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"abstract": "Neuropathies associated with plasma cell dyscrasias are a major cause of morbidity for patients managed by medical oncologists. Because of similarities in clinical presentation and on nerve conduction studies, identifying the underlying disease leading to a paraproteinemic neuropathy can often be difficult. In addition, the degree of neurologic deficit does not strictly correlate with the extent of abnormalities on common clinical laboratory testing. Fortunately, with increasing understanding into the biologic mechanisms of underlying hematologic diseases, additional biomarkers have recently been developed, thus improving our diagnostic capacity. Neuropathies associated with plasma cells dyscrasias are seen with Monoclonal gammopathy of undetermined significance (MGUS) particularly IgM subtype, followed by IgG and IgA MGUS, multiple myeloma, Waldenström's macroglobulinemia, amyloid, Castleman's disease, and POEMS syndrome. The mechanisms of neuronal injury associated with plasma cell dyscrasia vary based on underlying diagnosis and include malignant infiltration, immune-mediated antibody deposition, or local compression of nerve roots. The polyneuropathies are frequently demyelinating, although axonal and mixed neuropathies can also be seen. As demonstrated by the cases included in this review, patients frequently present with symmetric sensory disturbance, followed by progressive motor weakness. Unfortunately, because of the complexity of diagnostic testing, patients are frequently examined late, often after receiving several ineffective therapies. The aim of this case-based review is to provide clinicians with insight on how to properly recognize these atypical neuropathies and send the appropriate diagnostic work, increasing the likelihood of accurately classify the patient's underlying hematologic disorder.",
"affiliations": "Division of Hematology & Oncology, Columbia University Medical Center, New York, NY, USA.;Division of Hematology & Oncology, Columbia University Medical Center, New York, NY, USA.;Division of Hematology & Oncology, Columbia University Medical Center, New York, NY, USA.",
"authors": "Rosenbaum|Evan|E|;Marks|Douglas|D|http://orcid.org/0000-0002-3690-7101;Raza|Shahzad|S|http://orcid.org/0000-0002-2739-2265",
"chemical_list": null,
"country": "England",
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"doi": "10.1002/hon.2417",
"fulltext": null,
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"issn_linking": "0278-0232",
"issue": "36(1)",
"journal": "Hematological oncology",
"keywords": "MGUS; POEMS; Waldenstrom Macroglobulinemia; amyloidosis; multiple myeloma; neuropathy",
"medline_ta": "Hematol Oncol",
"mesh_terms": "D006801:Humans; D010265:Paraproteinemias; D010523:Peripheral Nervous System Diseases",
"nlm_unique_id": "8307268",
"other_id": null,
"pages": "3-14",
"pmc": null,
"pmid": "28397326",
"pubdate": "2018-02",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Diagnosis and management of neuropathies associated with plasma cell dyscrasias.",
"title_normalized": "diagnosis and management of neuropathies associated with plasma cell dyscrasias"
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"abstract": "Myasthenia Gravis (MG) is a disorder of the neuromuscular junction (NMJ) that manifests as fluctuating fatiguable weakness of the muscles. There are many factors that can exacerbate myasthenia symptoms including a variety medications and drugs, systemic illness, and pregnancy. A number of medications have been implicated in exacerbating MG symptoms, including aminoglycosides. We present a case of an elderly female with newly diagnosed MG following the use of tobramycin eye drops for 3 days. There have been limited reports in the literature of topical medications that exacerbate MG symptoms. Clinicians prescribing tobramycin eye drops (or other associated medications) should have a high index of suspicion of MG as early discontinuation and therapy will limit long-term morbidity and mortality in these patients.",
"affiliations": "Department of Internal Medicine, University of Illinois College of Medicine at Peoria, Peoria, USA.;Internal Medicine, Advanced Cancer Care Center Illinois, Aurora, USA.;Windsor University School of Medicine, Cayon, St Kitts and Nevis.;Department of Critical Care/Pulmonary Medicine, University of Illinois College of Medicine at Peoria, Peoria, USA.",
"authors": "Hussain|Nooreen|N|0000-0002-6439-3865;Hussain|Faiz|F|0000-0002-6439-3865;Haque|Danish|D|;Chittivelu|Subramanyam|S|",
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"doi": "10.1080/20009666.2018.1487245",
"fulltext": "\n==== Front\nJ Community Hosp Intern Med PerspectJ Community Hosp Intern Med PerspectZJCHzjch20Journal of Community Hospital Internal Medicine Perspectives2000-9666Taylor & Francis 148724510.1080/20009666.2018.1487245Case ReportA diagnosis of late-onset Myasthenia gravis unmasked by topical antibiotics N. HUSSAIN ET AL.JOURNAL OF COMMUNITY HOSPITAL INTERNAL MEDICINE PERSPECTIVEShttp://orcid.org/0000-0002-6439-3865Hussain Nooreen ahttp://orcid.org/0000-0002-6439-3865Hussain Faiz bHaque Danish cChittivelu Subramanyam da Department of Internal Medicine, University of Illinois College of Medicine at Peoria, Peoria, USAb Internal Medicine, Advanced Cancer Care Center Illinois, Aurora, USAc Windsor University School of Medicine, Cayon, St Kitts and Nevisd Department of Critical Care/Pulmonary Medicine, University of Illinois College of Medicine at Peoria, Peoria, USACONTACT Nooreen Hussain Nhussain216@gmail.comDepartment of Internal Medicine, University of Illinois College of Medicine at Peoria530 NE Glen Oak Ave, Peoria, IL 61637, USA2018 22 6 2018 8 4 230 232 13 4 2018 30 5 2018 © 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group on behalf of Greater Baltimore Medical Center.2018The Author(s)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.ABSTRACT\nMyasthenia Gravis (MG) is a disorder of the neuromuscular junction (NMJ) that manifests as fluctuating fatiguable weakness of the muscles. There are many factors that can exacerbate myasthenia symptoms including a variety medications and drugs, systemic illness, and pregnancy. A number of medications have been implicated in exacerbating MG symptoms, including aminoglycosides. We present a case of an elderly female with newly diagnosed MG following the use of tobramycin eye drops for 3 days. There have been limited reports in the literature of topical medications that exacerbate MG symptoms. Clinicians prescribing tobramycin eye drops (or other associated medications) should have a high index of suspicion of MG as early discontinuation and therapy will limit long-term morbidity and mortality in these patients.\n\nKEYWORDS\nMyasthenia gravisaminoglycosidestobramycinantibioticsneuromusculareye drops\n==== Body\n1. Introduction\nMyasthenia gravis (MG) is a rare autoimmune disorder that affects about 5–15 per 100,000 people. MG is a disorder of the neuromuscular junction (NMJ) that manifests as fluctuating fatiguable weakness of the muscles. Symptoms manifest due to reduced binding of acetylcholine at the NMJ due to the presence of acetylcholine receptor (AchR) antibodies or less commonly, antibodies directed toward other postsynaptic skeletal muscle components, such as Muscle Specific Kinase. [1] A myasthenia crisis is a serious condition that carries a mortality rate of 3–8% [1]. Patients in a myasthenia crisis develop acute respiratory failure due to worsening MG symptoms, requiring admission to the intensive care unit. There are many factors that can exacerbate myasthenia symptoms including a variety of medications and drugs, systemic illness, and pregnancy. Infections are noted to be responsible for 40–70% of myasthenia crisis episodes [1,2].\n\nA number of medications have been implicated in exacerbating myasthenia symptoms, including various antibiotics. Antibiotics commonly associated to exacerbating myasthenia symptoms include fluroqinolones, aminoglycosides, macrolides, and beta-lactams. [2,3] We present a case of an elderly female with newly diagnosed MG following the use of tobramycin eye drops for 3 days.\n\n2. Case overview\nA 73-year-old female with a past medical history of a previous cerebrovascular accident, breast cancer, and vulvovaginal adenocarcinoma was admitted for diplopia and generalized weakness. Regarding the patient’s malignancy history, she was diagnosed with advanced stage vulvar cancer 8 years previously and underwent a total abdominal hysterectomy and bilateral salpingo-oophorectomy the following year. She was diagnosed with left breast cancer the following year and underwent breast conservation surgery and radiotherapy. She was placed on anastrazole therapy thereafter and followed regularly with her oncologist. Her recent imaging studies did not demonstrate new disease.\n\nThe patient’s initials symptoms were irritation of her left eye, and after seeing her primary care provider, she was started on tobramycin eye drops (0.3% solution, every 2–3 h) for a possible ocular infection. Three days after initiating tobramycin she began experiencing diplopia, generalized weakness (primarily in the neck), and increasing respiratory distress. The patient did not recall ever having symptoms like this before and denied a history of MG. Her laboratory studies were significant for AchR-binding antibody positive at 82 nmol/L, AchR-blocking antibody positive at 56% inhibition, AchR-modulating antibody positive at 95% inhibition, and a positive striate muscle antibody titer of 1:160. A computed tomography of her chest did not show the presence of a thymoma in the mediastinum.\n\nThe patient was started on pyridostigmine therapy with improvement of her symptoms. However, while she initially responded well to pyridostigmine, she begin experiencing increasing weakness and fatigue after receiving intravenous and oral magnesium the following day, despite an increase in the dosage of pyridostigmine. She subsequently underwent six cycles of plasma exchange therapy with improvement in her symptoms however she did not tolerate nasal cannula for long periods of time. She continued to require pressure support ventilation via facemask throughout her admission. Her long-term plan was to undergo weekly PLEX therapy for 3–6 months at a long-term acute care facility, with continued ventilator support through a tracheostomy.\n\nUnfortunately the patient’s clinical status continued to deteriorate as she developed an upper GI bleed, developed a significant anemia due to blood loss, and was intubated for respiratory failure due to prolonged periods of apnea. Shortly thereafter she went into a pulseless electrical activity cardiac arrest and underwent 30 min of cardiopulmonary resuscitation. Her family made the decision to withdraw care and she died shortly after.\n\n3. Discussion\nThere are many medications that are known to interfere with neuromuscular transmission, and this has been seen in patients with and without a previous diagnosis of MG. [4] Fluroqinolones, aminoglycosides, macrolides, and beta-lactams are common antibiotics that have been reported to exacerbate symptoms of MG. Aminoglycosides are known to have the most potent effect on neuromuscular transmission as they exert a combined presynaptic and postsynaptic effect. [5] The drug competes with calcium for receptors and hinders the release of acetylcholine from the presynaptic membrane. By competitive inhibition it impairs the depolarization induced by acetylcholine at the postsynaptic membrane. The action potential of the myocyte membrane cannot form, which results in a blockade to the NMJ. [5] Aminoglycosides have also been described in the literature to cause a form of drug-induced myasthenic syndrome [4]. This syndrome is described as a reversible myasthenic disorder in patients with no evidence of a preexisting defect in neuromuscular transmission. Symptoms usually develop relatively soon after the drug is started. Categorizing these symptoms as a myasthenic syndrome verses newly diagnosed MG usually depends on the recovery after the medication is stopped. A myasthenic syndrome is considered when there is prompt resolution of symptoms after drug withdrawal. A prolonged recovery period after withdrawal of the medication however, is more indicative of classic MG. Our patient had a prolonged recovery after drug withdrawal and she eventually required plasma exchange therapy when her symptoms did not improve significantly with pyridostigmine. Given her clinical picture and her laboratory findings, it is likely that she had a form of late onset MG.\n\nPatients with a generalized form of MG are classified by age of onset (earlier or later than age 50). Patients with late onset form (age of onset greater than 50) are less likely to have a thymoma, and the subtype predominately affects males. Elderly patients are also more likely to have autoantibodies against striated muscle proteins. This form is usually more severe and patients may frequently experience bulbar signs and severe respiratory crises. [6] In the early onset form (age of onset less than 50), patients are known to have other autoantibodies and can develop other autoimmune diseases such as thyroiditis. Our patient was diagnosed with late-onset MG due to her age of diagnosis and her laboratory studies being positive for AchR antibodies and her titer of striate muscle antibodies being elevated. It is well documented in the literature that the presence of striation antibodies is associated with severe disease in all MG subgroups. [7–9] This is consistent with her clinical picture as she required prolonged plasma exchange therapy and respiratory support during her course.\n\nWhile it is well known that aminoglycosides can exacerbate MG symptoms, there are very limited case reports in the literature that discuss topical medications that exacerbate symptoms. We report this rare case to highlight the use of tobramycin eye drops as a precipitant of a myasthenia crisis and to characterize a form of late-onset MG in our patient who was newly diagnosed with MG at age 73. Clinicians prescribing tobramycin eye drops (or other associated medications) should have a high index of suspicion of MG as early discontinuation and therapy will limit long-term morbidity and mortality in these patients.\n\nDisclosure statement\nThe authors have no conflict of interest with this work.\n==== Refs\nReferences\n[1] Jani-Acsadi A , Lisak RP. Myasthenic crisis: guidelines for prevention and treatment . J Neurol Sci . 2007 ;261 :127 –133 .17544450 \n[2] Van Berkel MA , Twilla JD , England BS \nEmergency department management of a myasthenia gravis patient with community-acquired pneumonia: does initial antibiotic choice lead to cure or crisis? J Emerg Med . 2016 ;50 (2 ):281 –285 .26472607 \n[3] Bershad EM , Feen ES , Suarex JI \nMyasthenia gravis crisis . South Med J . 2008 ;101 :63 –69 .18176295 \n[4] Argov Z , Brenner T , Abramsky O \nAmpicillin may aggravate clinical and experimental myasthenia gravis . Arch Neurol . 1986 ;43 :255 –256 .3947272 \n[5] Changqin L , Fang H \nInvestigation on the mechanism of exacerbation of myasthenia gravis by aminoglycoside antibiotics in mouse model . J Huazhong Univ Sci Technol . 2005 ;25 (3 ):294 –296 .\n[6] Romi F , Aarli JA , Gilhus NE \nMyasthenia gravis patients with ryanodine receptor antibodies have distinctive clinical features . Eur J Neurol . 2007 ;14 :617 –620 .17539937 \n[7] Suzuki S , Utsugisawa K , Nagane Y , et al \nThree types of striational antibodies in myasthenia gravis . Autoimmune Dis . 2011 ;740583 .21785709 \n[8] Romi F , Skeie GO , Gilhus EN , et al \nStriational antibodies in myasthenia gravis: reactivity and possible clinical significance . Arch Neurol . 2005 3 ;62 (3 ):442 –446 .15767509 \n[9] Suzuki S , Satoh T , Yasuoka H , et al \nNovel autoantibodies to a voltage-gated potassium channel KV1.4 in a severe form of myasthenia gravis . J Neuroimmunol . 2005 ;170 (1 ):141 –149 .16182377\n\n",
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"issue": "8(4)",
"journal": "Journal of community hospital internal medicine perspectives",
"keywords": "Myasthenia gravis; aminoglycosides; antibiotics; eye drops; neuromuscular; tobramycin",
"medline_ta": "J Community Hosp Intern Med Perspect",
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"pages": "230-232",
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"pubdate": "2018",
"publication_types": "D002363:Case Reports",
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"title": "A diagnosis of late-onset Myasthenia gravis unmasked by topical antibiotics.",
"title_normalized": "a diagnosis of late onset myasthenia gravis unmasked by topical antibiotics"
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"abstract": "Radiation therapy is considered an optimal partner for immunotherapies. Several pre-clinical studies have demonstrated that regression of distant metastases, at remote non-irradiated sites of the body, termed the \"abscopal effect\", can be achieved by an appropriate timing and combination of radiation with immunotherapy. However, nearly all pre-clinical and clinical studies evaluating a combination of radiation and immunotherapies have used external beam radiation therapy. We present in this case report, the abscopal effect observed in a 30-year-old Japanese woman with metastatic renal cell carcinoma after the treatment with high-dose-rate interstitial brachytherapy combined with nivolumab. This is the first published report demonstrating an abscopal effect following brachytherapy for human malignancy. Our case indicates that immuno-oncology effects are not limited to external beam irradiation regimens as they can also be attained by brachytherapy.",
"affiliations": "Department of Radiology, Kyoto Prefectural University Graduate School of Medical Science, Kamigyo-ku, Kyoto, Japan.;Department of Radiology, Kyoto Prefectural University Graduate School of Medical Science, Kamigyo-ku, Kyoto, Japan.;Department of Radiology, Kyoto Prefectural University Graduate School of Medical Science, Kamigyo-ku, Kyoto, Japan.;Department of Radiology, Kyoto Prefectural University Graduate School of Medical Science, Kamigyo-ku, Kyoto, Japan.;Department of Radiology, Kyoto Prefectural University Graduate School of Medical Science, Kamigyo-ku, Kyoto, Japan.;Department of Urology, Kyoto Prefectural University Prefectural University Graduate School of Medical Science, Kamigyo-ku, Kyoto, Japan.;Department of Urology, Kyoto Prefectural University Prefectural University Graduate School of Medical Science, Kamigyo-ku, Kyoto, Japan.;Department of Urology, Kyoto Prefectural University Prefectural University Graduate School of Medical Science, Kamigyo-ku, Kyoto, Japan.;Department of Radiology, Kyoto Prefectural University Graduate School of Medical Science, Kamigyo-ku, Kyoto, Japan.",
"authors": "Suzuki|Gen|G|;Masui|Koji|K|;Yamazaki|Hideya|H|;Takenaka|Tadashi|T|;Asai|Syunsuke|S|;Taniguchi|Hidefumi|H|;Nakamura|Terukazu|T|;Ukimura|Osamu|O|;Yamada|Kei|K|",
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"fulltext": "\n==== Front\nJ Contemp BrachytherapyJ Contemp BrachytherapyJCBJournal of Contemporary Brachytherapy1689-832X2081-2841Termedia Publishing House 3844010.5114/jcb.2019.89365Case ReportAbscopal effect of high-dose-rate brachytherapy on pelvic bone metastases from renal cell carcinoma: a case report Suzuki Gen MD, PhD1Masui Koji MD1Yamazaki Hideya MD, PhD1Takenaka Tadashi RTT1Asai Syunsuke MD1Taniguchi Hidefumi MD, PhD2Nakamura Terukazu MD, PhD2Ukimura Osamu MD, PhD2Yamada Kei MD, PhD11 Department of Radiology, Kyoto Prefectural University Graduate School of Medical Science, Kamigyo-ku, Kyoto, Japan2 Department of Urology, Kyoto Prefectural University Prefectural University Graduate School of Medical Science, Kamigyo-ku, Kyoto, JapanAddress for correspondence: Gen Suzuki, MD, PhD, Department of Radiology, Kyoto Prefectural University of Medicine, 465 Kajiicho Kawaramachi Hirokoji, Kamigyo-ku, Kyoto 602-8566 Japan. phone: +81 752515618. fax: +81 752515840. e-mail: gensuzu@koto.kpu-m.ac.jp30 10 2019 10 2019 11 5 458 461 22 8 2019 08 10 2019 Copyright: © 2019 Termedia Sp. z o. o.2019This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License, allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.Radiation therapy is considered an optimal partner for immunotherapies. Several pre-clinical studies have demonstrated that regression of distant metastases, at remote non-irradiated sites of the body, termed the “abscopal effect”, can be achieved by an appropriate timing and combination of radiation with immunotherapy. However, nearly all pre-clinical and clinical studies evaluating a combination of radiation and immunotherapies have used external beam radiation therapy. We present in this case report, the abscopal effect observed in a 30-year-old Japanese woman with metastatic renal cell carcinoma after the treatment with high-dose-rate interstitial brachytherapy combined with nivolumab. This is the first published report demonstrating an abscopal effect following brachytherapy for human malignancy. Our case indicates that immuno-oncology effects are not limited to external beam irradiation regimens as they can also be attained by brachytherapy.\n\nbrachytherapyimmunotherapymetastatic renal cell carcinomanivolumabradiationabscopal effect\n==== Body\nPurpose\nThe abscopal effect refers to the regression of non-irradiated metastatic lesions at distant areas from the primary site of irradiation. In the last decade, the introduction of immune checkpoint inhibitors (ICIs), such as the PD-1 inhibitor, has revolutionized therapeutic strategy for a wide variety of advanced malignancies. Radiotherapy holds a significant promise as a potential partner for combination therapies. Particularly, combining radiation and immunotherapy in the clinical setting has shown to improve outcomes in several types of malignant tumors [1,2,3,4].\n\nThe abscopal effect has only rarely been observed prior to the widespread application of immunotherapy, and an increase in prevalence was observed with the recent introduction of ICIs [4]. Thus far, nearly all preclinical and clinical studies evaluating radiation therapy in combination with immunotherapies have used external beam radiotherapy (EBRT), and little is known about the efficacy of immune modulation combined with brachytherapy [5]. Herein, we describe a patient with intractable metastases of renal cell carcinoma (RCC) who exhibited the abscopal effect after a combination treatment with nivolumab and high-dose-rate interstitial brachytherapy (HDR-ISBT). To the best of our knowledge, this is the first published report demonstrating the abscopal effect following brachytherapy for human malignancy.\n\nCase presentation\nA 30-year-old woman underwent radical nephrectomy for clinically localized left RCC in 1998, and was pathologically diagnosed with clear cell RCC, pT2b and Fuhrman grade 2. Bilateral lung metastases were found eight years after nephrectomy, and both lesions were surgically removed, followed by postoperative interferon treatment. However, by 2010 she underwent five lung resections and also one radiofrequency ablation, and the patient achieved long-term response with adjuvant sunitinib. In May 2013, a right ovarian metastasis was detected, which was surgically excised. In July 2013, metastases to the bones (pelvic and lumber vertebrae) and hilar lymph nodes were detected, and she underwent treatment with axitinib followed by sunitinib. In 2016, her mediastinal lymph nodes were treated with EBRT of 60 Gy in 30 fractions at an external institution. In May 2018, liver metastasis was detected, and this lesion was treated with radiofrequency ablation. In September 2018, metastasis in the right ovary led to its surgical excision, followed by nivolumab at the standard dosage (infusions of 240 mg every alternate week) as third-line therapy. Four months after the initiation of nivolumab, computed tomography (CT) imaging revealed the progression of lung, liver and bone metastases and nivolumab monotherapy was further continued for two months. In January and February 2019, she underwent radiofrequency ablation for newly discovered liver metastases. In March 2019, CT imaging demonstrated gradual growth of the left iliac bone metastasis. The Tumor Board at our hospital decided that there was no surgical indication for this lesion.\n\nThe CT scan acquired prior to her visit to our hospital revealed an iliac crest tumor measuring 9.4 × 8.8 × 6.0 cm (Figure 1A) and tumor volume measuring 347.5 cm3. She was referred to our department for treatment and considering the large tumor burden other than metastases, we proposed HDR-ISBT for tumor control and volume reduction. Informed consent was obtained from the patient and her family. Nivolumab was continued until 10 days before the initiation of brachytherapy. After administration of spinal anesthesia, 13 applicator catheters were percutaneously inserted into the tumor under real-time CT guidance. These applicators were placed so that the whole tumor area was irradiated with simultaneous controlling the position of the needle against the adjacent structures.\n\nFig. 1 Clinical course of treatment and computed tomography (CT) imaging: A) CT image taken one month before brachytherapy shows left iliac bone metastasis; B) Pelvis scan with high-dose-rate interstitial brachytherapy (HDR-ISRT) dosimetry and applicator reconstruction shows 13 applicator needles percutaneously inserted into the target, and 7 Gy per fraction dose was prescribed in 100% of clinical target volume; C) CT image taken three months after brachytherapy and resumption of nivolumab shows shrinkage of the left iliac lesion (white arrow) and the left internal iliac lymph node (white arrowhead); D) CT image taken three months after brachytherapy and resumption of nivolumab shows complete remission of the metastatic spine disease (yellow arrow)\n\nAfter completion of this procedure, CT scan was taken for planning radiation therapy. In the treatment planning system (Oncentra® Brachy; Elekta AB, Stockholm, Sweden), clinical target volume (CTV) was set up based on the acquired CT images and 7 Gy per fractionated dose was prescribed in 100% of the CTV. The doses encompassing 90%, 95%, and 98% of the CTV (D90, D95, D98) were 9.2 Gy, 8.5 Gy, and 7.9 Gy per fraction, respectively. The minimum dose to the most exposed 0.1 cc, 1.0 cc, and 2.0 cc (D0.1cc, D1cc, D2cc) of the small bowel were 7 Gy, 6.5 Gy, and 6.3 Gy per fraction, respectively. The HDR-ISBT of 35 Gy in five fractions for three days (two times a day with six hours’ interval) was administered (Figure 1B). Brachytherapy was carried out using a 192Ir remote after-loading system (MicroSelectron v3® HDR, Nucletron, ELEKTA AB, Stockholm, Sweden).\n\nNivolumab was restarted nine days after HDR-ISBT. Three months after completion of HDR-ISBT, shrinkage of the irradiated left iliac lesion (Figure 1C) and left internal iliac lymph node (Figure 1C) was evident by CT. Simultaneously, the metastatic lesion in the lumbar vertebrae (L4), which was the non-irradiated site, showed evidence of disappearance on the same CT (Figure 1D). There was no apparent increase in size of the remaining non-irradiated metastatic lesions. Figure 1 presents the summarized imaging studies and clinical course after the initiation of nivolumab.\n\nDuring the HDR-ISBT period, pain associated with applicator placement was addressed using continuous venous analgesia. The day after the applicator was placed, a significant elevated serum lactate dehydrogenase (LDH) level was observed in the blood test (Figure 2) that lasted for seven months. As we suspected tumor lysis syndrome, we performed intravenous rehydration, which led to a decrease in serum LDH levels within a few days, and the treatment was completed without any problems, and reached the normal range three months after brachytherapy (Figure 2, reference range 124-222 U/l). After the treatment, there were no complications except for mild dermatitis.\n\nFig. 2 High levels of serum lactate dehydrogenase (LDH) that persisted for seven months improved to normal levels, three months after brachytherapy\n\nDiscussion\nHerein, we describe a 30-year-old Japanese female with intractable metastases of RCC who exhibited the abscopal effect after a combination treatment with nivolumab and HDR-ISBT. To the best of our knowledge, this is the first report demonstrating an abscopal effect following brachytherapy for human malignancy.\n\nAt a certain radiation dose, radiation-induced tumor cell damage is known to activate antitumor immune response through the release of tumor antigens and damage-associated molecular pattern, which, in turn, results in increased activation of antigen-presenting cells and T-lymphocytes. This activation of the immune system triggers antigen-specific, adaptive immunity, a phenomenon referred to as in situ radio-vaccination [6]. Several pre-clinical studies have demonstrated that regression of distant metastases, at remote non-irradiated sites of the body, termed the “abscopal effect”, can be achieved by an appropriate timing and combination of radiation with immunotherapy [7,8,9]. This effect has been vetted in several clinical studies showing improved responses by combining radiation and immunotherapy in several types of malignant tumors [1,2,3,4]. However, nearly all preclinical and clinical studies evaluating radiation therapy in combination with immunotherapies have used EBRT, which typically, must pass through considerable volumes of normal tissue to reach the targeted tumor volumes. Circulating lymphocytes are highly sensitive to radiation therapy, with a D90 of 0.5 Gy [10], and large treatment fields are viewed as a shortcoming in obtaining a clinically compelling response, leading to long-term lymphopenia in some cases [11]. Such effects may limit the efficacy of immune stimulatory agents in conjunction with EBRT. Pike et al. showed that extracranial or prolonged courses of radiation increase the risk of severe lymphopenia, which is associated with lesser survival than that of patients treated with ICI [12].\n\nVarious EBRT regimens and techniques, particularly conformal techniques such as intensity modulated radiation therapy (IMRT) or stereotactic body radiotherapy (SBRT), could play an important role. Contrary to SBRT/IMRT, radiation delivered using image-guided brachytherapy achieves unmatched dose conformality. This can be considered an advantage of brachytherapy compared with EBRT, because of the sparing of normal tissue and pertinent lymphoid organs from the low doses of radiation that may eradicate sensitive immune cell lineages. Moreover, heterogeneity of the radiation dose delivered to the target lesions may facilitate the ideal involvement of multiple immunogenic mechanisms, each with different dose response profiles [5]. In effect, regions closest to the source of a high dose of radiation exhibits greater tumor cell death than other regions, as observed in models of tumor response to radiation therapy [13]. Further, this region exhibits maximal immunogenic tumor cell death and release of tumor-specific antigens [14]. However, Vanpouille-Box et al. proposed not to deliver more than 12-14 Gy per fraction because of the potential activation of the 3’ repair exonuclease 1 (TREX1) [15]. TREX1 attenuates their immunogenicity by degrading DNA that accumulates in the cytosol upon radiation.\n\nOutside the highest dose regions, high-intermediate dose per fraction (8-12 Gy) may optimally induce cytoplasmic release of double-stranded DNA and phenotypic changes in the expression of immune susceptibility markers on tumor cells that survived radiation [15,16,17]. Moderate dose per fraction (2-5 Gy) may potentiate the release of immune stimulatory cytokines, leading to enhanced tumor infiltration by immune cells [18]. Some studies have shown that immunological response can also be initiated by trauma to the site [19,20]. Butterfield’s review on cancer vaccinations dwells upon how surgery and tumor-ablative procedures of various magnitudes can be considered as a sort of “cancer vaccine” [21]. In this respect, ISBT may offer significant advantages over EBRT in initiating the in situ vaccine effect.\n\nOur case had bulky iliac bone metastasis from RCC with a known radio-resistance phenotype. In general, bulky disease represents an important challenging obstacle for all currently available treatment options: in most cases surgery and EBRT cannot achieve more than a palliative effect; SBRT is not indicated for such large tumors; whereas chemoradiotherapy would induce intolerable levels of toxicity. The advantage of brachytherapy compared with EBRT, regardless of the histological type, is that the maximum radiation dose can be delivered directly to the tumor without damaging healthy surrounding tissues, leading to better local control. In our case presented in this report, nivolumab combined with HDR-ISBT resulted in a marked reduction in irradiated as well as non-irradiated lesions, despite being refractory to prior treatments with nivolumab. In order to trigger the abscopal effect, it may be essential for the maximum size of the tumor lesion to be irradiated. Brachytherapy could favor the targeting of the maximal tumor size and/or repeat and locally treat several tumor sites. Multi-site irradiation increases the chances of successfully priming an antitumor immune response and might also destroy, or potentiate the destruction of resistant subclonal populations that could impair a complete response to ICIs [22,23]. Therefore, multi-site brachytherapy may be an emerging paradigm for treating metastatic disease in the future.\n\nIn our patient, the high level of serum LDH that lasted for 7 months improved to normal levels 3 months after brachytherapy (Figure 2). Recently, it has been shown that serum LDH may be correlated to the prognosis of RCC, suggesting that the serum LDH level can be used as a valuable biomarker for monitoring prognoses [24]. Although the mechanisms involved in radiation response need to be elucidated to better understand the true effect of brachytherapy, we believe that HDR-ISBT may further play an important role in enhancing the activity of ICIs across a broad range of malignancies.\n\nConclusions\nThis is the first case report demonstrating the abscopal effect following brachytherapy and immunotherapy for human malignancy and the evidence indicates that immuno-oncology effects are not limited to EBRT regimens as they can also be attained by brachytherapy.\n\nDisclosure\nThe authors report no conflict of interest.\n==== Refs\nReferences\n1 Leary R Gardner RB Mockbee C Boosting abscopal response to radiotherapy with sargramostim: A review of data and ongoing studies Cureus 2019 11 e4276 31157137 \n2 De Ruysscher D Combination of radiotherapy and immune treatment: First clinical data Cancer Radiother 2018 22 564 566 30170788 \n3 Siva S MacManus MP Martin RF Abscopal effects of radiation therapy: A clinical review for the radiobiologist Cancer Lett 2015 356 82 90 24125863 \n4 Dagoglu N Karaman S Caglar HB Abscopal efect of radiotherapy in the immunotherapy era: Systematic review of reported cases Cureus 2019 11 e4103 31057997 \n5 Patel RB Baniel CC Sriramaneni RN Combining brachytherapy and immunotherapy to achieve in situ tumor vaccination: A review of cooperative mechanisms and clinical opportunities Brachytherapy 2018 17 995 1003 30078541 \n6 Herrera FG Bourhis J Coukos G Radiotherapy combination opportunities leveraging immunity for the next oncology practice CA Cancer J Clin 2017 67 65 85 27570942 \n7 Meng X Feng R Yang L The role of radiation oncology in immuno-oncology Oncologist 2019 24 Suppl 1 S42 S52 30819830 \n8 Ozpiskin OM Zhang L Li JJ Immune targets in the tumor microenvironment treated by radiotherapy Theranostics 2019 9 1215 1231 30867826 \n9 Weichselbaum RR Liang H Deng L Radiotherapy and immunotherapy: A beneficial liaison? Nat Rev Clin Oncol 2017 14 365 379 28094262 \n10 Nakamura N Kusunoki Y Akiyama M Radiosensitivity of CD4 or CD8 positive human T-lymphocytes by an in vitro colony formation assay Radiat Res 1990 123 224 227 2117766 \n11 Order SE The effects of therapeutic irradiation on lymphocytes and immunity Cancer 1977 39 737 743 300040 \n12 Pike LRG Bang A Mahal BA The impact of radiation therapy on lymphocyte count and survival in metastatic cancer patients receiving PD-1 immune checkpoint inhibitors Int J Radiat Oncol Biol Phys 2019 103 142 151 30227198 \n13 Fowler JF 21 years of biologically effective dose Br J Radiol 2010 83 554 568 20603408 \n14 Demaria S Kawashima N Yang AM Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer Clin Cancer Res 2005 11 728 734 15701862 \n15 Vanpouille-Box C Alard A Aryankalayil MJ DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity Nat Commun 2017 8 15618 28598415 \n16 Yoshimoto Y Suzuki Y Mimura K Radiotherapy-induced anti-tumor immunity contributes to the therapeutic efficacy of irradiation and can be augmented by CTLA-4 blockade in a mouse model PLoS One 2014 9 1 8 \n17 Cole WH Efforts to explain spontaneous regression of cancer J Surg Oncol 1981 17 201 209 6166811 \n18 Liu SZ Nonlinear dose-response relationship in the immune system following exposure to ionizing radiation: Mechanisms and implications Nonlinearity Biol Toxicol Med 2003 1 71 92 19330113 \n19 Lopez-Pastorini A Plönes T Brockmann M Spontaneous regression of non-small cell lung cancer after biopsy of a mediastinal lymph node metastasis: A case report J Med Case Rep 2015 9 2 5 25560475 \n20 Esplin N Fergiani K Legare TB Spontaneous regression of a primary squamous cell lung cancer following biopsy: A case report J Med Case Rep 2018 12 65 29526162 \n21 Butterfield LH Cancer Vaccines BMJ 2015 3 h988 \n22 Luke JJ Lemons JM Karrison TG Safety and clinical activity of pembrolizumab and multisite stereotactic body radiotherapy in patients with advanced solid tumors J Clin Oncol 2018 36 1611 1618 29437535 \n23 Brooks ED Chang JY Time to abandon single-site irradiation for inducing abscopal effects Nat Rev Clin Oncol 2019 16 123 135 30401936 \n24 Shen J Chen Z Zhuang Q Prognostic value of serum lactate dehydrogenase in renal cell carcinoma: A systematic review and meta-analysis PLoS One 2016 11 e0166482 27861542\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "2081-2841",
"issue": "11(5)",
"journal": "Journal of contemporary brachytherapy",
"keywords": "abscopal effect; brachytherapy; immunotherapy; metastatic renal cell carcinoma; nivolumab; radiation",
"medline_ta": "J Contemp Brachytherapy",
"mesh_terms": null,
"nlm_unique_id": "101506276",
"other_id": null,
"pages": "458-461",
"pmc": null,
"pmid": "31749855",
"pubdate": "2019-10",
"publication_types": "D002363:Case Reports",
"references": "6166811;31057997;31157137;28094262;15701862;30227198;28598415;25904595;29526162;20603408;29437535;30867826;30819830;24125863;30078541;2117766;26377170;24686897;27570942;30170788;27861542;19330113;300040;30401936",
"title": "Abscopal effect of high-dose-rate brachytherapy on pelvic bone metastases from renal cell carcinoma: a case report.",
"title_normalized": "abscopal effect of high dose rate brachytherapy on pelvic bone metastases from renal cell carcinoma a case report"
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"abstract": "Postmortem femoral blood concentrations of the antipsychotic drugs aripiprazole, chlorprothixene and its metabolite, and quetiapine were determined by LC-MS-MS in 25 cases for aripiprazole and 60 cases each for chlorprothixene and quetiapine. For cases where the cause of death was not related to the considered drugs, the following blood concentration intervals (10-90 percentiles) were observed: 0.049-0.69 mg/kg for aripiprazole, 0.006-0.24 mg/kg for chlorprothixene, and 0.006-0.37 mg/kg for quetiapine. These concentration ranges largely correspond to therapeutic plasma levels observed in vivo suggesting no or only limited postmortem redistribution for aripiprazole, chlorprothixene with metabolite, and quetiapine in these cases. One fatality caused by chlorprothixene with a blood level of 0.90 mg/kg was recorded, and in six cases chlorprothixene was judged to be contributing to death with concentrations 0.43-0.91 mg/kg. No fatalities exclusively ascribed to the two other drugs were observed, but aripiprazole was considered to be contributing to death in one case (1.9 mg/kg) and quetiapine in seven cases with concentrations 0.35-10.0 mg/kg. The presented values may serve as a reference for judgment of postmortem cases with presence of these antipsychotics.",
"affiliations": "Section of Forensic Chemistry, Department of Forensic Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Frederik V's Vej 11, DK-2100 Copenhagen Ø, Denmark louise.skov@sund.ku.dk.;Section of Forensic Chemistry, Department of Forensic Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Frederik V's Vej 11, DK-2100 Copenhagen Ø, Denmark.;Section of Forensic Chemistry, Department of Forensic Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Frederik V's Vej 11, DK-2100 Copenhagen Ø, Denmark.",
"authors": "Skov|Louise|L|;Johansen|Sys Stybe|SS|;Linnet|Kristian|K|",
"chemical_list": "D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D010879:Piperazines; D015363:Quinolones; D000069348:Quetiapine Fumarate; D000068180:Aripiprazole; D002749:Chlorprothixene",
"country": "England",
"delete": false,
"doi": "10.1093/jat/bku121",
"fulltext": null,
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"issn_linking": "0146-4760",
"issue": "39(1)",
"journal": "Journal of analytical toxicology",
"keywords": null,
"medline_ta": "J Anal Toxicol",
"mesh_terms": "D014150:Antipsychotic Agents; D000068180:Aripiprazole; D001344:Autopsy; D002749:Chlorprothixene; D002853:Chromatography, Liquid; D003987:Dibenzothiazepines; D006801:Humans; D010879:Piperazines; D000069348:Quetiapine Fumarate; D015363:Quinolones; D012016:Reference Values; D053719:Tandem Mass Spectrometry",
"nlm_unique_id": "7705085",
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"publication_types": "D016428:Journal Article",
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"title": "Postmortem femoral blood reference concentrations of aripiprazole, chlorprothixene, and quetiapine.",
"title_normalized": "postmortem femoral blood reference concentrations of aripiprazole chlorprothixene and quetiapine"
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"abstract": "Perampanel is a new antiepileptic drug with a long half-life, but there are currently no data on the effects of acute perampanel overdose in epilepsy patients. We report a patient who had such an overdose. A 39-year-old woman was admitted for altered consciousness after taking 10 times the daily dose of perampanel. Her blood level of the drug was predicted, by pharmacokinetic calculation, to decrease to a steady-state level after 7 days, followed by a full recovery 8 days after the overdose. During her hospital stay, the patient experienced pulmonary embolism, which may be associated with the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) antagonistic mechanism of perampanel. The present findings show that perampanel overdose can produce prolonged stupor and that caution should be exercised during transient hypercoagulable states.",
"affiliations": "Department of Neurology, Konkuk University School of Medicine, Seoul, Korea.;Department of Clinical Pharmacology, Konkuk University School of Medicine, Seoul, Korea.;Department of Neurology, Konkuk University School of Medicine, Seoul, Korea.;Department of Neurology, Konkuk University School of Medicine, Seoul, Korea.",
"authors": "Kim|Soojeong|S|;Kim|Tae-Eun|TE|;Kim|Dayoung|D|;Kim|Dong Wook|DW|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.14581/jer.18014",
"fulltext": "\n==== Front\nJ Epilepsy ResJ Epilepsy ResJournal of Epilepsy Research2233-62492233-6257Korean Epilepsy Society 10.14581/jer.18014er-8-2-87Case ReportProlonged Stupor in Perampanel Overdose and Pharmacokinetic Considerations Kim Soojeong MD1Kim Tae-Eun MD, PhD2Kim Dayoung MD1Kim Dong Wook MD, PhD1\n1 Department of Neurology, Konkuk University School of Medicine, Seoul, Korea\n2 Department of Clinical Pharmacology, Konkuk University School of Medicine, Seoul, KoreaCorresponding author: Dong Wook Kim, MD, PhD Department of Neurology, Konkuk University School of Medicine, 120-1 Neungdong-ro, Gwangjin-gu, Seoul 05030, Korea, Tel. +82-2-2030-7460, Fax. +82-2-2020-7460, E-mail; drdongwkim@kuh.ac.kr12 2018 31 12 2018 8 2 87 89 17 5 2018 18 9 2018 1 10 2018 Copyright © 2018 Korean Epilepsy Society2018This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Perampanel is a new antiepileptic drug with a long half-life, but there are currently no data on the effects of acute perampanel overdose in epilepsy patients. We report a patient who had such an overdose. A 39-year-old woman was admitted for altered consciousness after taking 10 times the daily dose of perampanel. Her blood level of the drug was predicted, by pharmacokinetic calculation, to decrease to a steady-state level after 7 days, followed by a full recovery 8 days after the overdose. During her hospital stay, the patient experienced pulmonary embolism, which may be associated with the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) antagonistic mechanism of perampanel. The present findings show that perampanel overdose can produce prolonged stupor and that caution should be exercised during transient hypercoagulable states.\n\nPerampanelOverdosePharmacokinetics\n==== Body\nIntroduction\nPerampanel is the first selective noncompetitive α-amino-3-hy-droxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist for treating epilepsy.1 Its efficacy and tolerability as an adjuvant treatment in adults with drug-resistant focal seizure were demonstrated in three randomized, double-blind, placebo-controlled studies, and its efficacy as an adjuvant treatment for generalized seizure was also shown in a randomized study.2,3 The usual starting dose of perampanel for focal and generalized seizures in adult patients who are not concomitantly taking an enzyme-inducing antiepileptic drug (AED) is 2 mg/day before sleep. Additionally, it is recommended that the dose be increased by 2 mg/day biweekly to reach the maximum tolerable dose (usually 4–8 mg/day), which provides excellent seizure control. Among the currently available AEDs, perampanel has the longest metabolic half-life, up to 105 hours; thus, a theoretical steady-state can be reached in approximately 2–3 weeks after the drug is introduced or the dose adjusted.4\n\nPerampanel treatment can be associated with various adverse effects. While the occurrence of psychiatric reactions is the most troublesome and often hinders the drug’s widespread use in epilepsy patients, adverse dose-dependent central nervous system (CNS) effects such as dizziness, somnolence, and fatigue are the most frequently observed. Therefore, severe adverse CNS effects may occur in patients with acute perampanel overdose and could be prolonged given the drug’s long half-life. However, there is currently no report on the acute overdose of perampanel in epilepsy patients. We recently treated a patient who took 10 times the usual perampanel maintenance dose in an attempted suicide.\n\nCase\nA 39-year-old woman with an unremarkable medical history visited our neurology department complaining of recurrent seizures. Magnetic resonance imaging showed non-enhancing diffuse enlargement of the right amygdala, hippocampus, and parahippocampal gyrus, and electroencephalography showed occasional spikes in corresponding areas. The patient was initially prescribed 1,000 mg of val-proic acid once a day before sleep, but her seizures persisted. Two mg/day of perampanel before sleep was added as adjunctive therapy and up-titrated to 4 mg/day after 2 weeks. Seizures were controlled with the combination therapy of 4 mg/day of perampanel and 1,000 mg/day of valproic acid. After 11 months without seizures, the patient was admitted to the intensive care unit for altered consciousness. Her records documented that she had recently episode had a depression because of job loss and that she had taken 10 times the daily dosage of the prescribed AEDs (40 mg of perampanel and 10,000 mg of valproic acid) in a suicide attempt. On neurological examination, her mental status was stuporous, but her reflexes were normal and there were no focal neurological signs or symptoms. Radiological evaluations, including brain computed tomography and diffusion-weighted magnetic resonance imaging, showed no abnormality, and continuous electroencephalography monitoring showed continuous low-amplitude slow activity without epileptiform discharges. Her blood valproic acid level on hospital day 2 exceeded 150 μg/mL and decreased to 88.39 and 3.44 μg/mL on day 3 and 7, respectively. The patient’s blood ammonia level on hospital day 3 was 125.2 μg/dL and decreased to 53.7 μg/dL, within the reference range. Because it was impossible to measure the blood level of perampanel, we attempted to predict the patient’s recovery time based on the known pharmacokinetics of per-ampanel (clearance, 0.75 L/h; volume of distribution, 100 L; absorption rate constant, 0.005 h−1). We assumed that perampanel was regularly administered at a dosage of 4 mg/day for 28 days to reach the steady-state level and that the 40 mg had been taken at the 696th hour (day 29). We calculated that the blood perampanel level would increase up to twice the usual steady-state level but would decrease to the steady-state level at day 36 (7 days after she took 40 mg of the drug; Fig. 1).\n\nDuring the patient’s hospital stay, vital signs and other laboratory results remained stable during the first 2 days, and there was no evidence of perampanel-induced systemic adverse effects such as hepatic or renal toxicity, hypotension, or respiratory suppression. However, we noted sudden respiratory difficulty on hospital day 3, and laboratory studies showed blood D-dimer levels exceeding 20 μg/mL and arterial hypoxia. Chest computed tomography also showed the development of a widespread pulmonary embolism. Under treatment with intravenous heparin anticoagulation and supportive mechanical ventilation, the patient began to regain consciousness on hospital day 6, returning to her baseline mental status on day 8. Due to the possible adverse psychiatric effect of per-ampanel, which may have been associated with the suicide attempt, we recommended changing to another AED during the patient’s hospital stay. However, the patient denied any causal relationship between the drug and the attempt and insisted that perampanel was effective for seizure control. At the 4-month follow-up at the out-patient clinic, she had remained seizure free with 4 mg/day of per-ampanel and 100 mg/day of valproic acid.\n\nDiscussion\nWe report here a patient who had a severe overdose of per-ampanel, 10 times the usual maintenance dose. Considering that the usual maintenance dose is 4–8 mg/day and the upper limit of the recommended daily dose is 12 mg/day,4 our patient had been administered a relatively low dose (4 mg/day), and the dose she accidentally took (40 mg/day) was only 3.3 times higher than the upper limit of the recommended daily dose. However, it took approximately 1 week for her to recover consciousness, and this prolonged adverse CNS effect was likely associated with perampanel’s long half-life. In previous reports of patients who had intoxication with other AEDs, systemic toxicity, including hyponatremia from oxcarbazepine, and cardiac arrhythmia from phenytoin, was occasionally observed, but patients recovered 2 or 3 days after admission.5,6 Our report shows that acute perampanel overdose may not produce serious adverse systemic effects, such as cardiac toxicity, respiratory depression, or other metabolic derangements, but that adverse CNS effects can be prolonged and that the recovery of consciousness may take longer in patients with high intoxication doses of the drug.\n\nPsychiatric reactions are well-noted and troublesome adverse events of perampanel, and patients with perampanel treatment should be monitored for the occurrence of psychiatric reactions. Suicidal ideation and behavior have been reported in patients treated with AEDs on several occasions. A specific role of perampanel treatment in neuropsychiatric adverse effects is also suggested by observational studies. In a study of 47 individuals treated with a median perampanel dose of 8 mg/day (range, 2–12 mg/day), behavioral alterations were the most frequent reason for discontinuation of treatment. In this cohort, three patients were reported to behave aggressively or experience suicidality.7\n\nOne remarkable finding was that our patient had pulmonary embolism during admission that necessitated anticoagulation therapy and mechanical ventilation. This was unexpected because AMPA receptors play an important role in modulating platelet activation and thrombosis, and AMPA receptor antagonists have been suggested for treating or preventing stroke, myocardial infarction, and other thrombotic diseases.8–11 The prolonged immobilization during hospital stay have been the main cause of pulmonary embolism in our patient, but it can also be speculated that the high blood level of perampanel during the acute overdose blocked the usual platelet activation; this might have induced a hypocoagulable state, and withdrawing the AMPA antagonist might have induced a transient hypercoagulable state that produced the embolism as a result of immobilization. In summary, these findings show that perampanel overdose can produce prolonged stupor due to its long half-life, and that caution should be exercised regarding the transient hypercoagulable state that could be associated with perampanel’s effect on AMPA receptors.\n\nConflicts of Interest\n\nNo conflicts of interest have been declared.\n\nFigure 1 Calculated changes in blood perampanel levels after a patient took 40 mg of the drug.\n==== Refs\nReferences\n1 Hanada T Hashizume Y Tokuhara N Perampanel: a novel, orally active, noncompetitive AMPA-receptor antagonist that reduces seizure activity in rodent models of epilepsy Epilepsia 2011 52 1331 40 21635236 \n2 Rosenfeld W Conry J Lagae L Efficacy and safety of perampanel in adolescent patients with drug-resistant partial seizures in three double-blind, placebo-controlled, phase III randomized clinical studies and a combined extension study Eur J Paediatr Neurol 2015 19 435 45 25823975 \n3 French JA Krauss GL Wechsler RT Perampanel for tonic-clonic seizures in idiopathic generalized epilepsy a randomized trial Neurology 2015 85 950 7 26296511 \n4 Greenwood J Valdes J Perampanel (fycompa): a review of clinical efficacy and safety in epilepsy P T 2016 41 683 98 27904300 \n5 van Opstal JM Janknegt R Cilissen J L’Ortije WH Nel JE De Heer F Severe overdosage with the antiepileptic drug oxcarbazepine Br J Clin Pharmacol 2004 58 329 31 15327594 \n6 Gaies E Charfi R Trabelsi S Salouage I Lakahl M Klouz A Acute pheny-toin intoxication: two cases report and literature review Therapie 2011 66 461 3 23189325 \n7 Coyle H Clough P Cooper R Mohanraj R Clinical experience with per-ampanel: focus on psychiatric adverse effects Epilepsy Behav 2014 41 193 6 25461214 \n8 Weiser T AMPA receptor antagonists for the treatment of stroke Curr Drug Targets CNS Neurol Disord 2005 4 153 9 15857300 \n9 Umemura K Shimakura A Nakashima M Neuroprotective effect of a novel AMPA receptor antagonist, YM90K, in rat focal cerebral ischaemia Brain Res 1997 773 61 5 9409705 \n10 Catarzi D Colotta V Varano F Competitive AMPA receptor antagonists Med Res Rev 2007 27 239 78 16892196 \n11 Morrell CN Sun H Ikeda M Glutamate mediates platelet activation through the AMPA receptor J Exp Med 2008 205 575 84 18283118\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2233-6249",
"issue": "8(2)",
"journal": "Journal of epilepsy research",
"keywords": "Overdose; Perampanel; Pharmacokinetics",
"medline_ta": "J Epilepsy Res",
"mesh_terms": null,
"nlm_unique_id": "101577886",
"other_id": null,
"pages": "87-89",
"pmc": null,
"pmid": "30809502",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports",
"references": "15327594;15857300;16892196;18283118;21635236;23189325;25461214;25823975;26296511;27904300;9409705",
"title": "Prolonged Stupor in Perampanel Overdose and Pharmacokinetic Considerations.",
"title_normalized": "prolonged stupor in perampanel overdose and pharmacokinetic considerations"
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"abstract": "Pulmonary hypertension is a serious complication of systemic sclerosis and remains one of the leading causes of mortality. Pulmonary veno-occlusive disease (PVOD), recently reclassified as pulmonary arterial hypertension (PAH) with overt features of venous/capillaries involvement, is a subgroup of group 1 pulmonary hypertension, which has been rarely reported in systemic sclerosis patients. It is symptomatically indistinguishable from idiopathic pulmonary arterial hypertension and should be suspected in those with manifestations of pulmonary arterial hypertension who have evidence of pulmonary venous congestion in the absence of left-sided heart disease. Thoracic high-resolution computed tomography can give important hints for the diagnosis, such as ground-glass opacities/nodules, mediastinal lymph node enlargement and interlobular septal thickening. Patients with PVOD usually have a poor prognosis and might experience acute pulmonary oedema after introduction of pulmonary vasodilators. Due to clinical similarities between scleroderma-related PAH and PVOD, some patients are misdiagnosed and this could explain, in part, the worse prognosis associated with this clinical condition, when compared with idiopathic PAH. We report the case of a 72-year-old woman with limited systemic sclerosis, who was initially diagnosed with systemic sclerosis-related pulmonary arterial hypertension. However, after introduction of sildenafil and bosentan, the patient developed acute pulmonary oedema, and findings from complementary exams were suggestive of PVOD.",
"affiliations": "Rheumatology Department, Hospital Garcia de Orta EPE, Avenida Torrado da Silva, 2805-267, Almada, Portugal. catarinaduarte89@gmail.com.;Rheumatology Department, Hospital Garcia de Orta EPE, Avenida Torrado da Silva, 2805-267, Almada, Portugal.;Cardiology Department, Hospital Garcia de Orta EPE, Avenida Torrado da Silva, 2805-267, Almada, Portugal.;Cardiology Department, Hospital Garcia de Orta EPE, Avenida Torrado da Silva, 2805-267, Almada, Portugal.",
"authors": "Duarte|Ana Catarina|AC|https://orcid.org/0000-0001-6128-2425;Cordeiro|Ana|A|;Loureiro|Maria José|MJ|;Ferreira|Filipa|F|",
"chemical_list": null,
"country": "Germany",
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"doi": "10.1007/s10067-020-04953-4",
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"issue": "39(5)",
"journal": "Clinical rheumatology",
"keywords": "Pulmonary arterial hypertension; Pulmonary hypertension; Pulmonary veno-occlusive disease; Systemic sclerosis",
"medline_ta": "Clin Rheumatol",
"mesh_terms": "D000368:Aged; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary; D008168:Lung; D011668:Pulmonary Veno-Occlusive Disease; D013902:Radiography, Thoracic; D012595:Scleroderma, Systemic; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "8211469",
"other_id": null,
"pages": "1687-1691",
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"pmid": "31965379",
"pubdate": "2020-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "23740572;24081346;17329309;29777409;11069841;26402988;22549387;27009171;20456932;25497573;19118230;2805280;15194175;16819327;15208112;16387942;24036241",
"title": "Pulmonary veno-occlusive disease: a probably underdiagnosed cause of pulmonary hypertension in systemic sclerosis.",
"title_normalized": "pulmonary veno occlusive disease a probably underdiagnosed cause of pulmonary hypertension in systemic sclerosis"
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... |
{
"abstract": "BACKGROUND\nBloodstream infections are a leading cause of death in the United States. Methicillin-resistant Staphylococcus aureus (MRSA) encompasses >50% of all S aureus strains in infected hospitalized patients and increases mortality, length of stay and healthcare costs. The objective of this study was to evaluate the treatment of MRSA bacteremia with daptomycin, linezolid and vancomycin.\n\n\nMETHODS\nPatients with MRSA bacteremia between June 2008 and November 2010 were reviewed retrospectively. A microbiology laboratory report identified patients with ≥ 1 positive MRSA blood culture. Patients ≥ 18 years receiving daptomycin, linezolid or vancomycin for ≥ 7 consecutive days were included. Polymicrobial blood cultures and patients treated concomitantly with >1 anti-MRSA agent were excluded.\n\n\nRESULTS\nOf 122 patients included, 53 received daptomycin, 15 received linezolid and 54 received vancomycin. Clinical and microbiologic cure rates were similar between daptomycin, linezolid and vancomycin (58.5% versus 60% versus 61.1%; 93.6% versus 100% versus 90%, respectively). Thirteen patients (daptomycin 4/24 versus linezolid 1/9 versus vancomycin 8/49, P = 0.5960) had recurrence while 12 patients had re-infection (daptomycin 5/42 versus linezolid 0/9 versus vancomycin 7/49, P = 0.4755). Treatment failure occurred in 11 patients treated with daptomycin, 4 with linezolid and 9 with vancomycin (P = 0.662). Compared with daptomycin and vancomycin, linezolid-treated patients had higher mortality (P = 0.0186).\n\n\nCONCLUSIONS\nNo difference in clinical or microbiologic cure rates was observed between groups. Daptomycin and vancomycin appear equally efficacious for MRSA bacteremia, whereas linezolid therapy was associated with higher mortality.",
"affiliations": "Department of Pharmacy (JBU, NHV, CKF, THS), Methodist University Hospital, and University of Tennessee Health Science Center, Department of Medicine (KOC, MSG), Department of Clinical Pharmacy (JBU, NV, CKF, THS), Memphis, TN.",
"authors": "Usery|Justin B|JB|;Vo|Ngan H|NH|;Finch|Christopher K|CK|;Cleveland|Kerry O|KO|;Gelfand|Michael S|MS|;Self|Timothy H|TH|",
"chemical_list": "D000081:Acetamides; D000900:Anti-Bacterial Agents; D023303:Oxazolidinones; D014640:Vancomycin; D000069349:Linezolid; D017576:Daptomycin",
"country": "United States",
"delete": false,
"doi": "10.1097/MAJ.0000000000000338",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9629",
"issue": "349(1)",
"journal": "The American journal of the medical sciences",
"keywords": null,
"medline_ta": "Am J Med Sci",
"mesh_terms": "D000081:Acetamides; D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents; D016470:Bacteremia; D017576:Daptomycin; D005260:Female; D017048:Health Care Costs; D006760:Hospitalization; D006801:Humans; D007362:Intensive Care Units; D007902:Length of Stay; D000069349:Linezolid; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus; D008875:Middle Aged; D023303:Oxazolidinones; D012189:Retrospective Studies; D013203:Staphylococcal Infections; D013714:Tennessee; D016896:Treatment Outcome; D014640:Vancomycin",
"nlm_unique_id": "0370506",
"other_id": null,
"pages": "36-41",
"pmc": null,
"pmid": "25233042",
"pubdate": "2015-01",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Evaluation of the treatment of methicillin-resistant Staphylococcus aureus bacteremia.",
"title_normalized": "evaluation of the treatment of methicillin resistant staphylococcus aureus bacteremia"
} | [
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"companynumb": "US-BAXTER-2015BAX017906",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"actiondrug": null,
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"activesubstancename": "VANCOMYCIN"
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"abstract": "Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyper activation of the immune system. Rare cases associated with HELLP syndrome and other similar conditions in pregnancy have been reported. Despite the improved survival rates with etoposide and dexamethasone-based regimens, HLH remains a challenging disease. Experience in pregnant patients is exceedingly rare.",
"affiliations": "Pacific Shoes Medical Group Long Beach California.;Division of Hematology and Oncology, Department of Medicine University of California, Irvine Irvine California.;Department of Pathology University of California, Irvine Irvine California.;Division of Infectious Disease, Department of Medicine University of California, Irvine Irvine California.;Division of Hematology and Oncology, Department of Medicine University of California, Irvine Irvine California.",
"authors": "Sarkissian|Sarmen|S|;Khan|Yasir|Y|;Farrell|Daniel|D|;Constable|David|D|;Brem|Elizabeth|E|0000-0002-3265-9841",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.1828",
"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.1828CCR31828Case ReportCase ReportsHemophagocytic lymphohistiocytosis in the setting of HELLP Syndrome XXXXSARKISSIAN et al.Sarkissian Sarmen \n1\nKhan Yasir \n2\nFarrell Daniel \n3\nConstable David \n4\nBrem Elizabeth http://orcid.org/0000-0002-3265-9841ebrem@uci.edu \n2\n\n1 \nPacific Shoes Medical Group\nLong Beach\nCalifornia\n\n2 \nDivision of Hematology and Oncology, Department of Medicine\nUniversity of California, Irvine\nIrvine\nCalifornia\n\n3 \nDepartment of Pathology\nUniversity of California, Irvine\nIrvine\nCalifornia\n\n4 \nDivision of Infectious Disease, Department of Medicine\nUniversity of California, Irvine\nIrvine\nCalifornia\n* Correspondence\n\nElizabeth Brem, Division of Hematology/Oncology, UC Irvine Health, Irvine, CA.\n\nEmail: ebrem@uci.edu\n05 11 2018 12 2018 6 12 10.1002/ccr3.2018.6.issue-122466 2470 20 3 2018 12 7 2018 19 8 2018 © 2018 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Key Clinical Message\nHemophagocytic lymphohistiocytosis (HLH) is a life‐threatening hyper activation of the immune system. Rare cases associated with HELLP syndrome and other similar conditions in pregnancy have been reported. Despite the improved survival rates with etoposide and dexamethasone‐based regimens, HLH remains a challenging disease. Experience in pregnant patients is exceedingly rare.\n\nEBVHELLP syndromehemophagocytic lymphohistiocytosishemophagocytosis source-schema-version-number2.0component-idccr31828cover-dateDecember 2018details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:version=5.5.4 mode:remove_FC converted:14.12.2018\n\n\nSarkissian \nS \n, \nKhan \nY \n, \nFarrell \nD \n, \nConstable \nD \n, \nBrem \nE \n. Hemophagocytic lymphohistiocytosis in the setting of HELLP Syndrome . Clin Case Rep . 2018 ;6 :2466 –2470 . 10.1002/ccr3.1828\n==== Body\n1 INTRODUCTION\nA 30‐year‐old woman (G1P0) presented at 35 weeks' gestation with fever and jaundice. Fever persisted after delivery, and she was diagnosed ultimately with hemophagocytic lymphohistiocytosis (HLH). Her outcome was poor despite aggressive therapy. Reports of HLH in the setting of HELLP syndrome and acute fatty liver of pregnancy are rare.\n\nHemophagocytic lymphohistiocytosis occurs when over‐reactive macrophages and histiocytes engulf erythrocytes in the bone marrow and spleen. Natural killer (NK) cell dysfunction leads to excess cytokine production from macrophages and cytotoxic lymphocytes. This uncontrolled release of cytokines leads to a spectrum of clinical symptoms ranging from flu‐like symptoms to end organ damage.1, 2, 3\n\n\nHemophagocytic lymphohistiocytosis is generally categorized as a primary or secondary phenomenon. Primary HLH occurs due to genetic mutations in the NK cell granzyme‐generating pathway and is generally diagnosed in childhood or early adulthood. Secondary HLH occurs in the setting of infection, autoimmune disease, or malignancy.4 Cases of HLH in pregnancy have only rarely been reported in the medical literature (Table 1). In some cases of secondary HLH, treating the underlying etiology (ie, initiating appropriate chemotherapy for the underlying malignancy or starting immunosuppression for rheumatologic disease) will lead to resolution of the HLH. In other cases, specific therapy targeting the HLH is necessary. There is no consensus standard of care therapy for HLH. The pediatric community's HLH‐94 protocol established the role of etoposide and dexamethasone as the backbone of therapy for primary HLH.5 The HLH‐2004 protocol has cyclosporine added to the protocol; long‐term results are pending.6 There is also published experience with CHOP (cyclophosphamide, adriamycin, vincristine, prednisone) chemotherapy and anti‐thymocyte globulin with encouraging results from small, nonrandomized studies.7, 8 Left untreated, HLH is uniformly fatal.\n\nTable 1 Summation of available case reports of HLH diagnosed during pregnancy\n\n\nPublication\n\tPresenting symptoms\tAssociated condition\tGestational age at diagnosis (wk)\tFetal outcome\tTreatment\tPatient outcome\t\nKerley et al11\n\tDyspnea; abdominal pain;\tHELLP syndrome\t22\tDelivered\tHLH‐2004a, followed by allogeneic BMT\tRelapsed 11 mo post‐transplant and died\t\nIkeda et al14\n\tFever, anorexia, pancytopenia\tEBV\t11\tDelivered at 37 4/7 weeks (abstract available in English, but paper in Japanese)\tEtoposide and cyclosporine remain in remission 10 mo post treatment.\t\t\nGiard et al12\n\tViral illness\tKikuchi‐Fujimoto Lymphadenitis, AFLP\t13\tSpontaneous abortion\tEtoposide with dexamethasone\tDied on day 48 secondary to PE\t\nPawar et al15\n\tFever, fatigue\tVisceral leishmania\t24\tDelivered\tDexamethasone and antibiotics\tIn remission at the time of publication\t\nSamra et al16\n\tCough, fever\tIdiopathic\t16\tCompleted pregnancy\tDexamethasone, in remission\tIn remission at the time of publication\t\nTumian et al17\n\tJaundice, anemia\tIdiopathic\t38\tDelivered\tDex, Cyclosporine, in remission\tIn remission at the time of publication\t\nKlein et al18\n\tDiarrhea, GI bleeding\tEBV\t30\tC‐section at 31 wk\tSteroids, Cyclosporine, etoposide\tDied\t\nChmait et al19\n\tRoutine checkup\tEBV\t29\tDelivery at 30 wk\t\tDied with multi organ failure.\t\nYamaguchi et al20\n\tFever, cytopenia\tHSV2\tMid gestation\tDelivery\tFailed steroids, remission with cyclosporin A\tIn remission at the time of publication\t\nHanaoka et al21\n\tFever, cytopenia\tB‐cell lymphoma\t23\tEmergent C‐section\tR‐CHOPb\n\tIn remission at the time of publication\t\nPerard et al22\n\tFevers\tSLE\t22\tPremature delivery\tIVIG with high dose pulse steroids.\tIn remission at the time of publication\t\nChien et al23\n\tFever\tUnclear\t23\tC‐section\tDexamethasone\tin remission at the time of publication\t\nTeng et al24\n\tFever, cytopenia\tAutoimmune hemolytic anemia\t23\tTerminated pregnancy\tFailed steroids\tRemission post termination of pregnancy\t\nArewa et al25\n\tJaundice\tHIV\t21\tDelivery\tHAARTc\n\tIn remission at the time of publication\t\nDunn et al26\n\tRash, fever, headache\tStill disease\t19\tDelivery\tHigh dose steroids\tIn remission at the time of publication\t\nShukla et al27\n\tFever x 2 wk\tUnclear etiology\t10\tSpontaneous abortion\tFailed steroids\tRemission after spontaneous abortion\t\nMayama et al28\n\tFever, pancytopenia\tParvovirus B19\t21\tDelivered at 37 4/7 weeks\tSteroids\tIn remission at the time of publication\t\na HLH‐2004 = etoposide, dexamethasone, cyclosporine.\n\nb R‐CHOP = rituximab, cyclophosphamide, hydroxydaunorubicin (adrimycin), vincristine (Oncovin), prednisone; common first‐line regimen for B‐cell lymphomas\n\nc Highly active antiretroviral therapy (HAART).\n\nJohn Wiley & Sons, LtdAcute fatty liver of pregnancy (AFLP) is a clinical diagnosis. It presents in the third trimester with nausea, vomiting, abdominal pain, and jaundice. Laboratories show elevated transaminases, alkaline phosphatase, and bilirubin. Differentiating between AFLP and HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) can be challenging. Evidence of hemolysis is considered to be more consistent with HELLP syndrome. The mainstays of management for both conditions are maternal stabilization as well as delivery of the fetus.9, 10, 11, 12\n\n\nIn this report, we present a young woman who received appropriate interventions for HELLP syndrome but soon after delivery was diagnosed with HLH. The clinical assessment was that the HELLP syndrome triggered the HLH. Despite initiation of HLH therapy, she ultimately passed away. This case raised for us the question of whether HLH that arises in the context of pregnancy and/or HELLP syndrome represents a subset of patients with a particularly poor prognosis. In addition to her case, we present a review of the (limited) literature available on this topic.\n\n2 CASE DESCRIPTION\nA 30‐year‐old G1P0 woman at 35 weeks and 2 days of gestation presented to obstetric (OB) triage with uterine contractions. She had a history of atrial septal defect repair as a child but was otherwise healthy. Ten days prior to admission, the patient had a noted oral mucosal lesions concerning for HSV‐1 infection but declined treatment with oral acyclovir. Five days prior to admission, she presented to urgent care with flu‐like symptoms and a temperature of up to 38.9°C for 2 weeks. She was given a course of azithromycin for presumed community‐acquired pneumonia.\n\nOn presentation to OB triage, vitals were notable for a temperature of 39.3°C and a heart rate of 105 beats per minute. Review of symptoms was positive for nausea and emesis. She was visibly jaundiced. Laboratories revealed alkaline phosphatase 591 U/L (normal 34‐104 U/L), total bilirubin 5.1 mg/dL (0‐1.4 mg/dL), aspartate aminotransferase (AST) 142 U/L (13‐39 U/L), hemoglobin 8.8 g/dL (11.5‐15 g/dL), platelets 67 000 (150‐400 × 103/μL), and fibrinogen 547 mg/dL (215‐438 mg/dL). Haptoglobin was normal, 149 mg/dL (44‐215 mg/dL), suggesting that hemolysis was not actively occurring, so a presumptive diagnosis of AFLP was made. The patient underwent an emergent cesarian section (C‐section). A healthy male infant was delivered; to our knowledge, he was without any evidence of liver disease, particularly neonatal hemochromatosis. There was evidence of hypertrophic decimal vasculopathy in the placenta, which is seen in gestational hypertension (classically HEELP and pre‐eclampsia). This pathology helped retrospectively change the diagnosis of her the acute hepatic failure to HELLP as these vascular changes are not seen in AFLP.\n\nAfter delivery, the patient continued to be febrile and was started on ampicillin, gentamicin, and clindamycin for a possible chorioamnionitis. CT angiogram was negative for PE, but showed a 20 cm liver with heterogeneous enhancement; no lymphadenopathy was seen. Sputum and bronchoscopy cultures were negative. On day 8, she remained febrile to >38.0°C, and the diagnosis of HLH was considered. Of note, there was no family history of HLH. Laboratories revealed a ferritin of 10 800 ng/mL (10‐107 ng/mL), increased from 2929 ng/mL on day 3, lactate dehydrogenase (LDH) 733 U/L (140‐271 U/L), increased from 409 on day 3, AST 736 U/L, triglycerides 707 mg/dL (<150 mg/dL). On day 9, bone marrow biopsy was without evidence of hemophagocytosis. Demonstration of hemophagocytes on bone marrow biopsy is helpful in making the diagnosis of HLH, but lack of hemophagocytes does not exclude the diagnosis. On day 11, biopsy of the liver did show evidence of hemophagocytosis (see Figure 1). Soluble IL‐2R (sIL‐2R) came back at 10 580 pg/mL (<1033 pg/mL). sIL‐2R levels of >2515 have a 100% sensitivity and 72.5% specificity for the diagnosis of HLH.13 She was started on dexamethasone with weekly etoposide per the HLH‐94 protocol.5 EBV viral load by PCR was 246 000 copies/mL via PCR. CMV viral load by PCR was positive at 104 161 IU/mL(<1600 IU/mL). She was negative for HIV, parvovirus, and influenza. She was started on antiviral therapy with ganciclovir. She clinically improved and was discharged home on day 52 to continue to receive etoposide in outpatient infusion (week 6 of HLH‐94).\n\nFigure 1 Liver biopsy at 20x (A) and 40x (B) magnifications. Hematoxylin and eosin (H&E) staining of the biopsy shows expanded portal tracts with hypertrophic Kupffer cells and patchy inflammatory infiltrates consisting of numerous macrophages, neutrophils, and rare plasma cells. Occasional macrophages demonstrating hemophagocytic activity (arrow) are identified\n\nUnfortunately, 3 days after discharge, she represented with fevers to 39.4°C. Of note, she had not been able to get the valganciclovir that had been prescribed at discharge. EBV viral titer had increased from undetectable on day 35 of her prior admission to 658 000 copies/mL by PCR upon readmission. On day 4 of readmission, laboratories were notable for LDH 1015 U/L and ferritin>15 000 ng/mL. Her fevers persisted. The HLH‐94 protocol was restarted, going back to twice‐weekly etoposide. She was given a dose of rituximab 375 mg/m2 on day 15 of readmission for the EBV viremia.\n\nHer clinical status was tenuous, requiring intensive care unit admission for supraventricular tachycardia, gastrointestinal bleeding from corticosteroid‐induced gastritis and thrombocytopenia, and hypoxic respiratory distress. She was severely neutropenic and was placed on both G‐CSF and GM‐CSF. On day 17, blood cultures from both PICC and peripheral sources grew multiple drug‐resistant organisms; this was the first time her cultures had been positive for bacteremia to date. Despite intensive antibiotic treatment, blood cultures remained persistently positive, and sepsis progressed to septic shock requiring multiple vasopressors. Granulocyte transfusions were considered, but declined by family given minimal likelihood of efficacy. She required mechanical intubation on day 20 due to acute respiratory distress syndrome. She passed on day 24 of her second admission due to ventricular fibrillation arrest.\n\n3 DISCUSSION\nOur patient developed HLH in the context of what was clinically thought to be AFLP at the time of her time of presentation. In retrospect, the liver biopsy and changes seen in the placenta were more consistent with HELLP. She had HSV1, EBV, and CMV viremias by PCR. It is unclear if one of these viremias was a driver of the HLH, or if the viremias were secondary to an immunocompromised state (although we suspect the latter). In our review of the literature, patients who develop HLH in the setting of pregnancy generally do well after delivery or termination of the pregnancy (Table 1). This, unfortunately, was not the case for our patient, perhaps suggesting that HLH that develops in the context of acute hepatic failure in pregnancy (either HELLP or AFLP) represents a subset of patients with a particularly poor prognosis. To this end, we found one available case report which describes a patient who developed HLH soon after an emergent C‐section for HELLP who was able to achieve a remission and went to allogenic bone marrow transplant. This patient unfortunately died of relapsed disease just under 1 year after transplant.11 Another patient who developed HLH in the setting of AFLP passed away due to complications of the HLH despite administration of etoposide‐based therapy, similar to our patient described here.12\n\n\nOur review of published case reports also suggests that patients who develop HLH during pregnancy with associated EBV viremia may have poor outcomes. In our patient, the EBV reactivation was felt to be secondary to her immunocompromised state, but the other case reports we found did not describe an antecedent serious illness like the HELLP syndrome our patient had. Of the three case reports, we found pregnant patients with HLH and EBV viremia, only one patient was alive at last follow‐up. Of note, this patient was diagnosed much earlier in her pregnancy (11 weeks, compared to 29 and 30 weeks for the other cases in the literature and 35 weeks for our patient). Our patient, as well as those presented in the literature, received an etoposide‐based regimen. Our patient was also given antiviral medication, but perhaps more prompt administration of rituximab for the EBV would have improved her outcome. Neither of the patients described in other case reports who developed EBV viremia and HLH in the third trimester received rituximab.\n\nThus, in the very limited published experience, development of HLH in the setting of HELLP syndrome or AFLP as well as HLH that develops in the third trimester with associated EBV viremia appears to have a poor prognosis, even when compared to other situations in which patients develop HLH peripartum. We encourage other clinicians to present their cases in order to better understand if indeed HLH in association with AFLP/HELLP or EBV in pregnancy is unique situations with a poor prognosis requiring prompt recognition and perhaps treatment that is not etoposide‐based; our patient and others described did not achieve or did not have durable responses after etoposide‐based therapies. Our experience suggests that patients who fit diagnostic criteria for HLH during pregnancy should be checked for EBV viremia and prompt administration of antiviral therapy and rituximab should be employed if EBV titers are positive.\n\nCONFLICT OF INTEREST\nThe authors have no relevant conflict of interests.\n\nAUTHOR CONTRIBUTION\nSS, YK, and EB: performed the literature search and wrote the manuscript. DF: provided pathology images. DC: helped provide clarification of the patient's infectious disease course.\n==== Refs\nREFERENCES\n1 \n\nLarroche \nC \n. Hemophagocytic lymphohistiocytosis in adults: Diagnosis and treatment . Joint Bone Spine . 2012 ;79 :356 ‐361 .22464018 \n2 \n\nEgeler \nRM \n, \nShapiro \nR \n, \nLoechelt \nB \n, \nFilipovich \nA \n. Characteristic immune abnormalities in hemophagocytic lymphohistiocytosis . J Pediatr Hematol Oncol . 1996 ;18 :340 ‐345 .8888739 \n3 \n\nLi \nJ \n, \nWang \nQ \n, \nZheng \nW \n, et al. Hemophagocytic lymphohistiocytosis: clinical analysis of 103 adult patients . Medicine (Baltimore) . 2014 ;93 :100 ‐105 .24646466 \n4 \n\nDalal \nBI \n, \nVakil \nAP \n, \nKhare \nNS \n, et al. Abnormalities of the lymphocyte subsets and their immunophenotype, and their prognostic significance in adult patients with hemophagocytic lymphohistiocytosis . Ann Hematol . 2015 ;94 :1111 ‐1117 .25800135 \n5 \n\nTrottestam \nH \n, \nHorne \nA \n, \nArico \nM \n, et al. Chemoimmunotherapy for hemophagocytic lymphohistiocytosis: long‐term results of the HLH‐94 treatment protoco . Blood . 2011 ;118 :4577 ‐4584 .21900192 \n6 \n\nHenter \nJI \n, \nHorne \nA \n, \nArico \nM \n, et al. HLH‐2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis . Pediatr Blood Cancer . 2007 ;48 :124 ‐131 .16937360 \n7 \n\nShin \nHJ \n, \nChing \nJS \n, \nLee \nJJ \n et al. Treatment outcomes with CHOP chemotherapy in adult patients with hemophagocytic lymphohistiocytosis . J Korean Med Sci . 2008 ;23 :439 ‐444 .18583880 \n8 \n\nMahlaoi \nN \n, \nOuachee‐Chardin \nM \n, \ndeSaint \nBG \n et al. Immunotherapy of familial hemophagocytic lymphohistiocytosis with antithymocyte globulins: a single‐center retrospective report of 38 patients . Pediatrics . 2007 ;120 :e622 –e628 .17698967 \n9 \n\nLiu \nJ \n, \nGhaziani \nTT \n, \nWolf \nJL \n. Acute fatty liver disease of pregnancy: updates in pathogenesis, diagnosis, and management . Am J Gastroenterol . 2017 ;112 :838 ‐846 .28291236 \n10 \n\nVirgin‐Degarcia \nP \n. Acute fatty liver and HELLP syndrome: two distinct pregnancy disorders . Int J Gynaecol Obstet . 2001 ;73 .\n11 \n\nKerley \nRN \n, \nKelly \nR \n, \nCahill \nMR \n, \nKenny \nLC \n. Haemophagocytic lymphohistiocytosis presenting as HELLP syndrome: a diagnostic and therapeutic challenge . BMJ Case Rep . 2017 .\n12 \n\nGiard \nJM \n, \nDecker \nKA \n, \nLai \nJC \n, \nGill \nRM \n, \nLogan \nAC \n, \nFix \nOK \n. Acute Liver Failure Secondary to Hemophagocytic Lymphohistiocytosis during Pregnancy . ACG Case Rep J . 2016 ;3 :e162 .27921061 \n13 \n\nAnna Hayden \nML \n, \nPark \nS \n, \nPudek \nM \n, \nmarion Schneider, Michael B. Jordan, Andre Mattman, Luke Y. C. Chem . . Soluble interleukin‐2 receptor is a sensitive diagnostic test in adult HLH. Blood . Advances . 2017 ;1 :2529 ‐2534 .\n14 \n\nIkeda \nM \n, \nOba \nR \n, \nYoshiki \nY \n, et al. Epstein‐Barr virus‐associated hemophagocytic lymphohistiocytosis during pregnancy . Rinsho Ketsueki . 2017 ;58 :216 ‐221 .28381688 \n15 \n\nPawar \nS \n, \nRagesh \nR \n, \nNischal \nN \n, et al. Unique triad of 'pregnancy, kala azar and hemophagocytic lymphohistiocytic syndrome from a non‐endemic region' . J Assoc Physicians India . 2015 ;63 :65 ‐68 .\n16 \n\nSamra \nB \n, \nYasmin \nM \n, \nArnaout \nS \n, \nAzzi \nJ \n. Idiopathic Hemophagocytic Lymphohistiocytosis During Pregnancy Treated with Steroids . Hematol Rep . 2015 ;7 :6100 .26487936 \n17 \n\nTumian \nNE \n, \nWong \nC \n. Pregnancy‐related hemophagocytic lymphohistiocytosis associated with cytomegalovirus infection: A diagnostic and therapeutic challenge . Taiwan J Obstet Gynecol . 2015 ;54 :432 ‐437 .26384065 \n18 \n\nKlein \nS \n, \nSchmidt \nC \n, \nLa Rosee \nP \n, et al. Fulminant gastrointestinal bleeding caused by EBV‐triggered hemophagocytic lymphohistiocytosis: report of a case . Z Gastroenterol . 2014 ;52 :354 ‐359 .24718941 \n19 \n\nChmait \nRH \n, \nMeimin \nDL \n, \nKoo \nCH \n, \nHuffaker \nJ \n. Hemophagocytic syndrome in pregnancy . Obstet Gynecol . 2000 ;95 :1022 ‐1024 .10808012 \n20 \n\nYamaguchi \nK \n, \nYamamoto \nA \n, \nHisano \nM \n, \nNatori \nM \n, \nMurashima \nA \n. Herpes simplex virus 2‐associated hemophagocytic lymphohistiocytosis in a pregnant patient . Obstet Gynecol . 2005 ;105 :1241 ‐1244 .15863596 \n21 \n\nHanaoka \nM \n, \nTsukimori \nK \n, \nHojo \nS \n, et al. B‐cell lymphoma during pregnancy associated with hemophagocytic syndrome and placental involvement . Clin Lymphoma Myeloma . 2007 ;7 :486 ‐490 .17875240 \n22 \n\nPerard \nL \n, \nCostedoat‐Chalumeau \nN \n, \nLimal \nN \n, et al. Hemophagocytic syndrome in a pregnant patient with systemic lupus erythematosus, complicated with preeclampsia and cerebral hemorrhage . Ann Hematol . 2007 ;86 :541 ‐544 .17340134 \n23 \n\nChien \nCT \n, \nLee \nFJ \n, \nLuk \nHN \n, \nWu \nCC \n. Anesthetic management for cesarean delivery in a parturient with exacerbated hemophagocytic syndrome . Int J Obstet Anesth . 2009 ;18 :413 ‐416 .19700307 \n24 \n\nTeng \nCL \n, \nHwang \nGY \n, \nLee \nBJ \n, \nWang \nRC \n, \nChou \nMM \n. Pregnancy‐induced hemophagocytic lymphohistiocytosis combined with autoimmune hemolytic anemia . J Chin Med Assoc . 2009 ;72 :156 ‐159 .19299225 \n25 \n\nArewa \nOP \n, \nAjadi \nA \n. Human immunodeficiency virus associated with haemophagocytic syndrome in pregnancy: a case report . West Afr J Med . 2011 ;30 :66 ‐68 .21863593 \n26 \n\nDunn \nT \n, \nCho \nM \n, \nMedeiros \nB \n, \nLogan \nA \n, \nUngewickell \nA \n, \nLiedtke \nM \n. Hemophagocytic lymphohistiocytosis in pregnancy: a case report and review of treatment options . Hematology . 2012 ;17 :325 ‐328 .23168071 \n27 \n\nShukla \nA \n, \nKaur \nA \n, \nHira \nHS \n. Pregnancy induced haemophagocytic syndrome . J Obstet Gynaecol India . 2013 ;63 :203 ‐205 .24431639 \n28 \n\nMayama \nM \n, \nYoshihara \nM \n, \nKokabu \nT \n, \nOguchi \nH \n. Hemophagocytic lymphohistiocytosis associated with a parvovirus B19 infection during pregnancy . Obstet Gynecol . 2014 ;124 :438 ‐441 .25004318\n\n",
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"issn_linking": "2050-0904",
"issue": "6(12)",
"journal": "Clinical case reports",
"keywords": "EBV; HELLP syndrome; hemophagocytic lymphohistiocytosis; hemophagocytosis",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "2466-2470",
"pmc": null,
"pmid": "30564350",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports",
"references": "10808012;11376667;15863596;16937360;17340134;17698967;17875240;18583880;19299225;19700307;21863593;21900192;22464018;23168071;24431639;24646466;24718941;25004318;25800135;26384065;26487936;26710404;27921061;28291236;28381688;28433984;29296904;8888739",
"title": "Hemophagocytic lymphohistiocytosis in the setting of HELLP Syndrome.",
"title_normalized": "hemophagocytic lymphohistiocytosis in the setting of hellp syndrome"
} | [
{
"companynumb": "US-MYLANLABS-2019M1005092",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AMPICILLIN"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nOur aim was to design and evaluate a new and easily administered recombinant tissue-type plasminogen activator (rt-PA) regimen for thrombolysis in acute myocardial infarction (AMI) based on established pharmacokinetic data that improve the reperfusion success rate.\n\n\nBACKGROUND\nRapid restoration of Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow is a primary predictor of mortality after thrombolysis in AMI. However, TIMI grade 3 patency rates 90 min into thrombolysis of only 50% to 60% indicate an obvious need for improved thrombolytic regimens.\n\n\nMETHODS\nPharmacokinetic simulations were performed to design a new rt-PA regimen. We aimed for a plateau tissue-type plasminogen activator (t-PA) plasma level similar to that of the first plateau of the Neuhaus regimen. These aims were achieved with a 20-mg rt-PA intravenous (i.v.) bolus followed by an 80-mg i.v. infusion over 60 min (regimen A). This regimen was tested in a consecutive comparative trial in 80 patients versus 2.25 10(6) IU of streptokinase/60 min (B), and 70 mg (C) or 100 mg (D) of rt-PA over 90 min. Subsequently, a confirmation trial of regimen A in 254 consecutive patients was performed with angiographic assessment by independent investigators of patency at 90 min.\n\n\nRESULTS\nThe comparative phase of the trial yielded, respectively, TIMI grade 3 and total patency (TIMI grades 2 and 3) of 80% and 85% (regimen A), 35% and 50% (B), 50% and 55% (C) and 60% and 70% (D). In the confirmation phase of the trial, regimen A yielded 81.1% TIMI grade 3 and 87.0% total patency. At follow-up angiography 7 (4.1%) of 169 vessels had reoccluded. In-hospital mortality rate was 1.2%. Nadir levels of fibrinogen, plasminogen and alpha2-antiplasmin were 3.6 +/- 0.8 mg/ml, 60 +/- 21% and 42 +/- 16%, respectively (mean +/- SD). Fifty-seven patients (22.4%) suffered from bleeding; 3.5% needed blood transfusions.\n\n\nCONCLUSIONS\nThe 60-min alteplase thrombolysis in AMI protocol achieved a TIMI grade 3 patency rate of 81.1% at 90 min with no indication of an increased bleeding hazard; it was associated with a 1.2% overall mortality rate. These results are substantially better than those reported from all currently utilized regimens. Head to head comparison with established thrombolytic regimens in a large-scale randomized trial is warranted.",
"affiliations": "Franz Volhard Clinic, Virchow Klinikum-Charité, Humboldt University of Berlin, Germany. gulba@fvk.-berlin.de",
"authors": "Gulba|D C|DC|;Tanswell|P|P|;Dechend|R|R|;Sosada|M|M|;Weis|A|A|;Waigand|J|J|;Uhlich|F|F|;Hauck|S|S|;Jost|S|S|;Rafflenbeul|W|W|;Lichtlen|P R|PR|;Dietz|R|R|",
"chemical_list": "D013300:Streptokinase; D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator",
"country": "United States",
"delete": false,
"doi": "10.1016/s0735-1097(97)00370-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-1097",
"issue": "30(7)",
"journal": "Journal of the American College of Cardiology",
"keywords": null,
"medline_ta": "J Am Coll Cardiol",
"mesh_terms": "D001780:Blood Coagulation Tests; D017023:Coronary Angiography; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction; D010960:Plasminogen Activators; D011446:Prospective Studies; D013300:Streptokinase; D015912:Thrombolytic Therapy; D013997:Time Factors; D010959:Tissue Plasminogen Activator; D014654:Vascular Patency",
"nlm_unique_id": "8301365",
"other_id": null,
"pages": "1611-7",
"pmc": null,
"pmid": "9385884",
"pubdate": "1997-12",
"publication_types": "D016430:Clinical Trial; D003160:Comparative Study; D018848:Controlled Clinical Trial; D016428:Journal Article",
"references": null,
"title": "Sixty-minute alteplase protocol: a new accelerated recombinant tissue-type plasminogen activator regimen for thrombolysis in acute myocardial infarction.",
"title_normalized": "sixty minute alteplase protocol a new accelerated recombinant tissue type plasminogen activator regimen for thrombolysis in acute myocardial infarction"
} | [
{
"companynumb": "DE-ROCHE-1921425",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"drugad... |
{
"abstract": "A 58-year old female patient presented to us with a three months' old fracture of the neck of femur. She underwent bipolar hemiarthroplasty. In the immediate postoperative period, she developed deep vein thrombosis for which she was started on anticoagulant therapy. Patient had persistent discharge from the wound since then and underwent regular dressings. On the eighth post-op day, she developed sciatic nerve palsy secondary to wound haematoma. The haematoma was decompressed immediately and she had a dramatic improvement in pain but her neurological deficit persisted. The wound healed completely without any complications. At three months follow up, she had recovered completely with grade 5/5 power in ankle and foot and full sensory recovery in the sciatic nerve distribution. She was ambulating comfortably with a walker. At final follow up around 20 months post-operation, she was pain-free and walking without any support. The wound had healed completely.",
"affiliations": "Department of Orthopaedics, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, India.;Department of Orthopaedics, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, India.;Department of Orthopaedics, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, India.",
"authors": "Balaji|G|G|;Sriharsha|Y|Y|;Sharma|D|D|",
"chemical_list": null,
"country": "Malaysia",
"delete": false,
"doi": "10.5704/MOJ.1907.010",
"fulltext": "\n==== Front\nMalays Orthop JMalays Orthop JmojMalaysian Orthopaedic Journal1985-25332232-111XMalaysian Orthopaedic Association Kuala Lumpur 3100138510.5704/MOJ.1907.010Case ReportDelayed Onset Sciatic Nerve Palsy Secondary to Wound Hematoma following Anticoagulant Therapy Post-Bipolar Hemiarthroplasty - an Uncommon Complication: A Case Report Balaji G MS OrthoSriharsha Y MS OrthoSharma D MS OrthoDepartment of Orthopaedics, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, IndiaDepartment of Orthopaedics, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Jipmer Campus Rd, Pondicherry, 605006, India Email: drgopi9596@gmail.com7 2019 13 2 49 51 1 3 2019 18 5 2019 © 2019 Malaysian Orthopaedic Association (MOA). All Rights Reserved2019This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly citedA 58-year old female patient presented to us with a three months’ old fracture of the neck of femur. She underwent bipolar hemiarthroplasty. In the immediate postoperative period, she developed deep vein thrombosis for which she was started on anticoagulant therapy. Patient had persistent discharge from the wound since then and underwent regular dressings. On the eighth post-op day, she developed sciatic nerve palsy secondary to wound haematoma. The haematoma was decompressed immediately and she had a dramatic improvement in pain but her neurological deficit persisted. The wound healed completely without any complications. At three months follow up, she had recovered completely with grade 5/5 power in ankle and foot and full sensory recovery in the sciatic nerve distribution. She was ambulating comfortably with a walker. At final follow up around 20 months post-operation, she was pain-free and walking without any support. The wound had healed completely.\n\nsciatic nervesciatic neuropathyvenous thrombosis\n==== Body\nIntroduction\nSciatic nerve palsy is a rare but potentially disabling complication in hip arthroplasty. There are few isolated reports of sciatic nerve palsy due to hematoma formation and it remains a rare complication1-5. We describe a case of delayed sciatic nerve palsy due to hematoma formation. Informed consent was obtained from the patient regarding case data to be used for research and educational purposes.\n\nCase Report\nA 58-year old female patient presented to us with pain in the left groin and inability to weight bear for three months following a fall from stairs at her home. She had taken traditional treatment in the form of oil massage and splinting initially. The patient was a known case of seropositive rheumatoid arthritis on regular disease-modifying drugs. She was diagnosed to have a sub-capital neck of femur fracture. She underwent cemented bipolar hemiarthroplasty through posterior (Moore’s) approach using Ormed implants (Batch No. 150925/2, Lot no. BP 037) with 41mm head size and Depuy Gentamycin bone cement (Fig. 1). Intra-operatively there were no complications observed and surgical wound was closed in layers with suction drain. Eight hours later, the patient had completely recovered from spinal anaesthesia with no sensory or motor deficit on examination.\n\nFig. 1: Plain AP radiograph of the pelvis in the immediate postoperative period with bipolar prosthesis in situ.\n\nOn the first post-operative day, the patient was taught isometric quadriceps exercises along with ankle range of motion exercises. On the second day, the drain was removed and she was mobilised weight bearing as tolerated with a walker. She developed swelling and erythema of the leg along with calf tenderness on the third day. Duplex ultrasonogram of the left lower limb revealed deep vein thrombosis (DVT) of the femoral vein (partial thrombus occluding the lumen and non-compressible with probe). She was started on Inj. Enoxaparin 40mg SC BD and Tab. Warfarin 5mg OD. Two days post-anticoagulation therapy, the patient developed severe pain in the left gluteal region with increasing intensity radiating to the great toe. A fluctuant swelling was noted over the operated site with associated serosanguinous discharge. Few skin staples were removed and around 100ml of fresh hematoma was drained from the wound, following which the patient was comfortable and symptoms reduced. On the eighth postoperative day, the patient again developed increased pain in the gluteal region radiating to the great toe associated with numbness of the foot. Examination revealed foot drop along with weakness of knee flexion and loss to fine touch and pinprick over dorsum and plantar aspect of the foot suggestive of sciatic palsy. Ultrasonogram (USG) showed a collection of fluid at the sub-muscular plane of the hip and around the sciatic nerve compressing it and a persisting thrombus in the femoral vein with no change as compared to the previous scan. The patient underwent an emergency wound debridement and decompression of the sciatic nerve.\n\nIntra-operatively, there was seropurulent collection in the submuscular plane compressing the sciatic nerve (Fig. 2,3). The joint was dislocated and thorough wound debridement carried out. There was no fluid collection in the joint. The prosthesis was stable. The nerve was decompressed completely and the joint was relocated. The wound was closed in layers with a drain in situ. The fluid and tissues were sent for culture and sensitivity study.\n\nFig. 2: Intraoperative image showing haematoma around the sciatic nerve.\n\nFig. 3: Image showing complete decompression of sciatic nerve.\n\nThe culture revealed methicillin-resistant Staphylococcus aureus. She was started on Inj. Vancomycin 15mg/kg TDS for two weeks. She had dramatic relief from her pain post-decompression but her neurological deficits persisted. The wound healed completely without any complications. In the meantime, anticoagulant therapy was titrated and she was started on Tab. Warfarin 5mg daily. Staples were removed on the sixteenth post-operative day. She was ambulated with a walker, weight bearing as tolerated, and was discharged on oral Linezolid 600mg twice a day for four weeks.\n\nAt three months follow up, her sciatic nerve had recovered completely with grade 5/5 power in ankle and foot and full sensory recovery in the sciatic nerve distribution. She was ambulating comfortably with a walker. She was advised to continue anticoagulant therapy for another three months by the physician. At the end of 20 months follow-up, the wound had healed completely, she was pain-free and walking without any support.\n\nDiscussion\nSciatic nerve palsy following hip arthroplasty is a well known complication secondary to direct injury to the nerve, traction injury to the nerve due to over lengthening of the limb (particularly in neglected cases and developmental dysplasia of the hip), compression due to retractors, damage to the nerve due to thermal injury from cement or fraying of the nerve over cement osteophyte4,5. Delayed sciatic nerve palsy secondary to wound haematoma in the postoperative period is a rare phenomenon1,2. Very few cases have been reported in the literature on delayed sciatic palsy secondary to wound haematoma. Fleming et al3 were among the earliest to report five cases of sciatic nerve palsy secondary to bleeding after hip surgery. Sorenson et al2 reported two cases of wound haematoma-induced sciatic nerve palsy following hip arthroplasty. They hypothesised that increase incompartment pressure beneath the closed fascia was responsible for nerve palsy.\n\nButt et al4 reported six cases of wound haematoma-induced sciatic nerve palsy post-THA secondary to anticoagulant therapy. They also found that five of their patients were less than 70kg in weight and received a full prophylactic dose of anticoagulants which could be the cause for haematoma formation. Hence they advised a reduced dose of anticoagulants in such patients.\n\nThere is no consensus regarding time from onset of sciatic nerve irritation to decompression and final clinical outcome in terms of return of sciatic nerve function5.\n\nSorenson et al2 in their report decompressed after 12 hours of initial complaints in one patient and after six hours in the other. The first one did not show nerve recovery while the second patient had good recovery of nerve function. They suggested that the timing of decompression plays a key role in the recovery of nerve function.\n\nAustin et al1 reported a case of late sciatic nerve palsy following THA on the 18th postoperative day secondary to wound haematoma. Though they decompressed immediately, their patient had persistent foot drop till final follow up. Beksac et al5 reported a case which was decompressed 26 hours after diagnosis. At nine months follow up, the patient still had a persistent neurological deficit. Our patient was decompressed within 12 hours after onset of foot drop. She showed good improvement with full recovery of sciatic nerve function.\n\nIf a patient required post-operative thromboprophylaxis due to high risk of thromboembolism, the clinician should be cautious regarding the bleeding complications that might occur. The dose of anticoagulant should be decided as per the weight of the patient4. Our patient had wound haematoma which was clinically evident as a swelling over the groin and serosanguinous discharge from the wound. Also ultrasonogram of the hip showed signs of collection compressing the sciatic nerve. Once diagnosis of wound hematoma is confirmed, immediate decompression is recommended.\n\nIn conclusion, sciatic nerve palsy is a significant disabling complication. Prompt diagnosis and timely intervention play a key role in reducing the overall complication rate and the serious morbidity associated with it.\n\nConflict of Interest\nThe authors declare no conflicts of interest.\n==== Refs\nReferences\n1 Austin MS Klein GR Sharkey PF Hozack WJ Rothman RH Late sciatic nerve palsy caused by hematoma after primary total hip arthroplasty1. J Arthroplasty. 2004 19 6 790 2 15343542 \n2 Sorensen JV Christensen KS Wound hematoma induced sciatic nerve palsy after total hip arthroplasty. J Arthroplasty. 1992 7 4 551 1336039 \n3 Fleming RE Michelsen CB Stinchfield FE Sciatic paralysis. J Bone Joint Surg Am. 1979 61 37 \n4 Butt AJ McCarthy T Kelly IP Glynn T McCoy G Sciatic nerve palsy secondary to postoperative haematoma in primary total hip replacement. J Bone Joint Surg Br. 2005 87 11 1465 7 16260659 \n5 Beksaç BP Della Valle AG Salvati EA Acute sciatic nerve palsy as a delayed complication of low-molecular-weight heparin prophylaxis after total hip arthroplasty. Am J Orthop (Belle Mead NJ). 2009 38 2 E28 30 19340383\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1985-2533",
"issue": "13(2)",
"journal": "Malaysian orthopaedic journal",
"keywords": "sciatic nerve; sciatic neuropathy; venous thrombosis",
"medline_ta": "Malays Orthop J",
"mesh_terms": null,
"nlm_unique_id": "101564672",
"other_id": null,
"pages": "49-51",
"pmc": null,
"pmid": "31467653",
"pubdate": "2019-07",
"publication_types": "D002363:Case Reports",
"references": "1336039;15343542;16260659;19340383;759433",
"title": "Delayed Onset Sciatic Nerve Palsy Secondary to Wound Hematoma following Anticoagulant Therapy Post-Bipolar Hemiarthroplasty - an Uncommon Complication: A Case Report.",
"title_normalized": "delayed onset sciatic nerve palsy secondary to wound hematoma following anticoagulant therapy post bipolar hemiarthroplasty an uncommon complication a case report"
} | [
{
"companynumb": "IN-SA-2019SA262617",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "WARFARIN SODIUM"
},
"drugadditional": "3",
... |
{
"abstract": "Intraosseous infusion is increasingly used as an alternative to intravenous infusion. It is recommended for the cardiac arrest of a child in the first instance and after two failed attempts of intravenous infusion in the cardiac arrest of adults. Its rapid use and its low failure rate justify its use in all life-threatening emergencies. It can be used to administer the same treatments as intravenous infusion. It does, nonetheless, present some rare complications, such as acute leg ischemia by extravasation of epinephrine, as we report here. Awareness of these complications is necessary to ensure compliance with the rules of placing this type of infusion.",
"affiliations": "Brigade des sapeurs-pompiers de Paris, 1 place Jules-Renard, 75017 Paris.;Service médical d'unité. 1er régiment des hussards parachutistes, Tarbes.;Service d'accueil des urgences de Djibouti, hôpital médico-chirurgical Bouffard, Djibouti.;Brigade des sapeurs-pompiers de Paris, 1 place Jules-Renard, 75017 Paris.;Service de réanimation, hôpital d'instruction des armées Sainte-Anne, Toulon.",
"authors": "Maurin|O|O|;de Régoix|S|S|;Legonidec|E|E|;Tourtier|J P|JP|;Kaiser|E|E|",
"chemical_list": "D004837:Epinephrine",
"country": "France",
"delete": false,
"doi": "10.1684/mst.2014.0328",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2261-3684",
"issue": "24(2)",
"journal": "Medecine et sante tropicales",
"keywords": "epinephrine; extravasation; intraosseous infusion; leg ischemia",
"medline_ta": "Med Sante Trop",
"mesh_terms": "D015730:Djibouti; D004837:Epinephrine; D005260:Female; D006323:Heart Arrest; D006801:Humans; D007223:Infant; D017148:Infusions, Intraosseous; D007511:Ischemia; D007866:Leg",
"nlm_unique_id": "101581406",
"other_id": null,
"pages": "214-6",
"pmc": null,
"pmid": "24854187",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Leg ischemia complicating the intraosseous infusion of epinephrine for a Djiboutian child.",
"title_normalized": "leg ischemia complicating the intraosseous infusion of epinephrine for a djiboutian child"
} | [
{
"companynumb": "FR-MYLANLABS-2015M1016049",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EPINEPHRINE"
},
"drugadditional": null,
... |
{
"abstract": "Analgesics are used most frequently in fatal and non-fatal medicinal self-poisonings. Knowledge about their relative toxicity in overdose is important for clinicians and regulatory agencies.\n\n\n\nUsing data for 2005-2012 we investigated case fatality (number of suicides relative to number of non-fatal self-poisonings) of paracetamol, aspirin, codeine, dihydrocodeine, tramadol, paracetamol with codeine (co-codamol), paracetamol with dihydrocodeine (co-dydramol), ibuprofen and co-proxamol (paracetamol plus dextropropoxyphene; withdrawn in the UK in 2008 due to high toxicity). Data on suicides obtained from the Office for National Statistics and on non-fatal self-poisonings from the Multicentre Study of Self-harm in England. Case fatality was estimated for each drug, using paracetamol as the reference category.\n\n\n\nCompared to paracetamol and based on single drug deaths the case fatality index of dihydrocodeine was considerably elevated (odds ratio (OR) 12.81, 95% Confidence Interval (CI) 10.19-16.12). Case fatality indices for tramadol (OR 4.05, 95% CI 3.38-4.85) and codeine (OR 2.21, 95% CI 1.81-2.70) were also significantly higher than for paracetamol. The results when multiple drug deaths were included produced similar results. The relative toxicity of co-proxamol far exceeded that of the other analgesics.\n\n\n\nData on fatal self-poisonings were based on national data, whereas those for non-fatal poisonings were based on local data.\n\n\n\nDihydrocodeine and tramadol are particularly toxic in overdose and codeine is also relatively toxic. They should be prescribed with caution, particularly to individuals at risk of self-harm.",
"affiliations": "Department of Psychiatry, University of Oxford, UK; Oxford Health NHS Foundation Trust, Oxford, UK. Electronic address: keith.hawton@psych.ox.ac.uk.;Department of Psychiatry, University of Oxford, UK.;Department of Psychiatry, University of Oxford, UK.;Office for National Statistics, UK.;Nuffield Department of Primary Care Health Sciences, University of Oxford, UK.;Nuffield Department of Primary Care Health Sciences, University of Oxford, UK.;Manchester Academic Health Sciences Centre, University of Manchester, UK.;Centre for Self-harm and Suicide Prevention Research, Derbyshire Healthcare NHS Foundation Trust, UK.;School of Social and Community Medicine, University of Bristol, UK.;Manchester Academic Health Sciences Centre, University of Manchester, UK; Greater Manchester Mental Health NHS Foundation Trust, UK.;Department of Psychiatry, University of Oxford, UK.",
"authors": "Hawton|Keith|K|;Ferrey|Anne|A|;Casey|Deborah|D|;Wells|Claudia|C|;Fuller|Alice|A|;Bankhead|Clare|C|;Clements|Caroline|C|;Ness|Jennifer|J|;Gunnell|David|D|;Kapur|Navneet|N|;Geulayov|Galit|G|",
"chemical_list": "D000700:Analgesics; D004338:Drug Combinations; C526278:acetaminophen, codeine drug combination; D000082:Acetaminophen; C011800:acetaminophen, dextropropoxyphene, drug combination; C014481:dihydrocodeine; D011431:Dextropropoxyphene; D003061:Codeine",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jad.2019.01.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0165-0327",
"issue": "246()",
"journal": "Journal of affective disorders",
"keywords": "Analgesics; Self-poisoning; Suicide; Toxicity",
"medline_ta": "J Affect Disord",
"mesh_terms": "D000082:Acetaminophen; D000328:Adult; D000700:Analgesics; D003061:Codeine; D011431:Dextropropoxyphene; D004338:Drug Combinations; D062787:Drug Overdose; D004739:England; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D013405:Suicide",
"nlm_unique_id": "7906073",
"other_id": null,
"pages": "814-819",
"pmc": null,
"pmid": "30634113",
"pubdate": "2019-03-01",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Relative toxicity of analgesics commonly used for intentional self-poisoning: A study of case fatality based on fatal and non-fatal overdoses.",
"title_normalized": "relative toxicity of analgesics commonly used for intentional self poisoning a study of case fatality based on fatal and non fatal overdoses"
} | [
{
"companynumb": "GB-JNJFOC-20190140040",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": "3",
"dru... |
{
"abstract": "OBJECTIVE\nHepatotoxicity is a major side-effect of antitubercular drugs (ATD). As these drugs are metabolized in the liver, there is a theoretical risk of increased hepatotoxicity in patients with underlying chronic liver disease (CLD). Ofloxacin has antitubercular activity and has exclusive renal clearance. The aim was to study the efficacy and safety of an ofloxacin-based antitubercular regimen for treating tuberculosis in patients with underlying CLD.\n\n\nMETHODS\nThirty-one cases were randomly assigned to two drug regimens using WHO dosage schedules: (i) regimen A (n = 15): isoniazid, rifampicin and ethambutol for 2 months, followed by isoniazid and rifampicin for a further 7 months; and (ii) regimen B (n = 16): isoniazid, pyrazinamide, ethambutol and ofloxacin for 2 months, followed by isoniazid, ethambutol and ofloxacin for a further 10 months. Hepatotoxicity was diagnosed if alanine aminotransferase/aspartate aminotransferase increased > fivefold from the baseline or to > 400 IU/L, or if bilirubin increased by > 2.5 mg/dL from the baseline.\n\n\nRESULTS\nThe response to ATD was achieved in all the patients who completed the therapy. Four (26.6%) patients on regimen A developed hepatotoxicity as compared to none on regimen B (P = 0.043). None of these patients could be restarted on ATD using the same regimen A because of the persistently deranged liver functions.\n\n\nCONCLUSIONS\nIn patients with tuberculosis who have underlying CLD: (i) an ofloxacin-based antitubercular regimen without rifampicin is as effective as a rifampicin-based regimen; and (ii) a combination of isoniazid with rifampicin is more hepatotoxic than a combination with ofloxacin and pyrazinamide.",
"affiliations": "Department of Gastroenterology, Govind Ballabh Pant Hospital, New Delhi, India.",
"authors": "Saigal|S|S|;Agarwal|S R|SR|;Nandeesh|H P|HP|;Sarin|S K|SK|",
"chemical_list": "D000995:Antitubercular Agents; D015242:Ofloxacin",
"country": "Australia",
"delete": false,
"doi": "10.1046/j.1440-1746.2001.02570.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0815-9319",
"issue": "16(9)",
"journal": "Journal of gastroenterology and hepatology",
"keywords": null,
"medline_ta": "J Gastroenterol Hepatol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000995:Antitubercular Agents; D056486:Chemical and Drug Induced Liver Injury; D002648:Child; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008103:Liver Cirrhosis; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D015242:Ofloxacin; D014395:Peritonitis, Tuberculous; D012307:Risk Factors; D014385:Tuberculosis, Gastrointestinal; D014397:Tuberculosis, Pulmonary",
"nlm_unique_id": "8607909",
"other_id": null,
"pages": "1028-32",
"pmc": null,
"pmid": "11595068",
"pubdate": "2001-09",
"publication_types": "D016430:Clinical Trial; D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Safety of an ofloxacin-based antitubercular regimen for the treatment of tuberculosis in patients with underlying chronic liver disease: a preliminary report.",
"title_normalized": "safety of an ofloxacin based antitubercular regimen for the treatment of tuberculosis in patients with underlying chronic liver disease a preliminary report"
} | [
{
"companynumb": "IN-LUPIN PHARMACEUTICALS INC.-2015-02223",
"fulfillexpeditecriteria": "2",
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"patient": {
"drug": [
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"activesubstance": {
"activesubstancename": "RIFAMPIN"
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"abstract": "A 43-year-old man presented with severe, saw-tooth pattern pain around the right eye that started with conjunctival injection, lacrimation and nasal discharge, lasting for about 1 hour, 4 months after the initial onset of lancinating pain in the same area. The patient was diagnosed with SUNCT (short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing) according to the International Classification of Headache Disorders 3rd edition (beta version). The symptoms improved in 2 months but recurred 6 months later. He developed a toxic eruption after receiving a variety of antiepileptic agents including lamotrigine, which suggested refractory SUNCT. Head magnetic resonance imaging (MRI) showed neurovascular compression (NVC) involving the right trigeminal nerve. Microvascular decompression (MVD) was performed, and the pain was relieved postoperatively. MVD should be considered when treating refractory SUNCT because NVC may be involved in some cases. (Received February 29, 2016; Accepted April 4, 2016; Published August 1, 2016).",
"affiliations": "Department of Neurology and Headache center, Tominaga hospital.",
"authors": "Kikui|Shoji|S|;Miyahara|Jun-Ichi|J|;Sugiyama|Hanako|H|;Kashiwaya|Yoshihiro|Y|;Takeshima|Takao|T|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.11477/mf.1416200535",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1881-6096",
"issue": "68(8)",
"journal": "Brain and nerve = Shinkei kenkyu no shinpo",
"keywords": null,
"medline_ta": "Brain Nerve",
"mesh_terms": "D000328:Adult; D006261:Headache; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D061145:Microvascular Decompression Surgery; D014276:Trigeminal Nerve",
"nlm_unique_id": "101299709",
"other_id": null,
"pages": "951-5",
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"pmid": "27503824",
"pubdate": "2016-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Effective Microvascular Decompression of the Trigeminal Nerve in a Patient with SUNCT.",
"title_normalized": "effective microvascular decompression of the trigeminal nerve in a patient with sunct"
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"companynumb": "JP-LUPIN PHARMACEUTICALS INC.-2016-04033",
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"activesubstancename": "LAMOTRIGINE"
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"abstract": "We present a brief observational report of clearance of significant molluscum contagiosum infection in a child taking methotrexate after one dose of intramuscular zoster immunoglobulin-VF (human) and suggest that this may indicate a potential new treatment option.",
"affiliations": "Department of Dermatology, Flinders Medical Centre, South Australia, Australia.;Department of Dermatology, Flinders Medical Centre, South Australia, Australia.",
"authors": "Maiolo|Corinne|C|;Marshman|Gillian|G|",
"chemical_list": "D007106:Immune Sera; C030799:varicella-zoster immune globulin",
"country": "United States",
"delete": false,
"doi": "10.1111/pde.12606",
"fulltext": null,
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"issn_linking": "0736-8046",
"issue": "32(4)",
"journal": "Pediatric dermatology",
"keywords": null,
"medline_ta": "Pediatr Dermatol",
"mesh_terms": "D002675:Child, Preschool; D005260:Female; D006801:Humans; D007106:Immune Sera; D016867:Immunocompromised Host; D008976:Molluscum Contagiosum",
"nlm_unique_id": "8406799",
"other_id": null,
"pages": "e193",
"pmc": null,
"pmid": "25962415",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Zoster Immunoglobulin-VF: A Potential Treatment for Molluscum Contagiosum in Immunosuppressed Children.",
"title_normalized": "zoster immunoglobulin vf a potential treatment for molluscum contagiosum in immunosuppressed children"
} | [
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"companynumb": "AU-ACCORD-031177",
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"activesubstance": {
"activesubstancename": "METHOTREXATE"
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"abstract": "We present a 60-year-old female patient with asymptomatic acute hepatitis E that was fortuitously detected during the course of ulcerative colitis (UC). She was admitted to hospital on October 30, 2015. Endoscopy and histological examination of the colon showed typical findings of UC. All parameters of liver function tests were normal on this date. Combination therapy with oral prednisolone and mesalazine was started and intravenous administration of infliximab once every 8 weeks was added later. Her symptoms gradually improved after these treatments, and she was discharged on February 7, 2016. In a periodic check-up on July 7, 2016, high levels of serum transaminases were detected in liver function tests. Although drug-induced liver injury was first suspected, anti-hepatitis E virus (HEV) immunoglobulin A was positive. The genotype and subgenotype of this HEV are 3 and 3a, respectively, although the infectious route of the HEV was unclear. Within 2 weeks after the onset of acute liver injury, the HEV viremia disappeared and her liver function tests improved. Examination of serum anti-HEV immunoglobulin A should be added at the time of abnormal liver function tests in patients with UC receiving immunosuppressive and biological drugs.",
"affiliations": "Department of Nutritional Science, Morioka University, 808 Sunakomi, Takizawa, Iwate, 020-0694, Japan. kasuzuki@morioka-u.ac.jp.;Department of Gastroenterology, Morioka City Hospital, 5-15-1 Motomiya, Morioka, Iwate, 020-0866, Japan.;Division of Hepatology, Department of Internal Medicine, Iwate Medical University School of Medicine, 19-1 Uchimaru, Morioka, Iwate, 020-8505, Japan.;Division of Hepatology, Department of Internal Medicine, Iwate Medical University School of Medicine, 19-1 Uchimaru, Morioka, Iwate, 020-8505, Japan.;Division of Hepatology, Department of Internal Medicine, Iwate Medical University School of Medicine, 19-1 Uchimaru, Morioka, Iwate, 020-8505, Japan.;Department of Gastroenterology, Morioka City Hospital, 5-15-1 Motomiya, Morioka, Iwate, 020-0866, Japan.;Department of Gastroenterology, Morioka City Hospital, 5-15-1 Motomiya, Morioka, Iwate, 020-0866, Japan.;Department of Gastroenterology, Morioka City Hospital, 5-15-1 Motomiya, Morioka, Iwate, 020-0866, Japan.;Division of Internal Medicine, Department of Oral Medicine, Iwate Medical University School of Dentistry, 19-1 Uchimaru, Morioka, Iwate, 020-8505, Japan.;Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.",
"authors": "Suzuki|Kazuyuki|K|;Kumagai|Ichiro|I|;Yoshida|Yuichi|Y|;Miyasaka|Akio|A|;Takikawa|Yasuhiro|Y|;Kamiya|Ryoichi|R|;Kondo|Kouryo|K|;Kato|Akinobu|A|;Chiba|Toshimi|T|;Okamoto|Hiroaki|H|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12328-017-0730-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1865-7265",
"issue": "10(3)",
"journal": "Clinical journal of gastroenterology",
"keywords": "Acute hepatitis E; Biological drug; Immunosuppressive drug; Opportunistic infection; Ulcerative colitis",
"medline_ta": "Clin J Gastroenterol",
"mesh_terms": "D000208:Acute Disease; D058345:Asymptomatic Infections; D003093:Colitis, Ulcerative; D005260:Female; D016751:Hepatitis E; D006801:Humans; D007166:Immunosuppressive Agents; D008875:Middle Aged",
"nlm_unique_id": "101477246",
"other_id": null,
"pages": "255-260",
"pmc": null,
"pmid": "28353200",
"pubdate": "2017-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19249101;12202555;15293134;20068345;25967740;24177295;25052345;22537448;26870785;15094239;26257097;17606958;20577000;12907011;23538480;25912835;18192058;27468219;23799211;27509518;12964128;25146162;14686743;20029817;23721425;19271116;16485490;23013075;20695796;12558914;22464811;21955431;19093204;27602239;27433141;27672291",
"title": "Asymptomatic acute hepatitis E in a female patient with ulcerative colitis.",
"title_normalized": "asymptomatic acute hepatitis e in a female patient with ulcerative colitis"
} | [
{
"companynumb": "JP-CONCORDIA PHARMACEUTICALS INC.-GSH201706-003534",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
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"dr... |
{
"abstract": "The serotonin syndrome is a serioius medical condition due due to an intensive stimulation of setonin receptors. It is a rare, but severe, consequence of interaction between serotomimetic agents. This is a report of a 70-year-old woman steadily in therapy with venlafaxine and rizatriptan for migraine and major depressive syndrome. She was admitted to neurology unit for decreased light reflex with miotic pupils, global hyperreflexia, tremor, anxiety, ataxia and incoordination. The patient was diagnosed as a probable case of serotonin syndrome due to a pharmacological interaction between venlafaxine and rizatriptan trigged by opioid intake. In this paper, the development of syntomatology, the clinical examination and the possible pharmacokinetics explanation were carefully discussed and analysed.",
"affiliations": "Department of Internal Medicine, Clinical Pharmacology and Toxicology Unit, University of Genoa, Genoa, Italy.;Neurology Unit, Istituto Clinico 'Salus', Alessandria, Italy.;Neurology Unit, Istituto Clinico 'Salus', Alessandria, Italy.;Department of Internal Medicine, Clinical Pharmacology and Toxicology Unit, University of Genoa, Genoa, Italy.;Department of Internal Medicine, Clinical Pharmacology and Toxicology Unit, University of Genoa, Genoa, Italy.",
