inhibitors are rarely administered to lung cancer patients with a history of interstitial pneumonia. However, some patients with non-small cell lung cancer and a history of mild idiopathic interstitial pneumonia have been treated with nivolumab.5,6 Nonetheless, there are few reports of the effectiveness of corticosteroids for immune checkpoint inhibitor-induced interstitial pneumonia among patients with a history of interstitial pneumonia, particularly in patients who were treated with atezolizumab and pembrolizumab. Therefore, we report on the effectiveness of corticosteroid treatment in 10 non-small cell lung cancer patients with a history of interstitial pneumonia who subsequently re-experienced immune checkpoint inhibitor-induced interstitial pneumonia.\n\nCase discussion\n\nPatients\n\nThe study was conducted in the Showa University Northern Yokohama Hospital. The study period lasted from December 2015 to March 2020. Patients, who had non-small cell lung cancer with a history of interstitial pneumonia, were included in the study. Patients were treated with nivolumab, pembrolizumab, or atezolizumab. We surveyed 183 patients.\n\nOf the 183 patients surveyed, 10 patients with a history of interstitial pneumonia experienced immune checkpoint inhibitor-induced interstitial pneumonia. The patient characteristics are shown in Table 1. All 10 patients had a history of smoking. One patient received combination therapy, whereas nine patients were treated with single-agent corticosteroid regimens. Four patients had radiation pneumonitis, without radiation fibrosis; four patients had interstitial pneumonia secondary to immune checkpoint inhibitors; and two patients had idiopathic interstitial pneumonia. The condition of four patients (cases 2, 5, 6, and 7) with a history of immune checkpoint inhibitor-induced interstitial pneumonia had previously improved. However, when rechallenged with immune checkpoint inhibitors, these four patients suffered from immune checkpoint inhibitor-induced interstitial pneumonia again.\n\nTable 1. Patient characteristics.\n\nCase\tSex\tAge (years)\tMedical history\tSmoking history\tHistory of interstitial pneumonia\tStage a\tHistory of surgery b\tHistory of radiation therapy c\t\n1\tM\t58\tAdjustment disorder\tYes\tCause unknown; present from the time of lung cancer diagnosis\tIV\tNo\tNo\t\n2\tM\t74\tType 2 diabetes mellitus, hypertension, abdominal aortic aneurysm\tYes\tNivolumab-induced interstitial pneumonia d\tIV\tYes\tNo\t\n3\tM\t74\tOsteoporosis\tYes\tCause unknown; present from the time of lung cancer diagnosis\tIV\tNo\tNo\t\n4\tM\t64\tHypothyroidism, hypertension\tYes\tRadiation pneumonitis\tIV\tNo\tYes\t\n5\tM\t75\tType 2 diabetes mellitus, prostatic hyperplasia, dyslipidemia\tYes\tPembrolizumab-induced interstitial pneumonia d\tIV\tNo\tNo\t\n6\tM\t68\tType 2 diabetes mellitus\tYes\tNivolumab-induced interstitial pneumonia d\tIV\tYes\tNo\t\n7\tM\t69\tRectal cancer, hyperuricemia, hypertension\tYes\tPembrolizumab-induced interstitial pneumonia d\tIII\tNo\tYes\t\n8\tM\t81\tBladder cancer\tYes\tRadiation pneumonitis\tIII\tNo\tYes\t\n9\tM\t50\tPulmonary emphysema, hypertension\tYes\tRadiation pneumonitis\tIII\tYes\tYes\t\n10\tM\t71\tNone\tYes\tRadiation pneumonitis\tIV\tYes\tYes\t\na At the time of initiating immune checkpoint inhibitors, doctor made a diagnosis based on the results of imaging and/or pathological examinations.\n\nb Non-small cell lung cancer resected prior to administration of immune checkpoint inhibitors.\n\nc Chest radiation therapy for non-small cell lung cancer.\n\nd Immune checkpoint inhibitor-induced interstitial pneumonia improved initially and then reoccurred when patients were rechallenged with immune checkpoint inhibitors.\n\nEffectiveness of corticosteroids on immune checkpoint inhibitor-induced interstitial pneumonia among patients with a history of interstitial pneumonia\n\nThe corticosteroids used to manage immune checkpoint inhibitor-induced interstitial pneumonia are listed in Table 2. Immune checkpoint inhibitor-induced interstitial pneumonia occurred after a median of 3.0 doses (range = 1–6 doses). Immune checkpoint inhibitor-induced interstitial pneumonia lasted for a median duration of 41.5 days (range = 22–127 days).\n\nTable 2. Effectiveness of corticosteroids on immune checkpoint inhibitor-induced interstitial pneumonia among patients with a history of interstitial pneumonia.\n\nCase\tImmune checkpoint inhibitors\tAnti-cancer drugs administered with immune checkpoint inhibitors\tTherapeutic line\tPre-treatment with anti-cancer drugs\tRadiological pattern of interstitial pneumonia\tNumber of immune checkpoint inhibitors used before onset of interstitial pneumonia\tTime to immune checkpoint inhibitor-induced interstitial pneumonia (days)\tCTCAE grade of pneumonitis\tInitial corticosteroid therapy\tOther treatment\tResults of treatment\t\n1\tPembrolizumab\tCarboplatin and pemetrexed\t1\tNone\tUsual interstitial pneumonia\t2\t126\tGrade 3\tMethylprednisolone sodium succinate IV infusion 500 mg over 3 days\tOral tacrolimus 4 mg\tOral corticosteroid administration continued while IV prednisolone was tapered\nRemission of interstitial pneumonia\t\n2\tNivolumab\tNone\t2\tFirst: Cisplatin and pemetrexed\tOrganizing pneumonia pattern\t3\t28\tGrade 3\tPrednisolone sodium succinate IV infusion 20 mg\tNone\tOral corticosteroid administration continued while IV prednisolone was tapered\nRemission of interstitial pneumonia\t\n3\tAtezolizumab\tNone\t2\tFirst: Cisplatin and pemetrexed\tOrganizing pneumonia pattern\t5\t127\tGrade 2\tOral prednisolone 30 mg (0.5 mg/kg)\tNone\tOral corticosteroid administration continued while IV prednisolone was tapered\nRemission of interstitial pneumonia\t\n4\tNivolumab\tNone\t3\tFirst: S-1 and carboplatin\nSecond: Pemetrexed and bevacizumab\tOrganizing pneumonia pattern\t2\t35\tGrade 3\tMethylprednisolone sodium succinate IV infusion 1000 mg over 3 days\tNone\tOral corticosteroid administration continued while IV prednisolone was tapered\nRemission of interstitial pneumonia\t\n5\tPembrolizumab\tNone\t5\tFirst: Afatinib\nSecond: Gefitinib\nThird: S-1 and carboplatin\nFourth: Afatinib\tOrganizing pneumonia pattern\t1\t22\tGrade 3\tPrednisolone sodium succinate IV infusion 50 mg (1 mg/kg)\tNone\tOral corticosteroid administration continued while IV prednisolone was tapered\nRemission of interstitial pneumonia\t\n6\tNivolumab\tNone\t4\tFirst: Cisplatin and vinorelbine\nSecond: Carboplatin and etoposide\nThird: Nogitecan\tOrganizing pneumonia pattern\t3\t38\tGrade 4 a\tMethylprednisolone sodium succinate IV infusion 1000 mg over 3 days\tNone\tPrednisolone sodium succinate IV infusion 60 mg (1 mg/kg)\nDeath due to disease progression\t\n7\tPembrolizumab\tNone\t1\tNone\tOrganizing pneumonia pattern\t4\t25\tGrade 1\tOral prednisolone 20 mg\tNone\tOral corticosteroid administration continued while IV prednisolone was tapered\nRemission of interstitial pneumonia\t\n8\tNivolumab\tNone\t2\tFirst: Carboplatin, paclitaxel, and radiation\tNonspecific interstitial pneumonia\t6\t85\tGrade 3\tPrednisolone sodium succinate IV infusion 60 mg (1 mg/kg)\tNone\tOral corticosteroid administration continued while IV prednisolone was tapered\nRemission of interstitial pneumonia\t\n9\tNivolumab\tNone\t5\tFirst: Cisplatin, docetaxel, and radiation\nSecond: Carboplatin, pemetrexed, and bevacizumab\nThird: Carboplatin and nab-paclitaxel\nFourth: S-1\tOrganizing pneumonia pattern\t1\t55\tGrade 2\tPrednisolone sodium succinate IV infusion in 70 mg (1 mg/kg)\tNone\tOral corticosteroid administration continued while IV prednisolone was tapered\nRemission of interstitial pneumonia\t\n10\tNivolumab\tNone\t3\tFirst: Carboplatin and nab-paclitaxel\nSecond: Docetaxel and ramucirumab\tNon-specific interstitial pneumonia\t3\t45\tGrade 3\tPrednisolone sodium succinate IV infusion 20 mg\tNone\tOral corticosteroid administration continued while IV prednisolone was tapered\nRemission of interstitial pneumonia\t\nCTCAE: Common Terminology Criteria for Adverse Events; IV, intravenous.\n\na Respiratory failure present.\n\nThe pneumonia in eight out of ten patients responded with corticosteroids alone. One patient responded to a combination of corticosteroids and the immunosuppressant tacrolimus. One patient did not improve after corticosteroid treatment and died, with persistent interstitial pneumonia as the probable cause of death.\n\nDiscussion\n\nTen non-small cell lung cancer patients experienced immune checkpoint inhibitor-induced interstitial pneumonia. Among them, eight responded well to corticosteroid monotherapy.\n\nThese cases indicate the effectiveness of corticosteroids against immune checkpoint inhibitor-induced interstitial pneumonia among patients with a history of interstitial pneumonia. Interstitial pneumonia can have severe outcomes, including death. In this case series, interstitial pneumonia was the probable cause of death in one patient. On the basis of their risks and benefits, immune checkpoint inhibitors should be considered for non-small cell cancer patients with a history of interstitial pneumonia. Patients with non-small cell lung cancer with interstitial pneumonia or active radiation pneumonia have been excluded from phase III trials.1–4 Therefore, it is necessary to consider the appropriateness of immune checkpoint inhibitors treatment among patients with a history of interstitial pneumonia. 7 Similarly in Japan, the Ministry of Health, Labor and Welfare, which controls the approval and proper use of medicines, has warned against the administration of immune checkpoint inhibitors to patients with, or with a history of, interstitial pneumonia.\n\nAmong 20 patients who developed interstitial lung disease due to anti-bodies against the programmed cell death-1 ligand, 18 patients had idiopathic organizing pneumonia and non-specific interstitial pneumonia. 8 There were only two cases of acute interstitial pneumonia and acute respiratory distress syndrome that were unresponsive to corticosteroids. In that study, 8 two patients with immune checkpoint inhibitor-induced interstitial pneumonia had melanoma and Hodgkin’s lymphoma. Our case series differs from the previous study because it only includes patients with non-small cell lung cancer and interstitial pneumonia.\n\nIn a review of interstitial pneumonia caused by immune checkpoint inhibitors, 9 organizing pneumonia pattern (23%), hypersensitivity pneumonia pattern (16%), non-specific interstitial pneumonia (8%), respiratory bronchiolitis-associated interstitial pneumonia (6%), and an unidentifiable pattern (36%) were reported. There is no report of acute interstitial pneumonia that is refractory to corticosteroids. Similarly, in our case series, there were no patients with acute interstitial pneumonia. Corticosteroids may be able to control immune checkpoint inhibitor-induced interstitial pneumonia among patients with a history of interstitial pneumonia.\n\nThere are a limited number of case reports on the use of corticosteroids to treat patients with immune checkpoint inhibitor-induced interstitial pneumonia and a history of interstitial pneumonia. This was a retrospective study and the histopathological classification of the interstitial pneumonia was not determined as this was a case series involving a limited number of cases in a single facility. Our case series contained patients with a history of immune checkpoint inhibitor-induced interstitial pneumonia, radiation pneumonitis, and idiopathic interstitial pneumonia. We did not determine the severity of interstitial pneumonia. Immune checkpoint inhibitors should be considered a cause of immune checkpoint inhibitor-induced interstitial pneumonia among patients with a history of interstitial pneumonia. In the future, we would like to compare patients with and without exacerbation of interstitial pneumonia following the administration of immune checkpoint inhibitors among patients with a history of interstitial pneumonia.\n\nConclusion\n\nIn non-small cell lung cancer patients with a history of interstitial pneumonia, immune checkpoint inhibitor-induced interstitial pneumonia generally responded well to corticosteroids.\n\nThe authors thank Editage (www.editage.com) for English language editing.\n\nDeclaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nEthical approval: This study was approved by the Institutional Review Board of Showa University Northern Yokohama Hospital, based on the ethical guidelines for medical and health research involving human subjects (approval no. 20H034).\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nInformed consent: Written informed consent was obtained from the patient(s) for their anonymized information to be published. This article included one deceased subject. Before death, the deceased subject obtained informed consent in writing that the findings will be published.\n\nORCID iD: Takenori Ichimura https://orcid.org/0000-0002-4731-6032\n==== Refs\nReferences\n\n1 Darnell EP Mooradian MJ Baruch EN , et al . Immune-related adverse events (irAEs): diagnosis, management, and clinical pearls. Curr Oncol Rep 2020; 22 (4 ): 39.32200442\n2 Borghaei H Paz-Ares L Horn L , et al . Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 2015; 373 (17 ): 1627–1639.26412456\n3 Reck M Rodríguez-Abreu D Robinson AG , et al . Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 2016; 375 (19 ): 1823–1833.27718847\n4 Rittmeyer A Barlesi F Waterkamp D , et al . Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet 2017; 389 (10066 ): 255–265.27979383\n5 Fujimoto D Morimoto T Ito J , et al . A pilot trial of nivolumab treatment for advanced non-small cell lung cancer patients with mild idiopathic interstitial pneumonia. Lung Cancer 2017; 111 : 1–5.28838377\n6 Fujimoto D Yomota M Sekine A , et al . Nivolumab for advanced non-small cell lung cancer patients with mild idiopathic interstitial pneumonia: a multicenter, open-label single-arm phase II trial. Lung Cancer 2019; 134 : 274–278.31182249\n7 Wang H Guo X Zhou J , et al . Clinical diagnosis and treatment of immune checkpoint inhibitor-associated pneumonitis. Thorac Cancer 2020; 11 (1 ): 191–197.31762218\n8 Nishino M Ramaiya NH Awad MM , et al . PD-1 inhibitor-related pneumonitis in advanced cancer patients: radiographic patterns and clinical course. Clin Cancer Res 2016; 22 (24 ): 6051–6060.27535979\n9 Kalisz KR Ramaiya NH Laukamp KR , et al . Immune checkpoint inhibitor therapy-related pneumonitis: patterns and management. Radiographics 2019; 39 (7 ): 1923–1937.31584861\n\n",
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"abstract": "Bone marrow fibrosis has been associated with different types of non-neoplastic conditions like granulomatous and autoimmune diseases and a variety of neoplastic disorders such as acute megakaryoblastic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma and myeloproliferative neoplsms. Therapy induced fibrosis is a rare phenomenon. Here we report a case of an incidentally diagnosed acute promyelocytic leukemia (APL) with t(11;17) which was treated with arsenic trioxide (ATO) for 45 days. However, the patient did not go into remission and developed massive fibrosis of bone marrow. Literature search does not reveal such documented marrow fibrosis following therapy with ATO in a case of APL.",
"affiliations": "Department of Hematology, All India Institute of Medical Sciences, New Delhi, India.;Department of Hematology, All India Institute of Medical Sciences, New Delhi, India.;Department of Hematology, All India Institute of Medical Sciences, New Delhi, India.;Department of Hematology, All India Institute of Medical Sciences, New Delhi, India.;Department of Hematology, All India Institute of Medical Sciences, New Delhi, India.;Department of Hematology, All India Institute of Medical Sciences, New Delhi, India.;Department of Hematology, All India Institute of Medical Sciences, New Delhi, India.;Department of Hematology, All India Institute of Medical Sciences, New Delhi, India.;Department of Hematology, All India Institute of Medical Sciences, New Delhi, India.;Department of Hematology, All India Institute of Medical Sciences, New Delhi, India.",
"authors": "Venkatesan|S|S|;Purohit|Abhishek|A|;Ahuja|Ankur|A|;Chandra|Dinesh|D|;Aggarwal|Mukul|M|;Amrita|R|R|;Kumar|Ravi|R|;Mahapatra|Manoranjan|M|;Pati|Hara P|HP|;Tyagi|Seema|S|",
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"fulltext": "\n==== Front\nLeuk Res RepLeuk Res RepLeukemia Research Reports2213-0489Elsevier S2213-0489(14)20010-010.1016/j.lrr.2015.06.001ArticleUnusual massive bone marrow fibrosis in acute promyelocytic leukemia following arsenic trioxide therapy Venkatesan S. ltcolsvenkatesan@gmail.comPurohit Abhishek purohitabhi80@gmail.com⁎Ahuja Ankur ankurahuja@gmail.comChandra Dinesh dinesh3224@gmail.comAggarwal Mukul mukulmamc@gmail.comAmrita R. amrita_4in@yahoo.co.inKumar Ravi ravi.aiims@gmail.comMahapatra Manoranjan mrmahapatra@hotmail.comPati Hara P. harappati@yahoo.comTyagi Seema drseematyagi@hotmail.comDepartment of Hematology, All India Institute of Medical Sciences, New Delhi, India⁎ Corresponding author. purohitabhi80@gmail.com15 7 2015 2015 15 7 2015 4 2 76 78 21 9 2014 2 6 2015 15 6 2015 © 2015 Published by Elsevier Ltd.2015This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Bone marrow fibrosis has been associated with different types of non-neoplastic conditions like granulomatous and autoimmune diseases and a variety of neoplastic disorders such as acute megakaryoblastic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma and myeloproliferative neoplsms. Therapy induced fibrosis is a rare phenomenon. Here we report a case of an incidentally diagnosed acute promyelocytic leukemia (APL) with t(11;17) which was treated with arsenic trioxide (ATO) for 45 days. However, the patient did not go into remission and developed massive fibrosis of bone marrow. Literature search does not reveal such documented marrow fibrosis following therapy with ATO in a case of APL.\n\nHighlights\n• During pre-op evaluation for hysterectomy in a 44 year old, a high TLC was noted.\n\n• APL with 45X,−X, t(11;17)(q23;q21) was diagnosed on bone marrow examination.\n\n• Treated with ATO, day+45 bone marrow biopsy revealed diffuse fibrosis.\n\n• Case is reported for this unusual feature of ATO-induced bone marrow fibrosis.\n\n\n\nKeywords\nAcute promyelocytic leukemiaArsenic trioxideMarrow fibrosis\n==== Body\nIntroduction\nBone marrow fibrosis is known to occur in several neoplastic and non-neoplastic conditions. Among neoplastic conditions such as acute leukemia, it is most often seen with acute megakaryoblastic leukemia [1]. Acute promyelocytic leukemia (APL) presenting with marrow fibrosis is a rare entity, with few cases reported in the past [2], [3], [4]. In one case series a reversible bone marrow collagenous fibrosis has been reported in cases of APL treated with tretinoin [5]. However literature search did not reveal any such occurrence of bone marrow fibrosis following therapy with arsenic trioxide (ATO) in a case of APL. Here we report a case of 44 year old female who was diagnosed as APL with t(11;17), who subsequently developed bone marrow collagenous fibrosis following induction therapy with ATO.\n\nCase history\nA 44 year old female, known hypothyroid and hypertensive on regular medication, presented with spontaneous skin bleed for five months, generalized weakness, fatigability and menorrhagia for three months duration. She was diagnosed to have fibroid uterus and underwent diagnostic dilatation and curettage (D&C) for her complaints at an outside hospital. As her bleeding per vaginum did not stop after D&C, hysterectomy was performed. During the post operative period she was found to have high total leukocyte count (TLC). Subsequently the patient developed pain abdomen, found to have hemoperitoneum and exploratory laparotomy was carried out to achieve hemostasis. Since she had high TLC, bone marrow examination and cytogenetics were carried out which revealed abnormal promyelocytes and 45X, −X, t(11;17)(q23;q21) respectively (Fig. 1). Based on the morphological and cytogenetic abnormality, diagnosis of APL was made and the patient was transferred to our center for further management. On examination she had pallor, fever, multiple purpuric spots over upper and lower limbs, a midline abdominal suture wound with gaping and necrotic slough along with foul smelling discharge. Respiratory system examination revealed diminished breath sounds in left infrascapular region suggestive of pleural effusion. CT scan chest showed bilateral ground glass opacities suggestive of fungal pneumonia and left sided pleural effusion. There was no organomegaly or peripheral lymphadenopathy. Laboratory parameters revealed hemoglobin of 69 g/L, TLC of 35.39×109/L with a differential leukocyte count of 50% promyelocytes, 19% myelocytes, 01% metamyelocyte, 27% mature neutrophils, 03% lymphocytes and platelet count of 44×109/L. After admission to our center, her coagulation parameters remained within normal limits and there was no laboratory evidence of disseminated intravascular coagulation. Bone marrow examination revealed 45% hypergranular promyelocytes with 03% blasts, 40% maturing myeloid forms and neutrophils, 06% erythroid cells and 06% lymphocytes. There were no Auer rods or fagot cells seen. Myeloperoxidase stain showed strong MPO positivity in these promyelocytes. The bone marrow biopsy showed near total replacement by immature myeloid forms without marrow fibrosis (Fig. 1). In view of foci of infections involving lung and gaping infected wound in anterior abdominal wall, patient was not offered Inj daunorubicin and all trans retinoic acid. Instead she was started on ATO at a dose of 0.15 mg/kg body weight along with supportive antibiotics and antifungals. During therapy she became afebrile, her abdominal wound healed and lung lesions resolved. The TLC reduced gradually along with signs of maturation in the peripheral smear. However by day+45, patient developed pancytopenia and hence bone marrow examination was performed to assess the disease status. Bone marrow aspiration yielded a dry tap and the bone marrow biopsy tissue obtained was pale and gray white on gross examination. The peripheral smear received along with the bone marrow revealed an occasional promyelocyte and the bone marrow aspirate smears were paucicellular which revealed 03% blasts, 08% promyelocytes, 11% myelocytes, 07% metamyelocytes, 10% neutrophils and 61% lymphocytes. The bone marrow biopsy tissue revealed dense diffuse marrow fibrosis with extensive collagen deposition suggestive of grade III marrow fibrosis [6] confirmed on Masson trichrome stain, with entrapped immature myeloid forms of similar morphology observed in the diagnostic marrow (Fig. 2). The therapy with ATO was discontinued in view of bone marrow fibrosis and patient was observed with supportive care. Subsequently, on follow up the TLC and promyelocyte count in peripheral smear increased in number. As the patient did not have any foci of infection, she is now started on induction chemotherapy with daunorubicin and all-trans retinoic acid.\n\nDiscussion\nBone marrow fibrosis is known to be associated with hematolymphoid malignancies such as acute leukemia, Hodgkin and non-Hodgkin lymphoma. Among the acute leukemias, marrow fibrosis is most often seen with acute megakaryoblastic leukemia. It is an uncommon finding in APL and till date only handful of case reports are seen in literature, however its presence does not seem to alter the prognosis of APL [4], [7]. Hatake et al. demonstrated bone marrow fibrosis following therapy with tretinoin and also proved that the fibrosis is reversible after stopping tretinoin and chemotherapy [5]. However there is no reports so far mentioned in literature regarding marrow fibrosis post ATO therapy, hence our case would be the first of its kind with this unique finding. In APL ATO has dose dependant effect on promyelocytes inducing preferential apoptosis at high concentration (0.5–2 μmol/L), inducing partial differentiation at low concentration (0.1–0.5 μmol/L) and causing modulation and degradation of PML-RARα protein at a dose of 0.1–0.2 μmol/L [8]. Mori et al. suggested a possible role of transforming growth factor beta (1) (TGF-β1) in causing the fibrosis in APL as they have noticed the overexpression of TGF-β1 by RT-PCR [2]. A similar mechanism is possible with ATO in inducing bone marrow fibrosis as brought out by Chu et al. who had established the role of ATO-induced TGF-β1secretion from cardiac fibroblasts which resulted in myocardial fibrosis [9]. In the same line Szymańska-Chabowska et al. demonstrated the role of arsenic in liver fibrosis leading to chronic hepatic failure [10]. Hence it can be said with reasonable confidence that, as ATO is capable of inducing fibrosis in heart and liver, it is possible for ATO to induce bone marrow fibrosis as well even though it is not mentioned in literature so far. Whether this ATO induced fibrosis in unique to the cytogenetic abnormality this patient has, needs to be explored. Also the outcome of this marrow fibrosis needs to be ascertained from further follow up of this patient. As RT-PCR for PML-RARα will not help in this case to assess the molecular remission, the patient needs to be followed up with conventional cytogenetics or FISH analysis for molecular remission status. This case had so many unusual features such as a long duration of illness, uncommon morphological findings, rare cytogenetic abnormality and ATO induced bone marrow fibrosis. Hence the case is reported for this constellation of unique features.\n\nSource of support\nNone.\n\nConflict of interest\nNone.\n\nFig. 1 Bone marrow aspirate – blast, promyelocyte along with mature myeloid cells (A, Jenner Giemsa stain, ×1000). Bone marrow biopsy showing diffuse replacement by immature myeloid cells with no fibrosis. (B, Hematoxylin & Eosin stain, ×400). Bone marrow aspirate – strong MPO positivity (C, myeloperoxidase stain, ×1000). Karyogram showing 45X, −X, t(11;17)(q23;q21) (D, karyotype).\n\nFig. 2 Bone marrow biopsy showing diffuse fibrosis with collagenisation along with entrapped immature myeloid cells (A – Hematoxylin & Eosin stain, ×100, B – Hematoxylin & Eosin stain, ×400, C – reticulin stain, ×100, and D – Masson trichrome stain, ×400).\n==== Refs\nReferences\n1 Manoharan A. Horsley R. Pitney W.R. The reticulin content of bone marrow in acute leukaemia in adults Br. J. Haematol. 43 1979 185 190 508627 \n2 Mori A. Wada H. Okada M. Acute promyelocytic leukemia with marrow fibrosis at initial presentation: possible involvement of transforming growth factor beta(1) Acta Haematol. 103 4 2000 220 223 11014898 \n3 Fukuno K. Tsurumi H. Yoshikawa T. A variant form of acute promyelocytic leukaemia with marked myelofibrosis Int. J. Hematol. 74 2001 322 326 11721970 \n4 Dutta Pankhi Hasan Syed Bhattacharya Jina Acute promyelocytic leukaemia with secondary myelofibrosis – case report and review of the literature Am. J. Hematol. 81 2006 470 477 16680752 \n5 Hatake K. Ohtsuki T. Uwai M. Tretinoin induces bone marrow collagenous fibrosis in acute promyelocytic leukaemia: new adverse, but reversible effect Br. J. Haematol. 93 3 1996 646 649 8652386 \n6 Thiele J. Kvasnicka H.M. Facchetti F. Franco V. van der Walt J. European consensus on grading bone marrow fibrosis and assessment of cellularity Haematologica 90 2005 1128 1132 16079113 \n7 Losada R. Cabrera H. Hernández P. Hernández C. Menéndez A. Mesa J. Plascencia A. Ramón L. Agramonte O. Espinosa E. Bone marrow reticulin fibrosis at diagnosis in promyelocytic leukaemia treated with all-trans retinoic acid has no adverse prognosis Acta Haematol. 108 2 2002 111 112 12187033 \n8 Guo-Qiang Chen Use of arsenic trioxide (As2 O3 ) in the treatment of acute promyelocytic leukemia (APL): I. As2 O3 exerts dose-dependent dual effects on APL cells Blood 89 9 1997 3345 3353 9129041 \n9 Chu W. Li C. Qu X. Arsenic-induced interstitial myocardial fibrosis reveals a new insight into drug-induced long QT syndrome Cardiovasc. Res. 96 2012 90 98 22853924 \n10 Szymańska-Chabowska A. Antonowicz-Juchniewicz J. Andrzejak R. Some aspects of arsenic toxicity and carcinogenicity in living organism with special regard to its influence on cardiovascular system, blood and bone marrow Int. J. Occup. Med. Environ. Health 15 2 2002 101 116 12216766\n\n",
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"keywords": "Acute promyelocytic leukemia; Arsenic trioxide; Marrow fibrosis",
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"title": "Unusual massive bone marrow fibrosis in acute promyelocytic leukemia following arsenic trioxide therapy.",
"title_normalized": "unusual massive bone marrow fibrosis in acute promyelocytic leukemia following arsenic trioxide therapy"
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"abstract": "Tumors with a rhabdoid phenotype are aggressive neoplasms with a dismal prognosis. Malignant extrarenal rhabdoid tumor (MERT) of the esophagus is an extremely rare disease with so far only 6 cases reported. We report on a 57-year-old male patient with rhabdoid tumor situated in the esophagus with metastases to the liver and local lymph nodes. Assuming an undifferentiated esophageal adenocarcinoma a palliative chemotherapy with 5-FU/folinic acid, oxaliplatin, and docetaxel (FLOT) was initiated which was changed towards a combination of doxorubicin and ifosphamide as immunohistochemistry of the primary and the liver metastases revealed a rhabdoid tumor. This treatment with doxorubicin and ifosphamide resulted in a short clinical and radiological response which lasted only for 2 months. Due to the bad general condition at the time of progression no further chemotherapy was initiated. The patient died due to tumor progression 6 months after initial diagnosis which is consistent with other reports on malignant extrarenal rhabdoid tumors (median survival of metastatic disease less than 6 months). Thus, metastatic MERT represents a disease with a poor prognosis and no established standard therapy.",
"affiliations": "HOP Ulm, Germany.;Gastroenterology, General Hospital, Blaubeuren, Germany.;Private Practice for Gastroenterology, Ulm, Germany.;Hematology and Oncology, German Army Forces Hospital, Ulm, Germany.;Gastroenterology, General Hospital, Blaubeuren, Germany.;Pathology, University of Ulm, Germany.",
"authors": "Kaechele|V|V|;Vogelpohl|J|J|;Boeck|W|W|;Riecke|A|A|;Eisele|R|R|;Barth|T|T|",
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"title": "Malignant extrarenal rhabdoid tumour (MERT) with liver metastases as a rare cause of an esophageal tumor in a 57 years old patient.",
"title_normalized": "malignant extrarenal rhabdoid tumour mert with liver metastases as a rare cause of an esophageal tumor in a 57 years old patient"
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"abstract": "Exophiala dermatitidis is a melanized fungus isolated from many environmental sources. Infections caused by Exophiala species are typically seen in immunocompromised hosts and manifest most commonly as cutaneous or subcutaneous disease. Systemic infections are exceedingly rare and associated with significant morbidity and mortality CASE PRESENTATION: A 28-year-old female originally from India presented with fevers, chills, weight loss and increasing back pain. She had a recent diffuse maculopapular rash that resulted in skin biopsy and a tentative diagnosis of sarcoidosis, leading to administration of azathioprine and prednisone. An MRI of her spine revealed a large paraspinal abscess requiring surgical intervention and hardware placement. Cultures from the paraspinal abscess grew a colony of dark pigmented mold. Microscopy of the culture revealed a melanized fungus, identified as Exophiala dermatitidis. Voriconazole was initially utilized, but due to relapse of infection involving the right iliac crest and left proximal humerus, she received a prolonged course of amphotericin B and posaconazole in combination and required 7 separate surgical interventions. Prolonged disease stability following discontinuation of therapy was achieved.\n\n\n\nDescribed is the first identified case of disseminated Exophiala dermatitidis causing osteomyelitis and septic arthritis in a patient on immunosuppressive therapy. A positive outcome was achieved through aggressive surgical intervention and prolonged treatment with broad-spectrum antifungal agents.",
"affiliations": "Department of Medicine, University of Calgary, Calgary, Alberta, Canada.;Regina Qu'Appelle Health Region, Department of Laboratory Medicine, University of Saskatchewan, College of Medicine, Regina, Saskatchewan, Canada.;Division of Infectious Diseases, Department of Medicine, University of Saskatchewan, Regina, Saskatchewan, Canada.;Division of Infectious Diseases, Department of Medicine, University of Saskatchewan, Regina, Saskatchewan, Canada. alexander.wong@usask.ca.",
"authors": "Lang|Raynell|R|;Minion|Jessica|J|;Skinner|Stuart|S|;Wong|Alexander|A|",
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"fulltext": "\n==== Front\nBMC Infect DisBMC Infect. DisBMC Infectious Diseases1471-2334BioMed Central London 317110.1186/s12879-018-3171-0Case ReportDisseminated Exophiala dermatitidis causing septic arthritis and osteomyelitis Lang Raynell Raynell.lang@ucalgary.ca 1Minion Jessica Jessica.Minion@saskhealthauthority.ca 2Skinner Stuart Stuart.skinner@usask.ca 34Wong Alexander alexander.wong@usask.ca 341 0000 0004 1936 7697grid.22072.35Department of Medicine, University of Calgary, Calgary, Alberta Canada 2 0000 0001 2154 235Xgrid.25152.31Regina Qu’Appelle Health Region, Department of Laboratory Medicine, University of Saskatchewan, College of Medicine, Regina, Saskatchewan Canada 3 0000 0001 2154 235Xgrid.25152.31Division of Infectious Diseases, Department of Medicine, University of Saskatchewan, Regina, Saskatchewan Canada 4 0000 0000 8589 754Xgrid.415757.54E - ID Clinic, Regina General Hospital, 1440 14th Avenue Regina, Regina, Saskatchewan Canada 4 6 2018 4 6 2018 2018 18 25514 3 2018 28 5 2018 © The Author(s). 2018Open 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\nExophiala dermatitidis is a melanized fungus isolated from many environmental sources. Infections caused by Exophiala species are typically seen in immunocompromised hosts and manifest most commonly as cutaneous or subcutaneous disease. Systemic infections are exceedingly rare and associated with significant morbidity and mortality\n\nCase presentation\nA 28-year-old female originally from India presented with fevers, chills, weight loss and increasing back pain. She had a recent diffuse maculopapular rash that resulted in skin biopsy and a tentative diagnosis of sarcoidosis, leading to administration of azathioprine and prednisone. An MRI of her spine revealed a large paraspinal abscess requiring surgical intervention and hardware placement. Cultures from the paraspinal abscess grew a colony of dark pigmented mold. Microscopy of the culture revealed a melanized fungus, identified as Exophiala dermatitidis. Voriconazole was initially utilized, but due to relapse of infection involving the right iliac crest and left proximal humerus, she received a prolonged course of amphotericin B and posaconazole in combination and required 7 separate surgical interventions. Prolonged disease stability following discontinuation of therapy was achieved.\n\nConclusions\nDescribed is the first identified case of disseminated Exophiala dermatitidis causing osteomyelitis and septic arthritis in a patient on immunosuppressive therapy. A positive outcome was achieved through aggressive surgical intervention and prolonged treatment with broad-spectrum antifungal agents.\n\nKeywords\nExophiala dermatitidisPhaeohyphomycosisWangiella dermatitidisDisseminatedSeptic arthritisOsteomyelitisissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nExophiala dermatitidis is a melanized fungus isolated from many environmental sources [1]. It is a saprobe, using extracellular digestion to obtain nutrients from dead or decaying organic matter [2, 3]. Infections caused by Exophiala species are known as phaeohyphomycosis, due to the appearance of dark pigmented, irregular branching, septate hyphae [1–5]. Infections are typically seen in immunocompromised hosts such as transplant recipients and manifest as subcutaneous disease [6, 7]. Systemic infections are rare and associated with significant morbidity and mortality [5, 8, 9].\n\nWe describe, to our knowledge, the first case of disseminated E. dermatitidis with widespread involvement including osteomyelitis and septic arthritis in a previously healthy 28-year-old female on immunosuppressive therapy. A positive outcome was achieved through aggressive surgical intervention and prolonged treatment with broad-spectrum antifungal agents.\n\nCase presentation\nA previously healthy 28-year-old female presented with complaints of increasing back pain and fevers. Originally from India, she had immigrated to Canada two years prior and within months of arrival, developed fevers associated with unintentional weight loss, and a diffuse rash localized to her torso, legs and scalp. The rash was annular, with dark-colored plaques and central clearing. Skin biopsy identified granulomatous inflammatory cell infiltrates with staining negative for mycobacteria and fungus. A diagnosis of sarcoidosis was suggested. The lesions resolved spontaneously within six months with no specific therapy, but her fevers and weight loss continued.\n\nThe patient elected to return to India for further investigations and treatment of her ongoing symptoms. Diffuse lymphadenopathy was identified and an inguinal lymph node biopsy revealed non-caseating granulomatous changes. Mycobacterial and fungal stains were negative. Brucella IgM and IgG serology were positive, but serum agglutination testing (SAT) to detect antibodies against the smooth lipopolysaccharide (S-LPS) of the outer membrane was negative. While in India, she received empiric treatment for tuberculosis and brucellosis with isoniazid, rifampin, pyrazinamide, ethambutol and injectable streptomycin. After nearly eight weeks of therapy, she experienced no clinical change. Her antimicrobials were discontinued, and she was started on high dose prednisone with rapid resolution of her malaise and fevers. She returned to Canada with a presumptive diagnosis of sarcoidosis on hydroxychloroquine, azathioprine, and tapering prednisone initiating at 40 mg daily.\n\nShortly after her return, the patient developed a large nodule on her back with progressive back pain, worsening left arm pain, and ongoing fevers. She was admitted to hospital for further testing. Hepatosplenomegaly was noted with no appreciable lymphadenopathy. A tender mass was identified medial to her left scapula. She had no focal neurologic deficits and the remainder of her physical exam was non-contributory.\n\nInvestigations revealed a white blood cell (WBC) count of 14.3 × 109 per liter (L) and a platelet count of 885 × 109/L. Her liver enzymes and creatinine kinase were within normal limits. Computed tomographic (CT) scanning of the spine showed a large heterogeneously attenuating area in the paraspinal tissue at the level of T3-T4 along with a large nodule in the left upper lung. Bone scan revealed abnormalities in the thoracic spine with increased uptake in the right sacroiliac (SI) joint. The differential diagnosis included sarcoidosis, tuberculosis, brucellosis, and disseminated fungal infection. Further investigations were pursued to identify the causal etiology.\n\nThe lung nodule was biopsied and smear-negative for acid-fast bacilli, and culture negative for fungus, bacteria, and mycobacteria. Histopathology reported caseating granulomas and fungal elements resembling budding yeast. A CT scan of her head revealed no abnormalities. Bronchoalveolar lavage (BAL) was performed. Mycobacterium tuberculosis complex polymerase chain reaction (PCR) and mycobacterial cultures were negative. Magnetic resonance imaging (MRI) revealed a large soft tissue mass at the spinal levels of T3-T5. Incision and drainage of this large paraspinal abscess was performed, along with a laminectomy at T4 and T5 with rod and pedicle screw placement due to involvement of the adjacent vertebral bodies. Liposomal amphotericin B was started empirically, as the only etiologic clue remained the yeast-like elements identified in the lung nodule biopsy.\n\nHistopathology from the paravertebral collection returned positive for yeast-like cells on PAS and GMS staining, suggestive of histoplasmosis. Bacterial cultures, originally submitted for Brucella, were found to be growing a colony of dark pigmented mold. Microscopy revealed numerous oval shaped conidia with rectangular phialides in keeping with a melanized fungus, identified as Exophiala species (Fig. 1). Fontana Masson staining confirmed the presence of pigmented fungi in original pathology specimens (Fig. 2). Voriconazole was added empirically and liposomal amphotericin B was continued. The patient developed progressive pain in her left shoulder and right SI joint. MRI of the pelvis revealed progression of an osteolytic lesion in the right iliac crest and fluid accumulation in the right sacro-iliac joint. Her therapy was changed from voriconazole to posaconazole empirically at 300 mg IV daily given her ongoing disease progression.Fig. 1 Exophiala dermatitidis isolated from surgically debrided paravertebral tissue. Lactofuchsin mount, 400X\n\nFig. 2 a, b Fungal elements visualized in surgically debrided paravertebral tissue, identified from culture as Exophiala dermatitidis. H&E staining, 400X. c, d Fungal elements visualized in surgically debrided paravertebral tissue, identified from culture as Exophiala dermatitidis. Fontana-Masson stain, 400X\n\n\n\nMultiple operative cultures and the BAL sample became positive for dark pigmented mold. Sequencing of the D1-D2 region of the large (28S) ribosomal subunit of the isolate resulted in 98.6% similarity to Exophiala dermatitidis, confirming a diagnosis of Exophiala dermatitidis [10]. Susceptibility testing results are listed in Table 1. Due to local availability of oral antifungals, posaconazole was changed to oral voriconazole 200 mg PO, and liposomal amphotericin B was discontinued following one month of combination therapy given the patient had experienced significant clinical improvement. Prior to discharge from hospital, a trough voriconazole level was found to be therapeutic at 2.99 mcg/mL (target range 2–5 mcg/mL).Table 1 Antifungal Susceptibility Testing of Exophiala dermatitidis isolate\n\nAntifungal\tMIC (mg/L)\t\n5-Flucytosine\t0.12\t\nAmphotericin B\t0.5\t\nItraconazole\t0.25\t\nPosaconazole\t0.12\t\nVoriconazole\t0.12\t\n\n\nThree weeks following discharge, she again presented with an enlarging mass over her left shoulder blade and ultrasound revealed a thick-walled hyper-dense lesion. A spontaneously draining sinus from her thoracolumbar incision was noted. Repeat MRI of her spine and pelvis revealed a bone marrow signal in the right iliac region (7.4 × 2.8 cm) and large peripherally enhancing fluid collections extending bilaterally down the spine, enveloping the spinal hardware. She was readmitted for irrigation and debridement of these collections. Voriconazole was discontinued, and combination therapy with liposomal amphotericin B 200 mg IV daily and posaconazole 300 mg IV daily was resumed.\n\nShe continued to have daily fevers with worsening pain and effusion of her left shoulder. MRI demonstrated dramatic changes suggestive of a highly aggressive process involving the right iliac crest and left proximal humerus. Her spinal hardware was removed and the surrounding area extensively debrided along with an excisional arthroplasty of the left shoulder. Operative cultures remained negative despite extended incubation. She remained on posaconazole and liposomal amphotericin B throughout hospitalization and received a six-week course of combination therapy. In total, she required 7 surgical interventions.\n\nTwo weeks following discharge, liposomal amphotericin B was discontinued, and posaconazole was continued at 400 mg orally once daily. After receiving nearly 500 days of antifungal therapy following her last surgery, with no clinical evidence of infection and normalized lab parameters, her posaconazole was discontinued. Over 1.5 years following discontinuation of antifungal therapy, she remains disease free with normalized inflammatory markers and continues to be followed closely by the infectious disease team. She has successfully received a shoulder prosthesis to regain significant function in her left arm.\n\nDiscussion and conclusions\nSeveral different species of Exophiala have been documented, with E. dermatitidis being known to cause cutaneous and subcutaneous phaeohyphomycosis [7]. Systemic infections are rare with an extensive literature review in 2013 documenting 40 cases [5, 8, 9]. Despite identification of E. dermatitidis in environmental samples globally, disseminated human infection is extremely rare in North America and nearly all cases are reported from Asia [7, 9]. Environmental samples have been noted in abundance in public steam baths, and water reservoirs, which may relate to the geographic differences in infection [11]. In this case, it is believed that the patient contracted the infection while residing in India. Extra-cutaneous manifestations include lymphadenitis, fungemia, cerebral infections, stomatitis, otitis media, corneal ulcers, esophagitis, pneumonia, liver cirrhosis, pancreatitis, inflammation of the gastrointestinal and biliary systems, endocarditis and peritonitis [2, 4, 9, 12]. Li et al. published a case series of seven fatal Exophiala sp. infections in China, two of which had bone involvement, however speciation revealed Exophiala spinifera as the etiologic agent [13]. E. dermatitidis has not previously been documented to cause bone or joint involvement.\n\nOf all reported cases, approximately 70% have an identifiable underlying risk factor such as an underlying immunocompromised state, intravenous drug use, long-term catheters, malignancy or cystic fibrosis [1, 9]. Case reports reveal that patients often present with hepatomegaly and lymphadenopathy [3, 5, 7]. Biopsies of liver and lymph nodes frequently show granulomas, which may lead to an early misdiagnosis of sarcoidosis, lymphoma or tuberculosis [2, 3].\n\nMost infections initially involve the skin and are suspected to spread hematogenously [7]. The initial skin lesions our patient presented with may have represented cutaneous or subcutaneous fungal infection. Several case reports have described patients being diagnosed with tinea versicolor prior to dissemination with E. dermatitidis, leading to the belief that inoculation occurred initially through the skin [3–5]. Since initial biopsies revealed non-specific granulomatous changes, empiric steroids and immunosuppressive agents initiated for sarcoidosis may have facilitated further dissemination of the organism.\n\nE. dermatitidis grows slowly and appears only after prolonged incubation of up to seven days, with one study suggesting cultures be held for at least four weeks [2, 14]. The organism may be missed if fungal cultures are not performed. Accurate identification of Exophiala species is enabled by molecular diagnostics involving sequencing of the internal transcribed space (ITS) region of the ribosomal DNA [6].\n\nA review of 20 disseminated infections from 1960 to 1992 revealed a mortality rate of 48%, however a subsequent review between 1993 and 2011 based on 24 cases revealed a mortality rate of 25% [1, 5]. Improved outcomes are believed to be due to the availability of improved antifungal therapies. If CNS involvement develops, the survival rate is 20% [1].\n\nNo large-scale controlled analyses of treatment options are available. Amphotericin B, flucytosine, itraconazole, voriconazole and posaconazole have all been used with varying degrees of success [2, 15]. In 2011, Badali et al. performed a study comparing 11 different antifungal drug susceptibilities to E. dermatitidis and noted that the MICs were similar between environmental and clinical strains of the organism as well as isolates from Asia, America and Europe [16]. The lowest MICs were observed to posaconazole and itraconazole followed by voriconazole [15, 16]. Fluconazole and amphotericin B appear to have poor activity against E. dermatitidis [2, 14, 16].\n\nCombination therapy of caspofungin with voriconazole, amphotericin or itraconazole may facilitate synergistic activity against E. dermatitidis, although monotherapy with an echinocandin is not recommended [14, 16]. Both voriconazole and posaconazole have good cerebral penetration, ideal for treating disseminated infections. There is limited data regarding the in vivo efficacy of antifungal therapy and there are no defined breakpoints available for antifungal agents [17]. In deep-seated infections, long-term survival has only been reported when complete surgical resection is obtained, however prognosis remains poor [15, 17]. The decision to discontinue therapy was based on demonstrated clinical stability, normalized lab parameters, expert opinion, and extensive discussion with the patient and her immediate family members.\n\nKey messages\n\nDescribed is the first identified case of disseminated Exophiala dermatitidis causing osteomyelitis and septic arthritis in a patient on immunosuppressive therapy.\n\nExophiala dermatitidis is a dematiaceous fungus isolated from environmental sources.\n\nSystemic infections are very rarely caused by E. dermatitidis, however when present are associated with significant morbidity and mortality.\n\nExophiala dermatitidis grows slowly and therefore fungal cultures need to be held for prolonged incubation or the organism may be missed.\n\nThrough aggressive surgical intervention and prolonged antifungal therapy, a positive outcome may be achieved in disseminated E. dermatitidis infections.\n\n\n\n\nAbbreviations\nBALBronchoalveolar lavage\n\nCTComputed tomography\n\nGMSGrocott’s methenamine silver stain\n\nITSInternal transcribed space\n\nMICMinimum inhibitory concentration\n\nMRIMagnetic resonance imaging\n\nPASPeriodic acid-Schiff stain\n\nPCRPolymerase chain reaction\n\nSATSerum agglutination testing\n\nSISacroiliac joint\n\nS-LPSSmooth lipopolysaccharide\n\nAcknowledgements\nWe would like to thank Dr. Tanis Dingle and the mycology department of the Provincial Laboratory for Public Health in Edmonton, Alberta, Canada for providing susceptibility testing and confirmatory identification.\n\nAvailability of data and materials\nData sharing is not applicable to this article as no datasets were generated or analyzed during the current study.\n\nAuthors’ contributions\nRL was involved in the literature review, planning and writing of the manuscript. JM was the medical microbiologist who performed the microbiological analysis of this case. SS was involved in patient care as well as reviewing the manuscript. AW was the lead physician involved in patient care as well as planning, writing and reviewing the manuscript. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Suzuki K Nakamura A Fujieda A Nakase K Katayama N Pulmonary infection caused by Exophiala dermatitidis in a patient with multiple myeloma: A case report and a review of the literature Med Mycol Case Rep 2012 1 95 98 10.1016/j.mmcr.2012.10.002 24371750 \n2. Alabaz D Kibar F Arikan S Sancak B Celik U Aksaray N Systemic phaeohyphomycosis due to Exophiala (Wangiella) in an immunocompetent child Med Mycol 2009 47 6 653 657 10.1080/13693780802715815 19184769 \n3. Oztas E Odemis B Kekilli M Kurt M Dinc BM Parlak E Systemic phaeohyphomycosis resembling primary sclerosing cholangitis caused by Exophiala dermatitidis J Med Microbiol 2009 58 1243 1246 10.1099/jmm.0.008706-0 19528179 \n4. Hiruma M Kawada A Ohata H Ohnishi Y Takahashi H Yamazaki M Systemic phaeohyphomycosis caused by Exophiala dermatitidis Mycoses 1993 36 1 2:1 2:7 \n5. Matsumoto T Matsuda T McGinnis MR Ajello L Clinical and mycological spectra of Wangiella dermatitidis infections Mycoses 1993 36 145 155 10.1111/j.1439-0507.1993.tb00743.x 8264710 \n6. Silva WC Gonçalves SS Santos DW Padovan AC Bizerra FC Melo AS Species diversity, antifungal susceptibility and phenotypic and genotypic characterisation of Exophiala spp. infecting patients in different medical centres in Brazil Mycoses 2017 60 5 328 337 10.1111/myc.12597 28139861 \n7. Kenney RT Kwon-Chung KJ Waytes AT Melnick DA Pass HI Merino MJ Successful treatment of systemic Exophiala dermatitidis infection in a patient with chronic granulomatous disease Clin Infec Dis 1992 14 1 235 242 10.1093/clinids/14.1.235 1571438 \n8. Chen M Zhang J Dong Z Wang F Cutaneous phaeohyphomycosis caused by Exophiala dermatitidis: A case report and literature review Indian J Dermatol Venereol Leprol 2016 82 2 173 177 10.4103/0378-6323.164214 26658392 \n9. Patel AK Patel KK Darji P Sinqh R Shivaprakash MR Chakrabarti A Exophiala dermatitidis endocarditis on native aortic valve in a postrenal transplant patient and review of literature on E.Dermatitidis Infections Mycoses 2013 56 365 372 10.1111/myc.12009 23013169 \n10. Clinical and Laboratory Standards Institute (CLSI). Interpretive Criteria for Identification of Bacteria and Fungi by DNA Target Sequencing, 1st Edition. CLSI document MM18-A. 2008. https://clsi.org/standards/products/molecular-methods/documents/mm18/. Accessed 23 Oct 2017.\n11. Matos T de Hoog GS de Boer AG de Crom I Haase G High prevalence of the neurotrope Exophiala dermatitidis and related oligotrophic black yeasts in sauna facilities Mycoses 2002 45 373 377 10.1046/j.1439-0507.2002.00779.x 12421284 \n12. Gold WL Vellend H Salit IE Campbell I Summerbell R Rinaldi M Successful treatment of systemic and local infections due to Exophiala species Clin Infect Dis 1994 19 339 341 10.1093/clinids/19.2.339 7986913 \n13. Li DM Li RY de Hoog GS Sudhadham M Wang DL Fatal Exophiala infections in China, with a report of seven cases Mycoses 2011 54 4 e136 e142 10.1111/j.1439-0507.2010.01859.x 20337943 \n14. Horre R Schaal KP Siekmeier R Sterzik B de Hoog GS Schnitzler N Isolation of fungi, especially Exophiala dermatitidis, in patients suffering from cystic fibrosis A prospective Study. Respiration 2004 71 4 360 366 15316209 \n15. Sun Y Liu W Wan Z Wang X Li R Antifungal activity of antifungal drugs, as well as drug combinations against Exophiala dermatitidis Mycopathologia 2011 171 2 111 117 10.1007/s11046-010-9358-6 20803255 \n16. Badali H De Hoog GS Sudhadham M Meis JF Microdilution in vitro antifungal susceptibility of Exophiala dermatitidis a systemic opportunist Med Mycol 2011 49 8 819 824 10.3109/13693786.2011.583285 21612562 \n17. Zheng JS Sutton DA Fothergill AW Rinaldi MG Harrack MJ de Hoog GS Spectrum of clinically relevant Exophiala species in the United States J Clin Microbiol 2007 45 11 3713 3720 10.1128/JCM.02012-06 17596364\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2334",
"issue": "18(1)",
"journal": "BMC infectious diseases",
"keywords": "Disseminated; Exophiala dermatitidis; Osteomyelitis; Phaeohyphomycosis; Septic arthritis; Wangiella dermatitidis",
"medline_ta": "BMC Infect Dis",
"mesh_terms": "D000328:Adult; D000666:Amphotericin B; D000935:Antifungal Agents; D001170:Arthritis, Infectious; D005093:Exophiala; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D008279:Magnetic Resonance Imaging; D010019:Osteomyelitis; D060446:Phaeohyphomycosis; D014230:Triazoles; D065819:Voriconazole",
"nlm_unique_id": "100968551",
"other_id": null,
"pages": "255",
"pmc": null,
"pmid": "29866071",
"pubdate": "2018-06-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20803255;15316209;17596364;26658392;20337943;28139861;19528179;7986913;23013169;12421284;1571438;21612562;24371750;8264710;8316255;19184769",
"title": "Disseminated Exophiala dermatitidis causing septic arthritis and osteomyelitis.",
"title_normalized": "disseminated exophiala dermatitidis causing septic arthritis and osteomyelitis"
} | [
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"companynumb": "CA-TEVA-2018-CA-926553",
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... |
{
"abstract": "Purpose: To describe posterior ocular involvement features of Whipple's disease (WD) in a patient with no gastrointestinal symptoms.Methods: Retrospective case report.Observation: A 53-year-old man with a 2-year history of seronegative arthritis presented with bilateral intraocular inflammation, optic disc edema, and cystoid macular edema (CME) in the left eye. A diagnosis of noninfectious uveitis was made and oral prednisolone was started. Despite initial improvement, after 6 weeks, CME was found in both eyes. Because of the initial response, the anti-tumor necrosis factor agent Adalimumab was started. Twelve weeks after initiation of adalimumab, fundus examination revealed widespread dot-blot retinal hemorrhages and multifocal chorioretinal lesions at the posterior pole and mid-periphery. The chorioretinal lesions appeared as hyperreflective drusen-like deposits located in the sub-retinal pigment epithelium (RPE) space on the tomographic scan. WD was considered and confirmed by polymerase chain reaction test and duodenal biopsy.Conclusion: Posterior ocular involvement in WD may present with a wide clinical spectrum including intraocular inflammation and unique features of sub-RPE deposits, widespread retinal hemorrhages, and optic disc edema.",
"affiliations": "Department of Neurosciences, Biomedicine and Movement Sciences, Eye Clinic, Ocular Immunology and Neuroophthalmology Service, AOUI-University of Verona, Verona, Italy.;Oftalmico Hospital, ASST Fatebenefratelli Sacco, Milan, Italy.;Department of Neurosciences, Biomedicine and Movement Sciences, Eye Clinic, Ocular Immunology and Neuroophthalmology Service, AOUI-University of Verona, Verona, Italy.;Ophthalmology Department, Sacro Cuore Don Calabria Hospital, Negrar di Valpolicella, Italy.;Department of Neurosciences, Biomedicine and Movement Sciences, Eye Clinic, Ocular Immunology and Neuroophthalmology Service, AOUI-University of Verona, Verona, Italy.;Department of Neurosciences, Biomedicine and Movement Sciences, Eye Clinic, Ocular Immunology and Neuroophthalmology Service, AOUI-University of Verona, Verona, Italy.",
"authors": "Bosello|Francesca|F|;Casalino|Giuseppe|G|https://orcid.org/0000-0002-0208-0740;Neri|Enrico|E|;Alfano|Alessandro|A|;Bonora|Adriana|A|;Marchini|Giorgio|G|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/09273948.2020.1859548",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0927-3948",
"issue": null,
"journal": "Ocular immunology and inflammation",
"keywords": "Whipple’s disease; intraocular inflammation; optic disc edema; posterior ocular involvement; retinal imaging",
"medline_ta": "Ocul Immunol Inflamm",
"mesh_terms": null,
"nlm_unique_id": "9312169",
"other_id": null,
"pages": "1-4",
"pmc": null,
"pmid": "33545009",
"pubdate": "2021-02-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Unique Features of Posterior Ocular Involvement of Whipple's Disease in a Patient with No Gastrointestinal Symptoms.",
"title_normalized": "unique features of posterior ocular involvement of whipple s disease in a patient with no gastrointestinal symptoms"
} | [
{
"companynumb": "IT-MYLANLABS-2021M1051620",
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"activesubstancename": "PREDNISOLONE"
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{
"abstract": "We report a case of a 76-year-old British man living in Malta who presented with a 7-month history of recurrent epistaxis and an enlarging right nasal vestibular lesion. Of note, his medical history included rheumatoid arthritis for which he was on long-term methotrexate. Blood results were unremarkable other than a mild lymphopaenia. Despite the use of various antibiotics and intranasal steroids, the lesion failed to resolve. This was eventually biopsied, and the histological picture was that of mucosal leishmaniasis. Leishmania donovani complex was detected by PCR. The patient was treated with liposomal amphotericin B on alternate days for a total of 20 doses. The lesion was found to have healed well at follow-up and the patient denied any further episodes of epistaxis.",
"affiliations": "Department of General Medicine, Mater Dei Hospital, Msida, Malta paulagrech93@gmail.com.;Department of Medicine, Mater Dei Hospital, Msida, Malta.;Department of Infectious Disease, Mater Dei Hospital, Tal Qroqq, Malta.",
"authors": "Grech|Paula|P|;Vella|Sarah M|SM|;Piscopo|Tonio|T|",
"chemical_list": "D000981:Antiprotozoal Agents",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-237687",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "13(11)",
"journal": "BMJ case reports",
"keywords": "ear; infections; infectious diseases; nose and throat",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D000818:Animals; D000981:Antiprotozoal Agents; D001706:Biopsy; D003937:Diagnosis, Differential; D006801:Humans; D007893:Leishmania donovani; D007897:Leishmaniasis, Mucocutaneous; D008297:Male; D008319:Malta; D009297:Nasal Mucosa",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33139372",
"pubdate": "2020-11-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Leishmania donovani mucosal leishmaniasis in Malta.",
"title_normalized": "leishmania donovani mucosal leishmaniasis in malta"
} | [
{
"companynumb": "MT-PFIZER INC-2020462653",
"fulfillexpeditecriteria": "1",
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE SODIUM"
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"drugadditional": "3",... |
{
"abstract": "Despite adverse effects like hyperglycemia, new-onset diabetes after transplant (NODAT), and infectious complications, corticosteroid use remains an important part of liver transplantation (LT) immune suppression. Budesonide, a synthetic corticosteroid, undergoes extensive first-pass hepatic metabolism with only 10% systemic bioavailability, providing an opportunity for an improved toxicity-therapeutic ratio. Although effective in the treatment of autoimmune hepatitis, the effects of budesonide for LT immune suppression are unknown. We conducted a single-center phase 2a trial to study the safety and efficacy of budesonide immunosuppressive therapy. From July 2017 to November 2018, 20 patients undergoing a first LT received budesonide tapering doses (from 9 to 3 mg) for 12 weeks. Patients were compared with matched control patients who received prednisone from the same time period. Additionally, both groups received calcineurin inhibitors and mycophenolate mofetil. Outcome measures at week 24 included rates of biopsy-proven acute cellular rejection (ACR), NODAT (hemoglobin A1c >6.4%), and infectious complications. In the budesonide arm, 1 patient developed ACR at week 5 and was removed from the study. Another patient stopped the study drug at week 8 due to persistent nausea. Rates of ACR were similar between the budesonide and control groups (5% versus 5%, P = 1.00). Three patients in the control group developed NODAT versus none in the budesonide group (15% versus 0%; P = 0.23). There were 6 infections in the control group compared with none in the budesonide group (30% versus 0; P = 0.02). These pilot data suggest that budesonide has the potential to be a safe and effective alternative to prednisone for LT immune suppression while reducing steroid-induced infections and NODAT. Randomized controlled trials are required to validate these findings.",
"affiliations": "Divisions of, Division of, Digestive Diseases, University of Cincinnati, Cincinnati, OH.;Division of, Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Cincinnati, Cincinnati, OH.;Divisions of, Division of, Digestive Diseases, University of Cincinnati, Cincinnati, OH.;Transplant Surgery, Department of Surgery, University of Cincinnati, Cincinnati, OH.;Divisions of, Division of, Digestive Diseases, University of Cincinnati, Cincinnati, OH.;Department of Internal Medicine, University of Cincinnati, Cincinnati, OH.;Divisions of, Division of, Digestive Diseases, University of Cincinnati, Cincinnati, OH.",
"authors": "Bari|Khurram|K|0000-0002-4346-840X;Shah|Shimul A|SA|0000-0003-3406-7310;Kaiser|Tiffany E|TE|;Cohen|Robert M|RM|;Anwar|Nadeem|N|;Kleesattel|David|D|;Sherman|Kenneth E|KE|0000-0002-0560-0019",
"chemical_list": "D065095:Calcineurin Inhibitors; D019819:Budesonide",
"country": "United States",
"delete": false,
"doi": "10.1002/lt.25837",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1527-6465",
"issue": "26(11)",
"journal": "Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society",
"keywords": null,
"medline_ta": "Liver Transpl",
"mesh_terms": "D019819:Budesonide; D065095:Calcineurin Inhibitors; D006084:Graft Rejection; D006801:Humans; D007165:Immunosuppression Therapy; D016031:Liver Transplantation",
"nlm_unique_id": "100909185",
"other_id": null,
"pages": "1430-1440",
"pmc": null,
"pmid": "32602616",
"pubdate": "2020-11",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "16552802;25152574;28192125;16623815;20600032;9311706;6958498;27105755;27567694;17198248;20417047;23940730;30811890;23458449;16162148;9123120;27074818;9158013;10500075;17206943;11726831;15754377;20130772;15704045;17969201;12176487;12717237;16297052;8475553;20098286;16487622;22006869;17098598;21189424;15690537;25307034;28126427;9049215;15558584;29688072;19453997;29988867;10360582;16933236;10578335;3061075;25379858;17511685;18383081;7570337",
"title": "Safety and Efficacy of Budesonide for Liver Transplant Immune Suppression: Results of a Pilot Phase 2a Trial.",
"title_normalized": "safety and efficacy of budesonide for liver transplant immune suppression results of a pilot phase 2a trial"
} | [
{
"companynumb": "US-ASTELLAS-2020US043352",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
... |
{
"abstract": "In addition to the usual adverse effects, the chronic use of the valproic acid can entail dementia syndrome. We describe the case of a 68-year-old woman who had presented a dementia syndrome due to the use of valproic acid for one year. This drug was prescribed in order to prevent a potential convulsive crisis after an ischemic stroke in a patient who did not have a history of epilepsy. This case shows that each clinician must be careful about all medications consumed by the patient in the face of cognitive disorders.",
"affiliations": "Service de médecine interne gériatrie, hôpital de jour, hôpital de Champmaillot, CHU, Dijon, France. patrick.manckoundia@chu-dijon.fr",
"authors": "Manckoundia|P|P|;Disson-Dautriche|A|A|;Rouaud|O|O|;Richard|D|D|;Tavernier-Vidal|B|B|;Pfitzenmeyer|P|P|",
"chemical_list": "D000927:Anticonvulsants; D014635:Valproic Acid",
"country": "France",
"delete": false,
"doi": "10.1016/j.revmed.2008.01.016",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0248-8663",
"issue": "29(10)",
"journal": "La Revue de medecine interne",
"keywords": null,
"medline_ta": "Rev Med Interne",
"mesh_terms": "D000368:Aged; D000927:Anticonvulsants; D003704:Dementia; D005260:Female; D006801:Humans; D014635:Valproic Acid",
"nlm_unique_id": "8101383",
"other_id": null,
"pages": "827-9",
"pmc": null,
"pmid": "18572280",
"pubdate": "2008-10",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Dementia syndrome in an elderly subject related to valproic acid use: a case report.",
"title_normalized": "dementia syndrome in an elderly subject related to valproic acid use a case report"
} | [
{
"companynumb": "FR-ACTAVIS-2009B-03241",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VALPROIC ACID"
},
"drugadditional": "1",
... |
{
"abstract": "OBJECTIVE\nThe combination of methotrexate (MTX) with infliximab can modify infliximab pharmacokinetics and lower the incidence of antibodies against infliximab (ATIs). We hypothesised that the pharmacokinetic interaction between MTX and infliximab is related to activation of MTX to immunosuppressive MTX polyglutamates (MTXPGs).\n\n\nMETHODS\nAdult patients with rheumatoid arthritis receiving weekly MTX with infliximab for more than 3 months were enrolled in a cross-sectional study. Blood was collected at trough before the infusion of infliximab. Red blood cell (RBC) MTXPGs were measured using liquid chromatography, and circulating levels of infliximab were measured using a cell-based assay. ATIs were measured using enzyme immunoassays. Statistical analyses consisted of multiple regression and Wilcoxon tests.\n\n\nRESULTS\nIn the 61 patients enrolled in the study, ATIs were detected in 11 (18%). Regression analyses revealed that lower infliximab levels (median 3.3 µg/ml) were associated with the presence of ATIs and lower RBC MTXPG levels (median 28 nmol/l) (p<0.05). Logistic regression revealed that RBC MTXPG levels above 25 nmol/l were associated with a 4.7-fold lower likelihood of having ATIs (OR=4.7; 95% CI 1.1 to 20.8; p=0.02). None of the 12 patients with RBC MTXPG levels above 50 nmol/l tested positive for ATIs.\n\n\nCONCLUSIONS\nThese hypothesis-generating data indicate that MTXPGs are associated with infliximab pharmacokinetics and ATI formation.",
"affiliations": "R&D Department, Exagen Diagnostics, Vista, California 92081, USA. tdervieux@exagen.com",
"authors": "Dervieux|Thierry|T|;Weinblatt|Michael E|ME|;Kivitz|Alan|A|;Kremer|Joel M|JM|",
"chemical_list": "D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D018501:Antirheumatic Agents; D011099:Polyglutamic Acid; C014085:methotrexate polyglutamate; D000069285:Infliximab; D008727:Methotrexate",
"country": "England",
"delete": false,
"doi": "10.1136/annrheumdis-2012-202591",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-4967",
"issue": "72(6)",
"journal": "Annals of the rheumatic diseases",
"keywords": "Anti-TNF; Methotrexate; Pharmacokinetics; Rheumatoid Arthritis",
"medline_ta": "Ann Rheum Dis",
"mesh_terms": "D000368:Aged; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D002853:Chromatography, Liquid; D003430:Cross-Sectional Studies; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004912:Erythrocytes; D005260:Female; D006801:Humans; D000069285:Infliximab; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D011099:Polyglutamic Acid",
"nlm_unique_id": "0372355",
"other_id": null,
"pages": "908-10",
"pmc": null,
"pmid": "23161901",
"pubdate": "2013-06",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Methotrexate polyglutamation in relation to infliximab pharmacokinetics in rheumatoid arthritis.",
"title_normalized": "methotrexate polyglutamation in relation to infliximab pharmacokinetics in rheumatoid arthritis"
} | [
{
"companynumb": "US-JNJFOC-20130514983",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,
... |
{
"abstract": "Thionamides, such as methimazole and propylthiouracil, are used for the management of hyperthyroidism. Agranulocytosis is a rare adverse effect of thionamides and elderly patients are especially vulnerable. Here we discuss a case of an 80-year-old woman who developed agranulocytosis and pneumonia approximately 4 weeks after starting low dose methimazole therapy. Despite aggressive treatment with broad-spectrum antibiotics and granulocyte colony stimulating factor, she developed multiorgan failure and died. Our goals are to identify risk factors common to elderly patients and hopefully improve outcomes in this population when prescribed thionamides.",
"affiliations": "Department of Internal Medicine, St Francis Medical Center, Seton Hall University, Trenton, New Jersey, USA.;Department of Internal Medicine, St Francis Medical Center, Seton Hall University, Trenton, New Jersey, USA.;Department of Internal Medicine, St Francis Medical Center, Seton Hall University, Trenton, New Jersey, USA.;Department of Endocrinology, St Francis Medical Center, Seton Hall University, Trenton, New Jersey, USA.",
"authors": "Bukhari|Sumera|S|http://orcid.org/0000-0002-6680-4779;Khan|Muhammad|M|;Kumar|Naresh|N|;Mohan|Vinuta|V|",
"chemical_list": "D000900:Anti-Bacterial Agents; D013956:Antithyroid Agents; D016179:Granulocyte Colony-Stimulating Factor; D008713:Methimazole; D011441:Propylthiouracil",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-220924",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "drugs and medicines; general guidance on prescribing; haematology (drugs and medicines); thyroid disease",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000367:Age Factors; D000369:Aged, 80 and over; D000380:Agranulocytosis; D000900:Anti-Bacterial Agents; D013956:Antithyroid Agents; D017809:Fatal Outcome; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D006980:Hyperthyroidism; D008713:Methimazole; D011441:Propylthiouracil; D012307:Risk Factors",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28716776",
"pubdate": "2017-07-17",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "10671911;12506270;14678335;15523286;15745981;15785251;16370960;17053291;1751364;19445623;2310281;24419309;27747601;3755286;6687345",
"title": "Increased risk for thionamide-induced agranulocytosis in elderly patients: a case presentation and literature review.",
"title_normalized": "increased risk for thionamide induced agranulocytosis in elderly patients a case presentation and literature review"
} | [
{
"companynumb": "US-HERITAGE PHARMACEUTICALS-2017HTG00244",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MEMANTINE"
},
"drugadditional... |
{
"abstract": "Drug-induced tremors after long-term administration of anti-epileptics have been described in the literature. Such tremors are usually postural or action in nature with infrequent resting nature.\n\n\n\nA 23-year-old female presented in status epilepticus. Past and family histories were negative for seizures. She was managed per protocol with valproate. Within hours, she developed resting tremors. The tremors subsided on changing the anti-epileptic.\n\n\n\nResting tremors have mostly been described in the literature as long-term side-effects of valproate. This case illustrates that even short-term infusion of valproate can cause resting tremors.",
"affiliations": "Department of Neurology, Institute of Human Behavior and Allied Sciences, Delhi, IN.;Department of Neurology, Institute of Human Behavior and Allied Sciences, Delhi, IN.",
"authors": "Gupta|Ashutosh|A|;Kushwaha|Suman|S|",
"chemical_list": "D000927:Anticonvulsants; D014635:Valproic Acid",
"country": "England",
"delete": false,
"doi": "10.7916/D8DV32T3",
"fulltext": "\n==== Front\nTremor Other Hyperkinet Mov (N Y)Tremor Other Hyperkinet Mov (N Y)TOHMTremor and Other Hyperkinetic Movements2160-8288Columbia University Libraries/Information Services 10.7916/D8DV32T3Case ReportsDisabling Resting Tremors Induced by the Short‐term Infusion of Valproate: A Reversible Phenomenon Resting Tremors after Valproate in Status Epilepticus Gupta Ashutosh *Kushwaha Suman 1 Department of Neurology, Institute of Human Behavior and Allied Sciences, Delhi, INLouis Elan D. Yale University, USA*To whom correspondence should be addressed. E-mail: drashutosh.gupta24@gmail.com2018 8 12 2018 8 61521 10 2018 15 11 2018 © 2018 Gupta et al.2018Gupta et al.This is an open-access article distributed under the terms of the Creative Commons Attribution–Noncommerical–No Derivatives License, which permits the user to copy, distribute, and transmit the work provided that the original author and source are credited; that no commercial use is made of the work; and that the work is not altered or transformed.Background\nDrug-induced tremors after long-term administration of anti-epileptics have been described in the literature. Such tremors are usually postural or action in nature with infrequent resting nature.\n\nCase Report\nA 23-year-old female presented in status epilepticus. Past and family histories were negative for seizures. She was managed per protocol with valproate. Within hours, she developed resting tremors. The tremors subsided on changing the anti-epileptic.\n\nDiscussion\nResting tremors have mostly been described in the literature as long-term side-effects of valproate. This case illustrates that even short-term infusion of valproate can cause resting tremors.\n\nValproateresting tremorsstatus epilepticus\n==== Body\nIntroduction\nValproate is one of the most widely used first-line anti-epileptics in the management of epilepsy and status epilepticus. Tremors are one of the most common neurological side effects of valproate, and are thought to occur in 6–45% of patients. Approximately 25% of patients taking valproate are found to develop tremors within 3–12 months of initiating therapy.1 The drug-induced tremors described with valproate are of mild severity and do not require treatment in 76.3% of cases.2 Mostly, such tremors are postural or action in nature with infrequent resting tremors.1,2 Such resting tremors occur after long-term administration of valproate. To our knowledge, such resting type of disabling tremors after short-term infusion of valproate in the management of status epilepticus is a novel finding.\n\nCase report\nA 23-year-old female with no prior comorbidities presented as a neurologic emergency at the Institute of Human Behavior and Allied Sciences, Delhi, India, with generalized status epilepticus. The patient was actively having generalized tonic–clonic seizures that had been going on for about 30 minutes prior to presentation. Her birth and childhood histories were uneventful. There was no prior history of fever, head injury, or loss of consciousness. She was not on any long-term medication or oral contraceptives. Also, there was no family history of seizures. On examination, there was no sign of injury. She was afebrile, stuporous, and responsive to pain. No meningeal or focal neurological signs were apparent. Her pupils were normal in size and reactive to light. Both sides displayed the extensor plantar reflex. She was treated according to the status epilepticus management protocol. After administration of intravenous lorazepam and sodium valproate in accordance with her body weight, generalized tonic–clonic movements subsided; however, she remained in a postictal drowsy state. The non-contrast computed tomography scan of the head, at this stage, was normal. Thereafter, she was moved to the Neurology Department Intensive Care Unit and was administered intravenous ceftriaxone, pantoprazole, and fluids. Two hours after infusion of valproate, she started to have generalized, large amplitude, resting tremors all over her body at a frequency of 4–6 hertz (Video 1). The patient was clinically examined again in the ICU. She remained drowsy and afebrile but still there was no focal neurological deficit. There was no rigidity on examination. Additional signs of bradykinesia and the postural/action nature of the tremors could not be elicited, as the patient was in a postictal drowsy state. All the investigations including further neuro-imaging (brain magnetic resonance imaging), hematological, and biochemical tests of serum as well as cerebrospinal fluid were normal. A bedside electroencephalography (EEG) was done at this stage, which showed movement artifacts, but epileptiform discharges were absent. The patient could not be tested for entrainment or distractibility as she was not conscious enough for the tests.\n\nVideo 1. Generalized, Large Amplitude, Resting Tremors all Over the Body at a Frequency of 4–6 Hertz Induced by the Short Term Infusion of Valproate for Status Epilepticus. The video demonstrates disabling resting tremors all over the body of the patient after infusion of valproate.\nA further dose of valproate was discontinued, and she was switched to levetiracetam. On the fourth day, the patient regained consciousness. She was evaluated clinically. Astonishingly, there were minimal tremors with no signs of entrainment or distractibility, no rigidity, bradykinesia, or sensory or cerebellar deficits. The EEG was non-revealing. Five days after the initial valproate infusion, the tremors subsided completely (Video 2). The patient was discharged in a stable and seizure-free state 10 days after admission. The patient has been under outpatient department follow-up since then.\n\nVideo 2. The Patient from Video 1 at Initial Follow-up. The video shows complete disappearance of resting tremors after 5 days of stopping valproate.\nDiscussion\nTremors are one of the common side effects of certain anti-epileptics, commonly sodium valropate.3 Such drug-induced tremors are usually postural or action in nature, with infrequent resting tremors, which develop over a period of time.4 This case is unusual in three aspects: firstly, tremors were disabling and not mild; secondly, disabling resting tremors occurred after a short-term infusion of valproate for the management of status epilepticus; and, thirdly, such resting tremors are completely reversible within a short timespan, after switching to another anti-epileptic.\n\nPhysicians have to be aware of the appearance of valproate-induced tremors after a short-term infusion in the management of status epilepticus. Other common anti-epileptics, where tremors are reported, include lamotrigine and zonisamide.3 In our case, although the seizures were controlled after the valproate infusion, she subsequently developed, as a side effect, large-amplitude rest tremors involving the whole body. She remained seizure and tremor free after switching to levetiracetam, another first-line antiepileptic in the management of status epilepticus and is doing well in the follow up.\n\nAcknowledgment\nI would like to acknowledge Mr. S.M. Gupta, my father and mentor, for providing useful direction in making this report.\n\nFunding: None.\n\nFinancial Disclosures: None.\n\nConflict of Interest: The authors report no conflict of interest.\n\nEthics Statement: All patients that appear on video have provided written informed consent; authorization for the videotaping and for publication of the videotape was provided.\n==== Refs\nReferences\n1 Rinnerthaler M Luef G Mueller J Seppi K Wissel J Trinka E et al Computerized tremor analysis of valproate-induced tremor: a comparative study of controlled-release versus conventional valproate Epilepsia 2005 46 320 323 10.1111/j.0013-9580.2005.36204.x 15679514 \n2 Alonso-Juarez M Torres-Russotto D Crespo-Morfin P Baizabal-Carvallo JF The clinical features and functional impact of valproate-induced tremor Parkinsonism Relat Disord 2017 44 147 150 10.1016/j.parkreldis.2017.09.011 28941829 \n3 Zadikoff C Munhoz R P Asante A N Politzer N Wennberg R Carlen P et al Movement disorders in patients taking anticonvulsants J Neurol Neurosurg Psychiatry 2007 78 147 151 10.1136/jnnp.2006.100222 17012337 \n4 He Z-F Chen J Zhou C-N Rao Z Wang X-H Disabling tremor induced by long-term use of sodium valproate and lamotrigine: case report Medicine 2017 96 e8711 10.1097/MD.0000000000008711 29381960\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2160-8288",
"issue": "8()",
"journal": "Tremor and other hyperkinetic movements (New York, N.Y.)",
"keywords": "Valproate; resting tremors; status epilepticus",
"medline_ta": "Tremor Other Hyperkinet Mov (N Y)",
"mesh_terms": "D000927:Anticonvulsants; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007262:Infusions, Intravenous; D013997:Time Factors; D014202:Tremor; D014635:Valproic Acid; D028761:Withholding Treatment; D055815:Young Adult",
"nlm_unique_id": "101569493",
"other_id": null,
"pages": "615",
"pmc": null,
"pmid": "30619645",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15679514;17012337;28941829;29381960",
"title": "Disabling Resting Tremors Induced by the Short-term Infusion of Valproate: A Reversible Phenomenon.",
"title_normalized": "disabling resting tremors induced by the short term infusion of valproate a reversible phenomenon"
} | [
{
"companynumb": "IN-ABBVIE-19P-078-2618536-00",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PANTOPRAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "Fanconi anemia is primarily inherited as an autosomal recessive genetic disorder with common delays in diagnosis and challenging treatments. Fanconi anemia patients have a high risk of developing solid tumors, particularly in the head and neck or anogenital regions. The diagnosis of Fanconi anemia is primarily based on the chromosomal breakage but FA gene sequencing is recommended in all patients with a positive chromosome fragility test. Here, we present a 32-year-old man with advanced tonsil squamous cell carcinoma and fatal toxicity after the first cycle of chemotherapy. No anemia was present. A recent variant mutation if the FANCM gene was detected (c1511_1515delGAGTA (pArg504AsnfsTer29)). Homozygous or double heterozygous pathogenic variants have been reported in FANCM and linked to azoospermia and primary ovarian failure without anemia. Alterations in this gene have also been associated with a genetic predisposition for solid tumors (breast and ovarian cancer) and hematological malignancies (B-cell acute lymphoblastic leukemia). Due to the hypersensitivity of these patients to DNA-damaging agents such as chemotherapy and radiotherapy, surgery is the best treatment option for malignant solid tumors. Dose reductions or alternative regimens of chemotherapy and/or radiotherapy are recommended in FA patients who develop a malignant tumor.",
"affiliations": "Servicio de Oncología Radioterápica Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain. Electronic address: juanan881@hotmail.es.;Servicio de Oncología Médica Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain.;Servicio de Hematología y Hemoterapia Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain.;Servicio de Oncología Médica Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain.;Servicio de Medicina Intensiva, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain.;Servicio de Oncología Radioterápica Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain.;Centro Inmunológico de Alicante, Spain; Servicio de Biología Molecular de Cialab Ribera Salud, Spain.;Servicio de Farmacia, Hospital General Universitario Santa Lucía, Cartagena, Spain.;Genome Instability and DNA Repair Syndromes Group, Sant Pau Biomedical Research Institute (IIB Sant Pau), Join Unit UAB-IR Sant Pau on Genomic Medicine, 08041, Barcelona, Spain; Genetics Department, Hospital de la Santa Creu I Sant Pau, 08041, Barcelona, Spain; Genetics and Microbiology Department, Universitat Autònoma de Barcelona, 08193, Bellaterra, Spain; Center for Biomedical Network Research on Rare Diseases (CIBERER), Sant Pau Biomedical Research Institute (IIB Sant Pau), 08041, Barcelona, Spain.;Genome Instability and DNA Repair Syndromes Group, Sant Pau Biomedical Research Institute (IIB Sant Pau), Join Unit UAB-IR Sant Pau on Genomic Medicine, 08041, Barcelona, Spain; Genetics Department, Hospital de la Santa Creu I Sant Pau, 08041, Barcelona, Spain; Genetics and Microbiology Department, Universitat Autònoma de Barcelona, 08193, Bellaterra, Spain; Center for Biomedical Network Research on Rare Diseases (CIBERER), Sant Pau Biomedical Research Institute (IIB Sant Pau), 08041, Barcelona, Spain.",
"authors": "Encarnación|J A|JA|;Cerezuela|P|P|;Español|I|I|;García|M R|MR|;Manso|C|C|;De la Fuente|I|I|;Garrigós|N|N|;Viney|A|A|;Minguillon|J|J|;Surrallés|J|J|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.ejmg.2021.104399",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1769-7212",
"issue": "65(1)",
"journal": "European journal of medical genetics",
"keywords": "FANCM gene; Fanconi anemia; Targeted therapy; Tonsil cancer; c1511_1515delGAGTA",
"medline_ta": "Eur J Med Genet",
"mesh_terms": null,
"nlm_unique_id": "101247089",
"other_id": null,
"pages": "104399",
"pmc": null,
"pmid": "34793962",
"pubdate": "2021-11-15",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Fanconi-like anemia related to a FANCM mutation.",
"title_normalized": "fanconi like anemia related to a fancm mutation"
} | [
{
"companynumb": "ES-TEVA-2022-ES-2023613",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUCONAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "Thrombotic thrombocytopenic purpura (TTP) is a rare and potentially lethal syndrome characterized by severe thrombocytopenia, microangiopathic haemolytic anaemia, and aspecific neurologic symptoms. This syndrome is the result of an abnormal intravascular platelet aggregation which induces transient ischemia in various organs, especially in the central nervous system. Platelet aggregation causes also fragmentation of erythrocytes, thus leading to the characteristic anaemia. The exact cause of TTP is unknown, but a large body of evidence suggest that this syndrome might be due to acquired (immunological) or congenital ADAMTS13 deficiency. The dysregulation of ADAMTS 13 activity could promote massive release of high molecular weight multimers of von Willebrand factor (VWF) from endothelium and, as a consequence, could cause intravascular platelet aggregation. Pregnancy is commonly associated with numerous metabolic, immunological, and haemostatic changes which could increase thrombotic risk: during pregnancy, in fact, it is generally observed an increase of procoagulant activity and a decrease of fibrinolytic activity; moreover, at the end of pregnancy, it is not rare to find thrombocytopenia. All these reasons lead us to consider pregnancy itself as a triggering event for the onset of TTP. The authors describe a case of TTP occurred during puerperium, in a patient who underwent caesarean section.",
"affiliations": null,
"authors": "Laganà|A S|AS|;Sofo|V|V|;Salmeri|F M|FM|;Chiofalo|B|B|;Ciancimino|L|L|;Triolo|O|O|",
"chemical_list": "D000925:Anticoagulants; D005938:Glucocorticoids; D014841:von Willebrand Factor",
"country": "China",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0390-6663",
"issue": "42(1)",
"journal": "Clinical and experimental obstetrics & gynecology",
"keywords": null,
"medline_ta": "Clin Exp Obstet Gynecol",
"mesh_terms": "D000328:Adult; D000925:Anticoagulants; D001803:Blood Transfusion; D002585:Cesarean Section; D019468:Disease Management; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D019106:Postoperative Hemorrhage; D049590:Postpartum Period; D011247:Pregnancy; D011697:Purpura, Thrombotic Thrombocytopenic; D016896:Treatment Outcome; D014841:von Willebrand Factor",
"nlm_unique_id": "7802110",
"other_id": null,
"pages": "90-4",
"pmc": null,
"pmid": "25864290",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Post-partum management in a patient affected by thrombotic thrombocytopenic purpura: case report and review of literature.",
"title_normalized": "post partum management in a patient affected by thrombotic thrombocytopenic purpura case report and review of literature"
} | [
{
"companynumb": "IT-BAYER-2015-153833",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHYLDOPA"
},
"drugadditional": null,
... |
{
"abstract": "Inherited defects in detoxification of reactive metabolites of drugs predispose patients to \"hypersensitivity\" reactions. Covalent interaction of metabolites with cell macromolecules leads to cytotoxic and immunologic outcomes, manifested clinically by multisystem syndromes with variable organ involvement. Hypothyroidism developed in 5 of 202 patients (age range, 1 to 81 years) we investigated for hypersensitivity reactions to anticonvulsants or sulfonamides shortly after their reaction. None had previous personal or family histories of autoimmune disease. All had low thyroxine levels, elevated levels of thyroid stimulating hormone, and autoantibodies including antimicrosomal antibodies. Patients were 2 to 18 years of age at presentation, and two were male. All returned to a euthyroid state within a year of presentation, and all remain well. The demographics, clinical presentation, and course of the patients is atypical of idiopathic lymphocytic thyroiditis. We investigated the pathogenesis of thyroid toxicity using the hydroxylamine metabolite of sulfamethoxazole as a model. The hydroxyalmine was toxic to thyroid cells in vitro, which did or did not express thyroid peroxidase activity, whereas the parent sulfonamide was toxic only to cells with active thyroid peroxidase. The purified enzyme converted sulfamethoxazole to the hydroxylamine. Formation of reactive drug metabolites by thyroid peroxidase in a host who is genetically unable to detoxify the metabolites may lead directly to cytotoxicity. Covalent binding to macromolecules, including thyroid peroxidase, also may lead to expression of neoantigens and formation of autoantibodies. Patients who have sustained hypersensitivity reactions to drugs should be investigated for possible involvement of the thyroid.",
"affiliations": "Faculty of Medicine, Department of Paediatrics, University of Toronto.",
"authors": "Gupta|A|A|;Eggo|M C|MC|;Uetrecht|J P|JP|;Cribb|A E|AE|;Daneman|D|D|;Rieder|M J|MJ|;Shear|N H|NH|;Cannon|M|M|;Spielberg|S P|SP|",
"chemical_list": "D000927:Anticonvulsants; D013449:Sulfonamides; D007453:Iodide Peroxidase; D013420:Sulfamethoxazole",
"country": "United States",
"delete": false,
"doi": "10.1038/clpt.1992.8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0009-9236",
"issue": "51(1)",
"journal": "Clinical pharmacology and therapeutics",
"keywords": null,
"medline_ta": "Clin Pharmacol Ther",
"mesh_terms": "D000293:Adolescent; D000818:Animals; D000917:Antibody Formation; D000927:Anticonvulsants; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D004342:Drug Hypersensitivity; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007037:Hypothyroidism; D007453:Iodide Peroxidase; D008297:Male; D009928:Organ Specificity; D012756:Sheep; D013420:Sulfamethoxazole; D013449:Sulfonamides; D013961:Thyroid Gland",
"nlm_unique_id": "0372741",
"other_id": null,
"pages": "56-67",
"pmc": null,
"pmid": "1732077",
"pubdate": "1992-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Drug-induced hypothyroidism: the thyroid as a target organ in hypersensitivity reactions to anticonvulsants and sulfonamides.",
"title_normalized": "drug induced hypothyroidism the thyroid as a target organ in hypersensitivity reactions to anticonvulsants and sulfonamides"
} | [
{
"companynumb": "CA-PFIZER INC-2016243918",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PHENYTOIN"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo describe the pattern of drug resistance at virological failure in the NEAT001/ANRS143 trial (first-line treatment with ritonavir-boosted darunavir plus either tenofovir/emtricitabine or raltegravir).\n\n\nMETHODS\nGenotypic testing was performed at baseline for reverse transcriptase (RT) and protease genes and for RT, protease and integrase (IN) genes for patients with a confirmed viral load (VL) >50 copies/mL or any single VL >500 copies/mL during or after week 32.\n\n\nRESULTS\nA resistance test was obtained for 110/805 (13.7%) randomized participants qualifying for resistance analysis (61/401 of participants in the raltegravir arm and 49/404 of participants in the tenofovir/emtricitabine arm). No resistance-associated mutation (RAM) was observed in the tenofovir/emtricitabine plus darunavir/ritonavir arm, and all further analyses were limited to the raltegravir plus darunavir arm. In this group, 15/55 (27.3%) participants had viruses with IN RAMs (12 N155H alone, 1 N155H + Q148R, 1 F121Y and 1 Y143C), 2/53 (3.8%) with nucleotide analogue RT inhibitor RAMs (K65R, M41L) and 1/57 (1.8%) with primary protease RAM (L76V). The frequency of IN mutations at failure was significantly associated with baseline VL: 7.1% for a VL of <100,000 copies/mL, 25.0% for a VL of ≥100,000 copies/mL and <500,000 copies/mL and 53.8% for a VL of ≥500,000 copies/mL (PTREND = 0.007). Of note, 4/15 participants with IN RAM had a VL < 200 copies/mL at time of testing.\n\n\nCONCLUSIONS\nIn the NEAT001/ANRS143 trial, there was no RAM at virological failure in the standard tenofovir/emtricitabine plus darunavir/ritonavir regimen, contrasting with a rate of 29.5% (mostly IN mutations) in the raltegravir plus darunavir/ritonavir NRTI-sparing regimen. The cumulative risk of IN RAM after 96 weeks of follow-up in participants initiating ART with raltegravir plus darunavir/ritonavir was 3.9%.",
"affiliations": "Sorbonne Universités, UPMC Univ Paris 06, Institut Pierre Louis d'Epidémiologie et de Santé Publique, INSERM, UMR_S 1136, AP-HP, Hôpital Pitié-Salpêtrière, Service de Virologie, Paris, F-75013, France sidonie.lambert@psl.aphp.fr.;MRC Clinical Trials Unit at UCL, London, UK.;Chelsea and Westminster Hospital, London, UK.;MRC Clinical Trials Unit at UCL, London, UK.;INSERM, ISPED, Centre INSERM U897-Epidemiologie-Biostatistique, Bordeaux, France.;Gemeinschaftspraxis Jessen-Stein, Berlin, Germany.;Department of HIV Medicine, Royal Free Hospital, London, UK.;MRC Clinical Trials Unit at UCL, London, UK.;Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy.;HIV Unit and Retrovirology Laboratory 'Irsicaixa' Foundation, Hospital Universitari Germans Trias i Pujol, UAB, Badalona, Catalonia, Spain.;Ifi-institut, an der Asklepios-Klinik St Georg, Hamburg, Germany.;Department of Infectious Diseases, Venhaelsan-Sodersjukhuset, Stockholm, Sweden.;Department of Therapeutic Research and Medicine Evaluation, Istituto Superiore di Sanità, Rome, Italy.;INSERM, ISPED, Centre INSERM U897-Epidemiologie-Biostatistique, Bordeaux, France CHU de Bordeaux, Pôle de Santé Publique, Service d'Information Médicale, Bordeaux, France Université de Bordeaux, ISPED, Centre INSERM U897-Epidemiologie-Biostatistique, Bordeaux, France.;Sorbonne Universités, UPMC Univ Paris 06, Institut Pierre Louis d'Epidémiologie et de Santé Publique, INSERM, UMR_S 1136, AP-HP, Hôpital Pitié-Salpêtrière, Service de Virologie, Paris, F-75013, France.;Sorbonne Universités, UPMC Univ Paris 06, Institut Pierre Louis d'Epidémiologie et de Santé Publique, INSERM, UMR_S 1136, AP-HP, Hôpital Pitié-Salpêtrière, Service de Virologie, Paris, F-75013, France.;CMIT, 46 Rue Henri Huchard, 75018 Paris, France.",
"authors": "Lambert-Niclot|S|S|;George|E C|EC|;Pozniak|A|A|;White|E|E|;Schwimmer|C|C|;Jessen|H|H|;Johnson|M|M|;Dunn|D|D|;Perno|C F|CF|;Clotet|B|B|;Plettenberg|A|A|;Blaxhult|A|A|;Palmisano|L|L|;Wittkop|L|L|;Calvez|V|V|;Marcelin|A G|AG|;Raffi|F|F|;|||",
"chemical_list": "D019380:Anti-HIV Agents",
"country": "England",
"delete": false,
"doi": "10.1093/jac/dkv427",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0305-7453",
"issue": "71(4)",
"journal": "The Journal of antimicrobial chemotherapy",
"keywords": null,
"medline_ta": "J Antimicrob Chemother",
"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D024882:Drug Resistance, Viral; D005260:Female; D005500:Follow-Up Studies; D015658:HIV Infections; D015497:HIV-1; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009154:Mutation; D017211:Treatment Failure; D016896:Treatment Outcome; D019562:Viral Load",
"nlm_unique_id": "7513617",
"other_id": null,
"pages": "1056-62",
"pmc": null,
"pmid": "26702926",
"pubdate": "2016-04",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Antiretroviral resistance at virological failure in the NEAT 001/ANRS 143 trial: raltegravir plus darunavir/ritonavir or tenofovir/emtricitabine plus darunavir/ritonavir as first-line ART.",
"title_normalized": "antiretroviral resistance at virological failure in the neat 001 anrs 143 trial raltegravir plus darunavir ritonavir or tenofovir emtricitabine plus darunavir ritonavir as first line art"
} | [
{
"companynumb": "FR-CIPLA LTD.-2016FR02031",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RALTEGRAVIR"
},
"drugadditional": null,
... |
{
"abstract": "Despite improvements in therapy amyloid light-chain (AL) amyloidosis, there are few studies comparing different regimens. Here we present a matched comparison with 69 patients in each cohort examining upfront therapy with cyclophosphamide, bortezomib and dexamethasone (CVD) vs cyclophosphamide, thalidomide and dexamethasone (CTD). On an intention-to-treat basis, the overall response rates were 71.0% vs 79.7% in the CVD and CTD arms, respectively, (P=0.32). A higher complete response (CR) rate was observed in the CVD arm (40.5%) vs CTD (24.6%), P=0.046. One-year overall survival (OS) was 65.2% and 66.7% for CVD and CTD, respectively (P=0.87). The median progression-free survival (PFS) was 28.0 and 14.0 m for CVD and CTD, respectively (P=0.039). In a landmark analysis assessing outcomes performed at 6 months, the CR rate with CVD was 59.6% vs 34.0% for CTD (P=0.03). The 1-year OS was 96% with CVD and 92% with CTD (P=0.40). The median PFS with CVD was not reached and was 19.2 m with CTD, P=0.028). In summary, both regimens are unable to overcome the high rate of early deaths in AL amyloidosis. However, CVD correlates with improved depth of response and superior PFS supporting its use in the frontline setting. Further optimisation and better supportive-care strategies are required to increase the proportion of patients fully benefiting from therapy.",