"authors": "Milano|Giulia|G|;Natta|Werner Maria|WM|;Bello|Alfredo|A|;Martelli|Antonietta|A|;Mattioli|Francesca|F|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.9758/cpn.2017.15.3.292",
"fulltext": "\n==== Front\nClin Psychopharmacol NeurosciClin Psychopharmacol NeurosciClinical Psychopharmacology and Neuroscience1738-10882093-4327Korean College of Neuropsychopharmacology 2878394210.9758/cpn.2017.15.3.292cpn-15-292Case ReportCodeine Precipitating Serotonin Syndrome in a Patient in Therapy with Antidepressant and Triptan Milano Giulia 1Natta Werner Maria 2Bello Alfredo 2Martelli Antonietta 1Mattioli Francesca 1\n1 Department of Internal Medicine, Clinical Pharmacology and Toxicology Unit, University of Genoa, Genoa, \nItaly\n2 Neurology Unit, Istituto Clinico ‘Salus’, Alessandria, \nItalyAddress for correspondence: Giulia Milano, MD, Department of Internal Medicine, Clinical Pharmacology and Toxicology Unit, University of Genoa, Viale Benedetto XV, 2. I-16132 Genoa, Italy, Tel: +39-0103538850, Fax: +39-0103538232, E-mail: giuliamilano86@yahoo.it8 2017 31 8 2017 15 3 292 295 19 1 2017 22 2 2017 16 3 2017 Copyright © 2017, Korean College of Neuropsychopharmacology2017This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.The serotonin syndrome is a serioius medical condition due due to an intensive stimulation of setonin receptors. It is a rare, but severe, consequence of interaction between serotomimetic agents. This is a report of a 70-year-old woman steadily in therapy with venlafaxine and rizatriptan for migraine and major depressive syndrome. She was admitted to neurology unit for decreased light reflex with miotic pupils, global hyperreflexia, tremor, anxiety, ataxia and incoordination. The patient was diagnosed as a probable case of serotonin syndrome due to a pharmacological interaction between venlafaxine and rizatriptan trigged by opioid intake. In this paper, the development of syntomatology, the clinical examination and the possible pharmacokinetics explanation were carefully discussed and analysed.\n\nDrug-drug interactionsCodeineSerotonin syndromePrescription drug misuseMigraine disordersMajor depressive disorder\n==== Body\nINTRODUCTION\nDrug interactions are nowadays a very serious problem and they can frequently include common prescribed drugs and over-the-counter (OTC) medicines.1,2) Antidepressants are very frequently prescribed drugs, they include selective serotonin reuptake inhibitors (SSRIs) and serotonin-noradrenaline reuptake inhibitors (SNRIs), prescribed for the treatment of major depressive disorder.3)\n\nThe SSRIs mechanism of action is to increase the intra-synaptic level of seronin with the inhibition of serotonin reuptake. The same is true for SNRIs respect to noradrenaline. As a secondary mechanism of action, SSRIs increase efficacy of 5-hydroxytryptamine (5-HT) neurons by desensitizing 5-HT autoreceptors of the serotonin nerve terminals.4,5)\n\nAdverse events (AEs) of SSRIs and SNRIs include: hyponatremia, risk of ischemic stroke and intracranial hemorrhages,6) suicidality and mania.7) The serotonin syndrome (SS) is an example of AE, induced by drug interaction; it is a rare consequence of interaction between serotomimetic agents. The SS is considered to be due to an intensive stimulation of 5-HT1A (in central grey nuclei and in the medulla) and of 5-HT2A (in the central and peripheral nervous system) receptors by serotonergic medicines8); it is characterized by neuromuscular hyperactivity (myoclonus and hyperreflexia), cognitive alterations (agitation and confusion) and autonomic disorders (hyperthermia and tachycardia).9) The SS is caused by the serotonergic agent’s use and it usually occurs within 24 hours after the serotomimetic drugs intake.8–10) Abadie et al.11) described the mostly involved medicines in SS, based on the French pharmacovigilance reports; SSRIs seem to be involved in 42.1% and SNRIs (mainly venlafaxine) in 9.1%.\n\nTriptans (5-HT receptor agonists) are another drug category selectively acting on the serotonin receptors. Triptans are 5-HT1B/1D receptor agonists with lower affinity also for 5-HT1A and 5-HT2A receptors,12) they are used in migraine’s therapy and they usually have dose-dependent side effects (paresthesia, nausea, fatigue, dry mouth and facial flushing).13,14)\n\nWe report a case of SS probably induced by interaction between one antidepressant and one triptan with codeine.\n\nCodeine, 3-methylmorphine, is a natural methylated form of morphine. Codeine is metabolized into morphine (and its metabolites) and into codeine-6-glucuronide and norcodeine; the principal cytochromes involved in metabolic codeine pathway are CYP2D6 and CYP3A4.15) Worldwide codeine, in combined preparation with acet-aminophen, is the most commonly opiate prescribed used in the treatment of mild to moderate pain and as an anti-tussive medicine, indeed in different countries (i.e., United Kingdom, South Africa, Ireland, France, and Australia) is an OTC medicine.16–18) The AEs of codeine are the same of those of opioid category (sedation, nausea, vomiting, constipation and respiratory depression).19)\n\nThe aim of this report is to describe an interesting and not yet reported AE observed in one patient steadily in therapy with venlafaxine and rizatriptan. We have analyzed the development of symptomatology after added therapy with codeine and the possible association with opioid treatment.\n\nCASE\nThe patient is a 70-year-old woman, she has a long clinical history of migraine and major depressive syndrome. She describes tension-type headache and depressive syndrome with anxiety and insomnia since she was 20 years old.\n\nDuring the last 10 years she was treated with individual support psychotherapy and she received several psycho-pharmacological therapies, such as valproate, topiramate, propranolol and amitryptiline (as a long term therapy), acetaminophen, indomethacin, or other non-steroidal anti-inflammatory drugs (as needed medications). Migraine attack, major depressive disorder and analgesic drugs misuse were the main reasons for her hospital admissions.\n\nOn November 21, 2015, due to a severe migraine attack she took for the first time in her life codeine 30 mg in combination with acetaminophen 500 mg. In that moment, she was prescribed with venlafaxine 225 mg/day (150 mg in the morning and 75 mg in the afternoon) and diazepam 5 mg/three times a day (recommended dose). Nevertheless she reported, over the past few mounths that she also took, without any medical supervision, rizatriptan 10 mg as needed use. Her drug intake was basically as needed use and she demonstrated a poor compliance with prescribed medications and doses, but, to the best of our knowledge, she never became dependent to any illicit substances, nether to opiate medications or acohol.\n\nAround 30 to 36 hours after her first codeine intake she contacted a general practitioner reporting symptoms as nervousness, irritability, agitation, mania, confusion, tremor, diaphoresis and nausea. On November 23, she was hospitalized.\n\nThe inpatient parameters was: body temperature 37.5°C; pulse 100 beats/minute; blood pressure 140/90 mmHg and respiratory rate 21 breaths/minute. Complete blood test (including liver and kidney function tests, creatinine kinase, and serum electrolyte values) were all within normal limits and also the electrocardiogram resulted in the normal range. During the neurological examination it was detected: miotic pupils with decreased light reflex, global hyperreflexia, tremor in both hands, ataxia and incoordination. She had tremors in both hands and anxiety during the interview. No lateralizing neurological signs were observed. The neuropsychological test MODA (Milan Overall Dementia Assessment) was performed and the total score was 87.7/100 (with an age and education adjusted score of 88.5/100),20) so the test score results in the normal limits. Cranial computed tomography scan were normal and it did not reveal any significant vascular abnormalities.\n\nVenlfaxine and codeine were immediately stopped and endovenous hydration was started with saline solution 0.9%. Diazepam 5 mg was continued orally twice a day for agitation. Approximately 8 hours after the discontinuation of venlafaxine and codeine, the described symptoms disappeared and her hypervigilance improved. Five days later the patient was discharged.\n\nDISCUSSION\nThe SS is a predictable response to the increase of serotonin neurotransmission, due to a serotonin drug-drug interaction21) as well as to an individual vulnerability.22) In humans the increased risk of developing the SS is hypothesized by Gelener et al.10) with a possible serotonin transporter polymorphism.\n\nThe SS, following concomitant triptan and SSRI (or SNRI) use, is biologically possible. Both of these medications increase serotonin trasmission, therefore, it is predictable that their concomitant use would result in higher serotonin activity.4,8,11) The combination of agitation, diaphoresis, tremor and hyperreflexia in our patient led clinicians to hypothesize a diagnosis of SS, according to Sternbach criteria23) and Hunter criteria.24) Specifically agitation, diaphoresis, tremor and confusion are the Sternbach criteria detected in the patient. Tremor and hyperreflexia are the Hunter criteria observed.\n\nWe hypothesize that the development of the SS is connected to the interaction with venlafaxine and rizatriptan triggered by codeine.\n\nIt is also reasonable to suspect that the symptomatology described was associated with an acute opiate poisoning and/or withdrawal. However, in our opinion the opiate intoxication seems to be less probable because the physicians dind’t observe any somnolence, bradycardia, hypotension or bradypnea (inpatient parameters: 100 beats/minute; 140/90 mmHg; 21 breaths/minute). In the same perspective the opiate withdrawal doesn’t seem more likely because the patient never stop to ingest codeine, netheir other opiate substances.\n\nAs previously mentioned the concomitant use of SSRIs/SNRIs and triptans25) could induce the SS: the United States Food and Drug Adminstration Alert26) reporting the potential for life-threatening SS in patients taking SSRIs/SNRIs and triptans concomitantly. This information is based on 27 cases of SS occurring in patients treated with concomitant SSRI or SNRI and triptans.\n\nAfter a systematic literature review on Medline/ PubMed database we have discovered several cases of SS induced by a combination of antidepressants plus triptans, or antidepressants plus opioids,27) expecially tramadol.28–31) The tramadol involvement in the SS is probably due to the mechanism of action: it binds to mu opioid receptors but also inhibits the monoamine (norepinephrine and 5-HT) reuptake.28,32,33) Contrary to synthetic piperidine (i.e., fentanyl34) and tramadol28–31)), codeine, a phenanthrene, does not work as a serotonin uptake inhibitor.33,35,36) Several authors35,36) reported that morphine analogues may potentially increase the intrasynaptic serotonin levels with some unknown mechanisms.\n\nWe will propose, as a possible pathophysiological explanation, for the development of SS the cytochromes (CYP2D6 and CYP3A4) involvement,14,36) as also reported by Direk.9) The genetic individual vulnerability may offer an additional and explanation.9) Addictionally, there are few reportes37,38) indicating that opiates may differentially modulate 5-HT neurotransmission in the central nervous system.\n\nAs mentioned in the indroduction, the metabolite morphine, wich has a high affinity for the mu opioid receptor, is primarily responsible for positive and negative effects of codeine tharapy. Altrought the amount of morphine metabolized from codeine is not the same for everybody. This interindividual variability is in part due to the polymorphic cytochrome CYP2D6 enzyme (the mediator of codeine transformation into morphine). As reported by Tao and Auerbach,38) morphine infusion into the dorsal raphe nucleus of rats increased extracellular 5-HT in the nucleus accumbens. So, one of the possible pathophysiological explanation of this SS case is the iper-biotrasformation of codeine into morphine, mediated in this patient by a high CYP2D6 activity. This mechanism could explain the increase of 5-HT and the consequent trigger role of codeine in our patient, already in therapy with SNRI and triptan.\n\nIn conclusion, SS is a severe clinical condition with high mortality. Physicians should be aware of all serotonergic agents prescription.\n\nTo the best of our knowledge there are no reports of serotonin toxicity triggered by codeine in a patient in therapy with venlafaxine and rizatriptan was never reported. SS should be kept in mind if patients are in therapy with all substances that may interact with serotonergic drugs through the CYP450 pathway,39) including OTC medications and illicit substances. Moreover meticulous collection of AEs by patients, doctors and pharmaceutical companies should be necessary to investigate in more detail the underlying causes of severe pharmacological interactions.\n==== Refs\nREFERENCES\n1 Stone JA Lester CA Aboneh EA Phelan CH Welch LL Chui MA A preliminary examination of over-the-counter medication misuse rates in older adults Res Social Adm Pharm 2017 13 187 192 10.1016/j.sapharm.2016.01.004 \n2 Fergusson D Doucette S Glass KC Shapiro S Healy D Hebert P Association between suicide attempts and selective serotonin reuptake inhibitors: systematic review of randomised controlled trials BMJ 2005 330 396 10.1136/bmj.330.7488.396 15718539 \n3 Abbing-Karahagopian V Huerta C Souverein PC de Abajo F Leufkens HG Slattery J Antidepressant prescribing in five European countries: application of common definitions to assess the prevalence, clinical observations, and methodological implications Eur J Clin Pharmacol 2014 70 849 857 10.1007/s00228-014-1676-z 24793010 \n4 Blier P de Montigny C Chaput Y A role for the serotonin system in the mechanism of action of antidepressant treatments: preclinical evidence J Clin Psychiatry 1990 51 Suppl 14 20 discussion 21 2157700 \n5 Lee YC Lin CH Lin MS Lu Y Chang CH Lin JW Comparison of the effects of serotonin-norepinephrine reuptake inhibitors versus selective serotonin reuptake inhibitors on cerebrovascular events J Clin Psychiatry 2016 77 e1 e7 10.4088/JCP.14m09394 26845272 \n6 Shin D Oh YH Eom CS Park SM Use of selective serotonin reuptake inhibitors and risk of stroke: a systematic review and meta-analysis J Neurol 2014 261 686 695 10.1007/s00415-014-7251-9 24477492 \n7 Vaswani M Linda FK Ramesh S Role of selective serotonin reuptake inhibitors in psychiatric disorders: a comprehensive review Prog Neuropsychopharmacol Biol Psychiatry 2003 27 85 102 10.1016/S0278-5846(02)00338-X 12551730 \n8 Birmes P Coppin D Schmitt L Lauque D Serotonin syndrome: a brief review CMAJ 2003 168 1439 1442 12771076 \n9 Direk MÇ Yıldırım V Güneş S Bozlu G Okuyaz Ç Serotonin syndrome after clomipramine overdose in a child Clin Psychopharmacol Neurosci 2016 14 388 390 10.9758/cpn.2016.14.4.388 27776393 \n10 Gelener P Gorgulu U Kutlu G Ucler S Inan LE Serotonin syndrome due to duloxetine Clin Neuropharmacol 2011 34 127 128 10.1097/WNF.0b013e31821b3aa0 21586918 \n11 Abadie D Rousseau V Logerot S Cottin J Montastruc JL Montastruc F Serotonin syndrome: analysis of cases registered in the french pharmacovigilance database J Clin Psychopharmacol 2015 35 382 388 26082973 \n12 Evans RW The FDA alert on serotonin syndrome with combined use of SSRIs or SNRIs and Triptans: an analysis of the 29 case reports MedGenMed 2007 9 48 18092054 \n13 Goadsby PJ Goldberg J Silberstein SD Migraine in pregnancy BMJ 2008 336 1502 1504 10.1136/bmj.39559.675891.AD 18583683 \n14 Davanzo R Bua J Paloni G Facchina G Breastfeeding and migraine drugs Eur J Clin Pharmacol 2014 70 1313 1324 10.1007/s00228-014-1748-0 25217187 \n15 Madadi P Amstutz U Rieder M Ito S Fung V Hwang S Clinical practice guideline: CYP2D6 genotyping for safe and efficacious codeine therapy J Popul Ther Clin Pharmacol 2013 20 e369 e396 24214521 \n16 Nielsen S Van Hout MC Over-the-counter codeine-from therapeutic use to dependence, and the grey areas in between Curr Top Behav Neurosci 2016 10.1007/7854_2015_422 [Epub ahead of print] 26768736 \n17 Seif-Barghi T Moghadam N Kobarfard F Morphine/ codeine ratio, a key in investigating a case of doping Asian J Sports Med 2015 6 e28798 10.5812/asjsm.28798 26715976 \n18 Foley M Breindahl T Hindersson P Deluca P Kimergård A Misuse of ‘over-the-counter’ codeine analgesics: does formulation play a role? Public Health 2016 130 95 96 10.1016/j.puhe.2015.10.006 26612458 \n19 Magnus P Ghavimi B Coe JW Access to 7β-analogs of codeine with mixed μ/δ agonist activity via 6,7-α-epoxide opening Bioorg Med Chem Lett 2013 23 4870 4874 10.1016/j.bmcl.2013.06.084 23880538 \n20 Brazzelli M Capitani E Della Sala S Spinnler H Zuffi M A neuropsychological instrument adding to the description of patients with suspected cortical dementia: the Milan overall dementia assessment J Neurol Neurosurg Psychiatry 1994 57 1510 1517 10.1136/jnnp.57.12.1510 7798982 \n21 Dvir Y Smallwood P Serotonin syndrome: a complex but easily avoidable condition Gen Hosp Psychiatry 2008 30 284 287 10.1016/j.genhosppsych.2007.09.007 18433663 \n22 Fox MA Jensen CL Gallagher PS Murphy DL Receptor mediation of exaggerated responses to serotonin-enhancing drugs in serotonin transporter (SERT)-deficient mice Neuropharmacology 2007 53 643 656 10.1016/j.neuropharm.2007.07.009 17765930 \n23 Sternbach H The serotonin syndrome Am J Psychiatry 1991 148 705 713 10.1176/ajp.148.6.705 2035713 \n24 Dunkley EJ Isbister GK Sibbritt D Dawson AH Whyte IM The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity QJM 2003 96 635 642 10.1093/qjmed/hcg109 12925718 \n25 Rolan PE Drug interactions with triptans: which are clinically significant? CNS Drugs 2012 26 949 957 10.1007/s40263-012-0002-5 23018546 \n26 U.S. Food and Drug Administration FDA ALERT [7/2006]: Potentially life-threatening serotonin syndrome with combined use of SSRIs or SNRIs and Triptan medications [Internet] Rockville, MD U.S. FDA 2013 8 14 [cited 2016 Feb 12]. Available from: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm085845.htm \n27 Greenier E Lukyanova V Reede L Serotonin syndrome: fentanyl and selective serotonin reuptake inhibitor interactions AANA J 2014 82 340 345 25842648 \n28 Shakoor M Ayub S Ahad A Ayub Z Transient serotonin syndrome caused by concurrent use of tramadol and selective serotonin reuptake inhibitor Am J Case Rep 2014 15 562 564 10.12659/AJCR.892264 25540831 \n29 Albiñana Pérez MS Cea Pereira L Bilbao Salcedo J Rodríguez Penín I Possible serotonin syndrome associated with administration of venlafaxine and tramadol Farm Hosp 2012 36 548 Spanish 23461451 \n30 Sauget D Franco PS Amaniou M Mazere J Dantoine T Possible serotonergic syndrome caused by combination of tramadol and sertraline in an elderly woman Therapie 2002 57 309 310 French 12422548 \n31 Takeshita J Litzinger MH Serotonin syndrome associated with tramadol Prim Care Companion J Clin Psychiatry 2009 11 273 10.4088/PCC.08l00690 19956471 \n32 Mittino D Mula M Monaco F Serotonin syndrome associated with tramadol-sertraline coadministration Clin Neuropharmacol 2004 27 150 151 10.1097/00002826-200405000-00012 15190240 \n33 Codd EE Shank RP Schupsky JJ Raffa RB Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception J Pharmacol Exp Ther 1995 274 1263 1270 7562497 \n34 Ailawadhi S Sung KW Carlson LA Baer MR Serotonin syndrome caused by interaction between citalopram and fentanyl J Clin Pharm Ther 2007 32 199 202 10.1111/j.1365-2710.2007.00813.x 17381671 \n35 Rastogi R Swarm RA Patel TA Case scenario: opioid association with serotonin syndrome: implications to the practitioners Anesthesiology 2011 115 1291 1298 22037635 \n36 Gillman PK Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity Br J Anaesth 2005 95 434 441 10.1093/bja/aei210 16051647 \n37 Karunatilake H Buckley NA Serotonin syndrome induced by fluvoxamine and oxycodone Ann Pharmacother 2006 40 155 157 10.1345/aph.1E671 16368927 \n38 Tao R Auerbach SB Opioid receptor subtypes differentially modulate serotonin efflux in the rat central nervous system J Pharmacol Exp Ther 2002 303 549 556 10.1124/jpet.102.037861 12388635 \n39 Pilgrim JL Gerostamoulos D Drummer OH Review: Pharmacogenetic aspects of the effect of cytochrome P450 polymorphisms on serotonergic drug metabolism, response, interactions, and adverse effects Forensic Sci Med Pathol 2011 7 162 184 10.1007/s12024-010-9188-3 21052868\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1738-1088",
"issue": "15(3)",
"journal": "Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology",
"keywords": "Codeine; Drug-drug interactions; Major depressive disorder; Migraine disorders; Prescription drug misuse; Serotonin syndrome",
"medline_ta": "Clin Psychopharmacol Neurosci",
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"nlm_unique_id": "101207332",
"other_id": null,
"pages": "292-295",
"pmc": null,
"pmid": "28783942",
"pubdate": "2017-08-31",
"publication_types": "D002363:Case Reports",
"references": "18092054;23880538;7562497;2157700;19956471;24793010;12551730;15718539;22037635;25842648;12422548;12388635;12925718;17765930;21052868;25540831;26845272;26715976;18583683;23018546;24477492;15190240;24214521;26082973;26612458;7798982;2035713;12771076;23461451;21586918;27776393;26853833;17381671;16051647;25217187;26768736;16368927;18433663",
"title": "Codeine Precipitating Serotonin Syndrome in a Patient in Therapy with Antidepressant and Triptan.",
"title_normalized": "codeine precipitating serotonin syndrome in a patient in therapy with antidepressant and triptan"
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"abstract": "Autologous stem cell transplantation (ASCT) and novel therapies have improved the prognosis for patients with multiple myeloma (MM). For those who undergo ASCT while on dialysis, a similar survival compared with the overall MM population has been reported. Therefore, for patients achieving remission following ASCT, kidney transplantation is an attractive option, offering an improved quality of life and significant economic advantage.\nThis case series investigates the outcome of five patients who underwent an ASCT for MM with subsequent kidney transplantation between 2006 and 2012.\nFour patients presented with end-stage renal disease (ESRD) and one progressed to ESRD shortly after diagnosis. Induction chemotherapy regimens with novel agents including thalidomide and bortezomib were utilized. Following attainment of very good partial remission or complete remission, high-dose melphalan ASCTs were performed after a median of 10 months. Kidney transplantation (living donor n = 3, deceased donor n = 2) with tacrolimus-based immunosuppression regimens was completed at a median of 27 months after ASCT. Patients 1 and 3 experienced relapse of myeloma at 6 and 16 months after kidney transplantation. Patients 2, 4 and 5 remain alive at 55 months (median) after kidney transplantation with no evidence of relapse.\nForty percent of our cohort experienced a relapse in MM within 2 years of kidney transplantation. Death-censored graft survival and patient survival were 80% at 4 years. Our study adds to the growing literature supporting kidney transplantation following successful ASCT for MM and is useful when counselling patients regarding renal and haematological outcomes.",
"affiliations": "King's College London, London, UK.;King's College Hospital NHS Trust, London, UK.;East Kent Hospital University NHS Foundation Trust, Kent, UK.;King's College Hospital NHS Trust, London, UK.;Cardiff and Vale University Health Board, Cardiff, UK.;Guy's and St Thomas' NHS Foundation Trust, London, UK.;King's College Hospital NHS Trust, London, UK.",
"authors": "Shah|Sapna|S|;Ibrahim|Maria|M|;Delaney|Michael|M|;Schey|Steve|S|;Bygrave|Ceri|C|;Streetly|Matthew|M|;Benjamin|Reuben|R|",
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"fulltext": "\n==== Front\nClin Kidney JClin Kidney JckjClinical Kidney Journal2048-85052048-8513Oxford University Press 10.1093/ckj/sfy137sfy137OnconephrologyRisk of relapse of multiple myeloma following kidney transplantation Shah Sapna 1Ibrahim Maria 2Delaney Michael 3Schey Steve 2Bygrave Ceri 4Streetly Matthew 5Benjamin Reuben 21 King’s College London, London, UK2 King’s College Hospital NHS Trust, London, UK3 East Kent Hospital University NHS Foundation Trust, Kent, UK4 Cardiff and Vale University Health Board, Cardiff, UK5 Guy’s and St Thomas’ NHS Foundation Trust, London, UKCorrespondence and offprint requests to: Sapna Shah; E-mail: sapna.shah@nhs.net4 2019 25 1 2019 25 1 2019 12 2 216 223 23 8 2018 18 12 2018 © The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA.2019This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nBackground\nAutologous stem cell transplantation (ASCT) and novel therapies have improved the prognosis for patients with multiple myeloma (MM). For those who undergo ASCT while on dialysis, a similar survival compared with the overall MM population has been reported. Therefore, for patients achieving remission following ASCT, kidney transplantation is an attractive option, offering an improved quality of life and significant economic advantage.\n\nMethod\nThis case series investigates the outcome of five patients who underwent an ASCT for MM with subsequent kidney transplantation between 2006 and 2012.\n\nResults\nFour patients presented with end-stage renal disease (ESRD) and one progressed to ESRD shortly after diagnosis. Induction chemotherapy regimens with novel agents including thalidomide and bortezomib were utilized. Following attainment of very good partial remission or complete remission, high-dose melphalan ASCTs were performed after a median of 10 months. Kidney transplantation (living donor n = 3, deceased donor n = 2) with tacrolimus-based immunosuppression regimens was completed at a median of 27 months after ASCT. Patients 1 and 3 experienced relapse of myeloma at 6 and 16 months after kidney transplantation. Patients 2, 4 and 5 remain alive at 55 months (median) after kidney transplantation with no evidence of relapse.\n\nConclusion\nForty percent of our cohort experienced a relapse in MM within 2 years of kidney transplantation. Death-censored graft survival and patient survival were 80% at 4 years. Our study adds to the growing literature supporting kidney transplantation following successful ASCT for MM and is useful when counselling patients regarding renal and haematological outcomes.\n\nautologous stem cell transplantationkidney transplantationmultiple myelomaoutcome\n==== Body\nINTRODUCTION\nMultiple myeloma (MM) is the second most common haematological malignancy, accounting for 1% of all cancers [1]. Induction chemotherapy with novel anti-myeloma agents followed by high-dose melphalan autologous stem cell transplantation (ASCT) remains the gold standard of therapy for younger patients with MM and has led to significantly increased progression-free and overall survival [2].\n\nEnd-stage renal disease (ESRD) has a substantial impact on morbidity and mortality [3]. Historically, patients with MM and ESRD had a 2.5 times higher relative risk of death relating to a higher tumour burden, lower tolerated chemotherapy doses and higher treatment-related mortality [4–6]. However, since the introduction of novel agents such as bortezomib, thalidomide and lenalidomide, there have been improvements in the rate of response even in patients with renal impairment [7, 8]. Furthermore, after ASCT, a similar survival for patients with ESRD compared with the overall MM population has been reported [1, 9].\n\nKidney transplantation improves survival compared with remaining on dialysis [5]. Previously, poor outcomes related to infection and disease progression in the context of immunosuppression were reported following kidney transplantation in patients with MM [10]. However, with current treatments and subsequent superior patient survival, successful kidney transplantation in patients with MM in remission is now possible [11].\n\nMATERIALS AND METHODS\nThis case series reports on the risk of relapse of MM of five patients after kidney transplantation in King’s College and Guys and St Thomas’ Hospitals, London, UK, between 2006 and 2012. The patients were defined as having very good partial remission (VGPR) or complete remission (CR) in concordance with International Myeloma Working Group consensus criteria [12]. Clinical information and data were collected from medical records. Induction immunosuppression following kidney transplantation consisted of with two doses of basiliximab 20 mg on the day of the transplant and four days later. Maintenance immunosuppression included tacrolimus or ciclosporin with mycophenolate mofetil and prednisolone. This study was exempted from approval from an ethics’ board.\n\nRESULTS\nCase reports\nThree subjects were male and two were female. Median age at diagnosis of MM was 54 years (range 37–64). All patients were Caucasian. Median duration of follow-up from the time of kidney transplantation was 55 months (range 48–56). Results are summarized in Table 1 and Figure 1.\nTable 1. Demographics, clinical characteristics, MM treatment course and renal transplant outcomes\n\n\tPatient 1\tPatient 2\tPatient 3\tPatient 4\tPatient 5\t\nDemographics\t\n Age (at time of diagnosis MM, years)\t63\t54\t37\t48\t64\t\n Sex\tM\tM\tM\tF\tF\t\n Ethnicity\tCaucasian\tCaucasian\tCaucasian\tCaucasian\tCaucasian\t\nTimeline\t\n Date of diagnosis of MM and presentation of renal disease\tDecember 2006\tJuly 2010\tMarch 2008\tMarch 2011\tMarch 2012\t\n Time from MM diagnosis to ASCT (months)\t25\t10\t11\t10\t10\t\n Time from ASCT to kidney transplantation (months)\t42\t33\t14\t27\t16\t\n Time from MM diagnosis to kidney transplantation (months)\t67\t43\t25\t37\t26\t\n Time from kidney transplantation to relapse (months)\t6\tN/A\t16\tN/A\tN/A\t\n Date of death\tFebruary 2016\tN/A\tApril 2014\tN/A\tN/A\t\n Time of follow-up from kidney transplantation (months)\t55\t53\t48\t56\t55\t\nDetails of MM\t\n Stage at diagnosis\tStage III ISS\tStage III ISS\tStage III ISS\tStage III ISS\tStage III ISS\t\n SFLC at diagnosis (mg/L)\tNot available at our hospital in 2006\tKappa 9.25\n\nLambda 23 400.00\n\nRatio <0.01\n\n\tKappa 2150.00\n\nLambda 18.50\n\nRatio 116.22\n\n\tKappa 3090.00\n\nLambda 18.10\n\nRatio 170.2\n\n\tKappa 7.97\n\nLambda 163.00\n\nRatio <0.01\n\n\t\n Bone marrow biopsy\t50% plasma cells, IgA Kappa\t90% plasma cells, Lambda Light Chain\t80% plasma cells, IgG Kappa\t5% plasma cells, non-secretory\t90% plasma cells, Lambda Light chain\t\n Chemotherapy pre-ASCT\tTD × 6\tCTD × 1\n\nVCD × 6\n\n\tCTD × 6\tTD × 6\tCTD × 1\n\nPAD × 2\n\nCVTD × 6\n\n\t\n Achieved VGPR/CR (months after diagnosis MM)\t25\t8\t11\t10\t10\t\n ASCT chemotherapy\tHDM 100 mg/m2\tHDM 140 mg/m2\tHDM 140 mg/m2\tHDM 140 mg/m2\tHDM 140 mg/m2\t\nDetails of relapse of MM\t\n First relapse of MM post ASCT (months)\t48\tNo, remains in CR\t30\tNo, remains in CR\tNo, remains in CR\t\n First relapse of MM post kidney transplantation (months)\t6\tN/A\t16\tN/A\tN/A\t\n SFLC at first relapse (mg/L)\tKappa 1488.00\n\nLambda 0.63\n\nRatio 2361.9\n\n\tN/A\tKappa 817.65\n\nLambda 16.89\n\nRatio 48.4\n\n\tN/A\tN/A\t\n Bone marrow biopsy at first relapse\t50% plasma cells\tN/A\tNot conducted\tN/A\tN/A\t\n Chemotherapy for first relapse\tVCD × 3\tN/A\tVCD × 5\n\nlenalidomide/dexamethasone\n\nbendamustine/bortezomib × 4\n\nCTD × 6\n\n\tN/A\tN/A\t\n Haematological response achieved after treatment of first relapse\tCR\tN/A\tVGPR\tN/A\tN/A\t\n Second relapse of MM post kidney transplantation (months)\t38\tN/A\t31\tN/A\tN/A\t\n SFLC at second relapse (mg/L)\tKappa 1464\n\nLambda 1.25\n\nRatio 1171.20\n\n\tN/A\tKappa 683.24\n\nLambda 15.80\n\nRatio 43.2\n\n\tN/A\tN/A\t\n Bone marrow biopsy at second relapse\t70% plasma cells\tN/A\tNot conducted\tN/A\tN/A\t\n Chemotherapy for second relapse\tBendamustine/dexamethasone × 7\tN/A\tMelphalan\tN/A\tN/A\t\n Adverse impacts of chemotherapy\tNo\tNo\tBortezomib – peripheral neuropathy\tNo\tBortezomib – peripheral neuropathy\t\nDetails of renal disease and transplantation\t\n Renal involvement at presentation of MM\tYes\tYes\tYes\tYes\tYes\t\n Renal biopsy results\tCast nephropathy\tCast nephropathy and tubule-interstitial nephritis\tCast nephropathy\tCast nephropathy\tCast nephropathy\t\n Type of renal allograft\tABO-incompatible, live related\tLive unrelated\tLive related\tDeceased DBD\tDeceased DBD\t\n HLA mismatch\t1-2-1\t1-2-1\t1-1-1\t0-0-0\t1-1-0\t\n Induction immunosuppression\t(Pre-transplant: 5 × sessions of double filtration plasmapheresis\n\nRituximab 375 mg/m2)\n\nBasiliximab\n\n\tBasiliximab\tBasiliximab\tBasiliximab\tBasiliximab\t\n Maintenance immunosuppression\tTacrolimus, MMF and prednisolone\tTacrolimus, MMF and prednisolone\tCiclosporin, MMF and prednisolone\tTacrolimus, MMF and prednisolone\tTacrolimus, MMF and prednisolone\t\n eGFR (mL/min) at:\t\t\t\t\t\t\n 1 year\t78\t63\t43\t15\t35\t\n 2 years\t76\t61\t38\tHaemodialysis\t38\t\n Last follow-up\t29\tHaemodialysis\t14\tHaemodialysis\t27\t\n UPCR (mg/mmol) at:\t\t\t\t\t\t\n Pre-transplant\t13\t19\tNot tested\tNot tested\tNot tested\t\n 1 year\t15\t13\t11\tNot tested\tNot tested\t\n 2 years\t48\t20\t35\tNot tested\tNot tested\t\nDBD, donation after brain death; F, female; M, male; ISS, International Staging System; HDM, high-dose melphalan; N/A, not applicable; MMF, mycophenolate mofetil; TD, thalidomide/dexamethasone.\n\n\n\nFIGURE 1 Timeline of diagnosis of MM to last follow-up.\n\nPatient 1\nA 63-year-old male presented with ESRD related to cast nephropathy and immunoglobulin A (IgA) Kappa-related MM and was treated with thalidomide and dexamethasone inducing a VGPR followed by ASCT 25 months after diagnosis of MM. An ABO-incompatible living-related donor kidney transplant was performed 42 months later. Pre-transplant treatment with double filtration plasmapheresis and a single dose of rituximab 375/m2 was administered to achieve anti-A1 titres of 1:8. MM relapse occurred 6 months after kidney transplantation and was treated with bortezomib, cyclophosphamide and dexamethasone (VCD) to CR. A second relapse, 32 months after the first relapse, was treated with bendamustine and dexamethasone. After the seventh cycle, he developed neutropenic sepsis related to H1N1 infection and chest infection with acute kidney injury requiring haemodialysis. Renal biopsy undertaken at this time demonstrated acute tubular necrosis with no evidence of myeloma-related kidney disease or rejection (no donor-specific antibody was detected, C4d stains were negative). His kidney function recovered to an estimated glomerular filtration rate (eGFR) of 29 mL/min but unfortunately, he died from pneumonia at 55 months after kidney transplantation.\n\nPatient 2\nA 54-year-old male presented with ESRD related to lambda light chain myeloma and was treated with cyclophosphamide, thalidomide and dexamethasone (CTD) followed by VCD achieving CR. An ASCT was performed 10 months after CR and 33 months later he received a living donor kidney transplant. Two years after kidney transplantation, his eGFR was 61 mL/min. During a routine clinic visit, 28 months after transplantation, a reduction in eGFR to 40 mL/min was detected. Renal biopsy confirmed cellular rejection (Banff Type IIA [13]) and chronic antibody-mediated rejection [donor-specific antibody present to HLA A1 (MFI 1999), B8 (MFI 4071), B38 (MFI 1822), DQB1*06:03 (MFI 5619), C4d stains positive]. Despite treatment with intravenous methylprednisolone, his renal function continued to decline, and he started dialysis 53 months after transplantation. He remains in CR and is currently being assessed for re-transplantation.\n\nPatient 3\nA 37-year-old male presented IgG kappa myeloma and ESRD as a consequence of cast nephropathy. He was treated with CTD achieving VGPR followed by ASCT 11 months after diagnosis. He underwent living donor kidney transplantation 14 months after ASCT.\n\nHe suffered a relapse of MM 16 months after kidney transplantation and was treated with VCD chemotherapy, which was limited by peripheral neuropathy. Serum-free light chains (SFLC) concentrations decreased but the response was short-lived, and he then received lenalidomide and dexamethasone. This was stopped after 2 weeks despite reduction in SFLC due to renal graft dysfunction. A biopsy confirmed cellular rejection (Banff Type IIB [13]) with features of acute antibody-mediated rejection although C4d stain was negative and no donor-specific antibody was detected. He was treated with intravenous methylprednisolone and Ig and plasma exchange. Renal function improved (eGFR 27 mL/min). He received bendamustine and bortezomib and then CTD to a VGPR. He subsequently experienced a second relapse, 15 months after the first relapse in association with a decline in eGFR to 17 mL/min. Melphalan (25 mg/m2) and dexamethasone were commenced but not tolerated. Unfortunately, the patient experienced a myocardial infarction and cardiorespiratory arrest resulting in death at 48 months after kidney transplantation with a eGFR of 14 mL/min.\n\nPatient 4\nA 48-year-old female was diagnosed with a non-secretory Kappa light chain myeloma and cast nephropathy. Her eGFR was 15 mL/min, and she received thalidomide and dexamethasone to CR, followed by ASCT 10 months later. She developed ESRD 1 month after presentation with MM and underwent deceased donor kidney transplantation 27 months after ASCT. Her transplant function remained suboptimal and a biopsy confirmed cellular rejection (Banff Type IIA [13]), which was treated with intravenous methylprednisolone. A subsequent biopsy showed ongoing cellular rejection. A second course of intravenous methylprednisolone was administered and a further biopsy showed resolution of the rejection but evidence of calcineurin-inhibitor toxicity. Her eGFR at 1 year after transplantation was 15 mL/min, and she recommenced haemodialysis 24 months after transplantation. She is currently listed for further renal transplantation but remains in CR 56 months after kidney transplantation.\n\nPatient 5\nA 64-year-old female presented with Lambda light chain myeloma and cast nephropathy requiring dialysis. She was treated with bortezomib, adriamycin and dexamethasone (PAD), cyclophosphamide, bortezomib and thalidomide (CVTD) followed by CTD as she developed bortezomib-related peripheral neuropathy. She achieved a VGPR and underwent ASCT 10 months after diagnosis of MM and then deceased donor kidney transplantation 166 months after ACST. Her eGFR is 27 mL/min at 55 months after kidney transplantation and she remains in CR.\n\nDISCUSSION\nThis study describes the outcome of patients who underwent kidney transplantation following ASCT for MM. ASCTs for MM were performed after a median of 10 months (range 10–25) following diagnosis of MM. Kidney transplantation was performed at a median of 27 months after ASCT (range 16–42). Three patients did not experience relapse of MM with median follow-up period of 55 months (range 53–56) after kidney transplantation. Two patients experienced relapse of myeloma at a median of 11 months after kidney transplantation. These two patients died at a median of 52 months after kidney transplantation. Patient 1 received an ABO-incompatible transplant and therefore received additional immunosuppressive treatment with plasmapheresis and rituximab. It is conceivable that this contributed to the early relapse of MM. However, this relapse was successfully treated to CR and the patient developed a second relapse 38 months after kidney transplantation. The first relapse for Patient 3 was also treated to VGPR and he remained in remission for a further 15 months. Both patients died with a functioning renal transplant at a median of 52 months after transplantation.\n\nFor the two of the three patients who remain in CR, the transplant failed at a median of 39 months after transplantation. Graft loss in both cases was attributed to rejection. Of note, treatment of the rejection episodes was not de-escalated due to the history of MM.\n\nThis case series report contributes to the small number of case series that have previously been reported in patients with MM treated with contemporary chemotherapeutic regimens with successful outcomes following kidney transplantation (Table 2). Lum et al. reported on two patients who received bortezimib-based treatments and continued with fortnightly bortezomib after kidney transplantation [10]. Induction immunosuppression for kidney transplantation consisted of basiliximab, similar to our patient cohort. At 25 and 13 months, both patients remain in remission with serum creatinine of 1–2 mg/dL. Hassoun et al. reported on two patients treated with thalidomide, dexamethasone, melphalan and doxorubicin followed by ASCT and kidney transplantation 14.1 and 45.7 months after achieving CR [14]. At 21.8 and 24.1 months, respectively, both patients remain in remission with functioning renal allografts. Sánchez Quintana et al. reported on two patients treated with lenalidomide followed by ASCT and then kidney transplantation [15]. At 48 and 36 months, both patients remain in remission with functioning renal allografts. Le et al. reported on four patients treated with bortezomib, lenalidomide, cyclophosphamide and thalidomide followed by ASCT and then kidney transplantation at between 20 and 66 months after remission [16]. At between 16 and 58 months of follow-up, the patients have an eGFR of 59–73 mL/min. Two patients continued with maintenance therapy of lenalidomide or bortezomib and one patient relapsed but was treated successfully with carfilzomib, cyclophosphamide and dexamethasone. It is interesting to note that the patient who relapsed received antithymocyte induction in the context of ABO-incompatible transplantation. In summary for these case series, the median time to transplant from remission was 39 months and median follow-up after transplantation was 31 months. Only one patient suffered with a relapse but that was treated successfully to CR. Patient and kidney transplant survival was 100% with no episodes of rejection reported. One patient developed BK viraemia necessitating a reduction in immunosuppression.\nTable 2. Published case reports of renal transplantation in patients treated with autologous stem cell transplantation for multiple myeloma\n\nReference\tPatient demographics\tNative kidney biopsy\tMM treatment\tTime to kidney transplant after remission (months)\tType of kidney transplant and immunosuppression\tLast follow-up after kidney transplant (months)\tHaematological response at last follow-up\teGFR at last follow-up (mL/min)\t\nLum et al. [10]\t67-year-old male\tNo biopsy but renal disease thought to be hypertensive nephrosclerosis.\tDexamethasone/bortezomib; bortezomib maintenance\t12\tLiving unrelated transplant with basiliximab induction and maintenance with tacrolimus, mycophenolic acid and prednisolone and then ciclosporin and prednisolone (due to BK viraemia)\t25\tCR\t34\t\n62-year-old female\tCast nephropathy\tPlasmapheresis; dexamethasone/bortezomib; bortezomib maintenance\t24\tLiving unrelated transplant with basiliximab induction and maintenance with tacrolimus and prednisolone\t13\tCR\t60\t\nHassoun et al. [13]\t42-year-old male\tLCDD\tThalidomide/dexamethasone; dexamethasone; melphalan/dexamethasone/ doxorubicin/dexamethasone; cyclophosphamide mobilization; melphalan conditioning; ASCT\t14\tNo details given\t22\tCR\tNormal\t\n\t51-year-old female\tLCDD\tThalidomide/dexamethasone; dexamethasone; melphalan/dexamethasone/ doxorubicin/dexamethasone; cyclophosphamide mobilization; melphalan conditioning; ASCT\t46\tNo details given\t24\tCR\tNormal\t\nSánchez Quintana et al. [14]\t38-year-old male\tLCDD\tDexamethasone; ASCT; lenalidomide maintenance\t48\tDeceased donor transplantation (DBD); no induction details given; maintenance with tacrolimus and prednisolone\t48\tCR\tNot given\t\n\t44-year-old female\tNo biopsy\tVincristine/adriamycin/dexamethasone; ASCT; maintenance with thalidomide then lenalidomide\t48\tDeceased donor transplantation (DBD); no induction details given; maintenance with tacrolimus and prednisolone\t36\tVGPR\tNot given\t\nLe et al. [15]\t52-year-old male\tLCDD with cryoglobul-inaemic GN\tPlasmapheresis, thalidomide/dexamethasone; vincristine/doxil/dexamethasone; cyclophosphamide mobilization; melphalan conditioning then ASCT\t66\tNo details given\t58\tCR\t73\t\n\t50-year-old male\tNo biopsy\tBortezomib/dexamethasone; lenalidomide/ doxorubicin/cyclophosphamide/dexamthasone; melphalan conditioning then ASCT lenalidamide followed by bortezomib maintenance; lenalidomide/dexamethasone (progression); carfilzomid/cyclophosphamide/dexamethasone; pomalidomide/cyclophosphamide/dexamethasone\t20\tABO-incompatible kidney transplant with antithymocyte globulin induction\t48\tSD\t59\t\n\t50-year-old male\tLCDD\tBortezomib/dexamethasone/lenalidomide; melphalan conditioning then ASCT; lenalidomide, then bortezomib maintenance\t32\tNo transplant details given; no induction details given; maintenance with tacrolimus, mycophenolic acid and prednisolone\t43\tCR\t59\t\n\t47-year-old male\tNo biopsy\tBortezomib/dexamethasone/lenalidomide; cyclophosphamide mobilization; melphalan conditioning then ASCT; lenalidamide maintenance\t53\tNo transplant details given with basiliximab induction and maintenance with tacrolimus and mycophenolic acid\t16\tCR\t60\t\nSD, stable disease; LCDD, light chain deposition disease; DBD, donation after brain death; GN, glomerulonephropathy.\n\n\n\nIn comparison with the published case series, our patients were transplanted 12 months earlier after ASCT and we have follow-up data for a further 21 months. In this study, all the patients had renal disease attributable to cast nephropathy and received an ASCT. The only patient that experienced relapse of MM also received intensive induction immunosuppression for an ABO-incompatible transplant. In our case series, the relapse rate was increased with inferior patient and graft survival compared with previous cases. Our 4-year death-censored graft survival was 80% and 4-year patient survival after transplantation was 80%. Of note, our patients did not receive maintenance chemotherapy after kidney transplantation, and our patients had longer follow-up, and these factors may account for the differences observed.\n\nTreatment of relapsed myeloma remains challenging. In our series, both patients were treated effectively for the first relapse resulting in disease-free interval of 24 months (median). However, treatment of the second relapse was not successful. Patient 3 was treated with lenalidomide, which can precipitate kidney transplant rejection [17, 18], and therefore perhaps these agents should be avoided. However, others have reported maintenance as well as treatment for relapse with lenalidomide without adverse impact to the transplant kidney (Table 2). In addition, sepsis is the second most common cause of death following kidney transplantation [19]. Relapse of myeloma confers an additional risk of sepsis related to immunoparesis and chemotherapy. Careful consideration of immunosuppression regimens and immunological risk of the transplant, to avoid sepsis and minimize the risk of kidney transplant rejection, is imperative.\n\nThe main limitation of our study is the small number of patients and therefore caution must be applied when considering the relapse rate and graft outcome data. However, the strength is the length of follow-up. Our study supports kidney transplantation as the preferred treatment for ESRD following successful ASCT for MM and is useful when counselling patients regarding outcomes following kidney transplantation after MM. Furthermore, there are emerging novel agents that are suitable to be employed in ESRD which may improve the depth of response prior to transplant and can be employed to treat relapse following transplantation.\n\nEuropean Best Practice Guidelines advise a waiting period of 2 years between successful induction treatment and renal transplantation [20]. In the future, it may be possible to risk-stratify and select a subgroup of patients with myeloma who are predicted to have a deep response following ASCT [12], and these patients with a better prognosis could be considered for earlier kidney transplantation. However, further evidence is needed to support this [21]. Uncertainty remains around the role of continuing chemotherapy after kidney transplantation to prevent relapse and the optimal treatment of relapsed MM.\n\nWe have presented a case series of five patients submitted for renal transplantation after ASCT and CR of MM and demonstrated that 40% of our cohort experienced a relapse in MM within 2 years of kidney transplantation. Death-censored graft survival and patient survival was 80% at 4 years. From our experience, we suggest avoiding transplantation from donors, which would require intensive immunosuppression and immunomodulatory chemotherapy agents to reduce the risk of MM relapse and renal rejection.\n\nCONFLICT OF INTEREST STATEMENT\nNo disclosures or conflicts of interest for all authors. The results presented in this article have not been published previously in whole or part, except in abstract format.\n==== Refs\nREFERENCES\n1 \nBaraldi O , Grandinetti V , Donati G \net al\nHematopoietic cell and renal transplantation in plasma cell dyscrasia patients . Cell Trans 2015 ; 25 : 995 –1005 \n2 \nJurczyszyn A , Nahi H , Avivi I \net al\nCharacteristics and outcomes of patients with multiple myeloma aged 21–40 years versus 41–60 years: a multi-institutional case-control study . Br J Haematol 2016 ; 175 : 884 –891 27682187 \n3 \nAugustson BM , Begum G , Dunn JA \net al\nEarly mortality after diagnosis of multiple myeloma: analysis of patients entered onto the United Kingdom Medical Research Council trials between 1980 and 2002 - Medical Research Council Adult Leukaemia Working Party . J Clin Oncol 2005 ; 23 : 9219 –9226 16275935 \n4 \nAbbott KC , Agodoa LY. \nMultiple myeloma and light chain-associated nephropathy at end-stage renal disease in the United States: patient characteristics and survival . Clin Nephrol 2001 ; 56 : 207 –210 11597035 \n5 \nTsakiris DJ , Stel VS , Finne P \net al\nIncidence and outcome of patients starting renal replacement therapy for end-stage renal disease due to multiple myeloma or light-chain deposit disease: an ERA-EDTA Registry study . Nephrol Dial Transplant 2009 ; 25 : 1200 –1206 20037169 \n6 \nKorbet SM , Schwartz MM. \nMultiple myeloma . J Am Soc Nephrol 2006 ; 17 : 2533 –2545 16885408 \n7 \nLudwig H , Adam Z , Greil R. \nReversal of acute renal impairment by bortezomib-doxorubicin-dexamethasone in multiple myeloma. Results from a phase II study . Haematologica 2009 ; 94 (Suppl) : 154 , Abstr 38519118377 \n8 \nTosi P , Zamagni E , Cellini C \net al\nThalidomide alone or in combination with dexamethasone in patients with advanced, relapsed or refractory multiple myeloma and renal failure . Eur J Haematol 2004 ; 73 : 98 –103 15245508 \n9 \nFloro L , Lazana I , Streetly M \net al\nRetrospective analysis of the impact of kidney function on the outcomes of first autografts for de novo myeloma patients in the era of novel agents . Clin Lymphoma Myeloma Leuk 2015 ; 15 : e160 –e161 \n10 \nLum EL , Kogut N , Pham T \net al\nKidney transplantation in patients with active multiple myeloma: case reports . Transplant Direct 2017 ; 3 : e200 28795151 \n11 End-Stage Renal Disease in the United States. U.S. Renal Data System (USRDS) Annual Report 2012 \nhttps://www.usrds.org/2012/pdf/v2_ch7_12.pdf (4 January 2019, date last accessed)\n12 \nChng WJ , Dispenzieri A , Chim C-S \net al\nIMWG consensus on risk stratification in multiple myeloma . Leukemia 2014 ; 28 : 269 –277 23974982 \n13 \nHaas M , Loupy A , Lefaucheur C \net al\nThe Banff 2017 Kidney Meeting Report: Revised diagnostic criteria for chronic active T cell-mediated rejection, antibody-mediated rejection, and prospects for integrative endpoints for next-generation clinical trials . Am J Transplant 2018 ; 18 : 293 –307 29243394 \n14 \nHassoun H , Flombaum C , D'Agati VD \net al\nHigh-dose melphalan and auto-SCT in patients with monoclonal Ig deposition disease . Bone Marrow Transplant 2008 ; 42 : 405 –412 18574442 \n15 \nSánchez Quintana A , Rull PR , Atienza JB \net al\nRenal transplant in plasma cell dyscrasias with lenalidomide treatment after autologous stem cell transplantation . Nephrology 2013 ; 18 : 641 –643 23980813 \n16 \nLe TX , Wolf JL , Peralta CA \net al\nKidney transplantation for kidney failure due to multiple myeloma: case reports . Am J Kidney Dis 2017 ; 69 : 858 –862 28320553 \n17 \nLum EL , Huang E , Bunnapradist S \net al\nAcute kidney allograft rejection precipitated by lenalidomide treatment for multiple myeloma . Am J Kidney Dis 2017 ; 69 : 701 –704 28189378 \n18 \nWalavalkar V , Adey DB , Laszik ZG \net al\nSevere renal allograft rejection resulting from lenalidomide therapy for multiple myeloma: case report . Transplant Proc 2018 ; 50 : 873 –876 29661456 \n19 \nYalci A , Celebi ZK , Ozbas B \net al\nEvaluation of infectious complications in the first year after kidney transplantation . Transplant Proc 2015 ; 47 : 1429 –1432 26093735 \n20 EBPG (European Expert Group on Renal Transplantation); European Renal Association (ERA-EDTA); European Society for Organ Transplantation (ESOT). \nEuropean Best Practice Guidelines for Renal Transplantation (Part 1) . Nephrol Dial Transplant 2000 ; 15 (Suppl 7) : 1 –85 \n21 \nBansal T , Garg A , Snowden JA \net al\nDefining the role of renal transplantation in the modern management of multiple myeloma and other plasma cell dyscrasias . Nephron Clin Pract 2012 ; 120 : c228 –c235 23051666\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2048-8505",
"issue": "12(2)",
"journal": "Clinical kidney journal",
"keywords": "autologous stem cell transplantation; kidney transplantation; multiple myeloma; outcome",
"medline_ta": "Clin Kidney J",
"mesh_terms": null,
"nlm_unique_id": "101579321",
"other_id": null,
"pages": "216-223",
"pmc": null,
"pmid": "30976399",
"pubdate": "2019-04",
"publication_types": "D016428:Journal Article",
"references": "11286185;11597035;15245508;16275935;16885408;18574442;20037169;23051666;23974982;23980813;26093735;26160700;27682187;28189378;28320553;28795151;29243394;29661456",
"title": "Risk of relapse of multiple myeloma following kidney transplantation.",
"title_normalized": "risk of relapse of multiple myeloma following kidney transplantation"
} | [
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"companynumb": "GB-ASPEN-GLO2019GB008087",
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"activesubstancename": "BENDAMUSTINE"
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{
"abstract": "Autosomal recessive (AR) STAT1 deficiency is a severe inborn error of immunity disrupting cellular responses to type I, II, and III IFNs, and IL-27, and conferring a predisposition to both viral and mycobacterial infections. We report the genetic, immunological, and clinical features of an international cohort of 32 patients from 20 kindreds: 24 patients with complete deficiency, and 8 patients with partial deficiency. Twenty-four patients suffered from mycobacterial disease (bacillus Calmette-Guérin = 13, environmental mycobacteria = 10, or both in 1 patient). Fifty-four severe viral episodes occurred in sixteen patients, mainly caused by Herpesviridae viruses. Attenuated live measles, mumps, and rubella and/or varicella zoster virus vaccines triggered severe reactions in the five patients with complete deficiency who were vaccinated. Seven patients developed features of hemophagocytic syndrome. Twenty-one patients died, and death was almost twice as likely in patients with complete STAT1 deficiency than in those with partial STAT1 deficiency. All but one of the eight survivors with AR complete deficiency underwent hematopoietic stem cell transplantation. Overall survival after hematopoietic stem cell transplantation was 64%. A diagnosis of AR STAT1 deficiency should be considered in children with mycobacterial and/or viral infectious diseases. It is important to distinguish between complete and partial forms of AR STAT1 deficiency, as their clinical outcome and management differ significantly.",
"affiliations": "Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Paris, France; jacinta.bustamante@inserm.fr levoyertom@gmail.com.;Department of Pediatrics, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.;Department of Pediatrics, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.;Division of Translational Medicine, Sidra Medicine, Doha, Qatar.;Clinical Immunology and Primary Immunodeficiencies Unit, Pediatric Allergy and Clinical Immunology Department, and Functional Unit of Immunology, Sant Joan de Déu Hospital, Institut de Recerca Sant Joan de Déu, University of Barcelona, Barcelona, Spain.;Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.;Department of Pediatrics, Pediatric Allergy and Immunology Unit, Kayseri Education and Research Hospital, Erkilet, Kayseri, Turkey.;Department of Pediatric Immunology, Bai Jerbai Wadia Hospital for Children, Mumbai, India.;Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Paris, France.;Department of Clinical Immunology, Aarhus University Hospital, Aarhus N, Denmark.;Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.;Sheikh Khalifa Medical City-Union71, Abu Dhabi and Department of Immunology, College of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates.;Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Paris, France.;Department of Pediatrics, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.;Department of Pediatrics, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.;Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Paris, France.;Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Paris, France.;Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Paris, France.;Clinical Immunology and Primary Immunodeficiencies Unit, Pediatric Allergy and Clinical Immunology Department, and Functional Unit of Immunology, Sant Joan de Déu Hospital, Institut de Recerca Sant Joan de Déu, University of Barcelona, Barcelona, Spain.;Pediatric Hematology and Oncology Unit, Istinye University, School of Medicine, İstanbul, Turkey.;Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Paris, France.;Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Paris, France.;Pediatric İnfectious Disease Unit, Department of Pediatrics, Kayseri Education and Research Hospital, Erkilet, Kayseri, Turkey.;Sheikh Khalifa Medical City-Union71, Abu Dhabi and Department of Immunology, College of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates.;Sheikh Khalifa Medical City-Union71, Abu Dhabi and Department of Immunology, College of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates.;Molecular Biology Laboratory, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.;Department of Virology, Cochin Hospital, University of Paris, Assistance Publique Hôpitaux de Paris, Paris, France.;Center for Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.;Department of Pediatric Hematology and Oncology, University Hospital Bonn, Bonn, Germany.;Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.;Pediatric Department, Security Forces Hospital, Riyadh, Saudi Arabia.;Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.;Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.;Department of Immunology, The Royal Children's Hospital, Melbourne, Australia.;Division of Allergy & Immunology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL.;Department of Paediatric Allergy and Immunology, Lydia Becker Institute of Immunology and Inflammation, Royal Manchester Children's Hospital, University of Manchester, Manchester, United Kingdom.;Institute of Molecular Medicine Angelo Nocivelli, University of Brescia, Civil Hospital of Brescia, Brescia, Italy.;Clinical Immunology and Primary Immunodeficiencies Unit, Pediatric Allergy and Clinical Immunology Department, and Functional Unit of Immunology, Sant Joan de Déu Hospital, Institut de Recerca Sant Joan de Déu, University of Barcelona, Barcelona, Spain.;Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Paris, France.;Department of Pediatric Immunology, Bai Jerbai Wadia Hospital for Children, Mumbai, India.;Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.;Department of Clinical Immunology and Allergy, Center for Pediatric Hematology, Oncology and Immunology, Moscow, Russia.;Division of Translational Medicine, Sidra Medicine, Doha, Qatar.;Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Paris, France.;Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Paris, France.;Department of Pediatrics, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.;Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Paris, France; jacinta.bustamante@inserm.fr levoyertom@gmail.com.",
"authors": "Le Voyer|Tom|T|;Sakata|Sonoko|S|;Tsumura|Miyuki|M|;Khan|Taushif|T|https://orcid.org/0000-0002-7917-8965;Esteve-Sole|Ana|A|https://orcid.org/0000-0002-0542-0587;Al-Saud|Bandar K|BK|;Gungor|Hatice Eke|HE|https://orcid.org/0000-0002-0102-8123;Taur|Prasad|P|;Jeanne-Julien|Valentine|V|;Christiansen|Mette|M|https://orcid.org/0000-0001-5158-3670;Köhler|Lisa-Maria|LM|;ElGhazali|Gehad Eltayeb|GE|;Rosain|Jérémie|J|https://orcid.org/0000-0002-2822-161X;Nishimura|Shiho|S|;Sakura|Fumiaki|F|;Bouaziz|Matthieu|M|;Oleaga-Quintas|Carmen|C|https://orcid.org/0000-0002-6057-0959;Nieto-Patlán|Alejandro|A|https://orcid.org/0000-0002-8668-6853;Deyà-Martinez|Àngela|À|;Altuner Torun|Yasemin|Y|;Neehus|Anna-Lena|AL|https://orcid.org/0000-0002-8573-6820;Roynard|Manon|M|https://orcid.org/0000-0003-0668-002X;Bozdemir|Sefika Elmas|SE|;Al Kaabi|Nawal|N|https://orcid.org/0000-0003-2180-4158;Al Hassani|Moza|M|;Mersiyanova|Irina|I|https://orcid.org/0000-0003-0471-2956;Rozenberg|Flore|F|;Speckmann|Carsten|C|;Hainmann|Ina|I|;Hauck|Fabian|F|https://orcid.org/0000-0001-9644-2003;Alzahrani|Mohammed Hamdan|MH|;Alhajjar|Sami Hussain|SH|https://orcid.org/0000-0003-4664-9748;Al-Muhsen|Saleh|S|;Cole|Theresa|T|https://orcid.org/0000-0002-8272-4074;Fuleihan|Ramsay|R|;Arkwright|Peter D|PD|https://orcid.org/0000-0002-7411-5375;Badolato|Raffaele|R|;Alsina|Laia|L|https://orcid.org/0000-0002-3559-0018;Abel|Laurent|L|;Desai|Mukesh|M|;Al-Mousa|Hamoud|H|;Shcherbina|Anna|A|https://orcid.org/0000-0002-3113-4939;Marr|Nico|N|;Boisson-Dupuis|Stéphanie|S|;Casanova|Jean-Laurent|JL|;Okada|Satoshi|S|;Bustamante|Jacinta|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.4049/jimmunol.2001451",
"fulltext": null,
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"issn_linking": "0022-1767",
"issue": null,
"journal": "Journal of immunology (Baltimore, Md. : 1950)",
"keywords": null,
"medline_ta": "J Immunol",
"mesh_terms": null,
"nlm_unique_id": "2985117R",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34183371",
"pubdate": "2021-06-28",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Genetic, Immunological, and Clinical Features of 32 Patients with Autosomal Recessive STAT1 Deficiency.",
"title_normalized": "genetic immunological and clinical features of 32 patients with autosomal recessive stat1 deficiency"
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"companynumb": "FR-SA-2021SA238462",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
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"activesubstancename": "FLUDARABINE PHOSPHATE"
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{
"abstract": "miR-26a-5p is a short noncoding RNA that is abnormally expressed in drug-induced liver injury (DILI), but its pathophysiologic role in the mechanism of disease in DILI is still vague.\nThe expression of miR-26a-5p, viability of hepatic stellate cells (HSCs) proliferation, and apoptosis were explored via real-time PCR, CCK-8 assay, Tunel fluorescence, and flow cytometry. The expression of Bid was detected via Western blot assays, real-time PCR, and immunofluorescence. The apoptosis-associated proteins were determined through Western blot. The interaction between miR-26a-5p and Bid was measured via Dual luciferase reporter assay.\nmiR-26a-5p expression was greatly decreased in HSCs and serum treated with azithromycin, simvastatin and diclofenac sodium, respectively. Hepatocyte viability was largely suppressed while hepatocyte apoptosis was markedly increased in DILI. Correspondingly, the apoptosis-associated proteins including Bid, caspase-8 and cytochrome C in HSCs were significantly upregulated when treated with either of these drugs. Moreover, miR-26a-5p interacted with Bid, and hepatocyte proliferation and apoptosis influenced by miR-26a-5p mimics were obviously reversed when co-treated with overexpressed Bid plasmids.\nmiR-26a-5p played a protective role against DILI via targeting Bid.",
"affiliations": "Department of Geriatrics, the third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.;Department of Geriatrics, the third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.;Department of Neurology, The Gucheng County Hospital of Hebei Province, Hebei, China.;Department of Geriatrics, the third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.;Department of Geriatrics, the third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.;Department of Infectious Diseases, the third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.;Department of Geriatrics, the third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.",
"authors": "Zhang|Qian|Q|;Liu|Yan|Y|;Yuan|Yujie|Y|;Yao|Feifei|F|;Zhang|Hongmei|H|;Zhao|Caiyan|C|;Luo|Yanli|Y|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/15376516.2021.2003919",
"fulltext": null,
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"issn_linking": "1537-6516",
"issue": null,
"journal": "Toxicology mechanisms and methods",
"keywords": "bid; caspase-8; cytochrome C; drug-induced liver injury; miR-26-5p",
"medline_ta": "Toxicol Mech Methods",
"mesh_terms": null,
"nlm_unique_id": "101134521",
"other_id": null,
"pages": "1-8",
"pmc": null,
"pmid": "34749575",
"pubdate": "2021-11-25",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "miR-26a-5p protects against drug-induced liver injury via targeting bid.",
"title_normalized": "mir 26a 5p protects against drug induced liver injury via targeting bid"
} | [
{
"companynumb": "CN-ORGANON-O2112CHN001626",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
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"activesubstance": {
"activesubstancename": "SIMVASTATIN"
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... |
{
"abstract": "Autoimmune thyroid disease may occasionally associate with unspecific neurological symptoms, which are more commonly insidious, include cognitive or behavioural symptoms, and may associate with tremor, myoclonus, or ataxia. We report a 61-year-old female patient who presented with chronic headache, insidious mood, and cognitive disturbance which evolved in a few months to dementia associated with exuberant limb myoclonus. Diagnostic workup revealed high anti-thyroid peroxidase antibody titers and an inflammatory CSF profile, and it was negative for other possible etiologies. Treatment with steroids induced significant improvement. The diagnosis of encephalopathy associated with autoimmune thyroid disease is still controversial given the fact that the clinical presentation and diagnostic workup are unspecific, the pathophysiology is still undetermined, and the diagnosis is mostly of exclusion. No direct correlation is found between anti-thyroid antibody titers and clinical presentation, and it is currently speculated that other still unrecognized antibodies may be responsible for this clinical entity. It is extremely important to recognize this entity because it is potentially treatable with immunotherapies. It is also increasingly recognized that clinical improvement with first-line treatment with steroids may be absent or incomplete, and other immunotherapies as immunosuppressants, intravenous immunoglobulin, or plasma exchange must be attempted in the clinical suspicion of EEAT.",
"affiliations": "Department of Neurology, Centro Hospitalar e Universitário de Coimbra, Praceta Professor Mota Pinto, 3000-075 Coimbra, Portugal.;Department of Neurology, Centro Hospitalar e Universitário de Coimbra, Praceta Professor Mota Pinto, 3000-075 Coimbra, Portugal.;Department of Internal Medicine, Centro Hospitalar e Universitário de Coimbra, Praceta Professor Mota Pinto, 3000-075 Coimbra, Portugal.;Department of Neurology, Centro Hospitalar e Universitário de Coimbra, Praceta Professor Mota Pinto, 3000-075 Coimbra, Portugal.",
"authors": "Correia|Inês|I|;Marques|Inês B|IB|;Ferreira|Rogério|R|;Sousa|Lívia|L|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2016/9183979",
"fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIMCase Reports in Medicine1687-96271687-9635Hindawi Publishing Corporation 10.1155/2016/9183979Case ReportEncephalopathy Associated with Autoimmune Thyroid Disease: A Potentially Reversible Condition Correia Inês \n1\n\n*\nMarques Inês B. \n1\nFerreira Rogério \n2\nSousa Lívia \n1\n1Department of Neurology, Centro Hospitalar e Universitário de Coimbra, Praceta Professor Mota Pinto, 3000-075 Coimbra, Portugal2Department of Internal Medicine, Centro Hospitalar e Universitário de Coimbra, Praceta Professor Mota Pinto, 3000-075 Coimbra, Portugal*Inês Correia: mcorreia.ines@gmail.comAcademic Editor: Di Lazzaro Vincenzo\n\n2016 5 4 2016 2016 918397923 12 2015 13 3 2016 22 3 2016 Copyright © 2016 Inês Correia 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.Autoimmune thyroid disease may occasionally associate with unspecific neurological symptoms, which are more commonly insidious, include cognitive or behavioural symptoms, and may associate with tremor, myoclonus, or ataxia. We report a 61-year-old female patient who presented with chronic headache, insidious mood, and cognitive disturbance which evolved in a few months to dementia associated with exuberant limb myoclonus. Diagnostic workup revealed high anti-thyroid peroxidase antibody titers and an inflammatory CSF profile, and it was negative for other possible etiologies. Treatment with steroids induced significant improvement. The diagnosis of encephalopathy associated with autoimmune thyroid disease is still controversial given the fact that the clinical presentation and diagnostic workup are unspecific, the pathophysiology is still undetermined, and the diagnosis is mostly of exclusion. No direct correlation is found between anti-thyroid antibody titers and clinical presentation, and it is currently speculated that other still unrecognized antibodies may be responsible for this clinical entity. It is extremely important to recognize this entity because it is potentially treatable with immunotherapies. It is also increasingly recognized that clinical improvement with first-line treatment with steroids may be absent or incomplete, and other immunotherapies as immunosuppressants, intravenous immunoglobulin, or plasma exchange must be attempted in the clinical suspicion of EEAT.\n==== Body\n1. Introduction\nEncephalopathy associated with autoimmune thyroid disease (EAAT) is a rare clinical entity, which presents with unspecific neurological symptoms. The clinical presentation is more frequently insidious, with cognitive and behavioural disturbance that may associate with tremor, myoclonus, or ataxia. More rarely, clinical onset may be acute as stroke-like episodes, epilepsy, or psychosis [1–6].\n\nDiagnostic investigation is usually unspecific and there is no direct correlation between thyroid hormone levels or anti-thyroid antibody titers and the clinical presentation [1–3]. The current diagnostic criteria are based on the association of neurological or psychiatric symptoms, presence of anti-thyroid antibodies, exclusion of other possible causes, and significant improvement with immunotherapies [7], which make this entity mostly a diagnosis of exclusion.\n\nWe report a 61-year-old female patient who presented with chronic headache, insidious mood, and cognitive disturbance evolving to rapidly progressive dementia with exuberant limb myoclonus. Diagnostic workup identified high anti-thyroid antibody titers and excluded other causes, leading to diagnosis of EAAT. Significant improvement was achieved with steroid treatment.\n\nWith this paper we underline the importance of considering EAAT when approaching patients with rapidly progressive neurological or psychiatric symptoms, since it is a potentially reversible condition with appropriate treatment.\n\n2. Case Report\nWe report a 61-year-old Caucasian woman who first presented to our Neurology Emergency Department in March 2012 complaining of severe chronic daily headache. The headache was started 9 months before and was described as bilateral, with pressing-type quality, without associated symptoms such as nausea, photophobia, or phonophobia, and did not worsen with recumbency, exercise, or Valsalva manoeuvres. The patient also presented apathy with progressive loss of interest in life for 18 months and had already been evaluated by a Psychiatrist who diagnosed depressive syndrome given that these features immediately followed the return to her country after 40 years living abroad, leaving behind her children and grandchildren. However, despite antidepressive treatment, she presented gradual worsening and became unable to perform her usual activities of daily living without supervision (such as cooking, using the telephone, handling money, and taking her medication) and she spent most days in bed in the last three months. The patient also complained of upper limb tremor with left predominance for the same period.\n\nShe had history of arterial hypertension, dyslipidemia, and hypothyroidism due to Hashimoto's thyroiditis chronically treated with levothyroxine. There was no history of recent or chronic infections or toxic exposure. Familial medical history was unremarkable.\n\nThe general physical examination was normal. The neurological examination revealed cognitive impairment with Mini Mental State Examination of 23 points (3 years of education). She presented frontal functions impairment with low verbal fluency, perseveration, impairment of abstract thinking, and signs of frontal release, namely, glabellar reflex. Visuospatial impairment was also observed with inability to copy a drawing or perform the clock-drawing test. An upper limb rest and postural tremor with left predominance was identified, without other focal signs in the neurological examination.\n\nA brain computerized tomography (CT) and blood analysis were performed in the Emergency Department with normal results. On discharge a follow-up appointment was planned for dementia study. In the next weeks, a rapidly progressive neurological deterioration occurred; the patient became unable to walk and totally dependent and presented exuberant myoclonus in the distal upper limbs, so she was admitted for more investigations.\n\nExtensive blood workup including full blood count, coagulation study, liver function test, creatinine, erythrocyte sedimentation rate, c-reactive protein, protein electrophoresis, vitamin B12, folic acid, thyroid function, and serologies (Treponema pallidum, Brucella spp., Borrelia burgdorferi, Coxiella burnetii, Rickettsia conorii, HIV, and hepatitis B and C) was normal. Study of systemic autoimmunity, including antinuclear antibodies, anti-ds-DNA, anti-SSA, anti-SSB, anti-RNP, anti-Scl70, anti-Jo1, anti-neutrophil cytoplasmic antibodies, and anti-thyroid antibodies, revealed only high titers of anti-thyroid peroxidase antibodies (anti-TPO antibodies) equal to 1008 UI/mL (normal <40 UI/mL). Onconeural antibodies (anti-Hu, anti-Ri, anti-Yo, anti-amphiphysin, anti-Ma2, and anti-CV2) and tumoral markers (Carcinoembryonic Antigen, CA 19.9, CA 125, and CA 15.3) were negative. Antibodies against neuronal surface antigens (LGI-1 protein, NMDA AMPA, and GABA-B receptors) were also negative.\n\nCerebrospinal fluid (CSF) analysis revealed slightly increased proteins (72 mg/dL) and lymphocytic pleocytosis with 17 cells/mm3. CSF direct microscopy, cultures, and serologies (Herpes simplex 1 and 2, Cytomegalovirus, Epstein-Barr virus, Treponema pallidum, Borrelia burgdorferi, and Brucella spp.) were negative. Oligoclonal bands were absent and CSF dementia biomarkers (beta-amyloid peptide, tau protein, and phosphorylated tau protein) were normal.\n\nElectroencephalogram (EEG) revealed rhythmic slow activity in both temporal regions, with normal background rhythm and without paroxysmal activity.\n\nBrain Magnetic Resonance Imaging (MRI) was unremarkable and brain perfusion single-photon emission computed tomography (SPECT) imaging revealed hypoperfusion in frontal, temporal, and parietal regions with left predominance (Figure 1).\n\nThe rapidly progressive neurological and psychiatric symptoms presented by the patient were unspecific and it could be the presentation of several different conditions including metabolic or toxic encephalopathy, CNS infection, cerebrovascular disease, CNS tumor, and CNS inflammatory conditions, such as cerebral vasculitis, autoimmune encephalitis, or paraneoplastic syndromes, or, more remotely, a rapidly progressive presentation of a degenerative dementia. The clinical history and diagnostic investigations excluded most of these causes and given that the only relevant findings were an inflammatory CSF profile and an increased anti-TPO antibodies titer, encephalopathy associated with autoimmune thyroid disease was diagnosed and treatment with intravenous methylprednisolone (1 g/day for 5 days) was performed. A significant improvement occurred after five days of therapy with complete resolution of mood and cognitive disturbance (MMSE = 29) and disappearance of the myoclonic movements. EEG was repeated with normal result. No steroid side effects occurred and, after improvement, the patient was discharged with oral prednisolone (1 mg/kg/day).\n\nOne month after discharge, steroid dosage reduction was attempted, but neurocognitive symptoms and distal limb myoclonus rapidly returned (anti-TPO antibodies = 217 UI/mL). Improvement was promptly seen after prednisolone reincrease to 1 mg/kg/day; however, steroid side effects developed, including Diabetes and Cushing Syndrome, so azathioprine was added as a steroid sparing agent. Although steroid gradual withdrawal was possible after 6 months without symptoms recurrence, the patient developed toxic hepatitis in relation to azathioprine and the drug was stopped. Neurological and psychiatric symptoms and myoclonic movements returned and were rapidly controlled with low prednisolone dosage (10 mg/day) without associated side effects, and other therapies such as plasma exchange, intravenous immunoglobulins, or other immunosuppressive drugs were not necessary. Three years later the patient was still asymptomatic, although anti-TPO antibody titer remains elevated (493 UI/mL). She is currently on prednisolone 5 mg/day as she is reluctant to discontinue for the risk of recurrence of symptoms.\n\nFigures 2 and 3 represent the evolution in time of anti-TPO antibody titers and thyroid hormones levels and their relation with clinical presentation. Although anti-TPO antibody titer is increased, there is no direct relationship with clinical presentation, including asymptomatic periods associated with elevated antibodies.\n\n3. Discussion\nEncephalopathy associated with autoimmune thyroid disease, also called Hashimoto's encephalopathy or Steroid-Responsive Encephalopathy associated with Autoimmune thyroid disease, is a controversial entity as its pathophysiology is not yet well defined and it is usually a diagnosis of exclusion. It is known to be associated with clinical or subclinical autoimmune thyroid disease, most commonly Hashimoto's thyroiditis, but there are also some reports of association with Graves Disease, a clinical entity without true thyroiditis [8–13].\n\nAlthough autoimmune thyroiditis and the presence of anti-thyroid antibodies are relatively common in the population, with an estimated prevalence of Hashimoto thyroiditis of 0.3 to 2% [14–16] and detection of anti-thyroid antibodies in up to 10% healthy population [17–19], encephalopathy associated with thyroiditis or anti-thyroid antibodies is very uncommon, with an estimated prevalence of 2.1 per 100.000 habitants [20]. It occurs more commonly in females (4 : 1 ratio), and, although there are cases reported from childhood through the eighth decade of life, the mean age of onset is in the fourth decade [1, 2].\n\nSince the first description of Hashimoto's encephalopathy in 1966 [21], the clinical spectrum has been widened and different possible presentations are now recognized, including acute-onset presentations as stroke-like episodes, epilepsy, or psychosis, and a slowly progressive presentation, which appears to be more common, characterized by cognitive and behavioral disturbances which may be associate with tremor, myoclonus, or ataxia [1–4].\n\nThe diagnostic criteria of EAAT include the association of neurological or psychiatric manifestations, high titers of anti-thyroid antibodies, exclusion of other possible causes with complementary exams, and a good response to immunosuppressive therapy [3, 7]. However, these vague diagnostic criteria may contribute to masquerade of other autoimmune encephalopathies instead.\n\nIn fact, blood workup is usually normal, except for the presence of increased anti-thyroid antibodies, more commonly against thyroid peroxidase (86%), but anti-thyroglobulin antibodies may be present in some cases (48%) [1–3]. Despite this association, there is no direct correlation between antibody titers and the clinical severity, with some asymptomatic patients having high antibody titers and some patients with severe encephalopathy having only mildly increased antibody titers. The absence of direct correlation between clinical presentation and anti-thyroid antibodies levels complicates the diagnosis and therefore the evidence of CNS inflammation, assessed in the cerebrospinal fluid (CSF), so the exclusion of other causes is essential to the assumption of this diagnosis. Thyroid hormones levels are also not related to the course of the disease with the majority of patients being euthyroid (18–45%) or hypothyroid (clinical in 25–35% and subclinical in 17–20%) and less commonly hyperthyroidism (7%) [1–3]. In fact thyroid hormone levels are usually normal or only mildly abnormal not to explain the psychiatric or neurological symptoms.\n\nCSF analysis usually reveals mild and nonspecific inflammation that is mild mononuclear pleocytosis or slightly increased proteins [2, 13]; oligoclonal bands have been reported [6].\n\nEEG abnormalities are usually present, occurring in 90 to 98% of patients, usually with unspecific findings [22]. The most common presentations are diffuse background slowing and frontal intermittent rhythmic delta activity (FIRDA) [1, 6], but other EEG patterns have been described such as periodic lateralized epileptiform discharges (PLEDs) [23] and temporal epileptiform activity [24, 25]. There is usually a correlation between the slowing severity and the encephalopathy severity [6, 24, 26] and an EEG normalization occurs with successful treatment, which may also be used to support the diagnosis [3, 27].\n\nBrain MRI may be normal or, in up to 50% of cases, present unspecific anomalies, and it is very important to exclude other etiologies [1, 6]. The abnormalities that may be seen are cerebral atrophy, or less frequently, focal cortical abnormalities or unspecific focal or diffuse subcortical white matter hyperintensities which may be reversible with treatment [1, 3].\n\nSPECT scan is not routinely used, but it was performed in some previous reports, with unspecific patterns of reduced perfusion, which can be diffuse or patchy and may involve multiple different regions [3, 28–30]. Positron emission tomography (PET) is also unspecific and usually shows widespread multifocal hypometabolism [31, 32]. The findings in SPECT and PET do not appear to be correlated with the clinical presentation, EEG, or neuroradiological findings and usually improve after successful treatment.\n\nThe pathogenesis underlying the encephalopathy associated with autoimmune thyroid disease is still unknown. Although anti-thyroid antibodies have no established pathogenic role, as there is no direct correlation between antibody titers and clinical severity [1–3], the high prevalence of coexistence of thyroid autoimmune diseases and other autoimmune diseases is well described [33, 34]. Therefore, the presence of anti-thyroid antibodies may be related to an autoimmune predisposition and the presence of other, still unrecognized, antibodies responsible for the encephalopathy may be speculated.\n\nAntibodies against alpha-enolase, an antigen present in thyroid and also diffusely in the brain, have been described in some patients [35, 36]; however, their involvement in the pathogenesis has not been yet documented. The presence of antibodies against neuronal antigens is also suggested although it remains to be proven [37].\n\nGiven that EAAT is considered an inflammatory condition, the current treatment is based on immunotherapy. The most commonly used treatment is intravenous methylprednisolone (500–1000 g/day, for 3 to 5 days) followed by oral prednisone (1-2 mg/kg/day), which is gradually tapered with clinical improvement. Immunosuppressants, more commonly azathioprine, may be used as steroid sparing agents [3].\n\nA prompt response to steroids occurs in most patients, usually with a favourable prognosis [3]. However, there is only partial benefit in some patients, no response to steroids is seen in a few cases, and, even after successful treatment, some patients may have relapses, usually during treatment withdrawal [3, 13, 25, 37–40]. However, the absence of response to steroids should not be regarded as a factor against this diagnosis, and other immunotherapies must be tried in cases of strong clinical suspicion. In cases of suboptimal or absent response to first-line treatment with steroids, good results have been reported with immunosuppressants (methotrexate, azathioprine, and cyclophosphamide), periodic intravenous immunoglobulin [41, 42], and plasma exchange [25]. More recently [43] a role for levetiracetam in patients ineligible to steroid treatment has been suggested, as having, in addition to its antiepileptic effects, a possible anti-inflammatory effect mediated through interleukin-1 beta and transforming growth factor beta 1.\n\nIn our case, both clinical presentation and response to treatment are in favour of an autoimmune encephalopathy and criteria to EAAT are met. However, both the absence of CSF oligoclonal bands and the correlation between blood antibodies and clinical exacerbation may favour the hypothesis of an autoimmune encephalopathy due to unknown antibodies, where anti-thyroid antibodies are just indicative of autoimmune predisposition.\n\nIn conclusion, encephalopathy associated with autoimmune thyroid disease is a diagnostic challenge as the clinical presentation and complementary exams are unspecific and no diagnostic markers are currently available. This condition is probably underdiagnosed in our clinical practice and, therefore, a high clinical suspicion is required. With this clinical case we underline the importance of making the diagnosis of this entity, since it can be treated with immunotherapy and patient prognosis can be significantly improved.\n\nAbbreviations\nEAAT:Encephalopathy associated with autoimmune thyroid disease.\n\nAdditional Points\n\nClinical presentation of EAAT is variable and unspecific.\n\nComplementary exams results are unspecific and no diagnostic biomarker is available.\n\nThere is no direct correlation between anti-thyroid antibody titers and the clinical presentation.\n\nThe diagnosis consists mostly of exclusion of other possible causes.\n\nEAAT recognition is extremely important as it usually improves with immunotherapies.\n\n\n\n\nConsent\nA signed release from the patient authorizing publication has been obtained.\n\nCompeting Interests\nAll authors report that they have no conflict of interests.\n\nFigure 1 Brain perfusion SPECT. Reduced 99mTc-HMPAO uptake in parietal, temporal, and frontal lobes. Hypoperfusion is more severe on the left hemisphere.\n\nFigure 2 Evolution of anti-thyroid peroxidase antibodies (anti-TPO antibodies) titers in time and their relationship with clinical exacerbation.\n\nFigure 3 Evolution of thyroid hormone levels in time and their relationship with clinical exacerbation.\n==== Refs\n1 Chong J. Y. Rowland L. P. Utiger R. D. Hashimoto encephalopathy: syndrome or myth? Archives of Neurology 2003 60 2 164 171 10.1001/archneur.60.2.164 2-s2.0-0037320310 12580699 \n2 Ferracci F. Carnevale A. The neurological disorder associated with thyroid autoimmunity Journal of Neurology 2006 253 8 975 984 10.1007/s00415-006-0170-7 2-s2.0-33748973370 16786216 \n3 de Holanda N. C. P. de Lima D. D. Cavalcanti T. B. Lucena C. S. Bandeira F. Hashimoto's encephalopathy: systematic review of the literature and an additional case Journal of Neuropsychiatry and Clinical Neurosciences 2011 23 4 384 390 10.1176/jnp.23.4.jnp384 2-s2.0-84858128565 22231308 \n4 Sánchez Contreras A. Rojas S. A. Manosalva A. Hashimoto encephalopathy (autoimmune encephalitis) Journal of Clinical Rheumatology 2004 10 6 339 343 10.1097/01.rhu.0000147055.27513.f8 2-s2.0-10044290597 17043544 \n5 Payer J. Petrovic T. Lisy L. Langer P. Hashimoto encephalopathy: a rare intricate syndrome International Journal of Endocrinology and Metabolism 2012 10 2 506 514 10.5812/ijem.4174 2-s2.0-84864014464 23843812 \n6 Kothbauer-Margreiter I. Sturzenegger M. Komor J. Baumgartner R. Hess C. W. Encephalopathy associated with Hashimoto thyroiditis: diagnosis and treatment Journal of Neurology 1996 243 8 585 593 10.1007/bf00900946 2-s2.0-0029790583 8865025 \n7 Tamagno G. Federspil G. Murialdo G. Clinical and diagnostic aspects of encephalopathy associated with autoimmune thyroid disease (or Hashimoto's encephalopathy) Internal and Emergency Medicine 2006 1 1 15 23 10.1007/BF02934715 2-s2.0-33750098246 16941808 \n8 Cantón A. de Fàbregas O. Tintoré M. Mesa J. Codina A. Simó R. Encephalopathy associated to autoimmune thyroid disease: a more appropriate term for an underestimated condition? Journal of the Neurological Sciences 2000 176 1 65 69 10.1016/s0022-510x(00)00302-6 2-s2.0-0343729913 10865094 \n9 Seo S. W. Lee B. I. Lee J. D. Thyrotoxic autoimmune encephalopathy: a repeat positron emission tomography study Journal of Neurology, Neurosurgery & Psychiatry 2003 74 4 504 506 10.1136/jnnp.74.4.504 2-s2.0-0037381186 \n10 Utku U. Asil T. Çelik Y. Tucer D. Reversible MR angiographic findings in a patient with autoimmune Graves disease American Journal of Neuroradiology 2004 25 9 1541 1543 2-s2.0-16644394162 15502134 \n11 Dihné M. Schuier F. J. Schuier M. Hashimoto encephalopathy following iodine 131 (131I) radiotherapy of Graves disease Archives of Neurology 2008 65 2 282 293 10.1001/archneurol.2007.49 2-s2.0-39049085341 18268203 \n12 Gelosa G. DiFrancesco J. C. Tremolizzo L. Autoimmune encephalopathy in Graves' disease: remission after total thyroidectomy Journal of Neurology, Neurosurgery and Psychiatry 2009 80 6 698 699 10.1136/jnnp.2008.152413 2-s2.0-66149148720 \n13 Tamagno G. Celik Y. Simó R. Encephalopathy associated with autoimmune thyroid disease in patients with Graves' disease: clinical manifestations, follow-up, and outcomes BMC Neurology 2010 10, article 27 10.1186/1471-2377-10-27 2-s2.0-77951603993 \n14 Staii A. Mirocha S. Todorova-Koteva K. Glinberg S. Jaume J. C. Hashimoto thyroiditis is more frequent than expected when diagnosed by cytology which uncovers a pre-clinical state Thyroid Research 2010 3 1, article 11 10.1186/1756-6614-3-11 2-s2.0-78651090542 \n15 Vanderpump M. P. J. Tunbridge W. M. G. French J. M. The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey Clinical Endocrinology 1995 43 1 55 68 10.1111/j.1365-2265.1995.tb01894.x 2-s2.0-0029046372 7641412 \n16 Wang C. Crapo L. M. The epidemiology of thyroid disease and implications for screening Endocrinology and Metabolism Clinics of North America 1997 26 1 189 218 10.1016/S0889-8529(05)70240-1 2-s2.0-0030960547 9074859 \n17 Afshari M. Afshari Z. S. Schuele S. U. Pearls & oy-sters: Hashimoto encephalopathy Neurology 2012 78 22 e134 e137 10.1212/wnl.0b013e3182582fd4 2-s2.0-84863626530 22641407 \n18 Punzi L. Betterle C. Chronic autoimmune thyroiditis and rheumatic manifestations Joint Bone Spine 2004 71 4 275 283 10.1016/j.jbspin.2003.06.005 2-s2.0-3843109060 15288851 \n19 Mavragani C. P. Danielides S. Zintzaras E. Vlachoyiannopoulos P. G. Moutsopoulos H. M. Antithyroid antibodies in antiphospholipid syndrome: prevalence and clinical associations Lupus 2009 18 12 1096 1099 10.1177/0961203309106763 2-s2.0-70349487002 19762385 \n20 Ferracci F. Bertiato G. Moretto G. Hashimoto's encephalopathy: epidemiologic data and pathogenetic considerations Journal of the Neurological Sciences 2004 217 2 165 168 10.1016/j.jns.2003.09.007 2-s2.0-0347357709 14706219 \n21 Brain L. Jellinek E. H. Ball K. Hashimoto's disease and encephalopathy The Lancet 1966 2 7462 512 514 2-s2.0-0014005126 \n22 Henchey R. Cibula J. Helveston W. Malone J. Gilmore R. L. Electroencephalographic findings in Hashimoto’s encephalopathy Neurology 1995 45 5 977 981 10.1212/wnl.45.5.977 2-s2.0-0029072735 7746418 \n23 Doherty C. P. Schlossmacher M. Torres N. Bromfield E. Samuels M. A. Hashimoto's encephalopathy mimicking Creutzfeldt-Jakob disease: brain biopsy findings Journal of Neurology Neurosurgery and Psychiatry 2002 73 5 601 602 10.1136/jnnp.73.5.601 2-s2.0-0036829497 \n24 Schäuble B. Castillo P. R. Boeve B. F. Westmoreland B. F. EEG findings in steroid-responsive encephalopathy associated with autoimmune thyroiditis Clinical Neurophysiology 2003 114 1 32 37 10.1016/S1388-2457(02)00343-7 2-s2.0-0037213742 12495761 \n25 Nagpal T. Pande S. Hashimoto's encephalopathy: response to plasma exchange Neurology India 2004 52 2 245 247 2-s2.0-4344660057 15269483 \n26 Rodriguez A. J. Jicha G. A. Steeves T. D. L. Benarroch E. E. Westmoreland B. F. EEG changes in a patient with steroid-responsive encephalopathy associated with antibodies to thyroperoxidase (SREAT, Hashimoto's encephalopathy) Journal of Clinical Neurophysiology 2006 23 4 371 373 10.1097/01.wnp.0000214542.21735.49 2-s2.0-33746791028 16885711 \n27 Mijajlovic M. Mirkovic M. Dackovic J. Zidverc-Trajkovic J. Sternic N. Clinical manifestations, diagnostic criteria and therapy of Hashimoto's encephalopathy: report of two cases Journal of the Neurological Sciences 2010 288 1-2 194 196 10.1016/j.jns.2009.09.030 2-s2.0-71149095448 19846119 \n28 Forchetti C. M. Katsamakis G. Garron D. C. Autoimmune thyroiditis and a rapidly progressive dementia: global hypoperfusion on SPECT scanning suggests a possible mechanism Neurology 1997 49 2 623 626 10.1212/wnl.49.2.623 2-s2.0-0030765805 9270613 \n29 Bocchetta A. Tamburini G. Cavolina P. Serra A. Loviselli A. Piga M. Affective psychosis, Hashimoto's thyroiditis, and brain perfusion abnormalities: case report Clinical Practice and Epidemiology in Mental Health 2007 3, article 31 10.1186/1745-0179-3-31 2-s2.0-39049117482 \n30 Mahmud F. H. Lteif A. N. Renaud D. L. Reed A. M. Brands C. K. Steroid-responsive encephalopathy associated with Hashimoto's thyroiditis in an adolescent with chronic hallucinations and depression: case report and review Pediatrics 2003 112 3 686 690 10.1542/peds.112.3.686 2-s2.0-0041336965 12949305 \n31 Kaida K.-I. Takeda K. Nagata N. Kamakura K. Alzheimer's disease with asymmetric parietal lobe atrophy: a case report Journal of the Neurological Sciences 1998 160 1 96 99 10.1016/s0022-510x(98)00221-4 2-s2.0-0032544724 9804125 \n32 Pari E. Rinaldi F. Premi E. A follow-up 18 F-FDG brain PET study in a case of Hashimoto's encephalopathy causing drug-resistant status epilepticus treated with plasmapheresis Journal of Neurology 2014 261 4 663 667 10.1007/s00415-013-7228-0 2-s2.0-84898880750 24390201 \n33 Boelaert K. Newby P. R. Simmonds M. J. Prevalence and relative risk of other autoimmune diseases in subjects with autoimmune thyroid disease The American Journal of Medicine 2010 123 2 183.e1 183.e9 10.1016/j.amjmed.2009.06.030 2-s2.0-74549169972 20103030 \n34 Knapp P. E. Risk of other autoimmune diseases increased in people with Graves' disease or Hashimoto's thyroiditis relative to the general UK population Evidence-Based Medicine 2010 15 5 158 159 10.1136/ebm1091 2-s2.0-78049269533 20667903 \n35 Fujii A. Yoneda M. Ito T. Autoantibodies against the amino terminal of α -enolase are a useful diagnostic marker of Hashimoto's encephalopathy Journal of Neuroimmunology 2005 162 1-2 130 136 10.1016/j.jneuroim.2005.02.004 2-s2.0-20144388973 15833368 \n36 Ochi H. Horiuchi I. Araki N. Proteomic analysis of human brain identifies α -enolase as a novel autoantigen in Hashimoto's encephalopathy FEBS Letters 2002 528 1–3 197 202 10.1016/s0014-5793(02)03307-0 2-s2.0-18644372755 12297304 \n37 Oide T. Tokuda T. Yazaki M. Anti-neuronal autoantibody in Hashimoto's encephalopathy: neuropathological, immunohistochemical, and biochemical analysis of two patients Journal of the Neurological Sciences 2004 217 1 7 12 10.1016/j.jns.2003.08.005 2-s2.0-0347480498 14675602 \n38 Castillo P. Woodruff B. Caselli R. Steroid-responsive encephalopathy associated with autoimmune thyroiditis Archives of Neurology 2006 63 2 197 202 10.1001/archneur.63.2.197 2-s2.0-32944482187 16476807 \n39 Lopez-Giovaneli J. Moreaud O. Faure P. Debaty I. Chabre O. Halimi S. Cortico-responsive encephalopathy associated with autoimmune thyroiditis (SREAT): about two case reports characterized by a gap between the diagnosis of autoimmune thyroiditis and neurological disorders Annales d'Endocrinologie 2007 68 2-3 173 176 10.1016/j.ando.2007.05.001 2-s2.0-34547653046 \n40 Mocellin R. Lubman D. I. Lloyd J. Tomlinson E. B. Velakoulis D. Reversible dementia with psychosis: Hashimoto's encephalopathy Psychiatry and Clinical Neurosciences 2006 60 6 761 763 10.1111/j.1440-1819.2006.01593.x 2-s2.0-33750956005 17109712 \n41 Cornejo R. Venegas P. Goñi D. Salas A. Romero C. Successful response to intravenous immunoglobulin as rescue therapy in a patient with Hashimoto's encephalopathy BMJ Case Reports 2010 2010 10.1136/bcr.09.2010.3332 \n42 Jacob S. Rajabally Y. A. Hashimoto's encephalopathy: steroid resistance and response to intravenous immunoglobulins Journal of Neurology, Neurosurgery and Psychiatry 2005 76 3 455 456 10.1136/jnnp.2004.049395 2-s2.0-14544298291 \n43 Wong L. C. Freeburg J. D. Montouris G. D. Hohler A. D. Two patients with Hashimoto's encephalopathy and uncontrolled diabetes successfully treated with levetiracetam Journal of the Neurological Sciences 2015 348 1-2 251 252 10.1016/j.jns.2014.11.007 2-s2.0-84921022580 25467138\n\n",
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"title": "Encephalopathy Associated with Autoimmune Thyroid Disease: A Potentially Reversible Condition.",
"title_normalized": "encephalopathy associated with autoimmune thyroid disease a potentially reversible condition"
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"abstract": "5-fluorouracil is a chemotherapeutic agent that plays an important role in the treatment of various cancers including head and neck and gastrointestinal malignancies. Therapy with 5-fluorouracil is rarely associated with cardiotoxic effects including angina, heart failure, myocardial infarction and cardiac arrest, resulting in discontinuation at the expense of sub-optimal treatment of the targeted malignancy. In this article, we review the literature reported on 5-fluorouracil-associated cardiotoxicity and present a case of a patient who experienced chest pain on 5-fluorouracil. The cardiac symptoms subsided after initiation of capecitabine, the oral formulation of 5-fluorouracil. To our knowledge, this is only the second reported case where 5-fluorouracil was successfully replaced by capecitabine without recurrence of cardiac symptoms. Capecitabine may be a viable option for patients who develop 5-fluorouracil-induced chest pain. However, large clinical trials are warranted to confirm these findings. Currently, there is insufficient evidence to recommend an optimal approach for safe and effective alternative treatment for patients who experience 5-fluorouracil-induced cardiac adverse events.",
"affiliations": "Department of Pharmacy, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.;Department of Pharmacy, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.;Department of GI Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA amit.mahipal@moffitt.org.",
"authors": "Saneeymehri|Seyyedeh S|SS|;Markey|Kelly R|KR|;Mahipal|Amit|A|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D000069287:Capecitabine; D005472:Fluorouracil",
"country": "England",
"delete": false,
"doi": "10.1177/1078155215579303",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "22(3)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "5-fluorouracil; capecitabine; cardiotoxicity; coronary vasospasm",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D000069287:Capecitabine; D066126:Cardiotoxicity; D002637:Chest Pain; D015179:Colorectal Neoplasms; D005472:Fluorouracil; D006801:Humans; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "552-5",
"pmc": null,
"pmid": "25852107",
"pubdate": "2016-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Paradoxical effect of capecitabine in 5-fluorouracil-induced cardiotoxicity: A case vignette and literature review.",
"title_normalized": "paradoxical effect of capecitabine in 5 fluorouracil induced cardiotoxicity a case vignette and literature review"
} | [
{
"companynumb": "US-FRESENIUS KABI-FK201603211",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": null,... |
{
"abstract": "BACKGROUND\nDual human epidermal growth factor receptor 2 (HER2) blockade has been preclinically and clinically assessed in HER2-overexpressing metastatic breast cancer (mBC) with encouraging results.\n\n\nMETHODS\nThis is a descriptive retrospective study of trastuzumab plus lapatinib activity in patients with HER2-overexpressing mBC from two centers. The primary endpoints were to assess objective response rate (ORR) and toxicity. The secondary endpoints were to assess progression-free survival (PFS) and overall survival.\n\n\nRESULTS\nA total of 23 HER2-positive mBC patients previously treated with trastuzumab received a trastuzumab plus lapatinib based therapy. Chemotherapy (CT) was added to the dual HER2 blockade treatment in 13 patients (56%), whereas hormonotherapy (HT) was added in 8 patients (35%) and 2 patients (9%) received lapatinib plus trastuzumab without any other agent. ORR was 22% (5/23) and 39% (9/23) of patients had stable disease. PFS in the overall population was 4 months. PFS in patients with CT was 5 months, whereas PFS in patients with HT was 2 months. Grade≥3 adverse events were diarrhea (26%) and hand-and-foot syndrome (9%).\n\n\nCONCLUSIONS\nThese findings suggest that dual HER2 blockade in combination with CT is feasible in pretreated HER2-positive mBC patients.",
"affiliations": "Department of Medical Oncology, Hospital Universitario Clínico San Carlos, Spain.",
"authors": "Sotelo|Miguel J|MJ|;García-Sáenz|Jose Angel|JA|;Manso|Luis|L|;Moreno|Fernando|F|;Ciruelos|Eva|E|;Callata|Hector R|HR|;Mendiola|Cesar|C|;Cabezas|Santiago|S|;Ghanem|Ismael|I|;Díaz-Rubio|Eduardo|E|",
"chemical_list": "D000970:Antineoplastic Agents; D011799:Quinazolines; D000077341:Lapatinib; C508053:ERBB2 protein, human; D018719:Receptor, ErbB-2; D000068878:Trastuzumab",
"country": "India",
"delete": false,
"doi": "10.4103/0973-1482.138017",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1998-4138",
"issue": "10(4)",
"journal": "Journal of cancer research and therapeutics",
"keywords": null,
"medline_ta": "J Cancer Res Ther",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D000077341:Lapatinib; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011799:Quinazolines; D018719:Receptor, ErbB-2; D012189:Retrospective Studies; D000068878:Trastuzumab; D016896:Treatment Outcome",
"nlm_unique_id": "101249598",
"other_id": null,
"pages": "967-72",
"pmc": null,
"pmid": "25579538",
"pubdate": "2014",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Lapatinib plus trastuzumab in pretreated human epidermal growth factor receptor 2-positive metastatic breast cancer.",
"title_normalized": "lapatinib plus trastuzumab in pretreated human epidermal growth factor receptor 2 positive metastatic breast cancer"
} | [
{
"companynumb": "ES-ROCHE-1248902",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRASTUZUMAB"
},
"drugadditional": null,
"dru... |
{
"abstract": "Combination ribociclib and aromatase inhibitors are currently the preferred treatment in Australia for newly diagnosed hormone receptor positive metastatic breast cancer in the absence of visceral crisis. In our case series of 32 patients, 28% experienced grade 1 elevations in creatinine, a toxicity that was under-recognised in large phase III studies. Creatinine rise appears to be due to a reversible inhibition of renal efflux transporters rather than an acute kidney injury in the majority of cases.",
"affiliations": "Department of Medical Oncology, Liverpool Hospital, Sydney, New South Wales, Australia.;Department of Medical Oncology, Liverpool Hospital, Sydney, New South Wales, Australia.;Department of Medical Oncology, Campbelltown Hospital, Sydney, New South Wales, Australia.;Department of Medical Oncology, Liverpool Hospital, Sydney, New South Wales, Australia.;Department of Medical Oncology, Liverpool Hospital, Sydney, New South Wales, Australia.",
"authors": "Wilson|Brooke E|BE|0000-0001-6557-7298;Mok|Kelly|K|;Kiely|Belinda E|BE|;Nguyen|Rebecca|R|0000-0001-8940-3161;Moylan|Eugene|E|",
"chemical_list": "D000631:Aminopyridines; D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D011687:Purines; D003404:Creatinine; D018719:Receptor, ErbB-2; C000589651:ribociclib",
"country": "Australia",
"delete": false,
"doi": "10.1111/imj.14629",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1444-0903",
"issue": "49(11)",
"journal": "Internal medicine journal",
"keywords": "creatinine; cyclin-dependent kinase 4/6 inhibitor; metastatic breast cancer; ribociclib",
"medline_ta": "Intern Med J",
"mesh_terms": "D000368:Aged; D000631:Aminopyridines; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D047072:Aromatase Inhibitors; D001943:Breast Neoplasms; D003404:Creatinine; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009517:New South Wales; D011687:Purines; D018719:Receptor, ErbB-2; D012189:Retrospective Studies",
"nlm_unique_id": "101092952",
"other_id": null,
"pages": "1438-1442",
"pmc": null,
"pmid": "31713335",
"pubdate": "2019-11",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Association between ribociclib and changes in creatinine in patients with hormone receptor positive metastatic breast cancer.",
"title_normalized": "association between ribociclib and changes in creatinine in patients with hormone receptor positive metastatic breast cancer"
} | [
{
"companynumb": "NVSC2019AU035543",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RIBOCICLIB"
},
"drugadditional": null,
"drug... |
{
"abstract": "BACKGROUND\nThe aim of our study was to evaluate the clinical outcomes in patients on preinjury Ibuprofen with traumatic brain injury.\n\n\nMETHODS\nWe performed a 2-year analysis of all patients on prehospital Ibuprofen with traumatic brain injury and intracranial hemorrhage. Patients on preinjury Ibuprofen were matched using propensity score matching to patients not on Ibuprofen in a 1:2 ratio for age, Glasgow Coma Scale, head-abbreviated injury scale, injury severity score, International Normalized Ratio, and neurologic examination. Outcome measures were progression on repeat head computed tomography (RHCT) and neurosurgical intervention.\n\n\nRESULTS\nA total of 195 matched (Ibuprofen 65, no-Ibuprofen 130) patients were included. There was no difference in the progression on RHCT (Ibuprofen 18% vs. no-Ibuprofen 24%; P = .50). The neurosurgical intervention rate was 18.9% (n = 37). There was no difference for need for neurosurgical intervention (26% vs. 16%; P = .10) between the 2 groups.\n\n\nCONCLUSIONS\nIn a matched cohort of trauma patients, preinjury Ibuprofen use was not associated with progression of initial intracranial hemorrhage and the need for neurosurgical intervention. Preinjury use of Ibuprofen as an independent variable should not warrant the need for a routine RHCT scan.",
"affiliations": "Division of Trauma, Department of Surgery, University of Arizona, Tucson, AZ, USA.;Division of Trauma, Department of Surgery, University of Arizona, Tucson, AZ, USA.;Division of Trauma, Department of Surgery, University of Arizona, Tucson, AZ, USA.;Division of Trauma, Department of Surgery, University of Arizona, Tucson, AZ, USA.;Division of Trauma, Department of Surgery, University of Arizona, Tucson, AZ, USA.;Division of Trauma, Department of Surgery, University of Arizona, Tucson, AZ, USA.;Division of Trauma, Department of Surgery, University of Arizona, Tucson, AZ, USA.;Division of Trauma, Department of Surgery, University of Arizona, Tucson, AZ, USA.;Division of Trauma, Department of Surgery, University of Arizona, Tucson, AZ, USA.;Division of Trauma, Department of Surgery, University of Arizona, Tucson, AZ, USA.;Division of Trauma, Department of Surgery, University of Arizona, Tucson, AZ, USA. Electronic address: bjoseph@surgery.arizona.edu.",
"authors": "Zangbar|Bardiya|B|;Pandit|Viraj|V|;Rhee|Peter|P|;Khalil|Mazhar|M|;Kulvatunyou|Narong|N|;O'Keeffe|Terence|T|;Tang|Andrew|A|;Gries|Lynn|L|;Green|Donald J|DJ|;Friese|Randall S|RS|;Joseph|Bellal|B|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D007052:Ibuprofen",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9610",
"issue": "209(6)",
"journal": "American journal of surgery",
"keywords": "Ibuprofen; Motrin; Neurosurgical Intervention; Nonsteroidal anti-inflammatory drugs; Repeat head computed tomography; Traumatic brain injury",
"medline_ta": "Am J Surg",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001930:Brain Injuries; D005260:Female; D006801:Humans; D007052:Ibuprofen; D020300:Intracranial Hemorrhages; D016015:Logistic Models; D008297:Male; D016555:Matched-Pair Analysis; D008875:Middle Aged; D017063:Outcome Assessment, Health Care; D057216:Propensity Score; D012189:Retrospective Studies; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "0370473",
"other_id": null,
"pages": "921-6",
"pmc": null,
"pmid": "25190545",
"pubdate": "2015-06",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article",
"references": null,
"title": "Clinical outcomes in patients on preinjury ibuprofen with traumatic brain injury.",
"title_normalized": "clinical outcomes in patients on preinjury ibuprofen with traumatic brain injury"
} | [
{
"companynumb": "US-JNJFOC-20150807073",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional": null,
"... |
{
"abstract": "BACKGROUND\nThe coronavirus disease 2019 (COVID-19) infection, caused by severe acute respiratory syndrome corona virus 2 (SARS-CoV-2), involves several organs through participation of angiotensin-conversion enzyme 2 (ACE2) receptors. The presence of ACE2 receptors in the liver renders this organ a potential target for the novel coronavirus.\n\n\nMETHODS\nWe performed 14 complete autopsies of patients infected with SARS-CoV-2. In each case we stained liver tissue sections with haematoxylin/eosin, Masson blue trichrome stain, periodic acid-Schiff (PAS), Perls, and performed cytokeratin-7 (CK7) immunochemistry.\n\n\nRESULTS\nMacroscopically, livers were pale and yellowish in 8 of 14 (57%) patients, and had a nutmeg appearance in the other 6 cases (42%). Histologically, centrolobular necrosis was observed in 12 cases (86%), and was associated with discreet to moderate lobular or portal inflammation. Steatosis was seen in 8 cases (57%), but fibrosis was rare. Cholestasis and discrete bile duct proliferation was observed in 5 cases (36%).\n\n\nCONCLUSIONS\nThe main histological changes can be explained by the hypoxic status as a result of severe hypoxemic pneumonia leading to death. Drug toxicity may also play a role in certain cases. Other histological changes may be explained by previous hepatic conditions or underlying hepatic diseases. We concluded that COVID-19 infection was not associated with a specific histopathological pattern of the liver.",
"affiliations": "Center of Forensic Medicine, Department of Pathology, Cliniques Universitaires Saint-Luc, Brussels, Belgium, gregory.schmit@uclouvain.be.;Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium.;Center of Forensic Medicine, Department of Pathology, Cliniques Universitaires Saint-Luc, Brussels, Belgium.;Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium.;Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium.;Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium.",
"authors": "Schmit|Grégory|G|;Lelotte|Julie|J|;Vanhaebost|Jessica|J|;Horsmans|Yves|Y|;Van Bockstal|Mieke|M|;Baldin|Pamela|P|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000512008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1015-2008",
"issue": "88(1)",
"journal": "Pathobiology : journal of immunopathology, molecular and cellular biology",
"keywords": "Autopsy; COVID-19; Liver; Pathology; SARS-CoV-2",
"medline_ta": "Pathobiology",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D001344:Autopsy; D000086382:COVID-19; D005260:Female; D006801:Humans; D008099:Liver; D008297:Male; D008875:Middle Aged; D011014:Pneumonia; D000086402:SARS-CoV-2",
"nlm_unique_id": "9007504",
"other_id": null,
"pages": "88-94",
"pmc": null,
"pmid": "33108789",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The Liver in COVID-19-Related Death: Protagonist or Innocent Bystander?",
"title_normalized": "the liver in covid 19 related death protagonist or innocent bystander"
} | [
{
"companynumb": null,
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE"
},
"drugadditional": "4",
"drugadminis... |
{
"abstract": "BACKGROUND\nThe conception of collagenase Clostridium histolyticum (CCH) as treatment for Peyronie's disease (PD) was a vital first step in providing a nonsurgical, minimally invasive FDA-approved treatment for men with PD.\n\n\nOBJECTIVE\nTo review the origins, clinical research history, and ultimately FDA approval of collagenase as PD treatment.\n\n\nMETHODS\nA PubMed search using (Peyronie's or Peyronie) AND collagenase, and limited to clinical research studies, returned nine papers that were examined in the current review.\n\n\nRESULTS\nCollagenase as a PD treatment arose in response to a lack of effective nonsurgical treatments and the incomplete understanding of underlying PD etiology. Awareness of dense collagen in PD scarring and parallel initial exploration of collagenase to treat herniated lumbar discs coincided with and inspired laboratory-based investigation of collagenase effects on excised PD plaque tissue. The foundational conceptual work and the critical development of purified injectable collagenase allowed the pursuit of clinical studies. Progression of clinical studies into large-scale robust trials culminated in two important outcomes: development of the first validated, PD-specific measure of psychosexual function, the Peyronie's Disease Questionnaire, and the first FDA-approved treatment for PD.\n\n\nCONCLUSIONS\nCollagenase therapy began as an attempt to modify the structure of PD-related tunica albuginea scarring, despite the lack of a fundamental understanding of the scar's origin. If we wish to advance PD treatment beyond this first effective step, the future needs to bring us full circle to the starting point: We need a greater understanding of the control of collagen deposition and wound healing in men with PD.",
"affiliations": "Urology Associates Medical Group, Burbank, CA, USA.;Auxilium Pharmaceuticals, Chesterbrook, PA, USA.;Auxilium Pharmaceuticals, Chesterbrook, PA, USA.",
"authors": "Gelbard|Martin K|MK|;Chagan|Larisa|L|;Tursi|James P|JP|",
"chemical_list": "D003012:Microbial Collagenase",
"country": "Netherlands",
"delete": false,
"doi": "10.1111/jsm.12904",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1743-6095",
"issue": "12(6)",
"journal": "The journal of sexual medicine",
"keywords": "Microbial Collagenase; Penile Induration; Peyronie's Disease",
"medline_ta": "J Sex Med",
"mesh_terms": "D047009:Clostridium histolyticum; D006801:Humans; D015552:Injections, Intralesional; D008297:Male; D003012:Microbial Collagenase; D010411:Penile Induration; D011795:Surveys and Questionnaires; D016896:Treatment Outcome",
"nlm_unique_id": "101230693",
"other_id": null,
"pages": "1481-9",
"pmc": null,
"pmid": "25940867",
"pubdate": "2015-06",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": null,
"title": "Collagenase Clostridium histolyticum for the Treatment of Peyronie's Disease: The Development of This Novel Pharmacologic Approach.",
"title_normalized": "collagenase clostridium histolyticum for the treatment of peyronie s disease the development of this novel pharmacologic approach"
} | [
{
"companynumb": "US-ENDO PHARMACEUTICALS INC-2015-002057",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "COLLAGENASE CLOSTRIDIUM HISTOLYTICUM"
},... |
{
"abstract": "Weight-loss medications have been associated with many conditions, including valvular heart disease, ischemic colitis, and pulmonary hypertension. There is a constant increase in the use of these drugs, especially new medications with better efficacy. Phentermine is one such drug, approved for short-term use to lose weight. We report a case of ischemic colitis in a female patient linked to inappropriate phentermine intake. The patient presented with symptoms of severe abdominal pain and repeated bowel movement associated with rectal bleeding for two weeks. Initial blood work was unremarkable for infectious and inflammatory causes. A CT scan was performed which revealed findings of ischemic colitis extending from transverse to descending colon. A biopsy study confirmed the same. Upon further questioning, the patient admitted to taking 37.5 mg of phentermine for two years beyond her prescribed period of 12 weeks. Hence, we propose that inappropriate use of phentermine caused ischemic colitis. With the widespread use of these medications, there is a need for heightened awareness among clinicians regarding adverse effects of phentermine.",
"affiliations": null,
"authors": "Sharma|Prabin|P|;Krishnamoorthy|Parasuram|P|",
"chemical_list": "D001067:Appetite Depressants; D010645:Phentermine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0010-6178",
"issue": "80(4)",
"journal": "Connecticut medicine",
"keywords": null,
"medline_ta": "Conn Med",
"mesh_terms": "D000328:Adult; D001067:Appetite Depressants; D017091:Colitis, Ischemic; D003113:Colonoscopy; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D010645:Phentermine",
"nlm_unique_id": "0372745",
"other_id": null,
"pages": "213-5",
"pmc": null,
"pmid": "27265924",
"pubdate": "2016-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Colon Ischemia After Weight-Loss Medication in a 36-Year-Old Woman.",
"title_normalized": "colon ischemia after weight loss medication in a 36 year old woman"
} | [
{
"companynumb": "US-INGENUS PHARMACEUTICALS, LLC-ING201607-000011",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PHENTERMINE HYDROCHLORIDE"
},
... |
{
"abstract": "Bacterial infection is one of the main causes of preterm premature rupture of membranes (PPROM) leading to preterm delivery, pulmonary hypoplasia, sepsis and joint deformities. Expectant management, broad-spectrum antibiotics and antenatal corticosteroids are routinely used in this condition with very limited success to prevent bacteremia, chorioamnionitis, funisitis and intra-amniotic infection syndrome. Here, we report a case in which we attempted to treat PPROM at 26+3 weeks of gestation with anhydramnion colonized by multiresistant Klebsiella. A perinatal port system was implanted subcutaneously at 28+0 weeks of gestation, enabling long-term continuous lavage of the amniotic cavity with a hypotonic aqueous composition similar to human amniotic fluid combined with intra-amniotic antibiotic application. The patient gave birth to a preterm female infant at 31+1 weeks without any signs of infection. The girl was discharged with a weight of 2,730 g in very good condition. In the follow-up examinations at 5 months and 1 year of age, there was no apparent neurological disturbance, developmental delay or Klebsiella colonization.",
"affiliations": "Department of Obstetrics and Prenatal Medicine, Center of Fetal Surgery, University Hospital Halle (Saale), Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.",
"authors": "Tchirikov|Michael|M|;Zhumadilov|Zhaxybay|Z|;Winarno|Andreas Suhartoyo|AS|;Haase|Roland|R|;Buchmann|Jörg|J|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000438483",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1015-3837",
"issue": "42(1)",
"journal": "Fetal diagnosis and therapy",
"keywords": "Amnioinfusion; Anhydramnion; Klebsiella; Port; Preterm premature rupture of membranes",
"medline_ta": "Fetal Diagn Ther",
"mesh_terms": "D000328:Adult; D000653:Amniotic Fluid; D000900:Anti-Bacterial Agents; D019072:Antibiotic Prophylaxis; D001691:Biological Therapy; D002408:Catheters, Indwelling; D002821:Chorioamnionitis; D003131:Combined Modality Therapy; D024901:Drug Resistance, Multiple, Bacterial; D004359:Drug Therapy, Combination; D005260:Female; D005322:Fetal Membranes, Premature Rupture; D006801:Humans; D007231:Infant, Newborn; D036502:Infusions, Intralesional; D007623:Kazakhstan; D007711:Klebsiella pneumoniae; D050498:Live Birth; D016104:Oligohydramnios; D011247:Pregnancy; D012720:Severity of Illness Index; D007507:Therapeutic Irrigation; D016896:Treatment Outcome",
"nlm_unique_id": "9107463",
"other_id": null,
"pages": "71-76",
"pmc": null,
"pmid": "26447923",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Treatment of Preterm Premature Rupture of Membranes with Oligo-/Anhydramnion Colonized by Multiresistant Bacteria with Continuous Amnioinfusion and Antibiotic Administrations through a Subcutaneously Implanted Intrauterine Port System: A Case Report.",
"title_normalized": "treatment of preterm premature rupture of membranes with oligo anhydramnion colonized by multiresistant bacteria with continuous amnioinfusion and antibiotic administrations through a subcutaneously implanted intrauterine port system a case report"
} | [
{
"companynumb": "DE-BAYER-2017-157226",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METRONIDAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nPharmacokinetics of antiepileptic drugs (AEDs) can be altered by age-related changes in physiology, thereby altering clinical effects, especially tolerability, in older adults. We compared two dosages of topiramate (TPM) in a pilot study of patients >or=60 years of age with partial-onset seizures.\n\n\nMETHODS\nIn this 24-week, double-blind, randomized, parallel-group study, patients with one or more seizures in previous 6 months were randomized to treatment with 50 or 200 mg/day TPM. TPM was initiated as monotherapy or added to one AED and titrated by 25 mg/day per week to target or maximum tolerated dose as the concomitant AED, if any, was withdrawn.\n\n\nRESULTS\nThirty-eight patients were randomized to the 50 mg/day TPM (mean age, 68 years) and 39-200 mg/day TPM (69 years). Seizure control was similar with the two dosages when TPM could be used as monotherapy, whereas 200 mg TPM was more effective than 50 mg in patients requiring adjunctive therapy. The overall incidence of adverse events was similar for the two dosages--66% with 50 mg and 62% with 200 mg TPM. Most common adverse events were somnolence (TPM 50, 13%; TPM 200, 8%), dizziness (13% vs. 8%), and headache (13% vs. 5%). Of 10 (13%) patients reporting a cognitive-related adverse event, six patients were assigned to the 50-mg group. A total of 14 patients (18%; seven in each group) discontinued TPM due to adverse events.\n\n\nCONCLUSIONS\nThis pilot study supports the practice of using low-to-moderate dosages of AEDs in older adults.",
"affiliations": "Miami VA Medical Center, Miami, Florida, USA. eramsay@epiworld.com",
"authors": "Ramsay|R Eugene|RE|;Uthman|Basim|B|;Pryor|Flavia M|FM|;Rowan|A James|AJ|;Bainbridge|Jacquelyn|J|;Spitz|Mark|M|;Sirven|Joseph I|JI|;Frederick|Tim E|TE|",
"chemical_list": "D000927:Anticonvulsants; D000077236:Topiramate; D005632:Fructose",
"country": "United States",