"affiliations": "1] National Amyloidosis Centre, Department of Medicine, University College London Medical School, Royal Free Hospital Campus, London, UK [2] Department of Medical Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada.;National Amyloidosis Centre, Department of Medicine, University College London Medical School, Royal Free Hospital Campus, London, UK.;National Amyloidosis Centre, Department of Medicine, University College London Medical School, Royal Free Hospital Campus, London, UK.;National Amyloidosis Centre, Department of Medicine, University College London Medical School, Royal Free Hospital Campus, London, UK.;National Amyloidosis Centre, Department of Medicine, University College London Medical School, Royal Free Hospital Campus, London, UK.;National Amyloidosis Centre, Department of Medicine, University College London Medical School, Royal Free Hospital Campus, London, UK.;National Amyloidosis Centre, Department of Medicine, University College London Medical School, Royal Free Hospital Campus, London, UK.;1] National Amyloidosis Centre, Department of Medicine, University College London Medical School, Royal Free Hospital Campus, London, UK [2] Department of Clinical Haematology, Manchester Royal Infirmary, Central Manchester University Hospitals, Manchester, UK.;National Amyloidosis Centre, Department of Medicine, University College London Medical School, Royal Free Hospital Campus, London, UK.;National Amyloidosis Centre, Department of Medicine, University College London Medical School, Royal Free Hospital Campus, London, UK.;National Amyloidosis Centre, Department of Medicine, University College London Medical School, Royal Free Hospital Campus, London, UK.;National Amyloidosis Centre, Department of Medicine, University College London Medical School, Royal Free Hospital Campus, London, UK.;National Amyloidosis Centre, Department of Medicine, University College London Medical School, Royal Free Hospital Campus, London, UK.",
"authors": "Venner|C P|CP|;Gillmore|J D|JD|;Sachchithanantham|S|S|;Mahmood|S|S|;Lane|T|T|;Foard|D|D|;Rannigan|L|L|;Gibbs|S D J|SD|;Pinney|J H|JH|;Whelan|C J|CJ|;Lachmann|H J|HJ|;Hawkins|P N|PN|;Wechalekar|A D|AD|",
"chemical_list": "D001897:Boronic Acids; D007147:Immunoglobulin Light Chains; D011719:Pyrazines; D013792:Thalidomide; D000069286:Bortezomib; D003907:Dexamethasone; D003520:Cyclophosphamide",
"country": "England",
"delete": false,
"doi": "10.1038/leu.2014.218",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0887-6924",
"issue": "28(12)",
"journal": "Leukemia",
"keywords": null,
"medline_ta": "Leukemia",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000686:Amyloidosis; D000971:Antineoplastic Combined Chemotherapy Protocols; D001897:Boronic Acids; D000069286:Bortezomib; D015331:Cohort Studies; D003520:Cyclophosphamide; D003907:Dexamethasone; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007147:Immunoglobulin Light Chains; D008297:Male; D008875:Middle Aged; D011719:Pyrazines; D013792:Thalidomide; D016896:Treatment Outcome",
"nlm_unique_id": "8704895",
"other_id": null,
"pages": "2304-10",
"pmc": null,
"pmid": "25027514",
"pubdate": "2014-12",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": "11236934;23183428;22707405;16044444;22475872;12719281;15044258;22690902;23479568;19164601;15572585;22331953;23014566;21859734;21828140;22331187;22517904;18245653;23091105;15070667;17855669;23167457;22331188;22983583;17606766;21562045;20085941;21220614;16990593;22504925;21533608;23144200;22493299;9110907",
"title": "A matched comparison of cyclophosphamide, bortezomib and dexamethasone (CVD) versus risk-adapted cyclophosphamide, thalidomide and dexamethasone (CTD) in AL amyloidosis.",
"title_normalized": "a matched comparison of cyclophosphamide bortezomib and dexamethasone cvd versus risk adapted cyclophosphamide thalidomide and dexamethasone ctd in al amyloidosis"
} | [
{
"companynumb": "GB-CELGENEUS-167-20785-14075309",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional":... |
{
"abstract": "Edaravone Dexborneol is a novel neuroprotective agent that comprised edaravone and (+)-borneol, a food additive with an anti-inflammatory effect in animal ischaemic stroke models. This study aims to assess the safety and efficacy of Edaravone Dexborneol compared with edaravone in treating patients with acute ischaemic stroke (AIS).\n\n\n\nIn this multicentre, randomised, double-blind, multiple-dose, active-controlled, phase II clinical trial, patients with AIS within 48 hours after stroke onset were randomly assigned (1:1:1:1) to low-dose (12.5 mg), medium-dose (37.5 mg) or high-dose (62.5 mg) Edaravone Dexborneol groups, and an active control group with edaravone (30 mg) by 30 min intravenous infusion every 12 hours, for 14 consecutive days. The primary efficacy outcome was the proportion of modified Rankin Scale (mRS)score ≤1 at 90 days and National Institutes of Health Stroke Scale (NIHSS) score change from baseline to 14 days after randomisation. The safety outcome included any adverse event during 90 days after treatment.\n\n\n\nOf 385 patients included in the efficacy analysis, 94 were randomised to low-dose group, 97 to medium-dose group, 98 to high-dose group and 96 to the control group. No significant difference was observed among the four groups on mRS score (mRS ≤1, p=0.4054) at 90 days or NIHSS score change at 14 days (p=0.6799). However, a numerically higher percentage of patients with mRSscore ≤1 at 90 days in the medium-dose (69.39%) and high-dose (65.63%) groups was observed than in the control group (60.64%). No significant difference in severe adverse events was found among the four groups (p=0.3815).\n\n\n\nCompared with edaravone alone, Edaravone Dexborneol was safe and well tolerated at all doses, although no significant improvement in functional outcomes was observed at 90days.\n\n\n\nNCT01929096.",
"affiliations": "Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.;Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.;Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.;Department of Neurology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.;Department of Neurology, The First Affiliated Hospital of Hunan Normal University, Changsha, China.;Department of Neurology, General Hospital, PLA Shenyang Military Region, Shenyang, China.;Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.;Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.;Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.",
"authors": "Xu|Jie|J|0000-0002-8320-218X;Wang|Yilong|Y|;Wang|Anxin|A|0000-0003-4351-2877;Gao|Zhiqiang|Z|;Gao|Xiaoping|X|;Chen|Huisheng|H|0000-0002-8490-9435;Zhou|Junshan|J|;Zhao|Xingquan|X|;Wang|Yongjun|Y|0000-0002-9976-2341",
"chemical_list": "D018696:Neuroprotective Agents; D000077553:Edaravone",
"country": "England",
"delete": false,
"doi": "10.1136/svn-2018-000221",
"fulltext": "\n==== Front\nStroke Vasc NeurolStroke Vasc NeurolsvnbmjsvnStroke and Vascular Neurology2059-8696BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR svn-2018-00022110.1136/svn-2018-000221Original Article15061507Safety and efficacy of Edaravone Dexborneol versus edaravone for patients with acute ischaemic stroke: a phase II, multicentre, randomised, double-blind, multiple-dose, active-controlled clinical trial http://orcid.org/0000-0002-8320-218XXu Jie 12Wang Yilong 12http://orcid.org/0000-0003-4351-2877Wang Anxin 12Gao Zhiqiang 3Gao Xiaoping 4http://orcid.org/0000-0002-8490-9435Chen Huisheng 5Zhou Junshan 6Zhao Xingquan 12http://orcid.org/0000-0002-9976-2341Wang Yongjun 12\n1 \nDepartment of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China\n\n2 \nChina National Clinical Research Center for Neurological Diseases, Beijing, China\n\n3 \nDepartment of Neurology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China\n\n4 \nDepartment of Neurology, The First Affiliated Hospital of Hunan Normal University, Changsha, China\n\n5 \nDepartment of Neurology, General Hospital, PLA Shenyang Military Region, Shenyang, China\n\n6 \nDepartment of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China\nCorrespondence to Prof. Xingquan Zhao; zxq@vip.163.com and Professor Yongjun Wang; yongjunwang@ncrcnd.org.cn9 2019 22 4 2019 4 3 109 114 29 12 2018 20 2 2019 25 2 2019 © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.2019This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.Background\nEdaravone Dexborneol is a novel neuroprotective agent that comprised edaravone and (+)-borneol, a food additive with an anti-inflammatory effect in animal ischaemic stroke models. This study aims to assess the safety and efficacy of Edaravone Dexborneol compared with edaravone in treating patients with acute ischaemic stroke (AIS).\n\nMethods\nIn this multicentre, randomised, double-blind, multiple-dose, active-controlled, phase II clinical trial, patients with AIS within 48 hours after stroke onset were randomly assigned (1:1:1:1) to low-dose (12.5 mg), medium-dose (37.5 mg) or high-dose (62.5 mg) Edaravone Dexborneol groups, and an active control group with edaravone (30 mg) by 30 min intravenous infusion every 12 hours, for 14 consecutive days. The primary efficacy outcome was the proportion of modified Rankin Scale (mRS)score ≤1 at 90 days and National Institutes of Health Stroke Scale (NIHSS) score change from baseline to 14 days after randomisation. The safety outcome included any adverse event during 90 days after treatment.\n\nResults\nOf 385 patients included in the efficacy analysis, 94 were randomised to low-dose group, 97 to medium-dose group, 98 to high-dose group and 96 to the control group. No significant difference was observed among the four groups on mRS score (mRS ≤1, p=0.4054) at 90 days or NIHSS score change at 14 days (p=0.6799). However, a numerically higher percentage of patients with mRSscore ≤1 at 90 days in the medium-dose (69.39%) and high-dose (65.63%) groups was observed than in the control group (60.64%). No significant difference in severe adverse events was found among the four groups (p=0.3815).\n\nConclusions\nCompared with edaravone alone, Edaravone Dexborneol was safe and well tolerated at all doses, although no significant improvement in functional outcomes was observed at 90days.\n\nTrial registration number\nNCT01929096.\n\ncompound edaravoneischemic strokeneuroprotectionedaravoneSimcere Pharmaceutical Group supported the present studyspecial-featureunlockedspecial-featureeditors-choice\n==== Body\nIntroduction\nStroke is the leading cause of death and acquired adult disability in China and has significant economic burden.1 2 However, numerous neuroprotective agents have failed to show any benefit in the treatment of patients with acute ischaemic stroke (AIS), making the search for new treatments imperative.3 Edaravone is an effective free radical scavenger4 5 recommended for AIS treatment by Chinese and Japanese stroke care guidelines.6 7 Edaravone scavenges free radicals, such as hydroxyl free radical (·OH), nitric oxide free radicals (NO·) and peroxynitrite anion (ONOO−), sequentially relieves cerebral oedema, and inhibits delayed neuronal death.4 8 9 However, cerebral ischaemic injury is extremely complex and involves free radicals and inflammatory response. (+)-Borneol inhibits the production or expression of inflammation-related proteins and prevents brain injury or impairment. Edaravone Dexborneol is a novel neuroprotective agent that comprised edaravone and (+)-borneol in a 4:1 ratio10 that may have a better therapeutic effect.11 12 Complementarity exists between edaravone and (+)-2-campheol. Pharmacological research on the efficacy of edaravone combined with (+)-borneol showed that, compared with edaravone alone, Edaravone Dexborneol showed synergistic effect and longer treatment time, which indicated that the protective effect of Edaravone Dexborneol on cerebral ischaemic injury was better than that of the marketed edaravone. The present multicentre, randomised, active-controlled, double-blind study aims to verify the safety and efficacy of Edaravone Dexborneol in patients with AIS.\n\nMethods\nStudy design\nThis was designed as a phase II, multicentre, randomised, double-blind, multiple-dose, active-controlled clinical trial conducted at 28 centres in China between May 2013 and February 2015. Patients were assigned to treatment after they had given informed consent.\n\nPatient selection\nPatients who met the following inclusion criteria were eligible for enrolment: age 35–75 years, diagnosis of AIS, ability to start the study drug within 48 hours after stroke onset, a National Institutes of Health Stroke Scale (NIHSS) score between 4 and 24, and a total score of upper and lower limbs ≥2 on motor deficits.\n\nStudy intervention\nFor this trial, 400 cases were planned to be randomised into four groups: control group (edaravone injection, 30 mg/dose, once every 12 hours, continued for 14 days), low-dose group (Edaravone Dexborneol injection, 12.5 mg/dose [edaravone 10 mg, (+)-borneol 2.5 mg], one dose every 12 hours, continued for 14 days), medium-dose group (Edaravone Dexborneol injection, 37.5 mg/dose [edaravone 30 mg, (+)-borneol 7.5 mg], one dose every 12 hours, continued for 14 days) and high-dose group (Edaravone Dexborneol injection, 62.5 mg/dose [edaravone 50 mg, (+)-borneol 12.5 mg], one dose every 12 hours, continued for 14 days). Randomisation was stratified according to the interval between the stroke onset and enrolment (≤24 hours vs between 24 hours and 48 hours). The randomisation number was assigned by an automated randomisation system.\n\nEfficacy outcome assessment\nThe primary efficacy outcome was defined as the proportion of modified Rankin Scale (mRS) score ≤1 at 90 days and NIHSS score change from baseline to 14 days after randomisation; the secondary efficacy outcomes included (1) NIHSS score ≤1 at 14, 30 and 90 days after randomisation; (2) Barthel Index ≥95 at 14, 30 and 90 days after randomisation; (3) Montreal Cognitive Assessment score at 14, 30 and 90 days after randomisation; and (4) Stroke Impact Scale score at 90 days.\n\nSafety outcome assessment\nData for safety assessment included adverse reactions observed during the trial and changes in laboratory data before and after treatment. Severe adverse events (SAEs) included disability, prolonged hospitalisation and death.\n\nStatistical analysis\nBased on the principle of intention-to-treat analysis, all randomised patients were included in the safety analysis, and patients who had at least one valid assessment were included in the efficacy analysis. The last observation was used for patients who withdrew from the study and counted as lack of efficacy. Data for patients who withdrew because of safety or other reasons were included throughout the last visit and before the termination of the study. The baseline characteristics in four groups were compared. Proportions were used for categorical variables, and means with SD were used for continuous variables. Differences in efficacy and safety outcomes among four groups were analysed. Continuous data were analysed by analysis of variance or Kruskal-Wallis test, and categorical data examined by χ2 test or Fisher’s exact test. All tests were two-sided, and a p value of 0.05 was considered statistically significant. All statistical analyses were performed using SAS V.9.2 software.\n\nResults\nBaseline characteristics\nThe trial enrolled 400 patients: 98 in the control group, 102 in the low-dose group, 101 in the medium-dose group and 99 in the high-dose group. All received the treatment for the first time and included in the safety analysis. Fifteen patients lost to follow-up before the first assessment were excluded in the efficacy analysis. Of the remaining 385 patients, 303 completed the study according to the protocol (figure 1). Baseline demographic and clinical characteristics were well matched among the four groups analysed based on the efficacy data (table 1).\n\nFigure 1 Flow chart of the clinical trial.\n\nTable 1 Baseline characteristics (FAS)\n\nCharacteristics\tControl\tLow-dose\tMedium-dose\tHigh-dose\tP value\t\nn\t94\t97\t98\t96\t\t\nAge (years)\t59.71±8.33\t58.13±8.46\t59.11±8.95\t59.55±9.53\t0.6020\t\n ≤65, n (%)\t67 (71.28)\t75 (77.32)\t75 (76.53)\t68 (70.83)\t0.6264\t\n >65, n (%)\t29 (28.72)\t22 (22.68)\t23 (23.47)\t28 (29.17)\t\nGender, n (%)\t\t\t\t\t\t\n Male\t65 (69.15)\t67 (69.07)\t65 (66.33)\t64 (66.67)\t0.9606\t\n Female\t29 (30.85)\t30 (30.93)\t33 (33.67)\t32 (33.33)\t\nWeight (kg)\t\t\t\t\t\t\n Male\t71.95±10.33\t72.13±10.25\t74.45±9.77\t72.80±10.51\t0.4892\t\n Female\t62.50±7.99\t64.53±9.82\t61.48±11.81\t60.69±9.36\t0.4591\t\nHeight (cm)\t\t\t\t\t\t\n Male\t169.70±5.10\t170.33±5.42\t171.00±5.24\t170.94±4.28\t0.4246\t\n Female\t158.69±3.70\t159.60±4.75\t158.79±4.46\t158.09±5.21\t0.6397\t\nBMI (kg/m2)\t\t\t\t\t\t\n Male\t25.00±3.22\t24.82±3.15\t25.44±3.02\t24.88±3.18\t0.6763\t\n Female\t24.81±3.07\t25.31±3.56\t24.38±4.73\t24.22±3.12\t0.6578\t\nTemperature (°C)\t36.48±0.31\t36.46±0.27\t36.47±0.32\t36.50±0.32\t0.8285\t\nBreath (breaths per minute)\t18.32±1.57\t18.13±1.74\t18.34±1.51\t18.75±5.05\t0.4913\t\nHR (beats per minute)\t74.82±9.51\t72.59±10.14\t75.92±12.46\t74.22±10.21\t0.1707\t\nSBP (mm Hg)\t150.91±20.93\t150.61±24.83\t148.91±19.18\t149.46±19.59\t0.8891\t\nDBP (mm Hg)\t88.53±12.26\t88.70±13.11\t88.43±11.75\t88.55±12.84\t0.9987\t\nStroke history, n (%)\t25 (26.60)\t24 (24.74)\t25 (25.51)\t27 (28.13)\t0.9560\t\nFamily stroke history, n (%)\t9 (9.57)\t7 (7.22)\t14 (14.29)\t11 (11.46)\t0.6241\t\nHypertension, n (%)\t57 (60.64)\t64 (65.98)\t78 (79.59)\t65 (67.71)\t0.0315\t\nHyperlipidaemia, n (%)\t4 (4.26)\t11 (11.34)\t11 (11.22)\t8 (8.33)\t0.4435\t\nDiabetes, n (%)\t21 (22.34)\t26 (26.80)\t28 (28.57)\t24 (25.00)\t0.7887\t\nCardiac disease, n (%)\t16 (17.02)\t14 (14.43)\t19 (19.39)\t19 (19.79)\t0.7315\t\nSmoking, n (%)\t43 (45.74)\t47 (48.45)\t44 (44.90)\t41 (42.71)\t0.8842\t\nHeavy alcohol consumption, n (%)\t6 (6.38)\t10 (10.31)\t8 (8.16)\t7 (7.29)\t0.7981\t\nObesity, n (%)\t42 (45.16)\t45 (46.39)\t47 (47.96)\t42 (43.75)\t0.9449\t\nOther comorbidities, n (%)\t86 (91.49)\t92 (93.81)\t95 (96.94)\t90 (93.75)\t0.4396\t\nNIHSS score at baseline\t7.01±3.41\t7.23±3.12\t6.99±3.31\t6.75±2.85\t0.6723\t\nmRS before onset, n (%)\t\t\t\t\t\t\n 0\t81 (86.17)\t87 (89.69)\t91 (92.86)\t86 (89.58)\t0.5135\t\n 1\t13 (13.83)\t10 (10.31)\t7 (7.14)\t10 (10.42)\t\t\nTime since stroke onset (hours)\t27.57±11.75\t29.08±12.16\t27.50±12.11\t28.05±12.37\t0.7595\t\nBMI, body mass index; DBP, diastolic blood pressure; HR, heart rhythm; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale; SBP, systolic blood pressure.\n\nSafety analysis\nThe incidence of adverse reactions was 6.12%, 8.82%, 10.89% and 14.14% in the control, low-dose, medium-dose and high-dose groups, respectively. The details of adverse reactions are listed in online supplementary table 1. The severe adverse reactions leading to withdrawal were observed in 3 (3.06%), 2 (1.96%), 3 (2.97%) and 4 (4.04%) patients in the control, low-dose, medium-dose and high-dose groups, respectively. The major adverse reactions included pruritus, skin rash, acute liver injury and kidney injury. SAEs were observed in 10 (10.20%), 4 (3.92%), 6 (5.94%) and 7 (7.07%) patients in the control, low-dose, medium-dose and high-dose groups, respectively, and no significant difference was found (p=0.3815). Among a total of 29 SAEs, 2 events (severe liver and kidney damage) were related to Edaravone Dexborneol, both of which happened in one patient in the high-dose group. However, recovery was achieved after the treatment. Two patients in the edaravone control group and 0 patient in the Edaravone Dexborneol group died. These two deaths in the edaravone control group were considered as unrelated to the treatment, and the causes of death were worsening of stroke and septicaemia.\n\n10.1136/svn-2018-000221.supp1Supplementary file 1 \n\n\n\n Efficacy outcomes\nThe incidence of primary efficacy outcome (mRS scores of ≤1 after treatment at 90 days) in the control, low-dose, medium-dose and high-dose groups was 60.64%, 58.76%, 69.39% and 65.63%, respectively. No significant difference was observed (p=0.4054). However, the proportion of mRS score of ≤1 in medium-dose and high-dose groups had possible higher trend than in the control group (69.39% and 65.63% vs 60.64%; figure 2A). Moreover, no significant difference was seen among the four groups in terms of NIHSS score changes from baseline to 14 days after treatment (p=0.6799; figure 2B). The secondary efficacy outcomes in this trial are summarised in table 2. There were no significant differences among the four groups in terms of these secondary efficacy outcomes.\n\nFigure 2 Primary efficacy outcomes. (A) % of mRS score 0–1 at 90 days. (B) NIHSS score change from baseline to 14 days. mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale.\n\nTable 2 Secondary efficacy outcomes among the four groups\n\nVariables\tTime (days)\tControl \nn=94\tLow-dose \nn=97\tMedium-dose \nn=98\tHigh-dose \nn=96\tP value\t\nNIHSS score ≤1, n (%)\t14\t27 (28.72)\t20 (20.62)\t20 (20.41)\t21 (21.88)\t0.4975\t\n30\t32 (35.16)\t35 (36.46)\t36 (38.30)\t37 (38.95)\t0.9505\t\n90\t49 (54.44)\t49 (51.04)\t51 (54.26)\t54 (58.06)\t0.8180\t\nBI score ≥95, n (%)\t14\t40 (42.55)\t43 (44.79)\t41 (42.27)\t44 (45.83)\t0.9514\t\n30\t50 (54.35)\t48 (50.00)\t56 (59.57)\t58 (61.05)\t0.3994\t\n90\t66 (71.74)\t61 (63.54)\t68 (71.58)\t63 (67.02)\t0.5672\t\nMoCA, mean±SD\t14\t21.29±6.46\t20.54±6.35\t22.07±6.36\t20.69±7.20\t0.3325\t\n30\t23.31±5.75\t22.52±6.35\t23.00±6.34\t22.56±6.80\t0.8773\t\n90\t23.99±5.68\t23.67±5.37\t23.53±6.84\t22.56±6.80\t0.7897\t\nSIS, mean±SD\t90\t635.48±141.91\t618.50±152.51\t637.52±143.67\t623.68±159.71\t0.8230\t\nBI, Barthel Index; MoCA, Montreal Cognitive Assessment; NIHSS, National Institutes of Health Stroke Scale; SIS, Stroke Impact Scale.\n\nDiscussion\nIn this phase II, multicentre, randomised, double-blind, multiple-dose, active-controlled clinical trial, Edaravone Dexborneol at different doses was compared with edaravone alone for efficacy and safety. Our result showed that, compared with edaravone alone, Edaravone Dexborneol was safe and well tolerated at all doses, although no significant improvement in functional outcomes was observed.\n\nNeuroprotective drugs might extend the therapeutic time window after stroke for thrombolysis or thrombectomy therapy by delaying cell death and blocking reperfusion injury. Edaravone Dexborneol could provide as a new and effective treatment of stroke in the future.13 After onset of ischaemic stroke, several risk factors were associated with the damage process of neurons under ischaemia: energy failure, free radicals production, formation of neurotoxin, inflammatory responses and apoptosis.14 Although vascular recanalisation could effectively salvage reversible ischaemic tissue,15 the risk of reperfusion injury was high. Edaravone could limit vascular endothelial cell injury, brain oedema,16 17 tissue injury18 and delayed neuronal death, and consequently reduced neurological deficits.19 Additionally, as seen on sequential magnetic resonance spectroscopy, preservation of N-acetyl-aspartate, a neuron-specific amino acid, in the ischaemic brain of edaravone-treated patients has been reported.20 Edaravone Dexborneol is a novel neuroprotective agent indicated for AIS.10 It is a compound preparation comprising edaravone and (+)-borneol in a 4:1 ratio. The natural borneol consists of over 96% borneol that could inhibit the production or expression of inflammation-related proteins such as tumour necrosis factor-α (TNF-α), interleukin-1β, cyclo-oxygenase-2 and induced nitric oxide synthase (iNOS), and prevent brain injury or impairment.11 Borneol has been widely used to treat cerebrovascular disease, but is rarely used alone.21\n\n\nIn this trial, the major adverse reactions included pruritus, skin rash, acute liver injury and kidney injury. The adverse reactions of Edaravone Dexborneol seemed to show a dose-dependent relationship. It is worth noting that, among a total of 29 SAEs, 2 events (severe liver and kidney damage) were related to Edaravone Dexborneol, both of which happened in one patient in the high-dose group. The underlying pharmacological mechanisms remained unclear. In consideration of safety, high-dose Edaravone Dexborneol should not be recommended for further clinical investigation.\n\nAlthough no significant difference was found among the four groups in the primary efficacy outcome, proportions of the patients with mRS score of ≤1 at 90 days in the group treated with medium-dose (69.39%) or high-dose (65.63%) Edaravone Dexborneol were higher than in the group treated with edaravone (60.64%), and we found the efficacy of the medium-dose Edaravone Dexborneol was likely to be even better than the high-dose one. In combination with efficacy and safety data, a phase III clinical trial with the medium-dose edaravone group, with a dose of 37.5 mg/time (edaravone 30 mg, (+)-borneol 7.5 mg) is suggested.\n\nEdaravone Dexborneol can improve acute brain injury considerably in animal models of focal cerebral ischaemia (reperfused or permanent) and whole cerebral ischaemia reperfusion.22 No drug interaction in vivo between edaravone and (+)-borneol was observed from the preclinical pharmacokinetic study, including absorption, distribution, metabolism and excretion. Edaravone and (+)-borneol rapidly distributed in most tissues and excreted mainly from urine and bile in a conjunction form. Edaravone, (+)-borneol and Edaravone Dexborneol were not inhibitors or inducers of major CYP (Cytochrome P450 proteins) enzymes (online supplementary table 2). The risk of genetic and reproductive toxicity was not observed in the preclinical studies (online supplementary tables 3 and 4). The pathophysiological mechanism of cerebral ischaemic injury is complex, involving factors such as excitatory amino acids, calcium overload, free radicals, inflammatory response and apoptosis.18 Pharmacological intervention alone cannot affect this complex process effectively.9 Studies that engage multiple targets to improve ischaemic injury are ongoing.23–25 In theory, using two different agents to target different steps of ischaemic injury is likely superior to a single agent in preventing ischaemia.26\n\n\nEdaravone Dexborneol enhanced inhibition of iNOS and TNF-α expression and lower level of ONOO− in the ischaemic brain. It could contribute to the synergetic effect of edaravone and borneol in combination. However, this study has several limitations. First, since the study is a phase II study and the sample is small, we cannot make further explorations on the effect of Edaravone Dexborneol on each TOAST (Trial of Org 10 172 in Acute Stroke Treatment) type with stratification analysis, which will be done in the phase III study. Second, for ethical reasons, only a positive control group (edaravone group) was set up in the study and there was no placebo control group. Third, since no blood samples were collected from the patients in the study, we cannot measure the changes in inflammatory factors before and after medication, and inflammatory factors will be used as secondary indicators to analyse the anti-inflammatory effect of Edaravone Dexborneol.\n\nConclusion\nMedium-dose Edaravone Dexborneol was safe in this phase II, multicentre, randomised, double-blind, multiple-dose, active-controlled clinical trial. However, the efficacy still needs to be explored in a large trial. The medium-dose edaravone group (37.5 mg/time) (edaravone 30 mg, (+)-borneol 7.5 mg) will be the optimal dose for a phase III clinical trial.\n\nJX and YW contributed equally.\n\nContributors: YoW had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. JX and YiW contributed equally to this work. Study concept and design: YoW. Supplying patients: XZ, YiW, ZG, XG, HC and JZ. Drafting of the manuscript: JX and YiW. Critical revision of the manuscript for important intellectual content: XZ and YiW. Statistical analysis: AW. Study supervision: YoW.\n\nFunding: Simcere Pharmaceutical Group supported the present study.\n\nCompeting interests: None declared.\n\nEthics approval: The study was approved by the institutional review board of each study centre and was conducted in accordance with the principles of the Declaration of Helsinki.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n\nCorrection notice: This article has been corrected since it first published. The chemical name of the medicine ’compound edaravone‘ has been changed to ’edaravone dexborneol' throughout the article.\n\nPatient consent for publication: Parental/guardian consent obtained.\n==== Refs\nReferences\n1. \nMendis S \nPrevention and care of stroke in low- and middle-income countries; the need for a public health perspective . Int J Stroke 2010 ;5 :86 –91 . 10.1111/j.1747-4949.2010.00406.x \n20446942 \n2. \nGlobal Burden of Disease Study 2013 Collaborators . Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries,1990-2013: a systematic analysis for the Global Burden of Disease Study 2013 . Lancet 2015 ;386 :743 –800 . 10.1016/S0140-6736(15)60692-4 \n26063472 \n3. \nChamorro Á , Dirnagl U , Urra X , et al \nNeuroprotection in acute stroke: targeting excitotoxicity, oxidative and nitrosative stress, and inflammation . Lancet Neurol 2016 ;15 :869 –81 . 10.1016/S1474-4422(16)00114-9 \n27180033 \n4. \nEdaravone Acute Infarction Study Group . Effect of a novel free radical scavenger, edaravone (MCI-186), on acute brain infarction. Randomized, placebo-controlled, double-blind study at multicenters . Cerebrovasc Dis 2003 ;15 :222 –9 . 10.1159/000069318 \n12715790 \n5. \nWada T , Yasunaga H , Inokuchi R , et al \nEffects of edaravone on early outcomes in acute ischemic stroke patients treated with recombinant tissue plasminogen activator . J Neurol Sci 2014 ;345 :106 –11 . 10.1016/j.jns.2014.07.018 \n25085762 \n6. \nWang Y , Liu M , Pu C \n2014 Chinese guidelines for secondary prevention of ischemic stroke and transient ischemic attack . Int J Stroke 2017 ;12 :302 –20 . 10.1177/1747493017694391 \n28381199 \n7. \nShinohara Y , Yanagihara T , Abe K , et al \nII. Cerebral infarction/transient ischemic attack (TIA) . J Stroke Cerebrovasc Dis 2011 ;20 :S31 –S73 . 10.1016/j.jstrokecerebrovasdis.2011.05.004 \n21835356 \n8. \nCheng B , Guo Y , Li C , et al \nEdaravone protected PC12 cells against MPP(+)-cytoxicity via inhibiting oxidative stress and up-regulating heme oxygenase-1 expression . J Neurol Sci 2014 ;343 :115 –9 . 10.1016/j.jns.2014.05.051 \n24930399 \n9. \nZhang N , Komine-Kobayashi M , Tanaka R , et al \nEdaravone reduces early accumulation of oxidative products and sequential inflammatory responses after transient focal ischemia in mice brain . Stroke 2005 ;36 :2220 –5 . 10.1161/01.STR.0000182241.07096.06 \n16166574 \n10. \nWu HY , Tang Y , Gao LY , et al \nThe synergetic effect of edaravone and borneol in the rat model of ischemic stroke . Eur J Pharmacol 2014 ;740 :522 –31 . 10.1016/j.ejphar.2014.06.035 \n24975100 \n11. \nAlmeida JR , Souza GR , Silva JC , et al \nBorneol, a bicyclic monoterpene alcohol, reduces nociceptive behavior and inflammatory response in mice . ScientificWorldJournal 2013 ;2013 :1 –5 . 10.1155/2013/808460 \n\n12. \nYoshida H , Yanai H , Namiki Y , et al \nNeuroprotective effects of edaravone: a novel free radical scavenger in cerebrovascular injury . CNS Drug Rev 2006 ;12 :9 –20 . 10.1111/j.1527-3458.2006.00009.x \n16834755 \n13. \nBarinaga M \nFinding new drugs to treat stroke . Science 1996 ;272 :664 –6 .8614822 \n14. \nSchaller B , Graf R \nCerebral ischemia and reperfusion: the pathophysiologic concept as a basis for clinical therapy . J Cereb Blood Flow Metab 2004 ;24 :351 –71 . 10.1097/00004647-200404000-00001 \n15087705 \n15. \nLiu A , Fang H , Wei W , et al \nIschemic preconditioning protects against liver ischemia/reperfusion injury via heme oxygenase-1-mediated autophagy . Crit Care Med 2014 ;42 :e762 –e771 . 10.1097/CCM.0000000000000659 \n25402296 \n16. \nAbe K , Yuki S , Kogure K \nStrong attenuation of ischemic and postischemic brain edema in rats by a novel free radical scavenger . Stroke 1988 ;19 :480 –5 . 10.1161/01.STR.19.4.480 \n2834836 \n17. \nNishi H , Watanabe T , Sakurai H , et al \nEffect of MCI-186 on brain edema in rats . Stroke 1989 ;20 :1236 –40 . 10.1161/01.STR.20.9.1236 \n2505409 \n18. \nMizuno A , Umemura K , Nakashima M \nInhibitory effect of MCI-186, a free radical scavenger, on cerebral ischemia following rat middle cerebral artery occlusion . Gen Pharmacol 1998 ;30 :575 –8 . 10.1016/S0306-3623(97)00311-X \n9522178 \n19. \nOkabe TA , Kishimoto C , Shimada K , et al \nEffects of MCI-186 (edaravone), a novel free radical scavenger, upon experimental atherosclerosis in apolipoprotein E-deficient mice . Circ J 2006 ;70 :1216 –9 . 10.1253/circj.70.1216 \n16936439 \n20. \nHoukin K , Nakayama N , Kamada K , et al \nNeuroprotective effect of the free radical scavenger MCI-186 in patients with cerebral infarction: clinical evaluation using magnetic resonance imaging and spectroscopy . J Stroke Cerebrovasc Dis 1998 ;7 :315 –22 . 10.1016/S1052-3057(98)80049-9 \n17895107 \n21. \nXu P , Li Y , Du SY , Sy D , et al \nComparative pharmacokinetics of borneol in cerebral ischemia-reperfusion and sham-operated rats . J Zhejiang Univ Sci B 2014 ;15 :84 –91 . 10.1631/jzus.B1300141 \n24390748 \n22. \nNoor JI , Ueda Y , Ikeda T , et al \nEdaravone inhibits lipid peroxidation in neonatal hypoxic-ischemic rats: an in vivo microdialysis study . Neurosci Lett 2007 ;414 :5 –9 . 10.1016/j.neulet.2006.10.024 \n17280782 \n23. \nCho KH , Oh JK , Jang YS , et al \nCombination drug therapy using edaravone and Daio-Orengedoku-to after transient focal ischemia in rats . Methods Find Exp Clin Pharmacol 2008 ;30 :443 –50 . 10.1358/mf.2008.30.6.1254248 \n18850045 \n24. \nNonaka Y , Shimazawa M , Yoshimura S , et al \nCombination effects of normobaric hyperoxia and edaravone on focal cerebral ischemia-induced neuronal damage in mice . Neurosci Lett 2008 ;441 :224 –8 . 10.1016/j.neulet.2008.06.033 \n18577423 \n25. \nGao C , Li X , Li Y , et al \nPharmacokinetic interaction between puerarin and edaravone, and effect of borneol on the brain distribution kinetics of puerarin in rats . J Pharm Pharmacol 2010 ;62 :360 –7 . 10.1211/jpp.62.03.0011 \n20487220 \n26. \nPérez de la Ossa N , Dávalos A \nNeuroprotection in cerebral infarction: the opportunity of new studies . Cerebrovasc Dis 2007 ;24 Suppl 1 (Suppl 1 ):153 –6 . 10.1159/000107391 \n17971651\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2059-8696",
"issue": "4(3)",
"journal": "Stroke and vascular neurology",
"keywords": "compound edaravone; edaravone; ischemic stroke; neuroprotection",
"medline_ta": "Stroke Vasc Neurol",
"mesh_terms": "D000368:Aged; D002681:China; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D000077553:Edaravone; D005260:Female; D000085542:Functional Status; D006801:Humans; D007262:Infusions, Intravenous; D000083242:Ischemic Stroke; D008297:Male; D008875:Middle Aged; D018696:Neuroprotective Agents; D020127:Recovery of Function; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "101689996",
"other_id": null,
"pages": "109-114",
"pmc": null,
"pmid": "31709115",
"pubdate": "2019-09",
"publication_types": "D017427:Clinical Trial, Phase II; D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "16166574;26063472;17280782;17895107;28381199;25085762;24390748;23710149;24930399;16936439;21835356;2834836;20446942;16834755;17971651;18577423;2505409;25402296;24975100;27180033;12715790;9522178;18850045;15087705;8614822;20487220",
"title": "Safety and efficacy of Edaravone Dexborneol versus edaravone for patients with acute ischaemic stroke: a phase II, multicentre, randomised, double-blind, multiple-dose, active-controlled clinical trial.",
"title_normalized": "safety and efficacy of edaravone dexborneol versus edaravone for patients with acute ischaemic stroke a phase ii multicentre randomised double blind multiple dose active controlled clinical trial"
} | [
{
"companynumb": "CN-MTPC-MTPC2019-0075013",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EDARAVONE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nPropylthiouracil (PTU) is a synthetic antithyroid drug that can induce ANCA-associated vasculitis.\n\n\nMETHODS\nA 27-year-old woman diagnosed with Graves' disease was on PTU for the past 10 years. She developed purpuric lesions of the legs and on the tip of the nose diagnosed as vasculitis. ANCAs were positive, with anti-MPO and anti-PR3 on blood ELISA. After discontinuation of PTU, she was able to fully recover.\n\n\nCONCLUSIONS\nAll synthetic antithyroid drugs can induce ANCA-associated vasculitis, more often PTU. In most cases, antibodies are directed against MPO. Dual anti-MPO and anti-PR3 positivity is possible, but rare. The mechanism could be through an accumulation of PTU in neutrophils, altering the structure of MPO and making it immunogenic. PTU can also induce ANCA-free or lupus vasculitis, maculopapular rashes or urticaria. Many other drugs can induce ANCA-associated vasculitis.",
"affiliations": "Service de dermatologie, hôpital Henri-Mondor, AP-HP, 51, avenue du Maréchal-de-Lattre-de-Tassigny, 94000 Créteil, France.;Service de dermatologie, hôpital Henri-Mondor, AP-HP, 51, avenue du Maréchal-de-Lattre-de-Tassigny, 94000 Créteil, France.;Service d'endocrinologie, hôpital Henri-Mondor, AP-HP, Créteil, France.;Service de médecine interne, hôpital Henri-Mondor, AP-HP, Créteil, France.;Service d'anatomopathologie, hôpital Henri-Mondor, AP-HP, Créteil, France.;Centre régional de pharmacovigilance, hôpital Henri Mondor, AP-HP, Créteil, France.;Service de dermatologie, hôpital Henri-Mondor, AP-HP, 51, avenue du Maréchal-de-Lattre-de-Tassigny, 94000 Créteil, France.;Service de médecine nucléaire, hôpital Henri-Mondor, AP-HP, Créteil, France.;Service de dermatologie, hôpital Henri-Mondor, AP-HP, 51, avenue du Maréchal-de-Lattre-de-Tassigny, 94000 Créteil, France.;Laboratoire d'immunologie, hôpital Henri-Mondor, AP-HP, Créteil, France.;Service de dermatologie, hôpital Henri-Mondor, AP-HP, 51, avenue du Maréchal-de-Lattre-de-Tassigny, 94000 Créteil, France; UPEC, université Paris Est Créteil EpidermE, Créteil, France. Electronic address: saskia.oro@aphp.fr.",
"authors": "Giraud-Kerleroux|L|L|;Bernigaud|C|C|;Droumaguet|C|C|;Thai|L H|LH|;Marciano-Fellous|L|L|;Thomas|L|L|;Charpentier|C|C|;Helbert-Davidson|S|S|;Fardet|L|L|;Hüe|S|S|;Ingen-Housz-Oro|S|S|",
"chemical_list": "D019268:Antibodies, Antineutrophil Cytoplasmic; D013956:Antithyroid Agents; D011441:Propylthiouracil",
"country": "France",
"delete": false,
"doi": "10.1016/j.revmed.2021.03.330",
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"issn_linking": "0248-8663",
"issue": "42(7)",
"journal": "La Revue de medecine interne",
"keywords": "ANCA; Anti-thyroid drugs; Anti-thyroïdiens de synthèse; Hyperthyroidism; Hyperthyroïdie; Propylthiouracil; Propylthiouracile; Vascularite; Vasculitis",
"medline_ta": "Rev Med Interne",
"mesh_terms": "D000328:Adult; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; D019268:Antibodies, Antineutrophil Cytoplasmic; D013956:Antithyroid Agents; D005260:Female; D006801:Humans; D006980:Hyperthyroidism; D011441:Propylthiouracil; D011693:Purpura",
"nlm_unique_id": "8101383",
"other_id": null,
"pages": "509-512",
"pmc": null,
"pmid": "33846035",
"pubdate": "2021-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Purpura in a young woman with hyperthyroidism.",
"title_normalized": "purpura in a young woman with hyperthyroidism"
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"abstract": "Morphine is one of the many, and\npharmacologically most important,\nopium poppy alkaloid (Papaver somniferum).\nA poppy plant consists of a\nlot of alkaloids. Most of them are morphine,\ncodeine, narcotine, papaverine,\nthebaine, narceine and narcotoline.\nMost of the alkaloid is in the poppy\nmilk - opium..It is a dried and properly\nprocessed juice with precut immature\npoppy-heads. It induces euphoria,\nsomnolence, has an analgesic effect.\nIn the study was presented a 24-yearold\npatient who was admitted to the Department\nof Toxicology and Cardiology\nbecause of suspicion of poisoning with\nunknown drugs. In retrospect, it turned\nout that he was poisoned brew with 5\nkg of poppy and dextromethorphan.\nIn the past, he drank alcohol heavily,\nused legal highs, amphetamine, methamphetamine,\nopiates, diazepam, cannabinoids.\nAt the time of admission to\nthe department, his general condition\nwas severe, he was unconscious, with\nperiodic breathing disorders, pinpoint\npupils. In the laboratory: opiates>2000\nng/ml, other toxicological tests were\nnegative. On the subsequent days of\nhis stay he remained in a generally\nvery severe condition; he was unconscious.\nSome electrolyte disorders\nwere observed, as well as characteristics\nof developing rhabdomyolysis.\nWith the applied intensive medical\ntherapy, a gradual improvement of his\ngeneral condition was achieved. Due\nto quadriplegia on the 30th day of the\nhospitalization, the patient was transferred\nto the Department of Neurology\nfor further treatment.",
"affiliations": null,
"authors": "Kwiecień-Obara|Ewelina|E|;Szponar|Jaroslaw|J|;Krajewska|Anna|A|;Witkowska|Agnieszka|A|;Radoniewicz|Anna|A|;Szponar|Magda|M|",
"chemical_list": "D003915:Dextromethorphan; D009020:Morphine",
"country": "Poland",
"delete": false,
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"issn_linking": "0033-2240",
"issue": "73(8)",
"journal": "Przeglad lekarski",
"keywords": null,
"medline_ta": "Przegl Lek",
"mesh_terms": "D003915:Dextromethorphan; D006801:Humans; D008297:Male; D009020:Morphine; D010207:Papaver; D011041:Poisoning; D012206:Rhabdomyolysis; D055815:Young Adult",
"nlm_unique_id": "19840720R",
"other_id": null,
"pages": "596-8",
"pmc": null,
"pmid": "29677437",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Morphine (obtained from poppy seeds) and dextrometorfan poisoning– a case report.",
"title_normalized": "morphine obtained from poppy seeds and dextrometorfan poisoning a case report"
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"abstract": "Malignant lymphoma is known to cause various types of arrhythmia, including ventricular fibrillation. However, radiofrequency catheter ablation of ventricular fibrillation associated with malignant lymphoma has never been reported. We describe the case of a 53-year-old man with refractory ventricular fibrillation that was associated with malignant lymphoma. Electrophysiological testing revealed that a Purkinje potential appeared before ventricular contraction at the tumour site. We successfully treated the ventricular fibrillation with radiofrequency catheter ablation, using the Purkinje potential as an indicator. Physicians should consider this treatment if ventricular fibrillation cannot be controlled using other strategies.",
"affiliations": "Department of Cardiology, Seirei Hamamatsu General Hospital, Hamamatsu, Shizuoka, Japan.;Department of Cardiology, Seirei Hamamatsu General Hospital, Hamamatsu, Shizuoka, Japan.;Department of Cardiology, Seirei Hamamatsu General Hospital, Hamamatsu, Shizuoka, Japan.",
"authors": "Nakabayashi|Keisuke|K|;Sugiura|Ryo|R|;Oka|Toshiaki|T|",
"chemical_list": null,
"country": "England",
"delete": false,
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"issn_linking": "1757-790X",
"issue": "2015()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D017115:Catheter Ablation; D004562:Electrocardiography; D017809:Fatal Outcome; D006338:Heart Neoplasms; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008875:Middle Aged; D011690:Purkinje Fibers; D014693:Ventricular Fibrillation; D054088:Ventricular Septum",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "26040826",
"pubdate": "2015-06-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11879868;10500048;25309694;11028168;11428484;12325461;21091730;12186801;23743140",
"title": "Catheter ablation targeting Purkinje potentials controlled ventricular fibrillation in a patient with a malignant lymphoma occurring in the ventricular septum.",
"title_normalized": "catheter ablation targeting purkinje potentials controlled ventricular fibrillation in a patient with a malignant lymphoma occurring in the ventricular septum"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2017RR-134524",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
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"abstract": "BACKGROUND\nAcute thrombosis of a transplanted renal artery is a serious vascular complication following renal allograft transplantation, which usually occurs within the first month after transplantation and often results in graft loss. It rarely occurs beyond the first month, except in a rejected kidney or in a kidney with high-grade transplant renal artery stenosis.\n\n\nRESULTS\nA 65-year-old male with a history of type 2 diabetes mellitus, hypertension, pulmonary tuberculosis, and end-stage renal disease was previously treated with hemodialysis (HD). He received a kidney transplant and had a well-functioning graft for 2 years. He presented to our emergency department with gastric ulcer bleeding and received treatment involving an endoscopic submucosal epinephrine injection, a proton pump inhibitor, and blood transfusions. Nine days later, he complained of sudden lower abdominal pain and had acute anuric kidney failure. Renal ultrasonography revealed an absence of blood flow to the allograft kidney. Renal artery angiogram demonstrated complete occlusion of the transplanted renal artery. After thrombectomy and percutaneous transluminal angioplasty (PTA) with stent placement, 60% stenosis of the proximal renal artery with distal perfusion was noted. However, his graft function did not improve, and he received HD again. Histopathology of the transplanted kidney revealed ischemic tubular nephropathy with focal infarction without rejection.\n\n\nCONCLUSIONS\nThis is the first case of acute thrombosis of the transplanted renal artery following gastric ulcer bleeding in a patient with a long-term well-functioning graft kidney.",
"affiliations": "Division of Nephrology, Department of Internal Medicine, Shin-Kong Wu Ho-Su Memorial Hospital Institute of Clinical Medicine, National Yang-Ming University, Taipei Schoolof Medicine, Fu-Jen Catholic University, New Taipei City Division of Cardiology, Department of Internal Medicine, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.",
"authors": "Wu|Chung-Kuan|CK|;Leu|Jyh-Gang|JG|;Wei|Cheng-Chun|CC|;Hsieh|Shih-Chung|SC|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000004301",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 2747270510.1097/MD.0000000000004301043015200Research ArticleClinical Case ReportAcute thrombosis of a transplanted renal artery after gastric ulcer bleeding in a patient with a long-term well-functioning renal allograft A case report and literature reviewWu Chung-Kuan MDabLeu Jyh-Gang MD, PhDacWei Cheng-Chun MDdHsieh Shih-Chung MDa∗Ichii. Hirohito a Division of Nephrology, Department of Internal Medicine, Shin-Kong Wu Ho-Su Memorial Hospitalb Institute of Clinical Medicine, National Yang-Ming University, Taipeic Schoolof Medicine, Fu-Jen Catholic University, New Taipei Cityd Division of Cardiology, Department of Internal Medicine, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.∗ Correspondence: Shih-Chung Hsieh, Division of Nephrology, Department of Internal Medicine, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan, 95, Wen Chang Rd., Shih Lin District, Taipei 11101, Taiwan (e-mail: m008533@ms.skh.org.tw).7 2016 29 7 2016 95 30 e430118 12 2015 23 4 2016 28 6 2016 Copyright © 2016 the Author(s). Published by Wolters Kluwer Health, Inc. All rights reserved.2016This is an open access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0, where it is permissible to download, share and reproduce the work in any medium, provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0Abstract\nBackground:\nAcute thrombosis of a transplanted renal artery is a serious vascular complication following renal allograft transplantation, which usually occurs within the first month after transplantation and often results in graft loss. It rarely occurs beyond the first month, except in a rejected kidney or in a kidney with high-grade transplant renal artery stenosis.\n\nResult:\nA 65-year-old male with a history of type 2 diabetes mellitus, hypertension, pulmonary tuberculosis, and end-stage renal disease was previously treated with hemodialysis (HD). He received a kidney transplant and had a well-functioning graft for 2 years. He presented to our emergency department with gastric ulcer bleeding and received treatment involving an endoscopic submucosal epinephrine injection, a proton pump inhibitor, and blood transfusions. Nine days later, he complained of sudden lower abdominal pain and had acute anuric kidney failure. Renal ultrasonography revealed an absence of blood flow to the allograft kidney. Renal artery angiogram demonstrated complete occlusion of the transplanted renal artery. After thrombectomy and percutaneous transluminal angioplasty (PTA) with stent placement, 60% stenosis of the proximal renal artery with distal perfusion was noted. However, his graft function did not improve, and he received HD again. Histopathology of the transplanted kidney revealed ischemic tubular nephropathy with focal infarction without rejection.\n\nConclusion:\nThis is the first case of acute thrombosis of the transplanted renal artery following gastric ulcer bleeding in a patient with a long-term well-functioning graft kidney.\n\nKeywords\nacute transplant renal artery thrombosisgastric ulcer bleedingrenal allograft thrombosisOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nArterial thrombosis in a transplanted kidney is a serious complication that often results in graft loss.[1] It typically occurs within the first month following transplantation, and more than 90% of cases occur within the first year.[2,3] The incidence of transplant renal artery thrombosis ranges between 0.2% and 3.5%. It is associated with technical surgical problems such as vessel kinking, torsion, and intimal injuries, drugs such as cyclosporine and orthoclone OKT3, hypercoagulable states, and hyperacute and acute rejection.[1,2,4–7] Beyond the first month after transplantation, transplant renal artery thrombosis rarely occurs, except in a rejected kidney or in a kidney with high-grade arterial stenosis.\n\nHere, we report the case of a patient with a long-term well-functioning renal allograft who suffered from acute graft loss because of transplant renal artery thrombosis after gastric ulcer bleeding.\n\n2 Case report\nA 65-year-old male with type 2 diabetes mellitus and hypertension had a history of pulmonary tuberculosis and end-stage renal disease. He had been on hemodialysis (HD) for 6 years before receiving a deceased donor kidney transplant. The transplanted renal artery was anastomized end-to-side to the recipient's external iliac artery. His graft function continued functioning appropriately under immunosuppression therapy for 2 years. His serum creatinine and tacrolimus levels were 0.9 mg/dL (reference range, 0.5–1.3 mg/dL) and 9.4 ng/mL (reference range, 5–20 ng/mL), respectively, in the half-year before admission. Type 2 diabetes mellitus and hypertension were in control, and his past medical regimen included gliquidone, barnidipine, carvedilol, and irbesartan.\n\nHe visited our emergency department because of tarry stool for 1 day. Physical examination revealed a blood pressure of 120/55 mm Hg, pulse rate of 88 beats/min, and temperature of 36.2°C. Hemogram revealed a hematocrit (Hct) of 20.3% (reference range, 35–48%), leukocyte count of 6.1 × 103/μL (reference range, 3.8–10 × 103/μL), and platelet count of 1.82 × 105/μL (reference range, 1.4–4.5 × 105/μL). Prothrombin time and activated partial thromboplastin time were 12 (range, 9.4–12.5 seconds) and 32 seconds (range, 26–38 seconds), respectively. Biochemistry assay revealed blood urea nitrogen (BUN) and serum creatinine levels of 36 (range, 7–25 mg/dL) and 1.3 mg/dL, respectively. Panendoscopy revealed a huge gastric ulcer with active bleeding, and 28 mL of diluted epinephrine (1:10,000) was injected locally. He was treated with proton pump inhibitors and transfused with 4 packed red blood units. He was hospitalized thereafter.\n\nOn hospital day 1, follow-up panendoscopy showed a giant ulcer 3 cm in diameter with little fresh blood oozing in the antrum; 16 mL of diluted epinephrine was injected locally, and 1 metallic clip was applied. After treatment, the Hct levels increased from 20.3% to 27.2%, and BUN and serum creatinine levels were 31 and 0.9 mg/dL, respectively. On hospital day 4, Hct increased to 31%.\n\nOn hospital day 9, he complained of sudden onset of lower abdominal pain followed by anuria and intermittent tarry stool. BUN and serum creatinine levels were 23 and 1.9 mg/dL, respectively, on hospital day 10, and they were 29 and 3.1 mg/dL, respectively, on hospital day 11. During this period, he had been anuric even after diuretic treatment. His tacrolimus level was 15.0 ng/mL. Renal duplex ultrasonography detected an absence of blood flow to the allograft kidney. Renal artery angiogram revealed complete occlusion of the transplant artery and no distal perfusion. After thrombectomy, 60% stenosis of the orifice of the transplanted renal artery was observed. Distal flow was subsequently detected after percutaneous transluminal angioplasty (PTA) with stent placement (Fig. 1).\n\nFigure 1 Angiogram of the transplanted renal artery. (A) Thrombus in the anastomosis of the transplanted renal artery and external iliac artery (arrow), and complete occlusion of the transplanted renal artery (arrowheads) before thrombectomy. (B) Significant (60%) stenosis of the proximal transplant renal artery (arrow) after thrombectomy, and still thrombus in the distal transplant renal artery (arrow). (C) Perfusion of the transplanted renal artery after percutaneous transluminal angioplasty with stent placement.\n\nAfter treatment, the daily urine output was 30 mL. BUN and serum creatinine levels increased to 40 and 4.7 mg/dL, respectively, on hospital day 12 and to 64 and 7.6 mg/dL, respectively, on hospital day 13. Other laboratory data revealed anticardiolipin concentration of 4.1 (range: 0–11) μL/mL and negative lupus anticoagulant. Histopathological examination of the transplanted kidney on hospital day 16 showed ischemic tubular nephropathy with focal infarction (Fig. 2) without antibody-mediated and T-cell mediated rejection. He returned to chronic HD subsequently.\n\nFigure 2 Histopathology of the transplanted kidney. (A) Coagulative necrosis of the glomerulus. (B) Ischemic necrosis of tubules.\n\n3 Discussion\nAcute thrombosis of a transplanted renal artery beyond the first month after transplantation is distinctly uncommon, except in a rejected kidney or in a kidney with high-grade arterial stenosis. The histology of the transplanted kidney in our patient demonstrated ischemic tubular nephropathy with coagulative necrosis without rejection. In addition to no signs of acute rejection, our patient did not interrupt his immunosuppressive therapy because acute rejection usually develops in patients discontinuing immunosuppressive therapy.\n\nAn end-to-end anastomosis of the transplanted renal artery to the internal iliac artery and end-to-side anastomosis of the transplanted renal artery to the external iliac artery are the most common techniques for arterial anastomosis in kidney transplantation. The end-to-end anastomosis involves a higher incidence of stenosis compared with end-to-side anastomosis, although the procedure is easier and faster to perform and does not compromise circulation to the leg.[8] Furthermore, more than 75% stenosis of the transplanted renal artery is called high-grade arterial stenosis.[9] Here, the renal artery was anastomized end-to-side to the patient's external iliac artery. After thrombectomy, angiogram revealed 60% stenosis of the proximal transplant renal artery. These findings indicate that high-grade transplant renal arterial stenosis is not the etiology of transplant renal artery thrombosis.\n\nTwo case studies have reported that patients with long-standing renal transplant developed acute transplant renal artery thrombosis because of late hemolytic uremic syndrome (HUS)[10] and had increased levels of antiphospholipid antibodies.[11] A study on a patient with HUS revealed classic findings of renal failure, hemolytic anemia, schistocytes, and thrombocytopenia. Cyclosporin[12] or tacrolimus-associated HUS[13] following renal transplantation has been reported. Increased incidence of acute thrombosis of the transplanted renal artery is also associated with increased use of cyclosporin. The underlying mechanism for this may be the effect of this drug on endothelial cells, thus minimizing prostacyclin production and predisposing a patient to thrombosis. Our patient did not have thrombocytopenia, and Hct levels were maintained at approximately 27.2% to 31% before acute thrombosis of the transplanted renal artery. In addition, our patient did not receive cyclosporin treatment, and the tacrolimus dosage was adjusted according to the serum tacrolimus level. HUS seemed unlikely; therefore, we did not perform blood smear to confirm schistocytes.\n\nAntiphospholipid syndrome (APS), which is diagnosed on the basis of the presence of antiphospholipid antibodies, is an acquired disorder associated with vascular thrombosis.[14] The most commonly known antiphospholipid antibodies are the lupus anticoagulant and anticardiolipin antibody. Our patient was negative for lupus anticoagulant and IgM anticardiolipin antibody. Moreover, our patient had no history of an autoimmune disorder.\n\nExcept for HUS and APS, 4 studies have reported acute thrombosis in patients with long-standing renal transplant. In 2 of these reported cases, the event was associated with significant medical problems such as myocardial infarction and sepsis.[15,16] In the third case of acute transplant renal artery thrombosis, the patient had severe hypertension.[17] In the fourth case, the patient developed acute transplant renal artery thrombosis following hip surgery.[8] We did not encounter the aforementioned situations in our patient.\n\nHowever, risk factors for arterial thrombosis are not limited to antiphospholipid antibodies and lupus anticoagulants. Other hypercoagulable states include factor V Leiden mutation,[18] antithrombin deficiency,[19] and methylene tetrahydrofolate reductase mutation and hyperhomocysteinemia.[20] Furthermore, infectious and inflammatory states such as polyarteritis nodosa,[21] Takayasu arteritis,[22] and Behcet disease[23] are associated with renal artery thrombosis. These diseases might still possibly endanger acute thrombosis of a transplanted renal artery; hence, careful evaluation and screening of the aforementioned diseases should be required. Our patient did not present any cutaneous or musculoskeletal joint symptoms, and infectious and inflammatory states seemed unlikely. However, we did not perform an activated protein C resistance test or measure for antithrombin and total homocysteine levels in our patient.\n\nOne of the pathogenic mechanisms in our patient may be anemia, engendered by bleeding, that enhanced thrombosis because studies have reported a relationship between bleeding and cerebral infarction onset.[24,25] Hypercatecholaminemia caused by the systemic absorption of submucosal epinephrine injected for gastric ulcer bleeding and acute stress may be another pathogenic mechanism in our patient that may have resulted in thrombosis through vasoconstriction and platelet aggregation.[26] The patient had a history of hypertension, diabetes mellitus, and kidney disease, which indicated a high risk of a cardiovascular event. However, he was not taking acetylsalicylic acid. This event could be attributed to thrombosis formation of atherosclerotic lesions and plaque rupture.\n\nThe timing of diagnosis as well as the method of treatment are critical for renal infarction; therefore, previously reported cases of transplanted renal artery thrombosis, medical problems, timing of diagnosis, methods of treatment, and outcomes are reviewed, and are tabulated in Table 1. Graft thrombosis treatment is generally unsatisfactory, and only few cases were effectively rescued by surgical revascularization or intraarterial thrombolytic therapy.[27]\n\nTable 1 Review of previous and present cases with late transplant renal artery thrombosis.\n\nIn summary, we report the first case of a patient with a long-term well-functioning renal allograft who suffered from acute thrombosis of the renal transplant artery after gastric ulcer bleeding.\n\nAcknowledgment\nWe thank our patient for contributing clinical data to this report.\n\nAbbreviations: APS = antiphospholipid syndrome, BUN = blood urea nitrogen, Hct = hematocrit, HD = hemodialysis, HUS = hemolytic uremic syndrome, PTA = percutaneous transluminal angioplasty.\n\nEthical statement: Ethical approval was not necessary for this study because our case study was focused on the retrospective observation of a patient's hospital course. Informed consent was obtained from the patient regarding the reporting and publication of this case report.\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n1 Bakir N Sluiter WJ Ploeg RJ \nPrimary renal graft thrombosis . Nephrol Dial Transplant \n1996 ; 11 :140 –147 .\n2 Penny MJ Nankivell BJ Disney AP \nRenal graft thrombosis. A survey of 134 consecutive cases . Transplantation \n1994 ; 58 :565 –569 .8091483 \n3 Kobayashi K Censullo ML Rossman LL \nInterventional radiologic management of renal transplant dysfunction: indications, limitations, and technical considerations . Radiographics \n2007 ; 27 :1109 –1130 .17620470 \n4 Akbar SA Jafri SZ Amendola MA \nComplications of renal transplantation . Radiographics \n2005 ; 25 :1335 –1356 .16160115 \n5 Palleschi J Novick AC Braun WE \nVascular complications of renal transplantation . Urology \n1980 ; 16 :61 –67 .6994326 \n6 Abramowicz D Pradier O Marchant A \nInduction of thromboses within renal grafts by high-dose prophylactic OKT3 . Lancet \n1992 ; 339 :777 –778 .1347805 \n7 Morrissey PE Ramirez PJ Gohh RY \nManagement of thrombophilia in renal transplant patients . Am J Transplant \n2002 ; 2 :872 –876 .12392294 \n8 Groggel GC \nAcute thrombosis of the renal transplant artery: a case report and review of the literature . Clin Nephrol \n1991 ; 36 :42 –45 .1889150 \n9 Buturovic-Ponikvar J \nRenal transplant artery stenosis . Nephrol Dial Transplant \n2003 ; 18 \nsuppl 5 :v74 –v77 .12817078 \n10 Kiykim AA Ozer C Yildiz A \nDevelopment of transplant renal artery thrombosis and signs of haemolytic-uraemic syndrome following the change from cyclosporin to tacrolimus in a renal transplant patient . Nephrol Dial Transplant \n2004 ; 19 :2653 –2656 .15388824 \n11 Karassa FB Avdikou K Pappas P \nLate renal transplant arterial thrombosis in a patient with systemic lupus erythematosus and antiphospholipid syndrome . Nephrol Dial Transplant \n1999 ; 14 :472 –474 .10069218 \n12 Bren AF Kandus A Buturovic J \nCyclosporine-related hemolytic-uremic syndrome in kidney graft recipients: clinical and histomorphologic evaluation . Transplant Proc \n1998 ; 30 :1201 –1203 .9636487 \n13 Neto P Lopes K Macario F \nDe novo tacrolimus-associated hemolytic uremic syndrome after renal transplantation—case report . Nefrologia \n2013 ; 33 :152 –154 .23364650 \n14 Giannakopoulos B Krilis SA \nThe pathogenesis of the antiphospholipid syndrome . N Engl J Med \n2013 ; 368 :1033 –1044 .23484830 \n15 Swanson DA Sullivan MJ \nThromboendarterectomy for anuria 4 1/2 years post-renal transplant: a case report . J Urol \n1976 ; 116 :799 –801 .137327 \n16 Lee HM Mendez-Picon G Pierce JC \nRenal artery occlusion in transplant recipients . Am Surg \n1977 ; 43 :186 –192 .320927 \n17 Nerstrom B Ladefoged J Lund F \nVascular complications in 155 consecutive kidney transplantations . Scand J Urol Nephrol \n1972 ; 6 \nsuppl 15 :65 –74 .\n18 Klein O Bernheim J Strahilevitz J \nRenal colic in a patient with anti-phospholipid antibodies and factor V Leiden mutation . Nephrol Dial Transplant \n1999 ; 14 :2502 –2504 .10528686 \n19 Miura K Takahashi T Takahashi I \nRenovascular hypertension due to antithrombin deficiency in childhood . Pediatr Nephrol \n2004 ; 19 :1294 –1296 .15338392 \n20 Queffeulou G Michel C Vrtovsnik F \nHyperhomocysteinemia, low folate status, homozygous C677T mutation of the methylene tetrahydrofolate reductase and renal arterial thrombosis . Clin Nephrol \n2002 ; 57 :158 –162 .11863127 \n21 Templeton PA Pais SO \nRenal artery occlusion in PAN . Radiology \n1985 ; 156 :308 .2861623 \n22 Teoh MK \nTakayasu's arteritis with renovascular hypertension: results of surgical treatment . Cardiovasc Surg \n1999 ; 7 :626 –632 .10519671 \n23 Akpolat T Akkoyunlu M Akpolat I \nRenal Behcet's disease: a cumulative analysis . Semin Arthritis Rheum \n2002 ; 31 :317 –337 .11965596 \n24 Kim JS Kang SY \nBleeding and subsequent anemia: a precipitant for cerebral infarction . Eur Neurol \n2000 ; 43 :201 –208 .10828649 \n25 Takaoka M Matsusaka M Ishikawa K \nMultiple border-zone infarcts after hemorrhagic shock in trauma victims: three case reports . J Trauma \n2004 ; 56 :1152 –1155 .15179265 \n26 Birk AV Leno E Robertson HD \nInteraction between ATP and catecholamines in stimulation of platelet aggregation . Am J Physiol Heart Circ Physiol \n2003 ; 284 :H619 –H625 .12388296 \n27 Ponticelli C Moia M Montagnino G \nRenal allograft thrombosis . Nephrol Dial Transplant \n2009 ; 24 :1388 –1393 .19182239\n\n",
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"mesh_terms": "D000208:Acute Disease; D000368:Aged; D064591:Allografts; D000792:Angiography; D017130:Angioplasty; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D010438:Peptic Ulcer Hemorrhage; D012077:Renal Artery; D006435:Renal Dialysis; D015607:Stents; D017131:Thrombectomy; D013927:Thrombosis",
"nlm_unique_id": "2985248R",
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"pages": "e4301",
"pmc": null,
"pmid": "27472705",
"pubdate": "2016-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "17620470;10828649;320927;12392294;15179265;6994326;10519671;11863127;15338392;10069218;8091483;23364650;2861623;8649623;16160115;23484830;4566261;1347805;137327;11965596;1889150;10528686;12388296;9636487;19182239;15388824;12817078",
"title": "Acute thrombosis of a transplanted renal artery after gastric ulcer bleeding in a patient with a long-term well-functioning renal allograft: A case report and literature review.",
"title_normalized": "acute thrombosis of a transplanted renal artery after gastric ulcer bleeding in a patient with a long term well functioning renal allograft a case report and literature review"
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"abstract": "Fingolimod is an oral sphingosine-1-phosphate (S1P) receptor modulator and the first oral therapy for relapsing-remitting multiple sclerosis. Its use has been complicated by a low rate of cystoid macular edema usually in the first 3 months after commencement of the medication. We report the case of a 34-year-old male with relapsing-remitting multiple sclerosis, who developed acute anterior uveitis on day 5 of fingolimod treatment. He responded to appropriate treatment and cessation of drug, but developed low-grade chronic anterior uveitis without cystoid macular edema. We discuss possible mechanisms of uveitis onset in this group of patients. Urgent ophthalmological review is recommended for patients receiving fingolimod therapy who develop a red, painful eye, which may occur within 5 days of fingolimod treatment initiation.",
"affiliations": "Cabrini Medical Centre, Malvern, VIC, Australia; Melbourne Health, Parkville, VIC, Australia; Department of Surgery, University of Melbourne, Parkville, VIC, Australia; Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.;National Healthcare Group Eye Institute, Tan Tock Seng Hospital, Singapore, Singapore.;Cabrini Medical Centre, Malvern, VIC, Australia; Melbourne Health, Parkville, VIC, Australia.",
"authors": "Mack|Heather Gwen|HG|;Tien|Melissa Chih-Hui|MC|;White|Owen Bruce|OB|",
"chemical_list": null,
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"doi": "10.1159/000453392",
"fulltext": "\n==== Front\nCase Rep OphthalmolCase Rep OphthalmolCOPCase Reports in Ophthalmology1663-2699S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000453392cop-0007-0284Case ReportAcute Anterior Uveitis in a Patient Taking Fingolimod (FTY720) for Multiple Sclerosis Mack Heather Gwen abcd*Tien Melissa Chih-Hui eWhite Owen Bruce abaCabrini Medical Centre, Malvern, VIC, AustraliabMelbourne Health, Parkville, VIC, AustraliacDepartment of Surgery, University of Melbourne, Parkville, VIC, AustraliadWalter and Eliza Hall Institute of Medical Research, Parkville, VIC, AustraliaeNational Healthcare Group Eye Institute, Tan Tock Seng Hospital, Singapore, Singapore*Dr. Heather G. Mack, Eye Surgery Associates, Cabrini Medical Centre, Isabella Street, Malvern, VIC 3144 (Australia), E-Mail hmack@eyesurgery.com.auSep-Dec 2016 8 12 2016 8 12 2016 7 3 284 288 3 10 2016 10 11 2016 Copyright © 2016 the Author(s)2016This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Fingolimod is an oral sphingosine-1-phosphate (S1P) receptor modulator and the first oral therapy for relapsing-remitting multiple sclerosis. Its use has been complicated by a low rate of cystoid macular edema usually in the first 3 months after commencement of the medication. We report the case of a 34-year-old male with relapsing-remitting multiple sclerosis, who developed acute anterior uveitis on day 5 of fingolimod treatment. He responded to appropriate treatment and cessation of drug, but developed low-grade chronic anterior uveitis without cystoid macular edema. We discuss possible mechanisms of uveitis onset in this group of patients. Urgent ophthalmological review is recommended for patients receiving fingolimod therapy who develop a red, painful eye, which may occur within 5 days of fingolimod treatment initiation.\n\nKey Words\nFingolimodUveitisRelapsing-remitting multiple sclerosisFTY720Rebound syndrome\n==== Body\nIntroduction\nFingolimod (FTY720, Gilenya, Novartis Pharmaceuticals, Basel, Switzerland) is the first oral sphingosine-1-phosphate (S1P) receptor modulator therapy found to be effective for relapsing-remitting multiple sclerosis (RRMS) [1, 2, 3]. Fingolimod binds to lymphocyte S1P receptors, altering T-cell lymphocyte recirculation by entrapping them in secondary lymphoid organs and reducing infiltration into the central nervous system (CNS). Additional immunomodulatory mechanisms may include influencing the blood-brain barrier function, and interaction with S1P1, S1P3, and S1P5 receptors expressed by many CNS neural and non-neural cells [4, 5].\n\nIn clinical practice, fingolimod is associated with development of cystoid macular edema (CME) in a dose-dependent manner and occurs at a higher rate in patients with a past history of uveitis [6, 7]. To date, there are no case reports of other forms of ocular inflammation associated with fingolimod; however, uveitis has also been reported in a fingolimod-treated patient who developed varicella zoster virus encephalopathy [8].\n\nCase History\nA 34-year-old male with a 7-year history of RRMS was treated with fingolimod 0.5 mg daily orally. His RRMS was previously stable on monthly infusions of natalizumab (Tysabri, Biogen Idec). However, JC virus testing became positive and treatment was changed to reduce the risk of progressive multifocal leukoencephalopathy. He had a normal ophthalmic examination with best-corrected visual acuity of 20/20 in both eyes and normal screening macular optical coherence scan (OCT) prior to commencing fingolimod. He had no ophthalmic history of ocular involvement with RRMS or any previous history of uveitis. He had received a chickenpox vaccine as a child.\n\nFive days post initiation of treatment, he developed a painful red right eye with blurred vision (Fig 1) and consulted an ophthalmologist after 14 days of fingolimod treatment. Visual acuity was 20/80 in the right eye and 20/20 in the left eye. The right eye was markedly injected with 1+ anterior chamber cells and flare, keratic precipitates, and 360° posterior synechiae. Vitreoretinal examination was normal, with no pars planitis. No CME was found, both clinically and on OCT (Fig 2). The left eye was unaffected. Syphilis serology, ACE testing, and HLA-B27 testing were negative. Fingolimod was discontinued and dimethyl fumarate was commenced. A tapering regime of topical 1% prednisolone and 1% atropine was instituted with good clinical response, albeit mild CME was present on OCT scanning at 6 weeks, which resolved spontaneously (Fig 2). He re-presented 16 weeks and 6 months after fingolimod cessation with further episodes of mild right anterior uveitis without CME and continued to have further flare-ups of anterior uveitis, eventually developing chronic anterior uveitis, which was controlled with topical 1% prednisolone daily. At last review, visual acuity was 20/20 in both eyes and no iris atrophy, uveitis, or CME were found. Intraocular pressure was normal throughout his clinical course. His RRMS was stable with no new CNS lesions.\n\nDiscussion\nOur patient developed anterior uveitis without significant CME on day 5 of fingolimod treatment and did not show typical features of herpetic related uveitides. Whilst it is known that bilateral intermediate uveitis does occur in approximately 1% of patients with MS and between 0.8 and 14% of uveitis patients have MS [9, 10], our patient had no evidence of intermediate uveitis prior to commencing fingolimod or during fingolimod treatment.\n\nThe cause of uveitis in patients receiving fingolimod therapy is unknown. One possible mechanism could be a breakdown of the blood-eye barrier in the uvea, similar to the proposed mechanism for development of CME, where agonism of S1P1 and S1P3 receptors increases vascular permeability [11, 12]. Other potential mechanisms include functional agonism of Th1 and Th17 lymphocyte S1P1 receptors found in patients with multiple sclerosis and uveitis, through activation of herpes virus infection or via fingolimod immunomodulatory activities independent of S1P receptors [13]. Our patient developed unilateral anterior uveitis, in contrast to patients who develop fingolimod-associated CME, which is usually bilateral but can be asymmetrical. Similar to all forms of inflammatory eye disease, the reasons for unilateral presentation are not known.\n\nOur patient developed chronic uveitis, despite ceasing fingolimod at uveitis diagnosis. This may be related to post-fingolimod rebound phenomenon and possibly due to lymphocyte reentry to the uvea or S1P1 receptor dysmodulation [14], although it should be noted he did not develop clinical post-fingolimod CNS rebound syndrome. Consideration should be given to continuing or ceasing fingolimod, due to the risk of post-fingolimod MS rebound syndrome and some patients may elect to have local uveitis treatment while continuing oral fingolimod.\n\nTo our knowledge, this is the first report of acute-on-chronic anterior uveitis, which developed 5 days after initiation of fingolimod treatment in a patient with RRMS and no preexisting uveitis. While the development of uveitis may be a coincidence, it raises the possibility of that fingolimod is pro-inflammatory in the eye and able to cause uveitis in a minority of patients, in addition to the well-described side effect of CME. Patients on fingolimod should be advised of possible adverse visual symptoms and/or pain, which may occur as early as 5 days after treatment initiation [15]. As the S1P1 receptor is present in the heart, as well as other organs, patients need to be also warned of possible systemic side effects and have appropriate systemic monitoring, particularly at treatment initiation. Ophthalmologists need to consider the role of anterior chamber paracentesis and viral polymerase chain reaction testing in similar patients. We agree with recommendations to undertake ophthalmological examination prior to treatment and suggest urgent ophthalmology review for patients with visual symptoms and/or pain. Further case reports are required to better determine whether there is a causal relationship between fingolimod and acute anterior uveitis in a minority of patients.\n\nStatement of Ethics\nThis case was in accordance with the principles of the Declaration of Helsinki. The patient gave informed consent to its publication.\n\nDisclosure Statement\nThe authors have no financial disclosures.\n\nFig. 1 Right eye at presentation 14 days after initiation of fingolimod treatment for relapsing-remitting multiple sclerosis demonstrating conjunctival injection, constricted pupil, and lack of purulent discharge.\n\nFig. 2 Right-eye macular optical coherence scan (Spectralis, Heidelberg Engineering) in a patient who developed acute anterior uveitis after treatment with fingolimod for relapsing-remitting multiple sclerosis. a At 14 days, when fingolimod was discontinued. b At 6 weeks, demonstrating cystoid macular edema and vitreous cells. c At 16 weeks.\n==== Refs\nReferences\n1 Chun J Hartung HP Mechanism of action of oral fingolimod (FTY720) in multiple sclerosis Clin Neuropharmacol 2010 33 91 101 20061941 \n2 Cohen JA Barkhof F Comi G Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis N Engl J Med 2010 362 402 415 20089954 \n3 Kappos L Radue EW O'Connor P A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis N Engl J Med 2010 362 387 401 20089952 \n4 Horga A Montalban X FTY720 (fingolimod) for relapsing multiple sclerosis Expert Rev Neurother 2008 8 699 714 18457527 \n5 Groves A Kihara Y Chun J Fingolimod: direct CNS effects of sphingosine 1-phosphate (S1P) receptor modulation and implications in multiple sclerosis therapy J Neurol Sci 2013 328 9 18 23518370 \n6 Jain N Bhatti MT Fingolimod-associated macular edema: incidence, detection, and management Neurology 2012 78 672 680 22371414 \n7 Zarbin MA Jampol LM Jager RD Ophthalmic evaluations in clinical studies of fingolimod (FTY720) in multiple sclerosis Ophthalmology 2013 120 1432 1439 23531349 \n8 Issa NP Hentati A VZV encephalitis that developed in an immunised patient during fingolimod therapy Neurology 2015 84 99 100 25416038 \n9 Burkholder BM Dunn JP Multiple sclerosis-associated uveitis Expert Rev Ophthalmol 2013 7 587 594 \n10 Hildebrandt AL Mackensen F Uveitis in multiple sclerosis: overview and perspectives Ophthalmologe 2014 111 733 739 25092024 \n11 Rotstein NP Miranda GE Abrahan CE Regulating survival and development in the retina: key roles for simple sphingolipids J Lipid Res 2010 51 1247 1262 20100817 \n12 Brinkmann V Baumruker T Pulmonary and vascular pharmacology of sphingosine 1-phosphate Curr Opin Pharmacol 2006 6 244 250 16563863 \n13 Chi H Sphingosine 1-phosphate and immune regulation: trafficking and beyond Trends Pharmacol Sci 2011 32 16 24 21159389 \n14 Cavone L Felici R Lapucci A Dysregulation of sphingosine 1 phosphate receptor-1 (S1P1) signaling and regulatory lymphocyte-dependent immunosuppression in a model of post-fingolimod MS rebound Brain Behav Immun 2015 50 78 86 26130058 \n15 Liu L Cuthbertson F Early bilateral cystoid macular oedema secondary to fingolimod in multiple sclerosis Case Rep Med 2012 2012 134636 23056052\n\n",
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"issue": "7(3)",
"journal": "Case reports in ophthalmology",
"keywords": "FTY720; Fingolimod; Rebound syndrome; Relapsing-remitting multiple sclerosis; Uveitis",
"medline_ta": "Case Rep Ophthalmol",
"mesh_terms": null,
"nlm_unique_id": "101532006",
"other_id": null,
"pages": "284-288",
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"pmid": "28101047",
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"title": "Acute Anterior Uveitis in a Patient Taking Fingolimod (FTY720) for Multiple Sclerosis.",
"title_normalized": "acute anterior uveitis in a patient taking fingolimod fty720 for multiple sclerosis"
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"abstract": "Early initiation of antiretroviral therapy (ART) in human immunodeficiency virus (HIV)-infected patients who have tuberculosis reduces mortality among patients with low CD4 counts, but it increases the risk of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (IRIS).\n\n\n\nWe conducted this randomized, double-blind, placebo-controlled trial to assess whether prophylactic prednisone can safely reduce the incidence of paradoxical tuberculosis-associated IRIS in patients at high risk for the syndrome. We enrolled HIV-infected patients who were initiating ART (and had not previously received ART), had started tuberculosis treatment within 30 days before initiating ART, and had a CD4 count of 100 cells or fewer per microliter. Patients received either prednisone (at a dose of 40 mg per day for 14 days, then 20 mg per day for 14 days) or placebo. The primary end point was the development of tuberculosis-associated IRIS within 12 weeks after initiating ART, as adjudicated by an independent committee.\n\n\n\nAmong the 240 patients who were enrolled, the median age was 36 (interquartile range, 30 to 42), 60% were men, and 73% had microbiologically confirmed tuberculosis; the median CD4 count was 49 cells per microliter (interquartile range, 24 to 86), and the median HIV type 1 RNA viral load was 5.5 log10 copies per milliliter (interquartile range, 5.2 to 5.9). A total of 120 patients were assigned to each group, and 18 patients were lost to follow-up or withdrew. Tuberculosis-associated IRIS was diagnosed in 39 patients (32.5%) in the prednisone group and in 56 (46.7%) in the placebo group (relative risk, 0.70; 95% confidence interval [CI], 0.51 to 0.96; P=0.03). Open-label glucocorticoids were prescribed to treat tuberculosis-associated IRIS in 16 patients (13.3%) in the prednisone group and in 34 (28.3%) in the placebo group (relative risk, 0.47; 95% CI, 0.27 to 0.81). There were five deaths in the prednisone group and four in the placebo group (P=1.00). Severe infections (acquired immunodeficiency syndrome-defining illnesses or invasive bacterial infections) occurred in 11 patients in the prednisone group and in 18 patients in the placebo group (P=0.23). One case of Kaposi's sarcoma occurred in the placebo group.\n\n\n\nPrednisone treatment during the first 4 weeks after the initiation of ART for HIV infection resulted in a lower incidence of tuberculosis-associated IRIS than placebo, without evidence of an increased risk of severe infections or cancers. (Funded by the European and Developing Countries Clinical Trials Partnership and others; PredART ClinicalTrials.gov number, NCT01924286 .).",
"affiliations": "From the Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine (G. Meintjes, C. Stek, L.B., F.T., C. Schutz, A.N., A.J., R.J.W.), the Department of Medicine (G. Meintjes, C. Stek, F.T., C. Schutz, R.J.W.), and the Division of Clinical Pharmacology, Department of Medicine (G. Maartens), University of Cape Town, Cape Town, South Africa; the Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium (C. Stek, J.B., R.R., H.L., R.C., L.L.); the Department of Internal Medicine, University Hospital of Zurich, Zurich, Switzerland (F.T.); and the Department of Medicine, Imperial College London and the Francis Crick Institute, London (R.J.W.).;From the Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine (G. Meintjes, C. Stek, L.B., F.T., C. Schutz, A.N., A.J., R.J.W.), the Department of Medicine (G. Meintjes, C. Stek, F.T., C. Schutz, R.J.W.), and the Division of Clinical Pharmacology, Department of Medicine (G. Maartens), University of Cape Town, Cape Town, South Africa; the Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium (C. Stek, J.B., R.R., H.L., R.C., L.L.); the Department of Internal Medicine, University Hospital of Zurich, Zurich, Switzerland (F.T.); and the Department of Medicine, Imperial College London and the Francis Crick Institute, London (R.J.W.).;From the Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine (G. Meintjes, C. Stek, L.B., F.T., C. Schutz, A.N., A.J., R.J.W.), the Department of Medicine (G. Meintjes, C. Stek, F.T., C. Schutz, R.J.W.), and the Division of Clinical Pharmacology, Department of Medicine (G. Maartens), University of Cape Town, Cape Town, South Africa; the Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium (C. Stek, J.B., R.R., H.L., R.C., L.L.); the Department of Internal Medicine, University Hospital of Zurich, Zurich, Switzerland (F.T.); and the Department of Medicine, Imperial College London and the Francis Crick Institute, London (R.J.W.).;From the Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine (G. Meintjes, C. Stek, L.B., F.T., C. Schutz, A.N., A.J., R.J.W.), the Department of Medicine (G. Meintjes, C. Stek, F.T., C. Schutz, R.J.W.), and the Division of Clinical Pharmacology, Department of Medicine (G. Maartens), University of Cape Town, Cape Town, South Africa; the Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium (C. Stek, J.B., R.R., H.L., R.C., L.L.); the Department of Internal Medicine, University Hospital of Zurich, Zurich, Switzerland (F.T.); and the Department of Medicine, Imperial College London and the Francis Crick Institute, London (R.J.W.).;From the Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine (G. Meintjes, C. Stek, L.B., F.T., C. Schutz, A.N., A.J., R.J.W.), the Department of Medicine (G. Meintjes, C. Stek, F.T., C. Schutz, R.J.W.), and the Division of Clinical Pharmacology, Department of Medicine (G. Maartens), University of Cape Town, Cape Town, South Africa; the Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium (C. Stek, J.B., R.R., H.L., R.C., L.L.); the Department of Internal Medicine, University Hospital of Zurich, Zurich, Switzerland (F.T.); and the Department of Medicine, Imperial College London and the Francis Crick Institute, London (R.J.W.).;From the Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine (G. Meintjes, C. Stek, L.B., F.T., C. Schutz, A.N., A.J., R.J.W.), the Department of Medicine (G. Meintjes, C. Stek, F.T., C. Schutz, R.J.W.), and the Division of Clinical Pharmacology, Department of Medicine (G. Maartens), University of Cape Town, Cape Town, South Africa; the Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium (C. Stek, J.B., R.R., H.L., R.C., L.L.); the Department of Internal Medicine, University Hospital of Zurich, Zurich, Switzerland (F.T.); and the Department of Medicine, Imperial College London and the Francis Crick Institute, London (R.J.W.).;From the Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine (G. Meintjes, C. Stek, L.B., F.T., C. Schutz, A.N., A.J., R.J.W.), the Department of Medicine (G. Meintjes, C. Stek, F.T., C. Schutz, R.J.W.), and the Division of Clinical Pharmacology, Department of Medicine (G. Maartens), University of Cape Town, Cape Town, South Africa; the Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium (C. Stek, J.B., R.R., H.L., R.C., L.L.); the Department of Internal Medicine, University Hospital of Zurich, Zurich, Switzerland (F.T.); and the Department of Medicine, Imperial College London and the Francis Crick Institute, London (R.J.W.).;From the Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine (G. Meintjes, C. Stek, L.B., F.T., C. Schutz, A.N., A.J., R.J.W.), the Department of Medicine (G. Meintjes, C. Stek, F.T., C. Schutz, R.J.W.), and the Division of Clinical Pharmacology, Department of Medicine (G. Maartens), University of Cape Town, Cape Town, South Africa; the Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium (C. Stek, J.B., R.R., H.L., R.C., L.L.); the Department of Internal Medicine, University Hospital of Zurich, Zurich, Switzerland (F.T.); and the Department of Medicine, Imperial College London and the Francis Crick Institute, London (R.J.W.).;From the Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine (G. Meintjes, C. Stek, L.B., F.T., C. Schutz, A.N., A.J., R.J.W.), the Department of Medicine (G. Meintjes, C. Stek, F.T., C. Schutz, R.J.W.), and the Division of Clinical Pharmacology, Department of Medicine (G. Maartens), University of Cape Town, Cape Town, South Africa; the Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium (C. Stek, J.B., R.R., H.L., R.C., L.L.); the Department of Internal Medicine, University Hospital of Zurich, Zurich, Switzerland (F.T.); and the Department of Medicine, Imperial College London and the Francis Crick Institute, London (R.J.W.).;From the Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine (G. Meintjes, C. Stek, L.B., F.T., C. Schutz, A.N., A.J., R.J.W.), the Department of Medicine (G. Meintjes, C. Stek, F.T., C. Schutz, R.J.W.), and the Division of Clinical Pharmacology, Department of Medicine (G. Maartens), University of Cape Town, Cape Town, South Africa; the Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium (C. Stek, J.B., R.R., H.L., R.C., L.L.); the Department of Internal Medicine, University Hospital of Zurich, Zurich, Switzerland (F.T.); and the Department of Medicine, Imperial College London and the Francis Crick Institute, London (R.J.W.).;From the Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine (G. Meintjes, C. Stek, L.B., F.T., C. Schutz, A.N., A.J., R.J.W.), the Department of Medicine (G. Meintjes, C. Stek, F.T., C. Schutz, R.J.W.), and the Division of Clinical Pharmacology, Department of Medicine (G. Maartens), University of Cape Town, Cape Town, South Africa; the Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium (C. Stek, J.B., R.R., H.L., R.C., L.L.); the Department of Internal Medicine, University Hospital of Zurich, Zurich, Switzerland (F.T.); and the Department of Medicine, Imperial College London and the Francis Crick Institute, London (R.J.W.).;From the Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine (G. Meintjes, C. Stek, L.B., F.T., C. Schutz, A.N., A.J., R.J.W.), the Department of Medicine (G. Meintjes, C. Stek, F.T., C. Schutz, R.J.W.), and the Division of Clinical Pharmacology, Department of Medicine (G. Maartens), University of Cape Town, Cape Town, South Africa; the Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium (C. Stek, J.B., R.R., H.L., R.C., L.L.); the Department of Internal Medicine, University Hospital of Zurich, Zurich, Switzerland (F.T.); and the Department of Medicine, Imperial College London and the Francis Crick Institute, London (R.J.W.).;From the Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine (G. Meintjes, C. Stek, L.B., F.T., C. Schutz, A.N., A.J., R.J.W.), the Department of Medicine (G. Meintjes, C. Stek, F.T., C. Schutz, R.J.W.), and the Division of Clinical Pharmacology, Department of Medicine (G. Maartens), University of Cape Town, Cape Town, South Africa; the Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium (C. Stek, J.B., R.R., H.L., R.C., L.L.); the Department of Internal Medicine, University Hospital of Zurich, Zurich, Switzerland (F.T.); and the Department of Medicine, Imperial College London and the Francis Crick Institute, London (R.J.W.).;From the Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine (G. Meintjes, C. Stek, L.B., F.T., C. Schutz, A.N., A.J., R.J.W.), the Department of Medicine (G. Meintjes, C. Stek, F.T., C. Schutz, R.J.W.), and the Division of Clinical Pharmacology, Department of Medicine (G. Maartens), University of Cape Town, Cape Town, South Africa; the Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium (C. Stek, J.B., R.R., H.L., R.C., L.L.); the Department of Internal Medicine, University Hospital of Zurich, Zurich, Switzerland (F.T.); and the Department of Medicine, Imperial College London and the Francis Crick Institute, London (R.J.W.).",
"authors": "Meintjes|Graeme|G|;Stek|Cari|C|;Blumenthal|Lisette|L|;Thienemann|Friedrich|F|;Schutz|Charlotte|C|;Buyze|Jozefien|J|;Ravinetto|Raffaella|R|;van Loen|Harry|H|;Nair|Amy|A|;Jackson|Amanda|A|;Colebunders|Robert|R|;Maartens|Gary|G|;Wilkinson|Robert J|RJ|;Lynen|Lutgarde|L|;|||",
"chemical_list": "D000893:Anti-Inflammatory Agents; D044966:Anti-Retroviral Agents; D000995:Antitubercular Agents; D011241:Prednisone",
"country": "United States",
"delete": false,
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"issue": "379(20)",
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"medline_ta": "N Engl J Med",
"mesh_terms": "D017088:AIDS-Related Opportunistic Infections; D000328:Adult; D000893:Anti-Inflammatory Agents; D044966:Anti-Retroviral Agents; D000995:Antitubercular Agents; D018791:CD4 Lymphocyte Count; D004311:Double-Blind Method; D005260:Female; D015658:HIV Infections; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome; D008297:Male; D011241:Prednisone; D014397:Tuberculosis, Pulmonary",
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"other_id": null,
"pages": "1915-1925",
"pmc": null,
"pmid": "30428290",
"pubdate": "2018-11-15",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Prednisone for the Prevention of Paradoxical Tuberculosis-Associated IRIS.",
"title_normalized": "prednisone for the prevention of paradoxical tuberculosis associated iris"
} | [
{
"companynumb": "ZA-MYLANLABS-2019M1003211",
"fulfillexpeditecriteria": "1",
"occurcountry": "ZA",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ETHAMBUTOL HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "Intravesical instillation of BCG (Bacille Calmette-Guerin) is a therapy prepared with weakened strains of Mycobacterium bovis and is an effective complementary treatment for high-risk (non-musculoinfiltrating or non-invasive) bladder cancer. Although its safety for clinical use is high, endovesical immunotherapy is not without complications. Arthralgia and arthritis are infrequent, but potentially severe, complications, the early diagnosis of which can allow adequate medical treatment and avoid chronification of the pathology. This case shows the therapeutic management of hip osteoarthritis in a 59-year-old woman, a rare and serious complication, secondary to a rare pathology such as reactive arthritis due to BCG instillation.",
"affiliations": "Servicio de Cirugía Ortopédica y Traumatología. Hospital Universitario Miguel Servet. Zaragoza. alberto.hdez.fdez@gmail.com.",
"authors": "Hernández Fernández|A|A|;Pinilla-Gracia|C|C|;Rodríguez Nogué|L|L|;Panisello Sebastiá|J J|JJ|;Martínez Delgado|F|F|",
"chemical_list": "D001500:BCG Vaccine",
"country": "Spain",
"delete": false,
"doi": "10.23938/ASSN.0875",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1137-6627",
"issue": "43(2)",
"journal": "Anales del sistema sanitario de Navarra",
"keywords": null,
"medline_ta": "An Sist Sanit Navar",
"mesh_terms": "D000283:Administration, Intravesical; D016918:Arthritis, Reactive; D001500:BCG Vaccine; D005260:Female; D006801:Humans; D007167:Immunotherapy; D008875:Middle Aged; D009163:Mycobacterium bovis; D001749:Urinary Bladder Neoplasms",
"nlm_unique_id": "9710381",
"other_id": null,
"pages": "267-271",
"pmc": null,
"pmid": "32814932",
"pubdate": "2020-08-31",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Unusual evolution of reactive arthritis after endovesical immunotherapy with BCG.",
"title_normalized": "unusual evolution of reactive arthritis after endovesical immunotherapy with bcg"
} | [
{
"companynumb": "ES-009507513-2009ESP000751",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BACILLUS CALMETTE-GUERIN SUBSTRAIN TICE LIVE ANTIGEN"
... |
{
"abstract": "Purpose: We report a case of unilateral acute iris transillumination (AIT) and iris sphincter paralysis in a 63-year-old male undergone uneventful phacoemulsification surgery with intracameral moxifloxacin (ICM).Case presentation: This is a case of AIT with no history of viral disease or use of systemic fluoroquinolone but an association with ICM after uneventful phacoemulsification. The clinical features of the affected eye are perfectly similar to what has been described in BAIT and hence we consider that unilateral AIT and BAIT share the same etiopathogenesis. At the end of the phacoemulsification, the patient received 0.15 ml of 5mg/ml moxifloxacin, which is notably higher than the dose that is commonly used for ICM. This may have caused the patient to develop BAIT-like syndrome after the ICM.Conclusion: 0.1 ml of 5mg/ml moxifloxacin or less should be used to reduce the risk of occurrences of this toxic effect caused by ICM.",
"affiliations": "Department of Ophthalmology, Selcuk University Faculty of Medicine, Konya, Turkey.;Department of Ophthalmology, Selcuk University Faculty of Medicine, Konya, Turkey.",
"authors": "Gonul|Saban|S|https://orcid.org/0000-0003-0803-1197;Eker|Serhat|S|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/09273948.2021.1916042",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0927-3948",
"issue": null,
"journal": "Ocular immunology and inflammation",
"keywords": "Bilateral acute depigmentation of the iris; Bilateral acute iris transillumination; Endophthalmitis prophylaxis; Intracameral moxifloxacin; Toxic effect",
"medline_ta": "Ocul Immunol Inflamm",
"mesh_terms": null,
"nlm_unique_id": "9312169",
"other_id": null,
"pages": "1-4",
"pmc": null,
"pmid": "34003710",
"pubdate": "2021-05-18",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Unilateral Acute Iris Transillumination Syndrome following Uneventful Phacoemulsification Surgery with Intracameral Moxifloxacin.",
"title_normalized": "unilateral acute iris transillumination syndrome following uneventful phacoemulsification surgery with intracameral moxifloxacin"
} | [
{
"companynumb": "US-AKORN-168518",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MOXIFLOXACIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "BACKGROUND\nThe relationship between body mass index (BMI) and the severity of cardioembolic stroke (CES) remains poorly understood.\n\n\nMETHODS\nA total of 419 consecutive CES patients with nonvalvular atrial fibrillation (NVAF), and with a modified Rankin Scale (mRS) score of 0 or 1 before onset admitted within 48hours after onset to the Hirosaki Stroke and Rehabilitation Center were studied. The patients were divided into three groups, low BMI (L-BMI; n = 36, BMI < 18.5 kg/m2), normal BMI (N-BMI; n = 284, 18.5 ≤ BMI < 25.0), and high BMI (H-BMI; n = 99, BMI ≥ 25.0). We compared stroke severity and functional outcome among the three groups.\n\n\nRESULTS\nStroke severity on admission, assessed by the National Institutes of Health Stroke Scale (NIHSS) showed that patients with L-BMI had the highest NIHSS score (median, 16 [11-25]), followed by N-BMI and H-BMI (11 [5-19] and 9 [3-19], P = .002). Functional outcome at discharge, assessed by mRS, was most severe in L-BMI patients (5 [3-5]), followed by N-BMI and H-BMI (3 [1-4] and 2 [1-4], P = .001). Multivariate analyses revealed that L-BMI was a significant determinant of severe stroke (NIHSS scores ≥8) at admission (odds ratio [OR] to N-BMI = 2.79, 95% confidence interval [CI], 1.17-7.78, P = .02) and poor functional outcome (mRS scores ≥3) at discharge (OR = 2.53, 95% CI, 1.12-6.31, P = .02). However, H-BMI did not affect stroke severity at admission or functional outcome at discharge.\n\n\nCONCLUSIONS\nLow BMI is a risk factor for severe stroke on admission and unfavorable functional outcome at discharge in Japanese CES patients with NVAF.",