"delete": false,
"doi": "10.1111/j.1528-1167.2008.01584.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0013-9580",
"issue": "49(7)",
"journal": "Epilepsia",
"keywords": null,
"medline_ta": "Epilepsia",
"mesh_terms": "D000368:Aged; D000927:Anticonvulsants; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005632:Fructose; D006261:Headache; D006801:Humans; D008297:Male; D008875:Middle Aged; D010507:Periodicity; D010865:Pilot Projects; D012008:Recurrence; D012640:Seizures; D012720:Severity of Illness Index; D000077236:Topiramate",
"nlm_unique_id": "2983306R",
"other_id": null,
"pages": "1180-5",
"pmc": null,
"pmid": "18494791",
"pubdate": "2008-07",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": null,
"title": "Topiramate in older patients with partial-onset seizures: a pilot double-blind, dose-comparison study.",
"title_normalized": "topiramate in older patients with partial onset seizures a pilot double blind dose comparison study"
} | [
{
"companynumb": "US-JNJFOC-20130910786",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TOPIRAMATE"
},
"drugadditional": null,
... |
{
"abstract": "Treatment containing FOLFIRINOX was planned to be administered to a 51-year-old man with locally advanced pancreatic cancer as second-line chemotherapy and to a 66-year-old woman with recurrent pancreatic cancer as third-line chemotherapy in their treatments. Since both patients were revealed to harbor UGT1A1 polymorphisms, which were highly associated with irinotecan-induced toxicity(the former: UGT1A1 *6/*28, the latter: UGT1A1*6/*6), there was no alternative hopeful treatment other than FOLFIRINOX for them. Therefore, FOLFIRINOX was administered very carefully. Although both patients showed Grade 4 neutropenia during the initial course, it was controllable with G-CSF administration and following stepwise reduction of the irinotecan dose. Severe diarrhea and other adverse events were not observed in both cases. Since the determined regimen of FOLFIRINOX for patients with high-risk UGT1A1 polymorphisms has not been developed yet, it would be critical to accumulate and review an experience of FOLFIRINOX administration for these patients.",
"affiliations": "Dept. of Surgery, Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Fukushima Medical University.",
"authors": "Ishigame|Teruhide|T|;Kimura|Takashi|T|;Tsukida|Shigeyuki|S|;Suzushino|Seiko|S|;Muto|Makoto|M|;Sato|Naoya|N|;Kofunato|Yasuhide|Y|;Okada|Ryo|R|;Kenjo|Akira|A|;Shimura|Tatsuo|T|;Marubashi|Shigeru|S|",
"chemical_list": "C000627770:folfirinox; D000077150:Oxaliplatin; D000077146:Irinotecan; C418331:UGT1A1 enzyme; D014453:Glucuronosyltransferase; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "46(4)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002166:Camptothecin; D005260:Female; D005472:Fluorouracil; D014453:Glucuronosyltransferase; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin; D008297:Male; D008875:Middle Aged; D000077150:Oxaliplatin; D010190:Pancreatic Neoplasms; D011110:Polymorphism, Genetic",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "754-756",
"pmc": null,
"pmid": "31164525",
"pubdate": "2019-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "FOLFIRINOX for Locally Advanced and Recurrent Pancreatic Cancer with UGT1A1 *6 and or UGT1A1*28 Polymorphisms-A Report of Two Cases.",
"title_normalized": "folfirinox for locally advanced and recurrent pancreatic cancer with ugt1a1 6 and or ugt1a1 28 polymorphisms a report of two cases"
} | [
{
"companynumb": "JP-TEVA-2019-JP-1098275",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IRINOTECAN HYDROCHLORIDE"
},
"drugadditional": ... |
{
"abstract": "Systemic and intrathecal methotrexate is widely used in treatment protocols for childhood acute lymphoblastic leukemia. Its side effects vary in characteristics, intensity and time of onset, and depend on the administration route. Interactions with several drugs are known. Side effects of nitrous oxide sedation, often used for moderately painful procedures, typically occur after long time use and include neurological symptoms. We present a child who experienced a severe and long-lasting neurotoxicity after the third intrathecal application of methotrexate with short sedation by nitrous oxide during induction therapy for acute lymphoblastic leukemia. Symptoms completely resolved after 12 months.",
"affiliations": "Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.",
"authors": "Löbel|U|U|;Trah|J|J|;Escherich|G|G|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D007166:Immunosuppressive Agents; D009609:Nitrous Oxide; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.25270",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "62(3)",
"journal": "Pediatric blood & cancer",
"keywords": "leukemia; methotrexate; neurotoxicity; nitrous oxide",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D018712:Analgesics, Non-Narcotic; D002648:Child; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D007278:Injections, Spinal; D020300:Intracranial Hemorrhages; D008727:Methotrexate; D020258:Neurotoxicity Syndromes; D009609:Nitrous Oxide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011859:Radiography",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "539-41",
"pmc": null,
"pmid": "25360802",
"pubdate": "2015-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe neurotoxicity following intrathecal methotrexate with nitrous oxide sedation in a child with acute lymphoblastic leukemia.",
"title_normalized": "severe neurotoxicity following intrathecal methotrexate with nitrous oxide sedation in a child with acute lymphoblastic leukemia"
} | [
{
"companynumb": "DE-WATSON-2015-07505",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHOTREXATE SODIUM"
},
"drugadditional": null,
... |
{
"abstract": "Objective The objective of this study is to investigate the effectiveness of discontinuation of risedronate for patients with systemic lupus erythematosus (SLE) treated with glucocorticoid (GC). Methods The participants were patients with SLE treated with prednisolone (PSL) ≥ 2 mg/day and risedronate for at least three years. Lumbar spine and total hip bone mineral density (BMD) measurements were taken at baseline and 24 and 48 weeks after discontinuation of risedronate, and bone turnover markers were evaluated at baseline, 12, 24, 36, and 48 weeks. Results A total of 36 patients were enrolled, 25 of whom discontinued risedronate. The mean age was 46.8 ± 11.2 years, and 23 were female. The mean duration of GC treatment was 14.8 ± 11.4 years, the mean dose of PSL was 7.8 ± 3.9 mg/day, and the mean duration of risedronate was 5.8 ± 2.4 years. Seventeen patients showed decreased lumbar spine BMD at 48 weeks after discontinuation of risedronate, with a mean lumbar spine lumbar decrease of 1.42% ± 3.20% ( p = 0.034); 17 patients (71%) showed a decreased total hip BMD at 48 weeks after discontinuation of risedronate, with a mean total hip BMD decrease of 0.99% ± 2.10% ( p = 0.021). Serum tartrate-resistant acid phosphatase 5b (TRACP-5b) ≥ 309 mU/dl at baseline was a risk factor for decreased total hip BMD at 48 weeks compared with serum TRACP-5b < 309 mU/dl (56% vs 0%, p = 0.0098). One patient developed a clinical fracture of the lumbar spine at 20 weeks. Conclusions Discontinuation of risedronate treatment in patients with SLE who had received GC therapy led to decreases in lumbar spine and total hip BMD, particularly in patients with high baseline serum TRACP-5b levels.",
"affiliations": "Department of Internal Medicine (IV), Osaka Medical College, Osaka, Japan.;Department of Internal Medicine (IV), Osaka Medical College, Osaka, Japan.;Department of Internal Medicine (IV), Osaka Medical College, Osaka, Japan.;Department of Internal Medicine (IV), Osaka Medical College, Osaka, Japan.;Department of Internal Medicine (IV), Osaka Medical College, Osaka, Japan.;Department of Internal Medicine (IV), Osaka Medical College, Osaka, Japan.;Department of Internal Medicine (IV), Osaka Medical College, Osaka, Japan.;Department of Internal Medicine (IV), Osaka Medical College, Osaka, Japan.",
"authors": "Ishida|T|T|;Yoshida|S|S|;Kimura|Y|Y|;Fujiki|Y|Y|;Kotani|T|T|;Takeuchi|T|T|;Makino|S|S|;Arawaka|S|S|",
"chemical_list": "D015415:Biomarkers; D050071:Bone Density Conservation Agents; D005938:Glucocorticoids; D011239:Prednisolone; C000605510:ACP5 protein, human; D000071681:Tartrate-Resistant Acid Phosphatase; D000068296:Risedronic Acid",
"country": "England",
"delete": false,
"doi": "10.1177/0961203318784649",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0961-2033",
"issue": "27(10)",
"journal": "Lupus",
"keywords": "Osteoporosis; bisphosphonate; discontinuation; glucocorticoid; systemic lupus erythematosus",
"medline_ta": "Lupus",
"mesh_terms": "D000328:Adult; D015415:Biomarkers; D015519:Bone Density; D050071:Bone Density Conservation Agents; D004334:Drug Administration Schedule; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D008159:Lumbar Vertebrae; D008180:Lupus Erythematosus, Systemic; D008297:Male; D008875:Middle Aged; D010024:Osteoporosis; D010384:Pelvic Bones; D011239:Prednisolone; D065840:Protective Factors; D000068296:Risedronic Acid; D012307:Risk Factors; D000071681:Tartrate-Resistant Acid Phosphatase; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "9204265",
"other_id": null,
"pages": "1636-1643",
"pmc": null,
"pmid": "29954283",
"pubdate": "2018-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Efficacy of discontinuing risedronate for patients with systemic lupus erythematosus: a prospective study.",
"title_normalized": "efficacy of discontinuing risedronate for patients with systemic lupus erythematosus a prospective study"
} | [
{
"companynumb": "JP-TEVA-2018-JP-957523",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "We present a case of 29/m with a history of sickle cell disease who presented to the emergency department with sudden onset of chest, trunk, extremity, and back pain, consistent in quality and severity with the patient's usual pain crises. Soon after admission to the medical unit for acute chest syndrome (ACS), the patient developed sudden onset of hypertension associated with left sided hemiplegia, lethargy, dysarthria, aphasia, and left sided facial droop. Neuroimaging revealed that on MRI Brain there was multifocal extensive signal abnormality and a small focal areas of hemorrhage compatible with posterior reversible leukoencephalopathy syndrome (PRES). Patient was treated with levetiracetam and phenytoin and improved soon afterwards, with resolution seen on follow-up MRI two months later.",
"affiliations": "Hofstra Northwell Health, Staten Island University Hospital, Department of Psychiatry, Staten Island, NY, USA.;Hofstra Northwell Health, Staten Island University Hospital, Department of Radiology, Staten Island, NY, USA.;Hofstra Northwell Health, Staten Island University Hospital, Department of Neurology, Staten Island, NY, USA.",
"authors": "Aiyer|Rohit|R|0000-0001-5066-4014;Klein|Daniel|D|;El-Sherif|Yasir|Y|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2016/4346953",
"fulltext": "\n==== Front\nCase Rep RadiolCase Rep RadiolCRIRACase Reports in Radiology2090-68622090-6870Hindawi Publishing Corporation 10.1155/2016/4346953Case ReportRare Case of Posterior Reversible Leukoencephalopathy Syndrome Secondary to Acute Chest Syndrome http://orcid.org/0000-0001-5066-4014Aiyer Rohit \n1\n\n*\nKlein Daniel \n2\nEl-Sherif Yasir \n3\n1Hofstra Northwell Health, Staten Island University Hospital, Department of Psychiatry, Staten Island, NY, USA2Hofstra Northwell Health, Staten Island University Hospital, Department of Radiology, Staten Island, NY, USA3Hofstra Northwell Health, Staten Island University Hospital, Department of Neurology, Staten Island, NY, USA*Rohit Aiyer: rohitaiyer@gmail.comAcademic Editor: Alberto Spalice\n\n2016 10 11 2016 2016 434695326 5 2016 27 9 2016 5 10 2016 Copyright © 2016 Rohit Aiyer 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.We present a case of 29/m with a history of sickle cell disease who presented to the emergency department with sudden onset of chest, trunk, extremity, and back pain, consistent in quality and severity with the patient's usual pain crises. Soon after admission to the medical unit for acute chest syndrome (ACS), the patient developed sudden onset of hypertension associated with left sided hemiplegia, lethargy, dysarthria, aphasia, and left sided facial droop. Neuroimaging revealed that on MRI Brain there was multifocal extensive signal abnormality and a small focal areas of hemorrhage compatible with posterior reversible leukoencephalopathy syndrome (PRES). Patient was treated with levetiracetam and phenytoin and improved soon afterwards, with resolution seen on follow-up MRI two months later.\n==== Body\n1. Case\nPatient is a 29/m, with a history of sickle cell disease and presenting to the emergency department with sudden onset of diffuse pain to chest, extremities, trunk, and back. This presentation in pain, with regards to quality and severity, was consistent with previous usual pain crises that the patient describes having in the past, and the patient was typically admitted to our inpatient medicine service for pain management with no current home medications. In the emergency department, the patient was given intravenous hydromorphone 4 mg for management of his pain. Patient's vital signs were within normal limits, including blood pressure of 113/64. Initial labs indicated hemoglobin of 8.0 and hematocrit of 21.1, as well as reticulocyte count of 9.58% and immature reticulocyte fraction of 42.2%, consistent with acute chest syndrome (ACS) secondary to sickle cell disease. All other laboratory findings were within normal range, including the patient's renal function (creatinine: 0.46 mg/dL, blood urea nitrogen: 9 mg/dL). Due to the patient's low hemoglobin levels, they were transfused 10 units of packed red blood cells before being admitted to the inpatient medical unit.\n\nWhile on the inpatient medical floor, patient's pain was managed by the pain management team. After two weeks, the patient had a sudden onset of hypertension secondary to acute kidney injury (creatinine: 5.19 mg/dL, blood urine nitrogen: 57 mg/dL), with a blood pressure reading of 212/96, and was found to have witnessed generalized tonic-clonic seizure lasting 1 minute. After the seizure, patient was found to have on examination, left facial droop, left upper extremity power of 3/5, left lower extremity power of 3/5, sensory neglect, dysarthria, perservation, and confusion. Based on neurological clinical findings, the weakness was likely due to a right focal onset with secondary generalization. Left hemiparesis was clearly present and was initially suspected to be due to an infarct. After Computed Tomography (CT) head imaging was performed it was reported as abnormal signal intensity in periventricular white matter, subcortical internal and external capsules, basal ganglia, and corpus callosum suspicious for posterior reversible encephalopathy syndrome (PRES) (Figures 1(a), 1(b), and 1(c)).\n\nThese findings prompted further neuroradiological imaging. Subsequently, magnetic resonance imaging (MRI GE, 3 Tesla) of the brain, with and without gadolinium (DTPA), was ordered. MRI indicated that the patient had extensive white matter signal abnormality within the bilateral frontal and parietal lobes with extension into the temporal lobes supporting and initial impression of PRES (Figures 2(a), 2(b), 3(a), and 3(b)). As a result, patient was started on levetiracetam 500 milligrams intravenous q12h and phenytoin 100 milligrams intravenous q8h and placed on a video electroencephalogram (vEEG). The vEEG demonstrated focal slowing in right hemisphere, suggestive of underlying structural lesion. After a few days, the patient's symptoms resolved and became neurologically stable, and the patient was discharged on oral preparation of phenytoin 100 mg q8h and levetiracetam 500 milligrams q12h. After 8 weeks, the patient was tapered off phenytoin, and after 8 months the patient continues to be treated at the same dose of oral levetiracetam.\n\nFollow-up MRI Brain was done 10 days later, which showed partial resolution of the abnormal signal within the periventricular white matter, subcortical white matter, basal ganglia, and brainstem (Figures 4(a) and 4(b)). A further follow-up MRI was done 2 months later, which showed near complete resolution of hemorrhage and white matter abnormalities, as well as a completely normal neurological exam (Figures 4(a) and 4(b)).\n\n2. Discussion\nPosterior reversible leukoencephalopathy syndrome (PRES) was described by Hinchey et al. as a syndrome consistent with neurologic symptoms including headache, visual changes, seizures, or altered consciousness. Neuroimaging can confirm PRES, with MRI illustrating subcortical edema in the posterior regions of the cerebral hemispheres without infarction [1]. The risk factors for PRES can include the consumption of cytotoxic and immunosuppressive drugs, hypertensive encephalopathy, and eclampsia. Lesions in PRES are thought to be secondary to vasogenic edema that occurs mainly in the posterior cerebral hemispheres [2].\n\nThe pathophysiology of PRES is still relatively unknown with different perspectives. One hypothesis is that severe hypertension causes impaired cerebrovascular autoregulation, vasodilatation, and vasogenic edema [3]. Literature reviews on PRES and hypertension widely discuss the “endothelial hypothesis” as the pathophysiological cause for a patient's high blood pressure [4]. This hypothesis is based on the fact that endothelial dysfunction is due to insufficient production of nitric oxide (a potent vasodilator). In addition, there is endothelial activation which causes an increase in cell adhesion and narrowing of vessel lumen, which also contributes to hypertension [4]. These endothelial injuries cause for a narrowing of blood vessels and therefore create difficult in the flow of erythrocytes, leading to mechanical stress and resulting in many of the clinical signs and symptoms of PRES [4].\n\nAnother proposed idea is that toxicity of immunosuppressive drugs can lead to impaired endothelial homeostasis. However, PRES appears to be related to endothelial dysfunction that leads to cerebrovascular autoregulation impairment and vasogenic edema. Evidently, since endothelial dysfunction is thought to play a part in the cerebrovascular disease observed in Sickle Cell (SC) anemia, SC patients may have an increased risk of developing PRES [3].\n\nAlthough seizures are the most common presentation, such as in our case presentation, PRES can also present with headache, visual disturbances, altered mental status, vomiting, ataxia, aphasia, or hemiparesis [3]. PRES is characterized by reversible radiographic signs of posterior leukoencephalopathy in the presence of headache, altered level of consciousness, and seizures with or without visual disturbances [5].\n\nOur literature review showed that there are only 15 patients from the pediatric population (<18 years), and even less from the adult population (two patients). Therefore, to our knowledge, we believe that our case is only the third reported case in literature in an adult with PRES secondary to sickle cell crisis [6]. It should be noted that cases reported as stroke in the literature were unrecognized PRES, and therefore a literature search would overlook these findings [3]. Investigating the difference between PRES from a stroke can be difficult, yet the distinction is important as cerebral infarction suggests irreversible tissue injury. However, vasogenic edema and reversibility are thought to be the core sign of PRES [7].\n\nCompeting Interests\nThe authors declare that they have no competing interests.\n\nFigure 1 CT Head-Axial images demonstrate extensive multifocal areas of white matter hypoattenuation/edema.\n\nFigure 2 MRI Brain-Axial FLAIR-weighted images demonstrate the multifocal areas of edema involving the subcortical and deep white matter as well as the deep grey structures. Edema is also noted in the genu of the corpus collosum.\n\nFigure 3 MRI Brain-Axial gradient echo-weighted images demonstrate susceptibility effect in the genu and splenium of the corpus collosum as well as the left frontal periventricular white matter compatible with multifocal hemorrhage.\n\nFigure 4 MRI Brain-Axial FLAIR-weighted images demonstrate improvement in the areas of edema over 10 days and 2 months.\n==== Refs\n1 Hinchey J. Chaves C. Appignani B. A reversible posterior leukoencephalopathy syndrome The New England Journal of Medicine 1996 334 8 494 500 10.1056/nejm199602223340803 2-s2.0-13344284635 8559202 \n2 Landais A. Lemonne N. Etienne-Julan M. Uncommon posterior reversible encephalopathy syndrome in a sickle-cell patient Journal of Clinical Neurology 2015 11 3 287 288 10.3988/jcn.2015.11.3.287 2-s2.0-84937032447 26022462 \n3 Solh Z. Taccone M. Marin S. Athale U. Breakey V. R. Neurological PRESentations in sickle cell patients are not always stroke: a review of posterior reversible encephalopathy syndrome in sickle cell disease Pediatric Blood & Cancer 2016 63 983 989 26871763 \n4 Marra A. Vargas M. Striano P. Del Guercio L. Buonanno P. Servillo G. Posterior reversible encephalopathy syndrome: the endothelial hypotheses Medical Hypotheses 2014 82 5 619 622 10.1016/j.mehy.2014.02.022 2-s2.0-84897111755 24613735 \n5 Wang W. C. Central nervous system complications of sickle cell disease in children: an overview Child Neuropsychology 2007 13 2 103 119 10.1080/09297040600788136 2-s2.0-33847776875 17364568 \n6 Geevasinga N. Cole C. Herkes G. K. Barnett Y. Lin J. Needham M. Sickle cell disease and posterior reversible leukoencephalopathy Journal of Clinical Neuroscience 2014 21 8 1329 1332 10.1016/j.jocn.2013.10.028 2-s2.0-84904254157 24656986 \n7 Henderson J. N. Noetzel M. J. McKinstry R. C. White D. A. Armstrong M. DeBaun M. R. Reversible posterior leukoencephalopathy syndrome and silent cerebral infarcts are associated with severe acute chest syndrome in children with sickle cell disease Blood 2003 101 2 415 419 10.1182/blood-2002-04-1183 2-s2.0-0037438366 12393443 12393443\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6870",
"issue": "2016()",
"journal": "Case reports in radiology",
"keywords": null,
"medline_ta": "Case Rep Radiol",
"mesh_terms": null,
"nlm_unique_id": "101580187",
"other_id": null,
"pages": "4346953",
"pmc": null,
"pmid": "27957377",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": "17364568;24613735;26871763;8559202;24656986;12393443;26022462",
"title": "Rare Case of Posterior Reversible Leukoencephalopathy Syndrome Secondary to Acute Chest Syndrome.",
"title_normalized": "rare case of posterior reversible leukoencephalopathy syndrome secondary to acute chest syndrome"
} | [
{
"companynumb": "US-UCBSA-2017000601",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "PHENYTOIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "Few advances in the treatment of advanced epithelial ovarian cancer have improved patient overall survival. However, the incorporation of intraperitoneal administration of platinum based chemotherapy to standard treatment was one such advancement. It is understood that the intraperitoneal regimen is associated with increased toxicity when compared to intravenous administration alone; however, information regarding the specific risk of ototoxicity is lacking in the literature. We report a case of almost complete sensorineural hearing loss after one cycle of intraperitoneal cisplatin. Three days after receiving an intravenous 24 h paclitaxel at 135 mg/m2 and subsequent intraperitoneal infusion of cisplatin at 75 mg/m2, the patient presented with profound bilateral sensorineural hearing loss. The patient experienced no recovery of hearing despite an aggressive systemic steroid taper and change in chemotherapy regimen to alternative agents. She is currently under consideration for cochlear device implantation. Generally, cisplatin related ototoxicity during treatment of epithelial ovarian cancer is gradual, limited to high-frequency ranges and dose-related; however, the toxicity with only one standard dose can be profound and irreversible. This risk should be addressed when counseling patients prior to initiation of treatment.",
"affiliations": "Division of Gynecologic Oncology, The University of Iowa Hospitals and Clinics, Iowa City, IA, United States.;Department of Obstetrics and Gynecology, The University of Iowa Hospitals and Clinics, Iowa City, IA, United States.;Division of Gynecologic Oncology, The University of Iowa Hospitals and Clinics, Iowa City, IA, United States.",
"authors": "McDonald|Megan E|ME|;Mattson|Jordan|J|;Hill|Emily|E|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.gore.2017.03.011",
"fulltext": "\n==== Front\nGynecol Oncol RepGynecol Oncol RepGynecologic Oncology Reports2352-5789Elsevier S2352-5789(17)30033-410.1016/j.gore.2017.03.011Case ReportProfound sensorineural hearing loss after one cycle of intraperitoneal cisplatin in treatment of advanced ovarian cancer McDonald Megan E. megan-e-mcdonald@uiowa.edua⁎Mattson Jordan bHill Emily aa Division of Gynecologic Oncology, The University of Iowa Hospitals and Clinics, Iowa City, IA, United Statesb Department of Obstetrics and Gynecology, The University of Iowa Hospitals and Clinics, Iowa City, IA, United States⁎ Corresponding author at: Division of Gynecologic Oncology, The University of Iowa, 200 Hawkins Dr., Iowa City, IA 52242, United States.Division of Gynecologic OncologyThe University of Iowa200 Hawkins Dr.Iowa CityIA52242United States megan-e-mcdonald@uiowa.edu21 3 2017 5 2017 21 3 2017 20 103 104 19 12 2016 10 3 2017 16 3 2017 © 2017 The Authors2017This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Few advances in the treatment of advanced epithelial ovarian cancer have improved patient overall survival. However, the incorporation of intraperitoneal administration of platinum based chemotherapy to standard treatment was one such advancement. It is understood that the intraperitoneal regimen is associated with increased toxicity when compared to intravenous administration alone; however, information regarding the specific risk of ototoxicity is lacking in the literature. We report a case of almost complete sensorineural hearing loss after one cycle of intraperitoneal cisplatin. Three days after receiving an intravenous 24 h paclitaxel at 135 mg/m2 and subsequent intraperitoneal infusion of cisplatin at 75 mg/m2, the patient presented with profound bilateral sensorineural hearing loss. The patient experienced no recovery of hearing despite an aggressive systemic steroid taper and change in chemotherapy regimen to alternative agents. She is currently under consideration for cochlear device implantation. Generally, cisplatin related ototoxicity during treatment of epithelial ovarian cancer is gradual, limited to high-frequency ranges and dose-related; however, the toxicity with only one standard dose can be profound and irreversible. This risk should be addressed when counseling patients prior to initiation of treatment.\n\nHighlights\n• Cisplatin induced ototoxicity can be severe and irreversible after just one dose.\n\n• The mainstay of treatment remains early recognition and treatment modification.\n\n• Counseling regarding cisplatin induced ototoxicity should be included in the consent process.\n\n\n\nKeywords\nIntraperitoneal cisplatin chemotherapyAdvanced ovarian cancerOtotoxicity\n==== Body\n1 Case report\nThe patient is a 57-year-old G4P3 female who presented with abdominal pain. She initially underwent a transvaginal ultrasound with suboptimal visualization of gynecologic organs due to abdominal ascites. A subsequent CT scan demonstrated omental caking and large volume ascites. Serum Ca-125 was elevated at 1196. The patient underwent an exploratory laparotomy, total abdominal hysterectomy, bilateral salpingo oophorectomy, infracolic and infragastric omentectomy, optimal cytoreductive surgery, and intraperitoneal port placement with a final diagnosis of stage IIIC high grade serous adenocarcinoma of the ovary. Her post-operative course was uncomplicated other than an ileus and she was discharged to home on post-operative day 9. Prior to discharge, the patient was noted to have an erythematous patch over the sacrum with vesicular lesions in multiple stages of healing. Herpes Simplex Virus 2 (HSV2) PCR returned positive. The patient was started on Valacyclovir 1 g three times a day for a one week course. Additionally, the patient was prescribed a 1 g daily suppressive dose of Valacyclovir to be continued throughout chemotherapy. Unfortunately, the suppressive Valacyclovir was not taken as recommended due to miscommunication.\n\nOn post-operative day 30, the patient was admitted to the hospital for cycle 1 of intravenous paclitaxel and intraperitoneal cisplatin chemotherapy. The patient received a 24 h infusion of paclitaxel at a dose of 135 mg/m2 on cycle day 1. On cycle day 2, the patient received 25 g of mannitol intravenously, followed by cisplatin 75 mg/m2. Per institutional protocol, the cisplatin was diluted in 1 L normal saline and infused as rapidly as possible via the intraperitoneal port. The patient tolerated the infusions well and there were no immediate complications.\n\nOn cycle day 6, the patient presented to clinic after calling with complaints of bilateral hearing loss. Audiogram with the Otolaryngologist confirmed profound sensorineural hearing loss bilaterally with a word discrimination score of 0% in both ears (ototoxicity grade 4). The same day, she was started on a 60 mg prednisone taper over the next 18 days. Day 8 intraperitoneal paclitaxel was held. On cycle day 9, the patient was admitted to the hospital with neutropenic fever of unknown origin and acute kidney injury, both of which resolved after antibiotics and hydration. Following discharge, the patient underwent an MRI of the brain to evaluate for metastatic lesions as a potential cause of hearing loss, which was normal. Repeat audiogram after completion of the steroid taper revealed no recovery in hearing. Chemotherapy treatment was switched to Docetaxel 60 mg/m2 and Carboplatin AUC 5 for cycle 2. The Carboplatin dose was escalated to an AUC 6 for cycles 3–6, as this regimen was well tolerated with no grade 3–4 toxicities or readmissions. Six months after the initiation of chemotherapy, the patient has had minimal recovery from her profound hearing loss and is currently undergoing implantation of a cochlear device.\n\n2 Discussion\nOtotoxicity related to cisplatin can be attributed to the inhibition of adenylate cyclase and subsequent damage within the organ of Corti due to severe destruction of outer hair cells in the basal turn of the cochlea (Bagger-Sjoback et al., 1980, Guarino et al., 1979). Whereas the half-life of cisplatin in the serums is < 1 h, an increase in cisplatin concentration over 24 h is seen within the organ or Cori (Nakai et al., 1982). This explains its particular sensitivity to the adverse effects of the drug. Cisplatin related ototoxicity is generally thought to be dose dependent, with development of clinically detectable high frequency hearing loss occurring only after high accumulated doses of > 500 mg/m2 (Chiuten et al., 1983). However, a wide variation in individual ototoxicity among patients has been reported and is thought to be multifactorial in etiology, with factors including the presence of genetic polymorphisms in the cisplatin metabolism pathway, method of cisplatin administration, presence of baseline hearing loss and dose per treatment (Riedemann et al., 2008, Peters et al., 2000, Pussegoda et al., 2013, Brock et al., 2012). Another possibly related co-existent medical condition in our patient was a recent infection with HSV, as there is data that viral infection, particularly with herpes zoster or simplex 1, can be implicated in idiopathic sudden sensorineural hearing loss (Awad et al., 2012, Stokroos et al., 1998). Despite the known risk of ototoxicity, there is insufficient data to recommend concomitant use of otoprotective agents with cisplatin, such as amifostine, vitamin E, or intratympanic dexamethasone. The mainstay in treatment of cisplatin related ototoxicity is early recognition and, if possible, treatment modification.\n\nA series of phase III randomized controlled trials have demonstrated an overall survival benefit with intraperitoneal chemotherapy in the treatment of optimally debulked epithelial ovarian cancer, which led to an NCI Clinical Announcement in 2006 (Alberts et al., 1996, Markman et al., 2001, Armstrong et al., 2006). As such, intraperitoneal chemotherapy has become the standard of care in this patient population. The use of cisplatin in this group is often hindered by its dose-limiting adverse effects on kidney function, myelosuppression, gastrointestinal toxicity, and peripheral neurotoxicity; however, the specific risks of ototoxicity are poorly defined. While the rates of overall neurotoxicity are higher in the intraperitoneal arm of GOG 114 and 172, this more frequently reflects peripheral sensorial neuropathy (Markman et al., 2001, Armstrong et al., 2006). Only GOG 104 specifically comments on the frequency of tinnitus and hearing loss. Within this trial, the frequency of ≥ grade 2 ototoxicity was actually found to be less in the intraperitoneal arm than the intravenous arm; tinnitus 7% vs 14% (p = 0.01) and hearing loss 5% vs 15% (p < 0.0001) (Alberts et al., 1996).\n\nAlthough the precise rate of ototoxicity with the currently used intraperitoneal chemotherapy regimens remains somewhat unclear, there are available reports of patients developing severe hearing loss during this treatment. A 2011 phase II trial attempted to limit the toxicity of the intraperitoneal chemotherapy through modification of the GOG 172 treatment regimen. In this study, paclitaxel 135 mg/m2 was infused over 3 h on day 1 and cisplatin 50 mg/m2 was given intraperitoneally on day 1 and day 8. Despite the split dosing of cisplatin, of the 21 patients receiving this modified regimen, two were unable to complete the recommended treatment due to grade 3–4 hearing loss (Landrum et al., 2011). Additionally, there has been one other case report demonstrating profound hearing loss after one dose of intraperitoneal cisplatin for treatment of ovarian cancer (Nieves et al., 2007). Our case differs in that she received a lower dose of cisplatin (75 mg/m2 rather than 100 mg/m2) and at a longer interval from surgery (4 vs. 2 weeks). Our report further corroborates the finding that ototoxicity after minimal amounts of cisplatin can be significant and despite prompt management with systemic steroids, most likely permanent. This has considerable potential to negatively affect patient quality of life, which is an important consideration in a cancer where upfront treatment is rarely curative. The possibility of profound ototoxicity should be included in patient counseling about adverse effects associated with intraperitoneal cisplatin chemotherapy and consideration given to auditory testing before and during treatment.\n\nDisclosures\nThe authors have no conflicts to disclose.\n==== Refs\nReferences\nBagger-Sjoback D. Filipek C.S. Schacht J. Characteristics and drug responses of cochlear and vestibular adenylate cyclase Arch. Otorhinolaryngol. 228 3 1980 217 222 6968555 \nGuarino A.M. Platinate toxicity: past, present, and prospects Cancer Treat Rep. 63 9–10 1979 1475 1483 159127 \nNakai Y. Ototoxicity of the anticancer drug cisplatin. An experimental study Acta Otolaryngol. 93 1–6 1982 227 232 7199807 \nChiuten D. Vogl S. Kaplan B. Camacho F. Is there cumulative or delayed toxicity from cis- platinum? Cancer 52 1983 211 214 6683119 \nRiedemann L. Megalin genetic polymorphisms and individual sensitivity to the ototoxic effect of cisplatin Pharmacogenomics J. 8 1 2008 23 28 17457342 \nPeters U. Glutathione S-transferase genetic polymorphisms and individual sensitivity to the ototoxic effect of cisplatin Anti-Cancer Drugs 11 8 2000 639 643 11081456 \nPussegoda K. Replication of TPMT and ABCC3 genetic variants highly associated with cisplatin-induced hearing loss in children Clin. Pharmacol. Ther. 94 2 2013 243 251 23588304 \nBrock P.R. Platinum-induced ototoxicity in children: a consensus review on mechanisms, predisposition, and protection, including a new International Society of Pediatric Oncology Boston ototoxicity scale J. Clin. Oncol. 30 19 2012 2408 2417 22547603 \nAwad Z. Huins C. Pothier D.D. Antivirals for idiopathic sudden sensorineural hearing loss Cochrane Database Syst. Rev. 8 2012 CD006987 22895957 \nStokroos R.J. Albers F.W. Schirm J. The etiology of idiopathic sudden sensorineural hearing loss. Experimental herpes simplex virus infection of the inner ear Am. J. Otol. 19 4 1998 447 452 9661753 \nAlberts D.S. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer N. Engl. J. Med. 335 26 1996 1950 1955 8960474 \nMarkman M. Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume stage III ovarian carcinoma: an intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group J. Clin. Oncol. 19 4 2001 1001 1007 11181662 \nArmstrong D.K. Intraperitoneal cisplatin and paclitaxel in ovarian cancer N. Engl. J. Med. 354 1 2006 34 43 16394300 \nLandrum L.M. Phase II trial of intraperitoneal cisplatin combined with intravenous paclitaxel in patients with ovarian, primary peritoneal and fallopian tube cancer Gynecol. Oncol. 122 3 2011 527 531 21664657 \nNieves L. Ototoxicity after intraperitoneal chemotherapy: a case report Int. J. Gynecol. Cancer 17 5 2007 1133 1135 17433058\n\n",
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"journal": "Gynecologic oncology reports",
"keywords": "Advanced ovarian cancer; Intraperitoneal cisplatin chemotherapy; Ototoxicity",
"medline_ta": "Gynecol Oncol Rep",
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"pages": "103-104",
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"pubdate": "2017-05",
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"title": "Profound sensorineural hearing loss after one cycle of intraperitoneal cisplatin in treatment of advanced ovarian cancer.",
"title_normalized": "profound sensorineural hearing loss after one cycle of intraperitoneal cisplatin in treatment of advanced ovarian cancer"
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"abstract": "Cefiderocol is a new cephalosporin displaying against extensively resistant (XDR) Gram-negative bacteria. We report our experience with cefiderocol-based combination therapies as \"rescue\" treatments in immunocompromised or critically ill patients or in patients with post-surgical infections who had failed previous regimens. A total of 13 patients were treated from 1 September 2020 to 31 March 2021. In total, 5/13 (38%) patients were classified as critically ill, due to severe COVID-19 lung failure; 4/13 (31%) patients had post-surgical infections and 4/13 (31%) had severe infections in immunocompromised subjects due to solid organ transplantation (2/4) or hematological malignancy (2/4). Overall, 10/13 infections were caused by carbapenem-resistant Acinetobacter baumannii, one by KPC-positive ceftazidime/avibactam-resistant Klebsiella pneumonia and two by Pseudomonas aeruginosa XDR. Based on clinical, microbiological and hematobiochemical evaluation, cefiderocol was associated with different companion drugs, particularly with fosfomycin, high-dose tigecycline and/or colistin. Microbiological eradication was achieved in all cases and the 30-day survival rate was 10/13; two patients died due to SARS-CoV-2 lung failure, whereas one death was attributed to subsequent infections. No recurrent infections within 30 days were reported. Finally, we hereby discuss the therapeutic potential of cefiderocol and the possible place in the therapy of this novel drug.",
"affiliations": "Clinic of Infectious Diseases, Department of Biomedical Sciences and Human Oncology, University of Bari \"Aldo Moro\", 70124 Bari, Italy.;Clinic of Infectious Diseases, Department of Biomedical Sciences and Human Oncology, University of Bari \"Aldo Moro\", 70124 Bari, Italy.;Clinic of Infectious Diseases, Department of Biomedical Sciences and Human Oncology, University of Bari \"Aldo Moro\", 70124 Bari, Italy.;Anesthesia and Intensive Care Unit, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy.;Section of Microbiology and Virology, University of Bari, 70124 Bari, Italy.;Segreteria Scientifica Comitato Etico Area 2, University of Bari, 70124 Bari, Italy.;Section of Microbiology and Virology, University of Bari, 70124 Bari, Italy.;Section of Microbiology and Virology, University of Bari, 70124 Bari, Italy.;Segreteria Scientifica Comitato Etico Area 2, University of Bari, 70124 Bari, Italy.;Direttore Farmacia Ospedaliera AOU Policlinico di Bari, University of Bari, 70124 Bari, Italy.;Section of Microbiology and Virology, University of Bari, 70124 Bari, Italy.;Anesthesia and Intensive Care Unit, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy.;Anesthesia and Intensive Care Unit, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy.;Clinic of Infectious Diseases, Department of Biomedical Sciences and Human Oncology, University of Bari \"Aldo Moro\", 70124 Bari, Italy.",
"authors": "Bavaro|Davide Fiore|DF|0000-0002-4833-7118;Belati|Alessandra|A|;Diella|Lucia|L|;Stufano|Monica|M|;Romanelli|Federica|F|;Scalone|Luca|L|;Stolfa|Stefania|S|;Ronga|Luigi|L|;Maurmo|Leonarda|L|0000-0003-1687-504X;Dell'Aera|Maria|M|;Mosca|Adriana|A|;Dalfino|Lidia|L|;Grasso|Salvatore|S|;Saracino|Annalisa|A|",
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"country": "Switzerland",
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"doi": "10.3390/antibiotics10060652",
"fulltext": "\n==== Front\nAntibiotics (Basel)\nAntibiotics (Basel)\nantibiotics\nAntibiotics\n2079-6382\nMDPI\n\n34072342\n10.3390/antibiotics10060652\nantibiotics-10-00652\nArticle\nCefiderocol-Based Combination Therapy for “Difficult-to-Treat” Gram-Negative Severe Infections: Real-Life Case Series and Future Perspectives\nhttps://orcid.org/0000-0002-4833-7118\nBavaro Davide Fiore 1*†\nBelati Alessandra 1†\nDiella Lucia 1†\nStufano Monica 2\nRomanelli Federica 3\nScalone Luca 4\nStolfa Stefania 3\nRonga Luigi 3\nMaurmo Leonarda 4\nDell’Aera Maria 5\nMosca Adriana 3\nDalfino Lidia 2\nGrasso Salvatore 2\nSaracino Annalisa 1\nMaraolo Alberto Enrico Academic Editor\n1 Clinic of Infectious Diseases, Department of Biomedical Sciences and Human Oncology, University of Bari “Aldo Moro”, 70124 Bari, Italy; alessandra.belati@hotmail.it (A.B.); diella.lucia@libero.it (L.D.); annalisa.saracino@uniba.it (A.S.)\n2 Anesthesia and Intensive Care Unit, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy; monistufa@gmail.com (M.S.); lidia.dalfino@yahoo.com (L.D.); salvatore.grasso@uniba.it (S.G.)\n3 Section of Microbiology and Virology, University of Bari, 70124 Bari, Italy; federicarosaromanelli@gmail.com (F.R.); stolfastefania@gmail.com (S.S.); rongalu@yahoo.it (L.R.); adriana.mosca@uniba.it (A.M.)\n4 Segreteria Scientifica Comitato Etico Area 2, University of Bari, 70124 Bari, Italy; l.scalo91@virgilio.it (L.S.); leamaurmo94@gmail.com (L.M.)\n5 Direttore Farmacia Ospedaliera AOU Policlinico di Bari, University of Bari, 70124 Bari, Italy; maria.dellaera@policlinico.ba.it\n* Correspondence: davidebavaro@gmail.com\n† These authors contributed equally to this work.\n\n29 5 2021\n6 2021\n10 6 65229 4 2021\n27 5 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/).\nCefiderocol is a new cephalosporin displaying against extensively resistant (XDR) Gram-negative bacteria. We report our experience with cefiderocol-based combination therapies as “rescue” treatments in immunocompromised or critically ill patients or in patients with post-surgical infections who had failed previous regimens. A total of 13 patients were treated from 1 September 2020 to 31 March 2021. In total, 5/13 (38%) patients were classified as critically ill, due to severe COVID-19 lung failure; 4/13 (31%) patients had post-surgical infections and 4/13 (31%) had severe infections in immunocompromised subjects due to solid organ transplantation (2/4) or hematological malignancy (2/4). Overall, 10/13 infections were caused by carbapenem-resistant Acinetobacter baumannii, one by KPC-positive ceftazidime/avibactam-resistant Klebsiella pneumonia and two by Pseudomonas aeruginosa XDR. Based on clinical, microbiological and hematobiochemical evaluation, cefiderocol was associated with different companion drugs, particularly with fosfomycin, high-dose tigecycline and/or colistin. Microbiological eradication was achieved in all cases and the 30-day survival rate was 10/13; two patients died due to SARS-CoV-2 lung failure, whereas one death was attributed to subsequent infections. No recurrent infections within 30 days were reported. Finally, we hereby discuss the therapeutic potential of cefiderocol and the possible place in the therapy of this novel drug.\n\ncefiderocol\nmultidrug resistant gram-negative bacteria\nnovel antimicrobial strategies\nPseudomonas aeruginosa\nAcinetobacter baumannii\nKlebsiella pneumoniae\nimmunocompromised hosts\ncritically ill patients\n==== Body\n1. Introduction\n\nCefiderocol (formerly S-649266) is a new generation siderophore cephalosporin which inhibits bacterial wall synthesis, utilizing a “Trojan horse” mechanism based on iron active transporters. It has been developed to be active against extensively resistant (XDR) Gram-negative bacteria (GNB), including carbapenemase-producing Enterobacterales (CPE) and non-fermentative GNB [1]. These pathogens are often involved in difficult-to-treat (DTT) healthcare-associated infections (HCAI) [2], such as ventilator-associated pneumonia (VAP), [3] bloodstream infections (BSIs) [4] and intra-abdominal infections (IAIs) [5], and are burdened by elevated rates of morbidity and mortality, mostly in critically ill patients and immunocompromised hosts [6].\n\nAlthough carbapenem-resistant Klebsiella pneumoniae (CR-Kp) represent a major concern in hospital settings, due to the production of carbapenemases [7], other pathogens, such as Pseudomonas spp. and Acinetobacter spp., are emerging causes of DTT and difficult-to-eradicate infections, leading to recurrent infections, additional costs and length of hospital stay and dramatic mortality risk [8].\n\nColistin has been long considered the backbone of therapeutical strategies against XDR GNB; however, the unpredictable pharmacodynamic/pharmacokinetic (PK/PD) properties and the considerable kidney toxicity have forced clinicians to search for alternative antimicrobials or combination regimens in order to increase success rates [9]. Additionally, colistin resistance significantly increased in recent years, causing a further reduction of possible treatment options for XDR GNB infections [10]. In this scenario, cefiderocol represents a novel and very promising therapeutic opportunity.\n\nWith the exception of the three randomized non-inferiority clinical trials (the CREDIBLE-CR [11], the APEKS-NP [12] and the APEKS-cUTI [13]), only a few case reports and small case series described the use of cefiderocol in real-life settings [14,15,16], showing encouraging results. Accordingly, the aim of this study is to provide a description of our compassionate use clinical experience, and discuss possible future perspective of this new molecule in the treatment of severe infections in critically ill and immunocompromised hosts.\n\n2. Case Series\n\nOverall, 13 patients underwent treatment with cefiderocol. Median (q1–q3) age was 63 (53–69) years, and 11 subjects (84%) were males. Importantly, cefiderocol was used in three specific settings in our series:(i) 5/13 (38%) critically ill patients with severe lung failure due to underlying SARS-CoV-2 infection;\n\n(ii) 4/13 (31%) post-surgical infections;\n\n(iii) 4/13 (31%) severe infections in immunocompromised patients due to solid organ transplantation (2/4) or hematological malignancy (2/4).\n\nMedian time to diagnosis of the infection since hospital admission (or surgical procedures) was 10 (9–21) days. Overall, 10 carbapenem-resistant A. baumannii (CRAB), 1 ceftazidime/avibactam-resistant KPC producing K. pneumoniae (KPC-Kp) and 2 XDR P. aeruginosa (XDR-PA) were isolated from blood cultures (10/13), purulent abdominal drainages (2/13), tracheobronchial aspirates (2/13) and purulent drainage from a neurosurgical site (1/13). In the following paragraphs, the three different groups of patients are thoroughly described.\n\n2.1. Critically Ill Patients Due to Severe Lung Failure in the Course of SARS-CoV-2 Infection\n\nAll five critically ill patients included in this group were affected by primary central venous catheter (CVC)-CRAB BSI, which occurred during hospitalization: in 3/5 presenting as a septic shock and in 2/5 as a sepsis, with a median Sequential Organ Failure Assessment (SOFA) score of 6 (5–8).\n\nAt symptoms onset, 2/5 were mechanically ventilated, while the remaining 3/5 were hospitalized in sub-acute medical wards; all patients were treated with a colistin-based combination therapy and CVC removal, as shown in Table 1; however, after a median of 5 (4–7) days, the regimen was discontinued due to unsatisfactory clinical response, colistin resistance or colistin toxicity with persistence of positive blood cultures. Hence, a subsequent cefiderocol-based therapy, combined with fosfomycin, tigecycline or colistin, was initiated and continued for a median of 8 (5–10) days. Follow-up blood cultures were obtained at 48 h from the initial cefiderocol-based therapy (one set every day for aerobes and anaerobes), documenting complete bacteriemia clearance in all cases. Notably, no cefiderocol-related adverse events were recorded.\n\nIn all cases, a full dosage of 2 g of cefiderocol every 8 h was prescribed, excluding patient 5, who was affected by mild/moderate kidney failure due to colistin toxicity. In this case, a dosage of 1.5 g every 8 h was prescribed due to a median creatinine clearance of 45 mL/min, as per the SmPC guideline.\n\nClinical success, along with microbiological eradication from blood cultures, was achieved in all cases; however, one patient (Pt1) died due to worsening of SARS-CoV-2-related respiratory failure. Importantly, this patient was also affected by Huntington Chorea and immobilization syndrome; hence, he was not suitable for intubation and ICU hospitalization and deceased due to progressive muscular failure despite appropriate non-invasive ventilation. No Ventilator Associated Pneumonia (VAP) was documented by non-invasive upper respiratory lung sampling.\n\n2.2. Post-Surgical Infections\n\nHerein, we reported the use of cefiderocol in four male patients who developed severe “difficult-to-treat” gram-negative infections in the immediate post-surgical phases. The general characteristics of patients are reported in Table 2.\n\nAs opposed to the previously described group, four types of infections were diagnosed in this case:(i) A VAP caused by CRAB, in a patient mechanically ventilated post neurosurgical treatment for cerebral hemorrhage (Pt6);\n\n(ii) A CRAB BSI post-coronary angioplasty in a subject hospitalized for myocardial infarction in course of mild SARS-CoV-2 infection (Pt7);\n\n(iii) A neurosurgical wound infection post-parietal bone excision caused by XDR-P. aeruginosa (Pt8);\n\n(iv) A tertiary peritonitis with polymicrobial intrabdominal abscesses caused by CRAB, XDR-E. cloacae complex, M. morganii and ampicillin-resistant E. faecium in a patient hospitalized in the ICU (Pt9).\n\nNotably, all patients began cefiderocol-based combination therapy due to unsatisfactory clinical response to previous therapy; in addition, both Pt8 and Pt9 required a concurrent surgical debridement in order to achieve clinical success, which was obtained for all patients. At presentation, the median SOFA score was 3 (0–4). In all cases, a full antibiotic dosage was prescribed since no patient presented an altered kidney or hepatic function.\n\nThe duration of compassionate treatment was defined according to current guidelines for different infections, excluding the case of Pt9, whose critical conditions and fever persisted for 8 days after the initiation of cefiderocol; consequently, a prolonged duration of treatment was administered (21 days) until the resolution of intrabdominal abscesses as assessed by ultrasonography.\n\nWith the exception of one case (Pt7), where cefiderocol was used in addition to colistin and fosfomycin while awaiting results for sensitivity testing on a CRAB strain, the drug was prescribed in combination with fosfomycin or tigecycline. No adverse events to cefiderocol were recorded.\n\n2.3. Severe Infections in Immunocompromised Patients\n\nThe last four patients of this series were severely immunocompromised at the time of XDR GNB infection (Table 3). Importantly, two of them were solid organ transplant recipients (heart and liver, respectively), and both were affected by hematologic malignancies; in one case a myelodysplastic syndrome, in the other case an acute myeloid leukemia treated with allogenic stem cells transplantation. Additionally, in these cases, different types of infections were recorded:(i) Liver abscesses with BSI occurred 6 months after liver transplantation caused by KPC-producing K. pneumoniae resistant to ceftazidime/avibactam (Pt10);\n\n(ii) VAP with BSI caused by CRAB in a heart transplant recipient (Pt11);\n\n(iii) BSI due to CRAB in a patient with myelodysplastic syndrome, hospitalized for COVID-19 (Pt12);\n\n(iv) Severe multifocal pneumonia caused by XDR-P. aeruginosa in a patient with acute myeloid leukemia who underwent allogenic stem cells transplantation (Pt13).\n\nImportantly, patients in this group presented with a median SOFA score of 6 (4–11); additionally, two of them, Pt11 and Pt12, were hospitalized in intensive care unit at time of infection due to severe general clinical condition.\n\nIn all cases, the cefiderocol-based therapy was initiated due to unsatisfactory response to previous treatments and/or failure in microbiological eradication as assessed by biological samples. Herein, a prolonged treatment (at least 10 days) was administered in all patients, considering their impaired immune response, in order to reduce the risk of infection recurrence. Differently from previous cases, a combination with colistin plus an additional third drug was prescribed, excluding the case of XDR-P. aeruginosa pneumonia (due to the limited penetration of colistin in lung tissues).\n\nFor all patients, the 2 g T.I.D. cefiderocol regimen was prescribed, including Pt11, who was undergoing high effluent (4 L/hr) rate continuous-renal-replacement-therapy (CRRT) and a full dose of the antibiotic was requested according to the manufacturer sheet.\n\nNoteworthy, a complete microbiological eradication was achieved in all cases, although two patients deceased within 30 days. In one case, the unfavorable outcome was caused by the worsening of COVID-19 pneumonia (Pt12), without the occurrence of any new secondary infection, as documented by multiple negative microbiologic sampling, including upper and lower respiratory tract sampling. In the other case (Pt11), the patient suffered from multiple hospital complications, including gastroenteric bleeding due to congenital coagulopathy, a CVC-related BSI due to methicillin-resistant Staphylococcus epidermidis and a hepatosplenic invasive candidiasis due to C. parapsilosis, a hemophagocytic syndrome. Moreover, he also suffered from C. difficile colitis during the course of cefiderocol-based combination therapy.\n\n3. Discussion and Future Perspectives\n\nThis is among the most extensive case series describing the real-life use of cefiderocol for the treatment of severe XDR gram-negative bacterial infections, along with the multicentric experience by Bleibtreu and colleagues [17] and the monocentric experience of Falcone et al. [18]. In addition, this series enrolled “difficult-to-treat” patients, due to their important comorbidities, severe clinical conditions requiring ICU admission or deep immunocompromission. Indeed, the hardest treatment challenge is often fought in these settings, where multiple variables could severely influence the patient outcome; consequently, pathogens causing the infections, PK/PD characteristics of antibiotics and the need of combination therapy should be carefully considered along with patients’ features, so as to obtain the correct place in the therapy of different drugs and achieve optimal results.\n\nImportantly, beside the improvement of different therapeutic options, infection control remains the first and most important intervention to hamper the spreading of multidrug resistant organisms and reduce the morbidity of these infections. In the following paragraphs, the microbiological, pharmacological and possible clinical uses of cefiderocol are discussed.\n\n3.1. Spectrum of the Activity of Cefiderocol Against “Difficult-To-Treat” Bacteria\n\nCefiderocol has a significant antibacterial activity against Gram-negative bacteria such as Enterobacterales and non-fermenting bacilli [1]. Indeed, it shows minimal inhibitory concentration (MIC) values ≤2 μg/mL against Acinetobacter spp., Klebsiella spp. and Pseudomonas spp. [19]. On the other hand, cefiderocol demonstrates a weaker activity against aerobic Gram-positive or anaerobic pathogens. While the mechanism behind the inefficacy against aerobic Gram-positive bacteria has not been sufficiently investigated, for anaerobic microorganisms, it seems to be partially explained by a lower reliance on the siderophore-iron transporter system for growth under anaerobic conditions [20,21].\n\nIn Gram-negative bacteria, cefiderocol is able to penetrate into the periplasmic space and overcome the most common mechanisms of β-lactam resistance among Gram-negative microorganism, including porin deficiency, up-regulation of efflux pump expression and the production of β-lactamases. Indeed, it has an increased stability against hydrolysis by various types of β-lactamases, including both serine-based (KPC, OXA) and metallo-type (VIM, IMP, NDM) carbapenemases. Cefiderocol also presents antibacterial effectiveness against AmpC-overproducing strains of P. aeruginosa and E. cloacae, low affinity for chromosomal AmpC β-lactamases and low induction [22].\n\nImportantly, new antimicrobial agents recently approved for treatment of Gram-negative bacilli, such as new β-lactam/β-lactamase inhibitors (ceftazidime/avibactam, ceftolozane/tazobactam, meropenem/vaborbactam), show gaps of activity against some carbapenemases; thus, cefiderocol could play an important role in effective therapy against “difficult to-treat” Gram-negative bacteria, particularly MBL-producing Enterobacterales or ceftazidime/avibactam resistant KPC-K. pneumoniae, as well as XDR-P. aeruginosa and CRAB [23,24,25].\n\n3.2. Pharmacologic Aspects of Cefiderocol\n\nCefiderocol is a third-generation cephalosporin antibiotic class and is the first siderophore antibiotic approved by the FDA [26]. It is an injectable siderophore cephalosporin with potent broad-spectrum activity against aerobic MDR GNB, including the three pathogens declared as critical priority by the WHO: A. baumannii, P. aeruginosa and Enterobacterales resistant to carbapenems [27]. In addition, it displays in vitro activity against bacteria expressing enzymes that confer resistance, and therefore, those that are difficult to eradicate, such as ESBLs, AmpC, serine and metallo-beta lactamases.\n\nThe structural characteristics of cefiderocol show similarities with both ceftazidime and cefepime. Particularly, the addition of a catechol moiety on the C-3 side chain, with iron chelating activity mimics siderophore molecules produced by bacteria, conferring cefiderocol’s resistance to hydrolysis induced by β-lactamases. After the iron chelation, cefiderocol is actively transported across the bacterial outer membrane into the periplasmic space, through specific iron transport channels [28]. These channels allow cefiderocol to move easily within the cell wall, unlike other β-lactam antibiotics which can only act outside of this membrane and through other membrane permeability structures.\n\nIn vitro studies have shown that cefiderocol is 10 to 100 times more stable to different types of carbapenemases compared to ceftazidime. As opposed to other novel antibiotics and antibiotic/inhibitor combinations, cefiderocol also displays excellent in vitro activity against most of the class A, B, C and D β-lactamases of the Enterobacterales species [29].\n\nIn phase I studies, cefiderocol demonstrated a linear pharmacokinetics in the dose range of 100 mg to 4000 mg, a renal-type excretion, a 2–3 h elimination half-life and 58% protein binding in human plasma. Cefiderocol is a time-dependent cephalosporin: based on animal PK models, a fT > MIC of 75% of the dosing interval was selected as the target for cefiderocol. During this period, the free-drug concentration exceeding the minimum inhibitory concentration (ƒT/MIC) for the strains bacterial with a MIC ≤ 4 μg/mL can be reached with a regimen of 3-h infusion of 2 g every 8 h. Markers of renal function are the most influential covariates for the cefiderocol pharmacokinetics for patients with renal failure or increased renal clearance (ARC) [29].\n\nDose adjustment is recommended for patients with impaired renal function; moreover, in patients with ARC showing a creatinine clearance > 120 mL/minute, a more frequent dosing regimen was planned to achieve the target fT > MIC, i.e., 2 g every 6 h. The single and multiple doses of cefiderocol tested were well tolerated in both healthy subjects and those with renal insufficiency. Furthermore, in healthy subjects, neither QT interval prolongation nor drug–drug interaction via organic anion transporters were observed [28,29].\n\nThe most commonly reported adverse reactions were diarrhea (8.2%), vomiting (3.6%), nausea (3.3%) and cough (2%), as well as rash including macular rash, maculo-papular rash, erythematous rash and drug eruption and infusion site reactions including infusion site pain, injection site pain, infusion site erythema and injection site phlebitis. Less common events were hypersensitivity reactions, including skin reactions and pruritus.\n\nThe CREDIBLE-CR study demonstrated the cefiderocol efficacy and safety compared to Best Available Therapy (BAT) in the treatment of severe infections caused by carbapenem-resistant Gram-negative bacteria: this was a randomized Phase III, open label, multicenter, pathogen-focused and descriptive study [11].\n\nIn 71% of the patients assigned to BAT, the treatment was represented by combination therapy, with approximately 28 different combination regimens used, whereas in the 80% of patients treated with cefiderocol, this drug was used alone. Lastly, in 66% of BAT regimens, colistin backbone was employed for the treatment of severe infections caused by multidrug-resistant gram-negative bacteria, against which no other antibiotics proved their efficacy.\n\nColistin is an antibiotic belonging to the cationic glycopeptide antibiotics class and can be deemed as bacterial cell membrane surfactant: it acts against Gram-negative bacteria, by binding to the anionic component of the lipopolysaccharide membrane, resulting in the death of the bacteria [30]. Over time, bacteria could develop resistance mechanisms by modifying the lipid fraction of the lipopolysaccharide outer membrane: these changes positively charge the cell surface, which lacks affinity for positively charged polymyxins [31]. Therefore, in case of severe gram-negative infections with few therapeutic alternatives showing resistance to colistin, the use of cefiderocol proved decisive.\n\nThe results of the CREDIBLE-CR study [11] highlighted cefiderocol’s efficacy and safety in Gram-negative infections in a highly heterogeneous population of patients, who frequently have complex comorbidities. Clinical and microbiological outcomes were generally similar between cefiderocol and BAT. An imbalance of risk factors in the subgroup of patients with Acinetobacter spp. infections likely contributed to the difference in mortality observed between the two treatment arms. No differences in mortality were observed in patients with P. aeruginosa- or Enterobacterales- sustained infections without Acinetobacter spp. co-infections. None of the deaths were attributed to cefiderocol-related adverse events, as reviewed by the participating investigators and regulatory bodies assessing the mortality imbalance. Still, although not fully elucidated and currently under investigation, the CREDIBLE-CR resulted in a higher mortality in the cefiderocol group if compared with the BAT group. Therefore, the Food and Drug Administration included a warning box on this topic, recommending cefiderocol as a first line treatment only for complicated urinary tract infections.\n\n3.3. The Role of Combination Therapy\n\nThe role of combination therapy for the treatment of severe XDR gram-negative infections has long been debated [31]. Overall, in clinical practice, when a multidrug resistant gram-negative pathogen sustained infection is suspected, combination therapy is usually preferred in order to increase the possibility of initiating at least one effective treatment against the underlying cause of infection, especially in course of severe infections. However, definitive data are still lacking. In addition, beside the main benefit mostly driven by the increased spectrum of activity, combination therapy could have other advantages; for instance, in case of CRAB BSI, studies suggested a possible increased survival rate with combination therapy if compared with monotherapy [32], with beneficial effects of some combinations over others [33]. Indeed, several advantages could derive from the use of combination therapies: (i) synergistic effects with faster bacterial clearance; (ii) reduced emergence of resistant strains; (iii) broad spectrum activity (particularly useful in polymicrobial infections) [31].\n\nFirstly, upon combination of different classes of antibiotics, a synergistic effect can be obtained, determining a greater bactericidal action, since the therapeutic action is greater than the sum of each drug. A synergistic effect could determine a reduction in length of symptoms and possibly overall duration of antibiotic therapy [32]. Furthermore, a combination therapy could overcome antimicrobial resistance, allowing the use of agents against which bacteria had become resistant [34]. Indeed, several studies have compared the use of monotherapy vs combination therapy in difficult-to-treat infections caused by MDR pathogens. For example, Lenhard and colleagues demonstrated that the use of colistin + meropenem against XDR A. baumannii (colistin, meropenem and ampicillin/sulbactam resistant) did not lead to eradication of the infection, whereas addition of ampicillin/sulbactam made it possible [35]. Bulman and colleagues showed a similar effect on mcr1 + blaNDM + E. coli using colistin, aztreonam and amikacin alone or in combination. The bacterium was resistant to each single agent, but susceptible and completely eradicated by combination therapy [36].\n\nSecondly, another advantage of combination therapy is the reduction of onset of resistance. The spontaneous development of resistance often occurs by chance. Therefore, the use of more antibiotics reduces the risk of concurrent selection of spontaneous resistance. However, the development of resistance does not always target a single molecule, but in some cases, a cross-resistance to multiple classes of antibiotics may develop. This is the case of efflux pumps and porin mutations that confer resistance to multiple agents [37,38]. Moreover, recent experiences also explored this effect in vivo: the initiation of combination therapy could possibly reduce the risk of developing a subsequent multidrug-resistant Gram-negative BSI or fungemia in patients with BSI, if compared with those treated with monotherapy [39].\n\nA third aspect is represented by the broader spectrum of activity that is associated with increased possibility of initiating an empirical antibiotic regimen with at least one active drug, providing adequate coverage for potential MDR pathogens, especially in settings with high rates of antimicrobial resistance, thus causing a decreased mortality rate [40,41]. However, recent studies demonstrated that in settings with lower rates of antimicrobial resistance, expanding the spectrum of activity of initial antimicrobial therapy did not reduce mortality but increased toxicity [42].\n\nOn the other hand, combination therapy surely has some disadvantages, such as: (i) increasing toxicity due to pharmacokinetic interactions (i.e., vancomycin plus piperacillin/tazobactam can cause an increase of acute kidney failure) [43]; (ii) increasing the risk of C. difficile infections; (iii) risk of fungal overgrowth and invasive fungal infections; (iv) need of dedicated catheter accesses (complicating nursing management and risk of catheter-associated complications). Cefiderocol-based combination therapy has not been studied yet taking these issues into account.\n\nA few in vitro reports suggested a potential beneficial effect of combination therapies, especially for “difficult-to-treat” pathogens [44]; until further data are available, clinicians need to outweigh the risks and benefits of cefiderocol, and consideration should be given to combination therapy.\n\nHowever, due to the pharmacodynamic characteristics of cefiderocol, the choice of a combination therapy appears to be the safest, in order to avoid resistance development and to exploit a potential synergistic/additional effect. Therefore, the choice of “companion drug(s)” need to be tailored according to the involved pathogen(s) in order to obtain the maximum efficacy. Overall, the use of a second drug displaying full activity against the isolated pathogen should be encouraged, at least until future studies will demonstrate a clear synergistic effect between cefiderocol and other antibiotics. For instance, in our experience, cefiderocol displayed a high efficacy against P. aeruginosa when combined with Fosfomycin, while colistin or a high dose of tigecycline were preferred against CRAB. Conversely, our experience was limited to treating ceftazidime/avibactam-resistant KPC-K. pneumoniae; however, the definitive treatment regimen was built with fosfomycin due to its reduced toxicity. Further studies are certainly warranted on this topic.\n\n3.4. Place in Therapy in Critically Ill Patients\n\nIn our series, the group of critically ill patients was mainly composed of subjects suffering of severe acute respiratory failure with underlying COVID-19 disease. However, a few patients, enrolled in the post-surgical group or the immunocompromised group, were also critical and hospitalized in intensive care units (ICUs). Interestingly, these categories are very different for multiple reasons, and the spectrum of “critically ill patients” is remarkably wider; therefore, certain considerations can be applied only in our setting.\n\nOverall, it should be acknowledged that within the group of “critically ill,” only patients with CVC-related BSI by CRAB were enrolled. Particularly, excluding the case of (Pt1), all patients were known to be colonized by CRAB, and a colistin-based therapy was immediately started at symptoms onset, along with the vascular device removal when the blood culture was positive. Consequently, the use of cefiderocol was restricted to the later phases of the infection, when patients were already hemodynamically stabilized, and the device removed. Still, blood cultures remained persistently positive, and the drug was used to achieve complete resolution of bacteremia. Interestingly, all patients enrolled obtained negative blood cultures within 48 h from therapy initiation, although one subject (Pt1) deceased a few days later due to COVID-19-related complications along with the detrimental effects of sepsis, as the anti-CRAB treatment was started with a 48 h delay due to his unknown colonization status. Indeed, one of the main concerns in ICU is the appropriateness of initial antibiotic therapy upon diagnosis of septic shock [45], whereby treatment delay is markedly associated with increased risk of death. Accordingly, international sepsis management guidelines [46] suggested to use a wide spectrum antibiotic therapy, possibly within 1 h from the clinical diagnosis of septic shock [47], in order to reduce mortality. However, in the context of patients colonized by multiple MDR or XDR bacteria, such as those hospitalized in ICU for a long time, selecting an early empirical antibiotic therapy with at least one active drug against the causative pathogen could be challenging without mixing multiple drugs.\n\nA future place in the therapy of cefiderocol could, eventually, be as initial antibiotic therapy in patients colonized by XDR Gram-negative pathogens with limited treatment options or colonized by multiple pathogens with different spectrums of sensitivity, in case of high risk of sepsis caused by those resistant strains. Indeed, by exploiting its high bactericidal and broad spectrum of activity [21], clinicians could provide an early complete coverage against Gram-negative bacteria. However, the use of cefiderocol in septic shock should be discouraged until further evidence will suggest its effectiveness. Indeed, according to the FDA label and CREDIBLE-CR study [11], cefiderocol in this setting has been related to a higher mortality compared to the best available therapy, although the precise explanation has still not been elucidated. Yet, the advantages of this choice should be balanced with the risk of developing resistance, particularly in case of inappropriate use, or in case of inadequate compliance with PK/PD [48,49], and therefore, it should be reserved for the treatment of severe infections in selected patients.\n\nMoreover, our experience confirmed the remarkable efficacy of cefiderocol in treating nosocomial pneumonia: notably, three patients (Pt6, Pt11, Pt13) successfully eradicated the lung infections after failing the conventional treatment based on currently available drugs. This result is in line with previous reports suggesting the efficacy of cefiderocol for the treatment of VAP [18] caused by different carbapenem-resistant Gram-negative bacteria.\n\nOf note, VAP still remains a difficult-to-treat infection, particularly when the underlying cause are XDR pathogens; indeed, treatment strategies are controversial, often involving inhaled antibiotics [50], along with intravenous administration, although their role is not well established yet [51]. On the other hand, the higher efficacy of Cefiderocol-based regimens in the reported series can be possibly explained by its convenient PK/PD properties in lung tissues [52], along with its linear killing kinetics of resistant bacteria, including Enterobacterales, P. aeruginosa, A. baumannii and S. maltophilia [52].\n\nFinally, cefiderocol demonstrated its efficacy for the treatment of complicated intrabdominal infections (cIAI) caused by multiple pathogens. According to previous reports [53,54], in one case (Pt9), we decided to start a cefiderocol plus a high dose of daptomycin, tigecycline and fosfomycin to treat the infection along with an appropriate source control procedure. The main driver of this combination strategy was the sensitivity pattern of bacteria and the high tolerability of drugs selected, if compared with colistin and aminoglycosides, or vancomycin, considering the prolonged planned duration of the therapy (21 days). As a fact, in the other cIAI case in our series (Pt10), colistin was discontinued early due to toxicity. Accordingly, a possible further place in therapy of cefiderocol could be represented by long-lasting therapies for complicated infections due to its higher safety when compared with other second line drugs for XDR pathogens.\n\nFuture studies should explore the best clinical use for this complex setting, as often, these patients are at risk of increased mortality for many different causes. Future research should preferably use composite efficacy outcomes (microbiological eradication, time to signs and symptoms resolution, occurrence of adverse events etc.) along with crude mortality to appropriately evaluate the efficacy of cefiderocol in these settings.\n\n3.5. Place in the Therapy of Immunocompromised Hosts\n\nWithin the context of DTT infections, a special focus should be made on immunocompromised patients, such as solid organ transplant recipients and those affected by hematological malignancies.\n\nImportantly, solid organ transplant recipients are at high risk of bacterial infections, especially during the first month after transplantation, including donor-derived or pre-existing recipient infections [55,56], which represent one of the main causes of mortality and graft failure [57]. Not surprisingly, nosocomial infections and surgical complications caused by DTT bacteria, above all carbapenem-resistant Gram-negatives and non-fermentative Gram-negatives, play a major role in terms of incidence [58] and risk of mortality [59].\n\nThe same issue can be highlighted among patients affected by solid tumors and hematologic malignancies; indeed, in the era of multidrug resistance, the occurrence of severe infections in this setting is associated with extremely high mortality [60,61]. Finally, the category of patients affected by autoimmune diseases, exposed to immunosuppressive drugs, are at higher risk of secondary infections and need to be included in future studies exploring possible management and treatment options tailored according to their particular conditions [62]. Additionally, in the setting of immunocompromised hosts, multiple factors contribute to the severity of infections, such as neutropenia, long-term use of immunosuppressive drugs, exposure to empirical broad-spectrum antibiotic, indwelling catheters, chemotherapy-induced mucositis and intestinal bacterial translocation [63]. Moreover, the occurrence of further physio-pathological changes, such as cachexia, hypoalbuminemia and augmented renal function, may negatively affect antimicrobial pharmacokinetics, increasing the risk of treatment failure and occurrence of antibiotic resistance [64]. Considering all these factors, the need of highly effective antimicrobials which may overcome the reduced immune function of these patients is highly warranted.\n\nCurrently, the backbone of carbapenem-resistant anti Gram-negative therapy is represented by colistin, which expresses its therapeutic efficacy according to efficacy parameters determined by the Concentration-Dependent and Time-Dependent pharmacokinetic index (AUC/MIC) [65]; however, the aforementioned metabolic changes in immunocompromised patients cause larger volumes of distribution with lower drug plasmatic concentrations and highly unpredictable efficacy, eventually requiring the need of administering higher doses of colistin to achieve proper bactericidal activity, and consequential important risk of nephrotoxicity.\n\nThese conditions raise the risk of failure in treatment of infections caused by XDR GNB, particularly when mortality and microbiologic eradication are compared between antimicrobials with linear kinetics, such as cephalosporins, and other active antibiotics [66]. However, the use of penicillins should also be improved in this setting; according to recent studies, penicillins’ and cephalosporins’ Time > MIC target should be closer to 100% in order to achieve higher chances of efficacy on GNB infections in immunosuppressed hosts, while in immunocompetent, a T > MIC target of 50–70% is considered adequate to ensure standard efficacy [67].\n\nOverall, in our experience, cefiderocol-based combination therapy was used in all cases for the treatment of severe infections upon failure with previous antibiotic regimens. Importantly, we recorded two cases of mortality in among immunocompromised hosts treated in our series: in both cases (Pt11 and Pt12), the negative outcome occurred following microbiological eradication. In one case (Pt11, heart transplant recipient), death was due to concurrent secondary complications and worsening of clinical conditions deriving from the underlying CRAB infection, whereas in the other case (Pt12, affected by myelodysplastic syndrome), death was due to worsening of COVID-19 disease.\n\nIn this setting, with highly fragile patients, an early effective treatment with lower risk of treatment failure, toxicity and prolonged duration of infection could significantly impact overall survival. In this sense, cefiderocol, as well as other cephalosporins, represents a valuable therapeutic backbone for immunocompromised hosts with severe XDR GNB infections.\n\nStarting from these considerations, a possible future place in therapy of cefiderocol, along with the treatment of severe infections caused by CRAB, XDR P.aeruginosa or metallo-beta-lactamase producing Enterobacterales, may represent an option as empirical therapy for the management of febrile neutropenia in hematological patients colonized by these pathogens or in the perioperative prophylaxis of donor-derived infections (DDIs) in transplant recipients when the donor was colonized or infected by XDR GNB [68]. For instance, recent studies suggested the efficacy and safety of ceftazidime/avibactam or ceftolozane/tazobactam as empiric therapies of febrile neutropenia in hematological patients colonized by multidrug-resistant organisms [69,70]; however, using this approach, a rapid, programmed and structured de-escalation approach needs to be implemented in order to reduce the risk of developing resistance as well as to preserve the activity of these new antibiotics. Similarly, as discussed before, an important role of new cephalosporins will be played in the treatment of XDR GNB that caused DDIs [68]. A recent experience with ceftazidime/avibactam as rescue treatment for recipients receiving a solid organ transplant, whereby the organ donor was colonized by carbapenem resistant GNB, demonstrated a valuable activity of these cephalosporins in this setting [71]. A similar cefiderocol-based strategy may be proposed in the future, expanding the reservoirs of transplantable organs, including those colonized by XDR pathogens, such as CRAB, XDR P. aeruginosa or metallo-beta-lactamase producing Enterobacterales. At any rate, the complexity of infection management in immunocompromised hosts requires further extensive studies.\n\n4. Materials and Methods\n\n4.1. Patients and Treatments\n\nWe prospectively collected data of patients with XDR GNB infections who were treated with cefiderocol in the tertiary-care University Hospital of Bari (Azienda Ospedaliera Universitaria Policlinico di Bari) from 1 September 2020 to 20 April 2021. As a University Hospital, our Center took part to the Early Access Program of Shionogi & Co. Ltd. (closed on 26 April 2021). Consequently, each cefiderocol treatment was requested after the approval of our Ethical Committee in compassionate use. Finally, each treatment was furnished by the Inceptua Group (https://www.inceptua.com/) after submitting a request through their website. Patients were selected if they had documented infections due to fermenting or non-fermenting GNB resistant to carbapenems and susceptible to cefiderocol (MIC ≤ 2 μg/mL) and experienced clinical failure and/or severe adverse events from previous antibiotic regimens.\n\nEach enrolled patient was affected by severe infections/multidrug resistant organism(s) and underwent revision every 48–72 h by an Infectious Diseases specialist during treatment. Clinical failures/cures were assessed according to the achievement or not of at least one item, among the following, at each programmed re-evaluation: (i) clinical or microbiological improvement, (ii) persistence of signs and symptoms of infection, (iii) worsening of clinical condition or (iv) dissemination of the infection in course of treatment.\n\nAs stated by our internal protocol, patients with bloodstream infections repeated follow-up blood cultures after 48 h from the initiation of targeted antimicrobial treatment, consisting of one culture set/day for both aerobes and anaerobes for three consecutive days.\n\nSecondary infections, including VAP, tracheobronchitis, pneumonia [72], CVC-related BSI [73], surgical site infections [74] and intrabdominal infections [75], were defined according to current guidelines.\n\nClinical conditions of patients with COVID-19 were defined as mild/moderate, severe or critical according to the current guidelines [76]:Mild/Moderate, if they had clinical signs of pneumonia (fever, cough, dyspnea, fast breathing) but no signs of severe pneumonia, including SpO2 ≥ 90% on room air;\n\nSevere, if they had signs of pneumonia (fever, cough, dyspnea, fast breathing) plus one of the following: respiratory rate > 30 breaths/min; severe respiratory distress; or SpO2 < 90% on room air;\n\nCritical, if a diagnosis of acute respiratory distress syndrome (ARDS) was made.\n\nCefiderocol was administered as a 3-h IV infusion at a standard dose of 2 g, diluted in at least 100 mL of saline solution, intravenously every 8 h, with adjustments for renal impairment made according to the manufacturer’s recommendations (SmPC). All patients were prospectively followed up to day 30 or until death occurred. Recovery was defined as a composite endpoint: survival, resolution of signs and symptoms of infection and absence of recurrent infection. Microbiological eradication was defined as negative blood culture in case of BSI or negative culture result of sampling of previous site of infection, when possible, after the end of the therapy.\n\n4.2. Bacterial Strains\n\nAll Gram-negative isolates from patients included were defined as multidrug resistant (MDR), extensively drug resistant (XDR) or pandrug resistant (PDR) according to the following definitions [77]:\n\nMDR: non-susceptible to ≥1 agent in >3 antimicrobial categories.\n\nXDR: non-susceptible to ≥1 agent in all but ≤2 categories.\n\nPDR: non-susceptible to all antimicrobial agents listed.\n\n4.3. Sampling Process\n\nSamples were collected for microbiological assessment before starting empirical cefiderocol therapy. According to the current guidelines, blood cultures were performed by collecting 20–30 mL of blood per culture set. Two bottles per set were used and immediately placed into a BACT/ALERT® 3D instrument (Biomerieux Inc., France). Positive aerobic blood cultures were subcultured on MacConkey agar, CNA blood agar, Sabouraud dextrose agar, mannitol-salt agar and Chocolate agar and incubated aerobically at 37 °C for 24 h\n\nTracheobronchial aspirates and purulent drainages were directly inoculated and incubated aerobically at 37 °C for 24 h on MacConkey agar, CNA blood agar, Sabouraud dextrose agar, mannitol-salt agar and Chocolate agar. Moreover, purulent drainages were also transferred to enriched brain heart infusion (BHI) broths and incubated at 37 °C for 24 h. Identification was performed using VITEK-MS (Biomerieux Inc., France) according to the manufacturer’s instructions.\n\n4.4. Antibiotic Susceptibility Testing\n\nSusceptibility testing was performed using the Vitek® 2 automated system (biòMerieux, France). In addition, cefiderocol susceptibility testing was performed both with disk diffusion (Liofilchem srl) and broth dilution (SensititreTM, Thermo Fisher Scientific). MIC values were interpreted according to the clinical breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST, 2020).\n\n5. Limitations\n\nOverall, this study has some limitations requiring acknowledgement. Indeed, we were unable to perform bacterial genetic typing; hence, a more precise bacterial description, including mechanisms of resistance of all pathogens and precise MIC estimation for different antibiotics, are lacking. Moreover, therapeutic drug monitoring of antimicrobials, in particular colistin, cefiderocol and fosfomycin, was not available in our center. To conclude, as a small retrospective case series, our results are not generalizable.\n\n6. Conclusions\n\nCefiderocol will provide a new tool against “difficult-to-treat” GNB, expanding the clinician armamentarium. Because of its potential, it is essential to increase real-life data and deepen the knowledge on its correct place in therapy in both empirical and targeted strategies, avoiding at the same time the emergence of resistance. In addition, multiple settings, including critically ill, post-surgical and immunocompromised hosts, will benefit from studies tailored according to their specific characteristics.\n\nAcknowledgments\n\nWe gratefully acknowledge Shionogi & Co. Ltd., Osaka, Japan, for providing the Cefiderocol for compassionate use and Inceptua Group, (Headquarters) Luxembourg, Luxembourg for their indispensable help. We also want to give a special thanks to Giada (Inceptua Group). We are very thankful to our Ethical Committee for the help and supervision of our work. Finally, we would like to gratefully acknowledge the patients for providing their consent for the use of their data for research purposes, and all colleagues for their essential support.\n\nAuthor Contributions\n\nConceptualization, A.S., D.F.B., A.B. and L.D. (Lucia Diella); methodology, L.R., F.R., S.S. and A.M.; formal analysis, D.F.B.; investigation, D.F.B., A.B., L.D. (Lucia Diella), L.S., L.M., M.D., M.S. and L.D. (Lidia Dalfino); data curation, D.F.B., A.B., L.D. (Lucia Diella). and M.S.; writing—original draft preparation, all authors; writing—review and editing, all authors; supervision, A.S., S.G., M.D., A.M. and L.D. (Lidia Dalfino). 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 compassionate use of cefiderocol was approved by our Ethical Committee for all patients. Moreover, this study was performed with the formal approval of our Ethical Committee (study number: 6527) and in accordance with the Declaration of Helsinki and national and institutional standards. The patients provided a written informed consent (available from corresponding author) for the use of their data for re-search purposes. Finally, data were previously pseudo-anonymized, according to the requirements set by Italian Data protection Code (leg. Decree 196/2003) and European general data protection regulation (GDPR 2016/679).\n\nInformed Consent Statement\n\nInformed consent was obtained from all subjects involved in the study.\n\nData Availability Statement\n\nData available on request from the corresponding author on reasonable request.\n\nConflicts of Interest\n\nD.F.B. received personal honoraria as speaker for Shionogi & Co. Ltd. The remaining authors declare no conflict of interest.\n\nantibiotics-10-00652-t001_Table 1 Table 1 Characteristics of patients of Group 1, classified as “critically ill.”.\n\n\tAge\n(Year)\tSex\tCause of Hospitalization\tUnderlying Diseases\tWard\tPathogen\tType of Infection\tInitial Therapy (*)\tCause of Failure\tCefiderocol Based Therapy (*)\tOutcome\tOutcome at 30 Days\t\nPt1\t68\tM\tCOVID-19\tHuntington Chorea, Immobilization syndrome, Severe COVID-19 disease\tInternal Medicine, COVID Unit\tCRAB\tCVC-related BSI with Septic Shock\tCST, TG, FOF (4)\tUnsatisfactory clinical response\tFDC, FOF, TGC (5)\tMicrobiological Eradication\tDeath†\t\nPt2\t62\tF\tCOVID-19\tFibromyalgia\tIntensive Care Unit\tCRAB\tCVC-related BSI with Septic Shock\tMEM, CST (7)\tCST resistance\tFDC, CST, MEM (13)\tRecovery\tSuccess\t\nPt3\t69\tM\tCOVID-19\tHypertension, Diabetes\tIntensive Care Unit\tCRAB\tCVC-related BSI with Septic Shock\tMEM, CST (10)\tUnsatisfactory clinical response\tFDC, CST (10)\tRecovery\tSuccess\t\nPt4\t78\tM\tCOVID-19\tHypertension, COPD, Diabetes\tInternal Medicine, COVID Unit\tCRAB\tCVC-related BSI with Sepsis\tMEM, CST, TG (2)\tUnsatisfactory clinical response\tFDC, TGC (8)\tRecovery\tSuccess\t\nPt5\t75\tF\tCOVID-19\tDiabetes\tInfectious Diseases\tCRAB\tCVC-related BSI with Sepsis\tMEM, CST, FOF (5)\tCST toxicity\tFDC, FOF (5)\tRecovery\tSuccess\t\nAbbreviations: Pt, patient; CRAB, Carbapenem Resistant A. baumannii; CR-Kp, Carbapenem-Resistant Klebsiella pneumoniae; CST, Colistin; DAP, Daptomycin; FDC, Cefiderocol; FOF, Fosfomycin; SAM, Ampicillin/Sulbactam; TEC, Teicoplanin; VAN, Vancomycin; VAP, Ventilator Associated Pneumoniae; XDR, Extensive Drug Resistant; † Microbiological eradication, death from COVID-19; (*), (duration in days).\n\nantibiotics-10-00652-t002_Table 2 Table 2 Characteristics of patients in Group 2, with a post-surgical infection.\n\nt\tAge\n(Year)\tSex\tCause of Hospitalization\tUnderlying Diseases\tWard\tPathogen\tType of Infection\tInitial Therapy (*)\tCause of Failure\tCefiderocol Based Therapy (*)\tOutcome\tOutcome at 30 Days\t\nPt6\t38\tM\tDyspnea post orotracheal intubation for cerebral hemorrhage\tHypertension, Pulmonary Embolism\tThoracic Surgery\tCRAB\tVAP\tCST, FOF, TGC (4)\tUnsatisfactory clinical response\tFDC, FOF, TGC (9)\tRecovery\tSuccess\t\nPt7\t70\tM\tPTCA due to myocardial Infarction in course of COVID-19\tMild COVID-19, Diabetes, Ischemic heart disease, Dyslipidemia\tInternal Medicine, COVID Unit\tCRAB\tBloodstream infection\tMEM, CST, FOF, SAM (2)\tUnsatisfactory clinical response\tFDC, CST, FOF (8)\tRecovery\tSuccess\t\nPt8\t64\tM\tNeurosurgical wound Infection\tPrevious drainage of post-traumatic subarachnoid hematoma, Hypertension, Iatrogenic hypothyroidism\tInfectious Diseases\tP. aeruginosa XDR\tNeurosurgical Wound Infection\tCST, FOF (5)\tUnsatisfactory clinical response\tFDC, FOF (10)\tRecovery\tSuccess\t\nPt9\t25\tM\tSubocclusion and volvulus treated with gut surgical resection\tColostomy, Hip and Arm fracture\tIntensive Care Unit\tPolymicrobial **\tPerihepatic Abscess, Septic Shock\tMEM, TGC, DAP, FOF (5)\tUnsatisfactory clinical response\tFDC, TGC, DAP, FOF (21)\tRecovery\tSuccess\t\nAbbreviations: Pt, patient; CRAB, Carbapenem Resistant A. baumannii; CR-Kp, Carbapenem-Resistant Klebsiella pneumoniae; CST, Colistin; FDC, Cefiderocol; LZD, Linezolid; MEM, Meropenem; SAM, ampicillin/sulbactam; VAP, Ventilator Associated Pneumoniae; XDR, Extensive Drug Resistant; (*), (duration in days); PTCA, percutaneous transluminal coronary angiography. **, CRAB, MDR-E. cloacae complex, M. morganii, Ampicillin-resistant E. faecium.\n\nantibiotics-10-00652-t003_Table 3 Table 3 Characteristics of patients of Group 3, with immunocompromised patients.\n\n\tAge\n(Year)\tSex\tCause of Hospitalization\tUnderlying Diseases\tWard\tPathogen\tType of Infection\tInitial Therapy (*)\tCause of Therapeutic Failure, Day\tCefiderocol Based Therapy (*)\tOutcome\tOutcome at 30 Days\t\nPt10\t60\tM\tSepsis\tHepatic transplantation for HBV-related cirrhosis and HCC, Previous ischemic heart disease\tGastroenterology\tCR-Kp (KPC)\tHepatic Abscess, Bloodstream infection\tTGC, CZA, CST (3)\tUnsatisfactory clinical response\tFDC, TGC, CST (17), then FDC, FOF (11) *\tRecovery\tSuccess\t\nPt11\t43\tM\tMyocardial Infarction and cardiogenic shock, Arrhythmic storm, Acute pulmonary edema\tHeart transplantation, Hepatic failure, Renal failure in CRRT\tCardiosurgical Intensive Care Unit\tCRAB\tVAP, Bloodstream infection\tCST, MEM, DAP, TGC (12)\tUnsatisfactory clinical response\tFDC, TGC, CST, FOF (16)\tMicrobiological Eradication\tDeath ‡\t\nPt12\t57\tM\tCOVID-19\tMyelodysplastic syndrome, Hypertension, Basedow’s disease\tIntensive Care Unit\tCRAB\tBloodstream infection\tMEM, CST (3)\tUnsatisfactory clinical response\tFDC, CST (12)\tMicrobiological Eradication\tDeath †\t\nPt13\t68\tM\tPneumonia\tAcute Myeloid Leukemia, Chronic Kidney Disease, Hypertension\tHematology\tP. aeruginosa XDR\tPneumonia\tCST, MEM, FOF (10)\tUnsatisfactory clinical response\tFDC, FOF (10)\tRecovery\tSuccess\t\nAbbreviations: Pt, patient; TGC, Tigecycline; CZA, Ceftazidime/Avibactam; GEN, Gentamycin; CRAB, Carbapenem Resistant A. baumannii; CR-Kp, Carbapenem-Resistant Klebsiella pneumoniae; CST, Colistin; FDC, Cefiderocol; LZD, Linezolid; MEM, Meropenem; VAP, Ventilator Associated Pneumoniae; XDR, Extensive Drug Resistant; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; CRRT, continuous-renal-replacement-therapy. *, Changed for toxicity (Decreased renal function, Bilirubin increased). †, Microbiological eradication, death from COVID-19. ‡ Microbiological eradication, death from subsequent new infections. (*), (duration in days).\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Zhanel G.G. Golden A.R. Zelenitsky S. Wiebe K. Lawrence C.K. Adam H.J. Idowu T. Domalaon R. Schweizer F. Zhanel M.A. Cefiderocol: A Siderophore Cephalosporin with Activity Against Carbapenem-Resistant and Multidrug-Resistant Gram-Negative Bacilli Drugs 2019 79 271 289 10.1007/s40265-019-1055-2 30712199\n2. Mehrad B. Clark N.M. Zhanel G.G. Lynch J.P. 3rd Antimicrobial resistance in hospital-acquired gram-negative bacterial infections Chest 2015 147 1413 1421 10.1378/chest.14-2171 25940252\n3. Rouby J.J. Sole-Lleonart C. Rello J. European Investigators Network for Nebulized Antibiotics in Ventilator-associated Pneumonia. Ventilator-associated pneumonia caused by multidrug-resistant Gram-negative bacteria: Understanding nebulization of aminoglycosides and colistin Intensive Care Med. 2020 46 766 770 10.1007/s00134-019-05890-w 31915838\n4. Leal H.F. Azevedo J. Silva G.E.O. Amorim A.M.L. de Roma L.R.C. Arraes A.C.P. Gouveia E.L. Reis M.G. Mendes A.V. de Oliveira Silva M. Bloodstream infections caused by multidrug-resistant gram-negative bacteria: Epidemiological, clinical and microbiological features BMC Infect. Dis. 2019 19 609 10.1186/s12879-019-4265-z 31296179\n5. Lob S.H. Kazmierczak K.M. Badal R.E. Hackel M.A. Bouchillon S.K. Biedenbach D.J. Sahm D.F. Trends in susceptibility of Escherichia coli from intra-abdominal infections to ertapenem and comparators in the United States according to data from the SMART program, 2009 to 2013 Antimicrob. Agents Chemother. 2015 59 3606 3610 10.1128/AAC.05186-14 25801558\n6. Santoro A. Franceschini E. Meschiari M. Menozzi M. Zona S. Venturelli C. Digaetano M. Rogati C. Guaraldi G. Paul M. Epidemiology and Risk Factors Associated with Mortality in Consecutive Patients with Bacterial Bloodstream Infection: Impact of MDR and XDR Bacteria Open Forum Infect. Dis. 2020 7 461 10.1093/ofid/ofaa461 33209951\n7. Zhu W.M. Yuan Z. Zhou H.Y. Risk factors for carbapenem-resistant Klebsiella pneumoniae infection relative to two types of control patients: A systematic review and meta-analysis Antimicrob. Resist. Infect. Control 2020 9 23 10.1186/s13756-020-0686-0 32005246\n8. Du X. Xu X. Yao J. Deng K. Chen S. Shen Z. Yang L. Feng G. Predictors of mortality in patients infected with carbapenem-resistant Acinetobacter baumannii: A systematic review and meta-analysis Am. J. Infect. Control. 2019 47 1140 1145 10.1016/j.ajic.2019.03.003 31003750\n9. Bassetti M. Peghin M. Vena A. Giacobbe D.R. Treatment of Infections Due to MDR Gram-Negative Bacteria Front. Med. 2019 16 74 10.3389/fmed.2019.00074 31041313\n10. Aghapour Z. Gholizadeh P. Ganbarov K. Bialvaei A.Z. Mahmood S.S. Tanomand A. Yousefi M. Asgharzadeh M. Yousefi B. Kafil H.S. Molecular mechanisms related to colistin resistance in Enterobacteriaceae Infect. Drug Resist. 2019 12 965 975 10.2147/IDR.S199844 31190901\n11. Bassetti M. Echols R. Matsunaga Y. Ariyasu M. Doi Y. Ferrer R. Lodise T.P. Naas T. Niki Y. Paterson D.L. Efficacy and safety of cefiderocol or best available therapy for the treatment of serious infections caused by carbapenem-resistant Gram-negative bacteria (CREDIBLE-CR): A randomised, open-label, multicentre, pathogen-focused, descriptive, phase 3 trial Lancet Infect. Dis. 2021 21 226 240 10.1016/S1473-3099(20)30796-9 33058795\n12. Wunderink R.G. Matsunaga Y. Ariyasu M. Clevenbergh P. Echols R. Kaye K.S. Kollef M. Menon A. Pogue J.M. Shorr A.F. Cefiderocol versus high-dose, extended-infusion meropenem for the treatment of Gram-negative nosocomial pneumonia (APEKS-NP): A randomised, double-blind, phase 3, non-inferiority trial Lancet Infect. Dis. 2021 21 213 225 10.1016/S1473-3099(20)30731-3 33058798\n13. Portsmouth S. van Veenhuyzen D. Echols R. Machida M. Ferreira J.C.A. Ariyasu M. Tenke P. Nagata T.D. Cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infections caused by Gram-negative uropathogens: A phase 2, randomised, double-blind, non-inferiority trial Lancet Infect. Dis. 2018 18 1319 1328 10.1016/S1473-3099(18)30554-1 30509675\n14. Bavaro D.F. Romanelli F. Stolfa S. Belati A. Diella L. Ronga L. Fico C. Monno L. Mosca A. Saracino A. Recurrent neurosurgical site infection by extensively drug-resistant P. aeruginosa treated with cefiderocol: A case report and literature review Infect. Dis. 2021 53 206 211 10.1080/23744235.2020.1856921 33295821\n15. Oliva A. Ceccarelli G. De Angelis M. Sacco F. Miele M.C. Mastroianni C.M. Venditti M. Cefiderocol for compassionate use in the treatment of complicated infections caused by extensively and pan-resistant Acinetobacter baumannii J. Glob. Antimicrob. Resist. 2020 23 292 296 10.1016/j.jgar.2020.09.019 33065329\n16. Zingg S. Nicoletti G.J. Kuster S. Junker M. Widmer A. Egli A. Hinic V. Sendi P. Battegay M. Bättig V. Cefiderocol for Extensively Drug-Resistant Gram-Negative Bacterial Infections: Real-world Experience from a Case Series and Review of the Literature Open Forum Infect. Dis. 2020 7 185 10.1093/ofid/ofaa185\n17. Bleibtreu A. Dortet L. Bonnin R.A. Wyplosz B. Sacleux S.C. Mihaila L. Dupont H. Junot H. Bunel V. Grall N. The Cefiderocol French Study Group, OBO. Susceptibility Testing Is Key for the Success of Cefiderocol Treatment: A Retrospective Cohort Study Microorganisms 2021 9 282 10.3390/microorganisms9020282 33573148\n18. Falcone M. Tiseo G. Nicastro M. Leonildi A. Vecchione A. Casella C. Forfori F. Malacarne P. Guarracino F. Barnini S. Cefiderocol as rescue therapy for Acinetobacter baumannii and other carbapenem-resistant Gram-Negative infections in ICU patients Clin. Infect. Dis. 2020 17 1410 10.1093/cid/ciaa1410\n19. Taheri Y. Joković N. Vitorović J. Grundmann O. Maroyi A. Calina D. The Burden of the Serious and Difficult-to-Treat Infections and a New Antibiotic Available: Cefiderocol Front. Pharmacol. 2021 11 578823 10.3389/fphar.2020.578823 33628170\n20. Simner P.J. Patel R. Cefiderocol Antimicrobial Susceptibility Testing Considerations: The Achilles’ Heel of the Trojan Horse? J. Clin. Microbiol. 2020 59 00951-20 10.1128/JCM.00951-20\n21. Ito A. Sato T. Ota M. Takemura M. Nishikawa T. Toba S. Kohira N. Miyagawa S. Ishibashi N. Matsumoto S. In Vitro Antibacterial Properties of Cefiderocol, a Novel Siderophore Cephalosporin, against Gram-Negative Bacteria Antimicrob. Agents Chemother. 2017 62 e01454-17 10.1128/AAC.01454-17 29061741\n22. Ito A. Sato T. Ota M. Ito-Horiyama T. Ishibashi N. Sato T. Tsuji M. Yamano Y. Stability and low induction propensity of cefiderocol against chromosomal AmpC β-lactamases of Pseudomonas aeruginosa and Enterobacter cloacae J. Antimicrob. Chemother. 2019 74 539 10.1093/jac/dky482 30445536\n23. Sato T. Yamawaki K. Cefiderocol: Discovery, Chemistry, and In Vivo Profiles of a Novel Siderophore Cephalosporin Clin. Infect. Dis. 2019 69 S538 S543 10.1093/cid/ciz826 31724047\n24. Wu J.Y. Srinivas P. Pogue J.M. Cefiderocol: A Novel Agent for the Management of Multidrug-Resistant Gram-Negative Organisms Infect. Dis. Ther. 2020 9 17 40 10.1007/s40121-020-00286-6 32072491\n25. Parsels K.A. Mastro K.A. Steele J.M. Thomas S.J. Kufel W.D. Cefiderocol: A novel siderophore cephalosporin for multidrug-resistant Gram-negative bacterial infections J. Antimicrob. Chemother. 2021 76 1379 1391 10.1093/jac/dkab015 33532823\n26. Bonomo R.A. Cefiderocol: A Novel Siderophore Cephalosporin Defeating Carbapenem-resistant Pathogens Clin. Infect. Dis. 2019 69 S519 S520 10.1093/cid/ciz823 31724046\n27. Page M.G.P. The Role of Iron and Siderophores in Infection, and the Development of Siderophore Antibiotics Clin. Infect. Dis. 2019 69 S529 S537 10.1093/cid/ciz825 31724044\n28. Jean S.S. Hsueh S.C. Lee W.S. Hsueh P.R. Cefiderocol: A promising antibiotic against multidrug-resistant Gram-negative bacteria Expert. Rev. Anti. Infect. Ther. 2019 17 307 309 10.1080/14787210.2019.1612240 31055983\n29. Katsube T. Echols R. Wajima T. Pharmacokinetic and Pharmacodynamic Profiles of Cefiderocol, a Novel Siderophore Cephalosporin Clin. Infect. Dis. 2019 69 S552 S558 10.1093/cid/ciz828 31724042\n30. Bialvaei A.Z. Samadi Kafil H. Colistin, mechanisms and prevalence of resistance Curr. Med. Res. Opin. 2015 31 707 721 10.1185/03007995.2015.1018989 25697677\n31. Tamma P.D. Cosgrove S.E. Maragakis L.L. Combination therapy for treatment of infections with gram-negative bacteria Clin. Microbiol. Rev. 2012 25 450 470 10.1128/CMR.05041-11 22763634\n32. Schmid A. Wolfensberger A. Nemeth J. Schreiber P.W. Sax H. Kuster S.P. Monotherapy versus combination therapy for multidrug-resistant Gram-negative infections: Systematic Review and Meta-Analysis Sci. Rep. 2019 9 15290 10.1038/s41598-019-51711-x 31664064\n33. Russo A. Bassetti M. Bellelli V. Bianchi L. Cattaneo F.M. Mazzocchetti S. Paciacconi E. Cottini F. Schiattarella A. Tufaro G. Efficacy of a Fosfomycin-Containing Regimen for Treatment of Severe Pneumonia Caused by Multidrug-Resistant Acinetobacter baumannii: A Prospective, Observational Study Infect. Dis. Ther. 2021 10 187 200 10.1007/s40121-020-00357-8 33068255\n34. Coates A.R.M. Hu Y. Holt J. Yeh P. Antibiotic combination therapy against resistant bacterial infections: Synergy, rejuvenation and resistance reduction Expert. Rev. Anti. Infect. Ther. 2020 18 5 15 10.1080/14787210.2020.1705155 31847614\n35. Lenhard J.R. Thamlikitkul V. Silveira F.P. Garonzik S.M. Tao X. Forrest A. Shin B.S. Kaye K.S. Bulitta J.B. Nation R.L. Polymyxin-resistant, carbapenem-resistant Acinetobacter baumannii is eradicated by a triple combination of agents that lack individual activity J. Antimicrob. Chemother. 2017 72 1415 1420 10.1093/jac/dkx002 28333347\n36. Bulman Z.P. Chen L. Walsh T.J. Satlin M.J. Qian Y. Bulitta J.B. Peloquin C.A. Holden P.N. Nation R.L. Li J. Polymyxin Combinations Combat Escherichia coli Harboring mcr-1 and blaNDM-5: Preparation for a Postantibiotic Era mBio 2017 8 e00540-17 10.1128/mBio.00540-17 28743810\n37. Fischbach M.A. Combination therapies for combating antimicrobial resistance Curr. Opin. Microbiol. 2011 14 519 523 10.1016/j.mib.2011.08.003 21900036\n38. Munck C. Gumpert H.K. Wallin A.I. Wang H.H. Sommer M.O. Prediction of resistance development against drug combinations by collateral responses to component drugs Sci. Transl. Med. 2014 6 262ra156 10.1126/scitranslmed.3009940\n39. Guillamet M.C.V. Vazquez R. Noe J. Micek S.T. Fraser V.J. Kollef M.H. Impact of Baseline Characteristics on Future Episodes of Bloodstream Infections: Multistate Model in Septic Patients with Bloodstream Infections Clin. Infect. Dis. 2020 71 3103 3109 10.1093/cid/ciz1206 31858141\n40. Kumar A. Ellis P. Arabi Y. Roberts D. Light B. Parrillo J.E. Dodek P. Wood G. Kumar A. Simon D. Cooperative Antimicrobial Therapy of Septic Shock Database Research Group. Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock Chest 2009 136 1237 1248 10.1378/chest.09-0087 19696123\n41. Lee C.C. Lee C.H. Yang C.Y. Hsieh C.C. Tang H.J. Ko W.C. Beneficial effects of early empirical administration of appropriate antimicrobials on survival and defervescence in adults with community-onset bacteremia Crit. Care 2019 23 363 10.1186/s13054-019-2632-1 31747950\n42. De Vries Schultink A.H.M. Sallevelt B.T.G.M. Meinders A.J. van de Garde E.M.W. Roescher N. The need for gentamicin adjunctive to cefuroxime as empirical sepsis therapy: A local protocol evaluation Clin. Microbiol. Infect. 2021 10.1016/j.cmi.2021.03.032\n43. Scully M. Hassoun A. Increasing evidence of potential toxicity of a common antibiotic combination J. Infect. Public. Health 2018 11 594 595 10.1016/j.jiph.2017.07.001 28757294\n44. Biagi M. Vialichka A. Jurkovic M. Wu T. Shajee A. Lee M. Patel S. Mendes R.E. Wenzler E. Activity of Cefiderocol Alone and in Combination with Levofloxacin, Minocycline, Polymyxin B, or Trimethoprim-Sulfamethoxazole against Multidrug-Resistant Stenotrophomonas maltophilia Antimicrob. Agents Chemother. 2020 64 e00559-20 10.1128/AAC.00559-20 32571820\n45. Kollef M.H. Niederman M.S. Why is Acinetobacter baumannii a problem for critically ill patients? Intensive Care Med. 2015 41 2170 2172 10.1007/s00134-015-4096-3 26474995\n46. Singer M. Deutschman C.S. Seymour C.W. Shankar-Hari M. Annane D. Bauer M. Bellomo R. Bernard G.R. Chiche J.D. Coopersmith C.M. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) JAMA 2016 315 801 810 10.1001/jama.2016.0287 26903338\n47. Levy M.M. Evans L.E. Rhodes A. The Surviving Sepsis Campaign Bundle: 2018 update Intensive Care Med. 2018 44 925 928 10.1007/s00134-018-5085-0 29675566\n48. Adembri C. Cappellini I. Novelli A. The role of PK/PD-based strategies to preserve new molecules against multi-drug resistant gram-negative strains J. Chemother. 2020 32 219 225 10.1080/1120009X.2020.1786634 32628094\n49. Adembri C. Novelli A. Nobili S. Some Suggestions from PK/PD Principles to Contain Resistance in the Clinical Setting-Focus on ICU Patients and Gram-Negative Strains Antibiotics 2020 9 676 10.3390/antibiotics9100676 33036190\n50. Feng J.Y. Peng C.K. Sheu C.C. Lin Y.C. Chan M.C. Wang S.H. Chen C.M. Shen Y.C. Zheng Z.R. Lin Y.T. T-CARE (Taiwan Critical Care and Infection) Group. Efficacy of adjunctive nebulized colistin in critically ill patients with nosocomial carbapenem-resistant Gram-negative bacterial pneumonia: A multi-centre observational study Clin. Microbiol. Infect. 2021 10.1016/j.cmi.2021.01.020 33540113\n51. Sweeney D.A. Kalil A.C. The last breath for inhaled antibiotics and VAP? Not so fast Lancet Infect. Dis. 2020 20 265 266 10.1016/S1473-3099(19)30690-5 31866325\n52. Nakamura R. Ito-Horiyama T. Takemura M. In Vivo Pharmacodynamic Study of Cefiderocol, a Novel Parenteral Siderophore Cephalosporin, in Murine Thigh and Lung Infection Models Antimicrob. Agents Chemother. 2019 63 e02031-18 10.1128/AAC.02031-18 31262762\n53. Stevens R.W. Clancy M. Compassionate Use of Cefiderocol in the Treatment of an Intraabdominal Infection Due to Multidrug-Resistant Pseudomonas aeruginosa: A Case Report Pharmacotherapy 2019 39 1113 1118 10.1002/phar.2334 31550054\n54. Contreras D.A. Fitzwater S.P. Nanayakkara D.D. Schaenman J. Aldrovandi G.M. Garner O.B. Yang S. Coinfections of Two Strains of NDM-1- and OXA-232-Coproducing Klebsiella pneumoniae in a Kidney Transplant Patient Antimicrob. Agents Chemother. 2020 64 e00948-19 10.1128/AAC.00948-19 31527031\n55. Fishman J.A. Infection in Organ Transplantation Am. J. Transpl. 2017 17 856 879 10.1111/ajt.14208\n56. Abbo L.M. Grossi P.A. AST ID Community of Practice. Surgical site infections: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice Clin. Transpl. 2019 33 e13589 10.1111/ctr.13589\n57. Kinnunen S. Karhapää P. Juutilainen A. Finne P. Helanterä I. Secular Trends in Infection-Related Mortality after Kidney Transplantation Clin. J. Am. Soc. Nephrol. 2018 13 755 762 10.2215/CJN.11511017 29622669\n58. Lanini S. Costa A.N. Puro V. Procaccio F. Grossi P.A. Vespasiano F. Ricci A. Vesconi S. Ison M.G. Carmeli Y. Donor-Recipient Infection (DRIn) Collaborative Study Group. Incidence of carbapenem-resistant gram negatives in Italian transplant recipients: A nationwide surveillance study PLoS ONE 2015 10 e0123706 10.1371/journal.pone.0123706 25835018\n59. Bartoletti M. Giannella M. Tedeschi S. Viale P. Multidrug-Resistant Bacterial Infections in Solid Organ Transplant Candidates and Recipients Infect. Dis. Clin. N. Am. 2018 32 551 580 10.1016/j.idc.2018.04.004\n60. Garcia-Vidal C. Cardozo-Espinola C. Puerta-Alcalde P. Marco F. Tellez A. Agüero D. Romero-Santana F. Díaz-Beyá M. Giné E. Morata L. Risk factors for mortality in patients with acute leukemia and bloodstream infections in the era of multiresistance PLoS ONE 2018 13 e0199531 10.1371/journal.pone.0199531 29953464\n61. Bavaro D.F. Pizzutilo P. Catino A. Signorile F. Pesola F. Di Gennaro F. Cassiano S. Marech I. Lamorgese V. Angarano G. Incidence of Infections and Predictors of Mortality during Checkpoint Inhibitors Immunotherapy in Patients with Advanced Lung Cancer: A Retrospective Cohort Study Open Forum Infect. Dis. 2021 10.1093/ofid/ofab187\n62. Bavaro D.F. Fiordelisi D. Angarano G. Monno L. Saracino A. Targeted therapies for autoimmune/idiopathic nonmalignant diseases: Risk and management of opportunistic infections Expert Opin Drug Saf. 2020 19 817 842 10.1080/14740338.2020.1767585 32394759\n63. Alagna L. Palomba E. Mangioni D. Bozzi G. Lombardi A. Ungaro R. Castelli V. Prati D. Vecchi M. Muscatello A. Multidrug-Resistant Gram-Negative Bacteria Decolonization in Immunocompromised Patients: A Focus on Fecal Microbiota Transplantation Int. J. Mol. Sci. 2020 21 5619 10.3390/ijms21165619\n64. Theuretzbacher U. Pharmacokinetic and pharmacodynamic issues for antimicrobial therapy in patients with cancer Clin. Infect. Dis. 2012 54 1785 1792 10.1093/cid/cis210 22437238\n65. Bergen P.J. Bulitta J.B. Forrest A. Tsuji B.T. Li J. Nation R.L. Pharmacokinetic/pharmacodynamic investigation of colistin against Pseudomonas aeruginosa using an in vitro model Antimicrob. Agents Chemother. 2010 54 3783 3789 10.1128/AAC.00903-09 20585118\n66. Falcone M. Daikos G.L. Tiseo G. Bassoulis D. Giordano C. Galfo V. Leonildi A. Tagliaferri E. Barnini S. Sani S. Efficacy of ceftazidime-avibactam plus aztreonam in patients with bloodstream infections caused by MBL- producing Enterobacterales Clin. Infect. Dis. 2020 10.1093/cid/ciaa586\n67. Kowalska-Krochmal B. Dudek-Wicher R. The Minimum Inhibitory Concentration of Antibiotics: Methods, Interpretation, Clinical Relevance Pathogens 2021 10 165 10.3390/pathogens10020165 33557078\n68. Bunsow E. Los-Arcos I. Martin-Gómez M.T. Bello I. Pont T. Berastegui C. Ferrer R. Nuvials X. Deu M. Peghin M. Donor-derived bacterial infections in lung transplant recipients in the era of multidrug resistance J. Infect. 2020 80 190 196 10.1016/j.jinf.2019.12.006 31843689\n69. Clerici D. Oltolini C. Greco R. Ripa M. Giglio F. Mastaglio S. Lorentino F. Pavesi F. Farina F. Liberatore C. The place in therapy of ceftazidime/avibactam and ceftolozane/tazobactam in hematological patients with febrile neutropenia Int. J. Antimicrob. Agents 2021 57 106335 10.1016/j.ijantimicag.2021.106335 33838223\n70. Criscuolo M. Trecarichi E.M. Ceftazidime/Avibactam and Ceftolozane/Tazobactam for Multidrug-Resistant Gram Negatives in Patients with Hematological Malignancies: Current Experiences Antibiotics 2020 9 58 10.3390/antibiotics9020058\n71. Chen W. Sun L. Guo L. Cao B. Liu Y. Zhao L. Lu B. Li B. Chen J. Wang C. Clinical outcomes of ceftazidime-avibactam in lung transplant recipients with infections caused by extensively drug-resistant gram-negative bacilli Ann. Transl. Med. 2020 8 39 10.21037/atm.2019.10.40 32154284\n72. Torres A. Niederman M.S. Chastre J. Ewig S. Fernandez-Vandellos P. Hanberger H. Kollef M. Li Bassi G. Luna C.M. Martin-Loeches I. International ERS/ESICM/ESCMID/ALAT guidelines for the management of hospital-acquired pneumonia and ventilator-associated pneumonia: Guidelines for the management of hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP) of the European Respiratory Society (ERS), European Society of Intensive Care Medicine (ESICM), European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and Asociación Latinoamericana del Tórax (ALAT) Eur. Respir J. 2017 10 1700582\n73. Mermel L.A. Allon M. Bouza E. Craven D.E. Flynn P. O’Grady N.P. Raad I.I. Rijnders B.J. Sherertz R.J. Warren D.K. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 Update by the Infectious Diseases Society of America Clin. Infect. Dis. 2009 149 1 45 10.1086/599376\n74. Global Guidelines for the Prevention of Surgical Site Infection 2nd ed. World Health Organization Geneva, Switzerland 2018\n75. Sartelli M. Chichom-Mefire A. Labricciosa F.M. Hardcastle T. Abu-Zidan F.M. Adesunkanmi A.K. Ansaloni L. Bala M. Balogh Z.J. Beltrán M.A. The management of intra-abdominal infections from a global perspective: 2017 WSES guidelines for management of intra-abdominal infections World J. Emerg. Surg. 2017 10 12 29\n76. World Health Organization Clinical management of COVID-19. Interim Guidance 20 4 2020 Available online: https://apps.who.int/iris/bitstream/handle/10665/332196/WHO-2019-nCoV-clinical-2020.5-eng.pdf?sequence=1&isAllowed=y (accessed on 20 April 2021)\n77. Magiorakos A.P. Srinivasan A. Carey R.B. Carmeli Y. Falagas M.E. Giske C.G. Harbarth S. Hindler J.F. Kahlmeter G. Olsson-Liljequist B. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: An international expert proposal for interim standard definitions for acquired resistance Clin. Microbiol. Infect. 2012 18 268 281 10.1111/j.1469-0691.2011.03570.x 21793988\n\n",
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"title": "Cefiderocol-Based Combination Therapy for \"Difficult-to-Treat\" Gram-Negative Severe Infections: Real-Life Case Series and Future Perspectives.",
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"abstract": "The treatment of a man who attempted suicide after experiencing symptoms of anxiety and aggressiveness associated with the use of androgenic-anabolic steroids (AAS) is described. This report includes 30 days of inpatient treatment and a 6-month follow-up. Regular use of fluoxetine apparently prevented the onset of anxiety, depression, aggressiveness, and suicide ideation, even with the concurrent use of AAS. The urinary concentration of androgens, metabolites of AAS, and fluoxetine were monitored through analysis of urinary samples by the Brazilian Laboratory of Doping Control. Our results are congruent with previous findings describing the risk of suicide prompted by AAS use as well as the efficacy of fluoxetine in the treatment of mood disorders associated with the use of anabolic steroids.",
"affiliations": "Institute of Psychiatry, Substance Abuse Research Program (PROJAD), Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil.;Chemistry Institute, Brazilian Laboratory of Doping Control (LBCD - LADETEC), UFRJ, Rio de Janeiro, Brazil.;Brazilian Institute of Geography and Statistics (IBGE), Rio de Janeiro, Brazil.;Hong Kong Baptist University - Center for Health and Exercise Science Research, Hong Kong, China.;Engineering & Physical Sciences, University of West of Scotland - School of Computing, Paisley, UK.;UFRJ, Department of Internal Medicine and Endocrine Unit, Rio de Janeiro, Brazil.;Chemistry Institute, Brazilian Laboratory of Doping Control (LBCD - LADETEC), UFRJ, Rio de Janeiro, Brazil.;Institute of Psychiatry, Substance Abuse Research Program (PROJAD), Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil.",
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"title": "Effective treatment and prevention of attempted suicide, anxiety, and aggressiveness with fluoxetine, despite proven use of androgenic anabolic steroids.",
"title_normalized": "effective treatment and prevention of attempted suicide anxiety and aggressiveness with fluoxetine despite proven use of androgenic anabolic steroids"
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"abstract": "Although best managed by surgical resection, we present a case of Listeria monocytogenes endovascular graft infection alternatively treated with graft retention and antibiotic induction followed by a lifelong suppressive course. The epidemiological, pathological, and clinical features of this unique entity are reviewed.",
"affiliations": "Department of Medicine, Division of Infectious Diseases and International , University of Virginia School of Medicine , Charlottesville.;Department of Medicine, Division of Infectious Diseases and International , University of Virginia School of Medicine , Charlottesville.",
"authors": "Heysell|Scott K|SK|;Hughes|Molly A|MA|",
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"fulltext": "\n==== Front\nOpen Forum Infect DisOpen Forum Infect DisofidofidsOpen Forum Infectious Diseases2328-8957Oxford University Press 10.1093/ofid/ofv203ofv203Brief ReportsListeria monocytogenes Endovascular Graft Infection Heysell Scott K. Hughes Molly A. Department of Medicine, Division of Infectious Diseases and International, University of Virginia School of Medicine, CharlottesvilleCorrespondence: S. K. Heysell, 345 Crispell Drive, Carter Harrison Building, Room 1523, Charlottesville, VA 22908-1340 (skh8r@virginia.edu).1 2016 17 12 2015 3 1 ofv2032 11 2015 15 12 2015 © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.2015This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com.Although best managed by surgical resection, we present a case of Listeria monocytogenes endovascular graft infection alternatively treated with graft retention and antibiotic induction followed by a lifelong suppressive course. The epidemiological, pathological, and clinical features of this unique entity are reviewed.\n\naneurysmdoxycyclineendovascular graftListeria monocytogenes cover-dateWinter 2016\n==== Body\nEndovascular graft infection with Listeria monocytogenes is quite rare despite the pathogen's predilection for bacteremia [1, 2]. Endovascular infections with L monocytogenes may be smoldering in onset thus causing diagnostic delay [3]. However, once diagnosed, the best chance of cure necessitates prolonged antimicrobial therapy and graft removal. We describe an illustrative case in which the endovascular graft was preserved and an induction course of antibiotics was followed by lifelong suppression without recurrence of infection.\n\nCASE PRESENTATION\nA 68-year-old woman with idiopathic cardiomyopathy, atrial fibrillation with Maze III procedure, and thoracic aortic aneurysm with endovascular repair 2 years before presentation was referred for 3 months of antecedent outpatient symptoms. Before symptom onset, she had spent time on a rural farm where she consumed unpasteurized dairy and developed 1 week of nonbloody diarrhea. Stool studies were not performed. One month before presentation she had generalized malaise and a nonsustained subjective fever. She was seen by her primary care physician, and blood cultures were obtained that grew Gram-positive rods in 1 of 2 bottles from each of 2 peripheral venipunctures. She was admitted to the hospital where a repeat venous blood culture also grew Gram-positive rods in 1 of 2 bottles. All cultured growth was ultimately identified as L monocytogenes by the Vitek System (BioMérieux, France) with susceptibility to penicillin (minimum inhibitory concentration 1.0 µg/mL), vancomycin (≤1.0 µg/mL), rifampin (≤0.5 µg/mL), gentamicin (≤1.0 µg/mL), ciprofloxacin (≤1.0 µg/mL), trimethoprim/sulfamethoxazole (≤0.5 µg/mL), and doxycycline (≤4.0 µg/mL), and presumed resistance to azithromycin (>1.0 µg/mL) performed at Mayo Laboratories. The patient's other laboratory parameters were remarkable for a hemoglobin of 10.7 g/dL and an erythrocyte sedimentation rate of 27 mm/hour.\n\nGiven concern for prior gastroenteritis, consequent bacteremia, and then endovascular seeding, a computed tomography (CT) angiogram of the chest was performed revealing new thoracic aortic perigraft inflammation from root to arch with subcarinal and paratracheal lymphadenopathy consistent with infection (Figure 1). Because graft removal was deemed too high of risk, a cautious trial of antimicrobial therapy alone was initiated. Ampicillin and synergistic gentamicin were administered until acute kidney injury forced discontinuation of the gentamicin and presumed angioedema compelled ampicillin discontinuation after only 2 days of administration. She completed 6 weeks of intravenous vancomycin at 1 gram (15 mg/kg) every 12 hours. After intravenous therapy, intolerance to ciprofloxacin and trimethoprim/sulfamethoxazole ultimately led to lifelong suppression with doxycycline at 100 mg (1.5 mg/kg) twice daily. A follow-up CT angiogram after 10 weeks of antimicrobial therapy revealed resolution of periaortic inflammation (Figure 1), and she remains without recurrence of infection, including normal erythrocyte sedimentation rate and C-reactive protein, more than 3 years after diagnosis.\nFigure 1. The graphic illustrates initial computed tomography (CT) angiography of the chest (A) demonstrating ascending thoracic aortic repair and new perigraft inflammation (arrow) from root to arch with associated lymphadenopathy. A follow-up CT angiography (B) with resolution of inflammation is also shown.\n\n\n\nDISCUSSION\nDespite persistent outbreaks of listeriosis with bacteremia as a common consequence, we report 1 of the few cited cases of endovascular graft infection. The Centers for Disease Control and Prevention estimate that 1600 illnesses and 260 deaths due to listeriosis occur annually in the United States [4], yet as few as 18 cases of primary aneurysmal infection with L monocytogenes have been reported (2 of the thoracic aorta), with only 7 cases of endovascular graft infection (1 of the thoracic aorta) [1–3, 5, 6]. Similar to the case presented and unlike most other adult cases of listeriosis, immunosuppression and hematologic malignancy do not appear to be predisposing factors for endovascular graft infection.\n\nThe duration from infection to invasive endovascular disease is variable with a mean of 30 days reported and is likely due to the bacteria's remarkable ability to infect epithelial cells, escape phagosomes, divide using host machinery, push to the cell surface to form a filapod for ingestion by an adjacent cell, and thereby escape neutrophil, antibody, or complement [7–9]. Despite the increased risk for endovascular graft infections early in the perioperative period before purported “endothelialization,” our case and the majority in the literature presented more than 6 months after graft placement [3].\n\nCONCLUSIONS\nAlthough controlled trials do not exist to guide management, endovascular graft infections with L monocytogenes are likely best managed by graft resection in combination with long-term antimicrobial therapy with ampicillin or sulfonamides. If ampicillin is used, then gentamicin can be given at synergistic doses. Rifampin is effective in vitro, but when given in combination it is not superior to ampicillin alone [8]. Mortality remains high in cases of L monocytogenes endovascular graft infections. The review of reported cases through 1998 described death in 41% of patients, including all who did not undergo surgical resection. However, more recently, graft retention with successful outcome has been described. A case of abdominal aortic endograft preservation was treated with perigraft catheter drainage, intravenous amoxicillin/clavulanic acid (unspecified dose and duration), and ultimately 6 weeks of trimethoprim/sulfamethoxazole (800 mg/160 mg) 3 times daily, and the patient remained cured after ∼1 year [6]. Another patient with thoracic aortic endograft infection was treated with 21 days of ampicillin but the infection recurred, and given the complexity of the proposed repair the patient underwent another 6 weeks of ampicillin (2 grams every 6 hours), initially with 4 overlapping weeks with gentamicin, followed by amoxicillin (1 gram every 8 hours) for 8 weeks, and at 1 year the patient remained asymptomatic [3]. It is possible that other recent examples of graft retention and poor outcome were simply not reported in literature. Hence, in the absence of compelling evidence to the contrary, in cases such as ours where the graft is preserved, we would favor a lifelong suppressive course of a tolerable oral antibiotic with the narrowest of spectrum.\n\nAcknowledgments\nPotential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.\n==== Refs\nReferences\n1 Heikkinen L , Valtonen M , Lepantalo M et al \nInfrarenal endoluminal bifurcated stent graft infected with Listeria monocytogenes . J Vascul Surg \n1999 ; 29 :554 –6 .\n2 Gauto AR , Cone LA , Woodard DR et al \nArterial infections due to Listeria monocytogenes: report of four cases and review of world literature . Clin Infect Dis \n1992 ; 14 :23 –8 .1571436 \n3 Rohde H , Horstkotte MA , Loeper S et al \nRecurrent Listeria monocytogenes aortic graft infection: confirmation of relapse by molecular subtyping . Diagn Microbiol Infect Dis \n2004 ; 48 :63 –7 .14761724 \n4 Scallan E , Hoekstra RM , Angulo FJ et al \nFoodborne illness acquired in the United States--major pathogens . Emerg Infect Dis \n2011 ; 17 :7 –15 .21192848 \n5 Paccalin M , Amoura Z , Brocheriou I et al \n[Infectious aneurysm due to Listeria monocytogenes: a new case and review of the literature] . Rev Med Interne \n1998 ; 19 :661 –5 .9793154 \n6 Saleem BR , Berger P , Zeebregts CJ et al \nPeriaortic endograft infection due to Listeria monocytogenes treated with graft preservation . J Vasc Surg \n2008 ; 47 :635 –7 .18295117 \n7 Lorber B \nListeria monocytogenes In: Mandell GL , Bennett JE , Dolin R , ed. Principles and Practice of Infectious Diseases , 7th ed \nPhiladelphia, PA : Churchill, Livingstone, Elsevier ; 2010 : pp 2707 –14 .\n8 Lorber B \nListeriosis . Clin Infect Dis \n1997 ; 24 :1 –11 .8994747 \n9 Wing EJ , Gregory SH \nListeria monocytogenes: clinical and experimental update . J Infect Dis \n2002 ; 185 :18 –24 .\n\n",