"affiliations": "Hirosaki Stroke and Rehabilitation Center, Hirosaki 036-8104, Japan.;Hirosaki Stroke and Rehabilitation Center, Hirosaki 036-8104, Japan.;Hirosaki Stroke and Rehabilitation Center, Hirosaki 036-8104, Japan.;Hirosaki Stroke and Rehabilitation Center, Hirosaki 036-8104, Japan.;Hirosaki Stroke and Rehabilitation Center, Hirosaki 036-8104, Japan.;Hirosaki Stroke and Rehabilitation Center, Hirosaki 036-8104, Japan.;Hirosaki Stroke and Rehabilitation Center, Hirosaki 036-8104, Japan.;Hirosaki Stroke and Rehabilitation Center, Hirosaki 036-8104, Japan.;Hirosaki Stroke and Rehabilitation Center, Hirosaki 036-8104, Japan.;Hirosaki Stroke and Rehabilitation Center, Hirosaki 036-8104, Japan.;Hirosaki Stroke and Rehabilitation Center, Hirosaki 036-8104, Japan.;Hirosaki Stroke and Rehabilitation Center, Hirosaki 036-8104, Japan.;Hirosaki Stroke and Rehabilitation Center, Hirosaki 036-8104, Japan.;Hirosaki Stroke and Rehabilitation Center, Hirosaki 036-8104, Japan.;Hirosaki Stroke and Rehabilitation Center, Hirosaki 036-8104, Japan.;Department of Cardiology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan; Department of Hypertension and Stroke Medicine, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan. Electronic address: tomitah@hirosaki-u.ac.jp.",
"authors": "Hagii|Joji|J|;Metoki|Norifumi|N|;Saito|Shin|S|;Fujita|Ayaka|A|;Shiroto|Hiroshi|H|;Sasaki|Satoko|S|;Takahashi|Koki|K|;Hitomi|Hiroyasu|H|;Baba|Yoshiko|Y|;Seino|Satoshi|S|;Kamada|Takaatu|T|;Uchizawa|Takamitsu|T|;Iwata|Manabu|M|;Matsumoto|Shigeo|S|;Yasujima|Minoru|M|;Tomita|Hirofumi|H|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.jstrokecerebrovasdis.2018.07.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1052-3057",
"issue": "27(11)",
"journal": "Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association",
"keywords": "Low body mass index; cardioembolic stroke; functional outcome; nonvalvular atrial fibrillation; stroke severity",
"medline_ta": "J Stroke Cerebrovasc Dis",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D001281:Atrial Fibrillation; D015992:Body Mass Index; D004185:Disability Evaluation; D005260:Female; D006304:Health Status; D006801:Humans; D020766:Intracranial Embolism; D007564:Japan; D008297:Male; D010343:Patient Admission; D010351:Patient Discharge; D011379:Prognosis; D020127:Recovery of Function; D012307:Risk Factors; D012720:Severity of Illness Index; D020521:Stroke",
"nlm_unique_id": "9111633",
"other_id": null,
"pages": "3155-3162",
"pmc": null,
"pmid": "30093200",
"pubdate": "2018-11",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Low Body Mass Index is a Poor Prognosis Factor in Cardioembolic Stroke Patients with NonValvular Atrial Fibrillation.",
"title_normalized": "low body mass index is a poor prognosis factor in cardioembolic stroke patients with nonvalvular atrial fibrillation"
} | [
{
"companynumb": "JP-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2018-BI-057898",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
... |
{
"abstract": "OBJECTIVE\nWe retrospectively examined the venous thromboembolism (VTE) events diagnosed in the Prophylaxis of High-Risk Ambulatory Cancer Patients Study (PHACS), a multi-center randomized trial, to assess the value of screening vascular imaging for the diagnosis of incidental VTE in high-risk cancer patients.\n\n\nMETHODS\nA total of 117 asymptomatic cancer patients with a Khorana score ≥3 starting a new systemic chemotherapy regimen were enrolled in a prospective randomized control trial. Patients underwent baseline venous ultrasound (US) of the lower extremities (LEs) and screening contrast-enhanced chest computed tomography (CT). Those without preexisting VTE were then randomized into observation or dalteparin prophylaxis groups and were screened with serial US every 4 weeks for up to 12 weeks and imaged with contrast-enhanced chest CT at 12 weeks. Any additional imaging performed during the study period was also evaluated for VTE.\n\n\nRESULTS\nBaseline prevalence of incidental VTE was 9% (n = 10) with 58% percent of VTEs diagnosed by screening US. Incidence of VTE in the randomized phase of the trial was 16% (n = 16) with 21% (n = 10) of patients in the control arm and 12% (n = 6) of patients in the dalteparin arm developing VTE, a non-significant 9% absolute risk reduction (HR = 0.69, 95% CI 0.23-1.89). Sixty-nine percent of these patients were asymptomatic with 31% of patients diagnosed by screening US.\n\n\nCONCLUSIONS\nAdding screening US to routine oncologic surveillance CT in high-risk ambulatory cancer patients with a Khorana score ≥3 can lead to increased VTE detection, with potential for decreased morbidity, mortality, and health care spending.",
"affiliations": "Department of Imaging Sciences, University of Rochester Medical Center, Rochester, New York, USA.;Department of Imaging Sciences, University of Rochester Medical Center, Rochester, New York, USA.;Department of Imaging Sciences, University of Rochester Medical Center, Rochester, New York, USA.;Department of Imaging Sciences, University of Rochester Medical Center, Rochester, New York, USA.;Department of Medicine, University of Rochester Medical Center, Rochester, New York, USA.;Department of Hematology and Oncology, Cleveland Clinic Main Campus, Cleveland, Ohio, USA.;Department of Imaging Sciences, University of Rochester Medical Center, Rochester, New York, USA.;Department of Imaging Sciences, University of Rochester Medical Center, Rochester, New York, USA.",
"authors": "Loftus|James Ryan|JR|https://orcid.org/0000-0001-7059-1158;Hu|Zhongxia|Z|;Morin|Burke R|BR|;Hobbs|Susan K|SK|;Francis|Charles W|CW|;Khorana|Alok A|AA|;Rubens|Deborah J|DJ|;Kaproth-Joslin|Katherine A|KA|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/jum.15701",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0278-4297",
"issue": null,
"journal": "Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine",
"keywords": "Khorana score; oncologic imaging; pulmonary embolism (PE); screening; venous Doppler ultrasound (US); venous thromboembolism (VTE)",
"medline_ta": "J Ultrasound Med",
"mesh_terms": null,
"nlm_unique_id": "8211547",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33772825",
"pubdate": "2021-03-27",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Vascular Imaging in the Asymptomatic High-risk Cancer Population: A Role for Thrombosis Screening and Therapy Management.",
"title_normalized": "vascular imaging in the asymptomatic high risk cancer population a role for thrombosis screening and therapy management"
} | [
{
"companynumb": "US-PFIZER INC-2021430679",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DALTEPARIN SODIUM"
},
"drugadditional": "3",
... |
{
"abstract": "We report an unusual case of co-infection of invasive pulmonary aspergillosis (IPA) and fusarial skin infection in a patient with classic pyoderma gangrenosum with unknown causes, which were previously controlled with oral prednisolone, cyclosporine. The diagnosis was made on direct microscopy and culture of endobronchial washing, bronchoalveolar lavage and skin lesion biopsy. The treatment failed, and the patient expired 12 days following hospitalization. This report highlights the rarity of coexistence of IPA and a chronic fusarial skin infection and thereby reinforcing the physician's attention toward the possibility of invasive fungal infection in the immunosuppressed patients.",
"affiliations": "Student Research Committee, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran ; Department of Laboratory Sciences, School of Paramedical Sciences and Tropical Medicine Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.;Department of Pulmonary Diseases, Mazandaran University of Medical Sciences, Sari, Iran.;Department of Medical Mycology and Parasitology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.;Department of Infectious Disease, North Iranian Tropical and Infectious Disease Research Center, Mazandaran University of Medical Sciences, Sari, Iran.;Department of Radiology, Mazandaran University of Medical Sciences, Sari, Iran.;Skin Research Center, Shahid Beheshti University of Medical Sciences, Shohada-e Tajrish Hospital, Tehran, Iran.;Department of Medical Mycology and Parasitology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran ; Invasive Fungi Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.",
"authors": "Amirrajab|Nasrin|N|;Aliyali|Masoud|M|;Mayahi|Sabah|S|;Najafi|Narges|N|;Abdi|Ruhollah|R|;Nourbakhsh|Omid|O|;Shokohi|Tahereh|T|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": null,
"fulltext": "\n==== Front\nJ Res Med SciJ Res Med SciJRMSJournal of Research in Medical Sciences : The Official Journal of Isfahan University of Medical Sciences1735-19951735-7136Medknow Publications & Media Pvt Ltd India JRMS-20-199Case ReportCo-infection of invasive pulmonary aspergillosis and cutaneous Fusarium infection in a patient with pyoderma gangrenosum Amirrajab Nasrin 12Aliyali Masoud 3Mayahi Sabah 4Najafi Narges 5Abdi Ruhollah 6Nourbakhsh Omid 7Shokohi Tahereh 481 Student Research Committee, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran2 Department of Laboratory Sciences, School of Paramedical Sciences and Tropical Medicine Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran3 Department of Pulmonary Diseases, Mazandaran University of Medical Sciences, Sari, Iran4 Department of Medical Mycology and Parasitology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran5 Department of Infectious Disease, North Iranian Tropical and Infectious Disease Research Center, Mazandaran University of Medical Sciences, Sari, Iran6 Department of Radiology, Mazandaran University of Medical Sciences, Sari, Iran7 Skin Research Center, Shahid Beheshti University of Medical Sciences, Shohada-e Tajrish Hospital, Tehran, Iran8 Invasive Fungi Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, IranAddress for correspondence: Prof. Tahereh Shokohi, Department of Medical Mycology and Parasitology and Invasive Fungi Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran. E-mail: shokohi.tahereh@gmail.com2 2015 20 2 199 203 20 8 2013 06 11 2013 28 7 2014 Copyright: © Journal of Research in Medical Sciences2015This 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.We report an unusual case of co-infection of invasive pulmonary aspergillosis (IPA) and fusarial skin infection in a patient with classic pyoderma gangrenosum with unknown causes, which were previously controlled with oral prednisolone, cyclosporine. The diagnosis was made on direct microscopy and culture of endobronchial washing, bronchoalveolar lavage and skin lesion biopsy. The treatment failed, and the patient expired 12 days following hospitalization. This report highlights the rarity of coexistence of IPA and a chronic fusarial skin infection and thereby reinforcing the physician's attention toward the possibility of invasive fungal infection in the immunosuppressed patients.\n\nAspergillusFusariuminvasive pulmonary aspergillosispyoderma gangrenosum\n==== Body\nINTRODUCTION\nInvasive fungal infections (IFIs) have an increased frequency in the immunocompromised patients and are major causes of morbidity and mortality.[1] The incidence and mortality rates of IFI may vary considerably based on immune status and the management of the patients and the environmental infection control of the ward and hospitals.[2] Reported incidences and mortality rate of invasive aspergillosis extremely variable in different patient groups, affecting 24-60% of those with chronic granulomatous disease, acute leukemia and organ transplant recipients and patients with long-term steroid use or profound neutropenia.[34]\n\nIn report by Aspergillus study group the occurrence of IA in hematological patients reported more than 60%.[5] The mortality rate can exceed 90% in bone marrow transplant recipients.[6] It seems that mortality rate for aspergillosis has declined from 60-70% to approximately 40%.[27] As these fungi are ubiquitous in environment and always isolated from skin and respiratory secretion, The diagnosis needs to be confirmed using both culture and histopathology.[8] Pyoderma gangrenosum (PG) is a rare cutaneous disease and often appears as an inflammatory nodule or pustule with gradual peripheral enlargement.[910] Clinically it starts with sterile pustules rapidly progresses and turn into painful ulcers of variable depth and size with undetermined violaceous borders. Course could be mild or malignant, chronic or relapsing with marked morbidity. In many cases, PG is related to an underlying disease, most commonly with inflammatory bowel disease, collagen vascular, rheumatic or hematological diseases, viral infections and malignancy. Approximately, 25% of cases are not associated with any underlying disease. Diagnosis of PG is based on history of an underlying disease, typical clinical presentation, histopathology, and excluding the other diseases that could lead to similar appearance. The peak of incidence occurs between the ages of 20-50 years more often in women. Etiology has not been cleared yet.[11] The treatment of PG is often done by systemic corticosteroids or nonsteroidal immunosuppressive agents, such as, azathioprine and cyclosporine. Systemic corticosteroids or other T-cell suppressive agents have been considered to predispose patients to infection. We describe an acute ill-patient with progression of the chronic PG lesions, despite treatment, therefore, was subjected to further evaluation for the possibility of secondary infection.\n\nCASE REPORT\nIn 2012, a 32-year-old man with 5-year history of classic PG was admitted to the Intensive Care Unit of Shafa Hospital (Sari, Iran) with a complaint of cough, sputum and dyspnea in the last 4 days. The patient had received methylprednisolone pulses 1 week prior to admission. His current medication was oral prednisolone, cyclosporine and surgical wound therapy. The diagnosis of PG was confirmed by biopsy, but the cause was left unknown. On physical examination, the patient had respiratory rate of 30 breaths/min, temperature of 39°C, heart rate of 150 beats/min, oxygen saturation (below 90%). Large and deeply diffuse necrotic skin lesions appeared on the upper limbs and over the chest and back [Figure 1]. During dermatology examination, skin lesions were observed, and initial lung and heart examinations were unremarkable. Initial laboratory evaluation showed: White blood cell count was 9.8 × 109/l with a differential of 79% neutrophils, 22% lymphocytes, 3% monocytes, and 1% eosinophil. Platelets were 25 × 109/L. No vegetation was found in transthoracic echocardiogram. A computed tomography (CT) scan of the lungs revealed multiple 1-2 cm nodules in various stages with feeding vessels sign and cavitations in some of them, well as the halo sign, an area of low attenuation surrounding a nodular lesion, and the air-crescent signs with small size left pleural effusion [Figures 2 and 3]. Respiratory failure developed 2 days after admission, and patient was intubated and mechanically ventilated. Bronchoscopy was performed, and bronchoalveolar lavage (BAL) specimen was obtained. The diagnosis of probable invasive pulmonary aspergillosis (IPA) was made on based on European Organization for Research and Treatment of Cancer/IFIs Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group definitions.[12] Direct microscopy examination of endobronchial washing and BAL samples demonstrated acute branching septate hyphae, consistent with aspergillosis and the culture of the samples revealed Aspergillus flavus. The diagnosis of cutaneous fusariosis was made on Fusarium proliferatum is isolated from skin lesion biopsy in multiple media. The polymerase chain reaction assays have been performed with BAL sample and tissue biopsy. The fungal internal transcribed spacer (ITS) region of rRNA gene in these samples were amplified and sequenced for accurate identification of the fungal species. The ITS sequences of A. flavus and F. proliferatum were submitted to the NCBI GenBank and received the accession no. KJ000075 and KJ000076, respectively. The voriconazole (6 mg/kg body weight IV. BD) and antimicrobial drugs such as linezolid (600 mg BD), meropenem (1 g IV. TDS), and ciprofloxacin (400 mg BD) were administered to treat fungal and bacterial infection. The dose of these drugs was adjusted based on creatinine clearance. The treatment failed, and the patient expired 12 days following hospitalization due to sepsis.\n\nFigure 1 Large and diffuse deeply necrotic skin lesions were found on upper limbs and over the chest and back\n\nFigure 2 Computed tomography scan of the lungs reveal two nodules with irregular borders in the posterior segment of the right upper lobe. A cavity lesion is in the anterior segment of the right upper lobe\n\nFigure 3 Computed tomography scan of the lungs showing two cavitary lesions in the right middle lobe. There is a patchy consolidation in the left lower lobe. Pleural effusion on the left side is also seen\n\nDISCUSSION\nSystemic corticosteroids have been considered to predispose patients to infection, but there is a little report on the invasive fungal infection.[8] Aspergillus and Fusarium species are saprophytic fungus with worldwide distribution. They can grow on most decaying organic materials. This fungus has recently emerged as the two most common pathogenic mold, which can cause disseminated invasive fungal disease in severely immunocompromised patients.[121314] In our patient, using of long-term systemic corticosteroid and the multiple debridement could be a predisposing factor in developing of the invasive IPA and cutaneous Fusarium infection. Corticosteroids influence the function of neutrophils and lymphocytes and stimulate the growth of Aspergillus.[13] In the compromised host, Aspergillus colonizes the tracheobronchial tree, invades the walls of large bronchi, but less the trachea, leading to a focal or diffuse and intense acute inflammatory reaction along with ulceration and endoluminal sloughing of the epithelium, hyphae, mucus and cellular debris. When infection is limited to the airway canal or has minimal, patchy extension into the surrounding parenchyma, the chest images are normal or reveal foci of atelectasis, that is due to the local airway obstruction by hyphae laden mucus and inflammatory debris, but the patients might be quite symptomatic.[15]\n\nThe genus Aspergillus comprises about approximately 200 species.[8] Aspergillus fumigatus is the most common species isolated from invasive aspergillosis cases, followed by A. flavus and less commonly Aspergillus niger and Aspergillus terreus. A. flavus survives at higher temperatures and a predominant pathogen in areas with hot and dry climates.[1617] A. flavus produces potent hepatotoxin known to man. The culture of the BAL specimens and the biopsy of the skin lesion afforded the microbiological and histopathological clues for diagnosis of invasive fungal infection. On the CT images, lesions of invasive aspergillosis may often show characteristic appearance. The most common appearance is a rounded mass, representing necrotic lung, infiltrated with Aspergillus hyphae,[9] surrounded and separated from normal lung by a thin zone of ground-glass opacity with lower attenuation than the surrounding normal lung.[1819] This characteristic appearance termed the “CT halo sign. The halo of ground-glass attenuation pathologically represents pulmonary hemorrhage.[19] Though this sign is not specific for IPA but this sign is most often secondary to IPA. The halo sign appears early in the course of infection, often preceding the development of cavitations or air crescent by 2-3 weeks.[18]\n\nDespite radiographic regressions of the infection, IPA does not frequently extend into the pleural space to form an empyema. Pleural aspergillosis is more frequently a complication of thoracic surgery or the result of rupture of a mycetoma cavity into the pleural space.[1920]\n\nIn our case, CT halo sign which is highly specific for invasive aspergillosis was presented before getting the positive microbiological and histopathological results. The patient had a stable course of PG under maintenance therapy with oral prednisolone. Furthermore, 1 week prior to admission he had received methylprednisolone pulses due to the progression of lesions. Hospitalization and the skin biopsy did not favor the progression of PG.\n\nPyoderma gangrenosum is a rare, inflammatory, non-infective and nonneoplastic skin disorder, often associated with systemic diseases, such as inflammatory bowel disease, rheumatoid arthritis or hematological malignancy, but up to 50% of patients have some degree of variations. The cause of PG remains obscure, It is believed that it has no relation with bacterial infection, hence makes the term pyoderma redundant.[21]\n\nFusarium species are filamentous saprophyte with worldwide distribution in the soil and air. They cause superficial, locally invasive, and disseminated infections in humans. The clinical form of fusariosis depends largely on the immune status of the host and the portal of entry. Invasive and necrotic fusarial skin infections are rare and found in immunosupressed subjects.[1422] Fusarium species have recently appeared as the second most prevalent pathogenic mold in immunocompromised patients and are moderately resistant to most antifungals. The fusarial skin infection typically manifests as multiple red or violaceous macules or nodules, often ulcerated and covered by a black eschar.[23] We speculate that the skin lesions of our patient was localized and as a result of skin breakdown caused by multiple surgical debridement and corticosteroid pulse therapy. These lesions are erythematous, papular or nodular, painful, and frequently with central necrosis giving the lesions an echthyma gangrenosum like appearance. Fusarial skin lesions can involve any site, with a predominance in the extremities, and evolve rapidly, usually within few days.[24]\n\nPatients with IFIs are now classified according EORTC/MSG consensus group definitions.[12] These definitions may serve as a useful model for improving the quality of clinical studies and diagnosis with a variable certainty including proven, probable or possible groups. Diagnosis of probable IFI in our patient was based on host factor, clinical criteria and mycological finding. The host factor of our patient was prolonged use of corticosteroids. The two signs of lower respiratory tract involvement including a halo and air-crescent revealed in CT. Direct microscopy exam and the fungi grown in culture media constituted mycological support. In this case study, autopsy and biopsy were not performed; therefore, we were not able to report the definite IPA and fusarial infection.\n\nVoriconazole is often used for the treatment of serious infections caused by Aspergillus and Fusarium. Baden et al., demonstrated that in severely immunocompromised patients with life-threatening IFI who have failed or intolerant to standard antifungal therapy, voriconazole had a substantial efficacy, but with an acceptable level of toxicity.[25]\n\nThe study subject had progressive respiratory failure and ulcerative lesions and unresponsive to prompt voriconazole therapy. Alternative options to traditional amphotericin B treatment could be considered if clinical response is not satisfactory. The alternative includes high-dose liposomal amphotericin B that has the highest effect against Aspergillus and Fusarium species, whereas itraconazole had no activity against Fusarium species. It was found that caspofungin efficacy during empirical antifungal therapy in neutropenic patients or severely ill-patients with refractory invasive Aspergillus infections but administration of anidulafungin is generally avoided due to the intrinsic resistance.[262728]\n\nThe present report highlights the rarity of coexistence of Invasive IPA and cutaneous Fusarium infection in a patient with chronic PG, and should bring the attention of physicians toward the possibility of invasive fungal infection superimposed on chronic skin lesion. Early skin biopsy and CT scan are recommended for the early diagnosis.\n\nAUTHOR'S CONTRIBUTION\nTS contributed in the conception of the work, conducting the study, revising the draft, approval of the final version of the manuscript, and agreed for all aspects of the work. NA contributed in the conception of the work, drafting, approval of the final version of the manuscript, and agreed for all aspects of the work. MA contributed in the conception of the work, revising the draft, approval of the final version of the manuscript, and agreed for all aspects of the work. SM contributed in the conception of the work, approval of the final version of the manuscript, and agreed for all aspects of the work. NN contributed in the conception of the work, conducting the study, revising the draft, approval of the final version of the manuscript, and agreed for all aspects of the work. RA contributed in the conception of the work, revising the draft, approval of the final version of the manuscript, and agreed for all aspects of the work. ON contributed in the conception of the work, revising the draft, approval of the final version of the manuscript, and agreed for all aspects of the work.\n\nACKNOWLEDGMENTS\nWe are grateful to Mr. Vahedi for his critical editing. We would like to thank Elham Mosayebi and Iman Haghani for their technical assistance.\n\nSource of Support: This study is funded by Mazandaran University of Medical Sciences, Sari, Iran\n\nConflict of Interest: None declared.\n==== Refs\nREFERENCES\n1 Arendrup MC Bille J Dannaoui E Ruhnke M Heussel CP Kibbler C ECIL-3 classical diagnostic procedures for the diagnosis of invasive fungal diseases in patients with leukaemia Bone Marrow Transplant 2012 47 1030 45 22231461 \n2 Nabili M Shokohi T Janbabaie G Hashemi-Soteh MB Ali-Moghaddam K Aghili SR Detection of invasive aspergillosis in bone marrow transplant recipients using real-time PCR J Glob Infect Dis 2013 5 68 75 23853434 \n3 Denning DW Invasive aspergillosis Clin Infect Dis 1998 26 781 803 9564455 \n4 Cornet M Fleury L Maslo C Bernard JF Brücker G Invasive Aspergillosis Surveillance Network of the Assistance Publique-Hôpitaux de Paris. Epidemiology of invasive aspergillosis in France: A six-year multicentric survey in the Greater Paris area J Hosp Infect 2002 51 288 96 12183144 \n5 Patterson TF Kirkpatrick WR White M Hiemenz JW Wingard JR Dupont B Invasive aspergillosis. Disease spectrum, treatment practices, and outcomes. I3 Aspergillus Study Group Medicine (Baltimore) 2000 79 250 60 10941354 \n6 Yeghen T Kibbler CC Prentice HG Berger LA Wallesby RK McWhinney PH Management of invasive pulmonary aspergillosis in hematology patients: A review of 87 consecutive cases at a single institution Clin Infect Dis 2000 31 859 68 11049762 \n7 Pagano L Caira M Candoni A Offidani M Fianchi L Martino B The epidemiology of fungal infections in patients with hematologic malignancies: The SEIFEM-2004 study Haematologica 2006 91 1068 75 16885047 \n8 Yang CC Hsu PC Cheng CW Lee MH Coexistence of fatal disseminated invasive aspergillosis and pyoderma gangrenosum: A case report Med Princ Pract 2011 20 380 3 21577002 \n9 van Burik JA Colven R Spach DH Cutaneous aspergillosis J Clin Microbiol 1998 36 3115 21 9774549 \n10 Yoshida A Sato T Akasaka T A case of primary pyoderma-like aspergillosis occurring in a patient with a cervical spinal cord injury Jpn J Med Mycol 2002 43 5 9 \n11 Wollina U Pyoderma gangrenosum – a review Orphanet J Rare Dis 2007 2 19 17433111 \n12 De Pauw B Walsh TJ Donnelly JP Stevens DA Edwards JE Calandra T Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group Clin Infect Dis 2008 46 1813 21 18462102 \n13 Ng TT Robson GD Denning DW Hydrocortisone-enhanced growth of Aspergillus spp.: Implications for pathogenesis Microbiology 1994 140 2475 9 7952197 \n14 Nucci M Anaissie E Cutaneous infection by Fusarium species in healthy and immunocompromised hosts: Implications for diagnosis and management Clin Infect Dis 2002 35 909 20 12355377 \n15 Bazan ²³³ C McCarthy MJ Rosado-de-Christenson ML Chintapalli K Anaissie EJ McGinnis MR Pfaller MA Radiology of fungal infections Clinical Mycology 2003 London, Philadelphia Churchill Livingstone 117 9 \n16 Dagenais TR Keller NP Pathogenesis of Aspergillus fumigatus in invasive aspergillosis Clin Microbiol Rev 2009 22 447 65 19597008 \n17 Krishnan S Manavathu EK Chandrasekar PH Aspergillus flavus : An emerging non-fumigatus Aspergillus species of significance Mycoses 2009 52 206 22 19207851 \n18 Kuhlman JE Fishman EK Siegelman SS Invasive pulmonary aspergillosis in acute leukemia: Characteristic findings on CT, the CT halo sign, and the role of CT in early diagnosis Radiology 1985 157 611 3864189 \n19 Aquino SL Kee ST Warnock ML Gamsu G Pulmonary aspergillosis: Imaging findings with pathologic correlation AJR Am J Roentgenol 1994 163 811 5 8092014 \n20 Curtis AM Smith GJ Ravin CE Air crescent sign of invasive aspergillosis Radiology 1979 133 17 21 472287 \n21 Ahmadi S Powell FC Pyoderma gangrenosum: Uncommon presentations Clin Dermatol 2005 23 612 20 16325070 \n22 Zribi J Boudaya S Sallemi A Masmoudi A Chaabène H Makni F Atypical cutaneous Fusarium infection in an immunocompetent patient Ann Dermatol Venereo 2010 137 630 4 \n23 Hsu CK Hsu MM Lee JY Fusariosis occurring in an ulcerated cutaneous CD8+T cell lymphoma tumor Eur J Dermatol 2006 16 297 301 16709499 \n24 Nucci M Anaissie E Fusarium infections in immunocompromised patients Clin Microbiol Rev 2007 20 695 704 17934079 \n25 Baden LR Katz JT Fishman JA Koziol C DelVecchio A Doran M Salvage therapy with voriconazole for invasive fungal infections in patients failing or intolerant to standard antifungal therapy Transplantation 2003 76 1632 7 14702539 \n26 Glasmacher A Cornely OA Orlopp K Reuter S Blaschke S Eichel M Caspofungin treatment in severely ill, immunocompromised patients: A case-documentation study of 118 patients J Antimicrob Chemother 2006 57 127 34 16308418 \n27 Ozdemir HG Oz Y Ilkit M Kiraz N Antifungal susceptibility of ocular fungal pathogens recovered from around the world against itraconazole, voriconazole, amphotericin B, and caspofungin Med Mycol 2012 50 130 5 21599550 \n28 Carneiro HA Coleman JJ Restrepo A Mylonakis E Fusarium infection in lung transplant patients: Report of 6 cases and review of the literature Medicine (Baltimore) 2011 90 69 80 21200188\n\n",
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"keywords": "Aspergillus; Fusarium; invasive pulmonary aspergillosis; pyoderma gangrenosum",
"medline_ta": "J Res Med Sci",
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"title": "Co-infection of invasive pulmonary aspergillosis and cutaneous Fusarium infection in a patient with pyoderma gangrenosum.",
"title_normalized": "co infection of invasive pulmonary aspergillosis and cutaneous fusarium infection in a patient with pyoderma gangrenosum"
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"abstract": "We present a case of an HIV-positive man with systemic immunoglobulin light chain (AL) amyloid with cardiac involvement. At relapse, he was treated with lenalidomide and dexamethasone having previously developed autonomic neuropathy with bortezomib-based chemotherapy. The patient achieved a serological complete response with symptomatic improvement. After 11 cycles, lenalidomide was discontinued due to extensive ischaemia of the gastrointestinal tract. The patient remains symptomatically stable with normal levels of serum-free light chains 11 months after the treatment was discontinued. Lenalidomide can be a good treatment option for AL amyloidosis in HIV-infected patients on antiretroviral therapy.",
"affiliations": "Genitourinary Medicine, Queen Elizabeth Hospital, Birmingham, UK.;Genitourinary Medicine, Queen Elizabeth Hospital, Birmingham, UK.;Genitourinary Medicine, Queen Elizabeth Hospital, Birmingham, UK.",
"authors": "Denman|Johanna|J|;Manavi|Kaveh|K|;Cook|Mark|M|",
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"issue": "28(10)",
"journal": "International journal of STD & AIDS",
"keywords": "HIV; amyloid; lenalidomide",
"medline_ta": "Int J STD AIDS",
"mesh_terms": "D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069286:Bortezomib; D003907:Dexamethasone; D006679:HIV Seropositivity; D006801:Humans; D000075363:Immunoglobulin Light-chain Amyloidosis; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D010265:Paraproteinemias; D012008:Recurrence; D013792:Thalidomide; D016896:Treatment Outcome",
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"title": "Lenalidomide as a treatment for relapsed AL amyloidosis in an HIV-positive patient.",
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"abstract": "Drug-induced immune hemolytic anemia (DIIHA) is a rare type of immune-mediated hemolytic anemia, and mainly it is caused by antibiotics. There have been few case reports of contrast medium-induced immune hemolytic anemia. Here, we report a case of a 70-year-old woman who was admitted with community-acquired pneumonia. She had a CT abdomen and pelvis using iohexol (omnipaque), which resulted in severe hemolytic anemia and contributed to the patient's death. This case illustrates a very rare complication of IV contrast medium that may result in death.",
"affiliations": "Medicine, Oman Medical Speciality Board, Muscat, OMN.;Medicine, Sultan Qaboos University Hospital, Muscat, OMN.;Medicine, Sultan Qaboos University Hospital, Muscat, OMN.",
"authors": "Al Ghailani|Hajar H|HH|;Al Alawi|Abdullah M|AM|;Al Hashim|Abdul Hakeem|AH|",
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"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.14522\nRadiology\nAllergy/Immunology\nHematology\nContrast Media-Induced Immune Hemolytic Anemia\nMuacevic Alexander\nAdler John R\nAl Ghailani Hajar H 1\nAl Alawi Abdullah M 2\nAl Hashim Abdul Hakeem 2\n1 Medicine, Oman Medical Speciality Board, Muscat, OMN\n2 Medicine, Sultan Qaboos University Hospital, Muscat, OMN\nAbdullah M. Al Alawi dr.abdullahalalawi@gmail.com\n16 4 2021\n4 2021\n13 4 e1452216 4 2021\nCopyright © 2021, Al Ghailani et al.\n2021\nAl Ghailani et al.\nhttps://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nThis article is available from https://www.cureus.com/articles/56152-contrast-media-induced-immune-hemolytic-anemia\nDrug-induced immune hemolytic anemia (DIIHA) is a rare type of immune-mediated hemolytic anemia, and mainly it is caused by antibiotics. There have been few case reports of contrast medium-induced immune hemolytic anemia. Here, we report a case of a 70-year-old woman who was admitted with community-acquired pneumonia. She had a CT abdomen and pelvis using iohexol (omnipaque), which resulted in severe hemolytic anemia and contributed to the patient’s death. This case illustrates a very rare complication of IV contrast medium that may result in death.\n\na radiographic contrast medium\nimmune-mediated hemolysis\nhemolysis\nhemolytic anemia\npneumonia\nThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\n\nDrug-induced autoimmune hemolytic anemia (DIIHA) is relatively rare, may go undiagnosed in many cases, and the magnitude of hemolysis can vary widely [1]. Drugs may induce the formation of antibodies against red blood cell (RBC) membrane or intrinsic RBC antigen, which may induce immune-mediated hemolysis. The incidence of DIIHA is approximately 1 per million/year [2]. More than 130 drugs have been associated with DIIHA but the most commonly reported include cephalosporins, diclofenac, rifampicin, oxaliplatin, and fludarabine [3].\n\nCase presentation\n\nA 70-year-old woman was brought to the emergency department at Sultan Qaboos University Hospital (SQUH) with a cough, shortness of breath, and fever of five days duration. Her medical background included ischemic stroke with severe disability (modified Rankin scale 5/6), type 2 diabetes mellitus, hypertension, depression, severe osteoarthritis, and atrial fibrillation. Her regular medications were quetiapine (25 mg BID), amlodipine (5 mg daily), esomeprazole (20 mg daily), glargine insulin (20 units at night), metformin (500 mg BID), bisoprolol (5mg daily), spironolactone (25 mg daily), and ferrous sulfate (200 mg daily).\n\nOn examination, the patient appeared sick and confused. Her vitals were as follows: temperature 37.2 °C, blood pressure 96/25 mmHg, pulse 130 beats per minute, respiratory rate 40/minute, and oxygen saturation 50% on ambient air. The chest examination revealed bilateral basal crackles, and on abdominal examination, she had a distended abdomen but no organomegaly. Other systemic examinations were unremarkable.\n\nLaboratory findings are presented in Table 1. As summarized, the patient blood showed raised inflammation markers, deranged coagulation profile, raised lactate, acute kidney injury, and deranged liver functions.\n\nTable 1 Important work-up results on the day of admission.\n\nWBC: white cell count; PT: prothrombin time; aPTT: activated partial thromboplastin time; INR: international normalized ratio.\n\nTest\tAdmission day\tNormal range\t\nHemoglobin (g/dL)\t11.7\t11-14.4\t\nWBC (109/L)\t17.5\t2.4-9.5\t\nNeutrophil count (109/L)\t13.9\t1-4.8\t\nPlatelets count (109/L)\t133\t150-450\t\nPT (second)\t20.1\t10.5-12.7\t\naPTT (second)\t41\t25.6-37.7\t\nINR\t1.83\t0.92-1.08\t\nFibrinogen (g/L)\t3.8\t1.7-3.6\t\nC-reactive protein\t25\t<5\t\nVenous PH\t7.2\t7.35-7.45\t\nLactate (mmol/L)\t7.7\t0.5-1.6\t\nCreatinine (mmol/L)\t112\t59-104\t\nHCO3 (mmol/L)\t22.5\t22-24\t\nPotassium (mmol/L)\t7.2\t3.5-5\t\nSodium (mmol/L)\t144\t135-145\t\nUrea (mmol/L)\t11.5\t2.8-8.1\t\nAlanine transaminase (U/L)\t6658\t0-33\t\nAspartate aminotransferase (U/L)\t7771\t0-17\t\nAlkaline phosphatase (mmol/L)\t107\t35-104\t\nTotal bilirubin (µmol/L)\t9\t0-17\t\nSARS-COV-2 PCR\tnegative\t \t\n\nChest X-ray demonstrated bibasilar infiltrates (Figure 1).\n\nFigure 1 Chest X-ray shows bilateral pulmonary infiltrates and consolidation.\n\nThe patient was admitted with the impression of severe community-acquired pneumonia, causing septic shock, which led to multi-organ failure. The patient was intubated, mechanically ventilated, and started on IV antibiotics (piperacillin/tazobactam and azithromycin). She also required vasopressors for the management of her septic shock. Despite antibiotics, she remained febrile for the following 48 hours after; therefore, piperacillin/tazobactam was upgraded to meropenem. A CT scan of the abdomen and pelvis with IV contrast was done to look for an intraabdominal source of sepsis or hepatic vein thrombosis given the grossly deranged liver function test. The scan showed bilateral basal pulmonary consolidation and fatty liver without any other significant finding. Fourteen hours following the CT scan with IV contrast, her hemoglobin dropped from 10.6 to 7.6 g/dL (normal 11-14.4). There was no evidence of active bleeding. A blood film was performed, and it revealed normocytic normochromic red cells with anisocytosis, polychromia, bite cell, blister cells, acanthocytes, highly toxic neutrophils, and there were no fragmented cells. Other hemolytic workups were suggestive of active intravascular hemolysis (Table 2).\n\nTable 2 Hemolytic work-up results.\n\nG6PD: glucose-6-phosphate dehydrogenase, SLA/LP: soluble liver antigen/liver-pancreas, LC-1: liver cytosol antigen type 1, AMA-M2: anti-mitochondrial M2 antibody, LKM-1: liver-kidney microsome type 1, gp210: glycoprotein-210, PML: promyelocytic leukemia.\n\n \tResult\tNormal range\t\nReticulocyte count %\t4.6\t0.5-1.5\t\nLactate dehydrogenase (U/L)\t5970\t135-214\t\nHaptoglobin (g/L)\t<0.1\t0.3-2\t\nPlatelets count (109/L)\t118\t150-450\t\nG6PD\t40-70% activity\t \t\naPTT (second)\t46.1\t25.6-37.7\t\nPT (second)\t16.4\t10.5-12.7\t\nINR\t1.47\t0.92-1.08\t\nFibrinogen (g/L)\t3.9\t1.7-3.6\t\nBilirubin\t89\t0-17\t\nDirect anti-globulin test\tPositive for IgG \t \t\nMycoplasma serology\tNegative\t \t\nAnti-SLA/LP\tNegative\t \t\nAnti-LC-1\tNegative\t \t\nAMA-M2\tNegative\t \t\nAnti-Ro52\tNegative\t \t\nAnti-LKM-1\tNegative\t \t\nAnti-gp210\tNegative\t \t\nAnti-PML\tNegative\t \t\nAnti-Sp100\tNegative\t \t\n3E (BPO)\tNegative\t \t\n\nThe patient was supported with blood transfusion, and despite that, unfortunately, she had a severe hemolysis course, which led to a further drop in her hemoglobin to 4 g/dL (normal 11-14.4). Her course was complicated by atrial fibrillation with a fast ventricular rate and acute kidney injury requiring renal replacement therapy. The patient’s condition deteriorated further, and she had cardiopulmonary arrest 48 hours after receiving IV contrast, and cardiopulmonary resuscitation was unsuccessful.\n\nDiscussion\n\nThe patient was admitted with severe community-acquired pneumonia. Her intensive unit care admission was complicated by a severe course of hemolysis leading to patient deterioration. The differential diagnosis of hemolytic anemia in this clinical context included disseminated intravascular coagulopathy (DIC), glucose-6-phosphate dehydrogenase (G6PD) deficiency-induced hemolysis, and autoimmune hepatitis. However, normal fibrinogen level, blood film findings, negative autoimmune hepatitis screening largely excluded these differential diagnoses. The clinical presentation with cough and fever, deranged liver enzymes, and the positive direct anti-globulin test could be explained by the Ebstein Bar virus, which unfortunately was not tested. However, the early onset of severe hemolysis, absence of lymphocytosis or lymphopenia, and the absence of other clinical features, including inflamed throat, lymphadenopathy, hepatosplenomegaly, were against infective mononucleosis. Mycoplasma pneumonia can cause autoimmune hemolytic anemia; however, the clinical presentation and the negative mycoplasma serology test made this possibility unlikely [4]. The patient received piperacillin/tazobactam for the first 48 hours; however, hemolysis's abrupt onset followed the cessation of piperacillin/tazobactam made it an unlikely differential diagnosis.\n\nThe patient did not receive any of the medications which are known to be associated with DIIHA. It was evident that the patient developed a severe hemolysis course within hours after receiving 100 ml of iohexol (omnipaque) contrast, which makes contrast-induced immune intravascular hemolysis is the likely diagnosis [5].\n\nNonimmune hyperosmolar contrast-induced sickling and hemolysis were described in a patient with sickle cell disease following coronary angiography [6]. Only three cases of contrast medium induced immune intravascular hemolysis were reported in medical literature [2,7,8]. One patient developed severe hemolysis after the injection of Isopaque, an older ionic contrast medium, and serologic studies provided evidence for immunoglobulin (Ig)M, whereas the other two patients had intravascular hemolysis after administration of iomeprol contrast medium [2,8]. Drug-induced immune hemolysis (drug-dependent type) is the most likely explanation of the hemolysis in our case, evidenced by the abrupt severe hemolysis after the administration of iohexol (omnipaque), the positive DAT (IgG class), and the absence of other factors explaining the sever onset hemolysis. Cessation of the culprit drug and blood products transfusion are the main aspects in the management of drug-induced hemolytic anemia [9]. Steroids, intravenous immunoglobulins (IVIG), plasmapheresis, or immunosuppressants may be tried in refractory cases [10,11].\n\nWe report the first case report of severe immune-mediated hemolytic anemia precipitated by iohexol administration (omnipaque). Unfortunately, severe hemolytic anemia may have contributed to patient deterioration and death.\n\nConclusions\n\nThis case reports the first case of iohexol (contrast media) induced immune hemolytic anemia in a critically sick patient. It highlights a very rare but serious complication of contrast medium. Contrast-induced immune hemolytic anemia should be known to clinicians and considered in the differential diagnosis of unexplained hemolysis after administration of contrast media.\n\nHuman Ethics\n\nThe authors have declared that no competing interests exist.\n\nConsent was obtained or waived by all participants in this study\n==== Refs\nReferences\n\n1 Immune hemolytic anemia caused by drugs Expert Opin Drug Saf Garratty G 635 642 11 2012 22502777\n2 Immune hemolysis secondary to injection of contrast medium Transfusion Maurin C Vassal O Darien M Raba M Allaouchiche B Piriou V 2113 2114 58 2018 30153332\n3 Drug-induced immune hemolytic anemia Expert Opin Drug Saf Salama A 73 79 8 2009 19236219\n4 Severe hemolytic anemia associated with mild pneumonia caused by Mycoplasma pneumonia Case Rep Med Kurugol Z Onen SS Koturoglu G 649850 2012 2012 23049568\n5 Haemolytic anaemia caused by piperacillin-tazobactam Acta Clin Belg Dapper I Nauwynck M Selleslag D Hidajat M Bourgeois M Martens P Wilmer A 517 519 64 2009 20101875\n6 Angiographic contrast agent-induced acute hemolysis in a patient with hemoglobin SC disease Arch Intern Med Rao AK Thompson R Durlacher L James F 759 760 145 1985 https://pubmed.ncbi.nlm.nih.gov/3985742/ 3985742\n7 Immune-mediated hemolysis associated with the administration of a radiographic contrast medium Transfusion Nordhagen R Vik H Wolthuis K Bøhn HP Urdahl P Michaelsen TE 843 846 31 1991 1755090\n8 Intravascular immune hemolysis caused by the contrast medium iomeprol Transfusion Mayer B Leo A Herziger A Houben P Schemmer P Salama A 2141 2144 53 2013 23347254\n9 Drug-induced immune hemolytic anemia due to amoxicillin-clavulanate: a case report and review Cureus Chan Gomez J Saleem T Snyder S Joseph M Kanderi T 0 12 2020\n10 Ceftriaxone-induced hemolytic anemia with severe renal failure: a case report and review of literature BMC Pharmacol Toxicol Leicht HB Weinig E Mayer B Viebahn J Geier A Rau M 67 19 2018 30359322\n11 Co-amoxiclav induced immune haemolytic anaemia: a case report Case Rep Hematol Karunathilaka HG Chandrasiri DP Ranasinghe P Ratnamalala V Fernando AH 9841097 2020 2020 32292611\n\n",
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"title": "Contrast Media-Induced Immune Hemolytic Anemia.",
"title_normalized": "contrast media induced immune hemolytic anemia"
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"abstract": "A case of intraocular coenurosis was clinically diagnosed and treated with praziquantel. The drug destroyed the coenurus, but vision was lost through toxic endophthalmitis and retinal detachment. There were no systemic side effects.",
"affiliations": "Department of Ophthalmology, Jos University Teaching Hospital, Nigeria.",
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"issue": "75(7)",
"journal": "The British journal of ophthalmology",
"keywords": null,
"medline_ta": "Br J Ophthalmol",
"mesh_terms": "D000328:Adult; D002590:Cestode Infections; D009877:Endophthalmitis; D015822:Eye Infections, Parasitic; D006801:Humans; D008297:Male; D011223:Praziquantel; D012163:Retinal Detachment",
"nlm_unique_id": "0421041",
"other_id": null,
"pages": "430-1",
"pmc": null,
"pmid": "1854698",
"pubdate": "1991-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "3883789;13820487;3031965;5129969",
"title": "Intraocular coenurosis: a case report.",
"title_normalized": "intraocular coenurosis a case report"
} | [
{
"companynumb": "NG-BAYER-2016-157452",
"fulfillexpeditecriteria": "1",
"occurcountry": "NG",
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"activesubstancename": "PREDNISOLONE"
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... |
{
"abstract": "ST-segment elevation is a dreadful finding in the emergency department because it is often associated with myocardial infarction and demands a prompt and definitive treatment. However, the clinical and echocardiographic assessment of a patient with electrocardiographic changes trumps any electrocardiology expert and should always lead to a clinical decision. (Level of Difficulty: Intermediate.).",
"affiliations": "Cardiology Department, Centro Hospitalar de Vila Nova de Gaia/Espinho, Porto, Portugal.;Cardiology Department, Centro Hospitalar de Vila Nova de Gaia/Espinho, Porto, Portugal.;Cardiology Department, Centro Hospitalar de Vila Nova de Gaia/Espinho, Porto, Portugal.;Cardiology Department, Centro Hospitalar de Vila Nova de Gaia/Espinho, Porto, Portugal.",
"authors": "Sousa-Nunes|Fábio|F|;Dias|Adelaide|A|;Ribeiro|José|J|;Fontes-Carvalho|Ricardo|R|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jaccas.2021.06.035",
"fulltext": "\n==== Front\nJACC Case Rep\nJACC Case Rep\nJACC Case Reports\n2666-0849\nElsevier\n\nS2666-0849(21)00634-3\n10.1016/j.jaccas.2021.06.035\nEcg Teaching Competition\nImaging Vignette: ECG Challenge\nA Pleasant Surprise in the Face of ST-Segment Elevation\nSousa-Nunes Fábio MD fabiosnun@gmail.com\nab∗\nDias Adelaide MD a\nRibeiro José MD a\nFontes-Carvalho Ricardo MD, PhD ab\na Cardiology Department, Centro Hospitalar de Vila Nova de Gaia/Espinho, Porto, Portugal\nb Cardiovascular Research and Development Center, Faculty of Medicine of the University of Porto, Porto, Portugal\n∗ Address for correspondence: Dr Fábio Sousa-Nunes, Cardiology Department, Centro Hospitalar de Vila Nova de Gaia/Espinho, R. Conceição Fernandes S/N, 4434-502 Vila Nova de Gaia, Portugal. fabiosnun@gmail.com\n01 9 2021\n01 9 2021\n01 9 2021\n3 11 13841386\n16 4 2021\n28 5 2021\n3 6 2021\n© 2021 The Authors\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nST-segment elevation is a dreadful finding in the emergency department because it is often associated with myocardial infarction and demands a prompt and definitive treatment. However, the clinical and echocardiographic assessment of a patient with electrocardiographic changes trumps any electrocardiology expert and should always lead to a clinical decision. (Level of Difficulty: Intermediate.)\n\nCentral Illustration\n\nKey Words\n\nhypertrophic cardiomyopathy\nSTEMI mimic\nsyncope\nAbbreviations and Acronyms\n\nAF, atrial fibrillation\nAMI, acute myocardial infarction\nECG, electrocardiography\nHCM, hypertrophic cardiomyopathy\nLV, left ventricular\nLVH, left ventricular hypertrophy\n==== Body\npmcCASE\n\nAn 85-year-old woman, with a medical history of hypertension and atrial fibrillation (AF), which was treated with apixaban, bisoprolol, and furosemide, came to the emergency department with complaints of atypical chest pain and a syncopal event at home. It was one of the coldest days of the year, and the patient had a tympanic temperature of 34 ºC at admission. While awaiting medical observation, the patient had a new syncopal event with quick recovery. She was brought to the resuscitation room where electrocardiography (ECG) was performed (Figure 1A). The previous ECG, taken 2 months before, is also shown (Figure 1B).Figure 1 Electrocardiograms\n\n(A) 12-lead electrocardiogram taken at presentation. (B) 12-lead electrocardiogram taken 2 months before this presentation.\n\nWHAT IS THE DIAGNOSIS?\n\nBesides AF, what is your diagnosis?\n\nA. Acute myocardial infarction (AMI) involving the anterior descending artery\n\nB. Vasospasm\n\nC. Acute pulmonary embolism\n\nD. Hypertrophic cardiomyopathy\n\nE. Hypothermia\n\nThe correct answer is D.\n\nExplanation\n\nAll the answers are causes of ST-segment elevation and may present with syncopal events. However, a careful examination soon found the correct diagnosis.\n\nThe ECG (Figure 1A) shows AF with an average heart rate of 131 beats/min, pathological Q waves in the inferior leads, and significant convex ST-segment elevation in leads V1 to V3. This ECG meets the criteria for left ventricular hypertrophy (LVH) (deepest S-wave in lead V1 and tallest R-wave in lead V5/V6 ≥35 mm and associated left ventricular [LV] strain pattern) (1).\n\nOn observation, the patient was remarkably stable. More significantly, a similar ECG pattern was present on a previous examination (Figure 1B), thus making it less likely that acute events, such as AMI, pulmonary embolism, or vasospasm, would be the cause of these ECG changes. Sometimes, hypothermia may be associated with Osborn waves (or camel hump waves because of their characteristic shape), which are better seen in the inferior and lateral leads, but they should not be present on separate occasions, as in this case (2).\n\nThis correct diagnosis was made with bedside echocardiography that showed normal LV function, but severe LVH, mainly at the interventricular septum and apical LV (Video 1). The inferior vena cava was collapsible. The empiric diagnosis of hypertrophic cardiomyopathy (HCM) was made. The combination of HCM with dehydration caused by furosemide intake placed the patient at risk of low stroke volume, which may have caused the syncope. Notably, upon further questioning, the patient stated that several of her kindred had heart conditions, which were later found out to be HCM. Syncope is one of the presenting symptoms of HCM and is related to the dynamic outflow tract obstruction caused by the hypertrophied myocardium, which is made worse due to dehydration. Familial association of HCM cases is common, reflecting the genetic basis of this disease (3).\n\nThe patient was treated with intravenous fluids and discharged with a recommendation to stop furosemide.\n\nAlthough syncope is a classic finding in patients with HCM, other causes of syncope should be excluded, particularly ventricular arrythmias and tachy-brady syndrome with a possible period of supraventricular tachycardia being succeeded by a pause, particularly in a patient with AF. Because of these diagnostic possibilities, it would be reasonable to recommend an ambulatory prolonged ECG monitoring.\n\nFunding Support and Author Disclosures\n\nThe authors have reported that they have no relationships relevant to the contents of this paper to disclose.\n\nAppendix\n\nSupplemental Video 1\n\nBedside Echocardiograph. The video is looped and has been slowed down to highlight these structural changes.\n\nThe authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.\n\nAppendix\n\nFor a supplemental video, please see the online version of this paper.\n==== Refs\nReferences\n\n1 Hancock E.W. Deal B.J. Mirvis D.M. AHA/ACCF/HRS recommendations for the standardization and interpretation of the electrocardiogram. Part V: electrocardiogram changes associated with cardiac chamber hypertrophy: a scientific statement from the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society. Endorsed by the International Society for Computerized Electrocardiology J Am Coll Cardiol 53 11 2009 992 1002 19281932\n2 Alhaddad I.A. Khalil M. Brown E.J. Jr. Osborn waves of hypothermia Circulation 101 25 2000 e233-244\n3 Geske J.B. Ommen S.R. Gersh B.J. Hypertrophic cardiomyopathy: clinical update J Am Coll Cardiol HF 6 5 2018 364 375\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2666-0849",
"issue": "3(11)",
"journal": "JACC. Case reports",
"keywords": "AF, atrial fibrillation; AMI, acute myocardial infarction; ECG, electrocardiography; HCM, hypertrophic cardiomyopathy; LV, left ventricular; LVH, left ventricular hypertrophy; STEMI mimic; hypertrophic cardiomyopathy; syncope",
"medline_ta": "JACC Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101757292",
"other_id": null,
"pages": "1384-1386",
"pmc": null,
"pmid": "34505078",
"pubdate": "2021-09-01",
"publication_types": "D016428:Journal Article",
"references": "10869275;19281932;29655825",
"title": "A Pleasant Surprise in the Face of ST-Segment Elevation.",
"title_normalized": "a pleasant surprise in the face of st segment elevation"
} | [
{
"companynumb": "PT-MLMSERVICE-20220127-3341504-1",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FUROSEMIDE"
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"drugadditional": "1",
... |
{
"abstract": "OBJECTIVE\nFew studies have examined conventional catheter directed thrombolysis (CDT) for the treatment of submassive pulmonary embolism (PE). Moreover, angiographic resolution of thrombus burden following CDT has infrequently been characterized. This study describes a single-center experience treating submassive PE with CDT while utilizing repeat angiography to determine treatment efficacy.\n\n\nMETHODS\nA retrospective analysis of 140 consecutive patients who underwent CDT for submassive PE from December 2012 to June 2019 was performed. Angiographic resolution of thrombus burden after CDT was reported as high (>75%), moderate (51-75%), low (26-50%), or insignificant (≤25%). All angiograms were reviewed by two interventional radiologists. Secondary endpoints included reduction in pulmonary artery pressure (PAP) and clinical outcomes. Bleeding events were classified according to the Society of Interventional Radiology (SIR) adverse event criteria.\n\n\nRESULTS\nCDT was performed in 140 patients with a mean rtPA dose of 25.3 mg and a mean treatment time of 26.0 hours. Angiographic resolution of thrombus burden was high in 70.0%, moderate in 19.3%, low in 5.7%, and insignificant in 3.6%; in 2 patients (1.4%) repeat angiography was not performed. Systolic PAP was reduced (47 vs. 35 mmHg, p < 0.001), mean PAP was reduced (25 vs 21 mmHg, p < 0.001), and 129 patients (92.1%) improved clinically. Patients with high or moderate resolution of thrombus burden had a clinical improvement rate of 95.2%, while patients with low or insignificant thrombus burden resolution had a clinical improvement rate of 76.9% (p=0.011). Ten patients (7.1%) had hemodynamic or respiratory decompensation requiring mechanical ventilation, systemic thrombolysis, cardiopulmonary resuscitation, or surgical intervention. Seven patients (5.0%) experienced moderate bleeding events and one patient (0.7%) with metastatic disease developed severe gastrointestinal bleeding that resulted in death. Thirty-day mortality was 1.4%.\n\n\nCONCLUSIONS\nIn patients with submassive PE undergoing CDT, angiographic resolution of thrombus burden is a safe and directly observable metric that can be used to determine procedural success. In this study, CDT with repeat angiography was associated with a 5.7% bleeding event rate and thirty-day mortality of 1.4%.",
"affiliations": "Department of Radiology, Indiana University School of Medicine, Indianapolis, Indiana, US.;Department of Radiology, Indiana University School of Medicine, Indianapolis, Indiana, US.;Department of Radiology, Indiana University School of Medicine, Indianapolis, Indiana, US.",
"authors": "Schmitz|Adam|A|;Schacht|Michael|M|;Butty|Sabah|S|",
"chemical_list": "D005343:Fibrinolytic Agents",
"country": "Turkey",
"delete": false,
"doi": "10.5152/dir.2021.20573",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1305-3825",
"issue": "27(5)",
"journal": "Diagnostic and interventional radiology (Ankara, Turkey)",
"keywords": null,
"medline_ta": "Diagn Interv Radiol",
"mesh_terms": "D000792:Angiography; D057785:Catheters; D005343:Fibrinolytic Agents; D006801:Humans; D011655:Pulmonary Embolism; D012189:Retrospective Studies; D015912:Thrombolytic Therapy; D016896:Treatment Outcome",
"nlm_unique_id": "101241152",
"other_id": null,
"pages": "664-670",
"pmc": null,
"pmid": "34559051",
"pubdate": "2021-09",
"publication_types": "D016428:Journal Article",
"references": "26716031;21422387;29073366;27630267;25427436;11888976;27318043;25704224;25680885;30915912;25173341;24996605;12814982;10859287;27481877;31072507;26315743;28757285;24716681;22275389;22723513;24848835;29872248;22993221;24226805;25633189;5155756;29980817;23601295;25856269;31492420",
"title": "Repeat angiography in patients undergoing conventional catheter-directed thrombolysis for submassive pulmonary embolism: a large single-center experience.",
"title_normalized": "repeat angiography in patients undergoing conventional catheter directed thrombolysis for submassive pulmonary embolism a large single center experience"
} | [
{
"companynumb": "US-MYLANLABS-2022M1030488",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": "3",
... |
{
"abstract": "Nephrogenic diabetes insipidus due to the inability of the kidneys to concentrate urine is frequently observed during lithium therapy. Lithium concentrates into principal cells in collecting ducts in the kidney and downregulates aquaporin 2 expression, which reduces renal reabsorption of water. This disease is characterized by polyuria - polydipsia leading to intracellular dehydration and hypernatremia. Water deprivation test is performed to confirm insipidus diabetes. The desmopressin permits to distinguish nephrogenic from cranial insipidus diabetes. We report the case of a 64 years old women who presented with global dehydration and severe hypernatremia. Four years ago, she was hospitalized for nephrogenic diabetes insipidus related to a self-induced lithium intoxication. Persistent nephrogenic insipidus diabetes after cessation of lithium therapy are described in literature, and this hypothesis may be consistent with this case report.",
"affiliations": "Laboratoire de biochimie, Hôpital Lapeyronie, CHU Montpellier, France.;Laboratoire de biochimie, Hôpital Lapeyronie, CHU Montpellier, France, Phymedexp, Université de Montpellier, Inserm, CNRS, CHU de Montpellier, Montpellier, France.;Laboratoire de pharmacologie médicale et toxicologie, Hôpital Lapeyronie, CHU Montpellier, France.;Laboratoire de biochimie, Hôpital Lapeyronie, CHU Montpellier, France, Phymedexp, Université de Montpellier, Inserm, CNRS, CHU de Montpellier, Montpellier, France.;Laboratoire de biochimie, Hôpital Lapeyronie, CHU Montpellier, France, Phymedexp, Université de Montpellier, Inserm, CNRS, CHU de Montpellier, Montpellier, France.;Laboratoire de biochimie, Hôpital Lapeyronie, CHU Montpellier, France, Phymedexp, Université de Montpellier, Inserm, CNRS, CHU de Montpellier, Montpellier, France.",
"authors": "Fayolle|Martin|M|;Souweine|Jean-Sébastien|JS|;Mathieu|Olivier|O|;Bargnoux|Anne-Sophie|AS|;Cristol|Jean-Paul|JP|;Badiou|Stéphanie|S|",
"chemical_list": "D018020:Lithium Compounds; D014867:Water; D012964:Sodium",
"country": "France",
"delete": false,
"doi": "10.1684/abc.2020.1570",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-3898",
"issue": "78(4)",
"journal": "Annales de biologie clinique",
"keywords": "diuretic; hypernatremia; lithium; nephrogenic diabetes insipidus",
"medline_ta": "Ann Biol Clin (Paris)",
"mesh_terms": "D001714:Bipolar Disorder; D003681:Dehydration; D018500:Diabetes Insipidus, Nephrogenic; D005260:Female; D006801:Humans; D018020:Lithium Compounds; D008875:Middle Aged; D012964:Sodium; D014867:Water; D014869:Water Intoxication",
"nlm_unique_id": "2984690R",
"other_id": null,
"pages": "449-453",
"pmc": null,
"pmid": "32618565",
"pubdate": "2020-08-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Water, lithium and sodium: watch out for dangerous injuries.",
"title_normalized": "water lithium and sodium watch out for dangerous injuries"
} | [
{
"companynumb": "FR-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-253154",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LITHIUM"
},
"drugadd... |
{
"abstract": "Long-term functional outcomes of sofosbuvir-based antiviral treatment were evaluated in a cohort study involving 16 Italian centres within the international compassionate use programme for post-transplant hepatitis C virus (HCV) recurrence. Seventy-three patients with cirrhosis (n=52) or fibrosing cholestatic hepatitis (FCH, n=21) received 24-week sofosbuvir with ribavirin±pegylated interferon or interferon-free sofosbuvir-based regimen with daclatasvir/simeprevir+ribavirin. The patients were observed for a median time of 103 (82-112) weeks. Twelve of 73 (16.4%) died (10 non-FCH, 2 FCH) and two underwent re-LT. Sustained virological response was achieved in 46 of 66 (69.7%): 31 of 47 (66%) non-FCH and 15 of 19 (79%) FCH patients. All relapsers were successfully retreated. Comparing the data of baseline with last follow-up, MELD and Child-Turcotte-Pugh scores improved both in non-FCH (15.3±6.5 vs 10.5±3.8, P<.0001 and 8.4±2.1 vs 5.7±1.3, P<.0001, respectively) and FCH (17.3±5.9 vs 10.1±2.8, P=.001 and 8.2±1.6 vs 5.5±1, P=.001, respectively). Short-treatment mortality was higher in patients with baseline MELD≥25 than in those with MELD<25 (42.9% vs 4.8%, P=.011). Long-term mortality was 53.3% among patients with baseline MELD≥20 and 7.5% among those with MELD<20 (P<.0001). Among deceased patients 75% were Child-Turcotte-Pugh class C at baseline, while among survivors 83.9% were class A or B (P<.0001). Direct acting antivirals-based treatments for severe post-transplant hepatitis C recurrence, comprising fibrosing cholestatic hepatitis, significantly improve liver function, even without viral clearance and permit an excellent long-term survival. The setting of severe HCV recurrence may require the identification of \"too-sick-to-treat patients\" to avoid futile treatments.",
"affiliations": "Centro di Ricerca per lo Studio delle Epatiti, Dipartimento di Scienze Mediche e Chirurgiche, Università degli Studi di Bologna, Bologna, Italy.;Centro di Ricerca per lo Studio delle Epatiti, Dipartimento di Scienze Mediche e Chirurgiche, Università degli Studi di Bologna, Bologna, Italy.;Dipartimento di Medicina Specialistica e dei Trapianti, U.S.C. Gastroenterologia Epatologia e Trapiantologia, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy.;Centro di Ricerca per lo Studio delle Epatiti, Dipartimento di Scienze Mediche e Chirurgiche, Università degli Studi di Bologna, Bologna, Italy.;Dipartimento di Medicina Specialistica e dei Trapianti, U.S.C. Gastroenterologia Epatologia e Trapiantologia, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy.;Dipartimento di Medicina Specialistica e dei Trapianti, U.S.C. Gastroenterologia Epatologia e Trapiantologia, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy.;AUSL della Romagna, Presidio Ospedaliero di Faenza, Faenza, Italy.;Centro di Ricerca per lo Studio delle Epatiti, Dipartimento di Scienze Mediche e Chirurgiche, Università degli Studi di Bologna, Bologna, Italy.;Centro di Ricerca per lo Studio delle Epatiti, Dipartimento di Scienze Mediche e Chirurgiche, Università degli Studi di Bologna, Bologna, Italy.;Centro di Ricerca per lo Studio delle Epatiti, Dipartimento di Scienze Mediche e Chirurgiche, Università degli Studi di Bologna, Bologna, Italy.;Gastroenterologia ed Epatologia, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico ed Univerisità di Milano, Milan, Italy.;Gastroenterologia ed Epatologia, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico ed Univerisità di Milano, Milan, Italy.;Gastroenterologia ed Epatologia, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico ed Univerisità di Milano, Milan, Italy.;Centro di Ricerca per lo Studio delle Epatiti, Dipartimento di Scienze Mediche e Chirurgiche, Università degli Studi di Bologna, Bologna, Italy.;Centro di Ricerca per lo Studio delle Epatiti, Dipartimento di Scienze Mediche e Chirurgiche, Università degli Studi di Bologna, Bologna, Italy.;Dipartimento di Epatologia e Gastroenterologia, Ospedale Niguarda, Milan, Italy.;Dipartimento di Epatologia e Gastroenterologia, Ospedale Niguarda, Milan, Italy.;Chirurgia biliopancreatica e Trapianto di Fegato, Università di Pisa, Pisa, Italy.;Dipartimento di Chirurgia, Oncologia e Gastroenterologia, Unità di Trapianto Multiviscerale, Ospedale Universitario Padova, Padua, Italy.;Dipartimento di Chirurgia, Oncologia e Gastroenterologia, Unità di Trapianto Multiviscerale, Ospedale Universitario Padova, Padua, Italy.;Unità di Epatologia, Università Tor Vergata, Rome, Italy.;Medicina Interna Sezione di Trapianto di Fegato, Università di Udine, Udine, Italy.;Dipartimento di Medicina Clinica La Sapienza, Gastroenterologia, Università di Roma, Rome, Italy.;I.R.C.C.S. L. Spallanzani, Rome, Italy.;Chirurgia Oncologica Epato-bilio-pancreatica e Chirurgia dei Trapianti di fegato, AOU di Modena, Modena, Italy.;Unità di Malattie Infettive ed Epatologia, AOU di Parma, Parma, Italy.;Dipartimento di Medicina, Unità delle Emergenze epatologiche e dei Trapianti di fegato, Università di Padova, Padua, Italy.;Dipartimento di Medicina Interna, Università degli Studi di Genova, Genova, Italy.;Unità Operativa Gastroenterologia ed Endoscopia Digestiva, Policlinico Universitario di Bari, Bari, Italy.;Centro di Ricerca per lo Studio delle Epatiti, Dipartimento di Scienze Mediche e Chirurgiche, Università degli Studi di Bologna, Bologna, Italy.",
"authors": "Vukotic|R|R|;Conti|F|F|;Fagiuoli|S|S|;Morelli|M C|MC|;Pasulo|L|L|;Colpani|M|M|;Foschi|F G|FG|;Berardi|S|S|;Pianta|P|P|;Mangano|M|M|;Donato|M F|MF|;Malinverno|F|F|;Monico|S|S|;Tamè|M|M|;Mazzella|G|G|;Belli|L S|LS|;Viganò|R|R|;Carrai|P|P|;Burra|P|P|;Russo|F P|FP|;Lenci|I|I|;Toniutto|P|P|;Merli|M|M|;Loiacono|L|L|;Iemmolo|R|R|;Degli Antoni|A M|AM|;Romano|A|A|;Picciotto|A|A|;Rendina|M|M|;Andreone|P|P|0000-0002-4794-9809;|||",
"chemical_list": "D000998:Antiviral Agents; D012367:RNA, Viral",
"country": "England",
"delete": false,
"doi": "10.1111/jvh.12712",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1352-0504",
"issue": "24(10)",
"journal": "Journal of viral hepatitis",
"keywords": "antiviral therapy; fibrosing cholestatic hepatitis; liver transplant; long-term outcome; severe hepatitis C virus recurrence",
"medline_ta": "J Viral Hepat",
"mesh_terms": "D000368:Aged; D000998:Antiviral Agents; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus; D006505:Hepatitis; D006526:Hepatitis C; D006801:Humans; D053208:Kaplan-Meier Estimate; D008103:Liver Cirrhosis; D008111:Liver Function Tests; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D012367:RNA, Viral; D012008:Recurrence; D012720:Severity of Illness Index; D013997:Time Factors; D016896:Treatment Outcome; D019562:Viral Load",
"nlm_unique_id": "9435672",
"other_id": null,
"pages": "858-864",
"pmc": null,
"pmid": "28370880",
"pubdate": "2017-10",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Long-term outcomes of direct acting antivirals in post-transplant advanced hepatitis C virus recurrence and fibrosing cholestatic hepatitis.",
"title_normalized": "long term outcomes of direct acting antivirals in post transplant advanced hepatitis c virus recurrence and fibrosing cholestatic hepatitis"
} | [
{
"companynumb": "IT-JNJFOC-20171000293",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RIBAVIRIN"
},
"drugadditional": null,
"... |
{
"abstract": "Although the effectiveness of subarachnoid continuous drug infusion has been established in cancer pain management, its clinical use in children is rare. A 14-year-old girl with neurofibromatosis type I complained of right leg pain stemming from a growing tumor on her right buttock. Continuous and breakthrough right leg pain were unbearable, even at high doses of systemic opioids that caused severe constipation and deep sedation. Subsequent continuous infusion of bupivacaine and morphine through a subarachnoid catheter effectively relieved the girl's pain. The corresponding decrease in systemic opioid also improved her activities of daily living. The patient eventually died of cachexia due to the rapidly growing buttock lesion that was pathologically confirmed post-mortem as a malignant peripheral nerve sheath tumor. Subarachnoid continuous drug infusion may be very useful in controlling severe pain with few side-effects, even in the field of pediatric palliative care.",
"affiliations": "Department of General Pediatrics, Nagano Children's Hospital, Azumino, Nagano, Japan.;Department of General Pediatrics, Nagano Children's Hospital, Azumino, Nagano, Japan.;Department of General Pediatrics, Nagano Children's Hospital, Azumino, Nagano, Japan.;Department of General Pediatrics, Nagano Children's Hospital, Azumino, Nagano, Japan.;Department of General Pediatrics, Nagano Children's Hospital, Azumino, Nagano, Japan.;Department of Anesthesiology and Resuscitology, Shinshu University School of Medicine, Matsumoto, Nagano, Japan.",
"authors": "Higuchi|Tsukasa|T|;Shimada|Kazuhiro|K|;Cho|Yoshiaki|Y|;Minami|Kisei|K|;Takeuchi|Kouichi|K|;Sakamoto|Akiyuki|A|",
"chemical_list": "D000701:Analgesics, Opioid",
"country": "Australia",
"delete": false,
"doi": "10.1111/ped.12952",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1328-8067",
"issue": "58(8)",
"journal": "Pediatrics international : official journal of the Japan Pediatric Society",
"keywords": "bupivacaine; malignancy; morphine; neuropathic pain; subarachnoid",
"medline_ta": "Pediatr Int",
"mesh_terms": "D000293:Adolescent; D000701:Analgesics, Opioid; D000072716:Cancer Pain; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007278:Injections, Spinal; D010147:Pain Measurement; D010386:Pelvic Neoplasms; D013346:Subarachnoid Space",
"nlm_unique_id": "100886002",
"other_id": null,
"pages": "760-3",
"pmc": null,
"pmid": "27273434",
"pubdate": "2016-08",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Effectiveness of subarachnoid drug infusion for pediatric tumor-related pain.",
"title_normalized": "effectiveness of subarachnoid drug infusion for pediatric tumor related pain"
} | [
{
"companynumb": "JP-INTERNATIONAL MEDICATION SYSTEMS, LIMITED-1058393",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PENTAZOCINE"
},
"... |
{
"abstract": "Immune-related adverse events have been described in 86%-96% of high-risk melanoma patients treated with immune checkpoint inhibitors (ICI), while in 17%-59% of cases these are classified as severe or even life-threatening. The most common immune-related adverse events include diarrhea, fatigue, hypothyroidism, and hepatitis. Bilateral uveitis and unspecific vertigo have been described in 1% of cases, respectively, in the pivotal studies of ICIs, but the affection of the vestibule-cochlear system has not been reported before. In this case series, we present 3-stage IV melanoma patients with sudden onset of otovestibular dysfunction (hearing loss and vestibulopathy), partly combined with uveitis because of ICIs. We describe detailed diagnostic work-up and therapeutic interventions and discuss possible pathogenic mechanisms of this rare and disabling event.",
"affiliations": "Department of Dermatology and Allergy, University Hospital.;Department of Otorhinolaryngology, Head and Neck Surgery, Großhadern Medical Center, Ludwig-Maximilians University, Munich.;Department of Dermatology and Allergy, University Hospital.",
"authors": "Stürmer|Suzan H|SH|;Lechner|Axel|A|;Berking|Carola|C|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/CJI.0000000000000367",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1524-9557",
"issue": "44(5)",
"journal": "Journal of immunotherapy (Hagerstown, Md. : 1997)",
"keywords": null,
"medline_ta": "J Immunother",
"mesh_terms": null,
"nlm_unique_id": "9706083",
"other_id": null,
"pages": "193-197",
"pmc": null,
"pmid": "33734141",
"pubdate": "2021-06-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Sudden Otovestibular Dysfunction in 3 Metastatic Melanoma Patients Treated With Immune Checkpoint Inhibitors.",
"title_normalized": "sudden otovestibular dysfunction in 3 metastatic melanoma patients treated with immune checkpoint inhibitors"
} | [
{
"companynumb": "DE-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-059583",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NIVOLUMAB"
},
"drugaddi... |
{
"abstract": "Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycemia in neonates and infants. In medically unresponsive CHI, subtotal pancreatectomy is performed to achieve euglycemia with consequent diabetes in later life. Sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, has been reported to obviate the need for pancreatectomy, but experience is limited.\n\n\n\nWe have investigated the efficacy and adverse effect profile of mTOR inhibitors in the treatment of severe CHI.\n\n\n\nThis was an observational review of 10 severe CHI patients treated with mTOR inhibitors, in France and the United Kingdom, with the intention of achieving glycemic control without pancreatectomy. Safety information was recorded.\n\n\n\nWe examined whether mTOR inhibitors achieved glycemic control, fasting tolerance, and weaning of supportive medical therapy.\n\n\n\nmTOR inhibition achieved euglycemia, fasting tolerance, and reduced medical therapy in only three patients (30%). Triglyceride levels were elevated in five patients (50%). One child required a blood transfusion for anemia, four had stomatitis, two had sepsis, one developed varicella zoster, and two patients developed gut dysmotility in association with exocrine pancreatic insufficiency. In silico analysis of transcriptome arrays from CHI patients revealed no significant association between mTOR signaling and disease. Pancreatic tissue from two patients who did not respond to sirolimus showed no reduction in cell proliferation, further suggesting that mTOR signaling did not down-regulate proliferation in the CHI pancreas.\n\n\n\nmTOR inhibitor treatment is associated with very limited success and must be used with caution in children with severe CHI.",
"affiliations": "Department of Pediatrics (M.S.), Centre Hospitalier Universitaire Estaing, 63003 Clermont-Ferrand Cedex 1, France; Department of Pediatric Endocrinology (M.S.E., R.P., I.B.), Royal Manchester Children's Hospital, Manchester M13 9WL, United Kingdom; Faculty of Life Science (B.H., K.M., A.S., M.J.D.), University of Manchester, Manchester M13 9PL, United Kingdom; Department of Pediatrics (L.D., F.P.-L.B., E.L.), Sud Hospital, 35203 Rennes, France; Department of Pediatrics (R.R., C.F.), Timone Hospital, 13385 Marseille Cedex 5, France; Metabolism Unit (C.B., P.d.L., J.-B.A.), Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, 75743 Paris Cedex 15, France; Imagine-Genetic Disease Institute (P.d.L.), 75015 Paris, France; Paris Descartes University (P.d.L.), 75270 Paris, France; and Department of Genetics (C.S.-M.), Assistance Publique-Hôpitaux de Paris Groupe Hospitalier Pitié-Salpêtrière, Pierre et Marie Curie University, 75013 Paris Cedex 13, France.;Department of Pediatrics (M.S.), Centre Hospitalier Universitaire Estaing, 63003 Clermont-Ferrand Cedex 1, France; Department of Pediatric Endocrinology (M.S.E., R.P., I.B.), Royal Manchester Children's Hospital, Manchester M13 9WL, United Kingdom; Faculty of Life Science (B.H., K.M., A.S., M.J.D.), University of Manchester, Manchester M13 9PL, United Kingdom; Department of Pediatrics (L.D., F.P.-L.B., E.L.), Sud Hospital, 35203 Rennes, France; Department of Pediatrics (R.R., C.F.), Timone Hospital, 13385 Marseille Cedex 5, France; Metabolism Unit (C.B., P.d.L., J.-B.A.), Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, 75743 Paris Cedex 15, France; Imagine-Genetic Disease Institute (P.d.L.), 75015 Paris, France; Paris Descartes University (P.d.L.), 75270 Paris, France; and Department of Genetics (C.S.-M.), Assistance Publique-Hôpitaux de Paris Groupe Hospitalier Pitié-Salpêtrière, Pierre et Marie Curie University, 75013 Paris Cedex 13, France.;Department of Pediatrics (M.S.), Centre Hospitalier Universitaire Estaing, 63003 Clermont-Ferrand Cedex 1, France; Department of Pediatric Endocrinology (M.S.E., R.P., I.B.), Royal Manchester Children's Hospital, Manchester M13 9WL, United Kingdom; Faculty of Life Science (B.H., K.M., A.S., M.J.D.), University of Manchester, Manchester M13 9PL, United Kingdom; Department of Pediatrics (L.D., F.P.-L.B., E.L.), Sud Hospital, 35203 Rennes, France; Department of Pediatrics (R.R., C.F.), Timone Hospital, 13385 Marseille Cedex 5, France; Metabolism Unit (C.B., P.d.L., J.-B.A.), Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, 75743 Paris Cedex 15, France; Imagine-Genetic Disease Institute (P.d.L.), 75015 Paris, France; Paris Descartes University (P.d.L.), 75270 Paris, France; and Department of Genetics (C.S.-M.), Assistance Publique-Hôpitaux de Paris Groupe Hospitalier Pitié-Salpêtrière, Pierre et Marie Curie University, 75013 Paris Cedex 13, France.;Department of Pediatrics (M.S.), Centre Hospitalier Universitaire Estaing, 63003 Clermont-Ferrand Cedex 1, France; Department of Pediatric Endocrinology (M.S.E., R.P., I.B.), Royal Manchester Children's Hospital, Manchester M13 9WL, United Kingdom; Faculty of Life Science (B.H., K.M., A.S., M.J.D.), University of Manchester, Manchester M13 9PL, United Kingdom; Department of Pediatrics (L.D., F.P.-L.B., E.L.), Sud Hospital, 35203 Rennes, France; Department of Pediatrics (R.R., C.F.), Timone Hospital, 13385 Marseille Cedex 5, France; Metabolism Unit (C.B., P.d.L., J.-B.A.), Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, 75743 Paris Cedex 15, France; Imagine-Genetic Disease Institute (P.d.L.), 75015 Paris, France; Paris Descartes University (P.d.L.), 75270 Paris, France; and Department of Genetics (C.S.-M.), Assistance Publique-Hôpitaux de Paris Groupe Hospitalier Pitié-Salpêtrière, Pierre et Marie Curie University, 75013 Paris Cedex 13, France.;Department of Pediatrics (M.S.), Centre Hospitalier Universitaire Estaing, 63003 Clermont-Ferrand Cedex 1, France; Department of Pediatric Endocrinology (M.S.E., R.P., I.B.), Royal Manchester Children's Hospital, Manchester M13 9WL, United Kingdom; Faculty of Life Science (B.H., K.M., A.S., M.J.D.), University of Manchester, Manchester M13 9PL, United Kingdom; Department of Pediatrics (L.D., F.P.-L.B., E.L.), Sud Hospital, 35203 Rennes, France; Department of Pediatrics (R.R., C.F.), Timone Hospital, 13385 Marseille Cedex 5, France; Metabolism Unit (C.B., P.d.L., J.-B.A.), Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, 75743 Paris Cedex 15, France; Imagine-Genetic Disease Institute (P.d.L.), 75015 Paris, France; Paris Descartes University (P.d.L.), 75270 Paris, France; and Department of Genetics (C.S.-M.), Assistance Publique-Hôpitaux de Paris Groupe Hospitalier Pitié-Salpêtrière, Pierre et Marie Curie University, 75013 Paris Cedex 13, France.;Department of Pediatrics (M.S.), Centre Hospitalier Universitaire Estaing, 63003 Clermont-Ferrand Cedex 1, France; Department of Pediatric Endocrinology (M.S.E., R.P., I.B.), Royal Manchester Children's Hospital, Manchester M13 9WL, United Kingdom; Faculty of Life Science (B.H., K.M., A.S., M.J.D.), University of Manchester, Manchester M13 9PL, United Kingdom; Department of Pediatrics (L.D., F.P.-L.B., E.L.), Sud Hospital, 35203 Rennes, France; Department of Pediatrics (R.R., C.F.), Timone Hospital, 13385 Marseille Cedex 5, France; Metabolism Unit (C.B., P.d.L., J.-B.A.), Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, 75743 Paris Cedex 15, France; Imagine-Genetic Disease Institute (P.d.L.), 75015 Paris, France; Paris Descartes University (P.d.L.), 75270 Paris, France; and Department of Genetics (C.S.-M.), Assistance Publique-Hôpitaux de Paris Groupe Hospitalier Pitié-Salpêtrière, Pierre et Marie Curie University, 75013 Paris Cedex 13, France.;Department of Pediatrics (M.S.), Centre Hospitalier Universitaire Estaing, 63003 Clermont-Ferrand Cedex 1, France; Department of Pediatric Endocrinology (M.S.E., R.P., I.B.), Royal Manchester Children's Hospital, Manchester M13 9WL, United Kingdom; Faculty of Life Science (B.H., K.M., A.S., M.J.D.), University of Manchester, Manchester M13 9PL, United Kingdom; Department of Pediatrics (L.D., F.P.-L.B., E.L.), Sud Hospital, 35203 Rennes, France; Department of Pediatrics (R.R., C.F.), Timone Hospital, 13385 Marseille Cedex 5, France; Metabolism Unit (C.B., P.d.L., J.-B.A.), Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, 75743 Paris Cedex 15, France; Imagine-Genetic Disease Institute (P.d.L.), 75015 Paris, France; Paris Descartes University (P.d.L.), 75270 Paris, France; and Department of Genetics (C.S.-M.), Assistance Publique-Hôpitaux de Paris Groupe Hospitalier Pitié-Salpêtrière, Pierre et Marie Curie University, 75013 Paris Cedex 13, France.;Department of Pediatrics (M.S.), Centre Hospitalier Universitaire Estaing, 63003 Clermont-Ferrand Cedex 1, France; Department of Pediatric Endocrinology (M.S.E., R.P., I.B.), Royal Manchester Children's Hospital, Manchester M13 9WL, United Kingdom; Faculty of Life Science (B.H., K.M., A.S., M.J.D.), University of Manchester, Manchester M13 9PL, United Kingdom; Department of Pediatrics (L.D., F.P.-L.B., E.L.), Sud Hospital, 35203 Rennes, France; Department of Pediatrics (R.R., C.F.), Timone Hospital, 13385 Marseille Cedex 5, France; Metabolism Unit (C.B., P.d.L., J.-B.A.), Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, 75743 Paris Cedex 15, France; Imagine-Genetic Disease Institute (P.d.L.), 75015 Paris, France; Paris Descartes University (P.d.L.), 75270 Paris, France; and Department of Genetics (C.S.-M.), Assistance Publique-Hôpitaux de Paris Groupe Hospitalier Pitié-Salpêtrière, Pierre et Marie Curie University, 75013 Paris Cedex 13, France.;Department of Pediatrics (M.S.), Centre Hospitalier Universitaire Estaing, 63003 Clermont-Ferrand Cedex 1, France; Department of Pediatric Endocrinology (M.S.E., R.P., I.B.), Royal Manchester Children's Hospital, Manchester M13 9WL, United Kingdom; Faculty of Life Science (B.H., K.M., A.S., M.J.D.), University of Manchester, Manchester M13 9PL, United Kingdom; Department of Pediatrics (L.D., F.P.-L.B., E.L.), Sud Hospital, 35203 Rennes, France; Department of Pediatrics (R.R., C.F.), Timone Hospital, 13385 Marseille Cedex 5, France; Metabolism Unit (C.B., P.d.L., J.-B.A.), Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, 75743 Paris Cedex 15, France; Imagine-Genetic Disease Institute (P.d.L.), 75015 Paris, France; Paris Descartes University (P.d.L.), 75270 Paris, France; and Department of Genetics (C.S.-M.), Assistance Publique-Hôpitaux de Paris Groupe Hospitalier Pitié-Salpêtrière, Pierre et Marie Curie University, 75013 Paris Cedex 13, France.;Department of Pediatrics (M.S.), Centre Hospitalier Universitaire Estaing, 63003 Clermont-Ferrand Cedex 1, France; Department of Pediatric Endocrinology (M.S.E., R.P., I.B.), Royal Manchester Children's Hospital, Manchester M13 9WL, United Kingdom; Faculty of Life Science (B.H., K.M., A.S., M.J.D.), University of Manchester, Manchester M13 9PL, United Kingdom; Department of Pediatrics (L.D., F.P.-L.B., E.L.), Sud Hospital, 35203 Rennes, France; Department of Pediatrics (R.R., C.F.), Timone Hospital, 13385 Marseille Cedex 5, France; Metabolism Unit (C.B., P.d.L., J.-B.A.), Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, 75743 Paris Cedex 15, France; Imagine-Genetic Disease Institute (P.d.L.), 75015 Paris, France; Paris Descartes University (P.d.L.), 75270 Paris, France; and Department of Genetics (C.S.-M.), Assistance Publique-Hôpitaux de Paris Groupe Hospitalier Pitié-Salpêtrière, Pierre et Marie Curie University, 75013 Paris Cedex 13, France.;Department of Pediatrics (M.S.), Centre Hospitalier Universitaire Estaing, 63003 Clermont-Ferrand Cedex 1, France; Department of Pediatric Endocrinology (M.S.E., R.P., I.B.), Royal Manchester Children's Hospital, Manchester M13 9WL, United Kingdom; Faculty of Life Science (B.H., K.M., A.S., M.J.D.), University of Manchester, Manchester M13 9PL, United Kingdom; Department of Pediatrics (L.D., F.P.-L.B., E.L.), Sud Hospital, 35203 Rennes, France; Department of Pediatrics (R.R., C.F.), Timone Hospital, 13385 Marseille Cedex 5, France; Metabolism Unit (C.B., P.d.L., J.-B.A.), Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, 75743 Paris Cedex 15, France; Imagine-Genetic Disease Institute (P.d.L.), 75015 Paris, France; Paris Descartes University (P.d.L.), 75270 Paris, France; and Department of Genetics (C.S.-M.), Assistance Publique-Hôpitaux de Paris Groupe Hospitalier Pitié-Salpêtrière, Pierre et Marie Curie University, 75013 Paris Cedex 13, France.;Department of Pediatrics (M.S.), Centre Hospitalier Universitaire Estaing, 63003 Clermont-Ferrand Cedex 1, France; Department of Pediatric Endocrinology (M.S.E., R.P., I.B.), Royal Manchester Children's Hospital, Manchester M13 9WL, United Kingdom; Faculty of Life Science (B.H., K.M., A.S., M.J.D.), University of Manchester, Manchester M13 9PL, United Kingdom; Department of Pediatrics (L.D., F.P.-L.B., E.L.), Sud Hospital, 35203 Rennes, France; Department of Pediatrics (R.R., C.F.), Timone Hospital, 13385 Marseille Cedex 5, France; Metabolism Unit (C.B., P.d.L., J.-B.A.), Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, 75743 Paris Cedex 15, France; Imagine-Genetic Disease Institute (P.d.L.), 75015 Paris, France; Paris Descartes University (P.d.L.), 75270 Paris, France; and Department of Genetics (C.S.-M.), Assistance Publique-Hôpitaux de Paris Groupe Hospitalier Pitié-Salpêtrière, Pierre et Marie Curie University, 75013 Paris Cedex 13, France.;Department of Pediatrics (M.S.), Centre Hospitalier Universitaire Estaing, 63003 Clermont-Ferrand Cedex 1, France; Department of Pediatric Endocrinology (M.S.E., R.P., I.B.), Royal Manchester Children's Hospital, Manchester M13 9WL, United Kingdom; Faculty of Life Science (B.H., K.M., A.S., M.J.D.), University of Manchester, Manchester M13 9PL, United Kingdom; Department of Pediatrics (L.D., F.P.-L.B., E.L.), Sud Hospital, 35203 Rennes, France; Department of Pediatrics (R.R., C.F.), Timone Hospital, 13385 Marseille Cedex 5, France; Metabolism Unit (C.B., P.d.L., J.-B.A.), Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, 75743 Paris Cedex 15, France; Imagine-Genetic Disease Institute (P.d.L.), 75015 Paris, France; Paris Descartes University (P.d.L.), 75270 Paris, France; and Department of Genetics (C.S.-M.), Assistance Publique-Hôpitaux de Paris Groupe Hospitalier Pitié-Salpêtrière, Pierre et Marie Curie University, 75013 Paris Cedex 13, France.;Department of Pediatrics (M.S.), Centre Hospitalier Universitaire Estaing, 63003 Clermont-Ferrand Cedex 1, France; Department of Pediatric Endocrinology (M.S.E., R.P., I.B.), Royal Manchester Children's Hospital, Manchester M13 9WL, United Kingdom; Faculty of Life Science (B.H., K.M., A.S., M.J.D.), University of Manchester, Manchester M13 9PL, United Kingdom; Department of Pediatrics (L.D., F.P.-L.B., E.L.), Sud Hospital, 35203 Rennes, France; Department of Pediatrics (R.R., C.F.), Timone Hospital, 13385 Marseille Cedex 5, France; Metabolism Unit (C.B., P.d.L., J.-B.A.), Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, 75743 Paris Cedex 15, France; Imagine-Genetic Disease Institute (P.d.L.), 75015 Paris, France; Paris Descartes University (P.d.L.), 75270 Paris, France; and Department of Genetics (C.S.-M.), Assistance Publique-Hôpitaux de Paris Groupe Hospitalier Pitié-Salpêtrière, Pierre et Marie Curie University, 75013 Paris Cedex 13, France.;Department of Pediatrics (M.S.), Centre Hospitalier Universitaire Estaing, 63003 Clermont-Ferrand Cedex 1, France; Department of Pediatric Endocrinology (M.S.E., R.P., I.B.), Royal Manchester Children's Hospital, Manchester M13 9WL, United Kingdom; Faculty of Life Science (B.H., K.M., A.S., M.J.D.), University of Manchester, Manchester M13 9PL, United Kingdom; Department of Pediatrics (L.D., F.P.-L.B., E.L.), Sud Hospital, 35203 Rennes, France; Department of Pediatrics (R.R., C.F.), Timone Hospital, 13385 Marseille Cedex 5, France; Metabolism Unit (C.B., P.d.L., J.-B.A.), Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, 75743 Paris Cedex 15, France; Imagine-Genetic Disease Institute (P.d.L.), 75015 Paris, France; Paris Descartes University (P.d.L.), 75270 Paris, France; and Department of Genetics (C.S.-M.), Assistance Publique-Hôpitaux de Paris Groupe Hospitalier Pitié-Salpêtrière, Pierre et Marie Curie University, 75013 Paris Cedex 13, France.;Department of Pediatrics (M.S.), Centre Hospitalier Universitaire Estaing, 63003 Clermont-Ferrand Cedex 1, France; Department of Pediatric Endocrinology (M.S.E., R.P., I.B.), Royal Manchester Children's Hospital, Manchester M13 9WL, United Kingdom; Faculty of Life Science (B.H., K.M., A.S., M.J.D.), University of Manchester, Manchester M13 9PL, United Kingdom; Department of Pediatrics (L.D., F.P.-L.B., E.L.), Sud Hospital, 35203 Rennes, France; Department of Pediatrics (R.R., C.F.), Timone Hospital, 13385 Marseille Cedex 5, France; Metabolism Unit (C.B., P.d.L., J.-B.A.), Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, 75743 Paris Cedex 15, France; Imagine-Genetic Disease Institute (P.d.L.), 75015 Paris, France; Paris Descartes University (P.d.L.), 75270 Paris, France; and Department of Genetics (C.S.-M.), Assistance Publique-Hôpitaux de Paris Groupe Hospitalier Pitié-Salpêtrière, Pierre et Marie Curie University, 75013 Paris Cedex 13, France.;Department of Pediatrics (M.S.), Centre Hospitalier Universitaire Estaing, 63003 Clermont-Ferrand Cedex 1, France; Department of Pediatric Endocrinology (M.S.E., R.P., I.B.), Royal Manchester Children's Hospital, Manchester M13 9WL, United Kingdom; Faculty of Life Science (B.H., K.M., A.S., M.J.D.), University of Manchester, Manchester M13 9PL, United Kingdom; Department of Pediatrics (L.D., F.P.-L.B., E.L.), Sud Hospital, 35203 Rennes, France; Department of Pediatrics (R.R., C.F.), Timone Hospital, 13385 Marseille Cedex 5, France; Metabolism Unit (C.B., P.d.L., J.-B.A.), Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, 75743 Paris Cedex 15, France; Imagine-Genetic Disease Institute (P.d.L.), 75015 Paris, France; Paris Descartes University (P.d.L.), 75270 Paris, France; and Department of Genetics (C.S.-M.), Assistance Publique-Hôpitaux de Paris Groupe Hospitalier Pitié-Salpêtrière, Pierre et Marie Curie University, 75013 Paris Cedex 13, France.",
"authors": "Szymanowski|Marie|M|;Estebanez|Maria Salomon|MS|;Padidela|Raja|R|;Han|Bing|B|;Mosinska|Karolina|K|;Stevens|Adam|A|;Damaj|Lena|L|;Pihan-Le Bars|Florence|F|;Lascouts|Emilie|E|;Reynaud|Rachel|R|;Ferreira|Catherine|C|;Bansept|Claire|C|;de Lonlay|Pascale|P|;Saint-Martin|Cécile|C|;Dunne|Mark J|MJ|;Banerjee|Indraneel|I|;Arnoux|Jean-Baptiste|JB|",
"chemical_list": "D007166:Immunosuppressive Agents; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus",
"country": "United States",
"delete": false,
"doi": "10.1210/jc.2016-2711",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0021-972X",
"issue": "101(12)",
"journal": "The Journal of clinical endocrinology and metabolism",
"keywords": null,
"medline_ta": "J Clin Endocrinol Metab",
"mesh_terms": "D002675:Child, Preschool; D044903:Congenital Hyperinsulinism; D000068338:Everolimus; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D007223:Infant; D008297:Male; D017063:Outcome Assessment, Health Care; D012720:Severity of Illness Index; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases",
"nlm_unique_id": "0375362",
"other_id": null,
"pages": "4719-4729",
"pmc": null,
"pmid": "27691052",
"pubdate": "2016-12",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "mTOR Inhibitors for the Treatment of Severe Congenital Hyperinsulinism: Perspectives on Limited Therapeutic Success.",
"title_normalized": "mtor inhibitors for the treatment of severe congenital hyperinsulinism perspectives on limited therapeutic success"
} | [
{
"companynumb": "FR-PFIZER INC-2016578620",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SOMATOSTATIN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nCKF is an overwhelming illness, especially in children. Kidney transplantation is considered the definitive management of CKF. It has substantial benefits, including increased patient survival, improved skeletal growth, social adjustment, neuropsychological development, and better quality of life compared to chronic dialysis.\n\n\nMETHODS\nThis is a retrospective, clinical, observational study in 13 children ≤16 years old who underwent kidney transplantation at IALCH in KwaZulu-Natal, South Africa, from May 2015 to December 2019.\n\n\nRESULTS\nOver 4 years and 7 months, 13 kidney transplants were performed; 7 (53.8%) were males, and 6 (46.2%) were females. Eleven (84.6%) were Black African and 2 (15.4%) Indian children. The mean age ± (SD) of transplantation was 10.1 ± 2.8 years (range 5.8-15.8). Eight (61.5%) children were from a rural setting. The mean ± (SD) duration of follow-up was 29.5 ± 15.9 months. All kidney transplants done were from live related donors; 8 (61.5%) were parents of the recipients. None were pre-emptive transplants. Graft loss occurred in 2 (15.4%) children with 100% patient survival. Two (15.4%) children developed acute rejection.\n\n\nCONCLUSIONS\nThe commissioning of transplant services in KwaZulu-Natal, South Africa, has improved access to this modality of treatment, particularly in our Black African patients. The significant limitations we experienced were a shortage of cadaveric donors and resource limitations with no dedicated transplant unit for pediatric patients together with staffing constraints. Enhancing patient and healthcare personal education will hopefully overcome cultural and religious barriers to organ donation.",
"affiliations": "Department of Paediatrics and Child Health, Nelson R Mandela School of Medicine, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa.;Department of Paediatrics and Child Health, Nelson R Mandela School of Medicine, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa.;Department of Biostatistics, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.;Department of Paediatrics and Child Health, Nelson R Mandela School of Medicine, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa.",
"authors": "Sinada|Nisreen Seed Ahmed|NSA|https://orcid.org/0000-0001-7245-0519;Naicker|Elaene|E|;Tinarwo|Partson|P|;Bhimma|Rajendra|R|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.14016",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "25(4)",
"journal": "Pediatric transplantation",
"keywords": "children; kidney transplantation; outcome; rejection",
"medline_ta": "Pediatr Transplant",
"mesh_terms": null,
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "e14016",
"pmc": null,
"pmid": "33773014",
"pubdate": "2021-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Kidney transplantation in children in KwaZulu-Natal, South Africa.",
"title_normalized": "kidney transplantation in children in kwazulu natal south africa"
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"activesubstancename": "MYCOPHENOLATE MOFETIL"
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... |
{
"abstract": "Patients with heterotaxy syndrome (HS) can present with an associated complete dorsal pancreas agenesis (DPA). They are considered to be at increased risk for developing diabetes due to a reduced functional beta cell mass (FBM) as well as for chronic pancreatitis leading to unmanageable pain. We report the case of a young woman with chronic pancreatitis due to HS and associated DPA. She presented with a severe persisting upper abdominal pain refractory to nonsurgical treatment. Unlike in previously reported cases, she had a high FBM (ie, 150% of normoglycemic controls) as determined by hyperglycemic clamp. She underwent a total pancreatectomy followed within 24 hours by an intraportal autologous islet cell transplant containing 4 × 106 beta cells (4700 islet equivalent)/kg body weight. After surgery, the pain resolved, eliminating the need for analgesics. The intraportal implant established an adequate FBM (72% of controls at posttransplant month 2), achieving glycemic control without need for insulin administration. A hyperglycemic clamp can assess the utility and efficacy of an intraportal islet cell autotransplant following total pancreatectomy in patients with HS and complete DPA.",
"affiliations": "Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium.;Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium.;Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium.;Center for Algology & Pain Management, University Hospitals Leuven, Leuven, Belgium.;Department of Radiology, University Hospitals Leuven, Leuven, Belgium.;Department of Radiology, University Hospitals Leuven, Leuven, Belgium.;Clinical Division of Intensive Care Medicine, University Hospitals Leuven, Leuven, Belgium.;Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium.;Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium.;Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium.;Department of Abdominal Transplant Surgery and Transplantation Coordination, University Hospitals Leuven, Leuven, Belgium.;Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium.;Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium.",
"authors": "De Paep|Diedert L|DL|0000-0001-8969-6531;Gillard|Pieter|P|0000-0001-9111-4561;Ling|Zhidong|Z|;Verbeke|Hilde|H|;Maleux|Geert|G|0000-0003-0598-0258;Vandecaveye|Vincent|V|;Debaveye|Yves|Y|0000-0003-1784-8297;Keymeulen|Bart|B|0000-0002-8671-4527;van der Merwe|Schalk|S|0000-0002-9891-2686;Pipeleers|Daniel|D|0000-0002-6440-2485;Pirenne|Jacques|J|0000-0002-8147-8801;van Malenstein|Hannah|H|0000-0003-0673-0939;Jacobs-Tulleneers-Thevissen|Daniel|D|0000-0001-5758-9547",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/ajt.16084",