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"keywords": "Listeria monocytogenes; aneurysm; doxycycline; endovascular graft",
"medline_ta": "Open Forum Infect Dis",
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"title": "Listeria monocytogenes Endovascular Graft Infection.",
"title_normalized": "listeria monocytogenes endovascular graft infection"
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"abstract": "The safety and efficacy of ondansetron has led to its wider clinical use and this could increase unusual serious adverse events. Therefore, we emphasize the need for cautious use of ondansetron and beware and prepare for unusual adverse events.",
"affiliations": "Department of Medicine Bharatpur Hospital Chitwan Nepal.;ICU Department of Medicine Bharatpur Hospital Chitwan Nepal.",
"authors": "Sapkota|Kalyan|K|https://orcid.org/0000-0003-4011-6430;Bhagat|Roshan|R|",
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"doi": "10.1002/ccr3.4110",
"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904\nJohn Wiley and Sons Inc. Hoboken\n\n10.1002/ccr3.4110\nCCR34110\nCase Report\nCase Reports\nFatal anaphylaxis to intravenous ondansetron: A case report\nSAPKOTA and BHAGAT\nSapkota Kalyan https://orcid.org/0000-0003-4011-6430\n1 kalyansapkota@gmail.com\n\nBhagat Roshan 2\n1 Department of Medicine Bharatpur Hospital Chitwan Nepal\n2 ICU Department of Medicine Bharatpur Hospital Chitwan Nepal\n* Correspondence\nKalyan Sapkota, Department of Medicine, Bharatpur Hospital, Chitwan, Nepal.\nEmail: kalyansapkota@gmail.com\n\n05 5 2021\n5 2021\n9 5 10.1002/ccr3.v9.5 e0411005 3 2021\n04 12 2020\n16 3 2021\n© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.\n\nAbstract\n\nThe safety and efficacy of ondansetron has led to its wider clinical use and this could increase unusual serious adverse events. Therefore, we emphasize the need for cautious use of ondansetron and beware and prepare for unusual adverse events.\n\nThe safety and efficacy of ondansetron has led to its wider clinical use and this could increase unusual serious adverse events. Therefore, we emphasize the need for cautious use of ondansetron and beware and prepare for unusual adverse events.\n\nanaphylaxis\ncase report\nfatal\nondansetron\nsource-schema-version-number2.0\ncover-dateMay 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.2 mode:remove_FC converted:15.05.2021\nSapkota K , Bhagat R . Fatal anaphylaxis to intravenous ondansetron: A case report. Clin Case Rep. 2021;9 :e04110. 10.1002/ccr3.4110\n==== Body\n1 INTRODUCTION\n\nOndansetron is commonly used for nausea and vomiting. Serious adverse drug reactions are rare but not uncommon. We report a case who developed fatal anaphylaxis to intravenous ondansetron. This article emphasizes the need for cautious use of drugs and importance of recognition and treatment of this serious adverse event.\n\nOndansetron is a selective serotonin 5‐HT3 receptor antagonist, which is widely used in the prevention and treatment of chemotherapy‐induced nausea and vomiting. The most commonly reported side effects (occurring in more than 10% of adults) include headache, fatigue, malaise, and constipation. Serious side effects include QT prolongation and severe allergic reaction. Hypersensitivity reactions to Ondansetron are rare but have been reported. 1 , 2 , 3 , 4 Ondansetron can cause anaphylaxis, so one should be careful while using the drug.\n\n2 CASE PRESENTATION\n\nAn 82‐year‐old woman presented to the Emergency Room (ER) at 0430 hours with complaints of acute onset of vertigo and multiple episodes of nonprojectile, nonbilious vomiting. She also complained of generalized weakness and dry mouth. Her past history was unremarkable except for the use of calcium supplementation and aceclofenac for pain due to osteoarthritis. On examination, she was afebrile, had pulse rate of 96/min, and blood pressure was 90/60 mm Hg. Patient was thin built, alert but slightly ill‐looking with dry tongue. Systemic examination was unremarkable.\n\nShe was treated with single 4 mg dose of Ondansetron (brand name “Tilset”) intravenously. Immediately following the medication, she became restless, developed respiratory distress, and quickly progressed to falling oxygen saturation, drop in blood pressure from 90/60 mm Hg to 70/40 mm Hg, and decreasing level of consciousness. Patient was cyanosed, and diffuse wheeze heard on chest auscultation. However, there were no urticaria, rashes, angioedema, or pruritus.\n\nAn allergic reaction to ondansetron was suspected, immediate resuscitation was started and 0.5 mg epinephrine (1 mg/1 mL) was given intramuscularly. Volume expansion with normal saline was initiated and bolus of IV Hydrocortisone and IV Pheniramine were administered. There was no improvement seen clinically and hemodynamically. Because of deteriorating condition as evidence by rapidly falling oxygen saturation, unstable hemodynamic parameters, and falling level of consciousness, airway was secured with endotracheal intubation. Bag and mask ventilation with 100 percent oxygen started and continued. Continuous noninvasive hemodynamic monitoring and pulse oximetry monitoring were performed throughout the period. As there was no response and no sign of improvement, IM Epinephrine 0.3 mg repeated every 3 minutes 5 , 6 ; however, the hypotension persisted and continuous infusion of adrenaline was started. With all these resuscitation attempts, SPO2 displayed on monitor was 54%. ECG monitoring showed bradycardia with heart rate of 30 bpm. Further drop in blood pressure was noted and was unrecordable immediately which quickly progressed to cardiac arrest. High‐quality chest compression was started and advanced cardiac life support was continued. However; return of spontaneous circulation could not be achieved and the patient died after 30 minutes of resuscitation due to refractory cardiorespiratory arrest.\n\nShe had no history of ondansetron exposure, drug, or food allergies. As no other drugs were administered and onset of signs and symptoms developed immediately after administration of ondansetron, it is believed that this reaction was most probably caused by ondansetron. 7 Using Naranjo adverse drug reaction probability scale, the score was 5, the relationship between the drug and the event was categorized as “probable.” 8\n\n3 DISCUSSION\n\nSelective 5‐HT3 receptor antagonists such as ondansetron, granisetron, dolasetron, and palonosetron are widely used for their antiemetic properties in cancer chemotherapy. They are generally associated with a wide safety margin; however, there are some reports of life‐threatening adverse events such as anaphylaxis and tachyarrhythmias. Although this drug is well‐tolerated, there have been multiple reports of adverse reactions associated with various clinical manifestations of anaphylaxis. 2 Anaphylaxis is an acute, potentially fatal, multiorgan system reaction caused by the release of chemical mediators from mast cells and basophils. Anaphylaxis due to ondansetron could be due to immune‐mediated or nonimmune mediated. Exposure to ondansetron was unknown in our patient and, therefore, the exact mechanism for anaphylaxis could not be identified.\n\nTreatment of signs and symptoms of anaphylaxis is epinephrine with cardiovascular and respiratory support. But, due to rapid onset and severe presentation in our case, even with aggressive treatment and all the efforts of providing cardiorespiratory support, patient could not be survived. Ondansetron was considered to be the event‐producing drug because respiratory and hemodynamic manifestation occurred immediately after injection and no other medications were given at that time. Because of the rapid onset of clinical event and life‐threatening condition, blood samples could not be obtained in our patient and skin testing could not be done.\n\nAnaphylaxis to ondansetron is a rare event, but the easy availability of ondansetron has promoted the widespread off‐label use of these drugs in conditions other than clinically indicated in Nepal. Though rare but serious adverse events could occur with injudicious use of these agents, and simple treatment for the minor ailments could be life‐threatening. Our case report emphasizes the judicious use of ondansetron so as to avoid and reduce similar untoward events and we need to be cautious while using this drug and be aware when using it in out‐of‐hospital set‐up.\n\nCONFLICT OF INTEREST\n\nNone.\n\nAUTHOR CONTRIBUTIONS\n\nKS: involved in the writing, revisions, and final review of the manuscript. RB: involved in the writing, revisions, and final review of the manuscript.\n\nETHICAL APPROVAL\n\nWritten‐informed consent was obtained from the patient's legal guardian for publication of any detail that might identify an individual.\n\nACKNOWLEDGMENTS\n\nAll the emergency medical staffs who did their best to manage the patient.\n\nDATA AVAILABILITY STATEMENT\n\nThe data that support the findings of this study are available on request from the corresponding author.\n==== Refs\nREFERENCES\n\n1 Mehra KK , Gogtay NJ , Ainchwar R , Bichile LS . Hypersensitivity to intravenous ondansetron: a case report. J Med Case Rep. 2008;2 (1 ):274. 10.1186/1752-1947-2-274 18702811\n2 Weiss KS . Anaphylactic reaction to ondansetron. Arch Intern Med. 2001;161 (18 ):2263. 10.1001/archinte.161.18.2263 11575988\n3 Kossey JL , Kwok KK . Anaphylactoid reactions associated with ondansetron. Ann Pharmacother. 1994;28 (9 ):1029‐1030. 10.1177/106002809402800906 7803876\n4 Fernando SL , Broadfoot AJ . Ondansetron anaphylaxis: a case report and protocol for skin testing. Br J Anaesth. 2009;102 (2 ):285‐286. 10.1093/bja/aen376 19151059\n5 Kemp SF , Lockey RF , Simons FER , the World Allergy Organization ad hoc Committee on Epinephrine in A . Epinephrine: the drug of choice for anaphylaxis–a statement of the world allergy organization. World Allergy Organ J. 2008;1 (2 ):S18. 10.1186/1939-4551-1-S2-S18 23282530\n6 Sampson HA , Muñoz‐Furlong A , Bock SA , et al. Symposium on the definition and management of anaphylaxis: summary report. J Allergy Clin Immunol. 2005;115 (3 ):584‐591. 10.1016/j.jaci.2005.01.009 15753908\n7 Kramer MS , Leventhal JM , Hutchinson TA , Feinstein AR . An algorithm for the operational assessment of adverse drug reactions: i. background, description, and instructions for use. JAMA. 1979;242 (7 ):623‐632. 10.1001/jama.1979.03300070019017 449002\n8 Naranjo CA , Busto U , Sellers EM , et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30 (2 ):239‐245. 10.1038/clpt.1981.154 7249508\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2050-0904",
"issue": "9(5)",
"journal": "Clinical case reports",
"keywords": "anaphylaxis; case report; fatal; ondansetron",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "e04110",
"pmc": null,
"pmid": "34026152",
"pubdate": "2021-05",
"publication_types": "D002363:Case Reports",
"references": "7803876;7249508;18702811;15753908;449002;18691308;11575988;19151059",
"title": "Fatal anaphylaxis to intravenous ondansetron: A case report.",
"title_normalized": "fatal anaphylaxis to intravenous ondansetron a case report"
} | [
{
"companynumb": "NP-AMNEAL PHARMACEUTICALS-2021-AMRX-01807",
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"activesubstancename": "EPINEPHRINE"
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{
"abstract": "We investigated outcomes in living-donor kidney transplant recipients with preformed donor-specific antibodies (detected with flow cytometry and specified with the LABScreen single antigen test) under desensitization pretransplant and immunosuppression posttransplant.\n\n\n\nOf 15 recipients included, 8 had ABO-incompatible kidney transplant. Six patients had sensitization caused by pregnancy, 8 by blood transfusion, 5 by previous transplants, and 1 by unknown cause. Desensitization was initiated using calcineurin inhibitors, methylprednisolone, and mycophenolate mofetil 30 days pretransplant, with rituximab administered 1 and 10 days pretransplant. Patients underwent plasmapheresis 1, 3, and 5 days pretransplant. Antithymocyte globulin was admi nistered for 5 days posttransplant as induction therapy. At 3 and 12 months posttransplant, all recipients underwent protocol renal allograft biopsies, with donor-specific antibodies simultaneously measured with the single antigen test.\n\n\n\nT-cell complement-dependent cytotoxicity crossmatch was negative in all 15 recipients, but T-cell and B-cell flow cytometry was positive in 8 and 14 recipients, respectively. Anti-HLA class I antibodies became negative, except in 1 recipient 3 months posttransplant. Class II antibodies remained positive in 8 recipients 3 months posttransplant. No clinical or subclinical T-cell-mediated rejection occurred, but 1 recipient experienced clinical acute antibody-mediated rejection. At 3 and 12 months posttransplant, 8 and 5 recipients had subclinical acute antibody-mediated rejection. Cytomegalovirus test showed positivity in 14 recipients, but none developed cytomegalovirus disease. BK viremia was detected in 2 recipients, with 1 developing BK virus nephropathy, which was reversed by reducing immunosuppression.\n\n\n\nTransplant patients with preformed donor-specific antibodies showed good outcomes in terms of desensitization and immunosuppression. However, most anti-HLA class II donor-specific antibodies remained, and microvascular inflammation score could indicate long-term risk of renal allograft dysfunction.",
"affiliations": "From the Department of Nephrology, Toho University, Faculty of Medicine, Tokyo, Japan.",
"authors": "Itabashi|Yoshihiro|Y|;Aikawa|Atsushi|A|;Muramatsu|Masaki|M|;Hyoudou|Youji|Y|;Shinoda|Kazunobu|K|;Takahashi|Yusuke|Y|;Sakurabayashi|Kei|K|;Mizutani|Toshihide|T|;Oguchi|Hideyo|H|;Arai|Taichi|T|;Kawamura|Takeshi|T|;Hamasaki|Yuko|Y|;Sakai|Ken|K|;Shishido|Seiichiro|S|",
"chemical_list": "D006680:HLA Antigens; D007166:Immunosuppressive Agents; D007518:Isoantibodies",
"country": "Turkey",
"delete": false,
"doi": "10.6002/ect.MESOT2018.L42",
"fulltext": null,
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"issn_linking": "1304-0855",
"issue": "17(Suppl 1)",
"journal": "Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation",
"keywords": null,
"medline_ta": "Exp Clin Transplant",
"mesh_terms": "D000328:Adult; D003602:Cytotoxicity, Immunologic; D005260:Female; D005434:Flow Cytometry; D006084:Graft Rejection; D006085:Graft Survival; D006680:HLA Antigens; D006648:Histocompatibility; D006650:Histocompatibility Testing; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D007518:Isoantibodies; D016030:Kidney Transplantation; D019520:Living Donors; D008297:Male; D008875:Middle Aged; D009894:Opportunistic Infections; D010956:Plasmapheresis; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "101207333",
"other_id": null,
"pages": "43-49",
"pmc": null,
"pmid": "30777522",
"pubdate": "2019-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Living-Donor Kidney Transplant With Preformed Donor-Specific Antibodies.",
"title_normalized": "living donor kidney transplant with preformed donor specific antibodies"
} | [
{
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{
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"activesubstancename": "MYCOPHENOLIC ACID"
},
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... |
{
"abstract": "We present a case of cerebral venous thrombosis diagnosed by magnetic resonance venography, magnetic resonance imaging, and angiography. Selective direct thrombolytic treatment with streptokinase via highly selective venography was successful.",
"affiliations": "Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.",
"authors": "Yang|Yuan-Han|YH|;Shih|Ming-Chen|MC|;Chou|Min-Shon|MS|;Liu|Ching-Kuan|CK|",
"chemical_list": "D005343:Fibrinolytic Agents; D013300:Streptokinase",
"country": "China (Republic : 1949- )",
"delete": false,
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"issue": "19(8)",
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"keywords": null,
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"mesh_terms": "D000328:Adult; D002533:Cerebral Angiography; D005343:Fibrinolytic Agents; D006801:Humans; D002542:Intracranial Embolism and Thrombosis; D008279:Magnetic Resonance Imaging; D008297:Male; D010690:Phlebography; D012851:Sinus Thrombosis, Intracranial; D013300:Streptokinase",
"nlm_unique_id": "100960562",
"other_id": null,
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"pmid": "12962430",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Streptokinase in the treatment of venous sinus thrombosis: a case report.",
"title_normalized": "streptokinase in the treatment of venous sinus thrombosis a case report"
} | [
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"companynumb": "TW-PFIZER INC-2020422821",
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"activesubstancename": "PHENYTOIN SODIUM"
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{
"abstract": "Cat scratch disease, usually a benign infectious disease, may develop as multisystem disease with multiorgan involvement, particularly in immunocompromised patients. We report on a patient who developed disseminated bartonellosis while receiving mycophenolate mofetil monotherapy treating steroid-dependent nephrotic syndrome, highlighting that severe infection can be observed in those patients. Therefore, this category of patients should be cautious when having contact with kittens and receives proper prevention advice.",
"affiliations": "Centre de référence des Maladies rénales rares, service de néphrologie, rhumatologie et dermatologie pédiatriques, Hôpital Femme-Mère-Enfant, Hospices civils de Lyon, 59, boulevard Pinel, 69677 Bron cedex, France.;Centre de référence des Maladies rénales rares, service de néphrologie, rhumatologie et dermatologie pédiatriques, Hôpital Femme-Mère-Enfant, Hospices civils de Lyon, 59, boulevard Pinel, 69677 Bron cedex, France.;Service des maladies infectieuses pédiatriques, Hôpital Femme-Mère-Enfant, Hospices civils de Lyon, 59, boulevard Pinel, 69677 Bron cedex, France.;Centre de référence des Maladies rénales rares, service de néphrologie, rhumatologie et dermatologie pédiatriques, Hôpital Femme-Mère-Enfant, Hospices civils de Lyon, 59, boulevard Pinel, 69677 Bron cedex, France.;Centre de référence des Maladies rénales rares, service de néphrologie, rhumatologie et dermatologie pédiatriques, Hôpital Femme-Mère-Enfant, Hospices civils de Lyon, 59, boulevard Pinel, 69677 Bron cedex, France.;Service d'imagerie médicale, Hôpital Femme-Mère-Enfant, Hospices civils de Lyon, 59, boulevard Pinel, 69677 Bron cedex, France.;Centre de référence des Maladies rénales rares, service de néphrologie, rhumatologie et dermatologie pédiatriques, Hôpital Femme-Mère-Enfant, Hospices civils de Lyon, 59, boulevard Pinel, 69677 Bron cedex, France; Faculté de médecine Lyon Est, Université de Lyon, Lyon, France.;Centre de référence des Maladies rénales rares, service de néphrologie, rhumatologie et dermatologie pédiatriques, Hôpital Femme-Mère-Enfant, Hospices civils de Lyon, 59, boulevard Pinel, 69677 Bron cedex, France. Electronic address: bruno.ranchin@chu-lyon.fr.",
"authors": "Tram|Nathalie|N|;Cheyssac|Élodie|É|;Toumi|Chadia|C|;Laurent|Audrey|A|;Bertholet-Thomas|Aurélia|A|;Viremouneix|Loïc|L|;Bacchetta|Justine|J|;Ranchin|Bruno|B|",
"chemical_list": "D007166:Immunosuppressive Agents; D013256:Steroids; D009173:Mycophenolic Acid",
"country": "France",
"delete": false,
"doi": "10.1016/j.nephro.2021.02.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1769-7255",
"issue": "17(6)",
"journal": "Nephrologie & therapeutique",
"keywords": "Bartonellosis; Mycophenolate mofetil; Steroid-dependent nephrotic syndrome",
"medline_ta": "Nephrol Ther",
"mesh_terms": "D000818:Animals; D001474:Bartonella Infections; D002415:Cats; D002648:Child; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid; D009404:Nephrotic Syndrome; D013256:Steroids; D016896:Treatment Outcome",
"nlm_unique_id": "101248950",
"other_id": null,
"pages": "463-465",
"pmc": null,
"pmid": "33985919",
"pubdate": "2021-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Disseminated bartonellosis in a child with steroid-dependent nephrotic syndrome receiving mycophenolate mofetil monotherapy.",
"title_normalized": "disseminated bartonellosis in a child with steroid dependent nephrotic syndrome receiving mycophenolate mofetil monotherapy"
} | [
{
"companynumb": null,
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"occurcountry": "FR",
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"drug": [
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "1",
"drugadmi... |
{
"abstract": "Secondary hyperparathyroidism is one of the most common complications of chronic kidney failure. If prolonged, parathyroid hormone release gains autonomy and tertiary hyperparathyroidism with parathyroid adenoma or hyperplasia can be develop. Tertiary hyperparathyroidism is associated with increased risk of mortality and morbidity; thus, treatment is recommended. Medical treatment includes phosphate binders, vitamin D analogues, and calcimimetic agents. Most cases of tertiary hyperparathyroidism can be controlled with medical treatment. When medical treatment options prove insufficient, parathyroidectomy is recommended. However, recurrence after parathyroidectomy is possible, which requires an alternative treatment. We present our percutaneous embolization experience, which has not been tried in the treatment of tertiary hyperparathyroidism in renal transplantation patients diagnosed with tertiary hyperparathyroidism.",
"affiliations": "Department of Nephrology, Hacettepe University Faculty of Medicine, Altındag, Ankara, Turkey. Electronic address: silacank@hotmail.com.;Department of Nephrology, Hacettepe University Faculty of Medicine, Altındag, Ankara, Turkey.;Department of Nephrology, Hacettepe University Faculty of Medicine, Altındag, Ankara, Turkey.;Department of Radiology, Hacettepe University Faculty of Medicine, Altındag, Ankara, Turkey.;Department of Radiology, Hacettepe University Faculty of Medicine, Altındag, Ankara, Turkey.;Department of Nephrology, Hacettepe University Faculty of Medicine, Altındag, Ankara, Turkey.",
"authors": "Koc|Neriman Sila|NS|;Yilmaz|Rahmi|R|;Yildirim|Tolga|T|;Eldem|Gonca|G|;Peynircioglu|Bora|B|;Erdem|Yunus|Y|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2020.08.033",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "53(3)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000328:Adult; D004621:Embolization, Therapeutic; D057510:Endovascular Procedures; D005260:Female; D006801:Humans; D006962:Hyperparathyroidism, Secondary; D016030:Kidney Transplantation; D008297:Male; D012008:Recurrence",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "1010-1013",
"pmc": null,
"pmid": "32951863",
"pubdate": "2021-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A New Approach to Tertiary Hyperparathyroidism: Percutaneous Embolization: Two Case Reports.",
"title_normalized": "a new approach to tertiary hyperparathyroidism percutaneous embolization two case reports"
} | [
{
"companynumb": "TR-AMGEN-TURSP2021062347",
"fulfillexpeditecriteria": "2",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CINACALCET HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "Tocilizumab (TCZ) was administered from 2004 to 2008 in a 52-year-old woman with rheumatoid arthritis (RA) refractory to methotrexate (MTX) as a clinical trial. TCZ therapy with MTX was resumed in March 2009 due to exacerbation of RA. The patient was an human T-lymphotropic virus type I (HTLV-I) carrier, and, in April 2011, a peripheral blood smear showed many atypical lymphocytes, thus leading to a diagnosis of adult T-cell leukemia (ATL). Complete remission of ATL was achieved with a standard therapeutic regimen.",
"affiliations": "Department of Immunology and Rheumatology, Nagasaki University Graduate School of Biomedical Sciences, Japan. nhideki@nagasaki-u.ac.jp",
"authors": "Nakamura|Hideki|H|;Ueki|Yukitaka|Y|;Saito|Shigeki|S|;Horai|Yoshiro|Y|;Suzuki|Takahisa|T|;Naoe|Tomoki|T|;Eguchi|Katsumi|K|;Kawakami|Atsushi|A|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; C502936:tocilizumab",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.52.0468",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0918-2918",
"issue": "52(17)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": null,
"medline_ta": "Intern Med",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D001172:Arthritis, Rheumatoid; D005260:Female; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell; D008875:Middle Aged; D016896:Treatment Outcome",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "1983-6",
"pmc": null,
"pmid": "23994996",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Development of adult T-cell leukemia in a patient with rheumatoid arthritis treated with tocilizumab.",
"title_normalized": "development of adult t cell leukemia in a patient with rheumatoid arthritis treated with tocilizumab"
} | [
{
"companynumb": "JP-ROXANE LABORATORIES, INC.-2014-RO-01018RO",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugaddi... |
{
"abstract": "We present a man with clinically stable systemic myasthenia gravis (MG) which flared with a low dose of peripherally injected botulinum toxin type A (BTX-A). Botulinum toxin drugs generally have an excellent safety profile, however, they are contentious in patients with neuromuscular disorders. Despite this, there remain limited reports on the systemic effects of botulinum therapy in patients with MG. This man is one of less than 10 reported patients worldwide in whom MG was exacerbated by a peripheral BTX-A injection. This is an important reminder to Australian clinicians of the potential risks of this common place medication in patients with neuromuscular disorders, even those with stable disease.",
"affiliations": "St Vincents Hospital, Victoria Street, Darlinghurst, NSW 2010, Australia. Electronic address: jwatts@globaldial.com.;St Vincents Hospital, Victoria Street, Darlinghurst, NSW 2010, Australia; University of New South Wales, Kingsford, NSW, Australia.;St Vincents Hospital, Victoria Street, Darlinghurst, NSW 2010, Australia; University of New South Wales, Kingsford, NSW, Australia.",
"authors": "Watts|Jennifer|J|;Brew|Bruce|B|;Tisch|Stephen|S|",
"chemical_list": "D009465:Neuromuscular Agents; D019274:Botulinum Toxins, Type A",
"country": "Scotland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0967-5868",
"issue": "22(12)",
"journal": "Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia",
"keywords": "Botulinum toxin; Epiphora; Myasthenia gravis; Neuroimmunology; Neuromuscular junction",
"medline_ta": "J Clin Neurosci",
"mesh_terms": "D060433:Administration, Ophthalmic; D000368:Aged; D001315:Australia; D019274:Botulinum Toxins, Type A; D006257:Head; D006801:Humans; D007766:Lacrimal Apparatus Diseases; D008297:Male; D009157:Myasthenia Gravis; D009465:Neuromuscular Agents",
"nlm_unique_id": "9433352",
"other_id": null,
"pages": "1979-81",
"pmc": null,
"pmid": "26188667",
"pubdate": "2015-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Myasthenia gravis exacerbation with low dose ocular botulinum toxin for epiphoria.",
"title_normalized": "myasthenia gravis exacerbation with low dose ocular botulinum toxin for epiphoria"
} | [
{
"companynumb": "AU-MERZ NORTH AMERICA, INC.-15MRZ-00418",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugaddition... |
{
"abstract": "The results of treatment of acute promyelocytic leukemia, when combination ATRA + chemotherapy is used in induction and maintainance therapy and risk adapted strategy applied in consolidation, improved at present time. Enhanced supportive therapy also contribute to improved outcome of APL patients. 3 - year relapse free, overall survival and clinical and biological presenting features of APL patients were evaluated. Since January, 2001 till March, 2009, 32 patients treated with modified spanish treatment scheme were assessed. After june 2003 risk adapted strategy in protocol therapy according to spanish treatment group with ATRA and anthracyclines in consolidation therapy in high and intermediate risk patients was used. Cytoreduction therapy in patients with initially high leukocyte count was the modification of spanish treatment scheme. 29 (90.6%) patients achieved complete hematologic remission, 2 (6.3 %) molecular relapses were observed, death was observed in 4 patients (12.5%). The estimated 3-year OS was 90.6%; 95% CI (80.5%-100.0%), and estimated 3-year RFS was 95.5 %; 95 % CI (86.8%-100.0%). Survival results correspond with other published clinical studies. The number of relapses was slightly lower and the incidence of ATRA syndrome (50%) was higher when compare with the results of other study groups. Current recommendations for treatment with risk-adapted strategy for patients with newly diagnosed acute promyelocytic leukemia resulted in our patients group to comparable outcome and good compliance like in other published studies.",
"affiliations": "Department of Clinical Oncology, National Cancer Institute (NCI), Bratislava, Slovakia. iveta.nemova@nou.sk",
"authors": "Oravcova|I|I|;Czako|B|B|;Demeckova|E|E|;Demitrovicova|L|L|;Greksak|R|R|;Kotoucek|P|P|;Mego|M|M|;Mikuskova|E|E|;Richterova|K|K|;Al Sabti|F|F|;Mistrik|M|M|",
"chemical_list": "D014212:Tretinoin",
"country": "Slovakia",
"delete": false,
"doi": "10.4149/neo_2010_03_270",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-2685",
"issue": "57(3)",
"journal": "Neoplasma",
"keywords": null,
"medline_ta": "Neoplasma",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute; D008297:Male; D008875:Middle Aged; D014212:Tretinoin",
"nlm_unique_id": "0377266",
"other_id": null,
"pages": "270-9",
"pmc": null,
"pmid": "20353280",
"pubdate": "2010",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Treatment of newly diagnosed patients with acute promyelocytic leukemia with modified spanish treatment protocol.",
"title_normalized": "treatment of newly diagnosed patients with acute promyelocytic leukemia with modified spanish treatment protocol"
} | [
{
"companynumb": "SK-ZO SKIN HEALTH-2020ZOS00008",
"fulfillexpeditecriteria": "1",
"occurcountry": "SK",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "IDARUBICIN"
},
"drugadditional": null,
... |
{
"abstract": "TKIs have become the standard of care for CML. Imatinib was the first to transform the outcomes of this disease. Dasatinib and nilotinib were recently added to the armamentarium for imatinib-resistant disease and, more recently, for first-line therapy. When choosing a TKI for patients, adverse effects, presence of mutations in the BCR-ABL kinase domain, and cost should be considered. Once chosen, drug interactions should be evaluated for all patients. New drugs are being studied to prevent disease progression and for patients with T315I mutations. This article reviews the pharmacotherapy of CML with the aid of a patient case.",
"affiliations": "Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA. harnicas@mskcc.org",
"authors": "Harnicar|Stephen|S|",
"chemical_list": "C498826:4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D000069439:Dasatinib",
"country": "United States",
"delete": false,
"doi": "10.6004/jnccn.2011.0130",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1540-1405",
"issue": "9 Suppl 3()",
"journal": "Journal of the National Comprehensive Cancer Network : JNCCN",
"keywords": null,
"medline_ta": "J Natl Compr Canc Netw",
"mesh_terms": "D001549:Benzamides; D000069439:Dasatinib; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D011743:Pyrimidines; D013844:Thiazoles",
"nlm_unique_id": "101162515",
"other_id": null,
"pages": "S25-35",
"pmc": null,
"pmid": "21357665",
"pubdate": "2011-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Pharmacotherapy for chronic myelogenous leukemia: a case-based approach.",
"title_normalized": "pharmacotherapy for chronic myelogenous leukemia a case based approach"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-15728744",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": null,
"drugadditional": "3",
"drugadministrationroute": "065",
... |
{
"abstract": "Alpelisib selectively inhibits the p110α catalytic subunit of PI3Kα and is approved for treatment of breast cancers harboring canonical PIK3CA mutations. In head and neck squamous cell carcinoma (HNSCC), 63% of PIK3CA mutations occur at canonical hotspots. The oncogenic role of the remaining 37% of PIK3CA noncanonical mutations is incompletely understood. We report a patient with HNSCC with a noncanonical PIK3CA mutation (Q75E) who exhibited a durable (12 months) response to alpelisib in a phase II clinical trial. Characterization of all 32 noncanonical PIK3CA mutations found in HNSCC using several functional and phenotypic assays revealed that the majority (69%) were activating, including Q75E. The oncogenic impact of these mutations was validated in 4 cellular models, demonstrating that their activity was lineage independent. Further, alpelisib exhibited antitumor effects in a xenograft derived from a patient with HNSCC containing an activating noncanonical PIK3CA mutation. Structural analyses revealed plausible mechanisms for the functional phenotypes of the majority of the noncanonical PIK3CA mutations. Collectively, these findings highlight the importance of characterizing the function of noncanonical PIK3CA mutations and suggest that patients with HNSCC whose tumors harbor activating noncanonical PIK3CA mutations may benefit from treatment with PI3Kα inhibitors.",
"affiliations": "Department of Otolaryngology, Head and Neck Surgery, University of California San Francisco, San Francisco, California, USA.;Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea.;Department of Otolaryngology, Head and Neck Surgery, University of California San Francisco, San Francisco, California, USA.;Department of Otolaryngology, Head and Neck Surgery, University of California San Francisco, San Francisco, California, USA.;Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Yonsei Cancer Center, Seoul, South Korea.;Cardiovascular Research Institute and.;Cardiovascular Research Institute and.;Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, USA.;Department of Otolaryngology, Head and Neck Surgery, University of California San Francisco, San Francisco, California, USA.;Department of Otolaryngology, Head and Neck Surgery, University of California San Francisco, San Francisco, California, USA.;NovellusDx, Jerusalem, Israel.;NovellusDx, Jerusalem, Israel.;Department of Medicine, University of California San Francisco, San Francisco, California, USA.;Department of Medicine, University of Arizona, Tucson, Arizona, USA.;Department of Epidemiology and Biostatistics and.;Department of Otolaryngology, Head and Neck Surgery, University of California San Francisco, San Francisco, California, USA.;Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California, USA.;Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California, USA.;Department of Otolaryngology, Head and Neck Surgery, University of California San Francisco, San Francisco, California, USA.;Department of Otolaryngology, Head and Neck Surgery, University of California San Francisco, San Francisco, California, USA.",
"authors": "Jin|Nan|N|;Keam|Bhumsuk|B|;Cho|Janice|J|;Lee|Michelle J|MJ|;Kim|Hye Ryun|HR|;Torosyan|Hayarpi|H|;Jura|Natalia|N|;Ng|Patrick Ks|PK|;Mills|Gordon B|GB|;Li|Hua|H|;Zeng|Yan|Y|;Barbash|Zohar|Z|;Tarcic|Gabi|G|;Kang|Hyunseok|H|;Bauman|Julie E|JE|;Kim|Mi-Ok|MO|;VanLandingham|Nathan K|NK|;Swaney|Danielle L|DL|;Krogan|Nevan J|NJ|;Johnson|Daniel E|DE|;Grandis|Jennifer R|JR|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0021-9738",
"issue": "131(22)",
"journal": "The Journal of clinical investigation",
"keywords": "Head and neck cancer; Oncology",
"medline_ta": "J Clin Invest",
"mesh_terms": null,
"nlm_unique_id": "7802877",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34779417",
"pubdate": "2021-11-15",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D052061:Research Support, N.I.H., Extramural",
"references": "17646409;26685214;18787170;31678634;21266528;15930273;25915946;28676499;28885881;32971005;23607916;31091374;25631445;17307039;26646651;25593016;18079394;9804776;33189828;19805105;33059733;22120714;29747488;22949682;24395800;26627007;22214849;23619167;17376864;28131786;26013318;27126994;29284706;33433946;25873175;25450649;26876212;29533785;30563911;22588877;30350310;20593314;25193510;22358332;30860495;25105564;28528867;24916771;32918948;24425785;30996962;9488453;19029981;26122737;30064199;24586741;29401002;24608574;23550210;23558291;31600013;17626883;30207593;23903756;32929011",
"title": "Therapeutic implications of activating noncanonical PIK3CA mutations in head and neck squamous cell carcinoma.",
"title_normalized": "therapeutic implications of activating noncanonical pik3ca mutations in head and neck squamous cell carcinoma"
} | [
{
"companynumb": "US-MYLANLABS-2022M1042049",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": "3",
... |
{
"abstract": "Chemo-embolisation with drug-eluting beads loaded with irinotecan (DEBIRI) increased survival as compared with intravenous irinotecan in chemorefractory patients with liver-dominant metastases from colorectal cancer (LMCRC). First-line DEBIRI with systemic chemotherapy may increase survival and secondary resection.\n\n\n\nIn the FFCD-1201 single-arm Phase 2 study, patients with untreated, non-resectable LMCRC received DEBIRI plus mFOLFOX6. Four courses of DEBIRI were performed alternating right and left lobe or two sessions with both lobes treated during the same session.\n\n\n\nFifty-seven patients were enrolled. Grade 3-5 toxicities were more frequent when both lobes were treated during the same session (90.5% versus 52.8%). Nine-month PFS rate was 53.6% (95% CI, 41.8-65.1%). The objective response rate (RECIST 1.1) was 73.2%, and the secondary R0 surgery was 33%. With a median follow-up of 38.3 months, median OS was 37.4 months (95% CI, 25.7-45.8), and median PFS 10.8 months (95% CI, 8.2-12.3).\n\n\n\nFront-line DEBIRI + mFOLFOX6 should not be recommended as the hypothesised 9-month PFS was not met. However, high response rate, deep responses, and prolonged OS encourage further evaluation in strategies integrating biologic agent, in particular in patients with secondary surgery as the main goal.\n\n\n\nNCT01839877.",
"affiliations": "Département de Gastroentérologie et d'Oncologie Digestive, Hôpital Européen George Pompidou, Paris, France. simon.pernot@gmail.com.;Service de Radiologie, Hôpital Européen Georges Pompidou, Paris, France.;Institut de Cancérologie, Hôpital Privé Jean Mermoz, Lyon, France.;Département Biostatistiques, Fédération Francophone de Cancérologie Digestive, Dijon, France.;Service d'Oncologie, CHU Bordeaux Hôpital St. André, Bordeaux, France.;Département d'Oncologie Médicale, Institut Paoli Calmettes CAC, Marseille, France.;Service de Médecine, Centre Léon Bérard, Lyon, France.;Service d'HGE et d'Oncologie, CHU La Timone, Marseille, France.;Service d'HGE, CHU Toulouse Rangueil, Toulouse, France.;Hôpital Universitaire de Rouen, Normandie Université, Service d'Hépato-gastroentérologie, UNIROUEN, Inserm 1245, IRON Group, 76000, Rouen, France.;Service d'HGE, CHU Le Bocage (Dijon), Dijon, France.;EPICAD INSERM LNC-UMR 1231, Université de Bourgogne Franche Comté, Dijon, France.;Service d'Oncologie, CHU Poitiers, La Milétrie, Poitiers, France.;Département de Gastroentérologie et d'Oncologie Digestive, Hôpital Européen George Pompidou, Paris, France.",
"authors": "Pernot|Simon|S|http://orcid.org/0000-0003-4580-585X;Pellerin|Olivier|O|;Artru|Pascal|P|;Montérymard|Carole|C|;Smith|Denis|D|;Raoul|Jean-Luc|JL|;De La Fouchardière|Christelle|C|http://orcid.org/0000-0003-2291-5693;Dahan|Laetitia|L|;Guimbaud|Rosine|R|;Sefrioui|David|D|;Jouve|Jean-Louis|JL|;Lepage|Côme|C|;Tougeron|David|D|;Taieb|Julien|J|;|||",
"chemical_list": "D009944:Organoplatinum Compounds; D000077146:Irinotecan; D002955:Leucovorin; D005472:Fluorouracil",
"country": "England",
"delete": false,
"doi": "10.1038/s41416-020-0917-4",
"fulltext": "\n==== Front\nBr J Cancer\nBr J Cancer\nBritish Journal of Cancer\n0007-0920\n1532-1827\nNature Publishing Group UK London\n\n32507854\n917\n10.1038/s41416-020-0917-4\nArticle\nIntra-arterial hepatic beads loaded with irinotecan (DEBIRI) with mFOLFOX6 in unresectable liver metastases from colorectal cancer: a Phase 2 study\nhttp://orcid.org/0000-0003-4580-585X\nPernot Simon simon.pernot@gmail.com\n\n1\nPellerin Olivier 2\nArtru Pascal 3\nMontérymard Carole 45\nSmith Denis 6\nRaoul Jean-Luc 7\nhttp://orcid.org/0000-0003-2291-5693\nDe La Fouchardière Christelle 8\nDahan Laetitia 9\nGuimbaud Rosine 10\nSefrioui David 11\nJouve Jean-Louis 12\nLepage Côme 5\nTougeron David 13\nTaieb Julien 1\nfor FFCD1201-DEBIRI investigators/Collaborators\n1 Département de Gastroentérologie et d’Oncologie Digestive, Hôpital Européen George Pompidou, Paris, France\n2 grid.414093.b Service de Radiologie, Hôpital Européen Georges Pompidou, Paris, France\n3 grid.492693.3 0000 0004 0622 4363 Institut de Cancérologie, Hôpital Privé Jean Mermoz, Lyon, France\n4 grid.476348.a Département Biostatistiques, Fédération Francophone de Cancérologie Digestive, Dijon, France\n5 grid.5613.1 0000 0001 2298 9313 EPICAD INSERM LNC-UMR 1231, Université de Bourgogne Franche Comté, Dijon, France\n6 grid.414339.8 0000 0001 2200 1651 Service d’Oncologie, CHU Bordeaux Hôpital St. André, Bordeaux, France\n7 grid.418443.e 0000 0004 0598 4440 Département d’Oncologie Médicale, Institut Paoli Calmettes CAC, Marseille, France\n8 grid.418116.b 0000 0001 0200 3174 Service de Médecine, Centre Léon Bérard, Lyon, France\n9 grid.411266.6 0000 0001 0404 1115 Service d’HGE et d’Oncologie, CHU La Timone, Marseille, France\n10 grid.414295.f 0000 0004 0638 3479 Service d’HGE, CHU Toulouse Rangueil, Toulouse, France\n11 grid.460771.3 0000 0004 1785 9671 Hôpital Universitaire de Rouen, Normandie Université, Service d’Hépato-gastroentérologie, UNIROUEN, Inserm 1245, IRON Group, 76000 Rouen, France\n12 grid.31151.37 Service d’HGE, CHU Le Bocage (Dijon), Dijon, France\n13 grid.411162.1 0000 0000 9336 4276 Service d’Oncologie, CHU Poitiers, La Milétrie, Poitiers, France\n8 6 2020\n18 8 2020\n123 4 518524\n2 1 2020\n16 4 2020\n13 5 2020\n© The Author(s), under exclusive licence to Cancer Research UK 2020\nhttps://creativecommons.org/licenses/by/4.0/ Note This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).\nBackground\n\nChemo-embolisation with drug-eluting beads loaded with irinotecan (DEBIRI) increased survival as compared with intravenous irinotecan in chemorefractory patients with liver-dominant metastases from colorectal cancer (LMCRC). First-line DEBIRI with systemic chemotherapy may increase survival and secondary resection.\n\nMethods\n\nIn the FFCD-1201 single-arm Phase 2 study, patients with untreated, non-resectable LMCRC received DEBIRI plus mFOLFOX6. Four courses of DEBIRI were performed alternating right and left lobe or two sessions with both lobes treated during the same session.\n\nResults\n\nFifty-seven patients were enrolled. Grade 3–5 toxicities were more frequent when both lobes were treated during the same session (90.5% versus 52.8%). Nine-month PFS rate was 53.6% (95% CI, 41.8–65.1%). The objective response rate (RECIST 1.1) was 73.2%, and the secondary R0 surgery was 33%. With a median follow-up of 38.3 months, median OS was 37.4 months (95% CI, 25.7–45.8), and median PFS 10.8 months (95% CI, 8.2–12.3).\n\nConclusions\n\nFront-line DEBIRI + mFOLFOX6 should not be recommended as the hypothesised 9-month PFS was not met. However, high response rate, deep responses, and prolonged OS encourage further evaluation in strategies integrating biologic agent, in particular in patients with secondary surgery as the main goal.\n\nClinical trial registration\n\nNCT01839877.\n\nSubject terms\n\nMetastasis\nCancer therapy\nColorectal cancer\nDrug delivery\nBiocompatibles UK LTDissue-copyright-statement© Cancer Research UK 2020\n==== Body\npmcBackground\n\nOver 80% of patients with liver metastases from colorectal cancer (LMCRC) present with unresectable disease. The intensification of first-line chemotherapy in unresectable patients allows a significant rate of secondary resection and led to an increased survival.1–3 Intrahepatic arterial delivery of chemotherapy has been proposed in patients with liver-only disease to treat tumour cells with high local concentrations of anticancer agents and decreased systemic toxicity.\n\nTransarterial chemo-embolisation (TACE) is a standard treatment for hepatocellular carcinoma and has for many years been used to treat LMCRC, albeit with a lack of prospective and comparative studies. Most reports are of small retrospective studies with various chemotherapy regimens and embolisation procedures in heterogeneous patient populations.4 Intra-arterial hepatic administration of drug-eluting beads (DEB) loaded with chemotherapy drugs have been developed to standardise the embolisation procedure compared to conventional TACE with use of calibrated non-resorbable beads, which can load and continuously release cytotoxic drugs into the target tissues.\n\nIn a Phase 3 trial on 74 patients,5 DEB loaded with irinotecan (DEBIRI) plus intravenous 5-fluoro-uracil (5FU) was compared to intravenous 5FU plus irinotecan (Folfiri) in patients with unresectable LMCRC after failure of at least two lines of treatment. Overall survival (OS), progression-free survival (PFS), and response rate significantly improved in the DEBIRI arm. However, heavily pretreated patients with liver-limited disease (LLD) are not frequent and the rate of secondary resectability is very low in this subgroup of patients. Use of DEBIRI before surgery also increases the histological response, as suggested by the PARAGON II study,5 and thus may potentially reduce the risk of recurrence.6\n\nWe hypothesise that upfront use of DEBIRI combined with systemic chemotherapy in liver-dominant metastatic colorectal cancer (mCRC) patients could improve treatment efficacy, limit systemic toxicity, and thus improve survival and secondary resectability. Our prospective, multi-centre, single-arm, Phase 2 study evaluated the feasibility, safety, and efficacy of a conventional systemic chemotherapy regimen 5FU plus oxaliplatin (FOLFOX) combined with intra-arterial hepatic DEBIRI as first-line treatment of mCRC patients with liver-dominant mCRC.\n\nMethods\n\nStudy design\n\nThis multi-centre, single-arm, Phase 2 study was approved by the French ethics committee “CCP Ile de France 8” (No. 1212113). All patients provided informed consent before study enrolment. The main eligibility criterion was previously untreated mCRC with unresectable liver metastases, as defined at a local multidisciplinary team meeting. Main exclusion criteria included liver involvement >60% or impaired hepatic function and extrahepatic metastases on computed tomographic (CT) scan, except lung nodules if <4 and <1 cm each. Inclusion/exclusion criteria are detailed in Supplementary Information 1. Concomitant administration of any targeted therapies was not permitted, considering that toxicity of the combination of DEBIRI plus anti-vascular endothelial growth factor (anti-VEGF) or anti-epidermal growth factor receptor (anti-EGFR) is unknown (no Phase 1 study available), and the biliary or vascular cumulative toxicity that have been reported in other trials with hepatic arterial chemotherapy.7\n\nProcedures\n\nPatients received induction chemotherapy with FOLFOX: oxaliplatin 85 mg/m2 as a 2-h infusion at day 1, leucovorin 400 mg/m2 as a 120-min infusion at day 1 followed by 5FU 400 mg/m2 bolus at day 1 and 2400 mg/m2 46-h continuous 5FU infusion, 1 cycle every 2 weeks. Patients received treatment with DC Bead LUMI™ 100–300 (Biocompatibles UK limited) loaded with irinotecan 50 mg/ml, 1 vial per lobe and per treatment (meaning 1 vial in case of unilobar administration, and 2 vials in case of bilobar administration). Each treatment session was performed 48–72 h after a chemotherapy cycle. Treatment administration was performed using a unilateral femoral approach. Depending of patient case and according to the choice of the investigators, the treatment could be administered in a bilobar approach or a sequential unilobar approach: in patients treated with a bilobar approach, both lobes were treated at each session after the second and fourth chemotherapy cycles; in patients treated with a sequential unilobar approach, only one lobe was treated per session, each lobe being treated alternately, after the second, third, fourth, and fifth cycles of chemotherapy. After a preplanned safety analysis performed after 27 patients were treated, the safety board recommendation was to treat patients with the sequential unilobar approach because of better tolerability. The procedure and periprocedural medication are described in Supplementary Information 2 and 3.\n\nProphylaxis with granulocyte-colony stimulating factor (G-CSF) could be used as primary prophylaxis, at the investigator’s discretion. Patients continued treatment until unacceptable toxicity, disease progression, consent withdrawal, or investigator choice.\n\nEndpoints/statistical analysis\n\nThe primary endpoint was the rate of PFS at 9 months, according to the local investigator evaluation. A one-step Fleming plan was used, with an α risk of 5% and unilateral power (1 − β) of 90%, testing the following assumptions: H0: 55% of patients alive without progression at 9 months is uninteresting; H1: 75% is expected. Taking into account a rate of 20% of patients lost to follow-up (without evaluation during the first 9 months of treatment), 58 patients had to be included.\n\nSecondary endpoints included safety (according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.0), objective response rate (ORR) according to response evaluation criteria in solid tumours (RECIST) 1.1 criteria, PFS, OS, secondary resectability rate, depth of response and early tumour shrinkage at 8 weeks; definitions are provided in Supplementary Information 4.\n\nAll adverse events were graded according to the NCI-CTCAE version 4.0. All patients with LMCRC who received at least one dose of treatment were included in the analysis of safety population. An interim safety analysis was planned after treatment of 27 patients, and an independent safety committee board was implemented.\n\nThe primary endpoint was analysed in a modified intention-to-treat (mITT) population defined as all patients who fulfilled eligibility criteria and has received at least one session of chemo-embolisation, at least one dose of chemotherapy, and who had at least one radiological evaluation during the 9 months of follow-up. Secondary endpoint was analysed in the ITT population.\n\nExploratory analyses to determine prognostic factors of PFS and OS were performed using univariate and multivariate Cox proportional hazards models. Hazard ratios and 95% confidence interval (CI) were estimated. Variables with p < 0.20 in univariate analyses were used in multivariate analyses.\n\nAll data were reported using the usual descriptive statistics: qualitative variables are described with percentages and quantitative variables with mean, standard deviation, median, interquartile interval (Q1–Q3), and range (minimum–maximum). Analyses were done using SAS 9.4 (SAS Institute, Cary, NC).\n\nResults\n\nPatient characteristics\n\nFrom May 2013 to December 2016, 58 patients were included and treated in 10 participating centres in France. Diagnosis of LMCRC was reconsidered and requalified as LM from pancreatic adenocarcinoma after inclusion in one patient, who was excluded from the final analysis. One patient was not analysed in the mITT population because he had no evaluation after the treatment during the study period (9 months). Patient characteristics are described in Table 1. Briefly, all patients had synchronous metastatic disease with primary tumour removed in 10 patients, including one with preoperative radio-chemotherapy for rectal cancer. Patients had bilobar metastatic disease in 88% of cases and a mean 9 LM (range 1–20). Lung nodules were described in 12% of patients on CT scan in respect of inclusion criteria.Table 1 Patient and treatment characteristics.\n\n\tN = 57\t\nMedian age (min.–max., years)\t63 (44–78)\t\nGender (n, %)\t\n Female\t25 (44)\t\n Male\t32 (56)\t\nECOG-PS (n, %)\t\n 0\t24 (42.1)\t\n 1\t30 (52.6)\t\n 2\t3 (5.3)\t\n Median number of LM (min.–max.)\t9.5 (1–20)\t\nDistribution of LM (n, %)\t\n Right lobe only\t5 (8.8)\t\n Left lobe only\t2 (3.5)\t\n Bilobar disease\t50 (87.7)\t\n Lung metastases on CT scan (n, %)\t7 (12.3)\t\nMolecular status (n, %)\t\n Ras mutated\t30 (52.6)\t\n BRAF mutated\t2 (3.5)\t\n RAS/BRAF wild type\t23 (40.4)\t\n ND\t2 (3.5)\t\nCEA level (n, %)\t\n ≤5 ULN\t18 (31.6%)\t\n >5 ULN−≤15 ULN\t16 (28.1%)\t\n >15 ULN\t23 (40.4%)\t\nAdministration of DEBIRI (n, %)\t\n Unilobar administration\t36 (63.2)\t\n Bilobar administration\t21 (36.8)\t\nSidedness of primary tumour (n, %)\t\n Rectum\t11 (19.3)\t\n Left colon\t34 (59.6)\t\n Right colon\t12 (21.1)\t\n\nTreatment compliance\n\nAll patients received at least one session of DEBIRI. The full DEBIRI treatment plan (2 or 4 sessions) was performed in 49% of patients. Bilobar administration was performed in 36.8% of patients, and a sequential unilobar administration was performed in 63.2%. Six patients planned for 2 bilobar sessions received only one bilobar administration instead of 2 due to grade 3–4 toxicity after the first session. The median number of FOLFOX cycles was 8 (range 2–28). The median dose intensities (all cycles of FOLFOX) were 92.4% for oxaliplatin, 80% for 5FU bolus, and 97.8% for continuous 5FU infusion. Twenty-eight patients (49%) received G-CSF.\n\nEfficacy\n\nThe 6- and 9-month PFS rates according to investigators were 82.4% [95% CI 69.8–90.1] and 53.6% [95% CI 41.8–65.1], respectively, in mITT population. After a median follow-up of 38.3 months [95% CI 32.2–41.9], 4 patients were alive without progression in ITT population. Median PFS was 10.8 months [95% CI 8.2–12.3] (Fig. 1) and median OS was 37.4 months [95% CI, 25.7–45.8] (Fig. 2). Median-specific liver PFS was 10.9 months [95% CI, 8.2–12.4]. Post-progression treatments were available in 49 patients. After progression, patients received a median of two treatments (Supplementary Table S1).Fig. 1 Progression-free survival.\n\nY = probability of PFS.\n\nFig. 2 Overall survival.\n\nY = probability of survival.\n\nA blind central review assessment for the primary objective was made by a single independent radiologist. Results were concordant with investigator assessment, with a median PFS of 10.4 months [95% CI 7.2–13.6].\n\nAccording to investigator evaluation, an ORR was observed in 41 patients (73.2%) including 4 complete responses. Disease control rate (DCR) was 92.9%. The median depth of response was −43.6% (Q1: −61.7; Q3: −31) (Fig. 3). The rate of early tumour shrinkage was 52.1% [95% CI 37.2–66.7].Fig. 3 Depth of response.\n\nWaterfall plot of change from baseline in sum of diameters of target lesions (%).\n\nSecondary resection or ablative treatment\n\nNineteen patients (33%) underwent R0 resection of LM; for this subgroup, median PFS was 13 months [95% CI 8.8; 16.6] and median OS was not reached. OS rate at 2 and 3 years were 94.74% [95% CI 68.12; 99.24] and 75.49% [95% CI 45.80; 90.37], respectively. Of the 17 patients with recurrence after curative intent surgery, 11 were eligible for a second curative intent surgery/ablation. Altogether, 8 of these 19 patients were alive with no evidence of disease after a median follow-up of 3.7 years (range 2.5–4.7).\n\nA post hoc independent evaluation of resectability by three experienced hepatic surgeons was performed based on a CT scan at baseline. According to this centralised review, 53/56 patients (94.6%) were retrospectively confirmed as non-resectable by at least 2 surgeons (Fig. 4). Two patients were considered resectable at baseline (3.5%) by the 3 surgeons and 1 by 2 of the 3 surgeons.Fig. 4 Centralised review of resectability at baseline.\n\nPost hoc evaluation of resectability based on a CT scan at baseline for each patient, by three independant experienced hepatic surgeons. *Resected patients after Folfox + Debiri.\n\nPrognostic factors\n\nThe effect on survival of clinical and laboratory findings and unilobar versus bilobar administration was assessed. BRAF mutation was the only factor associated with worse PFS and OS in both univariate and multivariate analysis. Primary tumour location and administration modality were not prognostic (Supplementary Tables S2 and S3).\n\nSafety\n\nOne toxic death possibly related to DEBIRI was reported (peritonitis). The main grade 3–4 toxicities were neutropenia (24.6%), diarrhoea (12.3%), abdominal pain (14%), and pancreatitis/cholecystitis (8.8%/5.3). Importantly, almost all G3/4/5 toxicities were more frequent with the bilobar approach than the unilobar approach (87.5% versus 47.2%; Table 2). Adverse events are detailed in Supplementary Table S4. Two patients stopped chemotherapy due to major toxicity after 2 and 6 cycles of FOLFOX, respectively. A delay in administration of chemotherapy due to toxicity was reported in 16 patients.Table 2 Grade 3/4/5 adverse events in overall population and according to the treatment modality.\n\nToxicity\t\tGrade 3/4/5 toxicity\t\n\tAll, N = 57\tUnilobar, N = 36\tBilobar, N = 21\t\nAll\t38 (66.7)\t19 (52.8)\t19 (90.5)\t\nNon-hematologic\t\n Any non-hematologic\t27 (47.4)\t12 (33.3)\t15 (71.4)\t\n Asthenia\t3 (5.3)\t0\t3 (14.3)\t\n Hypertension\t1 (1.8)\t0\t1 (4.8)\t\n Any gastrointestinal\t20 (35.1)\t9 (25.0)\t11 (52.4)\t\n Nausea\t3 (5.3)\t1 (2.8)\t2 (9.5)\t\n Vomiting\t3 (5.3)\t3 (8.3)\t0\t\n Diarrhoea\t7 (12.3)\t3 (8.3)\t4 (19.0)\t\n Abdominal pain\t8 (14.0)\t2 (5.6)\t6 (28.6)\t\n Small bowel obstruction\t2 (3.5)\t1 (2.8)\t1 (4.8)\t\n Any extrahepatic perfusion\t7\t2 (5.6)\t5 (23.8)\t\n Peritonitis\t1 (1.8)\t0\t1 (4.8)\t\n Pancreatitis\t5 (8.8)\t1 (2.8)\t4 (19)\t\n Cholecystitis\t3 (5.3)\t2 (5.6)\t1 (4.8)\t\nHematologic\t20 (35.1)\t11 (30.6)\t9 (42.9)\t\n Anemia\t3 (5.3)\t2 (5.6)\t1 (4.8)\t\n Thrombocytopenia\t3 (5.3)\t0\t3 (14.3)\t\n Lymphopenia\t2 (3.5)\t2 (5.6)\t0\t\n Leucopenia\t1 (1.8)\t1 (2.8)\t0\t\n Neutropenia\t14 (24.6)\t6 (16.7)\t8 (38.1)\t\n Febrile neutropenia\t3 (5.3)\t2 (5.6)\t1 (4.8)\t\n\nPeriprocedural adverse events (occurring during the first 24 h after DEBIRI) of any grade was observed in 75.4% of patients. Post-embolisation syndrome was the most frequent adverse event, with significant abdominal pain (visual analogue scale >3) occurring in 75.4% of patients, nausea/vomiting in 22.8% of patients, and fever in 5.3% of patients. Cardiovascular side effects were not rare, with acute hypertension in 19.3% of patients, thoracic pain in 3 patients, among which 1 was identified as coronary spasm with transitory elevation of troponin, and 2 tachycardia (Supplementary Table S5, online only).\n\nDiscussion\n\nWe demonstrated that combination of DEBIRI plus FOLFOX is feasible in LLD mCRC, leading to a high ORR of 73.2% and allowing secondary resection in one-third of patients. Moreover, prolonged OS was observed, with a median of 37.4 months. However, our study did not meet the prespecified primary endpoint, as the 9-month PFS rate was under 75% expected (53.6%). A posteriori, 75% appears challenging considering recent trials with comparable populations in LMCRC.8 Nevertheless, a long OS may have been favoured by the depth of response and early tumour shrinkage,9 and the subsequent treatment lines considering the spare of targeted agent, and limited irinotecan systemic release10 with Folfox + DEBIRI. Finally, while the toxicity profile was manageable, DEBIRI + FOLFOX may lead to serious and specific side effects when two lobes are treated during the same session, but the safety profile was better when DEBIRI was administered in the hepatic lobes one by one.\n\nDoublet chemotherapies with a targeted agent led to an ORR between 33% and 53%, median PFS from 6.8 to 9.2 months, and median OS from 15.1 to 25.8 months.1–3,11 ORR reached 55–62% in recent trials in RAS wild-type patients only.12,13 Compared to doublet chemotherapies, FOLFOXIRI +/− bevacizumab significantly increased ORR and median PFS in patients with non-resectable LMCRC,1–3,14 ranging from 43% to 80% and 9.8 to 12.3 months, respectively. The ORR and PFS reported in our study therefore seem in line with those observed in patients treated with intensive systemic regimens such as FOLFOXIRI +/− bevacizumab. Median OS was 37.4 months compared to 25–29 months with the use of triplet +/− bevacizumab.1–3,14 However, we have to point that the trials studying triplet included unselected non-resectable mCRC patients, while our study included only liver-dominant patients. Nevertheless, our survival results seem promising in mCRC patients with liver-dominant disease, even though the primary 9-month PFS endpoint was not reached.\n\nReported secondary resection rates are around 15% with doublet CT + anti-VEGF or anti-EGFR15,16 and 23–60% in patients with exclusive LMCRC.11,14–17 However, in previous studies of LMCRC, secondary resectability may have been overestimated owing to a significant proportion of patients may actually have been resectable upfront. Indeed, in most of these studies, non-resectability at baseline was defined by the number of metastases >4 and/or size >5 cm and/or by the presence of bilobar metastases or no extrahepatic metastases. However, it is now accepted that these criteria no longer apply.18–21 The modern definition of resectability includes the potential for complete resection with tumour-free margins; preservation of viable vascular inflow, outflow, and biliary drainage; and a future minimal remnant liver volume of 30%.6,22 Interestingly, in the CELIM study and the FIRE-3 study, retrospective assessment of baseline resectability found that 30% and 22% of patients were technically resectable initially.15,23 Our non-resectability assessment before inclusion did not use these size/number criteria and was made by the local multidisciplinary team meeting and 95% of the patients were retrospectively confirmed as non-resectable at baseline by an independent committee of three experienced liver surgeons. Therefore, the resectability rate of 33% is solid and compared favourably with the other studies.\n\nOther intensified hepatic intra-arterial strategies have been or are currently being investigated. Radio-embolisation (selective internal radiation therapy (SIRT)) combined with FOLFOX failed to increase ORR, OS, PFS, or the resection rate, which remained <15% in the FOXFIRE GLOBAL large Phase 3 trial that included patient with liver-dominant disease.8 In this study, inclusion criteria and design were very close from our study, and this trial provides recent data in a very similar population and with an alternative transarterial approach and the same systemic regimen (despite that biologic agent could be added after the induction treatment in FOXFIRE GLOBAL trial according to the investigator choice). In this trial, FOLFOX + SIRT led to a median PFS of 11 months and a response rate of 72.4%, similar to those observed with FOLFOX + DEBIRI. The resection rate remained <15% and median OS was only 22.6 months, contrasting with the 33% and 38.3 months reported in our study, which may be explained in part by the depth of response and the early tumour shrinkage observed with DEBIRI, rather than by the liver-specific PFS, which was lower with DEBIRI than with SIRT.\n\nHepatic arterial infusion of floxuridine chemotherapy showed a response rate of 92% and conversion to resection in 47% of patients24 in a Phase 1 trial, but with some FUDR-related complications and biliary toxicity. Hepatic arterial infusion of oxaliplatin combined with systemic chemotherapy and targeted therapy is currently being tested in the PRODIGE 49 Phase 3 trial (NCT02885753). Compared to the latter, DEBIRI has the advantage of being an easy, accessible, and reproducible procedure, as TACE is used worldwide. When first-line DEBIRI in combination with FOLFOX +/− bevacizumab was assessed and compared with systemic chemotherapy alone, ORR increased with DEBIRI, as did resection rate (35% versus 6% [p = 0.05]).25 However, response was evaluated using the modified RECIST criteria, which are not adequate for DEBIRI in mCRC.26 When considering RECIST 1.1 criteria, this study found a response rate of 97% with DEBIRI + FOLFOX, but, more surprisingly, also 95% in patients treated with FOLFOX alone, a value far from those generally reported with this regimen.\n\nWe observed a high rate of grade 3–5 adverse events with one toxic death possibly due to DEBIRI. Most frequent toxicities were gastrointestinal and the consequence of extrahepatic perfusion. Interestingly, these specific toxicities, as well as non-specific toxicities, were notably more frequent after DEBIRI was used in a bilobar approach, whereas efficacy parameters were not affected by the bilobar or unilobar approach. This observation during a planned interim safety analysis led to the recommendation to treat patients preferentially with a unilobar approach after inclusion of 27 patients. The reported rate of post-embolisation syndrome in the literature is quite difficult to analyse due to the large heterogeneity in monitoring and reporting of this side effect, ranging from 6% to 100%.27 The post-embolisation syndrome rate still seemed high in our trial compared to previous studies. The timing of the procedure with respect to chemotherapy may be involved, since cumulative toxicities of chemotherapy followed by chemo-embolisation could have occurred. The use in front line could also be a reason to explain the higher rate of embolisation syndrome, compared to previous reports in late-line treatment in LMCRC. Indeed, it has been suggested that a majority of patients have a tumour load in late line remaining below their initial tumour load,28 and highest tumour load have been associated with more frequent post-embolisation syndromes.29\n\nThe addition of DEBIRI appears to have had limited impact on the administration of chemotherapy. Indeed, only two patients stopped chemotherapy due to unacceptable toxicity during the induction period. Nevertheless, the median number of cycles of FOLFOX was only eight, suggesting that a large part of patients had a stop-and-go strategy with early maintenance with 5FU or even a break from chemotherapy. Such strategy may have been favoured by the increased toxicity during the induction period.\n\nThe strength of our study is that it was conducted in patients carefully selected with non-resectable LMCRC, as confirmed by our panel expert, and was multicentric. Nevertheless, these results need confirmation in a randomised study compared with standard protocols, and in particular with other intensified regimens as triplet chemotherapy. As specified above, we decided to avoid targeted therapy, and FOLFOX + DEBIRI deserves to be tested in combination with targeted therapy. Another weakness is that we did not plan oxaliplatin continuation after the induction period, and some patients had a stop-and-go strategy with early maintenance with 5FU or even a break from chemotherapy, when others kept oxaliplatin until limiting toxicity. This heterogeneity may have impaired the evaluation of PFS.\n\nIn conclusion, although the primary endpoint was not met, front-line FOLFOX + DEBIRI without any targeted agent is feasible. Indeed, despite relevant toxicity, the unilobar approach showed a manageable tolerability profile and allows an excellent DCR in non-resectable LMCRC with deep responses, leading to resection in one-third of patients and prolonged survival. Induction treatment with FOLFOX + DEBIRI cannot be considered standard in unresectable patients as the present trial did not meet the prespecified primary endpoint. However, considering a promising response rate and OS, its optimal place in the therapeutic strategy must now be defined by further studies including biologic agents and a more selected patient population, possibly with secondary surgery as main goal, and should be used in a unilobar approach only.\n\nSupplementary information\n\nAppendix\n\nSupplementary information\n\nSupplementary information is available for this paper at 10.1038/s41416-020-0917-4.\n\nAcknowledgements\n\nThis study was presented at the European Society for Medical Oncology (ESMO) Annual Congress in Poster Discussion session, 19–23 October 2018; (Munich, Germany): Pernot, S., Artru, P., Tougeron, D., Montérymard, C., Smith, D., De La Fouchardière, C. et al. 461PD Folfox and intra-arterial DEBIRI as front-line treatment in patients with non resectable colorectal cancer liver metastases (FFCD 1201 Phase 2 trial). Ann. Oncol. 29(suppl_8), viii150–viii204 (2018).\n\nAuthor contributions\n\nStudy concepts: S.P., O.P., J.T. Study design: S.P., O.P., C.M., C.L., J.T. Data acquisition: S.P., O.P., P.A., D.S., J.-L.R., C.D.L.F., L.D., R.G., D.S., J.-L.J., D.T., J.T. Quality control of data and algorithms: C.M. Data analysis and interpretation: S.P., J.T., O.P., D.T. Statistical analysis: C.M., S.P., J.T. Manuscript preparation: S.P., C.M., J.T. Manuscript editing and review: all.\n\nEthics approval and consent to participate\n\nThis multi-centre, single-arm, Phase 2 study was approved by the French ethics committee “CPP Ile de France 8” (committee’s reference No. 1212113). All patients provided informed consent before study enrolment. The study was performed in accordance with the declaration of Helsinki.\n\nConsent for publish\n\nThis manuscript does not include any person’s individual data.\n\nData availability\n\nData can be found based on reasonable demand to the promoter “Fédération Française de Cancérologie digestive (FFCD)”.\n\nCompeting interests\n\nS.P. has received honoraria as a speaker and/or advisor from Sanofi, Amgen, and Servier. O.P. has received honoraria as a speaker and/or advisor from Merit Medical and COGITh-SAS. J.T. has received honoraria as a speaker and/or advisor from Merck KGaA, Sanofi, Roche Genentech, MSD, Lilly, Celgene, Servier, Pierre Fabre, and Amgen. J.-L.R. has received honoraria for speaker/advisory role from Astra Zeneca, Bayer, BTG, Ipsen, and Merck. D.T. has received honoraria for speaker or/and advisory role from Merck KGaA, Sanofi, Roche Genentech, MSD, Novartis, BMS, Servier, Bayer, and Amgen; D.S. has received honoraria for speaker or/and advisory role from Amgen, Ipsen, and Servier. C.D.L.F. has received honoraria for speaker/advisory role from Servier, Roche Genentech, MSD, Lilly, Celgene, Pierre Fabre, and Amgen. R.G. has received honoraria for speaker/advisory role from Pierre Fabre, Astra Zeneca, Amgen, Servier, and Novartis. All the remaining authors have declared no conflict of interest.\n\nFunding information\n\nThis work was supported, and product provided free of charge, by Biocompatibles UK Ltd.\n\nA full list of members and their affiliations appears in the Supplementary Information.\n\nPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nThese authors contributed equally: Simon Pernot, Olivier Pellerin\n==== Refs\nReferences\n\n1. Falcone A Ricci S Brunetti I Pfanner E Allegrini G Barbara C Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest J. Clin. Oncol. 2007 25 1670 1676 10.1200/JCO.2006.09.0928 17470860\n2. Souglakos J Androulakis N Syrigos K Polyzos A Ziras N Athanasiadis A FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a multicentre randomised phase III trial from the Hellenic Oncology Research Group (HORG) Br. J. Cancer 2006 94 798 805 10.1038/sj.bjc.6603011 16508637\n3. Cremolini C Loupakis F Antoniotti C Lupi C Sensi E Lonardi S FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study Lancet Oncol. 2015 16 1306 1315 10.1016/S1470-2045(15)00122-9 26338525\n4. Riemsma RP Bala MM Wolff R Kleijnen J Transarterial (chemo)embolisation versus no intervention or placebo intervention for liver metastases Cochrane Database Syst. Rev. 2013 4 CD009498\n5. Jones RP Malik HZ Fenwick SW Terlizzo M O’Grady E Stremitzer S PARAGON II - a single arm multicentre phase II study of neoadjuvant therapy using irinotecan bead in patients with resectable liver metastases from colorectal cancer Eur. J. Surg. Oncol. 2016 42 1866 1872 10.1016/j.ejso.2016.07.142 27561844\n6. Adam R Gramont AD Figueras J Guthrie A Kokudo N Kunstlinger F The oncosurgery approach to managing liver metastases from colorectal cancer: a multidisciplinary international consensus Oncologist 2012 17 1225 1239 10.1634/theoncologist.2012-0121 22962059\n7. Cercek A D’Angelica M Power D Capanu M Gewirtz A Patel D Floxuridine hepatic arterial infusion associated biliary toxicity is increased by concurrent administration of systemic bevacizumab Ann. Surg. Oncol. 2014 21 479 486 10.1245/s10434-013-3275-0 24154839\n8. Wasan HS Gibbs P Sharma NK Taieb J Heinemann V Ricke J First-line selective internal radiotherapy plus chemotherapy versus chemotherapy alone in patients with liver metastases from colorectal cancer (FOXFIRE, SIRFLOX, and FOXFIRE-Global): a combined analysis of three multicentre, randomised, phase 3 trials Lancet Oncol. 2017 18 1159 1171 10.1016/S1470-2045(17)30457-6 28781171\n9. Aprile G Fontanella C Bonotto M Rihawi K Lutrino SE Ferrari L Timing and extent of response in colorectal cancer: critical review of current data and implication for future trials Oncotarget 2015 6 28716 28730 10.18632/oncotarget.4747 26308250\n10. Martin RCG Scoggins CR Tomalty D Schreeder M Metzger T Tatum C Irinotecan drug-eluting beads in the treatment of chemo-naive unresectable colorectal liver metastasis with concomitant systemic fluorouracil and oxaliplatin: results of pharmacokinetics and phase I trial J. Gastrointest. Surg. 2012 16 1531 1538 10.1007/s11605-012-1892-8 22528576\n11. Hurwitz H Fehrenbacher L Novotny W Cartwright T Hainsworth J Heim W Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer N. Engl. J. Med. 2004 350 2335 2342 10.1056/NEJMoa032691 15175435\n12. Heinemann V von Weikersthal LF Decker T Kiani A Vehling-Kaiser U Al-Batran S-E FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial Lancet Oncol. 2014 15 1065 1075 10.1016/S1470-2045(14)70330-4 25088940\n13. Venook AP Niedzwiecki D Lenz H-J Innocenti F Fruth B Meyerhardt JA Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in patients with KRAS wild-type advanced or metastatic colorectal cancer: a randomized clinical trial JAMA 2017 317 2392 2401 10.1001/jama.2017.7105 28632865\n14. Gruenberger T Bridgewater J Chau I García Alfonso P Rivoire M Mudan S Bevacizumab plus mFOLFOX-6 or FOLFOXIRI in patients with initially unresectable liver metastases from colorectal cancer: the OLIVIA multinational randomised phase II trial Ann. Oncol. 2015 26 702 708 10.1093/annonc/mdu580 25538173\n15. Modest DP Denecke T Pratschke J Ricard I Lang H Bemelmans M Surgical treatment options following chemotherapy plus cetuximab or bevacizumab in metastatic colorectal cancer—central evaluation of FIRE-3 Eur. J. Cancer 2018 88 77 86 10.1016/j.ejca.2017.10.028 29195117\n16. Bokemeyer C Van Cutsem E Rougier P Ciardiello F Heeger S Schlichting M Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: pooled analysis of the CRYSTAL and OPUS randomised clinical trials Eur. J. Cancer 2012 48 1466 1475 10.1016/j.ejca.2012.02.057 22446022\n17. Wong R Cunningham D Barbachano Y Saffery C Valle J Hickish T A multicentre study of capecitabine, oxaliplatin plus bevacizumab as perioperative treatment of patients with poor-risk colorectal liver-only metastases not selected for upfront resection Ann. Oncol. 2011 22 2042 2048 10.1093/annonc/mdq714 21285134\n18. Chow FC-L Chok KS-H Colorectal liver metastases: an update on multidisciplinary approach World J. Hepatol. 2019 11 150 172 10.4254/wjh.v11.i2.150 30820266\n19. Omichi K Shindoh J Cloyd JM Mizuno T Chun YS Conrad C Liver resection is justified for patients with bilateral multiple colorectal liver metastases: a propensity-score-matched analysis Eur. J. Surg. Oncol. 2018 44 122 129 10.1016/j.ejso.2017.11.006 29208318\n20. Altendorf-Hofmann A Scheele J A critical review of the major indicators of prognosis after resection of hepatic metastases from colorectal carcinoma Surg. Oncol. Clin. North Am. 2003 12 165 192 10.1016/S1055-3207(02)00091-1\n21. Elias D Ouellet J-F Bellon N Pignon J-P Pocard M Lasser P Extrahepatic disease does not contraindicate hepatectomy for colorectal liver metastases Br. J. Surg. 2003 90 567 574 10.1002/bjs.4071 12734864\n22. Clavien P-A Petrowsky H DeOliveira ML Graf R Strategies for safer liver surgery and partial liver transplantation N. Engl. J. Med. 2007 356 1545 1559 10.1056/NEJMra065156 17429086\n23. Folprecht G Gruenberger T Bechstein WO Raab H-R Lordick F Hartmann JT Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: the CELIM randomised phase 2 trial Lancet Oncol. 2010 11 38 47 10.1016/S1470-2045(09)70330-4 19942479\n24. Kemeny NE Melendez FDH Capanu M Paty PB Fong Y Schwartz LH Conversion to resectability using hepatic artery infusion plus systemic chemotherapy for the treatment of unresectable liver metastases from colorectal carcinoma J. Clin. Oncol. 2009 27 3465 3471 10.1200/JCO.2008.20.1301 19470932\n25. Martin RCG Scoggins CR Schreeder M Rilling WS Laing CJ Tatum CM Randomized controlled trial of irinotecan drug-eluting beads with simultaneous FOLFOX and bevacizumab for patients with unresectable colorectal liver-limited metastasis Cancer 2015 121 3649 3658 10.1002/cncr.29534 26149602\n26. Akinwande O Philips P Scoggins CR Kelly L Tatum C Hahl M Comparison of tumor response assessment methods in patients with metastatic colorectal cancer after locoregional therapy J. Surg. Oncol. 2016 113 443 448 10.1002/jso.24141 27060707\n27. Akinwande O Dendy M Ludwig JM Kim HS Hepatic intra-arterial injection of irinotecan drug eluting beads (DEBIRI) for patients with unresectable colorectal liver metastases: a systematic review Surg. Oncol. 2017 26 268 275 10.1016/j.suronc.2017.05.003 28807246\n28. Palmieri L-J Fihri A Doat S Dubreuil O Manceau G Karoui M Tumor-size responses to first-line is a predictor of overall survival in metastatic colorectal cancer Eur. Radiol. 2019 29 3871 3880 10.1007/s00330-018-5967-0 30706121\n29. Martin RCG Howard J Tomalty D Robbins K Padr R Bosnjakovic PM Toxicity of irinotecan-eluting beads in the treatment of hepatic malignancies: results of a multi-institutional registry Cardiovasc. Intervent. Radiol. 2010 33 960 966 10.1007/s00270-010-9937-4 20661569\n\n",
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"journal": "British journal of cancer",
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"medline_ta": "Br J Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D016461:Chemoembolization, Therapeutic; D015179:Colorectal Neoplasms; D003131:Combined Modality Therapy; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds; D016019:Survival Analysis; D016896:Treatment Outcome",
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"pmid": "32507854",
"pubdate": "2020-08",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Intra-arterial hepatic beads loaded with irinotecan (DEBIRI) with mFOLFOX6 in unresectable liver metastases from colorectal cancer: a Phase 2 study.",
"title_normalized": "intra arterial hepatic beads loaded with irinotecan debiri with mfolfox6 in unresectable liver metastases from colorectal cancer a phase 2 study"
} | [
{
"companynumb": "FR-PFIZER INC-2020236888",
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"patient": {
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"activesubstancename": "OXALIPLATIN"
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"abstract": "Systemic chemotherapy and targeted agents are associated with various cutaneous toxicities. Even though cutaneous toxicities are manageable, it often results in treatment discontinuation and worsens the patients' quality of life.\n\n\n\nThe study aimed to determine the spectrum of cutaneous toxicities in patients receiving systemic chemotherapy and targeted agents for breast cancer patients.\n\n\n\nA total of 250 out of 720 patients with breast cancer who developed various cutaneous toxicities to chemotherapeutic or targeted agents were included in the study.\n\n\n\nAmong 250 patients, 57 patients were on neoadjuvant chemotherapy, 89 patients were on adjuvant chemotherapy, 68 were on palliative chemotherapy for metastatic breast cancer and 36 were on targeted treatment for metastatic breast cancer. The most frequently affected site was hair (96%), followed by skin (92%), nail (34%), and mucosa (26%). The most common dermatological toxicity noticed in our study involved the hair in the form of chemotherapy induced alopecia (anagen effluvium) in 93.6%, followed by skin toxicity with generalized xerosis in 92% and, nail toxicity in 34%, and mucosal toxicity in 26%. The most common chemotherapeutic agent which caused frequent cutaneous toxicities in our patients was docetaxel followed by paclitaxel, capecitabine, doxorubicin, epirubicine, cyclophosphamide, 5-flurouracil and targeted agents like lapatinib, everolimus, and tamoxifen.\n\n\n\nCutaneous toxicities are common following systemic chemotherapy and targeted agents. Early recognition of cutaneous side effects of these agents and prompt early interventions can reduce the significant morbidity, cosmetic disfigurement, unnecessary treatment interruptions, and psychological distress in women treated for breast cancers.",
"affiliations": "Department of Medical Oncology, Regional Cancer Center, Thiruvananthapuram, Kerala, India. Electronic address: dranooptm@yahoo.co.in.;Department of Medical Oncology, Regional Cancer Center, Thiruvananthapuram, Kerala, India.;KIMS Hospital, Thiruvananthapuram, Kerala, India.;Department of Medical Oncology, Regional Cancer Center, Thiruvananthapuram, Kerala, India.;Department of Medical Oncology, Regional Cancer Center, Thiruvananthapuram, Kerala, India.;Department of Medical Oncology, Regional Cancer Center, Thiruvananthapuram, Kerala, India.",
"authors": "Anoop|T M|TM|;Joseph P|Rona|R|;Pn|Mini|M|;Kp|Pranab|P|;Gopan|Gayatri|G|;Chacko|Steffi|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.clbc.2021.01.009",
"fulltext": null,
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"issn_linking": "1526-8209",
"issue": "21(4)",
"journal": "Clinical breast cancer",
"keywords": "Breast cancer; Capecitabine; Chemotherapy; Cutaneous toxicity; Dermatological toxicity; Docetaxel; Hand foot syndrome; Paclitaxel; Targeted agents; Taxanes",
"medline_ta": "Clin Breast Cancer",
"mesh_terms": null,
"nlm_unique_id": "100898731",
"other_id": null,
"pages": "e434-e447",
"pmc": null,
"pmid": "33608219",
"pubdate": "2021-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Cutaneous Toxicities in Breast Cancer Patients Receiving Chemotherapy and Targeted Agents--An Observational Clinical Study.",
"title_normalized": "cutaneous toxicities in breast cancer patients receiving chemotherapy and targeted agents an observational clinical study"
} | [
{
"companynumb": "IN-ROCHE-2946049",
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"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
"drugadditional": "3",
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{
"abstract": "OBJECTIVE\nTo find possible predictive factors to predict the failure of conservative treatment of non-tubal ectopic pregnancy. For that purpose, we assessed the rate of failure, complications and need for additional interventions of the different primary treatment regimens in non-tubal ectopic pregnancies that occurred in our center.\n\n\nMETHODS\nRetrospective single-center study conducted at Hospital Clínic of Barcelona (Spain). Conservative treatment regimens included medical (systemic single or multiple dose methotrexate; ultrasound-guided intrasaccular injection of methotrexate or chloride potassium; surgical (oophorectomy in case of ovarian ectopic pregnancy, surgical curettage). The main outcome measures were success of primary treatment and the need for additional interventions. The secondary outcomes were success rate of conservative treatment, incidence of complications, days to discharge from the hospital, days until negative β-hCG, days until complete resolution of the process. Possible predictor factors for primary treatment failure were assessed.\n\n\nRESULTS\nA total of 39 cases were included. Primary treatment was successful in 74 % (29/39). The rate of failure of primary treatment was higher in the group with presence of embryo heartbeat than in the group without, 46 % vs. 15 % respectively (p < 0.0001). Among the cases that required additional treatments, none of them required hysterectomy. Presence of embryo heartbeat significantly increased the likelihood of failure of the primary treatment (OR 4.71, 95 % CI 1.03-21.65, p < 0.05). Every doubling of the β-hCG levels increased the risk of treatment failure by 54 % (OR 1.54, 95 % CI 1.03-2.39, p < 0.05).\n\n\nCONCLUSIONS\nConservative treatment is a safe option for treatment of non-tubal ectopic pregnancy. The presence of embryo heartbeat and β-hCG levels at diagnosis may be used as predictive factors of failure of conservative treatment.",
"affiliations": "Department of Obstetrics and Gynecology, Institute of Clinical Sciences Lund, Lund University, Sweden. Electronic address: katerinanedopekina@yahoo.com.;Fetal Medicine Research Center, BCNatal - Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital Clínic and Hospital Sant Joan de Deu), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Spain; Centre for Biomedical Research on Rare Diseases (CIBER-ER), Barcelona, Spain.;Fetal Medicine Research Center, BCNatal - Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital Clínic and Hospital Sant Joan de Deu), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Spain; Centre for Biomedical Research on Rare Diseases (CIBER-ER), Barcelona, Spain.;Department of Obstetrics and Gynecology, Institute of Clinical Sciences Lund, Lund University, Sweden; Skane University Hospital, Malmö, Lund, Sweden.;Fetal Medicine Research Center, BCNatal - Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital Clínic and Hospital Sant Joan de Deu), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Spain; Centre for Biomedical Research on Rare Diseases (CIBER-ER), Barcelona, Spain.;Fetal Medicine Research Center, BCNatal - Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital Clínic and Hospital Sant Joan de Deu), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Spain; Centre for Biomedical Research on Rare Diseases (CIBER-ER), Barcelona, Spain.;Fetal Medicine Research Center, BCNatal - Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital Clínic and Hospital Sant Joan de Deu), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Spain; Centre for Biomedical Research on Rare Diseases (CIBER-ER), Barcelona, Spain.",
"authors": "Nedopekina|Ekaterina|E|;Escura|Silvia|S|;Cobo|Teresa|T|;Hansson|Stefan Rocco|SR|;Martinez|Josep Maria|JM|;Figueras|Francesc|F|;López|Marta|M|",
"chemical_list": "D000020:Abortifacient Agents, Nonsteroidal; D008727:Methotrexate",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.ejogrb.2020.11.067",
"fulltext": null,
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"issn_linking": "0301-2115",
"issue": "257()",
"journal": "European journal of obstetrics, gynecology, and reproductive biology",
"keywords": "Conservative treatment; Failure of treatment; Intrasaccular injection; Non-tubal ectopic pregnancy",
"medline_ta": "Eur J Obstet Gynecol Reprod Biol",
"mesh_terms": "D000020:Abortifacient Agents, Nonsteroidal; D000072700:Conservative Treatment; D005260:Female; D006801:Humans; D008727:Methotrexate; D011247:Pregnancy; D011271:Pregnancy, Ectopic; D011274:Pregnancy, Tubal; D012189:Retrospective Studies; D013030:Spain; D017211:Treatment Failure; D016896:Treatment Outcome",
"nlm_unique_id": "0375672",
"other_id": null,
"pages": "6-10",
"pmc": null,
"pmid": "33310657",
"pubdate": "2021-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Conservative treatment in non-tubal ectopic pregnancy and predictors of treatment failure.",
"title_normalized": "conservative treatment in non tubal ectopic pregnancy and predictors of treatment failure"
} | [
{
"companynumb": "SE-MYLANLABS-2021M1035206",
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"occurcountry": "ES",
"patient": {
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{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,
... |
{
"abstract": "An 82-year-old man was diagnosed with advanced gastric cancer(tub2, HER2-positive), and the clinical findings were T3N3M1(LYM), Stage Ⅳ. We started chemotherapy with capecitabine, cisplatin, and trastuzumab. After the first course, the dose of capecitabine was reduced and cisplatin was discontinued due to Grade 3 neutropenia. After 4 courses, the remarkable shrinking of the primary tumor and metastatic lymph nodes enabled us to assess the possibility of radical resection, but the patient and his family declined it because of his advanced age. Thereafter, we continued the chemotherapy with capecitabine and trastuzumab for 75 courses. Until multiple lung, liver, and lymph node metastasis occurred after 77 courses, he was adequately managed and maintained good performance status(PS)over a long period of about 53 months.",
"affiliations": "Dept. of Surgery, Kansai Rosai Hospital.",
"authors": "Yukawa|Yoshiro|Y|;Takeno|Atsushi|A|;Kawai|Kenji|K|;Sakamoto|Takuya|T|;Inatome|Junichi|J|;Naito|Atsushi|A|;Murakami|Kohei|K|;Katsura|Yoshiteru|Y|;Ohmura|Yoshiaki|Y|;Kagawa|Yoshinori|Y|;Masuzawa|Toru|T|;Egawa|Chiyomi|C|;Takeda|Yutaka|Y|;Murata|Kohei|K|",
"chemical_list": "D000069287:Capecitabine; D018719:Receptor, ErbB-2; D000068878:Trastuzumab; D002945:Cisplatin",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "45(13)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069287:Capecitabine; D002945:Cisplatin; D006801:Humans; D008297:Male; D018719:Receptor, ErbB-2; D013274:Stomach Neoplasms; D000068878:Trastuzumab",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "2273-2275",
"pmc": null,
"pmid": "30692435",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of an Elderly Patient with Unresectable HER2-Positive Gastric Cancer Successfully Treated by Chemotherapy Combined with Trastuzumab over a Long Period.",
"title_normalized": "a case of an elderly patient with unresectable her2 positive gastric cancer successfully treated by chemotherapy combined with trastuzumab over a long period"
} | [
{
"companynumb": "JP-CELLTRION INC.-2019JP021861",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RAMUCIRUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "Lymphomas afflict all age groups of people, with certain types demonstrating a female predilection in adolescents and young adults. A proportion of lymphomas that are diagnosed in this population demographic occur in the setting of pregnancy. Most of these behave aggressively at presentation and require immediate or urgent therapy. Treatment must consider both maternal and fetal health, and management approaches are therefore influenced by gestational age at diagnosis and treatment and timing of delivery. Although there is a paucity of literature on how to treat these patients, limited retrospective reports demonstrate generally good outcomes and highlight the necessity of an experienced multidisciplinary team approach to management.",
"affiliations": "Division of Hematology & Oncology, George Washington University Cancer Center, Washington, DC; and.;Women's HealthNB, Auckland City Hospital, Auckland, New Zealand.",
"authors": "Dunleavy|Kieron|K|;McLintock|Claire|C|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1182/blood.2019000961",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0006-4971",
"issue": "136(19)",
"journal": "Blood",
"keywords": null,
"medline_ta": "Blood",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D005260:Female; D005865:Gestational Age; D006689:Hodgkin Disease; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D011247:Pregnancy; D011250:Pregnancy Complications, Hematologic; D011252:Pregnancy Complications, Neoplastic; D011256:Pregnancy Outcome; D011295:Prenatal Care",
"nlm_unique_id": "7603509",
"other_id": null,
"pages": "2118-2124",
"pmc": null,
"pmid": "32797210",
"pubdate": "2020-11-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "How I treat lymphoma in pregnancy.",
"title_normalized": "how i treat lymphoma in pregnancy"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2021SP005252",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugaddition... |
{
"abstract": "BACKGROUND\nAllergy to lidocaine is extremely rare but if it occurs, one should switch to an alternative drug and discontinue the use of lidocaine so that adverse consequences do not occur.\n\n\nMETHODS\nWe present the case of a 70 year old male patient who had come to our department to undergo extraction of his decayed teeth under local anesthesia.\n\n\nCONCLUSIONS\nHe had history of allergy to lidocaine. Type IV hypersensitivity to lidocaine was confirmed by positive skin prick testing to the drug. Skin prick testing was also performed for articaine that was available with us, and the test was found to be negative without any wheal or flare reaction even after 72 h. Thus it was confirmed that he was non-allergic to articaine and successfully underwent exodontia by using the same.\n\n\nCONCLUSIONS\nArticaine can be a suitable alternative in patients with true lignocaine allergy and vice-versa. No cross-reactivity has been reported between lidocaine and articaine so far. However, the number of cases reported in the past are limited, hence more cases are required in the future to prove its authenticity.",
"affiliations": "Oral and Maxillofacial Surgery, ITS Centre for Dental Studies and Research, Muradnagar, Ghaziabad, Uttar Pradesh, India. Electronic address: shikhadey2904@gmail.com.;Oral and Maxillofacial Surgery, ITS Centre for Dental Studies and Research, Greater Noida, Uttar Pradesh, India. Electronic address: infodrprasad@gmail.com.;Oral Medicine and Radiology, ITS Centre for Dental Studies and Research, Muradnagar, Ghaziabad, Uttar Pradesh, India. Electronic address: tripathideepti@yahoo.com.;Hi-Tech Dental College and Hospital, Bhubaneswar, Odisha, India. Electronic address: abhijeeta.sahoo@gmail.com.",
"authors": "Dey|Mansi|M|;Mishra|Bibhu Prasad|BP|;Awasthi|Deepti|D|;Sahoo|Abhijeeta|A|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.ijscr.2020.11.044",
"fulltext": "\n==== Front\nInt J Surg Case Rep\nInt J Surg Case Rep\nInternational Journal of Surgery Case Reports\n2210-2612 Elsevier \n\nS2210-2612(20)31067-1\n10.1016/j.ijscr.2020.11.044\nCase Report\nArticaine as an alternative in lidocaine allergy: Case report of a seventy year old male patient\nDey Mansi shikhadey2904@gmail.coma⁎ Mishra Bibhu Prasad infodrprasad@gmail.comb Awasthi Deepti tripathideepti@yahoo.comc Sahoo Abhijeeta abhijeeta.sahoo@gmail.comd a Oral and Maxillofacial Surgery, ITS Centre for Dental Studies and Research, Muradnagar, Ghaziabad, Uttar Pradesh, India\nb Oral and Maxillofacial Surgery, ITS Centre for Dental Studies and Research, Greater Noida, Uttar Pradesh, India\nc Oral Medicine and Radiology, ITS Centre for Dental Studies and Research, Muradnagar, Ghaziabad, Uttar Pradesh, India\nd Hi-Tech Dental College and Hospital, Bhubaneswar, Odisha, India\n⁎ Corresponding author. shikhadey2904@gmail.com\n11 11 2020 \n2020 \n11 11 2020 \n77 941 943\n27 10 2020 8 11 2020 8 11 2020 © 2020 The Authors2020This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Highlights\n• Articaine can be a suitable alternative in patients with true lignocaine allergy.\n\n• Apart from our case report, this fact has also been supported by Khalid Al-Dosary who had reported a case of a 12 year old female patient who was allergic to lidocaine but could tolerate articaine without any cross reactivity between the two drugs.\n\n• On the other hand, few case reports have shown that patients who were allergic to articaine were able to tolerate lidocaine.\n\n• No cross-reactivity has been reported between the two drugs.\n\n\n\nIntroduction\nAllergy to lidocaine is extremely rare but if it occurs, one should switch to an alternative drug and discontinue the use of lidocaine so that adverse consequences do not occur.\n\nPresentation of case\nWe present the case of a 70 year old male patient who had come to our department to undergo extraction of his decayed teeth under local anesthesia.\n\nDiscussion\nHe had history of allergy to lidocaine. Type IV hypersensitivity to lidocaine was confirmed by positive skin prick testing to the drug. Skin prick testing was also performed for articaine that was available with us, and the test was found to be negative without any wheal or flare reaction even after 72 h. Thus it was confirmed that he was non-allergic to articaine and successfully underwent exodontia by using the same.\n\nConclusion\nArticaine can be a suitable alternative in patients with true lignocaine allergy and vice-versa. No cross-reactivity has been reported between lidocaine and articaine so far. However, the number of cases reported in the past are limited, hence more cases are required in the future to prove its authenticity.\n\nKeywords\nLidocaineAllergySkin Prick Testing (SPT)Articaine\n==== Body\n1 Introduction\nLocal anaesthesia plays a major role in painless extraction of the teeth. Lidocaine, which is the most common local anaesthetic, has been known to cause allergies or other adverse effects [1,2]. The allergic reactions range from mild symptoms, such as urticaria, erythema, and intense itching, to severe reactions in the form of angioedema and/or respiratory distress. Severe life-threatening anaphylactic responses are in the form of apnea, hypotension, and loss of consciousness [2,3]. Amide-type local anaesthetics are more extensively used as compared to ester-type local anaesthetics, because the latter tend to be more allergenic due to p-aminobenzoic acid (PABA) metabolite that is formed during the degradation process [4]. Patients with genetically abnormal pseudocholinesterase are more likely to suffer from adverse effects of ester local anesthetics while the patients with decreased liver function are more likely to suffer from adverse reactions caused by amide local anaesthetics [5]. We report a case of a patient who was allergic to lidocaine but could tolerate articaine (another amide local anesthetic) that served as an alternative.\n\n2 Case report\nA 70 year old male patient had reported to our department of Oral and Maxillofacial Surgery for the extraction of his decayed teeth. He had developed itching and hives 24 h after the treatment was done under local anesthesia, in the previous clinic where he had gone to seek treatment.\n\nSkin prick testing (SPT) was performed with 2% lidocaine. The patient was tested with incremental concentrations of 0.1 mL subcutaneous (SQ) injections. We started with 1:100 dilution, 1:10 dilution, and finally full concentration was injected. A sterile needle was placed through the test solution into the epidermis and gently lifted upward. Each injection was given at an interval of 15 min. The area was evaluated after 10 min for a wheal and flare reaction. The patient did not develop any erythema around the area of injection at that time. He was recalled on the next day and had developed a 6 mm wheal on skin around the site of injection (Fig. 1). Hence the skin test was positive and it was confirmed that the patient had Type IV hypersensitivity to lidocaine.Fig. 1 Allergic reaction as a result of type IV hypersensitivity to lidocaine.\n\nFig. 1\n\nSPT was then performed for 4% Articaine Hydrochloride. It was performed in the same way as it was performed for lidocaine, and it was found to be negative with 0 mm wheal. The patient was then tested with incremental concentrations of 0.1 mL subcutaneous (SQ) injections. Same as for lidocaine, we started with 1:100 dilution, 1:10 dilution, and finally full concentration was injected. Each injection was given at an interval of 15 min. The patient was recalled for follow-up the next day. There was no reaction to any of the injections after an interval of 24 h. Patient was again recalled on the next two days and reported no allergy. Thus it was confirmed that he was non-allergic to articaine. Hence the patient successfully underwent exondontia using articaine without showing any hypersensitivity reactions.\n\n3 Discussion\nLocal anesthetics are small molecules that induce allergic reactions by acting as haptens, where they bind to an unidentified protein in the serum. Allergic reactions can be of four types based on the immune system's antigen-antibody response [[6], [7], [8], [9]]. Types I, II, and III are immediate-type reactions whereas Type IV is a delayed-type reaction. In Type-I allergic reactions, the first exposure to the sensitizing dose of local anesthetic causes production of immunoglobulin E(IgE) antibody production from B cells without occurrence of any allergic symptom [[7], [8], [9], [10]]. This is followed by binding of the specific IgE antibody to basophils and mast cells. When reexposure to the agent occurs, there is bridging of surface bound antibodies leading to release of inflammatory mediators like histamine from basophils and mast cells [7,9]. Type I reactions manifest as anaphylaxis and can take place immediately, within a few seconds to a few minutes, but the symptoms may take 1–4 h to appear. Symptoms can be limited to the area of skin surrounding the site of administration, in the form of a mild rash, reddening, or urticaria. [7,8,[10], [11], [12]]. Severe generalized reactions may occur involving hypotension, bronchospasm, and cardiac arrest. Type I hypersensitivity reactions can be fatal enough to cause death within minutes of exposure to the offending drug [7,8,12].\n\nIn Type II reactions(cytotoxic reactions), IgG and IgM antibodies are primarily involved and are directed against antigens on an individual’s own cells [[7], [8], [9]]. Examples include hemolysis and agranulocytosis. In type III immunologic reactions, antigen-antibody complexes are formed that are not effectively removed by the reticuloendothelial system [[7], [8], [9]], but are deposited in the walls of the blood vessels with subsequent complement fixation causing vascular and connective tissue damage. Type II and Type III reactions have been rarely reported and hence they are not clinically significant with local anesthetics [8]. Type IV reactions are the most prominent with their use [8,9,13]. They involve cellular immunity where T cells are sensitized to the local anesthetic on first exposure, without formation of any antibody. Reexposure to the same local anesthetic causes the memory T cell to release lymphokines that induce inflammatory reactions and activate macrophages to release mediators of inflammatory reactions. Symptoms are similar to Type-1 hypersensitivity reactions but usually take 24–72 h and in some cases just 2 h to manifest.\n\nThe reason for increased chances of allergy with the use of ester-type local anesthetics is thought to be their hydrolysis that takes place by cholinesterase, resulting in the release of a metabolite known as para-aminobenzoic acid, which is a known allergen. However, no cases of this phenomenon have been reported by recent studies of ester agents for US Food and Drug Administration approval and marketing claims [[14], [15], [16], [17]]. Allergy caused by lidocaine is rare [1]. It can occur due to the presence of a preservative known as methylparaben, which is a bacteriostatic agent chemically related to para-amino benzoic acid [[18], [19], [20]]. Another similar preservative responsible for allergy by local anesthetics is propylparaben [19,20]. Epinephrine is a vasoconstrictor that is added to the local anesthetics in order to extend their duration of anesthesia. It can cause symptoms like pallor, tachycardia, anxiety, headache, tremor, and hypertension [21]. These symptoms must be distinguished from those caused by lidocaine allergy.\n\nOur reported patient had a classical Type IV hypersensitivity reaction to lidocaine in the form of “anaphylaxis”. Skin prick testing was found to be beneficial in testing the patient for allergy to local anesthetics.\n\nAmide and ester local anesthetics are rarely found to cross react [22]. Amide local anesthetics cross-react with each other occasionally, though less frequently than with esters [23,24]. Similar to our case report, Khalid Al-Dosary had also reported a case of a patient who was allergic to lidocaine but could tolerate articaine without any cross reactivity between the two drugs [25]. On the other hand, few case reports have shown that patients who were allergic to articaine were able to tolerate lidocaine [[26], [27], [28]]. Hence we can say that there is no cross-reactivity between both the drugs. It should also be remembered that we should avoid articaine in those patients who are allergic or hypersensitive to sulphite, because of the presence of sodium metabisulphite as the vasoconstrictor’s antioxidant in it [4]. Also, chances of neurotoxicity are more if articaine is used as a block. Hence it is advisable to administer it in the form of local infiltration. Since not many cases have been reported with the use of articaine as an alternative in lidocaine allergy, we cannot assume it as an only alternative in allergy to lidocaine. Had the patient been allergic to articaine as well, the other options we would have opted for were 1% diphenhydramine, which is a safe and inexpensive method in patients who are allergic to local anesthesics. Another option that we would have opted is general anesthesia. However it is an expensive procedure and not all patients are fit enough to undergo surgery under general anesthesia.\n\nThis work has been reported in line with the SCARE 2018 criteria [29].\n\n4 Conclusion\nThough the lignocaine allergy is rare, detailed medical history should be taken from any patient who is going to undergo treatment under local anesthesia. In case where there are chances of IgE mediated reaction to a local anesthetic, the patient should be tested before carrying out any procedure in order to prevent unwanted consequences. Articaine can be a suitable alternative in patients with true lignocaine allergy and vice-versa. However, due to the limited number of cases that have been reported in the literature, more number of cases are required to be reported in future to prove its authenticity.\n\nDeclaration of Competing Interest\nThe authors report no declarations of interest.\n\nFunding\nNo funding source.\n\nEthical approval\nEthical approval was given by Institutional Review Board of ITS Centre for Dental Studies and Research, Muradnagar, Ghaziabad, Uttar Pradesh, India.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\n\nAuthor contribution\nConcept or design: Dr. Mansi Dey.\n\nData collection: Dr. Bibhu Prasad Mishra, Dr. Deepti Awasthi, Dr. Abhijeeta Sahoo.\n\nData analysis: Dr. Mansi Dey, Dr. Bibhu Prasad Mishra, Dr. Abhijeeta Sahoo.\n\nWriting the paper: Dr. Mansi Dey, Dr. Deepti Awasthi.\n\nRegistration of research studies\nThe following statement applies for all listed authors:\n\nThere was no research involving human participants.\n\nThere was no trials or observational research undertaken.\n\nThis is a case report only.\n\nIt has not been reported in man for the first time.\n\nGuarantor\nDr. Mansi Dey.\n\nProvenance and peer review\nNot commissioned, externally peer-reviewed.\n==== Refs\nReferences\n1 Batinac T. Sotošek Tokmadžić V. Peharda V. Brajac I. Adverse reactions and alleged allergy to local anesthetics: analysis of 331 patients J. Dermatol. 40 July (7) 2013 522 527 23682746 \n2 Finder R.L. Moore P.A. Adverse drug reactions to local anesthesia Dent. Clin. 46 October (4) 2002 747 757 \n3 Speca S.J. Boynes S.G. Cuddy M.A. Allergic reactions to local anesthetic formulations Dent. Clin. 54 October (4) 2010 655 664 \n4 Jenerowicz D. Polańska A. Glińska O. Czarnecka-Operacz M. Schwartz Ra. Allergy to lidocaine injections: comparison of patient history with skin testing in five patients Adv. Dermatol. Allergol./Postȩpy Dermatologii i Alergologii 31 June (3) 2014 134 \n5 Liu P.L. Principles and Procedures in Anesthesiology 1992 Lippincott Williams & Wilkins Jun 15 \n6 Noormalin A. Shahnaz M. Rosmilah M. Mujahid S.H. Gendeh B.S. IgE-mediated hypersensitivity reaction to lignocaine – a case report Trop. Biomed. 22 2 2005 179 183 16883285 \n7 Canfield D.W. Gage T.W. A guideline to local anesthetic allergy testing Anesth. Prog. 34 September (5) 1987 157 3318567 \n8 Doyle K.A. Goepferd S.J. An allergy to local anesthetics? The consequences of a misdiagnosis ASDC J. Dent. Child. 56 2 1989 103 106 2723199 \n9 Shearer W.T. Huston D.P. The immune system: an overview Middleton E. Jr. Reed C.E. Ellis E.F. Adkinson N.F. Jr. Yunginger J.W. Busse W.W. Allergy Principles and Practice 4th ed. 1993 Mosby-Year Book St. Louis 3 21 \n10 MacColl S. Young E.R. An allergic reaction following injection of local anesthetic: a case report J. Can. Dent. Assoc. 55 December (12) 1989 981 984 2686824 \n11 Burgess J.O. Preventing adverse local anesthetic reactions: the use of the skin test Spec. Care Dent. 7 May (3) 1987 135 136 \n12 Kennedy K.S. Cave R.H. Anaphylactic reaction to lidocaine Arch. Otolaryngol. Head Neck Surg. 112 June (6) 1986 671 673 3964456 \n13 Schatz M. Fung D.L. Anaphylactic and anaphylactoid reactions due to anesthetic agents Clin. Rev. Allergy 4 May (2) 1986 215 3516361 \n14 Hersh E.V. Saraghi M. Moore P.A. Intranasal tetracaine and oxymetazoline: a newly approved drug formulation that provides maxillary dental anesthesia without needles Curr. Med. Res. Opin. 32 November (11) 2016 1919 1925 27646144 \n15 Giannakopoulos H. Levin L.M. Chou J.C. Cacek A.T. Hutcheson M. Secreto S.A. Moore P.A. Hersh E.V. The cardiovascular effects and pharmacokinetics of intranasal tetracaine plus oxymetazoline: preliminary findings J. Am. Dent. Assoc. 143 August (8) 2012 872 880 22855901 \n16 Hersh E.V. Ciancio S.G. Kuperstein A.S. Stoopler E.T. Moore P.A. Boynes S.G. Levine S.C. Casamassimo P. Leyva R. Mathew T. Shibly O. An evaluation of 10 percent and 20 percent benzocaine gels in patients with acute toothaches: efficacy, tolerability and compliance with label dose administration directions J. Am. Dent. Assoc. 144 May (5) 2013 517 526 23633700 \n17 Hersh E.V. Pinto A. Saraghi M. Saleh N. Pulaski L. Gordon S.M. Barnes D. Kaplowitz G. Bloom I. Sabti M. Moore P.A. Double-masked, randomized, placebo-controlled study to evaluate the efficacy and tolerability of intranasal K305 (3% tetracaine plus 0.05% oxymetazoline) in anesthetizing maxillary teeth J. Am. Dent. Assoc. 147 April (4) 2016 278 287 26822100 \n18 Latronica R.J. Goldberg A.F. Wightman J.R. Local anesthetic sensitivity: report of a case Oral Surg. Oral Med. Oral Pathol. 28 September (3) 1969 439 441 5257189 \n19 Speca S.J. Boynes S.G. Cuddy M.A. Allergic reactions to local anesthetic formulations Dent. Clin. 54 October (4) 2010 655 664 \n20 Grzanka A. Wasilewska I. Śliwczyńska M. Misiołek H. Hypersensitivity lo local anesthetics Anaesthesiol. Intensive Ther. 48 2 2016 128 134 26977853 \n21 Fisher M.M. Bowey C.J. Alleged allergy to local anaesthetics Anaesth. Intensive Care 25 December (6) 1997 611 614 9452840 \n22 Caron A.B. Allergy to multiple local anesthetics Allergy and Asthma Proceedings vol. 28 2007 600 601 No. 5. Sep 1 \n23 Calderon A.L. Diot N. Benatir F. Christin F. Hautin E. Truc C. Allaouchiche B. Boselli E. Immediate allergic cross‐reactivity to levobupivacaine and ropivacaine Anaesthesia 68 February (2) 2013 203 205 23121555 \n24 Fuzier R. Lapeyre‐Mestre M. Mertes P.M. Nicolas J.F. Benoit Y. Didier A. Albert N. Montastruc J.L. Immediate‐and delayed‐type allergic reactions to amide local anesthetics: clinical features and skin testing Pharmacoepidemiol. Drug Saf. 18 July (7) 2009 595 601 19402039 \n25 Al-Dosary K. Al-Qahtani A. Alangari A. Anaphylaxis to lidocaine with tolerance to articaine in a 12 year old girl J. Saudi Pharm. Soc. 22 July (3) 2014 280 282 \n26 Davila-Fernández G. Sánchez-Morillas L. Rojas P. Laguna J.J. Urticaria due to an intradermal test with articaine hydrochloride J. Investig. Allergol. Clin. Immunol. 22 5 2012 373 374 \n27 El-Qutob D. Morales C. Peláez A. Allergic reaction caused by articaine Allergol. Immunopathol. 33 January (2) 2005 115 116 \n28 Moreno E.M. Cruz G.S. Moya Q.M. Amat L.J. Urticaria due to articaine J. Investig. Allergol. Clin. Immunol. 21 2 2011 155 \n29 Agha R.A. Borrelli M.R. Farwana R. Koshy K. Fowler A. Orgill D.P. For the SCARE Group The SCARE 2018 Statement: Updating Consensus Surgical CAse REport (SCARE) Guidelines Int. J. Surg. 60 2018 132 136 30342279\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2210-2612",
"issue": "77()",
"journal": "International journal of surgery case reports",
"keywords": "Allergy; Articaine; Lidocaine; Skin Prick Testing (SPT)",
"medline_ta": "Int J Surg Case Rep",
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"nlm_unique_id": "101529872",
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"pages": "941-943",
"pmc": null,
"pmid": "33262079",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "2723199;9452840;19402039;21462809;23101314;16883285;27646144;2686824;23682746;25097483;20831929;18034981;23121555;26977853;3964456;5257189;25067903;23633700;26822100;30342279;12436829;2954241;22855901;3318567;15808120;3516361",
"title": "Articaine as an alternative in lidocaine allergy: Case report of a seventy year old male patient.",
"title_normalized": "articaine as an alternative in lidocaine allergy case report of a seventy year old male patient"
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"abstract": "Uterine torsion is defined as torsion of the uterus around its longitudinal axis exceeding 45 degrees. It is a rare obstetric complication. It is a dangerous complication that can lead to placental abruption and intrauterine fetal death. Although rare, early diagnosis is crucial to expedite intervention and optimize outcomes. While the few cases in the current literature have documented acute presentations of uterine torsion, our case is unique in that it had a slower evolution.\nA 38-year-old woman, G2P0, was admitted at 37 weeks 0 days of gestation for induction of labor for gestational diabetes mellitus, pre-eclampsia, and maternal BMI of 60. Due to a prolonged latent phase of labor and fetal intolerance of labor, primary cesarean was recommended. Through a sub-umbilical approach, the uterus was dextro-rotated almost 180 degrees and blanched with engorged uterine vessels. A vertical uterine incision was made, and a asphyxiated female infant was delivered via breech extraction. APGAR scores were 2, 7, and 8. The infant required brief respiratory support following delivery. The postoperative course was uncomplicated, with normal recovery time.\nUterine torsion poses significant risk to both mother and fetus. The phenomenon is so rare that epidemiological data are difficult to gather. In our case, the presentation was gradual compared with the acute presentations that have been reported, which may mislead clinicians toward more benign diagnoses. Our case report aims to add to the literature on uterine torsion, providing a unique presentation, clinical features, and treatment.",
"affiliations": "Harbor-UCLA Medical Center, Department of Obstetrics & Gynecology, Torrance, California 90502, United States.;Harbor-UCLA Medical Center, Department of Obstetrics & Gynecology, Torrance, California 90502, United States.",
"authors": "Huynh|Kimberly|K|;Andersen|H|H|",
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"doi": "10.1016/j.crwh.2021.e00353",