"fulltext": null,
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"issn_linking": "1600-6135",
"issue": "20(12)",
"journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons",
"keywords": "anatomy; autotransplantation; clinical research/practice; diabetes; endocrinology/diabetology; islet isolation; islet transplantation",
"medline_ta": "Am J Transplant",
"mesh_terms": "D064592:Autografts; D005260:Female; D059446:Heterotaxy Syndrome; D006801:Humans; D050417:Insulin-Secreting Cells; D016381:Islets of Langerhans Transplantation; D010179:Pancreas; D010180:Pancreatectomy; D050500:Pancreatitis, Chronic; D014182:Transplantation, Autologous; D016896:Treatment Outcome",
"nlm_unique_id": "100968638",
"other_id": null,
"pages": "3662-3666",
"pmc": null,
"pmid": "32476268",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Use of hyperglycemic clamp to assess pancreatectomy and islet cell autotransplant in patient with heterotaxy syndrome and dorsal pancreas agenesis leading to chronic pancreatitis.",
"title_normalized": "use of hyperglycemic clamp to assess pancreatectomy and islet cell autotransplant in patient with heterotaxy syndrome and dorsal pancreas agenesis leading to chronic pancreatitis"
} | [
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"activesubstancename": "DEXTROSE\\LIDOCAINE HYDROCHLORIDE"
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... |
{
"abstract": "Azacitidine (AZA) is commonly used in patients with myelodysplastic syndrome (MDS). To determine the role of AZA before allogeneic stem cell transplantation (allo-SCT), we conducted a prospective study of AZA pre-treatment followed by allo-SCT in patients with higher-risk MDS. Twenty-one patients who were scheduled for their third to sixth cycle of AZA pre-treatment followed by allo-SCT were enrolled. AZA pre-treatment was interrupted early in 3 patients (14.3%) because of leukaemic transformation or death. The overall response rate to AZA pre-treatment was 57.1%. There were 2 cases of complete remission, 1 case of partial remission, and 9 cases of haematologic improvement. Fourteen patients (66.7%) received the planned allo-SCT and 5 patients were alive at the last follow-up. Three-year progression-free survival (PFS) and 3-year overall survival (OS) in the 14 patients who received allo-SCT were 30.0% (95% CI 3.3-56.7) and 42.9% (95% CI 17.1-68.7), respectively. PFS and OS were not influenced by response to AZA pre-treatment (p > 0.05). In this study, AZA had a role as a bridge therapy to prevent leukaemic transformation prior to selection of a donor for allo-SCT and showed low toxicity. It may be considered in patients with higher-risk MDS.",
"affiliations": "Department of Hematology-Oncolgy, Chonnam National University Hwasun Hospital, Jeollanam-do, Korea.",
"authors": "Ahn|Jae-Sook|JS|;Kim|Yeo-Kyeoung|YK|;Min|Yoo Hong|YH|;Cheong|June-Won|JW|;Jang|Jun Ho|JH|;Jung|Chul Won|CW|;Kim|In Ho|IH|;Yoon|Hwi-Joong|HJ|;Lee|Hong Ghi|HG|;Sohn|Sang Kyun|SK|;Moon|Joon Ho|JH|;Kim|Hawk|H|;Kim|Yoo-Jin|YJ|;Won|Jong-Ho|JH|;Chung|Joo-Seop|JS|;Mun|Yeung Chul|YC|;Lee|Je-Hwan|JH|;Kim|Hyeoung-Joon|HJ|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D001374:Azacitidine",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000368711",
"fulltext": null,
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"issn_linking": "0001-5792",
"issue": "134(1)",
"journal": "Acta haematologica",
"keywords": null,
"medline_ta": "Acta Haematol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D064591:Allografts; D000964:Antimetabolites, Antineoplastic; D001374:Azacitidine; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes; D011446:Prospective Studies; D033581:Stem Cell Transplantation; D015996:Survival Rate",
"nlm_unique_id": "0141053",
"other_id": null,
"pages": "40-8",
"pmc": null,
"pmid": "26066466",
"pubdate": "2015",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Azacitidine Pre-Treatment Followed by Reduced-Intensity Stem Cell Transplantation in Patients with Higher-Risk Myelodysplastic Syndrome.",
"title_normalized": "azacitidine pre treatment followed by reduced intensity stem cell transplantation in patients with higher risk myelodysplastic syndrome"
} | [
{
"companynumb": "KR-CELGENE-KOR-2014124156",
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"patient": {
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"activesubstancename": "CYCLOSPORINE"
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... |
{
"abstract": "BACKGROUND\nVisceral leishmaniasis is a zoonosis characterized by chronic evolution of symptoms; it usually appears 2 to 4 months after the initial infection, with multiple cutaneous lesions and systemic involvement, which if left untreated results in death in 90 % of cases.\n\n\nMETHODS\nWe present a case of 29-year-old white male farmer, with chronic myeloid leukemia treated with imatinib who developed significant pancytopenia, leading to discontinuation of treatment. His neutrophil count fell to 0.5 × 10(9)/L, his platelets dropped to 85 × 10(9)/μL, and his hemoglobin was 6.4 g/dL. A bone marrow study was performed, showing complete remission of chronic myeloid leukemia and numerous Leishmania amastigotes within the macrophages. He used pentavalent antimonials replaced by amphotericin B due to acute cardiac toxicity. After 3 months, imatinib was restarted, and he again showed adequate control of the disease. The last polymerase chain reaction assessment showed a deep molecular response.\n\n\nCONCLUSIONS\nThe hypothesis of an adverse event or secondary resistance to tyrosine kinase inhibitors, with subsequent progression to advanced disease, was initially raised, although a detailed evaluation has shown that it was an associated infectious disease.",
"affiliations": "Department of Haematology, Walter Cantidio University Hospital, 1210 Captain Francisco Pedro St, 60430-350, Rodolfo Teofilo, Fortaleza, Ceará, Brazil. acy@uol.com.br.;Research Laboratory in Hemoglobinopathies and Genetics of Hematologic Diseases, Federal University of Ceará, Fortaleza, Ceará, Brazil.;Research Laboratory in Hemoglobinopathies and Genetics of Hematologic Diseases, Federal University of Ceará, Fortaleza, Ceará, Brazil.;Department of Surgery, Federal University of Ceará, Fortaleza, Ceará, Brazil.;Research Laboratory in Hemoglobinopathies and Genetics of Hematologic Diseases, Federal University of Ceará, Fortaleza, Ceará, Brazil.;Research Laboratory in Hemoglobinopathies and Genetics of Hematologic Diseases, Federal University of Ceará, Fortaleza, Ceará, Brazil.",
"authors": "Quixada|Acy|A|;Filho|Pedro Aurio Maia|PA|;Filho|Tarcísio Paulo Almeida|TP|;Duarte|Fernando Barroso|FB|;Moreira-Nunes|Caroline Aquino|CA|;Lemes|Romélia Pinheiro Gonçalves|RP|",
"chemical_list": "D047428:Protein Kinase Inhibitors; D000068877:Imatinib Mesylate",
"country": "England",
"delete": false,
"doi": "10.1186/s13256-016-0978-4",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 97810.1186/s13256-016-0978-4Case ReportPancytopenia during tyrosine kinase inhibitor treatment – coexistence of chronic myeloid leukemia and visceral leishmaniasis: a case report Quixada Acy +55 (85) 33668264acy@uol.com.br 1Filho Pedro Aurio Maia pedro_limo@hotmail.com 2Filho Tarcísio Paulo Almeida tarcisio_900@hotmail.com 2Duarte Fernando Barroso nutriquimio@uol.com.br 3Moreira-Nunes Caroline Aquino carolfam@gmail.com 2Lemes Romélia Pinheiro Gonçalves romeliagoncalves@gmail.com 21 Department of Haematology, Walter Cantidio University Hospital, 1210 Captain Francisco Pedro St, 60430-350, Rodolfo Teofilo, Fortaleza, Ceará Brazil 2 Research Laboratory in Hemoglobinopathies and Genetics of Hematologic Diseases, Federal University of Ceará, Fortaleza, Ceará Brazil 3 Department of Surgery, Federal University of Ceará, Fortaleza, Ceará Brazil 27 7 2016 27 7 2016 2016 10 20714 1 2016 8 6 2016 © The Author(s). 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nVisceral leishmaniasis is a zoonosis characterized by chronic evolution of symptoms; it usually appears 2 to 4 months after the initial infection, with multiple cutaneous lesions and systemic involvement, which if left untreated results in death in 90 % of cases.\n\nCase presentation\nWe present a case of 29-year-old white male farmer, with chronic myeloid leukemia treated with imatinib who developed significant pancytopenia, leading to discontinuation of treatment. His neutrophil count fell to 0.5 × 109/L, his platelets dropped to 85 × 109/μL, and his hemoglobin was 6.4 g/dL. A bone marrow study was performed, showing complete remission of chronic myeloid leukemia and numerous Leishmania amastigotes within the macrophages. He used pentavalent antimonials replaced by amphotericin B due to acute cardiac toxicity. After 3 months, imatinib was restarted, and he again showed adequate control of the disease. The last polymerase chain reaction assessment showed a deep molecular response.\n\nConclusion\nThe hypothesis of an adverse event or secondary resistance to tyrosine kinase inhibitors, with subsequent progression to advanced disease, was initially raised, although a detailed evaluation has shown that it was an associated infectious disease.\n\nKeywords\nChronic myeloid leukemiaTyrosine kinase inhibitorsVisceral leishmaniasisissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nChronic myeloid leukemia (CML) is a clonal myeloproliferative disorder that results from the malignant transformation of a hematopoietic stem cell. It is characterized by the Philadelphia chromosome (Ph+), which is formed by translocation and fusion of the long arms of chromosomes 9 and 22 in a multipotent hematopoietic progenitor cell. At the molecular level, the fusion generates a BCR-ABL protein with constitutive tyrosine kinase activity [1–7]. Tyrosine kinase inhibitors (TKIs) such as imatinib are able to suppress the BCR-ABL+ clone and induce molecular remission [8].\n\nLeishmaniasis is a zoonosis caused by an intracellular parasite belonging to the genus Leishmania. Leishmania parasites have a dimorphic life cycle, alternating between an extracellular promastigote and an intracellular amastigote form [9]. This disease is endemic in 98 countries, and an estimated 350 million people live in endemic areas. Despite T-cell-dependent immune responses, which produce asymptomatic and self-healing infection, or appropriate treatment, intracellular infection is probably lifelong because the targeted cells (tissue macrophages) allow residual parasites to persist [10].\n\nCase presentation\nA 29-year-old white male farmer sought medical attention because of left upper-quadrant abdominal discomfort and unintentional weight loss of 8 kg. His initial clinical examination revealed light pallor and splenomegaly, 10 cm below his left costal margin. However, no lymphadenopathy or hepatomegaly was detected. Laboratory analysis showed a leukocyte count of 38 × 109/L, a hemoglobin level of 10.5 g/dL, and a platelet count of 289 × 109/μL. He denied fever or drenching night sweats and was not taking medication.\n\nHe was referred to our Department of Hematology, at our university hospital, where a bone marrow aspiration and biopsy were performed. Microscopic examination showed a left-shifted granulopoiesis, and the Ph + was found with no other chromosomic aberrations. BCR-ABL fusion transcript was identified by polymerase chain reaction (PCR) and both transcripts (b2a2 and b3a2) were present. The diagnosis of CML in chronic phase was made: Sokal score 0.85 (low risk <0.8; moderate risk 0.8 to 1.2; high risk >1.2) and Hasford score 741 (low risk <780; moderate risk 780 to 1480; high risk >1480).\n\nHe was initially treated with hydroxyurea, which was later substituted by imatinib 400 mg daily starting in early January 2013. We observed a slow progression of the splenomegaly until complete spleen regression by 3 months. The first reevaluation was made at 3 months of imatinib (early response). During that period he showed no symptoms and gained weight (4 kg). Early response was detected through a cytogenetics analysis and quantitative polymerase chain reaction (qPCR) assessment. There was no cell growth to perform an analysis of the Ph + through the G-band method. Fluorescent in situ hybridization revealed 3.5 % of cells with the gene fusion, while PCR assessment was not conclusive due to the low quality of deoxyribonucleic acid (DNA). He was considered an optimal responder.\n\nHe persisted on imatinib 400 mg for 6 months before the agent was discontinued because of pancytopenia. His neutrophil count fell to 0.5 × 109/L, platelets dropped to 85 × 109/μL, and hemoglobin was 6.4 g/dL (Fig. 1). Transfusion was not necessary. After imatinib cessation, we waited 1 week until a new hemogram was done. Because there was no improvement in his hemogram we decided to examine his bone marrow. A bone marrow study was performed showing complete remission of CML and numerous Leishmania amastigotes within the macrophages (Figs. 2 and 3). IgM antibody to Leishmania K39 antigen was positive. He was admitted to our hospital and began treatment with pentavalent antimonials. His hemogram started to improve at 10 days of leishmaniasis treatment and normalized by 2 months. New bone marrow aspirate showed no more leishmaniasis after 60 days of therapy. Complete recovery of symptoms and examinations (bone marrow and hemogram) was seen after that time (Table 1).Fig. 1 Evolution of patient’s hemogram. The dotted line indicates the nadir counts (when imatinib suspension occurred)\n\nFig. 2 Bone marrow aspirate: macrophages containing Leishman-Donovan bodies\n\nFig. 3 Bone marrow aspirate: Leishman-Donovan bodies outside macrophages\n\nTable 1 Clinical and laboratory findings in the patient during leishmaniasis diagnosis and therapy\n\n\tBefore\tDuring treatment\tAfter\t\nHemoglobin (g/dL)\t6.4\t9.5\t12.6\t\nNeutrophil (×109/L)\t0.5\t1.7\t2\t\nPlatelet (×109/μL)\t85\t150\t145\t\n\n\nAcute cardiac toxicity required suspension from treatment. An electrocardiogram showed prolongation of the QT interval and bradycardia. The medication was stopped when his heart rate dropped below 45 beats per minute; it was replaced by amphotericin B regimen. After 3 months, TKI therapy was resumed and he again showed adequate response to imatinib. The last PCR showed deep molecular response (MR 4.0).\n\nDiscussion\nVisceral leishmaniasis (VL) is a well-known opportunistic infection in severe immunodeficiency, particularly in patients living in areas where leishmaniasis is endemic. In Brazil, VL or neotropical kala-azar, is an endemic/epidemic rural and periurban anthropozoonosis with a strong tendency towards urbanization. It is caused by different species of the genus Leishmania, and in the Americas, L. chagasi is the etiological agent of the disease. The importance of the canine reservoir derives from the close frequent contact between dogs and humans and the fact that the animals can present asymptomatic infection, despite a high degree of parasitism in healthy skin and viscera [11, 12].\n\nWe report the case of a farmer diagnosed with CML who presented with pancytopenia Grade 3/4 during treatment, which required imatinib suspension. Adherence was good, without the use of any other drugs. Profound involvement of the hematological system in the form of bone marrow and peripheral blood changes are consistently seen in VL and include the following.\n\nNormochromic normocytic anemia is a frequent and clinically significant feature of VL and hemoglobin levels of 7 to 10 g/dl are commonly found. Leucopenia is an early and striking manifestation of VL. Platelet counts are usually affected after long duration of illness. A varying degree of frequency and severity of pancytopenia has been reported. In this case we think that both imatinib treatment and concurrent Leishmania infection played a role in the cytopenias observed.\n\nThe most commonly reported Grade 3 or 4 adverse events experienced in 5 years of follow-up of newly diagnosed patients with CML treated with imatinib as a first-line therapy were neutropenia, thrombocytopenia, anemia, and elevated liver enzymes [13]. In our patient, the diagnosis of leishmaniasis was not anticipated. Pancytopenia was considered an adverse event, and spleen enlargement after imatinib cessation was attributed to TKI secondary resistance/progression. Adverse hematologic side-effects of imatinib include anemia, neutropenia, and thrombocytopenia. Hematologic toxicity appears mild to moderate in most instances and is often easily manageable and potentially reversible. Less than 10 % of the patients present persistent cytopenias that might preclude treatment. By the time of imatinib cessation our concern was about pancytopenia as an adverse effect. When we stopped imatinib we observed a progressive spleen enlargement. Our patient had low grade fever and was a farmer. We then arrived at a second diagnostic hypothesis. When a new evaluation of his bone marrow was performed, the infectious disease was diagnosed.\n\nConclusions\nTo the best of our knowledge, this report highlights the importance of careful management of patients with CML during treatment, with the formulation of different hypotheses on common situations in an attempt to increase the chance of elucidation of the etiologic diagnosis. Social context must always be taken into account. We should always try to explain the clinical conditions considering a single disease, but we need to recognize the possibility of a second pathology.\n\nAbbreviations\nCML, chronic myeloid leukemia; PCR, polymerase chain reaction; Ph+, Philadelphia chromosome; qPCR, quantitative polymerase chain reaction; TKI, tyrosine kinase inhibitor; VL, visceral leishmaniasis\n\nAcknowledgements\nThe authors would like to gratefully acknowledge the patient for his collaboration. We thank the Walter Cantidio University Hospital for its support. No funding was obtained for this report.\n\nAuthors’ contributions\nAQ, PAMF, TPF, RPGL, and CAMN wrote the paper; AQ and FBD have been involved in clinical follow-up; AQ and FBD have been involved in medical examinations and image capture; TPF and CAMN have been involved in molecular analysis; PAMF, TPF, CAMN, and RPGL have been involved in manuscript review. All authors read and approved the final manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this manuscript. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n==== Refs\nReferences\n1. Kantarjian HM Deisseroth A Kurzrock R Estrov Z Talpaz M Chronic myelogenous leukemia: a concise update Blood. 1993 82 691 703 8338938 \n2. Nowell PC Hungerford DA A minute chromosome in human chronic granulocytic leucemia [letter] Science. 1960 132 1497 \n3. Rowley JD A new consistent chromosomal abnormality in chronic myelogenous leukemia identified by quinacrine fluorescence and Giemsa staining Nature. 1973 243 290 3 10.1038/243290a0 4126434 \n4. Ben-Neriah Y Daley GQ Mes-Masson AM Witte ON Baltimore D The chronic myelogenous leukemia-specific p210 protein is the product of the bcr/abl hybrid gene Science. 1986 233 212 4 10.1126/science.3460176 3460176 \n5. Konopka JB Witte ON Detection of c-abl tyrosine kinase activity in vitro permits direct comparison of normal and altered abl gene products Mol Cell Biol. 1985 5 3116 23 10.1128/MCB.5.11.3116 3879812 \n6. Lugo TG Pendergast A Muller AJ Witte ON Tyrosine kinase activity and transformation potency of bcr-abl oncogene products Science. 1990 247 1079 82 10.1126/science.2408149 2408149 \n7. Calabretta B Perrotti D The biology of CML blast crisis Blood. 2004 103 4010 22 10.1182/blood-2003-12-4111 14982876 \n8. Bhamidipati PK Kantarjian H Cortes J Cornelison AM Jabbour E Management of imatinib-resistant patients with chronic myeloid leukemia Ther Adv Hematol. 2013 4 103 17 10.1177/2040620712468289 23610618 \n9. Podinovskaia M Descoteaux A Leishmania and the macrophage: a multifaceted interaction Future Microbiol 2015 10 1 111 29 10.2217/fmb.14.103 25598341 \n10. Kaye P Scott P Leishmaniasis: Complexity at the host-pathogen interface Nat Rev Microbiol. 2011 9 604 15 10.1038/nrmicro2608 21747391 \n11. Badaró R Carvalho EM Rocha H Queiroz AC Jones TC Leishmania donovani : An opportunistic microbe associated with progressive disease in three immunocompromised patients Lancet. 1986 1 647 9 10.1016/S0140-6736(86)91725-3 2869348 \n12. Madeira MF Schubach AO Schubach TMP Leal CA Marzochi MCA Identification of Leishmania chagasi isolated from healthy skin symptomatic and asymptomatic dogs seropositive for leishmaniasis in the Municipality of Rio de Janeiro, Brazil Braz J Infect Dis. 2004 8 440 4 10.1590/S1413-86702004000600008 15880235 \n13. Hughes TP Hochhaus A Branford S Long-term prognostic significance of early molecular response to imatinib in newly diagnosed chronic myeloid leukemia: an analysis from the International Randomized Study of Interferon and STI571 (IRIS) Blood 2010 116 19 3758 65 10.1182/blood-2010-03-273979 20679528\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1752-1947",
"issue": "10()",
"journal": "Journal of medical case reports",
"keywords": "Chronic myeloid leukemia; Tyrosine kinase inhibitors; Visceral leishmaniasis",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D000328:Adult; D006801:Humans; D000068877:Imatinib Mesylate; D007898:Leishmaniasis, Visceral; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008297:Male; D010198:Pancytopenia; D047428:Protein Kinase Inhibitors",
"nlm_unique_id": "101293382",
"other_id": null,
"pages": "207",
"pmc": null,
"pmid": "27461416",
"pubdate": "2016-07-27",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25598341;21747391;23610618;3879812;15880235;2408149;14982876;3460176;4126434;8338938;20679528;2869348",
"title": "Pancytopenia during tyrosine kinase inhibitor treatment - coexistence of chronic myeloid leukemia and visceral leishmaniasis: a case report.",
"title_normalized": "pancytopenia during tyrosine kinase inhibitor treatment coexistence of chronic myeloid leukemia and visceral leishmaniasis a case report"
} | [
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"abstract": "BACKGROUND\nThe population of developed countries is aging, leading to an increase in the use of medication in daily practice, which can lead to serious treatment costs and irrational polypharmacy. A collaborative care approach, such as providing medication review service provided by a clinical pharmacist (CP), is a possible way to reduce drug-related problems and irrational polypharmacy. The aim of this study was to determinate whether a CP's medication review service can improve the quality of drug prescribing in elderly patients treated with polypharmacy in primary care.\n\n\nMETHODS\nIn a retrospective observational medical chart review study, patients aged 65 years or more in the period 2012-2014 who received 10 or more medications concomitantly and who were screened by a CP were included. Data on pharmacotherapy and CPs' interventions were obtained from the patients' medical records (non-electronic chart review). Potential drug-drug interactions (pDDIs) were determined with Lexicomp Online™ 3.0.2. Only potential X-type DDIs (pXDDIs) were included. Potentially inappropriate medications in the elderly (PIMs) were identified using the PRICUS list.\n\n\nRESULTS\nNinety-one patients were included. The CPs suggested 625 interventions, of which 304 (48.6%) were accepted by the general practitioners (GPs). After adopting the CPs' interventions, the number of total medications decreased by 11.2% (p < 0.05) and the number of pXDDIs decreased by 42% (p < 0.05). The number of clinically important pXDDIs decreased by 50% (3 cases). The number of prescribed PIMs decreased by 20% (p = 0.069). The acceptance of CP's recommendations reduced the number of pXDDIs (p < 0.05) and improved the adherence to heart failure treatment guidelines.\n\n\nCONCLUSIONS\nA collaborative care approach offering a CP medication review service significantly improved the quality of pharmacotherapy by reducing the total number of medications and pXDDIs. The results support the implementation of this service in the Slovenian healthcare system.",
"affiliations": "Department of Clinical Pharmacy, Ormoz Psychiatric Hospital, Ptujska cesta 33, SI-2270, Ormoz, Slovenia. matejstuhec@gmail.com.;Faculty of Pharmacy, University of Ljubljana, Askerceva cesta 7, SI-1000, Ljubljana, Slovenia.;Faculty of medicine Maribor, University of Maribor, Taborska ulica 8, 2000, Maribor, Slovenia.",
"authors": "Stuhec|Matej|M|http://orcid.org/0000-0001-5909-6930;Gorenc|Katja|K|;Zelko|Erika|E|",
"chemical_list": null,
"country": "England",
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"doi": "10.1186/s12913-019-3942-3",
"fulltext": "\n==== Front\nBMC Health Serv ResBMC Health Serv ResBMC Health Services Research1472-6963BioMed Central London 394210.1186/s12913-019-3942-3Research ArticleEvaluation of a collaborative care approach between general practitioners and clinical pharmacists in primary care community settings in elderly patients on polypharmacy in Slovenia: a cohort retrospective study reveals positive evidence for implementation http://orcid.org/0000-0001-5909-6930Stuhec Matej 0038641239414matejstuhec@gmail.com 123Gorenc Katja katja.gorenc2009@gmail.com 2Zelko Erika erikazelko@gmail.com 31 Department of Clinical Pharmacy, Ormoz Psychiatric Hospital, Ptujska cesta 33, SI-2270 Ormoz, Slovenia 2 0000 0001 0721 6013grid.8954.0Faculty of Pharmacy, University of Ljubljana, Askerceva cesta 7, SI-1000 Ljubljana, Slovenia 3 0000 0004 0637 0731grid.8647.dFaculty of medicine Maribor, University of Maribor, Taborska ulica 8, 2000 Maribor, Slovenia 13 2 2019 13 2 2019 2019 19 11826 6 2018 31 1 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\nThe population of developed countries is aging, leading to an increase in the use of medication in daily practice, which can lead to serious treatment costs and irrational polypharmacy. A collaborative care approach, such as providing medication review service provided by a clinical pharmacist (CP), is a possible way to reduce drug-related problems and irrational polypharmacy. The aim of this study was to determinate whether a CP’s medication review service can improve the quality of drug prescribing in elderly patients treated with polypharmacy in primary care.\n\nMethods\nIn a retrospective observational medical chart review study, patients aged 65 years or more in the period 2012–2014 who received 10 or more medications concomitantly and who were screened by a CP were included. Data on pharmacotherapy and CPs’ interventions were obtained from the patients’ medical records (non-electronic chart review). Potential drug-drug interactions (pDDIs) were determined with Lexicomp Online™ 3.0.2. Only potential X-type DDIs (pXDDIs) were included. Potentially inappropriate medications in the elderly (PIMs) were identified using the PRICUS list.\n\nResults\nNinety-one patients were included. The CPs suggested 625 interventions, of which 304 (48.6%) were accepted by the general practitioners (GPs). After adopting the CPs’ interventions, the number of total medications decreased by 11.2% (p < 0.05) and the number of pXDDIs decreased by 42% (p < 0.05). The number of clinically important pXDDIs decreased by 50% (3 cases). The number of prescribed PIMs decreased by 20% (p = 0.069). The acceptance of CP’s recommendations reduced the number of pXDDIs (p < 0.05) and improved the adherence to heart failure treatment guidelines.\n\nConclusions\nA collaborative care approach offering a CP medication review service significantly improved the quality of pharmacotherapy by reducing the total number of medications and pXDDIs. The results support the implementation of this service in the Slovenian healthcare system.\n\nKeywords\nClinical pharmacistPrimary careGeneral practitionersService implementationHealthcare systemPolypharmacyElderlyhttp://dx.doi.org/10.13039/501100004329Javna Agencija za Raziskovalno Dejavnost RSissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nThe aging of the population in developed countries is accompanied by increasing medication and polypharmacy use [1]. According to the paper published by Maher et al., approximately 50% of older adults (aged > 65 years) took one or more medications that were not medically necessary [2]. Polypharmacy, defined as the use of multiple drugs or more than are medically necessary, often has negative consequences [3]. In a clinical setting, it is often connected with serious drug-drug interactions (DDIs) and potentially inappropriate medications (PIMs) in the elderly, which are an important cause of adverse events and increase morbidity, hospitalization rates, and total healthcare costs. In an Austrian cross-sectional study which included 48 out of 50 nursing homes in Austria, the authors found a high prevalence of PIMs. The prevalence of residents with at least one PIM was 70.3% (95% CI 67.2–73.4) [4, 5]. Inappropriate polypharmacy is wide-spread and potentially harmful and therefore requires prompt interventions [1, 6–8]. In addition, the literature review including 5 papers showed that polypharmacy continues to increase and its use was shown as a known risk factor for increased morbidity and mortality, which shows that health care professionals should check patients’ pharmacotherapy at each occasion [6].\n\nDifferent approaches are possible to manage these problems. One of the newest is a collaborative care approach in which clinical pharmacists (CPs) are included in the management of patients’ pharmacotherapy (either as dependent or independent prescribers or a non-prescribers) [1]. Many studies found that including a pharmacist as a full member of the care team was associated with a substantially lower rate of adverse drug effects and medical errors [9–12]. In addition, the last Cochrane review on this topic suggested that non-medical prescribing by CPs and nurses was as effective as usual care medical prescribing, although effect sizes were small (non-medical prescribing was undertaken by nurses in 26 studies and by CPs in 20 studies). According to the results of this paper, the main benefits were seen in various cardiovascular treatments, patient satisfaction, and quality of life [13].\n\nA collaborative care approach that includes CPs has been seen in some countries in which funders (e.g. national insurance companies) supported this service. In Slovenia, the support for collaborative care is due to a large increase in drug consumption in the last decade [14].\n\nAlthough this system has been well described in the US and UK, there is little data on this topic in Central European countries, primarily because, by convention, the roles of pharmacists and physicians in these countries are rigidly separate [15]. Hence, this study aims to evaluate aspects of the completely new pharmaceutical service in Slovenia by examining whether medical reviews performed by CPs can improve the quality of drug prescribing in elderly patients treated with polypharmacy, measured in terms of better treatment guidelines adherence, the number of PIMs and the number of potential X-type drug-drug interactions (pXDDIs), major interactions that should be avoided.\n\nMethods\nDesign and setting\nThis retrospective cohort study used paper medication reviews and medical charts, gathered from elderly patients (≥ 65 years), who were treated under the pilot trial Pharmacist Consultant (non-prescriber) at the Ljutomer Health Center, which caters to approximately 20.000 users in the northeast of Slovenia. The study was approved by the National Medical Ethics Committee of the Republic of Slovenia in 2016 (number = 0120–528/2016–2).\n\nParticipants and data collection\nPatients for this study were included from the pilot trial Pharmacist Consultant (non-prescriber) in Slovenia, which was funded by the Health Insurance Institute of Slovenia (ZZZS) between 2012 and 2015. In this pilot trial, a clinical pharmacy specialist (CP) was included into the general practitioners’ teams. Each CP was trained to perform a medication review and was a CP (a board-certified CP). All CPs in this pilot trial worked in the different hospital settings (e.g. psychiatric and general hospitals) and therefore they received their experiences on the hospital wards. Each team consisted of all only general practitioners (GPs). The CPs were based in primary community health centres (GPs’ offices). On the request of a GP, a patient could be referred to the CP for a medication review. After a consultation with the patient, the CP prepared a medication review that included potential drug-drug interactions (pDDIs), as identified by the Lexicomp Online™ software, possible adverse events, existing drug indications, potentially inappropriate medication in the elderly, an evaluation of drug adherence (refill-based system) and final recommendations depending on the patient’s outcomes. CPs mostly recommended drug discontinuation, drug initiation, dose adjustments and modifications of drug administration. GPs selected patients for referral to the CPs with a referral paper. The medication review was sent back to the GPs within a few days of the patient’s visit to the CP and the GPs could accept or reject their recommendations at the patient’s next regular visit. CPs communicated with GPs through the medication review and by phone call if necessary. On average, a CP produced 4–6 medication reviews in 6–8 h after a successful trial, this service has been adopted into the Slovenian healthcare system in 2016 [15].\n\nThe medication reviews and medical charts of the patients from the pilot trial Pharmacist Consultant (non-prescriber) were the source material for our retrospective study. The inclusion criteria for this study were the patients’ age (≥ 65 years), treatment at the Ljutomer Health Center, their referral to the CP in the period from 1.1.2012 to 31.12.2014, and concomittant use of 10 or more medications.\n\nOver-the-counter medications, eye drops, and various dermal medications were excluded because it was often impossible to identify the manner of their use from the patients’ medical charts and medication reviews. Data on diagnoses, patient pharmacotherapy and CPs’ interventions were obtained from the patients’ paper medical records (medical charts) and paper medication reviews. The pDDIs were differentiated by interaction classes using the software Lexicomp Online™ 3.0.2 (free program), described and used in many previous trials [14, 16, 17]. Only pXDDIs were included in the final analysis, based on previous work by other another study [17]. Data on the clinical relevance of the pXDDIs were obtained from paper medication reviews, in which the CP recorded any adverse events caused by pXDDIs. Clinical data were recorded for all CP interventions. Pharmacotherapy details (e.g. medications, dose, pXDDIs) were also obtained from the medication reviews. Acceptance of recommendations was obtained from the patients’ charts at the first GPs’ visit. The study only included three CPs’ interventions: medication discontinuation, medication initiation and dose adjustment. Other interventions (e.g. administration instructions) were excluded. A medication review was performed according to the standard process, which has been already described above [15]. The PRISCUS list was used to identify potentially inappropriate medications for elderly patients (PIM) [18].\n\nThe data was compiled by a MPharm student (KG) under the supervision of a clinical pharmacist specialist (MS) directly from the patients’ paper medical charts and paper medication reviews. pXDDIs were collected by KG from paper medication reviews, because each medical review included pXDDIs and their categorization according to the Lexicomp Online™ software. The clinical relevance of pXDDIs was assessed by KG and MS directly from medication reviews if specified by a CP in the original medication review. The researchers did not contact any of the included patients during the data gathering process. Only Lexicomp Online™ was used in this study, because only this software was used in the pilot trial Pharmacist Consultant. A multivariable regression model that defines predictive factors for the impact of pXDDIs was conducted.\n\nAnalysis\nThe baseline characteristics of patients were described as the mean ± standard deviation (SD) or median. Descriptive results were presented in graph form (number of PIMs according to the PRISCUS list before and after; total number of medications per patient before and after review; total number of pXDDIs before and after review). Total CP acceptance percentage by GPs (all recommendations) was calculated based on the three different CPs’ interventions: 1) medication discontinuation, 2) medication initiation, 3) dose adjustment. Analyses were carried out with the Statistical Package for Social Science 22.0 for Windows® (SPSS). A multivariable regression model (number of pXDDIs as a dependent variable) was developed with several independent variables (age, gender, total number of medications and clinical pharmacist acceptance), which were selected according to the important variables observed from the patients’ charts and medication reviews. In addition, heart failure treatment guidelines (European Society of Cardiology (ESC) Guidelines for the diagnosis and treatment of acute and chronic heart failure) were applied to evaluate the CPs’ adherence to these guidelines. For this purpose, the data of all patients with a diagnosis of heart failure was used [19].\n\nResults\nGeneral data and clinical pharmacists recommendations\nNinety-one patients were included in this study. Researchers excluded 19 patients before the study, because of incomplete datasets (e.g. missing variables, death patients without available medical charts). The study involved 56 women (61.5%) and 35 men (38.5%). The average age was 77.5 years (median 78, range 65–91). In total, patients received 1260 medications (mean 13.8, median 13) (regular therapy and therapy as needed) during the study. The highest number of prescribed medications was 21 per patient. The numbers of proposed CP’s interventions and GPs acceptances during the study are shown in Table 1. The CP proposed 625 interventions (median seven interventions per patient). The CP most often proposed seven different interventions per patient, which was the case in 103 (16.5%) patients. GPs accepted almost half of the proposed interventions (n = 304; 48.6%). Detailed results are presented in the Fig. 1 (flow chart).Table 1 The numbers of interventions proposed and interventions accepted by general practitioners during the study\n\nProposed interventions\tTotal\t\nNumber of proposed interventions by clinical pharmacists\t625\t\nNumber of interventions accepted by general practitioners\t304\t\nMedian of the proposed interventions\t7\t\nMedian accepted interventions\t3\t\nMaximum number of proposed interventions by clinical pharmacists\t15\t\nMaximum number of accepted interventions by general practitioners\t8\t\nFig. 1 A flow chart of main study outcomes\n\n\n\nAt the end of the study, patients received 1119 medications in total (mean 12.3, median 12), which is 141 fewer than they received before the CP’s review (total number of prescribed medications decreased by 11.2%). Patients, whose GPs accepted the CPs’ recommendations, overall had fewer medications per patient compared to those whose GPs did not accept the recommendations (Mann-Whitney’s U test; U = 68,000; p < 0.01).\n\nPotential and clinically important drug-drug interactions and potentially inappropriate medications in the elderly\nBefore the CPs’ observation, 50 pXDDIs were recorded in the patient’s therapy, while after medication review and the physician examination, patients received 29 pXDDIs in pharmacotherapy. The number of pXDDIs in the pharmacotherapy decreased by 42% (Mann-Whitney’s U test; U = 12,000; p < 0.041). The number of pXDDIs for which the CP recommended drug discontinuation are shown in the Table 2.Table 2 The number of pXDDIs, for which the CP recommended drug discontinuation\n\npXDDIs\tN prior\tN after\tpXDDIs\tN prior\tN after\t\n Amiodarone-torsemide\t1\t0\t\nipratropium / fenoterol-tiotropium\n\t\n3\n\t\n2\n\t\n Amiodarone-clozapine\t1\t0\t\nquetiapine-amiodarone\n\t\n1\n\t\n0\n\t\n Amiodarone-warfarin\t1\t0\t\nquetiapine -domperidone\n\t\n2\n\t\n1\n\t\n Etoricoxib-meloxicam\t1\t0\t\nquetiapine -escitalopram\n\t\n7\n\t\n3\n\t\n Haloperidol-sulpiride\t2\t1\t\nquetiapine-metoclopramide\n\t\n3\n\t\n2\n\t\n Haloperidol-metoclopramide\t1\t0\t\nquetiapine-sulpiride\n\t\n2\n\t\n1\n\t\n Cholecalciferol-calcitriol\t3\t0\t\nmetoclopramide-trimetazidine\n\t\n2\n\t\n1\n\t\n Ipratropium/fenoterol-Olanzapine\t2\t1\t\nsulpiride-risperidone\n\t\n1\n\t\n0\n\t\nNot accepted pXDDIs\tN prior\tN after\tpXDDIs\tN prior\tN after\t\n Amisulpride-sulpiride\t1\t1\t\nquetiapine-budenoside / formoterol\n\t\n1\n\t\n1\n\t\n Desloratadine-mirtazapine\t1\t1\t\nquetiapine-domperidone\n\t\n2\n\t\n1\n\t\n Escitalopram-sotalol\t1\t1\t\nquetiapine-escitalopram\n\t\n7\n\t\n3\n\t\n Haloperidol-sulpiride\t2\t1\t\nquetiapine-haloperidol\n\t\n3\n\t\n3\n\t\n Haloperidol- ipratropium/phenoterol\t1\t1\t\nquetiapine-metoclopramide\n\t\n3\n\t\n2\n\t\n Haloperidol ipratropium/phenoterol-\t1\t1\t\nquetiapine-sulpiride\n\t\n2\n\t\n1\n\t\n Olanzapine- ipratropium/phenoterol\t2\t1\t\nquetiapine-trazodone\n\t\n1\n\t\n1\n\t\n Quetiapine-tiotropium\t1\t1\t\nquetiapine-tiotropium\n\t\n1\n\t\n1\n\t\n Carbamazepine-clozapine\t3\t2\t\nmetoclopramide-trimetazidine\n\t\n2\n\t\n1\n\t\n Carvedilol- budenoside/formoterol\t2\t2\t\nolanzapine-thyrotropium\n\t\n1\n\t\n1\n\t\n Quetiapine- ipratropium/phenoterol\t1\t1\t\nsulpiride-trimetazidine\n\t\n1\n\t\n1\n\t\n\n\nThe pXDDIs were clinically relevant in six patients (n = 6; 6.6%), all of whom experienced a QT interval prolongation due to pXDDIs. In one patient, the QT prolongation occurred because of a pXDDI between haloperidol and quetiapine (a pharmacodynamic pXDDI), in three patients due to a pXDDI of escitalopram and quetiapine (a pharmacodynamic pXDDI) and in two patients due to a pXDDI of domperidone and quetiapine (a pharmacodynamic pXDDI). These results show that 12% of pXDDIs were clinically expressed.\n\nThe pXDDI of escitalopram and quetiapine was clinically expressed in 42.9% of the cases (the number of pXDDIs of escitalopram and quetiapine was seven) and the pXDDI of domperidone and quetiapine in 100% of the cases (the number patients with this pXDDIs was two). The CPs suggested drug discontinuation in all 6 clinically important pXDDIs and 50% of the suggestions were accepted by the GPs. Prior to the CP’s review, patients received 140 PIMs in total (12.5% of total medications), which was reduced to 112 PIMs (10.0% of total medications) after the review, which is a decrease of 28 (20%) (Mann-Whitney U test; U = 87,500; p = 0.069). All PIMs with their numbers before and after the review are shown in the Fig. 2.Fig. 2 Number of patients with PIMs before clinical pharmacist review and after review according to the PRISCUS List\n\n\n\nLinear regression model results for the occurrence of potential X DDIs\nIn the model for pXDDIs, a statistically significant model p (χ2 = 37,612, df = 4, p < 0.001) was obtained by logistic regression (Table 3). The number of pXDDIs was statistically influenced by the accepted CPs’ interventions and the total number of prescribed medications (p < 0.005). Accepted CPs’ recommendations led to a reduction in the number of pXDDIs.Table 3 Linear regression model results for the occurance of potential X DDIs\n\nIndependent variable\tβ value\tP value\t\nClinical pharmacist acceptance\t−1.955\t0.003\t\nAge\t0.024\t0.546\t\nTotal number of medicines\t−0.442\t< 0.001\t\nGender\t0.253\t0.686\t\n\n\nAdherence to heart failure treatment guidelines\nAdherence to treatment guidelines was checked in patients with a heart failure diagnosis in their charts. 36 patients were diagnosed with heart failure (Table 4). In nine cases (25.0%), the CP’s recommendations were accepted by GPs, which means that treatment guidelines adherence was improved through accepted CP’s recommendations.Table 4 Adherence to heart failure treatment guidelines (ESC Guidelines), GPs=general practitioners\n\nCase number\tTreatment guidelines issue\tClinical pharmacist recommendations\tGPs acceptance (YES/NO)\t\n\n1.\n\t\nMethyldigoxin treatment\n\t\nMethyldigoxin discontinuation and perindopril initiation\n\t\nYES\n\t\n2.\tMethyldigoxin treatment\tMethyldigoxin discontinuation and enalapril initiation\tNO\t\n\n3.\n\t\nMethyldigoxin treatment + β-blocker +ACE inhibitor\n\t\nMethyldigoxin treatment discontinuation\n\t\nYES\n\t\n\n4.\n\t\nMethyldigoxin treatment +ACE inhibitor\n\t\nMethyldigoxin treatment discontinuation + β-blocker initiation\n\t\nYES\n\t\n5.\tMethyldigoxin treatment\tβ-blocker initiation and ACE inhibitor initiation\tNO\t\n\n6, 7, 8, 9, 10.\n\t\nMethyldigoxin treatment + β-blocker\n\t\nMethyldigoxin treatment discontinuation\n\t\nYES, NO, YES, NO, YES\n\t\n11.\tMethyldigoxin treatment +ACE inhibitor\tMethyldigoxin treatment discontinuation + β-blocker initiation\tNO\t\n\n12.\n\t\n1.25 mg bisoprolol daily\n\t\nDrug adjustment (2,5 mg daily)\n\t\nYES\n\t\n13, 14, 15.\tACE inhibitor treatment\tβ-blocker adding\tNO, NO, NO\t\n16, 17, 18.\tACE inhibitor treatment with verapamil\tVerapamil discontinuation and selective β-blocker initiation\tNO, NO, NO\t\n19.\tInappropriate dosing of ACE inhibitor and β-blocker\tReduce the ACE inhibitor dose and increase the dose of the β-blocker\tNO\t\n\n20.\n\t\nNonselective β-blocker\n\t\nSwitching to bisoprolol\n\t\nNO, YES\n\t\n\n21.\n\t\nAmlodipine treatment\n\t\nAmlodipine discontinuation and β-blocker (bisoprolol) initiation\n\t\nYES\n\t\nInterventions where CP's recommendations were accepted are presented in a bold form\n\n\n\nDiscussion\nThe results of this study show that a medication review service provided by CPs in primary care had a significant impact on improving the quality of pharmacotherapy, measured as the reduction in the total number of medications, PIMs and pXDDIs, and improved treatment guidelines adherence. Results show that GPs accepted almost half of the suggested interventions, which is in line with a study from a Belgian hospital (56.6%) but not with a study in a Slovenian psychiatric hospital (88.0%), which may be explained by a different work environment [20, 21]. The results also show that the main role of the CP is not only medication reduction, but pharmacotherapy optimization (e.g. better treatment guidelines adherence), which can also lead to more medications in some patients (two patients in our study). In a study in the U.S., the researchers found that only 7% of the CPs’ interventions were connected with drug discontinuation [10]. In our study, drug discontinuation represented only 13.5% of the interventions, drug initiation 2.3%, and other interventions represented almost 85%. These results confirmed that the total number of medications decreased significantly after a CP’s intervention, which had previously been already discussed in some trials [6, 9, 10]. In addition, a systematic review and meta-analysis published in 2014 confirmed our positive results. Pharmacist interventions usually involved medication reviews (86.8%), with or without other activities delivered collaboratively with the GP (family physician) [22]. There are many studies describing the collaboration between GPs and CPs within a community pharmacy setting [23]. Although our study setting was a primary care community setting, the results were also positive. This study was funded by the ZZZS that established this work environment within the Slovenian primary care community settings before. The researchers did not have an impact on the study environment. Although this setting use in this study was supported by payer, in future, existing community pharmacy network in collaborative care with primary care should be studied, so that a broader scope of evidence will be also available in future on this same service in Slovenia.\n\nOne of the most important findings of this study is that CPs’ interventions significantly reduced the total number of medications and pXDDIs. Although the potential reduction of pXDDIs as a result of involving CPs have been described elsewhere, [6, 9, 10], our study extends the findings to at a primary care setting. The most frequent pXDDIs were between quetiapine and escitalopram which the CP’s interventions reduced from 6 to 3 cases. Quetiapine was a medication which was involved in most of pXDDIs and was discontinued in many cases as suggested by the CP. These results are in line with the clinical guidelines for antipsychotic use and insomnia treatment, according to which quetiapine is not a first line treatment, especially for insomnia, because the evidence is very weak [24–26]. Therefore the CP’s suggestions about quetiapine discontinuation were evidence-based [27, 28]. These results suggest that CPs can support GPs in treating insomnia and managing the use of antidepressants to avoid important pXDDIs. 6.6% of patients experienced clinically important pXDDIs as an adverse event and the CP suggested drug discontinuation to avoid pXDDIs. This means that a CP can also reduce clinically important pXDDIs, which is also in line with previous results [6, 9, 10]. Our regression model also showed that the number of pXDDIs was statistically influenced by the involvement of the CP and the total number of prescribed medications (< 0.005), which means that the CP’s interventions had an impact on the total number of pXDDIs (high β value) which is in line with previous results [6].\n\nThe next important finding is connected with a lower number of PIMs after CPs’ interventions. These results show that PIMs were very frequent in this study population, especially PIMs in psychotropics. The CPs’ interventions reduced PIMs by 20%, although non-significantly, which can be explained by the small sample size used in this study. Although the results were not significant, CPs’ interventions led to a reduction in several important PIMs (e.g. amitriptyline). CP’s interventions led to the discontinuation of several drugs (e.g. haloperidol, methyldigoxin, amitriptyline and different benzodiazepines), which is in line with the PRISCUS list [18].\n\nThe last important finding of this paper is connected with better treatment guidelines adherence, which is particulary important for better clinical outcomes. The CP suggested pregabalin in a case of neuropathic pain and the sedative antidepressant mirtazapine instead of amitriptyline, which is also supported by clinical guidelines [27]. Methyldigoxin was often replaced by beta-blockers and/or ACE inhibitors in patients with chronic heart failure, which is also in line with clinical guidelines [19]. These results show that patients, after the CP’s interventions, had fewer important PIMs and were more likely to use appropriate alternatives, which confirmed the important role CPs can play in reducing PIMs in a primary care setting. In this study, only chronic heart failure treatment guidelines adherence was examined. Interestingly, inconsistencies with the treatment guidelines were found in 58.3% of all patients with heart failure, especially regarding the lack of the most advisable treatment strategy, which can have an impact on final patient-survival (e.g. β-blockers and ACE-inhibitors or ARBs) [19]. These results show that treatments followed guidelines more appropriately if the recommendations by the CPs’ were accepted by the GP. These results are not in line with a small sized Slovenian study, where hospital CPs’ interventions were included. In this small-size randomized controlled trial (RCT) (intervention, n = 26; control, n = 25) pharmacist intervention significantly reduced the number of patients with clinically relevant DDIs, but not clinical endpoints 6 months from discharge (re-hospitalization or death) (10 vs. 7; p = 0.74) [29]. In our study, dose adjustment was suggested in patients with chronic heart failure in many cases, which is also in line with the clinical guidelines [19]. These results showed that a collaborative care approach including a CP is beneficial for patients with chronic heart failure, although more studies with bigger sample sizes are needed to confirm these results.\n\nIn addition, a clinical pharmacy service is often an cost-effectivenes approach in the medication management process in elderly patients, as was calculated by Lee and co-authors at a VA medical center. Our results were also economically positive with return on investment 5:1, which was calculated in MPharm thesis already (not included in the manuscript), which confirms a cost-effectivenes of these interventions in real clinical practice. However, these economic outcomes are interesting, there are many limitations predominantly because of a lack of Slovenian costs [30–32]. These results together with our previous results show that payers in Slovenia should stimulate clinical pharmacy service implementation in pharmacotherapy optimization process in elderly patients on polypharmacy (e.g. better clinical outcomes and lower costs) [31, 32].\n\nLastly, this study also has many important limitations, which should be addressed. The most important limitation is an absence of a control group as well as of humanistic and/or clinical outcome measures. (no between group difference and no treatment outcomes differences). These limitations are due to the design of the Pharmacist Consultant pilot trial, in which no control group or patient-specific measurements (e.g. questionnaires) were planned and it was impossible to obtain the data retrospectively. GPs also referred patients to CPs without strict protocol, which can be a source of selection bias. We also didn’t have any data about patient refusals, which can have an impact on the sample size. In addition, a retrospective cohort design has many other important limitations, which should be addressed (e.g. selection bias, attrition bias and missing data). The second limitation is that the results of pDDIs may also depend on the Lexicomp® software version, as the standards used are frequently updated [16, 33]. The third important limitation is that we included only X-type pDDIs, although some authors argue that the pDDIs of category C and D are also clinically relevant. This means some potentially important interventions were not included in the analysis to minimize the number of non-important pDDIs, so the effects of this study then might be lower than anticipated. We should also acknowledge the absence of socio-economic variables (e.g. no. school years, employment situation, income) collected which prevented to assess health equity issues of the intervention provided, as recommended for the evaluation of health care interventions, namely to compare differences in expected outcomes between low and high socio-economic subsets. A public health intervention (included those delivered by pharmacists) should ideally produce greater improvements in more deprived socio-economic patients to ensure health equity. This requires further investigation in future research.\n\nHowever, this observational study still offers new insights into the merits of a collaborative care model including GPs, expands the knowledge of collaborative model implementation in Central Europe and is one of the first papers describing elderly patients with polypharmacy in a collaborative primary care setting.\n\nConclusions\nA collaborative care model including CPs undertaking a medication review service in primary care led to fewer pXDDIs per patient, fewer total medications per patient, fewer PIMs per patient, and better treatment guidelines adherence in patients aged 65 years and older on 10 or more medications in Slovenia. Although these positive results, a further research considering an experimental randomized or quasi-randomized controlled design is necessary.\n\nAbbreviations\nACEAngiotensin-converting enzyme\n\nARBsAngiotensin II Receptor Blockers\n\nCPClinical pharmacist\n\nESCEuropean Society of Cardiology\n\nGPsGeneral practitioners\n\npDDIsPotential drug-drug interactions\n\nPIMsPotentially inappropriate medications in the elderly\n\npXDDIsPotential X-type DDIs\n\nRCTRandomized controlled trial\n\nSDStandard deviation\n\nZZZSHealth Insurance Institute of Slovenia\n\nAcknowledgements\nNot applicable.\n\nFunding\nThe author MS acknowledge the financial support from the Slovenian Research Agency for manuscript writing (research core funding No. P3–0036, Biopsychosocial model of quality of life).\n\nAvailability of data and materials\nThe data is not publicly available due to privacy reasons.\n\nAuthors’ contributions\nConceived and designed the study: MS, EZ, KG. Collected the data: KG, MS. Analyzed the data: KG, MS. Drafted the manuscript: KG, MS, EZ. Commented the draft of the manuscript: all authors. Read and approved the final version of the manuscript: all authors.\n\nEthics approval and consent to participate\nThis study was approved by the National Medical Ethics Committee of the Republic of Slovenia in 2016 (Number 0120–528/2016–2; approved 10.11.2016).\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. Akazawa M Imai H Igarashi A Tsutani K Potentially inappropriate medication use in elderly Japanese patients Am J Geriatr Pharmacother 2010 8 146 160 10.1016/j.amjopharm.2010.03.005 20439064 \n2. Maher RL Hanlon J Hajjar ER Clinical consequences of polypharmacy in elderly Expert Opin Drug Saf 2014 13 57 65 10.1517/14740338.2013.827660 24073682 \n3. Quality and Outwork framework. 2012.https://www.sehd.scot.nhs.uk/mels/CEL2012_36.pdf. Accessed 10 Jan 2019.\n4. Doan J Zakrzewski-Jakubiak H Roy J Turgeon J Tannenbaum C Prevalence and risk of potential cytochrome P450-mediated drug-drug interactions in older hospitalized patients with polypharmacy Ann Pharmacother 2013 47 324 332 10.1345/aph.1R621 23482734 \n5. Mann E Haastert B Böhmdorfer B Frühwald T Iglseder B Roller-Wirnsberger R Prevalence and associations of potentially inappropriate prescriptions in Austrian nursing home residents: secondary analysis of a cross-sectional study Wien Klin Wochenschr 2013 125 180 188 10.1007/s00508-013-0342-2 23536016 \n6. Hajjar ER Cafiero AC Hanlon JT Polypharmacy in elderly patients Am J Geriatr Pharmacother 2007 5 345 351 10.1016/j.amjopharm.2007.12.002 18179993 \n7. Gallagher PF Barry PJ Ryan C Hartigan I O'Mahony D Inappropriate prescribing in an acutely ill population of elderly patients as determined by beers’ criteria Age Ageing 2008 37 96 101 10.1093/ageing/afm116 17933759 \n8. Dechanont S Maphanta S Butthum B Kongkaew C Hospital admissions/visits associated with drug-drug interactions: a systematic review and meta-analysis Pharmacoepidemiol Drug Saf 2014 23 489 497 10.1002/pds.3592 24616171 \n9. Leape LL Cullen DJ Clapp MD Burdick E Demonaco HJ Erickson JI Pharmacist participation on physician rounds and adverse drug events in the intensive care unit JAMA 1999 282 267 270 10.1001/jama.282.3.267 10422996 \n10. Kucukarslan SN Peters M Mlynarek M Nafziger DA Pharmacists on rounding teams reduce preventable adverse drug events in hospital general medicine units Arch Intern Med 2003 163 2014 2018 10.1001/archinte.163.17.2014 14504113 \n11. Chisholm-Burns MA Kim Lee J Spivey CA Slack M Herrier RN Hall-Lipsy E US pharmacists' effect as team members on patient care: systematic review and meta-analyses Med Care 2010 48 923 933 10.1097/MLR.0b013e3181e57962 20720510 \n12. Trygstad TK Christensen D Garmise J Sullivan R Wegner S Pharmacist response to alerts generated from Medicaid pharmacy claims in a long-term care setting: results from the North Carolina polypharmacy initiative J Manag Care Pharm 2005 11 575 183 16137215 \n13. Weeks G George J Maclure K Stewart D Non-medical prescribing versus medical prescribing for acute and chronic disease management in primary and secondary care Cochrane Database Syst Rev 2016 22 11 CD011227 \n14. Stuhec M, Zelko E. A Collaborative Care Model between General Practitioners and Clinical Pharmacists in a Community Health Centre Setting in Depression Treatment: A Case Report and a Literature Review. Psychiatr Danub. 2019 (accepted for publication).\n15. Marušič PA Pharmacotherapy reviews in hospitals and at an outpatient clinic Farmakoterapijski pregledi v bolnišnicah in v ambulantah – izkušnje in evalvacija dela Farmacevtski vestnik 2014 65 187 190 \n16. Lexicomp - Clinical Drug Information (accessed on 10.1.2019) https://online.lexi.com/lco/help/lco-ug.pdf.\n17. Beovic B Plesnicar BK Potocan M Antibiotic prescribing in psychiatric hospitals and interactions between antibiotics and psychotropic drugs: a prospective observational study Infect Control Hosp Epidemiol 2016 37 233 235 10.1017/ice.2015.268 26514063 \n18. Holt S Schmiedl S Thürmann PA Potentially inappropriate medications in the elderly: the PRISCUS list Dtsch Arztebl Int 2010 107 543 551 20827352 \n19. Ponikowski P 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) developed with the special contribution of the heart failure association (HFA) of the ESC Eur Heart J 2016 37 2129 2200 10.1093/eurheartj/ehw128 27206819 \n20. Somers A Robays H De Paepe P Van Maele G Perehudoff K Petrovic M Evaluation of clinical pharmacist recommendations in the geriatric ward of a Belgian university hospital Clin Interv Aging 2013 8 703 709 10.2147/CIA.S42162 23807844 \n21. Stuhec M Pharmacotherapy review as a safety and cost tool in patients management in Slovenian psychiatric hospital. V: abstracts of the 27th ECNP congress, Berlin, Germany, 18-21 October 2014 Eur Neuropsychopharmacol 2014 24 S735 S736 10.1016/S0924-977X(14)71185-X \n22. Tan EC Stewart K Elliott RA George J Pharmacist services provided in general practice clinics: a systematic review and meta-analysis Res Social Adm Pharm 2014 10 608 622 10.1016/j.sapharm.2013.08.006 24161491 \n23. Gillespie U, Dolovich L, Dahrouge S. Activities performed by pharmacists integrated in family health teams: Results from a web-based survey. Can Pharm J (Ott). 2017;150:407–416.\n24. Taylor DM Young C Paton C Prior antipsychotic prescribing in patients currently receiving clozapine: a case note review J Clin Psychiatry 2003 64 30 34 10.4088/JCP.v64n0107 \n25. Howes OD Vergunst F Gee S McGuire P Kapur S Taylor D Adherence to treatment guidelines in clinical practice: study of antipsychotic treatment prior to clozapine initiation Br J Psychiatry 2012 201 481 485 10.1192/bjp.bp.111.105833 22955007 \n26. Hasan A Falkai P Wobrock T Lieberman J Glenthoj B Gattaz WF World Federation of Societies of biological psychiatry (WFSBP) task force on treatment guidelines for schizophrenia. Guidelines for biological treatment of schizophrenia, part 1: update 2012 on the acute treatment of schizophrenia and the management of treatment resistance. World Federation of Societies of biological psychiatry (WFSBP) World J Biol Psychiatry 2012 13 318 378 10.3109/15622975.2012.696143 22834451 \n27. Anderson SL Vande Griend JP Quetiapine for insomnia: a review of the literature Am J Health Syst Pharm 2014 71 394 402 10.2146/ajhp130221 24534594 \n28. Wilson SJ British Association for Psychopharmacology consensus statement on evidence-based treatment of insomnia, parasomnias and circadian rhythm disorders J Psychopharmacol 2010 24 1577 1601 10.1177/0269881110379307 20813762 \n29. Roblek T Deticek A Leskovar B Suskovic S Horvat M Belic A Clinical-pharmacist intervention reduces clinically relevant drug-drug interactions in patients with heart failure: a randomized, double-blind, controlled trial Int J Cardiol 2016 15 203 647 652 10.1016/j.ijcard.2015.10.206 \n30. Lee AJ Boro MS Knapp KK Meier JL Korman NE Clinical and economic outcomes of pharmacist recommendations in a veterans affairs medical center Am J Health Syst Pharm 2002 59 2070 2077 12434719 \n31. Gorenc K. Klinično ovrednotenje intervencij farmacevta v zdravstvenem domu Ljutomer pri starejših bolnikih s polifarmakoterapijo = Clinical evaluation of pharmacist consultant interventions in community health centre Ljutomer in elderly patients treated with polypharmacy : magistrska naloga: master's thesis. http://www.ffa.uni-lj.si/docs/default-source/knjiznicadoc/magistrske/2017/gorenc_katja_mag_nal_2017.pdf?sfvrsn=2. Accessed 20 Nov 2018.\n32. Štuhec M Gorenc K Klinično ovrednotenje intervencij farmacevta svetovalca v zdravljenju bolečine v ambulanti zdravstvenega Doma pri starejših bolnikih s polifarmakoterapijo = clinical evaluation of pharmacist consultant interventions in community health Centre in nociceptive and neuropathic pain pharmacotherapy in elderly patients treated with polypharmacy Farmacevtski vestnik : strokovno glasilo slovenske farmacije 2018 69 57 64 \n33. Mangerud WL Bjerkeset O Holmen TL Lydersen S Indredavik MS Smoking, alcohol consumption, and drug use among adolescents with psychiatric disorders compared with a population based sample J Adolesc 2014 37 1189 1199 10.1016/j.adolescence.2014.08.007 25190498\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1472-6963",
"issue": "19(1)",
"journal": "BMC health services research",
"keywords": "Clinical pharmacist; Elderly; General practitioners; Healthcare system; Polypharmacy; Primary care; Service implementation",
"medline_ta": "BMC Health Serv Res",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D003157:Community Pharmacy Services; D004347:Drug Interactions; D011307:Drug Prescriptions; D005260:Female; D058005:General Practitioners; D006801:Humans; D007400:Interprofessional Relations; D008297:Male; D008875:Middle Aged; D010348:Patient Care Team; D010595:Pharmacists; D019338:Polypharmacy; D000067561:Potentially Inappropriate Medication List; D011320:Primary Health Care; D012189:Retrospective Studies; D017524:Slovenia",
"nlm_unique_id": "101088677",
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"pmid": "30760276",
"pubdate": "2019-02-13",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": "10422996;12434719;12590620;14504113;16137215;17933759;18179993;20439064;20720510;20813762;20827352;22834451;22955007;23482734;23536016;23807844;24073682;24161491;24534594;24616171;25190498;26514063;26580349;27206819;27873322;29123600",
"title": "Evaluation of a collaborative care approach between general practitioners and clinical pharmacists in primary care community settings in elderly patients on polypharmacy in Slovenia: a cohort retrospective study reveals positive evidence for implementation.",
"title_normalized": "evaluation of a collaborative care approach between general practitioners and clinical pharmacists in primary care community settings in elderly patients on polypharmacy in slovenia a cohort retrospective study reveals positive evidence for implementation"
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"activesubstancename": "QUETIAPINE"
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{
"abstract": "Research examining illicit drug markets has shown that price affects consumption and mark ups are extremely high. However, the economics of black market pharmaceutical supply remains unknown, despite increasing harms due to pharmaceuticals.\n\n\n\nSemi-structured, telephone interviews were conducted in Australia with 51 people involved in supplying pharmaceuticals in the previous six months. Interviews were audio-recorded, transcribed and quantitative information on costs, sale price, quantity and frequency of supply were coded and used to calculate the mark up ratio for each drug transaction 'cycle', accounting for distribution via selling, gifting and trading. Mixed effects gamma regressions were used to identify predictors of price and mark up, clustering by participant.\n\n\n\nThere were 29 drugs supplied over 111 cycles, including hypnotic-sedatives (38%), pharmaceutical opioids (32%), stimulants (18%) and others (12%). Sedatives were sold at lower prices than opioids and there was a negative relationship between unit price and transaction size, consistent with a discount effect. For every dollar spent acquiring the drugs, the supplier earned a median of $3.19. Cycles involving the distribution of drugs sourced via intermediaries (e.g. friends/family) had lower mark up than drugs sourced directly from the medical system.\n\n\n\nTo our knowledge, this is one of few studies to analyse economic aspects of the pharmaceutical black market from a supply perspective. There were a small number of cycles that realised large profits that may warrant different types of policy responses, however for most suppliers in our sample gross revenue and gross profit was modest.",
"affiliations": "Drug Policy Modelling Program, National Drug and Alcohol Research Centre, UNSW, 22-32 King Street, Randwick, NSW 2031, Australia. Electronic address: shann.hulme@unsw.edu.au.;Drug Policy Modelling Program, National Drug and Alcohol Research Centre, UNSW, 22-32 King Street, Randwick, NSW 2031, Australia; Centre for Crime Policy and Research, Flinders University, SA, Australia.;Drug Policy Modelling Program, National Drug and Alcohol Research Centre, UNSW, 22-32 King Street, Randwick, NSW 2031, Australia; Monash Addiction Research Centre, Monash University, Peninsula Campus, McMahons Road, Frankston, VIC 3199, Australia.",
"authors": "Hulme|Shann|S|;Hughes|Caitlin Elizabeth|CE|;Nielsen|Suzanne|S|",
"chemical_list": "D000697:Central Nervous System Stimulants; D013287:Illicit Drugs",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.drugpo.2019.102626",
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"issue": "76()",
"journal": "The International journal on drug policy",
"keywords": "Australia; Black market; Pharmaceutical diversion; Pharmaceutical drugs; Price; Supply",
"medline_ta": "Int J Drug Policy",
"mesh_terms": "D001315:Australia; D000697:Central Nervous System Stimulants; D003132:Commerce; D003365:Costs and Cost Analysis; D016527:Drug Costs; D006801:Humans; D013287:Illicit Drugs",
"nlm_unique_id": "9014759",
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"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "The price and mark up of pharmaceutical drugs supplied on the black market.",
"title_normalized": "the price and mark up of pharmaceutical drugs supplied on the black market"
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"companynumb": "AU-COLLEGIUM PHARMACEUTICAL, INC.-AU-2019COL001588",
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"activesubstancename": "TAPENTADOL"
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"abstract": "A 92-year-old female ex-smoker with chronic obstructive pulmonary disease (COPD) GOLD III, was admitted because of communitarian pneumonia in November 2013. She had been using inhaled corticosteroids and bronchodilators and presented five exacerbations of COPD due to pneumonia in the same year, with hospitalizations in March and September. The patient underwent the routine protocol for exacerbated COPD, and bacilloscopy for tuberculosis (TB) was negative. On admission, she had intense dyspnea and a productive cough that improved by administration of levofloxacin. Tests with Ziehll-Neelsen staining in bronchopulmonary secretions resulted negative. Notwithstanding, during actual admission, the culture in Lowenstein-Jensen medium seeded in September was found positive for M. tuberculosis susceptible to isoniazid, rifampin, streptomycin, and ethambutol. Therefore, the patient underwent the standard regimen for tuberculosis. Except in September, when she used piperacillin-tazobactam, all previous exacerbations of COPD were treated with levofloxacin. This effective drug against M. tuberculosis can hinder its growth in culture. The use of levofloxacin in unsuspected TB may constitute an additional diagnostic challenge, and risk of late diagnosis is increased in patients with COPD in use of inhaled corticosteroids. Case studies may contribute to increase the suspicion index about TB associated with COPD.",
"affiliations": "Medicine Department from Armed Forces Hospital; Catholic University of Brasilia (UCB), Brasilia, Brazil.;Medicine Department from Armed Forces Hospital (HFA); Catholic University of Brasilia (UCB), Brasilia, Brazil.;Medicine Department from Armed Forces Hospital (HFA); Catholic University of Brasilia (UCB), Brasilia, Brazil.;Medicine Department from Armed Forces Hospital (HFA); Catholic University of Brasilia (UCB), Brasilia, Brazil.;Medicine Department from Armed Forces Hospital (HFA); Catholic University of Brasilia (UCB), Brasilia, Brazil.;Medicine Department from Armed Forces Hospital (HFA); Catholic University of Brasilia (UCB), Brasilia, Brazil.",
"authors": "Modesto dos Santos|Vitorino|V|;Martins|Rosane Rodrigues|RR|;Fachinelli|Letícia Rita|LR|;Araujo|Monique Chivatto Montes|MC|;dos Santos|Uliana Medeiros|UM|;Ribeiro|Kayursula Dantas de Carvalho|KD|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000995:Antitubercular Agents; D064704:Levofloxacin",
"country": "Italy",
"delete": false,
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"issn_linking": "1124-9390",
"issue": "22(4)",
"journal": "Le infezioni in medicina",
"keywords": null,
"medline_ta": "Infez Med",
"mesh_terms": "D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D000995:Antitubercular Agents; D015992:Body Mass Index; D057210:Delayed Diagnosis; D003937:Diagnosis, Differential; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D006949:Hyperlipidemias; D006973:Hypertension; D064704:Levofloxacin; D009169:Mycobacterium tuberculosis; D029424:Pulmonary Disease, Chronic Obstructive; D012307:Risk Factors; D012907:Smoking; D016896:Treatment Outcome; D014397:Tuberculosis, Pulmonary",
"nlm_unique_id": "9613961",
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"title": "Unsuspected tuberculosis in COPD and use of levofloxacin: diagnostic challenges.",
"title_normalized": "unsuspected tuberculosis in copd and use of levofloxacin diagnostic challenges"
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"activesubstancename": "LEVOFLOXACIN"
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"abstract": "Baclofen is a highly used centrally acting GABA agonist that continues to be an effective therapy for spasticity and chronic hiccups. The renally dependent excretion determines the circulating concentrations and guides effective dosing to decrease adverse reactions. Caution should be considered in administering baclofen to patients with decreased renal function. We present a patient with end stage renal disease on hemodialysis with recent baclofen ingestion who presented with toxic encephalopathy that was resolved with additional dialysis sessions.",
"affiliations": "Department of Medicine, Temple University Hospital, Philadelphia, PA, USA.;Department of Medicine, Temple University Hospital, Philadelphia, PA, USA.;Department of Medicine, Temple University Hospital, Philadelphia, PA, USA.",
"authors": "Meillier|Andrew|A|;Heller|Cara|C|;Patel|Shyam|S|",
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"doi": "10.1155/2015/203936",
"fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIMCase Reports in Medicine1687-96271687-9635Hindawi Publishing Corporation 10.1155/2015/203936Case ReportBaclofen-Induced Encephalopathy in End Stage Renal Disease Meillier Andrew \n*\nHeller Cara Patel Shyam Department of Medicine, Temple University Hospital, Philadelphia, PA, USA*Andrew Meillier: andrew.meillier@tuhs.temple.eduAcademic Editor: W. Zidek\n\n2015 29 7 2015 2015 2039366 6 2015 22 7 2015 Copyright © 2015 Andrew Meillier et al.2015This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Baclofen is a highly used centrally acting GABA agonist that continues to be an effective therapy for spasticity and chronic hiccups. The renally dependent excretion determines the circulating concentrations and guides effective dosing to decrease adverse reactions. Caution should be considered in administering baclofen to patients with decreased renal function. We present a patient with end stage renal disease on hemodialysis with recent baclofen ingestion who presented with toxic encephalopathy that was resolved with additional dialysis sessions.\n==== Body\n1. Introduction\nBaclofen (parachlorophenyl gamma-aminobutyric acid) is an agonist of the neurotransmitter gamma-aminobutyric acid (GABA) [1]. The centrally functioning mechanism of action has been used to treat spasticity and more recently chronic hiccups [2, 3]. Baclofen is well absorbed in the gastrointestinal tract ideally producing the determined therapeutic levels of 80–400 ng/mL [4]. The primary excretion is through the kidney (70–80%) with the remainder metabolized in the liver or processed through the gastrointestinal tract [4]. Only a small portion is able to cross the blood brain barrier, creating the desired effects. The half-life is approximately 6.8 hours [3]. Patients with decreased renal function have an extended half-life with more crossing of the blood brain barrier. The generalized central nervous system (CNS) depression effects are then further pronounced producing fatigue, syncope, hypotension, ataxia, psychological disturbances, and cardiovascular and respiratory depression [2, 4].\n\nIn patients with limited renal function, there have been reports of toxic side effects with the initial dosing of 5 mg t.i.d. within only a few days [5]. Baclofen toxicity has been shown to resolve with hemodialysis resembling excretion rates similar to normal renal function [6]. Here we report a case of baclofen-induced encephalopathy in a dialysis patient with recovery following hemodialysis sessions.\n\n2. Case Report\nOur patient is a 54-year-old male with a past medical history of end stage renal disease on hemodialysis, diabetes mellitus type 2, hypertension, and hepatitis C who presented for altered mental status. The patient had a recent internal medicine clinic visit with concern for pain due to paraspinal muscle spasm. The patient was started on baclofen 10 mg b.i.d. and tramadol 50 mg b.i.d. On the day of admission, the patient was found to be lying on the ground and speaking incoherently by an acquaintance. He was brought to the hospital and admitted to the intensive care unit for altered mental status.\n\nThe vital signs were the following: temperature 99.1°F, respiratory rate 21 breaths/minute, pulse 83 beats/minute, blood pressure 138/64 mmhg, and pulse oxygenation 99% on room air. On initial presentation, the patient was lethargic but arousable and unable to answer questions. The remainder of the exam was consistent with his known comorbidities including a left upper extremity arteriovenous fistula and right lower extremity transmetatarsal amputation. Laboratory tests showed the following: sodium 141 mEq/L, potassium 5.2 mEq/L, chloride 101 mEq/L, bicarbonate 26 mEq/L, blood urea nitrogen 55 mg/dL, creatinine 10.98 mg/dL. A white blood cell count was 12.4 mg/dL, hemoglobin 11.3 mg/dL, and platelet count 155/mm3. A venous blood gas included a pH of 7.41 and carbon dioxide 44 mmHg. A hepatic function panel had a total bilirubin of 0.8 mg/dL, AST 45 u/L, ALT 26 u/L, alkaline phosphatase 52 u/L, creatine kinase 1738 u/L, and ammonia 52 u/L. A head computed tomography was performed with no acute intracranial abnormalities. An abdominal ultrasound found hepatomegaly with fatty infiltration. A urine toxicology screen was negative. The patient's pharmacy confirmed fulfillment of the baclofen and tramadol prescription 3 days prior to admission. Compliance with his last hemodialysis session was confirmed. With high suspicion for baclofen-induced encephalopathy, the patient was immediately dialyzed. He received hemodialysis for two sessions with significant improvement in mental status without any residual symptoms. Upon discharge, the patient had baclofen discontinued with no similar episodes since the present hospitalization.\n\n3. Discussion\nBaclofen was originally found to be effective in treatment of spasticity concerning spinal cord lesions in the 1960s [7]. The mechanism of action is a centrally acting presynaptic agonist of GABA to enhance tone reduction and reduce spasticity [1]. In recent studies, it has been shown effective in treating persistent hiccups [3]. Baclofen is efficiently absorbed in the gastrointestinal tract and with variations of the half-life dependent largely on renal function being the primary mechanism of excretion [4]. A high correlation between renal clearance and creatinine clearance was shown to exist in a excretion kinetic study [8].\n\nBaclofen is a moderately lipophilic molecule and with increased circulating concentration crossing the blood brain barrier has a correlating amplified centrally acting response [9]. These adverse reactions include hypotension, bradycardia, respiratory depression, and toxic encephalopathy [5, 9]. There have been previous cases with chronic renal failure and symptoms of neurotoxicity. Serum concentrations of baclofen were measured to have progressively decreased during the sessions of hemodialysis with resolution of the neurologic sequel [5]. The effectiveness of hemodialysis was additionally seen in another case of baclofen overdose with normal renal function. In this case, a patient consumed 200 mg of extended release baclofen with subsequent ventilator dependent respiratory failure. Two sessions resolved the side effects with successful extubation and resolution of additional symptoms [9].\n\nIn a study of the efficiency in using hemodialysis, the filtration rate for baclofen was as effective as normal kidneys [6]. This high efficiency of filtration is because only 30% of the circulating concentration is bound to protein [6]. In case reports, there is a several-hour delay prior to improvement in symptoms with the theorized necessity of redistribution from the CNS to the intravascular system and filtration by dialysis [10]. Interestingly, the therapeutic range of baclofen 80–400 ng/mL has been found to cause negative side effects in patients with impaired renal function. The exact therapeutic level with the intended decrease in dosing remains unclear with continued susceptibility to adverse side effects [11].\n\nElectroencephalography (EEG) has been used in initial evaluations for the etiology of unconsciousness in baclofen overdose. These changes include pseudoperiodic sharp waves to periodic high-amplitude discharges and generalized slow waves [12]. Resolution of these EEG changes were seen following treatment [13]. These changes did not indicate the capacity to induce epilepsy and have been recommended not to treat with antiepileptic medications [13].\n\nBaclofen renal dosing continues to be nonspecific with renal adjustment recommendations. A study in 2011 highly recommended changes in labeling with improved guidelines in dosing. There was a proposal to avoid this medication with a GFR < 30 mL/min/1.73 m2. This was further detailed with a decrease in dosing and titrating in a GFR > 30 to 60 mL/min/1.73 m2 [14]. In following the reported history of decreased renal function and side effects, this continues to be a highly appropriate recommendation. Our case represents toxic encephalopathy with inappropriate dosing of baclofen that was resolved with hemodialysis. Special consideration is required with this renally excreted medication and more specific guidelines would likely further alleviate incidence of side effects.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n==== Refs\n1 Gerkin R. Curry S. C. Vance M. V. Sankowski P. W. Meinhart R. D. First-order elimination kinetics following baclofen overdose Annals of Emergency Medicine 1986 15 7 843 846 10.1016/s0196-0644(86)80388-2 2-s2.0-0022445306 3729110 \n2 Dario A. Tomei G. A benefit-risk assessment of baclofen in severe spinal spasticity Drug Safety 2004 27 11 799 818 10.2165/00002018-200427110-00004 2-s2.0-4544240153 15350152 \n3 Zhang C. Zhang R. Zhang S. Xu M. Zhang S. Baclofen for stroke patients with persistent hiccups: a randomized, double-blind, placebo-controlled trial Trials 2014 15, article 295 10.1186/1745-6215-15-295 2-s2.0-84904521984 \n4 Young R. R. Delwaide P. J. Drug therapy: spasticity (second of two parts) The New England Journal of Medicine 1981 304 2 96 99 10.1056/nejm198101083040207 2-s2.0-0019349998 7003385 \n5 Chou C.-L. Chen C.-A. Lin S.-H. Huang H.-H. Baclofen-induced neurotoxicity in chronic renal failure patients with intractable hiccups Southern Medical Journal 2006 99 11 1308 1309 10.1097/01.smj.0000247632.84949.27 2-s2.0-33845336459 17195438 \n6 Brvar M. Vrtovec M. Kovač D. Kozelj G. Pezdir T. Bunc M. Haemodialysis clearance of baclofen European Journal of Clinical Pharmacology 2007 63 12 1143 1146 10.1007/s00228-007-0371-8 2-s2.0-36148995411 17764008 \n7 Cartlidge N. E. F. Hudgson P. Weightman D. A comparison of baclofen and diazepam in the treatment of spasticity Journal of the Neurological Sciences 1974 23 1 17 24 10.1016/0022-510X(74)90137-3 2-s2.0-0016212264 4850175 \n8 Wuis E. W. Dirks M. J. M. Termond E. F. S. Vree T. B. Van der Kleijn E. Plasma and urinary excretion kinetics of oral baclofen in healthy subjects European Journal of Clinical Pharmacology 1989 37 2 181 184 10.1007/BF00558228 2-s2.0-0024386266 2792173 \n9 Dias L. S. Vivek G. Manthappa M. Acharya R. V. Role of hemodialysis in baclofen overdose with normal renal function Indian Journal of Pharmacology 2011 43 6 722 723 10.4103/0253-7613.89835 2-s2.0-81855206652 22144783 \n10 Chen K.-S. Bullard M. J. Chien Y.-Y. Lee S.-Y. Baclofen toxicity in patients with severely impaired renal function Annals of Pharmacotherapy 1997 31 11 1315 1320 2-s2.0-0030665128 9391686 \n11 Wu V.-C. Lin S.-L. Lin S.-M. Fang C.-C. Treatment of baclofen overdose by haemodialysis: a pharmacokinetic study Nephrology Dialysis Transplantation 2005 20 2 441 443 10.1093/ndt/gfh297 2-s2.0-14044252068 \n12 Sauneuf B. Totouom H. K. Savary B. Clinical and EEG features of acute intrathecal baclofen overdose Clinical Neurology and Neurosurgery 2012 114 1 84 86 10.1016/j.clineuro.2011.07.028 2-s2.0-84655164348 22014377 \n13 Fakhoury T. Abou-Khalil B. Blumenkopf B. EEG changes in intrathecal baclofen overdose: a case report and review of the literature Electroencephalography and Clinical Neurophysiology 1998 107 5 339 342 10.1016/s0013-4694(98)00085-6 2-s2.0-0032213043 9872436 \n14 El-Husseini A. Sabucedo A. Lamarche J. Courville C. Peguero A. Baclofen toxicity in patients with advanced nephropathy: proposal for new labeling American Journal of Nephrology 2011 34 6 491 495 10.1159/000333247 2-s2.0-80054983107 22041434\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "2015()",
"journal": "Case reports in medicine",
"keywords": null,
"medline_ta": "Case Rep Med",
"mesh_terms": null,
"nlm_unique_id": "101512910",
"other_id": null,
"pages": "203936",
"pmc": null,
"pmid": "26294912",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": "9872436;15615812;17764008;3729110;22144783;17195438;2792173;7003385;22014377;15350152;22041434;9391686;25052238;4850175",
"title": "Baclofen-Induced Encephalopathy in End Stage Renal Disease.",
"title_normalized": "baclofen induced encephalopathy in end stage renal disease"
} | [
{
"companynumb": "US-TEVA-594466USA",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BACLOFEN"
},
"drugadditional": null,
"druga... |
{
"abstract": "OBJECTIVE\nThe purpose of this study was to evaluate retrospectively the efficacy and tolerability of retigabine (RTG) in residential patients of an epilepsy center.\n\n\nMETHODS\nWe used an industry-independent noninterventional retrospective evaluation on the basis of paper and electronic records plus interrogation of the treating neurologists. All patients (N=20; 7 females; mean age: 31.8, range: 18-54years) started on RTG between May 2011 and March 2012 were included. Evaluation was carried out after 6, 12, and 24months. Changes in seizure frequency were measured as the number of seizures during three months on RTG compared with a three-month baseline period. The Clinical Global Impression scale was applied to include qualitative changes in seizure severity. All but one patient had symptomatic (structural; one patient: metabolic) or cryptogenic focal or multifocal epilepsy. All had grade III drug-resistant epilepsy and cognitive deficits of different degrees.\n\n\nRESULTS\nThe retention rates were 60% after 6months, 35% after 12months, and 20% after 24months. At 12months, there were 2 responders (10%): one had a >90% seizure reduction and the other had a >50% seizure reduction. Another 5 patients were still on RTG because of minor improvements. The reasons for discontinuation in 13 patients were adverse effects (6), lack of effect (6), and both (1). Cognitive or emotional changes were the side effects that most frequently led to discontinuation. Beyond the 12-month evaluation, 3 patients were discontinued as a consequence of the FDA warning regarding retinal pigmentation and discoloration of skin and nails in patients exposed to RTG. One patient had a moderate blue-gray finger coloring. Ophthalmological changes were not discovered.\n\n\nCONCLUSIONS\nRetigabine proved to be useful only for a small minority of patients in a sample of patients with particularly difficult-to-treat epilepsy.",
"affiliations": "Von Bodelschwinghsche Stiftungen Bethel, Bethel.regional, Ebenezerweg 18, 33617 Bielefeld, Germany. Electronic address: Bernd.Huber@Bethel.de.;Von Bodelschwinghsche Stiftungen Bethel, Bethel.regional, Ebenezerweg 18, 33617 Bielefeld, Germany. Electronic address: Michelina.Bocchicchio@Bethel.de.",
"authors": "Huber|Bernd|B|;Bocchicchio|Michelina|M|",
"chemical_list": "D000927:Anticonvulsants; D002219:Carbamates; D010655:Phenylenediamines; C101866:ezogabine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1525-5050",
"issue": "44()",
"journal": "Epilepsy & behavior : E&B",
"keywords": "Cognitive deficit; Drug-resistant epilepsy; Partial epilepsy; Retigabine; Side effect",
"medline_ta": "Epilepsy Behav",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants; D002219:Carbamates; D003071:Cognition; D003072:Cognition Disorders; D015331:Cohort Studies; D004827:Epilepsy; D005260:Female; D006801:Humans; D008607:Intellectual Disability; D008297:Male; D008875:Middle Aged; D010655:Phenylenediamines; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "100892858",
"other_id": null,
"pages": "234-7",
"pmc": null,
"pmid": "25836054",
"pubdate": "2015-03",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "A retrospective evaluation of retigabine in patients with cognitive impairment with highly drug-resistant epilepsy.",
"title_normalized": "a retrospective evaluation of retigabine in patients with cognitive impairment with highly drug resistant epilepsy"
} | [
{
"companynumb": "DE-GLAXOSMITHKLINE INC.-DE2015GSK052540",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
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"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "EZOGABINE"
},
"drugadditional":... |
{
"abstract": "This is a retrospective study of patients with multiple myeloma (MM) who were >75 years old. We identified 394 patients and for non-trial patients (n = 350), immunomodulatory drug (IMiD)+dex (32%) was the most commonly used regimen followed by alkylator with steroids or other therapy (21%), alkylator + proteasome inhibitor (PI)+steroid (18%), and IMiD + PI + dex (13%). Overall, achieving ≥ very good partial response was more in patients receiving a triplet compared to other therapies (46% vs. 21%, p < 0.0001). Also, the median overall survival (OS) was significantly longer in patients who were treated with a triplet (median OS: 50.2 vs. 32.8 months, p = 0.0006). In a multivariate for OS, receiving a triplet (HR: 0.65, p = 0.02), not having an R-ISS stage 3 (HR: 0.36, p = 0.0003), and bone marrow plasma cell percentage <60% (HR: 0.69, p = 0.03) were predictive. In conclusion, being able to receive triplet therapy was associated with better survival in our MM patients >75 years old.",
"affiliations": "Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.;Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.;Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.;Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.;Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.;Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.;Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.;Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.;Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.;Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.;Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.;Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.;Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.;Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.;Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.;Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.;Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.;Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.;Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.",
"authors": "Al Saleh|Abdullah S|AS|0000-0003-1111-556X;Visram|Alissa|A|;Parmar|Harsh|H|;Muchtar|Eli|E|0000-0003-2210-2174;Buadi|Francis K|FK|;Dispenzieri|Angela|A|0000-0001-8780-9512;Warsame|Rahma|R|;Lacy|Martha Q|MQ|;Dingli|David|D|;Leung|Nelson|N|0000-0002-5651-1411;Go|Ronald S|RS|0000-0002-8284-3495;Gonsalves|Wilson I|WI|;Kourelis|Taxiarchis V|TV|;Hayman|Suzanne R|SR|;Kapoor|Prashant|P|;Gertz|Morie A|MA|0000-0002-3853-5196;Kyle|Robert A|RA|;Rajkumar|S Vincent|SV|;Kumar|Shaji K|SK|0000-0001-5392-9284",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1080/10428194.2021.1950708",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1026-8022",
"issue": "62(12)",
"journal": "Leukemia & lymphoma",
"keywords": "Multiple myeloma; elderly; outcomes; treatment",
"medline_ta": "Leuk Lymphoma",
"mesh_terms": null,
"nlm_unique_id": "9007422",
"other_id": null,
"pages": "3011-3018",
"pmc": null,
"pmid": "34263694",
"pubdate": "2021-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Treatment and outcome of newly diagnosed multiple myeloma patients > 75 years old: a retrospective analysis.",
"title_normalized": "treatment and outcome of newly diagnosed multiple myeloma patients 75 years old a retrospective analysis"
} | [
{
"companynumb": "US-AMGEN-USASP2021193961",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CARFILZOMIB"
},
"drugadditional": "4",
... |
{
"abstract": "BACKGROUND\nThere is no consensus on the treatment of drug reaction with eosinophilia and systemic symptoms (DRESS). At our center, systemic steroids (SS) are used for severe cases while topical steroids (TS) are used for mild and moderate forms.\n\n\nOBJECTIVE\nTo investigate the short-term outcome for patients with DRESS receiving SS as first-line therapy before being transferred to our department and then switched to TS after admission.\n\n\nMETHODS\nA retrospective monocenter study in DRESS patients (RegiSCAR score≥4) transferred to our dermatology department from a different setting between 07/2012 and 06/2018 and who had received SS before being transferred. Epidemiological, clinical and laboratory data were collected, as well as details of treatment modalities and outcome.\n\n\nRESULTS\nTwenty patients were included. On admission to our department, 4 were assessed as having severe DRESS and continued on SS, while 16 were assessed as mild/moderate DRESS and were switched to TS. Among these 16 patients, the outcome on TS was favorable for 12 and quickly unfavorable for 4, who had to be switched back to SS. Retrospective analysis of the initial data (before transfer) showed that these 4 patients had previously had a greater number of severity criteria than the other 12.\n\n\nCONCLUSIONS\nCaution is needed not only when deciding to initiate SS in DRESS but also on withdrawal of these drugs. Our series suggests that when SS are used as first-line therapy in DRESS patients with initial severity criteria, they should not be withdrawn quickly for a switch to TS, even where progression appears favorable, due to the risk of relapse.",
"affiliations": "Service de dermatologie, AP-HP, hôpitaux universitaires Henri-Mondor, 51, avenue du Maréchal-de-Lattre-de-Tassigny, 94010 Créteil, France.;Service de dermatologie, AP-HP, hôpitaux universitaires Henri-Mondor, 51, avenue du Maréchal-de-Lattre-de-Tassigny, 94010 Créteil, France; Université Paris Est Créteil, EA7380 Dynamyc, EnvA, USC ANSES, rue du Général-Sarrail, 94010 Créteil cedex, France; Faculté de médecine de Créteil, université Paris-Est Créteil (UPEC), 61, avenue du Général-de-Gaulle, 94000 Créteil, France; Centre de référence des dermatoses bulleuses toxiques et toxidermies graves TOXIBUL, 51, avenue du Maréchal-de-Lattre-de-Tassigny, 94010 Créteil, France.;Service de dermatologie, AP-HP, hôpitaux universitaires Henri-Mondor, 51, avenue du Maréchal-de-Lattre-de-Tassigny, 94010 Créteil, France; Faculté de médecine de Créteil, université Paris-Est Créteil (UPEC), 61, avenue du Général-de-Gaulle, 94000 Créteil, France; Centre de référence des dermatoses bulleuses toxiques et toxidermies graves TOXIBUL, 51, avenue du Maréchal-de-Lattre-de-Tassigny, 94010 Créteil, France.;Service de dermatologie, AP-HP, hôpitaux universitaires Henri-Mondor, 51, avenue du Maréchal-de-Lattre-de-Tassigny, 94010 Créteil, France; Centre de référence des dermatoses bulleuses toxiques et toxidermies graves TOXIBUL, 51, avenue du Maréchal-de-Lattre-de-Tassigny, 94010 Créteil, France.;Service de dermatologie, AP-HP, hôpitaux universitaires Henri-Mondor, 51, avenue du Maréchal-de-Lattre-de-Tassigny, 94010 Créteil, France; Centre de référence des dermatoses bulleuses toxiques et toxidermies graves TOXIBUL, 51, avenue du Maréchal-de-Lattre-de-Tassigny, 94010 Créteil, France.;Service de dermatologie, AP-HP, hôpitaux universitaires Henri-Mondor, 51, avenue du Maréchal-de-Lattre-de-Tassigny, 94010 Créteil, France; Centre de référence des dermatoses bulleuses toxiques et toxidermies graves TOXIBUL, 51, avenue du Maréchal-de-Lattre-de-Tassigny, 94010 Créteil, France.;Faculté de médecine de Créteil, université Paris-Est Créteil (UPEC), 61, avenue du Général-de-Gaulle, 94000 Créteil, France; Service de réanimation médicale, AP-HP, hôpitaux universitaires Henri-Mondor, 51, avenue du Maréchal-de-Lattre-de-Tassigny, 94010 Créteil, France; Centre de référence des dermatoses bulleuses toxiques et toxidermies graves TOXIBUL, 51, avenue du Maréchal-de-Lattre-de-Tassigny, 94010 Créteil, France.;Service de dermatologie, AP-HP, hôpitaux universitaires Henri-Mondor, 51, avenue du Maréchal-de-Lattre-de-Tassigny, 94010 Créteil, France; Faculté de médecine de Créteil, université Paris-Est Créteil (UPEC), 61, avenue du Général-de-Gaulle, 94000 Créteil, France; Centre de référence des dermatoses bulleuses toxiques et toxidermies graves TOXIBUL, 51, avenue du Maréchal-de-Lattre-de-Tassigny, 94010 Créteil, France.;Service de dermatologie, AP-HP, hôpitaux universitaires Henri-Mondor, 51, avenue du Maréchal-de-Lattre-de-Tassigny, 94010 Créteil, France; Faculté de médecine de Créteil, université Paris-Est Créteil (UPEC), 61, avenue du Général-de-Gaulle, 94000 Créteil, France; Centre de référence des dermatoses bulleuses toxiques et toxidermies graves TOXIBUL, 51, avenue du Maréchal-de-Lattre-de-Tassigny, 94010 Créteil, France.;Service de dermatologie, AP-HP, hôpitaux universitaires Henri-Mondor, 51, avenue du Maréchal-de-Lattre-de-Tassigny, 94010 Créteil, France; Université Paris Est Créteil, EpidermE, 94010 Créteil, France; Centre de référence des dermatoses bulleuses toxiques et toxidermies graves TOXIBUL, 51, avenue du Maréchal-de-Lattre-de-Tassigny, 94010 Créteil, France. Electronic address: saskia.oro@aphp.fr.",
"authors": "Brin|C|C|;Bernigaud|C|C|;Hua|C|C|;Duong|T-A|TA|;Gaudin|O|O|;Colin|A|A|;de Prost|N|N|;Wolkenstein|P|P|;Chosidow|O|O|;Ingen-Housz-Oro|S|S|",
"chemical_list": "D013256:Steroids",
"country": "France",
"delete": false,
"doi": "10.1016/j.annder.2021.02.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0151-9638",
"issue": "148(3)",
"journal": "Annales de dermatologie et de venereologie",
"keywords": "DRESS; Drug reaction; Systemic steroids; Topical steroids",
"medline_ta": "Ann Dermatol Venereol",
"mesh_terms": "D000287:Administration, Topical; D000328:Adult; D063926:Drug Hypersensitivity Syndrome; D004802:Eosinophilia; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D013256:Steroids; D016896:Treatment Outcome",
"nlm_unique_id": "7702013",
"other_id": null,
"pages": "168-171",
"pmc": null,
"pmid": "33858692",
"pubdate": "2021-09",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": null,
"title": "Impact of systemic to topical steroids switch on the outcome of drug reaction with eosinophilia and systemic symptoms (DRESS): A monocenter retrospective study of 20 cases.",
"title_normalized": "impact of systemic to topical steroids switch on the outcome of drug reaction with eosinophilia and systemic symptoms dress a monocenter retrospective study of 20 cases"
} | [
{
"companynumb": "FR-LUPIN PHARMACEUTICALS INC.-2022-00964",
"fulfillexpeditecriteria": "2",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CLOBETASOL PROPIONATE"
},
"dru... |
{
"abstract": "When extranodal marginal zone B-cell lymphoma of mucosa associated lymphoid tissue (MALT), a low grade B-cell lymphoma, arises in the lung it is referred to as bronchus-associated lymphoid tissue (BALT) lymphoma. We describe a patient with a history of Sjögren's syndrome and rheumatoid arthritis with dyspnea and imaging consistent with lymphoid interstitial pneumonia (LIP). However, while histology and immunohistochemistry lacked definitive features of a lymphoma, immunoglobulin heavy chain (IgH) polymerase chain reaction testing demonstrated B-cell monoclonality, consistent with an early BALT lymphoma.",
"affiliations": "Department of Medicine, University of Alberta, Edmonton, AB, Canada T6G 2G3.;Department of Medicine, University of Alberta, Edmonton, AB, Canada T6G 2G3; Division of Critical Care Medicine, University of Alberta, Edmonton, AB, Canada T6G 2G3.;Department of Laboratory-Medicine and Pathology, University of Alberta, Edmonton, AB, Canada T6G 2B7.",
"authors": "Li|Pen|P|0000-0001-7815-741X;Cheung|Lawrence|L|;Chiu|Brian|B|",
"chemical_list": "D007143:Immunoglobulin Heavy Chains; D000069285:Infliximab",
"country": "Egypt",
"delete": false,
"doi": "10.1155/2016/7056035",
"fulltext": "\n==== Front\nCan Respir JCan. Respir. JCRJCanadian Respiratory Journal1198-22411916-7245Hindawi Publishing Corporation 10.1155/2016/7056035Clinico-Pathologic ConferencesEarly Bronchus-Associated Lymphoid Tissue Lymphoma Diagnosed with Immunoglobulin Heavy Chain Molecular Testing http://orcid.org/0000-0001-7815-741XLi Pen \n1\nCheung Lawrence \n1\n\n2\n\n*\nChiu Brian \n3\n1Department of Medicine, University of Alberta, Edmonton, AB, Canada T6G 2G32Division of Critical Care Medicine, University of Alberta, Edmonton, AB, Canada T6G 2G33Department of Laboratory-Medicine and Pathology, University of Alberta, Edmonton, AB, Canada T6G 2B7*Lawrence Cheung: lcheung@ualberta.ca2016 31 3 2016 2016 705603521 2 2015 3 5 2015 Copyright © 2016 Pen Li et al.2016This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.When extranodal marginal zone B-cell lymphoma of mucosa associated lymphoid tissue (MALT), a low grade B-cell lymphoma, arises in the lung it is referred to as bronchus-associated lymphoid tissue (BALT) lymphoma. We describe a patient with a history of Sjögren's syndrome and rheumatoid arthritis with dyspnea and imaging consistent with lymphoid interstitial pneumonia (LIP). However, while histology and immunohistochemistry lacked definitive features of a lymphoma, immunoglobulin heavy chain (IgH) polymerase chain reaction testing demonstrated B-cell monoclonality, consistent with an early BALT lymphoma.\n==== Body\n1. Case Presentation\nA 65-year-old female with a 10-year history of seropositive rheumatoid arthritis and secondary Sjögren's syndrome treated with infliximab monotherapy presented with 5 weeks of gradually increasing dyspnea, nonproductive cough, and 1-2 kg weight loss. She was given a one-week course of doxycycline without improvement. Eventually, her dyspnea worsened to the point that she was unable to walk one block. Apart from being a seven-pack-year ex-smoker, her medical history was unremarkable.\n\nPhysical exam revealed normal vital signs. She had mild crackles bilaterally on auscultation. Cardiac, abdominal, and musculoskeletal exams were unrevealing with no splenomegaly, lymphadenopathy, edema, or digital clubbing. Her blood work was unremarkable, including a normal complete blood count and differential, liver enzymes, lactate dehydrogenase (LDH), and creatinine.\n\nChest X-ray revealed coarse reticular nodular markings in the mid to lower lung zones bilaterally with a predominantly peripheral distribution. These findings had slightly progressed compared to chest X-rays 4 weeks and 6 months before presentation but were not present 14 months before this presentation. A computed tomography (CT) scan of the chest (Figure 1(a)) demonstrated bilateral widespread abnormalities with basal predominance, including multiple thin-walled cystic air spaces, patchy ground-glass opacities, scattered foci of consolidation, some interlobular septal thickening, and a trace right pleural effusion. There were enlarged hilar lymph nodes up to 1.5 cm in size (Figure 1(b)). The imaging findings were most suggestive of LIP, especially in the context of Sjögren's syndrome and rheumatoid arthritis; however, since lymphoma could not be excluded and lymphadenopathy was not a usual feature of LIP, further investigations were done.\n\nBronchoscopy with bronchoalveolar lavage of the right lower lobe and bronchial washing of the left lower lobe did not reveal microorganisms or malignant cells, and she did not respond to a trial of intravenous antibiotics. A video-assisted thoracoscopic lung biopsy of the right upper, middle, and lower lobes was performed 8 days after presentation to hospital. The biopsy revealed florid lymphoplasmacytic hyperplasia most suggestive of an LIP pattern related to her autoimmune diseases (Figures 2(a)–2(d)). There were no definitive features of a lymphoproliferative disorder; however, a few of the lymphoid follicles were somewhat nodular and obscured the lung architecture. As this was suspicious for lymphoma, subsequent B-cell receptor heavy chain (IgH) gene rearrangement assay testing was performed and demonstrated monoclonal B-cell proliferation, establishing the diagnosis of BALT lymphoma.\n\nAfter confirmation of BALT lymphoma, she received 6 cycles of bendamustine and rituximab delivered on a 28-day cycle for 6 months. Her symptoms resolved and there was mild regression of the ground-glass opacities, foci of consolidation, and septal thickening on CT chest. She subsequently received rituximab every three months for maintenance therapy.\n\n2. Discussion\nMucosa associated lymphoid tissue (MALT) lymphoma is a low grade B-cell lymphoma that arises in a number of glandular epithelial tissues including the stomach, lung, skin, bowel, conjunctiva, salivary glands, and thyroid [1]. MALT lymphoma involves the lung in about 15% of cases [2] and is referred to as BALT lymphoma.\n\nEvidence suggests that the pathogenesis of MALT lymphomas relates to chronic antigenic stimulation, either by pathogens or by autoimmunity [1, 3]. Chronic inflammation is thought to perpetuate antigen-dependent B-cells, eventually leading to the proliferation of monoclonal B-cells. Initially, this early MALT lymphoma remains localized to the site of inflammation until further mutations occur to allow systemic spread.\n\nBALT lymphoma is associated with connective tissue diseases including rheumatoid arthritis, systemic lupus erythematosus, and especially Sjögren's syndrome which increases the risk of developing lymphoma in general by 6.6–44 times [2]. Infectious associations with BALT lymphoma include Mycobacterium avium complex (MAC), Mycobacterium tuberculosis (TB), Epstein-Barr virus (EBV), and human herpesvirus 8; however, these associations are less established compared to other sites of MALT lymphoma, such as Helicobacter pylori in gastric MALT [3].\n\nThe most frequent reported symptoms in patients with BALT lymphoma include dry cough and dyspnea [2]. Patients may also, uncommonly, present with fever, night sweats, and weight loss. However, since many patients are asymptomatic or present with vague symptoms, there is often a delay in diagnosis. The largest review analyzed 63 cases of BALT lymphoma and reported that the median duration between initial symptoms and radiological abnormalities to diagnosis was 9 months, in which 44% of patients had presented with disseminated disease [2]. They found that laboratory findings were frequently normal, but some patients demonstrated anemia, thrombocytopenia, and elevated LDH levels. About one-third of patients produced a monoclonal gammopathy.\n\nThe most frequent patterns seen on CT scan of the chest include single or multiple nodules and areas of consolidation. Other potential findings include micronodules, ground-glass opacities, masses, septal lines, bronchiectasis, lymphadenopathy, and pleural effusions [2, 4]. 18F-2-Fluoro-2-deoxy-D-glucose- (FDG-) positron emission tomography (PET) scans often show mild uptake in the affected lung regions. False negatives are not uncommon, with reported sensitivities of 50–89%, given the indolent nature of this lymphoma [2].\n\nTissue biopsy is necessary for diagnosis and may be acquired by mucosal or transbronchial biopsies, CT-guided percutaneous needle biopsies, or surgical biopsies [2]. Pathological samples demonstrate polymorphous infiltrates of small lymphocytes, plasma cells, and B-cells. The B-cells infiltrate the epithelium and form characteristic lymphoepithelial lesions. About 14% of patients may have bone marrow involvement [2].\n\nIn this case, there were no definitive features of a lymphoproliferative disorder on histology and immunohistochemistry; however, a few of the areas of lymphoid hyperplasia appeared nodular and the suspicion of BALT lymphoma was raised. BALT lymphoma was confirmed when subsequent IgH molecular assay demonstrated monoclonality of the B-cell infiltrates and distinguished a low grade BALT lymphoma from a polyclonal LIP. This patient likely initially developed connective tissue disease-associated LIP which subsequently transformed into a lymphoma, which occurs in approximately 5% of cases [5].\n\nThe IgH gene encodes heavy chains for immunoglobulins and undergoes rearrangement early in the development of B-cells [6]. In a normal, polyclonal population of B-cells, each cell has a unique arrangement, resulting in a heterogeneous pattern when analyzed by polymerase chain reaction (PCR). In contrast, a monoclonal population of B-cells will produce a homogenous pattern. In the appropriate clinical context, the identification of a monoclonal IgH gene rearrangement confirms the diagnosis of a B-cell lymphoproliferative disorder. The sensitivity of this assay for nonfollicular B-cell lymphomas, such as BALT, is up to 84% and is about 63% for all B-cell lymphomas [6]. The specificity for B-cell lymphomas is about 94%, as some T-cell leukemias and lymphomas may produce a false positive result. The assay can be performed on peripheral blood, bone marrow aspirates, frozen tissue samples, or paraffin embedded tissue blocks.\n\nThe histologic differential diagnosis for LIP includes primary pulmonary lymphoma, hypersensitivity pneumonitis, and viral pneumonia (especially EBV) [5]. It is important to differentiate LIP from lymphoma, in our case BALT lymphoma, because of the different approach to therapy. Symptomatic patients with LIP who demonstrate progressive or severe disease are generally treated by immunosuppression with oral glucocorticoids or other medications such as azathioprine or cyclophosphamide. Conversely, current international treatment guidelines for BALT lymphoma [7] recommend first-line chemotherapy which typically includes an alkylating agent (such as chlorambucil, bendamustine, or cyclophosphamide) or purine analog (fludarabine), with or without rituximab. Surgery can be performed in patients with localized disease. Radiotherapy is reserved for patients with small lesions and/or contraindications to surgery. Overall, BALT lymphoma has a favorable prognosis with a 5-year survival of >85%, even with disseminated disease [2, 8].\n\nThis report describes the diagnosis of an early BALT lymphoma by demonstrating B-cell monoclonality with IgH molecular testing. We believe this test should be done whenever there are clinical, radiographic, or histologic suspicions for lymphoma but a lack of definitive histologic features on biopsy. Differentiating between an autoimmune or neoplastic process is important because of differences in therapy and prognosis. Further study is needed to determine the utility of routine IgH molecular testing on histologic specimens which show features of LIP alone but may, in fact, represent BALT lymphoma.\n\nAdditional Points\n\nLearning Objectives. (i) To recognize bronchus-associated lymphoid tissue (BALT) lymphoma as a pulmonary manifestation of connective tissue diseases, which may coexist with other lung pathologies. (ii) To understand immunoglobulin heavy chain (IgH) molecular testing and its clinical utility to diagnose early BALT lymphoma.\n\n\nCanMEDS Competency. Medical Expert.\n\n\nPretest Questions. (i) What are the risk factors for developing BALT lymphoma? (ii) What is the histologic differential diagnosis for lymphoid interstitial pneumonia (LIP)?\n\n\nPretest Answers. (i) What are the risk factors for developing BALT lymphoma? BALT lymphoma is an antigen-driven lymphoma and is associated with chronic antigenic stimulation such as from autoimmune diseases, as well as chronic lung infections. (ii) What is the histologic differential diagnosis for LIP? The most important differentiation is between LIP and lymphoma. Other considerations include hypersensitivity pneumonitis and viral pneumonia.\n\nCompeting Interests\nThe authors have no financial disclosures or competing interests to declare.\n\nFigure 1 (a) Computed tomography scan of the chest, showing widespread pulmonary changes, including multiple thin-walled cystic air spaces (single arrow), scattered foci of consolidation (arrowhead), and interlobular septal thickening (double arrow). Radiologic findings were most suggestive of lymphoid interstitial pneumonia, but lymphoma could not be excluded. (b) Computed tomography scan of the chest demonstrating enlarged hilar nodes.\n\nFigure 2 (a) Hematoxylin and eosin-stained lung wedge biopsy showing nodular and interstitial lymphoid infiltrates. Nodule (arrow head) interstitial infiltrate (arrow) (original magnification ×20). (b) Hematoxylin and eosin-stained lung wedge biopsy showing benign germinal centre (arrow) (original magnification ×1000). (c) Hematoxylin and eosin-stained lung wedge biopsy showing atypical lymphoplasmacytic infiltrate around bronchovascular bundle, around blood vessel (arrow head), and around bronchioles (arrow) (original magnification ×100). (d) Hematoxylin and eosin-stained lung wedge biopsy showing atypical small lymphoid cells within the nodular infiltrate (original magnification ×400).\n==== Refs\n1 Harris N. L. Jaffe E. S. Stein H. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group Blood 1994 84 5 1361 1392 2-s2.0-0028064764 8068936 \n2 Borie R. Wislez M. Thabut G. Clinical characteristics and prognostic factors of pulmonary MALT lymphoma European Respiratory Journal 2009 34 6 1408 1416 10.1183/09031936.00039309 2-s2.0-73249151812 19541720 \n3 Hussell T. Isaacson P. G. Spencer J. Crabtree J. E. The response of cells from low-grade B-cell gastric lymphomas of mucosa-associated lymphoid tissue to Helicobacter pylori \n The Lancet 1993 342 8871 571 574 10.1016/0140-6736(93)91408-e 2-s2.0-0027170870 \n4 Bae Y. A. Lee K. S. Han J. Marginal zone B-cell lymphoma of bronchus-associated lymphoid tissue: imaging findings in 21 patients Chest 2008 133 2 433 440 10.1378/chest.07-1956 2-s2.0-39449101158 18071012 \n5 Swigris J. J. Berry G. J. Raffin T. A. Kuschner W. G. Lymphoid interstitial pneumonia: a narrative review Chest 2002 122 6 2150 2164 10.1378/chest.122.6.2150 2-s2.0-0036932424 12475860 \n6 Bagg A. Braziel R. M. Arber D. A. Bijwaard K. E. Chu A. Y. Immunoglobulin heavy chain gene analysis in lymphomas: a multi-center study demonstrating the heterogeneity of performance of polymerase chain reaction assays Journal of Molecular Diagnostics 2002 4 2 81 89 10.1016/s1525-1578(10)60685-x 2-s2.0-0036100034 11986398 \n7 Zinzani P. L. Martelli M. Poletti V. Practice guidelines for the management of extranodal non-Hodgkin's lymphomas of adult non-immunodeficient patients. Part I: primary lung and mediastinal lymphomas. A project of the Italian Society of Hematology, the Italian Society of Experimental Hematology and the Italian Group for Bone Marrow Transplantation Haematologica 2008 93 9 1364 1371 10.3324/haematol.12742 2-s2.0-50849124773 18603558 \n8 Ahmed S. Kussick S. J. Siddiqui A. K. Bronchial-associated lymphoid tissue lymphoma: a clinical study of a rare disease European Journal of Cancer 2004 40 9 1320 1326 10.1016/j.ejca.2004.02.006 2-s2.0-2942542725 15177490\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1198-2241",
"issue": "2016()",
"journal": "Canadian respiratory journal",
"keywords": null,
"medline_ta": "Can Respir J",
"mesh_terms": "D000368:Aged; D001172:Arthritis, Rheumatoid; D001984:Bronchial Neoplasms; D003371:Cough; D004417:Dyspnea; D005260:Female; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D006801:Humans; D007143:Immunoglobulin Heavy Chains; D000069285:Infliximab; D018442:Lymphoma, B-Cell, Marginal Zone; D016133:Polymerase Chain Reaction; D012859:Sjogren's Syndrome; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "9433332",
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"title": "Early Bronchus-Associated Lymphoid Tissue Lymphoma Diagnosed with Immunoglobulin Heavy Chain Molecular Testing.",
"title_normalized": "early bronchus associated lymphoid tissue lymphoma diagnosed with immunoglobulin heavy chain molecular testing"
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"abstract": "Dexamethasone ± thalidomide with infusion of cisplatin, doxorubicin, cyclophosphamide, and etoposide [D(T)PACE] is generally reserved as salvage therapy for aggressive multiple myeloma (MM) or plasma cell leukaemia (PCL) resistant to conventional therapies. The efficacy and durability of this potentially toxic regimen in this setting is unclear. We identified 75 patients who received D(T)PACE for relapsed/refractory MM at two tertiary care centres: Princess Margaret Hospital, Toronto and Mayo Clinic Arizona. At time of D(T)PACE, 16 patients had PCL and three patients had leptomeningeal disease. Patients were heavily pretreated (median three prior regimens, range 1-12; prior autologous stem cell transplant [ASCT] 33%). Overall response rate was 49% (very-good partial response 16%, partial response 33%) with stable disease in an additional 36%. Median progression-free survival (PFS) was 5·5 months (95% confidence interval [CI]:4·3-9·8); overall survival (OS) 14·0 months (95% CI:8·7-19·3). Thirty-five patients proceeded to ASCT or clinical trial, with median PFS for this subset of 13·4 months (95% CI:7·7-20·1) and OS 20·5 months (95% CI:14·8-63·8). D(T)PACE is an effective salvage therapy for heavily pretreated MM patients. Although the overall response rate of 49% in this poor prognosis cohort is reasonable, the PFS is short, suggesting the best role for D(T)PACE is in bridging to definitive therapy, such as transplantation.",
"affiliations": "Hematology, University of British Columbia, Vancouver, BC, Canada. agerrie@bccancer.bc.ca",
"authors": "Gerrie|Alina S|AS|;Mikhael|Joseph R|JR|;Cheng|Lu|L|;Jiang|Haiyan|H|;Kukreti|Vishal|V|;Panzarella|Tony|T|;Reece|Donna|D|;Stewart|Keith A|KA|;Trieu|Young|Y|;Trudel|Suzanne|S|;Chen|Christine I|CI|",
"chemical_list": "D013792:Thalidomide; D005047:Etoposide; D003907:Dexamethasone; D004317:Doxorubicin; D003520:Cyclophosphamide; D002945:Cisplatin",
"country": "England",
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"journal": "British journal of haematology",
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"medline_ta": "Br J Haematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002945:Cisplatin; D003520:Cyclophosphamide; D003907:Dexamethasone; D004317:Doxorubicin; D005047:Etoposide; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D009367:Neoplasm Staging; D016879:Salvage Therapy; D013792:Thalidomide; D016896:Treatment Outcome",
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"references": null,
"title": "D(T)PACE as salvage therapy for aggressive or refractory multiple myeloma.",
"title_normalized": "d t pace as salvage therapy for aggressive or refractory multiple myeloma"
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"abstract": "Mildly elevated transaminases are often observed in anorexia nervosa patients, but severe hepatitis is less common. We suggest that hypoperfusion is the pathogenetic factor that causes severe hepatitis in a patient with a very poor nutritional status and present an overview of previous case reports. In our patient, early initiation of intravenous fluids resulted in rapid recovery of the liver test abnormalities, despite minimal oral caloric intake, the refusal of enteral feeding and the development of a hypoglycemic coma. Two months after admission, transaminases had normalized. Reversible severe hepatitis has been described in most of the cases, with only one anorexia nervosa-related fatal hepatitis. In general, both adequate hydration and gradual enteral feeding with monitoring of electrolytes are essential in the management of anorexia patients with severe hepatitis.",
"affiliations": "Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.",
"authors": "Ramsoekh|Dewkoemar|D|;Taimr|Pavel|P|;Vanwolleghem|Thomas|T|",
"chemical_list": "D015415:Biomarkers; D000410:Alanine Transaminase",
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"issue": "26(4)",
"journal": "European journal of gastroenterology & hepatology",
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"medline_ta": "Eur J Gastroenterol Hepatol",
"mesh_terms": "D000328:Adult; D000410:Alanine Transaminase; D000856:Anorexia Nervosa; D015415:Biomarkers; D004796:Clinical Enzyme Tests; D004750:Enteral Nutrition; D005260:Female; D005440:Fluid Therapy; D006505:Hepatitis; D006801:Humans; D008111:Liver Function Tests; D009752:Nutritional Status; D012720:Severity of Illness Index; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "9000874",
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"pubdate": "2014-04",
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"references": null,
"title": "Reversible severe hepatitis in anorexia nervosa: a case report and overview.",
"title_normalized": "reversible severe hepatitis in anorexia nervosa a case report and overview"
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"abstract": "Duplication of the methyl-CpG-binding protein 2 gene (MECP2) is a rare condition that results in epilepsy in half of the cases. Although this condition has been well characterized in the literature, there is a lack of research on MECP2 duplication-related epilepsy and its management. We present the case of an eleven-year old male with MECP2 duplication and epilepsy, who was resistant to polytherapy. The patient responded well to valproic acid (VPA) initially and upon re-challenge. This case report provides evidence for the use of VPA as an initial monotherapy for treatment of drug-resistant MECP2 duplication-related epilepsy.",
"affiliations": "Department of Pediatric Neurology, Children's Hospital of Eastern Ontario (CHEO), 401 Smyth Road, Ottawa, ON K1H 8L1, Canada.;Department of Pediatrics, Children's Hospital of Eastern Ontario (CHEO), 401 Smyth Road, Ottawa, ON K1H 8L1, Canada.;Department of Pediatric Neurology, Children's Hospital of Eastern Ontario (CHEO), 401 Smyth Road, Ottawa, ON K1H 8L1, Canada.",
"authors": "Rajaprakash|Meghna|M|;Richer|Julie|J|;Sell|Erick|E|",
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"doi": "10.1016/j.ebcr.2018.09.009",
"fulltext": "\n==== Front\nEpilepsy Behav Case RepEpilepsy Behav Case RepEpilepsy & Behavior Case Reports2213-3232Elsevier S2213-3232(18)30098-710.1016/j.ebcr.2018.09.009ArticleValproic acid as a monotherapy in drug-resistant methyl-CpG-binding protein 2 gene (MECP2) duplication-related epilepsy Rajaprakash Meghna meghna.rajaprakash@mail.utoronto.caad⁎Richer Julie bcSell Erick aca Department of Pediatric Neurology, Children's Hospital of Eastern Ontario (CHEO), 401 Smyth Road, Ottawa, ON K1H 8L1, Canadab Department of Pediatrics, Children's Hospital of Eastern Ontario (CHEO), 401 Smyth Road, Ottawa, ON K1H 8L1, Canadac University of Ottawa, 75 Laurier Avenue E, Ottawa, ON K1N 6N5, Canadad University of British Columbia, 2329 West Mall, Vancouver, BC V6T 1Z4, Canada⁎ Corresponding author at: Department of Pediatrics, 401 Smyth Road, Ottawa, ON K1H 8L1, Canada. meghna.rajaprakash@mail.utoronto.ca09 10 2018 2018 09 10 2018 10 133 136 22 7 2018 16 9 2018 19 9 2018 © 2018 The Authors2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Duplication of the methyl-CpG-binding protein 2 gene (MECP2) is a rare condition that results in epilepsy in half of the cases. Although this condition has been well characterized in the literature, there is a lack of research on MECP2 duplication-related epilepsy and its management.\n\nWe present the case of an eleven-year old male with MECP2 duplication and epilepsy, who was resistant to polytherapy. The patient responded well to valproic acid (VPA) initially and upon re-challenge. This case report provides evidence for the use of VPA as an initial monotherapy for treatment of drug-resistant MECP2 duplication-related epilepsy.\n\nKeywords\nX-linked syndromeEpilepsyGeneralized seizuresValproic acidAntiseizure drugsDrug reactions\n==== Body\n1 Introduction\nDuplications of Xq28 involving the methyl CpG binding protein 2 gene (MECP2) causes 0.5 to 2% of X-linked developmental disabilities and are predominantly inherited with full penetrance in males [1]. More severe mutations in MECP2 are lethal in males. Females with point mutations in MECP2 present with Rett syndrome. MECP2 duplication syndrome has been well-described in patients with mental retardation, absent to minimal speech, hypotonia replaced by progressive spasticity and/or ataxia, mild facial dysmorphisms (brachycephaly, large face, midface hypoplasia, depressed nasal bridge, upturned nares), severe recurrent respiratory infections, and in some cases, death before 25 years of age [2].\n\nApproximately half of patients with MECP2 duplication also present with epilepsy, although this varies with age. Seizures generally develop in late childhood and early adolescence. Seizures present as polymorphic crises (absences, focal seizures, generalized tonic–clonic) or myoclonic or myoclonic–astatic forms with drop attacks [3]. The onset of seizures is thought to correlate with neurological deterioration including loss of speech and motor skills.\n\nTo date, there are 151 reported patients with MECP2 duplication syndrome, 87 of whom also have epilepsy. For a full summary of the case studies and outcomes, see Table 1. Most of the cases described demonstrate that MECP2-related epilepsy is refractory to pharmacotherapy [4] or there was no reported response. In one case report [5], the patient responded to valproic acid initially, but seizures recurred after two years. Caumes et al. [4] reported seven patients on VPA, only one of which responded with complete control of atypical absence seizures at the 3-year follow-up. In another more recent study [6], two patients showed response with complete resolution of seizures with VPA in one case and a combination of VPA, Clobazam, and Lamotrigine in the other case. Limited research exists on patient attributes and epilepsy characteristics that make these patients responsive to therapy.Table 1 Previous studies of MECP2-related epilepsy.\n\nTable 1First author (year)\tStudy\t#of cases\tSeizure types\tManagement\tOutcome\t\nCaumes (2014)\tLate onset epileptic spasms is frequent in MECP2 gene duplication: electroclinical features and long-term follow-up of 8 epilepsy patients\t8/8\tFebrile seizures, complex partial, GTC myoclonic seizure\t7/8 on VPA or combination of VPA with LTG/LVT/CLB/CBZ\t6 refractory; 1 responsive to VPA\t\nVignoli (2012)\tElectroclinical pattern on MECP2 duplication syndrome: eight new reported cases and review of literature\t6/8\tAtonic head drop, drop attacks, GTC, head nodding\t6/6 on VPA or a combination of VPA with ETS/LEV/LTG/TPM\t2 patients seizure free, 4 patients resistant\t\nBartsch (2010)\tFour unrelated patients with Lubs X-linked mental retardation syndrome and different Xq28 duplications\t2/4\tFocal seizures, GTC\tAnticonvulsants unknown\t1 patient refractory, 1 patient responsive\t\nFernandez (2010)\tNovel association of severe neonatal encephalopathy and Hirschsprung's disease in a male with a supplication at the Xq28 region\t1/1\tFocal seizures, GTC\tN/A\tN/A\t\nRamocki (2010)\tThe MECP2 duplication syndrome\t9/14\tGTC, focal seizure, eating reflex seizure\tN/A\tN/A\t\nReardon (2010)\tProgressive cerebellar degenerative changes in the severe mental retardation syndrome caused by duplication of MECP2 and adjacent loci on Xq28\t4/7\tDrop attacks, nocturnal seizures, GTC\tN/A\tRefractory\t\nEchenne (2009)\tNeurological aspects of MECP2 gene duplication in male patients\t3/5\tGTC, myoclonic astatic, atypical absence\tVPA\tInitially responsive, refractory after two years\t\nKirk (2009)\tThe clinical variability of the MECP2 duplication syndrome: description of two families with duplications excluding L1CAM and FLNA\t2/3\tN/A\tN/A\tN/A\t\nLugtenberg (2009)\tStructural variation in Xq28: MECP2 duplication in 1% of patients with unexplained XLMR and in 2& of male patients with severe encephalopathy\t7/13\tLennox–Gastaut syndrome, GTC, focal seizure\tN/A\tRefractory\t\nClayton-Smith (2008)\tXq28 duplication presenting with intestinal and bladder dysfunction and a distinctive facial appearance\t8/16\tMyoclonic seizures\tN/A\tN/A\t\nPrescott (2008)\tTwo brothers with a microduplication including the MECP2 gene: rapid head growth in infancy and resolution of susceptibility to infection\t1/2\tN/A\tAnticonvulsants, vagal nerve stimulator\tN/A\t\nSmyk (2007)\tDifferent-sized duplications of Xq28, including MECP2, in the three males with mental retardation, absent, or delayed speech, and recurrent infections\t1/3\tGTCs\tN/A\tDeceased\t\nDel Gaudio (2006)\tIncreased MECP2 gene copy number as the result of genomic duplication in male patients\t1/7\tN/A\tN/A\tN/A\t\nFriez (2006)\tRecurrent infections, hypotonia, and mental retardation caused by duplication of MECP2 and adjacent region in Xq28.\t15/23\tAtonic, focal seizure\tN/A\tUnknown\t\nVan Esch (2005)\tMECP2 duplication syndrome\t4/9\tGTC\t\tUnknown\t\nMeins (2005)\tSubmicroscopic duplication in Xq28 causes increased expression of the MECP2 gene in a boy with severe mental retardation and features of Rett syndrome\t1/1\tAbsence, myoclonic astatic seizures, GTCs\tTPM/CLB/LTG/SUL\tRefractory\t\nSanlaville (2005)\tFunctional disomy of the Xq28 chromosome region\t5/13\tN/A\tN/A\tN/A\t\nLubs (1999)\tXLMR syndrome characterized by multiple respiratory infections, hypertelorism, severe CNS deterioration and early death localizes to distal Xq28\t2/5\tN/A\tN/A\tN/A\t\nPai (1997)\tA new X linked recessive syndrome of mental retardation and mild dysmorphism maps to Xq28\t4/6\tN/A\tN/A\tRefractory\t\nLahn (1994)\tXq-Yq interchange resulting in supernormal X-linked gene expression in severely retarded males with 46, XYq-karyotype\t3/3\tFocal seizure, GTC\tN/A\tN/A\t\n\t\tTotal\n87/151\t\t\t\t\n\n\nWe describe an eleven-year old boy with MECP2-related epilepsy, who responded to VPA initially and upon re-challenge. This case provides evidence of the efficacy of VPA as a first-line monotherapy for treatment of MECP2 related epilepsy.\n\n2 Case report\nAn eleven-year old boy was evaluated in the Neurology clinic. He was born at 39 weeks via emergency C-section in a pregnancy complicated by preeclampsia. Maternal history was significant for three prior miscarriages. There were no teratogen exposures during pregnancy. He was healthy with the exception of severe constipation as an infant. He had global developmental delays. He sat at 6 months, walked independently at 24 months, and was unable to ride a bike. He also had fine motor difficulties, particularly with writing letters and using utensils. From a language perspective, he was nonverbal and had deficits in receptive speech. His fourteen-year old brother had a genetic microarray confirming duplication of exons 3 and 4 MECP2 and triplication of exons 1 and 2 MECP2 and also had global developmental delay, absence of speech, and hypotonia. His younger brother and proband also had a duplication of MECP2 on testing. The patient's maternal grandmother had seizures and there was a history of epilepsy and cognitive impairment in other maternal relatives.\n\nThe patient presented with multiple dysmorphic features, including epicanthal folds, small palpebral fissures, long face, simplified helices, clinodactyly, small hands with poor capillary perfusion, and inverted nipples. He had mild scoliosis and kyphosis. His cranial nerve and motor exam were grossly normal. Reflexes were within normal limits. Cardiac auscultation revealed a systolic murmur at the left lower sternal border. He had a normal echocardiogram.\n\nThe patient presented with a history of seizures suggestive of focal dyscognitive seizures and generalized tonic–clonic seizures. The initial episodes were characterized by unresponsiveness, focal eye deviation, and post-ictal confusion with an unknown seizure frequency. He also developed tonic–clonic episodes involving his four extremities. Later, he mainly had episodes of drop seizures, occurring 20–30 times daily and lasting minutes. As a result of these drop seizures, he lost his ability to walk independently and required significant assistance for his activities of daily living including eating, dressing, and bathing. He had several falls per week often resulting in soft tissue injuries. He was reported to have difficulty with concentration and executive functioning both at school and at home due to his uncontrolled seizures.\n\nAn initial MRI was normal and an EEG noted mild nonspecific slowing (7 to 8 Hz background frequency) with no obvious epileptiform activity. A genetics referral was made with requests for chromosomal microarray, Rett syndrome testing, CK, and a metabolic work-up. Genetic testing revealed a microduplication at Xq28 of 430 megabases, involving three genes: IRAK1, MECP2 and FLNA.\n\nThe patient was started on valproic acid (VPA) at 10 mL BID to be continued for two years. Since starting VPA, he was seizure-free. His brother, who was found to have the same MeCP2 duplication, also remained seizure free on VPA.\n\nHowever, due to findings of thrombocytopenia and hyperbilirubinemia in the proband, the VPA was stopped. Following the discontinuation of VPA, he had a re-emergence of his epilepsy with an increase in his drop seizures. He was trialed on a multitude of other anticonvulsants, including Levetiracetam 1500 mg BID (9 months), Lamotrigine 150 mg BID (6 months), Oxcarbazepine 900 mg QAM–1200 mg QHS (4 months), Lacosamide 200 mg BID (3 months), Topiramate 150 mg BID (9 months), and Clobazam 10 mg QHS (ongoing) with no success. Given that the patient remained refractory to polytherapy and that the reported hyperbilirubinemia is a very rare occurrence, the VPA was re-started with close monitoring of transaminases and bilirubin levels. Laboratory studies showed a normalization of platelets and bilirubin levels.\n\nUpon re-challenge, his convulsive seizures were controlled with a significant decrease in frequency of his drop attacks occurring 1–2 times daily. Initially he would have 20–30 drop seizures each day accompanied with unresponsiveness, greatly affecting his ability to function. However, with the reduction in seizure activity, his activities of daily living and school performance improved markedly. In addition, as per parent report, the removal of the sedating anticonvulsants made him less drowsy. Overall, his improved functioning translated in reduced caregiver stress and better quality of life for the patient.\n\n3 Discussion\nThis case study describes a patient with MECP2-related epilepsy who had an initial favorable response to valproic acid (VPA), followed by discontinuation of therapy and re-emergence of symptoms despite polytherapy, and subsequently a re-challenge of VPA which achieved seizure control. This study provides unique evidence for the efficacy of VPA as an initial monotherapy in MECP2 duplication-related epilepsy.\n\nThe majority of previous cases of MECP2 duplication-related epilepsy in the literature have shown poor response to therapy or drug resistance. In one case series [6], two patients had complete seizure control following treatment. For both of these patients from the literature, VPA was part of the treatment regimen. The first patient developed epilepsy at the age of twelve years with atonic head drop and generalized tonic–clonic seizures with EEG showing irregular background activity. Valproic acid was started with complete seizure control. The second patient started having seizures at thirteen years of age. His episodes initially presented as drop attacks with an EEG showing rhythmic theta activity over the frontal areas and paroxysmal spike and slow waves and fronto-temporal predominance. The seizures were initially responsive to a polytherapy with VPA, Clobazam, and ethosuximide, but later re-emerged. Following the addition of Lamotrigine and removal of ethosuximide, the patient achieved complete seizure control. An additional patient also responded to VPA [4] and had a background of predominantly absence seizures.\n\nThe current case and the two previously documented reports demonstrate that seizure activity in MECP2 duplication syndrome can be responsive to VPA. The mechanism of action of VPA is not fully understood, but it is thought to act via multiple pathways including blockage of voltage-gated sodium channels and increased levels of gamma-aminobutyric acid (GABA) [7]. This generalized mechanism makes VPA an ideal initial antiepileptic in MECP2-duplication related epilepsy.\n\nIt is unknown as to which factors differentiate patients who were refractory to treatment versus those who responded to VPA. The difference may reflect varying genetic modifiers modulating the complex epileptic networks. Limited research exists on the polygene impact of IRAK1, MECP2 and FLNA. Fukushi et al. [8] identified one family with a similar combination of genes, who displayed hypotonia, severe intellectual disability and developmental delay, lack of speech, mild characteristic facial features, pyramidal signs, untreatable epilepsy, regression, recurrent infections, and mortality before they were 25 years old. However, these individuals had a duplication which also included the L1CAM gene. To date, the specific contribution of IRAKI is not well-delineated, but may modulate immune responses. FLNA duplications have been shown to be related to bowel dysfunction including constipation, which was identified in this patient [9].\n\nAll responders, including the patient under discussion, developed late-onset epilepsy occurring after the first year of life, with three of the patients developing seizures in early adolescence. The types of seizures in the responsive patients may also be different from those of the non-responders. In the previous studies, one treatment responder displayed atypical absence seizures exclusively [4] and the other two demonstrated atonic head drops and drop attacks respectively [6]. Our patient also predominantly had drop attacks as compared to other seizure types. This is in contrast to the many non-responders who had seizures of multiple types resembling Lennox–Gestalt syndrome. There were additionally similar electroclinical signatures in the responsive patients with unusual fast rhythmic activities occurring in addition to the slow background activity. These observations, however, require further study in a larger patient sample.\n\nNevertheless, the underlying seizure types that occur in MECP2-related epilepsy are well-suited to the generalized effects of VPA. Previous cases of MECP2 duplication syndrome demonstrate that seizures are often polymorphic occurring frequently in the form of generalized tonic–clonic, atypical absence, atonic, and myoclonic seizures [6]. As such, an antiepileptic drug with a broad spectrum of activity is a good initial consideration. The Standard and New Antiepileptic Drugs (SANAD) trial identified VPA as the first-line treatment for patients with generalized seizures [10].\n\nFurther, the EEG features associated with MECP2 duplication related epilepsy mimic a generalized pattern of activity. Specifically, in the documented cases, the interictal EEG showed a slowing of the background activity with generalized slow spike and wave asynchronous discharge with frontotemporal predominance. Sleep EEG also shows abnormal background activity with high voltage spindles [6]. This EEG pattern closely reflects activity present in myoclonic seizures and genetic generalized epilepsy syndromes. Given the widespread nature of cortical activity, VPA is a good choice due to its multiple mechanisms of action.\n\nVPA is also a possible option in MECP2 duplication syndrome as a majority of patients are males and do not have the added risk of pregnancy-related complications including teratogenicity. Current evidence states that VPA is the first-choice treatment option in males and post-menopausal women, while it is not recommended for use in women of child-bearing age and patients with obesity [10]. In these contraindicated cases, Lamotrigine can be used as an alternative agent. Lamotrigine is a phenyltriazine derivative that has a similar mechanism of action to that of VPA in that it inhibits voltage-activated sodium channels. As discussed, in a patient previously reported in the literature who responded to a combination of VPA and Lamotrigine, Lamotrigine served to augment the efficacy of VPA in controlling generalized seizures. This represents an additional reason for starting on VPA as an initial monotherapy as it can be combined with Lamotrigine in the case of treatment resistance [11].\n\nDespite the fact that VPA is the most effective monotherapy with lower treatment withdrawal in generalized epilepsy, the adverse event and side effect profile must be taken into consideration. VPA has multiple side effects including weight gain, hair loss, and gynecomastia [12]. In the current case, there was the additional issue of thrombocytopenia, which is a well-described hematological side effect of VPA. However, thrombocytopenia alone is not an indication to discontinue treatment, and recent evidence suggests that a reduction in dose with strict laboratory controls can be sufficient to normalize patient values [13]. Furthermore, while hepatotoxicity is common, there are no reported cases of hyperbilirubinemia in VPA, suggesting that this finding in our patient was either incidental or due to an unrelated etiology. As such, the patient was appropriately re-trialed on VPA with reduction of the dosage and close monitoring of platelets and transaminases.\n\n4 Conclusion\nTo our knowledge, this is the first reported case of drug-resistant MECP2 duplication related epilepsy, showing responsiveness to VPA both initially and upon a re-challenge, strongly supporting the efficacy of this anticonvulsant as a monotherapy. The case highlights the benefits of VPA in targeting the generalized seizure types and EEG activity seen in MECP2 duplication syndrome. It also suggests that side effects of VPA such as thrombocytopenia can be mitigated by a dose reduction and re-challenge with close monitoring of laboratory markers. Although most cases in the literature suggest that epilepsy associated with MECP2 duplication syndrome is treatment-resistant, we provide contrasting evidence that there may be a role for VPA as a monotherapy in achieving seizure control in some patients.\n==== Refs\nReferences\n1 Lugtenberg D. Kleefstra T. Oudakker A.R. Nillesen W.M. Yntema H.G. Tzschach A. Structural variation in Xq28: MECP2 duplication in 1% of patients with unexplained XLMR and in 2% of male patients with severe encephalopathy Eur J Hum Genet 17 4 2009 444 453 18985075 \n2 Van Esch H. Bauters M. Ignatius J. Jansen M. Raynaud M. Hollanders K. Duplication of the MECP2 region is a frequent cause of severe mental retardation and progressive neurological symptoms in males Am J Hum Genet 77 2005 442 453 16080119 \n3 Friez M.J. Jones J.R. Carkson K. Lubs H. Abeuelo D. Bier J.B. Recurrent infections, hypotonia, and mental retardation caused by duplication of MECP2 and adjacent region in Xq28 Pediatrics 118 6 2006 1687 1695 \n4 Caumes R. Boespflug-Tanguy O. Villeneuve N. Lambert L. Delanoe C. Leheup B. Late onset epileptic spasms is frequent in MECP2 gene duplication: electroclinical features and long-term follow-up of 8 epilepsy patients Eur J Pediatr Neurol 2014 475 481 \n5 Meins M. Lehmann J. Gerresheim F. Herchenback J. Hagedorn M. Hameister K. Submicroscopic duplications in Xq28 causes increased expression of the MECP2 gene in a boy with severe retardation and features of Rett syndrome J Med Genet 42 2005 e12 15689435 \n6 Vignoli A. Borgatti R. Peron A. Zucca C. Ballarati L. Bonaglia C. Electroclinical pattern in MECP2 duplication syndrome: eight new reported cases and review of literature Epilepsia 53 7 2012 1146 1155 22578097 \n7 Owens M.J. Nemeroff C.B. Pharmacology of valproate Psychopharmacol Bull 37 2 2003 17 24 14624230 \n8 Fukushi D. Yamada K. Nomura N. Naiki N. Kimura R. Yamada Y. Clinical characterization and identification of duplication breakpoints in a Japanese family with Xq28 duplication syndrome including MECP2 Am J Med Genet A 164A 2014 924 933 24478188 \n9 Clayton-Smith J. Walters S. Hobson E. Burkitt-Wright E. Smith R. Toutain A. Xq28 duplication presenting with intestinal and bladder dysfunction and a distinctive facial appearance Eur J Hum Genet 17 2009 434 443 18854860 \n10 Coppola G. Piccorossi A. Operto F.F. Verrotti A. Anticonvulsant drugs for generalized tonic–clonic epilepsy Expert Opin Pharmacother 18 9 2017 925 936 28481729 \n11 Brodie M.J. Yuen A.W.C. Lamotrigine substitution study: evidence for synergism with sodium valproate? Epilepsy Res 26 1997 423 432 9127723 \n12 Tang L. Ge L. Wu W. Yang X. Rui P. Wu Y. Lamotrigine versus valproic acid monotherapy for generalised epilepsy: a meta-analysis of comparative studies Seizure 51 2017 95 101 28826049 \n13 Lackmann G.M. Valproic-acid-induced thrombocytopenia and hepatotoxicity: discontinuation of treatment? Pharmacology 70 2004 57 58 14685007\n\n",
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"title": "Valproic acid as a monotherapy in drug-resistant methyl-CpG-binding protein 2 gene (MECP2) duplication-related epilepsy.",
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"abstract": "Pregnancy with liver cirrhosis is a rare and dangerous event that exposes mother and fetus to potentially lethal risks. During pregnancy, hepatic decompensation could suffice and the development of hepatic failure and encephalopathy could occur. The incidence of obstetric complications is also increased with a high rate of pre-eclampsia, postpartum bleeding, preterm delivery and stillbirth. We report a case of a 27-year-old woman with autoimmune hepatitis and liver cirrhosis complicated by splenomegaly, oesophageal varices and severe thrombocytopaenia. During pregnancy, close clinical and analytical surveillance was performed. She was medicated with corticosteroids, azathioprine and propranolol. At the 25th week of gestation, an upper gastrointestinal endoscopy was performed to control oesophageal varices. This patient had an uneventful pregnancy until 37 weeks. At 37th week of gestation, after spontaneous rupture of membranes, signs of acute fetal distress were observed, and an urgent caesarean was performed. Good neonatal and maternal outcomes were achieved.",
"affiliations": "Department of Obstetrics, Centro Hospitalar do Porto, Porto, Portugal.;Department of Obstetrics, Centro Hospitalar do Porto, Porto, Portugal.",
"authors": "Braga|António|A|;Braga|Jorge|J|",
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"abstract": "Posttransplant lymphoproliferative disorders (PTLDs) of T-cell orgin are rare biologically heterogeneous diseases of mature lymphoid cells manifesting in immunosuppressed patients. Only a few cases of mycosis fungoides diagnosed post allogeneic hematopoietic cell transplant (alloHSCT) have been described so far. We present a patient with myelodysplastic syndrome (MDS) post matched unrelated donor alloHSCT who was on long-term immunosuppressive therapy due to graft versus host disease. Three years after an alloHSCT, she developed generalized erythroderma and peripheral blood lymphocytosis. Both skin biopsy and peripheral blood flow cytometry revealed atypical CD4+ T-cell population consistent with diagnosis of Sezary syndrome. Chimerism studies revealed 100% donor engraftment. Therapy with extracorporeal photopheresis resulted in complete response in blood and skin.",
"affiliations": "Department of Internal Medicine, College of Medicine, University of South Florida, 12902 USF Magnolia Drive, Tampa, FL 33612, USA.;Department of Hematopathology and Laboratory Medicine, Moffitt Cancer Center, Tampa, FL, USA.;Department of Hematopathology and Laboratory Medicine, Moffitt Cancer Center, Tampa, FL, USA.;Department of Blood and Marrow Transplant, Moffitt Cancer Center, Tampa, FL, USA.;Department of Hematopathology and Laboratory Medicine, Moffitt Cancer Center, Tampa, FL, USA.;Department of Malignant Hematology, Moffitt Cancer Center, Tampa, FL, USA.",
"authors": "Afiat|Thanh-Phuong|TP|;Zhang|Xiaohui|X|;Zhang|Hailing|H|;Ayala|Ernesto|E|;Zhang|Ling|L|;Sokol|Lubomir|L|",
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"fulltext": "\n==== Front\nLeuk Res RepLeuk Res RepLeukemia Research Reports2213-0489Elsevier S2213-0489(18)30023-210.1016/j.lrr.2018.04.006ArticleSezary syndrome manifesting as posttransplant lymphoproliferative disorder Afiat Thanh-Phuong aZhang Xiaohui bZhang Hailing bAyala Ernesto cZhang Ling bSokol Lubomir Lubomir.Sokol@Moffitt.Orgd⁎a Department of Internal Medicine, College of Medicine, University of South Florida, 12902 USF Magnolia Drive, Tampa, FL 33612, USAb Department of Hematopathology and Laboratory Medicine, Moffitt Cancer Center, Tampa, FL, USAc Department of Blood and Marrow Transplant, Moffitt Cancer Center, Tampa, FL, USAd Department of Malignant Hematology, Moffitt Cancer Center, Tampa, FL, USA⁎ Corresponding author. Lubomir.Sokol@Moffitt.Org01 5 2018 2018 01 5 2018 9 72 75 7 3 2018 17 4 2018 30 4 2018 © 2018 Published by Elsevier Ltd.2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Graphical abstract\nImage, graphical abstract\n\nPosttransplant lymphoproliferative disorders (PTLDs) of T-cell orgin are rare biologically heterogeneous diseases of mature lymphoid cells manifesting in immunosuppressed patients. Only a few cases of mycosis fungoides diagnosed post allogeneic hematopoietic cell transplant (alloHSCT) have been described so far. We present a patient with myelodysplastic syndrome (MDS) post matched unrelated donor alloHSCT who was on long-term immunosuppressive therapy due to graft versus host disease. Three years after an alloHSCT, she developed generalized erythroderma and peripheral blood lymphocytosis. Both skin biopsy and peripheral blood flow cytometry revealed atypical CD4+ T-cell population consistent with diagnosis of Sezary syndrome. Chimerism studies revealed 100% donor engraftment. Therapy with extracorporeal photopheresis resulted in complete response in blood and skin.\n==== Body\n1 Background\nThe late complications of alloHSCT include secondary malignancies such as post-transplant lymphoproliferative disorder (PTLD), solid cancers and acute myeloid leukemia/myelodysplastic syndrome (AML/MDS). Among these, PTLD is the most common and typically manifests within six months to one year post-transplant. The majority of PTLDs (>90%) originate from Epstein-Barr virus (EBV) infected B-cells, are donor-derived and occur in the setting of significant immunosuppression leading to decreased immune surveillance of infected B-cells. Other risk factors include the degree of T-cell depleted grafts, host genetic factors, DNA damage secondary to chemotherapy and/or radiation. In contrast, EBV-negative PTLDs typically present more than 1 year after transplant and are non-B-cell in origin [1]. While it has been recognized that up to 15% of PTLDs after solid organ transplant are T-cell in origin, there has only been a handful of reports of T-cell lymphoma and even fewer reports of cutaneous T-cell lymphoma (CTCL) following alloHSCT [2]. Here, we report, a rare case of Sezary syndrome (SS) following alloHSCT from an HLA-matched unrelated donor.\n\n2 Case presentation\nSeventy-three year-old female with history of high risk MDS was treated with 5-azacitidine, followed by conditioning with busulfan and fludarabine and alloHSCT from a matched unrelated donor with achievement of complete remission (CR). She was on tacrolimus and sirolimus for immunosuppression. Her post-transplant course was complicated with chronic graft versus host disease (cGVHD).\n\nApproximately three years after alloHSCT, she developed a generalized confluent erythematous rash that was pruritic and continued to worsen. Other than chronic dry eyes and mouth secondary to cGVHD, she was asymptomatic. She was seen by a local dermatologist and underwent skin biopsy. The diagnosis of dermatitis possibly due to drug eruption was made and she was treated with 0.1% triamcinolone cream with minimal improvement. Labs at three months after rash manifestation showed leukocytosis of 12.75 k/uL with 1.66 K/uL atypical lymphocytes, elevated LDH of 261 U/L, hyperglycemia of 258 mg/dL and mildly elevated creatinine of 1.2 mg/dL. Peripheral blood flow cytometry revealed cytologically and phenotypically atypical lymphocytes (Fig. 1A), which prompted additional work up.Fig. 1 A. Circulating atypical lymphocytes with irregular nuclear contours in the peripheral blood. 1B. Slightly increased interstitial CD3+ T-cells in the bone marrow biopsy (CD3 immunohistochemical stain, ×100). 1C. Skin biopsy showing superficial dermal atypical lymphocytic infiltrate (H&E stain, ×200). 1D. The dermal atypical lymphocytes are mainly CD4+ cells (CD4 immunohistochemical stain, ×200). 1E. Flow cytometry performed on the peripheral blood showed an atypical CD4+ T-cell population, which decreased CD3 expression, dim CD7 and loss of CD26.\n\nFig 1\n\nSubsequent bone marrow biopsy revealed atypical lymphocytic infiltrate cytologically and phenotypically consistent with mature CD4+ T-cells with decreased expression of CD2, CD3, dim to loss of CD7, loss of CD26 and elevated CD4:CD8 ratio of 19.4 (Fig. 1B, E). Bone marrow was normocellular with trilineage hematopoiesis, and no evidence of recurrent MDS. Sorted CD3(+) and CD33(+) chimerism studies in peripheral blood and unsorted bone marrow chimerism revealed 100% donor engraftment suggesting that malignant T-cell population was donor derived. T-cell receptor (TCR) gene rearrangement studies were positive for clonal beta and gamma gene rearrangements. In-situ hybridization study for Epstein–Barr virus-encoded small RNAs (EBER) was negative. Positron emission tomography (PET) scan was negative for evidence of hypermetabolic lymphadenopathy or organomegaly. Prior skin biopsy was re-examined with multiple deeper sections and revealed dermal lymphocytic infiltrate composed almost entirely of CD4+ T-cells with CD4:CD8 ratio >10:1 (Fig. 1C, D). These findings met diagnostic criteria of Sezary syndrome. Immunosuppression reduction did not result in decrease of circulating clonal T-cells or improvement of erythroderma. The patient was treated with extracorporeal photopheresis (ECP) for two consecutive days every two weeks with complete resolution of erythroderma and pruritis after four treatments. Periodic monitoring of peripheral blood with flow cytometry identified residual Sezary cells until completion of fifth treatment and subsequently remained cytologically and phenotypically negative. Follow-up TCR gene rearrangements continued to show persistent gamma and beta gene rearrangements suggesting a possibility of minimal residual disease. The patient decided against maintenance therapy with ECP.\n\n3 Discussion\nPTLD is a rare but well-recognized complication of alloHSCT. An overwhelming majority (86%) of cases are donor-derived and B-cell origin, frequently associated with EBV (>90%), and manifesting within six months to one year post transplantation [1]. Even more rare, but recognized, is EBV-negative PTLD that are also donor-derived but most often of T and NK cell origin that typically present after one year post-transplant [2], [3], [4]. While patients with PTLD of T-cell origin are well-documented post solid organ transplantion, there has only been a handful of reports of T-cell lymphoma following alloHSCT since the early 2000s [5]. Most recently a few cases of CTCL following alloHSCT were described [Table 1]. Santos-Briz et al. reported the first case of post-transplant primary cutaneous T-cell lymphoproliferative disorder after alloHSCT in 2009, in which a male patient with mantle cell lymphoma underwent a matched-related donor alloHSCT and developed asymptomatic eczema-like cutaneous lesions six years after his transplant. Skin biopsy revealed dense superficial lichenoid infiltrate, mainly consisting of CD4+ atypical lymphocytes with clonal TCR gamma rearrangement. EBER was negative. Based on the findings, the patient was diagnose with PTLD consistent with CTCL, mycosis fungoides (MF) type. Although chimerism studies showed mixed donor-recipient DNA, two-color fluorescence in situ hybridization of chromosomes showed that the neoplastic cells had normal female karyotype, 46 XX, in contrast to transplant recipient's cutaneous cells which carried male karyotype, 46, XY [3]. Three other cases of donor-derived PTLD of mycosis fungoides type have been reported since that time. Two cases received matched-related donor and one matched-unrelated donor allograft. Dermatitis, in an otherwise asymptomatic patient, presented from three to eight years following alloHSCT [2], [5], [6]. In the two matched-related donor cases, the patient's sibling donor also developed rash and was diagnosed with mycosis fungoides at around the time of diagnosis of the recipient; the recipient was found to have 100% donor engraftment [5], [6]. In the matched-unrelated donor case, the patient also developed a rash three years after alloHSCT. The initial lichenoid rash with granulomatous features was suggestive of cutaneous sarcoidosis. Patient was treated with hydroxychloroquine, prenisolone and cyclosporine with some improvement but two months later, she developed erythroderma with palpable lymphadenopathy. A repeat skin biopsy was consistent with a diagnosis of folliculotropic mycosis fungoides. Malignant cells revealed CD3+, CD4+, dim CD7 immunophenotype in the skin infiltrate. Similar to present case, EBER was negative, TCR beta gene rearrangement was positive and the malignant clone was confirmed to be of donor origin with a male karyotype [2]. Although underlying malignancy leading to the need for alloHSCT vary from case to case, there are many features that are shared in these cases and in present patient. These include alloHSCT complicated by GVHD requiring immunosuppression, development of rashes, biopsy-confirmed donor-derived malignant cells with negative EBER and positive clonal TCR gene rearrangements. Since allograft donors undergo rigorous testing and patients with history of malignancy are usually excluded from donor participation, it is unlikely that Sezary cells were directly transmitted from the donor. A more plausible explanation is the effect of immunosuppression with development of PTLD by selection and immune evasion of malignant clones. We were not able to obtain medical records of the donor to rule out development of MF/SS. Recent genetic study of 19 patients with PTLD of T cell origin using targeted sequencing and high-resolution copy number analysis suggested that gene and genomic alterations in these diseases are similar to those identified in immunocompetent patients with peripheral T-cell lymphoma [7]. This case of SS and prior reports of MF emphasize the need for thorough evaluation, including repeat skin biopsies of any persistent dermatitis and the importance of continued monitoring even years after transplantation, and the general recognition of MF/SS as rare a late complication of alloHSCT.Table 1 Reported cases of MF/SS post allogeneic hematopoietic stem cell transplant.\n\nTable 1Reference\tOriginal diagnosis\tImmunosuppresant\tType of donor\tTime of rash development from alloHSCT\tRash presentation\tSkin biopsy findings\tEBV\tTCR gene rearrangement\tChimerism\tOther\tDiagnosis\tTreatment\t\nSantos-Briz et al. [3]\tMantle cell lymphoma, inducted with hyper-CVAD, reduced-intensity conditioning\tTacrolimus, prednisone\tMale recipient with matched-related sister\t6 years, 7 months\tAsymptomatic eczema-like cutaneous lesions, ill-defined brownish. Erythematous plaques, desquamation\tDense epidermal lichenoid infiltrate with atypical lymphocyte with indented, hyperchromatic nuclei, focal epidermotropism, spongiosis\tNegative\tGamma\tMixed chimerism\tTwo-color FISH: Neoplastic cells were XX vs. XY in native cutaneous cells\tMF\tNone\t\nFahy et al. [5]\tChronic myelogenous leukemia inducted with α-interferon, hydroxycarbamide, conditioned with busulfan, cyclophosphamide and mesna\tCyclosporine, methotrexate, oral steroids\tMale recipient with matched-related brother\t3 years\tIntensely pruritic erythematous, eczematous rash\tDense lymphoplasmacytic infiltrate with focal epidermal tropism by atypical medium-large lymphocytes\tNegative\tBeta and Gamma\t100% donor in peripheral blood, 78% donor in CTCL\tDonor's sibling biopsy was initially diagnosed with chronic superficial dermatitis. Later reviews showed mild dermal lymphocytic infiltrate with focal lymphocytis epidermotropism\tMF\tInvolved field radiotherapy, bexarotene, chemotherapy\t\nLoh et al. [6]\tChronic myelogenous leukemia inducted with α-interferon, conditioned with busulfan, cyclophosphamide\tCyclosporine, methotrexate, prednisone\tMale recipient with matched-related sister\t7 years\tErythematous plaque\t“consisten with MF”\tUnknown\tGamma\tUnknown\tAt the same time of rash development, donor was diagnosedwith MF. Review of photos prior to transplant noted donor to have a rash.\tMF\tClobetasol, narrow band UVB phototherapy, desatinib, bexarotene\t\nKinsella et al. [2]\tChronic myelogenous leukemia treated with dasatinib, conditioned with fludarabine, melphalan, in vivo T-cell depletion with alemtuzumab\tCyclosporine, prednisone\tFemale recipient with matched-unrelated male\t3 years\tPruritic, lichenoid, erythrodermic rash, accompanied by lymphadenopathy\tAtypical T-lymphocytic infiltrate with folliculotropism\tNegative\tbeta\tUnknown\tMicrosatellite and XY-FISH consistent with donor origin\tMF\tGemcitabine, ECP, brentuximab\t\n\n\nAppendix Supplementary materials\nImage, application 1 \n\nSupplementary material associated with this article can be found, in the online version, at doi:10.1016/j.lrr.2018.04.006.\n==== Refs\nReferences\n1 Majhail N.S. Secondary cancers following allogeneic haematopoietic cell transplantation in adults Br. J. Haematol. 154 2011 301 310 21615719 \n2 Kinsella F., Kashipaz M., Scarisbrick J., et al. Donor-derived mycosis fungoides following reduced intensity haematopoietic stell cell transplantation from a matched unrelated donor. BMJ Case Rep. 2017 Jan 10;2017.pii:bcr2016216331. doi: 10.1136/bcr-2016-216331. PubMed PMID: 28073814; PubMed Central PMCID: PMC5256493.\n3 Santos-Briz A. Romo A. Antuez P. Primary cutaneous T-cell lymphoproliferative disorder of donor origin after allogeneic haematopoietic stem-cell transplantation Clin. Exp. Dermatol. 34 2009 e778 e781 19817764 \n4 Gill H. Ip A.H.W. Leung R. Indolent T-cell large granular lymphocyte leukaemia after haematopoeitic SCT: a clinicopathologic and molecular analysis Bone Marrow Transplant 47 2012 952 956 22041849 \n5 Fahy C.M.R. Fortune A. Quinn F. Development of mycosis fungoides after bone marrow transplantation for chronic myeloid leukemia: transmission from an allogeneic donor Br. J. Dermatol. 170 2014 462 467 24116988 \n6 Loh J. Cassarino D. Grody W. A case of mycosis fungoides transmitted from donor to recipient, and review of literature of T-cell malignancies after transplantation Clin. Lymphoma, Myeloma, Leukemia 14 2014 e137 e140 \n7 Margolskee E. Jobanputra V. Jain P. Genetic landscape of T- and NK-cell post-transplant lymphoprolerative disorders Oncotarget 25 2016 37636 37648\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2213-0489",
"issue": "9()",
"journal": "Leukemia research reports",
"keywords": null,
"medline_ta": "Leuk Res Rep",
"mesh_terms": null,
"nlm_unique_id": "101608906",
"other_id": null,
"pages": "72-75",
"pmc": null,
"pmid": "29761072",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "22041849;21615719;24116988;28073814;24637131;19817764;27203213",
"title": "Sezary syndrome manifesting as posttransplant lymphoproliferative disorder.",
"title_normalized": "sezary syndrome manifesting as posttransplant lymphoproliferative disorder"
} | [
{
"companynumb": "US-PFIZER INC-2018231519",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "SIROLIMUS"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nIntra-lesional glucocorticosteroid (GCS) injections are used widely for painful musculoskeletal conditions in general practice.\n\n\nMETHODS\nA 26 year old female, was given an intra-lesional injection of 24 mg methyl prednisolone acetate (MPA) with 15 mg lidocaine for treatment of DeQuervain's tenosynovitis. She was six weeks postpartum and predominantly breast feeding. Lactation was suppressed at approximately 30 h post injection and this persisted for a period of approximately 36 h before spontaneous resumption of milk production. Lactation returned to normal 90 h after the injection.\n\n\nCONCLUSIONS\nStudies done in lactating animals have shown that injected GCS have led to a reduction of milk production, but there is limited data on these injections in lactating humans. The dose of GCS administered and the site of the GCS injection appear to contribute to this phenomenon. Very large doses of GCS have caused suppression of lactation in humans as opposed to low doses of GCS. Injections of GCS into areas of the body subjected to high activity level like the knee or wrist could lead to greater systemic absorption of GCS than GSC administered to body sites with lower physical activity like the shoulder.\n\n\nCONCLUSIONS\nLocal injection of MPA reversibly suppressed lactation in a young woman for a period of 24-48 h. Doctors using injectable GCS in lactating women should apprise patients of this possibility. Mothers can take precautions like expressing and storing enough breast milk to cover this period prior to receiving these injections.",
"affiliations": "Princes Town District Health Facility , Princes Town, Trinidad and Tobago.",
"authors": "Babwah|Terence J|TJ|;Nunes|Paula|P|;Maharaj|Rohan G|RG|",
"chemical_list": "D005938:Glucocorticoids; D000077555:Methylprednisolone Acetate; D008012:Lidocaine; D008775:Methylprednisolone",
"country": "England",
"delete": false,
"doi": "10.3109/13814788.2013.805198",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1381-4788",
"issue": "19(4)",
"journal": "The European journal of general practice",
"keywords": null,
"medline_ta": "Eur J Gen Pract",
"mesh_terms": "D000328:Adult; D001942:Breast Feeding; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D015552:Injections, Intralesional; D007774:Lactation; D008012:Lidocaine; D008775:Methylprednisolone; D000077555:Methylprednisolone Acetate; D013717:Tenosynovitis; D013997:Time Factors",
"nlm_unique_id": "9513566",
"other_id": null,
"pages": "248-50",
"pmc": null,
"pmid": "24261425",
"pubdate": "2013-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "An unexpected temporary suppression of lactation after a local corticosteroid injection for tenosynovitis.",
"title_normalized": "an unexpected temporary suppression of lactation after a local corticosteroid injection for tenosynovitis"
} | [
{
"companynumb": "TT-WATSON-2014-17828",
"fulfillexpeditecriteria": "1",
"occurcountry": "TT",
"patient": {
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{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE ACETATE"
},
"drugadditional": ... |
{
"abstract": "Tardive dyskinesia (TD) is an involuntary movement disorder associated with antipsychotic treatment. Because of the serious and potentially irreversible nature of TD, accurate diagnosis is crucial. However, diagnosing TD can be challenging, since the subtle and often fluctuating symptoms can be easily mistaken for symptoms of mental illness or other side effects. Although the risk of developing TD in relation to treatment with second-generation antipsychotics is lower than that associated with first-generation antipsychotics, the risk still exists and may be greater than once believed. Clinicians prescribe antipsychotics for a variety of illnesses and may underestimate the possibility of a patient developing TD, thus missing early signs of the disorder. In this ACADEMIC HIGHLIGHTS, experts review the prevalence, phenomenology, risk factors, and impact of TD, illustrated by case examples, and provide valuable clinical information to guide early recognition and accurate diagnosis.",
"affiliations": "Department of Psychiatry, Texas Tech University Health Sciences Center Medical School, Midland, Texas USA.;Department of Psychiatry and Molecular Medicine, Hofstra Northwell School of Medicine, Hempstead, New York, USA.",
"authors": "Jain|Rakesh|R|;Correll|Christoph U|CU|",
"chemical_list": "D014150:Antipsychotic Agents; D000069348:Quetiapine Fumarate; D000068180:Aripiprazole",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0160-6689",
"issue": "79(2)",
"journal": "The Journal of clinical psychiatry",
"keywords": null,
"medline_ta": "J Clin Psychiatry",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D000068180:Aripiprazole; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D007258:Informed Consent; D000069451:Long Term Adverse Effects; D008297:Male; D001523:Mental Disorders; D008875:Middle Aged; D010346:Patient Care Management; D011788:Quality of Life; D000069348:Quetiapine Fumarate; D012148:Restless Legs Syndrome; D012307:Risk Factors; D000071057:Tardive Dyskinesia",
"nlm_unique_id": "7801243",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29570969",
"pubdate": "2018",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D059040:Video-Audio Media",
"references": null,
"title": "Tardive Dyskinesia: Recognition, Patient Assessment, and Differential Diagnosis.",
"title_normalized": "tardive dyskinesia recognition patient assessment and differential diagnosis"
} | [
{
"companynumb": "US-APOTEX-2018AP016760",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"drugadditional": null,
... |
{
"abstract": "Suicide by injecting insulin is not uncommon both in diabetic and non-diabetic people. The victim usually uses an insulin syringe or a traditional syringe attached to a needle for the injection of insulin, of either animal or synthetic origin. We report a case of suicide by a non-diabetic physician by injecting lispro insulin through an intravenous cannula. To the best of our knowledge, the use of an intravenous cannula for the injection of insulin for suicide is unusual and is rarely reported in the medico-legal literature.",
"affiliations": "Department of Forensic Medicine & Toxicology, All India Institute of Medical Sciences, New Delhi, India drchitta75@rediffmail.com.;Department of Forensic Medicine & Toxicology, All India Institute of Medical Sciences, New Delhi, India.;Department of Pathology, All India Institute of Medical Sciences, New Delhi, India.;Department of Forensic Medicine & Toxicology, All India Institute of Medical Sciences, New Delhi, India.",
"authors": "Behera|C|C|;Swain|Rajanikanta|R|;Mridha|Asit Ranjan|AR|;Pooniya|Shashank|S|",
"chemical_list": "D007004:Hypoglycemic Agents; D061268:Insulin Lispro",
"country": "England",
"delete": false,
"doi": "10.1177/0025817215573171",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0025-8172",
"issue": "83(3)",
"journal": "The Medico-legal journal",
"keywords": "Hypoglycaemia; insulin lispro; intravenous cannula; pulmonary oedema; suicide",
"medline_ta": "Med Leg J",
"mesh_terms": "D000328:Adult; D001929:Brain Edema; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents; D061268:Insulin Lispro; D010822:Physicians, Women; D011654:Pulmonary Edema; D013405:Suicide; D062666:Vascular Access Devices",
"nlm_unique_id": "0412004",
"other_id": null,
"pages": "147-9",
"pmc": null,
"pmid": "25748289",
"pubdate": "2015-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Suicide by injecting lispro insulin with an intravenous cannula.",
"title_normalized": "suicide by injecting lispro insulin with an intravenous cannula"
} | [
{
"companynumb": "IN-SA-2020SA360064",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PROPRANOLOL HYDROCHLORIDE"
},
"drugadditional": "3",... |
{
"abstract": "A 3-month-old girl with Sturge-Weber syndrome presented with a morbilliform rash, eosinophilia, and fulminant liver failure to our tertiary pediatric hospital. She was diagnosed with drug reaction with eosinophilia and systemic symptoms complicated by viremia and evidence of viral hepatitis on liver biopsy. We discuss the role of viral reactivation in drug reaction with eosinophilia and systemic symptoms and the relevance of antiviral therapy in management.",
"affiliations": "Department of Dermatology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.;Department of Dermatology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.;Department of Dermatology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.;Department of Dermatology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.;Department of Dermatology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.",
"authors": "Chow|Maggie L|ML|http://orcid.org/0000-0002-0323-6751;Kim|David|D|;Kamath|Sonia|S|;Peng|David|D|;Luu|Minnelly|M|",
"chemical_list": "D000927:Anticonvulsants; D000998:Antiviral Agents; D005938:Glucocorticoids; D016756:Immunoglobulins, Intravenous; D008775:Methylprednisolone",
"country": "United States",
"delete": false,
"doi": "10.1111/pde.13408",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-8046",
"issue": "35(2)",
"journal": "Pediatric dermatology",
"keywords": "cytomegalovirus; drug reaction with eosinophilia and systemic symptoms; drug reactions; human herpesvirus; viral reactivation",
"medline_ta": "Pediatr Dermatol",
"mesh_terms": "D000927:Anticonvulsants; D000998:Antiviral Agents; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections; D063926:Drug Hypersensitivity Syndrome; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007223:Infant; D008775:Methylprednisolone; D013341:Sturge-Weber Syndrome",
"nlm_unique_id": "8406799",
"other_id": null,
"pages": "e114-e116",
"pmc": null,
"pmid": "29334124",
"pubdate": "2018-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Use of antiviral medications in drug reaction with eosinophilia and systemic symptoms (DRESS): A case of infantile DRESS.",
"title_normalized": "use of antiviral medications in drug reaction with eosinophilia and systemic symptoms dress a case of infantile dress"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2018US-171363",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"d... |
{
"abstract": "With an increasing number of patients with hepatocellular carcinoma (HCC) undergoing liver transplantation (LT), tumor recurrence remains the main limiting factor for long-term survival. Although sorafenib is available for advanced HCC, there is still a lack of data on the use of sorafenib for treatment of recurrent HCC after LT. Here, we report on four cases of the use of sorafenib for treatment of recurrent HCC after LT. The median time of recurrence from LT was 4 months (range, 1-16 months). Two of the four evaluated patients showed stable disease, which was the best response and the duration of stabilization was 11 months and 5 months, respectively. One patient also experienced stable disease and remained in stable disease without sorafenib therapy for 29 months and the total duration of stabilization was 38 months. The remaining patient showed partial response but stopped treatment due to radiological tumor progression during treatment. Although all cases were high risk group for recurrence such as above Milan criteria, vascular invasion and tumor biology, clinical outcomes showed some good results. Therefore, sorafenib may be an acceptable treatment option for recurrent HCC after LT.",
"affiliations": null,
"authors": "Hong|Young Mi|YM|;Yoon|Ki Tae|KT|;Cho|Mong|M|;Kang|Dae Hwan|DH|;Kim|Hyung Wook|HW|;Choi|Cheol Woong|CW|;Park|Su Bum|SB|;Heo|Jeong|J|;Woo|Hyun Young|HY|;Lim|Won|W|",
"chemical_list": "D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib",
"country": "Korea (South)",
"delete": false,
"doi": "10.4166/kjg.2015.65.4.246",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1598-9992",
"issue": "65(4)",
"journal": "The Korean journal of gastroenterology = Taehan Sohwagi Hakhoe chi",
"keywords": "Hepatocellular carcinoma; Liver transplantation; Recurrence; Sorafenib",
"medline_ta": "Korean J Gastroenterol",
"mesh_terms": "D000970:Antineoplastic Agents; D006528:Carcinoma, Hepatocellular; D005260:Female; D006801:Humans; D008113:Liver Neoplasms; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009536:Niacinamide; D010671:Phenylurea Compounds; D049268:Positron-Emission Tomography; D000077157:Sorafenib; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101189416",
"other_id": null,
"pages": "246-51",
"pmc": null,
"pmid": "25896160",
"pubdate": "2015-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Sorafenib in the treatment of recurrent hepatocellular carcinoma after liver transplantation: a report of four cases.",
"title_normalized": "sorafenib in the treatment of recurrent hepatocellular carcinoma after liver transplantation a report of four cases"
} | [
{
"companynumb": "KR-BAYER-2015-183593",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
... |
{
"abstract": "Radioiodine (RAI) therapy for Graves' disease is a well-accepted and effective treatment with a good side effect profile. Short-term adverse effects can occasionally include radiation-induced thyroiditis. To my knowledge, cervical lymphadenitis associated with RAI therapy for Graves' disease has not been reported before.\nA 38-year-old woman initially presented with uncontrolled thyrotoxicosis secondary to Graves' disease. She subsequently received RAI therapy for her condition. Within a week, she developed painful bilateral cervical lymphadenopathy that progressed to abscess formation requiring incision and drainage. No other causes (neoplastic or infective) were found. Symptomatic treatment was instituted, and within 2 months the lymphadenitis resolved completely.\nRAI therapy for Graves' disease can sometimes cause radiation-induced thyroiditis but associated cervical lymphadenopathy or lymphadenitis has not been described. This may represent a continuum of the proinflammatory state induced by RAI manifesting as a rare but potentially morbid complication.",
"affiliations": "Department of General Surgery, Tan Tock Seng Hospital, Singapore, Singapore.",
"authors": "Wong|Shi Hui Junice|SHJ|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000503457",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2235-0640",
"issue": "8(6)",
"journal": "European thyroid journal",
"keywords": "Graves' disease; Hyperthyroidism; Lymphadenitis; Lymphadenopathy; Radioiodine therapy",
"medline_ta": "Eur Thyroid J",
"mesh_terms": null,
"nlm_unique_id": "101604579",
"other_id": null,
"pages": "324-327",
"pmc": null,
"pmid": "31934559",
"pubdate": "2019-12",
"publication_types": "D002363:Case Reports",
"references": "13301073;21306240;27843811;25576511;22961916;17227727;18157381",
"title": "Suppurative Lymphadenitis after Radioactive Iodine Therapy for Graves' Disease: A Rare Complication?",
"title_normalized": "suppurative lymphadenitis after radioactive iodine therapy for graves disease a rare complication"
} | [
{
"companynumb": "SG-JUBILANT PHARMA LTD-2020SG000032",
"fulfillexpeditecriteria": "1",
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{
"actiondrug": "6",
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"activesubstancename": "LITHIUM"
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"drugadditional": null,... |
{
"abstract": "Pulmonary arterial hypertension (PAH) is a rare disorder that can be drug-induced, mostly following treatment by appetite-suppressant drugs. We report four cases of patients who developed PAH following a treatment by leflunomide for rheumatoid arthritis, psoriatic arthritis or undetermined connective tissue disease. All patients described a progressive dyspnea from grade II to IV of NYHA classification; clinical examination found signs of heart failure. PAH was finally diagnosed and confirmed by right heart catheterisation. Haemodynamic explorations found pre-capillary pulmonary hypertension with mean pulmonary arterial pressure above 25mmHg, and pulmonary capillary wedge pressure under 15mmHg. Explorations of this pre-capillary pulmonary hypertension were conducted according to international guidelines: pulmonary or chronic thromboembolic aetiologies were excluded after ventilation/perfusion lung scan and high-resolution computed tomography. All other etiologic explorations were negative. Imputability of leflunomide was finally retained. Leflunomide was stopped for all patients; three of them received specific PAH treatments. A favourable clinical and/or haemodynamic evolution was observed for all patients. The conclusions of the investigations conducted by our pharmacovigilance centre were communicated to the European Medicines Agency, leading to the addition of \"pulmonary hypertension\" in the paragraph \"special warning and precautions of use\" of the package leaflet of leflunomide.",
"affiliations": "Department of Internal Medicine, Rennes University Hospital, 35203 Rennes, France. Electronic address: valentin.coirier@gmail.com.;Department of Internal Medicine, Rennes University Hospital, 35203 Rennes, France; UMR INSERM U1085, Research Institute in Health, Environment and Occupation/Institut de Recherche sur la Santé, l'Environnement et le Travail (IRSET), Universisty of Rennes 1, 35203 Rennes, France.;Department of Cardiology, Rennes University Hospital, 35203 Rennes, France.;Department of Cardiology, Rennes University Hospital, 35203 Rennes, France.;Department of Rheumatology, Rennes University Hospital, 35203 Rennes, France.;Department of Pneumology, Rennes University Hospital, 35203 Rennes, France; UMR INSERM U1085, Research Institute in Health, Environment and Occupation/Institut de Recherche sur la Santé, l'Environnement et le Travail (IRSET), Universisty of Rennes 1, 35203 Rennes, France.;Department of Pharmacovigilance, Rennes University Hospital, 35203 Rennes, France.;Department of Internal Medicine, Rennes University Hospital, 35203 Rennes, France; UMR INSERM U1085, Research Institute in Health, Environment and Occupation/Institut de Recherche sur la Santé, l'Environnement et le Travail (IRSET), Universisty of Rennes 1, 35203 Rennes, France.",
"authors": "Coirier|Valentin|V|;Lescoat|Alain|A|;Chabanne|Céline|C|;Fournet|Maxime|M|;Coiffier|Guillaume|G|;Jouneau|Stéphane|S|;Polard|Elisabeth|E|;Jégo|Patrick|P|",
"chemical_list": "D007166:Immunosuppressive Agents; D000077339:Leflunomide",
"country": "France",
"delete": false,
"doi": "10.1016/j.jbspin.2017.12.014",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1297-319X",
"issue": "85(6)",
"journal": "Joint bone spine",
"keywords": "Leflunomide; Pulmonary arterial hypertension",
"medline_ta": "Joint Bone Spine",
"mesh_terms": "D001172:Arthritis, Rheumatoid; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary; D007166:Immunosuppressive Agents; D000077339:Leflunomide; D008297:Male; D008875:Middle Aged; D011669:Pulmonary Wedge Pressure; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "100938016",
"other_id": null,
"pages": "761-763",
"pmc": null,
"pmid": "29329993",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pulmonary arterial hypertension in four patients treated by leflunomide.",
"title_normalized": "pulmonary arterial hypertension in four patients treated by leflunomide"
} | [
{
"companynumb": "FR-SA-2018SA031615",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEFLUNOMIDE"
},
"drugadditional": "3",
"dr... |
{
"abstract": "Physiological fetal circulation requires patency of the ductus arteriosus. As gestation proceeds, the sensitivity of the ductus to dilating prostaglandins diminishes. The sensitivity to constricting agents like PGE-synthetase inhibitors, present in many analgetics, however, increases. Fetuses affected by an antenatal constriction of the ductus arteriosus (DC) may present with different signs of cardiac failure including dilated right ventricle, tricuspid regurgitation and abnormal venous Doppler. We report on four cases with prenatal DC, presenting at 34, 35, 36 and 37 weeks of gestation. They were referred to fetal echocardiography because of abnormal routine echo scans with unexplained signs of right heart decompensation. Three patients were medicated during pregnancy with either aspirin (low dose), metamizole or ibuprofen. One patient did not take any drugs, especially no pain medication drug in pregnancy. Immediate delivery was performed in all cases. The neonates were in a good condition; echocardiography showed different degrees of right heart hypertrophy which disappeared in all infants by the age of 3 months except in case 2. Unexplained fetal right heart decompensation requires detailed echocardiographic evaluation of the ductus arteriosus and a sophisticated medical history with regard to analgesics. In contrast to ibuprofen and high-dose aspirin, metamizole and low-dose aspirin have not yet been reported as possible agents constricting the fetal arterial duct. In any suspected context, early delivery as in our cases may save babies life. Any application of non-steroidal anti-inflammatory drugs in pregnancy requires close fetal follow-up due to their potentially life-threatening effect.",
"affiliations": "Department of Obstetrics and Gynecology, Fetal Medicine Unit, Ludwig-Maximilians-Universität, Munich, Germany. Barbara.Schiessl@med.uni-muenchen.de",
"authors": "Schiessl|B|B|;Schneider|K T|KT|;Zimmermann|A|A|;Kainer|F|F|;Friese|K|K|;Oberhoffer|R|R|",
"chemical_list": "D018712:Analgesics, Non-Narcotic",
"country": "Germany",
"delete": false,
"doi": "10.1055/s-2005-864116",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0948-2393",
"issue": "209(2)",
"journal": "Zeitschrift fur Geburtshilfe und Neonatologie",
"keywords": null,
"medline_ta": "Z Geburtshilfe Neonatol",
"mesh_terms": "D018712:Analgesics, Non-Narcotic; D004373:Ductus Arteriosus; D005260:Female; D005315:Fetal Diseases; D006801:Humans; D008431:Maternal-Fetal Exchange; D011247:Pregnancy; D011248:Pregnancy Complications; D011263:Pregnancy Trimester, Third; D016216:Ultrasonography, Prenatal; D014661:Vasoconstriction; D018497:Ventricular Dysfunction, Right",
"nlm_unique_id": "9508901",
"other_id": null,
"pages": "65-8",
"pmc": null,
"pmid": "15852232",
"pubdate": "2005-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Prenatal constriction of the fetal ductus arteriosus--related to maternal pain medication?",
"title_normalized": "prenatal constriction of the fetal ductus arteriosus related to maternal pain medication"
} | [
{
"companynumb": "DE-PFIZER INC-DE-WYE-H05445408",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional": "3",
... |
{
"abstract": "Cardiac toxicity is a widely reported complication of fluoropyrimidine chemotherapies (5-fluorouracil and capecitabine); however, Takotsubo syndrome (TS) is less widely reported. There is little data available describing the viability of fluoropyrimidine rechallenge after fluoropyrimidine-induced TS. We report the case of Ms X, a 41-year-old woman with metastatic oesophageal cancer, who developed acute onset left ventricular dysfunction, with a measured left ventricular ejection fraction of 15% on cycle 1 day 3 of FOLFOX chemotherapy, after disconnection of the fluorouracil infusion pump. Her symptoms resolved over 2 days, and an echocardiogram returned to normal within 2 weeks. 5-Fluorouracil was discontinued, and replaced with capecitabine, without recurrence of symptoms. The remainder of her treatment was uneventful. This is the second case to describe successful capecitabine retreatment following 5-fluorouracil-induced TS.",
"affiliations": "Department of Medical Oncology , University Hospital Limerick , Limerick , Ireland.;Department of Medical Oncology , University Hospital Limerick , Limerick , Ireland.;Department of Medical Oncology , University Hospital Limerick , Limerick , Ireland.;Department of Medical Oncology , University Hospital Limerick , Limerick , Ireland.",
"authors": "Abdelrahman|Mohamed|M|;McCarthy|Michael T|MT|;Yusof|Haliana|H|;Osman|Nemer|N|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/omcr/omv072",
"fulltext": "\n==== Front\nOxf Med Case ReportsOxf Med Case ReportsomcromcrOxford Medical Case Reports2053-8855Oxford University Press 10.1093/omcr/omv072omv0721500200Case ReportsSuccessful capecitabine rechallenge following 5-fluorouracil-induced Takotsubo syndrome Abdelrahman Mohamed McCarthy Michael T. Yusof Haliana Osman Nemer *Department of Medical Oncology, University Hospital Limerick, Limerick, Ireland* Correspondence address. Tel: +353-61-482013; Fax: +353-61-482517; E-mail: nemer.osman@hse.ie3 2016 16 3 2016 2016 3 47 50 4 11 2015 1 12 2015 3 12 2015 © The Author 2016. Published by Oxford University Press.2016This 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.comCardiac toxicity is a widely reported complication of fluoropyrimidine chemotherapies (5-fluorouracil and capecitabine); however, Takotsubo syndrome (TS) is less widely reported. There is little data available describing the viability of fluoropyrimidine rechallenge after fluoropyrimidine-induced TS. We report the case of Ms X, a 41-year-old woman with metastatic oesophageal cancer, who developed acute onset left ventricular dysfunction, with a measured left ventricular ejection fraction of 15% on cycle 1 day 3 of FOLFOX chemotherapy, after disconnection of the fluorouracil infusion pump. Her symptoms resolved over 2 days, and an echocardiogram returned to normal within 2 weeks. 5-Fluorouracil was discontinued, and replaced with capecitabine, without recurrence of symptoms. The remainder of her treatment was uneventful. This is the second case to describe successful capecitabine retreatment following 5-fluorouracil-induced TS.\n\nDepartment of Medical Oncology, University Hospital Limerick\n==== Body\nINTRODUCTION\nThe fluoropyrimidine chemotherapeutic drugs 5-fluorouracil and capecitabine have therapeutic activity in a wide range of cancers and are extensively employed in clinical practice. Cardiotoxicity—in the form of ischaemic events—is a well-described adverse effect of fluoropyrimidine therapy (reviewed by Sorrentino et al. [1]). Takotsubo syndrome (TS), the sudden onset of reversible left ventricular dysfunction, is less well documented, and only one previous case of successful capecitabine rechallenge following TS has been described in the literature [2]. Here, we report a second case of successful retreatment with oral capecitabine following resolution of 5-fluorouracil-induced TS, without the recurrence of cardiotoxicity.\n\nCASE REPORT\nMs X, a previously healthy 41-year-old woman, was diagnosed with metastatic oesophageal adenocarcinoma 2 months preceding this acute episode. She completed a course of palliative radiotherapy (30 Gy in 10 fractions) to the primary tumour for local symptom control, before commencing systemic therapy with FOLFOX chemotherapy. On day 3 of her first chemotherapy cycle, 8 h following disconnection of the 5-fluorouracil infusion pump, she presented acutely, complaining of progressive central chest pain, shortness of breath, palpitations and diaphoresis. Her blood pressure was 92/60, and her heart rate was 110, with a regular pulse. Systemic examination was otherwise normal.\n\nBlood tests revealed a troponin-T of 29 ng/l (twice the upper limit of normal) and D-dimers of 2.0 μg/ml (four times the upper limit of normal). A biochemistry profile and full blood count were otherwise unremarkable. An electrocardiogram (ECG) demonstrated T-wave inversion in the lateral leads, which was new compared with her baseline pre-chemotherapy ECG (Fig. 1). A transthoracic echocardiogram showed impaired left ventricular systolic function, with mid- and apical left ventricular hypokinesis, and an estimated ejection fraction of 25% (Fig. 2). Later that day, she proceeded to coronary artery catheterization, which demonstrated normal coronary arteries, severe left ventricular dysfunction and a measured ejection fraction of 15%. A CT pulmonary angiogram examination showed no evidence of pulmonary embolus.\nFigure 1: Electrocardiographic changes in 5-fluorouracil-induced Takotsubo syndrome. A routine baseline pre-chemotherapy ECG demonstrated normal sinus rhythm (A). (B) On the day of presentation with chest pain, the ECG showed T-wave inversion in the lateral leads, with no significant ST-segment changes.\n\n\nFigure 2: Resolution of left ventricular dilatation on echocardiogram. During the acute presentation, an echocardiogram revealed left ventricular dysfunction with marked apical and mid-left ventricular hypokinesis and an estimated left ventricular ejection fraction of 20% (A and B). Two weeks following discharge, a repeat echocardiogram demonstrated normal left ventricular function, with an estimated ejection fraction of 55% (C and D).\n\n\n\nMs X was treated with bisoprolol and ramipril, and analgesia as required for the chest pain, along with supportive measures. No further cardiac medications were indicated. Serial cardiac data demonstrated normalization of ECG changes and troponin within 2 days of presentation. Ms X's symptoms resolved over the same time period. A repeat echocardiogram carried out 2 weeks later demonstrated normal left ventricular function.\n\nFor her second chemotherapy cycle—commenced 3 weeks after cycle 1—5-fluorouracil was discontinued and replaced with capecitabine, which was well tolerated. Two weeks after commencing capecitabine, an echocardiogram demonstrated normal left ventricular function. She remained symptom free for the duration of her treatment.\n\nDISCUSSION\nFluorouracil- and capecitabine-induced cardiotoxicity is recognized in the literature, affecting between 1.2 and 18% of individuals treated with these drugs [1]. Cardiotoxicity is more common with infusional regimens, and rates of cardiotoxicity are higher in patients who also receive leucovorin [3]. Symptoms of cardiotoxicity recur in about half of those rechallenged with the drug [4]. The mechanism of cardiotoxicity remains unclear (reviewed by Polk et al. [5]).\n\nThe majority of adverse cardiac events is described as acute coronary syndrome (ACS), likely induced by vasospasm [3]. However, cases of TS are increasingly reported. TS is characterized by the onset of reversible left ventricular dysfunction. While TS is often aetiologically associated with intense emotional stress [6], chemotherapy-induced TS is now a recognized entity. In particular, TS has been reported in individuals treated with both capecitabine [7] and 5-fluorouracil [2, 8, 9]. The mechanism underlying the induction of TS by chemotherapy is unclear. Similar to fluoropyrimidine-induced ACS, coronary artery vasospasm had been proposed as a possible pathogenetic feature of fluoropyrimidine-induced TS [2]. However, coronary angiography during an acute episode of capecitabine-induced TS has demonstrated slow coronary artery blood flow in the absence of coronary artery vasospasm [7]. Current hypotheses include coronary microvascular dysfunction or catecholamine-induced cardiotoxicity [7]. Further evidence will be needed to clarify the importance of these mechanisms in the pathogenesis of fluoropyrimidine-induced TS.\n\nThere is little evidence describing the likely outcomes of fluoropyrimidine rechallenge following TS. Successful capecitabine administration in individuals following 5-fluorouracil-induced ACS [10] and TS [2] has been reported previously. Similarly, our patient tolerated capecitabine well, with no recurrence of cardiac symptoms, and a normal echocardiogram after one complete cycle of capecitabine therapy. It is also of note that onset of symptoms occurred following pump disconnection, and that previous doses had been well tolerated. While data supporting fluoropyrimidine challenge following TS remains limited, our case demonstrates that cautious rechallenge with capecitabine under close clinical supervision might be reasonable in this setting.\n\nCONFLICT OF INTEREST STATEMENT\nNone declared.\n\nFUNDING\nThis work was supported (publication costs) by the Department of Medical Oncology, University Hospital Limerick, Ireland.\n\nETHICAL APPROVAL\nNo ethical approval was sought.\n\nCONSENT\nThe patient has signed consent for publication of this case.\n\nGUARANTOR\nN.O. is guarantor of this study.\n==== Refs\nREFERENCES\n1 Sorrentino MF , Kim J , Foderaro AE , Truesdell AG \n5-Fluorouracil induced cardiotoxicity: review of the literature . Cardiol J \n2012 ;19 :453 –8 .23042307 \n2 Grunwald MR , Howie L , Diaz LA \nTakotsubo cardiomyopathy and fluorouracil: case report and review of the literature . J Clin Oncol \n2012 ;30 :e11 –4 .22147738 \n3 Kosmas C , Kallistratos MS , Kopterides P , Syrios J , Skopelitis H , Mylonakis N et al \nCardiotoxicity of fluoropyrimidines in different schedules of administration: a prospective study . J Cancer Res Clin Oncol \n2007 ;134 :75 –82 .17636329 \n4 Saif MW , Shah MM , Shah AR \nFluoropyrimidine-associated cardiotoxicity: revisited . Expert Opin Drug Saf \n2009 ;8 :191 –202 .19309247 \n5 Polk A , Vistisen K , Vaage-Nilsen M , Nielsen DL \nA systematic review of the pathophysiology of 5-fluorouracil-induced cardiotoxicity . BMC Pharmacol Toxicol \n2014 ;15 :47 .25186061 \n6 Wittstein IS , Thiemann DR , Lima JAC , Baughman KL , Schulman SP , Gerstenblith G et al \nNeurohumoral features of myocardial stunning due to sudden emotional stress . N Engl J Med \n2005 ;352 :539 –48 .15703419 \n7 Y-Hassan S , Tornvall P , Törnerud M , Henareh L \nCapecitabine caused cardiogenic shock through induction of global Takotsubo syndrome . Cardiovasc Revasc Med \n2013 ;14 :57 –61 .23218901 \n8 Knott K , Starling N , Rasheed S , Foran J , Cafferkey C , Rosen S et al \nA case of Takotsubo syndrome following 5-fluorouracil chemotherapy . Int J Cardiol \n2014 ;177 :e65 –7 .25449494 \n9 Iskandar MZ , Quasem W , El-Omar M \n5-Fluorouracil cardiotoxicity: reversible left ventricular systolic dysfunction with early detection . BMJ Case Rep \n2015 ; doi:10.1136/bcr-2015-209347 .\n10 Saneeymehri SS , Markey KR , Mahipal A \nParadoxical effect of capecitabine in 5-fluorouracil-induced cardiotoxicity: a case vignette and literature review . J Oncol Pharm Pract \n2015 ; doi:10.1177/1078155215579303 .\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2053-8855",
"issue": "2016(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": "47-50",
"pmc": null,
"pmid": "26989494",
"pubdate": "2016-03",
"publication_types": "D002363:Case Reports",