"fulltext": "\n==== Front\nCase Rep Womens Health\nCase Rep Womens Health\nCase Reports in Women's Health\n2214-9112\nElsevier\n\nS2214-9112(21)00071-0\n10.1016/j.crwh.2021.e00353\ne00353\nArticle\nUterine torsion in a full-term pregnancy presenting as prolonged latent phase and fetal intolerance of labor: A case report\nHuynh Kimberly kimberlyz.huynh@gmail.com\nab⁎1\nAndersen H. harold.andersen@wsu.edu\nab2\na Harbor-UCLA Medical Center, Department of Obstetrics & Gynecology, Torrance, California 90502, United States\nb Washington State University Elson S. Floyd College of Medicine, United States\n⁎ Corresponding author. kimberlyz.huynh@gmail.com\n1 Primary Author.\n\n2 Senior Author.\n\n20 8 2021\n10 2021\n20 8 2021\n32 e003531 8 2021\n16 8 2021\n18 8 2021\n© 2021 Published by Elsevier B.V.\n2021\n\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/).\nBackground\n\nUterine torsion is defined as torsion of the uterus around its longitudinal axis exceeding 45 degrees. It is a rare obstetric complication. It is a dangerous complication that can lead to placental abruption and intrauterine fetal death. Although rare, early diagnosis is crucial to expedite intervention and optimize outcomes. While the few cases in the current literature have documented acute presentations of uterine torsion, our case is unique in that it had a slower evolution.\n\nCase\n\nA 38-year-old woman, G2P0, was admitted at 37 weeks 0 days of gestation for induction of labor for gestational diabetes mellitus, pre-eclampsia, and maternal BMI of 60. Due to a prolonged latent phase of labor and fetal intolerance of labor, primary cesarean was recommended. Through a sub-umbilical approach, the uterus was dextro-rotated almost 180 degrees and blanched with engorged uterine vessels. A vertical uterine incision was made, and a asphyxiated female infant was delivered via breech extraction. APGAR scores were 2, 7, and 8. The infant required brief respiratory support following delivery. The postoperative course was uncomplicated, with normal recovery time.\n\nConclusion\n\nUterine torsion poses significant risk to both mother and fetus. The phenomenon is so rare that epidemiological data are difficult to gather. In our case, the presentation was gradual compared with the acute presentations that have been reported, which may mislead clinicians toward more benign diagnoses. Our case report aims to add to the literature on uterine torsion, providing a unique presentation, clinical features, and treatment.\n\nHighlights\n\n• Uterine torsion is torsion of the uterus around its longitudinal axis exceeding 45 degrees.\n\n• It is a rare obstetric complication.\n\n• Severe acute uterine torsion can result in placental abruption, intrauterine fetal death, and maternal death.\n\n• This case of uterine torsion presented as prolonged latent phase and fetal intolerance of labor.\n\n• Delivery was achieved via classical cesarean section.\n\nKeywords\n\nUterine torsion\nFetal intolerance of labor\nProlonged latent stage\n==== Body\npmc1 Introduction\n\nUterine torsion is defined as torsion of the uterus around its longitudinal axis exceeding 45 degrees, with most being approximately 180 degrees. It occurs at the junction of the cervix and uterine corpus. Torsion less than 45 degrees is considered physiologic. Uterine torsion is a rare obstetric complication, with most of the literature comprising single case reports. It is, however, a dangerous complication that can be harmful to mother and infant. Severe acute uterine torsion can lead to placental abruption [1,2], maternal death, and intrauterine fetal death [3]. The most common symptoms of uterine torsion in pregnancy are abdominal pain, fetal heart rate changes, and failure of cervical dilatation [4]. This report describes the clinical features, risk factors and treatment used for uterine torsion in term pregnancy.\n\n2 Case presentation\n\nA 38-year-old woman, G2P0010, was admitted at 37 weeks 0 days of gestation for induction of labor for poorly controlled gestational diabetes mellitus on insulin and metformin. Pregnancy was also complicated by gestational hypertension that later manifested as pre-eclampsia, advanced maternal age, group B Streptococcus-positive status, maternal body mass index of 60, concern for large for gestational age and maternal depression. Ultrasound scan at 36 weeks 6 days of gestation showed estimated fetal weight in the 94th percentile (3629 g), head circumference in the 82nd percentile, and abdominal circumference > 99th percentile. The patient was hemodynamically stable and afebrile during admission. Pre-operative hemoglobin was 11.5 g/dL.\n\nOn admission, oral misoprostol was used for induction of labor. Examination showed the cervix was closed/50%/−3. The fetus was cephalic presenting. Fetal monitoring was category I. The patient had two systolic blood pressure readings in the 160 s and 170 s but responded well to hydralazine. Patient denied any symptoms of severe pre-eclampsia.\n\nOver the first hospital day, six doses of oral misoprostol were administered for induction of labor and the cervix had progressed to 0.5/60%/−3. Low-dose oxytocin was started. Urine protein/creatine ratio was 0.8 and pre-eclampsia was diagnosed. Five hours later, artificial rupture of membranes yielded copious amounts of clear fluid. Due to maternal body habitus, external fetal heart monitoring was difficult. Fetal scalp electrode (FSE) and intrauterine placement catheter (IUPC) were placed. The cervix was 3/100/−2 after FSE and IUPC placement. Epidural was requested. Contractions were borderline adequate show by IUPC. Oxytocin augmentation was started.\n\nFive hours later, fetal heart tracing was judged as non-reassuring due to persistent decelerations, despite administration of supplemental oxygen, positional changes, and 300 mL amnioinfusion. The cervix was now 5/100%/−3. Due to slow progress, fetal intolerance of labor, and being remote from delivery, primary cesarean section was recommended. Due to the patient's body habitus and pannus, a sub-umbilical incision was recommended and discussed with the patient. Patient consented for a cesarean using a high incision.\n\nA sub-umbilical skin incision was made and carried down through the subcutaneous tissue to the fascia. The fascia was opened transversely 4 cm above the symphysis. The layers of the abdominal wall were opened with a combination of sharp and blunt dissection. Upon entering the abdomen, the uterus was noted to be rotated almost 180 degrees, with the left adnexa well right of the midline (dextro-rotation). The uterus was also blanched with engorged uterine vessels. No uterine anomalies, fibroids, or ovarian pathologies were seen. The uterus would not rotate with direct gentle palpation. Nonetheless, the physicians were able to manually rotate the uterus enough to make an incision to the left of midline with the knife and extend this incision bluntly. An asphyxiated female baby was delivered by breech extraction. Nuchal cord times three was reduced. The umbilical cord was clamped and cut, and the infant handed to the waiting neonatal team. A section of cord was preserved to draw cord gasses. The placenta was removed intact and appeared normal. The uterus was exteriorized. It appeared soft and boggy despite manual massage. Pitocin was administered. Both uterine tone and color improved. The uterine incision extended from the upper lower uterine segment to the fundus and disrupted the left fallopian tube. The uterine cavity was wiped clean. The uterine incision was closed with three layers: running non-locking, then interrupted, and lastly a running non-locking imbricating layer of suture. The uterus was returned to the abdomen and the uterine incision was re-inspected and found to be hemostatic. The uterus immediately returned into the original dextro-rotated position and would not be coaxed to stay midline. The gutters were cleared of all clots and debris. The rectus muscle beds were inspected and made hemostatic with minimal cautery. The fascia layer was closed in a running fashion. The subcutaneous tissue was made hemostatic with minimal cautery and closed in 2 layers. The skin incision was closed with staples. Blood loss was 875 mL. 2400 mL of intravenous fluids were given. 3 g of cefazolin was used as prophylaxis.\n\nThe newborn's Appearance, Pulse, Grimace, Activity, and Respiration (APGAR) scores at 1, 5, and 10 min were 2, 7, and 8 respectively. Weight was 3630 g, height 50 cm, and head circumference 34 cm. Arterial cord pH was 7.018 and arterial base deficit was 12.4 millimole/L. Venous cord pH was 7.081 and venous base deficient was 8.6 millimole/L. The infant required brief positive-pressure ventilation and continuous positive airway pressure therapy following delivery and was transferred to the neonatal intensive care unit on room air for observation and stayed due to hypoglycemia. The infant received a dextrose bolus and intravenous fluids but was weaned off without difficulty. The infant was discharged two days later with the mother in excellent condition.\n\nPostoperative course was uncomplicated, with normal post-operative recovery. Maternal insulin was adjusted postpartum. Blood pressure continued to be elevated and a second anti-hypertensive was added to the postpartum regimen. On the day of discharge, the patient met all post-operative milestones. There was no evidence of infection at the incision site. The patient was discharged on post-operative day 2.\n\n3 Discussion & conclusions\n\nUterine torsion is defined as the rotation of the uterus more than 45 degrees on its longitudinal axis. Due to the rarity of uterine torsion, it is difficult to study the actual epidemiology of this obstetric emergency [5]. While the definitive etiology remains elusive, risk factors have been identified, including abnormal fetal position, uterine ligament relaxation, uterine malformations, uterine fibroids, polyhydramnios, ovarian cysts, and pelvic adhesions [4,6,7]. However, this case falls under the 30% of cases that occur without discoverable cause [8].\n\nUterine torsion poses significant risk to both mother and fetus. Maternal complications include complete or partial placental abruption and maternal hemodynamic shock [1,2]. There have been no maternal deaths reported before 20 weeks, mortality rates of 17% reported between 20 and 28 weeks, 10% at 29 to 34 weeks, and 9% at term gestation [4]. Fetal complications associated with uterine torsion are fetal hypoxia, fetal antepartum hemorrhage, and death [3]. Perinatal mortality is approximately 12% [5].\n\nThe extreme difficulty in diagnosing uterine torsion preoperatively stems from the variable presentation, compounded with its rare occurrence. Clinical symptoms of uterine torsion in pregnancy are variable, ranging from an asymptomatic presentation to severe acute abdomen. Furthermore, slow progression of labor as well as a cervix that is high and difficult to examine, as in this case, may be additional manifestations of uterine torsion. Ultrasound, computed tomography, and magnetic resonance imaging can also be helpful in the diagnosis to a certain extent [3,9]. However, due to this patient's body habitus, ultrasound detection would have been difficult.\n\nUterine torsion should be treated with immediate surgery. Posterior hysterotomy, high incision from the anterior wall of the uterus, or classical incision have been documented as ways to deliver the fetus in a uterus that has undergone torsion [10]. In this case, the uterus could not be manually repositioned so a classical incision with breech extraction was made to ensure safe delivery of the fetus. The uterus was blanched but did not seem necrotic. The uterine vessels appeared engorged but improved after delivery of the fetus. If the uterus had been necrotic, a cesarean hysterectomy would have been indicated [4].\n\nIn this case the presentation was gradual compared with the more acute presentations that have been reported in the literature [2,4,10,11]. Non-reassuring fetal heart tracings and slow cervical progression despite labor induction and augmentation, as seen in this case, may mislead clinicians toward more common differential diagnoses, such as first- or second-stage arrest, failed induction of labor, or fetal intolerance of labor.\n\nThe diagnosis of uterine torsion before birth and cesarean section is extremely difficult and sometimes impossible. Successful birth after uterine torsion has been documented; however, there are too few reports to accurately depict the long-term implications of delivery after uterine torsion [12]. This patient will need cesarean delivery in all subsequent pregnancies, given the obstetric history and co-morbidities.\n\nContributors\n\nKimberly Huynh, MD was involved in patient care, acquired and interpreted the data, drafted the manuscript, revised the article critically for important intellectual content, and approved the final submitted version.\n\nH. Frank Andersen, MD drafted the manuscript, revised the article critically for important intellectual content, and approved the final submitted version.\n\nConflict of Interest\n\nThe authors declare that they have no conflict of interest regarding the publication of this case report.\n\nFunding\n\nNo funding from an external source supported the publication of this case report.\n\nPatient consent\n\nObtained.\n\nProvenance and peer review\n\nThis article was not commissioned and was peer reviewed.\n\nAcknowledgements\n\nAnne Camber, MD, was the attending physician and primary surgeon for this case. Richard Agress, MD, was the surgical assistant during the cesarean delivery.\n==== Refs\nReferences\n\n1 Ulu I. Güneş M.S. Kiran G. Gülşen M.S. A rare cause of placental abruption: uterine torsion J. Clin. Diagn. Res. 10 1 2016 QD06 QD7 10.7860/JCDR/2016/16531.7071\n2 Cook K.E. Jenkins S.M. Pathologic uterine torsion associated with placental abruption, maternal shock, and intrauterine fetal demise Am. J. Obstet. Gynecol. 192 6 2005 2082 2083 10.1016/j.ajog.2004.09.003 15970905\n3 Wang B. Zhou J.H. Jin H.M. Torsion of a rudimentary uterine horn at 22 weeks of gestation J. Obstet. Gynaecol. Res. 37 7 2011 919 920 10.1111/j.1447-0756.2010.01435.x 21450021\n4 Yin F.L. Huang H.X. Zhang M. Clinical analysis of uterine torsion and fibroids in full-term pregnancy: a case report and review of the literature J Int Med Res. 48 6 2020 10.1177/0300060520920404 300060520920404\n5 Dua A. Fishwick K. Deverashetty B. Uterine torsion in pregnancy: A review Internet J. Gynecol. and Obstetrics 6 1 2005\n6 Nash Kimberley Oji Victor C. Mitra Surajit Uterine torsion, a rare cause of acute abdominal pain in the third trimester of pregnancy: a case report J. Obstet. Gynaecol. 36 5 2016 668 669 10.3109/01443615.2015.1133580 26878395\n7 Wilson D. Mahalingham A. Ross S. Third trimester uterine torsion: case report J. Obstet. Gynaecol. Can. 28 6 2006 531 535 10.1016/S1701-2163(16)32180-6 16857121\n8 Piot D. Gluck M. Oxorn H. Torsion of the gravid uterus Can. Med. Assoc. J. 109 10 1973 1010 1011 4758858\n9 Kilicci C. Sanverdi I. Bostanci E. Abide C.Y. Eser S.K. Uterine torsion of 720 degrees in the third trimester of pregnancy and accompanying bladder torsion: a case report Pan Afr Med J. 29 2018 175 Published 2018 Mar 26 10.11604/pamj.2018.29.175.14101 30050639\n10 Moores K.L. Wood M.G. Foon R.P. A rare obstetric emergency: acute uterine torsion in a 32-week pregnancy BMJ Case Rep. 2014 10.1136/bcr-2013-202974 2014:bcr2013202974. Published 2014 Apr 11\n11 Pelosi M.A. 3rd Pelosi M.A. Managing extreme uterine torsion at term. A case report J Reprod Med. 43 2 1998 153 157 9513879\n12 Fatih F.F. Gowri V. Rao K. Uterine torsion in second trimester of pregnancy followed by a successful-term pregnancy BMJ Case Rep. 2012 10.1136/bcr-2012-006359 2012:bcr2012006359. Published 2012 Aug 21\n\n",
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"issue": "32()",
"journal": "Case reports in women's health",
"keywords": "Fetal intolerance of labor; Prolonged latent stage; Uterine torsion",
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"title": "Uterine torsion in a full-term pregnancy presenting as prolonged latent phase and fetal intolerance of labor: A case report.",
"title_normalized": "uterine torsion in a full term pregnancy presenting as prolonged latent phase and fetal intolerance of labor a case report"
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"abstract": "Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder caused by lack of the paternal copy of maternally imprinted, paternally expressed genes at the chromosome 15q11-13 region. In most cases, it is caused by a paternal deletion or a maternal disomy of chromosome 15. Behavioral problems with temper outbursts are common and often combined with physical aggressiveness and self-injury. They are the most frequent cause for a reduced quality of life in adulthood and represent a serious challenge for the individual and those surrounding the individual in everyday life. Until now, no promising pharmaceutical treatment option has been established, and only a few case reports on treatment with selective serotonin reuptake inhibitors (SSRIs) have been reported. In this case series, we investigated the effect of the SSRI sertraline in 14 individuals with PWS frequently showing severe temper outbursts with aggressiveness and self-injuries. After 6 months of treatment with sertraline, 13 of 14 patients (92.6%) either no longer displayed temper outbursts or showed a significant decrease in frequency and severity of temper outbursts. In one case, treatment was stopped due to severe sleep abnormalities. We conclude that sertraline is a promising and safe treatment option for severe temper outbursts in patients with PWS.",
"affiliations": "Department of Psychiatry, Social Psychiatry and Psychotherapy, Medical School Hannover, Hannover, Germany.;Department of Psychiatry, Social Psychiatry and Psychotherapy, Medical School Hannover, Hannover, Germany.;Department of Psychiatry, Social Psychiatry and Psychotherapy, Medical School Hannover, Hannover, Germany.;Department of Psychiatry, Social Psychiatry and Psychotherapy, Medical School Hannover, Hannover, Germany.;Department of Psychiatry, Social Psychiatry and Psychotherapy, Medical School Hannover, Hannover, Germany.;Department of Psychiatry, Social Psychiatry and Psychotherapy, Medical School Hannover, Hannover, Germany.",
"authors": "Deest|Maximilian|M|0000-0002-8759-8660;Jakob|Maximilian Michael|MM|;Seifert|Johanna|J|;Bleich|Stefan|S|;Frieling|Helge|H|;Eberlein|Christian|C|",
"chemical_list": "D000928:Antidepressive Agents; D020280:Sertraline",
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"issue": "185(3)",
"journal": "American journal of medical genetics. Part A",
"keywords": "Prader-Willi syndrome; sertraline; temper outbursts; treatment",
"medline_ta": "Am J Med Genet A",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000374:Aggression; D000928:Antidepressive Agents; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D011218:Prader-Willi Syndrome; D000066553:Problem Behavior; D011379:Prognosis; D011788:Quality of Life; D012189:Retrospective Studies; D016728:Self-Injurious Behavior; D020280:Sertraline; D055815:Young Adult",
"nlm_unique_id": "101235741",
"other_id": null,
"pages": "790-797",
"pmc": null,
"pmid": "33369086",
"pubdate": "2021-03",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Sertraline as a treatment option for temper outbursts in Prader-Willi syndrome.",
"title_normalized": "sertraline as a treatment option for temper outbursts in prader willi syndrome"
} | [
{
"companynumb": "DE-MYLANLABS-2021M1044626",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SERTRALINE HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "Direct oral anticoagulants (DOACs) have been developed as alternatives to conventional therapy with warfarin for the treatment of acute venous thromboembolism (VTE) events. The safety and efficacy of DOACs in Japanese patients with acute VTE has been investigated in small trials or subgroups from global randomized controlled trials (RCTs).\n\n\n\nWe conducted a systematic review and meta-analysis of RCTs, to compare the safety and efficacy of DOACs to those of conventional therapy in Japanese patients with acute VTE. Published research was systematically searched for RCTs that compared DOAC to conventional therapy in Japanese patients with acute VTE. Random-effects models were used to pool safety and efficacy data across RCTs. Three studies, including 386 patients, were identified. Patients randomized to DOAC had a decreased risk for all bleeding [risk ratio (RR) 0.69, 95% confidential interval (CI) 0.50-0.95], without any significant differences in recurrent VTE (RR 0.84, 95% CI 0.29-2.43) and recurrent VTE/all-cause death (RR 0.60, 95% CI 0.23-1.56).\n\n\n\nDOACs offer clinical benefit over conventional therapy in Japanese patients with acute VTE, showing a significant difference in their bleeding profile.",
"affiliations": "Department of Arrhythmia, Koseika Takeda Hospital, Kyoto, Japan; Department of Advanced Cardiovascular Therapeutics, Chiba University Graduate School of Medicine, Chiba, Japan. Electronic address: swcqg251@yahoo.co.jp.;Department of Advanced Cardiovascular Therapeutics, Chiba University Graduate School of Medicine, Chiba, Japan.;Department of Cardiovascular Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.;Department of Cardiology, Tokyo Metropolitan Tama Medical Center, Tokyo, Japan.;Department of Arrhythmia, Koseika Takeda Hospital, Kyoto, Japan.;Department of Cardiovascular Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.",
"authors": "Senoo|Keitaro|K|;Kondo|Yusuke|Y|;Miyazawa|Kazuo|K|;Isogai|Toshiaki|T|;Chun|Yeong-Hwa|YH|;Kobayashi|Yoshio|Y|",
"chemical_list": "D000925:Anticoagulants; D014859:Warfarin",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jjcc.2016.07.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0914-5087",
"issue": "69(5)",
"journal": "Journal of cardiology",
"keywords": "Direct oral anticoagulants; Japanese; Meta-analysis; Venous thromboembolism",
"medline_ta": "J Cardiol",
"mesh_terms": "D000284:Administration, Oral; D000925:Anticoagulants; D044466:Asians; D006470:Hemorrhage; D006801:Humans; D007564:Japan; D016032:Randomized Controlled Trials as Topic; D055502:Secondary Prevention; D054556:Venous Thromboembolism; D014859:Warfarin",
"nlm_unique_id": "8804703",
"other_id": null,
"pages": "763-768",
"pmc": null,
"pmid": "27502316",
"pubdate": "2017-05",
"publication_types": "D016428:Journal Article; D017418:Meta-Analysis; D016454:Review; D000078182:Systematic Review",
"references": null,
"title": "Safety and efficacy of direct oral anticoagulants over warfarin in Japanese patients with acute venous thromboembolism: A meta-analysis.",
"title_normalized": "safety and efficacy of direct oral anticoagulants over warfarin in japanese patients with acute venous thromboembolism a meta analysis"
} | [
{
"companynumb": "JP-CIPLA LTD.-2016JP17908",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nMetronomic chemotherapy (MC) consists of the administration of a low dose of chemotherapy on a daily or weekly basis without a long break to achieve an antitumoral effect through an antiangiogenic effect or stimulation of the immune system. The potential effect of MC with continuous oral cyclophosphamide and methotrexate in patients with high-grade operable osteosarcomas (OSTs) of the extremities was investigated.\n\n\nMETHODS\nPatients with high-grade OSTs who were 30 years old or younger were eligible for registration at diagnosis. Eligibility for randomization included 1) nonmetastatic disease and 2) complete resection of the primary tumor. The study design included a backbone of 10 weeks of preoperative therapy with methotrexate, adriamycin, and platinum (MAP). After surgery, patients were randomized between 2 arms to complete 31 weeks of MAP or receive 73 weeks of MC after MAP. The primary endpoint was event-free survival (EFS) from randomization.\n\n\nRESULTS\nThere were 422 nonmetastatic patients registered (May 2006 to July 2013) from 27 sites in 3 countries (Brazil, Argentina and Uruguay), and 296 were randomized to MAP plus MC (n = 139) or MAP alone (n = 157). At 5 years, the EFS cumulative proportions surviving in the MAP-MC group and the MAP-alone group were 61% (standard error [SE], 0.5%) and 64% (SE, 0.5%), respectively, and they were not statistically different (Wilcoxon [Gehan] statistic = 0.724; P =.395). The multivariate analysis showed that necrosis grades 1 and 2, tumor size, and amputation were associated with shorter EFS.\n\n\nCONCLUSIONS\nAccording to the current follow-up, EFS with MAP plus MC is not statistically superior to EFS with MAP alone in patients with high-grade, resectable OSTs of the extremities. Cancer 2017;123:1003-10. © 2016 American Cancer Society.",
"affiliations": "Institute of Pediatric Oncology/Support Group for Adolescents and Children With Cancer, Federal University of Sao Paulo, Sao Paulo, Brazil.;Institute of Pediatric Oncology/Support Group for Adolescents and Children With Cancer, Federal University of Sao Paulo, Sao Paulo, Brazil.;National Cancer Institute, Rio de Janeiro, Brazil.;Hospital de Pediatria SAMIC-Professor Dr. Juan P. Garrahan, Buenos Aires, Argentina.;Hospital de Pediatria SAMIC-Professor Dr. Juan P. Garrahan, Buenos Aires, Argentina.;Barretos Cancer Hospital, Barretos, Brazil.;Oswaldo Cruz Hospital, Oncohematology Pediatric Center, Recife, Brazil.;R. Gutierrez Children's Hospital, Buenos Aires, Argentina.;Amaral Carvalho Hospital, Jau, Brazil.;Pereira Rossell Hospital, Montevideo, Uruguay.;Clinical Hospital, Children's Institute, Sao Paulo, Brazil.;Santa Casa de Misericordia de Sao Paulo, Sao Paulo, Brazil.;Baleia Hospital, Sao Paulo, Brazil.;Hospital do Cancer do Ceara, Fortaleza, Brazil.;Cancer Clinic, Bahia Society of Oncology, Salvador, Brazil.;Joana de Gusmão Children's Hospital, Santa Catarina, Brazil.;Centro Infantil Boldrini, San Paulo, Brazil.;Childhood Cancer Institute, Porto Alegre, Brazil.;Sao Lucas Hospital, Porto Alegre, Brazil.;Federal University of Sao Paulo, Sao Paulo, Brazil.;Federal University of Sao Paulo, Sao Paulo, Brazil.;Institute of Pediatric Oncology/Support Group for Adolescents and Children With Cancer, Federal University of Sao Paulo, Sao Paulo, Brazil.",
"authors": "Senerchia|Andreza A|AA|;Macedo|Carla Renata|CR|;Ferman|Sima|S|;Scopinaro|Marcelo|M|;Cacciavillano|Walter|W|;Boldrini|Erica|E|;Lins de Moraes|Vera Lúcia|VL|;Rey|Guadalupe|G|;de Oliveira|Claudia T|CT|;Castillo|Luis|L|;Almeida|Maria Tereza|MT|;Borsato|Maria Luisa|ML|;Lima|Eduardo|E|;Lustosa|Daniel|D|;Barreto|José Henrique|JH|;El-Jaick|Tatiana|T|;Aguiar|Simone|S|;Brunetto|Algemir|A|;Greggiani|Lauro|L|;Cogo-Moreira|Hugo|H|;Atallah|Alvaro|A|;Petrilli|Antonio Sergio|AS|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/cncr.30411",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0008-543X",
"issue": "123(6)",
"journal": "Cancer",
"keywords": "chemotherapy; metronomic; nonmetastatic; osteosarcoma; survival",
"medline_ta": "Cancer",
"mesh_terms": "D059250:Administration, Metronomic; D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols; D001859:Bone Neoplasms; D002648:Child; D003131:Combined Modality Therapy; D019468:Disease Management; D005121:Extremities; D005260:Female; D006801:Humans; D008297:Male; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D012516:Osteosarcoma; D016016:Proportional Hazards Models; D016896:Treatment Outcome; D047368:Tumor Burden",
"nlm_unique_id": "0374236",
"other_id": null,
"pages": "1003-1010",
"pmc": null,
"pmid": "28263383",
"pubdate": "2017-05-15",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": null,
"title": "Results of a randomized, prospective clinical trial evaluating metronomic chemotherapy in nonmetastatic patients with high-grade, operable osteosarcomas of the extremities: A report from the Latin American Group of Osteosarcoma Treatment.",
"title_normalized": "results of a randomized prospective clinical trial evaluating metronomic chemotherapy in nonmetastatic patients with high grade operable osteosarcomas of the extremities a report from the latin american group of osteosarcoma treatment"
} | [
{
"companynumb": "BR-JNJFOC-20170413032",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": "3",
"d... |
{
"abstract": "ABO incompatibility has been considered as an important immunological barrier for renal transplantation. With the advent of effective preconditioning protocols, it is now possible to do renal transplants across ABO barrier. We hereby present a single center retrospective analysis of all consecutive ABOi renal transplants performed from November 2011 to August 2014. Preconditioning protocol consisted of rituximab, plasmapheresis and intravenous immunoglobulin (IVIG) and maintenance immunosuppression consisted of tacrolimus, mycophenolate sodium, and prednisolone. The outcome of these ABOi transplants was compared with all other consecutive ABO-compatible (ABOc) renal transplants performed during same time. Twenty ABOi renal transplants were performed during the study period. Anti-blood group antibody titer varied from 1:2 to 1:512. Patient and graft survival was comparable between ABOi and ABOc groups. Biopsy proven acute rejection rate was 15% in ABOi group, which was similar to ABOc group (16.29%). There were no antibody-mediated rejections in ABOi group. The infection rate was also comparable. We conclude that the short-term outcome of ABOi and ABOc transplants is comparable. ABOi transplants should be promoted in developing countries to expand the donor pool.",
"affiliations": "Department of Nephrology, Medanta Institute of Kidney and Urology, Medanta - The Medicity, Gurgaon, Haryana, India.;Department of Nephrology, Medanta Institute of Kidney and Urology, Medanta - The Medicity, Gurgaon, Haryana, India.;Department of Nephrology, Medanta Institute of Kidney and Urology, Medanta - The Medicity, Gurgaon, Haryana, India.;Department of Nephrology, Medanta Institute of Kidney and Urology, Medanta - The Medicity, Gurgaon, Haryana, India.;Department of Nephrology, Medanta Institute of Kidney and Urology, Medanta - The Medicity, Gurgaon, Haryana, India.;Department of Nephrology, Medanta Institute of Kidney and Urology, Medanta - The Medicity, Gurgaon, Haryana, India.;Department of Nephrology, Medanta Institute of Kidney and Urology, Medanta - The Medicity, Gurgaon, Haryana, India.;Department of Lab Medicine, Medanta Institute of Kidney and Urology, Medanta - The Medicity, Gurgaon, Haryana, India.;Department of Transfusion Medicine, Medanta Institute of Kidney and Urology, Medanta - The Medicity, Gurgaon, Haryana, India.;Department of Urology, Medanta Institute of Kidney and Urology, Medanta - The Medicity, Gurgaon, Haryana, India.;Department of Urology, Medanta Institute of Kidney and Urology, Medanta - The Medicity, Gurgaon, Haryana, India.;Department of Nephrology, Medanta Institute of Kidney and Urology, Medanta - The Medicity, Gurgaon, Haryana, India.",
"authors": "Jha|P K|PK|;Bansal|S B|SB|;Sethi|S K|SK|;Jain|M|M|;Sharma|R|R|;Nandwani|A|A|;Phanish|M K|MK|;Duggal|R|R|;Tiwari|A K|AK|;Ghosh|P|P|;Ahlawat|R|R|;Kher|V|V|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/0971-4065.159557",
"fulltext": "\n==== Front\nIndian J NephrolIndian J NephrolIJNIndian Journal of Nephrology0971-40651998-3662Medknow Publications & Media Pvt Ltd India IJN-26-11310.4103/0971-4065.159557Original ArticleABO-incompatible renal transplantation in developing world – crossing the immunological (and mental) barrier Jha P. K. Bansal S. B. Sethi S. K. Jain M. Sharma R. Nandwani A. Phanish M. K. Duggal R. 1Tiwari A. K. 2Ghosh P. 3Ahlawat R. 3Kher V. Department of Nephrology, Medanta Institute of Kidney and Urology, Medanta - The Medicity, Gurgaon, Haryana, India1 Department of Lab Medicine, Medanta Institute of Kidney and Urology, Medanta - The Medicity, Gurgaon, Haryana, India2 Department of Transfusion Medicine, Medanta Institute of Kidney and Urology, Medanta - The Medicity, Gurgaon, Haryana, India3 Department of Urology, Medanta Institute of Kidney and Urology, Medanta - The Medicity, Gurgaon, Haryana, IndiaAddress for correspondence: Dr. P. K. Jha, Department of Nephrology, Medanta Kidney and Urology Institute, Medanta - The Medicity, Gurgaon - 122 018, Haryana, India. E-mail: dr.pranaw@gmail.comMar-Apr 2016 26 2 113 118 Copyright: © 2016 Indian Journal of Nephrology2016This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.ABO incompatibility has been considered as an important immunological barrier for renal transplantation. With the advent of effective preconditioning protocols, it is now possible to do renal transplants across ABO barrier. We hereby present a single center retrospective analysis of all consecutive ABOi renal transplants performed from November 2011 to August 2014. Preconditioning protocol consisted of rituximab, plasmapheresis and intravenous immunoglobulin (IVIG) and maintenance immunosuppression consisted of tacrolimus, mycophenolate sodium, and prednisolone. The outcome of these ABOi transplants was compared with all other consecutive ABO-compatible (ABOc) renal transplants performed during same time. Twenty ABOi renal transplants were performed during the study period. Anti-blood group antibody titer varied from 1:2 to 1:512. Patient and graft survival was comparable between ABOi and ABOc groups. Biopsy proven acute rejection rate was 15% in ABOi group, which was similar to ABOc group (16.29%). There were no antibody-mediated rejections in ABOi group. The infection rate was also comparable. We conclude that the short-term outcome of ABOi and ABOc transplants is comparable. ABOi transplants should be promoted in developing countries to expand the donor pool.\n\nABO incompatibleABOideveloping worldIndiarenal transplantation\n==== Body\nIntroduction\nKidney transplantation is the best form of renal replacement therapy (RRT) for end-stage renal disease (ESRD) patients.[1] Only 10% of ESRD patients receive any form of RRT in India and only 2% undergo renal transplantation.[2] As per the Indian Chronic Kidney Disease (CKD) Registry, 39% of CKD 5 patients were on RRT and 2% were being worked up for renal transplant.[3] Renal transplant options for ESRD patients are limited. Deceased donor transplantation is still in its nascent stage. ABO incompatibility is an important limiting factor amongst willing donors, leading to rejection of approximately 35% donors.[4] In such a scenario, options are limited. One can opt for paired kidney exchange transplantation. Although it is being done at individual centers, there are no regional bodies to facilitate such exchanges between different centers and there is no national registry. This limits the number of such exchanges significantly. Also, many recipients are reluctant to accept kidney from donor outside their family in exchange of their own. ABO-incompatible (ABOi) transplant comes across as a viable alternative in such a scenario.\n\nAlthough worldwide popularity of ABOi renal transplant is increasing, experience from developing world is limited. Major concerns are high cost, risk of antibody-mediated rejection and increased incidence of posttransplant infections. We hereby present experience of ABOi renal transplant at our center, a tertiary care center in north India.\n\nSubjects and Methods\nThis is a single center retrospective analysis of consecutive renal transplants from November 2011, when the first ABOi renal transplant was performed at our center, till August 31, 2014. A total of 20 ABOi and 669 blood group compatible (ABOc) renal transplants were done.\n\nAntibody titer determination\nOnce a suitable donor was identified, recipient serum was tested for IgG and IgM antibody titer against donor ABO blood group antigens. This was done using column agglutination technology with Low-Ionic-Strength Saline-Indirect Antiglobulin Test Technique (Ortho-Clinical Diagnostics, Johnson and Johnson, USA). The cassettes used were anti-human globulin type. This method of antibody titer determination is known to be more sensitive than the conventional tube test.\n\nAll prospective donors underwent standard investigations after detailed history and physical examination. Crossmatch was performed by complement dependent cytotoxicity (CDC) and flow cytometry.\n\nPreconditioning and immunosuppression protocol\nPatients received intravenous rituximab (200 mg) 2 weeks pretransplant. After a week, tacrolimus (0.05 mg/kg/day in two divided doses) and mycophenolate sodium (720 mg twice daily) were started, and patient was admitted for plasmapheresis. Tacrolimus trough level was targeted at 8–12 ng/ml. Alternate day plasmapheresis was performed followed by administration of IVIG (100 mg/kg/dose) postplasmapheresis. Low dose of rituximab and IVIG were used based on previous published good outcomes with these doses.[567] Daily isoagglutinin IgG titer was monitored, and transplantation was done once it reached 1:8. Baseline antibody titer was ≤1:8 in 3 patients who did not require plasmapheresis. Of remaining 17 patients, first 5 received conventional plasma exchange while double filtration plasmapheresis (DFPP) was used for antibody removal in other 12. DFPP leads to selective removal of the immunoglobulin fraction from the serum, minimizing the volume of substitution fluid required.[8]\n\nIntraoperatively, patients received intravenous methylprednisolone (500 mg) and intravenous basiliximab (20 mg) induction. Dose of basiliximab was repeated on postoperative day four. One patient received anti-thymocyte globulin (ATG) as inducing agent (1.5 mg/kg intravenous for two doses) due to weakly positive B cell flowcytometry crossmatch and presence of donor specific antibodies. One of the renal transplant recipients did not receive any induction in view of presence of recent pulmonary tuberculosis. Intravenous hydrocortisone was given on the day of transplant followed by oral prednisolone at 40 mg/day next day onward. This was tapered to 20 mg/day on discharge. Isoagglutinin titer was monitored daily until discharge, and plasmapheresis was done in case of rising titers. Two patients required posttransplant plasmapheresis. All patients received trimethoprim-sulfamethoxazole prophylaxis for pneumocystis jiroveci infection and clotrimazole prophylaxis for fungal infection. Valganciclovir prophylaxis was given to patients receiving ATG induction or those with D+ R-cytomegalovirus (CMV) IgG serology.\n\nIn ABOc group, basiliximab induction was offered to all the patients. But as patients pay for the cost of transplant and drugs, only 55% received basiliximab induction. Thymoglobulin was offered to immunologically high-risk recipients such as those with previous history of multiple blood transfusions, second or more renal transplant, multiple pregnancies, and wife recipient. Five percent of patients received thymoglobulin induction.\n\nPost-transplant follow-up\nPatients were followed up twice weekly for 1st month, weekly for next 1-month, once a fortnight till the 3rd month and thereafter monthly for one year. After 1st year, follow-up was once in 2–3 months. During every visit, renal function tests including serum creatinine and hemogram were monitored. Isoagglutinin titer was done twice weekly for 2 weeks post-discharge and weekly for next 2 weeks thereafter. Tacrolimus/cyclosporine level was done as per the need, decided by the treating physician. Tacrolimus trough level target was 8–12 ng/ml during first 3 months, 5–8 ng/ml from 3 to 6 months and <5 ng/ml thereafter. Cyclosporine trough target level was 250–350 ng/ml during first 3 months, 100–250 ng/ml from 3 to 6 months and <100 ng/ml thereafter while C2 target level was 1000–1200 ng/ml during first 3 months and 600–1000 ng/ml thereafter. Prednisolone was tapered to 10 mg by the end of 3 months and 5 mg by the end of 6 months. Mycophenolate sodium was tapered to 360 mg twice daily by 6 months.\n\nProtocol biopsy was performed at 3 months post-transplant for all ABOi renal transplant recipients. Graft biopsies were also performed whenever indicated such as in case of rising serum creatinine. All the graft biopsies were examined by light microscopy and immunofluorescence including C4d. All rejections were biopsy proven. Acute cellular rejection was treated with intravenous methylprednisolone (500 mg od for three consecutive days).\n\nStatistical analysis was done using MedCalc for Windows, version 12.7.8 (MedCalc Software, Belgium). Data were reported as mean values ± standard deviation. Continuous variables were compared using unpaired t-test while categorical values were compared using Chi-square test or Fisher's exact test. P < 0.05 was considered as statistically significant.\n\nResults\nTable 1 shows the demographic characteristics of the 2 groups (i.e., ABOi and ABOc). Significantly more number of patients in ABOi group had chronic glomerulonephritis as the native kidney disease. Other demographic characteristics were comparable between the groups. One of the ABOi group patients was second transplant recipient. All the transplants in ABOi group were live related ones while in ABOc group 0.8% (n = 6) were deceased donor transplants.\n\nTable 1 Demographic characteristics and clinical profile of patients\n\nTable 2 shows the donor and recipient blood group distribution, starting antibody-titer and number of DFPP sessions required. It also shows the allograft biopsy details. The majority were O-blood group recipients (50%) followed by A and B (25% each). Most frequent titer was 1:256 (32%).\n\nTable 2 Blood group and titer distribution in ABOi group\n\nRecipient outcome is presented in Table 3. Mean duration of follow-up was 10.15 ± 9.34 months and 16.67 ± 9.63 months in ABOi and ABOc groups respectively. Patient and death censored graft survival was comparable between groups (P = 1). Figures 1 and 2 show Kaplan–Meier curves comparing patient and death censored graft survival between the two groups. Serum creatinine values at discharge and after 1-month were also comparable (P = 0.23 and 0.24 respectively). One patient died due to acute coronary syndrome. Although he had longstanding history of diabetes and hypertension, his pretransplant cardiac evaluation was normal. Another patient developed reduced urine output on the day of transplant. Graft biopsy showed thrombotic microangiopathy. There were no neutrophils or mononuclear cells in peritubular capillaries or glomeruli; neither there was any acute tubular injury. Staining for C4d in peritubular capillaries was negative. Repeat CDC and flow cytometry crossmatch was negative. Thrombotic microangiopathy was thought to be tacrolimus induced and hence it was withdrawn. He received plasma exchange sessions. He developed sepsis, which responded well to IV antibiotics. His renal functions and overall clinical condition started improving. Four weeks posttransplant, patient developed severe epigastric pain and recurrent bilious vomiting. Upper gastro-intestinal endoscopy showed hemorrhagic and necrotic ulcerative lesions in esophagus and stomach. Biopsy from these lesions revealed mucormycosis. Also, there was evidence of intranuclear inclusion bodies in gastric mucosa suggestive of CMV gastritis. He was treated with intravenous liposomal amphotericin B (3 mg/kg/day) and intravenous ganciclovir (2.5 mg/kg/day). Later his abdominal pain worsened, and he developed refractory hypotension. Exploratory laparotomy was done which showed 3 cm × 3 cm rent in posterior wall of stomach. Distal gastrectomy along with debridement and feeding jejunostomy was done. But despite these measures, he succumbed to sepsis.\n\nTable 3 Recipient outcome\n\nFigure 1 Kaplan–Meier graph comparing patient survival between ABOi and ABOc group. (ABOi: ABO incompatible; ABOc: ABO compatible)\n\nFigure 2 Kaplan–Meier graph comparing death censored graft survival between ABOi and ABOc group. (ABOi: ABO incompatible; ABOc: ABO compatible)\n\nOn analysis, infection rates were not significantly different between the ABOi and ABOc groups (P = 0.16). BKV infection and pneumonia were seen in one patient each. As mentioned above, one patient had CMV infection and gastric mucormycosis.\n\nA total of nine protocol and eight indication biopsies were done. Details of these biopsies are shown in Table 2. All protocol biopsies were normal. Staining for C4d was positive in 53% of cases. Of 8 patients whose biopsy was done for indication, two had delayed graft function. Of these, one had thrombotic microangiopathy as described above while another had diffuse cortical necrosis secondary to graft renal vein thrombosis. One patient had slow decline of serum creatinine in posttransplant period. In him, first renal biopsy showed acute tubular necrosis and protocol biopsy after 3 months showed borderline cellular rejection, which did not require any treatment, as renal function was stable. One of the patients developed nephrotic range proteinuria and active urine sediments. Graft renal biopsy showed C3 glomerulopathy. Her native kidney disease pretransplant was unknown. Her graft function is stable. Remaining 3 patients were biopsied for graft dysfunction. All had acute cellular rejections, which responded well to methylprednisolone pulse.\n\nDiscussion\nIn 1950s and 60s, initial attempts to do ABOi transplant in USA were met with high failure rate and very poor graft survival. It was concluded that ABO compatibility is a necessary prerequisite for successful renal transplant.[91011] In 1987, Alexandre et al. showed that successful ABOi transplants with good graft outcome could be achieved using pretransplant desensitization (or preconditioning) protocol. He used plasma exchange to remove anti-A or anti-B antibodies and splenectomy to prevent further antibody production. Antilymphocyte globulin was used for induction.[12] Subsequently, large number of ABOi transplants was done in Japan using preconditioning protocol of plasma exchange and splenectomy with good graft and patient outcome.[13] Later, it was realized that chemical splenectomy using anti-CD20 monoclonal antibody-Rituximab can replace surgical splenectomy with good results[14] and splenectomy associated complications could be avoided. Most centers have now stopped doing splenectomy for ABOi transplant. The majority of the European centers have used immunoadsorption, IVIG and rituximab based protocols with good success.[15161718] In United States, Montgomery et al. have used rituximab, plasma exchange, and CMV IVIG as preconditioning.[19] Selective methods of antibody removal such as immunoadsorption and DFPP is being preferred these days as large plasma volumes can be processed, and risk of bleeding due to elimination of coagulation factors is minimized. Lately, in an effort to reduce overall immunosuppression, Flint et al. and Montgomery et al. have done ABOi renal transplants without rituximab in their protocols with good graft and patient survival outcome.[2021] In our center, we have used preconditioning protocol of rituximab and conventional plasma exchange (5 patients)/DFPP (12 patients) followed by IVIG.\n\nPatient survival was 90% in the current study. This was 98% and 100% in the study by Tydén et al., Flint et al. and Lipshutz et al. respectively.[162022] Death censored graft survival of ABOi transplant group in our study was 95%. This is similar to the graft survival in the study by Tydén et al. (97%), Flint et al.(100%), and Lipshutz et al.(94.4%).[162022] In the present study, death censored graft survival and patient survival of ABOi recipients were comparable to that of ABOc group. These findings are similar to that of study by Genberg et al.[15] In our study, serum creatinine at 1-month was similar between the 2 groups without any significant difference.\n\nRate of biopsy proven acute rejection was comparable between the groups. Biopsy proven acute rejection rate in ABOi recipients in the current study was 15%. This was better than the BPAR of 40% in a study by Wilpert et al. with similar immunosuppression protocol.[23] Lipshutz et al. reported BPAR of 11% in their ABOi recipients while it was 32% in a study by Uchida et al.[2224] Most of the studies have reported higher incidence of antibody-mediated rejection in ABOi recipients, which has varied from 5 to 33%.[22232425] In our study, none of the ABOi recipients developed antibody-mediated rejection. Although one patient had TMA on biopsy, other features of AMR such as neutrophils or mononuclear cells in peritubular capillaries or glomeruli, acute tubular injury and C4d deposition in peritubular capillaries, were missing.[26] In addition, his renal function improved after stopping tacrolimus, which supported it to be drug induced TMA.\n\nGraft biopsies showed C4d staining in 53% of cases. In various studies, C4d positivity in protocol graft biopsies has been seen in 80–94% of patients and does not necessarily indicate antibody-mediated rejection.[2728] In fact, it may represent the phenomenon of accommodation, in which the graft continues to function normally despite the presence of anti-blood group antibodies.[28]\n\nThe infection rate in ABOi recipients was 15%, which was comparable to ABOc group. One ABOi patient developed CMV infection, and one had BKV infection. Most studies have shown a trend toward higher infection rate amongst ABOi transplant recipients, varying from 18 to 50%.[16172023]\n\nThere are some limitations of our study: The sample size of ABOi group is small. Also, the immunosuppression protocol was variable for ABOc group as mentioned in materials and methods. Follow-up of patients is short, and hence long-term outcome cannot be commented upon.\n\nConcluding, published reports of ABOi transplant experience from developing countries are very few. Ours is one of the first such series. Graft and patient survival have been excellent in the current study. Rate of biopsy proven acute rejection was at par with ABO compatible ones and more importantly there were no antibody-mediated rejections. The incidence of posttransplant infections, which is a major concern in developing world, was acceptable and, in fact, lower than other similar studies. Our experience has been encouraging so far and proves that it is the right time for widespread implementation of ABOi transplants even in developing countries.\n\nSource of Support: Nil\n\nConflict of Interest: None declared.\n==== Refs\n1 Wolfe RA Ashby VB Milford EL Ojo AO Ettenger RE Agodoa LY Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant N Engl J Med 1999 341 1725 30 10580071 \n2 Chugh KS Five decades of Indian nephrology: A personal journey Am J Kidney Dis 2009 54 753 63 19726117 \n3 Rajapurkar MM John GT Kirpalani AL Abraham G Agarwal SK Almeida AF What do we know about chronic kidney disease in India: First report of the Indian CKD registry BMC Nephrol 2012 13 10 22390203 \n4 Segev DL Gentry SE Warren DS Reeb B Montgomery RA Kidney paired donation and optimizing the use of live donor organs JAMA 2005 293 1883 90 15840863 \n5 Shirakawa H Ishida H Shimizu T Omoto K Iida S Toki D The low dose of rituximab in ABO-incompatible kidney transplantation without a splenectomy: A single-center experience Clin Transplant 2011 25 878 84 21175849 \n6 Toki D Ishida H Horita S Setoguchi K Yamaguchi Y Tanabe K Impact of low-dose rituximab on splenic B cells in ABO-incompatible renal transplant recipients Transpl Int 2009 22 447 54 19144092 \n7 Montgomery RA Renal transplantation across HLA and ABO antibody barriers: Integrating paired donation into desensitization protocols Am J Transplant 2010 10 449 57 20121749 \n8 Tanabe K Double-filtration plasmapheresis Transplantation 2007 84 12 Suppl S30 2 18162985 \n9 Hume DM Merrill JP Miller BF Thorn GW Experiences with renal homotransplantation in the human: Report of nine cases J Clin Invest 1955 34 327 82 13233354 \n10 Starzl TE Marchioro TL Rifkind D Holmes JH Rowlands DT Jr Waddell WR Renal homografts in patients with major donor-recipient blood group incompatibilities Surgery 1964 55 195 200 14121762 \n11 Dunea G Nakamoto S Straffon RA Figueroa JE Versaci AA Shibagaki M Renal homotransplantation in 24 patients Br Med J 1965 1 7 13 14213121 \n12 Alexandre GP Squifflet JP De Bruyère M Latinne D Reding R Gianello P Present experiences in a series of 26 ABO-incompatible living donor renal allografts Transplant Proc 1987 19 4538 42 3321614 \n13 Tanabe K Japanese experience of ABO-incompatible living kidney transplantation Transplantation 2007 84 S4 7 18162988 \n14 Tydén G Kumlien G Genberg H Sandberg J Lundgren T Fehrman I ABO incompatible kidney transplantations without splenectomy, using antigen-specific immunoadsorption and rituximab Am J Transplant 2005 5 145 8 15636623 \n15 Genberg H Kumlien G Wennberg L Berg U Tydén G ABO-incompatible kidney transplantation using antigen-specific immunoadsorption and rituximab: A 3-year follow-up Transplantation 2008 85 1745 54 18580466 \n16 Tydén G Donauer J Wadström J Kumlien G Wilpert J Nilsson T Implementation of a Protocol for ABO-incompatible kidney transplantation – A three-center experience with 60 consecutive transplantations Transplantation 2007 83 1153 5 17496528 \n17 van Agteren M Weimar W de Weerd AE Te Boekhorst PA Ijzermans JN van de Wetering J The first fifty ABO blood group incompatible kidney transplantations: The Rotterdam Experience J Transplant 2014 2014 913902 \n18 Oettl T Halter J Bachmann A Guerke L Infanti L Oertli D ABO blood group-incompatible living donor kidney transplantation: A prospective, single-centre analysis including serial protocol biopsies Nephrol Dial Transplant 2009 24 298 303 18728155 \n19 Montgomery RA Cooper M Kraus E Rabb H Samaniego M Simpkins CE Renal transplantation at the Johns Hopkins Comprehensive Transplant Center Clin Transpl 2003 199 213 15387112 \n20 Flint SM Walker RG Hogan C Haeusler MN Robertson A Francis DM Successful ABO-incompatible kidney transplantation with antibody removal and standard immunosuppression Am J Transplant 2011 11 1016 24 21449947 \n21 Montgomery RA Locke JE King KE Segev DL Warren DS Kraus ES ABO incompatible renal transplantation: A paradigm ready for broad implementation Transplantation 2009 87 1246 55 19384174 \n22 Lipshutz GS McGuire S Zhu Q Ziman A Davis R Goldfinger D ABO blood type-incompatible kidney transplantation and access to organs Arch Surg 2011 146 453 8 21502455 \n23 Wilpert J Fischer KG Pisarski P Wiech T Daskalakis M Ziegler A Long-term outcome of ABO-incompatible living donor kidney transplantation based on antigen-specific desensitization. An observational comparative analysis Nephrol Dial Transplant 2010 25 3778 86 20466677 \n24 Uchida J Kuwabara N Machida Y Iwai T Naganuma T Kumada N Excellent outcomes of ABO-incompatible kidney transplantation: A single-center experience Transplant Proc 2012 44 204 9 22310615 \n25 Toki D Ishida H Setoguchi K Shimizu T Omoto K Shirakawa H Acute antibody-mediated rejection in living ABO-incompatible kidney transplantation: Long-term impact and risk factors Am J Transplant 2009 9 567 77 19260836 \n26 Racusen LC Haas M Antibody-mediated rejection in renal allografts: Lessons from pathology Clin J Am Soc Nephrol 2006 1 415 20 17699240 \n27 Setoguchi K Ishida H Shimmura H Shimizu T Shirakawa H Omoto K Analysis of renal transplant protocol biopsies in ABO-incompatible kidney transplantation Am J Transplant 2008 8 86 94 18021283 \n28 Haas M Rahman MH Racusen LC Kraus ES Bagnasco SM Segev DL C4d and C3d staining in biopsies of ABO- and HLA-incompatible renal allografts: Correlation with histologic findings Am J Transplant 2006 6 1829 40 16889542\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0971-4065",
"issue": "26(2)",
"journal": "Indian journal of nephrology",
"keywords": "ABO incompatible; ABOi; India; developing world; renal transplantation",
"medline_ta": "Indian J Nephrol",
"mesh_terms": null,
"nlm_unique_id": "8914356",
"other_id": null,
"pages": "113-8",
"pmc": null,
"pmid": "27051135",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": "13233354;18162988;22310615;19384174;20466677;17496528;18728155;17699240;21502455;15636623;24672705;18162985;22390203;20121749;15840863;15387112;18021283;3321614;21175849;21449947;14213121;10580071;16889542;19144092;19726117;18580466;14121762;19260836",
"title": "ABO-incompatible renal transplantation in developing world - crossing the immunological (and mental) barrier.",
"title_normalized": "abo incompatible renal transplantation in developing world crossing the immunological and mental barrier"
} | [
{
"companynumb": "IN-ACCORD-039937",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CLOTRIMAZOLE"
},
"drugadditional": null,
"d... |
{
"abstract": "Pertuzumab plus trastuzumab plus docetaxel regimen is the first choice for the initial treatment of HER2-positive recurrent breast cancer. However, docetaxel causes many adverse events. A 48-year-old woman was admitted to our hospital for a left breast tumor and was diagnosed with left breast cancer(T1N0M0, Stage Ⅰ, Luminal A). We performed a breast-conserving surgery and sentinel lymph node biopsy, followed by irradiation of the remaining parts of the mammary gland and adjuvant therapy with tamoxifen. Three and a half years after the first surgery, she underwent local resection due to chest wall recurrence of breast cancer. The recurrent tumor was HER2-positive, and we administered fluorouracil, epirubicin, cyclophosphamide( FEC)and paclitaxel plus trastuzumab. Liver metastases were confirmed on completion of cycle 11 of trastuzumab administration, and the regimen was changed to pertuzumab plus trastuzumab plus docetaxel. A partial response was seen following this regimen. The next line of treatment was the administration of 5 cycles of T-DM1, which resulted in stabilizing the disease. The liver metastases progressed, and the regimen was changed to pertuzumab plus trastuzumab plus eribulin. Partial response was seen following this regimen for liver metastases without serious adverse events(20 cycles).",
"affiliations": "Dept. of Breast and Endocrine Surgery, Osaka City University Graduate School of Medicine.",
"authors": "Kouhashi|Rika|R|;Kashiwagi|Shinichiro|S|;Kawano|Yuko|Y|;Yabumoto|Akimichi|A|;Ishihara|Sae|S|;Goto|Wataru|W|;Asano|Yuka|Y|;Tauchi|Yukie|Y|;Morisaki|Tamami|T|;Noda|Satoru|S|;Takashima|Tsutomu|T|;Hirakawa|Kosei|K|;Ohira|Masaichi|M|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D005663:Furans; D007659:Ketones; D018719:Receptor, ErbB-2; C485206:pertuzumab; C490954:eribulin; D000068878:Trastuzumab",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "47(13)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D005260:Female; D005663:Furans; D006801:Humans; D007659:Ketones; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009364:Neoplasm Recurrence, Local; D018719:Receptor, ErbB-2; D000068878:Trastuzumab",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "2230-2232",
"pmc": null,
"pmid": "33468917",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case in Which Re-Administration of Pertuzumab/Trastuzumab with Eribulin Therapy Was Useful for Recurrent HER2 Breast Cancer.",
"title_normalized": "a case in which re administration of pertuzumab trastuzumab with eribulin therapy was useful for recurrent her2 breast cancer"
} | [
{
"companynumb": "JP-CELLTRION INC.-2021JP000911",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE\\EPIRUBICIN HYDROCHLORIDE\\FLUOROURACIL"
... |
{
"abstract": "Histological abnormalities, including chronic hepatitis, fibrosis, and steatosis, are increasingly reported in liver biopsies of children after LT. These changes may be progressive and represent a form of rejection. Liver biochemistry is often initially normal. Our LT program began in 2002, utilizing tacrolimus and low-dose steroids for the first year post-LT. Patients undergo a protocol biopsy at 1 year post-LT prior to stopping steroids, then at 5 years and every 5 years thereafter. Target tacrolimus levels are 5-8 μg/L and 3-5 μg/L after 3 and 12 months, respectively. Between 2002 and 2009, 51 LT were performed; 50 (98%) and 49 (96%) patients survived for 1 and 5 years, respectively. A total of 43 patients (median age at LT 2.3 years) underwent a protocol biopsy at 1 year (16 male; median time post-LT 12.5 months), and 44 (20 male; median time post-LT 5.1 years) at 5 years. By 5 years, 3 had transferred to adult services; 1 was re-transplanted for graft failure and 1 moved overseas. Biopsies were reviewed by 2 pathologists. Most patients (31/44) were on tacrolimus monotherapy at 5 years. At 1 and 5 years, 29 of 43 (67.5%) and 31 of 44 (71%) biopsies were normal, respectively. Two of 44 had chronic allograft hepatitis at 5 years. Two of 43 and 1 of 44 had isolated fibrosis, 3 of 43 and 3 of 44 steatosis, and 3 of 43 and 4 of 44 acute rejection at 1 and 5 years, respectively. Other findings included predominantly biliary changes (6/43 & 3/44 at 1 and 5 years, respectively). Tacrolimus levels at 5 years were slightly higher than anticipated (median trough level 5.8 μg/L). With an immunosuppressive regimen of tacrolimus and low-dose steroids for 1 year followed by tacrolimus monotherapy thereafter, the majority of PLB were normal and no progressive changes were observed at 5 years. Compared to other LT programs, we have lower rates of chronic allograft hepatitis, steatosis, and fibrosis at 5 years. However, the tacrolimus levels at 5 years were higher than planned and this may have played a role. Further evaluation is also required to determine the potential long-term adverse effects of corticosteroid use on linear growth and bone mineral density.",
"affiliations": "Paediatric Gastroenterology & Hepatology, Starship Child Health, Auckland, New Zealand.;Anatomical Pathology, Auckland City Hospital, Auckland, New Zealand.;Paediatric Gastroenterology & Hepatology, Starship Child Health, Auckland, New Zealand.",
"authors": "Sheikh|Amin|A|0000-0001-6147-5577;Chau|Kai Y|KY|;Evans|Helen M|HM|0000-0002-8860-2705",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.13212",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "22(5)",
"journal": "Pediatric transplantation",
"keywords": "fibrosis; graft abnormalities; immune hepatitis; immune suppression; pediatric liver transplant; protocol liver biopsy",
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D001706:Biopsy; D002675:Child, Preschool; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D007223:Infant; D007231:Infant, Newborn; D008099:Liver; D008107:Liver Diseases; D016031:Liver Transplantation; D008297:Male; D017063:Outcome Assessment, Health Care; D011183:Postoperative Complications; D012189:Retrospective Studies",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "e13212",
"pmc": null,
"pmid": "29749699",
"pubdate": "2018-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Histological findings in protocol biopsies following pediatric liver transplant: Low incidence of abnormalities at 5 years.",
"title_normalized": "histological findings in protocol biopsies following pediatric liver transplant low incidence of abnormalities at 5 years"
} | [
{
"companynumb": "PHHY2018NZ071854",
"fulfillexpeditecriteria": "1",
"occurcountry": "NZ",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "3",
... |
{
"abstract": "Whether successful catheter ablation for atrial fibrillation (AF) reduces risk of cerebrovascular events (CVEs) remains controversial and whether oral anticoagulation therapy (OAT) can be safely discontinued in patients rendered free of AF recurrences remains unknown. We evaluated OAT use patterns and examined long-term rates of CVEs (stroke/TIA) and major bleeding episodes (MBEs) in patients with nonparoxysmal AF treated with catheter ablation.\n\n\n\nFour hundred patients with nonparoxysmal AF (200 persistent, 200 longstanding persistent; mean age 60.3 ± 9.7 years, 82% male) undergoing first AF ablation were followed for 3.6 ± 2.4 years. OAT discontinuation during follow-up was permitted in selected patients per physician discretion. At last follow-up, allowing for multiple ablations, 172 (43.0%) patients were free of AF recurrence. Two hundred and seven (51.8%) discontinued OAT at some point; 174 (43.5%) were off OAT at last follow-up. Patients without AF recurrence were more likely to remain off OAT (HR 0.23 [95% CI 0.17-0.33]). Patients with persistent (versus longstanding persistent) AF type prior to ablation (HR 0.6 [CI 0.44-0.83]) and those with CHA2 DS2 -VASc score <2 (HR 0.56 [0.39-0.80]) were less likely to continue OAT. Seven patients had CVEs (incidence: 0.49/100 patient years) and 14 experienced MBE during follow-up (incidence: 0.98/100 patient years). Older age (P = 0.001) and coronary artery disease (P = 0.028) were associated with CVE.\n\n\n\nAnticoagulation discontinuation in well selected, closely monitored patients following successful ablation of nonparoxysmal AF was associated with a low rate of clinical embolic CVEs. Prospective studies are required to confirm safety of OAT discontinuation after successful AF ablation.",
"affiliations": "Cardiovascular Division, Electrophysiology Section, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.;Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.;Department of Neurology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.;Cardiovascular Division, Electrophysiology Section, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.;Cardiovascular Division, Electrophysiology Section, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.;Cardiovascular Division, Electrophysiology Section, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.;Cardiovascular Division, Electrophysiology Section, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.;Cardiovascular Division, Electrophysiology Section, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.;Cardiovascular Division, Electrophysiology Section, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.;Cardiovascular Division, Electrophysiology Section, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.;Cardiovascular Division, Electrophysiology Section, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.;Cardiovascular Division, Electrophysiology Section, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.;Cardiovascular Division, Electrophysiology Section, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.;Cardiovascular Division, Electrophysiology Section, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.;Cardiovascular Division, Electrophysiology Section, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.;Cardiovascular Division, Electrophysiology Section, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.;Cardiovascular Division, Electrophysiology Section, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.;Cardiovascular Division, Electrophysiology Section, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.;Cardiovascular Division, Electrophysiology Section, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.;Cardiovascular Division, Electrophysiology Section, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.;Cardiovascular Division, Electrophysiology Section, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.",
"authors": "Liang|Jackson J|JJ|0000-0001-8608-8899;Elafros|Melissa A|MA|;Mullen|Michael T|MT|;Muser|Daniele|D|;Hayashi|Tatsuya|T|;Enriquez|Andres|A|;Pathak|Rajeev K|RK|;Zado|Erica S|ES|;Santangeli|Pasquale|P|0000-0002-0023-9666;Arkles|Jeffrey S|JS|;Schaller|Robert D|RD|;Supple|Gregory E|GE|;Frankel|David S|DS|;Garcia|Fermin C|FC|;Deo|Rajat|R|;Lin|David|D|;Riley|Michael P|MP|;Nazarian|Saman|S|;Dixit|Sanjay|S|;Marchlinski|Francis E|FE|0000-0001-7962-9423;Callans|David J|DJ|",
"chemical_list": "D000925:Anticoagulants",
"country": "United States",
"delete": false,
"doi": "10.1111/jce.13476",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1045-3873",
"issue": "29(6)",
"journal": "Journal of cardiovascular electrophysiology",
"keywords": "anticoagulation; atrial fibrillation; bleed; catheter ablation; cerebrovascular; pulmonary vein isolation; stroke",
"medline_ta": "J Cardiovasc Electrophysiol",
"mesh_terms": "D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants; D001281:Atrial Fibrillation; D017115:Catheter Ablation; D004334:Drug Administration Schedule; D005260:Female; D006470:Hemorrhage; D006801:Humans; D002546:Ischemic Attack, Transient; D008297:Male; D008875:Middle Aged; D000077982:Progression-Free Survival; D012008:Recurrence; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D020521:Stroke; D013997:Time Factors",
"nlm_unique_id": "9010756",
"other_id": null,
"pages": "823-832",
"pmc": null,
"pmid": "29513397",
"pubdate": "2018-06",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Anticoagulation use and clinical outcomes after catheter ablation in patients with persistent and longstanding persistent atrial fibrillation.",
"title_normalized": "anticoagulation use and clinical outcomes after catheter ablation in patients with persistent and longstanding persistent atrial fibrillation"
} | [
{
"companynumb": "US-TEVA-2019-US-1138693",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "WARFARIN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nRisk factors for the development of post-ERCP pancreatitis (PEP) have not been identified in the pediatric population. It remains unclear what constitutes appropriate prophylaxis in this patient population.\n\n\nOBJECTIVE\nTo assess the prevalence and severity of PEP in the pediatric population and identify factors associated with developing PEP and to evaluate the effect of prophylactic pancreatic duct stenting in high-risk patients.\n\n\nMETHODS\nRetrospective analysis of an ERCP database at a single large pediatric center.\n\n\nMETHODS\nAcademic center.\n\n\nMETHODS\nA total of 432 ERCPs performed on 313 patients younger than 19 years of age from January 2004 to October 2013.\n\n\nMETHODS\nERCP for any indication.\n\n\nMETHODS\nRates and severity of PEP, preprocedural and procedural risk factors for the development of PEP, and the effect of pancreatic stents on preventing PEP in high-risk patients.\n\n\nRESULTS\nPEP occurred after 47 procedures (prevalence, 10.9%). Thirty-four cases were mild, 9 were moderate, and 4 were severe. There was no mortality. On multiple logistic analysis, pancreatic duct injection (P<.0001; odds ratio 30.8; 95% confidence interval [CI], 9.1-103.9) and pancreatic sphincterotomy (P<.01; OR 3.8; 95% CI, 1.6-9.8) were positively associated with PEP. A history of chronic pancreatitis was negatively associated with PEP (P<.05; OR 0.37; 95% CI, 0.15-0.93). On subset analysis, placing a prophylactic pancreatic stent was associated with significantly increased rates of PEP in patients with pancreatic duct injection compared with those who had no attempt at stent placement (P<.01). Two patients with severe pancreatitis had prophylactic pancreatic stents in place.\n\n\nCONCLUSIONS\nRetrospective investigation.\n\n\nCONCLUSIONS\nIn the pediatric population, pancreatic duct injection and pancreatic sphincterotomy are associated with significantly increased rates of PEP, whereas a history of chronic pancreatitis is negatively associated. Prophylactic pancreatic stenting is associated with higher rates of PEP in high-risk patients and does not eliminate severe PEP.",
"affiliations": "UT Southwestern Medical Center, Dallas, Texas, USA.;Children's Medical Center, Dallas, Texas, USA.;Children's Medical Center, Dallas, Texas, USA.;UT Southwestern Medical Center, Dallas, Texas, USA.",
"authors": "Troendle|David M|DM|;Abraham|Omana|O|;Huang|Rong|R|;Barth|Bradley A|BA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0016-5107",
"issue": "81(6)",
"journal": "Gastrointestinal endoscopy",
"keywords": null,
"medline_ta": "Gastrointest Endosc",
"mesh_terms": "D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D002760:Cholangiopancreatography, Endoscopic Retrograde; D005260:Female; D006801:Humans; D008297:Male; D016017:Odds Ratio; D010179:Pancreas; D010183:Pancreatic Ducts; D010195:Pancreatitis; D015995:Prevalence; D012189:Retrospective Studies; D012307:Risk Factors; D015607:Stents",
"nlm_unique_id": "0010505",
"other_id": null,
"pages": "1408-16",
"pmc": null,
"pmid": "25686874",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Factors associated with post-ERCP pancreatitis and the effect of pancreatic duct stenting in a pediatric population.",
"title_normalized": "factors associated with post ercp pancreatitis and the effect of pancreatic duct stenting in a pediatric population"
} | [
{
"companynumb": "US-GE HEALTHCARE MEDICAL DIAGNOSTICS-OMPQ-PR-1502L-0165",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "IOHEXOL"
},
"d... |
{
"abstract": "Introduction: Trends of disease activity during pregnancy, the postpartum period, and until 24 months from the delivery in the era of new drugs for the treatment of relapsing-remitting multiple sclerosis (RRMS) need to be investigated. Methods: In this cross-sectional Italian multicenter study, women with RRMS were included; the disease-modifying treatment (DMT) at the time of conception included were: interferons, glatiramer acetate, teriflunomide, dimethyl fumarate, fingolimod, and natalizumab. The main outcome of the study was to determine the rate of relapse occurrence during pregnancy and the postpartum period in all women grouped for each DMT. The secondary outcome was to determine the overall disease activity assessed by NEDA 3 (relapse, disability level, and radiological activity) at 24 months from the date of delivery. Results: Completed data were available for 81 pregnancies (in 74 women). Women on interferons and glatiramer had longer disease duration than women on dimethyl fumarate, fingolimod, and natalizumab (p < 0.05). Overall, we recorded 25 relapses during pregnancy (11 in 11 women) and the postpartum period (14 in 14 women). Natalizumab was the most commonly DMT in women (3) who experienced relapses during pregnancy. IFNs were the most commonly prescribed DMT in women (8) who experienced relapses during the postpartum period. At logistic regression analysis, specific treatment per se was not associated with relapse occurrence. No differences among the DMTs groups were recorded about NEDA 3 status at 24 months of follow-up. Conclusions: In our population, there was no difference in terms of relapses occurrence, disability status, and the overall disease activity during a follow up of 24 months.",
"affiliations": "Department \"G. F. Ingrassia\", University of Catania, Catania, Italy.;Department \"G. F. Ingrassia\", University of Catania, Catania, Italy.;Institute Foundation \"G. Giglio\", MS Center, Cefalù-Palermo, Italy.;Department \"G. F. Ingrassia\", University of Catania, Catania, Italy.;S. Andrea Hospital, Rome, Italy.;Institute Foundation \"G. Giglio\", MS Center, Cefalù-Palermo, Italy.;Department \"G. F. Ingrassia\", University of Catania, Catania, Italy.",
"authors": "Zanghì|Aurora|A|;D'Amico|Emanuele|E|;Callari|Graziella|G|;Chisari|Clara Grazia|CG|;Borriello|Giovanna|G|;Grimaldi|Luigi Maria Edoardo|LME|;Patti|Francesco|F|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fneur.2020.00105",
"fulltext": "\n==== Front\nFront Neurol\nFront Neurol\nFront. Neurol.\nFrontiers in Neurology\n1664-2295 Frontiers Media S.A. \n\n10.3389/fneur.2020.00105\nNeurology\nOriginal Research\nPregnancy and the Postpartum Period in Women With Relapsing-Remitting Multiple Sclerosis Treated With Old and New Disease-Modifying Treatments: A Real-World Multicenter Experience\nZanghì Aurora 1† D'Amico Emanuele 1*† Callari Graziella 2 Chisari Clara Grazia 1 Borriello Giovanna 3 Grimaldi Luigi Maria Edoardo 2 Patti Francesco 1 1Department “G. F. Ingrassia”, University of Catania, Catania, Italy\n2Institute Foundation “G. Giglio”, MS Center, Cefalù-Palermo, Italy\n3S. Andrea Hospital, Rome, Italy\nEdited by: Maria Pia Amato, University of Florence, Italy\n\nReviewed by: Melinda Magyari, Danish Multiple Sclerosis Center (DMSC), Denmark; Angel Perez Sempere, Hospital General Universitario de Alicante, Spain\n\n*Correspondence: Emanuele D'Amico emanuele.damico@unict.itThis article was submitted to Multiple Sclerosis and Neuroimmunology, a section of the journal Frontiers in Neurology\n\n†These authors have contributed equally to this work\n\n\n25 2 2020 \n2020 \n11 10522 9 2019 30 1 2020 Copyright © 2020 Zanghì, D'Amico, Callari, Chisari, Borriello, Grimaldi and Patti.2020Zanghì, D'Amico, Callari, Chisari, Borriello, Grimaldi and PattiThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Introduction: Trends of disease activity during pregnancy, the postpartum period, and until 24 months from the delivery in the era of new drugs for the treatment of relapsing-remitting multiple sclerosis (RRMS) need to be investigated.\n\nMethods: In this cross-sectional Italian multicenter study, women with RRMS were included; the disease-modifying treatment (DMT) at the time of conception included were: interferons, glatiramer acetate, teriflunomide, dimethyl fumarate, fingolimod, and natalizumab. The main outcome of the study was to determine the rate of relapse occurrence during pregnancy and the postpartum period in all women grouped for each DMT. The secondary outcome was to determine the overall disease activity assessed by NEDA 3 (relapse, disability level, and radiological activity) at 24 months from the date of delivery.\n\nResults: Completed data were available for 81 pregnancies (in 74 women). Women on interferons and glatiramer had longer disease duration than women on dimethyl fumarate, fingolimod, and natalizumab (p < 0.05). Overall, we recorded 25 relapses during pregnancy (11 in 11 women) and the postpartum period (14 in 14 women). Natalizumab was the most commonly DMT in women (3) who experienced relapses during pregnancy. IFNs were the most commonly prescribed DMT in women (8) who experienced relapses during the postpartum period. At logistic regression analysis, specific treatment per se was not associated with relapse occurrence. No differences among the DMTs groups were recorded about NEDA 3 status at 24 months of follow-up.\n\nConclusions: In our population, there was no difference in terms of relapses occurrence, disability status, and the overall disease activity during a follow up of 24 months.\n\nmultiple sclerosispregnancyNEDA 3old DMTsnew DMTs\n==== Body\nIntroduction\nIn women with the relapsing-remitting form of multiple sclerosis (RRMS), pregnancy still represents a challenge in terms of what to do before, during, and after such an event (1). Usually, women with RRMS and MS-physicians share a plan of pregnancy when patients become stabilized with absence of disease activity and are early in their disease course. Pregnancy has been associated with a 70% reduction in the annualized relapse rate (ARR) in the third trimester, compared to the year before pregnancy (2), but also with an increase in relapse frequency in the postpartum period (3). It is important to note that relapses occur most frequently in the 2–3 months postpartum (2–9).\n\nThe pathophysiologic pathways involved in the changes of MS activity during pregnancy and the postpartum period are still largely unknown. It is thought that estrogen and other sex hormones play a fundamental role in modulating T- and B-lymphocyte functions (10). Moreover, also the CD56 natural killer cells might play an active role in the reduction of disease activity during the third trimester (11). With the advent of new and potent—but less safe—disease-modifying treatments (DMTs) for RRMS, new issues in terms of management and pregnancy have arisen; of these, the timing of DMT wash-out pre-pregnancy, use during pregnancy, restart therapy after delivery, and the risk of disease activity rebound represent the most challenging. Literature provides data mainly for women who were on either interferon beta (IFN-β) or glatiramer acetate (GA) before conception (12–18), while few reports are disposable for the women on DMTs, which were released onto the market more recently (19–21).\n\nTherefore, we aimed to describe the trends of MS activity during pregnancy and the postpartum period in an Italian multicenter population of women who received old (injectables) and new (oral and injectables) DMTs before conception.\n\nMethods\nPatients' Cohort\nDatabase and Study Population\nIn this cross-sectional multicenter study, women with RRMS were identified from three large tertiary MS centers in Italy. The data entry used iMed© software (iMed, Merck Serono SA; Geneva), and a rigorous quality assurance procedure was ensured regularly and locally by the treatment clinics using patient health records while coordinating with the iMed© software data coordinators (22).\n\nThere were some key eligibility criteria: (i) women with a laboratory-supported or clinically established RRMS diagnosis (Poser or 2010 McDonald criteria) (23); and (ii) at least 12 months of follow-up after delivery.\n\nThere were some exclusion criteria: (a) women with others forms of MS than RRMS; and (b) women who were not on treatment at the time of conception. Ongoing pregnancies and abortions were also excluded.\n\nThe index window considered was from January 1st, 2005, to June 30th, 2017.\n\nEach patient is usually followed prospectively with scheduled visits (at least one visits every 6 months).\n\nThe minimum dataset for all enrolled women included demographic data and clinical characteristics (age at inclusion, age at onset, disease duration, number of relapses and level of disability before and during the pregnancy and postpartum period (3 months from the delivery), duration of pregnancy dichotomized by trimesters, breastfeeding, prior/ongoing use of DMTs, therapeutic washout period, and the number of lesions at brain MRI).\n\nOther general clinical data, such as body mass index (BMI), smoking status pre-, during, and post-pregnancy, and any comorbidities, were recorded at the time of enrollment; if any change occurred along the follow-up this was also recorded.\n\nData were extracted from the registry database on June 30th, 2018.\n\nProcedures and Outcomes\nRelapses were defined as new or recurrent neurologic symptoms not associated with fever or infection that lasted for at least 24 h. All relapses were treated with 1 g IV methyl prednisolone (IVMP) for 5 days.\n\nDisability was scored using the Expanded Disability Status Scale (EDSS) administered by trained neurologists with an online Neurostatus certification (https://www.neurostatus.net/) who considered a EDSS evaluation for at least 30 days from any clinical relapse.\n\nBrain MRI sequences were acquired with a 1.5 Tesla system. We collected the number of T2, T1, and T1 gadolinium (God+) lesions at the baseline (a scan performed within the 6 months prior the conception).\n\nThen, we followed up the women through a brain MRI scan within the first trimester after delivery and then through an annual MRI scan.\n\nRegarding treatment, changes in DMTs' use (including reasons for discontinuation/interruption) were noted. We considered old DMTs as the old injectables drugs: intramuscular IFN-β-1a, subcutaneous IFN-β-1a, subcutaneous IFN-β-1b, and GA. We considered the following as new DMTs: teriflunomide, dimethyl fumarate, fingolimod, and natalizumab. All DMTs were prescribed in accordance with the approved label instructions and the expected standards for good clinical practice.\n\nTo describe the presence of overall disease activity during the first 24 months of the postpartum period, we used the no evidence of disease activity (NEDA 3) score. NEDA 3 is a composite score obtained from three related measures of disease activity: (1) no evidence of relapses, (2) no EDSS score progression sustained for 6 or more months (1 EDSS step until the baseline score is EDSS 5.5 and 0.5 EDSS step if the baseline EDSS is >5.5), and (3) no MRI activity (new or newly enlarging lesions in T2 sequences and/or new God+ lesions at brain MRI) (24, 25).\n\nStudy Endpoints\nThe main outcome of the study was to determine the rate of relapse occurrence during pregnancy and the postpartum period in women with RRMS treated with different DMTs at the time of conception.\n\nRelations between any demographic and clinical factors and relapse occurrence during pregnancy and the postpartum period were assessed.\n\nThe secondary outcome was to determine the level of disease activity assessed by NEDA 3 at 24 months from the date of delivery.\n\nData Analysis\nBaseline characteristics were summarized as frequencies (%), mean with standard deviation, or median with range (min–max). Non-parametric tests (Mann–Whitney U-test) were utilized. Qualitative variables were analyzed with the Pearson χ2 and Fisher exact test.\n\nTwo different binary logistic regression models were built to binarily explore the effect of demographical and clinical variables on the probability of getting a relapse (expressed as dichotomic 0/1) during pregnancy and during the postpartum period, respectively.\n\nFor the event of relapse during pregnancy we investigated several variables: patient's age at inclusion (as a continuous variable), BMI (<19.5, 19.5–24, and >24), smoking status (as dichotomic 0/1), disease duration (as a continuous variable), DMT before pregnancy, length of the therapeutic washout period (as a continuous variable), number of relapses, and level of disability within 12 months before conception, number of T2, and T1 Gd+ brain MRI lesions within 12 months before conception (all as a continuous variable).\n\nFor the event of relapse during the postpartum period, we investigated several variables: relapses during pregnancy (as dichotomic 0/1), treatment continuation during pregnancy (as dichotomic 0/1), time to restart therapy after delivery (months, as continuous variable), and breastfeeding (as dichotomic 0/1).\n\nThe statistical software SPSS version 21.0 was used for all analyses (IBM SPSS Statistics 21, IBM©, Armonk, NY, USA).\n\nStandard Protocol Approval, Registration, and Patient Consent\nA generic informed consent form was given to the patient before data entry to grant their approval before data entry. Any specific information about the study was discussed with the patient. The institutional ethics committee Catania 1 approved the study, and informed consent forms were obtained from all patients. Confidentiality and data protection were ensured in keeping with the recommendations of the declaration of Helsinki; written informed consent was obtained from every patient at first visit.\n\nThis study received no financial support for the design, data collection, data analysis, data interpretation, or the writing of it.\n\nThe corresponding author had full access to the entire database and had the final responsibility of submitting this manuscript.\n\nResults\nA total of 120 pregnancies from the clinical datasets was identified. Eighty-one pregnancies (74 women) fulfilled the required criteria and were subsequently analyzed (see Figure 1).\n\nFigure 1 Patients' selection flow-chart. RRMS, relapsing-remitting multiple sclerosis.\n\nBaseline demographical, clinical, and radiological characteristics are showed in Table 1.\n\nTable 1 Baseline demographics and clinical characteristics of the studied cohort.\n\nVariables*\t\t\nMean age at inclusion, y\t36.2 ± 5.9\t\nMean BMI\t23.3 ± 3.5\t\nSmoking pre-conception, n (%)\t15 (18.5)\t\nMean age at delivery, y\t30.1 ± 4.7\t\nMean disease duration, y\t7.5 ± 7.5\t\nEDSS score within the year before pregnancy, median (IQR)\t2.0 (1.0–3.5)\t\nN. of MRI T2 lesions in the year before conception\t18 ± 17.1\t\nN. of MRI T1 Gad+ lesions in the year before conception\t0.7 ± 4.6\t\nn = 81 pregnancies, 74 women.\n\n* Values are mean ± SD when otherwise specified. BMI, Body Mass Index; DMT, disease-modifying therapy; Gad+, Gadolineum; MRI, magnetic resonance imaging; y, years.\n\nTable 2 shows the demographical, clinical and radiological data according to the name of DMTs' used before conception. Women on IFNs and GA had longer disease duration than women on dimethylfumarate, fingolimod, and natalizumab (p < 0.05). Incidental pregnancy occurred in one woman who was prescribed teriflunomide, and an accelerated clearance procedure was carried out on pregnancy confirmation.\n\nTable 2 Baseline characteristics according to DMT used.\n\nVariables*\tIFN-β\tGA\tTNF\tDMF\tFYG\tNTZ\t\nN. of pregnancies (n of women)\t40 (37)\t5 (3)\t1 (1)\t4 (4)\t4 (4)\t27 (25)\t\nMean age, y\t37.2 ± 6.2\t41 ± 3.5\t39\t35 ± 8.3\t34.2 ± 4.9\t35.8 ± 5.3\t\nAge at delivery, y\t29.7 ± 4.5\t30.3 ± 2.7\t37\t32 ± 7\t30 ± 5.1\t33.4 ± 4\t\nDisease duration, y\t12.4 ± 5.5\t15.9 ± 1.3\t8\t8.3 ± 4.8\t11.8 ± 4.3\t11.8 ± 4.6\t\nWash out period (months)\t0.6 ± 0.7\t2 ± 2\t0\t1.8 ± 0.9\t3.2 ± 3.6\t2.9 ± 0.6\t\nN. of relapses (n. of women) 12 months before pregnancy\t15 (15)\t1 (1)\t0\t1 (1)\t1 (1)\t4 (3)\t\nEDSS score, median (IQR) at conception\t1 (1.0–2.0)\t1.5 (1–2.0)\t1.5 (1.0–2.0)\t1.5 (1.0–2.0)\t1.5 (1.0–2.0)\t2 (1–2.5)\t\nN. of pregnancies (n. of women) with MRI activity 12 months before pregnancy\t2 (2)\t0\t0\t0\t2 (2)\t3 (3)\t\n* Data are expressed as mean ± standard deviation when otherwise specified.\n\nDMF, dimethylfumarate; DMTS, disease modifying therapy; EDSS, Expanded Disability Status Scale; FYG, fingolimod; GA, Glatiramer acetate; IFNs, interferons; MRI, Magnetic Resonance Imaging; n, number; NTZ, Natalizumab; TNF, teriflunomide; y, year.\n\nWomen on natalizumab (of whom three continued the treatment until the end of the second trimester on the basis of a shared physician/women decision) had a higher EDSS score than women on IFNs within the 12 months before conception. The other variables showed no differences (Table 2).\n\nTable 3 reports the trends of disease activity in terms of relapse occurrence during pregnancy and the postpartum period. Overall, we recorded 25 relapses during pregnancy and the postpartum period (in 24 women). The ARR pre-pregnancy was 0.40, while the ARRs during pregnancy and the postpartum period were 0.16 and 0.20, respectively.\n\nTable 3 Characteristics of relapses during pregnancy and the postpartum period.\n\nVariables\t\t\nRelapses during pregnancy\nn (n. of women)\t11 (11)\t\nIFNs\t1 (1)\t\nGA\t0\t\nTNF\t0\t\nDMF\t2 (2)\t\nFYG\t2 (2)\t\nNTZ\t6 (6)\t\nRelapses during post-partum\nn (n. of women)\t14 (14)\t\nIFNs\t8 (8)\t\nGA\t0\t\nTNF\t0\t\nDMF\t0\t\nFYG\t2 (2)\t\nNTZ\t3 (3)\t\nN, number.\n\nEleven relapses occurred during pregnancy. Most relapses were clustered around the first trimester (one at 8 weeks and six relapses at 12 weeks) and the third trimester (four relapses clustered from 28 to 34 weeks) of gestation. No relapses resulted in sustained residual disability.\n\nNatalizumab was the most commonly used DMT in women who experienced relapses during pregnancy (see Table 3).\n\nDuring the postpartum period, 14 relapses occurred. Most relapses were clustered around 4–8 weeks (11 relapses) and three around 10–12 weeks. IFNs was the most commonly prescribed DMT in women who experienced relapses during post-partum.\n\nTwo relapses resulted in sustained residual disability. One woman was treated with intramuscular IFN-β-1a; here the EDSS score before pregnancy was 1.5 and 12 months after delivery was 3.5, and no MRI load increase was observed.\n\nThe second women with residual disability had an EDSS score of 1.5 before pregnancy, and it moved to the value of 4.0 at 12 months after delivery. Here, MRI load increased (from 30 to 90 T2 MRI lesions).\n\nIn our cohort, 67 women had a natural delivery (labor was induced in two pregnancies after 41 weeks ± 5 days, and preterm birth between 34 and 37 weeks occurred in two pregnancies). Fourteen had a cesarean delivery. Thirty-nine patients breastfed, and the mean time to restart therapy was 1.6 ± 1.8 months.\n\nThe logistic regression models did not retain any variables. In detail, specific treatment per se was not associated with a relapse occurrence during pregnancy, and this was likely because of the low number of events once DMTs were dichotomized into specific variables.\n\nNEDA 3 at 24 months data was recorded for all women. No differences among the DMTs groups were recorded (Table 4).\n\nTable 4 NEDA 3 and its component distribution between the groups.\n\n\tNEDA 3\nN. pregnancies\n(n. of women)\tNEDA Relapse\tNEDA EDSS\tNEDA MRI\tp-value*\t\nIFNs\t30 (30)\t30 (30)\t36 (36)\t36 (36)\tns\t\nGA\t3 (3)\t3 (3)\t3 (3)\t3 (3)\tns\t\nTNF\t1\t1\t1\t1\tns\t\nDMF\t4 (4)\t4 (4)\t4 (4)\t4 (4)\tns\t\nFYG\t3 (3)\t3 (3)\t4 (4)\t4 (4)\tns\t\nNTZ\t18 (18)\t25 (22)\t22 (22)\t23 (22)\tns\t\n* via Fisher Exact test.\n\nNo major fetal anomalies or congenital malformations were observed. Three newborns had a low birth weight, and one reported neonatal jaundice that resolved spontaneously.\n\nDiscussion\nOur multicenter experience confirms the literature data, which showed that pregnancy and the postpartum period appears to have no influence on the progression of disability in MS. The rate of relapse in our population during and before pregnancy was in accordance to previous meta-analysis data (4). Moreover, among the DMTs that we use, there was no difference in the impact on the rate of relapse, disability status, and the overall disease activity during a follow up of 24 months.\n\nOur findings may raise questions regarding several practical points. Firstly, also women with active (in terms of relapse) MS history may plan their pregnancies, even if they are on high-efficacy therapies, such as natalizumab and fingolimod (in Italy both are licensed as second-line DMTs). It is described that continuing natalizumab during the first trimester could decrease the risk of relapses. Regarding fingolimod, it is suggested that the drug be withdrawn 2 months before pregnancy planning because fingolimod has been associated with teratogenic effects (26).\n\nFor teriflunomide and dimethyl fumarate the data are scarce. The former needs to be washed out with an elimination procedure, while a definitive washout period needs to be established for the latter. Some evidence, however, suggested about 2 weeks because of its short half-life (27). A similar issue was identified for alemtuzumab, which requires at least a 4-month washout period (27).\n\nWe did not find any specific role as predictors of relapse occurrence during pregnancy and the postpartum period for any of demographic and clinical investigated factors. It was recently found that longer washout treatment periods were linked to about 4-fold increase in the relapse occurrence during pregnancy (19); this was not the case in our cohort. Another study, analyzing data from 92 pregnancies in 83 women receiving natalizumab, showed that relapse rate during and after pregnancy was higher in women treated with natalizumab (p < 0.001) (28).\n\nIn the multivariable analysis, a longer natalizumab washout period was the only predictor of relapse occurrence during pregnancy (p = 0.001) (28). In a large registry study, performed on an international MS registry (MS Base) in which 893 pregnancies(674 women) were included, examining 3 period epochs (1967–2002; 2002–2006, and 2006–2010), any second-line or new DMTs were disposable (29). The women on DMTs were 39.0% in the 2-year period before conception (29). Here, the pre-conception ARR and DMT predicted early postpartum relapse in a multivariable model (29).\n\nTwo studies from Kuwait (DMT use rate 89.9%) and from Spain (DMT use rate 97.3%) showed an increase in the rate of relapses during pregnancy that was significantly higher in the group of women treated with natalizumab or fingolimod compared to the group of women treated with interferon beta or glatiramer acetate (5, 19, 30). Furthermore, in a Western Austria cohort, 387 pregnancies in 239 women with RRMS were analyzed; here, the risk of relapse during pregnancy and the postpartum period was predicted by the use of highly effective disease-DMTs pre-conception and by a prolonged washout period (6).\n\nIn the clinical practice, women with MS usually plan their pregnancies by sharing with MS physicians when the disease seems stable in terms of relapses and MRI activity; they and tend to consider pregnancy when they have low disability level. About DMTs used during gestation, most literature data are disposable for the old injectables, and, in 2017, pregnancy contraindication was removed from Copaxone 40 mg/ml three times a week (Teva Pharmaceuticals®) in Europe; more recently, in 2019, also Interferon Beta 1a at a dose of 44 mcg weekly (Merck-Serono®) was authorized to be used during pregnancy as clinically needed and while breastfeeding.\n\nObviously, the heterogeneity in terms of MS history (disease duration, relapses, and disability status) and in terms of different DMTs used might have influenced and affected our findings.\n\nHowever, to establish a definitive interval between time of cessation of the DMTs' effect and the beginning of pregnancy has not been possible so far. We have no proper pharmacokinetics studies, and the serum concentration of any drug does not reflect its effects, which can be sustained by different metabolites. In the clinical practice, we based our decision on clinical or laboratory observations of the normalization of lymphopenia in fingolimod-treated women.\n\nWe did not find any role for breastfeeding in terms of impacting the MS course. It was described that breastfeeding may have protective effects in the postpartum period, but the data are conflicting with two recent studies showing the opposite (31–33).\n\nOur study has some limitations. First, it has a retrospective design even if we referred to prospectively collected data. Second, we acknowledge the bias in saying that women who have milder disease were more likely to become pregnant, as described elsewhere (34). Overall, our data analyses may suffer from the fact that we were not able to perform subgroup analyses given the low number of women enrolled in the different DMTs groups.\n\nHowever, our study is among the first studies conducted with pregnant women who were previously on second-line therapies, such as natalizumab, fingolimod, and dimethyl fumarate.\n\nWe have confirmed that pregnancy and postpartum periods did not negatively impact disease evolution; and we suggest that further discussion about pregnancy topics is a priority in MS management that should also be initiated as soon as possible after MS diagnosis.\n\nWe need randomized and prospective studies to gain more insight into the benefits and risks of the different DMTs and their timing regarding washout and restart therapy.\n\nData Availability Statement\nThe datasets generated for this study are available on request to the corresponding author.\n\nEthics Statement\nThis study was carried out in accordance with the recommendations of the Ethics Committee of Catania (Catania 1) with written informed consent from all subjects. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the Ethics Committee of Catania (Catania 1) (No. 20/2018/PO).\n\nAuthor Contributions\nED'A and AZ contributed to data curation as well as the drafting, reviewing, and editing of the manuscript. GB, CC, and GC contributed to data curation. LG and FP contributed to the supervision and validation of the manuscript.\n\nConflict of Interest\nAZ received travel funding from Bayer-Schering and Sanofi Genzyme outside of the submitted work. ED'A received personal fees by Biogen and Sanofi. He also received travel funding from Bayer Biogen and Merck. GC received personal fees by Biogen and Sanofi. She also received travel funding from Bayer Biogen and Merck. GB received personal fees by Biogen and Sanofi. She also received travel funding from Bayer Biogen and Merck. CC has nothing to disclose LG and FP served on the advisory board for Bayer, Biogen Celgene, Merck, Novartis, Roche, Sanofi, Teva, and Almirall. They also received personal fees for speaking activities at congresses or sponsored symposia. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n==== Refs\nReferences\n1. Coyle PK . Management of women with multiple sclerosis through pregnancy and after childbirth\n. Ther Adv Neurol Disord. (2016 ) 9 :198 –210\n. 10.1177/1756285616631897 27134675 \n2. Confavreux C Hutchinson M Hours MM Cortinovis-Tourniaire P Moreau T . Rate of pregnancy-related relapse in multiple sclerosis. Pregnancy in Multiple Sclerosis Group\n. New Engl J Med. (1998 ) 339 :285 –91\n. 10.1056/NEJM199807303390501 9682040 \n3. Hellwig K Haghikia A Rockhoff M Gold R . Multiple sclerosis and pregnancy: experience from a nationwide database in Germany\n. Ther Adv Neurol Disord. (2012 ) 5 :247 –53\n. 10.1177/1756285612453192 22973421 \n4. Finkelsztejn A Brooks JB Paschoal FM JrFragoso YD . What can we really tell women with multiple sclerosis regarding pregnancy? A systematic review and meta-analysis of the literature\n. BJOG Int J Obstetr Gynaecol. (2011 ) 118 :790 –7\n. 10.1111/j.1471-0528.2011.02931.x 21401856 \n5. Berenguer-Ruiz L Gimenez-Martinez J Palazón-Bru A Sempere AP . Relapses and obstetric outcomes in women with multiple sclerosis planning pregnancy\n. J Neurol. (2019 ) 266 :2512 –7\n. 10.1007/s00415-019-09450-6 31256279 \n6. Bsteh G Algrang L Hegen H Auer M Wurth S Di Pauli F . Pregnancy and multiple sclerosis in the DMT era: a cohort study in Western Austria\n. Multiple Scler. (2020 ) 26 :69 –78\n. 10.1177/1352458518816614 30507345 \n7. Cuello JP Salgado Cámara P García Domínguez JM Lozano Ros A Mas Serrano M Martínez Ginés ML . Pregnancy exposure to disease-modifying drugs in multiple sclerosis: a prospective study\n. Med Clin. (2019 ). 10.1016/j.medcle.2019.05.018 . [Epub ahead of print].31420082 \n8. Langer-Gould AM . Pregnancy and family planning in multiple sclerosis\n. Continuum. (2019 ) 25 :773 –92\n. 10.1212/CON.0000000000000745 31162316 \n9. Nguyen AL Eastaugh A van der Walt A Jokubaitis VG . Pregnancy and multiple sclerosis: clinical effects across the lifespan\n. Autoimmun Rev. (2019 ) 18 :102360 . 10.1016/j.autrev.2019.102360 31401345 \n10. Schumacher A Costa SD Zenclussen AC . Endocrine factors modulating immune responses in pregnancy\n. Front Immunol. (2014 ) 5 :196 . 10.3389/fimmu.2014.00196 24847324 \n11. Airas L Saraste M Rinta S Elovaara I Huang YH Wiendl H . Immunoregulatory factors in multiple sclerosis patients during and after pregnancy: relevance of natural killer cells\n. Clin Exp Immunol. (2008 ) 151 :235 –43\n. 10.1111/j.1365-2249.2007.03555.x 18062798 \n12. Sandberg-Wollheim M Neudorfer O Grinspan A Weinstock-Guttman B Haas J Izquierdo G . Pregnancy Outcomes from the Branded Glatiramer Acetate Pregnancy Database\n. Int J MS Care. (2018 ) 20 :9 –14\n. 10.7224/1537-2073.2016-079 29507538 \n13. Dung AA Panda AK . Interferon β-1a therapy for multiple sclerosis during pregnancy: an unresolved issue\n. BMJ Case Rep. (2014 ) 2014 :bcr2013201273 . 10.1136/bcr-2013-201273 24711465 \n14. Romero RS Lünzmann C Bugge JP . Pregnancy outcomes in patients exposed to interferon beta-1b\n. J Neurol Neurosurg Psychiatry. (2015 ) 86 :587 –9\n. 10.1136/jnnp-2014-308113 25185209 \n15. Thiel S Langer-Gould A Rockhoff M Haghikia A Queisser-Wahrendorf A Gold R . Interferon-beta exposure during first trimester is safe in women with multiple sclerosis-A prospective cohort study from the German Multiple Sclerosis and Pregnancy Registry\n. Multiple Scler. (2016 ) 22 :801 –9\n. 10.1177/1352458516634872 26920382 \n16. Uçar I Ertekin T Nisari M Ceylan D Al Ö Ülger H . The potential teratogenic effects of interferon beta-1a and interferon beta-1b on in vitro embryonic development\n. Folia Morphol. (2016 ) 75 :257 –63\n. 10.5603/FM.a2015.0099 26711647 \n17. D'Amico E Leone C Caserta C Patti F . Oral drugs in multiple sclerosis therapy: an overview and a critical appraisal\n. Exp Rev Neurother. (2015 ) 15 :803 –24\n. 10.1586/14737175.2015.1058162 26098146 \n18. Patti F Nicoletti A Pappalardo A Castiglione A Lo Fermo S Messina S . Frequency and severity of headache is worsened by Interferon-beta therapy in patients with multiple sclerosis\n. Acta Neurol Scand. (2012 ) 125 :91 –5\n. 10.1111/j.1600-0404.2011.01532.x 21649611 \n19. Alroughani R Alowayesh MS Ahmed SF Behbehani R Al-Hashel J . Relapse occurrence in women with multiple sclerosis during pregnancy in the new treatment era\n. Neurology. (2018 ) 90 :e840 –6\n. 10.1212/WNL.0000000000005065 29429970 \n20. Fares J Nassar AH Gebeily S Kobeissy F Fares Y . Pregnancy outcomes in Lebanese women with multiple sclerosis (the LeMS study): a prospective multicentre study\n. BMJ Open. (2016 ) 6 :e011210 . 10.1136/bmjopen-2016-011210 27178979 \n21. Amato MP Portaccio E . Fertility, pregnancy and childbirth in patients with multiple sclerosis: impact of disease-modifying drugs\n. CNS Drugs. (2015 ) 29 :207 –20\n. 10.1007/s40263-015-0238-y 25773609 \n22. Trojano M Bergamaschi R Amato MP Comi G Ghezzi A Lepore V \nThe Italian multiple sclerosis register\n. Neurol Sci . (2019 ) 40 :155 –65\n. 10.1007/s10072-018-3610-0 30426289 \n23. McDonald WI Edan G Goodkin D Hartung HP Lublin FD McFarland HF . Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis\n. Ann Neurol. (2001 ) 50 :121 –7\n. 10.1002/ana.1032 11456302 \n24. Havrdova E Galetta S Stefoski D Comi G . Freedom from disease activity in multiple, sclerosis\n. Neurology. (2010 ) 74 (Suppl. 3 ):S3 –7\n. 10.1212/WNL.0b013e3181dbb51c 20421571 \n25. Giovannoni G Turner B Gnanapavan S Offiah C Schmierer K Marta M . Is it time to target no evident disease activity (NEDA) in multiple sclerosis?\n\nMultiple Scler Relat Disord . (2015 ) 4 :329 –33\n. 10.1016/j.msard.2015.04.006 26195051 \n26. Karlsson G Francis G Koren G Heining P Zhang X Cohen JA . Pregnancy outcomes in the clinical development program of fingolimod in multiple sclerosis\n. Neurology. (2014 ) 82 :674 –80\n. 10.1212/WNL.0000000000000137 24463630 \n27. Coyle PK . Multiple sclerosis and pregnancy prescriptions\n. Exp Opin Drug Safety. (2014 ) 13 :1565 –8\n. 10.1517/14740338.2014.973848 25406727 \n28. Portaccio E Moiola L Martinelli V Annovazzi P Ghezzi A Zaffaroni M . Pregnancy decision-making in women with multiple sclerosis treated with natalizumab: II: Maternal risks\n. Neurology. (2018 ) 90 :e832 –9\n. 10.1212/WNL.0000000000006430 29438041 \n29. Hughes SE Spelman T Gray OM Boz C Trojano M Lugaresi A . Predictors and dynamics of postpartum relapses in women with multiple sclerosis\n. Multiple Scler. (2014 ) 20 :739 –46\n. 10.1177/1352458513507816 24107309 \n30. Alroughani R Akhtar S Zeineddine M El Kouzi Y El Ayoubi NK Ahmed SF . Risk of relapses during pregnancy among multiple sclerosis patients\n. Multiple Scler Relat Disord. (2019 ) 34 :9 –13\n. 10.1016/j.msard.2019.06.007 31202959 \n31. Langer-Gould A Huang SM Gupta R Leimpeter AD Greenwood E Albers KB . Exclusive breastfeeding and the risk of postpartum relapses in women with multiple sclerosis\n. Arch Neurol. (2009 ) 66 :958 –63\n. 10.1001/archneurol.2009.132 19506118 \n32. Portaccio E Ghezzi A Hakiki B Martinelli V Moiola L Patti F \nBreastfeeding is not related to postpartum relapses in multiple sclerosis\n. Neurology. (2011 ) 77 :145 –50\n. 10.1212/WNL.0b013e318224afc9 21734184 \n33. Zuluaga MI Otero-Romero S Rovira A Perez-Hoyos S Arrambide G Negrotto L \nMenarche, pregnancies, and breastfeeding do not modify long-term prognosis in multiple sclerosis\n. Neurology. (2019 ) 92 :e1507 –16\n. 10.1212/WNL.0000000000007178 30824557 \n34. D'Amico E Leone C Patti F \nOffspring number does not influence reaching the disability's milestones in multiple sclerosis: a seven-year follow-up study\n. Int J Mol Sci. (2016 ) 17 :234 \n10.3390/ijms17020234 26907250\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1664-2295",
"issue": "11()",
"journal": "Frontiers in neurology",
"keywords": "NEDA 3; multiple sclerosis; new DMTs; old DMTs; pregnancy",
"medline_ta": "Front Neurol",
"mesh_terms": null,
"nlm_unique_id": "101546899",
"other_id": null,
"pages": "105",
"pmc": null,
"pmid": "32158424",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": "29429970;29438041;18062798;29507538;27178979;19506118;26907250;30824557;30426289;31256279;21734184;24847324;24107309;25773609;31401345;25406727;21401856;31162316;11456302;24463630;22973421;21649611;31202959;26711647;20421571;25185209;30507345;26195051;31420082;24711465;27134675;9682040;26920382;26098146",
"title": "Pregnancy and the Postpartum Period in Women With Relapsing-Remitting Multiple Sclerosis Treated With Old and New Disease-Modifying Treatments: A Real-World Multicenter Experience.",
"title_normalized": "pregnancy and the postpartum period in women with relapsing remitting multiple sclerosis treated with old and new disease modifying treatments a real world multicenter experience"
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"abstract": "The ongoing COVID-19 pandemic has affected most countries in the world, with significant economic and public health implications. There is rising concern that patients who recover from COVID-19 may be at risk of reinfection. Another potential concern is the uncommon clinical scenario of a patient having persistent SARS-CoV-2 RNA test over 3 months after the initial COVID-19 infection, as the patient presented. Whether presenting as a long-term infection (12 weeks) or reinfection, patients with COVID-19 will continue to have a severe inflammatory and prothrombotic state that could carry potential life-threatening thrombosis.",
"affiliations": "Department of Critical Care Medicine, BayCare Winter Haven Hospital, Jacksonville, Florida, USA.;Department of Critical Care Medicine, BayCare Winter Haven Hospital, Jacksonville, Florida, USA.;Department of Critical Care Medicine, BayCare Winter Haven Hospital, Jacksonville, Florida, USA.;Department of Emergency Medicine, University of Florida, Jacksonville, Florida, USA.;Department of Hematology, BayCare Winter Haven Hospital, Jacksonville, Florida, USA.",
"authors": "Betancourt|Manuel Francisco|MF|;Grant|Kimberly Michelle|KM|;Johnson|James Scott|JS|;Kelkar|Dhanashree S|DS|;Sharma|Kamal|K|",
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"doi": "10.4103/jgid.jgid_286_20",
"fulltext": "\n==== Front\nJ Glob Infect Dis\nJ Glob Infect Dis\nJGID\nJournal of Global Infectious Diseases\n0974-777X\n0974-8245\nWolters Kluwer - Medknow India\n\nJGID-13-42\n10.4103/jgid.jgid_286_20\nCase Report\nPositive SARS-CoV-2 RNA with Significant Inflammatory State and Thrombophilia after 12 Weeks of Initial Diagnosis of COVID-19 Infection\nBetancourt Manuel Francisco\nGrant Kimberly Michelle\nJohnson James Scott\nKelkar Dhanashree S. 1\nSharma Kamal 2\nDepartment of Critical Care Medicine, BayCare Winter Haven Hospital, Jacksonville, Florida, USA\n1 Department of Emergency Medicine, University of Florida, Jacksonville, Florida, USA\n2 Department of Hematology, BayCare Winter Haven Hospital, Jacksonville, Florida, USA\nAddress for correspondence: Dr. Manuel Francisco Betancourt, Department of Critical Care Medicine, BayCare Winter Haven Hospital, Florida, USA. E-mali: manuel.betancourt-ramirez@baycare.org\nJan-Mar 2021\n26 2 2021\n13 1 4243\n25 8 2020\n03 10 2020\n22 12 2020\nCopyright: © 2021 Journal of Global Infectious Diseases\n2021\nhttps://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.\nThe ongoing COVID-19 pandemic has affected most countries in the world, with significant economic and public health implications. There is rising concern that patients who recover from COVID-19 may be at risk of reinfection. Another potential concern is the uncommon clinical scenario of a patient having persistent SARS-CoV-2 RNA test over 3 months after the initial COVID-19 infection, as the patient presented. Whether presenting as a long-term infection (12 weeks) or reinfection, patients with COVID-19 will continue to have a severe inflammatory and prothrombotic state that could carry potential life-threatening thrombosis.\n\nKeywords:\n\nCOVID-19\npandemic\nreinfection\nSARS-CoV-2\nthrombophilia\n==== Body\nINTRODUCTION\n\nAs a novel coronavirus, information regarding persistent or reinfection of the SARS-CoV-2 virus during the pandemic is limited. Further, data on the effects of prolonged or recurrent viremia in patients with thrombophilia are scarce. This case report presents this unusual but clinically relevant scenario and highlights the critical need for further investigation in this setting.\n\nCASE REPORT\n\nA 33-year-old truck driver, male patient who developed symptoms of fever, chills, and dry cough in the month of March 2020. He was evaluated in an urgent care in the state of Florida. A few days prior to developing symptoms, the patient had been in New York City delivering a truck load. His nasopharyngeal swab SARS-CoV-2 reverse transcriptase-polymerase chain reaction (RT-PCR) test was positive on March 28, 2020. He was advised by the Florida Department of Health to self-isolate for 14 days and did so at their recommendation. The patient subsequently improved in 5 days. He did not undergo repeat testing at 14 days. The patient did not receive medications after obtaining results 5 days later as his symptoms had already resolved. On June 06, 2020, he presented to a hospital in Georgia due to right lower extremity pain. He was diagnosed with extensive right iliofemoral deep venous thrombosis. The patient underwent US access of right popliteal vein, venogram of the right lower extremity, chemical thrombolysis, and percutaneous mechanical thrombectomy. The patient was discharged on apixaban.\n\nThe patient was evaluated in the ED at our institution on June 26, 2020, due to complains of bilateral lower extremity swelling. Lower extremity US disclosed bilateral extensive deep venous thrombosis. The patient reported being compliant in taking apixaban as prescribed. He denied fever, chills, viral prodrome, cough, dyspnea, or exposure sick persons. On physical examination, vital signs were normal with oxyhemoglobin saturation of 98% on room air. The only positive finding on physical examination was bilateral lower extremity swelling with evidence of edema. A repeat nasopharyngeal swab SARS-CoV-2 RT-PCR test done on June 28, 2020 was again positive. The admission inflammatory markers were elevated including C-reactive protein 6.59 mg/dL, ferritin 1283 ng/ml, and lactate dehydrogenase of 473 IU/L. Quantitative D-dimer was 35200 ng/dL. Computed tomography (CT) angiogram chest was negative for pulmonary embolism. The CT scan of the chest disclosed clear lungs.\n\nThe SARS-CoV-2 IgG antibody collected on 07/08/2020 was positive ≥1.4. In order to try to understand if the patient was reinfected after 12 weeks of his initial COVID-19 infection diagnosis, SARS-CoV-2 IgM Antibody was ordered on July 7, 2020 and was negative. During this 3-month period, the patient was unaware of infecting any close contacts. Since the patient had no pulmonary complaints and did not require oxygen therapy at this visit, he did not receive steroids or antivirals.\n\nThe patient was started on anticoagulation with unfractionated heparin drip. He was evaluated by interventional radiology and underwent bilateral lower extremity venogram and placement of bilateral thrombolysis infusion catheters from the superficial femoral veins into the inferior vena cava. Hypercoagulable work up showed that the patient has a heterozygous factor V Leiden. Subsequently, the patient developed heparin-induced thrombocytopenia with both positive PF4-heparin antibody and serotonin release assay. The patient was discharged on Fondaparinux. He continued to follow as outpatient in the hematology clinic. Since the RT-PCR has a high specificity, the test was not repeated a third time.\n\nDISCUSSION\n\nThe WHO characterized COVID-19 infection as a pandemic on March 11, 2020. SARS-CoV-2 was initially recognized in Wuhan, China, in December 2019. One of the most important diagnostic tools to detect the infection is the SARS-CoV-2 RNA test. It has been noticed that in some cases viral RNA has been detected by RT-PCR even beyond week 6 following the first positive test.[1] There are also reported cases of recurrence of positive SARS-CoV-2 RNA in the convalescent period.[2] The patient described has a positive SARS-CoV-2 RNA test after 12 weeks of initial diagnosis of COVID-19 infection.\n\nClinical recurrences of COVID-19 symptoms have been reported after recovery, most described as pneumonia.[34] The patient described was found to have extensive deep venous thrombosis 3 months after his initial COVID-19 infection, with significant elevation in inflammatory markers and thrombophilia. This type of presentation along with a repeated positive nasopharyngeal SARS-CoV-2 RT-PCR test raises one more time the question of reinfection versus viral relapse.\n\nCOVID-19 infection can be detected indirectly by measuring IgM and IgG. ELISA-based IgM and IgG antibody tests have greater than 95% specificity for diagnosis of COVID-19. In the confirmed patients with COVID-19, sensitivity of IgM is 77.3% and negative predictive value is 80%.[5] Our patient had a positive nasopharyngeal SARS-CoV-2 RT-PCR test and positive IgG. The IgM was negative despite of the significantly elevated inflammatory markers and clinical thrombosis (thrombophilia). It is not completely clear whether the negative IgM represented a false negative result. Further research including the potential measurement of quantitative viral load could be beneficial to answer this question.\n\nThis is the first report of positive nasopharyngeal SARS-CoV-2 RT-PCR test 3 months after an initial diagnosis of COVID-19 infection. COVID-19 results in a unique, profoundly prothrombotic milieu leading to both arterial and venous thrombosis.[6] Thrombotic events have been observed in outpatients with COVID-19 infection, but data on the incidence are not available. Whether presenting as a potential long-term infection (up to 3 months as this case) or reinfection, patients with COVID-19 will continue to have a severe inflammatory and prothrombotic state that could carry potential life-threatening thrombosis.\n\nInformed consent was obtained from this patient to present this case report. The patient did not wish to present a patient perspective for this report.\n\nResearch quality and ethics statement\n\nThe authors of this manuscript declare that this scientific work complies with reporting quality, formatting, and reproducibility guidelines set forth by the EQUATOR Network. The authors all attest that this clinical investigation was determined to not require Institutional Review Board/Ethics Committee review, and the corresponding protocol/approval number is not applicable. We also certify we have not plagiarized the contents in this submission and have done a Plagiarism Check.\n\nDeclaration of patient consent\n\nThe authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\n\nNil.\n\nConflicts of interest\n\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n\n1 Sethuraman N Jeremiah SS Ryo A Interpreting Diagnostic Tests for SARS-CoV-2 JAMA 2020 323 2249 51 32374370\n2 Chen D Xu W Lei Z Gao Z Peng L Recurrence of positive SARS-CoV-2 RNA in COVID-19: A case report Int J Infect Dis 2020 93 297 9 32147538\n3 Zhou L Liu K Liu HG Cause analysis and treatment strategies of “recurrence” with novel coronavirus pneumonia (COVID-19) patients after discharge from hospital Zhonghua Jie He He Hu Xi Za Zhi 2020 43 281 4 32118391\n4 Ravioli S Ochsner H Lindner G Reactivation of COVID-19 pneumonia: A report of two cases J Infect 2020 81 e72 3\n5 Xiang F Wang X He X Peng Z Yang B Zhang J Antibody detection and dynamic characteristics in patients with COVID-19 Clin Infect Dis 2020 71 1930 4 32306047\n6 Abou-Ismail MY Diamond A Kapoor S Arafah Y Nayak L The hypercoagulable state in COVID-19: Incidence, pathophysiology, and management Thromb Res 2020 194 101 15 32788101\n\n",
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"issue": "13(1)",
"journal": "Journal of global infectious diseases",
"keywords": "COVID-19; SARS-CoV-2; pandemic; reinfection; thrombophilia",
"medline_ta": "J Glob Infect Dis",
"mesh_terms": null,
"nlm_unique_id": "101521436",
"other_id": null,
"pages": "42-43",
"pmc": null,
"pmid": "33911453",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "32147538;32118391;32306047;32374370;32389787;32788101",
"title": "Positive SARS-CoV-2 RNA with Significant Inflammatory State and Thrombophilia after 12 Weeks of Initial Diagnosis of COVID-19 Infection.",
"title_normalized": "positive sars cov 2 rna with significant inflammatory state and thrombophilia after 12 weeks of initial diagnosis of covid 19 infection"
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"abstract": "A 31-year-old female with an 18-year history of systemic lupus erythematosus (SLE) complained of epigastralgia and consulted the emergency outpatient department at our hospital. Her physical examination revealed tenderness at the scrobiculus cordis, which was a non-specific symptom of coronary heart disease (CHD). We ultimately gave a diagnosis of acute myocardial infarction based on coronary angiography and performed percutaneous coronary intervention. Although pre-interventional intravascular ultrasound demonstrated distinct atherosclerotic lesions in the coronary arteries, there were no atherosclerotic lesions in other systemic arteries. Although CHD in young SLE patients is a significant cause of morbidity and premature death, it tends to be misdiagnosed because their symptoms may be non-specific. In addition, this case highlights the fact that even SLE patients with no systemic atherosclerosis are at risk for the development of CHD. <Learning objective: Coronary heart disease (CHD) in young systemic lupus erythematosus (SLE) patients is a significant cause of morbidity and premature death, but it tends to be misdiagnosed because their symptoms may be non-specific. Moreover, SLE patients are at risk for the development of CHD.>.",
"affiliations": "Department of Laboratory Medicine, Fukuoka University School of Medicine, Fukuoka, Japan.;Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan.;Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan.;Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan.;Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan.;Department of Laboratory Medicine, Fukuoka University School of Medicine, Fukuoka, Japan.;Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan.",
"authors": "Komaki|Tomo|T|;Miura|Shin-Ichiro|SI|;Gondo|Kouki|K|;Nakamura|Ayumi|A|;Ike|Amane|A|;Matsunaga|Akira|A|;Saku|Keijiro|K|",
"chemical_list": null,
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"delete": false,
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"issue": "16(2)",
"journal": "Journal of cardiology cases",
"keywords": "Coronary heart disease; No systemic atherosclerosis; Non-specific symptoms; Systemic lupus erythematosus",
"medline_ta": "J Cardiol Cases",
"mesh_terms": null,
"nlm_unique_id": "101549579",
"other_id": null,
"pages": "56-61",
"pmc": null,
"pmid": "30279797",
"pubdate": "2017-08",
"publication_types": "D002363:Case Reports",
"references": "2389846;6977269;1442853;8154514;15922149;14681505;6634279;9048514;7211914;1115070;17439937;11600739",
"title": "A rare case of acute myocardial infarction with a non-specific symptom in a young female with systemic lupus erythematosus.",
"title_normalized": "a rare case of acute myocardial infarction with a non specific symptom in a young female with systemic lupus erythematosus"
} | [
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"companynumb": "JP-MYLANLABS-2017M1062452",
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"abstract": "Empagliflozin is a sodium glucose cotransporter-2 inhibitor that inhibits renal glucose reabsorption through an insulin-independent mechanism. This class of drugs is used in the management of type 2 diabetes. A 49-year-old female with type 2 diabetes treated with empagliflozin presented to the emergency department in diabetic ketoacidosis (DKA). This case report details the series of events leading to the diagnosis of drug-induced DKA, which led to a change in the patient's diagnosis from type 2 diabetes to type 1 diabetes.",
"affiliations": "The University of New Mexico College of Pharmacy, Department of Pharmacy Practice and Administrative Sciences, Albuquerque, New Mexico.;The University of New Mexico College of Pharmacy, Albuquerque, New Mexico.;The University of New Mexico College of Pharmacy, Albuquerque, New Mexico.;The University of New Mexico Hospitals, Department of Pharmacy, Albuquerque, New Mexico.;The University of New Mexico School of Medicine, Department of Family and Community Medicine, Albuquerque, New Mexico.;The University of New Mexico School of Medicine, Department of Internal Medicine, Division of Endocrinology, Diabetes, and Metabolism, Albuquerque, New Mexico.",
"authors": "Ray|Gretchen M|GM|;Rodriguez|Chelsea|C|;Schulman|Samantha M|SM|;Sarangarm|Preeyaporn|P|;Bardack|Michelle|M|;Bouchonville|Matthew F|MF|",
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"doi": "10.5811/cpcem.2019.2.41795",