"references": "22147738;23042307;25186061;25852107;25449494;25935919;17636329;19309247;23218901;15703419",
"title": "Successful capecitabine rechallenge following 5-fluorouracil-induced Takotsubo syndrome.",
"title_normalized": "successful capecitabine rechallenge following 5 fluorouracil induced takotsubo syndrome"
} | [
{
"companynumb": "IE-MYLANLABS-2017M1004384",
"fulfillexpeditecriteria": "1",
"occurcountry": "IE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LEUCOVORIN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nStereotactic radiosurgery (SRS) is increasingly considered for selected olfactory groove meningiomas (OGMs).\n\n\nOBJECTIVE\nTo investigate the safety and efficacy of SRS for OGMs.\n\n\nMETHODS\nFrom 20 institutions participating in the International Radiosurgery Research Foundation, we pooled patients who underwent SRS for histologically confirmed or radiologically suspected WHO grade I OGMs and were followed for 6 mo or more after the SRS.\n\n\nRESULTS\nIn total, 278 (median age 57 yr) patients underwent SRS for histologically confirmed (29%) or radiologically suspected (71%) WHO grade I OGMs Median treatment volume was 4.60 cm3 (range: 0.12-27.3 cm3), median prescription dose was 12 Gy, and median dose to the olfactory nerve was 11.20 Gy. During median post-SRS imaging follow-up of 39 mo (range: 6-240 mo), 43% of patients had partial or marginal response, 54% of patients had stable disease, and 3% of patients experienced progression. During median post-SRS clinical follow-up of 51 mo (range: 6-240 mo), 36 (13%) patients experienced clinical and/or radiological adverse radiation events (AREs). Elevated risk of AREs was associated with larger OGM volume (P = .009) and pre-SRS peritumoral T2/fluid-attenuated inversion-recovery signal abnormalities (P < .001). After the SRS, olfaction remained stable, improved, or deteriorated in 90%, 8%, and 2% of patients, respectively. Complete post-SRS anosmia was predicted by partial/complete anosmia before the SRS (odds ratio [OR] = 83.125; 95% CI [24.589-281.01], P < .001) and prior resection of OGM (OR = 3.919; 95% CI [1.713-8.970], P = .001).\n\n\nCONCLUSIONS\nSRS is associated with durable local control of the majority of OGM patients with acceptable safety profile. SRS allows preservation or improvement of olfactory function in the majority of OGM patients.",
"affiliations": "Department of Neurosurgery, University of Virginia, Charlottesville, Virginia, USA.;Department of Neurosurgery, University of Virginia, Charlottesville, Virginia, USA.;Department of Neurosurgery, University of Virginia, Charlottesville, Virginia, USA.;Department of Neurosurgery, Koç University School of Medicine, Istanbul, Turkey.;Department of Neurosurgery, Koç University School of Medicine, Istanbul, Turkey.;Department of Neurosurgery, University of Virginia, Charlottesville, Virginia, USA.;Department of Neurosurgery, University of Virginia, Charlottesville, Virginia, USA.;Gamma Knife Center Cairo, Nasser Institute Hospital, Cairo, Egypt.;Gamma Knife Center Cairo, Nasser Institute Hospital, Cairo, Egypt.;Gamma Knife Center Cairo, Nasser Institute Hospital, Cairo, Egypt.;Gamma Knife Center Cairo, Nasser Institute Hospital, Cairo, Egypt.;Gamma Knife Center Cairo, Nasser Institute Hospital, Cairo, Egypt.;Gamma Knife Center Cairo, Nasser Institute Hospital, Cairo, Egypt.;Department of Neurosurgery, Na Homolce Hospital, Prague, Czech Republic.;Department of Neurosurgery, Na Homolce Hospital, Prague, Czech Republic.;Hospital Ruber Internacional, Madrid, Spain.;Hospital Ruber Internacional, Madrid, Spain.;Department of Neurosurgery, Université de Sherbrooke, Centre de recherche du CHUS, Sherbrooke, Canada.;Department of Neurosurgery, Université de Sherbrooke, Centre de recherche du CHUS, Sherbrooke, Canada.;Department of Neurosurgery, Neurological Institute, Taipei Veteran General Hospital, Taipei, Taiwan.;Department of Neurosurgery, Neurological Institute, Taipei Veteran General Hospital, Taipei, Taiwan.;Department of Neurosurgery, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.;Gamma Knife Center, Jewish Hospital, Mayfield Clinic, Cincinnati, Ohio, USA.;Gamma Knife, Radiology Department Dominican Gamma Knife Center and CEDIMAT, Santo Domingo, Dominican Republic.;Gamma Knife, Radiology Department Dominican Gamma Knife Center and CEDIMAT, Santo Domingo, Dominican Republic.;Department of Neurosurgery, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.;Department of Neurosurgery, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.;Department of Neurosurgery, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.;Department of Neurosurgery, University of Southern California, Los Angeles, California, USA.;Department of Neurosurgery, University of Southern California, Los Angeles, California, USA.;Department of Radiation Oncology, University of Southern California, Los Angeles, California, USA.;Department of Neurosurgery, University of Puerto Rico, School of Medicine, San Juan, Puerto Rico.;Administración de Servicios Médicos de Puerto Rico, Centro Gamma Knife de Puerto Rico y El Caribe, San Juan, Puerto Rico.;Division of Radiation Oncology, University of Alberta, Edmonton, Canada.;Department of Neurosurgery, University of Virginia, Charlottesville, Virginia, USA.",
"authors": "Bunevicius|Adomas|A|0000-0003-0446-6898;Ahn|Jungeun|J|;Fribance|Sarah|S|;Peker|Selcuk|S|;Hergunsel|Batu|B|;Sheehan|Darrah|D|;Sheehan|Kimball|K|;Nabeel|Ahmed M|AM|;Reda|Wael A|WA|;Tawadros|Sameh R|SR|;Abdelkarim|Khaled|K|;El-Shehaby|Amr M N|AMN|;Emad|Reem M|RM|;Chytka|Tomas|T|;Liscak|Roman|R|;Alvarez|Roberto Martínez|RM|;Moreno|Nuria Martínez|NM|;Langlois|Anne-Marie|AM|;Mathieu|David|D|;Lee|Cheng-Chia|CC|;Yang|Huai-Che|HC|;Tripathi|Manjul|M|;Warnick|Ronald E|RE|;Speckter|Herwin|H|;Albert|Camilo|C|;Picozzi|Piero|P|;Franzini|Andrea|A|;Attuati|Luca|L|;Strickland|Ben A|BA|0000-0002-4620-9542;Zada|Gabriel|G|0000-0001-5821-902X;Chang|Eric L|EL|;Feliciano Valls|Caleb E|CE|;Carbini|Carlos H|CH|;Patel|Samir|S|;Sheehan|Jason|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1093/neuros/nyab291",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0148-396X",
"issue": "89(5)",
"journal": "Neurosurgery",
"keywords": "Olfactory groove meningioma; Radiosurgery",
"medline_ta": "Neurosurgery",
"mesh_terms": null,
"nlm_unique_id": "7802914",
"other_id": null,
"pages": "784-791",
"pmc": null,
"pmid": "34383951",
"pubdate": "2021-10-13",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Stereotactic Radiosurgery for Olfactory Groove Meningiomas: An International, Multicenter Study.",
"title_normalized": "stereotactic radiosurgery for olfactory groove meningiomas an international multicenter study"
} | [
{
"companynumb": "US-AMGEN-USASP2022002925",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": "4",
... |
{
"abstract": "The 2018 American Heart Association/American Stroke Association (AHA/ASA) guidelines stated that the administration of intravenous recombinant tissue-type plasminogen activator (rTPA) for acute ischaemic stroke is probably safe for patients with small (i.e. <10 mm) unruptured intracranial aneurysms. We present 2 cases of small (2 and 5 mm) lenticulostriate artery (LSA) aneurysms which ruptured immediately following rtPA infusion. The ensuing acute intracranial haemorrhages resulted in the death of one patient and severe functional impairment for the other. Given the limited literature available, the natural history of LSA aneurysms is largely unknown. This report suggests that LSA aneurysms, regardless of size, be considered separately from other conventional aneurysms as \"high-risk\" lesions and a contraindication to thrombolysis.",
"affiliations": "Department of Diagnostic Radiology, Changi General Hospital, Singapore. Electronic address: haiyuan.shi@mohh.com.sg.;Department of Neurology, National Neuroscience Institute, Singapore.;Department of Neurology, National Neuroscience Institute, Singapore.",
"authors": "Shi|Haiyuan|H|;Wee|Chee Keong|CK|;John|Sindhu|S|",
"chemical_list": "D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator",
"country": "Scotland",
"delete": false,
"doi": "10.1016/j.jocn.2018.10.087",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0967-5868",
"issue": "60()",
"journal": "Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia",
"keywords": "Acute ischaemic stroke; Intracranial haemorrhage; Lenticulostriate artery aneurysm; Thrombolysis",
"medline_ta": "J Clin Neurosci",
"mesh_terms": "D061605:Administration, Intravenous; D000368:Aged; D017542:Aneurysm, Ruptured; D020144:Basal Ganglia Cerebrovascular Disease; D005260:Female; D005343:Fibrinolytic Agents; D006801:Humans; D002532:Intracranial Aneurysm; D020300:Intracranial Hemorrhages; D008297:Male; D008875:Middle Aged; D020521:Stroke; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator",
"nlm_unique_id": "9433352",
"other_id": null,
"pages": "148-150",
"pmc": null,
"pmid": "30528357",
"pubdate": "2019-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Post-thrombolysis rupture of small lenticulostriate aneurysms: A report of 2 consecutive cases.",
"title_normalized": "post thrombolysis rupture of small lenticulostriate aneurysms a report of 2 consecutive cases"
} | [
{
"companynumb": "SG-ROCHE-2213304",
"fulfillexpeditecriteria": "1",
"occurcountry": "SG",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALTEPLASE"
},
"drugadditional": "3",
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{
"abstract": "Neurological disorders are the most unpredictable and feared complications after open surgery or endovascular aortic repair. Paraplegia because of spinal cord injury is well known after thoracoabdominal aortic surgery but not after valvular surgery. We herein present a case of paraplegia after mitral and tricuspid valve surgery in a patient with a history of surgery involving the thoracoabdominal and abdominal aorta. The paraplegia was likely caused by temporary postoperative hypotension as low as 40 mm Hg for more than 10 minutes with decreased spinal perfusion in the intensive care unit.",
"affiliations": "Department of Cardiovascular Surgery, Otakanomori Hospital, Kashiwa, Japan. Electronic address: masumasuyama@me.com.;Department of Cardiovascular Surgery, IMS Tokyo Katsushika General Hospital, Tokyo, Japan.;Department of Cardiovascular Surgery, Otakanomori Hospital, Kashiwa, Japan.;Department of Cardiovascular Surgery, Otakanomori Hospital, Kashiwa, Japan.",
"authors": "Masuyama|Shinji|S|;Isomura|Tadashi|T|;Inoue|Takehiko|T|;Ichihara|Tetsuya|T|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.athoracsur.2020.10.067",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-4975",
"issue": "112(1)",
"journal": "The Annals of thoracic surgery",
"keywords": null,
"medline_ta": "Ann Thorac Surg",
"mesh_terms": "D000368:Aged; D017545:Aortic Aneurysm, Thoracic; D019917:Blood Vessel Prosthesis Implantation; D057510:Endovascular Procedures; D019918:Heart Valve Prosthesis Implantation; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D010264:Paraplegia; D011183:Postoperative Complications; D014262:Tricuspid Valve Insufficiency",
"nlm_unique_id": "15030100R",
"other_id": null,
"pages": "e9-e11",
"pmc": null,
"pmid": "33421387",
"pubdate": "2021-07",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Paraplegia After Valvular Surgery After Remote Thoracoabdominal Aortic Aneurysm Repair.",
"title_normalized": "paraplegia after valvular surgery after remote thoracoabdominal aortic aneurysm repair"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-310312",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NICARDIPINE"
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{
"abstract": "Multiple myeloma (MM) progression is characterized by the seeding of cancer cells in different anatomic sites. To characterize this evolutionary process, we interrogated, by whole genome sequencing, 25 samples collected at autopsy from 4 patients with relapsed MM and an additional set of 125 whole exomes collected from 51 patients. Mutational signatures analysis showed how cytotoxic agents introduce hundreds of unique mutations in each surviving cancer cell, detectable by bulk sequencing only in cases of clonal expansion of a single cancer cell bearing the mutational signature. Thus, a unique, single-cell genomic barcode can link chemotherapy exposure to a discrete time window in a patient's life. We leveraged this concept to show that MM systemic seeding is accelerated at relapse and appears to be driven by the survival and subsequent expansion of a single myeloma cell following treatment with high-dose melphalan therapy and autologous stem cell transplant.",
"affiliations": "Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;NYU Perlmutter Cancer Center, New York, NY, USA.;Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, AR, USA.;NYU Perlmutter Cancer Center, New York, NY, USA.;Center for Hematological Malignancies, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Cytogenetics Laboratory, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Hematopathology Service, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Department of Medicine, Weill Cornell Medical College, New York, NY, USA.;Department of Medicine, Weill Cornell Medical College, New York, NY, USA.;Department of Medicine, Weill Cornell Medical College, New York, NY, USA.;Department of Medicine, Weill Cornell Medical College, New York, NY, USA.;Department of Medicine, Weill Cornell Medical College, New York, NY, USA.;Department of Medicine, Weill Cornell Medical College, New York, NY, USA.;Department of Medicine, Weill Cornell Medical College, New York, NY, USA.;Department of Medicine, Weill Cornell Medical College, New York, NY, USA.;Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, AR, USA.;NYU Perlmutter Cancer Center, New York, NY, USA.;Department of Medicine, Weill Cornell Medical College, New York, NY, USA.;Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. mauraf@mskcc.org.",
"authors": "Landau|Heather J|HJ|;Yellapantula|Venkata|V|;Diamond|Benjamin T|BT|;Rustad|Even H|EH|http://orcid.org/0000-0002-9320-4963;Maclachlan|Kylee H|KH|;Gundem|Gunes|G|;Medina-Martinez|Juan|J|;Ossa|Juan Arango|JA|;Levine|Max F|MF|http://orcid.org/0000-0001-5156-9086;Zhou|Yangyu|Y|;Kappagantula|Rajya|R|;Baez|Priscilla|P|;Attiyeh|Marc|M|http://orcid.org/0000-0002-9949-1449;Makohon-Moore|Alvin|A|;Zhang|Lance|L|;Boyle|Eileen M|EM|;Ashby|Cody|C|http://orcid.org/0000-0002-9361-0283;Blaney|Patrick|P|;Patel|Minal|M|;Zhang|Yanming|Y|;Dogan|Ahmet|A|http://orcid.org/0000-0001-6576-5256;Chung|David J|DJ|;Giralt|Sergio|S|;Lahoud|Oscar B|OB|;Peled|Jonathan U|JU|;Scordo|Michael|M|;Shah|Gunjan|G|;Hassoun|Hani|H|;Korde|Neha S|NS|;Lesokhin|Alexander M|AM|;Lu|Sydney|S|;Mailankody|Sham|S|;Shah|Urvi|U|http://orcid.org/0000-0001-8419-1091;Smith|Eric|E|;Hultcrantz|Malin L|ML|http://orcid.org/0000-0002-9045-6495;Ulaner|Gary A|GA|;van Rhee|Frits|F|;Morgan|Gareth J|GJ|;Landgren|Ola|O|http://orcid.org/0000-0001-6485-4839;Papaemmanuil|Elli|E|http://orcid.org/0000-0003-1709-8983;Iacobuzio-Donahue|Christine|C|http://orcid.org/0000-0002-4672-3023;Maura|Francesco|F|http://orcid.org/0000-0002-5017-1620",
"chemical_list": "D008558:Melphalan",
"country": "England",
"delete": false,
"doi": "10.1038/s41467-020-17459-z",
"fulltext": "\n==== Front\nNat Commun\nNat Commun\nNature Communications\n2041-1723 Nature Publishing Group UK London \n\n17459\n10.1038/s41467-020-17459-z\nArticle\nAccelerated single cell seeding in relapsed multiple myeloma\nLandau Heather J. 12 Yellapantula Venkata 34 Diamond Benjamin T. 4 http://orcid.org/0000-0002-9320-4963Rustad Even H. 4 Maclachlan Kylee H. 4 Gundem Gunes 3 Medina-Martinez Juan 3 Ossa Juan Arango 3 http://orcid.org/0000-0001-5156-9086Levine Max F. 3 Zhou Yangyu 3 Kappagantula Rajya 5 Baez Priscilla 5 http://orcid.org/0000-0002-9949-1449Attiye Marc 5 Makohon-Moore Alvin 5 Zhang Lance 5 Boyle Eileen M. 6 http://orcid.org/0000-0002-9361-0283Ashby Cody 7 Blaney Patrick 6 Patel Minal 8 Zhang Yanming 9 http://orcid.org/0000-0001-6576-5256Dogan Ahmet 10 Chung David J. 12 Giralt Sergio 12 Lahoud Oscar B. 12 Peled Jonathan U. 12 Scordo Michael 12 Shah Gunjan 12 Hassoun Hani 24 Korde Neha S. 24 Lesokhin Alexander M. 24 Lu Sydney 24 Mailankody Sham 24 http://orcid.org/0000-0001-8419-1091Shah Urvi 24 Smith Eric 24 http://orcid.org/0000-0002-9045-6495Hultcrantz Malin L. 24 Ulaner Gary A. 11 van Rhee Frits 7 Morgan Gareth J. 6 http://orcid.org/0000-0001-6485-4839Landgren Ola 24 http://orcid.org/0000-0003-1709-8983Papaemmanuil Elli 3 http://orcid.org/0000-0002-4672-3023Iacobuzio-Donahue Christine 5 http://orcid.org/0000-0002-5017-1620Maura Francesco mauraf@mskcc.org 4 1 0000 0001 2171 9952grid.51462.34Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY USA \n2 000000041936877Xgrid.5386.8Department of Medicine, Weill Cornell Medical College, New York, NY USA \n3 0000 0001 2171 9952grid.51462.34Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY USA \n4 0000 0001 2171 9952grid.51462.34Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY USA \n5 0000 0001 2171 9952grid.51462.34Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY USA \n6 0000 0004 1936 8753grid.137628.9NYU Perlmutter Cancer Center, New York, NY USA \n7 0000 0004 4687 1637grid.241054.6Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, AR USA \n8 0000 0001 2171 9952grid.51462.34Center for Hematological Malignancies, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY USA \n9 0000 0001 2171 9952grid.51462.34Cytogenetics Laboratory, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY USA \n10 0000 0001 2171 9952grid.51462.34Hematopathology Service, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY USA \n11 0000 0001 2171 9952grid.51462.34Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY USA \n17 7 2020 \n17 7 2020 \n2020 \n11 36174 3 2020 2 7 2020 © The Author(s) 2020Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Multiple myeloma (MM) progression is characterized by the seeding of cancer cells in different anatomic sites. To characterize this evolutionary process, we interrogated, by whole genome sequencing, 25 samples collected at autopsy from 4 patients with relapsed MM and an additional set of 125 whole exomes collected from 51 patients. Mutational signatures analysis showed how cytotoxic agents introduce hundreds of unique mutations in each surviving cancer cell, detectable by bulk sequencing only in cases of clonal expansion of a single cancer cell bearing the mutational signature. Thus, a unique, single-cell genomic barcode can link chemotherapy exposure to a discrete time window in a patient′s life. We leveraged this concept to show that MM systemic seeding is accelerated at relapse and appears to be driven by the survival and subsequent expansion of a single myeloma cell following treatment with high-dose melphalan therapy and autologous stem cell transplant.\n\nIn multiple myeloma, disease progresses via seeding to different anatomic sites and clonal expansion. Here, utilising autopsy material, the authors show that systemic seeding accelerates at relapse following treatment.\n\nSubject terms\nCancer genomicsChemotherapyMyelomaissue-copyright-statement© The Author(s) 2020\n==== Body\nIntroduction\nThe pathogenesis of multiple myeloma (MM) is characterized by a long and complex evolutionary process through two clinically defined precursor stages: monoclonal gammopathy of uncertain significance and smoldering MM1–4. The progression of precursor disease to invasive MM is characterized by branching evolutionary patterns and clonal sweeps together with local evolution and expansion of cancer cells in varying anatomical sites5,6. Divergence and progression at distinct sites of disease—spatial evolution—magnifies the genomic heterogeneity of MM, where a range of clones compete for dominance and are positively selected according to their genetic driver landscape, reflected in their ability to best adapt to the local environment7–12. Similar evolutionary patterns have also been observed in patients with MM at clinical relapse13–15. However, it is unclear if, at the time of relapse, the new disease sites reflect a pre-existing but previously undetected disease localization or a new dissemination of disease seeding. Furthermore, despite the unquestionable spatial heterogeneity of MM13, to our knowledge, its development over time has not been investigated in a systematic manner.\n\nSomatic mutations in cancer genomes are caused by different mutational processes, each of which generates a characteristic mutational signature16,17. Considering each single nucleotide variant (SNV) together with its neighboring bases at 5′ and 3′ (the trinucleotide context), more than 40 mutational signatures [or single base substitution (SBS) signatures] have been described, some of which are associated with defective DNA repair mechanisms, exposure to exogenous carcinogens, or radical oxygen stress16,17. Using large genomic datasets, we recently described the landscape of mutational processes active in MM8,18–22. At diagnosis (i.e., prior to therapy), the mutational landscape is shaped by seven main mutational processes, five of which have a recognized etiology: activation-induced cytidine deaminase (AID; SBS9), aging (SBS1 and SBS5), and apolipoprotein B mRNA Editing Catalytic Polypeptide-like (APOBEC; SBS2 and SBS13). At relapse, we reported a new mutational signature associated with melphalan exposure named SBS-MM121. Similar to other chemotherapy-related mutational signatures described in other malignancies, each surviving myeloma cell exposed to melphalan will acquire a unique set of mutations detectable by bulk sequencing only if a melphalan-exposed single cell is positively selected and expands (Fig. 1a)17,23,24. As a consequence, two different MM localizations after melphalan exposure can present three different scenarios. In the first, all cancer cells in both localizations will share an identical catalogue of melphalan-related mutations, suggesting that both anatomic sites were seeded by one cancer cell surviving the exposure to melphalan (Fig. 1b). In the second each localization will have a unique catalogue of melphalan-related mutations, suggesting that cells at the two localizations pre-existed the exposure to melphalan (Fig. 1c). Finally, it is possible that myeloma cells are reintroduced with the stem cell infusion during autologous transplant, avoiding in this way any exposure to melphalan and the associated mutational signature21. Although the impact of these chemotherapy-related mutations on cancer aggressiveness at clinical relapse is not fully understood, chemotherapy-related mutational signatures represent a unique single-cell genomic barcode for clonal cells derived from a single propagating cell linked to a discrete time point in each patient′s life.Fig. 1 The development of chemotherapy-related mutational signatures.\na A schema summarizing the single cell expansion model. In this model, chemotherapy-related mutational signatures will be detectable only if one cancer cell is selected and takes the clonal dominance. (SBS = single base substitution; CCF = cancer-cell fraction). b, c Two possible scenarios for the development of chemotherapy-related mutational signatures in two different disease localizations. In (b), chemotherapy is delivered to the trunk of the phylogenetic tree prior to any branching, while in (c) chemotherapy is delivered after branching. The phylogenetic tree trunk and branch lengths represent the mutational load.\n\n\n\nHere, to investigate the spatial and temporal systemic dissemination of MM at clinical relapse, we interrogated 25 samples collected at warm autopsy from four patients with relapsed/refractory MM by whole-genome sequencing (WGS). Leveraging the chemotherapy-related mutational signatures caused by melphalan and platinum-based chemotherapy, we show that disease seeding is accelerated at clinical relapse and appears to be driven by a single myeloma propagating cell that survives after high-dose melphalan therapy followed by autologous stem cell transplant.\n\nResults\nPhylogenetic trees and disease seeding\nTo investigate the spatial and temporal systemic dissemination of MM, we investigated the WGS profile of twenty-one tumor and four non-tumor samples collected from four patients (Fig. 2; Supplementary Tables 1–2). Normal samples were taken from uninvolved skeleton muscle. All patients consented to autopsy and sample collection as a part of the Last Wish Program at Memorial Sloan Kettering Cancer Center (MSKCC)25. An additional cohort of 125 published whole exomes collected from different disease localization in 51 patients was included (Supplementary Tables 3–4)13. To define the key evolutionary trajectories and drivers involved in MM systemic seeding, we reconstructed the clonal and subclonal composition of each patient included in the WGS and whole-exome sequencing (WXS) cohorts using the Dirichlet process (DP) (see Genomic analysis and Validation set paragraphs, the “Methods” section). Mutations shared as clonal by all samples from the same individual composed the trunk of the phylogenetic tree. Different late clonal or subclonal clusters could have arisen either directly from the trunk of the phylogenetic tree or from one of its branches. To define the evolutionary history of each patient's tumor, we reconstructed the most likely phylogenetic tree solution for each patient and defined the main evolutionary trajectories drawing a line from the tip of each branch, via any larger branches and down through the trunk, following the pigeonhole principle (Fig. 3 and Supplementary Figs. 1–2)21,26. A median of 10,938 (range 6977–13,239) mutations were detected by WGS. The trunk of the two longer-surviving myeloma patients in the WGS cohort accounted for 80.5 and 69% of all mutations. In contrast, the trunk was shorter and comprised of far fewer mutations for the two patients with shorter survival (34 and 22% of total mutational burden). This difference may be partially explained by the number of samples from each patient, but also by the major subclonal diversification observed in the patients with a short survival. Interestingly, each disease site in the WGS cohort showed a unique set of genomic drivers and aberrations, reflecting distinct evolutionary trajectories and (sub)clonal selection and expansion (Figs. 3 and 4; Supplementary Data 1). The majority of these aberrations were single and complex structural variants (SVs) and copy number aberrations (CNAs), confirming their critical importance in MM progression and evolution14,27,28. In line with previous observations, chromothripsis and templated insertion events were often observed in the trunk, while chromoplexy tended to occur in the branches (Figs. 3 and 4)14. All patients had at least one clone with a mutation involving the RAS pathway. In contrast to newly diagnosed MM, mutations in known driver genes20 were rarely identified in the branches of the phylogenetic tree.Fig. 2 Patient cohort and samples.\na Anatomical sites that were biopsied in each patient. L = left. b Summary of the treatment history of each patient. After the front-line therapy, only agents new to each patient were reported. Red, blue, and green vertical arrows represent the time at which patients were exposed to high-dose melphalan and autologous transplant, radiotherapy and platinum-based chemotherapy, respectively. For I-H-130718, the second high-dose melphalan exposure was an allogeneic stem cell transplant which is annotated with a red asterisk. (PACE = cisplatin, doxorubicin, cyclophosphamide and etoposide; SCT = stem cell transplant).\n\nFig. 3 Tumor phylogenies.\nPhylogenetic trees generated from the Dirichlet process analysis were drawn such that the trunk and branch lengths were proportional to the (sub)clone mutational load, a I-H-106917, b I-H-130718, c I-H-130719 and d I-H- 130720. All main drivers (CNA, copy number aberrations; SNV, single nucleotide variants and SV, structural variants) were annotated according to their chronological occurrence and colored according to the type of event. Known driver SNVs were annotated in green, single SVs and CNAs in black (HRD = hyperdiploid), translocations associated with copy number changes in dark red, chromothripsis in blue, other complex events in dark yellow, (TI = templated insertion). Lines from different subclone branches are separated by hooks. Patients with short survival are positioned on the right (I-H-130718 and I-H-130720). L = left.\n\nFig. 4 Genome plot and mutational signature landscape of all four patients included in this study.\nThe plots in the top row (a–d) show all the genomic events and mutational signatures shared by all samples in each patient (i.e., events in the trunk of the phylogenetic tree). The plots on the bottom row (e–h) show the events and mutational signatures not shared by all samples in each patient (i.e., events in the branches of the phylogenetic tree). Copy number aberrations are annotated in the periphery of the circos plots (blue = gain; red = loss of heterozygosity). Structural variants are reported within the circle (black = translocations; blue = inversions; green = tandem-duplications; red = deletions). The asterisks in the barplots reflect the presence of transcriptional strand bias for SBS-MM1 (melphalan-associated signature). Samples I-H-130718 and I-H-130720 were taken from the patients with short survival. Confidence interval of each mutational signature was generated by drawing 1000 mutational profiles from the multinomial distribution, each time repeating the signature fitting procedure, and finally taking the 2.5th and 97.5th percentile for each signature.\n\n\n\nComparing the phylogenetic tree structure and subclonal diversification of the WGS and WXS cohorts, we observed a higher number of evolutionary trajectories in the former. This could be explained by the larger number of specimens from each patient in the WGS series (Supplementary Fig. 3a), reflecting the high spatial heterogeneity of MM detectable in all patients included in this study. Across both series we observed a median of 57-nonsynonymous SNVs per patient (range 21–464). Interestingly, patients with relapsed disease showed a higher number of nonsynonymous SNVs compared with baseline (both WGS and WXS) (Supplementary Fig. 3b). This higher frequency was independent of the number of subclones and the coverage (which was corrected for sample ploidy and purity) (Supplementary Fig. 3c).\n\nMutational signatures landscape\nThe mutational signature profile of each sample was defined using our recently published workflow18. First, we performed de novo extraction of mutational signatures running SigProfiler (Supplementary Fig. 4; Supplementary Table 5)17. In addition to the eight known MM mutational signatures18,20,21, we extracted a new signature similar to the recently reported SBS35. This signature has been shown to be associated with exposure to platinum-based chemotherapy17,23,24,29, a drug class often included in intensive MM chemotherapy regimens. To confirm the presence of each extracted mutational signature and to estimate their contribution to the overall mutational profile, we ran our recently developed fitting algorithm (mmsig; Fig. 4). In the WGS cohort, SBS-MM1 and its characteristic transcriptional strand bias were observed all patients, consistent with our prior report27. As expected SBS35 was identified only in the two patients who received a platinum-based treatment (I-H-130718 and I-H-130720). In the WXS cohort, SBS35 and SBS-MM1 were observed only when examining mutations acquired or selected after treatment (Fig. 4 and Supplementary Fig. 5). These data suggest that, similarly to other cancers, the mutational landscape of clinically relapsed MM is heavily shaped by exposure to distinct chemotherapeutic agents, such as melphalan or platinum.\n\nTo investigate the impact of these chemotherapy-related mutations on the MM genomic profile, we combined the WGS and WXS cohorts and estimated the contribution of both SBS35 and SBS-MM1 among nonsynonymous SNVs24. Interestingly, 25.7% (CI 95% 20–32%) of all nonsynonymous mutations at clinical relapse were caused by one of these two mutational processes, suggesting that chemotherapy exposure might play a role in increasing genomic complexity, which has been associated with clinically aggressive disease at relapse (Fig. 5).Fig. 5 The mutational signature landscape of nonsynonymous mutations in MM.\nContribution of each MM mutational signature among nonsynonymous (nonsyn) mutations at diagnosis (a) and relapse (b). (SBS-MM1 = melphalan-associated signature; SBS35 = platinum-based chemotherapy associated signature). The asterisk reflects the presence of transcriptional strand bias for SBS-MM1. Confidence interval of each mutational signature was generated by drawing 1000 mutational profiles from the multinomial distribution, each time repeating the signature fitting procedure, and finally taking the 2.5th and 97.5th percentile for each signature.\n\n\n\nTo reconstruct the timeline of mutational processes for each patient, we ran mmsig on each DP cluster of mutations (Fig. 6a). In line with AID activity early in disease development, SBS9 was detected mostly in the trunk of the phylogenetic trees, while APOBEC activity was detected in both clonal and subclonal clusters4,8,20,21. SBS35 was only detected in the branches of the two patients who relapsed post-platinum-based therapy. SBS-MM1 showed a heterogenous landscape. In I-H-106917, SBS-MM1 was detected in the trunk and in all first level branches, but not in the second and third level ones (Fig. 6b). This profile is consistent with a melphalan signature common to all cells, with another subset of melphalan-induced mutations accrued from a second exposure. In I-H-130719, all SBS-MM1-associated mutations were assigned to the trunk, consistent with exposure to high-dose melphalan therapy followed by autologous stem cell transplant received as part of the administered front-line therapy. I-H-130718 was one of the two cases with short survival and platinum exposure. SBS-MM1 was detected in the trunk and in all the latest branches, reflecting the front-line high-dose melphalan therapy followed by autologous stem cell transplant as well as the allogeneic stem-cell transplant with melphalan-containing conditioning being used at clinical relapse (Fig. 6c). In these three patients, SBS-MM1 was detected in the trunk, consistent with the expansion and the clonal dominance of a single cell surviving the melphalan-exposure. In fact, the large number of SBS-MM1-related mutations shared by all different sites can only be explained by the existence of a recent common ancestor selected after high-dose melphalan therapy followed by autologous stem cell transplant (Fig. 1a–b). These data also show that in these three patients, differences between anatomic sites were not associated with pre-existing undetectable subclones, but by the dissemination from a single MM propagating cell that had survived high-dose melphalan therapy followed by autologous stem cell transplant. This model is also supported by positron emission tomography/computed tomography (PET/CT) imaging data available from serial relapses; demonstrating that the majority of end-stage lesions were not detectable until the last progression event before death and subsequent postmortem examination (Fig. 7; Supplementary Data 2).Fig. 6 Timeline of mutational signatures.\na Mutational signature contribution for each phylogenetic tree cluster for each sample. Asterisks indicate the presence of transcriptional strand bias for SBS-MM1. Red and green dashed arrows represent exposure to melphalan and platinum-based therapies, respectively. L = left; R = right. B-cc) A schema summarizing the relationship between chemotherapy, subclonal selection and seeding in (b) I-H-106917 and (c) I-H-130718. (HDM = high-dose melphalan, PACE = cisplatin, doxorubicin, cyclophosphamide and etoposide, SBS = single base substitution). Red and green dashed lines in (b) and (c) represent exposure to melphalan and platinum-based therapies, respectively.\n\nFig. 7 Tracking of biopsied lesions through the disease course by FDG-PET/CT.\nBiopsy sites and FDG-PET/CT correlates on Maximum Intensity Projection images for each patient arranged by the number of months following diagnosis (m = months). All included scans show phases of active disease. Biopsy sites were only annotated on FDG-PET/CT if identified on Radiologist review. L = left.\n\n\n\nIn I-H-130718, the time lag between the first and the second round of high-dose melphalan therapy was 25 months (Fig. 2b). In this short time window, we show that a single MM propagating cell survived exposure to high-dose melphalan and its subsequent dissemination drove relapse (Figs. 5 and 6). Then, the exposure of cells at these diverse sites when treated with both a platinum-containing regimen and high-dose melphalan, increased their mutational burden (Figs. 4a,e and 6c). The systemic seeding in I-H-130720 did not fit in the above described single-cell expansion model, having detectable SBS-MM1 only in two out of five branches (Fig. 6a). This distribution, together with the short survival and relapsed/refractory disease might reflect either the absence of a single cell expansion post-melphalan in some pre-existing disease localizations or the engraftment of clones re-infused with the autologous stem cell transplant21.The presence of unique chemotherapy and non- chemotherapy related mutations in all I-H-130720 branches is in contrast with the absence of single cell expansion (Figs. 3 and 6). The similar mutational burden of chemotherapy-related signatures across different branches in both I-H-130718 and I-H-130720 is in line with the synchronous exposure of these surviving cells to the same genotoxic agent (Fig. 6a).\n\nOverall, these data suggest that a single cell has the potential to drive disease progression, and that systemic seeding of a single clonal cell can occur rapidly at relapse. To further investigate this hypothesis and to explore potential differences between pre- and post-treatment disease seeding, we quantified the differential contribution of mutational signatures associated with aging (SBS1 and SBS5, described as clock-like) between the branches and the trunk17,30,31. The SBS5 profile has significant overlap with both SBS-MM1 and SBS35, and this can lead to the incorrect assignment of signatures, one of the major issues in mutational signature analysis18. To avoid this, we focused on the ratio of SBS1 between branches and the trunk in each patient included in the WGS and the WXS cohorts. The ratio for each patient was corrected for the number of evolutionary trajectories, avoiding the pooling of mutations that were acquired in parallel. Interestingly, the SBS1 ratios were significantly higher in the treatment-naive patients compared to those observed in the relapsed WXS and WGS cases (Fig. 8a and Supplementary Fig. 6), consistent with a subclonal diversification having occurred over a long period of time. These findings support the model in which MM seeding can be accelerated following high-dose treatment in comparison to that seen during spontaneous evolution. This acceleration and rapid development of myeloma lesions at relapse is supported by the PET/CT imaging data collected over time, where the majority of the investigated lesions occurred within a short time window (Fig. 7).Fig. 8 Early versus late divergence of disease sites.\na SBS1 is a mutational signature reflective of biological cell aging. By estimating changes in SBS1 in the trunk and the branches, we were able to study the speed of the tumor evolution in a given site at a given time-point. Here, we show the difference in SBS1 branch:trunk ratio between newly diagnosed and relapsed multiple myeloma (p-value estimated using Wilcoxon tests). A lower SBS1 branch:trunk ratio represents a highly accelerated evolution since divergence from the trunk (the most recent common ancestor). Boxplots show the median and interquartile range; observations outside this interval are shown as dots. b A schema summarizing the seeding patterns over time, starting as slow seeding and tumor growth during the precursor phase, with acceleration in advanced disease.\n\n\n\nDiscussion\nIn this study, we used multiple concurrent samples obtained from several rarely biopsied anatomical sites, obtained by warm autopsy in patients with relapsed/refractory MM. This unique sample source and study design allowed us to interrogate the spatio-temporal genomic heterogeneity of MM at the time of aggressive relapse in a set of patients previously exposed to high-dose melphalan. Investigating the mutational signature landscape, we showed the strong mutagenic activity of melphalan and platinum-based agents on the MM propagating cell and its contribution to the post relapse genomic landscape. While these mutations tend to occur in the late-replicating and non-coding parts of the genome21, we provide evidence that exposure to chemotherapy is responsible for a considerable proportion (>20%) of the nonsynonymous mutations acquired at clinical relapse. Future larger studies in the post-autologous stem cell transplantation setting will examine the impact of these mutations on evolutionary trajectories, disease aggressiveness, late toxicities, and subsequent survival.\n\nWe demonstrate that MM seeding is promoted by an evolutionary process in which distinct clones harboring distinct drivers are selected and expanded at varying anatomic sites. Using chemotherapy-related mutational signatures as a genomic barcode, we demonstrate that this complex process can be driven by a single surviving cell, potentially able to disseminate throughout the entire body. Linking these mutational signatures with the documented timing of chemotherapy exposure, we showed that, at clinical relapse, systemic seeding of MM can occur in a very short time window. Importantly, the patterns we demonstrate at relapse are strikingly different to the spatio-temporal patterns of evolution and selection that have been demonstrated during spontaneous evolution prior to the time of initial diagnosis and exposure to therapy. In fact, at diagnosis, different anatomic disease sites are characterized by high burden of clock-like mutation (i.e., SBS1)17,21,30, consistent with an early divergence from the most common recent ancestor followed by slow growth (Fig. 8a). The accelerated anatomic dissemination we describe at relapse is similar to the metastatic seeding recently reported in different solid cancers31,32. This process is likely the result of a combination of two factors: (1) the selection of a more aggressive/proliferative clones, and (2) treatment-related immunosuppression. While the first factor is often unpredictable and undetectable with the current bulk sequencing technologies, the second factor represents a rational approach to improve treatment efficacy. Indeed, strategies encouraging immune reconstitution may prevent this acceleration and reduce the incidence of clinical relapse.\n\nThese data highlight the importance of considering the complex spatial and temporal heterogeneity of MM in the evaluation of treatment-response and in minimal residual disease assessment and provide a strong rationale for comprehensive characterization of the MM genomic complexity to enhance clinical decision making.\n\nMethods\nPatient characteristics\nTwenty-one tumor and four non-tumor samples were collected from four patients enrolled in the Last Wish Program at MSKCC (Fig. 2a; Supplementary Table 1)25. The Last Wish Program is an ongoing research biospecimen protocol (protocol #15-021, approved by the Institutional Review Board of MSKCC) which permits the postmortem collection of tissue and other samples from deceased patients, from whom consent for the protocol was obtained antemortem. The protocol allows for the performance of a broad range of research studies using the collected samples. All patients were treated with multiple lines of therapy (median 6, ranges 5–8) including combinations of novel agents. All patients had previously received at least one round of high-dose melphalan therapy followed by autologous stem cell transplant (Fig. 2b). Two patients had an overall survival longer than 7 years (I-H-106917 and I-H-130719); in contrast, the other two died within 3 years of diagnosis (I-H-130718 and I-H-130720) (Fig. 2b).\n\nAll available 18F-fluorodeoxyglucose (FDG) PET/CT imaging studies for each patient were reviewed by a dual Diagnostic Radiology and Nuclear Medicine board certified radiologist with 15 years of FDG PET/CT experience (G.A.U.). Maximum intensity projection images of FDG-PET/CT studies and maximum standardized uptake values (SUVmax) of reference lesions were obtained using PET VCAR (GE Healthcare).\n\nSequencing and genomic analysis\nEach tumor sample was collected from a different disease localization site (Fig. 2a) and DNA was extracted from CD138+ purified cells. To avoid contamination related to late systemic disease dissemination, cells collected from skeletal muscles were used as matched normal controls. All normal samples were histologically reviewed to exclude microscopic foci of tumor. Tumor biopsies collected were commonly very cellular and only those with >70% cellularity based on histologic review were selected for DNA extraction. After PicoGreen quantification and quality control by Agilent BioAnalyzer, 500 ng of genomic DNA were sheared using a LE220-plus Focused-ultrasonicator (Covaris catalog # 500569) and sequencing libraries were prepared using the KAPA Hyper Prep Kit (Kapa Biosystems KK8504) with modifications. In brief, libraries were subjected to a 0.5X size select using aMPure XP beads (Beckman Coulter catalog # A63882) after post-ligation cleanup. Libraries not amplified by PCR (07652_C) were pooled equivolume and were quantitated based on their initial sequencing performance. Libraries amplified with 5 cycles of PCR (07652_D, 07652_F, 07652_G) were pooled equimolar. Samples were run on a NovaSeq 6000 in a 150 bp/150 bp paired end run, using the NovaSeq 6000 SBS v1 Kit and an S4 flow cell (Illumina).\n\nThe median coverage for tumor and normal samples was 92.1X and 58.8X respectively (Supplementary Table 2). All bioinformatics analyses were performed using our in-house pipeline Isabl (Medina et al., in preparation). In brief, FASTQ files were aligned to the GRCh37 reference genome using BWA-MEM, and de-duplicated aligned BAM files were analyzed using the following published tools: (1) Battenberg for clonal and subclonal CNAs33; (2) BRASS for SVs34; (3) CaVEMan and Pindel for SNVs and small indels35,36. The clonal composition and phylogenic tree of each MM patient was reconstructed by running the DP8,33. Only clusters with more than 50 mutations were considered (as recently described)8,14. In the only patient that underwent allogeneic stem cell transplant (I-H-130718), all samples had a subclonal DP cluster of 1594 mutations with a median cancer cell fraction <10%, reflecting the unique donor single-nucleotide polymorphism (SNP) profile. These mutations were not included in any subsequent analysis.\n\nThree main classes of complex SVs were observed in MM: chromothripsis, templated insertion and chromoplexy and defined according to the most recent criteria14,27,37,38.\n\nMutational signatures\nMutational signature analysis was performed applying our recently published workflow, based on three main steps: de novo extraction, assignment and fitting18. For the first step, we ran SigProfiler17 combining our multi-spatial WGS cohort with a recently published cohort of 52 WGS patients9,14,21,39. Then all extracted signatures were assigned to the latest COSMIC reference (https://cancer.sanger.ac.uk/cosmic/signatures/SBS/) in order to define which known mutational processes were active in our cohort. Finally, we applied our recently developed fitting algorithm (mmsig) to confirm the presence and estimate the contribution of each mutational signature in each sample21. Confidence intervals were generated by drawing 1000 mutational profiles from the multinomial distribution, each time repeating the signature fitting procedure, and finally taking the 2.5th and 97.5th percentile for each signature. Mutational signature transcriptional strand bias analysis was performed using SigProfiler and integrated into mmsig. The source code of mmsig is available on GitHub: https://github.com/evenrus/mmsig.\n\nValidation set\nWe imported recently published WXS data obtained from multiple samples (N = 125) collected from different anatomic loci from both newly diagnosed and relapsed MM patients (EGAS00001002111, n = 51)13. In 40 patients, multiple samples were collected at diagnosis from different sites; in the other 11 patients, at least one sample was collected at relapse after intensive treatment, such as platinum-containing regimens and high-dose melphalan with autologous stem cell transplant (Supplementary Tables 3–4). In total, 125 tumor and 51 normal WXS data were included in this study. FASTQ files were aligned to the reference genome using BWA-MEM. BAM files were analyzed for SNV and indels using CaVEMan and Pindel, similarly to the WGS cohort35,36. The CNA profile of each sample was estimated using Facets40. The clonal and subclonal architecture of each patient was reconstructed using the DP for 47 patients7. In four patients, the DP failed due to either low CNA quality or the low sample purity. These patients were removed from the study.\n\nData analysis and statistics\nData analysis was carried out in R version 3.6.1. Standard statistical tests are mentioned consecutively in the manuscript while more complex analyses are described above. All reported p-values are two-sided, with a significance threshold of <0.05.\n\nReporting summary\nFurther information on research design is available in the Nature Research Reporting Summary linked to this article.\n\nSupplementary information\n\nSupplementary Information\n\n \nPeer Review File\n\n \nDescription of Additional Supplementary Files\n\n \nSupplementary Data 1\n\n \nSupplementary Data 2\n\n \nReporting Summary\n\n \n\n\nPeer review information\nNature Communications thanks Ivan Borrello, Roger N Pearse and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.\n\nPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nThese authors contributed equally: Heather J. Landau, Venkata Yellapantula.\n\nThese authors jointly supervised this work: Ola Landgren, Elli Papaemmanuil, Christine Iacobuzio-Donahue, Francesco Maura.\n\nSupplementary information\nSupplementary information is available for this paper at 10.1038/s41467-020-17459-z.\n\nAcknowledgements\nThis work is supported by the Memorial Sloan Kettering Cancer Center NCI Core Grant (P30 CA 008748) and by Susan and Peter Solomon Divisional Genomics Program. FM is supported by the American Society of Hematology, the International Myeloma Foundation and The Society of Memorial Sloan Kettering Cancer Center. K.H.M. is supported by the Haematology Society of Australia and New Zealand New Investigator Scholarship and the Royal College of Pathologists of Australasia Mike and Carole Ralston Travelling Fellowship Award. G.J.M. is supported by The Leukemia Lymphoma Society. C.I.D. is supported by NCI grants R35 CA220508 and U2C CA233284 and the Kleberg Foundation. J.U.P. reports funding from NHLBI NIH Award K08HL143189 and the Parker Institute for Cancer Immunotherapy at Memorial Sloan Kettering Cancer Center.\n\nAuthor contributions\nH.L., F.M., E.P., C.I.D., and O.L. designed and supervised the study, collected and analyzed data and wrote the paper. V.Y. collected and analyzed data and wrote the paper. B.T.D., E.H.R., K.H.M., G.G., J.M.M., J.A.O., M.L., and Y.Z. analyzed data. R.K., P. Blaney., M.A., A.M.M., L.Z., M.P., E.B., C.A., Y.Z.H.A., A.D., D.C., S.G., O.B.L., J.U.P., M.S., G.S., H.H., M.L.H., A.M.L., S.L., N.S.K., S.M., E.S., U.S., P. Baez, F.V.R., G.A.U., and G.J.M. collected the data.\n\nData availability\nSequence data that support the findings of this study have been deposited in European Genome-phenome archive under the Accession codes EGAS00001002111 and EGAS00001004404\n\nCompeting interests\nJ.U.P. reports research funding, intellectual property fees, and travel reimbursement from Seres Therapeutics and consulting fees from DaVolterra. M.S. has served as a paid consultant for McKinsey & Company, Angiocrine Bioscience, Inc., and Omeros Corporation. He has received research funding from Angiocrine Bioscience, Inc. He has served on an ad hoc advisory board for Kite – A Gilead Company. H.J.L. has received research support for clinical trials from Takeda. She served on the advisory boards of Takeda, Celgene, Janssen, Sanofi, Caelum Biosciences and has been a consultant for Karyopharm and Pfizer. Other authors declare no competing interests.\n==== Refs\nReferences\n1. 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Bolli N Heterogeneity of genomic evolution and mutational profiles in multiple myeloma Nat. Commun. 2014 5 2997 10.1038/ncomms3997 24429703 \n8. Bolli N Genomic patterns of progression in smoldering multiple myeloma Nat. Commun. 2018 9 3363 10.1038/s41467-018-05058-y 30135448 \n9. Lohr JG Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy Cancer Cell 2014 25 91 101 10.1016/j.ccr.2013.12.015 24434212 \n10. Walker BA Intraclonal heterogeneity is a critical early event in the development of myeloma and precedes the development of clinical symptoms Leukemia 2014 28 384 390 10.1038/leu.2013.199 23817176 \n11. Bustoros, M. et al. Genomic profiling of smoldering multiple myeloma identifies patients at a high risk of disease progression. J. Clin. Oncol. 10.1200/JCO.20.00437 (2020).\n12. Misund K MYC dysregulation in the progression of multiple myeloma Leukemia 2020 34 322 326 10.1038/s41375-019-0543-4 31439946 \n13. Rasche L Spatial genomic heterogeneity in multiple myeloma revealed by multi-region sequencing Nat. Commun. 2017 8 268 10.1038/s41467-017-00296-y 28814763 \n14. Maura F Genomic landscape and chronological reconstruction of driver events in multiple myeloma Nat. Commun. 2019 10 3835 10.1038/s41467-019-11680-1 31444325 \n15. Jones JR Clonal evolution in myeloma: the impact of maintenance lenalidomide and depth of response on the genetics and sub-clonal structure of relapsed disease in uniformly treated newly diagnosed patients Haematologica 2019 104 1440 1450 10.3324/haematol.2018.202200 30733268 \n16. Alexandrov LB Signatures of mutational processes in human cancer Nature 2013 500 415 421 10.1038/nature12477 23945592 \n17. Alexandrov LB The repertoire of mutational signatures in human cancer Nature 2020 578 94 101 10.1038/s41586-020-1943-3 32025018 \n18. Maura F A practical guide for mutational signature analysis in hematological malignancies Nat. 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"title": "Accelerated single cell seeding in relapsed multiple myeloma.",
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"abstract": "In immunosuppressed hosts, the development of multidrug resistance complicates the treatment of cytomegalovirus (CMV) infection. Improved genotypic detection of impending drug resistance may follow from recent technical advances. A severely T-cell-depleted patient with chronic lymphocytic leukemia developed CMV pneumonia and high plasma viral loads that were poorly responsive to antiviral therapy. Serial plasma specimens were analyzed for mutant viral populations by conventional and high-throughput deep-sequencing methods. Uncharacterized mutations were phenotyped for drug resistance using recombinant viruses. Conventional genotyping detected viruses with the UL97 kinase substitution C607Y after ganciclovir treatment, a transient subpopulation of UL54 polymerase L773V mutants first detected 8 weeks after foscarnet was started, and a subpopulation of a mutant with deletion of UL54 codons 981 and 982 2 months after the addition of cidofovir. Deep sequencing of the same serial specimens revealed the same UL54 mutants sooner, along with a more complex evolution of known and newly recognized mutant subpopulations missed by conventional sequencing. The UL54 exonuclease substitutions D413N, K513R, and C539G were newly shown to confer ganciclovir-cidofovir resistance, while L773V was shown to confer foscarnet resistance and add to the ganciclovir resistance conferred by UL97 C607Y. Increased sequencing depth provided a more timely and detailed diagnosis of mutant viral subpopulations that evolved with changing anti-CMV therapy.",
"affiliations": "Division of Infectious Diseases, Oregon Health Science University, Portland, Oregon, USA Department of Veterans Affairs Medical Center, Portland, Oregon, USA chous@ohsu.edu.;Department of Veterans Affairs Medical Center, Portland, Oregon, USA.;Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.;Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.;Division of Infectious Diseases, Oregon Health Science University, Portland, Oregon, USA.;Department of Pathology, Stanford University School of Medicine, Stanford, California, USA Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford, California, USA.",
"authors": "Chou|Sunwen|S|;Ercolani|Ronald J|RJ|;Sahoo|Malaya K|MK|;Lefterova|Martina I|MI|;Strasfeld|Lynne M|LM|;Pinsky|Benjamin A|BA|",
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"pmid": "24890586",
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"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013486:Research Support, U.S. Gov't, Non-P.H.S.",
"references": "23650173;17942550;11981729;10364600;15010424;24806159;24273181;24189264;15980340;20463084;23896556;20930070;12637079;9527804;23985916;24086142;21295516",
"title": "Improved detection of emerging drug-resistant mutant cytomegalovirus subpopulations by deep sequencing.",
"title_normalized": "improved detection of emerging drug resistant mutant cytomegalovirus subpopulations by deep sequencing"
} | [
{
"companynumb": "US-GILEAD-2015-0136921",
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"abstract": "Digital ulcers are one of the earliest and most disabling manifestations of systemic sclerosis (SSc). We report the clinical case of a female patient with SSc and severe digital ulcers, recurrent and refractory to the classic treatments to whom it was prescribed off-label macitentan with complete resolution of the condition.",
"affiliations": "Internal Medicine Service, Coimbra Hospital and University Centre, Coimbra, Portugal.;Internal Medicine Service, Coimbra Hospital and University Centre, Coimbra, Portugal.",
"authors": "Gonçalves|Tatiana|T|;Santos|Lèlita|L|",
"chemical_list": "D011743:Pyrimidines; D013449:Sulfonamides; C533860:macitentan",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-228295",
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"issue": "12(8)",
"journal": "BMJ case reports",
"keywords": "connective tissue disease; musculoskeletal and joint disorders; musculoskeletal syndromes; skin; therapeutic indications",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D005260:Female; D005385:Fingers; D006801:Humans; D011743:Pyrimidines; D012595:Scleroderma, Systemic; D012883:Skin Ulcer; D013449:Sulfonamides",
"nlm_unique_id": "101526291",
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"pmid": "31409620",
"pubdate": "2019-08-12",
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"references": "24268960;20400463;27163986;28049880;27994906;24931950;20805294;24092682;27867974",
"title": "Macitentan in the treatment of severe digital ulcers.",
"title_normalized": "macitentan in the treatment of severe digital ulcers"
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"activesubstancename": "BOSENTAN"
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{
"abstract": "Hypogonadotropic hypogonadism is a rare congenital disorder characterised by the deficiency and the absence of puberty and infertility. It is caused by the deficient production, secretion or action of gonadotropin-releasing hormone, which is the master hormone regulating the reproductive axis. Gonadotropin-releasing hormone or gonadotropin injections and testosterone replacement therapy are required in the treatment of this disorder. Psychiatric symptoms and disorders may be seen with the use of anabolic androgenic steroids. In this case report, we present a case report in which a patient had behavioural symptoms in childhood and develops bipolar disorder after testosterone replacement therapy. This patient was reached to the remission by increasing the doses of psychiatric drugs without interfering with hormonal therapy. It should be considered that patients receiving testosterone replacement therapy may develop bipolar disorder or trigger mood changes in bipolar mood disease, so behavioural and mood state changes should be closely followed in patients who have bipolar mood disease.",
"affiliations": "Department of Psychiatry, School of Medicine, Gaziantep University, Gaziantep, Turkey.;Department of Endocrinology and Metabolism, School of Medicine, Gaziantep University, Gaziantep, Turkey.",
"authors": "Elboga|Gulcin|G|http://orcid.org/0000-0003-3903-1835;Sayiner|Zeynel Abidin|ZA|http://orcid.org/0000-0001-5105-0292",
"chemical_list": "D018692:Antimanic Agents; D014150:Antipsychotic Agents; D006063:Chorionic Gonadotropin; D013739:Testosterone; D014635:Valproic Acid; D018967:Risperidone",
"country": "England",
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"doi": "10.1136/bcr-2018-225108",
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"journal": "BMJ case reports",
"keywords": "bipolar I iisorder; psychiatry (drugs and medicines); unwanted effects / adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D018692:Antimanic Agents; D014150:Antipsychotic Agents; D001714:Bipolar Disorder; D006063:Chorionic Gonadotropin; D020249:Hormone Replacement Therapy; D006801:Humans; D007006:Hypogonadism; D008297:Male; D018967:Risperidone; D013739:Testosterone; D014635:Valproic Acid",
"nlm_unique_id": "101526291",
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"pmid": "30076163",
"pubdate": "2018-08-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "26347657;20689266;26074746;26790381;9501764;26194704;26945370;27692845;26924592",
"title": "Rare cause of manic period trigger in bipolar mood disorder: testosterone replacement.",
"title_normalized": "rare cause of manic period trigger in bipolar mood disorder testosterone replacement"
} | [
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"companynumb": "TR-MYLANLABS-2018M1064844",
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"activesubstancename": "GONADOTROPHIN, CHORIONIC"
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"abstract": "Two cases of High Anion Gap Metabolic Acidosis (HAGMA) due to pyroglutamic acid (5-oxoproline) are described. In both cases the HAGMA developed during an episode of hospital treatment, in conjunction with paracetamol and antibiotic prescription, and the surviving patient made an uneventful recovery after the drugs were withdrawn. Clinicians need to be aware of this cause for metabolic acidosis because it may be a more common metabolic disturbance in compromised patients than would be expected, and the discontinuation of drugs implicated in the aetiology is therapeutic.",
"affiliations": "Department of Anaesthetics, Derriford Hospital, Plymouth, UK.",
"authors": "Brooker|G|G|;Jeffery|J|J|;Nataraj|T|T|;Sair|M|M|;Ayling|R|R|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D000900:Anti-Bacterial Agents; D000082:Acetaminophen; D011761:Pyrrolidonecarboxylic Acid",
"country": "England",
"delete": false,
"doi": "10.1258/000456307780945769",
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"issn_linking": "0004-5632",
"issue": "44(Pt 4)",
"journal": "Annals of clinical biochemistry",
"keywords": null,
"medline_ta": "Ann Clin Biochem",
"mesh_terms": "D000082:Acetaminophen; D000136:Acid-Base Equilibrium; D000138:Acidosis; D000369:Aged, 80 and over; D018712:Analgesics, Non-Narcotic; D000900:Anti-Bacterial Agents; D005260:Female; D006801:Humans; D008297:Male; D044342:Malnutrition; D008875:Middle Aged; D011761:Pyrrolidonecarboxylic Acid",
"nlm_unique_id": "0324055",
"other_id": null,
"pages": "406-9",
"pmc": null,
"pmid": "17594793",
"pubdate": "2007-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "High anion gap metabolic acidosis secondary to pyroglutamic aciduria (5-oxoprolinuria): association with prescription drugs and malnutrition.",
"title_normalized": "high anion gap metabolic acidosis secondary to pyroglutamic aciduria 5 oxoprolinuria association with prescription drugs and malnutrition"
} | [
{
"companynumb": "GXKR2007GB06259",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
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"activesubstancename": "ACETAMINOPHEN"
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{
"abstract": "Children and adolescents with Tourette syndrome may suffer from comorbid psychological and behavioral difficulties, primarily Attention-Deficit Hyperactivity Disorder-related manifestations including impulsive, aggressive, and disruptive behavior, and Obsessive-Compulsive Disorder-related disturbances. Often, such additional problems represent the major cause of disability, requiring their prioritization above the tic symptomatology. Here, we present six cases of children and adolescents with treatment-resistant Tourette syndrome aged 11-17 years, whose symptoms, especially the non-tic symptoms such as aggressive behavior and obsessive symptoms, failed to respond adequately to at least two different antipsychotics and, where deemed appropriate, to a combination with a medication with a different therapeutic indication or chemical class (e.g., antidepressant or anticonvulsant). Such symptomatic manifestations were significantly reduced by the time of the subsequent control visit planned 30 days later, by using lurasidone as an add-on therapy to risperidone or aripiprazole (all p ≤ 0.009). No significant neuromotor or metabolic side effects were reported in all cases in a follow-up period ranging from 4 months to 6 months, supporting the stability of the observed clinical improvement. While still investigational, the preliminary evidence presented here gives reason to hope that lurasidone could possibly be an effective option in Tourette syndrome, warranting further investigation of its potential benefits in neurodevelopmental conditions.",
"affiliations": "Section of Psychiatry, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, 37134 Verona, Italy.;Child and Adolescent Neuropsychiatry Unit, Maternal-Child Integrated Care Department, Integrated University Hospital of Verona, 37126 Verona, Italy.;Child and Adolescent Neuropsychiatry Unit, Maternal-Child Integrated Care Department, Integrated University Hospital of Verona, 37126 Verona, Italy.",
"authors": "Colizzi|Marco|M|0000-0001-6139-1920;Bortoletto|Riccardo|R|;Zoccante|Leonardo|L|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/children8020121",
"fulltext": "\n==== Front\nChildren (Basel)\nChildren (Basel)\nchildren\nChildren\n2227-9067\nMDPI\n\n33572131\n10.3390/children8020121\nchildren-08-00121\nCommunication\nThe Effectiveness of Lurasidone Add-On for Residual Aggressive Behavior and Obsessive Symptoms in Antipsychotic-Treated Children and Adolescents with Tourette Syndrome: Preliminary Evidence from a Case Series\nhttps://orcid.org/0000-0001-6139-1920\nColizzi Marco 123*\nBortoletto Riccardo 3\nZoccante Leonardo 3\nAcra Sari A. Academic Editor\n1 Section of Psychiatry, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, 37134 Verona, Italy\n2 Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AF, UK\n3 Child and Adolescent Neuropsychiatry Unit, Maternal-Child Integrated Care Department, Integrated University Hospital of Verona, 37126 Verona, Italy; riccardo.bortoletto91@gmail.com (R.B.); leonardo.zoccante@aovr.veneto.it (L.Z.)\n* Correspondence: marco.colizzi@univr.it; Tel.: +39-045-812-6832\n09 2 2021\n2 2021\n8 2 12101 12 2020\n05 2 2021\n© 2021 by the authors.\n2021\nLicensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).\nChildren and adolescents with Tourette syndrome may suffer from comorbid psychological and behavioral difficulties, primarily Attention-Deficit Hyperactivity Disorder-related manifestations including impulsive, aggressive, and disruptive behavior, and Obsessive-Compulsive Disorder-related disturbances. Often, such additional problems represent the major cause of disability, requiring their prioritization above the tic symptomatology. Here, we present six cases of children and adolescents with treatment-resistant Tourette syndrome aged 11–17 years, whose symptoms, especially the non-tic symptoms such as aggressive behavior and obsessive symptoms, failed to respond adequately to at least two different antipsychotics and, where deemed appropriate, to a combination with a medication with a different therapeutic indication or chemical class (e.g., antidepressant or anticonvulsant). Such symptomatic manifestations were significantly reduced by the time of the subsequent control visit planned 30 days later, by using lurasidone as an add-on therapy to risperidone or aripiprazole (all p ≤ 0.009). No significant neuromotor or metabolic side effects were reported in all cases in a follow-up period ranging from 4 months to 6 months, supporting the stability of the observed clinical improvement. While still investigational, the preliminary evidence presented here gives reason to hope that lurasidone could possibly be an effective option in Tourette syndrome, warranting further investigation of its potential benefits in neurodevelopmental conditions.\n\ntreatment resistant Tourette disorder\npsychopharmacological treatment\naripiprazole\nrisperidone\ncase report\n==== Body\n1. Introduction\n\nBeyond pathognomonic motor and vocal tics, children and adolescents with Tourette syndrome (TS) suffer from comorbid psychological and behavioral difficulties, primarily Attention-Deficit Hyperactivity Disorder-related manifestations including impulsive, aggressive, and disruptive behavior, and Obsessive-Compulsive Disorder-related disturbances. Other symptoms less commonly reported are anxiety, mood swings, and personality alterations. Such additional problems often represent the major cause of disability, requiring their prioritization above the tic symptomatology [1].\n\nTS treatment can be conceptualized in three phases. First, psychosocial interventions (e.g., psychoeducation and social support) should be offered to all TS individuals and their families. Second, depending on the symptom severity and related impairment, active interventions can be pursued, including behavioral and pharmacological therapies. Antipsychotics are the most commonly used medications, followed by alpha agonists and other compounds including anticonvulsants, muscle relaxant agents, cannabis-derived formulations, and immunoglobulins. Third, when TS is refractory to both behavioral and pharmacological treatments, individuals may be eligible for neuromodulation interventions. However, such interventions can be invasive and less feasible in common clinical settings, and there is uncertainty regarding the selection of patients and target of intervention [2].\n\nMost of the evidence regarding the efficacy of antipsychotic drugs in TS comes from studies with haloperidol, pimozide, risperidone, and aripiprazole. More limited evidence also supports the use of ziprasidone, tiapride, and metoclopramide. While risperidone and aripiprazole are Food and Drug Administration (FDA)-approved medications for behavioral disturbances other than tics in children and adolescents, there is no solid evidence to establish superiority of one medication relative to another and side effects have been reported for all tested medications. Importantly, because of the phenotypic variability, no antipsychotic has proven effective for all patients with TS [3]. The last decade has seen the approval of new antipsychotic drugs, one of which is lurasidone. Unique to lurasidone is a potent antagonism at the serotonin 5-HT7 receptor, which, coupled with 5-HT1A partial agonism, could potentially be associated with additional cognitive-enhancing and antidepressant effects. In addition, lurasidone shows low affinity for the M1, H1, 5-HT2C, and α1 receptors, suggesting a low liability to cause peripheral and central anticholinergic side effects, somnolence, weight gain, and hypotension [4].\n\nEvidence indicates that antipsychotic polypharmacy (APP), i.e., the co-prescription of more than one antipsychotic medication for an individual patient, is a relatively frequent and consistent practice in adults, with a prevalence of up to 50% in clinical settings devoted to the treatment of severe psychosis [5]. While current treatment guidelines state that antipsychotic monotherapy (APM) should be preferred to APP, based on high-quality studies of the acute-phase treatment, recent evidence from a 20-year follow-up study conducted among a nationwide cohort of 62,250 psychosis patients indicates that certain APP may be superior to APM for maintenance treatment, indicating the need for a modification of categorical recommendations discouraging APP in the maintenance treatment of severe psychosis [6]. A systematic review of youth studies spanning 15 years found that APP is also common in children and adolescents, especially with Attention-Deficit Hyperactivity Disorder (ADHD) and oppositional defiant disorder (ODD), with a prevalence of APP among antipsychotic-treated youth of about 10% (6% in child studies and 12% in adolescent studies) [7]. Furthermore, APP has been shown to be used to control aggressive and disruptive behavior in acute pediatric settings, especially in the context of intellectual disability and developmental disorders [8].\n\nUsing two or more psychopharmacological medications may be more effective than monotherapy for symptom control, especially if the mechanisms of action are complementary (e.g., antipsychotic-antidepressant or antipsychotic-anticonvulsant combination) [9,10]. Instead, it may be argued that the concomitant use of two or more pharmacologically similar antipsychotics lacks scientific rationale, also exposing the patient to the risk of pharmacokinetic interactions that may have important implications for drug overdosing and adverse neuromotor or metabolic side effects, and thus raising particular concerns for youth populations [11]. Nevertheless, in the real-world clinical experience, APP may sometimes be the last or only feasible option to obtain greater therapeutic response than has been achieved with APM.\n\nWe investigated the use of lurasidone as an augmentation treatment of risperidone/aripiprazole in six consecutive cases of children and adolescents with treatment-resistant TS. The eligibility criteria included the presence of symptoms, especially non-tic symptoms such as aggressive behavior and obsessive symptoms, that failed to respond adequately to at least two different antipsychotics and, when deemed appropriate, to respond to a combination with a medication with a different therapeutic indication or chemical class (e.g., antidepressant or anticonvulsant).\n\n2. Patient Information\n\nAs expected in the context of a neurodevelopmental condition [12,13], some of the TS patients (age range, 11–17 years) presented with additional neurodevelopmental symptomatology (e.g., autistic traits, hyperactivity features or borderline cognitive functioning). However, the severity of the neuropsychiatric symptoms was not such as to fulfill the criteria set by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) for another neurodevelopmental disorder (e.g., autism spectrum disorder, ADHD, or intellectual disability). Nevertheless, the associated psychopathology certainly contributed to making the clinical presentation more complex, with significant implications for treatment response [14], as well as management, overall outcome, and quality of life of patients with such type of TS [15].\n\nAccording to clinical judgement, reasons for avoiding the administration of medications other than the ones prescribed were the following: (i) suicide risk and/or elevated aggressiveness (e.g., selective serotonin reuptake inhibitors, SSRI) and (ii) poor compliance to treatments requiring strict monitoring (e.g., clozapine or lithium). As an option, APP was extensively discussed with patients’ families in terms of potential benefits and risks, and it was agreed to proceed in the context of individual trials including close monitoring of clinical response, adverse effects, and physical health by medical examinations and blood tests. Notably, all of the patients were also receiving psychological treatment during the observation period, even though we could not formally assess the effect of such an intervention.\n\nTable 1 reports medical and family history of the patients as well as any relevant past pharmacological interventions and outcomes. Every effort was made to conduct the most accurate possible medication reconciliation, comprehensively determining the reasons for psychopharmacological treatment prescriptions (e.g., tics, aggressiveness, and obsessive symptoms); however, such process was not always possible due to the lower quality of certain medical records.\n\n3. Clinical Findings\n\nAfter failure to control aggressive behavior or obsessive symptoms with other single or combined agents, such symptomatic manifestations were regulated by the time of the subsequent control visit planned 30 days later, by using lurasidone as an add-on therapy to risperidone or aripiprazole. The following information is noteworthy: (i) Before the add-on therapy with lurasidone, children themselves and their parents considered the additional symptomatic manifestations unacceptable. (ii) In one case only, tics were sub-optimally controlled with the ongoing treatment and lurasidone add-on appeared to be less beneficial in reducing tics, while reducing aggressive behavior and obsessive symptoms. (iii) In the same case, lurasidone also improved depressive symptoms which were present in comorbidity. (iv) In another case, lurasidone was firstly tried as an add-on therapy to haloperidol, which was already in place; however, despite reducing aggressive behavior and obsessive symptoms, the combination was poorly tolerated due to reported sedation. All clinical data, including therapeutic interventions’ dosage and duration, are organized as a timeline in Table 1.\n\n4. Follow-Up and Outcomes\n\nTwo physicians independently performed the following: (a) the Clinical Global Impression (CGI) in order to assess (i) severity of illness (before lurasidone add-on, 5.83 ± 1.17 (Mean, M ± Standard Deviation, SD); after lurasidone add-on, 3.17 ± 0.75; t = 8.0, p < 0.001), (ii) global improvement, and (iii) treatment efficacy [16] (Table 2); (b) the Modified Overt Aggression Scale (MOAS) in order to assess (i) verbal aggression, (ii) aggression against property, (iii) auto-aggression, and (iv) physical aggression (weighted sum before lurasidone add-on, 12.50 ± 6.32; weighted sum after lurasidone add-on, 5.83 ± 2.64; t = 4.1, p = 0.009) [17] (Table 3); and (c) the Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS Symptom Checklist) in order to assess severity of (i) obsessions and (ii) compulsions (total score before lurasidone add-on, 22.00 ± 2.97; total score after lurasidone add-on, 15.50 ± 1.05; t = 7.1, p < 0.001) [18] (Table 4). In the rare instances of discrepant attribution, consensus was reached through discussion with a third senior clinical researcher. Symptom improvement as experienced by children’s parents was also collected from a narrative perspective. Quotes were extracted by medical records or parents’ written communications (Table 5).\n\nAt the time of writing, no significant neuromotor or metabolic side effects had been reported in all cases in a follow-up period ranging from a minimum of 4 months to 6 months, supporting the stability of the observed clinical improvement.\n\n5. Discussion\n\nLurasidone has high-affinity binding to D2 (antagonist), 5-HT2A (antagonist), 5-HT7 (antagonist), and 5-HT1A (partial agonist) receptors, and moderate affinity for noradrenergic α2C and α2A receptors, and a weak affinity for 5-HT2C receptors. It has FDA approval for use in pediatric populations, i.e., adolescent-onset schizophrenia (13–17 years) and bipolar depression (10–17 years). Evidence for its efficacy in children and adolescents with autism spectrum disorder is less conclusive, as an overall improvement in the Clinical Global Impression was not accompanied by an improvement in additional efficacy measures including irritability, hyperactivity, stereotypic behavior, inappropriate speech, lethargy/withdrawal, and obsessive-compulsive symptoms [19,20]. The available studies also support its efficacy in reducing negative symptoms, cognitive dysfunction, and depressive symptoms [4]. Furthermore, apart from a higher risk of akathisia, lurasidone has been suggested to contain metabolic and cardiovascular side effects as compared with prior second-generation antipsychotics, while keeping the risk of extrapyramidal symptoms low [4]. Our findings confirm and extend previous evidence, suggesting a good safety profile of lurasidone in the context of APP, and its effectiveness in reducing aggressive behavior and obsessive symptoms, as well as depressive symptoms in TS.\n\nIncreasing evidence-based studies are proving the benefit of APP [21]. In line with the very recent revision that a certain proportion of selected patients can benefit from APP without further negative consequences [21], despite very limited and observed outside of a clinical trial setting, evidence from our case series suggests that lurasidone add-on therapy may be well tolerated and effective in the treatment of complex forms of TS whose additional symptoms, namely aggressive behavior and obsessive symptoms, are refractory to APM or the combination of single antipsychotic medications with other classes of psychopharmacological treatments. Of course, longer follow-up evidence will be needed in order to assess long-term tolerability and efficacy of such polypharmacy. In addition, the efficacy of lurasidone monotherapy as compared with placebo in patients with TS remains to be tested. Furthermore, due to its purely clinical nature, the treatment dose was chosen based on patient’s response, thus requiring investigation of maximum exposure and dose levels in clinical trials. Finally, we cannot exclude a role of regression to the mean and placebo effects in accounting for the observed change. Thus, the nature of the present data, as well as the previous very limited and inconclusive evidence on the efficacy of lurasidone in neurodevelopmental conditions, calls for caution in the treatment of TS with lurasidone.\n\n6. Conclusions\n\nWhile still investigational, the preliminary evidence presented here gives reason to hope that lurasidone might be an effective option in TS, warranting further investigation of its potential benefits in neurodevelopmental conditions.\n\nAcknowledgments\n\nThe authors would like to acknowledge infrastructure from the Integrated University Hospital of Verona and the University of Verona.\n\nAuthor Contributions\n\nConceptualization, M.C., R.B. and L.Z.; methodology, M.C., R.B. and L.Z.; validation, M.C., R.B. and L.Z.; investigation, M.C., R.B. and L.Z.; resources, M.C., R.B. and L.Z.; data curation, M.C., R.B. and L.Z.; writing—original draft preparation, M.C. and R.B.; writing—review and editing, M.C., R.B. and L.Z.; visualization, M.C., R.B. and L.Z.; supervision, L.Z. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research received no external funding.\n\nInstitutional Review Board Statement\n\nThe study was conducted according to the guidelines of the Declaration of Helsinki, and ethical approval was not required.\n\nInformed Consent Statement\n\nPatients and their parents have agreed to this publication by written consent.\n\nData Availability Statement\n\nThe data reported in this paper are available from the medical history of the patient.\n\nConflicts of Interest\n\nM.C. has been a consultant/advisor to GW Pharma Limited, outside of this work. All the other authors declare no conflict of interest.\n\nchildren-08-00121-t001_Table 1 Table 1 Flow chart of pharmacological intervention up to lurasidone add-on therapy to risperidone or aripiprazole in six children/adolescents with Tourette syndrome.\n\nPatient\tAge\tGender\tAge of Onset\tPsychiatric Family History\tPsychiatric Comorbidity\tMedical Comorbidity\tMedication Attempted (Max Dose, Exposure Time) [Age at Time of Administration]\tTics\tAggressive Behavior\tObsessive Symptoms\t\nChild 1\t16\tMale\t11\tNo\tYes\n(autistic traits)\tYes\n(diabetes)\tAripiprazole (??)\tOptimal\tSuboptimal\tSuboptimal\t\nAripiprazole (up to 10 Mg/D, 11 months) + fluvoxamine (??, 11 months) [11 years, 7 months]\tOptimal\tSuboptimal\tSuboptimal\t\n\t\t\t\t\t\t\tAripiprazole (10 Mg/D, 11 months) [12 years, 6 months]\tOptimal\tSuboptimal\tSuboptimal\t\n\t\t\t\t\t\t\tAripiprazole (10 Mg/D, 3 months) + olanzapine (up to 7.5 Mg/D, 3 months) [13 years, 5 months]\tOptimal\tSuboptimal\tSuboptimal\t\n\t\t\t\t\t\t\tOlanzapine (10 Mg/D, 4 months) [13 years, 8 months]\tOptimal\tSuboptimal\tOptimal\t\n\t\t\t\t\t\t\tOlanzapine (10 Mg/D, 9 months) + topiramate (50 Mg/D, 9 months) [14 years]\tSuboptimal\tSuboptimal\tSuboptimal\t\n\t\t\t\t\t\t\tOlanzapine (10 Mg/D, 12 months) [14 years, 9 months]\tSuboptimal\tSuboptimal\tSuboptimal\t\n\t\t\t\t\t\t\tAripiprazole (up to 15 Mg/D, 12 months) [15 years, 9 months]\tOptimal\tSuboptimal\tSuboptimal\t\n\t\t\t\t\t\t\tAripiprazole (15 Mg/D, 1 month) + lurasidone (18.5 Mg/D, 1 month) [16 years, 9 months]\tOptimal\tOptimal\tSuboptimal\t\n\t\t\t\t\t\t\tAripiprazole (15 Mg/D, ongoing) + lurasidone (37 Mg/D, ongoing)\tOptimal\tOptimal\tOptimal\t\nChild 2\t12\tMale\t7\tYes\n(Mother line: tics, hyperactivity, learning disability, depression, anxiety; father line: OCD, depression)\tYes\n(autistic traits, hyperactivity features, borderline cognitive functioning)\tYes\n(GERD)\tRisperidone (up 0.75 Mg/D, 19 months) [6 years, 7 months]\tSuboptimal\tOptimal\tSuboptimal\t\n\t\t\t\tRisperidone (1 Mg/D, 7 months) + aripiprazole (up to 6 Mg/D, 7 months) [8 years, 2 months]\tOptimal\tSuboptimal\tSuboptimal\t\n\t\t\t\tRisperidone (1 Mg/D, 12 months) + aripiprazole (6 Mg/D, 12 months) + methylphenidate (10 Mg/D, 12 months) [8 years, 9 months]\tSuboptimal\tOptimal\tSuboptimal\t\n\t\t\t\tRisperidone (up to 4 Mg/D, 17 months) + aripiprazole (up to 15 Mg/D, 17 months) + methylphenidate (10 Mg/D, 17 months) + IVIG (15 g, 17 months) [9 years, 9 months]\tOptimal\tSuboptimal\tSuboptimal\t\n\t\t\t\tRisperidone (4 Mg/D, 4 months) + aripiprazole (15 Mg/D, 4 months) + clomipramine (up to 20 Mg/D, 4 months) + VPA (up to 600 Mg/D, 4 months) + IVIG (15 g, 4 months) [11 years, 2 months]\tOptimal\tSuboptimal\tSuboptimal\t\n\t\t\t\tRisperidone (4 Mg/D, 4 months) + aripiprazole (15 Mg/D, 4 months) + fluvoxamine (up to 100 Mg/D, 4 months) + VPA (600 Mg/D, 4 months) + IVIG (15 g, 4 months) [11 years, 6 months]\tOptimal\tSuboptimal\tSuboptimal\t\n\t\t\t\tRisperidone (4 Mg/D, 3 months) + aripiprazole (15 Mg/D, 3 months) + levomepromazine (up to 100 Mg/D, 3 months) + fluvoxamine (100 Mg/D, 3 months) + VPA (600 Mg/D, 3 months) + IVIG (15 g, 3 months) [11 years, 10 months]\tOptimal\tSuboptimal\tSuboptimal\t\n\t\t\t\tRisperidone (4 Mg/D, ongoing) + lurasidone (up to 74 Mg/D, ongoing) + VPA (to 600 Mg/D, ongoing) + IVIG (15 g, ongoing)\tOptimal\tOptimal\tOptimal\t\nChild 3\t11\tMale\t??\tNo\tYes (hyperactivity features, oppositional behavior, borderline cognitive functioning)\tNo\tAntipsychotic not better specified (??, ??)\tOptimal\tSuboptimal\tSuboptimal\t\nRisperidone (up to 5 Mg/D, at least 11 months) [10 years, 6 months]\tOptimal\tSuboptimal\tSuboptimal\t\nRisperidone (5 Mg/D, 2 months) + lurasidone (up to 74 Mg/D, 2 months) [11 years, 5 months]\tOptimal\tSuboptimal\tOptimal\t\nRisperidone (5 Mg/D, ongoing) + lurasidone (up to 148 Mg/D, ongoing)\tOptimal\tOptimal\tOptimal\t\nChild 4\t17\tMale\t??\tNo\tNo\tNo\tAripiprazole (??, ??)\tOptimal\tSuboptimal\tSuboptimal\t\n\t\t\t\t\t\t\tAripiprazole (??, ??) + ziprasidone (??, ??)\tOptimal\tSuboptimal\tSuboptimal\t\n\t\t\t\t\t\t\tAripiprazole (up to 8 Mg/D, ??) + quetiapine (up to 200 Mg/D, ??)\tOptimal\tSuboptimal\tSuboptimal\t\n\t\t\t\t\t\t\tAripiprazole (12 Mg/D, 8 months) + haloperidol (1.5 Mg/D, 8 months) [16 years, 9 months]\tOptimal\tSuboptimal\tSuboptimal\t\n\t\t\t\t\t\t\tAripiprazole (up to 24 Mg/D, 1 month) + haloperidol (up to 3 Mg/D, 1 month) + lithium sulphate PR (166 Mg/D, 1 month) [17 years, 5 months]\tOptimal\tSuboptimal\tSuboptimal\t\n\t\t\t\t\t\t\tHaloperidol (3 Mg/D, 20 days *) + lurasidone (74 Mg/D, 20 days) + lithium sulphate PR (166 Mg/D, 20 days) [17 years, 6 months]\tOptimal\tOptimal\tOptimal\t\n\t\t\t\t\t\t\tAripiprazole (up to 30 Mg/D, ongoing) + lurasidone (74 Mg/D, ongoing) + lithium sulphate PR (166 Mg/D, ongoing)\tOptimal\tOptimal\tOptimal\t\nChild 5\t12\tMale\t??\tYes (mother: depression, suicide attempt; sister: mood disorder)\tYes (low mood **)\tYes (Diabetes)\tAripiprazole (10 Mg/D, 10 months) [11 years, 1 month]\tSuboptimal\tOptimal\tSuboptimal\t\n\t\t\t\tAripiprazole (10 Mg/D, 2 months) + risperidone (4 Mg/D, 2 months) [11 years, 11 months]\tSuboptimal\tOptimal\tSuboptimal\t\n\t\t\t\tAripiprazole (10 Mg/D, ongoing) + lurasidone (37 Mg/D, ongoing)\tSuboptimal\tOptimal\tOptimal\t\nChild 6\t13\tMale\t9\tNo\tYes (hyperactivity features, borderline cognitive functioning)\tNo\tAntipsychotic not better specified (??, ??)\tOptimal\tSuboptimal\tSuboptimal\t\n\t\t\t\tRisperidone (6 Mg/D, 7 months) [11 years, 7 months]\tOptimal\tSuboptimal\tSuboptimal\t\n\t\t\t\tAripiprazole (7 Mg/D, 7 months) [12 years, 2 months]\tOptimal\tSuboptimal\tSuboptimal\t\n\t\t\t\tAripiprazole (up to 10 Mg/D, 8 months) + mirtazapine (1 Mg/D, 8 months) [12 years, 9 months]\tOptimal\tSuboptimal\tSuboptimal\t\nAripiprazole (10 Mg/D, 1 month) + lurasidone (74 Mg/D, 1 month) [13 years, 5 months]\tOptimal\tOptimal\tSuboptimal\t\nAripiprazole (10 Mg/D, ongoing) + lurasidone (111 Mg/D, ongoing)\tOptimal\tOptimal\tOptimal\t\nMg/D, milligrams per Day; OCD, obsessive compulsive disorder; GERD, gastroesophageal reflux disease; IVIG, intravenous immunoglobulin; VPA, valproic acid; ??, unknown; PR, prolonged release; * discontinued due to reported sedation; ** depressive symptoms were improved by lurasidone; Optimal, clinical impression of symptom improvement >50%; Suboptimal, clinical impression of symptom improvement <50%.\n\nchildren-08-00121-t002_Table 2 Table 2 Clinical Global Impression (CGI).\n\nPatient\tCGI-S before Lurasidone Add-On\tCGI-S after Lurasidone Add-On\tCGI-I\tCGI-E Treatment Efficacy\tCGI-E\nSide Effects\t\nChild 1\t5\t3\t2\tModerate\tDo not interfere with patient’s functioning\t\nChild 2\t6\t3\t2\tMarked\tDo not interfere with patient’s functioning\t\nChild 3\t7\t4\t2\tMarked\tNone\t\nChild 4\t6\t4\t3\tModerate\tDo not interfere with patient’s functioning\t\nChild 5\t4\t2\t2\tModerate\tNone\t\nChild 6\t7\t3\t1\tMarked\tNone\t\nCGI-S, CGI-Severity of illness; CGI-I, CGI-Global Improvement; CGI-E, CGI-Efficacy Index.\n\nchildren-08-00121-t003_Table 3 Table 3 The Modified Overt Aggression Scale (MOAS).\n\nPatient\tCurrent Treatment\tVA\tAAP\tAA\tPA\tWeighted Sum\t\nChild 1\tBefore lurasidone\t3\t0\t2\t2\t17\t\nLurasidone 18.5 Mg/D\t2\t0\t1\t1\t9\t\nLurasidone 37 Mg/D\t1\t0\t1\t1\t8\t\nChild 2\tBefore lurasidone\t1\t2\t0\t2\t13\t\nLurasidone 74 Mg/D\t0\t1\t0\t1\t6\t\nChild 3\tBefore lurasidone\t1\t0\t2\t3\t19\t\nLurasidone 111 Mg/D\t0\t0\t2\t2\t14\t\nLurasidone 148 Mg/D\t0\t0\t1\t1\t7\t\nChild 4\tBefore lurasidone\t0\t3\t0\t2\t14\t\nLurasidone 74 Mg/D\t0\t2\t0\t1\t8\t\nChild 5\tBefore lurasidone\t1\t0\t0\t0\t1\t\nLurasidone 37 Mg/D\t1\t0\t0\t0\t1\t\nChild 6\tBefore lurasidone\t3\t0\t0\t2\t11\t\nLurasidone 74 Mg/D\t1\t0\t0\t2\t9\t\nLurasidone 111 Mg/D\t1\t0\t0\t1\t5\t\nVA, verbal aggression; AAP, aggression against property; AA, auto-aggression; PA, physical aggression; Weighted Sum = (VAx1) + (AAPx2) + (AAx3) + (PAx4).\n\nchildren-08-00121-t004_Table 4 Table 4 Children’s Yale–Brown Obsessive Compulsive Scale (CY-BOCS Symptom Checklist).\n\nPatient\tLurasidone Treatment\tObsessions\tCompulsions\t\t\nTime Occupied\tInterference\tDistress\tResistance\tDegree of Control\tSub-Total\tTime Spent\tInterference\tDistress\tResistance\tDegree of Control\tSub-Total\tTotal\t\nChild 1\tBefore\tSevere\tModerate\tMild\tMild\tLittle\t10\tSevere\tSevere\tMild\tMild\tLittle\t11\tModerate (21)\t\n18.5 Mg/D\tModerate\tModerate\tMild\tMild\tModerate\t8\tModerate\tModerate\tMild\tMild\tModerate\t8\tModerate (16)\t\n37 Mg/D\tMild\tModerate\tMild\tMild\tModerate\t7\tMild\tModerate\tMild\tMild\tModerate\t7\tMild (14)\t\nChild 2\tBefore\tSevere\tSevere\tMild\tMild\tLittle\t11\tModerate\tModerate\tMild\tMild\tModerate\t8\tModerate (19)\t\n74 Mg/D\tModerate\tModerate\tMild\tMild\tModerate\t8\tMild\tModerate\tMild\tMild\tModerate\t7\tMild (15)\t\nChild 3\tBefore\tSevere\tSevere\tModerate\tModerate\tLittle\t13\tSevere\tSevere\tSevere\tModerate\tLittle\t14\tSevere (27)\t\n111 Mg/D\tModerate\tModerate\tModerate\tModerate\tModerate\t10\tModerate\tModerate\tModerate\tModerate\tModerate\t10\tModerate (20)\t\n148 Mg/D\tModerate\tModerate\tMild\tMild\tModerate\t8\tModerate\tModerate\tMild\tModerate\tModerate\t9\tModerate (17)\t\nChild 4\tBefore\tModerate\tModerate\tModerate\tMild\tModerate\t9\tSevere\tSevere\tModerate\tMild\tLittle\t12\tModerate (21)\t\n74 Mg/D\tModerate\tModerate\tMild\tMild\tModerate\t8\tModerate\tModerate\tMild\tMild\tModerate\t8\tModerate (16)\t\nChild 5\tBefore\tModerate\tModerate\tModerate\tMild\tLittle\t10\tModerate\tModerate\tModerate\tMild\tLittle\t10\tModerate (20)\t\n37 Mg/D\tModerate\tModerate\tMild\tMild\tModerate\t8\tModerate\tMild\tMild\tMild\tModerate\t7\tMild (15)\t\nChild 6\tBefore\tSevere\tSevere\tModerate\tMild\tLittle\t12\tSevere\tSevere\tModerate\tMild\tLittle\t12\tSevere (24)\t\n74 Mg/D\tSevere\tModerate\tModerate\tMild\tModerate\t10\tModerate\tModerate\tModerate\tMild\tModerate\t9\tModerate (19)\t\n111 Mg/D\tModerate\tModerate\tMild\tMild\tModerate\t8\tModerate\tModerate\tMild\tMild\tModerate\t8\tModerate (16)\t\nMg/D, milligrams per day; Time Occupied/Spent, extreme (4), severe (3), moderate (2), mild (1), none (0); Interference, extreme (4), severe (3), moderate (2), mild (1), none (0); Distress, extreme (4), severe (3), moderate (2), mild (1), none (0); Resistance, extreme (4), severe (3), moderate (2), mild (1), none (0); Degree of Control, no (4), little (3), moderate (2), much (1), complete (0); Total CY-BOCS, extreme (32–40), severe (24–31), moderate (16–23), mild (8–15), subclinical (0–7).\n\nchildren-08-00121-t005_Table 5 Table 5 Parents’ quotes.\n\nPatient\tLurasidone Add-on (dose)\tSymptom Improved\t\nChild 1\t“Since the beginning of the treatment he seems to be more cooperative and less tied to his control issues!” (18.5 Mg/D)\tAggressive behavior; Obsessive symptoms\t\n“He now shows fewer obsessive thoughts. He also appears to be more friendly with both his peers and adults.” (37 Mg/D)\t\nChild 2\t“He seems quieter at home now. Also, he’s quite less repetitive about his thoughts. He’s doing well.” (74 Mg/D)\tAggressive behavior; Obsessive symptoms\t\nChild 3\t“His behavior and compulsions at home have notably improved.” (111 Mg/D)\tObsessive symptoms\t\n“His behavior has improved at home and he is now also less worried about strangers and less prone to physically attack them.” (148 Mg/D)\tAggressive behavior\t\nChild 4\t“Fidgeting and aggression have greatly faded away since the discharge.” (74 Mg/D)\tAggressive behavior; Obsessive symptoms\t\nChild 5\t“Low mood and melancholy have softened. He is still very focused on his things, but the situation seems to be under control.” (37 Mg/D)\tObsessive symptoms\t\nChild 6\t“No more episodes of aggression have happened since the introduction of Lurasidone.” (74 Mg/D)\tAggressive behavior\t\n“He seems less absorbed in his thoughts.” (111 Mg/D)\tObsessive symptoms\t\nMg/D, Milligrams per Day.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Martino D. Ganos C. Pringsheim T.M. Tourette syndrome and chronic tic disorders: The clinical spectrum beyond tics Int. Rev. Neurobiol. 2017 134 1461 1490 28805580\n2. Martino D. Pringsheim T.M. Tourette syndrome and other chronic tic disorders: An update on clinical management Expert Rev. Neurother. 2018 18 125 137 10.1080/14737175.2018.1413938 29219631\n3. Pandey S. Dash D. Progress in pharmacological and surgical management of Tourette syndrome and other chronic tic disorders Neurologist 2019 24 93 108 10.1097/NRL.0000000000000218 31045720\n4. Corponi F. Fabbri C. Bitter I. Montgomery S. Vieta E. Kasper S. Pallanti S. Serretti A. Novel antipsychotics specificity profile: A clinically oriented review of lurasidone, brexpiprazole, cariprazine and lumateperone Eur. Neuropsychopharmacol. 2019 29 971 985 10.1016/j.euroneuro.2019.06.008 31255396\n5. Barnes T.R. Paton C. Antipsychotic polypharmacy in schizophrenia: Benefits and risks CNS Drugs 2011 25 383 399 10.2165/11587810-000000000-00000 21476610\n6. Tiihonen J. Taipale H. Mehtälä J. Vattulainen P. Correll C.U. Tanskanen A. Association of Antipsychotic Polypharmacy vs Monotherapy with Psychiatric Rehospitalization Among Adults with Schizophrenia JAMA Psychiatry 2019 76 499 507 10.1001/jamapsychiatry.2018.4320 30785608\n7. Toteja N. Gallego J.A. Saito E. Gerhard T. Winterstein A. Olfson M. Correll C.U. Prevalence and correlates of antipsychotic polypharmacy in children and adolescents receiving antipsychotic treatment Int. J. Neuropsychopharmacol. 2014 17 1095 1105 10.1017/S1461145712001320 23673334\n8. Saldaña S.N. Keeshin B.R. Wehry A.M. Blom T.J. Sorter M.T. DelBello M.P. Strawn J.R. Antipsychotic polypharmacy in children and adolescents at discharge from psychiatric hospitalization Pharmacotherapy 2014 34 836 844 10.1002/phar.1453 24990538\n9. Tohen M. Vieta E. Calabrese J. Ketter T.A. Sachs G. Bowden C. Mitchell P.B. Centorrino F. Risser R. Baker R.W. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression Arch. Gen. Psychiatry 2003 60 1079 1088 10.1001/archpsyc.60.11.1079 14609883\n10. Casey D.E. Daniel D.G. Tamminga C. Kane J.M. Tran-Johnson T. Wozniak P. Abi-Saab W. Baker J. Redden L. Greco N. Divalproex ER combined with olanzapine or risperidone for treatment of acute exacerbations of schizophrenia Neuropsychopharmacology 2009 34 1330 1338 10.1038/npp.2008.209 19052541\n11. Sohn M. Burgess M. Bazzi M. Antipsychotic polypharmacy among children and young adults in office-based or hospital outpatient department settings Pharmacy 2017 5 64 10.3390/pharmacy5040064 29168795\n12. Colizzi M. Ciceri M.L. Di Gennaro G. Morari B. Inglese A. Gandolfi M. Smania N. Zoccante L. Investigating gait, movement, and coordination in children with neurodevelopmental disorders: Is there a Role for motor abnormalities in atypical neurodevelopment? Brain Sci. 2020 10 601 10.3390/brainsci10090601\n13. Colizzi M. Sironi E. Antonini F. Ciceri M.L. Bovo C. Zoccante L. Psychosocial and behavioral impact of COVID-19 in autism spectrum disorder: An online parent survey Brain Sci. 2020 10 341 10.3390/brainsci10060341\n14. Farmer C.A. Brown N.V. Gadow K.D. Arnold L.E. Kolko D.G. Findling R.L. Molina B.S. Buchan-Page K.A. Rice R.R. Bangalore S.S. Comorbid symptomatology moderates response to risperidone, stimulant, and parent training in children with severe aggression, disruptive behavior disorder, and attention-deficit/hyperactivity disorder J. Child. Adolesc. Psychopharmacol. 2015 25 213 224 10.1089/cap.2014.0109 25885011\n15. Eapen V. Robertson M.M. Are there distinct subtypes in Tourette syndrome? Pure-Tourette syndrome versus Tourette syndrome-plus, and simple versus complex tics Neuropsychiatr. Dis Treat. 2015 11 1431 1436 10.2147/NDT.S72284 26089672\n16. Guy W. ECDEU Assessment Manual for Psychopharmacology Department of Health, Education, and Welfare Public Health Service Alcohol, Drug Abuse, and Mental Health Administration Rockville, MD, USA 1976\n17. Kay S.R. Wolkenfelf F. Murrill L.M. Profiles of aggression among psychiatric patients: I. nature and prevalence J. Nerv. Ment. Dis. 1988 176 539 546 10.1097/00005053-198809000-00007 3418327\n18. Scahill L. Riddle M.A. McSwiggin-Hardin M. Ort S.I. King R.A. Goodman W.K. Cicchetti D. Leckman J.F. Children’s Yale-Brown Obsessive Compulsive Scale: Reliability and validity J. Am. Acad. Child. Adolesc. Psychiatry 1997 36 844 852 10.1097/00004583-199706000-00023 9183141\n19. Lee E.S. Vidal C. Findling R.L. A focused review on the treatment of pediatric patients with atypical antipsychotics J. Child. Adolesc. Psychopharmacol. 2018 28 582 605 10.1089/cap.2018.0037 30312108\n20. Loebel A. Brams M. Goldman R.S. Silva R. Hernandez D. Deng L. Mankoski R. Findling R.L. Lurasidone for the treatment of irritability associated with autistic disorder J. Autism Dev. Disord. 2016 46 1153 1163 10.1007/s10803-015-2628-x 26659550\n21. Lin S.K. Antipsychotic Polypharmacy: A dirty little secret or a fashion? Int. J. Neuropsychopharmacol. 2020 23 125 131 10.1093/ijnp/pyz068 31867671\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2227-9067",
"issue": "8(2)",
"journal": "Children (Basel, Switzerland)",
"keywords": "aripiprazole; case report; psychopharmacological treatment; risperidone; treatment resistant Tourette disorder",
"medline_ta": "Children (Basel)",
"mesh_terms": null,
"nlm_unique_id": "101648936",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33572131",
"pubdate": "2021-02-09",
"publication_types": "D016428:Journal Article",
"references": "21476610;32503172;28805580;32887253;25885011;14609883;31255396;29219631;23673334;29168795;26659550;19052541;31045720;30312108;31867671;3418327;26089672;24990538;9183141;30785608",
"title": "The Effectiveness of Lurasidone Add-On for Residual Aggressive Behavior and Obsessive Symptoms in Antipsychotic-Treated Children and Adolescents with Tourette Syndrome: Preliminary Evidence from a Case Series.",
"title_normalized": "the effectiveness of lurasidone add on for residual aggressive behavior and obsessive symptoms in antipsychotic treated children and adolescents with tourette syndrome preliminary evidence from a case series"
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"abstract": "HELLP syndrome, a severe manifestation of preeclampsia characterised by haemolysis, elevated liver enzymes, and thrombocytopaenia, occurs in 0.5-0.9% of pregnancies and is associated with significant maternal and fetal morbidity and mortality. We present the case of a 30 year old primigravida (RL) who developed a wound haematoma nearly 72 h after an emergency caesarean section for failure to progress, with no prior hypertension or proteinuria documented. Although RL remained completely asymptomatic, investigations for delayed bleeding revealed severe class I HELLP syndrome with a platelet count of < 50,000 μL, significant haemolysis (haptoglobin < 0.06, LDH 1585), acute renal failure (eGFR 64, creatinine 103), fulminant hepatic failure (AST 2539, ALT 3200) and significant autoanticoagulation (INR 3.2, activated prothrombin time 46, fibrinogen 3.0). Paracetamol had been administered for post-operative analgesia and a paracetamol level was in the toxic level. Multidisciplinary input was sought from anaesthetics, intensive care, toxicology, general medicine, haematology and gastroenterology, with care subsequently coordinated in an intensive care unit. Blood pressure was strictly controlled with a sodium nitroprusside infusion. In addition to supportive care, vitamin K, a N-acetyl cysteine infusion, lactulose and mechanical thromboprophylaxis were administered. Eight weeks postpartum there were no residual biochemical abnormalities, the patient was well, and had a normal blood pressure. Our case reinforces the importance of a high level of clinical suspicion for the HELLP syndrome in women, irrespective of blood pressure in the first 48 h postpartum.",
"affiliations": "Obstetrics and Gynaecology, Monash Health, Clayton, Victoria, Australia.;Obstetrics and Gynaecology, Monash Health, Clayton, Victoria, Australia.",
"authors": "Pritchard|Natasha Louise|NL|;Keane|Jodi Leanne|JL|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.crwh.2015.08.001",
"fulltext": "\n==== Front\nCase Rep Womens HealthCase Rep Womens HealthCase Reports in Women's Health2214-9112Elsevier S2214-9112(15)30004-710.1016/j.crwh.2015.08.001ArticleWound haematoma: The first sign in a case of late postpartum HELLP syndrome☆☆☆ Pritchard Natasha Louise natasha.pritchard@monashhealth.orgnatasha.pritchard@monash.edunatashalpritchard@gmail.comab⁎Keane Jodi Leanne jodi.keane@monashhealth.orgjodi.keane@monash.eduaba Obstetrics and Gynaecology, Monash Health, Clayton, Victoria, Australiab Monash University, Clayton, Victoria, Australia⁎ Corresponding author at: 7/146 Princes Hwy, Dandenong, Victoria3175, Australia.7/146 Princes HwyDandenongVictoria3175Australia natasha.pritchard@monashhealth.orgnatasha.pritchard@monash.edunatashalpritchard@gmail.com22 8 2015 10 2015 22 8 2015 8 1 3 12 7 2015 20 7 2015 13 8 2015 © 2015 The Authors2015This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).HELLP syndrome, a severe manifestation of preeclampsia characterised by haemolysis, elevated liver enzymes, and thrombocytopaenia, occurs in 0.5–0.9% of pregnancies and is associated with significant maternal and fetal morbidity and mortality. We present the case of a 30 year old primigravida (RL) who developed a wound haematoma nearly 72 h after an emergency caesarean section for failure to progress, with no prior hypertension or proteinuria documented. Although RL remained completely asymptomatic, investigations for delayed bleeding revealed severe class I HELLP syndrome with a platelet count of < 50,000 μL, significant haemolysis (haptoglobin < 0.06, LDH 1585), acute renal failure (eGFR 64, creatinine 103), fulminant hepatic failure (AST 2539, ALT 3200) and significant autoanticoagulation (INR 3.2, activated prothrombin time 46, fibrinogen 3.0). Paracetamol had been administered for post-operative analgesia and a paracetamol level was in the toxic level.\n\nMultidisciplinary input was sought from anaesthetics, intensive care, toxicology, general medicine, haematology and gastroenterology, with care subsequently coordinated in an intensive care unit. Blood pressure was strictly controlled with a sodium nitroprusside infusion. In addition to supportive care, vitamin K, a N-acetyl cysteine infusion, lactulose and mechanical thromboprophylaxis were administered. Eight weeks postpartum there were no residual biochemical abnormalities, the patient was well, and had a normal blood pressure. Our case reinforces the importance of a high level of clinical suspicion for the HELLP syndrome in women, irrespective of blood pressure in the first 48 h postpartum.\n\nHighlights\n• A high level of clinical suspicion is necessary for HELLP syndrome even after 48 h postpartum.\n\n• Not every woman with HELLP syndrome will have symptoms.\n\n• Early diagnosis is important in HELLP syndrome to prevent complicated sequelae.\n\n\n\nKeywords\nHELLP syndromePreeclampsiaWound haematomaPostpartum\n==== Body\n1 Introduction\nPreeclampsia is a condition unique to human pregnancy underpinned by either fundamentally deficient placentation or placental dysfunction. This, via multiple pathways, leads to multiple organ system manifestations of widespread endetheliolitis/endothelial dysfunction, stereotypically identified with, but not limited to, high blood pressure (hypertension) and protein in the urine (proteinuria). 0.5–0.9% of pregnant women will develop HELLP syndrome, a severe manifestation of preeclampsia characterised by haemolysis, elevated liver enzymes, and thrombocytopaenia [1].\n\nAlthough risk factors for preeclampsia (including later maternal age, body mass index greater than 35, smoking, family history, multiple gestation and primiparity) have been identified, and the field of pre-eclampsia screening is an exciting and evolving area, there are as yet no routinely administered effective methods of detecting those who are at risk of developing this serious condition [2]. As approximately 30% of women who develop HELLP syndrome will develop it postpartum, a high level of clinical suspicion is paramount [3], [4].\n\n2 Case Report\nWe present the case of a 30 year old gravida two para one (RL) who developed a wound haematoma 72 h after an emergency caesarean section for an obstructed term spontaneous labour. RL had a history of one prior first trimester spontaneous miscarriage and no relevant medical or surgical history. Antenatal history was complicated by bothersome hyperemesis gravidarum in the first and second trimesters requiring short admissions for intravenous rehydration, and a low pre-pregnancy BMI with poor gestational weight gain but was otherwise entirely unremarkable. The patient had a booking blood pressure of 110/60, and was normotensive throughout the pregnancy. Booking and 28 week bloods were unremarkable. A pre-caesarean full blood count was haemolysed and not repeated as RL was normotensive and thrombocytopaenia not clinically suspected.\n\nRL presented in spontaneous labour at 40-weeks and 5-days gestation, and delivered a healthy 3.1 kg male by caesarean section after a labour obstructed at 6 cm. The procedure was uncomplicated, with minimal blood loss under spinal anaesthesia. The initial postpartum period was unremarkable, with blood pressures persistently below 120/80 for the first 48 h. On day three postpartum, an isolated blood pressure of 132/90 was recorded, taken with a standard sized adult cuff on a small adult arm. Later that day medical review was requested for a wound mass noticed by the patient, and a diagnosis of rapidly expanding wound haematoma was made. A full blood count was requested as the initial investigation and identified a platelet count of 52. A full pre-eclampsia screen followed, including a repeat confirmatory full blood examination and film, serum uric acid level, liver function testing, measurement of serum creatinine, urea and electrolytes, urine for spot protein creatinine ratio, and a coagulation profile (Table 1).Table 1 Serial pathology reports.a, b, c, d, e, f\n\nHours after delivery\t28/40\t72\t75\t84\t96\t108\t132\t180\t6 weeks\t\nHaemaglobin\t113\t121\t151\t103\t113\t93\t96\t84\t131\t\nWhite cell count\t10.1\t13.4\t9.8\t13.7\t12.1\t8.9\t12.1\t10.8\t5.2\t\nPlatelets\t205\t52\t40\t75\t105\t96\t125\t201\t221\t\nHaematocrit\t.033\t0.35\t0.44\t0.30\t0.33\t0.27\t0.28\t0.24\t0.38\t\nUrea\t\t\t5.3\t4.9\t5.1\t4.2\t3.5\t2.9\t3.7\t\nCreatinine\t\t\t103\t80\t74\t60\t61\t60\t55\t\neGFR\t\t\t64\t86\t> 90\t> 90\t> 90\t> 90\t> 90\t\nALPa\t\t\t325\t261\t307\t240\t253\t311\t95\t\nGGTb\t\t\t83\t69\t93\t79\t132\t494\t33\t\nASTc\t\t\t2539\t\t\t\t\t\t\t\nALTd\t\t\t3200\t2588\t2485\t1840\t1195\t692\t23\t\nBilirubin\t\t\t101\t77\t101\t72\t96\t96\t17\t\nAlbumin\t\t\t24\t20\t23\t18\t18\t21\t38\t\nINRe\t\t\t3.2\t\t\t2.0\t1.4\t1.1\t\t\nAPTTf\t\t\t46\t\t\t36\t29\t28\t\t\nFibrinogen\t\t\t3.0\t\t\t2.7\t3.1\t3.6\t\t\na Alkaline phosphate.\n\nb Gamma-glutamyl transferase.\n\nc Aspartate aminotransferase.\n\nd Alanine aminotransferase.\n\ne International normalised ratio.\n\nf Activated prothrombin time.\n\n\n\nNo symptoms other than haematoma were reported by the patient, and other than the isolated borderline blood pressure, no clinical signs were present to reflect the eventual diagnosis with no headache, epigastric pain, visual changes, neurological irritability, hyperreflexia, clonus or oedema.\n\nUrgent investigations revealed multiple significant biochemical derangements consistent with a diagnosis of HELLP, with acute hepatic failure (AST 2539, ALP 3200), acute renal failure (eGFR 64, creatinine 103), a positive haemolytic screen (LDH 1585, haptoglobin < 0.06), and significant coagulopathy (INR 3.2, APTT 46, fibrinogen 3.0).\n\nRL was admitted to the intensive care unit for ongoing investigation and management. Simultaneously, blood pressure began to rise rapidly up to 160/100, and was controlled with a sodium nitroprusside infusion.\n\nAs is customary for the post-caesarean state, RL had been taking regular paracetamol for analgesia since delivery and with undiagnosed impaired liver function required active management of a toxic paracetamol of 347 μmol/L, requiring an infusion of N-acetyl cysteine. This supratherapetic level occurred through oral administration of paracetamol at recommended dosages, with no intravenous administration. Other care was primarily supportive. Lactulose was given for liver failure and hepatotoxic medications were withheld. Vitamin K was administered to reverse her coagulopathy.\n\nInvestigations by medical, intensive care, haematology and gastroenterology teams revealed no other cause for RL's presentation.\n\nAn abdominal ultrasound showed a normal liver, no intra-abdominal pathology, and a haematoma under the caesarean wound above the muscle layer. RL was managed by a multidisciplinary team including gastroenterology, haematology, obstetrics, toxicology and intensive care. The worst biochemical state was reached approximately 75 h postpartum, and the patient steadily improved over the next week.\n\nThe patient was discharged from the intensive care unit after four days, with dramatically improved liver function, renal function and coagulation profile (Table 1). RL was followed up six weeks postpartum with a consultant obstetrician and had no residual issues, and completely normalised blood and urine results. Blood pressure was entirely normal without medication and she was asymptomatic and well.\n\n3 Discussion\nAlthough HELLP syndrome can occur postpartum, and is not preceded by hypertension or proteinuria in up to 10–15% of cases [5], our case was unusual in that the patient felt well and had no preceding signs or symptoms. Review articles suggest that up to 90% of cases present with epigastric pain as an early symptom, 90% with malaise, and 50% with nausea or vomiting [6]. In our case, despite significant biochemical abnormalities, the patient was completely asymptomatic, and was investigated only for a wound haematoma on what would have customarily been the day of discharge.\n\nIdentification and presentation would likely have been further delayed with a vaginal delivery as hospital discharge occurs 1 to 2 days earlier and would have only represented when grossly symptomatic. It is rare to have an asymptomatic, late postpartum case of HELLP syndrome with a woman who had been normotensive without proteinuria throughout the pregnancy, and reinforces the importance of a high level of clinical suspicion to ensure that a timely diagnosis is made. Additionally, this case demonstrates a salutary lesson of ensuring appropriate sized blood pressure cuffs available in a ward setting.\n\nClass I HELLP syndrome, or those with haemolysis, liver dysfunction and thrombocytopaenia with a platelet count at the nadir of less the 50,000 μL are associated with the highest levels of maternal morbidity [7]. However, it is important to be proactive and monitor carefully all women with HELLP syndrome regardless of their pathology results, as not all laboratory parameters are independent risk factors for adverse maternal outcomes [8]. Although we were fortunate in our case that no lasting effects occurred, a case report of postpartum HELLP syndrome led to a maternal death, despite timely intervention, with a similar biochemical profile to our patient [9].\n\nThe paracetamol toxicity that occurred in our patient was likely to be a result, rather than cause, of the liver dysfunction, as it had been administered at recommended dosages. However, this again highlights the importance of a high clinical suspicion for HELLP syndrome and early diagnosis, as paracetamol administration had continued for longer without realisation, long term or irreversible liver damage may have occurred.\n\nApproximately 8% of women with HELLP syndrome will also develop renal failure, as did our case. Development of HELLP syndrome postpartum appears to increase the incidence of renal dysfunction [3]. Development of acute renal failure is associated with disseminated intravascular coagulation (DIC), with up to 84% of women with acute renal failure also having DIC [8], [10].\n\nA study on the natural history of HELLP syndrome indicated that the worst biochemical state was reached within 24 to 48 h after delivery [11]. Our case reinforces the important clinical lesson that even after this period a high level of suspicion needs to occur with all women, regardless of their blood pressure, in order to enable timely intervention for a serious clinical condition associated with significant maternal morbidity.\n\n4 Conclusion\nHELLP syndrome is associated with significant morbidity and mortality. A high clinical suspicion is required for this condition, even in the late postpartum period.\n\nConflict of Interest\nNo author has a conflict of interest.\n\nAuthor's Contributions\nNatasha Louise Pritchard.\n\nGroup1 — conception and design, acquisition of data, analysis and interpretation of data.\n\nGroup 2 — drafting the article and critical revision of the article.\n\nGroup 3 — final approval of the version to be published.\n\nJodi Leanne Keane.\n\nGroup1 — analysis and interpretation of data.\n\nGroup 2 — drafting the article and critical revision of the article.\n\nGroup 3 — final approval of the version to be published.\n\nAcknowledgements\nNo further acknowledgements are required.\n\n☆ Guarantor of submission: The corresponding author is the guarantor of submission.\n\n☆☆ Consent: Written consent has been obtained by the patient discussed in this case report.\n==== Refs\nReferences\n1 Haram K. Svendsen E. Abildgaard U. The HELLP syndrome: clinical issues and management. A Review BMC Pregnancy Childbirth 9 8 2009 \n2 Clarke S. Nelson-Piercy C. Pre-eclampsia and HELLP syndrome Anaesth. Intensive Care Med. 9 3 2008 110 114 \n3 Sibai B. Ramadan M. Usta I. Salama M. Mercer B. Friedman S. Maternal morbidity and mortality in 442 pregnancies with hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome) Am. J. Obstet. Gynecol. 169 4 1993 1000 1006 8238109 \n4 Matthys L. Coppage K. Lambers D. Barton J. Sibai B. Delayed postpartum preeclampsia: an experience of 151 cases Am. J. Obstet. Gynecol. 190 2004 1464 1466 15167870 \n5 Siba B. Diagnosis, controversies, and management of the syndrome of hemolysis, elevated liver enzymes, and low platelet count Obstet. Gynecol. 103 5Pt1 2004 981 989 15121574 \n6 Sibai B. The HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets): much ado about nothing?” Am. J. Obstet. Gynecol. 162 2 1990 311 316 2309811 \n7 Martin J. Rinehart B. May W. Magann E. Terrone D. Blake P. The spectrum of severe preeclampsia: comparative analysis by HELLP (hemolysis, elevated liver enzyme levels, and low platelet count) syndrome classification Am. J. Obstet. Gynecol. 180 6 1999 1373 1384 10368474 \n8 Haddad B. Barton J. Livingston J. Chahine R. Sibai B. Risk factors for adverse maternal outcomes among women with HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome Am. J. Obstet. Gynecol. 183 2 2000 444 448 10942484 \n9 Pop-Tranjkovic Antic V. Kopitovic V. Popovic J. Trenkic M. Vacic N. Postpartum HELLP syndrome — the case of lost battle Ups. J. Med. Sci. 118 2013 51 53 23033875 \n10 Sibai B. Ramadan M. Acute renal failure in pregnancies complicated by hemolysis, elevated liver enzymes, and low platelets Am. J. Obstet. Gynecol. 168 1993 1682 1690 8317509 \n11 Martin J. Blake P. Kenneth P. James M. Hess L. Martin R. The natural history of HELLP syndrome: patterns of disease progression and regression Am. J. Obstet. Gynecol. 164 6 1991 1500 1513 2048596 \nSuggested Reading\n12 Weinstein L. It has been a great ride: the history of HELLP syndrome Am. J. Obstet. Gynecol. 193 3 2005 860 863 16150288 \n13 Cakmak B. Late postpartum HELLP syndrome 60 hours after delivery associated with mild preeclampsia J. Clin. Diagn. Res. 7 12 2013 2998 2999 24551706 \n14 Stella C. Sibai B. Preeclampsia: diagnosis and management of the atypical presentation The J. Matern. Fetal Neonatal Med. 19 7 2006 381 386 16923692 \n15 Poourrat O. Differentiation between severe HELLP syndrome and thrombotic microangiopathy, thrombotic thrombocytopenic purpura and other imitators Eur. J. Obstet. Gynecol. Reprod. Biol. 189 2015 68 72 25879992 \n16 Audibert F. Clinical utility of strict diagnostic criteria for the HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome Am. J. Obstet. Gynecol. 175 2 1996 460 464 8765269\n\n",
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"issn_linking": "2214-9112",
"issue": "8()",
"journal": "Case reports in women's health",
"keywords": "HELLP syndrome; Postpartum; Preeclampsia; Wound haematoma",
"medline_ta": "Case Rep Womens Health",
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"nlm_unique_id": "101682122",
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"pages": "1-3",
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"pmid": "29629310",
"pubdate": "2015-10",
"publication_types": "D002363:Case Reports",
"references": "24551706;15167870;25879992;8238109;19245695;8317509;2309811;8765269;15121574;10368474;23033875;16923692;2048596;16150288;10942484",
"title": "Wound haematoma: The first sign in a case of late postpartum HELLP syndrome.",
"title_normalized": "wound haematoma the first sign in a case of late postpartum hellp syndrome"
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"abstract": "The safety, efficacy, and appropriate timing of isoniazid therapy to prevent tuberculosis in pregnant women with human immunodeficiency virus (HIV) infection who are receiving antiretroviral therapy are unknown.\n\n\n\nIn this multicenter, double-blind, placebo-controlled, noninferiority trial, we randomly assigned pregnant women with HIV infection to receive isoniazid preventive therapy for 28 weeks, initiated either during pregnancy (immediate group) or at week 12 after delivery (deferred group). Mothers and infants were followed through week 48 after delivery. The primary outcome was a composite of treatment-related maternal adverse events of grade 3 or higher or permanent discontinuation of the trial regimen because of toxic effects. The noninferiority margin was an upper boundary of the 95% confidence interval for the between-group difference in the rate of the primary outcome of less than 5 events per 100 person-years.\n\n\n\nA total of 956 women were enrolled. A primary outcome event occurred in 72 of 477 women (15.1%) in the immediate group and in 73 of 479 (15.2%) in the deferred group (incidence rate, 15.03 and 14.93 events per 100 person-years, respectively; rate difference, 0.10; 95% confidence interval [CI], -4.77 to 4.98, which met the criterion for noninferiority). Two women in the immediate group and 4 women in the deferred group died (incidence rate, 0.40 and 0.78 per 100 person-years, respectively; rate difference, -0.39; 95% CI, -1.33 to 0.56); all deaths occurred during the postpartum period, and 4 were from liver failure (2 of the women who died from liver failure had received isoniazid [1 in each group]). Tuberculosis developed in 6 women (3 in each group); the incidence rate was 0.60 per 100 person-years in the immediate group and 0.59 per 100 person-years in the deferred group (rate difference, 0.01; 95% CI, -0.94 to 0.96). There was a higher incidence in the immediate group than in the deferred group of an event included in the composite adverse pregnancy outcome (stillbirth or spontaneous abortion, low birth weight in an infant, preterm delivery, or congenital anomalies in an infant) (23.6% vs. 17.0%; difference, 6.7 percentage points; 95% CI, 0.8 to 11.9).\n\n\n\nThe risks associated with initiation of isoniazid preventive therapy during pregnancy appeared to be greater than those associated with initiation of therapy during the postpartum period. (Funded by the National Institutes of Health; IMPAACT P1078 TB APPRISE ClinicalTrials.gov number, NCT01494038.).",
"affiliations": "From the Center for Clinical Global Health Education, Johns Hopkins University, Baltimore (A.G., V.M.), and the Division of AIDS, National Institute of Allergy and Infectious Diseases (K.S., P.J.-P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (N.C.), National Institutes of Health, Bethesda - all in Maryland; the Harvard T.H. Chan School of Public Health, Boston (G.M., L. Aaron, G.R.M.); the Family Clinical Research Unit, Department of Obstetrics and Gynaecology, Stellenbosch University, Cape Town (G.T.), the Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg (A.V.), and the Desmond Tutu TB Center, Department of Paediatrics and Child Health, Stellenbosch University, Tygerberg (A.H.) - all in South Africa; FHI 360, Durham, NC (K.M., S.B.); University of Zimbabwe College of Health Sciences Clinical Trials Research Centre, Harare (T.C., T.V., L.S.-C.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (C.O.-M.); Botswana Harvard AIDS Institute Partnership, Gaborone (G.R.M.); Kilimanjaro Christian Medical Centre, Moshi, Tanzania (B.T.M.); Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand (L. Aurpibul); Byramjee Jeejeebhoy Government Medical College (R.B.) and Byramjee Jeejeebhoy Government College-Johns Hopkins Clinical Research Site (A.G., V.M.), Pune, India; Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR), Port au Prince, Haiti (V.R.); Frontier Science Foundation, Amherst, NY (B.Z.); University of California, Los Angeles, Los Angeles (D.C.); Vanderbilt University Medical Center, Nashville (T.R.S.); and the University of Colorado Denver Anschutz Medical Campus, Aurora (A.W.).;From the Center for Clinical Global Health Education, Johns Hopkins University, Baltimore (A.G., V.M.), and the Division of AIDS, National Institute of Allergy and Infectious Diseases (K.S., P.J.-P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (N.C.), National Institutes of Health, Bethesda - all in Maryland; the Harvard T.H. Chan School of Public Health, Boston (G.M., L. Aaron, G.R.M.); the Family Clinical Research Unit, Department of Obstetrics and Gynaecology, Stellenbosch University, Cape Town (G.T.), the Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg (A.V.), and the Desmond Tutu TB Center, Department of Paediatrics and Child Health, Stellenbosch University, Tygerberg (A.H.) - all in South Africa; FHI 360, Durham, NC (K.M., S.B.); University of Zimbabwe College of Health Sciences Clinical Trials Research Centre, Harare (T.C., T.V., L.S.-C.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (C.O.-M.); Botswana Harvard AIDS Institute Partnership, Gaborone (G.R.M.); Kilimanjaro Christian Medical Centre, Moshi, Tanzania (B.T.M.); Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand (L. Aurpibul); Byramjee Jeejeebhoy Government Medical College (R.B.) and Byramjee Jeejeebhoy Government College-Johns Hopkins Clinical Research Site (A.G., V.M.), Pune, India; Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR), Port au Prince, Haiti (V.R.); Frontier Science Foundation, Amherst, NY (B.Z.); University of California, Los Angeles, Los Angeles (D.C.); Vanderbilt University Medical Center, Nashville (T.R.S.); and the University of Colorado Denver Anschutz Medical Campus, Aurora (A.W.).;From the Center for Clinical Global Health Education, Johns Hopkins University, Baltimore (A.G., V.M.), and the Division of AIDS, National Institute of Allergy and Infectious Diseases (K.S., P.J.-P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (N.C.), National Institutes of Health, Bethesda - all in Maryland; the Harvard T.H. Chan School of Public Health, Boston (G.M., L. Aaron, G.R.M.); the Family Clinical Research Unit, Department of Obstetrics and Gynaecology, Stellenbosch University, Cape Town (G.T.), the Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg (A.V.), and the Desmond Tutu TB Center, Department of Paediatrics and Child Health, Stellenbosch University, Tygerberg (A.H.) - all in South Africa; FHI 360, Durham, NC (K.M., S.B.); University of Zimbabwe College of Health Sciences Clinical Trials Research Centre, Harare (T.C., T.V., L.S.-C.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (C.O.-M.); Botswana Harvard AIDS Institute Partnership, Gaborone (G.R.M.); Kilimanjaro Christian Medical Centre, Moshi, Tanzania (B.T.M.); Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand (L. Aurpibul); Byramjee Jeejeebhoy Government Medical College (R.B.) and Byramjee Jeejeebhoy Government College-Johns Hopkins Clinical Research Site (A.G., V.M.), Pune, India; Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR), Port au Prince, Haiti (V.R.); Frontier Science Foundation, Amherst, NY (B.Z.); University of California, Los Angeles, Los Angeles (D.C.); Vanderbilt University Medical Center, Nashville (T.R.S.); and the University of Colorado Denver Anschutz Medical Campus, Aurora (A.W.).;From the Center for Clinical Global Health Education, Johns Hopkins University, Baltimore (A.G., V.M.), and the Division of AIDS, National Institute of Allergy and Infectious Diseases (K.S., P.J.-P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (N.C.), National Institutes of Health, Bethesda - all in Maryland; the Harvard T.H. Chan School of Public Health, Boston (G.M., L. Aaron, G.R.M.); the Family Clinical Research Unit, Department of Obstetrics and Gynaecology, Stellenbosch University, Cape Town (G.T.), the Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg (A.V.), and the Desmond Tutu TB Center, Department of Paediatrics and Child Health, Stellenbosch University, Tygerberg (A.H.) - all in South Africa; FHI 360, Durham, NC (K.M., S.B.); University of Zimbabwe College of Health Sciences Clinical Trials Research Centre, Harare (T.C., T.V., L.S.-C.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (C.O.-M.); Botswana Harvard AIDS Institute Partnership, Gaborone (G.R.M.); Kilimanjaro Christian Medical Centre, Moshi, Tanzania (B.T.M.); Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand (L. Aurpibul); Byramjee Jeejeebhoy Government Medical College (R.B.) and Byramjee Jeejeebhoy Government College-Johns Hopkins Clinical Research Site (A.G., V.M.), Pune, India; Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR), Port au Prince, Haiti (V.R.); Frontier Science Foundation, Amherst, NY (B.Z.); University of California, Los Angeles, Los Angeles (D.C.); Vanderbilt University Medical Center, Nashville (T.R.S.); and the University of Colorado Denver Anschutz Medical Campus, Aurora (A.W.).;From the Center for Clinical Global Health Education, Johns Hopkins University, Baltimore (A.G., V.M.), and the Division of AIDS, National Institute of Allergy and Infectious Diseases (K.S., P.J.-P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (N.C.), National Institutes of Health, Bethesda - all in Maryland; the Harvard T.H. Chan School of Public Health, Boston (G.M., L. Aaron, G.R.M.); the Family Clinical Research Unit, Department of Obstetrics and Gynaecology, Stellenbosch University, Cape Town (G.T.), the Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg (A.V.), and the Desmond Tutu TB Center, Department of Paediatrics and Child Health, Stellenbosch University, Tygerberg (A.H.) - all in South Africa; FHI 360, Durham, NC (K.M., S.B.); University of Zimbabwe College of Health Sciences Clinical Trials Research Centre, Harare (T.C., T.V., L.S.-C.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (C.O.-M.); Botswana Harvard AIDS Institute Partnership, Gaborone (G.R.M.); Kilimanjaro Christian Medical Centre, Moshi, Tanzania (B.T.M.); Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand (L. Aurpibul); Byramjee Jeejeebhoy Government Medical College (R.B.) and Byramjee Jeejeebhoy Government College-Johns Hopkins Clinical Research Site (A.G., V.M.), Pune, India; Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR), Port au Prince, Haiti (V.R.); Frontier Science Foundation, Amherst, NY (B.Z.); University of California, Los Angeles, Los Angeles (D.C.); Vanderbilt University Medical Center, Nashville (T.R.S.); and the University of Colorado Denver Anschutz Medical Campus, Aurora (A.W.).;From the Center for Clinical Global Health Education, Johns Hopkins University, Baltimore (A.G., V.M.), and the Division of AIDS, National Institute of Allergy and Infectious Diseases (K.S., P.J.-P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (N.C.), National Institutes of Health, Bethesda - all in Maryland; the Harvard T.H. Chan School of Public Health, Boston (G.M., L. Aaron, G.R.M.); the Family Clinical Research Unit, Department of Obstetrics and Gynaecology, Stellenbosch University, Cape Town (G.T.), the Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg (A.V.), and the Desmond Tutu TB Center, Department of Paediatrics and Child Health, Stellenbosch University, Tygerberg (A.H.) - all in South Africa; FHI 360, Durham, NC (K.M., S.B.); University of Zimbabwe College of Health Sciences Clinical Trials Research Centre, Harare (T.C., T.V., L.S.-C.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (C.O.-M.); Botswana Harvard AIDS Institute Partnership, Gaborone (G.R.M.); Kilimanjaro Christian Medical Centre, Moshi, Tanzania (B.T.M.); Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand (L. Aurpibul); Byramjee Jeejeebhoy Government Medical College (R.B.) and Byramjee Jeejeebhoy Government College-Johns Hopkins Clinical Research Site (A.G., V.M.), Pune, India; Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR), Port au Prince, Haiti (V.R.); Frontier Science Foundation, Amherst, NY (B.Z.); University of California, Los Angeles, Los Angeles (D.C.); Vanderbilt University Medical Center, Nashville (T.R.S.); and the University of Colorado Denver Anschutz Medical Campus, Aurora (A.W.).;From the Center for Clinical Global Health Education, Johns Hopkins University, Baltimore (A.G., V.M.), and the Division of AIDS, National Institute of Allergy and Infectious Diseases (K.S., P.J.-P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (N.C.), National Institutes of Health, Bethesda - all in Maryland; the Harvard T.H. Chan School of Public Health, Boston (G.M., L. Aaron, G.R.M.); the Family Clinical Research Unit, Department of Obstetrics and Gynaecology, Stellenbosch University, Cape Town (G.T.), the Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg (A.V.), and the Desmond Tutu TB Center, Department of Paediatrics and Child Health, Stellenbosch University, Tygerberg (A.H.) - all in South Africa; FHI 360, Durham, NC (K.M., S.B.); University of Zimbabwe College of Health Sciences Clinical Trials Research Centre, Harare (T.C., T.V., L.S.-C.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (C.O.-M.); Botswana Harvard AIDS Institute Partnership, Gaborone (G.R.M.); Kilimanjaro Christian Medical Centre, Moshi, Tanzania (B.T.M.); Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand (L. Aurpibul); Byramjee Jeejeebhoy Government Medical College (R.B.) and Byramjee Jeejeebhoy Government College-Johns Hopkins Clinical Research Site (A.G., V.M.), Pune, India; Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR), Port au Prince, Haiti (V.R.); Frontier Science Foundation, Amherst, NY (B.Z.); University of California, Los Angeles, Los Angeles (D.C.); Vanderbilt University Medical Center, Nashville (T.R.S.); and the University of Colorado Denver Anschutz Medical Campus, Aurora (A.W.).;From the Center for Clinical Global Health Education, Johns Hopkins University, Baltimore (A.G., V.M.), and the Division of AIDS, National Institute of Allergy and Infectious Diseases (K.S., P.J.-P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (N.C.), National Institutes of Health, Bethesda - all in Maryland; the Harvard T.H. Chan School of Public Health, Boston (G.M., L. Aaron, G.R.M.); the Family Clinical Research Unit, Department of Obstetrics and Gynaecology, Stellenbosch University, Cape Town (G.T.), the Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg (A.V.), and the Desmond Tutu TB Center, Department of Paediatrics and Child Health, Stellenbosch University, Tygerberg (A.H.) - all in South Africa; FHI 360, Durham, NC (K.M., S.B.); University of Zimbabwe College of Health Sciences Clinical Trials Research Centre, Harare (T.C., T.V., L.S.-C.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (C.O.-M.); Botswana Harvard AIDS Institute Partnership, Gaborone (G.R.M.); Kilimanjaro Christian Medical Centre, Moshi, Tanzania (B.T.M.); Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand (L. Aurpibul); Byramjee Jeejeebhoy Government Medical College (R.B.) and Byramjee Jeejeebhoy Government College-Johns Hopkins Clinical Research Site (A.G., V.M.), Pune, India; Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR), Port au Prince, Haiti (V.R.); Frontier Science Foundation, Amherst, NY (B.Z.); University of California, Los Angeles, Los Angeles (D.C.); Vanderbilt University Medical Center, Nashville (T.R.S.); and the University of Colorado Denver Anschutz Medical Campus, Aurora (A.W.).;From the Center for Clinical Global Health Education, Johns Hopkins University, Baltimore (A.G., V.M.), and the Division of AIDS, National Institute of Allergy and Infectious Diseases (K.S., P.J.-P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (N.C.), National Institutes of Health, Bethesda - all in Maryland; the Harvard T.H. Chan School of Public Health, Boston (G.M., L. Aaron, G.R.M.); the Family Clinical Research Unit, Department of Obstetrics and Gynaecology, Stellenbosch University, Cape Town (G.T.), the Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg (A.V.), and the Desmond Tutu TB Center, Department of Paediatrics and Child Health, Stellenbosch University, Tygerberg (A.H.) - all in South Africa; FHI 360, Durham, NC (K.M., S.B.); University of Zimbabwe College of Health Sciences Clinical Trials Research Centre, Harare (T.C., T.V., L.S.-C.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (C.O.-M.); Botswana Harvard AIDS Institute Partnership, Gaborone (G.R.M.); Kilimanjaro Christian Medical Centre, Moshi, Tanzania (B.T.M.); Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand (L. Aurpibul); Byramjee Jeejeebhoy Government Medical College (R.B.) and Byramjee Jeejeebhoy Government College-Johns Hopkins Clinical Research Site (A.G., V.M.), Pune, India; Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR), Port au Prince, Haiti (V.R.); Frontier Science Foundation, Amherst, NY (B.Z.); University of California, Los Angeles, Los Angeles (D.C.); Vanderbilt University Medical Center, Nashville (T.R.S.); and the University of Colorado Denver Anschutz Medical Campus, Aurora (A.W.).;From the Center for Clinical Global Health Education, Johns Hopkins University, Baltimore (A.G., V.M.), and the Division of AIDS, National Institute of Allergy and Infectious Diseases (K.S., P.J.-P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (N.C.), National Institutes of Health, Bethesda - all in Maryland; the Harvard T.H. Chan School of Public Health, Boston (G.M., L. Aaron, G.R.M.); the Family Clinical Research Unit, Department of Obstetrics and Gynaecology, Stellenbosch University, Cape Town (G.T.), the Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg (A.V.), and the Desmond Tutu TB Center, Department of Paediatrics and Child Health, Stellenbosch University, Tygerberg (A.H.) - all in South Africa; FHI 360, Durham, NC (K.M., S.B.); University of Zimbabwe College of Health Sciences Clinical Trials Research Centre, Harare (T.C., T.V., L.S.-C.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (C.O.-M.); Botswana Harvard AIDS Institute Partnership, Gaborone (G.R.M.); Kilimanjaro Christian Medical Centre, Moshi, Tanzania (B.T.M.); Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand (L. Aurpibul); Byramjee Jeejeebhoy Government Medical College (R.B.) and Byramjee Jeejeebhoy Government College-Johns Hopkins Clinical Research Site (A.G., V.M.), Pune, India; Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR), Port au Prince, Haiti (V.R.); Frontier Science Foundation, Amherst, NY (B.Z.); University of California, Los Angeles, Los Angeles (D.C.); Vanderbilt University Medical Center, Nashville (T.R.S.); and the University of Colorado Denver Anschutz Medical Campus, Aurora (A.W.).;From the Center for Clinical Global Health Education, Johns Hopkins University, Baltimore (A.G., V.M.), and the Division of AIDS, National Institute of Allergy and Infectious Diseases (K.S., P.J.-P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (N.C.), National Institutes of Health, Bethesda - all in Maryland; the Harvard T.H. Chan School of Public Health, Boston (G.M., L. Aaron, G.R.M.); the Family Clinical Research Unit, Department of Obstetrics and Gynaecology, Stellenbosch University, Cape Town (G.T.), the Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg (A.V.), and the Desmond Tutu TB Center, Department of Paediatrics and Child Health, Stellenbosch University, Tygerberg (A.H.) - all in South Africa; FHI 360, Durham, NC (K.M., S.B.); University of Zimbabwe College of Health Sciences Clinical Trials Research Centre, Harare (T.C., T.V., L.S.-C.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (C.O.-M.); Botswana Harvard AIDS Institute Partnership, Gaborone (G.R.M.); Kilimanjaro Christian Medical Centre, Moshi, Tanzania (B.T.M.); Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand (L. Aurpibul); Byramjee Jeejeebhoy Government Medical College (R.B.) and Byramjee Jeejeebhoy Government College-Johns Hopkins Clinical Research Site (A.G., V.M.), Pune, India; Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR), Port au Prince, Haiti (V.R.); Frontier Science Foundation, Amherst, NY (B.Z.); University of California, Los Angeles, Los Angeles (D.C.); Vanderbilt University Medical Center, Nashville (T.R.S.); and the University of Colorado Denver Anschutz Medical Campus, Aurora (A.W.).;From the Center for Clinical Global Health Education, Johns Hopkins University, Baltimore (A.G., V.M.), and the Division of AIDS, National Institute of Allergy and Infectious Diseases (K.S., P.J.-P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (N.C.), National Institutes of Health, Bethesda - all in Maryland; the Harvard T.H. Chan School of Public Health, Boston (G.M., L. Aaron, G.R.M.); the Family Clinical Research Unit, Department of Obstetrics and Gynaecology, Stellenbosch University, Cape Town (G.T.), the Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg (A.V.), and the Desmond Tutu TB Center, Department of Paediatrics and Child Health, Stellenbosch University, Tygerberg (A.H.) - all in South Africa; FHI 360, Durham, NC (K.M., S.B.); University of Zimbabwe College of Health Sciences Clinical Trials Research Centre, Harare (T.C., T.V., L.S.-C.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (C.O.-M.); Botswana Harvard AIDS Institute Partnership, Gaborone (G.R.M.); Kilimanjaro Christian Medical Centre, Moshi, Tanzania (B.T.M.); Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand (L. Aurpibul); Byramjee Jeejeebhoy Government Medical College (R.B.) and Byramjee Jeejeebhoy Government College-Johns Hopkins Clinical Research Site (A.G., V.M.), Pune, India; Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR), Port au Prince, Haiti (V.R.); Frontier Science Foundation, Amherst, NY (B.Z.); University of California, Los Angeles, Los Angeles (D.C.); Vanderbilt University Medical Center, Nashville (T.R.S.); and the University of Colorado Denver Anschutz Medical Campus, Aurora (A.W.).;From the Center for Clinical Global Health Education, Johns Hopkins University, Baltimore (A.G., V.M.), and the Division of AIDS, National Institute of Allergy and Infectious Diseases (K.S., P.J.-P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (N.C.), National Institutes of Health, Bethesda - all in Maryland; the Harvard T.H. Chan School of Public Health, Boston (G.M., L. Aaron, G.R.M.); the Family Clinical Research Unit, Department of Obstetrics and Gynaecology, Stellenbosch University, Cape Town (G.T.), the Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg (A.V.), and the Desmond Tutu TB Center, Department of Paediatrics and Child Health, Stellenbosch University, Tygerberg (A.H.) - all in South Africa; FHI 360, Durham, NC (K.M., S.B.); University of Zimbabwe College of Health Sciences Clinical Trials Research Centre, Harare (T.C., T.V., L.S.-C.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (C.O.-M.); Botswana Harvard AIDS Institute Partnership, Gaborone (G.R.M.); Kilimanjaro Christian Medical Centre, Moshi, Tanzania (B.T.M.); Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand (L. Aurpibul); Byramjee Jeejeebhoy Government Medical College (R.B.) and Byramjee Jeejeebhoy Government College-Johns Hopkins Clinical Research Site (A.G., V.M.), Pune, India; Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR), Port au Prince, Haiti (V.R.); Frontier Science Foundation, Amherst, NY (B.Z.); University of California, Los Angeles, Los Angeles (D.C.); Vanderbilt University Medical Center, Nashville (T.R.S.); and the University of Colorado Denver Anschutz Medical Campus, Aurora (A.W.).;From the Center for Clinical Global Health Education, Johns Hopkins University, Baltimore (A.G., V.M.), and the Division of AIDS, National Institute of Allergy and Infectious Diseases (K.S., P.J.-P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (N.C.), National Institutes of Health, Bethesda - all in Maryland; the Harvard T.H. Chan School of Public Health, Boston (G.M., L. Aaron, G.R.M.); the Family Clinical Research Unit, Department of Obstetrics and Gynaecology, Stellenbosch University, Cape Town (G.T.), the Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg (A.V.), and the Desmond Tutu TB Center, Department of Paediatrics and Child Health, Stellenbosch University, Tygerberg (A.H.) - all in South Africa; FHI 360, Durham, NC (K.M., S.B.); University of Zimbabwe College of Health Sciences Clinical Trials Research Centre, Harare (T.C., T.V., L.S.-C.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (C.O.-M.); Botswana Harvard AIDS Institute Partnership, Gaborone (G.R.M.); Kilimanjaro Christian Medical Centre, Moshi, Tanzania (B.T.M.); Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand (L. Aurpibul); Byramjee Jeejeebhoy Government Medical College (R.B.) and Byramjee Jeejeebhoy Government College-Johns Hopkins Clinical Research Site (A.G., V.M.), Pune, India; Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR), Port au Prince, Haiti (V.R.); Frontier Science Foundation, Amherst, NY (B.Z.); University of California, Los Angeles, Los Angeles (D.C.); Vanderbilt University Medical Center, Nashville (T.R.S.); and the University of Colorado Denver Anschutz Medical Campus, Aurora (A.W.).;From the Center for Clinical Global Health Education, Johns Hopkins University, Baltimore (A.G., V.M.), and the Division of AIDS, National Institute of Allergy and Infectious Diseases (K.S., P.J.-P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (N.C.), National Institutes of Health, Bethesda - all in Maryland; the Harvard T.H. Chan School of Public Health, Boston (G.M., L. Aaron, G.R.M.); the Family Clinical Research Unit, Department of Obstetrics and Gynaecology, Stellenbosch University, Cape Town (G.T.), the Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg (A.V.), and the Desmond Tutu TB Center, Department of Paediatrics and Child Health, Stellenbosch University, Tygerberg (A.H.) - all in South Africa; FHI 360, Durham, NC (K.M., S.B.); University of Zimbabwe College of Health Sciences Clinical Trials Research Centre, Harare (T.C., T.V., L.S.-C.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (C.O.-M.); Botswana Harvard AIDS Institute Partnership, Gaborone (G.R.M.); Kilimanjaro Christian Medical Centre, Moshi, Tanzania (B.T.M.); Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand (L. Aurpibul); Byramjee Jeejeebhoy Government Medical College (R.B.) and Byramjee Jeejeebhoy Government College-Johns Hopkins Clinical Research Site (A.G., V.M.), Pune, India; Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR), Port au Prince, Haiti (V.R.); Frontier Science Foundation, Amherst, NY (B.Z.); University of California, Los Angeles, Los Angeles (D.C.); Vanderbilt University Medical Center, Nashville (T.R.S.); and the University of Colorado Denver Anschutz Medical Campus, Aurora (A.W.).;From the Center for Clinical Global Health Education, Johns Hopkins University, Baltimore (A.G., V.M.), and the Division of AIDS, National Institute of Allergy and Infectious Diseases (K.S., P.J.-P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (N.C.), National Institutes of Health, Bethesda - all in Maryland; the Harvard T.H. Chan School of Public Health, Boston (G.M., L. Aaron, G.R.M.); the Family Clinical Research Unit, Department of Obstetrics and Gynaecology, Stellenbosch University, Cape Town (G.T.), the Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg (A.V.), and the Desmond Tutu TB Center, Department of Paediatrics and Child Health, Stellenbosch University, Tygerberg (A.H.) - all in South Africa; FHI 360, Durham, NC (K.M., S.B.); University of Zimbabwe College of Health Sciences Clinical Trials Research Centre, Harare (T.C., T.V., L.S.-C.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (C.O.-M.); Botswana Harvard AIDS Institute Partnership, Gaborone (G.R.M.); Kilimanjaro Christian Medical Centre, Moshi, Tanzania (B.T.M.); Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand (L. Aurpibul); Byramjee Jeejeebhoy Government Medical College (R.B.) and Byramjee Jeejeebhoy Government College-Johns Hopkins Clinical Research Site (A.G., V.M.), Pune, India; Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR), Port au Prince, Haiti (V.R.); Frontier Science Foundation, Amherst, NY (B.Z.); University of California, Los Angeles, Los Angeles (D.C.); Vanderbilt University Medical Center, Nashville (T.R.S.); and the University of Colorado Denver Anschutz Medical Campus, Aurora (A.W.).;From the Center for Clinical Global Health Education, Johns Hopkins University, Baltimore (A.G., V.M.), and the Division of AIDS, National Institute of Allergy and Infectious Diseases (K.S., P.J.-P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (N.C.), National Institutes of Health, Bethesda - all in Maryland; the Harvard T.H. Chan School of Public Health, Boston (G.M., L. Aaron, G.R.M.); the Family Clinical Research Unit, Department of Obstetrics and Gynaecology, Stellenbosch University, Cape Town (G.T.), the Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg (A.V.), and the Desmond Tutu TB Center, Department of Paediatrics and Child Health, Stellenbosch University, Tygerberg (A.H.) - all in South Africa; FHI 360, Durham, NC (K.M., S.B.); University of Zimbabwe College of Health Sciences Clinical Trials Research Centre, Harare (T.C., T.V., L.S.-C.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (C.O.-M.); Botswana Harvard AIDS Institute Partnership, Gaborone (G.R.M.); Kilimanjaro Christian Medical Centre, Moshi, Tanzania (B.T.M.); Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand (L. Aurpibul); Byramjee Jeejeebhoy Government Medical College (R.B.) and Byramjee Jeejeebhoy Government College-Johns Hopkins Clinical Research Site (A.G., V.M.), Pune, India; Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR), Port au Prince, Haiti (V.R.); Frontier Science Foundation, Amherst, NY (B.Z.); University of California, Los Angeles, Los Angeles (D.C.); Vanderbilt University Medical Center, Nashville (T.R.S.); and the University of Colorado Denver Anschutz Medical Campus, Aurora (A.W.).;From the Center for Clinical Global Health Education, Johns Hopkins University, Baltimore (A.G., V.M.), and the Division of AIDS, National Institute of Allergy and Infectious Diseases (K.S., P.J.-P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (N.C.), National Institutes of Health, Bethesda - all in Maryland; the Harvard T.H. Chan School of Public Health, Boston (G.M., L. Aaron, G.R.M.); the Family Clinical Research Unit, Department of Obstetrics and Gynaecology, Stellenbosch University, Cape Town (G.T.), the Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg (A.V.), and the Desmond Tutu TB Center, Department of Paediatrics and Child Health, Stellenbosch University, Tygerberg (A.H.) - all in South Africa; FHI 360, Durham, NC (K.M., S.B.); University of Zimbabwe College of Health Sciences Clinical Trials Research Centre, Harare (T.C., T.V., L.S.-C.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (C.O.-M.); Botswana Harvard AIDS Institute Partnership, Gaborone (G.R.M.); Kilimanjaro Christian Medical Centre, Moshi, Tanzania (B.T.M.); Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand (L. Aurpibul); Byramjee Jeejeebhoy Government Medical College (R.B.) and Byramjee Jeejeebhoy Government College-Johns Hopkins Clinical Research Site (A.G., V.M.), Pune, India; Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR), Port au Prince, Haiti (V.R.); Frontier Science Foundation, Amherst, NY (B.Z.); University of California, Los Angeles, Los Angeles (D.C.); Vanderbilt University Medical Center, Nashville (T.R.S.); and the University of Colorado Denver Anschutz Medical Campus, Aurora (A.W.).;From the Center for Clinical Global Health Education, Johns Hopkins University, Baltimore (A.G., V.M.), and the Division of AIDS, National Institute of Allergy and Infectious Diseases (K.S., P.J.-P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (N.C.), National Institutes of Health, Bethesda - all in Maryland; the Harvard T.H. Chan School of Public Health, Boston (G.M., L. Aaron, G.R.M.); the Family Clinical Research Unit, Department of Obstetrics and Gynaecology, Stellenbosch University, Cape Town (G.T.), the Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg (A.V.), and the Desmond Tutu TB Center, Department of Paediatrics and Child Health, Stellenbosch University, Tygerberg (A.H.) - all in South Africa; FHI 360, Durham, NC (K.M., S.B.); University of Zimbabwe College of Health Sciences Clinical Trials Research Centre, Harare (T.C., T.V., L.S.-C.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (C.O.-M.); Botswana Harvard AIDS Institute Partnership, Gaborone (G.R.M.); Kilimanjaro Christian Medical Centre, Moshi, Tanzania (B.T.M.); Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand (L. Aurpibul); Byramjee Jeejeebhoy Government Medical College (R.B.) and Byramjee Jeejeebhoy Government College-Johns Hopkins Clinical Research Site (A.G., V.M.), Pune, India; Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR), Port au Prince, Haiti (V.R.); Frontier Science Foundation, Amherst, NY (B.Z.); University of California, Los Angeles, Los Angeles (D.C.); Vanderbilt University Medical Center, Nashville (T.R.S.); and the University of Colorado Denver Anschutz Medical Campus, Aurora (A.W.).;From the Center for Clinical Global Health Education, Johns Hopkins University, Baltimore (A.G., V.M.), and the Division of AIDS, National Institute of Allergy and Infectious Diseases (K.S., P.J.-P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (N.C.), National Institutes of Health, Bethesda - all in Maryland; the Harvard T.H. Chan School of Public Health, Boston (G.M., L. Aaron, G.R.M.); the Family Clinical Research Unit, Department of Obstetrics and Gynaecology, Stellenbosch University, Cape Town (G.T.), the Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg (A.V.), and the Desmond Tutu TB Center, Department of Paediatrics and Child Health, Stellenbosch University, Tygerberg (A.H.) - all in South Africa; FHI 360, Durham, NC (K.M., S.B.); University of Zimbabwe College of Health Sciences Clinical Trials Research Centre, Harare (T.C., T.V., L.S.-C.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (C.O.-M.); Botswana Harvard AIDS Institute Partnership, Gaborone (G.R.M.); Kilimanjaro Christian Medical Centre, Moshi, Tanzania (B.T.M.); Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand (L. Aurpibul); Byramjee Jeejeebhoy Government Medical College (R.B.) and Byramjee Jeejeebhoy Government College-Johns Hopkins Clinical Research Site (A.G., V.M.), Pune, India; Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR), Port au Prince, Haiti (V.R.); Frontier Science Foundation, Amherst, NY (B.Z.); University of California, Los Angeles, Los Angeles (D.C.); Vanderbilt University Medical Center, Nashville (T.R.S.); and the University of Colorado Denver Anschutz Medical Campus, Aurora (A.W.).;From the Center for Clinical Global Health Education, Johns Hopkins University, Baltimore (A.G., V.M.), and the Division of AIDS, National Institute of Allergy and Infectious Diseases (K.S., P.J.-P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (N.C.), National Institutes of Health, Bethesda - all in Maryland; the Harvard T.H. Chan School of Public Health, Boston (G.M., L. Aaron, G.R.M.); the Family Clinical Research Unit, Department of Obstetrics and Gynaecology, Stellenbosch University, Cape Town (G.T.), the Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg (A.V.), and the Desmond Tutu TB Center, Department of Paediatrics and Child Health, Stellenbosch University, Tygerberg (A.H.) - all in South Africa; FHI 360, Durham, NC (K.M., S.B.); University of Zimbabwe College of Health Sciences Clinical Trials Research Centre, Harare (T.C., T.V., L.S.-C.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (C.O.-M.); Botswana Harvard AIDS Institute Partnership, Gaborone (G.R.M.); Kilimanjaro Christian Medical Centre, Moshi, Tanzania (B.T.M.); Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand (L. Aurpibul); Byramjee Jeejeebhoy Government Medical College (R.B.) and Byramjee Jeejeebhoy Government College-Johns Hopkins Clinical Research Site (A.G., V.M.), Pune, India; Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR), Port au Prince, Haiti (V.R.); Frontier Science Foundation, Amherst, NY (B.Z.); University of California, Los Angeles, Los Angeles (D.C.); Vanderbilt University Medical Center, Nashville (T.R.S.); and the University of Colorado Denver Anschutz Medical Campus, Aurora (A.W.).;From the Center for Clinical Global Health Education, Johns Hopkins University, Baltimore (A.G., V.M.), and the Division of AIDS, National Institute of Allergy and Infectious Diseases (K.S., P.J.-P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (N.C.), National Institutes of Health, Bethesda - all in Maryland; the Harvard T.H. Chan School of Public Health, Boston (G.M., L. Aaron, G.R.M.); the Family Clinical Research Unit, Department of Obstetrics and Gynaecology, Stellenbosch University, Cape Town (G.T.), the Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg (A.V.), and the Desmond Tutu TB Center, Department of Paediatrics and Child Health, Stellenbosch University, Tygerberg (A.H.) - all in South Africa; FHI 360, Durham, NC (K.M., S.B.); University of Zimbabwe College of Health Sciences Clinical Trials Research Centre, Harare (T.C., T.V., L.S.-C.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (C.O.-M.); Botswana Harvard AIDS Institute Partnership, Gaborone (G.R.M.); Kilimanjaro Christian Medical Centre, Moshi, Tanzania (B.T.M.); Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand (L. Aurpibul); Byramjee Jeejeebhoy Government Medical College (R.B.) and Byramjee Jeejeebhoy Government College-Johns Hopkins Clinical Research Site (A.G., V.M.), Pune, India; Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR), Port au Prince, Haiti (V.R.); Frontier Science Foundation, Amherst, NY (B.Z.); University of California, Los Angeles, Los Angeles (D.C.); Vanderbilt University Medical Center, Nashville (T.R.S.); and the University of Colorado Denver Anschutz Medical Campus, Aurora (A.W.).;From the Center for Clinical Global Health Education, Johns Hopkins University, Baltimore (A.G., V.M.), and the Division of AIDS, National Institute of Allergy and Infectious Diseases (K.S., P.J.-P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (N.C.), National Institutes of Health, Bethesda - all in Maryland; the Harvard T.H. Chan School of Public Health, Boston (G.M., L. Aaron, G.R.M.); the Family Clinical Research Unit, Department of Obstetrics and Gynaecology, Stellenbosch University, Cape Town (G.T.), the Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg (A.V.), and the Desmond Tutu TB Center, Department of Paediatrics and Child Health, Stellenbosch University, Tygerberg (A.H.) - all in South Africa; FHI 360, Durham, NC (K.M., S.B.); University of Zimbabwe College of Health Sciences Clinical Trials Research Centre, Harare (T.C., T.V., L.S.-C.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (C.O.-M.); Botswana Harvard AIDS Institute Partnership, Gaborone (G.R.M.); Kilimanjaro Christian Medical Centre, Moshi, Tanzania (B.T.M.); Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand (L. Aurpibul); Byramjee Jeejeebhoy Government Medical College (R.B.) and Byramjee Jeejeebhoy Government College-Johns Hopkins Clinical Research Site (A.G., V.M.), Pune, India; Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR), Port au Prince, Haiti (V.R.); Frontier Science Foundation, Amherst, NY (B.Z.); University of California, Los Angeles, Los Angeles (D.C.); Vanderbilt University Medical Center, Nashville (T.R.S.); and the University of Colorado Denver Anschutz Medical Campus, Aurora (A.W.).;From the Center for Clinical Global Health Education, Johns Hopkins University, Baltimore (A.G., V.M.), and the Division of AIDS, National Institute of Allergy and Infectious Diseases (K.S., P.J.-P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (N.C.), National Institutes of Health, Bethesda - all in Maryland; the Harvard T.H. Chan School of Public Health, Boston (G.M., L. Aaron, G.R.M.); the Family Clinical Research Unit, Department of Obstetrics and Gynaecology, Stellenbosch University, Cape Town (G.T.), the Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg (A.V.), and the Desmond Tutu TB Center, Department of Paediatrics and Child Health, Stellenbosch University, Tygerberg (A.H.) - all in South Africa; FHI 360, Durham, NC (K.M., S.B.); University of Zimbabwe College of Health Sciences Clinical Trials Research Centre, Harare (T.C., T.V., L.S.-C.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (C.O.-M.); Botswana Harvard AIDS Institute Partnership, Gaborone (G.R.M.); Kilimanjaro Christian Medical Centre, Moshi, Tanzania (B.T.M.); Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand (L. Aurpibul); Byramjee Jeejeebhoy Government Medical College (R.B.) and Byramjee Jeejeebhoy Government College-Johns Hopkins Clinical Research Site (A.G., V.M.), Pune, India; Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR), Port au Prince, Haiti (V.R.); Frontier Science Foundation, Amherst, NY (B.Z.); University of California, Los Angeles, Los Angeles (D.C.); Vanderbilt University Medical Center, Nashville (T.R.S.); and the University of Colorado Denver Anschutz Medical Campus, Aurora (A.W.).;From the Center for Clinical Global Health Education, Johns Hopkins University, Baltimore (A.G., V.M.), and the Division of AIDS, National Institute of Allergy and Infectious Diseases (K.S., P.J.-P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (N.C.), National Institutes of Health, Bethesda - all in Maryland; the Harvard T.H. Chan School of Public Health, Boston (G.M., L. Aaron, G.R.M.); the Family Clinical Research Unit, Department of Obstetrics and Gynaecology, Stellenbosch University, Cape Town (G.T.), the Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg (A.V.), and the Desmond Tutu TB Center, Department of Paediatrics and Child Health, Stellenbosch University, Tygerberg (A.H.) - all in South Africa; FHI 360, Durham, NC (K.M., S.B.); University of Zimbabwe College of Health Sciences Clinical Trials Research Centre, Harare (T.C., T.V., L.S.-C.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (C.O.-M.); Botswana Harvard AIDS Institute Partnership, Gaborone (G.R.M.); Kilimanjaro Christian Medical Centre, Moshi, Tanzania (B.T.M.); Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand (L. Aurpibul); Byramjee Jeejeebhoy Government Medical College (R.B.) and Byramjee Jeejeebhoy Government College-Johns Hopkins Clinical Research Site (A.G., V.M.), Pune, India; Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR), Port au Prince, Haiti (V.R.); Frontier Science Foundation, Amherst, NY (B.Z.); University of California, Los Angeles, Los Angeles (D.C.); Vanderbilt University Medical Center, Nashville (T.R.S.); and the University of Colorado Denver Anschutz Medical Campus, Aurora (A.W.).",
"authors": "Gupta|Amita|A|;Montepiedra|Grace|G|;Aaron|Lisa|L|;Theron|Gerhard|G|;McCarthy|Katie|K|;Bradford|Sarah|S|;Chipato|Tsungai|T|;Vhembo|Tichaona|T|;Stranix-Chibanda|Lynda|L|;Onyango-Makumbi|Carolyne|C|;Masheto|Gaerolwe R|GR|;Violari|Avy|A|;Mmbaga|Blandina T|BT|;Aurpibul|Linda|L|;Bhosale|Ramesh|R|;Mave|Vidya|V|;Rouzier|Vanessa|V|;Hesseling|Anneke|A|;Shin|Katherine|K|;Zimmer|Bonnie|B|;Costello|Diane|D|;Sterling|Timothy R|TR|;Chakhtoura|Nahida|N|;Jean-Philippe|Patrick|P|;Weinberg|Adriana|A|;|||",
"chemical_list": "D000995:Antitubercular Agents; D007538:Isoniazid",
"country": "United States",
"delete": false,
"doi": "10.1056/NEJMoa1813060",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-4793",
"issue": "381(14)",
"journal": "The New England journal of medicine",
"keywords": null,
"medline_ta": "N Engl J Med",
"mesh_terms": "D017088:AIDS-Related Opportunistic Infections; D000293:Adolescent; D000328:Adult; D000995:Antitubercular Agents; D004311:Double-Blind Method; D005260:Female; D015658:HIV Infections; D006801:Humans; D007223:Infant; D007226:Infant Mortality; D007231:Infant, Newborn; D019102:Infant, Very Low Birth Weight; D007538:Isoniazid; D008111:Liver Function Tests; D049590:Postpartum Period; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D011256:Pregnancy Outcome; D047928:Premature Birth; D011446:Prospective Studies; D014376:Tuberculosis; D055815:Young Adult",
"nlm_unique_id": "0255562",
"other_id": null,
"pages": "1333-1346",
"pmc": null,
"pmid": "31577875",
"pubdate": "2019-10-03",
"publication_types": "D000073843:Equivalence Trial; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013486:Research Support, U.S. Gov't, Non-P.H.S.",
"references": "16176115;19617813;1456591;26959511;4005387;24835842;30067931;27243774;26193126;17021358;29017245;11453606;10460815;25207782;2782741;22942202;26658057;25118796;10881762;1736764;29393655;22289568;9266585;21492926;30865794;21148136;14998501;30882723;16344522;23343913;17578786;2495549;21732833;23533318;22150035;25081933",
"title": "Isoniazid Preventive Therapy in HIV-Infected Pregnant and Postpartum Women.",
"title_normalized": "isoniazid preventive therapy in hiv infected pregnant and postpartum women"
} | [
{
"companynumb": "BW-ALKEM LABORATORIES LIMITED-BW-ALKEM-2019-09338",
"fulfillexpeditecriteria": "1",
"occurcountry": "BW",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ISONIAZID"
},
"drugad... |
{
"abstract": "This study explored the effect of thalidomide and cyclophosphamide on stem cell collection, in addition to assessing their efficacy as induction therapy for myeloma patients destined for autologous stem cell transplantation (ASCT). We analyzed newly diagnosed myeloma patients who received TCD (thalidomide 100 mg/day for 28 days, oral cyclophosphamide 150 mg/m 2 /day and dexamethasone 40 mg/day on days 1–4) as induction therapy prior to ASCT. Peripheral stem cells were mobilized with granulocyte colony-stimulating factor and cyclophosphamide. Thirty-six patients (median age 54 years) received TCD chemotherapy (median 4 cycles). The overall response rate to TCD was 77.8% (28/36). The median number of CD34+ cells was 6.5 × 10 6 /kg, and 2 patients failed to achieve the optimal number of CD34+ cells, i.e. 4.0 × 10 6 /kg, although they were able to attain >2.0 × 10 6 /kg. The overall response rate increased up to 94.4% (34/36) after ASCT; this included 9 patients with a stringent complete response without transplantation-related mortality. Four patients died due to disease progression and 17 were found to have progressed after ASCT (the median progression-free survival after ASCT was 19.6 months). TCD chemotherapy can be an effective and feasible induction regimen prior to ASCT for myeloma patients.",
"affiliations": null,
"authors": "Chang|Won Jin|WJ|;Kang|Eun-Suk|ES|;Lee|Seung-Tae|ST|;Kim|Sun-Hee|SH|;Kim|Dae Won|DW|;Kim|Seok Jin|SJ|;Kim|Kihyun|K|",
"chemical_list": "D001897:Boronic Acids; D007155:Immunologic Factors; D011719:Pyrazines; D013792:Thalidomide; D000069286:Bortezomib; D003907:Dexamethasone; D003520:Cyclophosphamide",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000357659",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0001-5792",
"issue": "132(2)",
"journal": "Acta haematologica",
"keywords": null,
"medline_ta": "Acta Haematol",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001897:Boronic Acids; D000069286:Bortezomib; D003248:Constipation; D003520:Cyclophosphamide; D003907:Dexamethasone; D018450:Disease Progression; D004334:Drug Administration Schedule; D004341:Drug Evaluation; D057915:Drug Substitution; D005240:Feasibility Studies; D005260:Female; D006402:Hematologic Diseases; D019650:Hematopoietic Stem Cell Mobilization; D006801:Humans; D007155:Immunologic Factors; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D036102:Peripheral Blood Stem Cell Transplantation; D011719:Pyrazines; D012074:Remission Induction; D012189:Retrospective Studies; D012678:Sensation Disorders; D013792:Thalidomide; D014182:Transplantation, Autologous; D016896:Treatment Outcome",
"nlm_unique_id": "0141053",
"other_id": null,
"pages": "226-32",
"pmc": null,
"pmid": "24732093",
"pubdate": "2014",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Thalidomide, cyclophosphamide and dexamethasone induction therapy: feasibility for myeloma patients destined for autologous stem cell transplantation.",
"title_normalized": "thalidomide cyclophosphamide and dexamethasone induction therapy feasibility for myeloma patients destined for autologous stem cell transplantation"
} | [
{
"companynumb": "KR-BAXTER-2015BAX025491",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
... |
{
"abstract": "Renal transplant recipients are at risk for opportunistic infections due to their immunosuppressed state. We describe the case of a 59-year-old renal transplant recipient who presented with sepsis and bilateral pulmonary emboli due to Candida parapsilosis She was treated with intravenous caspofungin and had a transoesophageal echocardiogram, which revealed vegetations on her pacemaker leads. She then underwent surgery to replace her pacemaker; however, her blood cultures remained positive for C. parapsilosis postoperatively. Her antifungal was switched to liposomal amphotericin B and flucytosine for 6 weeks, which yielded sterile blood cultures, and she was then initiated on lifelong fluconazole. Her recovery was complicated by tacrolimus toxicity 1 month after discharge due to fluconazole-induced CYP3A inhibition.",
"affiliations": "Nephrology Department, Beaumont Hospital, Dublin, Ireland hebertj@tcd.ie.;Nephrology Department, Beaumont Hospital, Dublin, Ireland.;Nephrology Department, Beaumont Hospital, Dublin, Ireland.",
"authors": "Hebert|Josephine|J|;Barr|Ellen|E|;Magee|Colm|C|",
"chemical_list": "D000935:Antifungal Agents; D015725:Fluconazole",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2021-242917",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(7)",
"journal": "BMJ case reports",
"keywords": "COVID-19; infectious diseases; renal system; renal transplantation",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000935:Antifungal Agents; D000074429:Candida parapsilosis; D005260:Female; D015725:Fluconazole; D016469:Fungemia; D006801:Humans; D016030:Kidney Transplantation; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D010138:Pacemaker, Artificial",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34230047",
"pubdate": "2021-07-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "26288749;15266524;33052591;31155770;18180354;22660960;11801579;26679628;16567242;18056277;32419877;10577295;32302076;17805589;18498304;16672393;32855352;31724720;20219079;31898417;25883698;22086858;26595825;31756280;12867214;26221097;30814115;9792309;32473113;32664309",
"title": "Pacemaker-related Candida parapsilosis fungaemia in an immunosuppressed renal transplant recipient.",
"title_normalized": "pacemaker related candida parapsilosis fungaemia in an immunosuppressed renal transplant recipient"
} | [
{
"companynumb": "IE-STRIDES ARCOLAB LIMITED-2021SP027337",
"fulfillexpeditecriteria": "1",
"occurcountry": "IE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MIDODRINE"
},
"drugadditional"... |
{
"abstract": "Management of ventricular tachycardia storm requires multimodal aggressive therapeutic interventions for a successful outcome. A 39-year-old man with dilated cardiomyopathy and severe left ventricular dysfunction presented with refractory ventricular tachycardia unresponsive to conventional treatment. He underwent an electrophysiology study and radiofrequency ablation with 3-dimensional mapping with partial control of the ventricular tachycardia. Further left sympathetic ganglion block followed by left cardiac sympathetic denervation also did not totally control the ventricular tachycardia. Right cardiac sympathetic denervation resulting in bilateral cardiac sympathetic denervation controlled the ventricular tachycardia.",
"affiliations": "Department of Cardiology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India.;Department of Cardiology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India.;Department of Cardiothoracic Surgery, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India.;Department of Cardiothoracic Surgery, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India.",
"authors": "Sai Satish|Oruganti|O|https://orcid.org/0000-0003-3650-8650;Vavilala|Satish Kumar Rao|SKR|https://orcid.org/0000-0002-3378-8872;Kaladhar|Bomma|B|;Surya Satya Gopal|Palanki|P|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/0218492320960898",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0218-4923",
"issue": "29(2)",
"journal": "Asian cardiovascular & thoracic annals",
"keywords": "Autonomic nervous system; radiofrequency ablation; sympathectomy; tachycardia; ventricular; ventricular fibrillation",
"medline_ta": "Asian Cardiovasc Thorac Ann",
"mesh_terms": "D000328:Adult; D002311:Cardiomyopathy, Dilated; D017115:Catheter Ablation; D003131:Combined Modality Therapy; D016757:Death, Sudden, Cardiac; D017147:Defibrillators, Implantable; D004554:Electric Countershock; D006321:Heart; D006339:Heart Rate; D006801:Humans; D008297:Male; D012008:Recurrence; D013233:Stellate Ganglion; D013562:Sympathectomy; D017180:Tachycardia, Ventricular; D016896:Treatment Outcome; D018487:Ventricular Dysfunction, Left; D016277:Ventricular Function, Left",
"nlm_unique_id": "9503417",
"other_id": null,
"pages": "122-124",
"pmc": null,
"pmid": "32938204",
"pubdate": "2021-02",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Multipronged approach to a patient with ventricular tachycardia storm.",
"title_normalized": "multipronged approach to a patient with ventricular tachycardia storm"
} | [
{
"companynumb": "IN-B.BRAUN MEDICAL INC.-2109758",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "AMIODARONE HYDROCHLORIDE"
},
"drugaddi... |
{
"abstract": "OBJECTIVE\nAcute ischemic stroke patients are at risk of early recurrence. We tested the feasibility and safety of initiating dabigatran in patients, within 24 hours of minor stroke in patients without atrial fibrillation.\n\n\nMETHODS\nMinor stroke patients (National Institutes of Health Stroke Scale score ≤3) without atrial fibrillation and evidence of acute infarction on magnetic resonance imaging were treated with dabigatran. Treatment began within 24 hours of onset and was continued for 30 days. The primary end point was symptomatic hemorrhagic transformation.\n\n\nRESULTS\nA total of 53 patients with median (interquartile range) age of 68 (57-77) years and National Institutes of Health Stroke Scale score of 1 (0-2) were enrolled. Baseline diffusion-weighted imaging volume was 0.8 (0.3-2.4) mL. No patients experienced symptomatic hemorrhagic transformation. Three patients had evidence of asymptomatic petechial hemorrhagic transformation on day 7, which remained stable at day 30, while continuing dabigatran.\n\n\nCONCLUSIONS\nDabigatran treatment within 24 hours of minor stroke is feasible. A larger randomized trial is required to confirm the safety and efficacy of this treatment approach.\n\n\nBACKGROUND\nURL: http://www.clinicaltrials.gov. Unique identifier: NCT 01769703.",
"affiliations": "From the Division of Neurology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.;From the Division of Neurology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.;From the Division of Neurology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.;From the Division of Neurology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.;From the Division of Neurology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.;From the Division of Neurology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.;From the Division of Neurology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada. ken.butcher@ualberta.ca.",
"authors": "Kate|Mahesh|M|;Gioia|Laura|L|;Buck|Brian|B|;Sivakumar|Leka|L|;Jeerakathil|Thomas|T|;Shuaib|Ashfaq|A|;Butcher|Kenneth|K|",
"chemical_list": "D000991:Antithrombins; D000069604:Dabigatran",
"country": "United States",
"delete": false,
"doi": "10.1161/STROKEAHA.115.010383",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0039-2499",
"issue": "46(9)",
"journal": "Stroke",
"keywords": "anticoagulants; brain infarction; dabigatran; stroke",
"medline_ta": "Stroke",
"mesh_terms": "D000368:Aged; D000991:Antithrombins; D002545:Brain Ischemia; D000069604:Dabigatran; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020521:Stroke; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "0235266",
"other_id": null,
"pages": "2685-7",
"pmc": null,
"pmid": "26304866",
"pubdate": "2015-09",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Dabigatran Therapy in Acute Ischemic Stroke Patients Without Atrial Fibrillation.",
"title_normalized": "dabigatran therapy in acute ischemic stroke patients without atrial fibrillation"
} | [
{
"companynumb": "CA-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2015-BI-47860BI",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
... |
{
"abstract": "While trials of systemic thrombolysis for submassive and massive pulmonary embolism (PE) report intracranial haemorrhage (ICH) rates of 2%-3%, the risk of ICH in patients with recent brain surgery or intracranial neoplasm is unknown since these patients were excluded from these trials. We report a case of massive PE treated with systemic thrombolysis in a patient with recent neurosurgery for an intracranial neoplasm. We discuss the risks and benefits of systemic thrombolysis for massive PE in the context of previous case reports, prior cohort studies and trials, and current guidelines. There may be times when the immediate risk of death from massive PE outweighs the risk of ICH from systemic thrombolysis, even when guideline-listed major contraindications exist. This case provides an example of how the haemodynamic benefit of systemic thrombolysis outweighed the impact of ICH in a patient who had undergone recent neurosurgical resection of a glioblastoma multiforme tumour.",
"affiliations": "Department of Internal Medicine, Columbia University Medical Center, New York City, New York, USA.;Division of Cardiology, Columbia University Medical Center, New York, NY.;Division of Cardiology, Columbia University Medical Center, New York, NY.;Division of Pulmonary and Critical Care Medicine, Columbia University College of Physicians and Surgeons, New York, NY.",
"authors": "Lampert|Joshua|J|;Bikdeli|Behnood|B|;Green|Philip|P|;Baldwin|Matthew R|MR|http://orcid.org/0000-0003-4670-3433",
"chemical_list": "D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-221578",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "Adult Intensive Care; Contraindications And Precautions; Pulmonary Embolism; Safety; Venous Thromboembolism",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D061605:Administration, Intravenous; D000359:Aftercare; D000072226:Computed Tomography Angiography; D005260:Female; D005343:Fibrinolytic Agents; D005909:Glioblastoma; D006801:Humans; D020300:Intracranial Hemorrhages; D008875:Middle Aged; D019635:Neurosurgical Procedures; D017410:Practice Guidelines as Topic; D011655:Pulmonary Embolism; D018570:Risk Assessment; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29191822",
"pubdate": "2017-11-29",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "26315743;25009081;16227546;24938564;16009801;23247303;19726752;17084012;10475182;2868337;25749665;24412030;26867832;11283388;15262836;19741062;16855059;21422387;9350909;24808778;16514104;24716681;8204123;10227218",
"title": "Systemic thrombolysis in a patient with massive pulmonary embolism and recent glioblastoma multiforme resection.",
"title_normalized": "systemic thrombolysis in a patient with massive pulmonary embolism and recent glioblastoma multiforme resection"
} | [
{
"companynumb": "US-WEST-WARD PHARMACEUTICALS CORP.-US-H14001-17-05209",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
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"abstract": "Assess the effect of a protocol of preoperative erythropoietin (EPO) and ferrous sulfate in addition to perioperative tranexamic acid (TXA) on blood transfusions in patients with coronal or metopic craniosynostosis undergoing cranial vault remodeling (CVR) with fronto-orbital advancement (FOA).\n\n\n\nRetrospective review of all coronal and metopic craniosynostosis patients undergoing CVR and FOA from March 2010 to June 2019 was performed. Before 2014 (\"Control group\"), all patients received blood transfusion at the start of surgery. In 2014, a protocol of preoperative EPO and ferrous sulfate with perioperative TXA and non-automatic transfusion was instituted (\"Study group\"). Patient demographics and anthropometrics, perioperative hemoglobin (Hb) levels, and transfusion details were collected and compared.\n\n\n\nThirty-six patients met inclusion criteria. Twenty-one patients were in the control group, and 15 in the Study group. Nineteen patients had metopic synostosis, 11 had unicoronal synostosis, and 6 had bicoronal synostosis. There were no significant differences between groups in demographics, operative time, intraoperative crystalloid volume, craniofacial syndromes, or sutures affected. The Study group had higher preoperative Hb (13.9 ± 1.0 vs. 12.6 ± 0.8 g/dL, p < 0.001), lower intraoperative Hb nadir (7.4 ± 1.8 vs. 9.2 ± 1.2 g/dL) lower intraoperative transfusion rate (66.7% vs. 100%, p = 0.008), lower postoperative transfusion rate (0% vs 28.6%, p = 0.03), and exposure to fewer unique units of packed red blood cells (0.7 ± 0.6 vs. 1.5 ± 0.9 units).\n\n\n\nOur protocol resulted in decreased transfusion needs. These results add valuable information to the growing body of work on transfusion reduction in craniosynostosis surgery.",
"affiliations": "University of Minnesota Medical School, Minneapolis, MN, USA.;Children's Hospital of Eastern Ontario, Ottawa, Canada.;Children's Minnesota Center for Bleeding and Clotting Disorders, Minneapolis, MN, USA.;Children's Minnesota Research Institute, Minneapolis, MN, USA.;Department of Neurosurgery, Children's Minnesota, Minneapolis, MN, USA.;Department of Neurosurgery, Children's Minnesota, Minneapolis, MN, USA.;Department of ENT and Craniofacial Surgery, Children's Minnesota, 2530 Chicago Ave. S, CSC 450, Minneapolis, MN, 55404, USA.;Department of ENT and Craniofacial Surgery, Children's Minnesota, 2530 Chicago Ave. S, CSC 450, Minneapolis, MN, 55404, USA. Robert.tibesar@childrensmn.org.",
"authors": "Escher|Paul J|PJ|;Tu|Albert D|AD|;Kearney|Susan L|SL|;Linabery|Amy M|AM|;Petronio|Joseph A|JA|;Kebriaei|Meysam A|MA|;Chinnadurai|Sivakumar|S|;Tibesar|Robert J|RJ|0000-0001-5338-5328",
"chemical_list": "D004921:Erythropoietin; D014148:Tranexamic Acid",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00381-020-04654-y",
"fulltext": null,
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"issn_linking": "0256-7040",
"issue": "37(1)",
"journal": "Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery",
"keywords": "Coronal craniosynostosis; Erythropoietin; Fronto-orbital advancement; Metopic craniosynostosis",
"medline_ta": "Childs Nerv Syst",
"mesh_terms": "D016063:Blood Loss, Surgical; D001803:Blood Transfusion; D003398:Craniosynostoses; D004921:Erythropoietin; D006801:Humans; D007223:Infant; D012189:Retrospective Studies; D014148:Tranexamic Acid",
"nlm_unique_id": "8503227",
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"pages": "269-276",
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"pubdate": "2021-01",
"publication_types": "D016428:Journal Article",
"references": "15168053",
"title": "A protocol of situation-dependent transfusion, erythropoietin and tranexamic acid reduces transfusion in fronto-orbital advancement for metopic and coronal craniosynostosis.",
"title_normalized": "a protocol of situation dependent transfusion erythropoietin and tranexamic acid reduces transfusion in fronto orbital advancement for metopic and coronal craniosynostosis"
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"abstract": "Negative pressure wound therapy with intermittent instillation, especially with the addition of antibiotics in the case of infection, is a versatile treatment modality for the closure of wounds and can be used both primarily after débridement and secondarily after failure of muscle flap coverage. We present a case in which negative pressure wound therapy with intermittent instillation of rifampin was used to successfully close a groin wound secondary to an infected prosthetic vascular graft that initially failed to close with a muscle flap. Consideration of this approach to wound closure and graft salvage is important because of the seriousness and relatively common incidence of prosthetic vascular graft infection after infrainguinal arterial bypass revascularization.",
"affiliations": "Center for Wound Healing and Hyperbaric Medicine, Department of Plastic Surgery, MedStar Georgetown University Hospital, Washington, D.C.;Center for Wound Healing and Hyperbaric Medicine, Department of Plastic Surgery, MedStar Georgetown University Hospital, Washington, D.C.;Center for Wound Healing and Hyperbaric Medicine, Department of Plastic Surgery, MedStar Georgetown University Hospital, Washington, D.C.;Center for Wound Healing and Hyperbaric Medicine, Department of Plastic Surgery, MedStar Georgetown University Hospital, Washington, D.C.;Center for Wound Healing and Hyperbaric Medicine, Department of Plastic Surgery, MedStar Georgetown University Hospital, Washington, D.C.;Center for Wound Healing and Hyperbaric Medicine, Department of Plastic Surgery, MedStar Georgetown University Hospital, Washington, D.C.",
"authors": "Lakhiani|Chrisovalantis|C|;Fleury|Christopher M|CM|;Black|Cara K|CK|;Janhofer|David E|DE|;Akbari|Cameron|C|;Evans|Karen Kim|KK|",
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"fulltext": "\n==== Front\nJ Vasc Surg Cases Innov TechJ Vasc Surg Cases Innov TechJournal of Vascular Surgery Cases and Innovative Techniques2468-4287Elsevier S2468-4287(19)30069-310.1016/j.jvscit.2019.04.008Vascular graft infectionNegative pressure wound therapy with intermittent instillation of rifampin for the treatment of an infected vascular bypass graft Lakhiani Chrisovalantis MDFleury Christopher M. MDBlack Cara K. BAJanhofer David E. BSAkbari Cameron MDEvans Karen Kim MDkaren.k.evans@gunet.georgetown.edu∗Center for Wound Healing and Hyperbaric Medicine, Department of Plastic Surgery, MedStar Georgetown University Hospital, Washington, D.C.∗ Correspondence: Karen Kim Evans, MD, Associate Professor, Department of Plastic and Reconstructive Surgery, 3800 Reservoir Rd NW, Center for Wound Healing and Hyperbaric Medicine, 1st Fl, Bles Bldg, Washington, D.C. 20007 karen.k.evans@gunet.georgetown.edu05 10 2019 12 2019 05 10 2019 5 4 435 437 26 2 2019 25 4 2019 © 2019 The Authors2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Negative pressure wound therapy with intermittent instillation, especially with the addition of antibiotics in the case of infection, is a versatile treatment modality for the closure of wounds and can be used both primarily after débridement and secondarily after failure of muscle flap coverage. We present a case in which negative pressure wound therapy with intermittent instillation of rifampin was used to successfully close a groin wound secondary to an infected prosthetic vascular graft that initially failed to close with a muscle flap. Consideration of this approach to wound closure and graft salvage is important because of the seriousness and relatively common incidence of prosthetic vascular graft infection after infrainguinal arterial bypass revascularization.\n\nKeywords\nNegative pressure wound therapyNPWTVAC instillRifampinInstillation\n==== Body\nProsthetic vascular graft infection after infrainguinal arterial bypass revascularization is a serious complication occurring in nearly 5% of procedures.1, 2 Traditionally, treatment of these complications involves graft excision and reconstruction with extra-anatomic bypass; however, these complex procedures are associated with a high rate of limb loss and mortality.1, 3, 4 A paradigm shift based on local wound treatment with preservation of the infected graft has resulted in improved outcomes using a combination of débridement and intravenous culture-directed antibiotic therapy, with either subsequent muscle flap coverage or, more recently, negative pressure wound therapy (NPWT) with vacuum-assisted closure of the wound.5, 6, 7, 8, 9, 10, 11 The recent resurgence of NPWT with intermittent instillation of fluid (NPWTi) presents a new opportunity in the treatment of infected prosthetic grafts after revascularization. The ability to provide local instillation of culture-directed antibiotic solutions combined with NPWT helps maximize the likelihood of resolution of infection and subsequent successful wound closure with graft preservation. A review of the literature revealed no reported cases involving the use of NPWTi with antibiotic solution for the treatment of deep perivascular groin wound and prosthetic graft infection after lower limb arterial bypass. Here we present a case using this modality for wound care and graft salvage after failed muscle flap coverage. The patient's consent was acquired for the writing of this case report and display of photographs.\n\nCase report\nThe patient is a 78-year-old man with hypertension, hyperlipidemia, type 2 diabetes (hemoglobin A1c, 7.1%), atrial fibrillation, peripheral artery disease, and chronic nonhealing lower extremity wounds. Three years before admission, the patient required a left below-knee amputation for an infected nonhealing foot wound. He received a right common femoral artery to posterior tibial artery bypass using a native saphenous vein graft in the past, which subsequently occluded, and required revision of the bypass with a polytetrafluoroethylene graft from the right common femoral artery to the posterior tibial artery. Given the prosthetic nature of the graft and because he had a copious amount of scar tissue in the groin from previous bypass surgery, the decision was made to cover the graft prophylactically with a sartorius muscle flap. We routinely use groin prophylactic muscle flap during secondary groin procedures. The sartorius muscle flap provides durable muscle coverage of the graft and can accelerate healing. This method has been reported in the literature as an effective means to control infection and to maintain the graft.12, 13 As is typical for our institution's protocol, we placed a drain at the muscle harvest site for possible seroma formation and used dry dressings with subsequent dressing changes every 2 days in the postoperative period.\n\nDespite sartorius coverage, the patient was readmitted to the hospital 10 days postoperatively with groin wound dehiscence and foul-smelling discharge. Cultures from fluid around the graft were positive, which suggested graft infection. He was admitted with fever, chills, and obvious systemic infection. On initial washout, the sartorius flap was adherent to the underlying graft, and no graft material was visible. The patient was started on vancomycin and piperacillin-tazobactam, with meropenem subsequently added. During the next 3 weeks, the patient was taken to the operating room six times for washouts. The patient underwent operative washouts approximately every 3 days during this time. Despite intravenous antibiotic therapy and repeated débridements, postdébridement cultures persistently grew Proteus vulgaris, Candida albicans, and vancomycin-resistant Enterococcus faecalis.\n\nIn an effort to mitigate persistent microbial colonization of the prosthetic material, NPWTi using a rifampin solution for instillation between washouts was performed. The rifampin solution (60 mL total, 0.6 mg of rifampin per milliliter of 0.9% saline solution) was instilled for 20 minutes of dwell time every 2 hours. During the 2-hour periods between rifampin instillation, the vacuum mechanism suctions off excess fluid. The patient was admitted to the hospital for the duration of these NPWT treatments, which was approximately 30 days for the treatment of the graft infection and management of other medical comorbidities. We used NPWT according to standard guidelines and settings as suggested by the manufacturer (V.A.C. Therapy, KCI Medical, United Kingdom) and used instillation per our previously published review of evidence and recommendations.14\n\nThe patient subsequently underwent two more washouts, with a rifampin instillation solution used between washouts. After the second washout, he was found to be culture negative, which was the intended end point of the instillation treatment. The graft was always protected by a nonadherent layer of wound dressing material during washouts to prevent direct exposure. A final operation was performed to readvance the sartorius flap and to close the defect over two drains. The patient did well postoperatively. At 2-year follow-up, the graft was still patent, and he had no further wound complications. The Fig shows the patient's closed groin wound at 3 years after treatment with NPWTi and rifampin.Fig Postoperative photograph of a groin wound closed with negative pressure wound therapy (NPWT) with intermittent instillation of rifampin. A 78-year-old man with various comorbidities developed a right groin wound secondary to an infected prosthetic vascular graft. After failure of sartorius muscle flap coverage of the wound, NPWT with intermittent instillation of rifampin helped close the wound successfully. The photograph is taken 3 years after application of this treatment modality.\n\n\n\nDiscussion\nSurgical site infections and subsequent vascular graft infections are among the most feared complications in vascular surgery. The incidence of infrainguinal prosthetic graft infections (as occurred in our patient) has been reported to be 4.7%, with amputation and mortality rates as high as 52% and 58%, respectively.4, 15 Traditional treatment consists of removal of the infected graft and subsequent extra-anatomic revascularization, a procedure that similarly results in a high rate of limb loss and mortality.1, 4 This traditional treatment is required in four conditions: disruption of the vascular anastomosis, infection of the entirety of the graft, uncontrolled sepsis, and infection with Pseudomonas aeruginosa.14\n\nIn the absence of any of these conditions, the treatment paradigm has shifted toward aggressive débridement and intravenous antibiotics, followed by either muscle flap coverage or NPWT placement. Muscle flap coverage has been reported to have up to 75% initial success rate; however, there is evidence of reinfection in up to 35% of cases.10, 11 Commonly used muscle flaps include the sartorius and the rectus femoris. However, as evidenced in the case of our patient, muscle flaps can fail and are susceptible to reinfection, which requires a new treatment plan. Several case reports have shown resolution of infection with débridement, intravenous antibiotics, and use of NPWT technology on the site, allowing preservation of the graft.5, 6, 7, 8, 9, 10, 11\n\nEarly use of NPWT technology to close infected groin wounds and to salvage infected grafts has been reported in patients who were unsuitable surgical candidates for muscle flap closure. These few cases show promise in achieving complete wound closure using a combination of débridement, culture-directed intravenous antibiotic therapy, and NPWT placement.8 These reports led to additional case series using vacuum-assisted closure after débridement and intravenous antibiotics, with good rates of complete closure and infection resolution.5, 6, 9 Furthermore, despite the manufacturer's reported contraindication to NPWT use in wounds with exposed vessels or vascular grafts, various techniques have been shown to be safe, including covering of the vessels and grafts with nonocclusive dressings, use of dual sponges, and relatively low-pressure NPWT.5, 6, 8, 9\n\nNPWTi has been available for nearly 15 years but was not widely used until the newest generation system was released in 2013.16 The initial international expert guidelines acknowledged the potential utility of intermittent instillation of antimicrobial fluids combined with vacuum-assisted closure therapy in both acute and chronic wounds and even in exposed orthopedic hardware but did not address the possible utility in infected vascular grafts. In 2014, Kim et al17 reported a retrospective trial of 142 hospitalized patients with acutely and chronically infected wounds and found that the patients receiving NPWT with instillation of polyhexanide-betaine solution required fewer operating room visits and a decreased overall hospital stay than patients receiving conventional NPWT. More recently, Kim et al18 compared outcomes of NPWTi using normal saline vs polyhexanide-betaine solution in 123 hospitalized patients with acute and chronic wounds and found no significant difference between the solutions used. Despite the efficacy of polyhexanide-betaine, rifampin was used as an instillation fluid because the vascular surgery literature supports the replacement of infected endovascular aneurysm repair and thoracic endovascular aortic repair with a rifampin-impregnated Dacron graft.\n\nWe were unable to find any case reports of infected prosthetic vascular grafts treated with NPWTi. Given the evidence for NPWT without instillation in the treatment of infected infrainguinal prosthetic vascular grafts as well as evidence showing improved outcomes of NPWTi over simple NPWT in acute wounds, we believe that NPWTi is a logical next step in the treatment of these infected grafts. Instillation of culture-guided antibiotic solutions in addition to débridement, intravenous antibiotics, and NPWT presents a promising approach.\n\nConclusions\nAs with conventional NPWT, NPWTi is a treatment modality that can be used either primarily after débridement or secondarily after failure of muscle flap coverage (as in our case). Furthermore, this versatile treatment can be used to completion of wound healing or simply as a means to stabilize the wound and to resolve the infection before definitive closure with a subsequent muscle flap. Given the lack of reported use of NPWTi technology for the purpose of treating infected prosthetic vascular grafts, we believe additional research is required in this field to investigate the efficacy of this new therapy option.\n\nAuthor conflict of interest: none.\n\nThe editors and reviewers of this article have no relevant financial relationships to disclose per the Journal policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest.\n==== Refs\nReferences\n1 Szilagyi D.E. Smith R.F. Elliott J.P. Vrandecic M.P. Infection in arterial reconstruction with synthetic grafts Ann Surg 176 1972 321 333 4262892 \n2 Leroy O. Meybeck A. Sarraz-Bournet B. d’Elia P. Legout L. Vascular graft infections Curr Opin Infect Dis 25 2012 154 158 22248976 \n3 Calligaro K.D. Veith F.J. Schwartz M.L. Goldsmith J. Savarese R.P. Dougherty M.J. Selective preservation of infected prosthetic arterial grafts: analysis of a 20 year experience with 120 extracavitary-infected grafts Ann Surg 220 1994 461 471 7944658 \n4 Edwards W.H. Martin R.S. Jenkins J.M. Edwards W.H. Mulherin J.L. Primary graft infections J Vasc Surg 6 1987 235 239 2957513 \n5 Acosta S. Monsen C. Outcome after VAC therapy for infected bypass grafts in the lower limb Eur J Vasc Endovasc Surg 44 2012 294 299 22818802 \n6 Berger P. de Bie D. Moll F.L. de Borst G.J. Negative pressure wound therapy on exposed prosthetic vascular grafts in the groin J Vasc Surg 56 2012 714 720 22554424 \n7 Colwell A.S. Donaldson M.C. Belkin M. Orgill D.P. Management of early groin vascular bypass graft infections with sartorius and rectus femoris flaps Ann Plast Surg 52 2004 49 53 14676699 \n8 Dosluoglu H.H. Schimpf D.K. Schultz R. Cherr G.S. Preservation of infected and exposed vascular grafts using vacuum assisted closure without muscle flap coverage J Vasc Surg 42 2005 989 992 16275458 \n9 Dosluoglu H.H. Loghmanee C. Lall P. Cherr G.S. Harris L.M. Dryjski M.L. Management of early (<30 day) vascular groin infections using vacuum-assisted closure alone without muscle flap coverage in a consecutive patient series J Vasc Surg 51 2010 1160 1166 20356703 \n10 Illig K.A. Alkon J.E. Smith A. Rhodes J.M. Keefer A. Doyle A. Rotational muscle flap closure for acute groin wound infections following vascular surgery Ann Vasc Surg 18 2004 661 668 15599623 \n11 Perler B.A. Kolk C.A. Manson P.M. Williams G.M. Rotational muscle flaps to treat localized prosthetic graft infection: long-term follow-up J Vasc Surg 18 1993 358 364 8377229 \n12 Armstrong P.A. Back M.R. Bandyk D.F. Johnson B.L. Shames M.L. Selective application of sartorius muscle flap and aggressive staged surgical debridement can influence long-term outcomes of complex prosthetic graft infections J Vasc Surg 46 2007 71 78 17606124 \n13 Fischer J.P. Mirabeigi M.N. Sieber B.A. Nelson J.A. Wu L.V. Kovach S.J. Outcome analysis of 244 consecutive flaps for managing complex groin wounds J Plast Reconstr Aesthet Surg 66 2013 1396 1404 23831123 \n14 Kim P.J. Attinger C.E. Crist B.D. Gabriel A. Galiano R.D. Gupta S. Negative pressure wound therapy with instillation: review of evidence and recommendations Wounds 27 2015 S2 19 26966814 \n15 Chang J.K. Calligaro K.D. Ryan S. Runyan D. Dougherty M.J. Stern J.J. Risk factors associated with infection of lower extremity revascularization: analysis of 365 procedures performed at a teaching hospital Ann Vasc Surg 17 2003 91 96 12522701 \n16 Kim P.J. Attinger C.E. Steinberg J.S. Evans K.K. Lehner B. Willy C. Negative-pressure wound therapy with instillation: international consensus guidelines Plast Reconstr Surg 132 2013 1569 1579 24005370 \n17 Kim P.J. Attinger C.E. Steinberg J.S. Evans K.K. Powers K.A. Hung R.W. The impact of negative-pressure wound therapy with instillation compared with standard negative-pressure wound therapy: a retrospective, historical, cohort, controlled study Plast Reconstr Surg 133 2014 709 716 24572860 \n18 Kim P.J. Attinger C.E. Oliver N. Garwood C. Evans K.K. Steinberg J.S. Comparison of outcomes for normal saline and an antiseptic solution for negative-pressure wound therapy with instillation Plast Reconstr Surg 136 2015 657e 664e 26397244\n\n",