"fulltext": "\n==== Front\nClin Pract Cases Emerg MedClin Pract Cases Emerg MedClinical Practice and Cases in Emergency Medicine2474-252XUniversity of California Irvine, Department of Emergency Medicine publishing Western Journal of Emergency Medicine 10.5811/cpcem.2019.2.41795cpcem-03-140Case ReportEmpagliflozin-induced Diabetic Ketoacidosis Unmasking a Type 1 Diabetes Diagnosis Ray Gretchen M. PharmD*Rodriguez Chelsea BIS†Schulman Samantha M. BA†Sarangarm Preeyaporn PharmD‡Bardack Michelle MD§Bouchonville Matthew F. MD¶\n* The University of New Mexico College of Pharmacy, Department of Pharmacy Practice and Administrative Sciences, Albuquerque, New Mexico\n† The University of New Mexico College of Pharmacy, Albuquerque, New Mexico\n‡ The University of New Mexico Hospitals, Department of Pharmacy, Albuquerque, New Mexico\n§ The University of New Mexico School of Medicine, Department of Family and Community Medicine, Albuquerque, New Mexico\n¶ The University of New Mexico School of Medicine, Department of Internal Medicine, Division of Endocrinology, Diabetes, and Metabolism, Albuquerque, New MexicoAddress for Correspondence: Gretchen M. Ray, PharmD, The University of New Mexico College of Pharmacy, Department of Pharmacy Practice and Administrative Sciences, MSC09 5360, 1 University of New Mexico, Albuquerque, NM 87131. Email: gray@salud.unm.edu.5 2019 05 3 2019 3 2 140 143 28 11 2018 31 1 2019 08 2 2019 Copyright: © 2019 Ray et al.2019This is an open access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) License. See: http://creativecommons.org/licenses/by/4.0/Empagliflozin is a sodium glucose cotransporter-2 inhibitor that inhibits renal glucose reabsorption through an insulin-independent mechanism. This class of drugs is used in the management of type 2 diabetes. A 49-year-old female with type 2 diabetes treated with empagliflozin presented to the emergency department in diabetic ketoacidosis (DKA). This case report details the series of events leading to the diagnosis of drug-induced DKA, which led to a change in the patient’s diagnosis from type 2 diabetes to type 1 diabetes.\n==== Body\nINTRODUCTION\nThe treatment of diabetes has rapidly evolved with the introduction of novel agents such as the sodium glucose cotransporter-2 (SGLT2) inhibitors. In 2013, the United States (U.S.) Food and Drug Administration (FDA) approved the first SGLT2 inhibitor, canagliflozin, for the treatment of non-insulin-dependent type 2 diabetes mellitus (T2DM). Since that time, three additional agents, empagliflozin, dapagliflozin, and ertugliflozin, have begun to be marketed in the U.S. These agents are now included into the American Diabetes Association (ADA) treatment guidelines as one of six possible add-on pharmacologic agents to metformin.1 SGLT2 inhibitors are effective for the treatment of T2DM as they inhibit renal glucose reabsorption through an insulin-independent mechanism, which in turn lowers glucose levels through increased urinary glucose excretion.2 This drug class is also associated with a reduction in body weight, as well as reduced blood pressure, which is largely due to their natriuretic effect.2 Additionally, two SGLT2 inhibitors, empagliflozin and canagliflozin, have been shown to reduce rates of major adverse cardiac events in high cardiovascular-risk patients in the Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes trial and Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes (CANVAS) trials.3,4 Accordingly, prescriptions for SGLT2 inhibitors have been on the rise, resulting in this class of medications being commonly encountered in the primary care and emergency department (ED) settings.5\n\nCommon side effects of this drug class include increased risk of urinary tract infections, genital mycotic infections, and volume depletion.1 Both diabetic ketoacidosis (DKA) and euglycemic diabetic ketoacidosis (euDKA) have since also been identified as rare but serious adverse effects of the SGLT2 inhibitors, and in 2015 the FDA released a safety alert to the public about this concern.6 In contrast to the low rates of DKA observed in SGLT2 inhibitor users with type 2 diabetes, the risks are remarkably higher in those with type 1 diabetes.7 This distinction has prompted a consensus statement by the American Association of Clinical Endocrinologists urging caution with the off-label use of SGLT2 inhibitors in patients with type 1 diabetes.8 We describe the case of a patient initially diagnosed with type 2 diabetes presenting in DKA in association with the use of an SGLT2 inhibitor.\n\nCASE REPORT\nA 49-year-old female presented to the ED after waking up with nausea and abdominal pain followed by multiple episodes of vomiting. Her past medical history included T2DM, diagnosed four years earlier, and hypertension. Antihyperglycemic medications at the time of presentation included insulin glargine 25 units subcutaneous once a day, exenatide 10 micrograms (mcg) subcutaneous twice a day, empagliflozin 25 milligrams (mg) once a day (started four months prior to admission), and metformin 1000 mg twice a day.\n\nPertinent laboratory values upon presentation to the ED included the following: hemoglobin A1C 10.5% (4.4–5.6%), glucose 251 mg/deciliter (dL) (60–100 mg/dL), chloride 93 millimols per liter (mmol/L) (98–111 mmol/L), carbon dioxide 12 mmol/L (20–30 mmol/L), anion gap 29 (6–14), c-peptide 0.1 nanogram per milliliter (ng/mL) (0.9–6.9 ng/mL), ketone beta-hydroxybutyrate > 2.0 mmol/L (0.02–0.27 mmol/L), serum osmolality 322 milliosmoles per kilogram (mOsmol/kg) (280–295 mOsmol/kg), lactate 2.7 mmol/L (0.4–2.0 mmol/L) and a urine analysis with abnormal glucose of 500 mg/dL and ketones 80 mg/dL, but otherwise unremarkable. She was diagnosed with DKA and admitted to the intensive care unit on intravenous hydration and insulin drip per institution protocol.\n\nDKA resolved two days following admission and the patient was discharged. At discharge, no precipitating factor leading to her DKA had been identified during the hospitalization. There had been no evidence of infection or pancreatitis, and she was discharged on all home medications with an increase in her insulin glargine to 30 units once a day.\n\nShe was seen in her primary care clinic six days post-discharge. Additional laboratory values were drawn including glutamic acid decarboxylase (GAD) antibody, which was elevated > 250 units/mL (< 0.5 units/mL). Given that the empagliflozin had been initiated four months prior to her hospital admission and that she had been admitted with euDKA with a glucose level of only 251 mg/dL at presentation, at the primary care follow-up, it was determined that this was a case of SGLT2 inhibitor-induced DKA. She had been managed as a type 2 diabetic for four years, but her low c-peptide level and elevated GAD antibody drawn at this post-discharge follow-up appointment resulted in a change in diagnosis to type 1 diabetes from type 2. All non-insulin antihyperglycemic agents including the empagliflozin that precipitated the DKA were discontinued and she was placed on a basal plus bolus insulin regimen.\n\nCPC-EM Capsule\nWhat do we already know about this clinical entity?\n\nSodium glucose cotransporter-2 (SGLT2) inhibitors are commonly used for the management of type 2 diabetes. This drug class has a known, rare side effect of diabetic ketoacidosis (DKA).\n\nWhat makes this presentation of disease reportable?\n\nThe SGLT2 inhibitor-induced DKA led to the unmasking of type 1 diabetes in a patient previously diagnosed with type 2 diabetes.\n\nWhat is the major learning point?\n\nDKA is a rare risk of the SGLT2 inhibitor drug class, and there are certain factors that may predispose the patient to this adverse event. In this case, the underlying risk was type 1 diabetes.\n\nHow might this improve emergency medicine practice?\n\nImprove identification of potential drug-induced DKA and underlying risk factors that may predispose the patient to this adverse effect.\n\nDISCUSSION\nThe ADA diagnostic criteria for DKA include hyperglycemia (blood glucose > 250 mg/dL), metabolic acidosis (arterial pH < 7.3 and serum bicarbonate < 18 mEq/L) and ketosis.9 Euglycemic DKA was originally described in the literature as severe ketoacidosis with a blood glucose level less than 300 mg/dL, but currently a more common definition is a blood glucose < 200 mg/dL.10,11 SGLT2 inhibitors have been hypothesized to lead to this condition as a result of glucosuria leading to a rapid reduction in plasma glucose levels.12,13 This reduction in plasma glucose leads to decreased insulin release from the beta cells, which then leads to stimulation of alpha cells and the increase in plasma glucagon concentrations further stimulating hepatic ketogenesis.12,13 These mechanisms of ketogenesis in combination with continued glucosuria lowering plasma glucose levels results in the presence of ketone bodies in the setting of normal glucose levels.13 A total of 73 cases of SGLT2 inhibitor-related ketoacidosis were identified during a review of the FDA Adverse Event Reporting System database from March 2013 to May 2015. All patients required hospitalization or treatment in the ED, and many cases were complicated by a delayed diagnosis due to the low blood glucose levels on presentation.6\n\nThe SGLT2 inhibitors have also been studied for use in patients with type 1 diabetes.14–16 Their insulin-independent mechanisms offer an attractive and likely effective option as an add-on to insulin therapy. It has been hypothesized that patients with autoimmune type diabetes (latent autoimmune diabetes of adulthood, or type 1 diabetes) would be at greater risk of DKA in the setting of SGLT2 inhibitor therapy given their lack of endogenous insulin production leading to inability to overcome the SGLT2 inhibitor-induced increase in glucagon, thus leading to the setting of unsuppressed hepatic ketogenesis.17 A recent systematic review aimed to identify precipitating factors of SGLT2 inhibitor-induced DKA.13 In this review, two-thirds of all cases involved patients with T2DM; however, nine out of 25 of those individuals were later diagnosed with latent autoimmune diabetes of adulthood following resolution of their DKA.13 Additionally, an analysis of several cases of DKA in patients who were taking canagliflozin for type 2 diabetes in the CANVAS trial series found that six out of the 12 patients were diagnosed with autoimmune diabetes or tested positive for GAD65 antibodies after the development of DKA.17\n\nOur case also describes a patient with presumed type 2 diabetes who, following her resolution of SGLT2 inhibitor-induced DKA, was further evaluated with antibody testing, and was revealed to have type 1 diabetes based on the presence of GAD antibodies. She had been treated as a type 2 diabetes patient for four years prior to her episode of DKA. Additionally, the causative agent, or precipitating factor, had not been identified at initial presentation to the hospital, or during the hospitalization. Although medications are not often identified as the precipitating factor for DKA, the SGLT2 inhibitors are being implicated with increased frequency in cases of DKA. In this case, the patient was discharged on the empagliflozin placing her at risk for a repeat event. The changes in diagnosis from type 2 to type 1 diabetes occurred after discharge at the primary care office.\n\nCONCLUSION\nWe report a case of DKA secondary to the use of empagliflozin that resulted in a change in diagnosis from type 2 diabetes to type 1 diabetes. This case also highlights a situation in which the diagnosis of SGLT2 inhibitor-induced DKA was not made while the patient was in the hospital and she was discharged on the offending agent, thus placing her at risk for a repeat event. Such an event indicates the need for emergency and critical care providers to remain vigilant in identifying drug-induced causes of DKA.\n\nSection Editor: John Ashurst, DO\n\nFull text available through open access at http://escholarship.org/uc/uciem_cpcem\n\nDocumented patient informed consent and/or Institutional Review Board approval has been obtained and filed for publication of this case report.\n\nConflicts of Interest: By the CPC-EM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias. The authors disclosed none.\n==== Refs\nREFERENCES\n1 American Diabetes Association 8. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes—2018 Diabetes Care 2018 41 Supplement 1 S73 S85 29222379 \n2 Vallon V Thomson SC Targeting renal glucose reabsorption to treat hyperglycaemia: the pleiotropic effects of SGLT2 inhibition Diabetologia 2017 60 2 215 25 27878313 \n3 Zinman B Wanner C Lachin JM Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes N Engl J Med 2015 373 22 2117 28 26378978 \n4 Neal B Perkovic V Mahaffey KW Canagliflozin and cardiovascular and renal events in type 2 diabetes N Engl J Med 2017 377 7 644 57 28605608 \n5 Hankins M Tsai K Kim J Early drug use of dapagliflozin prescribed by general practitioners and diabetologists in Germany Diabetes Res Clin Pract 2017 125 29 38 28131071 \n6 Research C for DE Drug Safety and Availability - FDA Drug Safety Communication: FDA revises labels of SGLT2 inhibitors for diabetes to include warnings about too much acid in the blood and serious urinary tract infections Available at: https://www.fda.gov/Drugs/DrugSafety/ucm475463.htm Accessed September 28, 2018 \n7 Peters AL Henry RR Thakkar P Diabetic ketoacidosis with canagliflozin, a sodium–glucose cotransporter 2 inhibitor, in patients with type 1 diabetes Diabetes Care 2016 39 4 532 8 26989182 \n8 Handelsman Y Henry RR Bloomgarden ZT American Association of Clinical Endocrinologists and American College of Endocrinology Position Statement on the Association of SGLT-2 Inhibitors and Diabetic Ketoacidosis Endocr Pract 2016 22 6 753 62 27082665 \n9 Kitabchi AE Umpierrez GE Miles JM Hyperglycemic crises in adult patients with diabetes Diabetes Care 2009 32 7 1335 43 19564476 \n10 Munro JF Campbell IW McCuish AC Euglycaemic diabetic ketoacidosis Br Med J 1973 2 5866 578 80 4197425 \n11 Modi A Agrawal A Morgan F Euglycemic diabetic ketoacidosis: a review Curr Diabetes Rev 2017 13 3 315 21 27097605 \n12 Taylor SI Blau JE Rother KI SGLT2 inhibitors may predispose to ketoacidosis J Clin Endocrinol Metab 2015 100 8 2849 52 26086329 \n13 Burke KR Schumacher CA Harpe SE SGLT2 inhibitors: a systematic review of diabetic ketoacidosis and related risk factors in the primary literature Pharmacotherapy 2017 37 2 187 94 27931088 \n14 Henry RR Rosenstock J Edelman S Exploring the potential of the SGLT2 inhibitor dapagliflozin in type 1 diabetes: a randomized, double-blind, placebo-controlled pilot study Diabetes Care 2015 38 3 412 9 25271207 \n15 Bell DSH Case reports that illustrate the efficacy of SGLT2 inhibitors in the type 1 diabetic patient Case Rep Endocrinol 2015 2015 1 4 \n16 Sands AT Zambrowicz BP Rosenstock J Sotagliflozin, a dual SGLT1 and SGLT2 inhibitor, as adjunct therapy to insulin in type 1 diabetes Diabetes Care 2015 38 7 1181 8 26049551 \n17 Erondu N Desai M Ways K Diabetic ketoacidosis and related events in the canagliflozin type 2 diabetes clinical program Diabetes Care 2015 38 9 1680 6 26203064\n\n",
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"title": "Empagliflozin-induced Diabetic Ketoacidosis Unmasking a Type 1 Diabetes Diagnosis.",
"title_normalized": "empagliflozin induced diabetic ketoacidosis unmasking a type 1 diabetes diagnosis"
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"abstract": "Although the risk of antipsychotic-induced venous thromboembolism (VTE) has been definitively established, guidelines recommending prophylactic anticoagulation do not yet exist. Several algorithms have been proposed that suggest possible prophylaxis with an anticoagulant medication on the basis of pre-existing VTE risk factors. We present a case of antipsychotic-induced VTE despite the patient's low-risk status so that practitioners may better understand which factors may or may not constitute a major risk in this population when making a determination about prophylactic anticoagulation.\n\n\n\nWe present a patient case of a 56-year-old man with schizoaffective disorder who was treated with clozapine at an inpatient psychiatric unit. Although he would be classified as low risk for VTE on the basis of the proposed algorithms, he experienced a pulmonary embolism by day 17 of treatment and required transfer to a medical unit. This patient displayed sensitivity to other adverse effects associated with clozapine during his treatment course, including tachycardia, sialorrhea, enuresis, and bowel obstruction.\n\n\n\nMany of the known risk factors for antipsychotic-induced VTE were not present in this patient, including immobility, hyperprolactinemia, and coagulation abnormalities. The recent initiation of clozapine and obesity seem to be the only identified risk factors, although malignancy and abnormal antiphospholipid antibody levels were not able to be ruled out. It is difficult to determine if this patient experienced a VTE owing to a relatively high degree of sensitivity to clozapine, as evidenced by the myriad of other adverse effects that he experienced. This case highlights the need to determine true antipsychotic-induced VTE risk factors, including evaluation of comorbid adverse effects that occur in addition to the VTE. This information will help to guide future decision-making regarding the risk versus benefit of providing prophylactic anticoagulation for patients during initiation of antipsychotic treatment.",
"affiliations": null,
"authors": "Waters|Kristin|K|;Goodwin|Heather|H|;Morrow|Gina|G|",
"chemical_list": "D000925:Anticoagulants; D014150:Antipsychotic Agents; D003024:Clozapine",
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"doi": "10.1016/j.japh.2020.07.017",
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"issue": "61(1)",
"journal": "Journal of the American Pharmacists Association : JAPhA",
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"medline_ta": "J Am Pharm Assoc (2003)",
"mesh_terms": "D000925:Anticoagulants; D014150:Antipsychotic Agents; D003024:Clozapine; D006801:Humans; D008297:Male; D008875:Middle Aged; D011655:Pulmonary Embolism; D012307:Risk Factors; D054556:Venous Thromboembolism",
"nlm_unique_id": "101176252",
"other_id": null,
"pages": "e53-e56",
"pmc": null,
"pmid": "32792294",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Clozapine-induced pulmonary embolism in a patient with minimal pre-existing risk factors.",
"title_normalized": "clozapine induced pulmonary embolism in a patient with minimal pre existing risk factors"
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"activesubstancename": "CLOZAPINE"
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"abstract": "We describe a case of a young female with lupus that complained about suprapubic pain, dysuria, fever and vomits, symptoms first interpreted as pyelonephritis, despite negative cultures and imaging studies showing hydroureteronephrosis with inflammatory changes. When she developed malar rash, anasarca and nephrotic syndrome, the diagnosis of lupus cystitis with stage IV nephropathy was made, and she started immunosuppressive induction treatment with three pulses of corticosteroids followed by oral prednisolone (60 mg/d) and mycophenolate (1.5 g/d). One month later she was admitted again with blood exams compatible with thrombotic microangiopathy, requiring aggressive immunosuppression and plasma exchange. After overcoming multiple complications, the patient gradually improved, and was discharged with close surveillance. This case poses the question: if the urogenital involvement had been recognized and treated in time, would it prevent the onset of lupus nephritis and other complications?",
"affiliations": null,
"authors": "Abelha-Aleixo|J|J|;Moura|M|M|;Bernardo|A|A|;Almeida|J|J|;Brito|I|I|",
"chemical_list": null,
"country": "Portugal",
"delete": false,
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"issue": "40(3)",
"journal": "Acta reumatologica portuguesa",
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"medline_ta": "Acta Reumatol Port",
"mesh_terms": "D000328:Adult; D003556:Cystitis; D057210:Delayed Diagnosis; D005260:Female; D006801:Humans; D008180:Lupus Erythematosus, Systemic",
"nlm_unique_id": "0431702",
"other_id": null,
"pages": "294-8",
"pmc": null,
"pmid": "25351785",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Lupus cystitis and repercussions of delayed diagnosis.",
"title_normalized": "lupus cystitis and repercussions of delayed diagnosis"
} | [
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"activesubstancename": "METHYLPREDNISOLONE"
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"abstract": "OBJECTIVE\nThe aim of this study was to add to the body of evidence on statin-induced gynecomastia based on data retrieved from the Italian spontaneous adverse drug reaction (ADR) reporting database.\n\n\nMETHODS\nSpontaneous ADR reports collected in the Italian database up to 31 December 2010 were assessed on a case-by-case basis in a search for evidence of a possible causal association between statins and gynecomastia. Cases of gynecomastia or possible gynecomastia, according to the Medical Dictionary of Regulatory Activities (MedDRA) classification, associated with statin use were retrieved from the database. The findings were compared with the available literature in PubMed.\n\n\nRESULTS\nThe database contained 90,448 ADR reports on 21 December 2010. At least one statin was listed as the suspected drug in 2,862 reports, of which 1,334 concerned a male patient. Among these reports, we identified eight cases with the preferred term “gynecomastia” with a statin as suspected drug: four reports of rosuvastatin and four of atorvastatin. One additional report of an unspecified “breast disorder” in a male patient attributed to fluvastatin was identified and included as a possible case. Four case-reports of statin-induced gynecomastia published between 2006 and 2010 were retrieved from PubMed.\n\n\nCONCLUSIONS\nOur findings suggest an association between gynecomastia and statins as a drug class, and the occurrence of this ADR would appear to be more likely with active substances that show an higher potency in inhibiting HMG-CoA reductase enzyme. To date, the safety information provided on the labels of different statin-containing medicines is not standardized. Harmonization of this information would be helpful for both healthcare practitioners and patients.",
"affiliations": "Department of Pharmacology, University of Bologna, Via Irnerio 48, Bologna, Italy.",
"authors": "Roberto|Giuseppe|G|;Biagi|Chiara|C|;Montanaro|Nicola|N|;Koci|Ariola|A|;Moretti|Ugo|U|;Motola|Domenico|D|",
"chemical_list": "D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00228-012-1218-5",
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"issn_linking": "0031-6970",
"issue": "68(6)",
"journal": "European journal of clinical pharmacology",
"keywords": null,
"medline_ta": "Eur J Clin Pharmacol",
"mesh_terms": "D016907:Adverse Drug Reaction Reporting Systems; D000368:Aged; D000369:Aged, 80 and over; D016208:Databases, Factual; D005260:Female; D006177:Gynecomastia; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007558:Italy; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "1256165",
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"references": "20393092;17881754;12650632;10082069;20346003;12270376;21477170;18363539;19408804;16863492;10325934",
"title": "Statin-associated gynecomastia: evidence coming from the Italian spontaneous ADR reporting database and literature.",
"title_normalized": "statin associated gynecomastia evidence coming from the italian spontaneous adr reporting database and literature"
} | [
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"companynumb": "IT-ALKEM LABORATORIES LIMITED-IT-ALKEM-2018-07300",
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"activesubstance": {
"activesubstancename": "ASPIRIN"
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{
"abstract": "Methotrexate has been used widely in dermatology, oncology and rheumatology fields. However, methotrexate-induced mucocutaneous lesions may occur in rare cases. In this case presentation, we report two cases of accidental poisoning with methotrexate. They had accidentally used methotrexate instead of digoxin. This case report emphasizes that early diagnosis and appropriate management is critical in order to improve outcome.",
"affiliations": "Research Center of Addiction and Behavioral Sciences, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.;Department of Psychiatry, Shahid Sadoughi University of Medical Sciences, Research Center of Addiction and Behavioral Sciences, Yazd, Iran.;Fellowship of toxicity, Assistant professor of Islamic Azad university of Yazd, Yazd, Iran.;Student Research Committee, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.;School of Medicine. Shahid Sadoughi University of Medical sciences, Yazd, Iran.",
"authors": "Bidaki|Reza|R|;Kian|Mojgan|M|;Owliaey|Hamid|H|;Babaei Zarch|Mojtaba|M|;Feysal|Masoud|M|",
"chemical_list": null,
"country": "Iran",
"delete": false,
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"fulltext": "\n==== Front\nEmerg (Tehran)Emerg (Tehran)EmergEmergency2345-45632345-4571Shahid Beheshti University of Medical Sciences Tehran, Iran 28894782emerg-5-e67Case ReportAccidental Chronic Poisoning with Methotrexate; Report of Two Cases Bidaki Reza 12Kian Mojgan 3Owliaey Hamid 4Babaei Zarch Mojtaba 5Feysal Masoud 6\n1 Research Center of Addiction and Behavioral Sciences, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.\n2 Diabetes Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.\n3 Department of Psychiatry, Shahid Sadoughi University of Medical Sciences, Research Center of Addiction and Behavioral Sciences, Yazd, Iran.\n4 Fellowship of toxicity, Assistant professor of Islamic Azad university of Yazd, Yazd, Iran.\n5 Student Research Committee, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.\n6 School of Medicine. Shahid Sadoughi University of Medical sciences, Yazd, Iran.* Corresponding Author: Reza Bidaki; Research Center of Addiction and Behavioral Sciences, Shahid Sadoughi University of Medical Sciences, Yazd, Iran; Tel: +983532633555; Email: reza_bidaki@yahoo.com2017 21 5 2017 5 1 e6712 2016 2 2017 © Copyright (2017) Shahid Beheshti University ofMedical SciencesThis is an Open Access article distributed under the terms of the Creative Commons Attribution License, (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Methotrexate has been used widely in dermatology, oncology and rheumatology fields. However, methotrexate-induced mucocutaneous lesions may occur in rare cases. In this case presentation, we report two cases of accidental poisoning with methotrexate. They had accidentally used methotrexate instead of digoxin. This case report emphasizes that early diagnosis and appropriate management is critical in order to improve outcome. \n\nKey Words\nMethotrexateskin ulcertoxicitypoisoningcase reportsemergency treatment\n==== Body\nIntroduction\nMethotrexate (MTX) is a systemic immunosuppressive agent that was introduced in the 1950s (1, 2). It is a folate antimetabolite that binds to an enzyme named dihydrofolate reductase, which ultimately leads to inhibition of DNA synthesis (3, 4). MTX is a drug used in treatment of various malignancies, early ectopic pregnancy or chronic inflammatory diseases such as some types of carcinoma, rheumatoid arthritis, psoriasis and etc. (5, 6). Accidental poisoning with MTX is not a common condition and was rarely reported in the literature (7). Most of our knowledge regarding MTX poisoning were derived from serious adverse reactions at therapeutic doses or reports about acute oral overdose (8). Unlike previously reported cases, here we report two cases of accidental chronic poisoning with MTX. \n\nCase report\n\nCase 1\n\n\nThe patient was an 88-year-old woman. She was admitted to the emergency department with weakness as main chief complaint. She had dyspnea, gastrointestinal symptoms such as nausea and vomiting, abdominal pain, dyspepsia, pruritus, epistaxis, and mouth sores from 3 days ago. The symptoms were progressive. \n\nIn evaluation of consumed drugs it was determined that she has been continuously taking MTX for about 5 months. In search for the cause of taking MTX and checking the prescriptions, it was revealed that the drug store had mistakenly given the patient MTX instead of digoxin.\n\nShe had used MTX 1.25 mg for 5 consecutive months and 2.5 mg five days a week in the last month. On admission, her vital signs were as follows: Blood Pressure = 90/60 mmHg, Pulse Rate = 82/minutes, Respiratory Rate = 12/minutes and Temperature = 38.2°C. \n\nOn physical examination, generalized erythema involving back and leg, face edema, mucositis, stomatitis and difficulty in gait were apparent. Examination of other organs did not reveal any positive findings. Figure 1 shows her mucocutaneous lesions at presentation.\n\nLaboratory test results on admission were as follows: Hemoglobin=9.1 g/dl, WBC=3200/mm3, Platelet counts = 50000/mm3, BUN = 81 mg/dl, creatinine=1.8 mg/dl, AST=18 IU/L, ALT=17 IU/L, PT=14s, PTT=36s, INR=1.14, Bilirubin total=1.2 mg/dl and Bilirubin Direct=0.3 mg/dl. \n\nShe was admitted to intensive care unit (ICU). Platelets, folinic acid (as MTX antidote), antibiotics and granulocyte colony stimulating factor (G-CSF) were administered and dermatology cares were considered for her. Finally, she died due to pulmonary edema resulting from her underlying cardiac disease 4 days after admission.\n\n\nCase 2\n\n\nThe patient was a 68-year-old woman, who was referred to the emergency department because of oral ulcer, limb paresthesia and difficulty initiating movement from one week ago. Muscular force was reduced gradually. The patient didn't have any history of trauma. The patient had accidentally used one MTX tablet each day, instead of Digoxin, since one month ago (due to a mistake in the drug store, she was given MTX instead of digoxin).\n\nIn the past medical history, the patient had a history of diabetes mellitus, hypertension, heart failure and hyperlipidemia. Other drugs used by the patient included losartan, aspirin, carvedilol, L-carnitine and triamterene-H. \n\nOn admission, she was alert and her vital signs were as follows: Blood Pressure = 110/70 mmHg, Pulse Rate = 74/minute, Respiratory Rate =16/minute and Temperature = 36.8°C. \n\nOn physical examination, level of consciousness was normal. There was no evidence of respiratory distress. Neurological examinations revealed normal cerebellar tests. Upper limb muscular force was normal and lower limb force was 4/5 in proximal and 3/5 in distal. Hemorrhagic ulcers were seen in palate and lips. Figure 2 shows her mucocutaneous lesions at presentation.\n\nLaboratory tests were as follows: Hemoglobin=11.2 g/dl, WBC=10.9/mm3, Platelet counts = 20000/mm3, Natrium = 140 mEq/l, Potassium = 3.5 mEq/l, urea=36 mg/dl, creatinine=0.85 mg/dl, PT=13 s, PTT=27 s, INR=1.3, ALT=43 IU/L, AST=34 IU/L, ALP=200 IU/L.\n\nMagnetic resonance imaging (MRI) and also electromyogram/nerve conduction velocity (EMG/NCV) tests were normal. Echocardiography revealed ejection fraction (EF) of 20%. With diagnosis of MTX poisoning, the patient underwent treatment with folinic acid for 10 days. The patient was discharged with good general condition and improvement of weakness and lower limb paresthesia 5 days later. \n\nDiscussion\nMTX toxicity is characterized by nausea, vomiting, diarrhea, myelosuppression, pancytopenia, liver dysfunction, acute renal failure (ARF), pulmonary symptoms, mucositis, stomatitis, ulceration/erosion of the gastrointestinal system and cutaneous ulcerations (9-11). Although methotrexate toxicity can cause kidney injury and change the renal function, sometimes renal dysfunction like an acute renal failure can also induce methotrexate toxicity (4, 12-14). However, cutaneous ulceration may be considered as an early clinical sign of imminent systemic toxicity and patients may only present with isolated cutaneous lesions (15-17).\n\nFigure 1 Mucocutaneous lesions in case number 1\n\nFigure 2 Mucocutaneous lesions in case number 2\n\nThe side effects of MTX may occur through dose dependent or idiosyncratic mechanisms. Interestingly, dose dependent mechanism occurs in bone marrow cells, epidermal cells and epithelial gastrointestinal system. Some factors such as drug interactions and incorrect administration of drugs are triggers for appearance of side effects (9). Simultaneous use of MTX with drugs interacting with it such as proton-pump inhibitors, trimethoprim/sulfamethoxazole, doxycycline, non-steroidal anti-inflammatory drugs (NSAIDs), and salicylates that decrease protein binding or reduce renal clearance, as well as excessive alcohol consumption could play an important role in this regard (18). \n\nElevation of serum aminotransferase levels, elevation in serum uric acid, leukopenia, thrombocytopenia, and anemia may be noticed in laboratory tests of MTX poisoned patients (19). Measurement of methotrexate concentration via radioimmunoassay in plasma, serum, or urine samples could lead to definite diagnosis (19). Diagnostic biopsy from ulceration sites is rarely required, but helpful (2).\n\nWithdrawal of MTX and administration of intravenous folinic acid (leucovorin) as early as possible after exposure is the most effective initial treatment that should not be delayed for any reason (2, 19).\n\nTreat persistent nausea and vomiting with several antiemetic agents such as metoclopramide, ondansetron, promethazine, haloperidol, benzodiazepines, or even corticosteroids. Intravenous fluids and urine alkalization via bicarbonate infusion are highly advised. Administration of colony stimulating factors is necessary if severe neutropenia exists. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia, or hemorrhage. The patient should be closely monitored for signs of bleeding, clinical evidence of infection, abnormalities in serum electrolytes, renal failure and hepatic function. A chest radiograph should be obtained in patients with respiratory symptoms and skin-directed therapy must to be applied (19).\n\nIn patients with impaired renal function who develop toxicity and in cases of acute overdose, glucarpidase has been used to rapidly catabolize MTX to an inactive metabolite, aiding its clearance (2, 19, 20). \n\nAlthough MTX toxicity can be a fatal poisoning, proper management, early diagnosis and follow-up of the patients in emergency department as well as in ICU can resolve the complications and save the patients’ lives. It seems that computerized prescription system is a promising method to reduce human errors.\n\nAcknowledgements\nThe authors thank the families of patients and nurses of internal medicine department and ICU of Shahid Beheshti Hospital, Taft, Iran for their cooperation. \n\nAuthors contribution\nAll the authors have contributed to drafting/revising the manuscript, study concept, or design, as well as data collection and interpretation.\n\nConflict of interest\nAll authors declare that there is no conflict of interest in this study.\n\nFunding\nAll authors declare that this study was accomplished without any funding or support.\n==== Refs\nReferences\n1 Shen S O’Brien T Yap LM Prince HM McCormack CJ The use of methotrexate in dermatology: a review Australasian Journal of Dermatology 2012 53 1 1 18 \n2 Weidmann A Foulkes AC Kirkham N Reynolds N Methotrexate toxicity during treatment of chronic plaque psoriasis: a case report and review of the literature Dermatology and therapy 2014 4 2 145 56 24942326 \n3 Tripathi R Chugh PK Verma V Mala YM Fatal methotrexate toxicity: could it have been avoided? BMJ case reports 2013 2013 \n4 Cudmore J Seftel M Sisler J Zarychanski R Methotrexate and trimethoprim-sulfamethoxazole: toxicity from this combination continues to occur Canadian family physician Medecin de famille canadien 2014 60 1 53 6 24452563 \n5 Czarnecka-Operacz M Sadowska-Przytocka A The possibilities and principles of methotrexate treatment of psoriasis - the updated knowledge Postepy dermatologii i alergologii 2014 31 6 392 400 25610355 \n6 Drug Information for the Health Care Professional. 24 ed 2004 Thomson Micromedex 1911 \n7 Souza C Suarez O Silva T Gorenstein A Quintella L Avelleira J Ulcerations due to methotrexate toxicity in a psoriasis patient Anais brasileiros de dermatologia 2015 91 3 375 7 \n8 Chan BS Dawson AH Buckley NA What can clinicians learn from therapeutic studies about the treatment of acute oral methotrexate poisoning? Clinical Toxicology 2017 55 2 88 96 28084171 \n9 Tan KW Tay YK A case of acute methotrexate toxicity Annals of the Academy of Medicine, Singapore 2011 40 2 97 9 \n10 Jakubovic BD Donovan A Webster PM Shear NH Methotrexate-induced pulmonary toxicity Canadian respiratory journal : journal of the Canadian Thoracic Society 2013 20 3 153 5 \n11 Shiver MB Hall LA Conner KB Brown GE Cheung WL Wirges ML Cutaneous erosions: a herald for impending pancytopenia in methotrexate toxicity Dermatology online journal 2014 20 7 \n12 Chatham WW Morgan SL Alarcon GS Renal failure: a risk factor for methotrexate toxicity Arthritis and rheumatism 2000 43 5 1185 6 10817575 \n13 Soon C Ilchyshyn A Methotrexate toxicity induced by acute renal failure Journal of the Royal Society of Medicine 2005 98 2 83 4 \n14 Strang A Pullar T Methotrexate toxicity induced by acute renal failure Journal of the Royal Society of Medicine 2004 97 11 536 7 15520148 \n15 Lawrence C Dahl M Two patterns of skin ulceration induced by methotrexate in patients with psoriasis Journal of the American Academy of Dermatology 1984 11 6 1059 65 6512051 \n16 Çaliskan E Tunca M Açikgöz G Arca E Akar A Accidental high-dose methotrexate toxicity due to an electronic prescribing error Indian journal of dermatology, venereology and leprology 2013 80 3 268 9 \n17 Koçak A Koçak O Aslan F Tektaş M Methotrexate toxicity presenting as cutaneous ulcerations on psoriatic plaques Cutaneous and ocular toxicology 2013 32 4 333 5 23537374 \n18 Bourré-Tessier J Haraoui B Methotrexate drug interactions in the treatment of rheumatoid arthritis: a systematic review The Journal of rheumatology 2010 37 7 1416 21 20436072 \n19 HSDB: METHOTREXATE U.S. National Library of Medicine: TOXNET Available from:https://toxnet.nlm.nih.gov/cgi-bin/sis/search2/r?dbs+hsdb:@term+@DOCNO+3123. \n20 Tuffaha H Al Omar S Glucarpidase for the treatment of life-threatening methotrexate overdose Drugs of today (Barcelona, Spain: 1998) 2012 48 11 705 11\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2345-4563",
"issue": "5(1)",
"journal": "Emergency (Tehran, Iran)",
"keywords": "Methotrexate; case reports; emergency treatment; poisoning; skin ulcer; toxicity",
"medline_ta": "Emerg (Tehran)",
"mesh_terms": null,
"nlm_unique_id": "101648866",
"other_id": null,
"pages": "e67",
"pmc": null,
"pmid": "28894782",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "28084171;6512051;10817575;23537374;23170306;15684366;20436072;21468464;15520148;25610355;22309324;23761602;23762881;27438211;24452563;25046458;24942326;24823414",
"title": "Accidental Chronic Poisoning with Methotrexate; Report of Two Cases.",
"title_normalized": "accidental chronic poisoning with methotrexate report of two cases"
} | [
{
"companynumb": "IR-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-245466",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"dr... |
{
"abstract": "Vancomycin is a glycopeptide antibiotic used in the prophylaxis and treatment of infections caused by Gram-positive resistant bacteria. In recent years, several cases of vancomycin-associated immune thrombocytopenia have been presented as case reports, but the real incidence of this side effect is still unknown. In this report, we would like to present a case during which we confronted with a great dilemma: urgent removal of whole defibrillator system due to highly suspected infective endocarditis or leaving the defibrillator in place and simply switching vancomycin to another antibiotic agent and wait.",
"affiliations": "Cardiology Department, Ankara University, Ankara, Turkey, Basarcandemir@yahoo.com.",
"authors": "Candemir|Basar|B|;Aribuca|Aynur|A|;Koca|Cigdem|C|;Ozcan|Ozgur Ulas|OU|;Gerede|Menekse|M|;Kaya|Cansin T|CT|",
"chemical_list": "D000900:Anti-Bacterial Agents; D014640:Vancomycin",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s10840-012-9738-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1383-875X",
"issue": "38(2)",
"journal": "Journal of interventional cardiac electrophysiology : an international journal of arrhythmias and pacing",
"keywords": null,
"medline_ta": "J Interv Card Electrophysiol",
"mesh_terms": "D000900:Anti-Bacterial Agents; D001327:Autoimmune Diseases; D020878:Device Removal; D003937:Diagnosis, Differential; D004696:Endocarditis; D005260:Female; D006801:Humans; D008875:Middle Aged; D010138:Pacemaker, Artificial; D016459:Prosthesis-Related Infections; D013921:Thrombocytopenia; D016896:Treatment Outcome; D014640:Vancomycin",
"nlm_unique_id": "9708966",
"other_id": null,
"pages": "143-5",
"pmc": null,
"pmid": "23080329",
"pubdate": "2013-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "17253882;9269071;9867731;17687133;17329697;19713420;10072125;10509053;2025149",
"title": "An unusual case of vancomycin-related systemic reaction accompanied with severe thrombocytopenia mimicking pacemaker-related infective endocarditis: a case report and review of literature.",
"title_normalized": "an unusual case of vancomycin related systemic reaction accompanied with severe thrombocytopenia mimicking pacemaker related infective endocarditis a case report and review of literature"
} | [
{
"companynumb": "TR-WATSON-2014-14863",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional": null,
"... |
{
"abstract": "We describe the case of a 51-year-old man with recently diagnosed ulcerative colitis who developed fever and elevated liver enzymes as well as cholestasis a few weeks after starting treatment with mesalazine. As no obvious cause was found and fever persisted, liver biopsy was performed and revealed granulomatous hepatitis. The patient recovered completely after cessation of mesalazine, so that a drug-induced granulomatous hepatitis after exclusion of other differential diagnoses in an extensive work up was assumed. The present case demonstrates that even though drug-induced liver injury due to mesalazine is rare, it should be considered in unclear cases and lead to prompt discontinuation of mesalazine.",
"affiliations": "Department of Internal Medicine, Spital Zollikerberg, Zollikerberg, Switzerland.;Department of Endocrinology, University Hospital Zurich, Zurich, Switzerland.;Department of Pathology, University Hospital Zurich, Zurich, Switzerland.;Department of Internal Medicine, Spital Zollikerberg, Zollikerberg, Switzerland.",
"authors": "Stelzer|Teresa|T|;Kohler|Sibylle|S|;Marques Maggio|Ewerton|E|;Heuss|Ludwig Theodor|LT|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D019804:Mesalamine",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2015()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D001706:Biopsy; D056486:Chemical and Drug Induced Liver Injury; D002779:Cholestasis; D003093:Colitis, Ulcerative; D005334:Fever; D006505:Hepatitis; D006801:Humans; D008099:Liver; D008297:Male; D019804:Mesalamine; D008875:Middle Aged",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "26113581",
"pubdate": "2015-06-25",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "6113258;21586591;10406274;22474447;11570976;9059966;19533803;22541705;28568;12235076;18473013;10323894;1360436;18312287;21055685",
"title": "An unusual cause of febrile hepatitis.",
"title_normalized": "an unusual cause of febrile hepatitis"
} | [
{
"companynumb": "CH-MEDA-2015090021",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
"d... |
{
"abstract": "OBJECTIVE\nTo assess the efficacy of vinorelbine (NVB)-based regimens in patients with metastatic triple negative breast cancer (mTNBC) pretreated with anthracyclines and taxanes.\n\n\nMETHODS\nClinical data of 48 patients diagnosed and treated for mTNBC between 2004 and 2012 at the Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) were retrospectively analyzed. All patients were pretreated with anthracyclines and at least one taxane in neo-adjuvant, adjuvant or chemotherapy for mTNBC and patients should be having at least one measurable metastatic lesion. Totally, 48 patients were included in this study, of which 21 cases received first-line chemotherapy and 27 cases received second-line chemotherapy. Based on the regimen they received, 22 patients were treated with NVB plus platinum (NP), and 26 patients with NVB plus capecitabine (NX).\n\n\nRESULTS\nAfter 70 months follow-up, in the total group of patients, the objective response rate was 20.8%, clinical benefit rate was 43.8%, median progression free survival (PFS) was 4.4 months and median overall survival (OS) was 15.5 months. In addition, the ORR was significantly better in the NP arm versus NX arm (33.8% vs.7.7%, P=0.029) as well as PFS was statistically improved in the NP arm than NX arm (5.3 m vs. 3.0 m, P=0.023). Similar trend was observed in the OS, although the difference was not statistically significant (27.7 m vs. 14.8 m, P=0.077). In all, the most frequently reported adverse events were G1/2 gastrointestinal toxicity (68.8%) and neutropenia (62.5%) . No significant difference was observed between the NP arm and NX arm (P>0.05). The percentage of patients who delayed chemotherapy administration in the NP arm and NX arm was 9.1% (n=2), and 3.8% (n=1), respectively.\n\n\nCONCLUSIONS\nNVB-based combination chemotherapy demonstrates moderate efficacy in mTNBC patients pretreated with anthracyclines and one taxane with manageable toxicity. NP regimen shows potential superiority over NX regimen, and should be further verified in randomized phase III clinical trial in larger cohort.",
"affiliations": "Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China.;Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China.;Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China.;Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China.;Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China.;Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China.;Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China.;Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China.;Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China.;Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China; Email: xubinghe@medmail.com.cn.",
"authors": "Du|Feng|F|;Yuan|Peng|P|;Luo|Yang|Y|;Wang|Jiayu|J|;Ma|Fei|F|;Cai|Ruigang|R|;Fan|Ying|Y|;Li|Qing|Q|;Zhang|Pin|P|;Xu|Binghe|B|",
"chemical_list": "D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D001952:Bridged-Ring Compounds; D043823:Taxoids; C080625:taxane; D014747:Vinblastine; D000069287:Capecitabine; D002945:Cisplatin; D000077235:Vinorelbine",
"country": "China",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0253-3766",
"issue": "37(10)",
"journal": "Zhonghua zhong liu za zhi [Chinese journal of oncology]",
"keywords": null,
"medline_ta": "Zhonghua Zhong Liu Za Zhi",
"mesh_terms": "D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D000971:Antineoplastic Combined Chemotherapy Protocols; D001952:Bridged-Ring Compounds; D000069287:Capecitabine; D002945:Cisplatin; D018572:Disease-Free Survival; D006801:Humans; D009503:Neutropenia; D012189:Retrospective Studies; D043823:Taxoids; D064726:Triple Negative Breast Neoplasms; D014747:Vinblastine; D000077235:Vinorelbine",
"nlm_unique_id": "7910681",
"other_id": null,
"pages": "788-92",
"pmc": null,
"pmid": "26813602",
"pubdate": "2015-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Efficacy and toxicity of vinorelbine (NVB)-based regimens in patients with metastatic triple negative breast cancer (mTNBC) pretreated with anthracyclines and taxanes.",
"title_normalized": "efficacy and toxicity of vinorelbine nvb based regimens in patients with metastatic triple negative breast cancer mtnbc pretreated with anthracyclines and taxanes"
} | [
{
"companynumb": "CN-MYLANLABS-2016M1045626",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VINORELBINE\\VINORELBINE TARTRATE"
},
"drugad... |
{
"abstract": "Dermatological toxicity is one of the most commonly reported immune-related adverse events in patients receiving checkpoint inhibitor immunotherapy. We report the gradual development of a widespread bullous pemphigoid-like reaction in a metastatic melanoma patient 8 months after commencing treatment with the programmed-death-1 (PD-1) inhibitor pembrolizumab, requiring prolonged corticosteroid therapy. This case highlights the potential for insidious and late development of severe cutaneous toxicity following PD-1 inhibitor therapy and suggests that even prolonged immunosuppression may not necessarily compromise the efficacy of PD-1 inhibition in advanced melanoma.",
"affiliations": "Medical Oncology Unit, Austin Health, Melbourne, Vic., Australia.;Dermatology Unit, Austin Health, Melbourne, Victoria, Australia.;Dermatology Unit, Austin Health, Melbourne, Victoria, Australia.;Medical Oncology Unit, Austin Health, Melbourne, Vic., Australia.",
"authors": "Parakh|Sagun|S|;Nguyen|Rebecca|R|;Opie|Jacinta M|JM|;Andrews|Miles C|MC|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; C582435:pembrolizumab",
"country": "Australia",
"delete": false,
"doi": "10.1111/ajd.12488",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0004-8380",
"issue": "58(3)",
"journal": "The Australasian journal of dermatology",
"keywords": "bullous pemphigoid; immunotherapy; melanoma; programmed death-1 inhibition",
"medline_ta": "Australas J Dermatol",
"mesh_terms": "D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D003875:Drug Eruptions; D006801:Humans; D008297:Male; D008545:Melanoma; D010391:Pemphigoid, Bullous; D012878:Skin Neoplasms; D013997:Time Factors",
"nlm_unique_id": "0135232",
"other_id": null,
"pages": "e109-e112",
"pmc": null,
"pmid": "27170423",
"pubdate": "2017-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Late presentation of generalised bullous pemphigoid-like reaction in a patient treated with pembrolizumab for metastatic melanoma.",
"title_normalized": "late presentation of generalised bullous pemphigoid like reaction in a patient treated with pembrolizumab for metastatic melanoma"
} | [
{
"companynumb": "PHHY2017AU134732",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DABRAFENIB"
},
"drugadditional": null,
"drug... |
{
"abstract": "We report two cases of patients with chronic renal failure showing rectal bleeding due to digestive ulcers, associated with Kayexalate(®) alone. Kayexalate(®) crystals correspond to a typical histological picture and it is important to know how to identify them in order to discuss a possible pathogenicity.",
"affiliations": "Service d'anatomie et de cytologie pathologiques, hôpital de la Source, 14, avenue de l'Hôpital, 45067 Orléans, France. Electronic address: berengereponroy@live.fr.;Service d'anatomie et de cytologie pathologiques, hôpital de la Source, 14, avenue de l'Hôpital, 45067 Orléans, France.;Service de rhumatologie, hôpital de la Source, 14, avenue de l'Hôpital, 45067 Orléans, France.;Service d'anatomie et de cytologie pathologiques, hôpital de la Source, 14, avenue de l'Hôpital, 45067 Orléans, France.;Service d'anatomie et de cytologie pathologiques, hôpital de la Source, 14, avenue de l'Hôpital, 45067 Orléans, France.;Service d'anatomie et de cytologie pathologiques, hôpital de la Source, 14, avenue de l'Hôpital, 45067 Orléans, France.",
"authors": "Ponroy|Bérengère|B|;Nadal|Marion|M|;Nardoux|Julien|J|;Kerdraon|Rémy|R|;Lecointre|Claire|C|;Michenet|Patrick|P|",
"chemical_list": "D011137:Polystyrenes; C003321:polystyrene sulfonic acid",
"country": "France",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0242-6498",
"issue": "35(2)",
"journal": "Annales de pathologie",
"keywords": "Colon; Côlon; Kayexalate(®); Polystyrène sulfonate de sodium; Sodium polystyrene sulfonate; Ulcers; Ulcérations",
"medline_ta": "Ann Pathol",
"mesh_terms": "D000328:Adult; D003108:Colonic Diseases; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011137:Polystyrenes; D014456:Ulcer",
"nlm_unique_id": "8106337",
"other_id": null,
"pages": "164-7",
"pmc": null,
"pmid": "25796574",
"pubdate": "2015-04",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Colonic ulcers associated with taking Kayexalate(®) (sodium polystyrene sulfonate): about two cases.",
"title_normalized": "colonic ulcers associated with taking kayexalate sodium polystyrene sulfonate about two cases"
} | [
{
"companynumb": "FR-CONCORDIA PHARMACEUTICALS INC.-CO-KX-FR-2016-001",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SODIUM POLYSTYRENE SULFONATE"
... |
{
"abstract": "A 13 year-old boy with Prader-Willi syndrome and steatohepatitis presented with diabetic ketoacidosis 4 weeks after the initiation of growth hormone (GH) treatment. He did not have signs or symptoms of type 2 diabetes mellitus (DM2) before the initiation of GH treatment. Hyperglycemia resolved 2 months after discontinuation of GH. He redeveloped DM2 6 months later associated with excessive weight gain. Diabetic ketoacidosis as a rare complication of GH therapy emphasizes the importance of screening for carbohydrate intolerance before and during GH treatment in patients with Prader-Willi syndrome. Steatohepatitis may be the only manifestation of insulin resistance and warrants further evaluation.",
"affiliations": "Department of Pediatric Endocrinology and Diabetes, Connecticut Children 's Medical Center, Hartford, CT 06119, USA.",
"authors": "Yigit|Sevket|S|;Estrada|Elizabeth|E|;Bucci|Karen|K|;Hyams|Jeffrey|J|;Rosengren|Sally|S|",
"chemical_list": "D007328:Insulin; D013006:Growth Hormone",
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"mesh_terms": "D000293:Adolescent; D003422:Critical Care; D003924:Diabetes Mellitus, Type 2; D016883:Diabetic Ketoacidosis; D004032:Diet; D004334:Drug Administration Schedule; D005234:Fatty Liver; D005544:Forecasting; D013006:Growth Hormone; D006760:Hospitalization; D006801:Humans; D007003:Hypoglycemia; D007328:Insulin; D008297:Male; D011218:Prader-Willi Syndrome; D013997:Time Factors; D017211:Treatment Failure; D015430:Weight Gain",
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"pages": "361-4",
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"pmid": "15112913",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Diabetic ketoacidosis secondary to growth hormone treatment in a boy with Prader-Willi syndrome and steatohepatitis.",
"title_normalized": "diabetic ketoacidosis secondary to growth hormone treatment in a boy with prader willi syndrome and steatohepatitis"
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"abstract": "Endogenous endophthalmitis is uncommon but potentially dangerous. We present a fatal presentation of endogenous Nocardial endophthalmitis in the context of steroid use for treatment of giant cell arteritis.\nAn 84-year-old Caucasian female presented to the local emergency room with severe headaches, myalgia and shoulder and calf muscle pain. She was treated for a presumed diagnosis of giant-cell arteritis with corticosteroids and subsequently developed an intense retro-orbital pain in the right eye. Fundus examination revealed a white, vascularized chorioretinal mass at the equator of the eye in the inferotemporal quadrant. Antibiotics were given and a vitrectomy was performed. The culture of the vitreous showed Nocardia nova and a diagnosis of disseminated Nocardiosis was made.\nAlthough uncommon, it is important that ophthalmologists are aware of Nocardial infections as a differential diagnosis of retinal mass, particularly in immunocompromised patients.",
"affiliations": "Département d'ophtalmologie et d'oto-rhino-laryngologie - chirurgie cervico-faciale, Université Laval, Québec, QC, Canada.;Département d'ophtalmologie et d'oto-rhino-laryngologie - chirurgie cervico-faciale, Université Laval, Québec, QC, Canada.",
"authors": "Gagnon|Steven|S|;Saab|Marc|M|",
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"fulltext": "\n==== Front\nInt Med Case Rep J\nInt Med Case Rep J\nimcrj\nimcrj\nInternational Medical Case Reports Journal\n1179-142X Dove \n\n277365\n10.2147/IMCRJ.S277365\nCase Report\nEndogenous Nocardial Endophthalmitis Misdiagnosed as Giant Cell Arteritis\nGagnon and SaabGagnon and SaabGagnon Steven 123 Saab Marc 12456 1 Département d’ophtalmologie et d’oto-rhino-laryngologie – chirurgie cervico-faciale, Université Laval, Québec, QC, Canada\n2 Hôpital Régional de Rimouski, Centre intégré de santé et de services sociaux du Bas-Saint-Laurent, Rimouski, QC, Canada\n3 Centre Universitaire d’ophtalmologie (CUO), Hôpital du Saint-Sacrement, Québec, QC, Canada\n4 Hôpital Charles-LeMoyne, Centre intégré de santé et de services sociaux de la Montérégie-Centre, Greenfield Park, QC, Canada\n5 Service d’ophtalmologie, Université de Sherbrooke, Sherbrooke, QC, Canada\n6 Département d’ophtalmologie, Université de Montréal, Montréal, QC, Canada\nCorrespondence: Steven Gagnon 1083, rue du Chevreau, Lévis, QCG6Z 3C3, Canada Email gagn0n@hotmail.com\n10 11 2020 \n2020 \n13 597 601\n03 9 2020 22 10 2020 © 2020 Gagnon and Saab.2020Gagnon and Saab.This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).Purpose\nEndogenous endophthalmitis is uncommon but potentially dangerous. We present a fatal presentation of endogenous Nocardial endophthalmitis in the context of steroid use for treatment of giant cell arteritis.\n\nCase Presentation\nAn 84-year-old Caucasian female presented to the local emergency room with severe headaches, myalgia and shoulder and calf muscle pain. She was treated for a presumed diagnosis of giant-cell arteritis with corticosteroids and subsequently developed an intense retro-orbital pain in the right eye. Fundus examination revealed a white, vascularized chorioretinal mass at the equator of the eye in the inferotemporal quadrant. Antibiotics were given and a vitrectomy was performed. The culture of the vitreous showed Nocardia nova and a diagnosis of disseminated Nocardiosis was made.\n\nConclusion and Significance\nAlthough uncommon, it is important that ophthalmologists are aware of Nocardial infections as a differential diagnosis of retinal mass, particularly in immunocompromised patients.\n\nKeywords\nNocardiosissystemicNocardiaeyeintraocularendophthalmitisendogenousNo funding or grant supportNo funding or grant support.\n==== Body\nIntroduction\nNocardia is a known opportunistic gram-positive infection. Nocardia can disseminate to virtually any organ, with the typical portal of entry being the respiratory tract.1 In a 1994 literature review of 1050 cases, 39% of Nocardia infections were pulmonary, 32% of the infections were systemic, 17% were cutaneous or affected the central nervous system alone and 12% were extrapulmonary, namely the eyes or bone.2 Eye presentations of Nocardiosis are uncommon, and endogenous bacterial endophthalmitis is even more rare, highlighting the importance of this report.\n\nCase Report\nAn 84-year-old Caucasian female presented to the local emergency department with a recent history of severe headaches, myalgia and shoulder and calf muscle pain. She had been recently diagnosed with polymyalgia rheumatic in the context of a three-month history of fatigue, weakness and fluctuating fever and was already on tapered dose of corticosteroids. The patient was otherwise known for atrial fibrillation on anticoagulation, atherosclerotic coronary heart disease, hypertension, and dyslipidemia. Past ocular history was unremarkable except for remote bilateral phacoemulsification cataract surgery.\n\nOn presentation at the ER, the patient was afebrile. There was no temporal artery tenderness or jaw pain, and C-reactive protein was mildly elevated at 52 mg/L. Platelets count was 313 x 109, white blood cells count was 19.9 x 109. No erythrocyte sedimentation was done. The tests were otherwise unremarkable.\n\nThe patient was prescribed oral prednisone 50 mg once daily and admitted. Twenty-four hours later, solumedrol 1g IV was prescribed once daily for 48 hours for a presumed diagnosis of polymyalgia rheumatica and atypical temporal arteritis as the symptoms worsen and C-reactive protein increased to 197 mg\\L. At this point, the patient had no ocular symptoms.\n\nDespite initial improvement, the patient relapsed after three days with worsening of symptoms and a new retro-orbital pain of the right eye. On examination by the ophthalmologist, the patient had 20/20 vision bilaterally, with normal adnexal structures and extraocular movements. Intraocular pressure was within normal limits and the visual field exam showed a superonasal quadranopsia. Anterior segment examination showed no sign of inflammation and fundus examination of the right eye showed a white, vascularized chorioretinal mass in the inferotemporal quadrant. The examination was unremarkable for the left eye. The diagnosis given by the general ophthalmologist was a possible malignant tumor and the patient was referred to a retinal specialist for further evaluation.\n\nInvestigations by an infectious disease specialist led to a concomitant diagnosis of emphysematous cystitis. Piperacillin tazobactam 3.3 g IV q 6 hours was prescribed to the patient and given the partial response to antibiotics, the corticosteroids were gradually eliminated. Piperacillin tazobactam was changed for ampicillin 2 g IV q 6 hours.\n\nOne day later, a PET scan was performed with results suggesting an inflammatory or infectious etiology. It showed two pulmonary opacities of unknown etiology and hypermetabolism in the right calf muscle, thought to be a hematoma. Large vessel arteritis was absent.\n\nThree days later at follow-up, the patient’s vision in the right eye was significantly decreased from 20/20 to counting fingers. Panuveitis was present with a stage 4 vitreal haze on fundus exam. A B-scan was performed and revealed that the mass had increased in size and was extending into the vitreous. A diagnosis of endogenous endophthalmitis with a probable fungal etiology was made. A vitrectomy with a chorioretinal biopsy of the lesion was performed the next day. Intravitreal amphotericin B 5 mg/0.1 mL, vancomycin 1 mg/0.1 mL and ceftazidime 2.25 mg/0.1 mL were administered during the procedure. A biopsy of the left calf mass was made by needle biopsy.\n\nThe culture of the vitreous (Figure 1) and biopsy of the left calf mass (Figure 2) showed high quantities of Nocardia nova. Disseminated Nocardiosis was therefore the final diagnosis.Figure 1 White chorioretinal mass. Posterior uveitis with a white chorioretinal mass at the inferotemporal quadrant seen during the vitrectomy and the biopsy.\n\nFigure 2 Left calf centesis. Disseminated Nocardia nova. Left calf centesis, 30 cc of pus. Direct examination with numerous polymorphonuclear neutrophils and aggregated gram positive rods and delicate, beaded, branching filaments. The Nocardia nova was found to be resistant to amoxicillin and clavulanate, tobramycin, ciprofloxacin and moxifloxacin.\n\n\n\nAmpicillin was stopped and changed for meropenem 2 g IV q 8h and TMP-SMX 400 mg IV q8h for 4 doses. A dose of 2 mg of intravitreal ceftriaxone was also planned. After the intraocular injection and the parenteral antibiotics, a regression of the intraocular mass, right calf mass and two pulmonary opacities was observed. A considerable improvement of the patient’s general condition was also noted. However, the patient decided to cease treatment given her age and other comorbidities. She was transferred to palliative care and died 18 days later.\n\nDiscussion\nWhile eye presentations of Nocardiosis are uncommon, endogenous bacterial endophthalmitis is even more rare. In a retrospective analysis of microbiological profile of culture-proven cases of exogenous and endogenous endophthalmitis by Ramakrishnan and al. between January 1997 and December 2006, no endogenous endophthalmitis was caused by Nocardia. Of the 364 bacterial infectious endophthalmitis in the study, only 24 isolated Nocardia spp. and were all exogenous endophthalmitis cases, mostly after intraocular surgeries or penetrating ocular injuries.3,4\n\nA search for other cases of endogenous intraocular Nocardial infections was conducted on PubMed. We searched for the keywords “nocardiosis”, “Nocardia”, “eye”, “intraocular”, “endophthalmitis” and “endogenous”. Between January 2000 and April 2020, only 26 cases of endogenous intraocular Nocardiosis infection have been reported.5–29 Most of these cases reported white masses or abscesses. One case reported a similar presentation of systemic Nocardiosis mimicking a giant-cell arteritis.29 This highlights the importance of keeping a large differential diagnosis, especially before prescribing corticosteroids.\n\nAside from the rarity of these cases, the diagnosis of Nocardia infection can be difficult as laboratories need adequate specimens, which often requires an invasive procedure to obtain.30 However, an earlier recognition of Nocardiosis upon eye examination may have saved the patient’s life. Prognosis could also have been different had she not have received large doses of corticosteroids the weeks prior to her ophthalmology consultation. Corticosteroids have inhibitory effects on a wide range of immune responses including profound effects on the cellular functions of leukocytes and endothelial cells, resulting in a reduction in the ability of leukocytes to adhere to the vascular endothelium and exit circulation.31–33 While this may be desired in the management of inflammatory and autoimmune disorders, corticosteroids can be detrimental to patients with active infections and should therefore be used with caution as it may delay diagnoses of infectious causes.\n\nConclusions\nWe present a case of endogenous Nocardia endophthalmitis, a rare but fatal condition. Although uncommon, it is important that ophthalmologists are aware of such entities and keep a large differential diagnosis upon seeing a retinal mass. Accordingly, Nocardia infection should always be considered in immunocompromised patients.\n\nAcknowledgment\nSpecial thanks to Dr Philippe Dolcé for the pictures of the cultures of the left calf centesis.\n\nConsent for Publication\nOur institution’s ethic committee does not require a consent for such articles as the patient is deceased and the case report does not contain any personal information. They did not need the family’s approval considering that the information was denominalised.\n\nAuthor Contributions\nAll authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.\n\nDisclosure\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Lerner \nPI . Nocardiosis\n. Clin Infect Dis . 1996 ;22 (6 ):891–903;quiz 904–895. doi:10.1093/clinids/22.6.891 \n2. Beaman \nBL , Beaman \nL . Nocardia species: host-parasite relationships\n. Clin Microbiol Rev . 1994 ;7 (2 ):213 –264\n. doi:10.1128/CMR.7.2.213 8055469 \n3. Ramakrishnan \nR , Bharathi \nMJ , Shivkumar \nC , et al. Microbiological profile of culture-proven cases of exogenous and endogenous endophthalmitis: a 10-year retrospective study\n. Eye . 2009 ;23 (4 ):945 –956\n. doi:10.1038/eye.2008.197 18600246 \n4. Hudson \nJD , Danis \nRP , Chaluvadi \nU , Allen \nSD . Posttraumatic exogenous nocardia endophthalmitis\n. Am J Ophthalmol . 2003 ;135 (6 ):915 –917\n. doi:10.1016/S0002-9394(02)02294-8 12788146 \n5. Wang \nS , Jiang \nB , Li \nY , Shang \nY , Liu \nZ , Zhang \nY . A case report of disseminated nocardiosis with ocular involvement in a myasthenia gravis patient and literature review\n. BMC Neurol . 2019 ;19 (1 ). doi:10.1186/s12883-019-1482-4 \n6. Horvath \nCE , Brinkmann \nCK , Ozdoba \nC , Leib \nSL , Wolf \nS , Wolf-Schnurrbusch \nUEK . Chorioretinal nocardiosis\n. Retin Cases Brief Rep . 2009 ;3 (3 ):263 –265\n. doi:10.1097/ICB.0b013e31817376eb 25389580 \n7. Bozbeyoglu \nS , Yilmaz \nG , Akova \nYA , Arslan \nH , Aydin \nP , Haberal \nM . Choroidal abscess due to nocardial infection in a renal allograft recipient\n. Retina . 2004 ;24 (1 ):164 –166\n. doi:10.1097/00006982-200402000-00027 15076963 \n8. Dutta Majumder \nP , Mukherjee \nM , Therese \nL , Gopal \nL , Biswas \nJ . Diagnostic challenge with nocardia subretinal abscess: a case report from tuberculosis-endemic region\n. Ocul Immunol Inflamm . 2019 ;27 (5 ):762 –765\n. doi:10.1080/09273948.2018.1462391 29746787 \n9. Pelayes \nDE , Colombero \nD , Gioino \nJM , Zarate \nJO , Piantoni \nG . [Endogenous Nocardia asteroides endophthalmitis in a patient with systemic lupus erythematosus]\n. Medicina . 2004 ;64 (2 ):146 –148\n. Spanish.15628303 \n10. Lee \nB , Drayna \nP , Maltry \nAC , Mason \nCM , Montezuma \nSR , Koozekanani \nD . Endogenous nocardia endophthalmitis presenting as a mass lesion in a patient with metatstatic nonsmall cell carcinoma of the lung\n. Retin Cases Brief Rep . 2019 ;13 (2 ):145 –149\n. doi:10.1097/ICB.0000000000000545 28129236 \n11. Kawakami \nH , Sawada \nA , Mochizuki \nK , Takahashi \nK , Muto \nT , Ohkusu \nK . Endogenous Nocardia farcinica endophthalmitis\n. Jpn J Ophthalmol . 2010 ;54 (2 ):164 –166\n. doi:10.1007/s10384-009-0782-4 20401568 \n12. Ravage \nZB , Singerman \nLJ . Endogenous Nocardial chorioretinitis in an immunocompetent patient\n. Retin Cases Brief Rep . 2009 ;3 (1 ):27 –30\n. doi:10.1097/ICB.0b013e31814fae6f 25390832 \n13. Trehan \nH , Kaushik \nJ , Jain \nVK , Parihar \nJKS , Avasthi \nA . Endogenous nocardial endophthalmitis in an immunosuppressed patient: a serious warning of an underlying life threatening and blinding disorder\n. J Ophthalmic Vis Res . 2017 ;12 (1 ):113 –116\n. doi:10.4103/2008-322X.200172 28299015 \n14. Kim \nJE , Landon \nRE , Connor \nTB , Kivlin \nJD . Endogenous ocular nocardiosis\n. J AAPOS . 2004 ;8 (2 ):194 –195\n. doi:10.1016/j.jaapos.2003.09.006 15088059 \n15. Eschle-Meniconi \nME , Guex-Crosier \nY , Wolfensberger \nTJ . Endogenous ocular nocardiosis—an interventional case report with a review of the literature\n. Surv Ophthalmol . 2011 ;56 (5 ):383 –415\n. doi:10.1016/j.survophthal.2011.03.003 21813147 \n16. de Silva \nT , Evans \nC , Mudhar \nHS , Rennie \nI , Green \nST . Isolated endogenous endophthalmitis secondary to Nocardia spp in an immunocompetent adult\n. J Clin Pathol . 2006 ;59 (11 ):1226 .\n17. Chen \nLY , Kesen \nMR , Ghafourian \nA , Nguyen \nQD , Eberhart \nCG , Do \nDV . Isolated endogenous Nocardia endophthalmitis after immunosuppression\n. J Ophthalmic Inflamm Infect . 2012 ;2 (3 ):141 –143\n. doi:10.1007/s12348-011-0057-3 22278699 \n18. Milman \nT , Trubnik \nV , Shah \nM , McCormick \nSA , Finger \nPT . Isolated Nocardia exalbida endogenous endophthalmitis\n. Ocul Immunol Inflamm . 2011 ;19 (4 ):237 –239\n. doi:10.3109/09273948.2011.563898 21770800 \n19. Navarrete-Navarrete \nN , Escobar Sevilla \nJ , Toribio García \nM , Urbano \nF , Sabio \nJM , Jiménez-Alonso \nJ . A man with unilateral endophthalmitis: a case of disseminated nocardiosis\n. Case Rep Infect Dis . 2015 ;2015 :607421 .25878910 \n20. Eisenberg \nMA , Wilker \nSC . Nocardia asteroides subretinal abscess in patient with acute myelogenous leukemia after allogeneic stem cell transplant\n. Retin Cases Brief Rep . 2014 ;8 (2 ):113 –115\n. doi:10.1097/ICB.0000000000000017 25372323 \n21. Yap \nEY , Fam \nHB , Leong \nKP , Buettner \nH . Nocardia choroidal abscess in a patient with systemic lupus erythematosus\n. Aust N Z J Ophthalmol . 1998 ;26 (4 ):337 –338\n. doi:10.1111/j.1442-9071.1998.tb01340.x 9843264 \n22. Schriever \nS , Mistry-Burchardi \nN , Grabein \nB , et al. Nocardia farcinica: schwere Chorioiditis mit lebensbedrohlicher Generalisierung unter systemischer Immunsuppression\n. Klin Monbl Augenheilkd . 2002 ;219 (3 ):164 –167\n. doi:10.1055/s-2002-26724 11987046 \n23. Scott \nM , Mehta \nS , Rahman \nHT , Grossniklaus \nHE , Yeh \nS . Nocardia veterana endogenous endophthalmitis in a cardiac transplant patient\n. J Ophthalmic Inflamm Infect . 2013 ;3 (1 ):44 . doi:10.1186/1869-5760-3-44 23548110 \n24. Giuliari \nGP , Sadaka \nA , Eagle \nR , Gonzalez \nVH . Ocular nocardiosis in a renal transplant patient\n. Retin Cases Brief Rep . 2012 ;6 (3 ):245 –248\n. doi:10.1097/ICB.0b013e31822477c4 25389722 \n25. Angermann \nR , Stattin \nM , Zehetner \nC . Ocular nocardiosis: a case report\n. Ocul Immunol Inflamm . 2018 ;27 (7 ):1114 –1116\n. doi:10.1080/09273948.2018.1506041 30095316 \n26. Lally \nDR , Sharma \nDK , Shields \nCL , Malloy \nBC , Garg \nSJ . Pulmonary nocardiosis initially manifesting as endogenous endophthalmitis\n. Can J Ophthalmol . 2014 ;49 (2 ):e59 –e62\n. doi:10.1016/j.jcjo.2014.02.003 24767244 \n27. Lakosha \nH , Pavlin \nCJ , Lipton \nJ . Subretinal abscess due to nocardia farcinica infection\n. Retina . 2000 ;20 (3 ):247 –269\n. doi:10.1097/00006982-200003000-00008 \n28. Dodds \nEM , Echandi \nLV , Puente \nSI , Kaufman \nS . Subretinal abscess due to nocardia farcinicaresistant to trimethoprim- sulfamethoxazole in a patient with systemic lupus erythematosus\n. Ocul Immunol Inflamm . 2006 ;14 (4 ):249 –251\n. doi:10.1080/09273940600760514 16911989 \n29. Héron \nE , Augustin \nP , Cervera \nP , et al. Systemic nocardiosis mimicking an ocular relapse of giant-cell arteritis\n. Rheumatology . 2006 ;45 (5 ):641 –643\n. doi:10.1093/rheumatology/kel064 16531438 \n30. Georghiou \nPR , Blacklock \nZM . Infection with Nocardia species in Queensland: a review of 102 clinical isolates\n. Med J Aust . 1992 ;156 (10 ):692 –697\n. doi:10.5694/j.1326-5377.1992.tb121509.x 1620016 \n31. Fauci \nAS , Dale \nDC , Balow \nJE . Glucocorticosteroid therapy: mechanisms of action and clinical considerations\n. Ann Intern Med . 1976 ;84 (3 ):304 –315\n. doi:10.7326/0003-4819-84-3-304 769625 \n32. Fauci \nAS , Murakami \nT , Brandon \nDD , Loriaux \nDL , Lipsett \nMB . Mechanisms of corticosteroid action on lymphocyte subpopulations. VI. Lack of correlation between glucocorticosteroid receptors and the differential effects of glucocorticosteroids on T-cell subpopulations\n. Cell Immunol . 1980 ;49 (1 ):43 –50\n. doi:10.1016/0008-8749(80)90054-4 6965362 \n33. Boumpas \nDT , Chrousos \nGP , Wilder \nRL , Cupps \nTR , Balow \nJE . Glucocorticoid therapy for immune-mediated diseases: basic and clinical correlates\n. Ann Intern Med . 1993 ;119 (12 ):1198 –1208\n. doi:10.7326/0003-4819-119-12-199312150-00007 8239251\n\n",
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"keywords": "Nocardia; Nocardiosis; endogenous; endophthalmitis; eye; intraocular; systemic",
"medline_ta": "Int Med Case Rep J",
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"nlm_unique_id": "101566269",
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"pages": "597-601",
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"references": "30095316;8783685;31638926;16911989;25390832;17071814;8055469;15088059;8239251;28299015;9843264;11987046;23548110;25372323;21770800;25389722;6965362;769625;18600246;25878910;25389580;15076963;10872932;21813147;16531438;1620016;28129236;24767244;22278699;15628303;12788146;29746787;20401568",
"title": "Endogenous Nocardial Endophthalmitis Misdiagnosed as Giant Cell Arteritis.",
"title_normalized": "endogenous nocardial endophthalmitis misdiagnosed as giant cell arteritis"
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"abstract": "Humoral rejection and its relationship with anti HLA antibodies have been extensively studied in organ transplantation with the exception of liver transplantation (LT). Recently, association between donor specific anti HLA antibodies (DSA) and increased risk of rejection and graft loss has been suggested in LT. When such antibodies appear, adequate treatment and monitoring are needed to avoid or delay allograft loss. We report here three cases of probable antibody-mediated rejection developed after pregnancy in liver transplanted women. Sera at the time of rejection and during follow-up have been retrospectively tested for the ability of DSA to bind complement components. These cases display different outcomes depending on the complement binding DSA capacity and titers after treatment of the rejection episodes. Thus, they highlight the potential interest of complement binding Luminex Single Antigen assays to monitor the efficiency of anti-rejection therapy.",
"affiliations": "Etablissement Français du Sang, Laboratoire d'Histocompatibilité, Lyon, France.;Hospices civils de Lyon, Hôpital Edouard Herriot, Fédération des Spécialités Digestives, Lyon, France.;Hospices civils de Lyon, Hôpital Edouard Herriot, Fédération des Spécialités Digestives, Lyon, France.;Hospices civils de Lyon, Hôpital Edouard Herriot, Service d'Immunologie et Transplantation, Lyon, France; Université Claude Bernard Lyon 1, Lyon, France.;Hospices civils de Lyon, Hôpital Edouard Herriot, Service d'Immunologie et Transplantation, Lyon, France; Université Claude Bernard Lyon 1, Lyon, France.;Université Claude Bernard Lyon 1, Lyon, France; Hospices civils de Lyon, Hôpital Edouard Herriot, Service d'Anatomie Pathologique, Lyon, France.;Hospices Civils de Lyon, Centre de Biologie et Pathologie Est, Laboratoire de Virologie, Lyon, France.;Hospices civils de Lyon, Hôpital Edouard Herriot, Fédération des Spécialités Digestives, Lyon, France; Université Claude Bernard Lyon 1, Lyon, France.;Université Claude Bernard Lyon 1, Lyon, France; Hospices civils de Lyon, Hôpital Edouard Herriot, Service d'Anatomie Pathologique, Lyon, France.;Etablissement Français du Sang, Laboratoire d'Histocompatibilité, Lyon, France.;Hospices civils de Lyon, Hôpital Edouard Herriot, Fédération des Spécialités Digestives, Lyon, France; Université Claude Bernard Lyon 1, Lyon, France.",
"authors": "Ducreux|Stéphanie|S|;Guillaud|Olivier|O|;Bosch|Alexie|A|;Thaunat|Olivier|O|;Morelon|Emmanuel|E|;Hervieu|Valérie|V|;Mekki|Yahia|Y|;Boillot|Olivier|O|;Scoazec|Jean-Yves|JY|;Dubois|Valérie|V|;Dumortier|Jérôme|J|",
"chemical_list": "D007518:Isoantibodies",
"country": "Netherlands",
"delete": false,
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"issn_linking": "0966-3274",
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"journal": "Transplant immunology",
"keywords": "Anti-HLA antibodies; Complement-binding antibodies; Liver transplantation; Pregnancy; Rejection; Therapy",
"medline_ta": "Transpl Immunol",
"mesh_terms": "D000328:Adult; D002648:Child; D005260:Female; D006084:Graft Rejection; D006801:Humans; D056724:Immunity, Humoral; D007518:Isoantibodies; D016031:Liver Transplantation; D011247:Pregnancy; D011248:Pregnancy Complications",
"nlm_unique_id": "9309923",
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"abstract": "OBJECTIVE\nWe aimed to provide real-life data on the outcomes of metastatic renal cell carcinoma (mRCC) patients treated with everolimus as second-line treatment after failure of first-line pazopanib.\n\n\nMETHODS\nData from the medical charts of mRCC patients from 8 centers in Greece and Spain were reviewed. All patients had received or were continuing to receive second-line everolimus treatment after failure of first-line treatment with pazopanib. No other previous therapies were allowed. The primary end point was the determination of progression-free survival (PFS).\n\n\nRESULTS\nIn total, 31 patients were enrolled. Of these, 26% had performance status (PS) >0, 88% were of intermediate/poor Memorial Sloan-Kettering Cancer Center (MSKCC) risk group, and only 61% had undergone prior nephrectomy. Median PFS was 3.48 months (95% CI: 2.37-5.06 months). Median overall survival (OS) from everolimus initiation was 8.9 months (95% CI: 6.47-13.14 months). Median OS from pazopanib initiation was 14.78 months (95% CI: 10.54-19.08 months). Furthermore, 32% of patients temporarily discontinued everolimus due to adverse events (AEs), and 22% of patients discontinued everolimus permanently due to toxicity. Most common toxicities were anemia (29%), stomatitis (26%), pneumonitis (19%), and fatigue (10%). Moreover, 14 AEs (27%) were graded as 3 or 4 and were reported by 13 patients (42%).\n\n\nCONCLUSIONS\nThis study provides data exclusively on the sequence pazopanib-everolimus in mRCC. Everolimus has a favorable safety profile and is active. The short PFS and OS could be attributed to the fact that the pazopanib-everolimus sequence was mainly offered to patients with adverse prognostic features, resulting in a modest increase in the combined OS of our population.",
"affiliations": "Hellenic Genito-Urinary Cancer Group.;Hellenic Genito-Urinary Cancer Group.;Hellenic Genito-Urinary Cancer Group.;Medical Oncology Department, Hospital Universitario Virgen del Rocío, Sevilla, Spain.;Department of Medical Oncology, University Hospital of Heraklion, Heraklion.;2nd Oncology Clinic, Metropolitan Hospital, Piraeus.;1st Department of Medical Oncology, Saint Savvas Anticancer Hospital, Athens.;Division of Oncology, Department of Medicine, University Hospital, University of Patras Medical School, Patras.;Medical Oncology Department, Hospital Universitario Virgen del Rocío, Sevilla, Spain.;Hellenic Genito-Urinary Cancer Group.",
"authors": "Koutsoukos|Konstantinos|K|;Bamias|Aristotelis|A|;Tzannis|Kimon|K|;Espinosa Montaño|Marta|M|;Bozionelou|Vasiliki|V|;Christodoulou|Christos|C|;Stefanou|Dimitra|D|;Kalofonos|Haralabos|H|;Duran|Ignacio|I|;Papazisis|Konstantinos|K|",
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"doi": "10.2147/OTT.S141260",
"fulltext": "\n==== Front\nOnco Targets TherOnco Targets TherOncoTargets and TherapyOncoTargets and therapy1178-6930Dove Medical Press 10.2147/OTT.S141260ott-10-4885Original ResearchReal-world experience of everolimus as second-line treatment in metastatic renal cell cancer after failure of pazopanib Koutsoukos Konstantinos 12Bamias Aristotelis 12Tzannis Kimon 1Espinosa Montaño Marta 3Bozionelou Vasiliki 4Christodoulou Christos 5Stefanou Dimitra 6Kalofonos Haralabos 7Duran Ignacio 3Papazisis Konstantinos 18\n1 Hellenic Genito-Urinary Cancer Group\n2 Oncology Unit, Department of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens, Athens, Greece\n3 Medical Oncology Department, Hospital Universitario Virgen del Rocío, Sevilla, Spain\n4 Department of Medical Oncology, University Hospital of Heraklion, Heraklion\n5 2nd Oncology Clinic, Metropolitan Hospital, Piraeus\n6 1st Department of Medical Oncology, Saint Savvas Anticancer Hospital, Athens\n7 Division of Oncology, Department of Medicine, University Hospital, University of Patras Medical School, Patras\n8 Euromedica General Clinic, Thessaloniki, GreeceCorrespondence: Konstantinos Koutsoukos, Oncology Unit, Department of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens, 80 Vasilissis Sofias Avenue, Lourou Strasse 2, 11528 Athens, Greece, Tel +30 21 0338 1554, Fax +30 21 3216 2511, Email koutsoukos.k@gmail.com2017 06 10 2017 10 4885 4893 © 2017 Koutsoukos et al. This work is published and licensed by Dove Medical Press Limited2017The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Aim\nWe aimed to provide real-life data on the outcomes of metastatic renal cell carcinoma (mRCC) patients treated with everolimus as second-line treatment after failure of first-line pazopanib.\n\nPatients and methods\nData from the medical charts of mRCC patients from 8 centers in Greece and Spain were reviewed. All patients had received or were continuing to receive second-line everolimus treatment after failure of first-line treatment with pazopanib. No other previous therapies were allowed. The primary end point was the determination of progression-free survival (PFS).\n\nResults\nIn total, 31 patients were enrolled. Of these, 26% had performance status (PS) >0, 88% were of intermediate/poor Memorial Sloan-Kettering Cancer Center (MSKCC) risk group, and only 61% had undergone prior nephrectomy. Median PFS was 3.48 months (95% CI: 2.37–5.06 months). Median overall survival (OS) from everolimus initiation was 8.9 months (95% CI: 6.47–13.14 months). Median OS from pazopanib initiation was 14.78 months (95% CI: 10.54–19.08 months). Furthermore, 32% of patients temporarily discontinued everolimus due to adverse events (AEs), and 22% of patients discontinued everolimus permanently due to toxicity. Most common toxicities were anemia (29%), stomatitis (26%), pneumonitis (19%), and fatigue (10%). Moreover, 14 AEs (27%) were graded as 3 or 4 and were reported by 13 patients (42%).\n\nConclusion\nThis study provides data exclusively on the sequence pazopanib–everolimus in mRCC. Everolimus has a favorable safety profile and is active. The short PFS and OS could be attributed to the fact that the pazopanib–everolimus sequence was mainly offered to patients with adverse prognostic features, resulting in a modest increase in the combined OS of our population.\n\nKeywords\npazopanibeverolimusrenal cell carcinoma\n==== Body\nIntroduction\nThe tyrosine-kinase inhibitors (TKIs) sunitinib and pazopanib, targeting vascular endothelial growth factor receptors (VEGFRs), and the combination of the anti-VEGF monoclonal antibody bevacizumab with interferon-α (IFN-α) are the approved first-line options for metastatic renal cell carcinoma (mRCC).1–3 For patients who fail first-line treatment with anti-VEGF/VEGFR therapy, 2 approved options exist: the VEGFR TKI axitinib and the mammalian target of rapamycin (mTOR) inhibitor everolimus.2\n\nThe optimal treatment following failure of first-line TKI has not been defined. There are no direct comparisons between the 2 current standards, while retrospective data have not suggested a superiority of one over the other.3–6 Furthermore, sufficient data regarding the activity of the approved second-line agents after exposure to first-line therapies exist only for sunitinib,7–12 but not for the other TKI standard, pazopanib. Pazopanib, an oral TKI targeting VEGFR, platelet-derived growth factor receptor (PDGFR), and c-kit receptor, has exhibited significant progression-free survival (PFS) benefit compared with placebo13 and has proven to be not inferior to sunitinib in first-line mRCC treatment,14 while a patient preference study showed that patients significantly preferred pazopanib over sunitinib.15 These results added important information in the decision-making process, and pazopanib has become a valid option in the first-line setting. Nevertheless, due to its later development, no patients pretreated with pazopanib were included in the 2 pivotal trials leading to the approval of everolimus and axitinib after first-line failure.12,16 For similar reasons, no such data could be extracted from the pivotal trial of pazopanib.13 Therefore, information regarding the activity of subsequent therapies after pazopanib is limited. Due to the approved indication of axitinib, ie, after first-line sunitinib, only the efficacy of everolimus after treatment with pazopanib can be realistically studied outside the context of a clinical trial.\n\nThe activity of everolimus in second-line treatment of mRCC following failure of anti-VEGF/VEGFR first-line treatment was shown in the RECORD-1 study,16 which reported a significant prolongation of PFS compared to placebo (4.9 vs 1.9 months; hazard ratio [HR], 0.33; p<0.001) in patients who previously received sunitinib, sorafenib, or both (previous cytokines and/or bevacizumab were also permitted). Because the antitumor mechanisms of the mTOR inhibitors largely differ from those of the anti-VEGFR agents used in the first-line treatment, with little overlap in their safety profiles, everolimus represents a rational option for post-TKI failure in mRCC. However, the results of the RECORD-1 study may not be fully applicable in the current mRCC treatment paradigm, since the RECORD-1 study did not include patients treated with first-line pazopanib. In addition, only 21% of patients received everolimus after only 1 previous anti-VEGF therapy. This is particularly relevant, since a subgroup analysis of RECORD-1 showed numerically longer median PFS in patients who previously received only 1 VEGFR-TKI than in patients who previously received more lines of therapy (5.4 and 4.0 months, respectively).8 Finally, outcomes of unselected patients outside the context of clinical trials may considerably differ from those of patients in controlled clinical trials.17\n\nFor all the aforementioned reasons, we conducted the RESCUE retrospective study, which provides real-life data on the outcomes of mRCC patients treated with everolimus as pure second-line treatment after failure of first-line pazopanib treatment.\n\nPatients and methods\nStudy design\nThis study was conducted at 8 study sites in Greece and Spain (Supplementary material). It was a retrospective, medical chart review study of patients with mRCC who fulfilled all eligibility criteria mentioned herein. To ensure uniformity of data collection, all necessary information was collected with the use of an electronic case record form (eCRF).\n\nInclusion and exclusion criteria\nOnly patients between 18 and 85 years of age, with histologically and/or cytologically documented mRCC, who had received or were continuing (at the time of study enrollment) to receive second-line everolimus treatment after failure of first-line treatment with pazopanib were selected. No other treatment sequence was allowed. Cytokine treatment prior to pazopanib was also not allowed. Patients should have had measurable disease and should have undergone at least 1 evaluation (per local investigator assessment) after commencement of everolimus treatment. Patients must have initiated everolimus within 6 weeks from the date of disease progression on, or after, pazopanib. A minimum of 6 months should have elapsed from the time of everolimus initiation to the inclusion in the study.\n\nExclusion criteria included participation in any interventional trial during treatment with everolimus, prior therapy with cytokines (eg, IFN or interleukin) or TKIs other than pazopanib, major surgery or radiation within 4 weeks prior to everolimus initiation (palliative radiotherapy for bone lesions within 2 weeks of everolimus treatment initiation was allowed), or chronic systemic treatment with corticosteroids (dose ≥10 mg/d methylprednisolone or equivalent) or other immunosuppressants.\n\nEverolimus was administered according to the approved product labels in the respective countries. Duration of treatment, assessment schedules, and follow-up were decided by the treating physician. Everolimus starting dose was 10 mg once daily. Dose interruptions, dose reduction to 5 mg once daily, or both could be used to manage adverse events (AEs) following the recommendations contained in the summary of product characteristics.\n\nThe study was approved by the ethical committees of the participating institutions (Supplementary material). Alive patients gave their written informed consent for collecting and analyzing their medical data pertinent to the objectives of this study. For deceased patients, a consent waiver by the ethical committees of the participating sites was granted.\n\nStudy end points and analysis\nThe primary end point was the determination of PFS, defined as the time elapsed between everolimus treatment initiation and the date of documentation of the first objective disease progression event as per local assessment, or the date of death, whichever occurred first. The secondary end points of the study were as follows: overall survival (OS), defined as the time from everolimus treatment initiation until death from any cause; and assessment of the safety profile of everolimus, including the incidence of the AEs recorded in the patients’ medical records during treatment with everolimus regardless of causal relationship with study medication (AEs were collected and coded to a preferred term using the Medical Dictionary for Regulatory Activities [MedDRA]); the impact of prior pazopanib duration of treatment on the PFS of second-line everolimus treatment; the determination of combined PFS, defined as the time from pazopanib treatment initiation until the time of documented tumor progression or death from any cause during everolimus treatment; the determination of clinical benefit rate (CBR), defined as the proportion of patients whose best response was complete response (CR), partial response (PR), or stable disease (SD) during second-line treatment with everolimus as per local assessment.\n\nContinuous variables were summarized with the use of descriptive statistical measures (mean value, standard deviation, median and range [minimum, maximum]), and categorical variables were displayed as frequency tables. Response to treatment was assessed according to local standards. Chi-squared test was used to correlate the duration of pazopanib therapy and occurrence of grade 3/4 AEs. The Kaplan–Meier method was used to estimate the median PFS, as well as the analysis of OS and combined PFS. Log-rank tests were used to test the equality of survivor functions across groups. The percentage of patients who experienced disease progression and died due to any cause was calculated along with the respective 95% CI. All data were collected from May 2014 to December 2014 (database lock). According to the methodological features of an observational noninterventional study, all analyses were descriptive, and the results presented should be interpreted as such. All statistical analyses were performed using the STATA/SE 14.1 software (copyright 1985–2015; StataCorp LLC, College Station, TX, USA).\n\nResults\nPatients\nData from 31 mRCC patients (Greece: 25, 81%; Spain: 6, 19%) were collected (Table 1). Patients started pazopanib between 1 February 2011 and 8 June 2013 and everolimus between 19 September 2011 and 16 January 2014. All but 1 patient discontinued pazopanib due to disease progression. Twenty-nine patients (94%) had clear cell histology, while 2 (6%) had mixed histology with a clear-cell component. Nineteen patients (61%) had undergone nephrectomy prior to initial treatment with pazopanib. Most patients were of intermediate (50%) or poor risk (33%) according to the Memorial Sloan-Kettering Cancer Center (MSKCC) prognostic survival risk score18 prior to commencement of pazopanib. The median number of disease sites was 2 (1–5). Six patients (19%) had only 1 disease site, 18 (42%) had 2, 8 (26%) had 3, 2 (6.5%) had 4, and 2 (6.5%) had 5 sites. All patients were eligible for efficacy and safety assessment. Median time from the diagnosis of metastatic disease to the initiation of pazopanib and everolimus was 1.1 and 7.8 months, respectively. Median duration of first-line pazopanib treatment was 5.6 months (range: 0.5–19 months).\n\nEfficacy\nAll patients were assessable for response to everolimus. No CR was reported. Best tumor response was PR in 4 (13%) patients and SD in 8 (26%) patients, resulting in a CBR of 39%, while in 19 patients (61%) progressive disease (PD) was reported as the best response during everolimus treatment.\n\nAt the time of analysis, all patients had progressed during or after cessation of everolimus treatment and 5 patients (16%) were still alive. The median follow-up for everoli-mus therapy was 27 months (95% CI: 14.9 months – not reached). Median PFS from everolimus treatment initiation was 3.5 months (95% CI: 2.4–5.1 months) (Figure 1) and median OS was 8.9 months (95% CI: 6.5–13.1 months) (Figure 1). Combined median PFS was 9.2 months (95% CI: 8–10.8 months). The median OS from the time of pazopanib initiation was 14.8 months (95% CI: 10.5–19.1 months).\n\nThere was no impact of first-line pazopanib treatment duration on everolimus PFS (p=0.170) when duration was used a continuous variable. When stratified according to time on first-line pazopanib duration (<3 months vs ≥3 months, <6 months vs ≥6 months, and <9 months vs ≥9 months), longer duration of previous pazopanib treatment tended to result in longer median PFS with second-line everolimus; however, no statistically significant differences were observed (Table 2). The respective analysis for OS after everolimus initiation yielded significant results. When time on pazopanib was studied as a continuous variable, there was a significant correlation with OS after everolimus initiation (p=0.005): for each additional month of pazopanib treatment, there was a 17% reduction in the risk of death. Similarly, when time on pazopanib was studied as a categorical variable, a significant correlation with post-everolimus OS was found for all time points studied, with a more pronounced difference observed when pazopanib was used for at least 9 months (Table 2, Figure 2).\n\nSafety\nThe median duration of everolimus therapy was 3.5 months (range: 1–20 months). The median everolimus daily dose was 10 mg (5–10 mg), while the mean daily dose was 9.3 mg. Nine patients (32%) temporarily discontinued everolimus treatment, 2 of them twice. There were 11 temporary discontinuations due to the following AEs: grade 2 edema (n=1), grade 3 proteinuria–acute renal failure (n=1), grade 4 anemia (n=1), grade 1 diarrhea and fever (n=2), hypercalcemia (n=1), grade 2 elevated gamma-glutamyl transferase (GGT) (n=1), grade 3 mucositis (n=2), grade 3 anemia (n=1), and grade 2 mucositis (n=1). At the time of analysis, all patients had permanently discontinued everolimus: 7 (23%) due to AEs, 23 (74%) due to disease progression, and 1 case (3%) due to unknown reasons. The toxicities that led to discontinuation were grade 3 stomatitis (n=1), grade 3 pneumonitis (n=2), grade 2 rash (n=1), grade 3 anemia (n=1), repeated episodes of grade 1 diarrhea and fever (n=1), and grade 2 gastric bleeding (n=1).\n\nTwenty-four patients (77%) reported 51 AEs (Table 3). From among these, only 14 (27%) were graded as 3 or 4 and were reported by 13 patients (42%). No deaths due to AEs were reported. The most common AEs were anemia (29%), stomatitis (26%), and pneumonitis (23%). The most common grade 3/4 AEs were anemia and stomatitis (10% each), while grade 3 pneumonitis was reported in 2 cases (7%).\n\nPrevious length of exposure to pazopanib was not associated with the occurrence of a grade 3/4 event: the median exposure to pazopanib was 5.1 months for the 18 patients with no such events vs 5.9 months for the 13 patients reporting grade 3 or 4 events.\n\nDiscussion\nData regarding the efficacy and safety of available agents following first-line pazopanib in mRCC are scarce. This is the only study providing data exclusively on the sequence pazopanib–everolimus in mRCC with no other first- or second-line therapies having been used. Limitations to this study are those inherent to the small number of patients, as well as the retrospective and noninterventional design, more importantly, the absence of standardized assessments at predefined intervals as there are in clinical trials. However, first- and second-line treatment was highly homogeneous (in contrast to most other similar studies, Table 4), and the median follow-up was among the longest reported for similar studies. Furthermore, observational noninterventional studies are important sources of information about the use of agents in the real-world clinical setting. Therefore, we believe that the information provided is reliable and of importance.\n\nEarlier, patients treated with everolimus after exposure to pazopanib have been included as part of a broader population in 6 studies,22 but results on this exact sequence have been reported only in one of them (Table 4). In all cases, patients treated with pure second-line everolimus after first-line pazopanib formed minority subgroups in the total population. In the randomized Phase III study METEOR,19 which compared cabozantinib with everolimus as second- or third-line treatment, first-line pazopanib was used in 41% of included patients in the everolimus arm, while 28% had received 2 previous lines of therapy. The median PFS in the everolimus arm was 3.8 months, but no information about the pazopanib pretreated subgroup yet exists. Similarly, in 2 other randomized trials,20,21 pazopanib was the first-line agent in 32% and 25%, respectively, while second-line everolimus formed 72% and 100% of the everolimus arm. Median PFSs of 4.4 and 5.5 months for the whole populations were reported. In the recently published prospective, observational CHANGE study,7 median PFS for mRCC patients receiving everolimus as second-line treatment (again a subgroup of the total population) was 6.9 months. However, only 4% of the patients had received pazopanib as first-line treatment. Interestingly, patients pretreated with pazopanib had the numerically shortest treatment duration with everolimus (only 3 months vs at least 6 months with any other agent administered in first line). Finally, in 2 retrospective studies including 35 patients each, all patients received first-line pazopanib.22,23 A median PFS of 5.7 months for a mixed population of everolimus and temsirolimus was found in the first study, while Bellmunt et al23 reported a median PFS of 2.8 months in a subpopulation of 13 patients, 2 of whom had received IFN-α prior to pazopanib.\n\nWe report a PFS of 3.5 months. Although the 13% response rate we found is encouraging, our median PFS as well as that reported by Bellmunt et al23 seem modest compared to those reported so far for everolimus given after failure of other anti-VEGF/VEGFR treatment in the largest series (Table 4). In most cases, pure second-line everolimus populations represented subgroups (thus limiting the power of those analyses) of broader populations who had been exposed to a variety of first-line agents and/or had received everolimus not only in second but also in subsequent lines of therapy. In the RECORD-1 study,8 the subgroup of patients who received only 1 previous VEGFR-TKI (21%) had a median PFS of 4.6 and 3.8 months for first-line sunitinib and sorafenib, respectively. In the recently reported prospective Phase II RECORD-4 study,9 a median PFS of 5.7 months was recorded for patients receiving first-line sunitinib. Similar PFS for pure second-line use of everolimus was also found in a pooled analysis of 4 noninterventional European studies10 (Table 3). The reasons for the numerically longer PFS reported in those studies, apart from the limitations inherent to across-studies comparisons, are unclear. It is unlikely that this was related to the use of pazopanib in the first line. Pazopanib has been shown to be noninferior to sunitinib14 in a randomized study, wherein the use of subsequent therapies, including everolimus, was balanced between the 2 arms.24 Differences in the prognostic characteristics of our population might account for the seemingly “inferior” PFS observed in our study. Several of the previously mentioned studies are prospective Phase II or III national or international studies. Patients enrolled in such trials do not reflect real-world patients and everyday clinical practice, since most trials have strict eligibility criteria, assessment times, and follow-up schedules. This results in selection of patients with better prognosis, as shown by a significantly shorter second-line PFS for trial-ineligible patients in a retrospective analysis of 768 patients.17 Features of poor prognosis were observed at the initiation of both first- and second-line therapies in our series. Indeed, only 13% were favorable-risk patients at the initiation of pazopanib, reflected by a respective median OS of 14.8 months, which is numerically shorter than that reported in the pivotal trial of pazopanib,13 but which is in line with data from unselected cohorts.25 Furthermore, at the initiation of second-line treatment, only 26% of patients had performance status (PS) 0, most belonged to the intermediate or poor MSKCC risk groups (88%), only 61% had undergone nephrectomy, while 80% had at least 2 metastatic sites. These features are indicative of poor outcome26–28 and are in sharp contrast with the 91% good or intermediate risk and 89% nephrectomy rate in the noninterventional study by Albiges et al10 in a non-pazopanib-treated population.\n\nThe reason for the inclusion of predominantly bad prognosis patients in our study is unclear. It could be suggested that pazopanib and everolimus were intuitively offered to patients of relatively poor prognosis due to their favorable toxicity profiles compared to other drugs.14,15 This hypothesis is supported by the lower-than-expected nephrectomy rate in our population, since nephrectomy is usually offered to patients of good PS.3 Therefore, it seems plausible that oncologists might offer this agent to patients of poor PS and, therefore, poor prognosis. A large multinational study of real-life pazopanib use,29 which has completed accrual, will shed light on the utilization of pazopanib in everyday practice. Another reason for the unfavorable outcome of our patients was the timing of everolimus treatment in this study, which did not allow for the inclusion of long-term responders to pazopanib. Indeed, 18 patients (58%) started everolimus prior to 2013, while pazopanib was approved in Greece and Spain in 2011. The possibility that long-term responders to pazopanib were offered a TKI rather than everolimus cannot also be excluded, while the inclusion of patients with favorable characteristics in clinical trials conducted at the same period could also represent another reason for a negative selection in the RESCUE study. It should be stressed that even in this population of unfavorable prognosis, median PFS on everolimus was numerically 2-fold higher than that reported in the RECORD-1 study for placebo, underlying the efficacy of everolimus after first-line pazopanib.\n\nThe correlation between response to a first-line VEGF-targeted agent and second-line therapy remains controversial. There is some evidence that longer exposure to first-line VEGF-targeted agents may be associated with increased efficacy of second-line everolimus therapy,7,30,31 although opposite results have also been published.10 Likewise, similar studies for second-line TKIs have been inconclusive.32 In our analysis, there was a significant prolongation of OS after everolimus with longer previous exposure to pazopanib. Similar findings were reported in a subanalysis of the AXIS trial33 for axitinib and sorafenib following sunitinib. These findings taken together suggest that longer first-line treatment duration may correspond to a less-aggressive tumor behavior rather than higher efficacy of everolimus after long exposure to pazopanib.\n\nThe safety profile of everolimus when used after pazopanib in mRCC patients was similar to that observed after other anti-VEGF therapies, as reported in clinical trials16,32 and noninterventional studies.7,10 Importantly, previous exposure to pazopanib does not seem to affect the tolerability of subsequent everolimus administration. Dose interruptions were similar to those reported in RECORD-1 (32% vs 38%). The rate of discontinuation due to AEs was higher (23%) than in the expanded access study (17%)23 or RECORD-1 (13%)16 but identical to those of the noninterventional studies by Albiges et al (25%)10 and Bergmann et al (21%).7 This discrepancy could be a result of the different methods of reporting AEs in clinical practice and clinical trials, but it could also reflect the poorer PS and higher incidence of comorbidities of patients in real-life practice.\n\nIt is important that our findings are viewed within the context of the rapid developments in the mRCC treatment paradigm. Recently, 2 Phase III randomized trials showed superiority of nivolumab, an immune checkpoint inhibitor, and cabozantinib, a multi-TKI of MET, AXL, and VEGF, over everolimus after VEGFR-targeted treatment failure.19,20 These results have granted these agents a dominant position in the treatment of relapsed mRCC patients.34 Nevertheless, only nivolumab is yet freely available in Europe, while availability of both agents may be a problem in some countries worldwide. Therefore, our results will still be applicable for the immediate future. More importantly, the recent improvements in the prognosis of mRCC patients have been achieved through the utilization of multiple effective agents. The emergence of new drugs should be viewed as a valuable addition to the existing agents rather than as a competing process of replacement, since they can all contribute toward an improved therapeutic effect for mRCC patients.\n\nConclusion\nWe showed that everolimus used as second-line treatment after pazopanib in mRCC patients is effective and safe in a real-life, multi-institutional setting. This sequence could be considered a standard option for these patients in cases of unavailability or contraindication of other more effective agents.\n\nSupplementary material\nThe centers that participated in the RESCUE study and the relevant ethical committees are as follows:\nHospital Virgen del Rocío, Sevilla, Spain; Ethics and Scientific Committee, Hospital Virgen del Rocío, Sevilla, Spain.\n\nDepartment of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens, Athens, Greece; Scientific Committee, Alexandra Hospital, Athens, Greece.\n\nUniversity Hospital of Heraklion, Heraklion, Greece; Scientific Committee, University Hospital of Heraklion, Heraklion, Greece.\n\n251 Airforce General Hospital, Department of Medical Oncology, Athens, Greece; Scientific Committee, 251 Airforce General Hospital, Athens, Greece.\n\nDepartment of Oncology, Euromedica Geniki Kliniki, Thessaloniki, Greece; Ethics and Scientific Committee, Euromedica General Clinic, Thessaloniki, Greece.\n\n2nd Oncology Clinic, Metropolitan Hospital, Piraeus, Greece; Scientific Committee, Metropolitan Hospital, Piraeus, Greece.\n\nSaint Savvas Anticancer Hospital, Athens, Greece; Scientific Committee, Saint Savvas Anticancer Hospital, Athens, Greece.\n\nDivision of Oncology, Department of Medicine, University Hospital, University of Patras Medical School, Patras, Greece; Scientific Committee, University Hospital, Patras, Greece.\n\n\n\nAcknowledgments\nThis study was sponsored by the Hellenic Genito-Urinary Cancer Group and supported by Novartis Pharmaceuticals. Study design, data collection, access to the data, and analysis, as well as writing of the manuscript, were solely the responsibility of the sponsor and the authors.\n\nThe following persons also contributed to data acquisition and analysis: Loukas Kontovinis (clinical investigator; Hellenic Genito-Urinary Cancer Group [HGUCG]; Euro-medica General Clinic, Thessaloniki, Greece), Angelos Koutras (clinical investigator; Division of Oncology, Department of Medicine, University Hospital, University of Patras Medical School, Patras, Greece), J Varkarakis (participating investigator; HGUCG; 2nd Urology Department, National and Kapodistrian University of Athens, Athens, Greece), J Adamakis (participating investigator; 1st Urology Department, National and Kapodistrian University of Athens, Athens, Greece), J Anastasiou (participating investigator; 1st Urology Department, National and Kapodistrian University of Athens, Athens, Greece), Nikolaos K Kentepozidis (clinical and participating investigator; HGUCG; Department of Oncology, Department of Medical Oncology, 251 Airforce General Hospital, Athens, Greece,), Alexandros Ardavanis (clinical and participating investigator; Saint Savvas Anticancer Hospital, Athens, Greece), Constantine A Constantinides (participating investigator; HGUCG; 1st Urology Department, National and Kapodistrian University of Athens, Athens, Greece), and Meletios A Dimopoulos (clinical and participating investigator; HGUCG; Oncology Unit, Department of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens, Athens, Greece).\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 Kaplan–Meier curves of PFS and OS from the initiation of everolimus in 31 patients with metastatic renal cell carcinoma treated with the sequence pazopanib–everolimus.\n\nAbbreviations: OS, overall survival; PFS, progression-free survival.\n\nFigure 2 Kaplan–Meier curves of overall survival from the initiation of everolimus in 31 patients with metastatic renal cell carcinoma treated with the sequence pazopanib–everolimus according to the time of exposure to first-line pazopanib: ≤9 months and >9 months.\n\nTable 1 Patient and disease characteristics in the overall study population, N=31\n\nCharacteristics\t\t\nMedian age (range), years\t58 (41–81)\t\nSex, n (%)\t\n Male\t19 (61)\t\n Female\t12 (39)\t\nHistology, n (%)\t\n Clear cell\t29 (94)\t\n Mixed histology\t2 (6)\t\nPerformance status, n (%)\t\n 0\t8 (26)\t\n 1\t16 (51)\t\n 2\t4 (13)\t\n Missing\t3 (10)\t\nPrevious nephrectomy, n (%)\t19 (61)\t\nDisease sites, n (%)\t\n Renal bed\t7 (23)\t\n Bones\t8 (26)\t\n Liver\t10 (32)\t\n Lungs\t22 (71)\t\n Lymph nodes\t14 (45)\t\n Brain\t2 (7)\t\n Other\t11 (36)\t\nPrevious treatment with pazopanib\t\nMSKCC risk score, n (%)\t\n Favorable\t4 (13)\t\n Intermediate\t12 (39)\t\n Poor\t8 (26)\t\n Missing\t7 (22)\t\nDuration of pazopanib therapy, months\t\n Median (range)\t5.6 (0.5–19)\t\n >3\t22 (70%)\t\n >6\t11 (35%)\t\n >9\t6 (19%)\t\nAbbreviation: MSKCC, Memorial Sloan-Kettering Cancer Center.\n\nTable 2 Median PFS and OS after everolimus initiation according to exposure to pazopanib\n\nTime on pazopanib, months\tn\tPFS, months\n\tOS, months\n\t\nMedian\t95% CI\tp-value\tMedian\t95% CI\tp-value\t\n<3\t9\t2.3\t0.9–7\t0.3704\t6.4\t1.8–8.7\t0.0021\t\n≥3\t22\t3.5\t2.6–5.5\t\t11.1\t7.5–16.4\t\t\n<6\t20\t3.2\t1.9–5\t0.5884\t7.5\t4.4–11.4\t0.0160\t\n≥6\t11\t3.5\t1–9.9\t\t15.9\t6.5–NR\t\t\n<9\t25\t2.8\t2.1–4.4\t0.0970\t7.9\t5.7–11.1\t0.0066\t\n≥9\t6\t6.4\t3–NR\t\tNR\t8.9–NR\t\t\nAbbreviations: NR, not reached; OS, overall survival; PFS, progression-free survival.\n\nTable 3 Adverse events on everolimus treatment\n\nAdverse event\tGrade, n (%)\n\tN (%)\n\t\n1\t2\t3\t4\tTotal\t\nAnemia\t2 (7)\t4 (13)\t2 (7)\t1 (3)\t9 (29)\t\nStomatitis\t4 (13)\t1 (3)\t3 (10)\t0\t8 (26)\t\nPneumonitis\t2 (7)\t2 (7)\t2 (7)\t0\t6 (19)\t\nFatigue\t1 (3)\t2 (7)\t0\t0\t3 (10)\t\nBone/joint pain/toothache\t2 (7)\t0\t1 (3)\t0\t3 (10)\t\nBleeding\t0\t1 (3)\t1 (3)\t0\t2 (7)\t\nLack of appetite\t1 (3)\t1 (3)\t0\t0\t2 (7)\t\nDiarrhea\t2 (7)\t0\t0\t0\t2 (7)\t\nFever\t2 (7)\t0\t0\t0\t2 (7)\t\nRash\t1 (3)\t1 (3)\t0\t0\t2 (7)\t\nHypercalcemia\t0\t1 (3)\t0\t1 (3)\t2 (7)\t\nLiver function test elevation\t1 (3)\t1 (3)\t0\t0\t2 (7)\t\nAlopecia\t1 (3)\t0\t0\t0\t1 (3)\t\nPleural effusion\t0\t0\t1 (3)\t0\t1 (3)\t\nPulmonary embolism\t0\t0\t1 (3)\t0\t1 (3)\t\nAcute renal failure–proteinuria\t0\t0\t1 (3)\t0\t1 (3)\t\nHyperlipidemia\t1 (3)\t0\t0\t0\t1 (3)\t\nEdema\t0\t1 (3)\t0\t0\t1 (3)\t\nTable 4 Efficacy of everolimus as second-line treatment in mRCC patients\n\nStudy (reference)\tDesign\tNumber of patients receiving second-line everolimus (% of everolimus-treated population)\tPrior therapy\tPFS\tOS\t\nRECORD-18\tPhase III\t43 (16)\tSunitinib\t4.6\tNR\t\n18 (6)\tSorafenib\t3.8\tNR\t\nRECORD-49\tPhase II\t58 (100)\tSunitinib\t5.7\tNR\t\nAlbiges et al10\tPooled analysis, noninterventional\t493 (78)\tSunitinib, sorafenib, and bevacizumab\t5.8\t11.2\t\nCHANGE7\tProspective, noninterventional\t211 (72)\tSunitinib, sorafenib, pazopanib (4%), bevacizumab, and cytokines\t6.9*\tNR\t\nMETEOR19\tPhase III\t136 (72)\tSunitinib, sorafenib, pazopanib (41%), bevacizumab, cytokines, and nivolumab\t3.8*,#\tNR\t\nCheckMate 02520\tPhase III\t297 (72)\tSunitinib, pazopanib (32%), and axitinib\t4.4*,#\t19.6*\t\nMotzer et al21\tPhase II\t50 (100)\tSunitinib, sorafenib, pazopanib (25%), axitinib, and bevacizumab\t5.5*\tNR\t\nVogelzang et al22\tRetrospective\t22 (100)\tPazopanib (100%)\t5.7**\t16.0**\t\nBellmunt et al23\tRetrospective\t13 (100)&\tPazopanib (100%)\t2.4\t20.8\t\nRESCUE\tRetrospective\t31 (100)\tPazopanib (100%)\t3.5\t8.9\t\nNotes: Median PFS and OS are provided in months.\n\n* PFS not reported for the pazopanib subgroup;\n\n# pure second-line everolimus analysis not reported;\n\n** PFS for both temsirolimus and everolimus treated patients.\n\n& 2 patients had received cytokines prior to pazopanib.\n\nAbbreviations: mRCC, metastatic renal cell carcinoma; NR, not recorded; OS, overall survival; PFS, progression-free survival.\n==== Refs\nReferences\n1 NCCN Clinical Practice Guidelines in Oncology: Kidney Cancer 2015 Version 1. Available from: http://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf Accessed August 28, 2017 \n2 Ljungberg B Bensalah K Canfield S EAU guidelines on renal cell carcinoma: 2014 update Eur Urol 2015 67 5 913 924 25616710 \n3 Escudier B Porta C Schmidinger M Renal cell carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up Ann Oncol 2014 25 suppl 3 iii49 iii56 25210086 \n4 Alimohamed N Lee JL Srinivas S A population-based overview of sequences of targeted therapy in metastatic renal cell carcinoma Clin Genitourin Cancer 2014 12 4 e127 e131 24485801 \n5 Ko JJ Choueiri TK Rini BI First-, second-, third-line therapy for mRCC: benchmarks for trial design from the IMDC Br J Cancer 2014 110 8 1917 1922 24691425 \n6 Heng DY Signorovitch J Swallow E Comparative effectiveness of second-line targeted therapies for metastatic renal cell carcinoma: a systematic review and meta-analysis of real-world observational studies PLoS One 2014 9 12 e114264 25493562 \n7 Bergmann L Kube U Doehn C Everolimus in metastatic renal cell carcinoma after failure of initial anti-VEGF therapy: final results of a noninterventional study BMC Cancer 2015 15 303 25925846 \n8 Calvo E Escudier B Motzer RJ Everolimus in metastatic renal cell carcinoma: subgroup analysis of patients with 1 or 2 previous vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapies enrolled in the phase III RECORD-1 study Eur J Cancer 2012 48 3 333 339 22209391 \n9 Motzer RJ Alyasova A Ye D Phase II trial of second-line everolimus in patients with metastatic renal cell carcinoma (RECORD-4) Ann Oncol 2016 27 3 441 448 26681676 \n10 Albiges L Kube U Eymard JC Everolimus for patients with metastatic renal cell carcinoma refractory to anti-VEGF therapy: results of a pooled analysis of non-interventional studies Eur J Cancer 2015 51 16 2368 2374 26276039 \n11 Kontovinis L Laschos K Karadimou A Sequential treatment with sorafenib and sunitinib in metastatic renal cell carcinoma: clinical outcomes from a retrospective clinical study Med Oncol 2012 29 2 750 754 21279702 \n12 Rini BI Escudier B Tomczak P Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial Lancet 2011 378 9807 1931 1939 22056247 \n13 Sternberg CN Davis ID Mardiak J Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial J Clin Oncol 2010 28 6 1061 1068 20100962 \n14 Motzer RJ Hutson TE Cella D Pazopanib versus sunitinib in metastatic renal-cell carcinoma N Engl J Med 2013 369 8 722 731 23964934 \n15 Escudier B Porta C Bono P Randomized, controlled, double-blind, cross-over trial assessing treatment preference for pazopanib versus sunitinib in patients with metastatic renal cell carcinoma: PISCES Study J Clin Oncol 2014 32 14 1412 1418 24687826 \n16 Motzer RJ Escudier B Oudard S Ravaud A RECORD-1 Study Group Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial Lancet 2008 372 9637 449 456 18653228 \n17 Heng DY Choueiri TK Rini BI Outcomes of patients with metastatic renal cell carcinoma that do not meet eligibility criteria for clinical trials Ann Oncol 2014 25 1 149 154 24356626 \n18 Motzer RJ Bacik J Schwartz LH Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma J Clin Oncol 2004 22 3 454 463 14752067 \n19 Choueiri TK Escudier B Powles T METEOR Investigators Cabozantinib versus everolimus in advanced renal-cell carcinoma N Engl J Med 2015 373 19 1814 1823 26406150 \n20 Motzer RJ Escudier B McDermott DF CheckMate 025 Investigators Nivolumab versus everolimus in advanced renal-cell carcinoma N Engl J Med 2015 373 19 1803 1813 26406148 \n21 Motzer RJ Hutson TE Glen H Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial Lancet Oncol 2015 16 15 1473 1482 26482279 \n22 Vogelzang NJ Hackshaw MD Hutson TE First-line and sequential use of pazopanib followed by mammalian target of rapamycin inhibitor therapy among patients with advanced renal cell carcinoma in a US community oncology setting Clin Genitourin Cancer 2015 13 3 210 217 25498215 \n23 Bellmunt J Pons F Foreshew A Sequential targeted therapy after pazopanib therapy in patients with metastatic renal cell cancer: efficacy and toxicity Clin Genitourin Cancer 2014 12 4 262 269 24795159 \n24 Motzer RJ Hutson TE McCann L Deen K Choueiri TK Overall survival in renal-cell carcinoma with pazopanib versus sunitinib N Engl J Med 2014 370 18 1769 1770 24785224 \n25 Soerensen AV Donskov F Hermann GG Improved overall survival after implementation of targeted therapy for patients with metastatic renal cell carcinoma: results from the Danish Renal Cancer Group (DARENCA) study-2 Eur J Cancer 2014 50 3 553 562 24215846 \n26 Heng DY Xie W Regan MM Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study J Clin Oncol 2009 27 34 5794 5799 19826129 \n27 Bamias A Tzannis K Papatsoris A Prognostic significance of cytoreductive nephrectomy in patients with synchronous metastases from renal cell carcinoma treated with first-line sunitinib: a European multi-institutional study Clin Genitourin Cancer 2014 12 5 373 383 24819319 \n28 Bamias A Tzannis K Beuselinck B Development and validation of a prognostic model in patients with metastatic renal cell carcinoma treated with sunitinib: a European collaboration Br J Cancer 2013 109 2 332 341 23807171 \n29 Bamias A Bono P Procopio G PRINCIPAL: a prospective observational study of real-world treatment patterns and treatment outcomes in patients with advanced or metastatic renal cell carcinoma (mRCC) receiving pazopanib J Clin Oncol 2014 32 5s sul;abstrTS4600^ \n30 Chen CC Hess GP Liu Z Second-line treatment outcomes after first-line sunitinib therapy in metastatic renal cell carcinoma Clin Genitourin Cancer 2012 10 4 256 261 22682982 \n31 Buchler T Bortlicek Z Poprach A Efficacy of everolimus in second- and third-line therapy for metastatic renal cell carcinoma: a registry-based analysis Urol Oncol 2014 32 5 569 575 24629497 \n32 Grunwald V Karakiewicz PI Bavbek SE REACT Study Group An international expanded-access programme of everolimus: addressing safety and efficacy in patients with metastatic renal cell carcinoma who progress after initial vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapy Eur J Cancer 2012 48 3 324 332 21803569 \n33 Escudier B Michaelson MD Motzer RJ Axitinib versus sorafenib in advanced renal cell carcinoma: subanalyses by prior therapy from a randomised phase III trial Br J Cancer 2014 110 12 2821 2828 24823696 \n34 Powles T Staehler M Ljungberg B Updated EAU guidelines for clear cell renal cancer patients who fail VEGF targeted therapy Eur Urol 2016 69 1 4 6 26508312\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1178-6930",
"issue": "10()",
"journal": "OncoTargets and therapy",
"keywords": "everolimus; pazopanib; renal cell carcinoma",
"medline_ta": "Onco Targets Ther",
"mesh_terms": null,
"nlm_unique_id": "101514322",
"other_id": null,
"pages": "4885-4893",
"pmc": null,
"pmid": "29062235",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": "24795159;24691425;22682982;25616710;21803569;24785224;26406150;19826129;14752067;21279702;24687826;26681676;25925846;24356626;25498215;24215846;26508312;24823696;26406148;23807171;24819319;24629497;22056247;26276039;24485801;22209391;26482279;18653228;25210086;20100962;23964934;25493562",
"title": "Real-world experience of everolimus as second-line treatment in metastatic renal cell cancer after failure of pazopanib.",
"title_normalized": "real world experience of everolimus as second line treatment in metastatic renal cell cancer after failure of pazopanib"
} | [
{
"companynumb": "PHHY2017GR161981",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EVEROLIMUS"
},
"drugadditional": "3",
"druga... |
{
"abstract": "Other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA-LPD) comprise lymphoid proliferations or lymphomas that arise in patients treated with immunosuppressive drugs for autoimmune diseases, especially rheumatoid arthritis (RA) treated with methotrexate (MTX). MTX has been increasingly administered to patients with RA, resulting in methotrexate-associated lymphoproliferative disorder (MTX-LPD) in patients. We report herein on four cases of patients with RA, who diagnosed with head and neck region. In two cases (one case MTX and another case tacrolimus) drug therapy was discontinued, when the patients were diagnosed as having OIIA-LPD in only a few local findings. These patients have followed good clinical courses for 24 months. In the other two cases, consultations were performed for cervical lymphadenopathy by the Division of Rheumatology. In one case drug therapy was discontinued and a good clinical course was followed. In case of the other patient, however, who had undergone tacrolimus therapy after MTX therapy was discontinued, she relapsed and died. In the case of patients with an autoimmune disease such as RA who are taking MTX, tacrolimus, or anti TNF-α therapy, when cervical lymphadenopathy and extranodal disease are detected, OIIA-LPD should be suspected. We should cooperate with a hematologist-oncologist, a rheumatologist, and pathologist in such a case.",
"affiliations": null,
"authors": "Fukasawa|Masahiko|M|;Akazawa|Yoshihiro|Y|;Kasugai|Shigeru|S|;Mikami|Koshi|K|;Saito|Yoshimitsu|Y|;Akutsu|Masatoshi|M|;Akashi|Aibi|A|;Ido|Kojiro|K|;Maeda|Ichiro|I|;Hoshikawa|Masahiro|M|;Koizuka|Izumi|I|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.3950/jibiinkoka.119.741",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0030-6622",
"issue": "119(5)",
"journal": "Nihon Jibiinkoka Gakkai kaiho",
"keywords": null,
"medline_ta": "Nihon Jibiinkoka Gakkai Kaiho",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006257:Head; D006801:Humans; D007049:Iatrogenic Disease; D008232:Lymphoproliferative Disorders; D008297:Male; D008875:Middle Aged; D009333:Neck; D016896:Treatment Outcome",
"nlm_unique_id": "7505728",
"other_id": null,
"pages": "741-9",
"pmc": null,
"pmid": "27459820",
"pubdate": "2016-05",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Four Cases of Other Iatrogenic Immunodeficiency-associated Lymphoproliferative Disorders in the Head and Neck Region.",
"title_normalized": "four cases of other iatrogenic immunodeficiency associated lymphoproliferative disorders in the head and neck region"
} | [
{
"companynumb": "PHHY2016JP152105",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FOLIC ACID"
},
"drugadditional": null,
"drug... |
{
"abstract": "BACKGROUND\nAcute promyelocytic leukaemia (APL) is a distinct clinical and biological subtype of acute myeloid leukaemia. APL is notorious for causing early death during induction therapy, resulting in induction failure. The aim of our study was to report the clinical characteristics, outcome and early induction deaths with regard to patients with APL seen at our hospital.\n\n\nMETHODS\nThis was a retrospective study carried out at Aga Khan University Hospital, Karachi, Pakistan. Patients aged > 15 years diagnosed with APL within the period September 2007-September 2012 were included in the study.\n\n\nRESULTS\nWithin the study period, 26 patients were diagnosed with APL based on morphology and the detection of t(15;17)(q24.1;q21.1) and promyelocytic leukaemia-retinoic acid receptor alpha (PML-RARA). The male to female ratio was 1:1. The median age of the patients was 41 (range 16-72) years. In all, there were 13 (50.0%) high-risk patients, and early induction death rate was 61.5%. Causes of early induction deaths (n = 16) included haemorrhage in 7 (43.8%) patients, differentiation (ATRA) syndrome in 7 (43.8%) and infection in 2 (12.5%). The survival rate among patients who survived the early period was 70% at 42 months. The relapse rate was 30%.\n\n\nCONCLUSIONS\nEarly induction death rate was very high in patients with APL. The most common cause of early induction death in our study was haemorrhage. Outcome among patients with APL was found to be better among those who survived the initial period.",
"affiliations": "Section of Hematology, Department of Pathology and Microbiology, Aga Khan University Hospital, Stadium Road, Karachi 74800, Pakistan. farheen.mahar@aku.edu.",
"authors": "Karim|Farheen|F|;Shaikh|Usman|U|;Adil|Salman Naseem|SN|;Khurshid|Mohammad|M|",
"chemical_list": null,
"country": "Singapore",
"delete": false,
"doi": "10.11622/smedj.2014105",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0037-5675",
"issue": "55(8)",
"journal": "Singapore medical journal",
"keywords": null,
"medline_ta": "Singapore Med J",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute; D008297:Male; D008875:Middle Aged; D010154:Pakistan; D012008:Recurrence; D012189:Retrospective Studies; D062606:Tertiary Care Centers; D013997:Time Factors; D014178:Translocation, Genetic; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "0404516",
"other_id": null,
"pages": "443-7",
"pmc": null,
"pmid": "25189308",
"pubdate": "2014-08",
"publication_types": "D016428:Journal Article",
"references": "23371042;10792270;12393590;13508085;3862359;12801292;3165295;18812465;21502956;8695858;6928105;20696473;19797519;18195095;12935961;22220250;1517784;9242531;21653939;18803891;11818666;21385856;14576047;17205057;18945964;22550558;11806975;18024380;18299451;20393132;15661272;12162911;23325837;15142116;7858250",
"title": "Clinical characteristics, outcome and early induction deaths in patients with acute promyelocytic leukaemia: a five-year experience at a tertiary care centre.",
"title_normalized": "clinical characteristics outcome and early induction deaths in patients with acute promyelocytic leukaemia a five year experience at a tertiary care centre"
} | [
{
"companynumb": "PK-ROCHE-1461458",
"fulfillexpeditecriteria": "1",
"occurcountry": "PK",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MITOXANTRONE HYDROCHLORIDE"
},
"drugadditional": null... |
{
"abstract": "Eikenella corrodens is a facultatively anaerobic gram-negative rod bacterium in the oropharynx and respiratory tract. It is a member of HACEK (Haemophilus spp., Aggregatibacter spp., Cardiobacterium hominis, E. corrodens, and Kingella kingae) group commonly associated with endocarditis and craniofacial infections. It is usually susceptible to penicillin, second and third-generation cephalosporins, and carbapenem, but has variable susceptibility to first-generation cephalosporin. We herein provide a description of the first case of pediatric acute dacryocystitis caused by E. corrodens. The patient did not respond to oral cephalexin and required surgical drainage followed by intravenous cefotaxime. Also provided is a brief review of the current literature.",
"affiliations": "Department of General Pediatrics, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan. Electronic address: miki_tanaka@tmhp.jp.;Division of Infectious Diseases, Department of Pediatrics, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan; Division of Immunology, Department of Pediatrics, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan.;Department of Laboratory, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan.;Division of Infectious Diseases, Department of Pediatrics, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan; Division of Immunology, Department of Pediatrics, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan.;Division of Infectious Diseases, Department of Pediatrics, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan; Division of Immunology, Department of Pediatrics, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan.;Department of General Pediatrics, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan.",
"authors": "Tanaka|Miki|M|;Araki|Kotaro|K|;Higuchi|Hiroshi|H|;Fukuoka-Araki|Kahoru|K|;Horikoshi|Yuho|Y|;Hataya|Hiroshi|H|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002439:Cefotaxime; D002506:Cephalexin",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jiac.2019.12.014",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-321X",
"issue": "26(5)",
"journal": "Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy",
"keywords": "Dacryocystitis; Eikenella corrodens; HACEK",
"medline_ta": "J Infect Chemother",
"mesh_terms": "D000208:Acute Disease; D064206:Aggregatibacter; D000900:Anti-Bacterial Agents; D044066:Cardiobacterium; D002439:Cefotaxime; D002506:Cephalexin; D002675:Child, Preschool; D003607:Dacryocystitis; D004333:Drug Administration Routes; D016124:Eikenella corrodens; D005260:Female; D016905:Gram-Negative Bacterial Infections; D006190:Haemophilus; D006801:Humans; D017881:Kingella; D008826:Microbial Sensitivity Tests; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "9608375",
"other_id": null,
"pages": "510-512",
"pmc": null,
"pmid": "31982291",
"pubdate": "2020-05",
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"abstract": "BACKGROUND\nIn situations where the time to delivery is urgent, but not critical within minutes, and otherwise contraindicated spinal anesthesia is the safer option of avoiding the risks and complications of general anesthesia, mainly difficult airway and risks of pulmonary aspiration.\n\n\nMETHODS\nA 35 years old woman (Gravida-7, para 6) having an emergency cesarean section under spinal anesthesia for the indication of cephalopulvic disproportion (CPD). Spinal anesthesia given at L3/L4, with a sensory block of T-4, the fetus delivered uneventfully. Meanwhile, the mother complains difficulty of breathing, developed hypotension, bradycardia, hypoxia, and loss of consciousness. Immediate maternal resuciation done with vasopressor support, endotracheal intubation, and mechanical ventilation. Over a week, the patient progressively regained motor and sensory functions and discharged without any neurological or clinical sequelae.\n\n\nCONCLUSIONS\nTotal spinal anesthesia is an uncommon incident that can happen during epidural anesthesia, caudal anesthesia, spinal anesthesia, lumbar plexus block, paravertebral block, stellate ganglion block, interscalene brachial blocks, and other regional anesthesia techniques performed at or near to the vertebral column. Often characterized by a sudden decrease in blood pressure, rapidly increasing motor block, difficulty of breathing, loss of consciousness, dilated pupils, apnea, and even cardiac arrest.\n\n\nCONCLUSIONS\nUnexpected total spinal anesthesia during neuraxial anesthesia can produce devastating consequences. Precautionary measures should be made during the conduct of regional anesthesia for high-risk patients and early identification and immediate intervention should be applied.",
"affiliations": "Department of Anesthesia, College of Medicine and Health Sciences, Bahir Dar University, Bahir Dar, Ethiopia. Electronic address: asfaw.57@gmail.com.;Department of Anesthesia, College of Medicine and Health Sciences, Bahir Dar University, Bahir Dar, Ethiopia.",
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"fulltext": "\n==== Front\nInt J Surg Case Rep\nInt J Surg Case Rep\nInternational Journal of Surgery Case Reports\n2210-2612 Elsevier \n\nS2210-2612(20)30850-6\n10.1016/j.ijscr.2020.09.177\nCase Report\nA case of total spinal anesthesia\nAsfaw Gebrehiwot asfaw.57@gmail.com⁎ Eshetie Atalay Department of Anesthesia, College of Medicine and Health Sciences, Bahir Dar University, Bahir Dar, Ethiopia\n⁎ Corresponding author. asfaw.57@gmail.com\n29 9 2020 \n2020 \n29 9 2020 \n76 237 239\n1 8 2020 26 9 2020 27 9 2020 © 2020 The Authors2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• Total spinal or a high neuraxial blockade is a recognized complication of central neuraxial techniques.\n\n• Total spinal anesthesia is characterized by acute onset hemodynamic instability, shortness of breath, dyspnea, with a precipitous decline in GCS.\n\n• It happened immediately after spinal anesthesia but it may happen even an hour after anesthesia.\n\n• The anesthetist performing these procedures must be aware of this serious complication and must remain vigilant throughout.\n\n• The management is mainly supportive care.\n\n\n\nIntroduction\nIn situations where the time to delivery is urgent, but not critical within minutes, and otherwise contraindicated spinal anesthesia is the safer option of avoiding the risks and complications of general anesthesia, mainly difficult airway and risks of pulmonary aspiration.\n\nCase presentation\nA 35 years old woman (Gravida-7, para 6) having an emergency cesarean section under spinal anesthesia for the indication of cephalopulvic disproportion (CPD). Spinal anesthesia given at L3/L4, with a sensory block of T-4, the fetus delivered uneventfully. Meanwhile, the mother complains difficulty of breathing, developed hypotension, bradycardia, hypoxia, and loss of consciousness. Immediate maternal resuciation done with vasopressor support, endotracheal intubation, and mechanical ventilation. Over a week, the patient progressively regained motor and sensory functions and discharged without any neurological or clinical sequelae.\n\nDiscussion\nTotal spinal anesthesia is an uncommon incident that can happen during epidural anesthesia, caudal anesthesia, spinal anesthesia, lumbar plexus block, paravertebral block, stellate ganglion block, interscalene brachial blocks, and other regional anesthesia techniques performed at or near to the vertebral column. Often characterized by a sudden decrease in blood pressure, rapidly increasing motor block, difficulty of breathing, loss of consciousness, dilated pupils, apnea, and even cardiac arrest.\n\nConclusion\nUnexpected total spinal anesthesia during neuraxial anesthesia can produce devastating consequences. Precautionary measures should be made during the conduct of regional anesthesia for high-risk patients and early identification and immediate intervention should be applied.\n\nKeywords\nComplete spinal blockHigh neuraxial blockObstetrics anesthesia Spinal anesthesiaTotal spinal\n==== Body\n1 Introduction\nCesarean section is the most frequently performed obstetric surgical procedure, and spinal anesthesia is a common anesthetic technique used across the world. It produces a rapid, dense, predictable block, is relatively easy to perform with a definite endpoint, and has a very high success rate. However, there are contraindications to its use, and complications associated with spinal anesthesia, which all patients should be counseled about. Spinal anesthesia is inevitably associated with hypotension and it is important to manage this to avoid adverse outcomes in the fetus and the mother. High neuraxial anesthesia is also one of the commonly faced problems, with a rare incidence of a complete spinal block; which is one of the life-threatening complications unless immediately identified and managed [1].\n\nThis work has been reported in line with the SCARE 2018 criteria [2].\n\n2 Case presentation and observation\nA 35 years old mother (Gravida 7, Para 6) in labor referred from a nearby primary hospital for better diagnosis and treatment to our hospital. After continuous follow-up by gynecology and obstetrics resident, the mother was scheduled for an emergency cesarean section for the indication of cephalopulvic disproportion (CPD). Her previous obstetric history was six spontaneous vaginal delivery at home. Apart from the symptoms caused by her pregnancy and having pregnancy-induced hypertension, she was in good health. Having discussed the options available, she had decided upon spinal anesthesia for the procedure.\n\nAccording to local routines, premedication with cimetidine 300 mg and metoclopramide 10 mg iv given and 500 mL normal saline solution infused as preload. Blood pressure (BP), heart rate (HR), and SPO2 were measured 148/88 mmHg, 110 b/min 95% respectively. Anesthesia student performed spinal anesthesia under the guidance of the attending anesthetist. Having confirmed the free flow of CSF, 3 mls of 0.5% isobaric bupivacaine which says not for spinal despite the national regulatory body approved to use it, was slowly injected. On completion of the injection, the patient was immediately placed in a supine position, with a left lateral tilt. The subsequent blood pressure measurements were in the normal range and the fetus delivered 16 min after the conduct of spinal anesthesia uneventfully.\n\nLate after delivery, she becomes; apprehensive, had chest heaviness, and difficulty breathing. Upon the patient’s complaints, we tried to reassure, gave 100% oxygen via facemask and there was no significant vital sign disturbance. However, amid of the procedure, she became apneic and unresponsive. She developed hypotension, bradycardia, and hypoxia with BP-80/34, heart rate-46, and SPO2-76 with no palpable peripheral pulse. As the patient failed to respond, we went ahead with rapid induction (with thiopental 200 mg) and orotracheal intubation. But hemodynamics continued to remain unstable and repeated adrenaline injections (30 μg m, 10 μg m 10 μg m/every 05 min) were given along with intraoperative volume replacement. After 10–15 min of resuscitation effort, she maintained her vital signs BP 105/60, HR 83, SPO2 97%, and resume spontaneous breathing effort. As the hemodynamics stabilized with signs of respiratory efforts, we gradually withdrew vasoactive drugs. However, she becomes unresponsive kept under artificial assisted controlled intermittent ventilation and pressure support until the end of the procedure (an hour and ten minutes).\n\nHowever, the case was futher complicated by pulmonary edema, hypoglcimia and manged with continuous positive pressure ventilation, intravenous furosemide and 40% glucose. Even with meticulous intervention the patient remained unresponsive with non-purposeful right-hand movement. To rule out other possible causes of loss of conciousness; organ function test, electrolyte and CT-scan results were collected which are within the normal range. After 24 h of follow up and mechanical ventilation in the ICU, she was extubated. Over a week, the patient progressively regained motor and sensory functions and discharged without any neurological or clinical sequelae.\n\n3 Discussion\nThe proportion of cesarean sections performed under regional anesthesia has increased over the last two decades, and this has avoided the problem of difficult airway during anesthesia [3]. Maternal mortality decreased significantly during the first half of the 20th century. Further reduction in obstetric mortality was seen after 1980 and is attributed to the increase in neuraxial anesthesia for Cesarean delivery, improved safety of neuraxial technique, as well as algorithms and airway devices to improve the safety of general anesthesia [4]. A review examining anesthesia-related maternal deaths from 1991 to 2002 and 1997 to 2002 noted maternal mortality rates for general anesthesia were reduced from 16.8 to 6.5 per million, and regional anesthesia mortality rates remained lower at 2.5 and 3.8 per million, respectively because of this regional anesthesia is the preferred choice of anesthesia for obstetrics [5].\n\nHowever, despite lower incidences of morbidity and mortality, regional anesthesia can cause troubling to crippling, life-threatening complications. One of the feared complications remained total spinal or complete spinal block; in which where there is unintended cephalad spread of local anesthetic agents in the subarachnoid space, which involves the brainstem and cranial nerves that end up with loss of consciousness. The incidences vary between 1:2,971 and 1:16,200 anesthetics [1]. On the other hand, it was stated as 1:100,000 [6]. Our hospital is a newly established teaching specialized hospital a year ago, and we had 416 Cesarean section done under spinal anesthesia over 12 months period and this was the first total spinal incident.\n\nReasons for high morbidity and mortality associated with spinal anesthesia may include inadequate experience and training of the anesthetist, inappropriate use of the technique in mothers with significant comorbidity, performing of both anesthesia and surgery by the same practitioner, and neonatal resuscitation by the anesthetist at the expense of dedicated care to the mother. Many problems are avoidable or amenable to treatment by attention to details of safe practice, intended to supplement the document on spinal anesthesia [7]. The provider was anesthesia student which necessitates the need for close follow up by their consultants throughout the conduct of anesthesia.\n\nThe volume of local anesthetics injected in susceptible patients like; obstetrics, short stature, old age, and obese patients need to be reduced to minimize the incidence of high neuraxial blockade. Bupivacaine is the commonly used local anesthetics agent, for spinal anesthesia for obstetrics in a typical dose range of 10–15 mg but in this case, 15 mg was used which is higher than most literature recommendation. Although successful Cesarean deliveries have occurred with doses <5 mg, logistic regression studies examining doses of intrathecal bupivacaine that provided a 95% rate of effective anesthesia (ED95) for Cesarean delivery when combined with fentanyl (10 mcg) and morphine (0.2 mg) were 11.2 and 13.0 mg for hyperbaric and isobaric bupivacaine, respectively [8,9].\n\nFrom the literature review, total spinal anesthesia can happen during epidural anesthesia, caudal anesthesia, spinal anesthesia, paravertebral block, stellate ganglion block, interscalene brachial blocks, and other regional anesthesia techniques performed at or near to the vertebral column. The clinical manifestations are often characterized by a sudden decrease in blood pressure, rapidly increasing motor block, temporary loss of breathing, loss of consciousness, dilated pupils, apnea, and even cardiac arrest [[8], [9], [10], [11], [12]].\n\nBefore complete spinal block patients often complain and manifest different clinical features, often depending on the level of spreads of local anesthetics agents. Hypotension with or without bradycardia is due to venous and arterial vasodilation resulting in a reduced venous return, cardiac output, and systemic vascular resistance, and due to direct blockage of the cardio accelerating fibers (T1-T4) [13,14]. Patients often complain mild shortness of breath secondary to blockade of abdominal and intercostal respiratory accessory muscles (T1-T12) and numbness or weakness in the arms, shoulders, and trunk (C5-T1), followed by nausea, with or without vomiting secondary to cerebral hypotension, respiratory arrest secondary to diaphragmatic paralysis (C3-C5), and loss of consciousness (brainstem) [13,15]. Cardiac arrest may occur due to hypotension and hypoxemia or unopposed vagal dominance [14,16].\n\nManagement comprises; reassurance, supplemental oxygen (intubation if required to support oxygenation and ventilation or for loss of airway reflexes), and IV fluid administration plus vasopressors such as ephedrine or phenylephrine (adrenaline may be required) to support maternal blood pressure. Early recognition is vital, as block progression may be mitigated by adjusting the patient’s position. If total spinal anesthesia occurs, placing the patient in a Trendelenburg position will increase venous return and improve cardiac output. If the patient has a high spinal (compared with a total spinal), the Trendelenburg position is not recommended as it can cause a further rise of the block that can progress to a total spinal. Sedation and mechanical ventilation need to continue until there is evidence of block regression in the form of adequate spontaneous respiratory function and stable hemodynamic parameters [1,[5], [6], [7],17,18].\n\nOccasionally, a patient can lose consciousness while hemodynamically stable, and this has been attributed to the subdural spread of anesthesia. There may be no warning before the loss of consciousness (LOC) suddenly occurs sometime after the block has been inserted. Other causes of LOC during CS include air or amniotic fluid embolism, pulmonary embolism, inadvertent sedative drug administration, or hysteria should be considered and need systematic exclusion [15,17,18].\n\n4 Conclusion\nA pregnant woman with increased oxygen requirements cannot withstand hypoxia or hypotension for long before sustaining damage to herself or her infant. Even if rare, unexpected total spinal anesthesia during conduction analgesia can produce devastating consequences. Precautionary measures should be made during the conduct of regional anesthesia for high-risk patients and early identification and immediate intervention should be applied.\n\nDeclaration of Competing Interest\nNone of the authors declare a conflict of interest.\n\nFunding\nNo funding source for this case report.\n\nEthical approval\nStudy of clinical case report is exempted from ethical approval in our institution once get the patient consent or the guarantee.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\n\nAuthor’s contribution\nAtalay Eshetie involved in: Data curation, Investigation; Resources; Writing - original draft.\n\nGebrehiwot Asfaw involved in: Conceptualization, literature review, Writing - review & editing, Validation.\n\nRegistration of research studies\n1. Name of the registry: other; case report.\n\n2. Unique identifying number or registration ID: researchregistry6027.\n\n\n\nGuarantor\nGebrehiwot Asfaw.\n\nProvenance and peer review\nNot commissioned, externally peer-reviewed.\n\nAcknowledgments\nOur gratitude goes to Tibebe Ghion specialized hospital and Bahir Dar University College of medicine and health science staffs. We would also like to thank the patient who gave us her permission for the publication.\n==== Refs\nReferences\n1 Rollins M. Lucero J. Overview of anesthetic considerations for Cesarean delivery Br. Med. Bull. 101 March (1) 2012 \n2 Agha R.A. Borrelli M.R. Farwana R. Koshy K. Fowler A. Orgill D.P. For the SCARE Group The SCARE 2018 statement: updating consensus Surgical CAse REport (SCARE) guidelines Int. J. Surg. 60 2018 132 136 30342279 \n3 Yeoh S.B. Leong S.B. Heng A.S. Anaesthesia for lower-segment caesarean section: changing perspectives Indian J. Anaesth. 54 September (5) 2010 409 21189878 \n4 Hawkins J.L. Chang J. Palmer S.K. Gibbs C.P. Callaghan W.M. Anesthesia-related maternal mortality in the United States: 1979–2002 Obstet. Gynecol. 117 January (1) 2011 69 74 21173646 \n5 Sivanandan S. Surendran A. Linical A Obstet. Anaesth. 2019 22 \n6 Obstetric Anaesthetists’ Association Guideline Initiative – High Regional Block Guideline https://www.oaa-anaes.ac.uk/assets/_managed/cms/files/Clinical%20Guidelines/HRB_Lancashire2_2017.pdf.\n7 Dyer R.A. Prevention and treatment of cardiovascular instability during spinal anaesthesia for caesarean section South Afr. Med. J. 94 May (5) 2004 367 372 \n8 Gutsche B.B. ED50 and ED95 of intrathecal hyperbaric bupivacaine coadministered with opioids for cesarean delivery Surv. Anesthesiol. 49 February (1) 2005 21 22 \n9 Javed S. Hamid S. Amin F. Mahmood K.T. Spinal anesthesia induced complications in caesarean section-A review J. Pharm. Sci. Res. 3 October (10) 2011 1530 \n10 Wu W. Yan Z. Intraoperative total spinal anesthesia as a complication of posterior percutaneous endoscopic cervical discectomy Eur. Spine J. 27 July (3) 2018 431 435 29275522 \n11 Obstetrics Williams Cunningham F.G. Side effects of spinal block for a C-section 2010 article/197023 retrieved on 18.4.2011 \n12 Turner F.N. Shih R.D. Fishman I. Calello D.P. Solano J.J. Total spinal anesthesia following an interscalene block treated with intravenous lipid emulsion Cureus 11 April (4) 2019 \n13 Dijkema L.M. Haisma H.J. Case report–Total spinal anaesthesia. Update in Anaesthesia 2002 14 \n14 Newman B. Complete Spinal Block Following Spinal Anaesthesia Anaesthesia Tutorial of the Week 180 24th May 2010 \n15 Pollard J.B. Cardiac arrest during spinal anesthesia: common mechanisms and strategies for prevention Anesth. Analg. 92 January (1) 2001 252 256 11133639 \n16 Chan Y.K. Gopinathan R. Rajendram R. Loss of consciousness following spinal anaesthesia for Caesarean section Br. J. Anaesth. 85 September (3) 2000 474 476 11103195 \n17 Guterres A.P. Newman M.J. Total spinal following labour epidural analgesia managed with non-invasive ventilation Anaesth. Intensive Care 38 March(2) 2010 373 375 20369776 \n18 Vasco M. Obstetric anaesthesia in resource limited settings Obstet. Anaesth. 2019 5\n\n",
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"keywords": "Complete spinal block; High neuraxial block; Obstetrics anesthesia Spinal anesthesia; Total spinal",
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"abstract": "OBJECTIVE\nData on the efficacy, dosing and safety of letermovir for the compassionate therapeutic use of CMV infections are limited.\n\n\nMETHODS\nClinical and virological efficacy of letermovir was assessed in a retrospective single-centre study of patients who received letermovir for the compassionate therapeutic use of CMV infections.\n\n\nRESULTS\nLetermovir initiation yielded prompt treatment response in 7 out of 9 patients (77.7%).\n\n\nCONCLUSIONS\nLetermovir may be an effective and well tolerated option in the compassionate treatment of CMV infections, although recurrence of CMV and emergence of resistance may be issues.",
"affiliations": "Division of Infectious Diseases and Tropical Medicine, Department of Medicine I, Medical University Vienna, Vienna, Austria.;Division of Infectious Diseases and Tropical Medicine, Department of Medicine I, Medical University Vienna, Vienna, Austria.;Division of Infectious Diseases and Tropical Medicine, Department of Medicine I, Medical University Vienna, Vienna, Austria.;Division of Infectious Diseases and Tropical Medicine, Department of Medicine I, Medical University Vienna, Vienna, Austria.;Division of Infectious Diseases and Tropical Medicine, Department of Medicine I, Medical University Vienna, Vienna, Austria. christoph.steininger@meduniwien.ac.at.",
"authors": "Schubert|Lorenz|L|;Fisecker|Lisa|L|;Thalhammer|Florian|F|;Burgmann|Heinz|H|;Steininger|Christoph|C|https://orcid.org/0000-0003-3500-7205",
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"fulltext": "\n==== Front\nEur J Clin Microbiol Infect Dis\nEur J Clin Microbiol Infect Dis\nEuropean Journal of Clinical Microbiology & Infectious Diseases\n0934-9723 1435-4373 Springer Berlin Heidelberg Berlin/Heidelberg \n\n32914220\n3990\n10.1007/s10096-020-03990-w\nBrief Report\nLetermovir for the compassionate therapeutic use of cytomegalovirus infection\nSchubert Lorenz Fisecker Lisa Thalhammer Florian Burgmann Heinz https://orcid.org/0000-0003-3500-7205Steininger Christoph christoph.steininger@meduniwien.ac.at grid.22937.3d0000 0000 9259 8492Division of Infectious Diseases and Tropical Medicine, Department of Medicine I, Medical University Vienna, Vienna, Austria \n11 9 2020 \n11 9 2020 \n2021 \n40 2 435 439\n16 5 2020 15 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.Purpose\nData on the efficacy, dosing and safety of letermovir for the compassionate therapeutic use of CMV infections are limited.\n\nMethods\nClinical and virological efficacy of letermovir was assessed in a retrospective single-centre study of patients who received letermovir for the compassionate therapeutic use of CMV infections.\n\nResults\nLetermovir initiation yielded prompt treatment response in 7 out of 9 patients (77.7%).\n\nConclusion\nLetermovir may be an effective and well tolerated option in the compassionate treatment of CMV infections, although recurrence of CMV and emergence of resistance may be issues.\n\nKeywords\nCytomegalovirus infectionLetermovirCompassionate therapeutic useViral kineticsMedical University of ViennaOpen access funding provided by Medical University of Vienna.\n\nissue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2021\n==== Body\nBackground\nCytomegalovirus (CMV) infections remain a prevalent cause for morbidity and mortality in immunosuppressed solid-organ and bone-marrow transplant patients [1]. The first line therapeutic agents, ganciclovir (GCV) and its oral prodrug valganciclovir (VGCV), inhibit CMV replication by targeting the viral DNA polymerase pUL54. However, haematological side effects limit its therapeutic potential in 10–20% of the cases. Furthermore, genetic mutations of UL97 and UL54, conferring antiviral resistance, were reported, especially in cases of prolonged antiviral therapy, lack of prior CMV immunity in transplant patients and strong immunosuppression [2].\n\nIn cases of clinical or virological treatment failure, guidelines recommend the escalation of valganciclovir dose or escalating to cidofovir or foscarnet [1]. Both options are often limited by the toxic profile. Furthermore, cross-resistances were reported [2]. Hence, novel drugs that target alternative viral mechanisms are urgently required. Recently, letermovir, a new antiviral compound, was approved for the prophylaxis of CMV disease in bone-marrow transplant recipients [3]. Letermovir inhibits the terminase complex, which is essential for viral replication, for cleavage and packaging of large concatemers of CMV-DNA [4].\n\nAccording to its licence, letermovir was mainly used as a prophylaxis agent for CMV infections. However, its different mechanism of action as well as its excellent side effect profile made it an appealing off-label option for the therapy of GCV resistant CMV infections, as well was for patients who reported severe leukopenia or reduced kidney function. However, data are limited to case series [5–7].\n\nIn the present report we document a case series of patients who have received letermovir for the compassionate use for CMV infections, highlighting its antiviral potential, but also pointing out possible difficulties, thus judging its efficacy in the clinical setting.\n\nMaterials and methods\nSubjects and data collection\nThe present retrospective single-centre study exclusively comprises patients suffering from CMV infections who received letermovir for the compassionate use for treatment of CMV infections. The study protocol was approved by the Ethics Committee of the Medical University of Vienna, Austria (ECS 2013/2019), and all study-related procedures were conducted according to the declaration of Helsinki. We included adult patients who got diagnosed with CMV infection, defined as CMV DNA copy levels > 200 IU/ml measured in plasma and were treated with letermovir due to ganciclovir refractory or resistant CMV viremia or patients who were intolerant to receive ganciclovir or foscarnet. Intolerance to receive ganciclovir or foscarnet was decided by the responsible team of clinicians.\n\nThe same dosage of LMV was used for treatment as for prophylaxis of CMV infection—480 mg qd or 240 mg if on concomitant cyclosporin [3]. As suggested in the international consensus guidelines, CMV infection was separated into three groups: asymptomatic infections, viral syndrome, or tissue invasive (“end organ”) disease [1]. CMV syndrome and tissue invasive disease were diagnosed according to Ljungman et al. [8]. Treatment was monitored closely, and patients were regularly controlled for adverse events or development of viral syndrome or tissue invasion. Baseline demographics, CMV associated symptoms, previously received CMV prophylaxis or therapy, viral kinetics, ongoing immunosuppression and clinical outcome were retrospectively collected. Clinical response was defined as a decline of viral load to < 200 IU/ml. Furthermore, viral half-life was calculated, according to the formula t1/2 = −ln2/slope [9]. Patients who achieved the endpoint were further controlled for reactivation of CMV.\n\nResults\nA total of 11 patients were identified who received letermovir for the compassionate use for CMV infection. One patient had to be excluded as the exact time of termination of treatment was not documented. Another patient was excluded as she was already discussed in an earlier case report, which has not yet been published. The other nine patients are discussed below. Table 1 gives an overview of the demographic characteristics. The median age was 66 years (45–70), and 77.8% of the patients was male. Five patients were solid organ transplant recipients (55.6%), two developed CMV infection after HSCT (22.2%), one patient suffered from TARFO syndrome (11.1%) and one patient suffered from systemic lupus erythematosus (SLE) (11.1%). Six patients experienced asymptomatic CMV viremia (66.7%), one CMV syndrome (11%), one a probable CMV pneumonia (11%) and one patient with probable CMV enteritis (11%) [8]. Clinical reasoning for compassionate use of letermovir was as follows: confirmed antiviral resistance against GCV (n = 2, 22.2%), virological treatment failure of GCV (n = 1, 11.1%) and HSCT associated with significant CMV viremia (n = 2, 22.2%). In the other four patients, the clinicians opted for letermovir instead of ganciclovir or foscarnet, to prevent aggravation of coexisting diseases. In three of the patients severe leukopenia and concomitant infection (two of them septic) were the reasons for letermovir selection. Finally, one patient (11.1%) suffering from a multicentric form of Castleman disease called TAFRO syndrome (an acronym for thrombocytopenia, anasarca, myelofibrosis, renal dysfunction and organomegaly), experienced CMV reactivation under therapy with high-dose cortisone and tocilizumab. To prevent further aggravation thrombocytopenia, which would have ultimately led to discontinuation of tocilizumab, clinicians decided for compassionate use of letermovir instead of valganciclovir.Table 1 Characteristics of the patients treated with letermovir\n\nPatients\tDemographics\tImmuno-suppression\tPresentation of CMV\tPrevious antivirals\tIndication for LMV\tDaily dose of LMV (mg)\tAdaption of immuno-suppression\tInitial CMV DNA IU/ml\tTime to suppression of virus replication (days)\tRecurrence of CMV infection\t\nPatient 1\tf, 69a, kidney transplantation\tMMF, TAC and cortisone\tAsymptomatic\tVGCV\tLeukopenia and GCV refractory viremia\t480\tMMF stopped\t833\t8\tNo\t\nPatient 2\tm, 60a, HSCT\tMMF, CsA and cortisone\tAsymptomatic\tNone\tPrevent aggravation of leuko- and thrombocytopenia after HSCT\t240\tMMF paused\t261\t14\tYes\t\nPatient 3\tm, 70a, heart transplantation\tMMF, TAC and cortisone\tProbable pneumonia\tGCV1\tLeukopenia under GCV and sepsis\t480\tMMF paused\t898\tNot achieved\t\t\nPatient 4\tm, 58a, heart transplantation\tMMF, TAC and cortisone\tAsymptomatic\tVGCV\tConfirmed resistance\t480\tNone\t39,600\t1852\tNo\t\nPatient 5\tm, 74a, kidney transplantation\tMMF and TAC\tCMV syndrome\tVGCV\tConfirmed resistance\t480\tMMF paused\t2770\t34\tBo\t\nPatient 6\tm, 45a, TARFO-syndrome\ttocilizumab and cortisone\tAsymptomatic\tNone\tPrevent aggravation of thrombocytopenia under tocilizumab\t480\tNone\t1610\t23\tNo\t\nPatient 7\tm, 68a, kidney transplantation\tMMF, TAC and cortisone\tAsymptomatic\tNone\tLeukopenia and sepsis\t480\tMMF dose reduction\t1550\t29\tNo\t\nPatient 8\tf, 65a, SLE\tMMF and cortisone\tProbable enteritis\tNone\tPrevent aggravation of leukopenia\t480\tNone\t16,000\t83\tNo\t\nPatient 9\tm, 61a, HSCT\tMMF and CsA\tAsymptomatic\tNone\tPrevent aggravation of leuko- and thrombocytopenia after HSCT\t240\tNone\t224\t23\tNo\t\nf female, m male, a age, HSCT haematopoietic stem cell transplantation, SLE systemic lupus erythematosus, MMF mycophenolate mofetil, TAC tacrolimus, CsA cyclosporine A, LMV letermovir, VGCV valganciclovir, GCV ganciclovir\n\n1CMV IgG co-administration\n\n2In patient 4 letermovir treatment was prematurely discontinued at CMV DNA load 739 IU/ml, and later on re-administered. Although treatment course was prolonged (185 days) no signs of CMV end-organ disease were reported\n\n\n\nInitiation of letermovir treatment yielded a viral response, after an initial viral load increase, in 7 out of 9 patients (77.8%). The median duration of letermovir treatment was 31 (8–127) days. The median duration to achieve a decrease of viral load < 200 IU/ml was 23 (8–83) days. Viral kinetic curves are shown in Fig. 1. In the other two patients (patients 3 and 4), treatment was discontinued prematurely at CMV DNA copy levels > 200 IU/ml, at 211 IU/ml and 739 IU/ml respectively. Both patients experienced an increase of viral load within the next month, and letermovir was re-administered. After re-administration, patient 4 experienced a slow but steady decrease of viral load, resulting in CMV DNA copies < 200 IU/ml within a total of 185 days of treatment. Re-administration of letermovir in patient 3 yielded a decrease of CMV copy load, but general estate of the patient further aggravated and the patient developed sepsis. In a discussion with the family treatment discontinuation was decided and the patient died within the following days. End-organ disease occurred in none of the asymptomatic CMV patients under letermovir treatment, but one patient (patient 2) experienced a CMV end-organ disease only 2 weeks after treatment discontinuation. The episode was subsequently treated with VGCV, as leukopenia had improved.Fig. 1 Relative change of CMV DNA copies in percent after initiation of letermovir treatment. The average increase was 2.7-fold (SD = 1.3). Final descent, defined by the definite negative movement, was seen as late as day 30 (mean = 8.7, SD = 8.8)\n\n\n\nThe initiation of letermovir therapy was associated with an initial increase of viral load in 7 out of 9 (77.8%) patients. The average increase was 2.7-fold (SD = 1.3) of the viral load at start of treatment. Final descent, defined by the definite negative movement, was seen as late as day 30 (median = 6, range [3–30]). The viral half-life was 7.1 (1.49–9.1) days.\n\nDiscussion\nThe present report demonstrates the potential of letermovir for the effective treatment of CMV infections. All present patients received letermovir as a monotherapy. The therapy was generally well tolerated, and no adverse events were reported. Treatment initiation yielded a decrease of viral load to < 200 copies/ml in 88.9% of the patients. However, one patient with complete clinical response experienced CMV end-organ disease within 2 weeks after treatment discontinuation. Immunosuppression was adapted in all SOT patients, by either dose reduction or pausing of cell-cycle inhibitor.\n\nTherapeutic strategies for clinical or virological failure of CMV infections include the escalation of valganciclovir dose or switching to cidofovir or foscarnet [1]. However, both drugs are associated with the potential for severe adverse events, such as nephrotoxicity and myelosuppression, which limit their therapeutic usefulness. Letermovir, a novel inhibitor of the terminase complex, was recently approved for the prophylaxis of CMV infection in allogenic HSCT, but is not yet approved for pre-emptive therapy [3]. Its favourable side effect profile has led to an increased off-label use for GCV-resistant CMV infections or if the patients were intolerant to receive other treatment options. However, first observations of letermovir resistance have been reported [10–13]. A recently published letermovir resistance analysis among HSCT recipients receiving letermovir prophylaxis identified all letermovir resistance associated variants within the UL 56 gene [13]. Although some treatment durations were prolonged, no viremia breakthrough was reported in our cohort.\n\nDosing of letermovir for preemptive therapy remains uncertain, as there is no approval for letermovir in this indication. Stoelben et al. successfully used lower letermovir doses of 40 bid or 80 qd for preemptive therapy in kidney transplant recipients, whereas Turner et al. used higher doses of up to 960 mg qd for the salvage therapy of drug-resistant CMV retinitis without an emergence of adverse events [6, 14]. Letermovir dose in our cohort coincided with the dose recommendations for the prophylaxis of CMV infection, 480 mg qd or 240 mg if on concomitant cyclosporin [3]. The same treatment protocol was recently chosen by Phoompoung et al. for the salvage therapy of CMV infections in transplant recipients [7].\n\nThe average duration until decrease of viral load to under < 200 mg/ml was 32.9 days. The viral half-life time under letermovir was 6.3 days, which is longer than previously published viral half-lives of solid-organ transplant patients treated with GCV [9]. As demonstrated in earlier reports, the viral load initially increases after therapy start. The average increase in our cohort was 2.7-fold of the viral load at treatment start. However, the increase in viral load was not associated with an increase in symptoms. This may be explicable by the mode of action of letermovir, as viral replication is blocked at a late stage, possibly yielding high intracellular titre of viral DNA in absence of a viable virus. This emphasizes the need for alternative methods to estimate the risk of CMV disease under letermovir treatment.\n\nThe present study has some limitations. As a result of the retrospective study design, the included cohort is heterogenous, leading to a broad spectrum of indication for letermovir. However, precisely this highlights the clinicians’ desire for alternative treatment options, as existing first-line therapies are often limited by their severe side effect profile, especially in patients with concomitant bacterial infections. Further, we could not exclude that the patient’s immune status contributed significantly to the treatment outcome, especially in patients with long lasting viremia.\n\nHence, prospective trials evaluating efficacy, safety, drug dosing, treatment duration and emergence of drug resistance are urgently required.\n\nPublisher’s note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nThe authors thank the members of the Division of Infectious Diseases and Tropical Medicine, Medical University Vienna, for their help.\n\nAuthor contribution\nAll authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Lisa Fisecker and Lorenz Schubert. The first draft of the manuscript was written by Lorenz Schubert and Christoph Steininger, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\n\nFunding\nOpen access funding provided by Medical University of Vienna.\n\nData availability\nThe datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.\n\nCompliance with ethical standards\nConflict of interest\nThe authors declare that they have no conflict of interest.\n\nEthics approval\nEthical approval was waived by the local Ethics Committee of the Medical University Austria in view of the retrospective nature of the study, and all the procedures being performed were part of the routine care.\n\nInformed consent\nNot applicable.\n==== Refs\nReferences\n1. Kotton CN Kumar D Caliendo AM Huprikar S Chou S Danziger-Isakov L The third international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation Transplantation 2018 102 900 931 10.1097/TP.0000000000002191 29596116 \n2. Lurain NS Chou S Antiviral drug resistance of human cytomegalovirus Clin Microbiol Rev 2010 23 689 712 10.1128/CMR.00009-10 20930070 \n3. Marty FM Ljungman P Chemaly RF Maertens J Dadwal SS Duarte RF Haider S Ullmann AJ Katayama Y Letermovir prophylaxis for cytomegalovirus in hematopoietic-cell transplantation N Engl J Med 2017 377 2433 2444 10.1056/NEJMoa1706640 29211658 \n4. Ligat G Cazal R Hantz S Alain S The human cytomegalovirus terminase complex as an antiviral target: a close-up view FEMS Microbiol Rev 2018 42 137 145 10.1093/femsre/fuy004 29361041 \n5. Kaul DR Stoelben S Cober E Ojo T Sandusky E Lischka P First report of successful treatment of multidrug-resistant cytomegalovirus disease with the novel anti-CMV compound AIC246 Am J Transplant 2011 11 1079 1084 10.1111/j.1600-6143.2011.03530.x 21521474 \n6. Turner N, Strand A, Grewal DS, Cox G, Arif S, Baker AW et al (2019) Use of letermovir as salvage therapy for drug-resistant cytomegalovirus retinitis. Antimicrob Agents Chemother 63. 10.1128/AAC.02337-18\n7. Phoompoung P, Ferreira VH, Tikkanen J, Husain S, Viswabandya A, Kumar D et al (2020) Letermovir as salvage therapy for cytomegalovirus infection in transplant recipients. Transplantation. 10.1097/TP.0000000000002785\n8. Ljungman P, Boeckh M, Hirsch HH, Josephson F, Lundgren J, Nichols G et al (2017) Definitions of cytomegalovirus infection and disease in transplant patients for use in clinical trials. Clin Infect Dis. 10.1093/cid/ciw668\n9. Humar A Kumar D Boivin G Caliendo AM Cytomegalovirus (CMV) virus load kinetics to predict recurrent disease in solid-organ transplant patients with CMV disease J Infect Dis 2002 186 829 833 10.1086/342601 12198618 \n10. Cherrier L Nasar A Goodlet KJ Nailor MD Tokman S Chou S Emergence of letermovir resistance in a lung transplant recipient with ganciclovir-resistant cytomegalovirus infection Am J Transplant 2018 18 3060 3064 10.1111/ajt.15135 30286286 \n11. Lischka P Michel D Zimmermann H Characterization of cytomegalovirus breakthrough events in a phase 2 prophylaxis trial of letermovir (AIC246, MK 8228) J Infect Dis 2016 213 23 30 10.1093/infdis/jiv352 26113373 \n12. Jung S, Michel M, Stamminger T, Michel D (2019) Fast breakthrough of resistant cytomegalovirus during secondary letermovir prophylaxis in a hematopoietic stem cell transplant recipient. BMC Infect Dis 19. 10.1186/s12879-019-4016-1\n13. Douglas CM, Barnard R, Holder D, Leavitt R, Levitan D, Maguire M et al (2020) Letermovir resistance analysis in a clinical trial of cytomegalovirus prophylaxis for hematopoietic stem cell transplant recipients. J Infect Dis. 10.1093/infdis/jiz577\n14. Stoelben S Arns W Renders L Hummel J Mühlfeld A Stangl M Preemptive treatment of Cytomegalovirus infection in kidney transplant recipients with letermovir: results of a phase 2a study Transpl Int 2014 27 77 86 10.1111/tri.12225 24164420\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0934-9723",
"issue": "40(2)",
"journal": "European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology",
"keywords": "Compassionate therapeutic use; Cytomegalovirus infection; Letermovir; Viral kinetics",
"medline_ta": "Eur J Clin Microbiol Infect Dis",
"mesh_terms": "D000085:Acetates; D000368:Aged; D000998:Antiviral Agents; D057176:Compassionate Use Trials; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011799:Quinazolines; D012189:Retrospective Studies; D016896:Treatment Outcome",
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"title": "Letermovir for the compassionate therapeutic use of cytomegalovirus infection.",
"title_normalized": "letermovir for the compassionate therapeutic use of cytomegalovirus infection"
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"abstract": "The impacts of gonadtropin-releasing hormone (GnRH) agonists on thyroid function have long been observed and the conclusions were controversial. We here reported three cases of transient hyperthyroidisms after triptorelin therapy. The three patients showed decreased thyroid-stimulating hormone (TSH), with or without elevated free triiodothyronine (FT3) and free thyroxine (FT4) 2 weeks after injection of triptorelin. Thyroid-specific autoantibody assays showed antithyroid microsome autoantibody (TMAb) and (or) antithyroglobulin autoantibody (TgAb) were positive in two patients while and antithyrotropin receptor autoantibody (TRAb) were negative in all three cases. One patient with all thyroid-specific autoantibodies negative showed enlarged thyroid in thyroid ultrasound scanning. Only mild symptoms of hyperthyroidism presented in one patient. Four weeks after triptorelin injection, thyroid function returned to normal in all three patients. These observations indicated transient hyperthyroidism due to thyroid destruction in patients receive triptorelin therapy. The hyperthyroidism was most possibly due to onset of the autoimmune thyroiditis, emphasizing monitoring thyroid function during triptorelin treatment in females.",
"affiliations": "a Department of Endocrinology , Jiangsu Province Hospital of Traditional Chinese Medicine/the Affiliated Hospital of Nanjing University of Traditional Chinese Medicine , Nanjing , China.;a Department of Endocrinology , Jiangsu Province Hospital of Traditional Chinese Medicine/the Affiliated Hospital of Nanjing University of Traditional Chinese Medicine , Nanjing , China.;a Department of Endocrinology , Jiangsu Province Hospital of Traditional Chinese Medicine/the Affiliated Hospital of Nanjing University of Traditional Chinese Medicine , Nanjing , China.;a Department of Endocrinology , Jiangsu Province Hospital of Traditional Chinese Medicine/the Affiliated Hospital of Nanjing University of Traditional Chinese Medicine , Nanjing , China.",
"authors": "Miao|Junjun|J|;Yan|Qianhua|Q|;Wang|Lijuan|L|;Wang|Xin|X|",
"chemical_list": "D001323:Autoantibodies; C006606:anti-thyroglobulin; D014284:Triiodothyronine; D017329:Triptorelin Pamoate; D013972:Thyrotropin; D013974:Thyroxine",
"country": "England",
"delete": false,
"doi": "10.1080/09513590.2018.1445710",
"fulltext": null,
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"issn_linking": "0951-3590",
"issue": "34(9)",
"journal": "Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology",
"keywords": "Gonadotropin-releasing hormone agonist; autoimmune thyroid disease; triptorelin",
"medline_ta": "Gynecol Endocrinol",
"mesh_terms": "D000328:Adult; D001323:Autoantibodies; D005260:Female; D006801:Humans; D006980:Hyperthyroidism; D013960:Thyroid Function Tests; D013972:Thyrotropin; D013974:Thyroxine; D014284:Triiodothyronine; D017329:Triptorelin Pamoate",
"nlm_unique_id": "8807913",
"other_id": null,
"pages": "734-735",
"pmc": null,
"pmid": "29484896",
"pubdate": "2018-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Three cases of transient hyperthyroidism after triptorelin treatment - case report and literature review.",
"title_normalized": "three cases of transient hyperthyroidism after triptorelin treatment case report and literature review"
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"abstract": "NFU1 deficiency is a rare metabolic disorder affecting iron-sulfur cluster synthesis, an essential pathway for lipoic acid-dependent enzymatic activities and mitochondrial respiratory chain complexes. It is a little-known cause of pulmonary arterial hypertension (PAH), while PAH is a prominent feature of the disease. We herein report on a female infant diagnosed as having idiopathic PAH since 1 month of age, who did not respond to bosentan plus sildenafil. NFU1 deficiency was only suggested and confirmed at 10 months of age when she demonstrated neurological deterioration along with high glycine levels in body fluids. Unexplained PAH in early infancy should prompt clinicians to perform amino acid chromatography searching for high glycine levels. Early recognition will avoid further invasive procedures and enable appropriate genetic counseling to be offered. No effective treatment is currently able to prevent the fatal course of this metabolic condition.",
"affiliations": "Department of Pediatric Neurology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.;Department of Pediatric Cardiology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.;Department of Pediatric Cardiology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.;Department of Cardiology, Pulmonary Vascular Diseases and Heart Failure Clinic, Cliniques Universitaires de Bruxelles-Hôpital Erasme, Brussels, Belgium.;Department Pediatric Cardiology, Clinique de l'Espérance, Montegnée, Belgium.;Center for Medical Genetics, UZ Brussel, Brussels, Belgium.;Department of Pediatric Cardiology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.;Department of Pediatric Neurology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.",
"authors": "Stéphanie|Paquay|P|;Catherine|Barrea|B|;Thierry|Sluysmans|S|;Jean-Luc|Vachiery|V|;Isabelle|Loeckx|L|;Sara|Seneca|S|;Christophe|Vô|V|;Marie-Cécile|Nassogne|N|",
"chemical_list": null,
"country": "India",
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"doi": "10.4103/apc.APC_136_18",
"fulltext": "\n==== Front\nAnn Pediatr CardiolAnn Pediatr CardiolAPCAnnals of Pediatric Cardiology0974-20690974-5149Wolters Kluwer - Medknow India APC-12-32510.4103/apc.APC_136_18Case Report“Idiopathic” pulmonary arterial hypertension in early infancy: Excluding NFU1 deficiency Stéphanie Paquay 1Catherine Barrea 2Thierry Sluysmans 2Jean-Luc Vachiery 3Isabelle Loeckx 4Sara Seneca 56Christophe Vô 2Marie-Cécile Nassogne 11 Department of Pediatric Neurology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium2 Department of Pediatric Cardiology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium3 Department of Cardiology, Pulmonary Vascular Diseases and Heart Failure Clinic, Cliniques Universitaires de Bruxelles-Hôpital Erasme, Brussels, Belgium4 Department Pediatric Cardiology, Clinique de l’Espérance, Montegnée, Belgium5 Center for Medical Genetics, UZ Brussel, Brussels, Belgium6 Research Group Reproduction and Genetics, Vrije Universiteit Brussel, Brussels, BelgiumAddress for correspondence: Dr. Paquay Stéphanie, Department of Pediatric Neurology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium. E-mail: stephanie.paquay@uclouvain.beSep-Dec 2019 12 3 325 328 Copyright: © 2019 Annals of Pediatric Cardiology2019This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.NFU1 deficiency is a rare metabolic disorder affecting iron–sulfur cluster synthesis, an essential pathway for lipoic acid-dependent enzymatic activities and mitochondrial respiratory chain complexes. It is a little-known cause of pulmonary arterial hypertension (PAH), while PAH is a prominent feature of the disease. We herein report on a female infant diagnosed as having idiopathic PAH since 1 month of age, who did not respond to bosentan plus sildenafil. NFU1 deficiency was only suggested and confirmed at 10 months of age when she demonstrated neurological deterioration along with high glycine levels in body fluids. Unexplained PAH in early infancy should prompt clinicians to perform amino acid chromatography searching for high glycine levels. Early recognition will avoid further invasive procedures and enable appropriate genetic counseling to be offered. No effective treatment is currently able to prevent the fatal course of this metabolic condition.\n\nHyperglycinemialipoic acidneurological regressionNFU1pulmonary hypertension\n==== Body\nINTRODUCTION\nIdiopathic pulmonary arterial hypertension (PAH) in early infancy is a severe condition, diagnosed when no other pediatric disease is found accounting for high pulmonary pressures. We herein report on an infant presenting with severe idiopathic PAH since the 1st month of life. The clinical evolution eventually prompted the clinicians to search for a rare genetic cause of PAH.\n\nCLINICAL SUMMARY\nThis female infant was the first child of second-degree consanguineous Portuguese parents. She was born full term and had an uneventful neonatal period. At 1 month of age, she presented with respiratory deterioration, rapidly requiring intensive care. Chest X-ray revealed diffuse pulmonary infiltrates with consolidation of the right lung. She exhibited acute respiratory distress syndrome (ARDS), with Bordetella pertussis detected in the respiratory secretions by polymerase chain reaction (PCR) analysis. Echocardiogram identified suprasystemic pulmonary artery pressures. The right ventricular systolic pressure was estimated at 70 mmHg based on tricuspid valve insufficiency. Concomitant systemic blood pressure was 64/29 mmHg. The right ventricle (RV) was dilated, and the pulmonary artery (PA) was severely enlarged (15 mm = Z score + 6.6). Prostaglandin E1 was administered with unfavorable outcome, after which nitric oxide was applied, improving the pulmonary pressures, which normalized within 1 week. RV size returned to normal values, and the nitric oxide was stopped. PAH was considered to be secondary to pertussis-related ARDS.\n\nAt 3 months of age, she presented with a new acute deterioration, including metabolic acidosis, hypoxemia, and tachycardia. She exhibited failure to thrive. Echocardiogram again revealed severe pulmonary hypertension with a dilated and hypertrophied RV [Figure 1], squeezing the left ventricle [Figure 2]. Pulmonary pressure was evaluated on the pulmonary valve insufficiency in the absence of tricuspid regurgitation. Mean PA pressure was estimated around 60 mmHg [Figure 3], while systemic blood pressure was 90/55 mmHg. Cardiac catheterization in FiO2 0.3 demonstrated a mean pulmonary pressure of 22 mmHg and pulmonary vascular resistance of 10 Wood unit/m2, which represented 50% of the systemic vascular resistance. Acute vasoreactivity testing showed no change under oxygen FiO2 1.00 and nitric oxide 20 ppm [Table 1].\n\nFigure 1 Apical four-chamber view showing a dilated heart and hypertrophied right ventricle. LA: Left atrium; RA: Right atrium; LV: Left ventricle; RV: Right ventricle\n\nFigure 2 Subcostal view showing a dilated pulmonary artery and right ventricle, squeezing the left ventricle with systolic septal bowing into the left ventricle\n\nFigure 3 Continuous wave Doppler recording the high-velocity pulmonary regurgitation related to high pulmonary artery pressure\n\nTable 1 Catheterization parameters at baseline and with vasoreactivity testing\n\n\tFiO2 0.3\tFiO2 1.00 + NO 20 ppm\t\nPAP (mmHg)\t37/11 (22)\t36/10 (21)\t\nSAP\t50/28 (42)\t50/29 (42)\t\nPVR (Wood units ×m2)\t10\t7.4\t\nSVR (Wood units ×m2)\t22\t17\t\nPVR/SVR\t0.47\t0.43\t\nQp (L/min/m2)\t1.6\t2.2\t\nQp/Qs\t1\t1\t\nPAP: Pulmonary arterial pressure, SAP: Systemic arterial pressure, PVR: Pulmonary vascular resistances, SVR: Systemic vascular resistances, Qp: Pulmonary flow, Qs: Systemic flow, NO: Nitric oxide\n\nGiven the presence of transient lactic acidosis upon this episode, urine organic acids and the plasma acylcarnitine profile were assessed, yet with unremarkable results, while plasma amino acids were not investigated. The girl's condition improved in the next 2 days after fluid infusion and bicarbonate therapy were administered. Diagnostic workup ruled out associated congenital heart disease, chronic lung or liver disorders, infections (HIV), and thromboembolic PAH. Causes of inheritable PAH were investigated. Sequencing of BMPR2, ACVRL1, ENG, and KCNK3 genes identified no causal mutations. Array comparative genomic hybridization proved normal. The diagnosis of idiopathic PAH was retained, given that no underlying causal condition was found. Due to disease severity, specific PAH therapy was initiated, using a combination of sildenafil and bosentan, progressively increased to 30 mg/day (3 × 10 mg) and 20 mg/day (2 × 10 mg), respectively. In the following weeks, serial echocardiograms showed persistent pulmonary hypertension of systemic level, without significant ventricular dysfunction. Bosentan had to be stopped due to liver dysfunction. Treatment with intravenous epoprostenol was considered yet not administered.\n\nAt 9 months of age, the child suffered her first episode of refractory seizures. Clinical examination revealed neurological regression, along with axial hypotonia, spastic quadriplegia, and poor visual contact. Brain imaging revealed symmetric lesions in the white matter with necrotic areas [Figure 4]. Metabolic screening revealed high glycine levels in both the plasma (337 mmol/L; normal: 74–290) and urine (1198 mmol/mol creatinine; normal: 114–445), without lactic acidosis. In the following weeks, her neurological condition progressively deteriorated. She died at 10 months of age from neurological and metabolic decompensation. PCR amplification and sequencing of the 8 exons and parts of the flanking introns of the NFU1 gene identified the repeatedly reported[1] pathogenic homozygous mutation c. 622G>T (p. Gly208Cys) (RefSeq: NM_001002755.2). Both parents proved to be heterozygous carriers of the pathogenic variant.\n\nFigure 4 Brain MRI, Axial T2 (a) and Flair (b), coronal T1 (c), diffusion (d) and apparent diffusion coefficient (e) sequences; Computed tomography (CT) scanner (f). Images showing diffuse abnormal intensity of the white matter involving periventricular regions\n\nDISCUSSION\nBiogenesis of the iron–sulfur (Fe–S) clusters (ISCs) is a complex process that requires several proteins for their synthesis, assembly, maturation, and delivery to their target apoproteins.[2] Among the ISC machinery components currently associated with human diseases, the NFU1 gene (OMIM 60810) is particularly essential to targeting the (4Fe–4S) clusters into lipoic acid synthetase and succinate dehydrogenase (complex II of the mitochondrial respiratory chain), in a late-acting function of the protein maturation (Fe–S) pathway.[1] NFU1 deficiency (OMIM #605711), an autosomal recessive inherited disorder, is therefore responsible for decreased lipoic acid synthesis and impaired respiratory chain function. Lipoic acid is an essential cofactor for the lipoylation of the E2 subunit of four mitochondrial dehydrogenases: pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, 2-oxoadipate dehydrogenase, and Branched chain keto acid dehydrogenase, as well as the H protein of the glycine cleavage system.[3] All these explain the biochemical hallmarks of NFU1-deficient patients,[1234] namely high glycine levels in body fluids, variable lactic acidosis, and urinary excretion of Krebs cycle intermediates. Approximately 40 NFU1-deficient patients have previously been described, presenting a relatively homogeneous clinical outcome. Symptoms appear in the 1st month of life, with death generally followed before 2 years of age. Failure to thrive, PAH, psychomotor retardation, and neurological regression are the main clinical features. No patients with antenatal symptoms have been described. Brain magnetic resonance imaging typically reveals diffuse cavitating leukoencephalopathy. More than 50% of infant patients were found to display significant PAH,[2] which could be an isolated and prominent finding initially, as was the case for our patient. Interestingly, pulmonary samples from the NFU1-deficient individuals with PAH showed obstructive vasculopathy with proximal and acinar arterial involvement.[1] Pulmonary vascular remodeling is thought to be secondary to dysregulated endothelial energy metabolism,[5] though the pathophysiological mechanisms are not yet fully understood. It should be noted that the clinical spectrum of NFU1 deficiency is probably not fully known since Tonduti et al.[6] described a milder phenotype in an adult patient with spastic paraplegia.\n\nWhile glycogen storage disease and Gaucher disease are metabolic disorders commonly associated with PAH, NFU1 deficiency is not mentioned among the metabolic disorders listed in the last updated clinical classification of pediatric pulmonary hypertension.[7] NFU1 deficiency should be considered in the differential diagnosis of pulmonary hypertension during infancy since its diagnosis can be rapidly established by amino and organic acid chromatography. Combined features of neurological deterioration, cavitating leukoencephalopathy, unexplained PAH, and hyperglycinemia are key findings that should prompt the clinician to perform NFU1 gene sequencing. Early recognition of this fatal multiple mitochondrial dysfunction syndrome should avoid a long diagnostic odyssey with useless molecular investigations and invasive procedures, while enabling adequate genetic counseling and prenatal testing to be offered.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Navarro-Sastre A Tort F Stehling O Uzarska MA Arranz JA Del Toro M A fatal mitochondrial disease is associated with defective NFU1 function in the maturation of a subset of mitochondrial Fe-S proteins Am J Hum Genet 2011 89 656 67 22077971 \n2 Tort F Ferrer-Cortes X Ribes A Differential diagnosis of lipoic acid synthesis defects J Inherit Metab Dis 2016 39 781 93 27586888 \n3 Mayr JA Feichtinger RG Tort F Ribes A Sperl W Lipoic acid biosynthesis defects J Inherit Metab Dis 2014 37 553 63 24777537 \n4 Ahting U Mayr JA Vanlander AV Hardy SA Santra S Makowski C Clinical, biochemical, and genetic spectrum of seven patients with NFU1 deficiency Front Genet 2015 6 123 25918518 \n5 Yu Q Chan SY Mitochondrial and metabolic drivers of pulmonary vascular endothelial dysfunction in pulmonary hypertension Adv Exp Med Biol 2017 967 373 83 29047100 \n6 Tonduti D Dorboz I Imbard A Slama A Boutron A Pichard S New spastic paraplegia phenotype associated to mutation of NFU1 Orphanet J Rare Dis 2015 10 13 25758857 \n7 Hansmann G Pulmonary hypertension in infants, children, and young adults J Am Coll Cardiol 2017 69 2551 69 28521893\n\n",
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"issn_linking": "0974-5149",
"issue": "12(3)",
"journal": "Annals of pediatric cardiology",
"keywords": "Hyperglycinemia; NFU1; lipoic acid; neurological regression; pulmonary hypertension",
"medline_ta": "Ann Pediatr Cardiol",
"mesh_terms": null,
"nlm_unique_id": "101495459",
"other_id": null,
"pages": "325-328",
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"pmid": "31516295",
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"references": "22077971;24777537;25758857;25918518;27586888;28521893;29047100",
"title": "\"Idiopathic\" pulmonary arterial hypertension in early infancy: Excluding NFU1 deficiency.",
"title_normalized": "idiopathic pulmonary arterial hypertension in early infancy excluding nfu1 deficiency"
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"abstract": "OBJECTIVE\nTo evaluate the efficacy and outcome of adding low-dose fractionated radiotherapy (LDFRT) to induction chemotherapy plus concurrent chemoradiation in locally advanced nasopharyngeal carcinoma (LANPC).\n\n\nMETHODS\nA single-institute, phase II-III, prospectively controlled randomized clinical trial was performed at King Faisal Specialist Hospital and Research Centre. Patients aged 18-70 years with WHO type II and III, stage III-IVB nasopharyngeal carcinoma, Eastern Cooperative Oncology Group performance score of 0-2, with adequate hematological, renal, and hepatic function were eligible. In total, 108 patients were enrolled in this trial. All patients received two cycles of induction docetaxel and cisplatin (75 mg/m2 each) chemotherapy on Days 1 and 22, followed by concurrent chemoradiation therapy. Radiation therapy consisted of 70 Gy in 33 fractions, with concurrent cisplatin 25 mg/m2 for 4 days on Days 43 and 64. Patients were randomly assigned to either adding LDFRT (0.5 Gy twice daily 6 hours apart for 2 days) to induction chemotherapy in the experimental arm (54 patients) or induction chemotherapy alone in the control arm (54 patients).\n\n\nRESULTS\nThere was no significant difference in the post-induction response rates (RRs) or in toxicity between the two treatment arms. The 3-year overall survival (OS), locoregional control (LRC), and distant metastases-free survival (DMFS) rates for experimental arm and control arm were 94% versus 93% (p = .8), 84.8% versus 87.5% (p = .58), and 84.1% versus 91.6% (p = .25), respectively.\n\n\nCONCLUSIONS\nThe results showed no benefit from adding LDFRT to induction chemotherapy in terms of RR, OS, LRC, and DMFS.",
"affiliations": "King Faisal Hospital and Research Centre, Riyadh, Saudi Arabia. Electronic address: nrajhi@kfshrc.edu.sa.;King Faisal Hospital and Research Centre, Riyadh, Saudi Arabia.;King Faisal Hospital and Research Centre, Riyadh, Saudi Arabia.;King Faisal Hospital and Research Centre, Riyadh, Saudi Arabia.;King Faisal Hospital and Research Centre, Riyadh, Saudi Arabia.;King Faisal Hospital and Research Centre, Riyadh, Saudi Arabia.;King Faisal Hospital and Research Centre, Riyadh, Saudi Arabia.;King Faisal Hospital and Research Centre, Riyadh, Saudi Arabia.;King Faisal Hospital and Research Centre, Riyadh, Saudi Arabia.",
"authors": "Al-Rajhi|Nasser M|NM|;Khalil|Ehab M|EM|;Ahmad|Shoaib|S|;Soudy|Hussein|H|;AlGhazi|Mohammad|M|;Fatani|Doha M|DM|;Memon|Muhammed|M|;Abouzied|Moheieldin|M|;Khafaga|Yasser M|YM|",
"chemical_list": "D000077143:Docetaxel; D002945:Cisplatin",
"country": "England",
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"keywords": "Chemotherapy; LDFRT; Nasopharyngeal carcinoma",
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"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D059248:Chemoradiotherapy; D002945:Cisplatin; D018572:Disease-Free Survival; D000077143:Docetaxel; D019583:Dose Fractionation, Radiation; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms; D015996:Survival Rate",
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"publication_types": "D017427:Clinical Trial, Phase II; D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": null,
"title": "Low-dose fractionated radiation with induction docetaxel and cisplatin followed by concurrent cisplatin and radiation therapy in locally advanced nasopharyngeal cancer: A randomized phase II-III trial.",
"title_normalized": "low dose fractionated radiation with induction docetaxel and cisplatin followed by concurrent cisplatin and radiation therapy in locally advanced nasopharyngeal cancer a randomized phase ii iii trial"
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"abstract": "We report a case of systemic lupus erythematosus (SLE) in a young woman who became pregnant amid a severe flare. She continued to have active disease in the face of aggressive treatments complicated by several side effects of immunosuppressive drugs including recurrent sepsis and gestational diabetes. Her fetus was at risk for congenital heart block during the second and third trimesters. Despite an extremely guarded prognosis, she delivered a healthy baby girl. This case highlights the complexities of SLE management during pregnancy. We discuss the therapeutic options available in pregnancy, and highlight the importance of cross-specialty multidisciplinary care in these women.",
"affiliations": "Imperial College London, London, UK.;Imperial College Healthcare NHS Trust, London, UK.;Imperial College London, London, UK.",
"authors": "Webster|Philip|P|;Nelson-Piercy|Catherine|C|;Lightstone|Liz|L|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2016-217546",
"fulltext": null,
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"mesh_terms": "D000328:Adult; D016640:Diabetes, Gestational; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D008180:Lupus Erythematosus, Systemic; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
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"pmid": "28179384",
"pubdate": "2017-02-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11153745;11229483;11434574;11508435;12838197;15023151;15590425;15722258;16712713;17075810;18074358;18346976;18693108;19059545;1984192;19946032;20131278;20391423;20447951;20688887;21242885;22626746;22878255;23349333;23740227;24352337;24928830;25406359;25880781;26098843;26221752;26924064;27496151;3107375;7020419;8496859;9626848",
"title": "A complicated multisystem flare of systemic lupus erythematosus during pregnancy.",
"title_normalized": "a complicated multisystem flare of systemic lupus erythematosus during pregnancy"
} | [
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"abstract": "Neonatal neutropenia is regularly seen with variable etiology. We describe a breastfed infant with maternal medication use as a probable cause of neonatal neutropenia. An 8 days old exclusively breastfed female infant of Arab-Berber descent was referred to our hospital because of an infection of the umbilicus. Complete blood count showed a picture of severe isolated neutropenia. After initiating intravenous antibiotic treatment, the infection quickly resolved, but the isolated neutropenia persisted. Bone marrow aspiration indicated severe congenital neutropenia. The mother was known to have Crohn's disease, treated with methylprednisolone and adalimumab up to 3 months before delivery, and latent tuberculosis, for which she used isoniazid postnatally. Breast-feeding was terminated and filgrastim was started, with an increase of the neutrophilic count. After several weeks, filgrastim could be terminated. Bone marrow and complete blood count were repeated and were completely normal. This case report describes a very young breastfed female infant with severe neutropenia, causing an infection, in which maternal adalimumab use could not be excluded as a possible cause. Maternal isoniazid use is highly unlikely.",
"affiliations": "Department of Pediatrics, Queen Paola Children's Hospital, Antwerp, Belgium, machielvdakker@gmail.com.;Department of Pediatric Hematology Oncology, UZ Brussel, Brussels, Belgium, machielvdakker@gmail.com.;Pharmacy, UZ Brussel, Brussels, Belgium.;Department of Pediatrics, Queen Paola Children's Hospital, Antwerp, Belgium, machielvdakker@gmail.com.;Department of Pediatrics, Queen Paola Children's Hospital, Antwerp, Belgium, machielvdakker@gmail.com.",
"authors": "van den Broek|Leonie|L|;van der Werff-Ten Bosch|Jutte|J|;Cortoos|Pieter-Jan|PJ|;van Steijn|Susanne|S|;van den Akker|Machiel|M|",
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"country": "New Zealand",
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"doi": "10.2147/IMCRJ.S173826",
"fulltext": "\n==== Front\nInt Med Case Rep JInt Med Case Rep JInternational Medical Case Reports JournalInternational Medical Case Reports Journal1179-142XDove Medical Press 10.2147/IMCRJ.S173826imcrj-11-333Case ReportSevere neutropenia in a breastfed infant: a case report and discussion of the differential diagnosis van den Broek Leonie 1van der Werff-ten Bosch Jutte 2Cortoos Pieter-Jan 3van Steijn Susanne 1van den Akker Machiel 12\n1 Department of Pediatrics, Queen Paola Children’s Hospital, Antwerp, Belgium, machielvdakker@gmail.com\n2 Department of Pediatric Hematology Oncology, UZ Brussel, Brussels, Belgium, machielvdakker@gmail.com\n3 Pharmacy, UZ Brussel, Brussels, BelgiumCorrespondence: Machiel van den Akker, Queen Paola Children’s Hospital, Lindendreef 1, Antwerp, 2020, Belgium, Tel +32 3 280 2134, Email machielvdakker@gmail.com2018 15 11 2018 11 333 337 © 2018 van den Broek et al. This work is published and licensed by Dove Medical Press Limited2018The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Neonatal neutropenia is regularly seen with variable etiology. We describe a breastfed infant with maternal medication use as a probable cause of neonatal neutropenia. An 8 days old exclusively breastfed female infant of Arab-Berber descent was referred to our hospital because of an infection of the umbilicus. Complete blood count showed a picture of severe isolated neutropenia. After initiating intravenous antibiotic treatment, the infection quickly resolved, but the isolated neutropenia persisted. Bone marrow aspiration indicated severe congenital neutropenia. The mother was known to have Crohn’s disease, treated with methylprednisolone and adalimumab up to 3 months before delivery, and latent tuberculosis, for which she used isoniazid postnatally. Breast-feeding was terminated and filgrastim was started, with an increase of the neutrophilic count. After several weeks, filgrastim could be terminated. Bone marrow and complete blood count were repeated and were completely normal. This case report describes a very young breastfed female infant with severe neutropenia, causing an infection, in which maternal adalimumab use could not be excluded as a possible cause. Maternal isoniazid use is highly unlikely.\n\nKeywords\ncongenital neutropenianeonatebreast-feedingadalimumabisoniazid\n==== Body\nIntroduction\nNeutrophils are the most abundant white blood cells in blood and play a critical role in recruiting and activating cells of the immune system, besides being a key player in the frontline defense against invading pathogens as part of the innate immune system. Reduction in neutrophils below an absolute count of 0.5×109/L is termed severe neutropenia or agranulocytosis.1\n\nNeutropenia can be the result of a decreased production of neutrophils, an increased neutrophil destruction, or a combination of these mechanisms (Box 1).2 One of the causes is drug induced. In drug-induced immune neutropenia, drug-dependent antibodies are formed against neutrophil membrane glycoprotein, causing neutrophil destruction. Severe neutropenia or agranulocytosis associated with exposure to nonchemotherapy drugs is seen in up to 15.4 cases per million population per year.2 We report a very young breastfed female infant with severe neutropenia, in which adalimumab and isoniazid (INH) were used by the mother.\n\nCase presentation\nAn 8 days old exclusively breastfed female infant was referred to our hospital because of an infection of the umbilicus without fever. She was the second child of nonconsanguineous parents, both of Arab-Berber descent, born after 39 weeks of pregnancy, complicated by intrauterine growth restriction. Birth weight 2.570 kg (SD –1.6), length 48 cm (SD –0.8), and head circumference 32 cm (SD –1.7). The mother was known to have Crohn’s disease, treated with oral methylprednisolone, in a gradually reducing dose with a maximum of 32 mg daily, and adalimumab, 40 mg subcutaneously every 2 weeks for up to 3 months before delivery. Additional investigations revealed a latent tuberculosis (positive interferon gamma release assay), for which she used INH 300 mg once a day, in combination with pyridoxine 125 mg, which both were started immediately after delivery. Family history is negative for hematologic diseases, syndromes, or early unexplained death.\nBox 1 Causes of neonatal neutropenia\nDecreased neutrophil production\nInfants of hypertensive mothers (possibly due to the presence of placenta-derived inhibitor)\nDonors of twin-to-twin transfusion\nRhesus-hemolytic disease (precursors diverted to erythroid differentiation)\nBone marrow failure\n Congenital genetic syndromes with bone marrow failure\n • Kostmann syndrome (severe congenital neutropenia: promyelocytic maturation arrest)\n • Reticular dysgenesis (severe combined immunodeficiency of both myeloid and lymphoid production)\n • Shwachman Diamond syndrome (exocrine pancreatic insufficiency, failure to thrive, skeletal Abnormalities, and neutropenia)\n • Cartilage hair dysplasia (dwarfism and neutropenia)\n • Cyclic neutropenia (cyclic hematopoiesis with nadirs at 3-week intervals)\n • Zinsser–Cole–Engman syndrome (dyskeratosis congenita: nail dystrophy, abnormalities in pigmentation, oral leukoplakia, and neutropenia) Inheritance patterns: X-linked recessive, autosomal dominant or recessive (in 85% boys are affected, in 15% girls). X-linked and autosomal recessive inheritance patterns vulnerable to aplastic anemia as well)\n • Chediak Higashi syndrome (oculocutaneous albinism and neutropenia)\n • Griscelli syndrome (hypopigmentation, hepatosplenomegaly, and neutropenia)\n • WHIM syndrome (Warts, Hypogammaglobulinemia, Immunodeficiency, and Myelokathexis with chronic noncyclic neutropenia)\n Inborn errors of metabolism\n • Organic acidemias (failure to thrive, vomiting, hypotonia and loss of neutrophil precursors)\n • Organic aciduria (Barth syndrome: short stature, hypotonia, dilated cardiomyopathy and neutropenia)\n • Glycogen storage disease type 1b (increased neutrophil apoptosis)\n Other causes of bone marrow failure\n • Leukemia, metastasis, or neuroblastoma\n • Aplastic anemia, Fanconi anemia, myeloproliferative syndromes\nCopper deficiency\nAlloimmune neutropenia associated with anti-HNA-1b antibodies (antigen on neutrophil precursors)\nIncreased neutrophil destruction\nAnti-neutrophil antibody mediated disorders (allo-/autoimmune)\nNecrotizing enterocolitis\nCombination\nInfection/sepsis (TORCHES [Toxoplasma, Rubella, Cytomegalovirus, Herpes infections, Syphilis], Ebstein-Barr virus, Parvovirus B19, bacterial, fungal), drug induced (β-lactam antibiotics, thiazides, ranitidine, acyclovir, etc), idiopathic\t\nNotes: Adapted with permission from Nittala S, Subbarao GC, Maheswari A. Evaluation of Neutropenia in preterm infants. J Matern Featal Neonatal Med. 2012;25(Suppl 5):100–103. Copyright © 2012 Taylor & Francis Ltd; www.tandfonline.com.23\n\n\n\nPhysical examination of the neonate was, besides a local infection of the umbilicus, normal for her age. No (skeletal) malformations, cutaneous, or nail abnormalities; hepato-splenomegaly; or hypotonia were noted. However, complete blood count showed a picture of severe isolated neutropenia (hemoglobin 18.2 g/dL, mean corpuscular volume 97, plate-lets 254×109/L, leukocytes 7.56×109/L, and absolute neutrophil count [ANC] 0.04×109/L; C-reactive protein 73.1 mg/L). The child was admitted and broad-spectrum intravenous antibiotic treatment (ampicillin and cefotaxime) was started. Cultures of the umbilicus revealed the growth of Staphylococcus aureus. Urine and blood cultures remained negative.\n\nThe infection improved; however, the isolated neutropenia persisted. No viral etiology (TORCH, which includes Toxoplasmosis, Other [syphilis, varicella-zoster, parvovirus B19], Rubella, cytomegalovirus, and herpes infections, [para] influenza, respiratory syncytial virus, adenovirus) could be demonstrated. Testing for antineutrophil antibodies was not done, as the tests often show false-positive and false-negative results.3 Bone marrow aspiration revealed a severe dysgranulopoiesis, characterized by a maturation stop after meta-/myelocyte stage (Figure 1), indicating severe congenital neutropenia. Maternal usage of adalimumab during pregnancy can cause neutropenia because it can cross the placenta from the maternal circulation into the fetal circula tion. Also, agranulocytosis due to INH, used by the mother while breast-feeding, could not be excluded. Tuberculosis was excluded in the child, and the complete blood count of the mother did not show neutropenia. As a probability scale, we use the Naranjo algorithm,4 and this case was scored for both medications separately. INH was scored “3,” while adalimumab was scored “4,” both as a “possible” likelihood to be responsible for the neutropenia (Naranjo scores: 9 or 10 indicate “definitely”; 5–8 rate the likelihood as “probable”; 1–4 “possible”; <1 “doubtful”).\n\nBreast-feeding was terminated, and filgrastim (Neupogen®, Amgen Inc., Thousand Oaks, CA, USA) 5 µg/kg subcutaneously was started. A very slow increase of ANC was seen, and so filgrastim dose was increased to 10 µg/kg subcutaneously, with good improvement. ANC increased to a maximum of 35.85×109/L. Two months after birth, filgrastim was terminated which, initially, led to a decrease of ANC, before it stabilized in the normal range (Figure 2). Two weeks after terminating, the filgrastim a new bone marrow aspiration (Figure 1) and a complete blood count was repeated. Both were normal, which excluded severe congenital neutropenia.\n\nDiscussion\nAdalimumab is a chimeric, monoclonal immunoglobulin G1 antibody directed against human TNF-α.5 Neutropenia is a common adverse reaction and may occur in up to 16% of patients receiving anti-TNF therapies, possibly due to a direct toxic effect on bone marrow.6 Adalimumab can cross the placenta from the maternal circulation into the fetal circulation,5 and peak levels (fetus) are reached during the third trimester of pregnancy.7–9 Consequently, these infants may be at increased risk for infection.10 Elimination of adalimumab is relatively long, half-life is about 2 weeks.7,9\n\nIn our case, the mother did not use adalimumab during the third trimester. Despite this, a case series demonstrated that significant levels of anti-TNF agents can be measured in cord blood, even when adalimumab was discontinued 8 weeks before delivery, and can be 2- to 3-fold higher than in the peripheral blood of the mother.8,9\n\nIn 2014, Guiddir et al5 reported four cases of severe neutropenia, all complicated by a skin infection, after maternal use of infliximab, which has similar anti-TNF-α activity as adalimumab, but a shorter half-life of 7–12 days.11 Similarly to our case, anti-TNF therapy was not given during the third trimester. We did not measure adalimumab levels in the mother or in the child. However, as far as we know, there is no other literature which describes a neonatal neutropenia due to the use of adalimumab during pregnancy.\n\nINH, a pyridine derivative of nicotinamide, is the most widely used first-line anti-tuberculosis drug and the mainstay in the treatment of latent tuberculosis.12–14 It is excreted in breast milk at relatively small concentrations15 and is considered to be compatible with breast-feeding by the American Academy of Pediatrics and Centers for Disease Control and Prevention.14–16 Well-known adverse reactions of INH are an asymptomatic elevation of serum liver enzyme concentrations, peripheral neuropathy, and hepatotoxicity.12 Neutrope-nia is a known adverse reaction, but less often described. INH is excreted in breast milk at relatively small concentrations, but limited data are available about the subsequent exposure to the nursing infant.14,15 Normally, peak plasma concentrations of INH are achieved around one hour after ingestion and a similar trend is seen in breast milk, indicating that INH is quickly absorbed and transferred to breast milk with a mean milk: plasma ratio of 0.9. The mean relative dose of INH (1.2%) transmitted to the infant via breast milk is below the 10% notional level of concern. Under normal circumstances, these amounts of drug transfer to breast milk are not directly toxic since they are much lower than the INH dose prescribed to the infant as a prophylactic dose of 10 µg/kg. These data suggest that INH therapy is safe during breast-feeding.14 However, pyridoxine supplements (1–2 mg/kg) are still recommended for breastfed infants if the mother uses INH.17,18\n\nAlthough concentrations are low and toxic concentrations are rarely reached, pharmacological activity is possible.14 Toddywalla et al19 reported that INH is capable of suppressing hepatic drug metabolizing activity in infants of mothers on chronic therapy, and Pariente-Khayat et al20 reported that the maturation of N-acetyltransferase 2, which is the main route of metabolizing INH,14 occurs in the first 4 years of life.14,17,20\n\nFinally, the rate of acetylation INH is also genetically determined with a bimodal distribution of slow and fast acetylators.20 Given the fact that the slow acetylator phenotype is the most common (72%) one in Moroccan/North-African populations, it is very well possible that for the mother peak concentrations in plasma and breast milk have been high and half-life time prolonged.21 Still, we cannot explain the severe neutropenia due to the most likely insignificant INH exposure to the infant via breast milk, which has been described by Garessus et al.22 When we consequently rule out INH as a possible cause of the congenital neutropenia, the Naranjo score of adalimumab will change to “7,” a “probable” likelihood to be responsible for the neutropenia.\n\nAlthough we realize a neonatal alloimmune neutropenia provoked by the maternal production of neutrophil-specific allo-antibodies is a more common cause, and, as said before, unfortunately we cannot prove that the persistence of adalimumab is the cause of the severe neutropenia in our child, we think this may be a good explanation. We would like to call for awareness of the side effects of the use of adalimumab in pregnancy, even in the first and second trimester. For each case, an individual risk/benefit analysis is advised. If INH-induced neutropenia is suspected, it is wise to examine the INH concentration in plasma and breastmilk before intervening in the INH treatment of the mother.22\n\nConclusion\nAdalimumab can cross the placenta from the maternal circulation into the fetal circulation, and peak levels are reached during the third trimester of pregnancy. Despite the advice of using adalimumab only in the first and second trimester, significant levels of anti-TNF agents are possible.\n\nINH is excreted in breast milk at relatively small concentrations, and so it is considered to be compatible with breast-feeding. Toxic concentrations are rarely reached, but pharmacologically active plasma concentrations in breastfed infants due to suppressing hepatic drug metabolizing activity and N-acetyltransferase 2 immaturity in infants are theoretically possible. No evidence is found in the literature to support this assumption yet.\n\nWe reported an exclusively breastfed infant with severe neutropenia and infection possibly due to maternal adalimumab, which illustrates that thoughtfulness with the prescription of adalimumab in pregnancy, even in the first and second trimester, is important. For each case, an individual risk/benefit analysis is advised.\n\nAuthor contributions\n\nLeonie van den Broek drafted the initial manuscript. Pieter-Jan Cortoos participated in the writing of the manuscript. Machiel van den Akker carried out the initial analyses and coordinated and supervised the writing of the manuscript. Jutte van der Werfften Bosch, Pieter-Jan Cortoos, Susanne van Steijn, and Machiel van den Akker critically reviewed the manuscript. All authors contributed toward data analysis, drafting and critically revising the paper, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 Microscopic view of the bone marrow aspirate.\n\nNotes: The upper picture shows a severe dysgranulopoiesis, characterized by a maturation stop after meta-/myelocyte stage, before starting filgrastim. The lower picture shows a normal bone marrow of our patient 2 weeks after terminating filgrastim.\n\nFigure 2 ANC (cells/µL) of the patient (the arrows symbolize the start and the terminating of filgrastim) over several months.\n\nAbbreviation: ANC, absolute neutrophil count.\n==== Refs\nReferences\n1 Curtis BR Drug-induced immune neutropenia/agranulocytosis Immunohematology 2014 30 2 95 101 25247619 \n2 Maheshwari A Neutropenia in the newborn Curr Opin Hematol 2014 21 1 43 49 24322487 \n3 Clay ME Schuller RM Bachowski GJ Granulocyte serology: current concepts and clinical signifcance Immunohematology 2010 26 1 11 21 20795313 \n4 Naranjo CA Busto U Sellers EM A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 2 239 245 7249508 \n5 Guiddir T Frémond ML Triki TB Anti-TNF-α therapy may cause neonatal neutropenia Pediatrics 2014 134 4 e1189 e1193 25266439 \n6 Bessissow T Renard M Hoffman I Vermeire S Rutgeerts P van Assche G Review article: non-malignant haematological complications of anti-tumour necrosis factor alpha therapy Aliment Pharmacol Ther 2012 36 4 312 323 22725726 \n7 Kane SV Acquah LA Placental transport of immunoglobulins: a clinical review for gastroenterologists who prescribe therapeutic monoclonal antibodies to women during conception and pregnancy Am J Gastroenterol 2009 104 1 228 233 19098873 \n8 Mahadevan U Wolf DC Dubinsky M Placental transfer of anti-tumor necrosis factor agents in pregnant patients with inflammatory bowel disease Clin Gastroenterol Hepatol 2013 11 3 286 292 quiz e24 23200982 \n9 Zelinkova Z de Haar C de Ridder L High intra-uterine exposure to infliximab following maternal anti-TNF treatment during pregnancy Aliment Pharmacol Ther 2011 33 9 1053 1058 21366638 \n10 Baddley JW Cantini F Goletti D ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Soluble immune effector molecules [I]: anti-tumor necrosis factor-α agents) Clin Microbiol Infect 2018 24 Suppl 2 S10 S20 29459143 \n11 Klotz U Teml A Schwab M Clinical pharmacokinetics and use of infliximab Clin Pharmacokinet 2007 46 8 645 660 .17655372 \n12 World Health Organization Guidelines on the Management of Latent Tuberculosis Geneva World Health Organization 2015 \n13 Getahun H Matteelli A Chaisson RE Raviglione M Latent mycobacterium tuberculosis infection N Engl J Med 2015 372 22 2127 2135 26017823 \n14 Singh N Golani A Patel Z Maitra A Transfer of isoniazid from circulation to breast milk in lactating women on chronic therapy for tuberculosis Br J Clin Pharmacol 2008 65 3 418 422 18093257 \n15 Tran JH Montakantikul P The safety of antituberculosis medications during breastfeeding J Hum Lact 1998 14 4 337 340 10205455 \n16 Centers for Disease Control and Prevention Latent Tuberculosis Infection: A Guide for Primary Health Care Providers Atlanta Centers for Disease Control and Prevention 2014 \n17 Baquero-Artigao F Mellado Pena MJ del Rosal Rabes T Spanish Society for Pediatric Infectious Diseases guidelines on tuberculosis in pregnant women and neonates (ii): prophylaxis and treatment Anales Pediatria 2015 83 4 286.e1 286.e7 \n18 Loto OM Awowole I Tuberculosis in pregnancy: a review J Pregnancy 2012 2012 379271 22132339 \n19 Toddywalla VS Patel SB Betrabet SS Kulkarni RD Kombo I Saxena BN Can chronic maternal drug therapy alter the nursing infant’s hepatic drug metabolizing enzyme pattern? J Clin Pharmacol 1995 35 10 1025 1029 8568011 \n20 Pariente-Khayat A Rey E Gendrel D Isoniazid acetylation metabolic ratio during maturation in children Clin Pharmacol Ther 1997 62 4 377 383 9357388 \n21 Guaoua S Ratbi I Laarabi FZ Distribution of allelic and genotypic frequencies of NAT2 and CYP2E1 variants in Moroccan population BMC Genet 2014 15 156 25544508 \n22 Garessus Edg MH Gundert-Remy U Influence of fast and slow metabolizer status on the pharmacokinetics of isoniazid in lactating women and breast-fed infants Naunyn-Schmiedeberg’s Arch Pharmacol 2018 391 S75 \n23 Nittala S Subbarao GC Maheswari A Evaluation of Neutropenia in preterm infants J Matern Featal Neonatal Med 2012 25 Suppl 5 100 103\n\n",
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"journal": "International medical case reports journal",
"keywords": "adalimumab; breast-feeding; congenital neutropenia; isoniazid; neonate",
"medline_ta": "Int Med Case Rep J",
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"pages": "333-337",
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"references": "26017823;18093257;21366638;25266439;22132339;19098873;23025781;10205455;25754314;20795313;7249508;24322487;8568011;23200982;29459143;9357388;25544508;17655372;22725726;25247619",
"title": "Severe neutropenia in a breastfed infant: a case report and discussion of the differential diagnosis.",
"title_normalized": "severe neutropenia in a breastfed infant a case report and discussion of the differential diagnosis"
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"abstract": "Gliadel placement in glioblastoma resection, particularly with concurrent chemoradiation, has demonstrated an improvement in survival. There have been several reported adverse effects, some of which lend to significantly increased morbidity and mortality. With only two other cases described in literature, cerebral vasospasm secondary to carmustine-impregnated wafers is an extremely rare side effect.\nWe report the case of a 51-year-old female who presented with the left lower limb paresis 8 days after high-grade glioma resection provoked by carmustine wafer placement.\nWe urge surgeons to reconsider placement of carmustine wafers in nations where the surgical resection cavity includes exposed large cerebral vasculature. We also propose the early identification of this devastating complication in the postoperative period by maintaining a high clinical suspicion and prompt utilization of computed tomography and digital subtraction angiography in the management and treatment of these patients accordingly.",
"affiliations": "Department of Neurosurgery, Saint Louis University, 3635 Vista Avenue, St, Louis, Missouri, United States.;Department of Neurosurgery, Saint Louis University, 3635 Vista Avenue, St, Louis, Missouri, United States.;Department of Neurosurgery, Saint Louis University, 3635 Vista Avenue, St, Louis, Missouri, United States.;Department of Neurosurgery, Saint Louis University, 3635 Vista Avenue, St, Louis, Missouri, United States.;Department of Neurosurgery, Saint Louis University, 3635 Vista Avenue, St, Louis, Missouri, United States.",
"authors": "Khan|Maheen Qamar|MQ|;Cirjan|Cristian|C|;Quadri|Nabiha|N|;Alexopoulos|Georgios|G|;Coppens|Jeroen|J|",
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"doi": "10.25259/SNI_257_2020",
"fulltext": "\n==== Front\nSurg Neurol Int\nSurg Neurol Int\nSurgical Neurology International\n2229-5097 2152-7806 Scientific Scholar USA \n\nSNI-11-168\n10.25259/SNI_257_2020\nCase Report\nSymptomatic cerebral vasospasm in the setting of carmustine wafer placement for glioblastoma: A case presentation and review of literature\nKhan Maheen Qamar maheen.khan@health.slu.edu Cirjan Cristian cristian.cirjan@health.slu.edu Quadri Nabiha nabiha.quadri@health.slu.edu Alexopoulos Georgios georgios.alexopoulos@health.slu.edu Coppens Jeroen jeroen.coppens@health.slu.edu Department of Neurosurgery, Saint Louis University, 3635 Vista Avenue, St, Louis, Missouri, United States.\n* Corresponding author: Maheen Qamar Khan, Department of Neurosurgery, Saint Louis University, 3635 Vista Avenue, St, Louis, Missouri, United States. maheen.khan@health.slu.edu\n2020 \n27 6 2020 \n11 16809 5 2020 08 6 2020 Copyright: © 2020 Surgical Neurology International2020This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Background: \nGliadel placement in glioblastoma resection, particularly with concurrent chemoradiation, has demonstrated an improvement in survival. There have been several reported adverse effects, some of which lend to significantly increased morbidity and mortality. With only two other cases described in literature, cerebral vasospasm secondary to carmustine-impregnated wafers is an extremely rare side effect.\n\nCase Description: \nWe report the case of a 51-year-old female who presented with the left lower limb paresis 8 days after high-grade glioma resection provoked by carmustine wafer placement.\n\nConclusion: \nWe urge surgeons to reconsider placement of carmustine wafers in nations where the surgical resection cavity includes exposed large cerebral vasculature. We also propose the early identification of this devastating complication in the postoperative period by maintaining a high clinical suspicion and prompt utilization of computed tomography and digital subtraction angiography in the management and treatment of these patients accordingly.\n\nCarmustine waferCerebral vasospasmGlial tumorGliomaTumor resection\n==== Body\nBACKGROUND\nCarmustine-impregnated wafers (Gliadel®, Eisai, Baltimore, Maryland, USA) are biodegradable polymers designed to deliver high concentrations of 1,3-bis-2-chloroethyl-1-nitrosourea (BCNU) into cerebral tumor resection cavities while surpassing the blood-brain barrier and avoiding the constitutional side effects of systemic chemotherapy.[13,14,26] Several studies have demonstrated the role of Gliadel in improving overall survival in patients with recurrent and newly diagnosed high-grade gliomas, particularly in the setting of concurrent radiation and chemotherapy.[2,3,6,9,12,15,16,32] Despite its efficacy, Gliadel has also been associated with a number of serious adverse events, including seizures, brain edema, intracranial hypertension, cerebrospinal fluid leakage, intracranial infection, healing abnormalities, hydrocephalus, and cyst formation.[2,3,15,32] Although symptomatic cerebral vasospasm (sCVS) has been described in the context of temporal lobectomy for refractory epilepsy[11,19,20,24] and largely in the setting of skull base tumor resection,[1,5] only two cases in the literature describe vasospasm as a result of carmustine-impregnated wafer implantation.[21,22] The phenomenon is believed to be secondary to a combination of the vasospastic properties of carmustine, local toxicity, and inflammation.[21,22] In this case report, we present a patient who experienced sCVS attributed to carmustine-impregnated wafer placement after the resection of glioblastoma (GBM). Given the high morbidity of sCVS, the authors propose high index of clinical suspicion, timing of this phenomenon, recommendations for placement, and early identification by utilizing CT angiography in the setting of postoperative symptoms. We aim to prepare physicians for the proactive identification and treatment of patients susceptible to this morbid phenomenon.\n\nCASE REPORT\nA 51-year-old female was transferred to our institution after the discovery of a large right temporal and insular lesion on magnetic resonance imaging (MRI). The patient initially presented with a few months of headaches and smelling odd odors to her primary care physician, who then prescribed the patient levetiracetam (Keppra, UCB Pharmaceuticals, Belgium) and referred her to our institution. The patient had no deficits on gross physical examination. Contrasted computed tomography (CT) with contrast revealed a large mass with irregular enhancement and MRI revealed moderate perilesional edema with mass effect [Figure 1].\n\nFigure 1: (a) FLAIR magnetic resonance imaging showing right temporal and insular lesion with right to left mass effect and surrounding edema. (b and c) CT with contrast demonstrating irregular enhancement of a large right temporal and insular lesion. (d) A coronal view of the preoperative CT with contrast, with an emphasis on the Sylvian fissure and middle cerebral artery (MCA) being pushed upward (asterisk).\n\nThe patient underwent an uncomplicated right frontotemporal craniotomy for tumor resection. At the anteromedial extent of the tumor, the Sylvian vessels were encountered and preserved. The dissection of the tumor was performed with preservation of the pial demarcation of the Sylvian fissure. The anterior choroidal artery and MCA branches were met and not manipulated as this indicated the anterior extent of the tumor. An amygdalohippocampectomy was also performed. Intraoperative monitoring, with somatosensory evoked potentials, motor evoked potentials, and electroencephalography, was performed throughout the course of the operation and remained at baseline. Frozen pathology confirmed the presence of high-grade glioma, and at that time, the decision was made to line the surgical cavity, including exposed Sylvian fissure and large cerebral vessels, with four carmustine wafers. Two wafers were placed along the cephalad resection cavity in direct contact with the exposed portion of the Sylvian fissure and the remainder along the posterior resection wall [Figure 1]. The wafers were secured with oxidized regenerated cellulose. There was minimal intraoperative bleeding.\n\nPostoperatively, the patient experienced no worsening deficits. Immediate postoperative CT revealed small volume hemorrhage within the posteromedial aspects of the resection cavity, measured to be about 1.7 cm3 per volumetric analysis through OsiriX software (Apple, California) [Figure 2]. MRI on postoperative day 1 revealed subtotal resection with improved mass effect but persistent edema [Figure 2]. She was eventually discharged from our care on postoperative day 5.\n\nFigure 2: (a) Postoperative CT with minimal hemorrhage in the posterior aspect of the resection cavity. (b) The T1 magnetic resonance imaging (MRI) with contrast respectively, with small amount of residual tumor anterosuperiorly and medially, with small amount of hemorrhage within the resection cavity and no evidence of hemorrhage within the basal cisterns. (c) Diffusion-weighted imaging without any evidence of infarct. (d) A T2 MRI with hypointensities along exposed middle cerebral artery (asterisks), representing Gliadel wafer lining the vessel and cavity.\n\nOn postoperative day 8, the patient experienced new left lower extremity weakness, which progressed to include slurring of speech and left facial weakness. Over the course of the next 24 h, this evolved to plegia in the left upper extremity and severe hemiparesis in the left lower extremity. MRI revealed stable edema and an acute ischemic stroke in the right posterior limb of the internal capsule [Figure 3]. CT angiography and digital subtraction angiography (DSA) on postoperative day 9 revealed moderate vasospasm in the right supraclinoid internal carotid artery (ICA), the carotid terminus, A1 of the anterior cerebral artery, and M1 of the MCA [Figure 3]. After intra-arterial injection of 20 mg of nicardipine and angioplasty of the right MCA and supraclinoid ICA, there was some improvement in vessel diameter and caliber [Figure 3]. The patient remained in the hospital for several days for medical management of vasospasm (fluids, oral nimodipine, and permissive hypertension) and intensive rehabilitation. Histopathology was finalized, showing features consistent with those of the World Health Organization Grade IV GBM, and the patient went onto receive concomitant temozolomide and radiation. At 36-month postoperative follow-up, the patient had resolution of dysphasia but had persistent left upper extremity plegia and left lower extremity paresis.\n\nFigure 3: (a) FLAIR magnetic resonance imaging revealing stable perilesional edema on postoperative day 8. (b) Diffusion-weighted imaging showcasing a right posterior limb of the internal capsule acute infarct. (c-f) Cerebral angiographic images of the anterior circulation displaying moderate vasospasm in the right supraclinoid internal carotid artery (ICA), the carotid terminus, A1 of the anterior cerebral artery, and M1 of the middle cerebral artery (MCA). (e and f) Improvement in caliber and diameter of supraclinoid ICA and MCA after angioplasty and intra-arterial injection of nicardipine.\n\nDISCUSSION\nCVS is a well-described entity in patients with aneurysmal subarachnoid hemorrhage (aSAH)[4,8,10,34] and following epilepsy surgery,[11,19,20,24] but its incidence in the postoperative course of tumor resection is low.[7] Bejjani et al. conducted a retrospective review of 470 patients with skull base tumors and noted 1.9% incidence of CVS postoperatively.[5] They proposed manipulation of nearby large cerebral vessels during dissection and increased blood spillage into the basal cisterns from skull base approaches as possible causes.[5] Alotaibi and Lanzino, in their systematic review of CVS in the setting of primarily skull base tumor resection, emphasized postoperative subarachnoid hemorrhage, preoperative vessel encasement, mechanical stretching and manipulation, hypothalamic dysfunction, tumor content spillage, and meningitis as contributive factors.[1]\n\nThis case does not include the aforementioned factors. There was no manipulation of exposed Sylvian vessels, given that this was the anterior extent of our resection. The vessels were identified and preserved. The delayed timing of the sCVS does not match the course of “traction hemiplegia,” which tends to manifest as CVS intraoperatively or immediately in the perioperative course and is short termed.[7,11,19,28,29] Although there was a minimal amount of hemorrhage within the posterior and medial aspects of the operative bed, there was no evidence of postoperative subarachnoid hemorrhage or hemorrhage within the basal cisterns. Lackner et al. implicated high bleeding volume on postoperative CT in the development of sCVS.[19] The volumetric analysis conducted in our study through OsiriX software, the same method as that used in Lackner et al.’s study, yielded a measurement of 1.8 cm3, lower than the mean postoperative bleeding in their anterior temporal lobectomy group (5.5 cm3).[19] Worsening edema has also been implicated in the development of sCVS.[18] In our case, postoperative edema immediately after surgery and at the time of sCVS 8 days later was stable and similar to preoperative imaging.\n\nGliadel polymers function through controlled release of contents over a period of 2–3 weeks after implantation.[13,14,26] The concentration of BCNU at the site of implantation is 1200 times higher than that achieved with administration of systemic carmustine.[13,14,21,22,26] The exact mechanism of sCVS secondary to BCNU implantation is unclear, though it is likely a combination of local toxicity, inflammatory mediators released in response to foreign body reaction to the polymer, and the vasospastic effects of carmustine.[21,22] High-dose intravenous carmustine (800/m2) has been associated with retinal artery narrowing and obstruction.[31] Carmustine has also been shown to induce vasospasm in rabbit models through inhibition of glutathione reductase activity, indicating presence of local inflammatory reactions secondary to the foreign wafers.[30] In addition, Shibahara et al. demonstrated a significant increase in surrounding immune cells with BCNU implantation in GBM patients and augmentation of inflammatory response in nearby tissue.\n\nThe previous cases of sCVS with Gliadel implantation along with ours are outlined in [Table 1]. The timing of the CVS is similar in two cases and differs in the other. sCVS occurred immediately after surgery in the case described by Muzii et al. and likely follows the course of sCVS secondary to manipulation.[7,11,19,21,28,29] Given the fact that, the peak effect of carmustine wafers occurs around day 5–7 after implantation,[13,14,26] a delayed course of vasospasm as displayed in our case and the case presented by Nakada et al. seems more likely to follow the pathogenesis.[22] Therefore, the delayed onset of symptoms in future cases of Gliadel placement should raise suspicion of this phenomenon for clinicians.\n\nTable 1: Cases of symptomatic cerebral vasospasm after Gliadel placement.\n\nIn all the cases of sCVS with Gliadel implantation [Table 1], Gliadel was laid directly over or in close proximity to the vasculature with vasospasm on angiographic imaging. Nakada et al. described a case in which Gliadel was placed in close proximity to the lenticulostriate artery, which manifested as selective sCVS.[22] In our case and the case described by Muzii et al., Gliadel lined the surgical cavity which included exposed large cerebral vessels.[21] Unfortunately, other than safety guidelines of the product label, there are no evidence- based recommendations to guide implantation of carmustine wafers.[15] Gutenberg et al. reported two cases of significant perioperative bleeding believed to be secondary to rupture, dissection, or thromboembolic events as a result of direct contact between the wafers and vasculature.[15] Sato et al. reported a case of delayed pseudoaneurysm formation and subsequent rupture secondary to dissection induced by similar proposed mechanisms.[27] Interestingly, all three cases of sCVS occur in temporal and insular regions. Several authors have proposed avoiding Gliadel placement in eloquent areas secondary to a risk of worsening cerebral edema and compressive deficits.[18] We argue for caution when directly applying carmustine wafers in close proximity to large cerebral vessels, particularly in the temporal and insular regions.[15,18] Further studies are necessary to elucidate the molecular mechanisms of this occurrence and whether there is an enhanced risk of vasospasm secondary to the interactions of BCNU and specific vasospastic mediators released by the peritumoral environment.\n\nTreatment of sCVS is similar to that instituted in aSAH.[4,21,22,35] The case described by Nakada et al. and our case both had delays in angiographic diagnosis and eventual treatment.[22] Both cases also had infarctions and lasting deficits.[22] Muzii et al. described a case with prompt diagnosis and treatment, with sudden resolution of symptoms.[21] Woo et al. recommended continued radiographic surveillance of CVS with TCDs and/or angiographic imaging, though the correlation between radiographic CVS and persistent symptoms is still unclear.[19,33,34] We urge clinicians to maintain a high suspicion for sCVS postoperatively in patients with delayed neurological deficits after Gliadel wafer placement in high-grade glioma. We propose the early use of CT angiography in this patient population. If CVS is identified, this should be promptly followed by DSA for further management and treatment.\n\nGiven that Gliadel does lend a survival benefit in a devastating disease,[2,3,6,9,12,15,16,32] prophylactic measures ought to be sought to prevent the occurrence of CVS rather than discontinuation of its use in high-risk cases. Perhaps, the topical administration of papaverine can alleviate the effect. Papaverine, a phosphodiesterase inhibitor, has often been used in skull base and cerebrovascular cases to mitigate CVS with success.[23,25] Recently, it has also been shown to harbor anti-cancerous properties by inhibiting GBM cell growth in mice models, making it an interesting adjunct in this setting.[17]\n\nCONCLUSION\nWe urge surgeons to reconsider universal placement of carmustine wafers in GBM in situations where large intracranial vasculature is exposed within the tumor resection cavity. We also propose the early identification of this devastating complication in the postoperative period by maintaining a high clinical suspicion and prompt utilization of CT and DSA in the management and treatment of these patients accordingly.\n\nHow to cite this article: Khan MQ, Cirjan C, Quadri N, Alexopoulos G, Coppens J. Symptomatic cerebral vasospasm in the setting of carmustine wafer placement for glioblastoma: A case presentation and review of literature. Surg Neurol Int 2020;11:168.\n\nDeclaration of patient consent\nPatient’s consent not required as patients identity is not disclosed or compromised.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Alotaibi NM Lanzino G Cerebral vasospasm following tumor resection J Neurointerv Surg 2013 5 413 8 22914745 \n2 Aoki T Nishikawa R Sugiyama K Nonoguchi N Kawabata N Mishima K A multicenter phase I/II study of the BCNU implant (gliadel® wafer) for Japanese patients with malignant gliomas Neurol Med Chir (Tokyo) 2014 54 290 301 24739422 \n3 Ashby LS Smith KA Stea B Gliadel wafer implantation combined with standard radiotherapy and concurrent followed by adjuvant temozolomide for treatment of newly diagnosed high-grade glioma: A systematic literature review World J Surg Oncol 2016 14 1 15 26732900 \n4 Bauer AM Rasmussen PA Treatment of intracranial vasospasm following subarachnoid hemorrhage Front Neurol 2014 5 1 7 24454306 \n5 Bejjani GK Sekhar LN Yost AM Bank WO Wright DC Vasospasm after cranial base tumor resection: Pathogenesis, diagnosis, and therapy Surg Neurol 1999 52 577 84 10660023 \n6 Champeaux C Weller J Implantation of carmustine wafers (Gliadel® ) for high-grade glioma treatment. A 9-year nationwide retrospective study J Neurooncol 2020 147 159 69 31974802 \n7 Chang SD Yap OW Adler JR Symptomatic vasospasm after resection of a suprasellar pilocytic astrocytoma: Case report and possible pathogenesis Surg Neurol 2015 51 521 7 \n8 Charpentier C Audibert G Guillemin F Civit T Ducrocq X Bracard S Multivariate analysis of predictors of cerebral vasospasm occurrence after aneurysmal subarachnoid hemorrhage Stroke 1999 30 1402 8 10390314 \n9 Chowdhary SA Ryken T Newton HB Survival outcomes and safety of carmustine wafers in the treatment of high-grade gliomas: A meta-analysis J Neurooncol 2015 122 367 82 25630625 \n10 Claassen J Bernardini GL Kreiter K Bates J Du YE Copeland D Effect of cisternal and ventricular blood on risk of delayed cerebral ischemia after subarachnoid hemorrhage: The fisher scale revisited Stroke 2001 32 2012 20 11546890 \n11 Dickerson JC Hidalgo JA Smalley ZS Shiflett JM Diffuse vasospasm after transcortical temporal lobectomy for intractable epilepsy Acta Neurochir (Wien) 2018 160 1883 7 29987392 \n12 Duntze J Litré CF Eap C Théret E Debreuve A Jovenin N Implanted carmustine wafers followed by concomitant radiochemotherapy to treat newly diagnosed malignant gliomas: Prospective, observational, multicenter study on 92 cases Ann Surg Oncol 2013 20 2065 72 23212763 \n13 Fleming AB Saltzman WM Pharmacokinetics of the carmustine implant Clin Pharmacokinet 2002 41 403 19 12074689 \n14 Fung LK Ewend MG Sills A Sipos EP Thompson R Watts M Pharmacokinetics of interstitial delivery of carmustine, 4-hydroperoxycyclophosphamide, and paclitaxel from a biodegradable polymer implant in the monkey brain Cancer Res 1998 58 672 84 9485020 \n15 Gutenberg A Lumenta CB Braunsdorf WE Sabel M Mehdorn HM Westphal M The combination of carmustine wafers and temozolomide for the treatment of malignant gliomas. A comprehensive review of the rationale and clinical experience J Neurooncol 2013 113 163 74 23535992 \n16 Hart MG Garside R Rogers G Somerville M Stein K Grant R Chemotherapy wafers for high grade glioma Cochrane Database Syst Rev 2011 3 CD007294 \n17 Inada M Shindo M Kobayashi K Sato A Yamamoto Y Akasaki Y Anticancer effects of a non-narcotic opium alkaloid medicine, papaverine, in human glioblastoma cells PLoS One 2019 14 e0216358 31100066 \n18 Kuramitsu S Motomura K Natsume A Wakabayashi T Double-edged sword in the placement of carmustine (BCNU) wafers along the eloquent area: A case report NMC Case Rep J 2015 2 40 5 28663961 \n19 Lackner P Koppelstaetter F Ploner P Sojer M Dobesberger J Walser G Cerebral vasospasm following temporal lobe epilepsy surgery Neurology 2012 78 1215 20 22442433 \n20 Mandonnet E Chassoux F Naggara O Roux FX Devaux B Transient symptomatic vasospasm following antero-mesial temporal lobectomy for refractory epilepsy Acta Neurochir (Wien) 2009 151 1723 6 19415179 \n21 Muzii VF Vaiano A Bracco S Carangelo BR Symptomatic cerebral vasospasm after glioblastoma resection and carmustine wafers implantation. A case report Interdiscip Neurosurg Adv Tech Case Manag 2018 14 24 7 \n22 Nakada M Tanaka S Oishi M Miyashita K Misaki K Mohri M Cerebral infarction related to carmustine wafers in glioblastoma: A case report NMC Case Rep J 2014 2 36 9 28663960 \n23 Rahmani P Rezvani M Sabouri M Nikbakht H Rafiee A Torkashvand M The effect of irrigation of intracisternal papaverine on cerebral blood flow in subarachnoid hemorrhage Adv Biomed Res 2013 2 45 24516845 \n24 Rao S Narayanan S Nanjireddy R Mittal S Basha M Pearls and oy-sters: Symptomatic cerebral vasospasm on conventional angiography following temporal lobe epilepsy surgery Neurology 2017 88 e230 2 28583939 \n25 Rath GP Mukta Prabhakar H Dash HH Suri A Haemodynamic changes after intracisternal papaverine instillation during intracranial aneurysmal surgery Br J Anaesth 2006 97 848 50 16984954 \n26 Sampath P Brem H Implantable slow-release chemotherapeutic polymers for the treatment of malignant brain tumors Cancer Control 1998 5 130 7 10761024 \n27 Sato K Dan M Yamamoto D Miyajima Y Hara A Kumabe T Chronic phase intracranial hemorrhage caused by ruptured pseudoaneurysm induced by carmustine wafer implantation for insulo-opercular anaplastic astrocytoma: A case report Neurol Med Chir (Tokyo) 2015 55 848 51 26423018 \n28 Schaller C Zentner J Vasospastic reactions in response to the transsylvian approach Surg Neurol 1998 49 170 5 9457267 \n29 Schaller C Haun D Schramm J Meyer B. Technique assessment the transsylvian approach is “minimally invasive” but not atraumatic Neurosurgery 2002 51 971 7 12234405 \n30 Seeger W Suttorp N Schmidt F Neuhof H The glutathione redox cycle as a defense system against hydrogen-peroxide-induced prostanoid formation and vasoconstriction in rabbit lungs Am Rev Respir Dis 1986 133 1029 36 3087249 \n31 Shibahara I Hanihara M Watanabe T Dan M Sato S Kuroda H Tumor microenvironment after biodegradable BCNU wafer implantation: Special consideration of immune system J Neurooncol 2018 137 417 27 29468445 \n32 Shingleton BJ Albert DM Bienfang DC Ensminger WD Chandler WF Greenberg HS Ocular toxicity associated with high-dose carmustine Arch Ophthalmol 1982 100 1766 72 7138345 \n33 Westphal M Hilt DC Bortey E Delavault P Olivares R Warnke PC A Phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (gliadel wafers) in patients with primary malignant glioma Neuro Oncol 2004 5 79 88 \n34 Woo PY See KW Chow JK Chan Y Wong HT Chan KY Hypertensive-nimodipine therapy for middle cerebral artery vasospasm after resection of glioblastoma multiforme: A case report and literature review Open J Mod Neurosurg 2015 5 76 83 \n35 Zhang JH Pluta RM Hansen-Schwartz J Dreier J Vajkoczy P Macdonald RL Cerebral vasospasm following subarachnoid hemorrhage: Time for a new world of thought Neurol Res 2009 31 151 8 19298755\n\n",
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"issn_linking": "2152-7806",
"issue": "11()",
"journal": "Surgical neurology international",
"keywords": "Carmustine wafer; Cerebral vasospasm; Glial tumor; Glioma; Tumor resection",
"medline_ta": "Surg Neurol Int",
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"nlm_unique_id": "101535836",
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"pmid": "32637221",
"pubdate": "2020",
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"title": "Symptomatic cerebral vasospasm in the setting of carmustine wafer placement for glioblastoma: A case presentation and review of literature.",
"title_normalized": "symptomatic cerebral vasospasm in the setting of carmustine wafer placement for glioblastoma a case presentation and review of literature"
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"abstract": "BACKGROUND\nCerebral radiation injury, including subacute radiation reactions and later stage radiation necrosis, is a severe side effect of brain tumor radiotherapy. A protocol of four infusions of the monoclonal antibody bevacizumab has been shown to be a highly effective treatment. However, bevacizumab is costly and can cause severe complications including thrombosis, bleeding and gastrointestinal perforations.\n\n\nMETHODS\nWe performed a retrospective analysis of patients treated in our clinic for cerebral radiation injury who received only a singular treatment with bevacizumab. Single-shot was defined as a singular administration of bevacizumab without a second administration during an interval of at least 6 weeks.\n\n\nRESULTS\nWe identified 11 patients who had received a singular administration of bevacizumab to treat cerebral radiation injury. Prior radiation had been administered to treat gliomas (ten patients) or breast cancer brain metastases (one patient). 9 of 10 patients with available MRIs showed a marked reduction of edema at first follow-up. Discontinuation of Dexamethasone was possible in 6 patients and a significant dose reduction could be achieved in all other patients. One patient developed pulmonary artery embolism 2 months after bevacizumab administration. The median time to treatment failure of any cause was 3 months.\n\n\nCONCLUSIONS\nSingle-shot bevacizumab therefore has meaningful activity in cerebral radiation injury, but durable control is rarely achieved. In patients where a complete protocol of four infusions with bevacizumab is not feasible due to medical contraindications or lack of reimbursement, single-shot bevacizumab treatment may be considered.",
"affiliations": "Dr. Senckenberg Institute of Neurooncology, University Hospital Frankfurt, Goethe University, Frankfurt/Main, Germany. martin.voss@kgu.de.;University Cancer Center Frankfurt (UCT), University Hospital Frankfurt, Goethe University, Frankfurt/Main, Germany.;University Cancer Center Frankfurt (UCT), University Hospital Frankfurt, Goethe University, Frankfurt/Main, Germany.;University Cancer Center Frankfurt (UCT), University Hospital Frankfurt, Goethe University, Frankfurt/Main, Germany.;Dr. Senckenberg Institute of Neurooncology, University Hospital Frankfurt, Goethe University, Frankfurt/Main, Germany.;Dr. Senckenberg Institute of Neurooncology, University Hospital Frankfurt, Goethe University, Frankfurt/Main, Germany.",
"authors": "Voss|Martin|M|http://orcid.org/0000-0001-8469-8204;Wenger|Katharina J|KJ|http://orcid.org/0000-0002-8640-6858;Fokas|Emmanouil|E|;Forster|Marie-Thérèse|MT|http://orcid.org/0000-0001-7055-543X;Steinbach|Joachim P|JP|;Ronellenfitsch|Michael W|MW|http://orcid.org/0000-0002-1402-6290",
"chemical_list": "D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D005938:Glucocorticoids; D000068258:Bevacizumab; D003907:Dexamethasone",
"country": "England",
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"doi": "10.1186/s12883-021-02103-0",