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"issue": "5(4)",
"journal": "Journal of vascular surgery cases and innovative techniques",
"keywords": "Instillation; NPWT; Negative pressure wound therapy; Rifampin; VAC instill",
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"title": "Negative pressure wound therapy with intermittent instillation of rifampin for the treatment of an infected vascular bypass graft.",
"title_normalized": "negative pressure wound therapy with intermittent instillation of rifampin for the treatment of an infected vascular bypass graft"
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"abstract": "OBJECTIVE\nAcute-on-chronic liver failure and its outcomes have not yet been evaluated in detail in children. We aimed to evaluate the etiology, acute events, and prognostic factors of acute-on-chronic liver failure in children.\n\n\nMETHODS\nPediatric patients (age 2-18 years) diagnosed with acute-on-chronic liver failure between April 2014 and April 2020 were evaluated retrospectively. Acute-on-chronic liver failure was defined as the presence of acute hepatic insult in previously diagnosed or undiagnosed chronic liver disease causing jaundice (total serum bilirubin ≥5 mg/dL) and coagulopathy (international normalized ratio of ≥2.0) and clinical and/or radiological ascites and/or hepatic encephalopathy within 4 weeks. Acute-on-Chronic Liver Failure Research Consortium and Chronic Liver Failure-Sequential Organ Failure Assessment scores were calculated for patients at first admission and at end of day 5 or before liver transplant.\n\n\nRESULTS\nOur study included 29 patients. Underlying chronic liver diseases were mostly autoimmune hepatitis (51.72%) and Wilson disease (27.58%), with flare-ups of these diseases also the most common acute events (48.28% and 27.58%, respectively). Seven patients (24.14%) received liver transplants. At first admission, Acute-on-Chronic Liver Failure Research Consortium and Chronic Liver Failure-Sequential Organ Failure Assessment cut-off scores to predict liver transplant were 7.5 and 6.5; at end of day 5 or before transplant, cut-off scores were 8.5 and 7.5, respectively. The 8.5 cut-off score on day 5 was the most specific and sensitive to predict liver transplant. International normalized ratio cut-off of 3.04 predicted transplant requirement with maximum sensitivity and specificity.\n\n\nCONCLUSIONS\nWilson disease and autoimmune hepatitis were the most common underlying chronic and acute events of acute-on-chronic liver failure in children. Although an Acute-on-Chronic Liver Failure Research Consortium score ≥ 8.5 best predicted liver transplant, for patients with scores ≥ 7.5 and being followed in a nontransplant center, patient referral to a transplant center is appropriate.",
"affiliations": "From the Department of Pediatric Gastroenterology, Atatürk University School of Medicine, Erzurum, Turkey.",
"authors": "Islek|Ali|A|;Keskin|Halil|H|;Aksungur|Nurhak|N|;Ozturk|Gurkan|G|",
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"issue": "19(7)",
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"title": "Acute-on-Chronic Liver Failure in Children: A Single-Center Experience.",
"title_normalized": "acute on chronic liver failure in children a single center experience"
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"abstract": "This multicenter phase 2 study assessed the combination of estramustine and weekly paclitaxel with metastatic castration-resistant prostate cancer (CRPC).\n\n\n\nWe enrolled 77 patients who had received no prior chemotherapy for CRPC between 1998 and 2000; a total of 74 subjects were eligible for the study. Each 8-week cycle included paclitaxel 90 mg/m2 provided intravenously weekly for 6 weeks, followed by 2 weeks off therapy and oral estramustine 280 mg twice daily for 3 days beginning 24 hours before the first dose of paclitaxel. The primary end point was rate of objective or prostate-specific antigen (PSA) response at 16 weeks. A 50% response rate was considered of further interest.\n\n\n\nEligible patients received a median of 3 cycles (range, 1-10 cycles). The response rate among patients with measurable disease was 34% (95% confidence interval [CI], 19-52). The PSA response rate was 58% (95% CI, 47-70). Clinical benefit rate was 45% (95% CI, 33-57). The median progression-free survival was 5.9 months (95% CI, 4.4-6.7). The median overall survival was 17.6 months (95% CI, 14.6-20.8). The most common clinical grade 3/4 toxicities were fatigue (14%) and sensory neuropathy (7%). Grade 3/4 hematologic toxicities included lymphopenia (21%) and anemia (9%). There was one toxicity-related death. Quality-of-life scores improved by week 8, but the change was not statistically significant.\n\n\n\nThe combination has activity defined by PSA declines in CRPC but did not meet the protocol-specified end point for efficacy as defined by objective response rate. Since this study was conducted, more effective, better-tolerated regimens have been developed.",
"affiliations": "Fox Chase Cancer Center, Philadelphia, PA. Electronic address: yuningwong123@gmail.com.;Dana-Farber Cancer Institute, ECOG-ACRIN Biostatistics Center, Boston, MA.;Fox Chase Cancer Center, Philadelphia, PA.;Indiana University, Indianapolis, IN.;Walter Reed Army Medical Center, Washington, DC.;Fox Chase Cancer Center, Philadelphia, PA.;Fox Chase Cancer Center, Philadelphia, PA.;Saint Vincent Hospital, Green Bay, WI.;University of Pennsylvania, Philadelphia, PA.;Indiana University, Indianapolis, IN.;University of Virginia, Charlottesville, VA.;Evanston Hospital, Evanston, IL.;Johns Hopkins University, Baltimore, MD.;University of Wisconsin Carbone Cancer Center, Madison, WI.",
"authors": "Wong|Yu-Ning|YN|;Manola|Judith|J|;Hudes|Gary R|GR|;Roth|Bruce J|BJ|;Moul|Judd W|JW|;Barsevick|Andrea M|AM|;Scher|Richard M|RM|;Volk|Michael J|MJ|;Vaughn|David J|DJ|;Williams|Stephen D|SD|;Fisch|Michael J|MJ|;Cella|David|D|;Carducci|Michael A|MA|;Wilding|George|G|",
"chemical_list": "D004961:Estramustine; D017430:Prostate-Specific Antigen; D017239:Paclitaxel",
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"mesh_terms": "D061605:Administration, Intravenous; D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D004334:Drug Administration Schedule; D004961:Estramustine; D006801:Humans; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel; D017430:Prostate-Specific Antigen; D064129:Prostatic Neoplasms, Castration-Resistant; D016019:Survival Analysis; D016896:Treatment Outcome",
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"pubdate": "2018-04",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural",
"references": "25920994;15470213;25199761;10506613;2207764;7579781;17942366;15470214;11445480;20888992;26433627;23228172;26903579;9294479;21864180;18794543;23863050;22119204;20818862;15536625;25354111",
"title": "Phase 2 Study of Weekly Paclitaxel Plus Estramustine in Metastatic Hormone-Refractory Prostate Carcinoma: ECOG-ACRIN Cancer Research Group (E1898) Trial.",
"title_normalized": "phase 2 study of weekly paclitaxel plus estramustine in metastatic hormone refractory prostate carcinoma ecog acrin cancer research group e1898 trial"
} | [
{
"companynumb": "US-PFIZER INC-2017522467",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DIPHENHYDRAMINE"
},
"drugadditional": null,
... |
{
"abstract": "While systemic lupus erythematosus is often complicated by preeclampsia, it is difficult to differentiate between its exacerbation and preeclampsia. The soluble fms-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PlGF) ratio is unknown in systemic lupus erythematosus with preeclampsia before 20 weeks of gestation. Three nulliparous women with systemic lupus erythematosus developed preeclampsia at 13, 13, and 17 weeks of gestation with sFlt-1/PlGF ratios of 427, 865, and 525, respectively. Two patients terminated their pregnancies and delivered within 2 weeks, while one experienced intrauterine fetal death 4 weeks after the measurements. Their symptoms gradually improved, and all patients were discharged within 3 months. The sFlt-1/PlGF ratio may be used in the differential diagnosis of preeclampsia and systemic lupus erythematosus exacerbation before 20 weeks of gestation.",
"affiliations": "Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan.;Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan.;Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan.;Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan.",
"authors": "Mimura|Kazuya|K|https://orcid.org/0000-0002-0950-7110;Tomimatsu|Takuji|T|;Endo|Masayuki|M|;Kimura|Tadashi|T|",
"chemical_list": null,
"country": "Australia",
"delete": false,
"doi": "10.1111/jog.15055",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-8076",
"issue": "47(12)",
"journal": "The journal of obstetrics and gynaecology research",
"keywords": "atypical; placental growth factor; preeclampsia; pregnancy; soluble fms-like tyrosine kinase 1; systemic lupus erythematosus",
"medline_ta": "J Obstet Gynaecol Res",
"mesh_terms": null,
"nlm_unique_id": "9612761",
"other_id": null,
"pages": "4461-4466",
"pmc": null,
"pmid": "34605122",
"pubdate": "2021-12",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Atypical preeclampsia with systemic lupus erythematosus and elevated soluble fms-like tyrosine kinase 1/placental growth factor ratio.",
"title_normalized": "atypical preeclampsia with systemic lupus erythematosus and elevated soluble fms like tyrosine kinase 1 placental growth factor ratio"
} | [
{
"companynumb": "JP-NOVARTISPH-NVSJ2022JP004401",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": "3",
... |
{
"abstract": "As intraventricular thrombolysis for intraventricular hemorrhage (IVH) has developed over the last 2 decades, hemorrhagic complications have remained a concern despite general validation of its safety in controlled trials in the Clot Lysis: Evaluation of Accelerated Resolution of Intraventricular Hemorrhage Phase III (CLEAR-IVH) program.\n\n\n\nTo analyze factors associated with symptomatic bleeding following IVH with and without thrombolysis in conjunction with the recently completed CLEAR III trial.\n\n\n\nWe reviewed safety reports on symptomatic bleeding events reported during the first year after randomization among subjects enrolled in the CLEAR III trial. Clinical and imaging data were retrieved through the trial database as part of ongoing quality and safety monitoring. A posthoc root-cause analysis was performed to identify potential factors predisposing to rebleeding in each case. Cases were classified according to onset of rebleeding (during dosing, early after dosing and delayed), the pattern of bleeding, and treatment rendered (alteplase vs saline).\n\n\n\nTwenty subjects developed a secondary symptomatic intracranial hemorrhage constituting 4% of subjects. Symptomatic rebleeding events occurred during the dosing protocol (n = 9, 67% alteplase), early after the protocol (n = 5, 40% alteplase), and late (n = 6, 0% alteplase). Catheter-related hemorrhages were the most common (n = 7, 35%) followed by expansion or new intraventricular (n = 6, 30%) and intracerebral (n = 5, 25%) hemorrhages. Symptomatic hemorrhages during therapy resulted from a combination of treatment- and patient-related factors and were at most partially attributable to alteplase. Rebleeding after the dosing protocol primarily reflected patients' risk factors.\n\n\n\nIntraventricular thrombolysis marginally increases the overall risk of symptomatic hemorrhagic complications after IVH, and only during the treatment phase.",
"affiliations": "Neurovascular Surgery Program, Section of Neurosurgery, The University of Chicago Medicine, Chicago, Illinois.;Neurovascular Surgery Program, Section of Neurosurgery, The University of Chicago Medicine, Chicago, Illinois.;Neurovascular Surgery Program, Section of Neurosurgery, The University of Chicago Medicine, Chicago, Illinois.;Neurovascular Surgery Program, Section of Neurosurgery, The University of Chicago Medicine, Chicago, Illinois.;Emissary International, LLC, Austin, Texas.;Brain Injury Outcomes Unit, Johns Hopkins University, Baltimore, Maryland.;Brain Injury Outcomes Unit, Johns Hopkins University, Baltimore, Maryland.;Brain Injury Outcomes Unit, Johns Hopkins University, Baltimore, Maryland.;Brain Injury Outcomes Unit, Johns Hopkins University, Baltimore, Maryland.;Brain Injury Outcomes Unit, Johns Hopkins University, Baltimore, Maryland.;Brain Injury Outcomes Unit, Johns Hopkins University, Baltimore, Maryland.;Neurovascular Surgery Program, Section of Neurosurgery, The University of Chicago Medicine, Chicago, Illinois.",
"authors": "Fam|Maged D|MD|;Stadnik|Agnieszka|A|;Zeineddine|Hussein A|HA|;Girard|Romuald|R|;Mayo|Steven|S|;Dlugash|Rachel|R|;McBee|Nichol|N|;Lane|Karen|K|;Mould|W Andrew|WA|;Ziai|Wendy|W|;Hanley|Daniel|D|;Awad|Issam A|IA|",
"chemical_list": "D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator",
"country": "United States",
"delete": false,
"doi": "10.1093/neuros/nyx587",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0148-396X",
"issue": "83(6)",
"journal": "Neurosurgery",
"keywords": null,
"medline_ta": "Neurosurgery",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000074042:Cerebral Intraventricular Hemorrhage; D017326:Clinical Trials, Phase III as Topic; D004311:Double-Blind Method; D005260:Female; D005343:Fibrinolytic Agents; D006801:Humans; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D060891:Root Cause Analysis; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator; D016896:Treatment Outcome",
"nlm_unique_id": "7802914",
"other_id": null,
"pages": "1260-1268",
"pmc": null,
"pmid": "29294116",
"pubdate": "2018-12-01",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": "21868730;10625726;26022637;10751114;3951686;25052321;7604411;19246695;9973653;19224404;11778824;20425231;25635887;25061080;28081952;9527003;17038942;24410156;22544476;897983;20733144;17220294;22002766;21471831;17041512;28245439",
"title": "Symptomatic Hemorrhagic Complications in Clot Lysis: Evaluation of Accelerated Resolution of Intraventricular Hemorrhage Phase III Clinical Trial (CLEAR III): A Posthoc Root-Cause Analysis.",
"title_normalized": "symptomatic hemorrhagic complications in clot lysis evaluation of accelerated resolution of intraventricular hemorrhage phase iii clinical trial clear iii a posthoc root cause analysis"
} | [
{
"companynumb": "US-ROCHE-2057784",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALTEPLASE"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "BACKGROUND\nPeripartum cardiomyopathy usually presents with systolic heart failure during the last months of pregnancy and up to five months postpartum. The disease is rare and can be fatal.\n\n\nMETHODS\nWe report a 30-year-old female who was diagnosed with acute myeloid leukemia, with maturation and cytogenetic finding of t(8;21)(q22;q22),del(9)(q22) in January 2004. She was treated with chemotherapy and achieved complete remission that lasts to date. She became pregnant and delivered a healthy newborn with caesarean section in 2009. Seven months later, she again became pregnant and delivered the second child with caesarean section in January 2011. Seven days after delivery she developed symptoms and signs of heart failure. Electrocardiogram showed sinus rhythm, low voltage and negative T-waves in inferior and lateral leads. Echocardiography revealed global left ventricular dysfunction with ejection fraction of 15%, with mobile thrombotic mass of 12 mm attached to the left ventricle wall. She was treated with both unfractionated and low-molecular heparin, diuretics, cardiotonics, and beta-blockers. Within six following weeks left ventricle systolic function improved up to 25-30%. The full clinical recovery was achieved in September 2013, resulting in absence of heart failure and left ventricular ejection fraction of 54%.\n\n\nCONCLUSIONS\nPeripartum cardiomyopathy is a rare condition. The cause of cardiomyopathy is unknown, but it is believed that it could be triggered by various conditions and risk factors. Although the patient was treated with cardiotoxic drugs (doxorubicin and mitoxantrone) in permitted doses, they could have been contributory factors of myocardial damage. Close monitoring of cardiac function in the peripartal period might be beneficial in patients treated with cardiotoxic drugs.",
"affiliations": null,
"authors": "Colović|Natasa|N|;Seferović|Petar|P|;Plećić|Miroslava|M|;Vidović|Ana|A|;Suvajdzić|Nada|N|;Tomin|Dragica|D|",
"chemical_list": "D000970:Antineoplastic Agents; D054715:Cardiotoxins",
"country": "Serbia",
"delete": false,
"doi": "10.2298/sarh1602077c",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0370-8179",
"issue": "144(1-2)",
"journal": "Srpski arhiv za celokupno lekarstvo",
"keywords": null,
"medline_ta": "Srp Arh Celok Lek",
"mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D009202:Cardiomyopathies; D054715:Cardiotoxins; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D058725:Peripartum Period; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular",
"nlm_unique_id": "0027440",
"other_id": null,
"pages": "77-80",
"pmc": null,
"pmid": "27276863",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Peripartum cardiomyopathy in a patient treated for acute myeloid leukemia.",
"title_normalized": "peripartum cardiomyopathy in a patient treated for acute myeloid leukemia"
} | [
{
"companynumb": "RS-PFIZER INC-2016356314",
"fulfillexpeditecriteria": "1",
"occurcountry": "RS",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MITOXANTRONE HYDROCHLORIDE"
},
"drugadditional... |
{
"abstract": "Patients treated for adult T-Cell leukemia/lymphoma (ATL) have a poor prognosis and are prone to infectious complications which are poorly described. As the French reference center for ATL, we retrospectively analyzed 47 consecutive ATL (acute, n = 23; lymphoma, n = 14; chronic, n = 8; smoldering, n = 2) patients between 2006 and 2016 (median age 51 years, 96% Afro-Caribbean origin). The 3-year overall survival (OS) was 15.8%, 11.3%, and 85.7% for acute, lymphoma, and indolent (chronic and smoldering) forms respectively. Among aggressive subtypes, 20 patients received, as frontline therapy, high dose of zidovudine and interferon alfa (AZT-IFN⍺) resulting in an overall response rate (ORR) of 39% (complete response [CR] 33%) and 17 chemotherapy resulting of an ORR of 59% (CR 50%). Ninety-five infections occurred in 38 patients, most of whom had an acute subtype (n = 73/95; 77%). During their follow-up, patients receiving frontline chemotherapy or frontline AZT-IFNα developed infections in 74% (n = 14/19) and 89% (n = 24/27) of the cases respectively. Sixty-four (67%) of infections were microbiologically documented. Among them, invasive fungal infections (IFI, n = 11) included 2 Pneumocystis jirovecii pneumonia, 5 invasive aspergillosis, and 4 yeast fungemia. IFI exclusively occurred in patients with acute subtype mostly exposed to AZT-IFNα (n = 10/11) and experiencing prolonged (> 10 days) grade 4 neutropenia. Patients with aggressive subtype experiencing IFI had a lower OS than those who did not (median OS 5.4 months versus 18.4 months, p = 0.0048). ATL patients have a poor prognosis even in the modern era. Moreover, the high rate of infections impacts their management especially those exposed to AZT-IFNα.",
"affiliations": "Service de Maladies Infectieuses et Tropicales, Centre d'Infectiologie Necker-Pasteur, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Université de Paris, Paris, France.;Service d'Hématologie Adultes, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Université de Paris, Paris, France.;Service de Maladies Infectieuses et Tropicales, Centre d'Infectiologie Necker-Pasteur, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Université de Paris, Paris, France.;Laboratoire de Microbiologie Clinique, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Université de Paris, Paris, France.;Laboratoire de Microbiologie Clinique, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Université de Paris, Paris, France.;Laboratoire de Microbiologie Clinique, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Université de Paris, Paris, France.;Service d'Hématologie Adultes, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Université de Paris, Paris, France.;Service d'Hématologie Adultes, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Université de Paris, Paris, France.;Service de Réanimation, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Université de Paris, Paris, France.;Département de Radiothérapie-Oncologie-Hématologie, Centre Hospitalier Universitaire de La Guadeloupe, Pointe à Pitre, France.;Service d'Oncologie-Hématologie, Centre Hospitalier Universitaire de La Martinique, Hôpital Pierre Zobda Quitman, Fort de France, France.;Centre Hospitalier de Cayenne, Guyane Française, France.;Service de Maladies Infectieuses et Tropicales, Centre d'Infectiologie Necker-Pasteur, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Université de Paris, Paris, France.;Service de Maladies Infectieuses et Tropicales, Centre d'Infectiologie Necker-Pasteur, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Université de Paris, Paris, France.;Service d'Hématologie Adultes, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Université de Paris, Paris, France.;Service de Maladies Infectieuses et Tropicales, Centre d'Infectiologie Necker-Pasteur, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Université de Paris, Paris, France.;Service d'Hématologie Adultes, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Université de Paris, Paris, France. ambroise.marcais@aphp.fr.",
"authors": "Guery|Romain|R|;Suarez|Felipe|F|;Lanternier|Fanny|F|;Bougnoux|Marie Elisabeth|ME|;Lecuyer|Hervé|H|;Avettand-Fenoel|Véronique|V|;Sibon|David|D|;Frenzel|Laurent|L|;Raphalen|Jean-Herlé|JH|;Helias|Philippe|P|;Renaudier|Philippe|P|;Santa|Florin|F|;Lecuit|Marc|M|;Lortholary|Olivier|O|;Hermine|Olivier|O|;Aguilar|Claire|C|;Marçais|Ambroise|A|http://orcid.org/0000-0002-6844-7920",
"chemical_list": "D016898:Interferon-alpha; D015215:Zidovudine",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00277-021-04622-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0939-5555",
"issue": "100(11)",
"journal": "Annals of hematology",
"keywords": "HTLV-1; Interferon alfa; Invasive fungal infection; Lymphoma; Outcome; Zidovudine",
"medline_ta": "Ann Hematol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D019072:Antibiotic Prophylaxis; D000971:Antineoplastic Combined Chemotherapy Protocols; D001228:Aspergillosis; D064147:Febrile Neutropenia; D005260:Female; D005335:Fever of Unknown Origin; D016469:Fungemia; D006801:Humans; D016898:Interferon-alpha; D000072742:Invasive Fungal Infections; D053208:Kaplan-Meier Estimate; D015459:Leukemia-Lymphoma, Adult T-Cell; D008297:Male; D008875:Middle Aged; D009894:Opportunistic Infections; D011020:Pneumonia, Pneumocystis; D015995:Prevalence; D011379:Prognosis; D012189:Retrospective Studies; D013322:Strongyloidiasis; D016896:Treatment Outcome; D055815:Young Adult; D015215:Zidovudine",
"nlm_unique_id": "9107334",
"other_id": null,
"pages": "2813-2824",
"pmc": null,
"pmid": "34387741",
"pubdate": "2021-11",
"publication_types": "D016428:Journal Article",
"references": "23162541;20585095;25733162;32199462;19064971;26361794;24960557;21668573;28321466;19489710;27550991;7760890;11426550;26206797;27641225;29545256;31866618;26524263",
"title": "Poor outcome and high prevalence of invasive fungal infections in patients with adult T-cell leukemia/lymphoma exposed to zidovudine and interferon alfa.",
"title_normalized": "poor outcome and high prevalence of invasive fungal infections in patients with adult t cell leukemia lymphoma exposed to zidovudine and interferon alfa"
} | [
{
"companynumb": "FR-VIIV HEALTHCARE LIMITED-FR2021GSK180260",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ZIDOVUDINE"
},
"drugaddition... |
{
"abstract": "BACKGROUND\nTreatment of lupus nephritis consists of six months of induction immunosuppression followed by years of maintenance immunosuppression. The aim of present study was to find the prevalence of remission after six months of induction immunosuppressive treatment with induction therapy in patients with lupus nephritis.\n\n\nMETHODS\nA descriptive cross-sectional study was conducted in the nephrology unit of department of internal medicine of a tertiary care hospital from September 2018 to September 2020. The study was approved by institutional review committee of same institution (reference number 184/2018). Convenience sampling method was used and Statistical Package for Social Sciences version 26 was used for statistical analysis. Point estimate at 90% Confidence Interval was calculated along with frequency and proportion for binary data.\n\n\nRESULTS\nOut of 24 patients, overall remission was seen in 21 patients (87.4%) (90% Confidence Interval= 76.26-98.54). Complete remission and partial remission were seen in 16 (66.6%) and 5 (20.8%) patients respectively resulting in an at the end of six months of induction immunosuppressive treatment. The most common class of lupus nephritis was class IV, 7 patients, followed by class IV+V, and class V, 6 patients in each respectively. The mean 24-hour urinary total protein, serum albumin and serum creatinine were 2492±1051 mg, 2.1±0.4 g/dl, and 0.9±0.1 mg/dl respectively. Adverse events were observed in 6 (25%) patients.\n\n\nCONCLUSIONS\nOur study shows that good proportions of patients with lupus nephritis achieve clinical remission at the end of six months of induction immunosuppressive treatment with induction therapy, however, at the cost of some tolerable side effects.",
"affiliations": "Nephrology Unit, Department of Internal Medicine, Nobel Medical College Teaching Hospital, Biratnagar, Nepal.;Nephrology Unit, Department of Internal Medicine, Nobel Medical College Teaching Hospital, Biratnagar, Nepal.",
"authors": "Shrestha|Shailendra|S|;Yadav|Rahul|R|",
"chemical_list": "D007166:Immunosuppressive Agents; D011239:Prednisolone; D009173:Mycophenolic Acid",
"country": "Nepal",
"delete": false,
"doi": "10.31729/jnma.6826",
"fulltext": "\n==== Front\nJNMA J Nepal Med Assoc\nJNMA J Nepal Med Assoc\nJ Nepal Med Assoc\nJNMA\nJNMA: Journal of the Nepal Medical Association\n0028-2715\n1815-672X\nJournal of the Nepal Medical Association\n\n34508471\n10.31729/jnma.6826\nOriginal Article\nRemission after Six Months of Induction Immunosuppressive Treatment with Mycofenolate Mofetil and Prednisolone in Patients with Lupus Nephritis: A Descriptive Cross-sectional Study\nShrestha Shailendra 1\nYadav Rahul 1\n1 Nephrology Unit, Department of Internal Medicine, Nobel Medical College Teaching Hospital, Biratnagar, Nepal\nCorrespondence: Dr. Shailendra Shrestha, Nephrology Unit, Department of Internal Medicine, Nobel Medical College Teaching Hospital, Biratnagar, Nepal. Email: shailendra_1975@hotmail.com, Phone: +977-9842054410\n8 2021\n31 8 2021\n59 240 791794\n© The Author(s) 2018.\n2018\nhttps://creativecommons.org/licenses/by/4.0/ This is an Open-Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nABSTRACT\n\nIntroduction:\n\nTreatment of lupus nephritis consists of six months of induction immunosuppression followed by years of maintenance immunosuppression. The aim of present study was to find the prevalence of remission after six months of induction immunosuppressive treatment with induction therapy in patients with lupus nephritis.\n\nMethods:\n\nA descriptive cross-sectional study was conducted in the nephrology unit of department of internal medicine of a tertiary care hospital from September 2018 to September 2020. The study was approved by institutional review committee of same institution (reference number: 184/2018). Convenience sampling method was used and Statistical Package for Social Sciences version 26 was used for statistical analysis. Point estimate at 90% Confidence Interval was calculated along with frequency and proportion for binary data.\n\nResults:\n\nOut of 24 patients, overall remission was seen in 21 patients (87.4%) (90% Confidence Interval= 76.26-98.54). Complete remission and partial remission were seen in 16 (66.6%) and 5 (20.8%) patients respectively resulting in an at the end of six months of induction immunosuppressive treatment. The most common class of lupus nephritis was class IV, 7 patients, followed by class IV+V, and class V, 6 patients in each respectively. The mean 24-hour urinary total protein, serum albumin and serum creatinine were 2492±1051 mg, 2.1±0.4 g/dl, and 0.9±0.1 mg/dl respectively. Adverse events were observed in 6 (25%) patients.\n\nConclusions:\n\nOur study shows that good proportions of patients with lupus nephritis achieve clinical remission at the end of six months of induction immunosuppressive treatment with induction therapy, however, at the cost of some tolerable side effects.\n\nKeywords\n\nimmunosuppression\nlupus nephritis\nremission induction\n==== Body\npmcINTRODUCTION\n\nSystemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease and lupus nephritis (LN) is seen in about 40-50 % of the patients.1,2 The treatment of LN consists of six months of intense immunosuppression called induction treatment, followed by years of low dose maintenance immunosuppression. Either cyclophosphamide (CYC) or mycophenolate mofetil (MMF) along with prednisolone (PNL) are being used as an induction regimen in the treatment of class III, IV V, and mixed LN.3-5\n\nThere has been scarcity of data from Nepal regarding the clinical outcomes after six months of induction immunosuppressive treatment in patients with LN.6,7\n\nHence present study was conducted to find the prevalence of remission after six months of induction immunosuppressive treatment with mycophenolate mofetil and PNL in patients with lupus nephritis.\n\nMETHODS\n\nA descriptive cross-sectional study was conducted in the nephrology unit of the department of internal medicine of Nobel Medical College Teaching Hospital (NMCTH), Biratnagar, Nepal. All patients with LN from September 2018 to September 2020, who received six months of induction immunosuppression with MMF were included in the study. The study was approved by the Institutional Review Committee of the hospital (NMCTH IRC reference number 184/2018). Written informed consent was taken from all patients. The inclusion criterion was newly diagnosed patients of SLE with renal biopsy proven class III, IV, V and mixed LN. Lupus nephritis (LN) was classified according to the International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification system.8 Patients were excluded if they had already received immunosuppressive therapy before enrolling in the study, if they disagreed to give the consent and when they failed to come monthly for at least six months. Convenience sampling method was used. The sample size was calculated using the formula:\n\nn = Z2 × p × q / e2\n\n = (1.645)2 × (0.88) × (0.12) / (0.11)2\n\n = 23.6\n\n = 24\n\nwhere,\n\nn = sample size,\n\nZ= 1.645 at 90% Confidence Interval,\n\np = prevalence, 88%,6\n\nq = 1-p\n\ne = margin of error, 11%\n\nThe calculated sample size was 24.\n\nThe baseline characteristics of the study population were digitally recorded at the time of enrollment in the study. After enrollment patients were started on induction immunosuppressive treatment for six months with MMF and PNL. Patients received MMF with a starting dose of 500 mg twice a day, which was increased after 2 weeks to 1000 mg twice a day for 6 months. Oral PNL was given with a starting dose of 0.5mg/kg for 2 months which was gradually tapered by 5 mg/every 2 weeks to reach 10mg/day. Injection methyl prednisolone (MP) 500 mg intravenous, once a day for three days was given at the start of induction regimen only if the serum creatinine was raised. Besides the immunosuppressive treatment, all patients also received angiotensin receptor blockers (ARBs) to titrate blood pressure below 125/75 mmHg, hydroxychloroquine 5mg/kg/day (maximum 400 mg/day), and a prophylactic antibiotic cotrimoxazole double strength (DS) ½ tablet once a day.\n\nClinical outcomes at the end of six months were assessed in terms of complete remission (CR), partial remission (PR) and no remission (NR) or deterioration, defined as per the Kidney Disease Improving Global Outcomes (KDIGO) guidelines.9 Complete remission (CR) was defined as return of serum creatinine to previous baseline, plus a decline in the urine protein creatinine ratio (uPCR) to <500 mg/g (<50 mg/mmol). Partial remission (PR) was defined as stabilization (±25%), or improvement of serum creatinine, but not to normal, plus a ≥50% decrease in uPCR.\n\nStatistical analysis was done using Statistical Package for Social Sciences version 26. Point estimate at 90% Confidence Interval and descriptive statistics were done.\n\nRESULTS\n\nOut of 24 patients, overall remission was seen in 21 patients (87.4%) (90% Confidence Interval= 76.26-98.54). Complete remission and partial remission were seen in 16 (66.6%) and 5 (20.8%) patients at the end of six months of induction immunosuppressive treatment. No response was seen in 3 (12.5%) patients (Table 1).\n\nTable 1 Clinical remission after six months of induction immunosuppressive treatment with MMF* and PNL†.\n\nRemission\tn (%)\t\nComplete remission\t16 (66.6)\t\nPartial remission\t5 (20.8)\t\nOverall remission\t21(87.4)\t\nNo response\t3 (12.5)\t\n* MMF: Mycofenolate mofetil;\n\n† PNL:Prednisolone.\n\nThe mean age of the patients was 23.6±7.0 years, and 23 (95.9%) of them were females. The most common class of lupus nephritis was class IV, 6 (29.16%) patients, followed by class IV+V and class V, 6 (25%) patients in each class respectively (Table 2).\n\nTable 2 Baseline characteristics of the patients (n=24).\n\nVariables\tn (%)\t\nGender\t\nMale\t1 (4.1)\t\nFemale\t23 (95.9)\t\nClass of LN*\t\nClass III\t3 (12.5)\t\nClass III+V\t1 (4.16)\t\nClass IV\t7 (29.16)\t\nClass IV+V\t6 (25)\t\nClass V\t6 (25)\t\nClass V+III\t1 (4.16)\t\n* LN: lupus nephritis.\n\nThe mean 24-hour UTP, serum albumin and serum creatinine were 2492±1051 mg, 2.1 ±0.4 g/dl, and 0.9±0.1 mg/dl respectively. Baseline characteristics of the patients are shown in (Table 3).\n\nTable 3 Clinicodemographic features.\n\nVariables\tMean±S.D.\t\nAge, years\t23.6±7.0\t\nIFTA† (%)\t11.0±2.0\t\n24-hour UTP‡, mg\t2492±1051\t\nSerum albumin, g/dl\t2.1±0.4\t\nSerum creatinine, mg/dl\t0.9±0.1\t\nHemoglobulin, g/dl\t10.8±1.5\t\n† IFTA: interstitial fibrosis tubular atrophy;\n\n‡ UTP: urinary total protein.\n\nAdverse events were observed in 6 (25%) patients during the six months of induction immunosuppression (Table 4).\n\nTable 4 Adverse events during the six months of induction immunosuppressive treatment (n = 6).\n\nAdverse events\tn (%)\t\nHerpes Zoster\t2 (33.33)\t\nDiarrhea\t2 (33.33)\t\nTubercular plural effusion\t1 (16.66)\t\nLeukopenia\t1 (16.66)\t\n\nNone of the patients died because of the adverse events.\n\nDISCUSSION\n\nIn the present study we analyzed the clinical remission rates and adverse events after six months of induction immunosuppression with mycophenolate mofetil and prednisolone in patients with lupus nephritis. We found that good proportions of patients achieve complete or partial remission at the cost of some adverse events.\n\nThe study done by Sedhai et al in Nepalese population had used NIH regimen 1.5 gm of mycophenolate mofetil along with prednisolone as an induction regimen.7 These are the only two published studies we could found from Nepal on extensive literature search, where the clinical outcomes were studied after six months of induction immunosuppressive treatment in patients with LN. Ours is the third study in the row.\n\nMycophenolate mofetil (MMF) as an alternative induction regimen in LN was introduced by Chen et al. in the year 2000; and the Aspreva Lupus Management Study (ALMS) established its role as a standard of care in the induction phase treatment of LN.10,11\n\nIn our study we used MMF in all our patients at a dose of 2 g/day (1 gm in two divided doses), which was less than the dose used in ALMS trial (3 g/day) but slightly more than the dose used in the Nepalese study (1.5 g/day).7-11\n\nIn the ALMS studies the response rate was 56.2% in the MMF group.11 In our study 66.6% of patients achieved complete remission and 20.8% of patients achieved partial remission. Overall remission rate was 87.4%. A higher rate of renal remission in our study as compared to western studies was also seen in previous studies done in Nepal.7 In another Nepalese study by Sedai et al,7 primary outcome (partial remission) and secondary outcome (complete response) were 28.6% and 66.7% in the mycophenolate mofetil group making an overall remission rate of 95.3 % in the MMF.7\n\nIndeed, studies done in other South Asian populations have also shown better remission rates as compared to western studies.12,13 In the study done by Sahay et al. from India the overall remission rate was 72.9% in MMF group.12 In another Indian study by Rathi et al. total response rate was 74% in the low dose of MMF group; the complete remission rate was 54% in MMF group.13\n\nIn our study adverse events were observed in 25% of the patients, and they were herpes zoster and diarrhea in two patients each and tubercular plural effusion and leucopenia in one patient each. None of our patients died due to adverse events in our study.\n\nThe limitation of present study was that it was a single center study with a small number of participants. Furthermore, we only included patients who received MMF as an induction regimen and did not compared the outcomes with patients who received CYC. We recommend multicenter randomized control studies in Nepal comparing the two different induction immunosuppressive regimens.\n\nCONCLUSIONS\n\nOur study demonstrates that good proportions of patients with lupus nephritis achieve clinical remission at the end of six months of induction immunosuppressive treatment with mycophenolate mofetil and prednisolone, however, at the cost of some tolerable adverse events.\n\nACKNOWLEDGMENTS\n\nWe would like to acknowledge Dr Nabin Paudyal, first year surgery resident in the Department of Surgery, Nobel Medical College Teaching Hospital, Biratnagar, Nepal, for generously helping us in the statistical analysis of the study.\n\nConflict of Interest\n\nNone.\n==== Refs\nREFERENCES\n\n1. Lisnevskaia L Murphy G Isenberg D Systemic lupus erythematosus. Lancet. 2014 Nov 22 384 9957 1878 88 10.1016/S0140-6736(14)60128-8 24881804\n2. Dörner T Furie R Novel paradigms in systemic lupus erythematosus. Lancet. 2019 Jun 8 393 10188 2344 58 10.1016/S0140-6736(19)30546-X 31180031\n3. Almaani S Meara A Rovin BH Update on Lupus Nephritis. Clin J Am Soc Nephrol. 2017 May 8 12 5 825 35 10.2215/CJN.05780616 27821390\n4. Parikh SV Almaani S Brodsky S Rovin BH Update on Lupus Nephritis: Core Curriculum 2020. Am J Kidney Dis. 2020 Aug 76 2 265 81 10.1053/j.ajkd.2019.10.017 32220510\n5. Morales E Galindo M Trujillo H Praga M Update on Lupus Nephritis: Looking for a New Vision. Nephron. 2021 145 1 1 13 10.1159/000511268 33147587\n6. Cortes-Hernandez J Torres-Salido MT Medrano AS Tarres MV Ordi-Ros J Long-term outcomes--mycophenolate mofetil treatment for lupus nephritis with addition of tacrolimus for resistant cases. Nephrol Dial Transplant. 2010 Dec 25 12 3939 48 10.1093/ndt/gfq322 20538787\n7. Sedhain A Hada R Agrawal RK Bhattarai GR Baral A Low dose mycophenolate mofetil versus cyclophosphamide in the induction therapy of lupus nephritis in Nepalese population: a randomized control trial. BMC Nephrol. 2018 Jul 11 19 1 175 10.1186/s12882-018-0973-7 29996800\n8. Weening JJ D'Agati VD Schwartz MM Seshan SV Alpers CE Appel GB et al International Society of Nephrology Working Group on the Classification of Lupus Nephritis; Renal Pathology Society Working Group on the Classification of Lupus Nephritis. The classification of glomerulonephritis in systemic lupus erythematosus revisited. Kidney Int. 2004 Feb 65 2 521 30 10.1111/j.1523-1755.2004.00443.x 14717922\n9. Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group. KDIGO Clinical Practice Guideline for Glomerulonephritis. Kidney inter. Suppl 2012 2 139 274\n10. Houssiau FA Vasconcelos C D'Cruz D Sebastiani GD Garrido Ed Ede R Danieli MG et al Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide. Arthritis Rheum. 2002 Aug 46 8 2121 31 10.1002/art.10461 12209517\n11. Appel GB Contreras G Dooley MA Ginzler EM Isenberg D Jayne D et al Aspreva Lupus Management Study Group. Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. J Am Soc Nephrol. 2009 May 20 5 1103 12 10.1681/ASN.2008101028 19369404\n12. Sahay M Saivani Y Ismal K Vali PS Mycophenolate versus cyclophosphamide for lupus nephritis. Indian J Nephrol 2018 28 35 40 10.4103/ijn.IJN_2_16 29515299\n13. Rathi M Goyal A Jaryal A Sharma A Gupta PK Ramachandran R et al Comparison of low-dose intravenous cyclophosphamide with oral mycophenolate mofetil in the treatment of lupus nephritis. Kidney Int. 2016 Jan 89 1 235 42 10.1038/ki.2015.318 26489028\n\n",
"fulltext_license": "CC BY",
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"issue": "59(240)",
"journal": "JNMA; journal of the Nepal Medical Association",
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"medline_ta": "JNMA J Nepal Med Assoc",
"mesh_terms": "D003430:Cross-Sectional Studies; D006801:Humans; D007166:Immunosuppressive Agents; D008181:Lupus Nephritis; D009173:Mycophenolic Acid; D011239:Prednisolone; D012074:Remission Induction; D016896:Treatment Outcome",
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"pages": "791-794",
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"pmid": "34508471",
"pubdate": "2021-08-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Remission after Six Months of Induction Immunosuppressive Treatment with Mycofenolate Mofetil and Prednisolone in Patients with Lupus Nephritis: A Descriptive Cross-sectional Study.",
"title_normalized": "remission after six months of induction immunosuppressive treatment with mycofenolate mofetil and prednisolone in patients with lupus nephritis a descriptive cross sectional study"
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"abstract": "BACKGROUND\nThe use of a new chemotherapy as adjuvant treatment of colorectal cancer is not free of complications. Monoclonal antibodies are associated with bleeding and intestinal perforations.\n\n\nOBJECTIVE\nTo report the case of a patient who developed a serious complication after treatment with an antiangiogenic drug for colorectal neoplasm.\n\n\nMETHODS\nThe case is presented of a 42-year-old male operated on due to subocclusive rectal cancer with metástasis at the time of diagnosis. Sixteen months after surgery during second-line adjuvant therapy, an intestinal perforation was observed with haemorrhage and intestinal leak to retroperitoneum and left lower extremity. Despite intensive medical and surgical treatment this complication had fatal consequences.\n\n\nCONCLUSIONS\nFuture research should be directed at obtaining biomarkers for the specific use of antiangiogenic agents in order to decrease the rate of adverse factors.",
"affiliations": "Sección de Coloproctología, Servicio de Cirugía General, Hospital Clínico Universitario de Zaragoza, Zaragoza, España. Electronic address: esti.egallego@hotmail.com.;Sección de Coloproctología, Servicio de Cirugía General, Hospital Clínico Universitario de Zaragoza, Zaragoza, España.;Sección de Coloproctología, Servicio de Cirugía General, Hospital Clínico Universitario de Zaragoza, Zaragoza, España.",
"authors": "Echazarreta-Gallego|Estíbaliz|E|;Elía-Guedea|Manuela|M|;Córdoba-Díaz de Laspra|Elena|E|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D011993:Recombinant Fusion Proteins; C533178:aflibercept; D040262:Receptors, Vascular Endothelial Growth Factor",
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"doi": "10.1016/j.circir.2016.03.011",
"fulltext": null,
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"issn_linking": "0009-7411",
"issue": "85(3)",
"journal": "Cirugia y cirujanos",
"keywords": "Aflibercept; Agentes antiangiogénicos; Antiangiogenic agents; Colorectal neoplasms; Intestinal perforation; Neoplasia colorrectal; Perforación intestinal",
"medline_ta": "Cir Cir",
"mesh_terms": "D000038:Abscess; D000230:Adenocarcinoma; D000328:Adult; D020533:Angiogenesis Inhibitors; D017024:Chemotherapy, Adjuvant; D003125:Colostomy; D017577:Cutaneous Fistula; D004322:Drainage; D000071938:Fasciotomy; D017809:Fatal Outcome; D005402:Fistula; D006801:Humans; D007412:Intestinal Fistula; D007416:Intestinal Perforation; D007418:Intestinal Pseudo-Obstruction; D007866:Leg; D008113:Liver Neoplasms; D008297:Male; D054843:Negative-Pressure Wound Therapy; D011183:Postoperative Complications; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins; D012004:Rectal Neoplasms; D012187:Retroperitoneal Space; D012771:Shock, Hemorrhagic",
"nlm_unique_id": "0372736",
"other_id": null,
"pages": "260-263",
"pmc": null,
"pmid": "27140945",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Devastating surgical complications after aflibercept chemotherapy.",
"title_normalized": "devastating surgical complications after aflibercept chemotherapy"
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"abstract": "OBJECTIVE\nInhibition of tumor necrosis factor (TNF) is an effective treatment for rheumatoid arthritis (RA), but safety concerns about malignancy remain. The aim of this study was to evaluate cancer risk in RA patients treated with TNF inhibitors (TNFi), based on Korean Nationwide Health Insurance claims data.\n\n\nMETHODS\nPatients with seropositive RA were selected from the health insurance database containing all citizens' medical information, based on both RA diagnosis codes and medications. Between 2010 and 2014, RA patients treated with conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) and TNFi were enrolled and followed up. We compared the cancer incidence between patients treated with TNFi and csDMARDs using incidence rate ratios (IRRs) after adjustment for age, gender, and observational periods.\n\n\nRESULTS\nOf 45,423 selected patients with seropositive RA, 2,337 were treated with TNFi and 43,086 were treated with csDMARDs. The TNFi group was younger and was followed-up for a longer duration. During the observational period, 1,732 and 49 cases of cancer were detected in patients treated with csDMARDs and TNFi, respectively. Old age and male sex were associated with cancer occurrence. Adjusted IRRs for all cancers and common cancers demonstrated that cancer incidence did not differ significantly between the TNFi group and csDMARDs group (IRR = 0.913 for all cancers, p = 0.546).\n\n\nCONCLUSIONS\nThis study revealed that cancer incidence was similar in RA patients treated with TNFi and csDMARDs. Anti-TNF therapy may be a safe therapeutic option for RA treatment, in terms of malignancy.",
"affiliations": "Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.;Division of Rheumatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.;Division of Rheumatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.;Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.;Division of Rheumatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.",
"authors": "Jung|Seung Min|SM|;Kwok|Seung-Ki|SK|;Ju|Ji Hyeon|JH|;Park|Yong-Beom|YB|;Park|Sung-Hwan|SH|",
"chemical_list": "D018501:Antirheumatic Agents; D000079424:Tumor Necrosis Factor Inhibitors",
"country": "Korea (South)",
"delete": false,
"doi": "10.3904/kjim.2016.374",
"fulltext": "\n==== Front\nKorean J Intern MedKorean J. Intern. MedKJIMThe Korean Journal of Internal Medicine1226-33032005-6648The Korean Association of Internal Medicine 2917240510.3904/kjim.2016.374kjim-2016-374Original ArticleRheumatologyRisk of malignancy in patients with rheumatoid arthritis after anti-tumor necrosis factor therapy: results from Korean National Health Insurance claims data Jung Seung Min 1Kwok Seung-Ki 2Ju Ji Hyeon 2Park Yong-Beom 1Park Sung-Hwan 2\n1 Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea\n2 Division of Rheumatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, KoreaCorrespondence to Sung-Hwan Park, M.D. The Center for Rheumatic Disease, Division of Rheumatology, Department of Internal Medicine, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, 222 Banpodaero, Seocho-gu, Seoul 06591, Korea Tel: 82-2-2258-6011 Fax: 82-2-3476-2274 E-mail: rapark@catholic.ac.kr5 2019 29 11 2017 34 3 669 677 21 11 2016 16 2 2017 30 4 2017 Copyright © 2019 The Korean Association of Internal Medicine2019This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Background/Aims\nInhibition of tumor necrosis factor (TNF) is an effective treatment for rheumatoid arthritis (RA), but safety concerns about malignancy remain. The aim of this study was to evaluate cancer risk in RA patients treated with TNF inhibitors (TNFi), based on Korean Nationwide Health Insurance claims data.\n\nMethods\nPatients with seropositive RA were selected from the health insurance database containing all citizens’ medical information, based on both RA diagnosis codes and medications. Between 2010 and 2014, RA patients treated with conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) and TNFi were enrolled and followed up. We compared the cancer incidence between patients treated with TNFi and csDMARDs using incidence rate ratios (IRRs) after adjustment for age, gender, and observational periods.\n\nResults\nOf 45,423 selected patients with seropositive RA, 2,337 were treated with TNFi and 43,086 were treated with csDMARDs. The TNFi group was younger and was followed-up for a longer duration. During the observational period, 1,732 and 49 cases of cancer were detected in patients treated with csDMARDs and TNFi, respectively. Old age and male sex were associated with cancer occurrence. Adjusted IRRs for all cancers and common cancers demonstrated that cancer incidence did not differ significantly between the TNFi group and csDMARDs group (IRR = 0.913 for all cancers, p = 0.546).\n\nConclusions\nThis study revealed that cancer incidence was similar in RA patients treated with TNFi and csDMARDs. Anti-TNF therapy may be a safe therapeutic option for RA treatment, in terms of malignancy.\n\nRheumatoid arthritisTumor necrosis factorTNF inhibitorsMalignancyCancer\n==== Body\nINTRODUCTION\nRheumatoid arthritis (RA) is a systemic autoimmune disease requiring treatment with immunosuppressive agents. Proper management of RA includes the use of disease-modifying anti-rheumatic drugs (DMARDs) to control systemic and local inflammation [1,2]. Recently, development of biological DMARDs, including tumor necrosis factor inhibitors (TNFi), has enabled more effective disease activity control. Because of the proinflammatory role of TNF, treatment with TNFi has proven to be beneficial for RA patients with inadequate responses to conventional synthetic DMARDs (csDMARDs) [3]. However, anti-TNF therapy has also raised safety concerns, because relative immune deficiency following TNF inhibition can increase the risk of infection and malignancy. Since TNF plays an important role in cancer pathogenesis, the risk for cancer during and after anti-TNF therapy has emerged as a major concern [4,5].\n\nTNF was primarily identified as an anti-tumor factor in the serum of Bacillus Calmette-Guérin-infected mice treated with endotoxin [6,7]. Serum transfer from these mice to other mice with subcutaneously transplanted sarcomas reduced the size of tumors. Several subsequent studies also indicated that systemic administration of TNF could suppress tumor progression, whereas other studies revealed that downregulation of TNF paradoxically reduced tumor formation and metastasis [4]. Like these preclinical studies, clinical trials were also inconclusive, with conflicting results regarding TNF effects on carcinogenesis. Both treatment with recombinant TNF and TNFi were found to be therapeutically ineffective in cancer patients [4,5].\n\nSince TNFi has become available and widely used in RA patients, the risk for malignancy in patients treated with TNFi has been constantly studied. Earlier data from clinical trials indicated that the risk for malignancy was greater in RA patients treated with TNFi than in TNFi-naïve patients [8]. However, these studies were limited by small sample sizes and heterogeneous study populations. The majority of subsequent studies based on a large national registry suggested that overall cancer incidence did not increase during or after anti-TNF therapy [9-12].\n\nDespite substantial previous research, efforts to elucidate the association between anti-TNF therapy and cancer are still ongoing. Because cancer incidence is influenced by genetic predisposition and environmental factors, cancer epidemiology differs between continents and countries [13]. Thus, it is desirable to estimate cancer incidence from a nationwide database. In South Korea, the national healthcare system provides insurance coverage for nearly all citizens. All hospitals and medical institutions submit insurance claims to the Health Insurance Review and Assessment Service (HIRA), which reviews all insurance claims and makes decisions regarding payment [14]. Because the submitted data include information about diagnosis and treatment for all citizens, the HIRA database can be used to obtain nationwide medical information.\n\nIn this study, we used the HIRA database to evaluate malignancy risk in RA patients following anti-TNF therapy. The incidence of all cancers and common cancers were compared in RA patients treated with TNFi or csDMARDs.\n\nMETHODS\nIdentification of RA patients\nWe retrieved data about RA patients from the HIRA database using both the diagnosis code from the International Classification of Disease, Revision 10 (ICD10) and patient medications, between January, 2010 and December, 2013. As previously reported, identification of RA patient is a critical step in studies conducted with the health insurance claims database [15,16]. The RA (M05) diagnostic code was primarily used to select the study population. We reviewed the lists of medications in patients with M05 codes to increase diagnostic reliability. Patients with RA codes were confirmed as RA patients if they had a prescription for TNFi, methotrexate, leflunomide, or more than one other csDMARD besides methotrexate or leflunomide (Fig. 1). TNFi included infliximab, etanercept, adalimumab, and golimumab. Because RA treatment with certolizumab was not covered by the National Health Insurance System during the study period, prescriptions for certolizumab were negligible. Other csDMARDs included hydroxychloroquine, sulfasalazine, cyclosporine, tacrolimus, azathioprine, mizoribine, and bucillamine. Although M06 codes possibly include seronegative RA, combination of M06 codes and medication review still showed low diagnostic reliability. Thus, patients with M06 codes were excluded from the analysis.\n\nAll identified patients with RA were classified according to their medications. The TNFi group was defined as patients who were prescribed with TNFi more than once. TNFi-naïve patients treated only with csDMARDs were categorized into the csDMARDs group. In the insurance claims database, patient names and national registration numbers were deleted to ensure the patient confidentiality. This study was approved by the HIRA Research Ethics Committee.\n\nMalignancy definition\nMalignancy occurrence was defined as the new appearance of a cancer-related ICD10 code (C00-D09) in the insurance claims during the study period. In these cases, previous records were reviewed to find out the past history of malignancy. If there was no reported cancer for more than 1 year prior to record acquisition, we defined that cancer as newly developed. Patients with comorbid cancer at the entry point were excluded. Since patients with cancer-related ICD10 codes were entered into a co-payment program based on the clinicopathologic evaluation, the diagnosis of cancer was quite reliable.\n\nFollow-up duration was determined by the interval between entry into and exit from this study for each patient (Fig. 2). The entry point for patients treated with csDMARDs was RA identification. When RA codes were initially introduced within the study period, patients were enrolled at the time of RA diagnosis. For patients with new RA onset, insurance claims from the year before entry were reviewed to rule out a prior RA diagnosis. If RA codes were found before the study period, the entry point was defined as initiation of the study period. In patients treated with TNFi, the entry point was determined by TNFi treatment initiation. If a patient began TNFi treatment before 2010, the patient was traced from the study beginning. Follow-up was terminated in cases of malignancy. If a malignancy was not found, patients were traced until the end of the study.\n\nStatistical analysis\nDemographic data such as age and gender were compared with Student t test and chi-square tests, respectively. Differences in time to cancer diagnosis between patients treated with TNFi and csDMARDs were analyzed with the Wilcoxon rank-sum test.\n\nCancer incidence was presented as events/100,000 person-years for the entire study population. The incidence rate ratio (IRR) was estimated with a Cox regression model, adjusted for age, gender, and follow-up duration. We compared the incidence for all cancers and site-specific cancers between the TNFi and csDMARDs groups with IRR. A p < 0.05 was considered significant. All statistical analyses were performed with SAS 9.1 software (SAS Institute Inc., Cary, NC, USA).\n\nRESULTS\nPatient characteristics\nWe retrieved 45,423 patients with seropositive RA from the HIRA database, based on the algorithm for patient selection (Fig. 1). Of the selected patients, 2,337 were treated with TNFi. Patient characteristics at study enrollment are presented in Table 1. The mean age of RA patients was 57.49 years, and 79.7% of patients were female. The TNFi group was younger than the csDMARDs group, but the sex ratios were similar between the two groups. More patients in the TNFi group were enrolled in 2010, and thus follow-up duration was longer for the TNFi group (3.49 years vs. 3.19 years for the csCMARDs group; p < 0.001). The most frequently used drug in the TNFi group was etanercept (40.95%), followed by adalimumab (39.97%), infliximab (17.93%), and golimumab (1.16%).\n\nCharacteristics of RA patients with cancer\nAmong 45,423 patients, 1,781 cancer cases were newly detected. Cancer diagnosis was more frequent in elderly patients, and the proportion of male patients was higher in cancer group. Distribution of TNFi did not differ significantly between patients with and without cancer (Table 2).\n\nDuring the observational period, 1,732 patients (4.02%) in the csDMARDs group and 49 patients (2.10%) in the TNFi group were diagnosed with cancer (Table 3). The crude incidence rates for cancer were 1,257/100,000 patient- years and 600/100,000 patient-years in patients treated with csDMARDs and TNFi, respectively. The median interval between enrollment and cancer diagnosis was 20.06 months for the entire study population, and the time to cancer diagnosis was comparable in patients with and without anti-TNF therapy (p = 0.471).\n\nCancer incidence\nIncidence rates for all cancers and common cancers are presented in Table 4. The most common cancer was thyroid cancer, followed by lung cancer, gastric cancer, colon cancer, breast cancer, and liver cancer in descending order. Lymphoma, a common cancer in RA patients, was not detected in patients treated with TNFi.\n\nThe overall cancer incidence was higher in the csDMARDs group than in the TNFi group. However, when the IRRs were adjusted for age, gender, and observational period, there was no difference in cancer incidence for any kind between patients treated with csDMARDs and those treated with TNFi.\n\nDISCUSSION\nThis study demonstrated that malignancy incidence was similar in seropositive RA patients treated with TNFi and those treated with csDMARDs. The IRRs adjusted for age, gender, and observational period revealed that the incidence for all cancers and site-specific cancers did not differ significantly between the groups.\n\nTo our knowledge, this is the first study comprising all citizens to investigate the cancer incidence in RA subsequent to anti-TNF therapy. A single study conducted in Taiwan included all citizens treated with TNFi [12]. The Taiwanese study also used their National Health Insurance Database, and selected matched controls from patients treated with csDMARDs. We were able to minimize the drop-out that affects the detection of cancer occurrence by using the HIRA database, because all citizens were registered in the HIRA database. Inclusion of all citizens requires proper selection of study population. Previously, Cho et al. [16] suggested that selecting patients according to diagnosis codes and prescribed drugs from the HIRA database was a reliable way to identify patients with RA. However, we could include only patients with seropositive RA, because of the reliability of diagnosis codes.\n\nPrevious studies have reported a wide range of cancer incidence rates, between 3.8 and 9.3 per 1,000 patientyears [10-12,17,18]. Estimation of cancer risk can vary due to ethnic diversity and environmental contributions [13]. Excluding thyroid cancer, the crude cancer incidence in Korean RA patient was 8.2/1,000 patient-years. Because we included the diagnosis of carcinoma in situ, the estimated incidence would be relatively higher compared to the previous research. In a prior study conducted in Korea between 2001 and 2007, the overall cancer incidence in RA patients was 4.6/1,000 patient-years [19]. This cancer occurrence could have been underestimated, because enrollment and follow-up for RA patients was limited to a single center. Nonetheless, the incidence was much lower than that identified in this study. This discrepancy may be due to differences in patient characteristics and study periods. The present study included a higher proportion of older and male patients, who develop cancers more frequently, according to the National Cancer Information Center [20]. Moreover, cancer incidence has increased continuously in the general population since 2000, and the same trend should be expected in RA patients.\n\nPreviously, clinical studies investigating the association between anti-TNF therapy and cancer have shown inconsistent results. An initial-stage meta-analysis of clinical trials revealed increased cancer incidence in patients treated with adalimumab and infliximab [8]. However, the observational period, ranging from 3 months to 1 year, was too short to evaluate the carcinogenic effects of TNFi. Subsequent observational studies with larger sample sizes and longer durations revealed similar cancer incidences, although there were controversies regarding several kinds of cancers [21]. Recently, a Taiwanese nationwide cohort study demonstrated that cancer risk was lower in patients treated with anti-TNF therapy [12]. The overall cancer incidence excluding hematologic malignancy and standardized incidence ratios for lung, breast, and genitourinary cancers were significantly lower in the biologics cohort [12]. Our study also indicated that crude cancer incidence was lower in patients treated with TNFi than in those treated with cs- DMARDs. However, there were significant differences between the groups in clinical characteristics affecting cancer incidence, such as age, gender, and follow-up duration. When the IRRs were adjusted for age, gender, and observational period, incidence rates for all cancers and site-specific cancers were comparable in patients treated with csDMARDs and TNFi.\n\nThe pathogenesis of cancer is closely linked to inflammation and immunity [22]. In general, chronic inflammation triggered by infection or autoimmunity can be a risk factor for cancer occurrence. In RA patients, longstanding disease and high disease activity were found to increase cancer risk, probably through chronic inflammatory response [23,24]. Thus, the effective control of inflammation by TNFi might reduce the cancer risk, although the effects of TNF on carcinogenesis are controversial [5]. However, to elucidate causal links between anti-TNF therapy and cancer, further research will be required.\n\nThe most common cancer in all patients with RA was thyroid cancer, followed by lung cancer, stomach cancer, and colon cancer in descending order. The high incidence of thyroid cancer is in line with its incidence in the general population during the study period, due to increased medical surveillance [25]. Except thyroid cancer, the most common site of cancer was lung in RA patients, whereas stomach cancer was most common in the general population during the study period. An increased risk for lung cancer in RA patients has been suggested by many previous studies [26]. In this study, lymphoma was not detected among TNFi-treated patients.\n\nThe present study has several limitations. First of all, it was difficult to analyze the effects of other confounding variables, such as comorbidities, medications, and disease activity and duration. Information about comorbidities and medications was insufficient for further analysis due to the limitations of the database. Moreover, disease-specific features were not accessible, because of personal information protection. However, we assumed that the csDMARDs group also had active RA requiring methotrexate, leflunomide, or combination of csDMARDs. Second, patients with seronegative RA were not included in the analysis. Third, the study period was 4 years, and the mean follow-up duration was 3.2 years, which is a relatively short period for evaluating TNFi effects on carcinogenesis. Finally, we did not compare cancer incidence between RA patients and the general population, due to limited HIRA database information and cancer statistics.\n\nThis study showed the nationwide cancer incidence in Korean patients with RA and evaluated the association between anti-TNF therapy and cancer risk, using the database of all citizens. However, we should be aware that this study provides only rudimentary information, which requires further evaluation using well-designed registry or cohort. Recently, the Korean College of Rheumatology has constructed a national biologics registry for safety evaluation in treatment with biologics [27]. Forthcoming data from this nationwide registry will provide a better understanding of the association between biologic therapies and cancer.\n\nIn conclusion, the risk of malignancy did not differ significantly between RA patients treated with TNFi and those treated with csDMARDs based on the insurance claim data. In terms of malignancy, anti-TNF therapy may be an effective therapeutic option with an acceptable safety profile for patients with inadequate responses to csDMARDs. This will be illuminated more thoroughly in a prospective observational registry set up.\n\nKEY MESSAGE\n1. We used the data from National Health Insurance claims database to determine the risk of cancer in patients with rheumatoid arthritis (RA).\n\n2. The risk of malignancy did not differ significantly between patients treated with tumor necrosis factor (TNF) inhibitors and conventional synthetic disease modifying anti-rheumatic drugs.\n\n3. Anti-TNF therapy would be a safe therapeutic option for active RA, in terms of malignancy.\n\nNo potential conflict of interest relevant to this article was reported.\n\nThis study was supported by a 2013-Grant from Korean Academy of Medical Sciences. The funding source had no involvement in the study design, collection, analysis, and interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication.\n\nFigure 1. Selection of rheumatoid arthritis (RA) patient from the Health Insurance Review and Assessment Service (HIRA) database. Patients were classified as having RA according to their diagnosis codes and medications. If patients with RA codes (M05) were prescribed with tumor necrosis factor inhibitors (TNFi), methotrexate, lef lunomide, or more than one conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), they were classified as RA patients. Other csDMARDs except methotrexate, and leflunomide included hydroxychloroquine, sulfasalazine, cyclosporine, tacrolimus, azathioprine, mizoribine, and bucillamine.\n\nFigure 2. Schematic diagram showing the study design. (A) Patients treated with conventional synthetic diseasemodifying anti-rheumatic drugs (csDMARDs) were enrolled at study initiation or rheumatoid arthritis (RA) diagnosis. Patients were traced until cancer occurrence or study termination. (B) Patients treated with tumor necrosis factor inhibitors (TNFi) were enrolled at introduction of anti-TNF therapy or study initiation. Follow-up was terminated when cancer was newly detected or the study period ended. R, diagnosis of RA; C, diagnosis of cancer; T, introduction of TNFi.\n\nTable 1. Baseline characteristics for Korean patients with rheumatoid arthritis\n\nCharacteristic\tAll patient (n = 45,423)\tPatient treated with csDMARD (n = 43,086)\tPatient treated with TNFi (n = 2,337)\tp value\t\nAge, yr\t57.49 ± 13.25\t57.70 ± 13.17\t53.63 ± 14.04\t< 0.001\t\nFemale sex\t36,212 (79.72)\t34,382 (79.80)\t1,830 (78.31)\t0.080\t\nUse of MTX\t33,366 (73.46)\t31,359 (72.78)\t2,007 (85.88)\t< 0.001\t\nCalendar year of enrollment\t\t\t\t< 0.001\t\n 2010\t33,432 (73.60)\t31,546 (73.22)\t1,886 (80.70)\t\t\n 2011\t3,728 (8.21)\t3,543 (8.22)\t185 (7.92)\t\t\n 2012\t3,959 (8.72)\t3,805 (8.83)\t154 (6.59)\t\t\n 2013\t4,304 (9.48)\t4,192 (9.73)\t112 (4.79)\t\t\nDuration of follow-up, yr\t3.21 ± 1.23\t3.19 ± 1.24\t3.49 ± 0.99\t< 0.001\t\nDistribution of TNFi\t\t\t\t\t\n Etanercept\t-\t-\t957 (40.95)\t\t\n Infliximab\t-\t-\t419 (17.93)\t\t\n Adalimumab\t-\t-\t934 (39.97)\t\t\n Golimumab\t-\t-\t27 (1.16)\t\t\nValues are presented as mean ± SD or number (%).\n\ncsDMARD, conventional synthetic disease-modifying anti-rheumatic drug; TNFi, tumor necrosis factor inhibitors; MTX, methotrexate.\n\nTable 2. Comparison between rheumatoid arthritis patients with and without cancer\n\nVariable\tPatient without cancer (n = 43,642)\tPatient with cancer (n = 1,781)\tp value\t\nAge, yr\t57.23 ± 13.23\t63.71 ± 12.07\t< 0.001\t\nMale sex\t8,695 (19.92)\t516 (28.97)\t< 0.001\t\nDistribution of TNFi\t\t\t0.268\t\n Etanercept\t941 (41.13)\t16 (32.65)\t\t\n Infliximab\t412 (18.01)\t7 (14.29)\t\t\n Adalimumab\t908 (39.69)\t26 (53.06)\t\t\n Golimumab\t27 (1.18)\t0\t\t\nValues are presented as mean ± SD or number (%).\n\nTNFi, tumor necrosis factor inhibitors.\n\nTable 3. Cancer detection in patients treated with csDMARDs and TNFi during the study period\n\nVariable\tAll patient (n = 45,423)\tPatient treated with csDMARD (n = 43,086)\tPatient treated with TNFi (n = 2,337)\tp value\t\nPatient-years\t145,944\t137,746\t8,037\t< 0.001\t\nCancer case\t1,781 (3.92)\t1,732 (4.02)\t49 (2.10)\t< 0.001\t\nEvents/100,000 patient-years\t1,220.33\t1,257.39\t600.26\t< 0.001\t\nCancer diagnosis calendar year, n (% within all cancer)\t\t\t\t0.038\t\n 2010\t378 (21.22)\t372 (21.48)\t6 (12.24)\t\t\n 2011\t465 (26.11)\t456 (26.33)\t9 (18.37)\t\t\n 2012\t472 (26.50)\t459 (26.50)\t13 (26.53)\t\t\n 2013\t466 (26.17)\t445 (25.69)\t21 (42.86)\t\t\nTime to cancer, mon\t20.06 (8.56–31.56)\t20.21 (8.66–31.77)\t18.60 (7.58–29.62)\t0.471\t\nValues are presented as number (%) or median (interquartile range).\n\ncsDMARD, conventional synthetic disease-modifying anti-rheumatic drug; TNFi, tumor necrosis factor inhibitors.\n\nTable 4. Cancer incidence in rheumatoid arthritis patients treated with csDMARDs and TNFi\n\nVariable\tTotal (n = 45,423)\tcsDMARD (n = 43,086)\tTNFi (n = 2,339)\tIRR (95% CI)a\tp value\t\nCase\tIncidenceb\tCase\tIncidenceb\tCase\tIncidenceb\tTNFi vs. csDMARDs\t\nAll cancer\t1,781\t1,220.33\t1,732\t1,257.39\t49\t599.57\t0.913 (0.679–1.227)\t0.546\t\n Thyroid cancer\t312\t404.52\t302\t415.98\t10\t205.94\t0.966 (0.510–1.830)\t0.916\t\n Lung cancer\t239\t299.13\t232\t306.81\t7\t156.44\t1.038 (0.484–2.227)\t0.923\t\n Gastric cancer\t194\t249.33\t188\t254.57\t6\t151.25\t1.146 (0.503–2.610)\t0.745\t\n Colon cancer\t180\t234.90\t177\t243.80\t3\t70.24\t0.623 (0.198–1.965)\t0.419\t\n Breast cancer (in female)\t147\t199.52\t142\t202.44\t5\t146.92\t1.184 (0.480–2.919)\t0.714\t\n Prostate cancer (in male)\t81\t158.09\t80\t119.25\t1\t13.54\t0.445 (0.061–3.246)\t0.425\t\n Liver cancer\t99\t132.33\t98\t138.52\t1\t20.20\t0.339 (0.047–2.445)\t0.283\t\n Lymphoma\t67\t76.39\t67\t80.53\t0\t0.00\t-\t-\t\ncsDMARD, conventional synthetic disease-modifying anti-rheumatic drug; TNFi, tumor necrosis factor inhibitors; IRR, incidence rate ratio; CI, confidence interval.\n\na Adjusted for age, gender, and observational period.\n\nb Defined as ‘cancer cases/100,000 patient-years.’\n==== Refs\nREFERENCES\n1 Singh JA Saag KG Bridges SL Jr 2015 American College of Rheumatology Guideline for the treatment of rheumatoid arthritis Arthritis Rheumatol 2016 68 1 26 \n2 Smolen JS Landewe R Breedveld FC EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update Ann Rheum Dis 2014 73 492 509 24161836 \n3 Nam JL Ramiro S Gaujoux-Viala C Efficacy of biological disease-modifying antirheumatic drugs: a systematic literature review informing the 2013 update of the EULAR recommendations for the management of rheumatoid arthritis Ann Rheum Dis 2014 73 516 528 24399231 \n4 Lebrec H Ponce R Preston BD Iles J Born TL Hooper M Tumor necrosis factor, tumor necrosis factor inhibition, and cancer risk Curr Med Res Opin 2015 31 557 574 25651481 \n5 Balkwill F Tumour necrosis factor and cancer Nat Rev Cancer 2009 9 361 371 19343034 \n6 Green S Dobrjansky A Carswell EA Partial purification of a serum factor that causes necrosis of tumors Proc Natl Acad Sci U S A 1976 73 381 385 54919 \n7 Carswell EA Old LJ Kassel RL Green S Fiore N Williamson B An endotoxin-induced serum factor that causes necrosis of tumors Proc Natl Acad Sci U S A 1975 72 3666 3670 1103152 \n8 Bongartz T Sutton AJ Sweeting MJ Buchan I Matteson EL Montori V Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials JAMA 2006 295 2275 2285 16705109 \n9 Lopez-Olivo MA Tayar JH Martinez-Lopez JA Risk of malignancies in patients with rheumatoid arthritis treated with biologic therapy: a meta-analysis JAMA 2012 308 898 908 22948700 \n10 Mercer LK Lunt M Low AL Risk of solid cancer in patients exposed to anti-tumour necrosis factor therapy: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis Ann Rheum Dis 2015 74 1087 1093 24685910 \n11 Buchbinder R Van Doornum S Staples M Lassere M March L Malignancy risk in Australian rheumatoid arthritis patients treated with anti-tumour necrosis factor therapy: analysis of the Australian Rheumatology Association Database (ARAD) prospective cohort study BMC Musculoskelet Disord 2015 16 309 26481039 \n12 Wu CY Chen DY Shen JL The risk of cancer in patients with rheumatoid arthritis taking tumor necrosis factor antagonists: a nationwide cohort study Arthritis Res Ther 2014 16 449 25267341 \n13 Torre LA Bray F Siegel RL Ferlay J Lortet-Tieulent J Jemal A Global cancer statistics, 2012 CA Cancer J Clin 2015 65 87 108 25651787 \n14 National Health Insurance Service Operational structure of Korea health care system [Internet] Wonju (KR) National Health Insurance Service c2013 [cited 2017 Sep 21]. Available from: http://www.nhis.or.kr/static/html/wbd/g/a/wbdga0401.html \n15 Jung SM Ju JH Park MS Risk of tuberculosis in patients treated with anti-tumor necrosis factor therapy: a nationwide study in South Korea, a country with an intermediate tuberculosis burden Int J Rheum Dis 2015 18 323 330 25557144 \n16 Cho SK Sung YK Choi CB Kwon JM Lee EK Bae SC Development of an algorithm for identifying rheumatoid arthritis in the Korean National Health Insurance claims database Rheumatol Int 2013 33 2985 2992 23918169 \n17 Mariette X Matucci-Cerinic M Pavelka K Malignancies associated with tumour necrosis factor inhibitors in registries and prospective observational studies: a systematic review and meta-analysis Ann Rheum Dis 2011 70 1895 1904 21885875 \n18 Chen YJ Chang YT Wang CB Wu CY The risk of cancer in patients with rheumatoid arthritis: a nationwide cohort study in Taiwan Arthritis Rheum 2011 63 352 358 21279991 \n19 Kim YJ Shim JS Choi CB Bae SC Mortality and incidence of malignancy in Korean patients with rheumatoid arthritis J Rheumatol 2012 39 226 232 22174211 \n20 National Cancer Information Center Cancer incidence [Internet] Goyang (KR) National Cancer Information Center c2012 [cited 2017 Sep 21]. Available from: http://www.cancer.go.kr/mbs/cancer/subview.jsp?id=cancer_040101000000 \n21 Chen Y Sun J Yang Y Huang Y Liu G Malignancy risk of anti-tumor necrosis factor alpha blockers: an overview of systematic reviews and meta-analyses Clin Rheumatol 2016 35 1 18 \n22 Grivennikov SI Greten FR Karin M Immunity, inflammation, and cancer Cell 2010 140 883 899 20303878 \n23 Abasolo L Judez E Descalzo MA Cancer in rheumatoid arthritis: occurrence, mortality, and associated factors in a South European population Semin Arthritis Rheum 2008 37 388 397 17977580 \n24 Baecklund E Iliadou A Askling J Association of chronic inflammation, not its treatment, with increased lymphoma risk in rheumatoid arthritis Arthritis Rheum 2006 54 692 701 16508929 \n25 Oh CM Jung KW Won YJ Shin A Kong HJ Lee JS Age-period-cohort analysis of thyroid cancer incidence in Korea Cancer Res Treat 2015 47 362 369 25672579 \n26 Simon TA Thompson A Gandhi KK Hochberg MC Suissa S Incidence of malignancy in adult patients with rheumatoid arthritis: a meta-analysis Arthritis Res Ther 2015 17 212 26271620 \n27 Korean College of Rheumatology Korean College of Rheumatology Biologics Registry [Internet] Seoul (KR) Korean College of Rheumatology c2006 [cited 2017 Sep 21]. Available from: http://www.rheum.or.kr/kobio/\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1226-3303",
"issue": "34(3)",
"journal": "The Korean journal of internal medicine",
"keywords": "Cancer; Malignancy; Rheumatoid arthritis; TNF inhibitors; Tumor necrosis factor",
"medline_ta": "Korean J Intern Med",
"mesh_terms": "D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D005260:Female; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D056910:Republic of Korea; D012189:Retrospective Studies; D000079424:Tumor Necrosis Factor Inhibitors",
"nlm_unique_id": "8712418",
"other_id": null,
"pages": "669-677",
"pmc": null,
"pmid": "29172405",
"pubdate": "2019-05",
"publication_types": "D016428:Journal Article",
"references": "1103152;16508929;16705109;17977580;19343034;20303878;21279991;21885875;22174211;22948700;23918169;24161836;24399231;24685910;25267341;25557144;25651481;25651787;25672579;26271620;26481039;26545940;26573205;54919",
"title": "Risk of malignancy in patients with rheumatoid arthritis after anti-tumor necrosis factor therapy: results from Korean National Health Insurance claims data.",
"title_normalized": "risk of malignancy in patients with rheumatoid arthritis after anti tumor necrosis factor therapy results from korean national health insurance claims data"
} | [
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"abstract": "BACKGROUND\nMOG-IgG-associated encephalomyelitis (MOG-EM), a of common type of autoimmune encephalomyelitis (AE), is an autoimmune disease (AID) of the central nervous system that predominantly affects the brain and spinal cord. Rituximab (RTX) - a chimeric anti-CD20 monoclonal antibody - has been increasingly used as an effective immunotherapeutic agent in the treatment of AE. However, interstitial lung disease (ILD) is an exceedingly rare but potentially fatal complication of RTX treatment. Case report and review of the literature: Herein, we describe the first case of RTX-induced ILD (R-ILD) in a teenager with MOG-EM. In addition, we systematically review the literature on R-ILD cases in patients with AID and discuss the clinical characteristics of R-ILD in individuals with differential diagnosis of AID.\n\n\nCONCLUSIONS\nR-ILD should be suspected in patients with AE undergoing RTX treatment who present with dyspnea and/or cough without any signs or symptoms of infection. Meanwhile, by reviewing the literature systematically, we suggest that regardless of the dosage, RTX therapy for AID should be very cautious and well-monitored especially in young individuals including age groups of children, adolescents, and young adults due to the possibility of relatively higher mortality caused by R-ILD.",
"affiliations": null,
"authors": "He|Zhanwen|Z|;Wu|Ruohao|R|;Bai|Ping|P|;Qiu|Kunyin|K|",
"chemical_list": "D000911:Antibodies, Monoclonal; D007155:Immunologic Factors; D000069283:Rituximab",
"country": "Germany",
"delete": false,
"doi": "10.5414/CP203840",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0946-1965",
"issue": "58(12)",
"journal": "International journal of clinical pharmacology and therapeutics",
"keywords": null,
"medline_ta": "Int J Clin Pharmacol Ther",
"mesh_terms": "D000911:Antibodies, Monoclonal; D001327:Autoimmune Diseases; D006801:Humans; D007155:Immunologic Factors; D017563:Lung Diseases, Interstitial; D000069283:Rituximab",
"nlm_unique_id": "9423309",
"other_id": null,
"pages": "740-748",
"pmc": null,
"pmid": "32909538",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D000078182:Systematic Review",
"references": null,
"title": "Rituximab may cause higher mortality in young autoimmune disease patients with rituximab-induced interstitial lung disease: A case report and systematic review of the literature.",
"title_normalized": "rituximab may cause higher mortality in young autoimmune disease patients with rituximab induced interstitial lung disease a case report and systematic review of the literature"
} | [
{
"companynumb": "CN-TAKEDA-2021TJP012907AA",
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
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... |
{
"abstract": "Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been relentless. We are into the 10th month of the pandemic, and we are still getting surprised every day. Although neutralizing antibodies are generated in response to coronavirus disease-19 (COVID-19), these antibodies do not appear to confer lifelong immunity, as lately there have been reports from various parts of the world of reinfection with the virus, starting from Hong Kong, Belgium, and the USA. The Indian Council of Medical Research (ICMR) has been on-record claiming three cases of reinfection in India. Herein, we report three patients of hematologic malignancy who most probably had reinfection with SARS-CoV-2, after complete documented recovery from first infection. All three patients were immunocompromised owing to their primary hematologic malignancy coupled with ongoing therapy, and the second infection was documented to be severe in all the three cases from the first episode.",
"affiliations": "Department of Medicine, Command Hospital, Kolkata, India.;Department of Medicine, Command Hospital, Kolkata, India.;Department of Medicine, Command Hospital, Kolkata, India.;Department of Pathology, Command Hospital, Kolkata, India.;Department of Pathology, Command Hospital, Kolkata, India.",
"authors": "Kapoor|Rajan|R|;Nair|Ranjith K|RK|;Nayan|Neelabh|N|0000-0002-5937-1215;Bhalla|Sharad|S|;Singh|Jasdeep|J|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1007/s42399-021-00790-x",
"fulltext": null,
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"issn_linking": "2523-8973",
"issue": null,
"journal": "SN comprehensive clinical medicine",
"keywords": "COVID-19; Hematologic malignancy; Reactivation; Reinfection; Severe COVID-19",
"medline_ta": "SN Compr Clin Med",
"mesh_terms": null,
"nlm_unique_id": "101740833",
"other_id": null,
"pages": "1-5",
"pmc": null,
"pmid": "33585797",
"pubdate": "2021-02-10",
"publication_types": "D016428:Journal Article",
"references": "32361324;33058797;32887979;32838134;32217618;32840608;29097492;33247596;32454513;32525558",
"title": "Reinfection or Reactivation of Coronavirus-19 in Patients with Hematologic Malignancies: Case Report Series.",
"title_normalized": "reinfection or reactivation of coronavirus 19 in patients with hematologic malignancies case report series"
} | [
{
"companynumb": "IN-BAXTER-2021BAX008762",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ASPARAGINASE"
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{
"abstract": "Drug-induced epithelial hemorrhage of the endolarynx is an unusual etiology of hemoptysis. We present a case of hemoptysis in a young female patient undergoing treatment for metastatic breast cancer with trastuzumab emtansine. Though previously associated with diffuse spontaneous hemorrhage of the gingiva, there have not been reports of laryngeal hemorrhage with trastuzumab emtansine treatment. In this case report, we suggest that trastuzumab emtansine played a contributory role in the development of diffuse epithelial laryngeal hemorrhage and describe the pathophysiology, history, laryngoscopic findings, and management of this condition.",
"affiliations": "University of Nebraska Medical Center, Department of Otolaryngology-Head and Neck Surgery, 981225 Nebraska Medical Center, Omaha, Nebraska 68198-1225, USA.;University of Nebraska Medical Center, Department of Otolaryngology-Head and Neck Surgery, 981225 Nebraska Medical Center, Omaha, Nebraska 68198-1225, USA.;University of Nebraska Medical Center, Department of Otolaryngology-Head and Neck Surgery, 981225 Nebraska Medical Center, Omaha, Nebraska 68198-1225, USA.;University of Nebraska Medical Center, Department of Otolaryngology-Head and Neck Surgery, 981225 Nebraska Medical Center, Omaha, Nebraska 68198-1225, USA.",
"authors": "Klute|Lauren|L|https://orcid.org/0000-0003-1664-7725;Solverson|Matthew|M|https://orcid.org/0000-0002-6562-1217;Bingcang|Christopher M|CM|;Dowdall|Jayme R|JR|",
"chemical_list": null,
"country": "United States",
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"doi": "10.1155/2020/8818905",
"fulltext": "\n==== Front\nCase Rep Otolaryngol\nCase Rep Otolaryngol\nCRIOT\nCase Reports in Otolaryngology\n2090-6765 2090-6773 Hindawi \n\n10.1155/2020/8818905\nCase Report\nDiffuse Spontaneous Laryngeal Hemorrhage with Trastuzumab\nhttps://orcid.org/0000-0003-1664-7725Klute Lauren lauren.klute@unmc.edu https://orcid.org/0000-0002-6562-1217Solverson Matthew Bingcang Christopher M. Dowdall Jayme R. University of Nebraska Medical Center, Department of Otolaryngology-Head and Neck Surgery, 981225 Nebraska Medical Center, Omaha, Nebraska 68198-1225, USA\nAcademic Editor: Dinesh K. Chhetri\n\n\n2020 \n22 8 2020 \n2020 881890521 5 2020 12 8 2020 Copyright © 2020 Lauren Klute et al.2020This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Drug-induced epithelial hemorrhage of the endolarynx is an unusual etiology of hemoptysis. We present a case of hemoptysis in a young female patient undergoing treatment for metastatic breast cancer with trastuzumab emtansine. Though previously associated with diffuse spontaneous hemorrhage of the gingiva, there have not been reports of laryngeal hemorrhage with trastuzumab emtansine treatment. In this case report, we suggest that trastuzumab emtansine played a contributory role in the development of diffuse epithelial laryngeal hemorrhage and describe the pathophysiology, history, laryngoscopic findings, and management of this condition.\n\nUniversity of Nebraska Medical Center\n==== Body\n1. Introduction\nHemoptysis is frequently encountered and includes a wide variety of pathologies of the upper airway, pulmonary, gastrointestinal, hematologic, immune, and cardiovascular systems [1]. In the absence of mechanical trauma, neoplasm, infection, and/or concomitant anticoagulation, hemoptysis originating from the larynx is rare [2]. Vocal-fold hemorrhage commonly refers to bleeding into the superficial lamina propria [3]. It can result from phonotrauma, small irregularities in the blood vessel wall, or mechanical trauma [2]. This type of hemorrhage is subepithelial in origin. To our knowledge, diffuse epithelial hemorrhage of the endolarynx has not been documented in the literature. This case report documents episodic hemoptysis secondary to spontaneous endolaryngeal epithelial hemorrhage in a 37-year-old female diagnosed with T2N1M1 right breast invasive ductal carcinoma treated with trastuzumab emtansine.\n\nTrastuzumab emtansine (T-DM1), a monoclonal antibody and human epidermal growth factor receptor 2 (HER-2) receptor inhibitor conjugated to emtansine DM-1, is a Food and Drug Administration-approved treatment for HER-2-positive breast cancer [4]. The most frequent adverse events with T-DM1 include fatigue, diarrhea, anemia, elevated transaminases, and mild-to-moderate hemorrhagic events thought to be related to induced thrombocytopenia [4]. The development of telangiectasias represents an uncommon but known adverse effect [5–7]. Case reports have documented hereditary hemorrhagic telangiectasia-like symptoms during treatment with T-DM1 treatment [5]. The mechanism is currently unknown; however, it has been postulated that HER-2 expression on endothelial cells could facilitate delivery of emtansine to these cells, leading to disruption of microtubules, impairment of angiogenesis, and the development of telangiectasias [5]. Furthermore, Sarmast et al. documented a case report of spontaneous and profuse gingival hemorrhage during treatment with paclitaxel and trastuzumab emtansine [8].\n\n2. Case Presentation\nThis case report describes a 37-year-old female currently undergoing treatment for metastatic breast cancer. The patient presented to the Otolaryngology Clinic with complaints of hemoptysis, odynophonia, and odynophagia. She expressed waking several times in two weeks choking on blood and the feeling of “water in her throat” when she coughed. She also showed recent upper respiratory infection symptoms with rhinorrhea and cough.\n\nShe had a pertinent past medical history of metastatic breast cancer with metastasis in the lungs, neck, and bone. Since starting chemotherapy, she had a history of iron deficiency anemia, menorrhagia, hematochezia, and thrombocytopenia. She was previously treated with docetaxel, standard trastuzumab, and pertuzumab every three weeks for six doses. Due to progression of disease, her chemotherapeutic regimen was changed to T-DM1, zolendronic acid, and tamoxifen. Her last infusion of T-DM1 was 26 days prior to the incidence of hemoptysis and had 15 total infusions of T-DM1 prior to presentation.\n\nA complete head and neck examination was performed, including nasopharyngolaryngoscopy, which revealed a friable, excoriated nasal septum, bilateral vocal fold edema with ulceration of vocal folds, and no associated submucosal hemorrhage, with epithelial bleeding noted on the supraglottic and glottic surfaces. There was no surrounding ecchymosis (Figures 1(a) and 1(b)). The patient had no prior history of laryngeal mucosal bleeding. We recommended admission to the hospital to rule out pulmonary hemorrhage, in addition to airway monitoring, humidification, cough suppression, and laryngopharyngeal reflux prevention. She was evaluated with computed tomography scan which was negative for contributing factors. The Pulmonology team determined that this was not related to progression of metastatic lung lesions or lung-related hemoptysis. Laryngoscopy was completed 24 hours after admission. Findings included petechia of the supraglottis, false vocal folds, interarytenoid region, and scabbing of the vocal folds (Figures 2(a) and 2(b)). Hematology and Oncology teams were consulted to evaluate for possible bleeding disorders, and von Willebrand disease was ruled out via laboratory studies. The patient was discharged with vocal hygiene and humidification. Upon discharge from the hospital, she has been followed in the Otolaryngology Clinic at four different occasions. Follow-up examinations revealed no further laryngeal hemorrhage but did reveal new, profuse, and recurrent epistaxis laryngitis, differential diagnosis including staphlococcus. She was treated appropriately with nasal hygiene and antibiotic therapy. Ultimately, the patient's cancer progressed, and the T-DM1 was discontinued. She has had no further episodes of hemoptysis.\n\n3. Discussion\nAlthough hemoptysis has several associated etiologies, the temporal relationship of the exposure and clinical manifestations of diffuse spontaneous epithelial hemorrhage of the endolarynx suggest that it may be related to T-DM1. Up to 32% of patients treated with T-DM1 reported abnormal bleeding [5]. The mechanism is currently unknown; however, it has been postulated that HER-2 expression on endothelial cells could facilitate delivery of emtansine to these cells, leading to disruption of microtubules, impairment of angiogenesis, and the development of cutaneous and mucosal telangiectasias [5, 7, 9].\n\nSibaud et al. postulated that drug-induced hepatic injury with associated elevation in transaminases resulting from T-DM1 infusion may also contribute to the development of telangiectasia [5]. Hemorrhagic complications have also been attributed to thrombocytopenia secondary to the inhibition of megakaryocyte differentiation by DM-1, thereby resulting in decreased platelet synthesis [6].\n\nOur patient, in the case above, experienced improvement in her laryngeal hemorrhage following treatment with humidification and voice therapy, in addition to discontinuation of T-DM1. In the setting of hemoptysis in a patient treated with trastuzumab emtansine, consideration should be given to drug-induced endolaryngeal hemorrhage.\n\nAcknowledgments\nThe authors thank Kristy Carlson, Ph.D., for comments that greatly improved the manuscript. This work was supported by the University of Nebraska Medical Center, Department of Otolaryngology-Head and Neck Surgery.\n\nData Availability\nNo data were used to support this study.\n\nDisclosure\nAn earlier version of this manuscript was a poster presentation at the Fall Voice Conference in 2019.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest regarding the publication of this article.\n\nFigure 1 Bilateral vocal fold edema with ulceration of vocal folds; supraglottic and glottic epithelial bleeding.\n\nFigure 2 Petechiae of the supraglottis and false vocal folds; scabbing of the interarytenoid region, glottis, and supraglottis.\n==== Refs\n1 Earwood J. S. Thompson T. D. Hemoptysis: evaluation and management American Family Physician 2015 91 4 243 249 25955625 \n2 Rhodes J. E. Hemorrhage of the larynx JAMA: The Journal of the American Medical Association 1904 XLIII 18 1284 1289 10.1001/jama.1904.92500180001d 2-s2.0-84943431547 \n3 Hemorrhage, https://voice.weill.cornell.edu/voice-disorders/hemorrhage \n4 Verma S. Miles D. Gianni L. Trastuzumab emtansine for HER2-positive advanced breast cancer 2012 https://www.ncbi.nlm.nih.gov/pubmed/23020162 \n5 Sibaud V. Niec R. E. Schindler K. Ado-trastuzumab emtansine-associated telangiectasias in metastatic breast cancer: a case series Breast Cancer Research and Treatment 2014 146 2 451 456 10.1007/s10549-014-3001-z 2-s2.0-84904102406 24929675 \n6 Uppal H. Doudement E. Mahapatra K. Potential mechanisms for thrombocytopenia development with trastuzumab emtansine (T-DM1) Clinical Cancer Research 2015 21 1 123 133 10.1158/1078-0432.CCR-14-2093 2-s2.0-84920521262 25370470 \n7 Sibaud V. Vigarios E. Combemale P. T-DM1-related telangiectasias: a potential role in secondary bleeding events Annals of Oncology 2015 26 2 436 437 10.1093/annonc/mdu533 2-s2.0-84925335065 25403586 \n8 Sarmast N. Gutierrez Quevedo M. Wang H. Gutierrez Herrera E. Acute local spontaneous and profuse gingival hemorrhage during neoadjuvant treatment with Paclitaxel and trastuzumab Dentistry Journal 2016 4 3 p. 22 10.3390/dj4030022 \n9 Kwon Y. Gomberg-Maitland M. Pritzker M. Thenappan T. Telangiectasia and pulmonary arterial hypertension following treatment with trastuzumab emtansine Chest 2016 149 4 10.1016/j.chest.2015.09.008 2-s2.0-84964474550\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6773",
"issue": "2020()",
"journal": "Case reports in otolaryngology",
"keywords": null,
"medline_ta": "Case Rep Otolaryngol",
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"nlm_unique_id": "101576603",
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"pages": "8818905",
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"pmid": "32908757",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "24929675;25370470;27055712;23020162;25403586;25955625;29563464",
"title": "Diffuse Spontaneous Laryngeal Hemorrhage with Trastuzumab.",
"title_normalized": "diffuse spontaneous laryngeal hemorrhage with trastuzumab"
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