"fulltext": "\n==== Front\nBMC Neurol\nBMC Neurol\nBMC Neurology\n1471-2377 BioMed Central London \n\n2103\n10.1186/s12883-021-02103-0\nResearch Article\nSingle-shot bevacizumab for cerebral radiation injury\nhttp://orcid.org/0000-0001-8469-8204Voss Martin martin.voss@kgu.de 1234 http://orcid.org/0000-0002-8640-6858Wenger Katharina J. 2345 Fokas Emmanouil 2346 http://orcid.org/0000-0001-7055-543XForster Marie-Thérèse 2347 Steinbach Joachim P. 1234 http://orcid.org/0000-0002-1402-6290Ronellenfitsch Michael W. 1234 1 grid.411088.40000 0004 0578 8220Dr. Senckenberg Institute of Neurooncology, University Hospital Frankfurt, Goethe University, Frankfurt/Main, Germany \n2 University Cancer Center Frankfurt (UCT), University Hospital Frankfurt, Goethe University, Frankfurt/Main, Germany \n3 grid.7497.d0000 0004 0492 0584German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Frankfurt/Main, Germany \n4 grid.418483.20000 0001 1088 7029Frankfurt Cancer Institute (FCI), Georg-Speyer-Haus, Frankfurt/Main, Germany \n5 grid.411088.40000 0004 0578 8220Institute of Neuroradiology, University Hospital Frankfurt, Goethe University, Frankfurt/Main, Germany \n6 grid.411088.40000 0004 0578 8220Department of Radiotherapy and Oncology, University Hospital Frankfurt, Goethe University, Frankfurt/Main, Germany \n7 grid.411088.40000 0004 0578 8220Department of Neurosurgery, University Hospital Frankfurt, Goethe University, Frankfurt/Main, Germany \n17 2 2021 \n17 2 2021 \n2021 \n21 7711 8 2020 8 2 2021 © The Author(s) 2021Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nCerebral radiation injury, including subacute radiation reactions and later stage radiation necrosis, is a severe side effect of brain tumor radiotherapy. A protocol of four infusions of the monoclonal antibody bevacizumab has been shown to be a highly effective treatment. However, bevacizumab is costly and can cause severe complications including thrombosis, bleeding and gastrointestinal perforations.\n\nMethods\nWe performed a retrospective analysis of patients treated in our clinic for cerebral radiation injury who received only a singular treatment with bevacizumab. Single-shot was defined as a singular administration of bevacizumab without a second administration during an interval of at least 6 weeks.\n\nResults\nWe identified 11 patients who had received a singular administration of bevacizumab to treat cerebral radiation injury. Prior radiation had been administered to treat gliomas (ten patients) or breast cancer brain metastases (one patient). 9 of 10 patients with available MRIs showed a marked reduction of edema at first follow-up. Discontinuation of Dexamethasone was possible in 6 patients and a significant dose reduction could be achieved in all other patients. One patient developed pulmonary artery embolism 2 months after bevacizumab administration. The median time to treatment failure of any cause was 3 months.\n\nConclusions\nSingle-shot bevacizumab therefore has meaningful activity in cerebral radiation injury, but durable control is rarely achieved. In patients where a complete protocol of four infusions with bevacizumab is not feasible due to medical contraindications or lack of reimbursement, single-shot bevacizumab treatment may be considered.\n\nKeywords\nRadiation necrosisBevacizumabDexamethasoneSide effectEdemaissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\nRadiation necrosis has been reported in approximately 6 % of patients with brain tumors after radiation therapy and can lead to significant morbidity and, if untreated, mortality by progressive necrosis and brain edema [1]. Additionally, the risk of misinterpreting radiation injury (including subacute radiation reactions and later stage radiation necrosis) for tumor progression can prevent adequate therapy [2]. The risk of radiation injury is highest in patients who undergo repeated courses of radiotherapy, even with prolonged intervals between the two treatments. Lee et al. reported a rate of 64 % radiation necrosis for hypofractionated re-irradiation (45 Gy in 15 fractions) in glioma patients at least 12 months post-treatment [3]. Conceptually, radiation-induced injury is thought to result from damage to vascular endothelial and glial cells. Secretion of vascular endothelial growth factor (VEGF)-A appears to be responsible for edema formation via increasing vascular permeability and inducing a pro-inflammatory environment [4].\n\nBevacizumab is an antibody targeting VEGF-A induced angiogenesis and has been evaluated as a treatment for malignant brain tumors. While several phase III trials of first-line therapy failed to show any effect on overall survival [5–7], there was still a pronounced effect of bevacizumab on the blood brain barrier with reduced gadolinium contrast enhancement and edema reducing the rate of pseudoprogression in MRI scans from 9.3 to 2.2 % in the AVAglio trial [8]. Bevacizumab has also been used in small clinical trials as a treatment for radiation necrosis. Levin et al. reported a randomized, placebo-controlled trial of four infusions of bevacizumab 7.5 mg/kg at 3-week intervals for radiation necrosis of the central nervous system [9]. This trial demonstrated an impressive clinical and radiological improvement in all patients receiving bevacizumab while no patient with placebo treatment improved spontaneously. This treatment efficacy came at the cost of a high rate of adverse events in the bevacizumab group (6 of 11 patients) while no adverse events occurred in the placebo group. Common serious side effects of bevacizumab regimens include pulmonary artery embolism, venous thrombosis and intracranial hemorrhage [10, 11]. Whether a reduced number of bevacizumab cycles could also suffice to adequately treat radiation injury with a potentially reduced side effect profile remains unclear. In tumor treatment, clinical trials comparing standard and low-dose bevacizumab regimens found no significant differences in efficacy [12] but suggested a more favorable toxicity profile [13, 14].\n\nBevacizumab has not been approved by the European Medicines Agency (EMA), neither for progressive glioblastoma nor for the treatment of radiation reaction (FDA approval for adult patients with progressive glioblastoma) but is often used as an individual, off-label therapy for dexamethasone-refractory radiation necrosis or following steroid discontinuation due to adverse effects. In cases of rapid clinical deterioration, immediate treatment with bevacizumab can be considered to prevent permanent damage to eloquent areas. However, reimbursement by insurance companies can be difficult. If a singular administration (single-shot) of bevacizumab, that is considered financially affordable, was sufficient to treat cerebral radiation injury, this would broaden options for both, patients and physicians due to lower financial as well as potential side effect risks, especially for patients with prior vascular contraindications.\n\nMethods\nWe performed a retrospective analysis of patients treated in our clinic between 2016 and 2019 to identify patients with cerebral radiation side effects who received a singular treatment with bevacizumab. Diagnosis of acute radiation reaction and radiation necrosis had been made in the interdisciplinary tumor board based on MRI and considering the field of radiation and the time from last radiation therapy (results section). Single-shot bevacizumab was defined as a singular administration of bevacizumab without a second administration during an interval of at least six weeks. The patient collective was evaluated with regard to histology, patient age at diagnosis of radiation injury, duration and maximum dose of dexamethasone, clinical course and possible side-effects, as well as the radiologic response to bevacizumab treatment. MRI scans included at least axial fluid-attenuated inversion recovery (FLAIR), T2-weighted, and T1-weighted images before and after application of gadolinium-based contrast agent. The extent of edema was estimated on the axial FLAIR or T2-weighted sequence. Response to bevacizumab treatment was defined as a reduction of the edema by at least 25 % [9].\n\nWritten consent by the individual patient for this retrospective data collection was waived by the ethics committee of the University Hospital Frankfurt; Goethe University which also approved the access to the patients’ data (IRB decision # 4/09, project SNO_01–08). Microsoft Excel was used for data management and analysis. Corel Draw 2019 was used to create figures.\n\nResults\nFrom 2016 until the end of 2019 approximately 400 patients received radiation of the brain for any reason (brain tumor or brain metastasis including primary therapy and re-irradiation therapy) at our cancer center. During this time, about 65 patients were treated with bevacizumab for radiation reaction. Retrospective analysis revealed 11 patients who were initially treated with a single-shot (Table 1). Ten patients had received prior fractionated radiation therapy for gliomas including 2 patients being treated primarily by radiotherapy at initial diagnosis (radiotherapy doses: 54 and 60 Gy) and 8 patients, who underwent re-irradiation for recurrent tumor (radiotherapy doses: 20–36 Gy), whereas one patient received re-irradiation (dose: 30 Gy) for recurrent brain metastasis of breast cancer after an initial radiosurgery.\nTable 1 Patient characteristics\n\nNumber of Patients\t11\t\nAge at treatment with BEV [years]\t\n Median (range)\t47 (22 – 73)\t\nHistology\t\n Glioma\t91% (10)\t\n Brain metastasis (breast cancer)\t9% (1)\t\nRadiation for\t\n Recurrent tumor\t82% (9)\t\n Primary therapy\t18% (2)\t\nLast radiation therapy prior to BEV [Gy]\t\n 5x4\t18% (2)\t\n 10x3\t9% (1)\t\n 10x3,5\t36% (4)\t\n 12x3\t9% (1)\t\n 15x2,67\t9% (1)\t\n 30x1,8\t9% (1)\t\n 30x2\t9% (1)\t\nTime from radiation to diagnosis of radiation injury [months]\t\n Median (range)\t2 (1-7)\t\nMaximum Dose of dexamethasone [mg]\t\n Before therapy, Median (range)\n\n After therapy, Median (range)\n\n\t8 (0 – 40)\n\n0 (0 - 4)\n\n\t\nKarnofsky-Score [%]\t\n Before therapy, Median (range)\t50 (40 – 80)\t\n After therapy, Median (range)\t60 (40 – 80)\t\nDose of BEV single-shot\t\n 7,5mg/kg\t73% (8)\t\n 10mg/kg\t27% (3)\t\nReported benefit by patient\t\n Yes\t64% (7)\t\n No\t36% (4)\t\nAbbreviation: BEV bevacizumab\n\n\n\nAs soon as acute radiation reaction / radiation necrosis was diagnosed, therapy with dexamethasone was started or an already established therapy with steroids was intensified following a mean interval of 2 months post-radiation therapy. Median peak dose of dexamethasone was 8 mg/day, with a maximum dose of 40 mg/day in 2 patients. Diagnosis of radiation injury was based on MRI in 10 patients using additional MR-perfusion in 6 patients. In one patient, diagnosis was confirmed by positron emission tomography (F-18-fluroethyltyrosine). In no case had a biopsy been performed to confirm the diagnosis histologically.\n\nWhen dexamethasone did not improve clinical symptoms or could not be tolerated at the required doses due to side effects, off-label treatment with bevacizumab was recommended at the institutional multidisciplinary tumor board. Four of these patients had a single-shot of bevacizumab treatment because of a high-risk situation for side effects rendering long-term repeat treatment with bevacizumab unfeasible (pulmonary embolism, deep vein thrombosis, fracture of several rips, hemorrhage of the tumor). In another patient there were concerns of possible increased toxicity as the patient received ongoing therapy with lomustin and temozolomide [15], and in a further patient bevacizumab was only administered once because of the ensuing palliative setting aimed at improving aphasia (Patient 1). Moreover, one patient initially received one singular infusion due to personal concerns with regard to side effects (patient 11), and two did not consent to further infusions (Patient 6 and patient 9). Two patients did not receive reimbursement by the insurance company for further treatment after the single-shot of bevacizumab.\n\nEight patients received 7.5 mg/kg as proposed by Levin et al., three patients received 10 mg/kg as used in the neuro-oncological trials for bevacizumab at that time [6, 9]. The treatment was well-tolerated without any acute side effects during the infusion. One patient with immobility developed deep vein thrombosis with subsequent pulmonary artery embolism two months after bevacizumab.\n\nAfter a median interval of 55 days following the administration of bevacizumab first MRI showed a marked reduction of brain edema (at least 25 %) in 9/10 evaluable patients. An example is given in Fig. 1.\n\n\nFig. 1 MRI scans of a 34 year old patient with IDH-mutated astrocytoma. a MRI revealed a small recurrent tumor adjacent to the dorsal resection cavity with small surrounding edema. b The patient was treated with re-radiation therapy with 35 Gy and concomitant temozolomide. First MRI after the treatment showed an increase of contrast enhancement and edema which was diagnosed as radiation necrosis. c Therapy with 8 mg of dexamethasone did neither improve the MRI nor the clinical symptoms and bevacizumab 7.5 mg/kg was administered as a single-shot. d First scan one month later displayed a marked reduction in contrast enhancement and of the edema. Treatment with dexamethasone could be stopped. The follow up 3 months later was stable (not shown)\n\n\n\nAfter single-shot bevacizumab, patients Karnofsky Performance Score (KPS) improved from a median of 50–60 % and 7 patients reported markedly improved clinical symptoms at the first visit after bevacizumab. Here, we noticed that the only slight improvement of KPS underestimated the clinical benefit in the activity of daily life. Indeed, the ability for an independent transfer from the wheelchair to a bed or toilet has a great impact on the patient’s quality of life that is not accurately reflected in the Karnofsky-Index. Notably, dexamethasone could be stopped in 6 of the patients. In all other patients, the dose of dexamethasone could be gradually reduced, finally reaching doses between 0.5 and 4 mg/day after a median time of 39 days after the single-shot.\n\nMean time to treatment failure was 3 months (range 1–10 months). Importantly, treatment failure to bevacizumab was due to tumor progression (patient 2, 4 and 6) or death (patient 1) in four patients, therefore, tumor progression should always be taken into account when interpreting clinical deterioration as the latter likely reflects a mixture of tumor progression and radiation necrosis (Fig. 2). One patient (patient 8) had both a marked improvement in clinical symptoms and MRI with a decline in contrast enhancement after single-shot. In this patient, however, treatment with bevacizumab was resumed 8 weeks after the first infusion, since the patient still experienced disabilities in the activities of daily life, and the single-shot had been tolerated well. Treatment failure in the other patients was diagnosed due to recurrent edema in follow-up MRI with or without clinical symptoms (Fig. 3).\nFig. 2 MRI scans of a 33 year old patient with IDH-wildtype glioblastoma. First (a) and second (b) MRI after resection and radiation therapy of recurrent glioblastoma showed not signs of tumor progression. Dexamethasone was started because of clinical deterioration before the third control (c) which showed a substantial increase in contrast enhancement and edema which were interpreted as late radiation necrosis. Bevacizumab 7.5 mg/kg was administered as a single-shot. d First scan 1.5 months later displayed a marked reduction of the edema while there was only a minor reduction of contrast enhancement. Diagnosis was changed from radiation necrosis to recurrent tumor\n\nFig. 3 Time to treatment failure. The swimmer plot shows the course of the individual patients labeled at the left side. The radiological diagnosis is indicated by color-coded dots (yellow: MRI, orange: MRI and MR-perfusion, purple: PET). The color-coded diamonds indicate the treatment failure of the single-shot bevacizumab (green: treatment of recurrent edema with corticosteroids, blue: treatment of recurrent edema with bevacizumab, blue border: resumed bevacizumab as the symptoms did not completely resolve, red: recurrent tumor, black: death of the patient because of recurrent tumor). Median time from single-shot to time of treatment failure of any cause) was three months\n\n\n\nDiscussion\nCerebral irradiation is an integral part of the treatment of brain cancer. One of the most severe complications is cerebral necrosis that can occur in patients with primary or metastatic brain tumors especially after a second course of irradiation for recurrent tumors. Despite promising efficacy in the treatment of cerebral radiation necrosis from smaller clinical trials, no application for bevacizumab approval for this indication has been filed. Reimbursement by insurance companies therefore remains difficult and is granted only on a case by case basis limiting the availability of bevacizumab. Assessing the efficacy of a singular bevacizumab treatment with a potentially more favorable side-effect profile and lesser financial burden than the cyclic treatment addresses a clinically important challenge. In the present work we show that a singular dose of bevacizumab resulted in significantly reduced edema on MRI sequences in all evaluable patients with two-thirds of patients reporting a meaningful improvement of clinical symptoms. In this context the very shot interval from radiation therapy to the development of brain lesions has to be noted. The mean time of two month is rather short for radiation necrosis in comparison to the trial by Levin et al. [9]. Therefore it is plausible that some of the patients suffered from a subacute or early delayed radiation reaction rather than manifest necrosis. Despite the small series, this study provides encouraging data, indicating that singular administration of bevacizumab might be a useful option for the treatment of radiation reaction / necrosis, especially in patients where prolonged bevacizumab treatment is not deemed feasible, as for example due to prior thromboembolic events or due to denial of therapy reimbursement. Additionally, even when bevacizumab is available for multiple treatments, a single-shot might be sufficient treatment for some patients. At the present time it is unclear whether a resumption of therapy in cases where a single-shot is not sufficient has disadvantages on the course of cerebral radiation necrosis.\n\nIn our analysis, we identified only one potentially severe side effect in one patient who was diagnosed with pulmonary artery embolism two months after bevacizumab. Whether this was instead attributable to immobility of the patient, who was later also diagnosed with deep vein thrombosis, or if this only contributed to the embolism remains unclear.\n\nAn interesting variant of the single-shot bevacizumab concept to further reduce the systemic side effects could be a local administration. The ongoing LIBERTI trial (NCT02819479) evaluates the efficacy of a single, intra-arterial dose of only 2.5 mg/kg bevacizumab [16]. Despite the large molecular mass of bevacizumab some penetration of the disrupted blood-brain barrier in regions of radiation injury appears possible [17]. The reduced side effect might come at the cost of a decreased duration of edema control. With a half-life of three weeks, the effect on the blood brain barrier might not be lasting, and the downside could be a rebound phenomenon with the need of bevacizumab re-challenge, as also indicated by the short time to treatment failure in our collective of only three months. The trial of Levin et al. with four administrations of 7.5 mg/ reported a relapse of radiation necrosis in 25 % of patients [9]. Zhuang et al. reported 14 patients with cerebral radiation necrosis who were treated with a lower dose of 5 mg/kg bevacizumab for at least 3 cycles of therapy [18]. MRI showed improvement in 13 of the 14 patients, but 10 of the 13 responsive patients exhibited a rebound phenomenon in the later follow-up. One option would be to further lower the dose of bevacizumab but keep the continuous administration. This approach of lowering the dose to 1 mg/kg bevacizumab every three weeks has revealed promising results in a phase 2 trial [19]. The trial included 21 patients and the grade of the edema index was improved in 19 patients. In contrast to Levin et al., no adverse events above grade 2 were reported. This concept has been further supported by case reports with low-dose bevacizumab and even longer intervals between the administration [20].\n\nProphylactic administration of a singular dose bevacizumab in high-risk situations (re-irradiation therapy, large irradiation fields or/and already present widespread edema prior to irradiation) could also be an option to consider. Thereby clinical deterioration might be prevented and the need for corticosteroids as well as the risk of a rebound effect after termination of bevacizumab treatment might be reduced. Such an approach has been explored in a phase 1 trial by Clarke et al. This trial included bevacizumab treatment to intensify the radiation dose of hypofractionated stereotactic re-irradiation [21]. This concept could be even more beneficial in cyber knife radiosurgery [22, 23].\n\nWhile histological confirmation of cerebral radiation necrosis is clearly limited to only the most ambiguous cases, we here report a cohort of 11 patients whose radiological scans and dynamics indicated radiation necrosis. Two patients (patient 2 and 6) had treatment failure shortly after the single-shot due to tumor progress in the MRI and these were also patients where diagnosis was based on conventional MRI without MR-perfusion or MR-spectroscopy. A more selected collective of histologically diagnosed radiation necrosis could have shown more sustained effects of bevacizumab.\n\nConclusions\nIn summary, bevacizumab is an effective treatment for patients with cerebral radiation injury. Optimal dosing and intervals still have to be defined but most likely lower doses and longer intervals than investigated in previous trials [9] are sufficient. In the case of patients at high risk for side effects, single-shot of bevacizumab may be used as a test-dose and treatment can be continued when necessary.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNone.\n\nAuthors’ contributions\nAll authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by M.V., K.W. E.F., MT.F. and M.W.R. The first draft of the manuscript was written by M.V., J.P.S. and M.W.R and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\n\nFunding\nThe authors received no specific funding for this work.\n\nAvailability of data and materials\nRaw data were generated at the Dr. Senckenberg Institute of Neurooncology. The datasets generated are available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\nWritten consent by the individual patient for this retrospective data collection was waived by the ethics committee of the University Hospital Frankfurt; Goethe University which also approved the access to the patients’ data (IRB decision # 4/09, project SNO_01–08).\n\nConsent for publication\nNo individual person’s data is included in this article.\n\nCompeting interests\nJ.P.S. has received honoraria for lectures or advisory board participation, consulting or travel grants from Abbvie, Roche, Boehringer, Bristol-Myers Squibb, Medac, Mundipharma and UCB. M.W.R. has received a grant from UCB. The other authors report no conflict of interest.\n==== Refs\nReferences\n1. Fetcko K Lukas RV Watson GA Zhang L Dey M Survival and complications of stereotactic radiosurgery: A systematic review of stereotactic radiosurgery for newly diagnosed and recurrent high-grade gliomas Med (Baltim) 2017 96 43 e8293 10.1097/MD.0000000000008293 \n2. Ellingson BM Chung C Pope WB Boxerman JL Kaufmann TJ Pseudoprogression, radionecrosis, inflammation or true tumor progression? challenges associated with glioblastoma response assessment in an evolving therapeutic landscape J Neurooncol 2017 134 3 495 504 10.1007/s11060-017-2375-2 28382534 \n3. Lee J Ahn SS Chang JH Suh CO Hypofractionated Re-irradiation after Maximal Surgical Resection for Recurrent Glioblastoma: Therapeutic Adequacy and Its Prognosticators of Survival Yonsei Med J 2018 59 2 194 201 10.3349/ymj.2018.59.2.194 29436186 \n4. Nordal RA Nagy A Pintilie M Wong CS Hypoxia and hypoxia-inducible factor-1 target genes in central nervous system radiation injury: a role for vascular endothelial growth factor Clin Cancer Res 2004 10 10 3342 53 10.1158/1078-0432.CCR-03-0426 15161688 \n5. Gilbert MR Dignam JJ Armstrong TS Wefel JS Blumenthal DT Vogelbaum MA A randomized trial of bevacizumab for newly diagnosed glioblastoma N Engl J Med 2014 370 8 699 708 10.1056/NEJMoa1308573 24552317 \n6. Herrlinger U Schafer N Steinbach JP Weyerbrock A Hau P Goldbrunner R Bevacizumab Plus Irinotecan Versus Temozolomide in Newly Diagnosed O6-Methylguanine-DNA Methyltransferase Nonmethylated Glioblastoma: The Randomized GLARIUS Trial J Clin Oncol 2016 34 14 1611 9 10.1200/JCO.2015.63.4691 26976423 \n7. Chinot OL Wick W Mason W Henriksson R Saran F Nishikawa R Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma N Engl J Med 2014 370 8 709 22 10.1056/NEJMoa1308345 24552318 \n8. Wick W Chinot OL Bendszus M Mason W Henriksson R Saran F Evaluation of pseudoprogression rates and tumor progression patterns in a phase III trial of bevacizumab plus radiotherapy/temozolomide for newly diagnosed glioblastoma Neuro Oncol 2016 18 10 1434 41 10.1093/neuonc/now091 27515827 \n9. Levin VA Bidaut L Hou P Kumar AJ Wefel JS Bekele BN Randomized double-blind placebo-controlled trial of bevacizumab therapy for radiation necrosis of the central nervous system Int J Radiat Oncol Biol Phys 2011 79 5 1487 95 10.1016/j.ijrobp.2009.12.061 20399573 \n10. Nalluri SR Chu D Keresztes R Zhu X Wu S Risk of venous thromboembolism with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis JAMA 2008 300 19 2277 85 10.1001/jama.2008.656 19017914 \n11. Li X Huang R Xu Z Risk of Adverse Vascular Events in Newly Diagnosed Glioblastoma Multiforme Patients Treated with Bevacizumab: a Systematic Review and Meta-Analysis Sci Rep 2015 5 14698 10.1038/srep14698 26423913 \n12. Sirven-Villaros L Bourg V Suissa L Mondot L Almairac F Fontaine D Bevacizumab: Is the lower the better for glioblastoma patients in progression? Bull Cancer 2018 105 12 1135 46 10.1016/j.bulcan.2018.07.010 30301554 \n13. Ajlan A Thomas P Albakr A Nagpal S Recht L Optimizing bevacizumab dosing in glioblastoma: less is more J Neurooncol 2017 135 1 99 105 10.1007/s11060-017-2553-2 28667595 \n14. Lorgis V Maura G Coppa G Hassani K Taillandier L Chauffert B Relation between bevacizumab dose intensity and high-grade glioma survival: a retrospective study in two large cohorts J Neurooncol 2012 107 2 351 8 10.1007/s11060-011-0748-5 22076449 \n15. Herrlinger U Tzaridis T Mack F Steinbach JP Schlegel U Sabel M Lomustine-temozolomide combination therapy versus standard temozolomide therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter (CeTeG/NOA-09): a randomised, open-label, phase 3 trial Lancet 2019 393 10172 678 88 10.1016/S0140-6736(18)31791-4 30782343 \n16. Dashti SR Spalding A Kadner RJ Yao T Kumar A Sun DA Targeted intraarterial anti-VEGF therapy for medically refractory radiation necrosis in the brain J Neurosurg Pediatr 2015 15 1 20 5 10.3171/2014.9.PEDS14198 25360851 \n17. Joshi S Ellis JA Ornstein E Bruce JN Intraarterial drug delivery for glioblastoma mutiforme: Will the phoenix rise again? J Neurooncol 2015 124 3 333 43 10.1007/s11060-015-1846-6 26108656 \n18. Zhuang H Yuan X Chang JY Song Y Wang J Yuan Z Exploration of the recurrence in radiation brain necrosis after bevacizumab discontinuation Oncotarget 2016 7 30 48842 9 10.18632/oncotarget.7768 26934327 \n19. Zhuang H Zhuang H Shi S Wang Y Ultra-Low-Dose Bevacizumab For Cerebral Radiation Necrosis: A Prospective Phase II Clinical Study Onco Targets Ther 2019 12 8447 53 10.2147/OTT.S223258 31632089 \n20. Meng X Zhao R Wu S Shen G Ding L Sun B Efficacy of repeated low-dose bevacizumab treatment with long-dosing interval for radiation-induced brain necrosis: A case report Cancer Biol Ther 2017 18 1 63 6 10.1080/15384047.2016.1276127 28152324 \n21. Clarke J Neil E Terziev R Gutin P Barani I Kaley T Multicenter, Phase 1, Dose Escalation Study of Hypofractionated Stereotactic Radiation Therapy With Bevacizumab for Recurrent Glioblastoma and Anaplastic Astrocytoma Int J Radiat Oncol Biol Phys 2017 99 4 797 804 10.1016/j.ijrobp.2017.06.2466 28870792 \n22. Xiangying M Rugang Z Lijuan D Yaowei Z Bing S Junliang W Low-dose bevacizumab as an effective pre-treatment for peri-tumoral brain edema prior to CyberKnife radiosurgery: A case report Cancer Biol Ther 2018 19 6 461 4 10.1080/15384047.2018.1433499 29420112 \n23. Wang Y Wang E Pan L Dai J Zhang N Wang X A new strategy of CyberKnife treatment system based radiosurgery followed by early use of adjuvant bevacizumab treatment for brain metastasis with extensive cerebral edema J Neurooncol 2014 119 2 369 76 10.1007/s11060-014-1488-0 24879376\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2377",
"issue": "21(1)",
"journal": "BMC neurology",
"keywords": "Bevacizumab; Dexamethasone; Edema; Radiation necrosis; Side effect",
"medline_ta": "BMC Neurol",
"mesh_terms": "D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D000068258:Bevacizumab; D001921:Brain; D001929:Brain Edema; D001930:Brain Injuries; D001932:Brain Neoplasms; D001943:Breast Neoplasms; D003907:Dexamethasone; D004305:Dose-Response Relationship, Drug; D005260:Female; D005910:Glioma; D005938:Glucocorticoids; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009336:Necrosis; D011832:Radiation Injuries; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult",
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"pubdate": "2021-02-17",
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"references": "15161688;26423913;22076449;25360851;31632089;28152324;24879376",
"title": "Single-shot bevacizumab for cerebral radiation injury.",
"title_normalized": "single shot bevacizumab for cerebral radiation injury"
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"abstract": "BACKGROUND\nRegorafenib, a receptor tyrosine kinase inhibitor, is a routinely used targeted agent in the current treatment of patients with refractory metastatic colorectal carcinoma (mCRC). The aims of this study were to detect the presence of bowel wall edema during regorafenib treatment via computed tomography (CT) and to assess the relationship between survival and regorafenib-induced bowel wall edema in patients with mCRC receiving regorafenib.\n\n\nMETHODS\nWe retrospectively evaluated the presence of bowel wall edema on CT of 25 mCRC patients who received regorafenib and analyzed its relationship with progression free survival (PFS) and overall survival (OS).\n\n\nRESULTS\nAmong the 25 patients, 25 had small bowel wall edema (SBWE) and 14 had large bowel wall edema (LBWE) on at least one CT examination. The median SBWE value was 4.85 milimeters (mm). Of the 25 patients, 14 had SBWE ≤4.85 mm and 11 had SBWE >4.85 mm. Regorafenib intolerance was significantly higher at SBWE >4.85 mm patients (p = 0.03). The median PFS was 4.6 months (95% CI: 2.4-6.8) and median OS was 9.3 months (95% CI: 3.1-15.4). Median PFS and OS were shorter in patients with SBWE > 4.85 mm than in those with ≤4.85 mm, but not statistically significant (median PFS: 3.9 vs 4.6 months, p: 0.523; median OS: 5.6 vs 9.3 months, p: 0.977).\n\n\nCONCLUSIONS\nRegorafenib caused SBWE in patients with mCRC. Patients who developed more SBWE had a higher regorafenib intolerance and a shorter survival. Further studies are needed to confirm the predictor value of SBWE on the survival outcomes of patients with mCRC receiving regorafenib.",
"affiliations": "Department of Medical Oncology, Necmettin Erbakan University School of Medicine, Konya, Turkey.;Department of Radiology, Necmettin Erbakan University School of Medicine, Konya, Turkey.;Department of Medical Oncology, Necmettin Erbakan University School of Medicine, Konya, Turkey.;Department of Medical Oncology, Batman Medical Park Hospital, Batman, Turkey.;Department of Medical Oncology, Necmettin Erbakan University School of Medicine, Konya, Turkey.;Department of Medical Oncology, Necmettin Erbakan University School of Medicine, Konya, Turkey.",
"authors": "Karakurt Eryılmaz|Melek|M|https://orcid.org/0000-0003-2597-5931;Kerimoğlu|Ülkü|Ü|;Karaağaç|Mustafa|M|https://orcid.org/0000-0003-4533-0620;Yalçın Müsri|Fatma|F|;Araz|Murat|M|;Artaç|Mehmet|M|https://orcid.org/0000-0003-2335-3354",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/1078155220978471",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": null,
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Regorafenib; metastatic colorectal cancer; regorafenib intolerance; small bowel wall edema",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": null,
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "1078155220978471",
"pmc": null,
"pmid": "33283629",
"pubdate": "2020-12-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Small bowel wall edema induced by regorafenib is associated with regorafenib intolerance and shorter survival in patients with metastatic colorectal cancer: A retrospective study.",
"title_normalized": "small bowel wall edema induced by regorafenib is associated with regorafenib intolerance and shorter survival in patients with metastatic colorectal cancer a retrospective study"
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"companynumb": "TR-BAYER-2020-280827",
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{
"abstract": "Lithium is a commonly used drug for bipolar mood disorder. Though effective, it has a narrow therapeutic range and has potentially life-threatening effects at higher serum levels. Lithium toxicity can be precipitated by several drug interactions. Many commonly used cardiac drugs have serious drug interaction with lithium which is not commonly known in clinical practice. We present a case where a patient on lithium therapy since 15 years, presented with sinus arrest and syncope due to lithium toxicity, within 2 weeks of initiation of low dose angiotensin converting enzyme (ACE) inhibitor. The patient however needed temporary pacemaker support and had an uneventful recovery, without the need for a permanent pacemaker, once the lithium levels fell down to normal.",
"affiliations": "Department of Cardiology, GB Pant Hospital and associated Maulana Azad Medical College, New Delhi, India.",
"authors": "Gupta|Mohit D|MD|;Girish|||;Goyal|Mayank|M|;Subhendu|Msk|M|;Tyagi|Sanjay|S|",
"chemical_list": "D016651:Lithium Carbonate",
"country": "United States",
"delete": false,
"doi": "10.1111/anec.12118",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1082-720X",
"issue": "19(4)",
"journal": "Annals of noninvasive electrocardiology : the official journal of the International Society for Holter and Noninvasive Electrocardiology, Inc",
"keywords": "angiotensin converting enzyme inhibitor; drug interaction; lithium toxicity; sinus node dysfunction",
"medline_ta": "Ann Noninvasive Electrocardiol",
"mesh_terms": "D001714:Bipolar Disorder; D003937:Diagnosis, Differential; D004562:Electrocardiography; D006801:Humans; D016651:Lithium Carbonate; D008297:Male; D008875:Middle Aged; D017202:Myocardial Ischemia; D013575:Syncope",
"nlm_unique_id": "9607443",
"other_id": null,
"pages": "395-7",
"pmc": null,
"pmid": "24286294",
"pubdate": "2014-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20021532;8834421;6603086;17347696;8217448",
"title": "Unusual cause of syncope in a patient with ischemic heart disease.",
"title_normalized": "unusual cause of syncope in a patient with ischemic heart disease"
} | [
{
"companynumb": "PHHY2014IN101243",
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... |
{
"abstract": "OBJECTIVE\nEmergence agitation (EA) is frequently observed in children undergoing general anaesthesia. This study tested whether the addition of an intra-operative low-dose infusion of dexmedetomidine to fentanyl treatment reduced the incidence of emergence delirium following desflurane anesthesia in children undergoing strabismus surgery.\n\n\nMETHODS\nA total of 96 children (1-5 years old) undergoing strabismus surgery were enrolled. Anaesthesia was induced with propofol and maintained with desflurane. After induction, fentanyl (1 μg/kg) was administered to all children. During surgery, patients were infused with 0.2 μg/(kg·h)⁻¹ dexmedetomidine (Group FD, n=47) or normal saline (Group F, n=47). Postoperative objective pain score (OPS), Paediatric Agitation and Emergence Delirium (PAED) score, and EA score were documented every 10 minutes in the post-anaesthesia care unit.\n\n\nRESULTS\nThere were no significant differences between the two groups in demographic characteristics and haemodynamic changes. The mean values of maximum EA, maximum PAED, and maximum OPS score were significantly lower in Group FD than in Group F at 0, 10, and 20 minutes after arrival at the post-anaesthesia care unit (p<0.001). The frequency of fentanyl rescue was lower in Group FD than in Group F (p<0.001). The incidence of severe EA was significantly lower in Group FD than in Group F (12.8% vs. 74.5%, p<0.001).\n\n\nCONCLUSIONS\nIntra-operative low-dose infusion of dexmedetomidine in addition to fentanyl reduces EA following desflurane anaesthesia in children undergoing strabismus surgeries.",
"affiliations": "Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Korea. koobn@yuhs.ac.",
"authors": "Kim|Jeongmin|J|;Kim|So Yeon|SY|;Lee|Jae Hoon|JH|;Kang|Young Ran|YR|;Koo|Bon-Nyeo|BN|",
"chemical_list": "D018685:Anesthetics, Inhalation; D020927:Dexmedetomidine; D000077335:Desflurane; D007530:Isoflurane; D005283:Fentanyl; D015742:Propofol",
"country": "Korea (South)",
"delete": false,
"doi": "10.3349/ymj.2014.55.2.508",
"fulltext": "\n==== Front\nYonsei Med JYonsei Med. JYMJYonsei Medical Journal0513-57961976-2437Yonsei University College of Medicine 2453252510.3349/ymj.2014.55.2.508Original ArticleAnesthesiologyLow-Dose Dexmedetomidine Reduces Emergence Agitation after Desflurane Anaesthesia in Children Undergoing Strabismus Surgery Kim Jeongmin Kim So Yeon Lee Jae Hoon Kang Young Ran Koo Bon-Nyeo Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, Korea.\nCorresponding author: Dr. Bon-Nyeo Koo, Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Korea. Tel: 82-2-2228-2420, Fax: 82-2-312-7185, koobn@yuhs.ac01 3 2014 10 2 2014 55 2 508 516 13 2 2013 15 7 2013 23 7 2013 © Copyright: Yonsei University College of Medicine 20142014This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Purpose\nEmergence agitation (EA) is frequently observed in children undergoing general anaesthesia. This study tested whether the addition of an intra-operative low-dose infusion of dexmedetomidine to fentanyl treatment reduced the incidence of emergence delirium following desflurane anesthesia in children undergoing strabismus surgery.\n\nMaterials and Methods\nA total of 96 children (1-5 years old) undergoing strabismus surgery were enrolled. Anaesthesia was induced with propofol and maintained with desflurane. After induction, fentanyl (1 µg/kg) was administered to all children. During surgery, patients were infused with 0.2 µg/(kg·h)-1 dexmedetomidine (Group FD, n=47) or normal saline (Group F, n=47). Postoperative objective pain score (OPS), Paediatric Agitation and Emergence Delirium (PAED) score, and EA score were documented every 10 minutes in the post-anaesthesia care unit.\n\nResults\nThere were no significant differences between the two groups in demographic characteristics and haemodynamic changes. The mean values of maximum EA, maximum PAED, and maximum OPS score were significantly lower in Group FD than in Group F at 0, 10, and 20 minutes after arrival at the post-anaesthesia care unit (p<0.001). The frequency of fentanyl rescue was lower in Group FD than in Group F (p<0.001). The incidence of severe EA was significantly lower in Group FD than in Group F (12.8% vs. 74.5%, p<0.001).\n\nConclusion\nIntra-operative low-dose infusion of dexmedetomidine in addition to fentanyl reduces EA following desflurane anaesthesia in children undergoing strabismus surgeries.\n\nDexmedetomidineemergence agitationobjective pain scorepediatrics\n==== Body\nINTRODUCTION\nEmergence delirium (ED) and emergence agitation (EA) are common phenomenon in paediatric patients undergoing general anaesthesia by inhalation agents. The incidence of ED or EA was reported to range from 18% to 80%.1,2 Agitated behaviour associated with ED can delay discharge from the post-anaesthesia care unit (PACU), decrease parent and caregiver satisfaction, and increase the overall cost to the institution.3 Risk factors for development of ED include preschool age, previous surgery, adaptability, ophthalmology or otorhinolaryngology procedure, and inhalation agents associated with fast emergence.1,4\n\nStrabismus surgery is one of the most common ophthalmologic operations in children under 5 years old and can be associated with moderate postoperative pain caused by the conjunctiva5 and a high incidence of EA (40-86%).6-9 As this procedure commonly elicits the oculo-cardiac reflex (OCR) by traction on extraocular muscles and their adnexa or by application of sudden pressure to the eye or orbit, arrhythmias such as bradycardia are frequently encountered during the procedure. Therefore, anaesthetic strategies for strabismus surgery in paediatric patients include prevention of haemodynamic instability as well as reduction of postoperative pain and EA.\n\nDesflurane is known to allow faster recovery than any other inhalation agent.10-12 However, it can be associated with a higher incidence of EA,10,11,13 which may negate the advantage of rapid emergence.11,14 Recently, dexmedetomidine has been reported to prevent EA in paediatric patients.14-16 However, there are few data related to the effect of dexmedetomidine on EA following general anaesthesia with desflurane. Therefore, we designed this prospective randomised double-blind controlled study to investigate whether intraoperative continuous infusion of low-dose dexmedetomidine (0.2 µg/kg/h) could reduce the incidence of EA without deterioration of haemodynamics and delay emergence in paediatric patients undergoing strabismus surgeries who were anaesthetised with desflurane.\n\nMATERIALS AND METHODS\nAfter obtaining approval from the Internal Review Board of Severance Hospital (4-2011-0466) and registering this study at www.ClinicalTrials.gov (ref. number: NCT01512355), written informed consent was obtained from the parents of the children. Ninety-six children aged 1-5 years with an American society of Anesthegiologists physical status classification system (ASA) between I-II who were undergoing strabismus surgery were enrolled from September 2011 to March 2012. Exclusion criteria included lack of consent, mental retardation, developmental delay, history of allergies, neurological or psychiatric illness that may be associated with improper communication, any kind of cardiac conduction disorder, and any previous cardiovascular disease. Patients were randomized into two groups, the fentanyl group (Group F) and the fentanyl plus dexmedetomidine group (Group FD), by computer-generated random numbers in a double blinded fashion. The random number sequence was generated by an internet site program (http://www.random.org). During the induction period, cooperation of the children was rated on a four-point cooperation on induction scale, where 1=sleeping/calm, 2=awake/calm, 3=awake/anxious, and 4=very anxious/combative.17\n\nAnaesthesia was induced with propofol (3 mg/kg) and rocuronium (0.3 mg/kg). Children were intubated and mechanically ventilated. Anaesthesia was maintained using desflurane with 50% air/O2. End tidal carbon dioxide was maintained between 30 and 35 mm Hg. After the induction, fentanyl (1 µg/kg) was administered to children in both groups. Patients in Group FD received continuous infusion with 0.2 µg/(kg·h)-1 dexmedetomidine (Precedex®, Hospira Inc, Rocky Mount, NC, USA; diluted with normal saline to a concentration of 2 µg/mL). For patients in Group F, an equivalent volume of normal saline [0.1 mL/(kg·h)-1] was continuously infused during surgery. The same investigator prepared all syringes containing drugs. All the evaluations and records were taken by a blinded observer outside the study. The bispectral index score (BIS VISTA™, Aspect Medical System Inc., MA, USA) was monitored during the surgery. The inhalation agent was titrated to maintain the bispectral index score between 40 and 60, and the baseline haemodynamic changes were kept within a 20% range. The concentration and age-adjusted minimal alveolar concentration of exhaled anaesthetic was monitored using an infrared analyser (Drager Primus®; Draeger Medical AG & Co KGaA, Luebeck, Germany). Intraoperative heart rate (HR), blood pressure (BP), haemoglobin oxygen saturation, bispectral index score, and end tidal desflurane concentration were recorded every 5 minutes from the start of infusion. Ondansetron and dexamethasone were administered intravenously for the prevention of postoperative nausea and vomiting. At the conclusion of the procedure, local anaesthetic eye drops containing 0.5% proparacaine (Alcaine, S.A. ALCON-COUVREUR N.V., Purrs, Belgium) were applied to the surgical site by an ophthalmologist for postoperative pain control, and infusion of the study drug and administration of desflurane were discontinued. Oral suction was performed and reversal agents (glycopyrrolate 0.004 mg/kg and neostigmine 0.02 mg/kg) were administered after confirming neuromuscular function had returned using train-of-four peripheral nerve stimulation. The patient's trachea was extubated after recovery of the cough and gag reflex, grimace, and purposeful movement. The time from discontinuation of anaesthetics to recovery of spontaneous respiration, eye opening on verbal command, and extubation was recorded.\n\nAfter confirmation of regular respiration and stable vital signs, each child was transported to the PACU and observed until fully awake. After arrival at the PACU all children were reunited with their parents. Oxygen saturation by pulse oxymetry, electrocardiography, and non-invasive BP measurements every 5 minutes were monitored between the operating room and the PACU. In addition, post-operative pain and EA were evaluated immediately after surgery by the objective pain score (OPS),18 Paediatric Agitation Emergence Delirium (PAED) scale,19 and EA 5-point scale as described by Cole, et al.,20 and subsequently recorded every 10 minutes in the PACU by a well-trained PACU nurse who was blinded to this study.\n\nThe PAED scale is composed of five items: eye contact with caregiver, purposeful action, awareness of surroundings, restlessness, and inconsolability. Our patients could not open their eyes due to postoperative pain; therefore, we modified the item 'eye contact with caregiver' to 'responsiveness to their parents'. Each item was scored by five grades (0-4) according to its degree, and the scores of each item were summed to obtain the total PAED scale score. The EA scale consists of five grades (1=sleeping, 2=awake and calm, 3=irritable and crying, 4=inconsolable and crying, and 5=severe restlessness and thrashing). According to the PACU protocol, patients with severe EA (EA score ≥4) or severe pain (OPS >8) were treated with intravenous fentanyl (0.5 µg/kg). The frequency of additional fentanyl use was compared between the two groups. Children with a score of 8 according to the Post-Anaesthetic Discharge Scoring System (PODSS)21 were discharged from PACU.\n\nAt postoperative 24 hours, a blinded investigator interviewed the patients' parents via telephone and evaluated their daily activity over the last 24 hours and the previous night's sleep quality using a 3-point scale as follows: resumption of normal activity, 0=normal activity, 1=depressed but performed normal daily activities, and 2=irritable and could not perform normal activities; sleep quality, 0=slept well, 1=woke up crying in the night, and 2=intermittent sleep.\n\nSevere EA was defined as an EA score of 4 and above. A power analysis (80% power at a 0.05 level of significance) indicated that 45 subjects were required per group to show that dexmedetomidine infusion could reduce the incidence of EA by 50%.22 The number of patients recruited was increased by 10% to account for possible dropouts.\n\nStatistical analysis was performed using PASW Statistics 18 (SPSS Inc., Chicago, IL, USA) or SAS software 9.2 (SAS Inc., Cary, NC, USA). All data were reported as mean±SD or percentage. Parametric data were analysed using an unpaired Student's t-test. Ordinal data were analysed using the Mann-Whitney ranked sum test. Nominal data were analysed using either the chi-square or Fisher's exact test. A linear mixed model was used for sequential variables (OPS scale, PAED scale, EA scale, and PODSS scale). The optimal cut-off point of maximum OPS score and maximum PAED score in relation to an EA score of 4 and above was chosen using the receiver operating characteristic (ROC) curve and Youden's index (sensitivity+specificity-1). The best discriminative accuracy corresponds to the area under the curve. After applying the new cut-off value, we compared the incidence of severe emergence agitation between the two groups. p<0.05 was considered statistically significant.\n\nRESULTS\nAmong the 96 patients enrolled in this study two patients were excluded, one due to operation delay and the other due to agenesis of kidney. The remaining patients were divided randomly between Group F and Group FD (n=47 per group).\n\nThere were no significant differences between the two groups with respect to patient's demographic data, cooperation on induction scale, and the duration of surgery and anaesthesia. Two patients in Group FD had history of asthma and were classified as ASA class II (Table 1). Intraoperative bispectral index score and age-adjusted minimal alveolar concentration were comparable between the two groups.\n\nThe means of maximum EA, maximum PAED, and maximum OPS score were significantly lower in Group FD than in Group F at 0, 10, and 20 minutes after arrival at PACU (Fig. 1). The maximum OPS and the frequency of fentanyl rescue were lower in Group FD than in Group F. The mean maximum OPS was 3.8 and 6.4 in group FD and group F, respectively (p<0.001). Five (10.6%) children in group FD required fentanyl rescue, compared with 24 (51.1%) children in group F (p<0.001).\n\nThe mean maximum EA and maximum PAED scores were lower in group FD (p=0.001) (Table 2). The percentage of patients with EA scores of 4 and above was significantly lower in Group FD than in Group F (14.9% vs. 70.2%, p<0.001). The mean maximum PAED score was also significantly lower in Group FD than in Group F (9.0±4.5 vs. 11.5±4.1, p=0.001).\n\nWe performed a ROC curve analysis for the PAED scale and the OPS scale to define the cut-off points of severe EA, defined as a 5-point EA score of 4 and above and identified cut-off values that maximised sensitivity and specificity based on the ROC analysis. Thresholds of 11 for PAED and 6 for OPS were the best discriminators of severe EA.\n\nThe area under the ROC curve for PAED >11 was 0.77, with a sensitivity of 0.76 and specificity of 0.78 (Fig. 2A). The area under the ROC curve for an OPS >6 was 0.80, with sensitivity of 0.76 and specificity of 0.84 (Fig. 2B). When we classified severe EA as a PAED score >11, the incidence of severe EA was significantly lower in Group FD than in Group F (12.8% vs. 74.5%, p<0.001). We also compared the ROC curves of PAED scale and OPS scale by the Delong method. There was no significant difference between PAED and OPS scales in predicting severe EA (p=0.562).\n\nHaemodynamic instability did not occur in any of the patients and vital signs remained within 20% of baseline in all patients. HR, systolic blood pressure, and diastolic blood pressure were similar in both groups (Fig. 3).\n\nThe intra-operative value of minimal alveolar concentration and bispectral index score were not different between the two groups (Fig. 4). When self-respiration (eye opening and extubation) occurred minimal alveolar concentration and bispectral index score values of the two groups were not different. Furthermore, there were no significant differences between groups with respect to the duration of emergence (Table 3).\n\nThere was no statistical difference in the incidence of postoperative respiratory complications between the two groups. One desaturation event (haemoglobin oxygen saturation <95%) and one bronchospasm occurred in Group FD, but none occured in Group F.\n\nThere were no serious complications or significant differences in the 24-hours post-operative daily activities and sleep quality assessed by telephone interview with the patients' parents (Table 3).\n\nDISCUSSION\nResults of our study indicate that continuous intra-operative infusion of low-dose dexmedetomidine (0.2 µg/kg/h) can reduce the incidence of EA following desflurane anaesthesia in paediatric patients undergoing strabismus surgery. Furthermore, low-dose dexmedetomidine reduced postoperative pain without any haemodynamic compromise or delay of emergence.\n\nOur primary outcome was the incidence of severe EA. When we defined severe EA as a 5-point EA score of 4 and above, low-dose dexmedetomidine reduced the incidence of severe EA by 79% compared with the saline control (14.9% vs. 70.2%, p<0.001) (Table 2). Previous studies reported a higher incidence of severe EA (up to 80%) after desflurane anaesthesia.1 Several studies report that 2.5 µg/kg fentanyl is effective in reducing severe EA without delay of emergence following desflurane anaesthesia in patients undergoing adenoidectomy or tonsillectomy.23,24 However, in our preliminary study, 2.5 µg/kg fentanyl delayed extubation time and PACU stay in children undergoing strabismus surgery despite a potent reduction of EA. Our data demonstrated that 1.0 µg/kg fentanyl and 0.2 µg/kg/h dexmedetomidine reduced the incidence of EA to the same level as 2.5 µg/kg fentanyl based on the previous study (7-24%)23,24 without delay of emergence. Many factors are associated with EA such as anaesthetic agents, rapid emergence from anaesthesia, the type of surgery, pain, preoperative anxiety and non-familiar environment.25,26 So far, the specific factors surrounding EA have been vague. EA in paediatric patients have complex causes. However, a strong connection between postoperative pain and EA has been supported by many studies.5,27-30 Postoperative satisfactory pain control is required to prevent EA, administration of 1.0 µg/kg fentanyl and local anaesthetic eye drops are considered to be enough for pain control in paediatric patients undergoing strabismus surgery. Recent meta-analysis reported propofol, pain prevention, ketamine and alpha 2-adrenergic receptor agonists appear to be effective to prevent EA.25 However, the superior drug among all of those drugs is not clear. Combined use of these agents and diversifying the routes of administration might be effective in reducing possible side effects.\n\nA reliable, valid, and simple rating scale to measure postoperative EA in children is very important when taking care of paediatric patients in PACU. Although there are various assessment tools for evaluating EA, none is sufficiently specific and sensitive to assess children's behaviour upon emergence.4 We simultaneously used two assessment tools of emergence behaviour, PAED and OPS, and compared the incidence of severe EA based on the cut-off values of PAED and OPS score as well as the maximum PAED and OPS scores.31 Our data revealed that low-dose dexmedetomidine significantly reduced both the maximum scores and the incidence of EA based on the cut-off values of PAED and OPS. Furthermore, our study showed that PAED scoring and OPS scoring are equally able to predict severe EA.\n\nThe PAED scale developed by Sikich and Lerman19 consisting of five psychometric items for evaluating ED in paediatric patients is known to be reliable and has been validated.32,33 Sikich and Lerman19 defined true EA as a child who received pain killer post-operatively and negative EA as a child who did not. They reported that for a PAED score of 10 and above, the sensitivity was 0.64, the specificity was 0.86, and area under the ROC curve was 0.77. However, the cut-off value of PAED to determine severe EA has been inconsistently reported to range from 8 to 16.31,33,34 When we considered true EA as a 5-point EA of 4 and above, the threshold of PAED score to discriminate severe EA was 11.\n\nThe OPS scale has been used to assess pain in many studies with paediatric patients.11,14,22,35-37 In preschool aged paediatric patients it is not easy to distinguish pain from agitation. The OPS scale includes haemodynamic change, emotional factors (crying, agitation, and movement), and localisation of pain. For preschool children, many parts of this scale overlap the parameters of the PAED scale. Low-dose dexmedetomidine significantly reduced the OPS score and the frequency of rescue fentanyl use (Fig. 1, Table 3). Fig. 1 also shows that the OPS scoring pattern after arrival at PACU was very similar to that of the PAED scale, consistent with a previous study.22 Dexmedetomidine actually exerts an analgesic effect; therefore, it could reduce postoperative opioid use and the incidence of opioid-related complications such as pruritus, nausea, and respiratory depression.30,38 Because we applied fentanyl after induction and eye drops containing local anaesthetics at the end of surgery for postoperative pain control, the high OPS score upon arrival at PACU may reflect psychiatric properties. In this respect dexmedetomidine appears to exert not only an analgesic effect, but also an anxiolytic and sedative effect.\n\nIn our study, low-dose continuous infusion of dexmedetomidine without a loading dose did not affect haemodynamic changes during the perioperative phase. Intraoperative HR, systolic blood pressure, and diastolic blood pressure were not different between the two groups (Fig. 3). This result is consistent with a previous study.14 As the haemodynamic effects of dexmedetomidine are similar to those of 2 other alpha agonists, dexmedetomidine produces a dose-dependent decrease in HR and blood pressure.39 Deutsch and Tobias40 reported that an intravenous administration of 0.5 µg/kg of dexmedetomidine over 5 minutes caused an approximate 10% and 25% reduction in blood pressure and HR, respectively, in paediatric patients undergoing general anaesthesia. In addition, Patel, et al.22 reported that mean HR and mean systolic blood pressure were significantly reduced after administration of 0.7 µg/kg/h dexmedetomidine following a 2 µg/kg loading dose. We were concerned about the haemodynamic effects of dexmedetomidine, thus we reduced the infusion dose to almost one third of the recommended dose and without an initial loading dose. Despite the relatively low dose used in our study, we found that 0.2 µg/(kg·h)-1 was sufficient to prevent postoperative severe EA in paediatric patients without compromising haemodynamics. Although a higher dose of dexmedetomidine might further reduce the incidence of EA, it may also cause delay emergence and excessive haemodynamic changes which may mask an OCR. However, a previous study reported that premedication with a single bolus injection of dexmedetomidine (0.5 µg/kg) prevented OCR in paediatric patients undergoing strabismus surgery under general anaesthesia.7\n\nBecause we did not compare the incidence of OCR between the two groups, we could not evaluate the influence of the haemodynamic effects of dexmedetomidine on OCR. Our study merely shows there was no significant difference in haemodynamic effects resulting from continuous intraoperative infusion of 0.2 µg/(kg·h)-1 dexmedetomidine. None of our patients required atropine to treat bradycardia resulting from either OCR or dexmedetomidine.\n\nGuler, et al.42 and Patel, et al.22 reported that a 0.5 µg/(kg·h)-1 of dexmedetomidine reduced agitation in paediatric tonsillectomy, but the emergence time was 2 minutes longer in the dexmedetomidine group compared with the control group. These delayed emergence could be explained by the administration time and total dose of dexmedetomidine. Considering the drug-onset time, administration of dexmedetomidine 5 minutes before the end of surgery35 could cause delayed awakening. In our study, the total infusion time was approximately 20 minutes and total dose of the drug was approximately 0.1 µg/kg. This is a relatively small dose, about one-fourth of that used in the previous studies. This low-dose dexmedetomidine infusion can facilitate rapid emergence as reflected by the extubation time, response on verbal command, PACU stay, and time to readiness for discharge (Table 3).\n\nThe major limitation of this study is the small number of patients recruited who underwent strabismus surgeries. More extensive randomized studies should be performed to determine the optimum dose of dexmedetomidine to prevent EA in paediatric patients in different types of surgery, which could affect the incidence of EA. Therefore, the dose of dexmedetomidine of this study might be modified according to the type of surgical procedure. Further studies are needed to evaluate the optimum dose of dexmedetomidine for variable types of surgery. Despite the small sample size, statistical power of our primary outcome was over 0.8 for each parameter and significant differences were found between Group FD and Group F. Limited to strabismus surgery, we demonstrated the preventive effect of dexmedetomidine. Further studies are required to evaluate the dexmedetomidine's effect on OCR. As mentioned above, we did not compare the incidence of OCR between the two groups. Nevertheless, our results show that low dose continuous infusion of dexmedetomidine without a loading dose did not induce hemodynamic change. Based on this result, a low dose infusion of dexmedetomidine might not affect the incidence of OCR.\n\nIn conclusion, intraoperative continuous infusion of low-dose dexmedetomidine [0.2 µg/(kg·h)-1] can reduce emergence agitation following desflurane anaesthesia without haemodynamic compromise or delayed awakening in paediatric patients undergoing strabismus surgery.\n\nThe authors have no financial conflicts of interest.\n\nFig. 1 Postoperative emergence agitation and objective pain score in post-anesthesia care unit. (A) EA score, emergence agitation 5 point scale, (B) PAED score, Pediatric Anesthesia Emergence Delirium score and (C) objective pain scale. *p<0.05 compared with Group F. **p<0.01 compared with Group F. EA, emergence agitation.\n\nFig. 2 Receiver operating characteristic (ROC) curve of PAED (A) and OPS score (B) for prediction of severe emergence agitation (EA≥4). Arrows indicate cut-off values. PAED, Paediatric Agitation Emergence Delirium; OPS, objective pain score.\n\nFig. 3 Intra-operative haemodynamic data. (A) Heart rate, (B) systolic blood pressure and (C) diastolic blood pressure.\n\nFig. 4 Intra-operative sequential comparison of the changes in the age-adjusted minimum alveolar concentration of desflurane (A) and the bispectral index (B) between the two groups. MAC, minimal alveolar concentration; BIS, bispectral index score.\n\nTable 1 Patient Demographics and Duration of Surgery and Anaesthesia\n\nASA, American Society of Anesthesiologists physical status classification system; CIS, Cooperation on Induction Scale1 where 1=excellent (unafraid, cooperative, and accepts mask readily), 2=good (slight fear of mask but easily calmed), 3=moderate fear, not calmed with reassurance), 4=poor (terrified, crying, and agitated).\n\nValues are given as mean±SD or number of patients.\n\nTable 2 Postoperative Pain and Severe Emergence Agitation\n\nEA, emergence agitation score; OPS, objective pain score; PAED, Paediatric Agitation and Emergence Delirium.\n\nValues are expressed as number of patients (percentage). The maximum EA, OPS and PAED scores are expressed as mean±SD.\n\nTable 3 Recovery Profiles\n\nBIS, bispectral index score; MAC, minimal alveolar concentration; PACU, post-anaesthesia care unit; POD, postoperative day; PODSS, Post-Anaesthetic Discharge Scoring System.\n\nValues given are mean±SD. Time to readiness for discharge means time from arrival at the PACU to achieving PODSS score of 8. Sleep quality on the night of operation (POD0): 0=slept well, 1=woke up crying in the night, 2=slept fitfully. Resumption of normal activity: 0=normal activity, 1=depressed but performed normal daily activities, 2=irritable and could not perform normal activity.\n==== Refs\n1 Voepel-Lewis T Malviya S Tait AR A prospective cohort study of emergence agitation in the pediatric postanesthesia care unit Anesth Analg 2003 96 1625 1630 12760985 \n2 Grundmann U Uth M Eichner A Wilhelm W Larsen R Total in travenous anaesthesia with propofol and remifentanil in paediatric patients: a comparison with a desflurane-nitrous oxide inhalation anaesthesia Acta Anaesthesiol Scand 1998 42 845 850 9698963 \n3 Dexter F Macario A Manberg PJ Lubarsky DA Computer simulation to determine how rapid anesthetic recovery protocols to decrease the time for emergence or increase the phase I postanesthesia care unit bypass rate affect staffing of an ambulatory surgery center Anesth Analg 1999 88 1053 1063 10320168 \n4 Vlajkovic GP Sindjelic RP Emergence delirium in children: many questions, few answers Anesth Analg 2007 104 84 91 17179249 \n5 Finley GA McGrath PJ Forward SP McNeill G Fitzgerald P Parents' management of children's pain following 'minor' surgery Pain 1996 64 83 87 8867249 \n6 Mizrak A Erbagci I Arici T Ozcan I Ganidagli S Tatar G Ketamine versus propofol for strabismus surgery in children Clin Ophthalmol 2010 4 673 679 20823929 \n7 Mizrak A Erbagci I Arici T Avci N Ganidagli S Oner U Dexmedetomidine use during strabismus surgery in agitated children Med Princ Pract 2011 20 427 432 21757931 \n8 Jung HJ Kim JB Im KS Oh SH Lee JM Effect of ketamine versus thiopental sodium anesthetic induction and a small dose of fentanyl on emergence agitation after sevoflurane anesthesia in children undergoing brief ophthalmic surgery Korean J Anesthesiol 2010 58 148 152 20498793 \n9 Aouad MT Yazbeck-Karam VG Nasr VG El-Khatib MF Kanazi GE Bleik JH A single dose of propofol at the end of surgery for the prevention of emergence agitation in children undergoing strabismus surgery during sevoflurane anesthesia Anesthesiology 2007 107 733 738 18073548 \n10 White PF Tang J Wender RH Yumul R Stokes OJ Sloninsky A Desflurane versus sevoflurane for maintenance of outpatient anesthesia: the effect on early versus late recovery and perioperative coughing Anesth Analg 2009 109 387 393 19608808 \n11 Welborn LG Hannallah RS Norden JM Ruttimann UE Callan CM Comparison of emergence and recovery characteristics of sevoflurane, desflurane, and halothane in pediatric ambulatory patients Anesth Analg 1996 83 917 920 8895263 \n12 Wachtel RE Dexter F Epstein RH Ledolter J Meta-analysis of desflurane and propofol average times and variability in times to extubation and following commands Can J Anaesth 2011 58 714 724 21630118 \n13 Davis PJ Cohen IT McGowan FX Jr Latta K Recovery characteristics of desflurane versus halothane for maintenance of anesthesia in pediatric ambulatory patients Anesthesiology 1994 80 298 302 8311312 \n14 Shukry M Clyde MC Kalarickal PL Ramadhyani U Does dexmedetomidine prevent emergence delirium in children after sevoflurane-based general anesthesia? Paediatr Anaesth 2005 15 1098 1104 16324031 \n15 Singh R Kharbanda M Sood N Mahajan V Chatterji C Comparative evaluation of incidence of emergence agitation and post-operative recovery profile in paediatric patients after isoflurane, sevoflurane and desflurane anaesthesia Indian J Anaesth 2012 56 156 161 22701207 \n16 Isik B Arslan M Tunga AD Kurtipek O Dexmedetomidine decreases emergence agitation in pediatric patients after sevoflurane anesthesia without surgery Paediatr Anaesth 2006 16 748 753 16879517 \n17 Weldon BC Watcha MF White PF Oral midazolam in children: effect of time and adjunctive therapy Anesth Analg 1992 75 51 55 1616162 \n18 Hannallah RS Broadman LM Belman AB Abramowitz MD Epstein BS Comparison of caudal and ilioinguinal/iliohypogastric nerve blocks for control of post-orchiopexy pain in pediatric ambulatory surgery Anesthesiology 1987 66 832 834 2884900 \n19 Sikich N Lerman J Development and psychometric evaluation of the pediatric anesthesia emergence delirium scale Anesthesiology 2004 100 1138 1145 15114210 \n20 Cole JW Murray DJ McAllister JD Hirshberg GE Emergence behaviour in children: defining the incidence of excitement and agitation following anaesthesia Paediatr Anaesth 2002 12 442 447 12060332 \n21 Chung F Chan VW Ong D A post-anesthetic discharge scoring system for home readiness after ambulatory surgery J Clin Anesth 1995 7 500 506 8534468 \n22 Patel A Davidson M Tran MC Quraishi H Schoenberg C Sant M Dexmedetomidine infusion for analgesia and prevention of emergence agitation in children with obstructive sleep apnea syndrome undergoing tonsillectomy and adenoidectomy Anesth Analg 2010 111 1004 1010 20705788 \n23 Cohen IT Finkel JC Hannallah RS Hummer KA Patel KM The effect of fentanyl on the emergence characteristics after desflurane or sevoflurane anesthesia in children Anesth Analg 2002 94 1178 1181 11973185 \n24 Demirbilek S Togal T Cicek M Aslan U Sizanli E Ersoy MO Effects of fentanyl on the incidence of emergence agitation in children receiving desflurane or sevoflurane anaesthesia Eur J Anaesthesiol 2004 21 538 542 15318465 \n25 Dahmani S Stany I Brasher C Lejeune C Bruneau B Wood C Pharmacological prevention of sevoflurane- and desflurane-related emergence agitation in children: a meta-analysis of published studies Br J Anaesth 2010 104 216 223 20047899 \n26 Kim MS Moon BE Kim H Lee JR Comparison of propofol and fentanyl administered at the end of anaesthesia for prevention of emergence agitation after sevoflurane anaesthesia in children Br J Anaesth 2013 110 274 280 23103775 \n27 Davis PJ Greenberg JA Gendelman M Fertal K Recovery characteristics of sevoflurane and halothane in preschool-aged children undergoing bilateral myringotomy and pressure equalization tube insertion Anesth Analg 1999 88 34 38 9895062 \n28 Cravero JP Beach M Thyr B Whalen K The effect of small dose fentanyl on the emergence characteristics of pediatric patients after sevoflurane anesthesia without surgery Anesth Analg 2003 97 364 367 12873918 \n29 Finkel JC Cohen IT Hannallah RS Patel KM Kim MS Hummer KA The effect of intranasal fentanyl on the emergence characteristics after sevoflurane anesthesia in children undergoing surgery for bilateral myringotomy tube placement Anesth Analg 2001 92 1164 1168 11323340 \n30 Messerer B Gutmann A Weinberg A Sandner-Kiesling A Implementation of a standardized pain management in a pediatric surgery unit Pediatr Surg Int 2010 26 879 889 20625751 \n31 Bong CL Ng AS Evaluation of emergence delirium in Asian children using the Pediatric Anesthesia Emergence Delirium Scale Paediatr Anaesth 2009 19 593 600 19645978 \n32 Blankespoor RJ Janssen NJ Wolters AM Van Os J Schieveld JN Post-hoc revision of the pediatric anesthesia emergence delirium rating scale: clinical improvement of a bedside-tool? Minerva Anestesiol 2012 78 896 900 22415436 \n33 Janssen NJ Tan EY Staal M Janssen EP Leroy PL Lousberg R On the utility of diagnostic instruments for pediatric delirium in critical illness: an evaluation of the Pediatric Anesthesia Emergence Delirium Scale, the Delirium Rating Scale 88, and the Delirium Rating Scale-Revised R-98 Intensive Care Med 2011 37 1331 1337 21567109 \n34 Chen J Li W Hu X Wang D Emergence agitation after cataract surgery in children: a comparison of midazolam, propofol and ketamine Paediatr Anaesth 2010 20 873 879 20716081 \n35 Erdil F Demirbilek S Begec Z Ozturk E Ulger MH Ersoy MO The effects of dexmedetomidine and fentanyl on emergence characteristics after adenoidectomy in children Anaesth Intensive Care 2009 37 571 576 19681413 \n36 Saadawy I Boker A Elshahawy MA Almazrooa A Melibary S Abdellatif AA Effect of dexmedetomidine on the characteristics of bupivacaine in a caudal block in pediatrics Acta Anaesthesiol Scand 2009 53 251 256 19076110 \n37 Akin A Bayram A Esmaoglu A Tosun Z Aksu R Altuntas R Dexmedetomidine vs midazolam for premedication of pediatric patients undergoing anesthesia Paediatr Anaesth 2012 22 871 876 22268591 \n38 Tufanogullari B White PF Peixoto MP Kianpour D Lacour T Griffin J Dexmedetomidine infusion during laparoscopic bariatric surgery: the effect on recovery outcome variables Anesth Analg 2008 106 1741 1748 18499604 \n39 Bhana N Goa KL McClellan KJ Dexmedetomidine Drugs 2000 59 263 268 10730549 \n40 Deutsch E Tobias JD Hemodynamic and respiratory changes following dexmedetomidine administration during general anesthesia: sevoflurane vs desflurane Paediatr Anaesth 2007 17 438 444 17474950 \n41 Braun U Feise J Mühlendyck H Is there a cholinergic and an adrenergic phase of the oculocardiac reflex during strabismus surgery? Acta Anaesthesiol Scand 1993 37 390 395 8322568 \n42 Guler G Akin A Tosun Z Ors S Esmaoglu A Boyaci A Single-dose dexmedetomidine reduces agitation and provides smooth extubation after pediatric adenotonsillectomy Paediatr Anaesth 2005 15 762 766 16101707\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0513-5796",
"issue": "55(2)",
"journal": "Yonsei medical journal",
"keywords": "Dexmedetomidine; emergence agitation; objective pain score; pediatrics",
"medline_ta": "Yonsei Med J",
"mesh_terms": "D017109:Akathisia, Drug-Induced; D000762:Anesthesia Recovery Period; D000768:Anesthesia, General; D018685:Anesthetics, Inhalation; D002675:Child, Preschool; D000077335:Desflurane; D020927:Dexmedetomidine; D005260:Female; D005283:Fentanyl; D006801:Humans; D007223:Infant; D007432:Intraoperative Period; D007530:Isoflurane; D008297:Male; D013508:Ophthalmologic Surgical Procedures; D015742:Propofol; D012372:ROC Curve; D013285:Strabismus",
"nlm_unique_id": "0414003",
"other_id": null,
"pages": "508-16",
"pmc": null,
"pmid": "24532525",
"pubdate": "2014-03",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": "8322568;8311312;9895062;19681413;22415436;11973185;20047899;2884900;1616162;22701207;11323340;15114210;12060332;21567109;12873918;20625751;19608808;18073548;10320168;22268591;23103775;20716081;21630118;17474950;15318465;19645978;17179249;20498793;16101707;16879517;9698963;12760985;20705788;10730549;8867249;16324031;18499604;8534468;19076110;8895263;20823929;21757931",
"title": "Low-dose dexmedetomidine reduces emergence agitation after desflurane anaesthesia in children undergoing strabismus surgery.",
"title_normalized": "low dose dexmedetomidine reduces emergence agitation after desflurane anaesthesia in children undergoing strabismus surgery"
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"abstract": "An 81-year-old woman visited a local clinic due to chest pain and a skin induration on the right precordia. She had a history of right breast cancer, and she had undergone a mastectomy and radiation therapy 10 years prior. Computed tomography (CT) imaging of the chest demonstrated a lobular mass that involved the right anterior thoracic wall and partially extruded from the thoracic cavity into the subcutaneous tissue. The tumor was surgically excised, and pathological analyses yielded a diagnosis of angiosarcoma. Five months after the operation, CT imaging showed multiple masses on the right pleura, indicating a local relapse and pleural dissemination of the angiosarcoma. Systemic chemotherapy composed of nanoparticle albumin-bound paclitaxel (nab-PTX) (80 mg/m(2)) was delivered weekly. After 4 courses of chemotherapy, the tumors regressed remarkably. Nab-PTX may be an effective treatment option for recurrent or metastatic angiosarcoma.",
"affiliations": "Department of Respiratory Medicine, Okayama Rosai Hospital.",
"authors": "Hara|Naofumi|N|;Fujimoto|Nobukazu|N|;Miyamoto|Yosuke|Y|;Yamagishi|Tomoko|T|;Asano|Michiko|M|;Fuchimoto|Yasuko|Y|;Wada|Sae|S|;Ozaki|Shinji|S|;Nishi|Hideyuki|H|;Kishimoto|Takumi|T|",
"chemical_list": "D000068196:Albumin-Bound Paclitaxel; D000418:Albumins; D000972:Antineoplastic Agents, Phytogenic",
"country": "Japan",
"delete": false,
"doi": "10.5582/ddt.2016.01005",
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"issn_linking": "1881-7831",
"issue": "10(2)",
"journal": "Drug discoveries & therapeutics",
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"medline_ta": "Drug Discov Ther",
"mesh_terms": "D000369:Aged, 80 and over; D000068196:Albumin-Bound Paclitaxel; D000418:Albumins; D000972:Antineoplastic Agents, Phytogenic; D005260:Female; D006394:Hemangiosarcoma; D006801:Humans; D010994:Pleura; D013899:Thoracic Neoplasms; D035441:Thoracic Wall; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "101493809",
"other_id": null,
"pages": "114-6",
"pmc": null,
"pmid": "26875587",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Angiosarcoma of the thoracic wall responded well to nanoparticle albumin-bound paclitaxel: A case report.",
"title_normalized": "angiosarcoma of the thoracic wall responded well to nanoparticle albumin bound paclitaxel a case report"
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{
"companynumb": "JP-CELGENE-JPN-2016025398",
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"abstract": "Antipsychotic medications are associated with significant weight gain, type 2 diabetes mellitus, dyslipidemia, and increased cardiovascular risk. The objective of this study was to determine whether mifepristone, a glucocorticoid receptor antagonist, could prevent risperidone-induced weight gain. Using a 2:2:1 randomization scheme, 76 lean, healthy men (BMI 18-23 kg/m(2)) age 18-40 years were randomized to risperidone (n = 30), risperidone plus mifepristone (n = 30) or mifepristone (n = 16) daily for 28 days in an institutional setting. Subjects were provided food ad libitum. Body weight was measured daily. Metabolic measures were taken at study onset, midpoint, and end. Analyses of covariance indicated that the group receiving risperidone plus placebo gained significantly more weight (P < 0.001) and exhibited a significantly greater increase in waist circumference (P < 0.05) than the group receiving risperidone plus mifepristone. Significant differences were also observed for metabolic measures including fasting insulin (P < 0.001) and triglyceride levels (P < 0.05). Mifepristone attenuated increases in weight and reduced the metabolic changes induced by risperidone use, replicating results from a prior study of olanzapine-induced weight gain. These findings suggest mechanistic involvement of the hypothalamic-pituitary-adrenal axis in the weight and cardiometabolic side effects of antipsychotic medications. Future research should continue to test the potential of glucocorticoid antagonists to alleviate the deleterious side effects associated with use of antipsychotic medications.",
"affiliations": "Corcept Therapeutics Incorporated, Menlo Park, California, USA.",
"authors": "Gross|Coleman|C|;Blasey|Christine M|CM|;Roe|Robert L|RL|;Belanoff|Joseph K|JK|",
"chemical_list": "D014150:Antipsychotic Agents; D006727:Hormone Antagonists; D007328:Insulin; D011965:Receptors, Glucocorticoid; D014280:Triglycerides; D015735:Mifepristone; D018967:Risperidone",
"country": "United States",
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"doi": "10.1038/oby.2010.51",
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"issn_linking": "1930-7381",
"issue": "18(12)",
"journal": "Obesity (Silver Spring, Md.)",
"keywords": null,
"medline_ta": "Obesity (Silver Spring)",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D014150:Antipsychotic Agents; D004311:Double-Blind Method; D006727:Hormone Antagonists; D006801:Humans; D007030:Hypothalamo-Hypophyseal System; D007328:Insulin; D008297:Male; D024821:Metabolic Syndrome; D015735:Mifepristone; D010913:Pituitary-Adrenal System; D011965:Receptors, Glucocorticoid; D012016:Reference Values; D018967:Risperidone; D014280:Triglycerides; D055105:Waist Circumference; D015430:Weight Gain; D055815:Young Adult",
"nlm_unique_id": "101264860",
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"pages": "2295-300",
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"pubdate": "2010-12",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Mifepristone reduces weight gain and improves metabolic abnormalities associated with risperidone treatment in normal men.",
"title_normalized": "mifepristone reduces weight gain and improves metabolic abnormalities associated with risperidone treatment in normal men"
} | [
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"companynumb": "US-JNJFOC-20120905315",
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"abstract": "Dexmedetomidine is an α2 adrenergic agonist which has recently been approved in the United States for procedural sedation in adults. This report describes an infant who inadvertently received an intravenous infusion of dexmedetomidine at a rate which was 60 times greater than intended. We describe the hemodynamic, respiratory, and sedative effects of this overdose.",
"affiliations": "Department of Anesthesia, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.",
"authors": "Max|Bryan A|BA|;Mason|Keira P|KP|",
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"country": "Egypt",
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"fulltext": "\n==== Front\nInt J PediatrInt J PediatrIJPEDInternational Journal of Pediatrics1687-97401687-9759Hindawi Publishing Corporation 2088592010.1155/2010/825079Case ReportExtended Infusion of Dexmedetomidine to an Infant at Sixty Times the Intended Rate Max Bryan A. \n1\nMason Keira P. \n2\n*1Department of Anesthesia, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA2Department of Anesthesia, Perioperative, and Pain Medicine, Children's Hospital Boston, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA*Keira P. Mason: keira.mason@childrens.harvard.eduAcademic Editor: Savithiri Ratnapalan\n\n2010 8 9 2010 2010 82507930 6 2010 6 8 2010 Copyright © 2010 B. A. Max and K. P. Mason.2010This 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.Dexmedetomidine is an α2 adrenergic agonist which has recently been approved in the United States for procedural sedation in adults. This report describes an infant who inadvertently received an intravenous infusion of dexmedetomidine at a rate which was 60 times greater than intended. We describe the hemodynamic, respiratory, and sedative effects of this overdose.\n==== Body\n1. Introduction\nInfants and children frequently require sedation in order to ensure motionless conditions for radiological imaging studies. At our institution, dexmedetomidine (Precedex; Hospira, Lake Forest, IL) is the standard sedative, approved by the Hospital Sedation Committee and Pharmacy and therapeutics Committee for MRI studies. Dexmedetomidine is a highly selective α2 adrenoceptor agonist that possesses both sedative and analgesic effects [1]. Recently approved by the Food and Drug Administration (FDA) for procedural sedation, dexmedetomidine approval is still limited to adults only. In children, when dexmedetomidine is used as a sole agent for sedation, the doses needed to achieve adequate sedation have been shown to be remarkably high and exceed those approved for use by the FDA [2]. \n\nThe potential hemodynamic effects of dexmedetomidine, notably sympatholysis due to α2 agonism at sympathetic ganglia, have been well described in healthy adults [3]. Bradycardia, hypotension, and the potential for hypertension have all been described when dexmedetomidine is administered to adults [4, 5]. The hemodynamic effects of dexmedetomidine in children, particularly when administered in greater than approved dosages, still remain to be clearly defined. Some series have reported that at higher dosages there is bradycardia and a tendency towards blood pressure variability [2, 6, 7]. The dosages required to accomplish MRI sedation with dexmedetomidine range from 2 to 3 mc/kg bolus and an infusion of 1-2 mcg/kg/hr [2, 6, 8].\n\nThe only case report in the literature of a dexmedetomidine overdosage in a child describes an elevated blood pressure and an extended recovery period [9]. Our case report describes a different sedative and hemodynamic response when an infant received an inadvertent administration of dexmedetomidine at an infusion rate of 60 times that prescribed for 20 minutes.\n\n2. Case Report\nA 21-month-old female with recent history of two febrile seizures (30 minutes apart) presented for an outpatient MR imaging study of the brain to complete the neurological evaluation. The infant was an otherwise healthy, full-term baby, and with an unremarkable medical history and review of systems. Upon presentation, the patient was not taking any medications although her mother carried Diastat (Acudial. Diazepam, Valeant Pharmaceuticals. Costa Mesa, CA) in the event the seizure recurred. The 9.9 kg infant presented in a calm, nonagitated state with a heart rate (HR) of 110 beats/minute, respiratory rate (RR) of 20 breaths/minute, and noninvasive brachial blood pressure (NIBP) measurement of 85/60 with a mean arterial pressure (MAP) of 68 and a room air oxygen saturation of 100%. \n\nAfter careful review of the infant, discussion with the mother, and a physical examination, the dexmedetomidine was ordered per protocol by the pediatric nurse practitioner under the supervision of an anesthesiologist. Written, informed consent was obtained from the mother for the dexmedetomidine sedation. A 24-gauge intravenous catheter was initiated and dexmedetomidine was ordered per protocol, specifying a bolus of 2 mcg/kg over 10 minutes and a subsequent infusion of 1 mcg/kg/hr. The bolus was administered at the ordered rate of 2 mcg/kg over a period of 10 minutes using an Iradimed 3850 mRidium MR IV pump (Iradimed Corp, Winter Park, Fla). Vital signs (NIBP, MAP, 3-lead EKG, pulse oximeter, and HR) were monitored continuously using an Invivo Precess monitor (Invivo Corp, Orlando, and Fla) and documented every five minutes. The patient achieved successful sedation conditions (Ramsay Sedation Score = 4) by the completion of the bolus. Upon completion of this 10-minute bolus, NIBP was 118/79 (MAP 92), HR 77 (normal sinus), RR 17, and oxygen saturation of 97% on 2 liters/min oxygen via nasal canula (see Figure 1). Sedation guidelines at our institution specify supplemental oxygen delivery throughout the sedation and recovery period until discharge criteria are met. Following the bolus, the infusion pump initiated delivery of the dexmedetomidine infusion at the rate that had been programmed in at the initiation of the sedation. The dexmedetomidine infusion was continued throughout the sedation until the MRI scan was complete. The patient remained hemodynamically stable throughout Vital signs were documented at five-minute intervals per our hospital standard for sedation, following initiation of this dexmedetomidine infusion (Table 1). \n\nAt the termination of the study, the radiology nurse noted that the dexmedetomidine remaining in the syringe was less than anticipated and medication reconciliation was immediately initiated with a second nurse. Reconciliation revealed that the 9.9-kg infant had received 196 mcg more dexmedetomidine than had been ordered. Review of the intravenous infusion pump revealed that the pump had been misprogrammed to deliver the infusion at a rate of mcg/kg/min rather than mcg/kg/hr. Thus, instead of delivering the usual 1 mcg/kg/hour as ordered, the infusion pump delivered the dose at 1 mcg/kg/minute (equivalent to 60 mcg/kg/hr). Because this error was not identified during the mandatory institutional nursing “double check” when the infusion pump was programmed, the error was not identified, and the dexmedetomidine infusion was continued for the 20 minutes. \n\nFollowing the imaging study, the patient was transferred uneventfully to the radiology recovery room at which time monitoring was continued. The patient arrived in the recovery room deeply sedated with an RSS 4. Per recovery room policy, NIBP, MAP, EKG, HR, O2 Sat, and RR are documented every 5 minutes until modified Aldrete discharge criteria are met [10]. A minimum Aldrete score for discharge from the recovery room is 9. Although documented every 5 minutes, pulse oximetry is monitored continuously. Throughout the recovery room course, all physiologic parameters remained within age-adjusted normal values. 20 minutes after the discontinuation of the dexmedetomidine, the infant had achieved a modified Aldrete score of 9 and maintained an Aldrete of 9-10 throughout the remainder of the recovery room stay. No cardiac arrhythmias were noted at any time, both during the sedation as well as in the recovery room period. As soon as the error in dosing was identified, Risk Management was notified and the parents were debriefed and all questions answered by the Risk Management team as well as the supervising anesthesiologist. The parents were informed that the intravenous infusion pump had been misprogrammed and that the child had received an infusion of 60 times that which was ordered and intended. The effects of such a high dosage of dexmedetomidine delivery to an infant had not to date been described nor documented. In adults, the distribution half-life (t1/2) is approximately 6 minutes and the terminal elimination half-life (t1/2) is approximately 2 hours [11]. \n\nThe infant returned to baseline neurological status, an Aldrete Score of 10, after a 2-hour recovery room period. Although the half-life of dexmedetomidine is relatively short, and the child met discharge criteria with a modified Aldrete Score of 10 within hours of discontinuing the dexmedetomidine, the physicians chose to admit her to the hospital for overnight, continuous cardiorespiratory monitoring. Subsequently, the patient was admitted to the intensive care unit (ICU) for overnight monitoring of EKG as well as pulse oximetry, blood pressure, and neurological status. The child remained hemodynamically and neurologically stable in the ICU throughout the night. There were no arrhythmias, no change in neurologic status nor any deviation in heart rate or blood pressure outside of age-adjusted anticipated normal values. The next morning, after reassessment by neurology and the intensive care unit service, the infant was discharged home with no subsequent sequela.\n\n3. Discussion\nDexmedetomidine (Precedex) is a relatively selective α2-adrenergic agonist with sedative properties. As an imidazole, dexmedetomidine has an α2 : α1 activity ratio of 1620 : 1, compared to 220 : 1 with clonidine [12]. It is known that spinal and supraspinal α2-adrenoreceptors mediate and modulate nociception. These receptors are widely distributed throughout the peripheral and central nervous systems and a variety of organs, including liver, kidney, and pancreas. α2-adrenoreceptors have been located at presynaptic, postsynaptic, and extrasynaptic sites. Of these, the presynaptic and postsynaptic receptors may be the more clinically important in analgesia. In general, activation of α2-presynaptic receptors inhibits norepinephrine release and possibly substance P release, thereby inhibiting pain signal transmission. Postsynaptic activation in the central nervous system inhibits sympathetic activity, thus moderating heart rate and blood pressure [13–18]. Together, these effects produce analgesia, sedation, and anxiolysis.\n\nRecently approved (October 2008) for procedural sedation outside of the intensive care unit setting, Dexmedetomidine is still not approved by the Food and Drug Administration (FDA) for pediatric use. Although not approved in children, its use has been described for pediatric sedation in the intensive care unit, for radiology, gastroenterology, and dental procedures, as well as for electroencephalograms [19–28]. The dosages required to achieve sedation in infants and children tend to be higher than for adults. The need for higher dosages in children as compared to adults is confirmed in a recent pharmacokinetic study [29]. \n\n In adults, dexmedetomidine can produce varying depths of sedation which have been compared to states of natural sleep with respect to cardiovascular and respiratory effects [1]. When administered to adults within clinical dosing guidelines, there are no demonstrated significant accompanying changes in resting ventilation [3, 30, 31]. In fact, there is an evidence to support that dexmedetomidine actually mimics some aspects of natural sleep in both children and adults [30, 32]. \n\nOur concern with this infant following the overdosage was the potential for hemodynamic compromise. In both adults and children, there may be an increased incidence of clinically significant bradycardia with hypotension and possibly even cardiac arrest with dexmedetomidine, especially when administered with other medications which possess negative inotropic or chronotropic effects [33]. The potential hemodynamic effects of dexmedetomidine, notably sympatholysis, have shown a biphasic physiologic response characterized by an initial increase in systolic blood pressure and a reflex-induced decrease in heart rate followed by stabilization of heart rate and blood pressure below baseline values. The initial increase in MAP reportedly lasts for 5–10 minutes with a subsequent decrease in MAP of approximately 10%–20% below baseline with an HR that usually stabilizes below baseline values. These effects have been attributed to an inhibition of the central sympathetic outflow [30, 34]. Hemodynamic variability with dexmedetomidine has been described in case reports of severe bradycardia in a child with digoxin, hypertension in a child with traumatic brain injury, and hypertension in a child with acute transverse myelitis [5, 35, 36]. Children who received dexmedetomidine (3 mcg/kg bolus and 2 mcg/kg infusion) are more likely to manifest hypertension if they are less than one year of age and have received more than one bolus of dexmedetomidine [7]. \n\nAt our institution, radiology sedation is administered by nurses under the direct supervision of a pediatric nurse practitioner and supervising anesthesiologist. All children must be medically appropriate to receive dexmedetomidine sedation and cannot have any conditions which our institutional Hospital Sedation Committee considers to be a contraindication to dexmedetomidine [2, 6, 8] (Table 2). Dexmedetomidine sedation is administered following protocols which are on preprinted, templated order sheets approved by the Pharmacy and Therapeutics Committee. The order sheet specifies the following. A bolus of dexmedetomidine is administered at a specified dose in mcg/kg over 10 minutes. The goal of the bolus is to achieve a minimum Ramsay Sedation Score (RSS) 4 [37]. An RSS 4 or RSS 5 is a clinically derived scoring system that is generally accepted as the depth of sedation adequate to facilitate diagnostic imaging studies [8, 38]. This bolus may be repeated at the same dosage and time interval if the patient fails to achieve or maintain the minimum RSS 4, at any time during the sedation. Following completion of the bolus, and confirmation of adequate sedation, an infusion at a specified dosage in mcg/kg/hr is immediately started and continued until completion of the study. Following completion of the MR scan, the dexmedetomidine is discontinued, the patient is transported to the radiology recovery room and monitored with documentation of vital signs every 5 minutes until discharge criteria are met. Per our institutional guidelines, discharge criteria require a minimum Aldrete Score of 9 points [10].\n\nIn summary, this report describes the outcome during and following a substantial, inadvertent overdosage of dexmedetomidine to an infant. The overdosage represents a continuous dexmedetomidine infusion for 20 minutes at a rate which was almost 80 times that was recommended by the Food and Drug Administration for adults. To date, most of the reports of inadvertent overdosage are in adults, with the degree of overmedication substantially less than cited in our report [39]. The child received 60 mcg/kg/hour for 20 minutes and maintained cardiovascular and respiratory stability. Our experience differs from a previous overdose report which described an increase in blood pressure [9]. The absence of a significant hypertensive response suggests that infants may not demonstrate the biphasic hemodynamic response for blood pressure and vascular resistance as is reported in the adult literature [40]. This report is important because it demonstrates that even in excessive dosages, dexmedetomidine may not elicit an extreme hemodynamic or respiratory effect. This child exhibited a prolonged recovery and somnolence, with almost 2 hours to meet Aldrete discharge criteria. This prolonged recovery period is longer than the average 30 minutes recovery time, when the prescribed dosage is administered [2]. \n\nAlthough the infant in this report did not suffer any noticeable short- or long-term adverse sequela, our experience, however, identifies a serious and important mishap; Dexmedetomidine is unusual in that it is administered as an infusion with an hourly rate rather than a rate expressed per minutes. Both nursing and physicians are more commonly habituated to administer infusions per minute. Thus, careful double checks of the programmed rate must be followed in order to ensure accurate delivery of dexmedetomidine. There are no clear guidelines from the Joint Commission for the programming and delivery of intravenous medication. Rather, standard practice in our institution requires that the accurate programming of the infusion pump be independently verified by two separate nurses. Even with this process in place and documentation by two separate nurses that each had independently performed and verified the drug concentration, bolus and infusion dosage, and rate of administration, the error occurred. As a result of this incident, our institution has added an additional safety measure. The dexmedetomidine program in the infusion pump has been restricted to deliver infusions in units of mcg/kg/hour and a bolus in units of mcg/kg. The ability to deliver dexmedetomidine at a mcg/kg/minute rate or mg/kg dosage has been lockedout.\n\nIn conclusion, despite a large overdose of dexmedetomidine, this infant demonstrated hemodynamic stability throughout without incidence of hypotension or hypertension. Aside from the prolonged sedation for up to 2 hours following discontinuation of the infusion, she suffered no additional sequela. This report reveals the need for continued study of dexmedetomidine in order to determine the optimal dosing to ensure successful sedation conditions, hemodynamic stability, and a safe recovery period.\n\nFigure 1 Table 1 Vital Signs at time points (minutes) prior to, during, and following initiation of the dexmedetomidine bolus and infusion. \n\n\n\tPresedation/Baseline\t0\t5\t10\t15\t20\t25\t30\t35\t40\t45\t\nNIBP\t85/60\t118/79\t123/85\t143/87\t126/82\t122/84\t127/86\t124/72\t117/79\t107/67\t106/57\t\nMAP (mmHg)\t68\t92\t100\t108\t103\t95\t95\t89\t88\t76\t68\t\nHeart Rate (BPM)\t110\t77\t75\t78\t82\t85\t79\t85\t89\t93\t90\t\nRR (breaths/min)\t20\t17\t13\t24\t13\t14\t14\t16\t18\t18\t18\t\nO2 Saturation\t100%\t97%\t96%\t96%\t96%\t97%\t97%\t98%\t98%\t99%\t99%\t\nEKG\tNSR\tNSR\tNSR\tNSR\tNSR\tNSR\tNSR\tNSR\tNSR\tNSR\tNSR\t\nNSR: Normal Sinus Rhythm\n\nMAP: noninvasive mean arterial blood pressure\n\nRR: Respiratory rate\n\n0–10 minutes: The dexmedetomidine bolus administered\n\n10–20 minutes: The dexmedetomidine infusion initiated and completed\n\n20–45 minutes: The recovery room period until discharge criteria, defined as a minimum modified Aldrete Score 9, are achieved.\n\nTable 2 Medical Conditions Which Contraindicate Dexmedetomidine Sedation. \n\nActive, uncontrolled gastroesophageal reflux—an aspiration risk\t\nActive, uncontrolled vomiting—an aspiration risk\t\nCurrent (or within past 3 months) history of apnea requiring an apnea monitor\t\nActive, current respiratory issues that are different from the baseline status (pneumonia, exacerbation of asthma, bronchiolitis, and respiratory synctitial virus)\t\nUnstable cardiac status (life threatening arrhythmias, abnormal cardiac anatomy, and significant cardiac dysfunction)\t\nCraniofacial anomaly, which could make it difficult to effectively establish a mask airway for positive pressure ventilation if needed\t\nCurrent use of digoxin\t\nUncontrolled hypertension\t\nMoya Moya Disease\t\nNew-onset stroke\n==== Refs\n1 Hsu Y-W Cortinez LI Robertson KM Dexmedetomidine pharmacodynamics: part I: crossover comparison of the respiratory effects of dexmedetomidine and remifentanil in healthy volunteers Anesthesiology 2004 101 5 1066 1076 15505441 \n2 Mason KP Zurakowski D Zgleszewski SE High dose dexmedetomidine as the sole sedative for pediatric MRI Paediatric Anaesthesia 2008 18 5 403 411 18363626 \n3 Talke P Richardson CA Scheinin M Fisher DM Postoperative pharmacokinetics and sympatholytic effects of dexmedetomidine Anesthesia and Analgesia 1997 85 5 1136 1142 9356115 \n4 Bloor BC Ward DS Belleville JP Maze M Effects of intravenous dexmedetomidine in humans: II. Hemodynamic changes Anesthesiology 1992 77 6 1134 1142 1361311 \n5 Shah S Sangari T Qasim M Martin T Severe hypertension and bradycardia after dexmedetomidine for radiology sedation in a patient with acute transverse myelitis Paediatric Anaesthesia 2008 18 7 681 682 18331550 \n6 Mason KP Zgleszewski SE Prescilla R Fontaine PJ Zurakowski D Hemodynamic effects of dexmedetomidine sedation for CT imaging studies Paediatric Anaesthesia 2008 18 5 393 402 18363628 \n7 Mason KP Zurakowski D Zgleszewski S Prescilla R Fontaine PJ Dinardo JA Incidence and predictors of hypertension during high-dose dexmedetomidine sedation for pediatric MRI Paediatric Anaesthesia 2010 20 6 516 523 20412458 \n8 Mason KP Zgleszewski SE Dearden JL Dexmedetomidine for pediatric sedation for computed tomography imaging studies Anesthesia and Analgesia 2006 103 1 57 62 16790626 \n9 Rosen DA Daume JT Short duration large dose dexmedetomidine in a pediatric patient during procedural sedation Anesthesia and Analgesia 2006 103 1 68 69 16790628 \n10 Aldrete JA Kroulik D A postanesthetic recovery score Anesthesia and Analgesia 1970 49 6 924 934 5534693 \n11 Precedex (Dexmedetomidine) Package Insert 2008 Lake Forest, Ill, USA Hospira \n12 Virtanen R Savola J-M Saano V Nyman L Characterization of the selectivity, specificity and potency of medetomidine as an α 2-adrenoceptor agonist European Journal of Pharmacology 1988 150 1-2 9 14 2900154 \n13 Belleville JP Ward DS Bloor BC Maze M Effects of intravenous dexmedetomidine in humans: I. Sedation, ventilation, and metabolic rate Anesthesiology 1992 77 6 1125 1133 1361310 \n14 Langer SZ Presynaptic regulation of the release of catecholamines Pharmacological Reviews 1980 32 4 337 362 6267618 \n15 Drew GM Whiting SB Evidence for two distinct types of postsynaptic α -adrenoceptor in vascular smooth muscle in vivo British Journal of Pharmacology 1979 67 2 207 215 40647 \n16 Laubie M Schmitt H Vincent M Vagal bradycardia produced by microinjections of morphine-like drugs into the nucleus ambiguus in anaesthetized dogs European Journal of Pharmacology 1979 59 3-4 287 291 527649 \n17 Muzi M Goff DR Kampine JP Roerig DL Ebert TJ Clonidine reduces sympathetic activity but maintains baroreflex responses in normotensive humans Anesthesiology 1992 77 5 864 871 1443738 \n18 Unnerstall JR Kopajtic TA Kuhar MJ Distribution of alpha 2 agonist binding sites in the rat and human central nervous system: analysis of some functional, anatomic correlates of the pharmacologic effects of clonidine and related adrenergic agents Brain Research 1984 319 1 69 101 6324960 \n19 Ray T Tobias JD Dexmedetomidine for sedation during electroencephalographic analysis in children with autism, pervasive developmental disorders, and seizure disorders Journal of Clinical Anesthesia 2008 20 5 364 368 18761245 \n20 Hammer GB Drover DR Cao H The effects of dexmedetomidine on cardiac electrophysiology in children Anesthesia and Analgesia 2008 106 1 79 83 18165557 \n21 König MW Mahmoud MA Fujiwara H Hemasilpin N Lee KH Rose DF Influence of anesthetic management on quality of magnetoencephalography scan data in pediatric patients Paediatric Anaesthesia 2009 19 5 507 512 19453583 \n22 Üstün Y Gündüz M Erdoǧan Ö Benlidayi ME Dexmedetomidine versus midazolam in outpatient third molar surgery Journal of Oral and Maxillofacial Surgery 2006 64 9 1353 1358 16916668 \n23 Ogawa S Seino H Ito H Yamazaki S Ganzberg S Kawaai H Intravenous sedation with low-dose dexmedetomidine: its potential for use in dentistry Anesthesia Progress 2008 55 3 82 88 18788843 \n24 Barton KP Munoz R Morell VO Chrysostomou C Dexmedetomidine as the primary sedative during invasive procedures in infants and toddlers with congenital heart disease Pediatric Critical Care Medicine 2008 9 6 612 615 18838928 \n25 Heard C Burrows F Johnson K Joshi P Houck J Lerman J A comparison of dexmedetomidine-midazolam with propofol for maintenance of anesthesia in children undergoing magnetic resonance imaging Anesthesia and Analgesia 2008 107 6 1832 1839 19020127 \n26 Carroll CL Krieger D Campbell M Fisher DG Comeau LL Zucker AR Use of dexmedetomidine for sedation of children hospitalized in the intensive care unit Journal of Hospital Medicine 2008 3 2 142 147 18438790 \n27 Lami RO Pereira ACP Transmucosal dexmedetomidine for computed tomography sedation Paediatric Anaesthesia 2008 18 4 349 378 18315656 \n28 Hammer GB Sam WJ Chen MI Golianu B Drover DR Determination of the pharmacodynamic interaction of propofol and dexmedetomidine during esophagogastroduodenoscopy in children Paediatric Anaesthesia 2009 19 2 138 144 19207899 \n29 Vilo S Rautiainen P Kaisti K Pharmacokinetics of intravenous dexmedetomidine in children under 11 yr of age British Journal of Anaesthesia 2008 100 5 697 700 18378546 \n30 Hall JE Uhrich TD Barney JA Arain SR Ebert TJ Sedative, amnestic, and analgesic properties of small-dose dexmedetomidine infusions Anesthesia and Analgesia 2000 90 3 699 705 10702460 \n31 Talke P Lobo E Brown R Systemically administered α 2-agonist-induced peripheral vasoconstriction in humans Anesthesiology 2003 99 1 65 70 12826844 \n32 Mason KP O’Mahony E Zurakowski D Libenson MH Effects of dexmedetomidine sedation on the EEG in children Paediatric Anaesthesia 2009 19 12 1175 1183 20017865 \n33 Ingersoll-Weng E Manecke GR Jr. Thistlethwaite PA Dexmedetomidine and Cardiac Arrest Anesthesiology 2004 100 3 738 739 15108994 \n34 Xu H Aibiki M Seki K Ogura S Ogli K Effects of dexmedetomidine, an α 2-adrenoceptor agonist, on renal sympathetic nerve activity, blood pressure, heart rate and central venous pressure in urethane-anesthetized rabbits Journal of the Autonomic Nervous System 1998 71 1 48 54 9722194 \n35 Erkonen G Lamb F Tobias JD High-dose dexmedetomidine-induced hypertension in a child with traumatic brain injury Neurocritical Care 2008 9 3 366 369 18491236 \n36 Berkenbosch JW Tobias JD Development of bradycardia during sedation with dexmedetomidine in an infant concurrently receiving digoxin Pediatric Critical Care Medicine 2003 4 2 203 205 12749653 \n37 Ramsay MA Savege TM Simpson BR Goodwin R Controlled sedation with alphaxalone-alphadolone British Medical Journal 1974 2 920 656 659 4835444 \n38 Mason KP Michna E Zurakowski D Value of bispectral index monitor in differentiating between moderate and deep Ramsay sedation scores in children Paediatric Anaesthesia 2006 16 12 1226 1231 17121551 \n39 Jorden VSB Pousman RM Sanford MM Thorborg PAJ Hutchens MP Dexmedetomidine overdose in the perioperative setting Annals of Pharmacotherapy 2004 38 5 803 807 15039474 \n40 Ebert TJ Hall JE Barney JA Uhrich TD Colinco MD The effects of increasing plasma concentrations of dexmedetomidine in humans Anesthesiology 2000 93 2 382 394 10910487\n\n",
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"title": "Extended infusion of dexmedetomidine to an infant at sixty times the intended rate.",
"title_normalized": "extended infusion of dexmedetomidine to an infant at sixty times the intended rate"
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"abstract": "Tumour necrosis factor (TNF) inhibitors are known to induce autoimmune diseases, such as lupus-like syndrome; in rare cases, TNF inhibitor-induced myositis has been reported. This report documents the case of a male patient with ulcerative colitis (UC) complicated by TNF inhibitor-induced myositis. After UC diagnosis and treatment with azathioprine and infliximab, he was evaluated for a recent 5-month history of muscle weakness and pain. Laboratory tests revealed elevated muscle enzymes, such as serum creatine kinase (CK) and aldolase. He also tested positive for anti-nuclear antibodies and anti-double stranded DNA antibodies. High-intensity signals in his quadriceps on magnetic resonance image (MRI) and fibrillation potentials in his proximal muscles on electromyography were demonstrated. Muscle biopsy revealed the endomysial infiltration of mononuclear cells surrounding myofibers. Eventually, the patient fulfilled the classification criteria for idiopathic inflammatory myopathies. Although an adverse drug reaction of infliximab had been speculated, his muscle involvements did not improve in 6 weeks from the last administration of infliximab; therefore, treatment with prednisolone was initiated. Subsequently, his muscle symptoms ameliorated, and his serum CK levels returned to normal. Repeat MRI revealed a complete resolution of the signal intensity, and he reported no symptoms of UC or myositis while prednisolone was tapered without resumption of infliximab. Clinicians should consider the diagnosis of drug-induced myositis if muscle symptoms develop in patients treated with TNF inhibitors.",
"affiliations": "Department of Rheumatology, Tokyo Women's Medical University School of Medicine, Tokyo, Japan.;Department of Rheumatology, Tokyo Women's Medical University School of Medicine, Tokyo, Japan.;Department of Rheumatology, Tokyo Women's Medical University School of Medicine, Tokyo, Japan.;Department of Rheumatology, Tokyo Women's Medical University School of Medicine, Tokyo, Japan.;Department of Rheumatology, Tokyo Women's Medical University School of Medicine, Tokyo, Japan.;Department of Neurology, Tokyo Women's Medical University School of Medicine, Tokyo, Japan.;Department of Rheumatology, Tokyo Women's Medical University School of Medicine, Tokyo, Japan.",
"authors": "Yoshida|Akitsu|A|;Katsumata|Yasuhiro|Y|0000-0003-1654-0119;Hirahara|Shinya|S|;Hanaoka|Masanori|M|;Ochiai|Moeko|M|;Kobayashi|Masaki|M|;Harigai|Masayoshi|M|",
"chemical_list": "D000079424:Tumor Necrosis Factor Inhibitors; D011239:Prednisolone; D000069285:Infliximab; D001379:Azathioprine",
"country": "England",
"delete": false,
"doi": "10.1080/24725625.2020.1800958",
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"issn_linking": "2472-5625",
"issue": "5(1)",
"journal": "Modern rheumatology case reports",
"keywords": "Anti-double stranded DNA antibody; infliximab; myositis; tumour necrosis factor inhibitor; ulcerative colitis",
"medline_ta": "Mod Rheumatol Case Rep",
"mesh_terms": "D001379:Azathioprine; D003093:Colitis, Ulcerative; D004576:Electromyography; D006801:Humans; D000069285:Infliximab; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009220:Myositis; D011239:Prednisolone; D016896:Treatment Outcome; D000079424:Tumor Necrosis Factor Inhibitors",
"nlm_unique_id": "101761026",
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"pages": "156-161",
"pmc": null,
"pmid": "32757711",
"pubdate": "2021-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Tumour necrosis factor inhibitor-induced myositis in a patient with ulcerative colitis.",
"title_normalized": "tumour necrosis factor inhibitor induced myositis in a patient with ulcerative colitis"
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{
"abstract": "Headache is a potential complication of epidural injection. We report a patient who developed headache 5 days after a lumbar epidural steroid injection, which was not related to the epidural procedure, but caused by Duloxetine induced hyponatremia. Antidepressant drug induced headache should be considered in the differential diagnosis of post dural puncture headache.",
"affiliations": "Department of Anesthesiology, Prince Sultan Military Medical City, PO Box 7897, Riyadh 11159, Kingdom of Saudi Arabia. E-mail: jsanwari@hotmail.com.",
"authors": "Anwari|Jamil S|JS|;Hazazi|Abdulaziz A|AA|",
"chemical_list": "D017367:Serotonin Uptake Inhibitors; D013876:Thiophenes; D000068736:Duloxetine Hydrochloride; D012964:Sodium",
"country": "Saudi Arabia",
"delete": false,
"doi": "10.17712/nsj.2015.2.20140769",
"fulltext": "\n==== Front\nNeurosciences (Riyadh)\nNeurosciences\nnsj\nnsj\nNeurosciences\nNeurosciences\n1319-6138\n1319-6138\nRiyadh : Armed Forces Hospital\n\n25864071\nNeurosciences-20-167\n10.17712/nsj.2015.2.20140769\nCase Report\nAnother cause of headache after epidural injection\nAnwari Jamil S. FFARCS\nHazazi Abdulaziz A. SB-Anaes\nFrom the Department of Anesthesiology, Prince Sultan Military Medical City, Riyadh, Kingdom of Saudi Arabia\nAddress correspondence and reprint request to: Dr. Jamil S. Anwari, Consultant Anesthetist, Department of Anesthesiology, Prince Sultan Military Medical City, PO Box 7897, Riyadh 11159, Kingdom of Saudi Arabia. E-mail: jsanwari@hotmail.com\n4 2015\n20 2 167169\n15 12 2014\n16 3 2015\nCopyright: © Neurosciences\n2015\nhttps://creativecommons.org/licenses/by-nc-sa/3.0/ Neurosciences is an Open Access journal and articles published are distributed under the terms of the Creative Commons Attribution-NonCommercial License (CC BY-NC). Readers may copy, distribute, and display the work for non-commercial purposes with the proper citation of the original work.\nHeadache is a potential complication of epidural injection. We report a patient who developed headache 5 days after a lumbar epidural steroid injection, which was not related to the epidural procedure, but caused by Duloxetine induced hyponatremia. Antidepressant drug induced headache should be considered in the differential diagnosis of post dural puncture headache.\n==== Body\nMultimodal analgesic therapy, which includes antiepileptic and antidepressant drugs, is commonly used to control chronic low back pain. In addition, interventions, such as lumbar epidural steroid injection (LESI) are offered to some patients. Headache after the epidural injection is a known potential complication, which is usually due to dural tap. This headache has its characteristic symptoms related to posture. When the headache after the epidural injection is atypical, other causes should be considered in the differential diagnosis. We present a case where the patient developed headache after the LESI not due to the epidural injection, but due to Duloxetine induced hyponatremia. Our objective in presenting this particular case is to highlight that antidepressant drugs should be considered in the differential diagnosis of post dural puncture headache.\n\nCase Report\n\nA 74-year-old woman presented to the pain clinic with a history of chronic left sided sciatic pain that also restricted her mobility. This pain was worse at night and affected her sleep. She had been treated with nonsteroidal antiinflammatory drugs, pregabalin, tramadol, and acetaminophen without much relief. In addition, she was taking beta and angiotensin receptor blockers and aspirin. On examination, this slim pleasant lady had limited left leg raising with tenderness in her lower back. After the death of her husband, she has lived with her daughter, and she has a good memory. Her lumbar spine MRI revealed multilevel disc prolapse and spinal canal stenosis. The routine laboratory results (blood cell count, urea and electrolytes, and clotting studies) were within normal limits. In the clinic, after discussion with the patient, we decided to perform LESI the next week, and Duloxetine 60 mg/day was prescribed. Taking full aseptic precautions, an LESI was performed using a Portex™ epidural set under C-arm fluoroscopy. The correct placement of the epidural needle was confirmed by an epidurogram with the radio-contrast (Omnipaque™), after which 10 ml of 0.9% normal saline (NS) containing 80 mg methyl prednisolone was injected into the epidural space. After the procedure, she was observed in the recovery room for an hour and then discharged home and advised to continue her medication and return to the pain clinic after 4 weeks. Three days after the LESI, she was contacted on the phone to inquire about her wellbeing, and she reported some reduction in pain and was able to sleep. Three days later, she came to the hospital in the morning, with a 24 hour history of severe headache and being unable to sleep despite extra doses of acetaminophen. Along with the headache, she also complained of persistent nausea and one episode of vomiting. The headache was continuous, not throbbing in nature, felt over her occiput, both temples, vertex, and forehead and not associated with neck pain or stiffness. The pain was relieved a bit in the sitting position. With a normal body temperature, she was alert, well orientated, a bit restless with no neurological deficit on examination. Except for some puffiness around her eyes, her clinical examination was normal and she appeared to be euvolemic. She denied any change in her urinary or bowel habit. A brain CT scan was unremarkable. Her blood tests revealed severe hyponatremia (sodium 112 mmol/L, normal range: 135-145 mmol/L) with low serum osmolality of 248 mosmol/Kg (normal range 280-295). The remaining electrolytes, urea, creatinine, and blood counts were within normal limits, and her urine osmolality was 328 mosmol/Kg.\n\nShe was diagnosed to have Duloxetine induced syndrome of inappropriate antidiuretic hormone secretion (SIADH) causing severe hyponatremia (Figure 1). Her treatment started with intravenous (IV) acetaminophen 1 gm and granisetron 1 mg and IV infusion of 3% hypertonic saline commenced at the rate of 50 ml/hour. Eight hours later, her headache was still bad but the nausea improved, and serum sodium improved to 118 mmol/L. She then received codeine 30 mg intramuscular along with a second 1 gm dose of IV acetaminophen. One hour later she went to sleep in a semi sitting position. Her vital signs remained normal. After 3 hours she woke up. The headache was there but better than before. Eighteen hours after her hospital admission, the serum sodium further improved to 122 mmol/L. Hypertonic saline infusion was then replaced with NS. The headache was mild with no nausea or vomiting. She had a bowl of soup, she took her daily medications except Duloxetine and slept for another few hours. The next morning, 30 hours after her admission, she described her headache as heaviness instead of pain. With a serum sodium of 128 mmol/L, the IV infusion of NS was discontinued. She was kept under observations for another 36 hours, when her headache completely resolved, and with serum sodium at 130 mmol/L, she was discharged home.\n\nFigure 1 Diagnostic criteria for the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Na - sodium\n\nDiscussion\n\nHeadache is high on the list of almost all informed consents taken for epidural injection.1 The most common cause of headache after epidural injection is an inadvertent dural puncture. This headache, also called post dural puncture headache (PDPH) is due to CSF leakage, and low intracranial pressure. This typically presents as a postural headache that is aggravated in the sitting and standing position and relieved by lying down. A PDPH may occur up to 5 days after the procedure is performed.2 Any atypical headache after an epidural procedure should be taken seriously and its cause should be identified (Table 1).\n\nTable 1 Differential diagnosis of post epidural injection headache.\n\nThe headache in our patient presented 5 days after having an epidural injection. Clinically, this headache did not mimic headaches that develop as a complication of the epidural injection, such as PDPH or meningitis. The only positive laboratory finding was hyponatremia that caused low serum osmolality. The pre-procedure urea/electrolytes were within normal limits. The probable diagnosis of SIADH was based on euvolemia, hyponatremia with low serum and high urine osmolality, and Duloxetine appeared to be the most likely cause of SIADH in our patient.\n\nDuloxetine is a serotonin-norepinephrine reuptake inhibitor (SNRI), which was introduced a decade ago in North America for the treatment of major psychiatric disorders.3 Later its indications expanded to include various painful conditions such as neuropathic pain and fibromyalgia.3 Maramattom in 20064 reported the first case of Duloxetine induced SIADH in a woman, where the drug was used as an antidepressant. Thereafter many cases of Duloxetine induced SIADH have been reported in the literature.5-8 Though hyponatremia is a rare side effect of Duloxetine, elderly females with a low body weight appear to be more susceptible.7 Duloxetine is a relatively new drug in the management of chronic pain, and appears to be a cost-effective post-first-line treatment for chronic low back pain.9 Worldwide, the use of SNRI has increasingly become common in chronic pain patients, especially in patients with diabetes with painful neuropathy and sciatica. Because of the risk of developing SIADH, it would be advisable to monitor serum sodium in patients who are taking SNRIs.\n\nFortunately, our patient, apart from headache and nausea did not have any other CNS symptoms (lethargy, disorientation, convulsion, coma). The SIADH can cause brain edema, an increase in intra cranial pressure, and may lead to brain stem herniation.10 There was clinical suspicion of raised intracranial pressure in our patient, because of pain relief in the sitting position and as the headache was associated with nausea and vomiting, we decided not to perform a diagnostic lumbar puncture. Symptomatic hyponatremia is a medical emergency and we started its treatment immediately with 3% hypertonic saline with a goal of slowly raising the serum sodium concentration, not more than 5 mmol/L per 12 hours. Rapid correction of hyponatremia may seriously harm the patient by causing demyelination of neurons.\n\nIn conclusion, our case is that of post epidural injection headache not caused by the epidural procedure per se, but coincidently caused by a Duloxetine induced hyponatremia.\n\nAcknowledgments\n\nWe thank Dr. Taqi Khan, Kidney Transplant Surgeon at Prince Salman Armed Forces hospital, Tabuk, Saudi Arabia for his expert advice in the preparation of this manuscript.\n\nCASE REPORTS\n\nCase reports will only be considered for unusual topics that add something new to the literature. All Case Reports should include at least one figure. Written informed consent for publication must accompany any photograph in which the subject can be identified. Figures should be submitted with a 300 dpi resolution when submitting electronically or printed on high-contrast glossy paper when submitting print copies. The abstract should be unstructured, and the introductory section should always include the objective and reason why the author is presenting this particular case. References should be up to date, preferably not exceeding 15.\n==== Refs\n1 Consent for epidural steroid injection procedure. Form No: 020938 Charlottesville (VA) University of Virginia Health System Available from: http://www.virginia.edu/uvaprint/HSC/pdf/020938.pdf\n2 Thoennissen J Herkner H Lang W Domanovits H Laggner AN Müllner M Does bed rest after cervical or lumbar puncture prevent headache? A systematic review and meta-analysis CMAJ 2001 165 1311 1316 11760976\n3 National Institute for health and Care Excellence (UK). Neuropathic pain – pharmacological management: The pharmacological management of neuropathic pain in adults in non-specialist settings NICE guidelines (CG173) 2013 London (UK) NICE Available from: http://www.nice.org.uk/guidance/cg173\n4 Maramattom BV Duloxetine-induced syndrome of inappropriate antidiuretic hormone secretion and seizures Neurology 2006 66 773 774 16534127\n5 Safdieh JE Rudominer R A case of hyponatremia induced by duloxetine J Clin Psychopharmacol 2006 26 675 676 17110834\n6 Krüger S Lindstaedt M Duloxetine and hyponatremia: a report of 5 cases J Clin Psychopharmacol 2007 27 101 104 17224730\n7 Jacob S Spinler SA Hyponatremia associated with selective serotonin-reuptake inhibitors in older adults Ann Pharmacother 2006 40 1618 1622 16896026\n8 Müssig K Mörike K Häring HU Severe and symptomatic hyponatremia following duloxetine treatment J Psychopharmacol 2009 23 338 339 18562431\n9 Liedgens H Henske R The cost-effectiveness of duloxetine in chronic low back pain: a US private payer perspective Value Health 2013 16 1172 24326172\n10 Hoorn EJ van der Lubbe N Zietse R SIADH and hyponatraemia: why does it matter? NDT Plus 2009 2 Suppl_3 iii5 iii11 19881934\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "1319-6138",
"issue": "20(2)",
"journal": "Neurosciences (Riyadh, Saudi Arabia)",
"keywords": null,
"medline_ta": "Neurosciences (Riyadh)",
"mesh_terms": "D000368:Aged; D000068736:Duloxetine Hydrochloride; D005260:Female; D006801:Humans; D007010:Hyponatremia; D007268:Injections, Epidural; D007405:Intervertebral Disc Displacement; D051299:Post-Dural Puncture Headache; D012585:Sciatica; D017367:Serotonin Uptake Inhibitors; D012964:Sodium; D013130:Spinal Stenosis; D013876:Thiophenes",
"nlm_unique_id": "101252453",
"other_id": null,
"pages": "167-9",
"pmc": null,
"pmid": "25864071",
"pubdate": "2015-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18562431;17110834;19881934;16534127;24326172;17224730;16896026;11760976",
"title": "Another cause of headache after epidural injection.",
"title_normalized": "another cause of headache after epidural injection"
} | [
{
"companynumb": "SA-ACTAVIS-2015-15871",
"fulfillexpeditecriteria": "1",
"occurcountry": "SA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
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"drugadditional": null,
... |
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